ARTICLE IN PRESS

The Chemical Synthesis

and Applications of Tropane
Alkaloids
Samson Afewerki*,†, Jia-Xin Wang‡, Wei-Wei Liao‡,1,
Armando Córdova*,†,1
*Department of Natural Sciences, Mid Sweden University, Sundsvall, Sweden
†
Berzelii Center EXSELENT, The Arrhenius Laboratory, Stockholm University, Stockholm, Sweden
‡
Department of Organic Chemistry, College of Chemistry, Jilin University, Changchun, China
1
Corresponding authors: e-mail address: [email protected]; [email protected]

Contents
1. Introduction 2
2. Occurrence 4
3. Synthesis 43
3.1 Cycloaddition Reactions 43
3.2 Cyclization Reactions 48
3.3 Metal-Catalyzed Reactions 55
3.4 Cascade Reactions 58
3.5 Miscellaneous Reactions 59
4. Reactions 62
4.1 Ring-Opening Transformations 62
4.2 Mo-Catalyzed Asymmetric Ring-Opening/Cross-Metathesis 62
4.3 Alkylation and Acylation 63
4.4 Rearrangement 66
4.5 Intramolecular Reductive Coupling 68
5. Synthesis and Applications 69
5.1 Applications as Catalysts and Ligands 69
5.2 Pharmacology of Tropane Alkaloids and Synthetic Derivatives 70
References 79

Abstract
Tropanes are an important class of alkaloid natural products that are found in plants all
over the world. These compounds can exhibit significant biological activity and are
among the oldest known medicines. In the early 19th century, tropanes were isolated,
characterized, and synthesized by notable chemical researchers. Their significant
biological activities have inspired tremendous research efforts toward their synthesis
and the elucidation of their pharmacological activity both in academia and in industry.
In this chapter, which addresses the developments in this field since 1994, the

The Alkaloids # 2018 Elsevier Inc. 1

ISSN 1099-4831 All rights reserved.
https://doi.org/10.1016/bs.alkal.2018.06.001
 ARTICLE IN PRESS

2 Samson Afewerki et al.

focus is on the synthesis of these compounds, and several examples of sophisticated

synthetic protocols involving both asymmetric and catalytic approaches are described.
In addition, the structures of more than 100 new alkaloids are included as well as the
applications and pharmacological properties of some tropane alkaloids.

1. INTRODUCTION
Tropane alkaloids are important natural products that are found in
plants throughout the world. They are pharmaceutically active and most
of them used as medicines.1 Their chemical synthesis has also played a fun-
damental role in the history of organic chemistry, and classical examples
include Willst€atter’s first synthesis of cocaine and Robinson’s ingenious
and efficient total synthesis of tropane.1 The tropane alkaloids are character-
ized by an 8-azabicyclo[3.2.1]octane structural motif (Fig. 1) I. This chapter
covers the chemical synthesis, reactions, applications such as catalysts and
ligands, and pharmacological properties of tropane alkaloids since 1994.
Our focus is on the Occurrence and Synthesis sections since major changes
and advances have been made in these areas. Notably, the structures of
>100 new alkaloids are presented in this update. This chapter follows the
same general outline as in the previous chapters of these series.1a In the
Occurrence section, the taxonomic Angiosperm Phylogeny Group (APG)
III classification system is employed since the older Cronquist system is
no longer reliable.2
The tables in this chapter are based on the APG III system (Tables 1 and 2).
The APG system, which is currently considered the most appropriate system,
is mainly based on the molecular biological evidence, and the current edition,
APG III, was published in 2009.2a Previous editions, the APG I system
and the APG II system, were established in 1998 and 2003, respectively.2b,c
Several changes concerning the classification of plants have been introduced in
the APG III system. The order Euphorbiales in the APG II (2003) system was
eliminated, and the plants involved were classified in the order of Malpighiales.

Fig. 1 The structure of tropane I.

 ARTICLE IN PRESS

The Chemical Synthesis and Applications of Tropane Alkaloids 3

Table 1 Botanical classification of plants containing tropane alkaloids

Order Family Genus Abbreviation used in Table 2
Gentianales Apocynaceae Alstonia
Brassicales Brassicaceae Cochlearia
Fabaceae Faboideae Colutea
Rosales Moraceae Morus M
Santalales Olacaceae Heisteria
Proteales Proteaceae Agastachys
Bellendena
Darlingia
Knightia
Malpighiales Erythroxylaceae Erythroxylum E
Phyllanthaceae Phyllanthus
Rhizophoraceae Bruguiera
Crossostylis
Pellacalyx
Solanales Convolvulaceae Calystegia
Convolvulus C
Ericybe
Evolvulus
Falkia
Ipomoea I
Merremia M1
Astripomoea
Solanaceae Anisodus A
Anthocercis
Anthotroche
Crenidium
Cyphanthera
Duboisia D1
Continued
 ARTICLE IN PRESS

4 Samson Afewerki et al.

Table 1 Botanical classification of plants containing tropane alkaloids—cont’d

Order Family Genus Abbreviation used in Table 2
Grammosolen
Symonanthus
Schizanthus S
Solanum
Physalis
Withania
Salpichroa
Latua
Datura D
Brugmansia
Solandra
Nicandra
Atropa
Hyoscyamus H
Mandragora
Physochlaina
Przewalskia
Scopolia

In addition, dozens of new tropane alkaloids have been discovered since 1993,
and several of them were isolated from genera and families not listed in the pre-
vious compilation in this series (The Alkaloids).1a

2. OCCURRENCE
As mentioned earlier, numerous tropane alkaloids have been discov-
ered and identified since 1993 (Table 2). We have included the new alka-
loids with confirmed structures and CAS registry numbers from references
dating back to 1994 or later. Compounds with a tropane structure hidden
within a considerable larger structure (i.e., demecolcinone) were not
included since they apparently belong to another alkaloid family. In the
Table 2 Tropane alkaloids
CAS register
Entry number Names Structure Genusa References
1 1256081-05-6 (3-endo,8-anti)-8-Methyl-8-azabicyclo[3.2.1] E 3
oct-3-yl 4-hydroxy-3,5-dimethoxybenzoate;
pungencine; 3α-(4-hydroxy-3,5-
dimethoxybenzoyloxy)tropane

2b 16655-60-0 3α-(O-Acetyltropoyloxy)tropane D 4
ARTICLE IN PRESS

3b 17488-50-5 3α-(20 -Hydroxytropoyloxy)tropane D 4

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
4 439929-14-3 3α-cis-Cinnamoyloxytropane E 5

5b 1341219-29-1 3α-(30 -O-Methyltropoyloxy)tropane D 6

ARTICLE IN PRESS

6 879560-99-3 3α-Methylmesaconyloxytropane S 7
7 862588-07-6 3β-Merresectine C M1 8b

8c 954099-40-2 Phyllalbine N-oxide C 9

ARTICLE IN PRESS

9 1008102-51-9 3α-Methylitaconyloxytropane S 7

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
10 1262764-33-9 3α-(3,4-Dimethoxybenzoyloxy)-N-2- C 11
hydroxyethylnortropane

11 750632-90-7 3α-Vanillyloxy-N-formylnortropane; C 12
confolidine
ARTICLE IN PRESS

12b 203263-67-6 3α-(p-Hydroxyphenyl)lactoyloxytropane; H 13

40 -hydroxylittorine
13 163132-00-1 3α-Isobutyryloxynortropane E 14

14 163131-97-3 3α-(4-Methylvaleroyloxy)tropane E 14
ARTICLE IN PRESS

15 3818-30-2 3α-(20 -Phenylpropionyloxy)tropane; D 15

dihydroapoatropine

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
0
16 47004-02-4 3α-(2 -Phenylpropionyloxy)nortropane D 15

17c 97534-16-2 Convolamine N-oxide C 16

ARTICLE IN PRESS

18 219829-73-9 Consiculine C 17
19 219829-74-0 Consabatine C 17

20 439791-49-8 3α-Isobutyryloxy-7β-hydroxynortropane E 5
ARTICLE IN PRESS

21 439791-50-1 3α-Hydroxy-7β-phenylacetoxynortropane E 5

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
22 628722-29-2 3α-Propionyloxy-7β-(E)- E 18
cinnamoyloxynortropane

23 628722-30-5 3α-Isobutyryloxy-7β-benzoyloxynortropane E 18
ARTICLE IN PRESS
24 628722-31-6 3α-Isobutyryloxy-7β-(Z)-(300 ,400 ,500 - E 18
trimethoxycinnamoyloxy)nortropane

25 910311-94-3 3α-Tigloyloxy-7β-isobutyryloxytropane D 19

26 1215119-42-8 3α-(1-Methylcitraconyloxy)- S 10,20

ARTICLE IN PRESS

6β-angeloyloxytropane

27 1215119-40-6 3α-(1-Methylcitraconyloxy)- S 20
6β-senecioyloxytropane

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
28 1215119-33-7 3α-(1-Methylitaconyloxy)- S 20
6β-senecioyloxytropane

29 1262109-75-0 3α-(E)-4-Hydroxysenecioyloxy- S 21
6β-angeloyloxytropane; schizanthine N

30 1262109-76-1 3α-(E)-4-Hydroxysenecioyloxy- S 21
6β-senecioyloxytropane; schizanthine O
ARTICLE IN PRESS

31 1262109-77-2 3α-Mesaconyloxy-6β-senecioyloxytropane; S 21
schizanthine P
32 263717-19-7 3α-(30 ,40 ,50 -Trimethoxybenzoyloxy)- E 22
6β-acetoxy-tropane; erythrozeylanine A

33 1270038-16-8 3α-[(4-Hydroxy-3,5-dimethoxybenzoyl)oxy]- E 23
6β-benzoyloxytropane

34 1341219-35-9 3α-Tropoyloxy-6β-isobutyryloxytropane D 6
ARTICLE IN PRESS

35 182015-07-2 3α-(1-Methylmesaconyloxy)- S 20,24

6β-senecioyloxytropane

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
36 182015-08-3 3α-(1-Methylmesaconyloxy)- S 24
6β-(E)-cinnamoyloxytropane

37 20399-79-5 3α-Hydroxy-6β-senecioyloxytropane S 10,24

O N
OH
ARTICLE IN PRESS

38 263717-20-0 3α-(Z)-(Cinnamoyloxy)-6β-acetoxytropane; E 22
erythrozeylanine C
39 392232-07-4 3α-(3,4,5-Trimethoxybenzoyloxy)-6β-(E)- MeO OMe E 25
(3,4,5-trimethoxycinnamoyloxy)tropane;
MeO
pervilleine B

