Stereoselective reactions:

diastereo- and enantio-

selectivities

1
 We•introduced the stereochemistry of structures in Chapter 16. We told you about two types of
Enantiomers—stereoisomers that are mirror images of one another
Introduction• Diastereoisomers—stereoisomers that are not mirror images of one
stereoisomers.
another
• Enantiomers and diastereoisomers
In this chapter we shall talk about how to make compounds as single diastereoisomers.
Making• Enantiomers—stereoisomers
single enantiomers is treated in that
Chapter 45. Chapter
are mirror images33 of
wasone
also about making single
another
diastereoisomers, and we hope that, having read thatthat
are chapter, you images
are usedoftoone
thinking stereo-
• Diastereoisomers—stereoisomers
chemically.
not mirror
another
In this chapter we shall talk about two different ways of making single diastereoisomers.
In this chapter we shall talk about how to make compounds as single diastereoisomers.
•
Making Reactions that make
single enantiomers single in
is treated diastereoisomers
Chapter 45. Chapter 33 was also about making single
diastereoisomers, and we hope that, having read that chapter, you are used to thinking stereo-
• Stereospecific reactions—reactions where the mechanism means that the
chemically.
stereochemistry of the starting material determines the stereochemistry of the
In this chapter we shall talk about two different ways of making single diastereoisomers.
product and there is no choice involved

•
•Reactions
Stereoselective reactions—reactions
that make where one stereoisomer of product is
single diastereoisomers
formed predominantly because the reaction has a choice of pathways, and one
• Stereospecific
pathway is more favourable than thewhere
reactions—reactions other the mechanism means that the
stereochemistry of the starting material determines the stereochemistry of the
product and there is no choice involved
• A common misapprehension is that stereospecific means merely very
• Stereoselective
stereoselective.
reactions—reactions where one stereoisomer of product is
formed predominantlythe
It doesn’t— two terms
because describe
the reaction quite different
has a choice properties
of pathways, and one of
the stereochemistry of a favourable
pathway is more reaction than the other

• For a stereoselective reaction we can specify two different stereoisomers of the

starting material and get the same product. In a stereospecific reaction,
different starting material stereochemistry means different product
stereochemistry 2
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Examples Making
of single diastereoisomers
stereospecific reactions using stereospecific reactions
These terms were introduced in Chapter 19 in connection with elimination reactions, and many
of alkenes
of the reactions we mention will be familiar from earlier chapters (particularly Chapters 17–20 and
• SN2 26–27).
The essence
reactions areof the definition we have
stereospecific: just reminded
they proceedyou of is inversion
with much easier to
sograsp
thatwith
thesome famil-
absolute
iar examples.
stereochemistry ofHere
theare two.
starting material determines the absolute stereochemistry of
Making singlearediastereoisomers
• SN2 reactions
the product using
stereospecific: they proceed stereospecific
with inversion reactions
so that the absolute stereochemistry
of the starting material determines the absolute stereochemistry of the product
of alkenes
H OTs 4 Bu N AcO AcO H TsO
4 H Bu N AcO H OAc
The essence of the definition we have just reminded you of is much easier to grasp with some famil-
iar examples. Here are two.
DMF DMF
(S) are stereospecific: they proceed
(R) with inversion(R) (S)
• SN2 reactions so that the absolute stereochemistry
of•theE2
starting material
reactions determines the
are stereospecific: absolute
they stereochemistry
proceed of the producttransition state, with the
through an anti-periplanar
hapter 17,
H relative
OTs Bu stereochemistry
4N AcO
of
AcOthe starting
H materialTsO
determining
H the geometry of theHproduct
Bu4N AcO OAc
• E2 reactions Me are stereospecific: H
H Me they proceed Me through an anti-periplanar Me transition
Ph
DMFNaOH DMF NaOH
state, with
Ph(S) the relative stereochemistry
Ph
(R) of the(R)starting material determining
Ph
(S) the
Ph
geometry of the product Ph Ph Ph
17, • E2 Br
reactions are stereospecific: they (Z)
proceed through an anti-periplanar
Br transition state, with
(E)the
relative stereochemistry of the starting material determining the geometry of the product
Both of these examples are very interesting because they show how, once we have some stereo-
Me H
H chemistry in a molecule, Me Me
we can change the functional Me
groups but keep the stereochemistry—this Ph is
Ph NaOH Ph weNaOH
Ph the essence of a stereospecific reaction. In the Ph second example, change the bromide to a double
bond, but we keep the stereochemistry
Ph Ph (or ‘stereochemical information’) because Ph the geometry of
Br (Z) Br (E)
the double bond tells us which bromide we started with.
BothThis is a good
of these placeare
examples to very
begininteresting
if we wantbecause
to makethey
single diastereoisomers,
show how, once we have because
some we stereo-
can reverse
this type
chemistry in aofmolecule,
reaction:weinstead of making
can change a single geometry
the functional groupsof alkene
but keep from a single diastereoisomer,
the stereochemistry—this is we
make aof
the essence single diastereoisomer
a stereospecific fromIna the
reaction. single geometry
second of double
example, [Link]
we change Here is an example
bromide of this—
to a double
bond,again,
but weonekeep
you the
havestereochemistry
already met (Chapter 19). Electrophilic
(or ‘stereochemical addition ofbecause
information’) brominethe to geometry
alkenes is stereo-
of 3
specificbond
the double and tells
leadsustowhich
anti addition
bromideacross a double
we started [Link]
Credits:
with. if [Link]
Clayden the anti
al. Organic dibromide
Chemistry we choose
- Oxford University Press
 the essence of a stereospecific reaction. In the second example, we change the bromide to
Examples of stereospecific reactions bond, but we keep the stereochemistry (or ‘stereochemical information’) because the geo
the double bond tells us which bromide we started with.
This is a good place to begin if we want to make single diastereoisomers, because we can
• Electrophilic additionthisof typebromine
of reaction: to alkenes
instead of makingisa single
stereospecific andfrom
geometry of alkene leads
a singleto anti
diastereoiso
addition across a double make abond. So if we want
single diastereoisomer fromthe anti
a single dibromide,
geometry of doublewe choose
bond. Here is to start
an example
!
with the trans doubleagain, bond;one ifyou
we want
have the
already metsyn dibromide
(Chapter we start
19). Electrophilic with of
addition the cis double
bromine to alkenes i
Chapterbond. The geometryspecific
of theand starting material
31 described the methods
leads to anti additiondetermines
across a double the
[Link] stereochemistry
So if we want the anti dibromide w
available for controlling the geometry of to start with the trans double bond; if we want the syn dibromide we start with the cis doub
double of the product
bonds.
The geometry of the starting material determines the relative stereochemistry of the produc

Me H Me Br H Br
Br2
Me anti dibromide
Me
H Me H Me
Br Br

H H H Br H Br
rotate about
Br central bond Br
Br2
Me syn dibromide
Me
Me Me Me Me Me Me
Br Br

Iodolactonization has a similar mechanism; notice how in these two examples the geomet
double bond in the starting material defines the relative stereochemistry highlighted in bla
For a stereospecific product. transformation, choose the right geometry of the starting
alkene
material to get the right diastereoisomer
E H of the product.
I Don’t try to follow
I any ‘rules’
over this, just work through the mechanism
O O
O O O O
I and O anti

4
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Stereoselective reactions
(see Chapter 45)
For most of the rest of the chapter we shall discuss stereoselective reactions. You have already met
Examples ofexamples
several
For most
stereoselective
andof
of the rest wethe
start with awe
chapter
reactions
summary of the stereoselective
shall discuss most important [Link] have already met
reactions.
eactions several examples and we start with a summary of the most important
OH methods.
H2SO4
• E1we
e chapter • discuss
reactions
shall are stereoselective:
E1 reactions [Link]
are stereoselective:
stereoselective they
You form
form
have predominantly
already met OH the more
H2SO4
stable
Ph alkene
• predominantly
art with a summary E1 reactions
of the thestereoselective:
are moremethods.
most important stable alkene
they form Ph
Ph
predominantly OH
the more stable alkene Ph O Ph OH
H SO
2 4
oselective: they form O Me Ph OH Me
Ph
re stable alkene • Nucleophilic
Ph attack on six-membered ring Me
PhLi
Me
• ketones is stereoselective:
Nucleophilic small nucleophiles
O attack on six-membered PhringOH
PhLi
N N
• Alkylationattack
ketonesaxially
of cyclic and large ones
enolates
is stereoselective:
Me
equatorially
issmall
stereoselective,
nucleophiles with reaction taking place on the less
Me
attack N N
hinderedring
n six-membered faceaxially
(four-and or
largefive-membered
ones PhLi
equatorially rings) or Me Me
via axial attack (six-membered
ve: small nucleophiles Me Me
rings) • Alkylation of cyclic enolates is stereoselective, with reaction taking place on the less hindered face
ones equatorially• (four- N N
or five-membered
Alkylation rings)
of cyclic enolates or via axial attack
is stereoselective, with(six-membered
reaction takingrings)
place on the less hindered face
(four- Me H rings)O or via axial Me
H or five-membered attack Me
O Ph (six-membered
OLi rings) O
Ph Ph H LDA MeI PhMe
lates is stereoselective,Hwith reaction
O taking place on
O the less hindered
Ph face OLi O
Ph or Ph LDA MeI Ph
d rings) or via axial attack (six-membered
O rings)
O O O
or
He reaction
O we Ph O OLi O Me O O O
erent
e reaction we LDA MeI Ph
e starting
erent
esame O
starting • EpoxidationOof cyclic alkenes is stereoselective,
O with reaction taking place on the less hindered
rd • Epoxidation
examples).
same • face, of cyclic
or directed
Epoxidation alkenes
by alkenesisbonding
hydrogen
of cyclic isstereoselective,
to a hydroxyl
stereoselective, with reaction
withgroup
reaction taking
taking place on theplace on the
less hindered
eaction,
aterial less hindered
rd examples). OAc or
face, face, or by
directed directed
hydrogen by
OAc hydrogen
bonding bonding
OHgroupto a hydroxyl group
to a hydroxyl OH
eaction,
ans different
alkenes
aterial OAc with reaction takingOAc
is stereoselective, OH
place on the less hindered OH
mistry.
ans different RCO3H RCO3H
rogen bonding to a hydroxyl group O O
mistry. RCO3H RCO3H
OAc OH OH
O O
5
RCO3H Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 hension is
Prochirality
means merely
It doesn’t—
Take another look at all the reactions in the chapter so far—in particular those that give single
diastereoisomers (rather than single enantiomers or geometrical isomers)—in other words, those
be quite
that are diastereoselective. They all involve the creation of a new, tetrahedral stereogenic centre at a
• Trigonalcarbon
of the carbons
that wasthat aren’t
planar stereogenic
and trigonal. This leads centers butnew
us to our first can be made
definition. into
Trigonal them
carbons thatare
reaction.
called prochiral
aren’t stereogenic (or chiral) centres but can be made into them are called prochiral.
new stereogenic centre new stereogenic centre
prochiral
O Ph OH Prochirality
Me
Ph OLi Prochirality
O
Me Me prochiral Ph
PhLi MeI
At the very start of Chapter 17, we introduced stereochemistry by O thinking about the reactions ofO
At the very start of Chapter
twoN sorts of carbonyl compounds. 17, we introduced stereochemistry by thinking about the reactions of
N They are shown again here: the first has a prochiral carbonyl
two
group. Thesorts of carbonyl
second, compounds.
on the other They
hand, is not are shown
prochiral again
because nohere: the firstcentre
stereogenic has aisprochiral carbonyl
created when
Megroup. The second, on the other
Me hand, is not prochiral because no stereogenic centre is created when
the compound reacts.
the compound reacts.
new stereogenic centre
new stereogenic centre
O HO CN O HO CN
O CN HO CN O CN HO CN
Ph CN Ph CN
Ph H Ph H
H H
prochiral not prochiral
prochiral not prochiral
Tetrahedral carbon atoms can be prochiral too—if they carry two identical groups (and so are not
• a chiral Tetrahedral
Tetrahedral centre) but carbon
carbon atoms
atoms of
replacement canone
can
be prochiral
be
too—if
of prochiral
them leads they
totoo: carry
a new two centre,
chiral identicalthen
replacement
groups
of the
one
(and so are
carbon
of is not
the two
a chiral centre) but replacement of one of them leads to a new chiral centre, then the carbon is
prochiral.
identical groups leads to a new stereocenter
prochiral.
HH replace one HD Me H replace one Me H
group
replace one Me H group
replace one Me H
HH HD
group group
H3N COO H3N COO HOOC COOH HOOC CO2Et
H3N COO H3N COO HOOC COOH HOOC CO2Et
prochiral prochiral
prochiral prochiral 6
Glycine is the only α amino acid without a chiral centre, but
Credits: replacing
J. Clayden et. [Link] of Chemistry
Organic the two -protons on Press
Oxford University
 If reaction
which on the
face of one double
of two faces
bondoforthecarbonyl
prochiralgroup
grouptogenerates
react ononeamounts
of two enantiomers,
to choosing the faces
which
Prochirality
are enantiotopic;
diastereoisomer if theInreaction
to form. generates
the third example,one theof twoofdiastereoisomers,
faces the faces
the prochiral carbonyl groupareare
diastereo-
enan-
topic. We
tiotopic: will now
choosing applyface
which this to
thinking
attack to the first to
amounts fewchoosing
reactionswhich
in thisenantiomer
chapter: theytoare shown
form. In again
the
• If the below. The first
reaction
fourth example, two
generates
the examples
two ofhave
facesone C=Oofprochiral
two
are C=C oran
homotopic: C=O
diastereoisomers, bondsproduct
identical with
thediastereotopic
faces faces:
arewhichever
is formed choosing
diastereotopic
face
is which
[Link] of the double bond or carbonyl group to react on amounts to choosing which
diastereoisomer
O to form. In Phthe third
OH example, the faces of the prochiral carbonyl group are enan-
PhchoosingOLi Me
tiotopic: choosing which face to attack amounts to which enantiomer to form. In O the
Me Me Ph
fourth example, PhLithe two faces of C=O are homotopic: an identical product MeIis formed whichever face
is attacked. O O
NO PhN OH
green carbonyl has
Ph
green double bond has
OLi Me O
Me diastereotopic
Me faces Me Me diastereotopic faces Ph
PhLi MeI
O HO CN O O HO CN O
CN CN
• If Phreaction
N on oneof two Phfaces
green carbonyl has
N of the prochiral group generates one of two
green double bond has
enantiomers, H the faces
diastereotopic faces are H
enantiotopic diastereotopic faces
Me Me
yellow carbonyl has brown carbonyl has
enantiotopic faces
O HO CN homotopic
O faces HO CN
CN CN
Ph Ph
Knowing this H throws some new light on the last
H chapter. Almost without exception, every stereo-
selective reaction there involved a double bond (usually C=C; sometimes C=O) with diastereotopic
yellow carbonyl has brown carbonyl has
enantiotopic faces homotopic faces

Knowing this throws some new light on the last chapter. Almost without exception, every stereo-
• Homotopic facesthere
selective reaction or groups
involved are always
a double chemically
bond (usually identicalC=O) with diastereotopic
C=C; sometimes

• Enantiotopic faces are also chemically identical, provided that all the reagents in the
reaction in question are achiral or racemic
7
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Prochirality

• Every stereoselective reaction involving a double bond (usually C=C; sometimes

C=O) occurs with diastereotopic faces

• The diastereotopic faces are distinguished by steric hindrance, or by a nearby

34 . Diastereoselectivity
hydrogen-bonding group, and so they can react differently with an incoming reagent
faces. The diastereotopic faces were distinguished by steric hindrance, or by a nearby hydrogen
bonding group, and so were able to react differently with an incoming reagent.
OAc OAc diastereotopic faces

RCO3H OAc
O
RCO3H reacts
on this face

OH OH diastereotopic faces
RCO3H reacts
on this face
RCO3H OH
O

Using an R/S-type system to name prochiral faces and groups

Just as stereogenic centres can be described as R or S, it Pro-R and pro-S can be assigned to a pair of enantiotopic
8
is possible to assign labels to the enantiotopic groups at groups simply by using the usual rules to assign R or S to
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Prochirality

• Homotopic faces or groups are always chemically identical

• Enantiotopic faces are also chemically identical, provided that all the reagents in the
reaction in question are achiral or racemic

• Diastereotopic faces are always different in principle, but sometimes not so in

practice

• In the example the C=O group has two diastereotopic faces, which, due to free
rotation about single bonds, average out to about the same reactivity, so we cannot
expect any reasonable level
Additions to of diastereoselectivity
carbonyl groups can be diastereoselective even without rings

diastereotopic faces
!
In C
O HO H Me
hom
NaBH4 O free rotation pro
Me Sim
Me H reacts on both Me H gro
faces ide
t-Bu H also
We put Chapter 33 first because in rings conformation is well defined, and this ‘averaging’ effect is tha
held at bay. We are about to let it out again, but we will show you how it can be tamed to surprising- in q
9 In C
ly good effect. Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press wha
Prochirality
Just as stereogenic centres can be described as R or S, it
is possible to assign labels to the enantiotopic groups at
Pro-R and pro-S can be assigned to a pair of enantiotopic
groups simply by using the usual rules to assign R or S to
Using
prochiralan R/S-type
tetrahedral carbonsystem to enantiotopic
atoms or the name prochiral thefaces and groups
centre created if the group in question is artificially
• Just as stereogenic centers can be described as R or S, it is possible to assign
faces of prochiral trigonal carbon atoms. The basis of the
system R,S system
is the usualcentres fordescribed
stereogenic
elevated to higher priority than its enantiotopic twin. We’ll
Just as stereogenic can be as centres,
R or S, it use Gand
Pro-R to replace
pro-S canH asbe we did in Chapter
assigned to a pair32: just assume
of enantiotopic
labels to the enantiotopic groups at prochiral tetrahedral carbon atoms or the
isbut pro-R and
possible pro-S are
to assign used
labels tofor
thegroups and Regroups
enantiotopic and Si at
for that G has
groups priority
simply immediately
by using the usualhigher than
rules to H. The
assign method
R or S to
faces. is illustrated for glycine.
enantiotopic faces of prochiral trigonal carbon atoms. The basis of the system is the
prochiral tetrahedral carbon atoms or the enantiotopic
faces of prochiral trigonal carbon [Link] The basis of the
the centre created if the group in question is artificially
elevated to higher priority than its enantiotopic twin. We’ll
G higher make G higher
usual R,S system for stereogenic centers, but pro-R and pro-S are used for groups
system is the usual R,S system for stereogenic centres,
priority than H use G to replace H as we did in Chapter 32: just assume
priority than H
but pro-R and pro-S are used for groups and Re and Si for that G has priority immediately higher than H. The method
and Re and Si for faces
faces. H H replace green 4 3
is illustrated 3 4
H HG H H for [Link] GH
orange H
make G higher make G higher
priority than H priority than H
H3N COO H3N COO H3N COO H3N COO
replace green 14 3 2 13 42
HH replace
H new H G is S
centre HH
orange H newGcentre
H is R
so green proton is pro-S so orange proton is pro-R
H3N COO H3N COO H3N COO H3N COO
1 2
Faces of a prochiral trigonal carbon atom are assigned Re 1
the left (anticlockwise) means it’s Si. Remember 2 our
and Si by viewing the carbon from that new
sidecentre is S
and counting advice from Chapter 16: think of turning a steering
new centre is wheel
R
so greenround
down the groups in priority 1–3. Counting pro-S
protontoisthe so orange proton is
in the direction of the numbers: does the car go to thepro-R
right (clockwise) means the face is Re; counting round to right or the left?
Faces of a prochiral trigonal carbon atom are assigned Re the left (anticlockwise) means it’s Si. Remember our
and Si by viewing the carbon from that side and counting advice from Chapter 16: think of turning a steering wheel
down the groups in priority 1–[Link] facesto the
Counting round in the direction of the numbers: does the car go to the
of benzaldehyde
right (clockwise) means the face is Re; counting round to right or the left?
clockwise
O
anticlockwise
Re face O1 1 O
enantiotopic faces Si face
view view from this side
of from this side
benzaldehyde
3 2 O 2 3
clockwiseH Ph Ph H
H anticlockwise
Re face O1 1 O
view from this side Ph view from this side Si face
3 2 2 3
H Ph Ph H
H
Ph
10
Like R and S, these stereochemical terms are merely labels: they are of no consequence
Credits: chemically.
J. Clayden et. al. Organic Chemistry - Oxford University Press
 O HO H Me In Ch
hom
Diastereoselective additions to carbonyl groups
ly good effect. NaBH4 O free rotation wha
prot
Me face
Sim
reag
• In theAdditions
example
Me H toC=O
the carbonyl on bothgroups
group
reacts hasMetwoHcan be diastereoselective
diastereotopic faces, which,even due to free grou
Additions to bonds,
carbonyl average
faces groups can be to
diastereoselective even without rings iden
rotation about single
without rings out about the same reactivity,
t-Bu H so anyalso
reasonable level of diastereoselectivity cannot be expected
We put Chapter 33 first because in rings conformation is well defined, and this ‘averaging’ effect is that
What
held athappens
bay. Weifare
weabout
bringto
the
letstereogenic
it out again,centre
but wecloser to theyou
will show carbonyl
how itgroup than
can befaces
diastereotopic it was
tamed in the last
to surprising- in qu
example? You might expect it to have a greater influence over the carbonyl group’s reactions. And it ! In Ch
ly good effect. wha
does. Here is anOexample. In Chap
HO H Me face
homoto
O NaBH4 O free rotation !
reag
Additions to carbonyl groups H OH
can beHOdiastereoselective
H
Me
even protons
We h
Similar
Ph LiAlH Ph Ph
without
Me H rings reacts on both4
Me H +
produced in a ratio of 3:1 dias
groups
two
identica
faces
Mehappens if we bring the stereogenic
Me t-Bu
Methe carbonyl group H alsooncho
What centre closer to than it was in the last
• If the stereogenic
example? You center
We put Chapter might isbecause
33 first brought
expect it to in
major havecloser
rings to the
conformation
a greater
diastereoisomer carbonyl
influence
minor
is over group,
well defined,
the it this
and
carbonyl
diastereoisomer is expected
‘averaging’
group’s iteffect
[Link]
have
is it a draw
that all
defin
held at bay. in ques
greater HereWe
influence
does. are about
over
is an thetocarbonyl
example. let it out again,
Me and but we
OH anti
group’s will Me
reactionsshow
andyou how it can be tamed to surprising-
OH syn
only
In Chap
ly good effect. whatwith
ThereOis three times as much of one H ofOH the two diastereoisomeric
HO H products as there is of the other, !ha
faces
Wewh
and the major (anti)
Ph diastereoisomer
LiAlH4 Ph is the one in which
Ph the nucleophile has added to the front face
produced in a ratio of 3:1 reagen
Additions to carbonyl groups can be diastereoselective even
of the carbonyl group as drawn here. We can make + these same two diastereoisomers by addition of
two
dias

without rings
an organometallic
Me to an [Link] For example, this Grignard
Me reagent gives three times as much of on o
the syn diastereoisomer as the anti diastereoisomer. The major product has changed, but the product draw
major diastereoisomer minor diastereoisomer
What
still happens if we
arises from bring
attack onthe
thestereogenic
front faceOH
Me and
centre
of closerMe
the carbonyl
anti
toasand
the carbonyl group than it was in the last
shown.
OH syn defin
example? You only
O might expect it to have H a greater influence over the carbonyl group’s reactions. And it
OH HO H
does. There
Here isisanthree times as much of one of the two diastereoisomeric products as there is of the other,
example. with
Ph the major (anti)
and EtMgBr Ph
diastereoisomer Ph
is the one+in which produced
the nucleophile in a ratio
has added toofthe
1:3front face
O H H OH HO H !
of the carbonyl group as drawn here. We can make these same two diastereoisomers by addition of We hav
Ph Me LiAlH Ph Me Ph Me produced in a ratio of 3:1
an organometallic to an
4 aldehyde. For example,+ this Grignard reagent gives three times as much of diaster
the syn diastereoisomer as the minor
antidiastereoisomer
diastereoisomer. major
The major product has changed, but the product two sub
diastereoisomer
Me Me
Me and OH anti MeMeand OH syn 11 on opp
still arises from attack on the front face of the carbonyl as shown. drawn.
major diastereoisomer minor Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
diastereoisomer
 888 34 . Diastereoselectivity
Diastereoselective
art of
ad it additions to carbonyl groups
pounds you met in the last chapter. But we do now need to explain why they are diastereoselective at
all, given the free rotation possible in an acyclic molecule. The key, as much with acyclic as with
e to
Thecyclic molecules, is conformation.
conformation of! a chiral aldehyde These two reactions are not nearly as diastereoselecti
O We shall draw heavily on the first part of pounds you met in the last chapter. But we do now need t
• The The key
conformation ofunderstand
point to Chaptera chiral
18 here:aldehyde
the diastereoselective
if you haven’t read it
addition
all, given the free to carbonyl
rotation possible groups
in an acyclic molecu
recently, now might be a good time to
H displaying
What will be 𝛂-stereocenter
anthe conformation of is
refresh your memory. theconformation
aldehyde in the margin?
cyclic Using
molecules, the principles we out-
is conformation.
lined in Chapter 17, we can expect it to be staggered, O with no eclipsing interactions, and also
with large substituents as far apart from one another as possible. The conformation of a chiral
A Newman projection aldehyde
of one of the
Ph
possible conformers might look like the one shownHin the What margin. There
will be the are no eclipsingofinterac-
conformation the aldehyde in th
up, Ph,
rom O tions, and the large phenyl group is held satisfactorily far awayinfrom
lined the O17,
Chapter andwethecanH expect
atoms of it the
to be staggered,
Me
H aldehyde. with large substituents as far apart from one another as po
no eclipsing
• By rotating
By rotatingabout the
about the central
central bond bond
interactions of the (the
of the aldehyde aldehyde (the one
one represented
possible conformers represented
by amight
circle in thelike
look theby
Newman oneashown
circlein t
largest group, Ph,
inprojection)
the Newman projection)
we can suggest a series ofOapossible
Me isseries of Opossible
furthestconformations.
from conformations
Provided
tions, and we move
the large phenyl can
ingroup
60° isbe
steps, suggested.
none
held satisfactorily fa
and H
Provided
of them willthey
havemove in 60°interactions.
any eclipsing steps, none The fullof set
them
of sixwill
aldehyde. have any
conformers eclipsing
is shown here. Lookinteractions.
at
themfull
The forset
a moment,
of sixand notice how they
conformers differ.
is shownPh below By rotating about the central bond of the aldehyde (the
projection) we can suggest a series of possible conformat
H H
Me O O Me
H
O O
of them H
will have
Ph
O eclipsing interactions.
any O
Ph
The full set
Newman projection of one them for a moment, and notice how they differ.
possible conformation
Ph H Me Ph H Me
Me O O Me H H
O
H H H Ph Ph H H Me Me H H
largest group, Ph, largest group, Ph, Ph H Me Ph
is furthest from O is furthest from O
and H andHH
H H Ph Ph H
largest group, Ph, large
• TheOnly
yellow
two ofboxed conformations
them, boxed place
in yellow, place thePh
the large is large
furthest Ph
groupfrom O group perpendicular
perpendicular to the carbonyl to the
is fur
and H
carbonyl group.
group. These These
yellow boxed are thereforearethe
conformations lowest-energy
therefore conformers
the lowest-energy conformers and, for
12
the purpose of the discussion that follows, they are theCredits:
only [Link] whose reactions we need to
Clayden et. al. Organic Chemistry - Oxford University Press
 Only two of them, boxed in yellow, place the large Ph group perpendicular to the carbonyl
Diastereoselective additions to carbonyl groups
group. These yellow boxed conformations are therefore the lowest-energy conformers and, for
the purpose of the discussion that follows, they are the only ones whose reactions we need to
The lowest energy conformations of a carbonyl compound
consider.

• The most important conformations of a carbonyl compound with a stereogenic

•
Lowest energy conformations of a carbonyl compound
center adjacent to the carbonyl group are those that place the largest group
perpendicular to the carbonyl
The most important groupof a carbonyl compound with a stereogenic
conformations
centre adjacent to the carbonyl group are those that place the largest group
perpendicular to the carbonyl group.
O M O O S
L
R most important conformations are L and L
S
M
L = large group, e.g. Ph S R R M
M = medium-sized group, e.g. Me
S = small group, e.g. H

The major product arises from the most reactive conformer

na Now that we have decided which are the important conformations, how do we know which gives the
product? We need to decide which is the most reactive. All we need to do is to remember that any
nucleophile attacking the carbonyl group will do so from the Bürgi–Dunitz angle—about 107° from
the C=O bond. The attack can be from either side of C=O, and the following diagrams show the pos-
sible trajectories superimposed on the two conformations we have selected, which are in equilibrium
with one another.

13
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Diastereoselective additions to carbonyl groups
The major product arises from the most reactive conformer

• Any nucleophile attacking the carbonyl group will do so from the Bürgi–Dunitz
angle, about 107° from the C=O bond. The attack can be from either side of C=O,
Additions
and the following diagramsto carbonyl
show thegroups can be
possible diastereoselective
trajectories even without
superimposed rings
on the two
selected conformations, which are in equilibrium with one another
Bürgi–Dunitz
angle:
O 107° O
Me H
unhindered
approach
Ph close close Ph
to Ph to Ph
Nu H H Nu Nu H Me Nu
close
to Me

the black flight path is the best the three brown flight paths are hindered by Ph or Me

• This model of four

Not all thepossible
way ‘flight
a nucleophile attacks aarecarbonyl
paths’ for the nucleophile compound,
equally favourable. called
For the three shownthe !
in brown,model,
Felkin–Anh the nucleophile passes within 30°
is supported byor theoretical
so of another substituent. But, for and
calculations the onenumerous
shown in Re
black, there is no substituent nearby except H to hinder attack: the conformation on the left is the th
experimental results. Notice that it is not necessary to decide which is the lower si
most reactive one, and it reacts to give the diastereoisomer shown below.
energy of the two conformations because the attack in black will occur even if the m
rotate to view from this direction
conformer on the left is the minor one in the mixture lo
pa
• This is an example Me O
of the Curtin-Hammett Me
principle, which says OH
that it is the dr
OH
relative energies of the transition states that control redraw selectivity, not the relative th
unhindered Ph no
energiesapproach
of the starting materials
Ph Nu Ph Nu 14 th
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Me
 Additions to carbonyl
to Ph groups can be to
diastereoselective
Ph even
Diastereoselective
without
Nu additions
H H
rings Nu to carbonylNugroups H Me
close
Nu
to Me
The major What
producthappens if we from
arises bring the
thestereogenic
most centre closer
reactive to the carbonyl group than it was in the last
conformer
theexample?
black flightYou
path might
is the best the three brown flight paths
expect it to have a greater influence over are the
hindered by Ph group’s
carbonyl or Me reactions. And it
• With Nu =does.
Not Here
Et all
the is possible
four an example.
right ‘flight paths’
product for the nucleophile
is formed and, more are equally [Link]
importantly, istheforthree
theshown
right !
reason in brown, Othe nucleophile passes within H 30°OHor so of another HO substituent.
H But, for the one shown in R
black,
Ph
there is no substituent nearby Ph
except H to hinder Ph
attack: the conformation on the left is the th
LiAlH4 produced in a ratio of 3:1
most reactive one, and it reacts to give the diastereoisomer+ shown below. s
m
Me rotate
Meto view from this direction
Me lo
major diastereoisomer minor diastereoisomer p
Me O OH anti OH
Me and Me Me and OH syn OH d
redraw th
unhindered
There is three times Ph n
approach
Ph as much of one
Nu of the two diastereoisomeric
Ph products as there is of the other,
Nu
and the major (anti) diastereoisomer is the one in which the nucleophile has added to the front face th
of H H group as drawn here. WeH can make H Me
Nuthe carbonyl these same two diastereoisomers by addition of
an organometallic to an aldehyde. For example, this Grignard reagent gives three times as much of
With
the synNu = Et we have the
diastereoisomer right
as the antiproduct and, moreThe
diastereoisomer. importantly, we can
major product bechanged,
has pretty sure butitthe
is for the
product
right
still reason: thisattack
arises from model on of
thethe
frontway
faceaofnucleophile
the carbonylattacks a carbonyl compound, called the
as shown. !
Felkin–Anh model, is supported by theoretical calculations and numerous experimental results. T
O H OH HO H
Notice that we don’t have to decide which is the lower energy of the two conformations: this is not C
Ph
necessary because EtMgBr
the Ph Ph
attack in black will occur even if the conformer onproduced
the leftinisathe
ratiominor
of 1:3 one in s
H + e
the mixture. th
Me Me Me
re
Cram’s rule minor diastereoisomer major diastereoisomer m
Me and OH anti Me and OH syn re
You may hear ‘Cram’s rule’ used to explain the outcome predict the right product, in this case it does so for the th
of reactions involving attack on chiral carbonyl wrong reason. Explanations and clear logical thinking are
compounds.
Drawing Cram was the first to realize that
diastereoisomers ofthese more important than rules, and you must be able to
acyclic molecules
reactions could be predicted, but we now know why these account for and predict the reactions of chiral aldehydes
compounds react in a predictable way. We will not and ketones usingmajorthediastereoisomer
Felkin–Anh model. 15
alternative view o
If you find it hard to see that these are still the same two Credits: J. Clayden et. al.
MeOrganic syn
and OH Chemistry - Oxford diastereoisomer,
University Press s
describe Cram’s rule because, although it often does
 necessary because
ly good the attack in black will occur even if the conformer on the left is the minor one in
effect.
Felkin–Anh model, is supported by theoretical calculations and numerous experimental energies what resht
of the
Diastereoselective
the mixture. additions to carbonyl groups
Notice that we don’t have to decide which is the lower energy of the two conformations:
faces
that control
this
selew
is
reagen
Additions
Cram’s rule to carbonyl
necessary because the groups can
attack in black willbe diastereoselective
occur even
even if the conformer on the
relative energies
left ismaterials.
the minor It’son
re
The major product arises from the most reactive conformer
without rings the mixture.
You may hear ‘Cram’s rule’ used to explain the outcome
reminder not to
predict the right product, in this case it does so for the than a principle.
of reactions involving attack on chiral carbonyl wrong reason. Explanations and clear logical thinking are
• With Nu =happens
What H weCram’s
compounds. Cram was the
ifthe right
we bring rule
first to realize
theproduct
stereogenic
that these
is centre
formed closerand,
to themore
carbonylimportantly,
group than ititwas
more important than rules, and you must be able to
is in
forthethelast right
reason example?
reactions could beYou might
predicted, butexpect it to why
we now know have a greater
these influence
account for and over
predictthe
the carbonyl
reactions ofgroup’s reactions. And it
chiral aldehydes
compounds
[Link]
Herein is You may
a predictable
an example. hear ‘Cram’s
way. We will not rule’ used to explain the outcome predict the
and ketones using the Felkin–Anh model. right product, in this case it does so for the
of reactions
describe Cram’s rule because, involving
although it oftenattack
does on chiral carbonyl wrong reason. Explanations and clear logical thinking ar
O compounds. Cram was theHfirstOH to realize that theseHO H more important than rules, and you must be able! to
reactions could be predicted, but we now know why these account for and predict the reactions of chiral aldehydes
We ha
The Phsame reasoning accounts
LiAlH4react
compounds forPh inthe
a predictable way. We willPh
diastereoselectivity of the reduction
not on
and ketonesp. 000:
using
produced infirst
the weofneed
Felkin–Anh
a ratio 3:1 model. diaste
describe Cram’s rule because, although +
it often does
to draw the two important conformers of the ketone; the ones that have the large group (Ph) perpen- two su
Me C=O group.
dicular to the Me Me on opp
The same reasoning accounts for the diastereoselectivity of the reduction on p. 000: firstdrawn.
major diastereoisomer minor diastereoisomer
we n
O to draw the two important O
Me and OH conformers
anti H of the
Me andketone; definit
OH syn the ones that have the large group (Ph) perp
Me
only re
dicular to the C=O group.
unhinderedThere is three times as much of one of the two diastereoisomeric products as there is of the other, with a
approach
Ph Ph
and the major (anti) diastereoisomer O O
is the one in which the nucleophile has added to the front face
Me H
H Et group as drawn here. We can
Nuof the carbonyl Et Me
make these same two diastereoisomers by addition of
unhindered
an organometallic to an aldehyde. For
approach
Phexample, this Grignard
Ph reagent gives three times as much of
Now choose the angle of attack that is the least hindered, and draw
the syn diastereoisomer as the anti diastereoisomer. The major product a Newman projection
has changed, butofthetheproduct
product. H Etprojection as a normal structure, Me
stillFinally, redraw
arises from the on
Nu
attack Newman
the front face of the carbonyl as shown. Et preferably with the longest
chain in the plane of the paper. redraw, rotating about
O Now choose the angle H OH of attack that isHO H hindered, and
the least draw a Newman projection of
central bond to put
Ph Me O [Link] Ph redraw
Finally, Me theOH Newman Phprojection as a normal structure,
OH longest
produced chain
in a ratio ofpreferably
in1:3
plane with
OHthe lon
H + Et of paper
chain in the plane of the paper. redraw
redraw, rotatin
unhinderedMe Ph Ph
approach
Ph HMe Ph Me H centralEt
bond
Me O OH longest chain i
minor diastereoisomer majorMe OH
diastereoisomer
H3Al H H Et Me andH OH antiEt Me and OH syn
Me redraw EtMe of paper
unhindered Ph
approach
Ph H Ph H 16
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Diastereoselective additions to carbonyl groups
34 . Diastereoselectivity
The effect of electronegative atoms
The effect of electronegative atoms anticancer
One of the most powerful agents known is dolastatin, isolated from the sea-hare
Dolabella. Dolastatin contains an unusual amino acid, with three stereogenic centres, and chemists
The effect ofinelectronegative atoms
• Conformations ofGermany managed
the chiral to exploit Felkin–Anh
carbonyl compound control
thatvery effectively
place an to make it from the much
electronegative more
atom
widespread
One of the most amino
powerful acid isoleucine.
anticancer agentsThis is the is
known sequence of reactions.
dolastatin, isolated from the sea-hare
perpendicular to the C=O bond will be more reactive
Dolabella. Dolastatin contains an unusual amino acid, with three stereogenic centres,protected
and chemists
version of
unusual amino acid found
in Germany managed to exploit Felkin–Anh control very effectively to make it from the much more
• An example: synthesis of Dolastatin.
1. BnBr Why the diastereoselectivity OMe is soinhigh? dolastatin
widespread amino acid isoleucine.
NH2 This is the
2. LiAlH4
sequence of reactions.
NBn2 NBn2
3. oxidize OLiprotected version of
CO2H CHO unusual amino acid found CO2Me
1. BnBr OMe in dolastatin
NH2 Me NBn2 Me NBn2 Me OH
2. LiAlH4
isoleucine >96:4 diastereoselectivity
3. oxidize OLi
CO2The
H key step is the aldol reaction of
CHO CO2Me
the enolate of methyl acetate with the protected amino alde-
Me hyde. To rationalize the stereoselectivity,
Me we first need to draw theMe
two most
OH important conforma-
isoleucinetions of this aldehyde with the large group perpendicular to >96:4C=[Link]
The trouble is—which do we
ourself putting alkyl choose as ‘large’: the –NBn2 group or the branched alkyl group? Since we know which diastereo-
icular to C=O: you will key
The get step is the aldol reaction of the enolate of methyl acetate with the protected amino alde-
isomer is produced we can work backwards to find that it must be the NBn2 group that sits perpen-
ng diastereoisomer.
hyde. To rationalize
dicularthe stereoselectivity,
to C=O in the reactivewe first need
transition to draw
state, thealkyl.
and not two most important conforma-
tions of this aldehyde with the large group perpendicular to C=O. The trouble is—which dobond
redraw, rotating we to put
l longest chain in plane of paper
choose as ‘large’: the –NBn2 group or the branched alkyl group? Since we know which diastereo-
will get H O is produced we can work O
isomer HO
backwards to find that it must NBn2
be the NBn2 group that sits perpen-
.
dicular to C=O in the reactive transition state, and not alkyl.
NBn2 Bn2N OLi Bn2N CO2Me
redraw, rotating bond to put
CO 2Me chain in plane
longest Meof paper
OH
H H H OMe H H
O O HO NBn2
unhindered attack alongside H
NBn2 Bn2N Bn2N 17
Now look at OLi
the diastereoselectivity ofCredits:
the reaction: it is much greater than COthe
2 Me
3:1 we saw
J. Clayden et. al. Organic Chemistry - Oxford University Press
u see a selectivity given
Diastereoselective additions to carbonyl groups
The effect of electronegative atoms