O
O N
O OMe
O OMe
OMe

40 392232-10-9 3α,6β-Bis-[(E)-(3,4,5- MeO OMe E 25

trimethoxycinnamoyloxy)]tropane;
MeO
pervilleine C
O
O N OMe
O
O OMe
OMe
ARTICLE IN PRESS

41 392232-16-5 3α-(3-Hydroxyphenylacetoxy)-6β-(E)-(3,4,5- MeO OMe E 25

trimethoxycinnamoyloxy)tropane;
pervilleine E MeO

O HO

O N
O
O

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
42 392232-17-6 3α-(2-Phenylacetoxy)-6β-(E)-(3,4,5- MeO OMe E 25
trimethoxycinnamoyloxy)tropane;
pervilleine F MeO

O
O N
O

43 426218-73-7 3α-(Z)-(3,4,5-Trimethoxycinnamoyloxy)- MeO E 26

6β-benzoyloxytropane OMe
O MeO

O N
O

O
ARTICLE IN PRESS

44 426258-84-6 3α-Benzoyloxy-6β-hydroxytropane E 26

O N
O OH
45 526217-09-4 3α-(1-Methyl-1H-pyrrol-2-carbonyloxy)- E 27
6β-(1H-pyrrol-2-carbonyloxy)tropane; O
N
catuabine D H
O

N
O N

46 526217-13-0 3α,6β-Bis(1-methyl-1H- E 27
pyrrol-2-carbonyloxy)tropane; catuabine E O
N
O

N
O N

O
ARTICLE IN PRESS

47 526217-18-5 3α-(4-Hydroxy-3,5-dimethoxybenzoyloxy)- E 27
6β-(1-methyl-1H-pyrrol-2-carbonyloxy)
tropane; catuabine F

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
48 862587-67-5 3α,6β-Bis-(4-methoxybenzoyloxy)tropane; MeO M1 8b
O
merredissine
O
N
O
OMe
O

49 864962-30-1 3α-Hydroxy-6β-(1-methyl-1H- O
E 28
pyrrol-2-pyrrol-2-carbonyloxy)tropane; N
catuabine H O
N
OH

50 864962-34-5 6β-Hydroxy-3α-(1-methyl-1H- HO E 28
pyrrol-2-pyrrol-2-carbonyloxy)tropane; O
catuabine I N N
O
ARTICLE IN PRESS

51c 864962-38-9 3α,6β-Bis(1-methyl-1H- E 28

N
pyrrol-2-pyrrol-2-carbonyloxy)tropane
N-oxide; catuabine E N-oxide O –
O O
O N N
+ O
52 876313-92-7 3α-(E)-(3,4,5-Trimethoxycinnamoyloxy)-6β- O E 29
hydroxytropane; pervilleine G N OMe
HO O

OMe
OMe

53 876313-94-9 3α-(3,4,5-Trimethoxybenzoyloxy)-6β-(Z)- OMe E 29

(3,4,5-trimethoxycinnamoyloxy)tropane;
cis-pervilleine B OMe

OMe
O
O
O
N OMe
O

OMe
OMe

54 876313-95-0 3α-Phenylacetoxy-6β-(Z)-(3,4,5- MeO E 29

OMe
trimethoxycinnamoyloxy)tropane;
pervilleine F
ARTICLE IN PRESS

OMe

O O
N
O O

55 263717-19-7 6β-Acetoxy-3α-(30 ,40 ,50 - E 22

trimethoxybenzoyloxy)tropane;
erythrozeylanine A

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
b
56 855784-81-5 3α-Formyloxy-6β-tigloyloxytropane D 15

O
O
H
N
O O

57b 855784-80-4 3α-Phenylacetoxy-6β-propionyloxytropane D 15

58 169626-32-8 3α-Veratroyloxy-6β-acetyloxytropane; C 16
convolacine N
O O

OMe
ARTICLE IN PRESS

O
OMe
O

59b 821787-77-3 3α-Tigloyloxy-6β-propionyloxy- D 15,30

7β-hydroxytropane
60 439791-51-2 3α-Hydroxy-6β-(30 -hydroxy-20 -methyl-30 - E 5
phenylpropionyloxy)-7β-hydroxytropane

61 426258-95-9 7β-Hydroxy-6β-(3,4,5- E 26
trimethoxybenzoyloxy)-3α-(E)-(3,4,5- O N
HO
trimethoxycinnamoyloxy)tropane MeO O OMe
OMe
MeO
OMe O
OMe
O

62 526217-11-8 3α-(1-Methyl-1H-pyrrol-2-ylcarbonyloxy)- E 27
6β-(1H-pyrrol-2-ylcarbonyloxy)-7β- HN
hydroxytropane; 7β-hydroxycatuabine D
O
ARTICLE IN PRESS

O N

N
HO O O

63 526217-15-2 3α,6β-Bis(1-methyl-1H- E 27
pyrrol-2-ylcarbonyloxy)-7β-hydroxytropane;
7β-hydroxycatuabine E

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
64 526217-17-4 7β-Acetoxy-3α,6β-bis(1-methyl-1H- E 27
pyrrol-2-ylcarbonyloxy)tropane;
7β-acetylcatuabine E

65 526217-19-6 3α-(4-Hydroxy-3,5-dimethoxybenzoyloxy)- E 27
6β-(1-methyl-1H-pyrrol-2-ylcarbonyloxy)7β-
hydroxytropane; 7β-hydroxycatuabine F
ARTICLE IN PRESS

66 526217-20-9 3α-(3-Hydroxyphenylacetoxy)- E 27
6β,7β-dihydroxytropane; catuabine G
67c 392232-04-1 3α-(3,4,5-Trimethoxybenzoyloxy)- E 25
6β-(E)-(3,4,5-trimethoxycinnamoyloxy)- O O N+
7β-hydroxytropane N-oxide; pervilleine MeO HO
O
A N-oxide OMe
MeO OMe
OMe
O
OMe
O

68 392232-13-2 3α,6β-Di-[(E)-(3,4,5- E 25
trimethoxycinnamoyloxy)]-
7β-hydroxytropane; pervilleine D
ARTICLE IN PRESS

69 876313-93-8 3α-(E)-(3,4,5-Trimethoxycinnamoyloxy)- E 29
6β,7β-dihydroxytropane; pervilleine H N OMe
HO
HO OMe

OMe
O

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
70 864962-32-3 3α,7β-Dihydroxy-6β-(1-methyl-1H- E 28
pyrrol-2-yl-carbonyloxy)tropane;
7β-hydroxycatuabine H

71 864962-35-6 6β,7β-Dihydroxy-3α-(1-methyl-1H- E 28
pyrrol-2-yl-carbonyloxy)tropane;
7β-hydroxycatuabine I
ARTICLE IN PRESS

72c 174024-40-9 7β-Hydroxy-6β-propenoyl- D 31

3α-tropoyloxytropane
73 628722-28-1 3α-Benzoyloxy-6β-hydroxy-7β-(20 -hydroxy- E 18
3-benzenepropanoyloxy)nortropane

74 307334-86-7 3a,7β-Bisbenzoyloxy-6β-hydroxytropane; E 32
alaternifoline
ARTICLE IN PRESS

75 1341219-39-3 3β-Tropoyloxy-6β-isovaleroyloxytropane D 6

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
76 1907634-18-7 3α-Hydroxy-6β,7β-dibenzoyloxytropane E 33

N
O O
O

O
OH

77 307334-87-8 3α-(3,4,5-Trimethoxy-cinnamoyloxy)- E 32
7β-(3,4,5-trimethoxybenzoyloxy)-
6α-hydroxy-tropane; erythrorotundine
ARTICLE IN PRESS

78b 1341219-10-0 3,7-Dihydroxy-6-propionyloxytropane D 6

O N
HO
O

OH
79b 1341219-27-9 3,7-Dihydroxy-6-(20 -methylbutyryloxy) D 6
tropane O N
HO
O

OH

80b 872205-33-9 3α-Tigloyloxy-6β-propionyloxy- D 19

7β-hydroxytropane N
O HO
O

81b 1341219-29-1 3-(30 -O-Methyltropoyloxy)tropane D 6

ARTICLE IN PRESS

82b 359723-70-9 3β,6β-Ditigloyloxynortropane H D 34

N

O
O
O
O

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
83b 1341219-12-2 6,7-Dehydro-3-tigloyloxytropane D 6
N

84b 1341219-24-6 6,7-Dehydroapoatropine D 6

N

O
ARTICLE IN PRESS

85b 1341219-18-8 3-Tigloyloxy-6,7-epoxytropane D 6,35

N

O
86 130288-54-9 3α-Phenylacetoxy-6β,7β-epoxytropane; E 31
phenylacetoxyscopane

87 1473386-63-8 7β-Acetoxy-2α-tigloyloxytropane; ipvelutine I 36

88 864962-33-4 3α,7α-Dihydroxy-6β-(1-methyl-1H- E 28
pyrrol-2-yl-carbonyloxy)tropane; N
O
7α-hydroxycatuabine H O
ARTICLE IN PRESS

N OH
OH

89 864962-31-2 3β-Hydroxy-6β-(1-methyl-1H- E 28
pyrrol-2-yl-carbonyloxy)tropane; N
isocatuabine H N
O
O

OH

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
90 864962-36-7 3α-Hydroxy-2α-(1-methyl-1H-pyrrol- E 28
2-yl-carbonyloxy)tropane; vaccinine A N
O
N
O

OH

91 864962-37-8 6α-Hydroxy-4α-(1-methyl-1H- E 28
pyrrol-2-yl-carbonyloxy)tropane; vaccinine B

92 455949-40-3 2α,3β-Dihydroxynortropane H M 37
N

OH
OH
ARTICLE IN PRESS

93 455949-41-4 2β,3β-Dihydroxynortropane M 37
NH
OH

OH

94 455325-03-8 2α,3β,6β-Trihydroxynortropane HO M 37
NH
OH

OH
95 455325-05-0 2α,3β,4α-Trihydroxynortropane H M 37
N

OH
OH
OH

96 366803-73-8 3β,6β-Dihydroxynortropane M 37,38

97 1575814-77-5 7β-Acetyloxy-3β,6β-dibenzoyloxytropane M 39
O
O N
O
O

O
ARTICLE IN PRESS

98 185344-70-1 3β-Z-Cinnamoyloxytropane E 40
N

O
O

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
99 156497-23-3 1-Hydroxytropacocaine E 41

100 1401623-40-2 3-(20 -Phenylpropionyloxy)-6,7- D 35b

epoxynortropane(dihydroaponorscopolamine)

101b 1401623-38-8 6,7-Dehydro-3-phenylacetoxytropane D 35a

ARTICLE IN PRESS

102b 1401623-36-6 3-Acetoxy-6,7-epoxytropane; acetylscopine D 35b

N
O

O
103 156705-04-3 Calystegine C1 HO OH M, D 42
NH
OH

OH
OH

104 190957-44-9 Calystegine C2 HO OH D 42a

NH
OH

OH
OH

105 188948-52-9 Nicotinoylecgonine methyl ester E 43

N
CO2Me
N
O
ARTICLE IN PRESS

106 188948-54-1 20 -Pyrroloylecgonine methyl ester E 43

N
CO2Me
HN
O

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
107 188948-53-0 20 -Furanoylecgonine methyl ester E 43
N
CO2Me
O
O

108 188948-51-8 30 -Furanoylecgonine methyl ester E 43

109 910295-42-0 3β-Propionyloxy-6β-hydroxytropane D 19a

ARTICLE IN PRESS

110 910295-44-2 3β-Hydroxy-6β-tigloyloxytropane D 19a

111 910295-49-7 3β-Tigloyloxy-6β-acetoxytropane D 19a

112c 438041-97-5 Anhydroecgonine methyl ester N-oxide E 44

113 821010-00-8 3α-Tropoyloxy-6β-acetoxytropane D 30b

ARTICLE IN PRESS

114 821787-78-4 3β-Tigloyloxy-6β-propionyloxy- D 30b

7β-hydroxytropane

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
115 182015-05-0 4-(6β-angeloyloxytropane-3α-yl),1-(tropane- S 24
3α-yl),2-methylenesuccinate

116 211444-30-3 Mooniine A E 45

117 211444-31-4 Mooniine B E 45

ARTICLE IN PRESS
118 1429196-01-9 Bishyoscyamine A 46
N

O N

O OH

119 1346256-66-3 Grahamine A S 47

N

O
ARTICLE IN PRESS

O O

O
N
O
HO2C
O

OH

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
120 1346256-67-4 Grahamine B S 47
N

O
O O

O
N
O
HO2C
O

OH

121 1346256-68-5 Grahamine C S 47

N
O
ARTICLE IN PRESS

O O

N O
OH
O
O O

OH
122 1346256-69-6 Grahamine D S 47
N
O
O O

N O
N
O
O
O O
OH
OH

123 1346256-70-9 Grahamine E S 47

N
O
O O

N O
N
O O

O O
ARTICLE IN PRESS

HO2C O
OH
O

124 222716-56-5 Schizanthine Z N

S 48
N
O
OH
O O
O
O
O

Continued
Table 2 Tropane alkaloids—cont’d
CAS register
Entry number Names Structure Genus References
125 222716-55-4 Schizanthine Y S 48
N N
O
OH
O O
O
O
O

a
Genus: A (Anisodus (Solanaceae)), S (Schizanthus (Solanaceae)), D (Datura (Solanaceae)), D1 (Duboisia (Solanaceae)), H (Hyoscyamus (Solanaceae)), C (Convolvulus (Convolvulaceae)),
I (Ipomoea (Convolvulaceae)), E (Erythroxylum (Erythroxylaceae)), M (Morus (Moraceae)), and M1 (Merremia (Solanaceae)).
b
The stereochemistry is postulated based on GC–MS.
c
The N-oxide oxygen can be positioned facing the five- or six-membered rings.
Genera names:
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The Chemical Synthesis and Applications of Tropane Alkaloids 43

previous edition, 203 tropane alkaloids (including 3 “invalid items”) were

included, while its precursor included 151 alkaloids.1a In this update, more than
100 new alkaloids are compiled covering the alkaloids identified during the
last 23 years.
Most of the new tropane alkaloids were discovered in the family
Solanaceae. However, these alkaloids can also be found in the plant families
Convolvulaceae, Proteaceae, and Rhizophoraceae. Only a few representa-
tives have been discovered in families corresponding Erythroxylaceae,
Apocynaceae, Brassicaceae, and Faboideae. The structures of these compounds
were elucidated based on an extensive literature search. Most of the literature
reports provided the relative or absolute stereochemistry of the compounds.
However, structures without α or β marks have not been stereochemically
defined. α-Substitution is when the substituent is below the equatorial surface
of bicyclic 8-azabicyclo[3.2.1]octane I, and β-substitution is when the substit-
uent is above the surface (Fig. 1).

3. SYNTHESIS
The construction of the bicyclic tropane skeleton has been accom-
plished by various synthetic methods. In the following sections, we describe
important examples reported since 1994. Readers with an interest in earlier
synthetic approaches should refer to the previous excellent review by
Lounasmaa and Tamminen.1 The organic synthesis section is sorted according
to the key reaction or reaction type.

3.1 Cycloaddition Reactions

Synthetic strategies using cycloaddition transformations for the synthesis of
cyclic and polycyclic skeletons are among the most efficient and direct
approaches for the construction of cyclic and polycyclic skeletons. In
this context, various cycloaddition and domino reactions have been devel-
oped for the selective synthesis of the 8-azabicyclo[3.2.1]octane skeleton.
Asymmetric induction during transition metal-promoted cycloadditions
represents a potentially effective method for the rapid assembly of
enantiomerically enriched polycyclic systems. In 1995, Rigby and Pigge
reported an asymmetric Cr(0)-mediated [6 + 2] cycloaddition between
azepine derivatives and chiral acrylate esters to construct homotropane alka-
loids.49 This transformation was also used in the total synthesis of the impor-
tant tropane alkaloid (+)-ferruginine (Scheme 1). The photocycloaddition
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44 Samson Afewerki et al.

Scheme 1 Synthesis of (+)-ferruginine ((+)-6) via an asymmetric Cr(0)-mediated [6 + 2]

cycloaddition. Reagents and conditions: (i) hν, (ii) Tl(ONO2)3  3H2O (6.0 equiv.), MeOH,
74%; (iii) LiOH (excess), MeOH/H2O, 84%; (iv) 1. ClCO2iBu (1.5 equiv.), N-methylmorpholine
(1.5 equiv.); 2. N-hydroxypyridine-2-thione, Na salt (1.8 equiv.), TEA (1.8 equiv.); 3. tBuSH
(9.9 equiv.), hν, 49%; (v) TFA, H2O/acetone; (vi) 1. MeMgBr (3.0 equiv.), Et2O; 2. LiAlH4,
Et2O; 3. Dess–Martin periodinane, CH2Cl2, 28%.

between tricarbonyl(N-(methoxycarbonyl)azepine)chromium(0) (1) and

(–)-8-phenylmenthyl acrylate (2) gave anticipated endo-adduct 3 in 58%
yield. Treatment of enantiomerically pure cycloadduct 3 with thallium trin-
itrate (TTN) in MeOH to perform an oxidative ring contraction provided
optically pure tropane 4 in excellent yield. The saponification of 4 followed
by decarboxylation afforded 5, which was further transformed into (+)-
ferruginine ((+)-6) via a series of routine functional group modifications.
In 2008, Shin and coworkers disclosed a gold-catalyzed internal redox
reaction–dipolar cycloaddition–cascade transformation for the synthesis of
azabicyclo[3.2.1]octane-containing compounds (Scheme 2).50 For example,
nitrone- and alkyne-containing precursor 7 was readily transformed into the
corresponding azabicyclo[3.2.1]octane 8 as a single diastereoisomer under
the optimized reaction conditions (2 mol% AuCl3, CH3NO2, 70°C). The
gold-catalyzed intramolecular transformation tolerated a variety of substitu-
ents on the enyne skeleton, and the corresponding azabicyclo[3.2.1]octanes
were constructed in good yields. The gold-catalyzed cascade transformation
can also be extended to an intermolecular pathway as shown by the reaction
between alkynylnitrone 9 and diethyl acetylenedicarboxylate, which gave
fused tropinone 10 in 58% yield.
In 2008, Ishii and coworkers disclosed a photochemical reaction
between bicyclic aziridines 11 and alkenes/alkynes 12 (Scheme 3).51 The
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The Chemical Synthesis and Applications of Tropane Alkaloids 45

Scheme 2 Synthesis of fused tropinones 8 and 10 via a gold-catalyzed intra- and inter-
molecular cycloaddition cascade. Reagents and conditions: (i) AuCl3 (cat.), CH3NO2,
70°C, 1 h. (ii) AuCl3 (cat.), CH3NO2, 70°C, 20 min.

Scheme 3 Ishii and coworkers’ synthesis of 8-azabicyclo[3.2.1]octane skeleton 13 via

the photoreaction of bicyclic aziridines 11 with alkenes or alkynes 12. Reagents and
conditions: hv, CH3CN, r.t. n ¼ 1 or 2, EWG ¼ CO2Me, CO2tBu, 3%–62%.

reaction has a broad scope and produces the corresponding 8-azabicyclo

[3.2.1]octane compounds 13 in good yields. The transformation involved
photochemical CdC bond cleavage of bicyclic aziridine 11 followed by
a [3 + 2] cycloaddition with electron-deficient alkenes and alkynes 12,
respectively. The authors proposed transition state I to account for
the exo-selectivity of the cycloaddition between biradical intermediate A
and electron-deficient alkenes or alkynes, which forms corresponding
exo-products 13. The stereochemical outcome of the transformation was
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46 Samson Afewerki et al.

proposed to be due to steric interactions between the exocyclic double bond

of intermediate A and the electron-deficient groups of the alkenes or
alkynes, respectively.
In 2011, Merino and coworkers disclosed a synthetic strategy based on
a consecutive nucleophilic allylation, oxidation, and intramolecular dipolar
cycloaddition reaction sequence, which afforded two new polyhydroxylated
nortropane analogues similar to calystegines in excellent yields with com-
plete stereoselectivity (Scheme 4).52 Thus, the allylation of 14 with
allylmagnesium bromide furnished hydroxylamine 15 as a single diastereo-
isomer in excellent yield. Subsequent oxidation of 15 with manganese(IV)
oxide gave nitrone 16, which was heated in toluene at 120°C to give cyclo-
adduct 17 with complete regio- and stereochemical control. The subsequent
Pd(OH)2/C-mediated NdO cleavage in acidic methanol furnished the
hydrochloride salt of corresponding amine 18 in quantitative yield.
In 2012, Wang et al. described a Lewis acid-catalyzed intramolecular
cycloaddition reaction for the synthesis of 8-azabicyclo[3.2.1]octane skele-
tons (Scheme 5).53 Treatment of compound 19 with p-anisidine (20) in the
presence of ytterbium(III) acetate followed by a gold(I)-catalyzed [4 + 2]
cycloaddition reaction gave desired azabicyclo[3.2.1]octane compound 21
in 47% yield.
Davis et al. disclosed the first synthesis of cocaine analogues having sub-
stituents at the C-1 position of the cocaine structural motif in which an
elegant intramolecular [3 + 2] cycloaddition reaction of compounds 23

Scheme 4 Synthesis of polyhydroxylated nortropane 18. Reagents and conditions:

(i) AllylMgBr (3.0 equiv.), THF, 0°C, 13 h, 98%, ds >98%; (ii) MnO2 (1.2 equiv.), CH2Cl2,
2 h, 73%; (iii) sealed tube, toluene, 120°C, 14 h, 97%; (iv) H2, Pd(OH)2/C (10%), MeOH,
HCl, 6 h (quantitative yield).