• With electronegative atoms X that are not leaving groups in the SN2 reaction (for
example, X = OR, NR2, SR, etc.), the π* and σ* orbitals (separated LUMO orbitals)
add together to form a new, lower-energy LUMO molecular orbital, more susceptible
to nucleophilic attack. But, if X is not a leaving group, attack on this orbital will result
not in nucleophilic substitution but in addition to the carbonyl group. This effect will
operate only when the C–X and C=O bonds are perpendicular so that the orbitals
align correctly
Additions to carbonyl groups can be diastereoselective even without rings 891

O two LUMOs new molecular LUMO in energy terms:

σ* of the σ* of the
X π* of the X C–X bond π* + σ*
X O C–X bond
C=O bond addition to C=O
X is an electronegative group X
but not a leaving group (OR, O combine O
NR2, SR, etc.) Nu
nucleophilic attack π* of the
What does this mean for stereoselectivity? Conformations of occurs easily here C=O bond
the chiral carbonyl compound that place an electronegative atom π* + σ*
Nu
perpendicular to the C=O bond will be more reactive—size
new molecular LUMO –
doesn’t matter. So, in the dolastatin amino acid example, the conformations with NBn2 perpen- lower energy; more reactive
dicular to C=O are the only conformations we need to consider.

•
• The conformations
Using the Felkin–Anh with
modelthe electronegative group perpendicular to C=O are the only
conformations we need to consider. This explains the high diastereoselectivity
To predict or explain the stereoselectivity of reactions of a carbonyl group with an
observed instereogenic
adjacent the Dolastatin
centre, useamino acid example
the Felkin–Anh model.
18
• Draw Newman projections of the conformations of theCredits: starting material that
J. Clayden et. al. Organic Chemistry - Oxford University Press
 2
nucleophilic attack
Diastereoselective additions
What does this mean for stereoselectivity? to carbonyl
Conformations of groups
occurs easily here
π* of th
C=O bo
the chiral carbonyl compound that place an electronegative atom
Nu
The perpendicular
Felkin-Anh to model
the C=O bond will be more reactive—size
new
doesn’t matter. So, in the dolastatin amino acid example, the conformations with NBn2 perpen- lower
dicular to C=O are the only conformations we need to consider.

•Using the Felkin–Anh model

To predict or explain the stereoselectivity of reactions of a carbonyl group with an
adjacent stereogenic centre, use the Felkin–Anh model.
• Draw Newman projections of the conformations of the starting material that
place a large group or an electronegative group perpendicular to C=O
• Allow the nucleophile to attack along the least hindered trajectory, taking into
account the Bürgi–Dunitz angle
• Draw a Newman projection of the product that arises from attack in this way
• Carefully flatten the Newman projection on to the page to produce a normal
structure, preferably with the longest chain of C atoms in the plane of the
page. Check that you have done this last step correctly: it is very easy to make
mistakes here. Use a model if necessary, or do the ‘flattening out’ in two
stages—first view the Newman projection from above or below and draw that;
then rotate some of the molecule about a bond if necessary to get the long
chain into the plane of the page.

As an illustration of two sorts of diastereoselectivity, our next example is a natural product called
penaresidin A. It was isolated from a Japanese sponge in 1991, and has the structure shown below
OH OH
19
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Effect of chelation on stereoselectivity
Chelation can reverse stereoselectivity
SMe SMe
Ph Li R3BH Ph

O OH
You should now be in a position to explain the outcome of this reaction without much di
• The use of the Felkin–Anh model justifies the correct diastereoselectivity
Sulfur is the electronegative atom, soChelation
the conformations we need
can reverse to consider are the two fol
stereoselectivity
Unhindered attack on the second gives the diastereoisomer shown.

O O
H Et HO Et SMe
redraw
SMe Chelation
MeS can reverse MeS
stereoselectivity
H Ph 893
Et
Et Ph Ph H H BH3 Ph H OH
O
Et HO Et unhindered SMe
approach
redraw
MeS Ph
MeS
But, from what we have toldH you so far, the next Et SMe SMe
• Changing reaction would present froma problem:
sodium changing the
Ph H HtheBHmetal to zincOH reverses the stereoselectivity. The use of
Ph H Ph ZnBH4 Ph
3
metal from
the simpleunhindered sodium to zinc has reversed the stereo-
Felkin–Anh model now does not work, it gives the wrong answer
selectivity. Using the simple Felkin–Anh model now
approach O OH
does not work: it gives the wrong answer.
we have told you so far, the next SMe SMe
The reason is that zinc can chelate sulfur and the carbonyl group. Chelation is the coordination of
esent a problem: changing the Ph ZnBH4 Ph atom, and here it changes the conformation
two heteroatoms carrying lone pairs to the same metal
to zinc has reversed the stereo-
of the starting material. No longer does the most reactive or most populated conformation place the
e simple Felkin–Anh model now O OH
electronegative S atom perpendicular to C=O; instead it prefers S to lie as close to the carbonyl oxy-
ves the wrong answer.
gen as possible so that Zn can bridge between S and O, like this. 20
t zinc can chelate sulfur and the carbonyl group. Chelation is the coordination of
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Et HO Et SMe
redraw
Effect of chelation
MeS MeS onHstereoselectivity
Ph
Et
Ph H
H BH3 Ph OH H Chelation can reverse stereoselectivity
Chelation may change the direction of diastereoselectivity
unhindered
approach
O O
H Et HO Et SMe
e have told you so far, the next SMe redraw SMe
sent a problem:SMe changing MeSthe Ph MeS ZnBH H Ph
4 Ph Et
to zincEthas reversed the stereo-
Ph Ph H H BH3 Ph H OH
simple Felkin–Anh model now O unhindered OH
es the wrong answer. approach

zinc can But,

chelate sulfur
from what and the carbonyl
we have told you so far, theChelation
group. next is theSMe
coordination of SMe
• Zinc
rying lone can chelate
pairswould
reaction to thepresent sulfur
same metal and the
atom,changing
a problem: carbonyl
and herethe it changes group
the conformation
ZnBH4
Ph Ph
metal from sodium to zinc has reversed the stereo-
ial. No longer does the most reactive or most populated conformation place the
• selectivity.
Chelation
m perpendicular Using is
the the
to C=O; simple coordination
insteadFelkin–Anh
it prefersmodel of
now
S to lie astwo
closeheteroatoms carrying OH
toO the carbonyl oxy- lone pairs to the same
does
at Zn can not work:
metal
bridge atom, it gives
between S the
and and wrong
here
O, likeitanswer.
changes the conformation of the starting material. No longer
this.
The reason is that zinc can chelate sulfur and the carbonyl group. Chelation is the coordination of
does
two the most
heteroatoms reactive
carrying Zn pairsor
lone to most
the samepopulated
metal atom, and conformation
here it changes theplace the electronegative S
conformation
atom
of perpendicular
the starting to does
material. No longer C=O; instead,
the most reactive oritmost
prefers
populatedS conformation
to lie as place
closethe to the carbonyl
O SPh
oxygen
to allow asSpossible
electronegative
rotate PhS so
atom perpendicularthat Zn can
to C=O; bridge
instead itPhS between
prefers S OH Sredraw
to lie as closeand
to theO
carbonyl oxy-
chelation
gen as possible so that Zn can bridge between S and O, like this. Ph
Ph H Ph Ph
Zn

hout chelation, O H Ph H Ph OH
Ph
BH 4 PhS O PhS SPh
et attack here rotate to allow OH
chelation
with chelation, get redraw
Ph
PhS attack here Ph H Ph Ph

is possible, this Ph OH
Ph H is the conformation
without chelation, to consider—the
BH4 H Ph one with the car-H
get attack here
her chelating atom almost eclipsing one [Link] is the most populated,
with chelation,
ed by the chelation, and it is also the most attack here
reactive, because the Lewis-acidic 21
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
the reactivity of the carbonyl group. Attack is still along the less hindered path-
 Effect of chelation on stereoselectivity
PhS SPh
• When OHchelation is possible, this is the conformation to consider: the one with the
redraw
Ph
carbonyl
H O
Ph and the other chelatingPh atom almost eclipsing one another. It is the most
populated,
H Ph because it is stabilized
OH by the chelation, and it is also the most reactive,
because the Lewis-acidic metal atom increases the reactivity of the carbonyl group.
Attack is still along the less hindered pathway, but this now leads to the other face of
the carbonyl group, and the stereochemical outcome is reversed
er—the one with the car-
r.•It is
Twothe things
most populated,
are needed for chelation to occur:
ve, because1. the aLewis-acidic
heteroatom with lone pairs available for coordination to a metal
along the less hindered path-
2. a metal ion that prefers to coordinate to more than one heteroatom at once.
e stereochemical outcome is
These are mainly more highly charged ions as shown in the table
Metals commonly Metals not
involved in usually involved
chelation in chelation
m at once. These are mainly
Li+ sometimes Li+ often
Mg2+ Na+
plained using a nonchelated
Zn2+ K+

u Cu2+

OMe Ti4+

Ce3+
Mn2+ 22
27% Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 4
get attack here
Effect of chelation on stereoselectivity
with chelation, get
attack here

When chelation is possible, this is the conformation to consider—the one with the car-
Chelation leads to higher
bonyl degree
O and the of stereoselectivity
other chelating atom almost eclipsing one another. It is the most populated,
because it is stabilized by the chelation, and it is also the most reactive, because the Lewis-acidic
• Stereoselectivities
metal atom in chelation-controlled
increases additions
the reactivity of the carbonyl group. to C=O
Attack is stillgroups arehindered
along the less typically
path-
>95:5. Indeed, stereoselectivity
way, but this now leads to theis likely
other tothebe
face of high group,
carbonyl if a cyclic transition state
and the stereochemical is is
outcome
reversed. involves just such a transition state, so it should be no surprise
involved. Chelation
Two things are needed for chelation to occur:
that it gives much higher levels of control than the acyclic Felkin-Anh model does
• a heteroatom with lone pairs available for coordination to a metal
• a metal ion that prefers to coordinate to more than one heteroatom at once. These are mainly
more highly charged ions as shown in the table
Here is another example of a reversal in selectivity that can be explained using a nonchelated
Felkin–Anh model with Na+ and a chelated model with Mg2+.
O OH Nu
Nu HO
OMe OMe OMe
Ph Ph Ph

NaBH4 (Nu = H) 73% 27%

Me2Mg (Nu = Me) 1% 99%

Not only does chelation control reverse the stereoselectivity, but it gives a much higher degree
of stereoselectivity. Stereoselectivities in chelation-controlled additions to C=O groups are
typically >95:5. But this fits in nicely with the ideas we presented at the end of the last chapter: stereo-
selectivity is likely to be high if a cyclic transition state is involved. Chelation involves just such a
transition state, so it should be no surprise that it lets us achieve much higher levels of control than
23
the acyclic Felkin–Anh model does.
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Chelation, rate, and stereoselectivity
elation, rate, and stereoselectivity
Effect of chelation on stereoselectivity
The correlation of rate of addition with increasingly bulky silyl ethers, both the rate of the magnesium ion. But with larger protec
orrelation of rate of addition with increasingly bulky silyl ethers, both the rate ofdecreased.
the magnesium ion. But 2+larger protecting gro
with
diastereoselectivity was demonstrated in a series reaction and the diastereoselectivity chelation of Mg between the two ox
ereoselectivity wasthat
demonstrated in a series reactionWith
and small
the diastereoselectivity 2+
of experiments involved reacting Me2Mg with protecting groups,decreased.
the reaction takeschelation of Mg between
frustrated: the two
the rate drops oxygen
off, ato
and the
Chelation
periments
protectedthat increases
involved reacting As
α-hydroxy-ketones. Methethe
2Mg the rate
with
protecting of
With small addition
protecting
place thereaction
through groups, the reaction
chelated transitiontakes
state—thefrustrated: the rate
becomes drops
more off,would
what and the
be selectiv
expecte
cted
group was changed from
α-hydroxy-ketones. As the protecting
a methyl ether to a place through the chelated
selectivity transition
shows this—and state—the
the rate is faster becomes more what
Felkin–Anh would be expected from
model.
was changed from
trimethylsilyl ethera and
methyl ether
then to a a series of selectivity
through showsof
because this—and the rate
the activating is faster
effect Felkin–Anh model.
of the Lewis-acidic
thylsilyl ether and then through a series of because of the activating effect of the Lewis-acidic
O Me OH Me OH
O Me2Mg R Ratio Relative
Me MeMe OH Me Me OH
Me2Mg + R
Ph Me Ratio >99:1 Relative rate
1000
THF, –70 °C Me
+ Ph Me Ph
Ph THF, –70 °C Ph Ph Me >99:1 1000
OR OR OR SiMe3 99:1 100
OR OR OR major product by SiMe3 99:1 100
major product by nonchelation
major product by
SiEt3 96:4 8
chelation
major product by control (Felkin-Anh) control SiEt3 96:4 8
nonchelation
chelation control (Felkin-Anh) control SiMe2t-Bu 88:12 2.5
Mg SiMe2t-Bu 88:12 2.5
Mg chelates if R Mgis small SiPh2t-Bu 63:37 0.82
Mg chelates if R is small SiPh2t-Bu 63:37 0.82
RO O O Si(i-Pr)3 42:58 0.45
Me
RO O O Si(i-Pr)3 42:58 0.45
Me unhindered
unhindered
approach
Me RO approach
unhindered unhindered
approach
Me RO
–OR perpendicular if approach
Nu H Ph R is large Ph H Nu
–OR perpendicular if
Nu H Ph R is large Ph H Nu

• Chelation
•Chelation
• The reaction takes place•through
may change thethe
chelated
directiontransition state (the selectivity shows
of diastereoselectivity
this) and the rate •
is may
faster because
• change
leads tothe of the
direction
high levels activating effect of the Lewis-acidic
ofofdiastereoselectivity
diastereoselectivity
magnesium ion. But• with larger
leads increases
to protecting
high levels of groups, chelation
diastereoselectivity of Mg 2+ between the
• the rate of the addition reaction
two oxygen atoms is•frustrated:
increases the raterate
the drops
of the off, reaction
addition and the selectivity becomes more
what would be expected from the
Chelation Felkin-Anh
is possible model
through six- as well as five-membered rings, and the reduction
24
Chelation
below isisapossible through
nice example of six- as well [Link]
the reversal
Credits: five-membered
et. al. Organicrings,
diastereoselectivity
Clayden and
observed
Chemistry the reduction
- Oxfordwhen of theC
chelating
University Press
 –OR perpendicular if
NuH H Ph –OR perpendicular
Nu if
Ph H
Effect of chelation on stereoselectivity
R is large
Nu Ph R is large Ph H Nu

• • Chelation
Chelation

• may•change
may change the direction of diastereoselectivity
the direction of diastereoselectivity
• to
• leads leads to high levels of diastereoselectivity
high levels of diastereoselectivity
• • increases
increases theofrate
the rate the of the addition
addition reaction
reaction
Chelation is possible through six- as well as five-membered rings, and the reduction of the keto
Chelation is possible through six- as well as five-membered rings, and the reduction of the ketone
• Chelation is possible through
below is a nice examplesix- asreversal
of the well as five-memberedobserved
of diastereoselectivity rings when chelating Ce3+ ions a
below is a nice example of the reversal of diastereoselectivity observed when chelating Ce3+ ions are
• The reduction addedofto athe
normalketone below is reduction.
sodium borohydride a niceTheexample of important
products were the reversal
added to a normal sodium borohydride reduction. The products were important for making single
for makingofsing
diastereoselectivity
geometricalobserved
geometrical isomers when
isomers of alkenes
of alkenes in
in chelating
a modificationCe
a modification of the
the ions
of 3+
Wittig are added
Wittig reaction
reaction
(Chapter
(Chapter to31).a Notice
31). Notice normal
too how
too ho
3+
sodium the the rate must
borohydride change: with
reduction Ce the reaction can be done at –78 °C.
rate must change: with Ce3+ the reaction can be done at –78 °C.
Ph2PO Ph2PO Ph2PO
Ph2PO Ph2PO Ph2PO
NaBH , CeCl3 NaBH4
NaBH4, CeCl43 NaBH4
R R R
R EtOH, –78 °C R MeOH, 20 °C R
EtOH, –78 °C MeOH, 20 °C
OH O
OH chelation control O Felkin-Anh (nonchelation) control OH
chelation control Felkin-Anh (nonchelation) control OH
O Ce O Me
O Ce six-membered
OO Me
six-membered
O
O chelated
P chelated P
Ph
P O transition state
PPh
Ph transition state Ph
Ph
Ph Me Ph H
Me Ph Nu
large, electro- H Nu
large, electro-
negative Ph2PO
Nu H H Ph negative Ph2PO
Nu Ph perpendicular to C=O
perpendicular to C=O
25
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Effect of chelation on stereoselectivity
Summary
Stereoselective reactions of acyclic alkenes