Scheme 5 Wang and coworkers’ synthesis of azabicyclo[3.2.1]octane skeleton 21.

Reagents and conditions: (i) Yb(OAc)3 (1.05 equiv.), 4 Å MS, CH3CN, 2 h, r.t.; (ii) PPh3AuCl/
AgOTf (10 mol%), (CH2Cl)2, 60–70°C, 0.5–2 h, 47%. PMP ¼ para-methoxyphenyl.
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The Chemical Synthesis and Applications of Tropane Alkaloids 47

Scheme 6 Synthesis of cocaine analogues 27 via an intramolecular [3 + 2] cycloaddition

of sulfinimine-derived pyrrolidine nitrones with an α,β-unsaturated ester side chain.
Reagents and conditions: (i) HCl (3 N), MeOH/THF, r.t., 16 h, 83%–100% yield;
(ii) MeReO3 (6.8 mol%), urea/H2O2 (3.25 equiv.), MeOH, r.t., 15 h; (iii) Al(OtBu)3 (50 mol%),
toluene, 110°C, <10%–70% yield; (iv) MeSO3Me (10 equiv.), CH2Cl2, reflux, 48–72 h,
100%; (v) Pd/C (5%), H2, MeOH, r.t, 48 h, 100% (complex mixture for R ¼ Ph); (vi) BzCl
(1.5 equiv.), pyridine, r.t., 20 h, 75%–94% yield.

serves as the key step (Scheme 6).54 Thus, deprotection of the ketal function-
ality in the α,β-unsaturated δ-amino esters 22 by HCl (3N) in THF/MeOH
with subsequent formation of the corresponding dehydropyrrolidines was
followed by a methyltrioxorhenium-catalyzed oxidation with urea hydrogen
peroxide (UHP) in one pot to give nitrones 23 (Scheme 6). Treatment
of 23 with 50 mol% of aluminum tert-butoxide gave corresponding tricyclic
isoxazolidines 24 in high yields. Next, alkylation of 24 with methyl
methanesulfonate (MeSO3Me) in dichloromethane gave quaternary ammo-
nium salts 25. Palladium on charcoal (Pd/C, 5 mol%) promoted NdO cleav-
age of 25 and furnished corresponding tropane derivatives 26. Subsequent
benzoylation constructed corresponding cocaine analogues 27 (Scheme 6).
Moreover, we developed a general strategy for the catalytic asymmetric
total synthesis of several tropane alkaloids ((+)-cocaine, ()-cocaine, (+)-
ferruginine, (+)-methylecgonine, and cocaine C-1 derivatives) using a com-
bination with catalytic enantioselective reaction sequences.55 The key steps
include a catalytic enantioselective aza-Michael–Wittig transformation (pro-
viding 31), a catalytic nitrone formation and methylation sequence (providing
of 33), a catalytic stereoselective intramolecular dipolar cycloaddition (33),
and a catalytic hydrogenation-benzoylation sequence 34 (Scheme 7). Notably,
the catalytic asymmetric synthesis of (R)-()-cocaine ((R)-()-(35)) can be
achieved from enal 28 using only two column chromatographic purification
steps. Both enantiomers of a broad range of different valuable tropane deriva-
tives could be accessed by this general strategy.
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48 Samson Afewerki et al.

Scheme 7 Asymmetric synthesis (R)-()-cocaine ((R)-()-(35)) via an intramolecular

[3 + 2] cycloaddition. Reagents and conditions: (i) 1. 4°C, 30 (20 mol%), CHCl3, 17 h;
2. Methyl 2-(triphenylphosphoranylidene)acetate (1.0 equiv.), r.t., 2 h, 70% yield, E:
Z > 20:1, 96% ee; (ii) 1. PdCl2 (10 mol%), Et3N (0.7 equiv.), Et3SiH (4.0 equiv.), CH2Cl2,
reflux, 6 h; 2. HCl (3 M)/THF (3:1), r.t., 2 h; (iii) toluene, r.t., 4 h then 150°C, 64 h; 2. MeSO3Me
(5.0 equiv.), CH2Cl2, reflux, 24 h; (iv) Pd/C (5%), H2 balloon, MeOH, r.t., 48 h; (v) PhCOCl
(2.0 equiv.), Et3N (16 equiv.), cat. DMAP, CH2Cl2, r.t., 17 h, 39% (two steps).

Scheme 8 Synthesis of indole-fused tropane derivative 40 via a [4 + 3] cycloaddition-

cyclization-elimination sequence. Reagents and conditions: (i) DMDO (3.0 equiv.), ZnCl2
(2.0 equiv.), 78°C to r.t., 4 Å MS, CH2Cl2, 50% yield; (ii) iPrMgCl–LiCl (5.0 equiv.), THF,
78°C, 30 min, 32% yield; (iii) tBuOK, CS2, THF, 0°C to r.t., 28% yield.

In 2014, Hsung and coworkers developed a [4 + 3] cycloaddition–

cyclization–elimination reaction sequence for the expeditious synthesis of
indole-fused tropane derivative 40 (Scheme 8).56 Here, N-aryl-N-
sulfonylaminoallene 36 was successfully reacted with N-Boc-protected pyr-
role 37 to afford cycloaddition adduct 38 as a single diastereomer in 50%
yield under the developed standard conditions (ZnCl2, dimethyldioxirane
(DMDO), and 4 Å MS in CH2Cl2). Next, an intramolecular Grignard
addition was accomplished by using an iPrMgClLiCl complex as the
magnesium–halogen exchange reagent to give tetracyclic alcohol 39 (63%
yield). Treatment of 39 with KOtBu and CS2 gave a desired indole-fused
tropane derivative 40.

3.2 Cyclization Reactions

In 1996, Rapoport and coworkers disclosed the asymmetric synthesis of (+)-
and ()-ferruginine via the cyclization of the iminium ion derived from the
pyrrolidine acid derivative 41 (Scheme 9).57 The stereospecific formation of
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The Chemical Synthesis and Applications of Tropane Alkaloids 49

Scheme 9 Synthesis of (+)-ferruginine ((+)-6) and ()-ferruginine (()-6). Reagents

and conditions: (i) 1. (COCl)2, 1,2-dichloroethane, 12°C to r.t., 2. Δ; (ii) H2, Pd/C
(10%), (Boc)2O (4.4 equiv.), MeOH, r.t., 3.5 h; (iii) KOH/H2O, iPrOH, 0°C to r.t., 40 min
to 3.6 h; (iv) 1. iBuO2CCl (1.5 equiv.), THF, Et3N (1.6 equiv.), 10°C, 20 min; 2.
N-hydroxypyridine-2-thione (2.1 equiv.), Et3N (2.2 equiv.), THF, r.t., 2.6 h; 3. hν, tBuSH
(11 equiv.), 2 h; (v) 1. NaH (5.3 equiv.), THF, 0°C, 14 h; 2. TBSCl (5.1 equiv.), Et3N (1.0 equiv.),
THF, 12°C to r.t., 9 h; (vi) 1. PhSeCl (1.9 equiv.), THF, 78°C, 2 h; 2. m-CPBA, 0°C, 30 min;
(vii) TFA, CH2Cl2, 3 h, r.t.; (viii) CH2O, NaBH3CN; (ix) 1. KHMDS/THF (0.94 M), 78°C, 45 min;
2. TMSCl; 3. O3, Me2S; (x) 1. LDA/THF, 78°C, 1 h; 2. PhSeCl; 3. NaIO4; (xi) KOH/H2O, iPrOH;
(xii) Et3N, isobutyl chloroformate, isoxazolidine hydrochloride, THF, CH2Cl2, 10°C;
(xiii) MeLi/Et2O (1.4 M), THF, 78°C to 0°C, 1 h.
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50 Samson Afewerki et al.

disubstituted 8-azabicyclo[3.2.1]octanes 42 and 43 was achieved by

decarbonylation–iminium ion cyclization of ketoacid 41 which was derived
from L-glutamic acid and 2-methylcyclopentanone. Bicycles 42 and 43 were
converted into (+)- and ()-ferruginine (6), respectively.
Later on, Royer and coworkers disclosed an asymmetric approach to
access (+)-ferruginine ((+)-6) employing a similar bond disconnection strat-
egy (Scheme 10).58 Treating chiral oxazolidine 58, which was obtained by a
multistep synthesis, with sulfuric acid afforded bicyclic compound 59 via an
intermolecular Mannich-type reaction. Subsequent N-deprotection by
hydrogenolysis followed by reductive amination (CH2O and NaCNBH3)
gave N-methyl derivative 60. Acid-promoted elimination of methanol gave
(+)-ferruginine 6.
Ikeda et al. developed an elegant Bu3SnH-mediated radical transloca-
tion/cyclization approach to construct 8-azabicyclo[3.2.1]octane skeletons
(Scheme 11a).59 Thus, treatment of 1-o-bromobenzoylpyrrolidine 61 with

Scheme 10 Synthesis of (+)-ferruginine via the conversion of an α,β-unsaturated ketone

onto a potential iminium system. Reagents and conditions: (i) H2SO4, MeOH, 60°C, 84%;
(ii) 1. H2/Pd(OH)2; 2. CH2O, NaBH3CN or CH2O, H2/Pd(OH)2, 62% and 73%, respectively;
(iii) p-TsOH, C6H6, 68%.