O is there a metal ion use chelation model:

is there a heteroatom yes yes
Z at the chiral centre? capable of chelation consider reactions on
R with the heteroatom? conformation with C=O
Y and heteroatom held
X close in space
no no

use Felkin–Anh model:

use Felkin–Anh model: consider reactions on
consider reactions on conformations with
conformations with most electronegative
largest group atom perpendicular to
perpendicular to C=O C=O

Stereoselective reactions of acyclic alkenes

Earlier in the chapter we discussed how to make single diastereoisomers by stereospecific additions
to double bonds of fixed geometry. But if the alkene also contains a chiral centre there will be a
stereoselective aspect to its reactions too: its faces will be diastereotopic, and there will be two possi-
ble outcomes even if the reaction is fully stereospecific. Here is an example where the reaction is an
epoxidation. epoxidation is stereospecific: both epoxides 26
retain the cis geometry of the starting alkene
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Stereoselective
The Houk modelreactions of acyclic alkenes !
K.N. H
In order to explain reactions of chiral alkenes like this, we need to assess which conformations are Califor
The Houk model and consider how they will react, just as we have done for chiral carbonyl compounds. provide
important, stereo
• Much of the work on alkene conformations was done by K.N. Houk using theoretical
Much of the work on alkene conformations was done by K.N. Houk using theoretical computer powerf
models,models.
computer and we willThesummarize
results the most important are:
of calculations conclusions of these studies. The theoretical
studies looked at two model alkenes, shown in the margin.
1. The lowest-energy conformation of a chiral alkene will have H eclipsing the
The calculations found that the low-energy conformations in each case were those in which a sub-
double bond
stituent eclipses the double bond. For the simple model alkene 1, the lowest-energy conformation is model
2. If there
the one that hasistheaproton
cis substituent
in the plane of on the alkene,
the alkene. this will conformation—only
Another low-energy be the only important3.1
conformation;
kJ mol –1 higher—has one if there is nogroups
of the methyl cis substituent, other
eclipsing the double conformations
bond, so that when we may
start be
important
looking tooof this type of alkene, we shall have to consider both conformations.
at reactions
this alkene has two low-energy conformations
Me Me Me
H H H H
H H Both conformations
H Me
Me must be considered
lowest energy: H eclipses Me slightly higher energy: Me H
eoselectivity plane of double bond eclipses plane of double bond

el alkene 2, with this alkene has only one low-energy conformation

, the conforma- The control of
Me Me Me
predictable and H H H H conformation by a cis
ergy conformer Me H Me Me substituent is known as
Me Me
h the hydrogen allylic strain or A1,3
Me H
ouble bond. There is no room for strain
p to eclipse the double bond only important conformer:
H eclipses double bond
high-energy conformation
due to Me–Me interaction
d it would get too close to the cis 27
he other end of the double bond. Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Stereoselective reactions of acyclic alkenes
Stereoselective reactions of acyclic alkenes
Stereoselective epoxidation with m-chloroperbenzoic acid (m-CPBA)
Earlier in the chapter we discussed how to make single diastereoisomers by stereospecific additions
to double bonds of fixed geometry. But if the alkene also contains a chiral centre there will be a
stereoselective aspect to its reactions too: its faces will be diastereotopic, and there will be two possi-
ble outcomes even if the reaction is fully stereospecific. Here is an example where the reaction is an
epoxidation. epoxidation is stereospecific: both epoxides
retain the cis geometry of the starting alkene

m-CPBA O O
this diastereoisomer arises
from attack on one
+ diastereotopic face
SiMe2Ph SiMe2Ph SiMe2Ph
epoxidation is
stereoselective: >95% of
the product is this SiMe2Ph
diastereoisomer this diastereoisomer m-CPBA
m-CPBA arises from attack on
the other
diastereotopic face

SiMe2Ph

The Houk model !

K.N. Houk works at the Unive
In order to explain reactions of chiral alkenes like this, we need to assess which conformations are California in Los Angeles. He
important, and consider how they will react, just as we have done for chiral carbonyl compounds. provided explanations for a n
stereochemical results by us
Much of the work on alkene conformations was done by K.N. Houk using theoretical computer powerful computational met
models, and we will summarize the most important conclusions of these studies. The theoretical Me28
studies looked at two model alkenes, shown in the margin. Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Me SiMe2Ph bond
O redraw
Stereoselective epoxidation
Stereoselective
cis-substituted alkene reactions of acyclic alkenes Me Me SiMe
We started this section with a diastereoselective epoxidation of an alkene. The alkene was this one,
m-CPBA attacks the less
and it has a substituent cishindered
Stereoselective epoxidation with m-chloroperbenzoic to the stereogenic
face centre. acid
We can(m-CPBA):
therefore expect
noit to have one important
coordination
conformation, with H eclipsing the double bond. When a reagent—m-CPBA here—attacks this con-
—draw the product in the formation, it will approach the less hindered face, and the outcome is shown.
conformation as the
Without the cis substituent, selectivity is much lower.
this face hindered bym-CPBAMe O O
g material, then flatten into large SiMe2Ph group
Me
ane of the page. Me Me +
Me only important Si Ph Si Ph
H H O
conformer has H
SiMe Ph H SiMe Ph H SiMe2Ph
eclipsing double Me2 H Me
2
bond H
Me SiMe2Ph redraw
O ratio of diastereoisomers
61:39
Me Me SiMe2Ph
cis-substituted alkene m-CPBA still attacks the less hindered face of the alkene, but with no cis substituent there ar
m-CPBA attacks theone
low-energy conformations: less with H eclipsing the double bond, and one with Me eclipsing
hindered face
gives a different stereochemical result, explaining the low stereoselectivity major
of theproduct (95%)
reaction.
aw the product in the eclipsing C=C Me selectivity is much lower. Me
ormation as the
Without the cis substituent,
Me O Me O
aterial, then flatten into m-CPBA
Si Ph Si Ph
Me H H O
of the page. Me
+
H H H H
SiMe2Ph SiMe
O 2Ph redraw SiMe2Ph
Me Me SiMe2Ph
61:39 ratio of diastereoisomers
major product (61%)
Me Me
m-CPBA attacks the less
m-CPBA still attacks
hindered facethe less hindered face of the alkene, but with no cis substituent there are two
SiMe2Ph low-energy conformations: one with H eclipsing the double bond, and one with Me eclipsing. Each
gives a different stereochemical result, explaining the O
low stereoselectivity of the reaction.
eclipsing
MeC=C H H
Me Me MeH
H redraw O
H Me
Me H MeMe
Si Ph Me Si Ph Me O
Me H Si Me H Si SiMe2Ph
minor
H conformer:
H H
Me eclipsing C=C Ph Me H Ph Me
O redraw minor product (39%)
Me Me SiMe2Ph 29
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
major product (61%)
 Stereoselective reactions of acyclic alkenes
Stereoselective reactions of acyclic alkenes
Youepoxidation
Stereoselective saw at the end with
of them-chloroperbenzoic
last chapter that the reactions
acidof (m-CPBA):
m-CPBA can becoordination
directed by hydroxyl
groups, and the same thing happens in the reactions of acyclic alkenes. This allylic alcohol epoxidizes
to give a 95:5 ratio of diastereoisomers.
m-CPBA O O
+

OH OH OH
95:5 ratio of diastereoisomers

Drawing the reactive conformation explains the result. The thing that counts is the cis methyl
group: the fact that there is a trans one too is irrelevant as it is just too far away from the stereogenic
centre to have an effect on the conformation.
hydrogen-bonding
delivers m-CPBA from
Ar same face as OH
‡
O Me
Me O O
Me Me O H OH
H H O
O H
H H Me H
Me OH Me redraw
H
cis-substituted alkene
Me
Me
only important conformer has
H eclipsing double bond
• The thing that counts is the cis methyl group: the fact that there is a trans one too is
irrelevant as it is just too far away from the stereogenic center to influence the
•
conformationTo explain the stereoselectivity of reactions of chiral alkenes: 30
• Draw the conformation with H eclipsing the
Credits: J. double
Clayden et. al. bond
Organic Chemistry - Oxford University Press
 • Redraw the product as a normal structure with the longest chain in the plane
Stereoselective reactions of acyclic alkenes
of the paper

Stereoselective enolate alkylation

Stereoselective
• Chiral enolates can enolate alkylation
be made from compounds with a stereogenic center β to a
Chiral enolates
carbonyl [Link] be madethe
fromcarbonyl
compounds with a stereogenic centreto
is deprotonated β toform
a carbonyl
thegroup. Once the
enolate,
the carbonyl is deprotonated to form the enolate, the stereogenic centre is next to the double bond
stereogenic center is next to the double bond and in a position to control the
and in a position to control the stereoselectivity of its reactions. The scheme below shows stereo-
stereoselectivity of its reactions
selectivity in the reactions of some chiral enolates with methyl iodide.
Me Me
R OEt R OEt R OEt R OEt
LDA MeI
+
Me O Me O Me O Me O
Li
77:23 (R = Ph); 83:27 (R = Bu); 95:5 (R = SiMe2Ph)

• The enolate is a cis-substituted

The enolate alkene,
is a cis-substituted alkene, because
because either Oeither O-must
– or OEt or OEt
be cis must be cis to the
to the stereogenic
stereogenic
centre, socenter, so that
that to explain to explain the
the stereoselectivity, we stereoselectivity
need consider only theitconformation
is necessary with to consider
H eclips-
only the conformation
ing 34
the double with how
bond. Notice
. Diastereoselectivity H eclipsing the double
the diastereoselectivity bondas the group R gets bigger, because
increases
there is then more contrast between the size of Me and R. In each case, the electrophile adds to the
less hindered face, opposite R.
I
alkylation on face
Me opposite to R
Me Me
Me Me
H OEt OEt R OEt
H O H O
redraw
H Me O
R Li R
hemistry of 31
The other diastereoisomer can be made just byCredits:
having the methyl group in place first and then
l is lost in the J. Clayden et. al. Organic Chemistry - Oxford University Press
 Me Me O H OH
H H O
H
Stereoselective reactions
H of acyclic
H alkenes O
Me H
Me OH Me redraw
H
cis-substituted alkene
Me
Me
only important conformer has
H eclipsing double bond

•To explain the stereoselectivity of reactions of chiral alkenes:

• Draw the conformation with H eclipsing the double bond
• Allow the reagent to attack the less hindered of the two faces or, if co-
ordination is possible, to be delivered to the face syn to the coordinating
group
• Draw the product in the same conformation as the starting material
• Redraw the product as a normal structure with the longest chain in the plane
of the paper

Stereoselective enolate alkylation

Chiral enolates can be made from compounds with a stereogenic centre β to a carbonyl group. Once
the carbonyl is deprotonated to form the enolate, the stereogenic centre is next to the double bond
and in a position to control the stereoselectivity of its reactions. The scheme below shows stereo-
selectivity in the reactions of some chiral enolates with methyl iodide.
Me Me
R OEt R OEt R OEt R OEt
LDA MeI + 32
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
e Me
O O Me Me Me Me
O O
R R Li Li R R
Diastereoselective aldol reactions
Aldol
Aldol reactions
reactions can can be stereoselective
be stereoselective
• In the following example, only one new stereogenic center is created, so there is no
In Chapter
In Chapter 27 you27 youthe
met met
aldol aldol reaction:
thereaction: reaction
reaction of an enolate
of an enolate with anwith an aldehyde
aldehyde or a ketone.
or a ketone. Many Many
question of diastereoselectivity
of the examples you saw approximated to this general pattern.
of the examples you saw approximated to this general pattern.
O O
O O O OOH OH
base base O O
X X
X X X X R2 R2
R1R2 R2 R1 R1
R1
one newone new stereogenic
stereogenic centre: centre:
no diastereoselectivity
no diastereoselectivity involvedinvolved

Only
Only one onestereogenic
new new stereogenic
centrecentre is created,
is created, so theresoisthere is no question
no question of diastereoselectivity.
of diastereoselectivity. But with
But with
substituted enolates, twostereogenic
new stereogenic
centrescentres are created, and we to need
be to betoable
• substituted
With substituted enolates, two new
enolates, two new stereogenic are created, and we
centers need
are created, able
and wetoneed
predict
predict to
whichwhich diastereoisomer
diastereoisomer will bewill be formed.
formed. Here isHere is an example
an example from [Link]
[Link]
000.
didWe notdid not consider
consider stereo-stereo-
be able chemistry
to predict that which diastereoisomer willthat
bethe
formed
chemistry at thatatstage, stage,
but webutcanwe
nowcanreveal
now reveal
that the syn diastereoisomer
syn diastereoisomer is the major
is the major productproduct
of of
the reaction.
the reaction. OOH OH
O

O O
O OLi Ph Ph
O OLi
not
ausebecause
of of syn aldol
syn aldol
LDA,
LDA, –78 °C,–78
THF°C, THF H
ack on
one of one of Me H
Me (major product)product)
(major
aces, but Ph Ph Ph Ph OOH OH
but O
hintwo
which two enolateenolate
bears abears
Me a Me
each
th twowith two substituent
substituent
Ph Ph
come anti aldol
LDA anti aldol
N (minor product)
(minor product)
Li two newtwo new stereogenic
stereogenic centres:centres:
two diastereoisomers possiblepossible
two diastereoisomers
33
The important point about substituted enolatesCredits:
istheyJ. Clayden
that they et. al.
can Organic Chemistry - Oxford University Press
The important point about substituted enolates is that can exist asexist
two asgeometrical
two geometrical
isomers,isomers,
Diastereoselective aldol reactions

•
• Diastereoselectivity in aldol reactions
Generally (but not always) in aldol reactions:
Generally (but certainly not always!) in aldol reactions:
O
OLi O OH
Me H R
X X R
cis-enolate syn aldol

O
OLi O OH
H R
X X R
trans-enolate Me anti aldol

Let’s start by showing some examples and demonstrating how we know this to be the case. Some
• enolates
These canreactions are diastereoselective not because of stereoselective attack on one
only exist as trans-enolates because they are derived from cyclic ketones. This enolate,
of example,
for two diastereotopic faces,
reacts with aldehydes butonly
to give because of the
the anti aldol way in which two prochiral reagents,
product.
each with two enantiotopic faces,Ocome together
O OLi O OH

• The important LDA point about substituted H Ph enolates is Ph

that they can exist as two
geometrical isomers, cis or trans. Which enolate H
is formed
anti aldolis an important factor

controlling the only diastereoselectivity

trans-enolate can form because it turns out that, in many examples of
theIf we
aldol reaction, cis-enolates give syn aldols preferentially and trans-enolates give
choose the group ‘X’, next to the carbonyl group, to be large, then we can be sure of getting
antithealdols
just preferentially
cis-enolate. So, for example, the lithium enolate of this t-butyl ketone forms just as one geo- 34
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 syn aldol
Diastereoselectivecis-aldol reactions
enolate avoids Me and t-Bu
coming into contact

CONVENCTION: cis and trans, E and Z, syn and anti

cis and trans, E and Z, syn and anti
• Here are two closely related ester enolate equivalents, drawn with the same double
Before going further, there are two points we must clarify. enolate equivalents, drawn with the same double bond
bond geometry.
The first is a problem of Is it E or Z?
nomenclature, and concerns the geometry. Is it E or Z?
enolates of esters. Here are two closely related ester
O OLi OSiMe3
LDA Me3SiCl
Me Me
MeO MeO MeO

The answer is both! For the Li enolate, the usual rule The other point concerns syn and anti. We said earlier that
makes OLi of lower priority than OMe, so it’s E, while the there is no precise definition of these terms: they are a
• The answer is both. For the Li enolate, the usual rule makes OLi of lower priority
silyl enol ether (or ‘silyl ketene acetal’) has OSi of higher useful way of distinguishing two diastereoisomers
than OMe, so it’s E, while the silyl enol ether (or ‘silyl ketene acetal’) has OSi of
priority than OMe, so it’s Z. This is merely a nomenclature provided the structure of at least one of them is presented
problem, but it would be irritating to have to reverse all our in diagrammatic form. For aldol products the convention is
higher priority than OMe, so it’s Z
arguments for lithium enolates simply because lithium is that syn or anti refers to the enolate substituent (the
of lower atomic number than carbon. So, for the sake of green Me in the last example) and the new hydroxyl group,
consistency, it is much better to avoid the use of E and Z provided the main chain is in the plane of the paper, the
• So, for the sake of consistency, it is much better to avoid the use of E and Z with
with enolates and instead use cis and trans, which then way we have encouraged you to draw molecules.
always refer to the relationship between the substituent
enolates and instead use cis and trans, which then always refer to the relationship
and the anionic oxygen (bearing the metal).
between the substituent and the anionic oxygen (bearing the metal)

• For aldol products the convention is that syn or anti refers to the enolate substituent
(the green Me in the example) and the new hydroxyl group, provided the main chain
is in the plane of the paper

35
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 OLi O syn aldol
OH
Diastereoselective aldol reactionsH cis-enolate
R
X O X R
OLi O OH
Some examples trans-enolate Me anti aldol
H R
X X R
• Some enolatesLet’scan only
start by exist
showing someasexamples
trans-enolates because
and demonstrating how we they are derived from
trans-enolate Me antiknow
aldol this to be the case. Some
cyclic ketones
enolates can only exist as trans-enolates because they are derived from cyclic ketones. This enolate,
for example, reacts with aldehydes to give only the anti aldol product.
Let’s start by showing some examples and demonstrating how we know this to be the case. Some
O
enolates OLi because they are derived
O can only exist as trans-enolates O fromOHcyclic ketones. This enolate,
for example, reacts with aldehydes to give only the anti aldol product.
LDA H Ph
O Ph
O OLi O OH anti aldol
H
LDA H form Ph
only trans-enolate can
Ph
anti aldol
If we choose the group ‘X’, next to the carbonyl group, toHbe large, then we can be sure of getting
just the cis-enolate.
only So, for
trans- example,
enolate the lithium enolate of this t-butyl ketone forms just as one geo-
can form
• If the group ‘X’ next
metrical to the
isomer, andcarbonyl group
reacts with aldols to is
givelarge, then
only the the product.
syn aldol cis-enolate is formed
If we choose the group ‘X’, next to the carbonyl group, to be large, then we can be sure of getting
just the cis-enolate. So, for example, the lithium enolate of this t-butylO ketone forms just as one geo-
O
metrical isomer, and reacts with aldols to giveOLi only the syn aldol product. O OH
LDA Me H Ph
O
Ph
O OLi O OH
H Ph syn aldol
LDA Me
cis-enolate avoids Me and t-Bu Ph
coming into contact
syn aldol
cis-enolate avoids Me and t-Bu
cis and trans, E and Z, syn anti
andinto
coming contact
36
Credits: enolate
Before going further, there are two points we must clarify. J. Clayden et. al. Organic
equivalents, Chemistry
drawn - Oxford
with the same University Press
double bond
 Diastereoselective aldol reactions
Rationalization: the aldol reaction has a chair-like transition state .
900 34 Diastereoselectivity
• During the reaction, the lithium is transferred from the enolate oxygen to the oxygen
of the carbonyl electrophile Li The aldol reaction has a chai
O
• A six-membered
900 ring is involved, and
34 we can Oexpect this ringThese
. Diastereoselectivity to adopt
are the more or less
experimental facts:
a chair conformation (lower energy) X H R
stereoselective process with a cycl
from the enolate oxygen to the oxy
34 . Diastereoselectivity
Li The aldol reaction Li
‡
6 has a chair-like both intransition
curly arrow state
terms and as a
O O 1O 5 A six-membered ring is involve
These are the O
experimental facts: how can we explain them? Aldo
The aldol reaction has a stereoselective
chair-like transitionprocessstatewith a cyclic transition state. During the reat
mation. The easiest way to draw
Li X H R
O O from theXenolate 2 H 4 R necessary. Here it is.
3 oxygen to the oxygen of the carbonyl electrophile. T
These are the experimental
6 ‡facts:
bothhow can we
in curly arrowexplain
terms them?
and asAldol reactions
aenolate
transition arestructure.
state another class of
! has no choice
stereoselective Li
process
• TheH cis-enolate has
1 O three 5 with a cyclic transition state. Duringring, the reaction, the lithium is transferred
Oatoms in The the six-membered therefore canitexpect
must thisplace
Asix-membered
six-membered over orientation: Me
R ring ring is involved,
transition must
and be
we
pseudoaxial
ring to ad
from the enolate oxygen to the oxygen of the carbonyl electrophile. This is represented in the cismargin
-enolate
the methyl group pseudoaxial (otherwise
mation.
state forit would
The
the
‡ both in curly arrow terms and as a transition state structure. easiest
aldol beway
reaction a to
wastrans-enolate)
draw this is first to draw the chair, and t
6
Li X 2 H 4 R proposed byHere
necessary. Zimmerman
it is. and aldehyde chooses to H
O 5 3
A six-membered ring is involved, and
Traxler and weis can expectcalled
sometimes this ring to adopt reactmore
with or
R less a chair confor-
O
• The aldehyde may place R equatorial
!mation. The easiest way to drawenolate thisor
the axial.
Zimmerman–Traxler
ishas Boththeare
firstnotochoice
draw possible
chair, and Xthenbut there
pseudoequatorial
convert atomsareto fewer
O or Li Me as
over orientation: Me
steric
H 4 Rinteractions
necessary.
The if Here
six-memberedR isring
itequatorial
is.
transition
transition state.
must be pseudoaxial H
3 cis-enolate Li cis-enolate
state for the aldol reaction was O
In drawing
R this chair, we have o
pseudoaxial:
enolate has no choice and
proposed by Zimmerman
over orientation: Me
X
aldehyde chooses to H BothX are disfavoured
O aldehyde
possible but, as youHshou
ered ring transition Traxler and is sometimes called react with R R
must be pseudoaxial H
cis-enolate pseudoequatorial Li cis-enolateNote Rthat the M enolate doesn’t have
ldol reaction was the Zimmerman–Traxler O Me R pseudoequatorial:
O Me
immerman and transition state.
aldehyde chooses to bered ring,
favoured as it must, it can do no
H O aldehyde H O
sometimes called react with R R HThe aldol formed from the favo
an–Traxler pseudoequatorial In drawing this chair, we have one choice: do we allow the aldehy
Me R pseudoequatorial: below—first
Me aldehyde in the conformation o
te. Both are possible but, as you should now expect, there are fewer ster
favoured
is syn. 37
Note that theCredits: enolate doesn’t have the luxury of choice. If itPress
is to ha
In drawing this chair, we have one choice: do [Link] Clayden et. aldehyde
the al. Organic Chemistry
toXplace- R Oxford Universityor
equatorial axial?
 stereoselective process with a cyclic transition state. During the reaction, the lithium is transferred
Diastereoselective aldol reactions
H R
from the enolate oxygen to the oxygen of the carbonyl electrophile. This is represented in the margin
‡ both in curly arrow terms and as a transition state structure.
LiLi
6 The aldol reaction has a chair-like transition state
Rationalization:
5
O O These
the aldol reaction
A six-membered
are the experimental
has a chair-like
ring is involved,
facts: howand canwewe transition
canexplain
expect this ring
them?
state
to
Aldoladopt more are
reactions or less a chairclass
another confor-
of
stereoselective process with a cyclic transition state. During the reaction, the lithium is transferredas
mation. The easiest way to draw this is first to draw the chair, and then convert atoms to O or Li
H •H4 The
R R reaction ofHere
necessary.
from cis-enolate.
the enolate it is. to theThe
oxygen oxygen newof theformed
carbonyl C-C bondThis
electrophile. is drawn in orange
is represented and
in the margin
6 the ‡syn-aldol
both
enolate isnoformed
in curly
has arrow
choiceterms and as a transition state structure. R pseudoaxial:
Li over
X X disfavoured
orientation: Me ring is involved, and we can expect this ring to adopt more or less a chair confor-
5 A six-membered
O
d ring transition must be pseudoaxial H R
cis-enolate Li cis-enolate M
reaction was mation. The easiest way to draw this is first
O to draw the chair, and then convert
O atoms to O or Li as
merman
H 4 and R aldehyde chooses
necessary. Here it to
is. H H
react with R
O aldehyde O
etimes called R H
pseudoequatorial
enolate has no choice R pseudoaxial:
Traxler Me
X R pseudoequatorial: X aldehyde
Me
over orientation: Me disfavoured
favoured
ing transition must be pseudoaxial H Li R M
cis-enolate cis-enolate
eaction was In drawing this chair, we have one choice:O do we allow the aldehyde toOplace R equatorial or axial?
rman and aldehyde chooses to H should now expect, H steric interactions
Both arewith
react possible
R but, as you O aldehyde
there are fewer O if R is equatorial.
times called R H
axler Note that the enolate doesn’t have the
pseudoequatorial luxury of choice. If it is to havealdehyde
R pseudoequatorial: three atoms in the six-mem-
Me Me
bered ring, as it must, it can do nothing but place the methyl group pseudoaxial.
favoured

InThe aldol formed

drawing from
this chair, we the
havefavoured transition
one choice: state structure,
do we allow withtoRplace
the aldehyde pseudoequatorial,
R equatorial oris axial?
shown
below—first
Both are possiblein the
but,conformation
as you shouldofnow
the expect,
transition state,
there areand then
fewer flattened
steric out oniftoRthe
interactions page, and it
is equatorial.
is syn.
Note that the enolate doesn’t have the luxury of choice. If it is to have three atoms in the six-mem-
X as it must, it can do nothing but
bered ring, X place the methyl group pseudoaxial.
H formedLifrom the favoured transition
The aldol H state
Li structure,
redraw withOR pseudoequatorial,
OH is shown
O O
below—first in the conformation of the transition state, and then flattened out on tosyn
thealdol
page, and it
H O H O X R
is syn. R R
Me
X Me
X Me
We can
H do the
Li same for a trans-enolate.
H TheLienolateredraw O
has no choice OH to put its methyl sub-
but
O
stituent pseudoequatorial, O can choose either pseudoequatorial
but the aldehyde syn or
aldolpseudoaxial.
H O H O X R 38
Again,R pseudoequatorial is better R Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 below—first
is syn. in the conformation of the transition state, and then flattened out on to the page, and it
Diastereoselective
is syn. X aldol reactions X
X H Li X H Li redraw O OH
Rationalization: Hthe Oaldol O
Li reaction has a Hchair-like
Li transition
redraw Ostate OH syn aldol
H O O H O O X R syn aldol
R R
H H
• The reaction
R
Me ofO trans-enolate. It O
R can be applied the same rationalization to
Me
X Me R
explain Me
the formation
We can of the
do the same for aanti-aldol
Me
trans-enolate. Me but to put its methyl sub-
The enolate has no choice
We canpseudoequatorial,
stituent do the same for abut
trans-enolate. Thecan
the aldehyde enolate haseither
choose no choice but to put itsormethyl
pseudoequatorial sub-
pseudoaxial.
stituent
Again, pseudoequatorial,
pseudoequatorial isbut the aldehyde can choose either pseudoequatorial or pseudoaxial.
better
Again, pseudoequatorial is better
enolate has no choice over R pseudoaxial:
orientation: Me must be
X X disfavoured
enolate has no choice over R pseudoaxial:
pseudoequatorial
orientation: Me must be trans-enolateX H Li trans-enolateX R
disfavouredM
pseudoequatorial O O
H Li R M
aldehyde chooses to trans-enolate
Me O
trans-enolate
aldehyde Me O
react with R
O O
aldehyde chooses to Me R Me H
pseudoequatorial O aldehyde O
react with R HR R pseudoequatorial: HH aldehyde
pseudoequatorial favoured
H R pseudoequatorial: H aldehyde
favoured
and the reaction gives the product shown—the anti aldol.
and the reaction
X gives the product shown—the
X anti aldol.
X H Li X H Li redraw O OH
O O O OH anti aldol
Me H Li Me H Li redraw
O O O O X R anti aldol
Me R Me R
O O X Me R
HR HR
H H Me
Stereoselective enolization is needed for stereoselective aldols
Stereoselective enolization
The cyclic transition is needed
statetransition
explains for stereoselective
howstate
enolate geometry aldols
controls the stereochemical outcome by of
• The six-membered ring for the aldol reaction was proposed
thecyclic
The aldol transition
reaction. But
statewhat controls
explains howthe geometry
enolate of thecontrols
geometry enolate?the
Forstereochemical
lithium enolates of ketones
outcome of
Zimmerman and Traxler and is sometimes called the Zimmerman–Traxler
thethealdol
mostreaction.
importantButfactor
whatiscontrols
the size the
of the group that
geometry is not
of the enolized.
enolate? For Large
lithiumgroups forceofthe
enolates enolate
ketones
transition
thetomost
adoptstate
the cis geometry;
important small
factor is the sizegroups
of the allow
groupthe
thattrans-enolate to form.
is not enolized. Becauseforce
Large groups we can’t 39
separate
the enolate
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 Diastereoselective aldol reactions
Diastereoselectivity originates from stereoselective enolization

• Geometry of lithium enolates is controlled by the size of the group that is not
enolized. Large groups Aldol
forcereactions
the enolate to adopt
can be the cis geometry; small groups
stereoselective 901
allow the trans-enolate to form
enolates, we don’t O OLi OLi
n the structure of the LDA
choose the groups on R R R
e can get either cis or
ng on which groups R = t-Bu 98% 2%
on enolates are made
R = Et 30% 70%
ketone with an amine
N or i-PrNEt2) and R2B–X, where X– is a good leaving group such as chloride or
–). With bulky groups on boron, such as two cyclohexyl groups, a trans-enolate forms
2 !
ones.• The
The geometry
boron of reliably
enolate reacts boronwithenolates,
aldehydes tois give
notanticontrolled by the
aldol products In fact,structure of the
geometrically defined
boron enolates give the aldol
substrate
me six-membered but bystate
transition choosing theforgroups
that you saw on boron
lithium enolates.
products with greater
stereospecificity than do lithium
• Boron enolates are made by treating the ketone with an amine base
enolates, (often
possibly becauseEtthe
3N
B(c-Hex)2 B–O bonds are shorter than Li–O
B or i-PrNEt2) and O R2B–X, where X– Ois a good leaving groupbonds,
suchso as chloride or
the six-membered ring
OH
Cltriflate (trifluoromethanesulfonate, OTf = CF3SO3 )
- is ‘tighter’.
RCHO
Ph Ph R
Et3N

trans-enolate anti aldol 40

Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 trans depending
substrate—we chooseonthewhich
groupsgroups
on R R = t-Bu 98% R 2%
Diastereoselective
these are. we
boron—and Boron aldol
can enolates
reactions
get eitherare
cis made
or
R
R = Et 30% 70%
by treating the ketone
trans depending on which groupswith an amine R = t-Bu 98% 2%
Diastereoselectivity
baseare. originates
(often Et3enolates from 2stereoselective
N or i-PrNEt ) and R2B–X, whereenolization
X– is a good leaving group such as chloride or
these Boron are made
by triflate
treating(CF
the3SO
–
2). With
ketone withbulky groups on boron, such as two Rcyclohexyl
an amine
= Et groups,
30% a trans-enolate 70%forms
• With bulky
base groups
from most
(often onorboron,
Et3ketones.
N suchenolate
The boron
i-PrNEt as tworeactscyclohexyl
reliably
– groups, toa give
with aldehydes trans-enolate
anti aldol products
2) and R2B–X, where X is a good leaving group such as chloride or
forms from most
through
triflate (CF3theketones.
SO The boron
same six-membered
– enolate
transition reacts
state that reliably
you saw with
for lithium aldehydes to
enolates.
2). With bulky groups on boron, such as two cyclohexyl groups, a trans-enolate forms
give antifrom aldol products
most ketones. through
The boron thereacts
enolate same
reliablysix-membered transition
with aldehydes to give anti aldol state
products
described for lithium
through the sameenolates
six-membered transition state that you saw for lithium enolates.
B B(c-Hex)2
O O O OH
Cl RCHO
B B(c-Hex)2
PhO PhO PhO R
Et3N OH
Cl RCHO
Ph Ph trans-enolate Ph anti aldolR
Et3N
With smaller B substituents, the cis-enolate forms selectively. Here, the boron is part of a bicyclic
trans-enolate anti aldol
structure known as 9-BBN (9-borabicyclononane—you will meet this in Chapter 47). The bicyclic
• With smallerWithB
part substituents,
may lookBlarge
smaller but, the cis-enolate
as far
substituents, theascis-enolate forms
the rest offorms selectively.
the molecule is Here,
selectively. Inboron
concerned,
the the example,
it’s ‘tied back’
is part the the
of abehind
bicyclic
boron isstructure
part
boron,ofknown
a bicyclic
and theasmethyl
9-BBNstructure
group can known asto9-BBN
easily lie cis
(9-borabicyclononane—you oxygen. (9-borabicyclononane).
willThe
meetcis-enolate then gives
this in Chapter 47). syn Theprod-
Thealdol
bicyclic
ucts.
bicyclic part
part isDi-n-butylboron
may ‘tiedlarge
look back’ triflate
as far as(Bu
but,behind the
the2BOTf) ofalso
boron,
rest thegives
andcis-enolates.
theismethyl
molecule concerned,group can
it’s ‘tied easily
back’ behindliethe
cis to oxygen
boron, and the methyl group can easily lie cis to oxygen. The cis-enolate then gives syn aldol prod-
ucts. Di-n-butylboron triflate (Bu2BOTf) also gives cis-enolates.
B O OH
B
O O
TfO RCHO PhO R
B OH
PhO B PhO
Et3N
TfO cis-enolate RCHO Ph syn aldolR 41
Ph Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Ph
 Me Me Me N
favoured

Comparison between ×
diastereo- PhLi
and enantioselectivity
Me Me
O
N N N
axial attack
• DiastereoselectiveMe synthesis relies Me on making the Me transitiondisfavoured
states (TSs) for
45 .leading
reactions to different
Asymmetric
Now, synthesis diastereoisomers
let’s go back as different
to the principle of resolution in how
and see energy asdevise
we can possible and
a way of impro
therefore favoring
uponthe formation
it that of oneusdiastereoisomer
doesn’t require to throw away 50%over another
of our product. Resolution works bec
attaching an Oenantiomerically pure resolving agent to the racemic substrate distinguishes the
equatorial
Ph OH Ph OH
strate’s two enantiomers as diastereoisomers (diastereoisomers are chemically attack different; e
Me Me Me favoured
N enantiomeric (and therefore equ
tiomers are not). Can we use this same idea to make Me two
PhLi Me
×
energy) transition states into diastereoisomeric ones (which will therefore be unequal in energy
O more of one enantio
N we can, the lower-energy
N transition Nstate will be favoured and we will get
than the other. axial attack
Me Me Me disfavoured
example: nucleophilic attack on a ketone in a chiral environment.
O Now, let’s go back to(–)the principle of resolution and see how we can devise a way of improving
upon it that doesn’t require
O us to throw away 50% of our product. Resolution works because
Me
attaching an enantiomerically pure resolving agent to the racemic substrate distinguishes the sub-
energy

diastereoisomeric
(–)
strate’s two enantiomers
Nu R1 R as
*2 diastereoisomers (diastereoisomers
transition states are(–)chemically different; enan-
O
Ntiomers are not). Can we use this same idea to make two enantiomeric (and therefore equal in
energy) transition states into diastereoisomeric ones (which will therefore be(–)unequal in energy)? If
Me
we can, the lower-energy transition state will be favoured and we will R1 get Nu of one enantiomer
R2 more
PhLi
than the other. *
mple: Ph OH nucleophilic attack on a ketone in a chiral environment.
O (–)
Me
O
Me
Nu OH O Nu OH
energy

diastereoisomeric
(–) (–)
transition states
N Nu R1 R2
R1
*R2 R1 *R2 O R1 *R2
N
Me enantiomeric products produced in unequal amounts
diastereomeric 42
Me The answer is most definitely yes—what is1needed (–)
2 Nuis an enantiomerically pure molecule or pa
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 BaSO4 H O the wrong e
tamic acid the wrong enantiomer! 10–15% o
(plus
Comparison between diastereo- and enantioselectivity (plus 10–15% of its E - isomer)

• Creation
Asymmetric synthesis
of a new stereogenic center in a previously achiral molecule using achiral
metric synthesis
reagents
When we affords a racemic
create a new mixture
stereogenic centre inbecause
a previouslythe transition
achiral moleculestates leading
using achiral to the two
reagents
create a (addition
new stereogenic
of CN –centre in a previously
tothemselves
aldehydes achiral molecule
was enantiomeric
the example you met using achiral reagents
enantiomers
– are andin Chapter
therefore 16), we get in
equal a racemic
energy mixture
of CN tobecause
aldehydes was the example
the transition you met
states leading to in
theChapter 16), we getare
two enantiomers a racemic mixture
themselves enantiomeric and there-
e transition
forestates
equalleading to the two enantiomers are themselves enantiomeric and there-
in energy.
in energy. nucleophilic attack on a ketone in an achiral environment.
nucleophilic attack on(–)
a ketone in an achiral environment. example:
(–)
O enantiomeric O example:
(–) transition(–)
O enantiomeric
states O
O
energy

(–) transition (–)

Nu 1 states
R 2
R (–) R1 R2 Nu
R 1 R 2 R1 R Nu
2

PhLi

Ph
Ph OH
Nu OH O Nu OH
Nu OH O Nu OH
R1 R2 R1 R2 R1 R2
R1 R2 Renantiomeric
1 R2 products
R1producedR2in exactly equal amounts
enantiomeric products produced in exactly equal amounts
Diastereoselective synthesis, on the other hand, relies on making the transition states for reactions
eoselective synthesis,
leading on the other
to different hand, relies on
diastereoisomers asmaking theintransition
different energy asstates for reactions
possible and therefore favouring the
differentformation
diastereoisomers as different in energy
of one diastereoisomer as possible
over another. Youand mettherefore
this type of favouring the
stereoselectivity in Chapter 33.
of one diastereoisomer
Here is a simpleover another.
example: You
PhLi mettothis
adds thistype of stereoselectivity
ketone in Chapter 33.
to give one diastereoisomer of the tertiary alcohol
imple example:
and notPhLi
the adds
[Link]
this ketone
on onetoor
give oneface
other diastereoisomer
of the ketoneofleads
the tertiary alcohol transition states: 43
to diastereomeric
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
e other. Attack on one or other face of the ketone leads to diastereomeric transition states:
Internal and external asymmetric induction
• Two enantiomeric (and therefore equal in energy) transition states can be converted
into diastereoisomeric ones (which will therefore be unequal in energy) if an
enantiomerically pure molecule or part of a molecule is present during the reaction
and interacts with the transition state of the reaction in such a way that it controls
the formation of the new stereogenic center