Scheme 11 (A) Construction of 8-azabicyclo[3.2.1]octane skeleton 63. Reagents and

conditions: (i) Bu3SnH, AIBN, toluene, reflux. (B) Construction of 8-azabicyclo[3.2.1]octane
skeleton 67. Reagents and conditions: (i) Bu3SnH, AIBN, toluene, reflux; (ii) p-TsOH,
CH3CN; (iii) OsO4, NaIO4.
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The Chemical Synthesis and Applications of Tropane Alkaloids 51

Bu3SnH in the presence of azobisisobutyronitrile (AIBN) gave a mixture

of 7-azabicyclo[2.2.1]heptane 62 (42% yield, 2:1 dr) and 8-azabicyclo
[3.2.1]octane 63 (30% yield). The radical-based transformation occurs via
1,5-hydrogen transfer of intermediate I providing the cyclic radical inter-
mediate II. Moreover, the same group reported that upon treatment with
tributyltin hydride in the presence of AIBN in boiling toluene of but-
ynylpyrrolidine 64 gave 8-azabicyclo[3.2.1]octane 65 with high regioselectivity.
Treatment of compound 65 with p-toluenesulfonic acid (p-TsOH) gave
8-azabicyclo[3.2.1]nonane 66, which was next converted to ketone 67 by a
Lemieux–Johnson oxidation (OsO4 and NaIO4, Scheme 11b).
Cook et al. employed D-(+)-tryptophan methyl ester 68 as a starting
material to prepare the tropane skeleton (Scheme 12).60,61 Under standard
conditions for an aprotic Pictet–Spengler reaction with tryptophan methyl
ester 68, δ-lactam 70 and diester 69 were obtained when different aprotic
acids were used. The Dieckmann cyclization of compounds 69 or 70 gave
71 with an 8-azabicyclo[3.3.1]octane skeleton, which underwent an acid-
mediated decarboxylation reaction to give ketone 72. The same group also

Scheme 12 Synthesis of compound 74 with a tropane skeleton via a Pictet–Spengler

reaction. Reagents and conditions: (i) (CH3O)2CH(CH2)2CO2Me or OHCCH2CH2CO2Me,
TFA, CH2Cl2, r.t., 72 h, 92%; (ii) α-ketoglutaric acid, PhH/dioxane, reflux, 48 h, p-TsOH,
DST (Dean–Stark trap), 86%, trans/cis ¼ 4/1; (iii) NaH (8 equiv.), MeOH, toluene, reflux;
(iv) HOAc, HCl, H2O, reflux, 8 h or KOH, dioxane, H2O, reflux, 8 h, 90%; (v) HCl (5%), EtOH,
H2, Pd/C, 88%; (vi) 1. tBuOCl/Et3N, CH2Cl2, r.t., 5 h; 2. HOAc/MeOH, reflux, 2 h, 80%.
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52 Samson Afewerki et al.

developed a convenient method to access several oxindole alkaloids includ-

ing the 8-azabicyclo[3.2.1]octane skeleton 74 on the basis of compound 71.
In 2004, Pearson and Mans reported the first use of an intramolecular
proline-catalyzed aldol reaction for the desymmetrization of dialdehydes
to generate aza-bridged bicyclic structures (Scheme 13),62 which finally
enabled an efficient total synthesis of (+)-cocaine. Here, meso-dialdehyde
75 underwent an intramolecular proline-catalyzed aldolization reaction
providing a 1:1 mixture of crude aldol products (2R)-76 and (2S)-76.
The group determined that the use of toluene as the solvent was essential
for generating compound 76. Crude aldol products (2R)-76 and (2S)-76
were converted to the corresponding methyl esters via oxidation to the acids
followed by esterification to provide β-hydroxy esters (2R)-77 and (2S)-77.
After benzoylation with benzoic anhydride and DMAP, tropane compound
(2S)-78 underwent Boc-deprotection followed by reductive amination to
provide (+)-cocaine (35).
In 2008, Martin and coworkers demonstrated the first application of
the Pauson–Khand reaction (PKR) for the synthesis of aza-bridged bicyclic
structures, which can be used for the construction of an azabicyclo[3.2.1]
octane ring fused to a cyclopentenone (Scheme 14).63 In this context, cis-
2,6-disubstituted piperidine 79 gave cyclopentenone-fused tropinone 80
as a mixture of diastereomers (3:1).
In 2009, Davis et al. reported a method for the asymmetric synthesis of
substituted tropinones by using an intramolecular Mannich reaction
(Scheme 15).64 Treatment of compound (SS, S)-(+)-81 with 3 N HCl/
MeOH in THF furnished pyrrolidine ()-(S)-82 in 66% yield. When
(S)-()-82 was treated with (Boc)2O/DMAP (cat.), the Mannich cyclization
provided tropinone (+)-83 in excellent yield. In a similar process, tropinone
(+)-86 was prepared as single isomer in 60% yield.

Scheme 13 Synthesis of (+)-cocaine via an intramolecular proline-catalyzed aldol reac-

tion. Reagents and conditions: (i) (S)-proline, PhCH3, r.t., 24 h; (ii) 1. NaClO2; 2. CH2N2, 76%
from 75; (iii) (PhCO)2O, DMAP, 60%; (iv) 1. TFA; 2. CH2O, NaBH3CN, 74% from (2S)-78.
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The Chemical Synthesis and Applications of Tropane Alkaloids 53

Scheme 14 Synthesis of cyclopentenone-fused tropinone 80 via a Pauson–Khand reac-

tion. Reagents and conditions: Co2(CO)8, DMSO, THF, 65°C, 33%.

Scheme 15 Synthesis of substituted tropinone 86 via a Mannich cyclization. Reagents

and conditions: (i) HCl (aq.), MeOH, THF; (ii) (Boc)2O, DMAP (cat.), CH2Cl2, r.t., 3 h, 60%.

In 2011, Huang and coworkers developed a highly diastereoselective

approach for the construction of a hydroxylated tropane skeleton65 88
and 89 from aldehyde 87 via a BH3OEt2/SmI2-mediated aza-pinacol cycli-
zation strategy (Scheme 16). On the basis of this, the enantioselective total
synthesis of ()-Bao Gong Teng A (90) was accomplished.
In 2012, Davies and coworkers developed a ring-closing iodoamination
for the synthesis of substituted 8-azabicyclo[3.2.1]octanes66 from enantiopure
cyclohept-4-enamine scaffolds, which enabled the rapid asymmetric synthesis
of (+)-pseudococaine (96) (Scheme 17). Treatment of 91 with I2 in CH2Cl2
gave a mixture of 92 and C(4)-iodo-substituted 8-azabicyclo[3.2.1]octane 93,
which was immediately subjected to reduction with Bu3SnH to provide 94
in 78% yield (from 91). Transesterification of 94 with SOCl2 in MeOH
gave 95 in 55% isolated yield and >99:1 dr. Subsequent benzoylation and
treatment with HCl in MeOH gave corresponding (+)-pseudococaine
hydrochloride (96).
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54 Samson Afewerki et al.

Scheme 16 Total synthesis of ()-Bao Gong Teng A (90). Reagents and conditions:
(i) BH3OEt2, SmI2, tBuOH, THF, 50°C, 56% and 5%, respectively; (ii) TMSOTf, 2,6-
lutidine, TBAF, THF.

Scheme 17 Synthesis of (+)-pseudococaine through a ring-closing iodoamination.

Reagents and conditions: (i) I2, CH2Cl2, 12 h; (ii) Bu3SnH, AIBN, toluene/MeOH, 80°C,
5 h; (iii) SOCl2, MeOH, 50°C, 5 h; (iv) PhCOCl, DMAP, Et3N, CH2Cl2, 12 h, then HCl, MeOH.

In 2013, the Huang group reported a halide-promoted cyclization to

construct functionalized 8-azabicyclo[3.2.1]octanes (Scheme 18).67,68 Treat-
ment of lactam 97 with TBSOTf and NEt3 gave corresponding silyl vinyl
ether 98, which was subsequently treated with Tf2O, 2,6-di-tert-butyl-4-
methylpyridine (DTBMP), and ZnCl2 to furnish ()-99. Further, radical
dechlorination of 99 gave (+)-(1R,5R,6S)-100, which underwent
stereoselective hydrogenation, desilylation, and esterification of the resulting
3α,6β-dihydroxytropane to give ester 101 in 90% overall yield. Further ester-
ification of (+)-101 furnished the unnatural (+)-pervilleine B (102) in 94% yield.
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The Chemical Synthesis and Applications of Tropane Alkaloids 55

Scheme 18 Huang and coworker’s preparation of (1R,5R,6S)-tropan-3-one derivatives

and synthesis of (+)-(1S,3S,5R,6S)-pervilleine B. Reagents and conditions:
(i) TBDMSOTf, Et3N, CH2Cl2, 0°C; (ii) Tf2O, DTBMP, CH2Cl2, ZnCl2, 78°C to r.t.; (iii) 1,10 -
azobis(cyclohexanecarbonitrile) (ACCN), Bu3SnH, toluene, 85°C; (iv) 1. PtO2, H2, EtOH;
2. p-TsOH, acetone, 50°C; 3. TmcCl, Et3N, toluene, reflux; (v) TmbCl, Et3N, DMAP, toluene,
reflux. Tmb ¼ 3,4,5-trimethoxybenzoyl, Tmc ¼ 3,4,5-trimethoxycinnamoyl.

Scheme 19 Tropane ring system construction via a chiral Rh-BINAP-catalyzed

enantiospecific isomerization. Reagents and conditions: (i) tBuMe2SiCl, imidazole,
DMF, 86%; (ii) [Rh{(R)-BINAP}(cod)]+ ClO4, 1,2-dichloroethane, reflux, 24 h, then TBAF,
THF, 0°C; (iii) HF–MeCN (1:19), 96%; (iv) MsCl pyridine, 0°C to r.t.; (v) MeNH2–MeOH
(40% aq.), r.t., 57%.

3.3 Metal-Catalyzed Reactions

In 1995, Ogasawara and coworkers69 reported a chiral Rh-BINAP-
catalyzed enantiospecific isomerization to construct the tropane ring system
(Scheme 19). The desymmetrization of cis-3,7-bis(tert-butyldimethylsilyloxy)
cycloheptene (104) in the presence of 2 mol% of the chiral Rh catalyst
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56 Samson Afewerki et al.