• This molecule might be:

1. a catalyst or

2. a chiral auxiliary (a chiral portion covalently attached to the starting material)

• In the case 1 stereoselectivity is achieved by external asymmetric induction

• In the case 2, stereoselectivity is achieved by internal asymmetric induction

44
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Me (–)
Chiral auxiliaries Nu
•
R 1 R2
PhLi This is what we mean by a chiral auxiliary strategy
OH 1. An enantiomerically pure compound (usually derived from a simple natural
Me product like an amino acid), called a chiral auxiliary, is attached to the starting
material. Nu OH O Nu OH
N 2. A diastereoselective reaction is carried out, which, because of the enantio-
meric purity R2 chiral auxiliary,
R1 of the R1 R2gives only R2
R1 one enantiomer of the
Me enantiomeric products produced in unequal amounts
product.
The answer is most definitely yes—what is needed is an enantiomerically pure molecule or part of
3. The chiral auxiliary is removed by, for example, hydrolysis, leaving the product
a molecule that will be present during the reaction and will interact with the transition state of the
of the reaction as a single enantiomer. The best chiral auxiliaries (of which the
reaction in such a way that it controls the formation of the new stereogenic centre. This molecule
example above is one) can be recycled, so although stoichiometric quantities are
might be a reagent or a catalyst, or it might be covalently attached to the starting material. We will
needed, there is no waste.
consider all of these possibilities, the last first, and you will see that they really are the most powerful
and versatile ways of making enantiomerically pure compounds.
• The product of a Diels-Alder reaction between cyclopentadiene and benzyl acrylate
‘l’.
must Chiral auxiliaries
necessarily be racemic as both reagents are achiral. Though only one
diastereoisomer,
The product ofthe endo product
a Diels–Alder is formed,
reaction between it must be
cyclopentadiene andformed as an
benzyl acrylate exactly
must 50:50
necessarily
mixture
be of enantiomers
racemic as both reagents are achiral. Though only one diastereoisomer—the endo product—is
formed, it must be formed as an exactly 50:50 mixture of enantiomers.
Diels–Alder reaction gives a racemic product one diastereoisomer (endo)

O O
BnOH
+
Cl OBn
O OBn
O OBn
achiral + achiral
50:50 mixture of two enantiomers
dienophile diene 45
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 you would expect from what we said in Chapter 35, both reactions a
single enantiomer single enantiomer achiral
Chiral auxiliaries derived from (S)-valine
generate mainly the+endo
of dienophile
product. In the first example, that is all
diene
formed is necessarily racemic because all the starting materials in the
thisthe

As far as stereoselectivity is concerned,But, theinkeythestep is theexample,

second Diels–Alder reaction—in
a green each case
chiral auxiliary the attac
has been
Examplediene 1: Diels-Alder
(cyclopentadiene, reaction
shown in black)[Link] across another
It contains the dienophile, an acrylic
stereogenic centre acid derivative.
and is As
enantiomerically
you would expect from what we said in Chapter
chiral pool 35, both reactions
strategy from the are diastereoselective
amino acid (S)–valine in that
(see they You
below).
• Replacement of thetheachiral
generate mainly benzyl
endo product. In theester groupthat
first example, withis allan amide
there is to say:derived
the product from the
that is
on the reaction—the extra stereogenic centre means that there are
natural formed aminois acid valine
necessarily does
racemic not all
because affect the diastereoselectivity
the starting materials in the reaction were of the process but
achiral.
meric endo products, Asymmetric
but only onesynthesis
is formed.
the chiralBut, environment createda green
in the second example, by thechiralsingle
auxiliary enantiomer
has been attached covalently
to one of thebonded to the
starting mate-
O
O is enantiomer
dienophile rials. induces
It containsthe formation
another stereogenicofcentre
only and one enantiomerically ofpure—it
the product
was, in fact, made by a
chiral auxiliary-controlled Diels–Alder
chiral pool reaction
strategy fromgives
theaamino
single enantiomer (see below). You can see that it has Oquite an effect
of the product
acid (S)–valine
O LiOBn
O on the reaction—the O
extra stereogenicO centre means N O there are now two possible diastereoiso-
that
Et2AlCl O O N O
meric endo products, but only one is formed.
HN O base LiOBn
Cl + N O
O O O
Et2AlCl N O O OBn
rem
O
chir
45 . Asymmetric synthesis
N O
LiOBn re
O this adduct is formed as com
Et2AlCl N O Oa singleOBn
diastereoisomer a sing
single enantiomer single enantiomer achiral this enantiomer only
We have introduced
derived from you to this chiral
(S)-valine ofauxiliary
dienophilebefore + any diene other because it is more commonly
used than any other. It is a member of the oxazolidinoneThe (thechiral
name of auxiliary wasremoval
the heterocyclic enantiomerically
ring) family of pure—every molecu
of the
As far as stereoselectivity is concerned, the
auxiliaries developed by David Evans at Harvard University, key step is the Diels–Alder
at its stereogenic reaction—in
and is easilycentre. chiral
That made
and cheaply each case
auxiliary
centrefrom the
was thenot involved in the D
reveals this
diene
amino (cyclopentadiene,
acid (S)-valine. Not shown onlyinisblack) addsmade:
it cheaply across
this itthe
adduct isdienophile,
products
can also
formedwill
beas an acrylic
similarly
recycled. The acid
havelastthestep
compound
derivative.
same ofas As
configuration
the route at the stereogen
you would
above, expect from what
transesterification we benzyl
with said in alcohol,
Chapterregenerates
a 35, both
single reactions So,are
diastereoisomer
[Link] auxiliary if diastereoselective
one
ready a single
diastereoisomer
for re-use. in thatof they
enantiomer the product is formed, all
generate mainly the endo product. In the first example, that is
product must all there is to say:
be of a single the product
configuration; that is
in other words the prod
synthesis of Evans's Theoxazolidinone
chiral chiral auxiliary
auxiliary was from (S)-valine
enantiomerically pure—every molecule O the same
had configuration
formed is necessarily racemic because all the starting materials in
enantiomerically the reaction were
[Link] achiral.
when we do the final stepsoofall
thethe !
sequenc
But, inNH the at its stereogenic
2 second example, a centre.
green NH 2 That
chiral centre
auxiliary haswas notattached
been involved to one the
of theDiels–Alder
starting mate-reaction,
products
Me2S·BH3
will similarly have the same
O
that enantiomeric
configuration at K2purity
the CO3 remains,
stereogenic HN despite
centre O in the the factpart
green thatofwethe haveYor
rials. It contains another stereogenic centre and OH is enantiomerically
+ sequential attachment pure—it was, in fact, made by a Et
CO H
molecule. So, if one diastereoisomer of the product is and
formed, removal
all the of the
stereogenic auxiliary
centreswe have
in thatmade t
se
chiral pool strategy2 from the amino acid (S)–valine (seeEtO below). You OEt can see that it has quite an effect
productextramuststereogenic
be of a single enantiomer.
configuration; in other di
on the reaction—the centre means that there are words
now two thepossible
productdiastereoiso-
is diastereoisomerically and
S)-valine enantiomerically pure. And when we do the final step of the sequence, to remove the chiral auxiliary, pr
meric (endo
•
products, but only one is formed. 46 in
The most that enantiomeric
versatile purity should
chiral auxiliaries remains, alsodespite This
the fact
be available is what
thatJ. we
Credits:
as both wehave
Claydenmean removed
et. al.
enantiomers. by
Organic
Now,aChemistry
chiral
its theauxiliary
forsource. Overall,
- Oxford strategy
University by
Press re
 Chiral auxiliaries
O O
O

1. NaH O
O Example 1: Diels-Alder LiOBn
Oreaction + HN O
N
2. O Et2AlCl O N O
Ph• Origin of stereoselectivity (diastereo- and enatioselectivity) O OBn Ph
Ph
ine- chiral auxiliary
Cl Ph recovered and
y In the auxiliary-bearing dienophile coordinated
single enantiomer with the
single diastereoisomer Lewis acid the
single enantiomer isopropyl
can be recycledgroup
shields theHowback faceauxiliaries
do these of the alkene from
fulfil their role?attack: when
If we go back thevaline-derived
to the cyclopentadiene
auxiliary moves
and drawin, it
approaches from the front
the auxiliary-bearing face coordinated
dienophile (it alignswith itself to gain
the Lewis maximum
acid you can clearlysecondary orbital
see that the iso-
stabilization
propyland
group therefore
shields the gives the
back face endo
of the product)
alkene from attack: when the cyclopentadiene moves in, it
must approach from the front face (and remember it will align itself to gain maximum secondary
orbital stabilization and therefore give the endo product).
cyclopentadiene must attack from top face
Et2
O O Al
O Et2
O
O Al O
N O Et2AlCl H
N O O

bottom face shielded

Note that the auxiliary also has the effect of fixing the conformation of the black single bond as
s-cis (we introduced this nomenclature on p. 000). Attack on the top face of the s-trans compound
would give the enantiomeric product.

47
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 O O O
Chiral auxiliaries
HN O base
O
LiOBn
Cl + N O
Et2AlCl O N O O OBn
Example 1: Diels-Alder reaction

• Origin of stereoselectivity (diastereo- and enantioselectivity)

single enantiomer
derived from (S)-valine
single enantiomer
of dienophile +
achiral
diene
Asymmetric
this enantiomer only synthesis
The chiral auxiliary also has the effect of fixing the conformation of the black single
far as stereoselectivity is concerned, the key step is the Diels–Alder reaction—in each case the
bond as s-cis
(cyclopentadiene, shown in black) Et2 adds across the dienophile, an acrylic acid derivative. As
ould expect from whats-we cis said inAlChapter
O s-cis are diastereoselective
35, both reactions Et2 in that theys-trans Et2
O
ate mainly the endo product. In the first example, that is all there O Al is toOsay: the product that is O Al O
d is necessarily racemic because all H H
N the starting
O materials in the reaction were O achiral. O
t, in the second example, a green chiral auxiliary has been attached to one of the starting mate-
t contains another stereogenic centre and is enantiomerically pure—it was, in fact,disfavoured made by aby
steric crowding
pool strategy from the amino acid (S)–valine (see below). You can see that it has quite an effect
e reaction—the extra stereogenic centre means
Asymmetric that there are now two possible diastereoiso-
synthesis 1229
attack on attack on
endo
The products,
‘s’ in thebut only‘s-cis’
terms one is
The [Link] succeeded in
auxiliary doing
the top facewhat we set out to do (p. 000)—itthehas topmade
face diastereoiso-
and ‘s-trans’
O
refers 𝜎 transition states leading to enantiomeric products, the difference in energy arising because
to athe
meric
O
ingle enantiomer of the product
bond and indicates that crowding ofOone face of the alkene.
of steric
O these O are conformations Lest you should imagine LiOBn
that all effective auxiliaries are oxazolidinones, here is a different one—
N O
about a single bond and O O
8-phenylmenthol—used
Et2AlCl N O by Corey in enantioselective
LiOBn O OBn prostaglandin synthesis. 8-Phenylmenthol is
not
N configurations
O about a
double bond made from the natural product pulegone (Chapter 51). Even in the starting material the role of the
O N O O OBn
Et2AlClphenyl group face Oof of
is clearly to crowd one removal the OBn
thedienophile. none of
chiral auxiliary O this enantiomer
reveals this O is formed
O this adduct is formed as compound as
a single diastereoisomer Ph a single enantiomer base
achiral + Cl
• Attack
enantiomer
ienophile + on the
diene
top face of the HO
s-trans
compound would give the Oendo product with
this enantiomer only
e chiralopposite configuration
auxiliary was enantiomerically pure—every molecule had the same configuration
! 48
key step is the
stereogenic Diels–Alder
centre. That reaction—in
centre
(S)-pulegone was not each case
involved the
in the Diels–Alder
8-phenylmenthol Credits:reaction, [Link]
J. Clayden et. the chiral dienophile
Chemistry - Oxford University Press
You may note the inclusion of the
 Alkylation of chiral enolates
Alkylationexcess
of chiral enolates
Chiral auxiliaries
Chiral Enantiomeric
auxiliaries can be used in plenty of other reactions, and one of the most common types is the
alkylationWhenof Chiral
enolates. auxiliaries
Evans’s
talking about
can be used in plenty
oxazolidinone
compounds
of other
auxiliaries
that are are reactions,
neither racemic particularly andappropriate
one of the most
nor enantiomerically here common types is th
purebecause
(usually called
Example 2: alkylation
alkylation
they are enantiomerically
readily turned intoof
of chiral
[Link]
enolizable
enriched
Evans’s oxazolidinone
or, carboxylic
occasionally, acidscalemic) auxiliaries
derivatives. are particularly appropriate
chemists talk not about ratios of enantiomers
here becaus
they are readily turned into enolizable carboxylic acid derivatives.
with base (usually LDA) at lowenantiomeric
but about temperature
O excess.
produces Enantiomeric
an enolate, and excessyou(or
can is defined as theLi excess of one enan-
ee)clearly
O O O O O Li
tiomertoover
iliary has been designed the
favour other, by O as a percentage
expressed of face
the whole.
thatOSo a 98:2 mixture of enantiomers Ocon-
O attack electrophiles on only one Oof LDA eno- O
that the bulky auxiliary +one enantiomer
sists ofmeans that only theinZ-enolate
96% excess overalkylation
forms: the other,ofand we call it an
the E-eno- LDAenantiomerically enriched
Cl HN O + N O N O
ace would give themixture with 96%
diastereoisomeric Cl ee. HN
Why
product. not O
just say
Coordination thatof we
the have 98%
lithium of
ion
N one
to enantiomer?
the
O Enantiomers N are not
O
oxygen makes the like other
whole isomers
structure because
rigid, fixingthey
theare simply group
isopropyl mirrorwhere
images. Thepro-
it can 2% of the wrong enantiomer makes
hindrance to attack a racemate
on the ‘wrong’of 2% of the right isomer so the mixture contains 4% racemate and 96% of one
face.
enantiomer. 96% ee. E+ electrophiles attack
O O top face of enolate
Treatment with base O O
(usually LDA) at low temperature Oproduces an enolate, O and you can clearly
Treatment with
see2Ithat the auxiliary has been designed base (usually LDA)
to favour attack at low
Liby Oelectrophiles on only oneanface
temperature produces enolate,
of thatand
eno-you can clear
PhCH LiOBn O
N theOauxiliary has been designedHto favour attack by electrophiles on only one face of that eno
O late. Notice too seethat
thattheNbulky Oauxiliary means that only the Z-enolate OBn forms:HN alkylation
O of the E-eno-
O plus
late onPhthe top face would give the diastereoisomeric product. Coordination of the lithiumalkylation
late. Notice too that the bulky auxiliary means that only the Z-enolate forms: ion to the of the E-eno
other carbonylPhlate on themakes
oxygen top face thewould
wholegive the diastereoisomeric
structure rigid, fixing the product.
Ph isopropylCoordination
group where of the pro-
it can lithium ion to th
vide maximum other carbonyl
hindrance tooxygen
attack on makes the whole
the ‘wrong’ structure rigid, fixing the isopropyl group where it can pro
face.
vide maximum hindrance to attack on
98:2face
bottom
the
mixture ‘wrong’ face. +
of enantiomers
shielded by
Li E electrophiles attack
O O
O 98:2 mixture
O of diastereoisomers
Li 96% enantiomeric
isopropyl group
O
excess electrophiles attack
top faceE+of enolate
Ratio of
mers O O O top face of enolate
the margin shows the ratio of diastereoisomers
diastereoisomers PhCH2I
produced by this reaction for a few O Li O
N O Li
As you can see, Nnone Oof these reactionsPhCH
ts.>99:1 is truly
2I 100% diastereoselective
N O and, H OO H O
ON O
he 98:2
best chiral auxiliaries (of which this is certainly one) give >98% of a single
• Coordination of the lithiumPhion makes the whole structure
r. The problem with less than perfect diastereoselectivity
Ph is that, when the chiral aux-
d, therigid. Attack on the unhindered
with some of thetop
otherface of the s-cis
94:6
final product is contaminated enantiomer. A 98:2 ratio
conformer
mers will gives
result in a 98:2 ratiothe target product with high enantiomeric
of enantiomers. bottom face shielded by
excess (ee) after removal of the chiral auxiliary bottom face shielded by
isopropyl group
isopropyl group
c excess The table in the margin shows the ratio of diastereoisomers produced by this reaction for a few
bout compounds that
alkylating are The
agents. Astable
neither in thesee,
racemic
you can margin
nornone shows the reactions
enantiomerically
of these ratio of diastereoisomers
pure (usually
is trulycalled produced by this reaction
100% diastereoselective and, 49 for a fe
ly enriched only alkylating
or, occasionally,
indeed, the best agents.
scalemic)
chiral As youtalk
chemists
auxiliariescannot
(of see, none
about
which of
ratios
this isthese
Credits: J. reactions
Clayden
ofcertainly
enantiomerset. al. is
one) trulyChemistry
Organic
give 100%of
>98% - diastereoselective
Oxford University Press and
a single
Chiral auxiliaries
Advantages and disadvantages

• Advantage: possibility to increase the final enantiomeric

Chiral reagents excess
and chiral through
catalysts
crystallization of the diastereomeric intermediate
of a single diastereoisomer in >99% purity, giving material of essentially 100% ee after removal of
the auxiliary.
O O 1. NaN(SiMe3)2 O O 1. LiAlH4
2. allyl iodide 2. t-BuMe2SiCl
N O N O OSiMe2t-Bu

Me Ph Me Ph >99% ee
98:2 diastereoisomers
recrystallize fragment of X-206
>99:1 diastereoisomers

This is one big bonus !

of using a chiral auxil- At this po
iary—it’s much easier O O about the
O reaction w
• Disadvantages:
to purify diastereoiso-chiral auxiliaries must be attached to the compound under
N O O
but 7% of this fact, the d
construction, therefore there are two
mers than enantiomers ‘unproductive’
Et2AlCl O N Osteps in the synthesis.
adduct is Not all fra
brown
and a auxiliaries
chiral chiral auxiliary
can be recycled O N O
formed as well
yield, with
reaction necessarily pro- accountin
duces diastereoisomeric recrystall
this adduct is the major product diastereo
products. material i 50
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 groups, which become tetrahedral by addition reactions. In all of the examples y
Chiral catalysts section, a prochiral alkene (we can count enolates as alkenes for this purpose) rea
one face because of the influence of the chiral auxiliary, which made the fa
Asymmetric reduction of ketones
diastereotopic.
• If we want to create a newOne stereocenter in a molecule,
of the simplest transformations youthe
couldstarting
imagine of material
a prochiralmust
unit into
1236 have prochirality (the . Asymmetric
reduction
45 ability of a synthesis
to [Link]
Although
inchiral
one auxiliary
simplestrategies have been used
transformation). to make
One
tion asymmetric, you will appreciate that, conceptually, the simplest way of gettin
of the simplest transformations of a prochiral unit into a chiral one is the reduction
single enantiomer would be to use a chiral reducing agent—in other words, to attac
of a ketone H
ence not to the substrateH(as we did with chiral auxiliaries) but to the reagent.
OH NMe2 Al O O
chiral
LiAlH4 O O
NaBH 4 NMe2
OH
reducing agent
Ph or LiAlH4 R1 R1
Ph
synthesis R Ph Ph
R
R2
prochiral chiral but racemic
"Darvon alcohol" chiral reducing agent 70
H H One of the earliest attempts to do this used LiAlH4 as the reducing agent and
•Al A highly effectiveOreducing
More agent
effective
attaching isisthethe
‘Darvon
chiral
chiral
chiral OHtoborohydride
borohydride
alcohol’ analogueanalogue
developed
it. Unfortunately, bydeveloped
this reagent Corey, Bakshi,
is not very byand
effective
O NMe2
Corey, Bakshi,1and based uponreducing
Shibita
strates aare
stable borontoheterocycle
confined
agent
1
made from
acetylenic alcohols, andan amino
even thenalcohol derived
the products arefrom pro
formed
R the CBS
knownofasabout 80%reagent
ee. afterR its developers.
h H R2H R2 H H
BnOCOCl 1. MeOH, H+ MeB(OH)2
Ph 1. HCl Ph
l reducing agent 70–80% ee
N CO2H NaOH N CO2H N Ph 2. NaOH N Ph N
H 2. 2xPhMgCl H
he chiral borohydride analogue
H2O developed
CO2Bn by Corey, Bakshi, andCO
Shibita. It is MeB
(S)-(–)-proline 2Bn OH OH
boron heterocycle made from an amino alcohol derived from proline, and is
agent after its developers. The active reducing agent is made by complexing the heterocycle with borane. On
!Catalysts not reagents
eOH, H+ that the reactionsH are amounts (usually
H about 10%) of the H
MeB(OH)2
boron heterocycle are needed because borane is
The fact
Ph 1. HCl reactive to reduce
Ph ketones only Ph
when complexed with the nitrogen atom. The rest of the
catalytic in the heterocycle means
N Ph 2. NaOHwaitsNuntil a molecule
Ph N Ph CBS reagent
that relatively little is needed and it
PhMgCl H of catalyst becomes free.
can be recovered
CO2atBnthe
OHend of the OH MeB O
reaction. Later in the chapter you H H O 51 OH
Ph BH3 Ph
Credits: J. Clayden et. al. Organic Chemistry - Oxford
~10%University
catalyst Press
will see catalytic reactions that use
 BnOCOCl H 1. MeOH, H+ H Ph 1. 1.
HCl
HCl H PhMeB(OH)2 2 H Ph
H H + Ph H Ph H Ph H
Chiral catalysts
CO2H NaOH
2H NaOH N
BnOCOCl
N CO2H
CO2H 2. 2xPhMgCl N
1. MeOH, H
N Ph 2. NaOH
Ph 2. NaOH
Ph 1. HCl
NH
N
Ph
Ph Ph MeB(OH)
N
N2
Ph
Ph Ph
N H2O CO2H CO
NaOHBn 2.
N 2xPhMgCl
CO 2H CO Bn OHN Ph 2. H
NaOH N
OH Ph MeB NO Ph
ine H O 2 2. 2xPhMgCl
2
MeB O
e Asymmetric2Hreduction
H2 CO BnO of ketones 2
2
CO Bn OH
CO2Bn
OHH
CO2Bn OH OH MeB O
(S)-(–)-proline
The active reducing agent is made by complexing the heterocycle with borane. Only catalytic
gents
ents
• The active The activereducing
reducing
The active agent
agent is made
is made by by
byiscomplexing complexing thethe
the heterocycle heterocycle
with [Link].
Only with borane
catalytic
alysts not amounts (usually
reagents about reducing
10%) ofagent
the boron made complexing
heterocycle are neededheterocycle
because with Only
borane is sufficiently catalytic
ons are (BH ).
amounts Only catalytic
(usually about
amountsketones amounts
10%)
(usuallyonly of
about the (10
boron
10%) mol%) of
heterocycle
of the boron the
are boron
needed heterocycle
because borane is are needed
sufficiently
st are
thatmeans
cle
3
the reactionsreactive
are to reduce when complexed withheterocycle
the nitrogenareatom.
needed
Thebecause
rest ofborane is sufficiently
the borane just
reactive
(borane to
can reduce ketones only when complexed with the nitrogen atom. The rest of the borane just
ec means
in theand
eded heterocycle
it means
waits until reduce
a moleculeketones
reactive to of catalystonly
reduce ketones only
becomes when free. complexed with the nitrogen atom)
when complexed with the nitrogen atom. The rest of the borane just
ed andlittle
atively it waits until a molecule
end of theis needed and it waits untilofa catalyst
moleculebecomes
of catalystfree.
becomes free.
nd of the at the end of the
recovered H H
apter you O OH
ter
n. youin the chapter you H
Later Ph H 3
BH H Ph H O O catalyst OH OH
ons that use Ph BH3 Ph BH3 Ph Ph ~10%
scatalytic
that usereactions thatNuse Ph N ~10% ~10%
catalyst catalyst
st than this
mes less
than N this
this catalyst than PhN Ph N N Ph
Ph Ph Ph Ph Ph
of the H3 B H B Ph Ph BH3 BH Ph
d, indeed, none of the
he MeB O MeB O H B MeB 3O
3 BH3 3
on
ns in the
we will mention MeB
in the O MeB O MeB O prochiralprochiral
prochiral
in the catalyst catalyst active reducing agent ketone ketone 99% yield, 97% ee
use
his chiral will use
chapter pre- catalyst
chiral active reducing active
agentreducing agent
ketone 99% yield,99%
97% yield,
ee 97% ee
e chiral
atalysts.
s—only chiral catalysts.
alysts. CBS reductionsCBSare are best when
reductions are thethewhen
best ketone’s
thetwotwo substituents
ketone’s are well-differentiated
two substituents are well-differentiatedsterically—
sterically—
m chiral
e distinction CBS reductions
from chiral best when ketone’s substituents are well-differentiated sterically—
chiral
gh • Only
es here: although when
just as Ph theandketone
just MePhare
as is
and complexed
in Me
theare example withOnly
above.
in the example the when
above. boron
Onlythe atom
when the in
ketone is the isring
complexed
ketone iswith
complexed it electrophilic
the ‘other’
with the ‘other’
just as Ph and Me are in the example above. Only when the ketone is complexed with the ‘other’
e,
es are
ble,
they
enough
recoverable,
they boron
they
boron toatom
be (in
atom reduced
(in the
boron
the
atom ring)
ring) by
(in
is it the
istheit ring)weak
electrophilic hydride
is it electrophilic
electrophilic enough to source
enough enough
to
be
be reduced(BH
to be
reduced
by ).theThe
reduced
by 3the by
weak
thehydride
weak hydride
weak hydride
hydride is delivered
source.
source.
The The
source.
The
have
in to be used in hydride is delivered
hydride is via delivered via a six-membered
a six-membered cyclic cyclic transition
transition state,the
state, with with the enantioselectivity
enantioselectivity arising
arising
ometric
es, and
via a
quantities, six-membered
hydride
and is delivered cyclic
via a TS,
six-membered with the
cyclic enantioselectivity
transition state, with arising
the from
enantioselectivity preference
arising of
from from
preference preference
of the largerof the
of larger
the of
ketone’sthe ketone’s
two two substituents
substituents (R ) for(R )
the
L for the pseudoequatorial
pseudoequatorial position
position
yand the
is usually
parate step. larger
a separate
from step. of the
preference ketone’s
of the largertwo of thesubstituents (RL) for (R
ketone’s two substituents the pseudoequatorial
)Lfor the pseudoequatorialposition position
rate step. on this ring. L
on this ring.
on this ring.
H
H Ph Ph Ph
H Ph Ph
Ph N Ph Ph PhPh
H H
B Ph
H3Ph HO H
MeB O O MeH H
O (turn reagentMe O
over) B hydride delivered OH
H
O (turn reagent over) Me hydride delivered
Nhydride via 6-membered ring OH
(turn reagent B delivered ring O OH H
O over) B
N
O N
BHvia
via 6-membered
O O N H
O 2 6-membered ring B RL RS
O O BH2 H OO N
ORL B B NH H B
H RL RS
H BH2 RL RS
RL RS H RL R RL group
large H
S
R H B H Me
R RL RS L
pseudoequatorial
large group B
RS Slarger RL RS large group RSMe H
smaller pseudoequatorial Me 52
substituent substituent
smaller
pseudoequatorial RS H
smaller
RS J. Clayden
Credits: H et. al. Organic Chemistry - Oxford University Press
 Chiral catalysts
This makes it relatively expensive, but the expense is offset by the economy of catalyst required in
such reactions. Whereas about 10 mol% catalyst is needed for CBS reductions, many hydrogenations
Asymmetric hydrogenation
of this of alkenes
type give high enantiomeric excesses with only 0.0002 mol% BINAP–ruthenium(II) catalyst!
Because such minuscule quantities of catalyst are needed, enantioselective hydrogenations are more
• An active catalyst in the asymmetric hydrogenation of alkenes with an amino
widely used by industry than any other asymmetric method. The other advantage of the resolution
groupis,isofacourse,
cationic complex
that either of rhodium
enantiomer is equally with the diphosphine DIPAMP. DIPAMP’s
available.
chirality BINAP–ruthenium(II)
resides in the istwo stereogenic
particularly phosphorus
good at catalysing atom of(unlike
the hydrogenation amines,
allylic alcohols, and
phosphines are configurationally
of α,β-unsaturated Chiral
carboxylic acids stable)
reagents
to give and [DIPAMP
chiral
acids bearing =centres
catalysts
α stereogenic (R,R)-1,2-bis(2-
(like naproxen 1
methoxyphenyl)(phenylphosphino)ethane
above).
H2 H
OMe
OH [(S)-BINAP]Ru(OAc)2 OH
HO CO2Hgeraniol (R)-citronellol
P P (R,R)-DIPAMP
H H
R2 NH2 R3 R2 R3
R2 R3
HO H2 H2
H H
[(S)-BINAP]Ru(OAc)2 MeO1 [(R)-BINAP]Ru(OAc)2
R1 CO2H R CO2H R1 CO2H
catalyst is a cationic complex of rhodium with another diphosphine, DIPAMP. DIPAMP’s
If the double bond also bears an amino group, the products of these reactions are α amino acids,
• The
y resides in theproduct can be
two stereogenic converted
phosphorus into
atoms: L-dopa,
unlike amines,aphosphines
drug used to treat Parkinson’s disease
are configura-
and in these cases there is another alternative that works even better, a catalyst based on rhodium.
y stable, (both reaction
Here is oneand very catalyst
important developed
synthesis of anby Monsanto)
rather like sulfoxides (which we will discuss in the next chapter). The catalyst imposes
unnatural amino acid using a rhodium catalyst. Again,
y on the hydrogenation by coordinating to both the amide group and the double bond of the
look first at the reaction and then we will discuss the catalyst.
ate. Two diastereoisomeric complexes result, since the chiral catalyst can coordinate to either
H H H
enantiotopic faces of the double bond. H 2
MeO Ar CO2H MeO CO2H
MeO O MeO MeO
[DIPAMP]RhL+2 H
NHAc NHAc
AcO Me N CO2Me (L = solvent) AcO
P Ar P 95% ee P Ar P
P P H +
Rh Rh O O Rh 53
L L The product can be converted into L-dopa, a drug used
Credits: to treat
J. Clayden et. Parkinson’s disease,
al. Organic Chemistry andUniversity
- Oxford it is this
Press
Chiral catalysts
Chiral reagents and chi
Asymmetric hydrogenation of alkenes
Chiral reagents and chiral catalysts
OMe
HO OMe CO2H
HO CO2HL-dopa (R,R)-DIP
P P
NH2 (R,R)-DIPAMP
L-dopa P P
NH2 HO
HO
MeO
MeO
• The
The catalyst imposes The catalyst
chirality on is athe
cationic complex of rhodium
hydrogenation by with another diphosphine,
coordinating to both DIPAM
the
catalyst is a cationic complex of rhodium
chirality resideswith another
in the diphosphine,
two stereogenic DIPAMP. DIPAMP’s
phosphorus atoms: unlike amines, phosphines
amide group and the
chirality resides in the two stereogenic double
phosphorus bond
atoms: of
unlike the substrate.
amines, phosphines areTwo diastereoisomeric
configura-
tionally stable, rather like sulfoxides (which we will discuss in the next chapter). The ca
complexes
tionally result,
stable, rather like since
sulfoxides (which the
we chiral
will discuss incatalyst
the next can
chapter). coordinate
The catalyst to
imposes
chirality on the hydrogenation by coordinating to both the amide either
group of
and the
the doub
enantiotopic faces of substrate.
chirality on the hydrogenation by the double
coordinating
Two bond
to both the amide group and the double bond of the
diastereoisomeric complexes result, since the chiral catalyst can coord
substrate. Two diastereoisomeric complexes result, since the chiral catalyst can coordinate to either
of the enantiotopic faces of the double bond.
of the enantiotopic faces of the double bond.
Ar
Ar O MeO
O MeO MeO MeO
MeO

Me N CO2Me Me N CO2Me Ar
Ar PAr P
P P H P P P H
P
+
P P
Rh O
Rh Rh Rh O O Rh
L L L L
two diastereoisomeric two diastereoisomeric
OMe OMe MeO2C OMeNcomplexes
Me formed Me 2C NOMeN CO2Me
MeOOMe Me
complexes formed
H H H
It turns
It turns out that the enantioselectivity in theout that the
reaction enantioselectivity
arises in the
because one of these reaction arises because one of these di
diastereoisomer-
ic complexes reacts much more rapidly ic complexes reacts than
with hydrogen muchthemore rapidly
other, withtransferring
ultimately hydrogen than
boththe other, ultimately tra
hydrogen atoms to the same face ofhydrogen
the doubleatoms
[Link] the same face of the double bond. 54
H et. al. Organic Chemistry - Oxford University
Credits: J. Clayden Ar H H
Press
Ph
substrate. Two diastereoisomeric complexes result, since the chiral catalyst can coordinate to either
Chiral catalysts
of the enantiotopic faces of the double bond.
Ar
Asymmetric hydrogenation
MeO O of alkenes MeO MeO

Me N CO2Me Ar Ar
P P H P P P P
Rh O + O Rh
• It turns L
Rhout that the enantioselectivity in the reaction arises because one of these
L
diastereoisomeric
OMe complexes reacts much
two diastereoisomeric
complexes formed MeO2C more
OMeN rapidly
Me with hydrogen
Me OMeN than the
CO2Me
H
other, ultimately transferring both hydrogen atoms to the same face ofHthe double
Itbond.
turns out that the enantioselectivity in the reaction arises because one of these diastereoisomer-
ic complexes reacts much more rapidly with hydrogen than the other, ultimately transferring both
hydrogen atoms to the same face of the double bond.
H Ar H
Ph An Ph
Ar H2 Ar O H
P P P H
O Rh O Rh H
An Ph An
Ar fast Me N CO2Me
O P
Me N CO2Me Me N An CO2Me H
H H
Ph major enantiomer
Me N CO2Me
H H
Ph An Ph
Ar H2 Ar H Ar
P P H P
H O
An Rh O Ph Rh O An H
+ [DIPAMP]RhL+2 slow P
MeO2C N Me MeO2C An N Me MeO2C N Me
H H
Ph H
(An = o-anisyl) minor enantiomer

Although more limited in scope than the BINAP–Ru(II)-catalysed hydrogenations, rhodium-

catalysed hydrogenations are of enormous commercial importance because of the demand for both
natural and unnatural amino acids on a vast scale. It is even economical for the more expensive of the
natural amino acids to be made synthetically rather than isolated from natural sources—phenylala-
nine, for example, of industrial importance as a component of the artificial sweetener aspartame, is 55
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
manufactured by enantioselective hydrogenation.
Chiral catalysts
Improving enantioselectivity by recrystallization

• This technique is quite frequently used to improve the ee of almost enantiomerically

pure samples, since, in general, crystals are most stable if they consist either of a
single enantiomer or of a racemic mixture

• Recrystallization of samples with ees greater than about 85% has a good chance of
improving the ee of the sample (the minor enantiomer remaining in the mother
liquors)

• Samples with ees less than about 70% tend to decrease in ee on recrystallization.
Much depends on crystal structure

• The difficulty of increasing low ees by recrystallization is one disadvantage of chiral

reagent techniques as opposed to chiral auxiliary techniques

56
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 45 Asymmetric synthesis
symmetric synthesis 1242 45 . A
Chiral catalysts
and this new reaction makes use of titanium, as titanium tetraisopropoxide, Ti(OiPr)4, to do the
Asymmetric
new reaction makesepoxidation
use of titanium, as titanium tetraisopropoxide, Ti(OiPr)4, to do the
same thing. Sharpless surmised that, by adding a chiral ligand to the titanium catalyst, he might be
and th
ng.•Sharpless surmised that, bythe
adding a chiral ligand The
to the titanium catalyst, same t
Transition-metal-catalyzed
able to make reaction epoxidations
asymmetric. developed
ligand that works ishediethyl
bestby might be
[Link],
Sharpless work with
and the reaction
make the reaction alcohols
asymmetric.
shown belowThe ligand that works able to
allylic (there
is just are
one of many fewbest
that is diethylthat
restrictions
demonstrate tartrate, and
this ison the reaction
what
a remarkably can
good be epoxidized
reaction.
elow shown
OH is just one of many that demonstrate that this is a remarkably
enantioselectively) t-BuOOHgood reaction.
t-BuOOH Ti(Oi -Pr)4 OH
CO2Et
Ti(Oi -Pr)4 O CO2Et
OH OH 2C
EtO
OH O L–(+)–DET
= L-(+)-diethyl tartrate OH OH
L–(+)–DET 85% yield, 94% ee OH
L-(+)-DET = L-(+)-diethyl tartrate
Transition-metal-catalysed epoxidations 85% yield,
work94% ee on allylic alcohols, so there is one limitation
only
to the method, but otherwise there are few restrictions on what can be epoxidized enantioselectively.
• The active
sition-metal-catalysed complex work
epoxidations is formed fromalcohols,
only on allylic two titanium
so there is atoms bridged by two tartrateTra
one limitation
When this reaction was discovered in 1981 it was by far the best asymmetric reaction known.
ligands.
otherwiseEach to the m
Because of titanium atom
a lot of retains twodiscovering
of enantioselectively.
itsexactly
isopropoxide
how the reactionligands
worked, andand is
ethod, but there are few restrictions on what can be epoxidized
its importance, work went into
his reaction was discovered in 1981 it was byis believed
far the best When
coordinated to one
the scheme ofshows
below the carbonyl
what groups
to be asymmetric
theofactive reaction
thecomplex,
tartrate known.
ligand.
formed When
from two theatoms
titanium oxidizing
of its importance, abridged
lot of work went intoligands
discovering Becaus
agent t-BuOOH by twois added
tartrate theexactly
to(shown how
inmixture,
gold). thetitanium
Each itreaction
displacesworked,
atom and
retainsone
two ofof the remaining
its isopropoxide
the sch
me below shows what is believed
ligands, to be the active
and is coordinated complex,
to one formedgroups
of the carbonyl from two titanium
of the tartrateatoms
ligand. The reaction works
isopropoxide
by two tartrate ligands
best if
ligands
(shown
the titanium
and
in gold). one
andEach
of the
titanium
tartrate
tartrate
atom
are left to retains
stir for
carbonyl
twosoof
a while
groups
itsthese
that isopropoxide
dimers can form cleanly. bridged
and is coordinated to one of the carbonyl groups ofCO the tartrate
i-Pr ligand. The reaction works CO2Et ligands
2Et
e titanium and tartrate are left to stir ifor i-Pr
-Pr a while so that these dimers can form cleanly. i-Pr best if
O O
CO2Et i-Pr O CO2Et O
i-Pr i-Pr i-Pr
O O O O O O
O O
i-Pr Ti CO2Et Ti i-Pr Ti CO2Et Ti CO2Et
O
Ti(Oi-Pr)4 + OEtO
O O O O O O
OL-(+)-DET O O O O
t-BuOOH O
O O
i-Pr Ti CO2Et Ti i-Pr Ti CO2Et Ti CO2Et
OEt
O i-Pr O Ti(Oi-Pr)4 +
O O O O O O
t-Bu L-(+)-DET
t-BuOOH
O O 57
O EtOi-Pr O EtO
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 O O O O O O
L-(+)-DET t-BuOOH
Chiral catalysts O
O
O
O i-Pr
Asymmetric epoxidation t-Bu