[Rh{(R)-BINAP}(cod)]+ C1O4 (cod ¼ cycloocta-1,5-diene) gave a mixture

(ca. 4:1) of silyl vinyl ether 105 and siloxy ketone 106, which was exposed
to tetrabutylammonium fluoride (TBAF) to afford only ketone 106 in 96%
yield. Further treatment of 106 with hydrofluoric acid gave the corresponding
(S)-4-hydroxycycloheptenone (107a), which was transformed into mesylate
108. Upon treatment with aqueous methanolic methylamine, 108 furnished
()-(S)-physoperuvine (109). Compounds such as 107a and 109 are in equi-
librium with unstable bicyclo[3.2.1]octane structures due to intramolecular
hemiacetal or hemiaminal formation, respectively.
In 1997, Ham and coworkers developed a palladium-catalyzed intramolec-
ular aminocarbonylation to prepare the tropane skeleton (Scheme 20).70
4-Cycloheptenone (110) was treated with hydroxylamine to afford the
corresponding oxime, which was reduced with LiAlH4, and the corresponding
amine was protected with methyl chloroformate to afford carbamate 111.
The intramolecular aminocarbonylation of 111 gave corresponding bicyclic
methyl ester 112 using catalytic amounts of palladium(II) chloride, copper(II)
chloride as an oxidant, and carbon monoxide (1 atm.) in methanol. Compound
112 was converted to bicyclic compound 113, which is a key precursor in
the synthesis of (+)-ferruginine (6), by deprotection with HBr-HOAc (30%)
and subsequent protection with (Boc)2O.35
In 2011, Wolfe and coworkers developed a new method for the
synthesis of enantiomerically enriched benzo-fused tropane analogues via
an intramolecular Pd-catalyzed alkene carboamination reaction (Scheme
21).71 In this protocol, the Pd-catalyzed carboamination reactions of a range
of γ-aminoalkene substrates 117, which contain a 2-bromoaryl (or
2-bromoalkenyl) group adjacent to the amino moiety, could generate two
bonds and one or two stereogenic centers in a controlled fashion and
provided various benzo- or cycloalkenyl-fused tropane derivatives 118,
respectively. The required enantioenriched substrates 117 were readily
prepared in four steps from accessible o-bromobenzaldehydes or β-bromo-α,

Scheme 20 Synthesis of key precursor 113, a precursor of (+)-ferruginine 6. Reagents

and conditions: (i) NH2OH  HCl, Na2CO3, MeOH, reflux, 85%; (ii) LiAlH4, THF, reflux, 89%;
(iii) CH3OCOCl, CH2Cl2, 0°C, 39%; (iv) cat. PdCl2, CuCl2, CO, MeOH, 49%; (v) aqueous HBr
(30%), HOAc; (vi) (Boc)2O, dioxane, r.t., 69% from 112.
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The Chemical Synthesis and Applications of Tropane Alkaloids 57

Scheme 21 Pd-catalyzed intramolecular alkene carboamination for the synthesis of

fused tropanes and the synthesis of NMDA antagonist 116. Reagents and conditions:
(i) Pd2(dba)3, PCy3  HBF4, NaOtBu, toluene, 95°C; (ii) Pd2(dba)3, S-Phos, NaOtBu, 100°C;
(iii) ceric ammonium nitrate (CAN), MeCN (aq.).

Scheme 22 Application of an allylic amination/Grubbs ring-closing metathesis (RCM)

sequence to the synthesis of a tropane derivative 122. Reagents and conditions:
(i) [Ir(cod)Cl]2, 1,2-dichloroethane, 0°C to r.t., 67%; (ii) Grubbs’ second-generation
catalyst, toluene, 120°C or xylene, 150°C, 29% and 34%, respectively.

β-unsaturated aldehydes. The synthetic utility of this method was further

demonstrated by the total synthesis of MK-801 analogue 116, which exhibits
modest N-methyl-D-aspartate (NMDA) receptor antagonist activity.72,73
Later, Brawn et al. reported an approach to prepare tropane derivatives
through an iridium-catalyzed bis-allylic amination/Grubbs ring-closing
metathesis (RCM) sequence.74 Bisimidates 119 underwent iridium(I)-
catalyzed cyclization with cumylamine to form piperidine 121 (Scheme 22).
Treatment of diene 121 with Grubbs’ second-generation catalyst gave tropane
derivative 122.
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58 Samson Afewerki et al.

3.4 Cascade Reactions

In 2002, Nicolaou et al. found that the IBX-mediated dehydrogenation of
carbonyl compounds was general and could be tuned to afford products in
different oxidation states. Based on this, they developed a cascade transfor-
mation to prepare tropinone (124) in one pot by employing cycloheptanol
(123) as a starting material (Scheme 23).75 Treatment of cycloheptanol (123)
with IBX followed by the sequential addition of K2CO3 and methylamine
hydrochloride furnished tropinone (124) in 58% yield.
Hanna and coworkers developed a three-step zinc-mediated reductive
ring opening–imine formation–allylation reaction sequence as a key step
for the synthesis of (+)-calystegine B2 (131).76,77 Final product 131 could
be obtained in 25% overall yield in six steps starting from 125 (Scheme 24).
Davies and coworkers have previously developed a rhodium(II)-catalyzed
tandem cyclopropanation–Cope rearrangement (TCCR) between vin-
ylcarbenoids and pyrroles for the racemic synthesis of tropanes, which was
mentioned in the previous chapter of this series.1 In 1997, the same group
reported the asymmetric version of this tandem sequence to access
enantiomerically enriched tropanes by using either a chiral rhodium catalyst
or a chiral auxiliary on the vinylcarbenoid (Scheme 25).78 Diastereoselective
induction was best achieved in these transformations of compounds 136a–d
when using (S)-lactate or (R)-pantolactone as a chiral auxiliary on
vinyldiazomethanes 132 or 133, respectively (Scheme 25a and b), while only
moderate asymmetric induction was obtained for compound 136e along
with the formation of isomeric azabicyclooctane side products when the

Scheme 23 Nicolaou and coworkers’ one-pot total synthesis of tropinone 124 from
cycloheptanol 123. Reagents and conditions: IBX (4.0 equiv.), DMSO, 25–85°C, 22 h,
cooled to 25°C, K2CO3 addition followed by MeNH3+ Cl, 3 h, 58%.
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The Chemical Synthesis and Applications of Tropane Alkaloids 59

Scheme 24 Triple domino reaction as a key step for the synthesis of (+)-calystegine B2
(131). Reagents and conditions: (i) Zn, THF, sonication, BnNH2, then allyl bromide,
dr ¼ 85:15, combined 73% yield; (ii) CbzCl, NaHCO3, AcOEt, 94% yield; (iii) Grubbs’ cat-
alyst (7.7%), CH2Cl2, r.t., 4.5 h, 97% yield; (iv) 1. BH3SMe2, Et2O, 30°C to 0°C, 18 h. 2.
H2O2 (30%), NaOH (2 N), 3 h, 128/129 ¼ 2.6:1, 84% combined yield; (v) PCC, CH2Cl2,
93%; (vi) 1. Pd/C (10%), H2, AcOH/H2O, 96 h; 2. NH4OH, 79%.

reaction was carried out with the chiral catalyst tetrakis-[N-(4-tert-

butylbenzenesulfonyl)-L-prolinato]dirhodium [Rh2(S-TBSP)4] (Scheme
25c). Later, the authors found that the asymmetric rhodium(II)-catalyzed tan-
dem reaction between 2-(siloxy)vinyldiazoacetate 134 and pyrrole 135 can be
improved to give tropane 136f in good yield with 92% ee using
Rh2(S-PTAD)4 as the catalyst (Scheme 25c).79 Above enantiomerically
enriched tropane products can be readily converted to several tropane alkaloids
such as ()-ferruginine ()-(6) using well-known procedures. In 2016, Opatz
and coworkers employed this method for the synthesis of 6,7-dehydrotropine
and subsequently used it as a key intermediate in the total synthesis of
scopolamine.80

3.5 Miscellaneous Reactions

In 1999, Pollini et al. reported that ()-quinic acid (137), a ubiquitous plant
metabolite featuring a cyclohexane skeleton, can serve as a chiral building
block for the enantioselective preparation of tropan-6α-ol (141) in a multistep
synthesis (Scheme 26).81 Reduction of the azido group of azidosulfate 138,
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60 Samson Afewerki et al.

Scheme 25 Rhodium(II)-catalyzed asymmetric tandem cyclopropanation/Cope

rearrangement (TCCR). Reagents and conditions: (i) Rh2(OOct)4 (1 mol%), hexane, reflux;
(ii) cat. I or cat. II (1 mol%), pentane or 2,2-dimethylbutane, 50°C; Oct ¼ octanoyl.

Scheme 26 Synthesis of tropane-6α-ol 141 from ()-quinic acid()-(137). Reagents

and conditions: (i) H2, 40 psi, Pd/C (10%), THF–H2O, 60°C, 1 h; (ii) dioxane, H2SO4,
H2O, 60°C, 1 h; (iii) ClCO2Et, K2CO3, r.t., 5 h; (iv) LiAlH4, THF, reflux 1 h.
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The Chemical Synthesis and Applications of Tropane Alkaloids 61

Scheme 27 Stereoselective synthesis of a tropane skeleton from a D-pipecolinic acid

derivative. Reagents and conditions: (i) NaHMDS, THF, 78°C to r.t., 86%, >99% ee;
(ii) NaOH, MeOH, 60°C.

Scheme 28 Synthesis of compound 148 with a polyhydroxylated nortropane skeleton.

Reagents and conditions: (i) TFA, CH2Cl2, 0°C, 30min; (ii) NaOH, pH 11, combined 65% yield.

which was prepared from ()-quinic acid in 18 steps, afforded the

corresponding amino derivative, which underwent internal displacement
to give inner salt 139. Treatment of salt 139 with ethyl chloroformate pro-
duced N-protected 8-azabicyclo[3.2.1]octane derivative 140, which was
converted into optically pure tropan-6α-ol (141) by reduction with LiAlH4.
In 2008, Onomura et al. reported the synthesis of enantiomerically pure
bicyclic proline derivative 145 containing a tropane skeleton (Scheme 27).82
The synthesis started with a cis-selective allylation of D-pipecolinic acid
derivative 142 followed by diastereospecific intramolecular alkylation.
The electrochemical methoxylation of D-pipecolinic acid derivative 142
gave 6-methoxypipecolinate, which was allylated with allyltrimethylsilane
using a catalytic amount of BF3OEt2 to give diastereomerically enriched
6-allylated pipecolinate. The transformation of the 6-allyl group into a
tosyloxyethyl group was carried out by an ozonolysis, NaBH4 reduction,
and tosylation sequence to give 143. Next, base-catalyzed intramolecular
alkylation of compound 143 gave corresponding enantiomerically pure
8-azabicyclo[3.2.1]octane skeleton 144. Alkaline hydrolysis of ester 144
completed the synthesis of bicyclic amino acid derivative 145.
Desvergnes, Landais, and coworkers demonstrated that silyl-calystegine
148, which possesses a polyhydroxylated nortropane skeleton, can be
prepared from ketone 147 by removal of the Boc-protecting group
with trifluoroacetic acid resulting in intramolecular hemiaminal for-
mation (Scheme 28).83 Starting ketone 147 was prepared from (phe-
nyldimethylsilyl)methylcycloheptatriene 146 in six steps.
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62 Samson Afewerki et al.