• For this oxidizing complex

EtO to react with an allylic alcohol, EtO the alcohol must become
coordinated to oxidizing
When the the titanium too, displacing
agent (t-BuOOH, shown inagreen)
further isopropoxide
is added to the mixture,ligand. Because
it displaces one of of
the shape of theisopropoxide
the remaining complex ligands
the reactive oxygen
and one of atom
the tartrate of the
carbonyl bound hydroperoxide has
groups.
to be delivered tooxidizing
Now, for this the lower faceto of
complex the
react alkene,
with an allylicand thethe
alcohol, epoxide is formed
alcohol must in high
become co-
ordinated toexcess
enantiomeric the titanium too, displacing a further isopropoxide ligand. Because of the shape of the
complex the reactive oxygen atom of the bound hydroperoxide has to be delivered to the lower face
of the alkene (as drawn), and the epoxide is formed in high enantiomeric excess.
CO2Et CO2Et

Oi-Pr O O
i-PrO O O O O HO
Ti CO2Et Ti E Ti E O
O O O O O R
O O O
R R
t-Bu t-Bu

EtO
CO2Et group at back simplified to 'E' for clarity

Different allylic alcohols coordinate in the same way to the titanium and reliably present the same
• The reaction works
enantiotopic face tobest if the
the bound titanium
oxidizing and
agent, andtartrate are for
the preference leftoxidation
to stir for
withaL-(+)-DET
while sois that
the initial
showncomplex can form
in the schematic cleanly
diagram below. Tartrate is ideal as a chiral ligand because it is available
relatively cheaply as either enantiomer. L-tartrate is extracted from grapes; D-(–)-tartrate is rarer
and more expensive—it is sometimes called unnatural tartrate, but, in fact, it too is natural. By using58
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Chiral catalysts
Asymmetric epoxidation
• Different allylic alcohols coordinate in the same way to the titanium and reliably
present the same enantiotopic face to the bound oxidizing agent

• Tartrate is ideal as a chiral ligand because it is available relatively cheaply as either

Chiral reagents and chiral catalysts
enantiomer. L-tartrate is extracted from grapes; D-(–)-tartrate is rarer and more
expensive (it is sometimes called unnatural tartrate but, in fact, it too is natural)
D-(–)-tartrate it is, of course, possible to produce the other enantiomer of the epoxide equally
selectively.

•Enantioselectivity in the Sharpless asymmetric epoxidation

enantioselectivity in the Sharpless asymmetric expoxidation
D-(–)-diethyl
tartrate delivers
oxygen to top face of alkene
arrange allylic
alcohol with
hydroxyl group HO
top left
R

L-(+)-diethyl
tartrate delivers
oxygen to bottom face of alkene

Sharpless also found that this reaction works with only a catalytic amount of titanium–tartrate
59
complex, because the reaction products can be displaced from the metal centre by more of the two
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
Chiral catalysts
Asymmetric dihydroxylation
Asymmetric dihydroxylation
The last asymmetric oxidation we will mention really is probably the best asymmetric reaction of all.
It is a chiral version of the syn dihydroxylation of alkenes by osmium tetroxide. Here is an example—
• It isthough
a chiral version
the concept of the
is quite syn the
simple, dihydroxylation of alkenes
recipe for the reactions is quite by osmiumsotetroxide
complicated we need to
approach it step by step.
asymmetric dihydroxylation–the reaction: OH
catalytic OsO4
oxidant, other additives
solvent (H2O/t-BuOH)
plus chiral ligand OH
97% ee
The active reagent is based on osmium(VIII) and is used in just catalytic amounts. This means that
• Because OsO
there has to is volatilequantity
be a 4stoichiometric and toxic, theoxidant
of another osmium is usually
to reoxidize added
the osmium afteras Kcatalyt-
each 2OsO4 2H2O
.

(potassium osmate
ic cycle—K3Fe(CN) dihydrate),
6 is most commonlywhich formsOsO
used. Because OsO in the
4 is 4volatile reaction
and mixtureis usual-
toxic, the osmium
ly added as K2OsO2(OH)4, which forms OsO4 in the reaction mixture. The ‘other additives’ include
• K2CO
The 3 and methanesulfonamide
active reagent is based(MeSO 2NH2), which increases
on osmium(VIII) and the rate of the
is used in reaction. Now for amounts.
just catalytic the
chiral ligand. The best ones are based on the alkaloids dihydroquinidine and dihydroquinine, whose
This means that there has to be a stoichiometric quantity of another oxidant to
structures are shown below. They coordinate to the osmium through the yellow nitrogen.
reoxidize the osmium (VI) after each catalytic cycle: K3Fe(CN)6 (potassium
ferricyanide)
dihydroquinidine is most commonly used
(when Ar = H)
dihydroquinine
(when Ar = H)
= DHQD N N = DHQ

• The ‘other additives’ include

O K2CO3 and methanesulfonamide
O (MeSO2NH2), which
increases the rateHof the reaction
Ar Ar H
MeO OMe

N N
60
The alkaloids (usually abbreviated to DHQD and DHQ, respectively)
Credits: J. Clayden [Link] be attached
al. Organic Chemistry -to an aro-
Oxford University Press
 The last asymmetric oxidation we will mention really is probably the best asymmetric reaction of all.
asymmetric dihydroxylation–the reaction: OH
Chiral
It is acatalysts
chiral version of the syn dihydroxylation of alkenes catalytic OsO4
by osmium tetroxide. Here is an example—
though the concept is quite simple, the recipe foroxidant, other additives
the reactions is quite complicated so we need to
Asymmetric dihydroxylation
approach it step by step. solvent (H2O/t-BuOH)
plus chiral ligand OH
asymmetric dihydroxylation–the reaction: OH 97% ee
catalytic OsO4
The active reagent is based onother
oxidant, osmium(VIII)
additives and is used in just catalytic amounts. This means that
there has to be a stoichiometric
solvent quantity
(H2O/t-BuOH)of another oxidant to reoxidize the osmium after each catalyt-
ic cycle—K3Fe(CN)6 is mostplus commonly used. Because OsO4 is volatile
chiral ligand OH and toxic, the osmium is usual-
ly added as K2OsO2(OH)4, which forms OsO4 in the reaction97% ee
mixture. The ‘other additives’ include
• The Thechiral ligand:
activeKreagent
2CO3 and the best
is based ones are (MeSO
on osmium(VIII)
methanesulfonamide based on2),in
and is2used
NH the
justalkaloids
whichcatalytic
increases dihydroquinidine
amounts.
the rateThis
of themeans (DHQ)
that Now
reaction. for the
and dihydroquinine
there has to bechiral ligand.(DHQD).
a stoichiometric
The best They
quantity
ones of
are coordinate
another
based oxidant to the
to reoxidize
on the alkaloids osmium
the osmium after
dihydroquinidine through
andeach the yellow
catalyt-
dihydroquinine, whose
ic cycle—K3Fe(CN)
nitrogen structures6 isare
most commonly
shown below. used.
They Because
coordinate OsO is volatile
to4the osmium and toxic, the
through theosmium is usual-
yellow nitrogen.
ly added as K2OsO2(OH)4, which forms OsO4 in the reaction mixture. The ‘other additives’ include
dihydroquinidine dihydroquinine
K2CO3 and methanesulfonamide
(when Ar = H) (MeSO2NH2), which increases the rate of the reaction. Now (whenfor
Ar =the
H)
= DHQD
chiral ligand. The best ones are basedN on the alkaloids dihydroquinidine and dihydroquinine, N = DHQ
whose
structures are shown below. They coordinateOto the osmium through the yellow O nitrogen.
H Ar Ar H
dihydroquinidine dihydroquinine
(when Ar = H) MeO (when Ar = H) OMe
= DHQD N N = DHQ

O O
H Ar N Ar H N
MeO The alkaloids (usually abbreviated to DHQD and DHQ, respectively)
OMe must be attached to an aro-
matic group
• Dihydroquinine Ar, the choice of whichare
and dihydroquinidine (likenot
the enantiomeric
choice of ligand for enantioselective
(the green centershydrogenation
are
with Rh) varies
inverted in dihydroquinidine, according to the substrate.
the black ones remains The most generally
the same). DHQ and DHQDtwo
applicable ligands are these
N N
phthalazines in which each aromatic group Ar carries two alkaloid ligands.
are named pseudo-enantiomers
The alkaloids (usually abbreviated to because they respectively)
affect enantioselectivity as they were
N DHQD
N and DHQ, must
N beNattached to an aro-
enantiomers (opposite
matic group Ar, the choice stereoinduction)
of which (like the choice of ligand for enantioselective hydrogenation
O O O O
with Rh) varies according to the substrate. The most 61
"DHQD 2PHAL" DHQD DHQDgenerally DHQapplicable ligands areDHQ these"DHQtwo2PHAL"
phthalazines in which each aromatic group Ar carries twoCredits: J. Clayden et. al. Organic Chemistry - Oxford University Press
alkaloid ligands.
 ly added
there has toasbeKa2stoichiometric
OsO2(OH)4, which forms
quantity OsO4 inoxidant
of another the reaction mixture.
to reoxidize theThe ‘otherafter
osmium additives’ include
each catalyt-
Chiral catalysts
ic K 2CO3 and
cycle—K methanesulfonamide
3Fe(CN) (MeSO
6 is most commonly 2NH
used. 2), which
Because OsO increases theand
4 is volatile ratetoxic,
of thethe
reaction.
osmium Now for the
is usual-
ly chiral
addedligand.
as K2OsO The2(OH)
best ones are based
4, which formson
OsOthe4 alkaloids dihydroquinidine
in the reaction mixture. Theand dihydroquinine,
‘other whose
additives’ include
Asymmetric dihydroxylation
K2structures are shown below. They(MeSO
coordinate
CO3 and methanesulfonamide 2NH2to the osmium
), which through
increases theof
the rate yellow [Link] for the
the reaction.
chiral ligand. The best ones are based on the alkaloids dihydroquinidine and dihydroquinine,
dihydroquinidine dihydroquinine
whose
structures
(when Arare
= H)shown below. They coordinate to the osmium through the yellow nitrogen. (when Ar = H)
= DHQD N N = DHQ
dihydroquinidine dihydroquinine
(when Ar = H) O O (when Ar = H)
= DHQD HN Ar Ar N H = DHQ

MeO O O OMe
H Ar Ar H
MeO OMe
N N
The alkaloids (usually abbreviated to DHQD and DHQ, respectively) must be attached to an aro-
• For thematic
generation
group Ar, the of choice
theN chiral
of whichligand,
(like theDHQD
choice ofand NDHQ
ligand must be attached
for enantioselective to an
hydrogenation
aromaticThespecies
with Rh)
alkaloids (ligand),
varies(usually
according the
to thechoice
abbreviated substrate.
to DHQD ofThewhich
and DHQ,varies
most generally according
applicable
respectively) to the
must beligands aretosubstrate.
attached these two
an aro-
The most
matic generally
phthalazines
group in the
Ar, applicable
which
choice ligands
eachofaromatic
which group
(like are these
Archoice
the carries
oftwo two phthalazines
alkaloid
ligand for ligands.
enantioselective(PHAL) in which
hydrogenation
each with
aromatic group
Rh) varies carries
according two
to the
N alkaloidThe
N substrate. ligands
most generallyN applicable
N ligands are these two
phthalazines in whichOeach aromatic group O Ar carries two alkaloid
O ligands. O
"DHQD2PHAL" DHQD N N DHQD DHQ N N DHQ "DHQ2PHAL"
O O O O
"DHQD2PHAL" DHQD DHQD DHQ DHQ "DHQ2PHAL"
phthalazine-based ligands

Dihydroquinine and dihydroquinidine are not enantiomeric (although the green centres are
phthalazine-based
inverted in dihydroquinidine, the black ones remains ligands
the same), but they act on the dihydroxylation
asDihydroquinine
though they were—here, after all thatare
and dihydroquinidine introduction, is a real(although
not enantiomeric example, the and green
probably the most
centres are
remarkable
inverted of any in this chapter.
in dihydroquinidine, the black ones remains the same), but they act on the dihydroxylation
as though 62
OH they were—here,
K2OsO2(OH) after all that introduction, is Ka2OsO
4, K3Fe(CN)6,
real2(OH)
example, and probably
4, K3Fe(CN)6, OH the most
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
remarkable of any in this chapter.
Chiral catalysts phthalazine-based ligands
Asymmetric dihydroxylation
Dihydroquinine and dihydroquinidine are not enantiomeric (although the green centres are
inverted in dihydroquinidine, the black ones remains the same), but they act on the dihydroxylation
• Trans-(E)-stilbene dihydroxylates
as though they were—here, with
after all that a very high
introduction, is a level of enantioselectivity
real example, and probably the most
remarkable of any in this chapter.
OH K2OsO2(OH)4, K3Fe(CN)6, K2OsO2(OH)4, K3Fe(CN)6, OH
K2CO3, MeSO2NH2 K2CO3, MeSO2NH2
Ph Ph Ph
Ph tBuOH,
Ph tBuOH,
Ph
H2O, 0 ˚C H2O, 0 ˚C
OH DHQD2PHAL trans-stilbene DHQD2PHAL OH
99.8% ee DHQ2PHAL >99.5% ee

trans-(E)-Stilbene dihydroxylates more selectively than any other alkene, and we would probably
Chiral reagents and chiral catalysts
• Thenot
asymmetric
be exaggerating dihydroxylation (often abbreviated
if we said that this particular to AD)
example is the most reagent catalytic
enantioselective is a remarkable
reac-
tion ever
reagent, invented.
since It is also much
it oxidizes morelessorfussy
lessabout
anythesort
alkenes it will oxidize
of alkene, than the asymmetric
electron-rich or electron-
(often abbreviated to AD) reagent. The following example illustrates both this and a synthetic use for
poorepoxidation. Osmium tetroxide itself is a remarkable reagent, since it oxidizes more or less any sort
the diolelectron-rich
of alkene, product. or electron-poor, and the same is true of the asymmetric dihydroxylation
O OH O

OsO4, K3Fe(CN)6, K2CO3,

OEt OEt
DHQD–containing ligand OH
O2N O2N
89% yield, 96% ee

The diol is produced from a double bond that is more electron-poor than most, and can be con-
verted to the antibiotic chloramphenicol in a few more steps.
OH O OH O
TsCl, Et3N K2CO3
63
OEt OEt
Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 attack of azide on the epoxide must be because of the electron-withdrawing p-nitro
Chiral catalysts group—acidic silica encourages the reaction to proceed through an SN1-like (or ‘loose
SN2’) transition state, with cationic character on the reaction centre. Substitution next to
O2N OH

Asymmetric dihydroxylation
the ring is disfavoured, and the 1,3-diol is formed selectively. disfavoured

• With the substrate

We can sum arranged with the
up the usual selectivity largest
of the (RL) inand
AD reaction next
another largest
diagram, showngroups
below. With(RM)
bottom left and top
the substrate right,
arranged respectively,
as shown, DHQD-based
with the largest ligands
(RL) and next largest groupswill
(RMdirect
) bottomOsO 4 to
left and
dihydroxylate from
top right, the top
respectively, face of ligands
DHQD-based the double
will directbond
OsO4 toand DHQ-based
dihydroxylate from theligands
top face ofwill
direct it to
thedihydroxylate the bottom
double bond and DHQ-based ligands will direct it to dihydroxylate the bottom.

•Enantioselectivity in the Sharpless asymmetric dihydroxylation

Enantioselectivity in the Sharpless asymmetric dihydroxylation

DHQD

steric hindrance OsO4

RS RM

RL H
steric hindrance
OsO4
"attractive area"
DHQ

• The detailedThemechanism of the

reason for this must, asymmetric
of course, dihydroxylation
lie in the way in which the substrate is still under
interacts discussion.
with the osmi-
What is known
um–ligand iscomplex.
that the ligandeven
However, forms
as wesome a sort
write this book,of the‘chiral
detailed pocket’
mechanism (like
of theanasymmet-
enzyme
ric dihydroxylation
active site) with the osmium is still under discussion.
sitting at theWhat bottomis known is that
of it. Alkenesthe ligand
can forms
only some sort of
approach
the osmium if they are correctly aligned in the chiral pocket. Moreover it appears
that part of the pocket is ‘attractive’ to aromatic or strongly hydrophobic groups. This
part appears to accommodate RL, thus explaining the high selectivity of AD
64
reactions Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
 This chapter, more than most, deals with topics under active investigation. New and more power-
Asymmetric
ful methods aresynthesis
appearing all the time and it is quite certain that the decade 2000–10 will see many
Summary of methods
important advances infor asymmetric
asymmetric synthesis
synthesis.

•Summary of methods for asymmetric synthesis

Method Advantages Disadvantages Examples
resolution both enantiomers available maximum 50% yield synthesis of BINAP
chiral pool 100% ee guaranteed often only 1 enantiomer amino acid- and sugar-
available derived syntheses

chiral auxiliary often excellent ees; can extra steps to introduce oxazolidinones
recrystallize to purify to and remove auxiliary
high ee
chiral reagent often excellent ees; can only a few reagents are enzymes, CBS
recrystallize to purify to successful and often for reducing agent
high ee few substrates

chiral catalyst economical: only small only a few reactions are asymmetric
amounts of recyclable really successful; hydrogenation,
material used recrystallization can improve epoxidation,
only already high ees dihydroxylation

• The chiral pool strategy relies on finding a suitable enantiomerically pure

natural product that can easily be transformed into the target molecule. The
mmetric synthesis of amino acids, starting 2. This is a synthesis of the racemic drug tazadolene. If the enan-
chiral
orks. Explain pool is that
the stereoselectivity collection
of each ofthecheap,
tiomers of readily
drug are to available
be evaluated pure
for biological natural
activity, they
products, usually amino acids or sugars, from which pieces containing
must be separated. At which stage would you advocate separating the
required chiral centers canthe beenantiomers,
taken and andincorporated
how would you dointo
it? the product
NH3 O O O O O 65
CO2Me Credits: J. Clayden et. al. Organic Chemistry - Oxford University Press
N