4. REACTIONS
4.1 Ring-Opening Transformations
Olivo et al. reported a ring-opening transformation of tropinone derivatives
via an ionic hydrogenation.84 For example, tertiary alcohol 149, derived
from tropinone, was subjected to ionic hydrogenation conditions
(triethylsilane–trifluoroacetic acid) and pyrrolidine derivative 151 was
obtained via intermediates 150a and 150b (Scheme 29). Pyrrolidine 151
was demonstrated to be a useful intermediate for the synthesis of pyrrolidine
analogues such as 152 on the way to epibatidine (Scheme 29).

4.2 Mo-Catalyzed Asymmetric Ring-Opening/Cross-Metathesis

Hoveyda, Schrock, and coworkers disclosed an elegant Mo-catalyzed
asymmetric ring-opening/cross-metathesis (AROM/CM) of unsaturated
tropane derivatives for the synthesis of functionalized 2,6-disubstituted
piperidines with >98% E-selectivity and up to 98% ee (Scheme 30).85 Chiral

Scheme 29 Ring-opening transformation of tropinone derivatives via ionic hydrogena-

tion. Reagents and conditions: Et3SiH/TFA (1:5), 80°C, 8 h.

Scheme 30 Catalytic enantioselective synthesis of functionalized piperidines via an

AROM/CM. Reagents and conditions: 155 (5 mol%), C6H6, 22°C, 95%, 94% ee.
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The Chemical Synthesis and Applications of Tropane Alkaloids 63

adamantylimido complex 155 proved to be the optimal catalyst to promote

the AROM/CM of a range of unsaturated tropinone derivatives.

4.3 Alkylation and Acylation

Willand and coworkers developed a new strategy for the preparations of
N-substituted nortropinone derivatives starting from tropinone (124)
(Scheme 31).86 The synthesis starts with the preparation of 8,8-
dimethyl-3-oxo-8-azonia-bicyclo[3.2.1]octane iodide (IDABO) (157),
which is a stable synthetic equivalent of cyclohepta-2,6-dienone, in 94%
yield on a large scale (5–100 g) by reacting iodomethane with tropinone
(124) in acetone. The elimination of dimethylamine followed by the addi-
tion of a primary amine afforded corresponding tropinone derivatives 158
(Scheme 31). In 2015, Saito and coworkers disclosed a novel approach
for the N-methylation of amines with methanol at room temperature using
a silver-containing titanium dioxide (Ag/TiO2) photocatalyst and irradia-
tion with UV–vis light.87 Notably, N-methyltropinone 158 (R ¼ H) can
also be prepared in 84% yield from tropinone 158 using this method.
The N-demethylation and N-acylation reactions of morphine- and
tropane-type alkaloids have been extensively studied. In this context,
Hudlicky and coworkers developed a palladium(II) acetate-catalyzed
one-pot N-demethylation/N-acylation protocol for the conversion of
hydrocodone into various N-acyl derivatives, and this method is also appli-
cable to tropane alkaloids (Scheme 32).88 For example, treatment of tropane

Scheme 31 One-step synthesis of nortropinone analogues starting from IDABO.

Reagents and conditions: (i) MeI, acetone, r.t., 94%; (ii) NH2R, K2CO3, H2O, EtOH, reflux,
up to 80%.

Scheme 32 N-Acetylation of tropane alkaloids. Reagents and conditions: cat. Pd(OAc)2,

Ac2O, neat, 80°C, 14 h or cat. Pd(OAc)2, Ac2O, C6H6, 80°C, 60 h.
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64 Samson Afewerki et al.

derivatives with catalytic amounts of palladium(II) acetate in the presence of

acetic anhydride furnished N-acetylnortropane derivative (160). In addi-
tion, Hoff and coworkers reported the synthesis of [phenyl-13C6]-labeled
derivatives of cocaine, benzoylecgonine, norcocaine, and cocaethylene
from the esterification of the corresponding natural tropane alkaloids and
[phenyl-13C6]-benzoyl chloride.89 The synthesized 13C-labeled compounds
can be regarded as reference samples of the active molecules and their metab-
olites, which are useful for identification and quantification studies involving
mass spectrometric techniques.
Hou and coworkers reported an elegant transformation of bicyclo-
[3.2.1]-3-ones 161 to stereogenic tropane and nortropane-3-one alka-
loids.90 Palladium-catalyzed asymmetric allylic alkylation was used for the
desymmetrization of compounds 161 to form optically active tropane deriv-
atives 164 in good yields and high drs and ees (Scheme 33).
Functionalized synthetic tropanes containing various substituents are
often of pharmacological interest. A general approach for their efficient syn-
thesis has been disclosed by Majewski and Lazny. Their method is based on
the enantioselective deprotonation of a commercially available tropinone
(8-methyl-8-azabicyclo[3.2.1]octan-3-one, 124) followed by aldol or
alkylation to give the corresponding α-substituted tropane derivatives.91
Moreover, Lazny and coworkers reported that the α-alkylation of N,N-
dimethylhydrazone 165 of tropinone promoted high endo-selectivity by
using n-butyllithium and alkyl halides (Scheme 34).92 Subsequent acidic
hydrazone cleavage of corresponding alkyl hydrazones 166 provided various
α-alkyltropinones 167.
The same group recently found that direct aldol reactions between
tropinone 124 and aromatic aldehydes were promoted by the presence of
water (Scheme 35).93 This is a simple, economical, and scalable method
for the synthesis of valuable tropinone analogues 169.

Scheme 33 Desymmetrization of 8-azabicyclo[3.2.1]octane-3-ones 161 via a

Pd-catalyzed allylic alkylation. Reagents and conditions: LiHMDS (2.0 equiv.), 0°C, THF;
(ii) [Pd(η3-C3H5)Cl]2 (2.5 mol%), 163 (5 mol%), LiCl (4.0 equiv.), 0°C, 162.
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The Chemical Synthesis and Applications of Tropane Alkaloids 65

Scheme 34 Alkylation of tropinone from N,N-dimethylhydrazones. Reagents and con-

ditions: (i) Me2NNH2, p-TsOH; (ii) nBuLi or LDA or 168, next RX, 0°C to r.t.; (iii) 50°C, 20 h,
TFA–H2O–THF (v/v/v 2:1:7). RX ¼ BnBr, MeI, nPrI, iPrI, allyl bromide, pentyl iodide, heptyl
iodide, or p-MeOC6H4CH2Cl.

Scheme 35 Preparation of exo,anti- and exo,syn-aldols products 169 of tropinone (124).

Reagents and conditions: R1CHO, H2O, r.t. R1 ¼ Ph (a), p-NO2-C6H4 (b), p-F-C6H4 (c),
p-Cl-C6H4 (d), p-CF3-C6H4 (e), m-MeO-C6H4 (f), and α-naphthyl (g).

Scheme 36 Synthesis of tropinone-derived alkenyl nonaflate and its synthetic applica-

tions. Reagents and conditions: (i) LDA, THF, NfF, 78°C to r.t.; (ii) dibenzo-18-crown-6,
KF, NfF, THF, r.t.; (iii) alkene, Pd(OAc)2, LiCl, Et3N, DMF; (iv) Pd(OAc)2, PPh3, CuI, DMF,
(iPr)2NH, r.t., phenylacetylene. EWG: CO2Me, CN, SO2Ph.

Reissig and coworkers disclosed that the employment of tropinone-

derived alkenyl nonaflates (nonafluorobutanesulfonates, 172) in the
palladium-catalyzed reaction leads to the diversity-oriented syntheses of
interesting compounds containing the 8-azabicyclo[3.2.1]octane scaffold
(Scheme 36).94 Nonaflate 172, which was either prepared by LDA
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66 Samson Afewerki et al.

treatment of ketone 170 followed by trapping with NfF (non-

afluorobutanesulfonyl fluoride) or generated in situ by the fluoride-catalyzed
reaction of silyl vinyl ether 171 with NfF, underwent Heck and Sonogashira
reactions to give corresponding 1,3-diene 173 and enyne 174 in good yields,
respectively. Alternatively, the one-pot Heck protocol starting from silyl
vinyl ether 171 has been demonstrated to provide 173 and 174 in good
yields. It should be noted that the corresponding N-methyl analogue of
172 derived from 124 is an unstable substrate for Heck reactions.

4.4 Rearrangement
Bai and coworkers have developed a novel approach to prepare the
7-azabicyclo[2.2.1]heptane ring systems from tropinone (124) by contraction
of the tropinone skeleton via a Favorskii rearrangement (Scheme 37).95,96
Tropinone (124) was converted to N-(ethoxycarbonyl)nortropinone 170
by treatment with ethyl chloroformate. Subsequently, the monobrominated
compound 175 was obtained after treatment of 170 with copper(II) bromide,
followed by a Favorskii rearrangement using sodium methoxide to give
7-azabicyclo[2.2.1]heptane 176 in good yield. Compound 176 is a key
intermediate in the synthesis of ()-epibatidine (()-177).
During the synthesis of 6- and 7-hydroxy-substituted 3-aryl-2-
(methoxycarbonyl)tropanes, which can function as dopamine transporter
inhibitors, Meltzer et al. reported a ring-opening rearrangement of

Scheme 37 Synthesis of 7-azabicyclo[2.2.1]heptane ring system from tropinone 124 via

a Favorskii rearrangement. Reagents and conditions: (i) ClCO2Et (2 equiv.), K2CO3 (cat.),
toluene, reflux, 3 h, 86%; (ii) CuBr2 (2 equiv.), CHCl3, EtOAc, reflux, 1 h; (iii) NaOMe
(3 equiv.), DME, r.t., 30 min.
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The Chemical Synthesis and Applications of Tropane Alkaloids 67

Scheme 38 Ring-opening rearrangement of 6β-hydroxytropinone 178. Reagents and

conditions: MOMCl, iPr2NEt.

6β-hydroxytropinone (178), which resulted in the formation of bicyclic

oxazolidine 179 (Scheme 38).97 Treatment of 6β-hydroxytropinone
(178) with chloromethyl methyl ether (MOMCl) in the presence of
ethyldiisopropylethylamine led to ring opening and formation of bicyclic
oxazolidine 179 instead of anticipated tropinone 180. As possible mecha-
nism was proposed in which initial alkylation of tropinone 178 with
MOMCl at the preferred equatorial position resulted in the formation of
181, subsequent intramolecular attack of the hydroxy group on the hem-
iaminal group formed intermediate oxazolidinium compound 182, which
then undergoes ring opening upon deprotonation at C-4 to give oxazolidine
179. Moreover, B€ackvall and coworkers disclosed the total synthesis of race-
mic ferruginine (6) by a BF3-induced rearrangement of an N-protected
cyclohexane aziridino cyclopropane derivatives.98
In 2015, Altundas and coworkers demonstrated that a protected
tropinone derivative 184 with an alkenenitrile moiety can undergo a con-
jugate addition–Claisen rearrangement–tandem process to afford functionalized
tropinones 186 bearing a quaternary stereocenter (Scheme 39).99 Attempts to
prepare 184 via bromo ketone 183 failed. However, 184 was elegantly prepared
from 170 via a chloroformylation, aldoxime formation, and dehydration reac-
tion sequence. Next, compound 184 was treated with a mixture of propargylic
alcohol, NaH, and 15-crown-5 ether in THF to give intermediate 185a, and
subsequent direct thermolysis afforded tropinone 186a in 62% yield.
A similar reaction sequence of 184 with propargylic alcohol gave allenyl
tropinone 186b in 51% yield as a single diastereomer.
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68 Samson Afewerki et al.

Scheme 39 Synthesis of functionalized tropinones 186, bearing a quaternary center,

via a conjugate addition–Claisen rearrangement–tandem process. Reagents and condi-
tions: (i) 1. DMF, POCl3, 0–50°C; 2. NH2OHHCl, 50°C; (ii) 2-methylprop-2-en-1-ol or but-3-
yn-2-ol, respectively, NaH, 15-crown-5, toluene, 0°C; (iii) toluene, 110°C.

Scheme 40 Synthesis of ()-erycibelline (190) via a SmI2-induced intramolecular reduc-

tive coupling. Reagents and conditions: (i) SmI2 (0.1 M, 2 equiv.), tBuOH, THF, 78°C,
10 min; (ii) Pd/C (10%), H2, MeOH, HCl (6 N), 2 h, r.t.; (iii) Fe/Cu(OAc)2/HOAc, r.t., 87% yield,
six steps.

4.5 Intramolecular Reductive Coupling

Yu et al. devised a protocol for the stereoselective synthesis of
()-erycibelline (190) via an intramolecular reductive coupling as a key step
(Scheme 40).100 The reductive coupling of compound 187, which proceeds
via intermediate III, was promoted by SmI2, resulting in the sole diastereo-
isomer 188 as a single diastereomer. Furthermore, the group noticed the
importance of having tBuOH as an additive. In fact, the reaction did not
proceed without an additive that could function as a proton source. Subse-
quent Pd-catalyzed deprotection and Fe/Cu(OAc)2/HOAc treatment pro-
vided ()-erycibelline (190) in high yield (Scheme 40).
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The Chemical Synthesis and Applications of Tropane Alkaloids 69

5. SYNTHESIS AND APPLICATIONS

5.1 Applications as Catalysts and Ligands
Bicyclic compounds based on the 8-azabicyclo[3.2.1]octane scaffold
have been found to be useful catalysts for several asymmetric reactions.
For example, Onomura and coworkers reported that enantiomerically pure
azabicyclo-N-oxyls 193, which were prepared from tropane 191, can medi-
ate in the enantioselective electrooxidation of racemic sec-alcohols to afford
optically active sec-alcohols (Scheme 41).101
Laschat and coworkers developed a class of novel BINOL-containing
tropanes, which were accessible from enantiopure (6S)-tropinone acetals,
and applied them in Cu-catalyzed enantioselective conjugate additions of
organozinc reagents to afford α,β-unsaturated carbonyl compounds
(Scheme 42).102 When applied to Cu-catalyzed 1,4-additions of dialkylzinc
reagents to generate enones 197, bidentate phosphoramidite (S,S)-199,
bearing two (S)-binaphthol units, provided high enantioselectivity in most
cases (up to 90% ee). In addition, (S,S)-199 also proved to be superior to the
other investigated ligands for the Rh-catalyzed hydrogenations of dimethyl
itaconate 200 and methyl acetamidocinnamate 202 (85% ee and 95% ee,

Scheme 41 Synthesis of azabicyclo-N-oxyls 193 and kinetic resolution of sec-alcohols

194 catalyzed by an electrooxidation in the presence of 193. Reagents and conditions:
(i) DIPEA, DMAP, acyl chloride, CH2Cl2, 50°C, 12 h; (ii) TMS-I, CH2Cl2, r.t., 12 h; (iii) m-CPBA,
CH2Cl2, r.t., 3 h; (iv) 193 (0.05–0.5 equiv.), NaBr (4 equiv.), Pt(+)–Pt(), 1.5 F/mol, 20 mA,
NaHCO3 (sat. aq.)/CH2Cl2 0°C. PG (protecting group) ¼ acetyl, pivaloyl, benzoyl, 3,5-
dimethylbenzoyl, 2-phenylbenzoyl, 1-naphthoyl, 1-(2-methylnaphthoyl), 2-naphthoyl,
tosyl, and phenylcarbamoyl.
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70 Samson Afewerki et al.

Scheme 42 Cu-catalyzed conjugate 1,4-addition of diethylzinc to acyclic enones 197.

Conditions: (i) Cu(OAc)2H2O (1 mol%), 199 (2 mol%), toluene, Et2Zn, 12 h, 20°C or 0°C.
R ¼ nBu, Ph, 2-thienyl, 2-furyl, 4-MeOC6H4 or 4-ClC6H4. R1 ¼ Me or Ph.

Scheme 43 Ru-catalyzed enantioselective hydrogenation of dimethyl itaconate (200)

and methyl 2-acetamidocinnamate (202) employing chiral ligands with a tropane skel-
eton. Reagents and conditions: [Rh(cod)]BF4 (1 mol%), (S,S)-199 (1–2 mol%), H2, CH2Cl2,
r.t., 12 h.

respectively) (Scheme 43). In both reactions, a matched/mismatched case

was observed for (S,S)-199 and its congener (R,R)-199.
Moreover, the same group has thoroughly investigated tropane-derived
phosphorus–olefin hybrid ligands bearing various combinations of P-units
(chiral BINOL-derived units/achiral PPh2-units) with chiral and achiral
tropane skeletons and evaluated them in Cu-catalyzed conjugate 1,4-
additions of diethylzinc to cyclic enones and in Rh-catalyzed 1,4-additions
of phenylboronic acid (Hayashi–Miyaura reaction) to cyclic and acyclic
enones.103

5.2 Pharmacology of Tropane Alkaloids and Synthetic

Derivatives
As previously mentioned, the biological and medicinal activities of tropane
alkaloids have sparked great interest within the industrial and academic
research communities. In 1917, Sir Robert Robinson established the
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The Chemical Synthesis and Applications of Tropane Alkaloids 71

foundation for understanding the biosynthesis of the tropane structural

motif, which he observed during his classical synthesis of tropinone
124.104 However, the biosynthetic pathways of most tropane alkaloids are
still unclear. Thus, only a few pathways are understood in detail. The pre-
cursors of alkaloids are amino acids, and alkaloid biosynthesis proceeds
through a series of pathways including transamination reactions. For a
deeper understanding of the biosyntheses of tropane alkaloids, readers are
referred to the previous reviews on this topic.1,104,105 In this section, we will
cover examples of recently synthesized tropane alkaloid derivatives and
briefly outline their pharmacological properties. Dizocilpine (INN), also
known as MK-801 (Fig. 2), is an antagonist of the NMDA receptor in
the glutamate category involved with the central nervous system (CNS).
This antagonist blocks receptors in a use- and voltage-dependent manner.
The drug binds inside the ion channel of the receptor and prevents the flow
of ions, including calcium ions (Ca2+), through the channel.106 The drug dis-
plays a variety of physiological actions such as anesthetic and anticonvulsant
properties.107 MK-801 and its derivatives such as compounds 116 have been
synthesized according to the above described procedures (Scheme 21).71,72
Another derivative is stable α-iodo secondary amine 204.
In 2010, Jensen and coworkers demonstrated the synthesis of the
alkaloid noeurostegine and its inhibition activity against glycoside hydro-
lases.108 The compound noeurostegine (206) was prepared in 22 synthetic
steps starting from levoglucosan (205) (Scheme 44). Compound 206

Figure 2 The structure of the alkaloid MK-801 and its analogue 204.

Scheme 44 Synthesis of noeurostegine (206) starting from levoglucosan (205) in

22 steps.
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72 Samson Afewerki et al.

inhibited sweet almond, Thermotoga maritima β-glucosidase, coffee bean

α-galactosidase, and Aspergillus oryzae β-galactosidase. Notably, the study
also showed that it is a competitive inhibitor of almond and T. maritima
β-glucosidase.
The same group later synthesized two nojirimycin analogues and verified
their biological activity.109 The synthesis of nojiristegine (208) and manno-
nojiristegine (210) was mainly based on the previous synthesis reported by
the same group for the preparation of noeurostegine and calystegine
A3.108,110 However, 208 and 210 could be obtained after 21 steps starting
from 207 and 209, respectively (Scheme 45). The two compounds were
tested for their antibiotic activity and inhibitory activity against broad range
of glycosidases. However, no or only weak inhibition was observed. Only
nojiristegine (208) showed moderate inhibition of α-glucosidase. Further-
more, the antibiotic evaluation of the compounds did not give any satisfac-
tory results.
Chronic obstructive pulmonary disease (COPD) is a fatal lung disease
characterized by progressive and irreversible airflow limitation with systemic
consequences. In 2013, Bream and coworkers presented the development of
the synthesis of muscarinic antagonist 218, containing a tropane framework,
which was designed as a long-acting, selective, and reversible muscarinic
antagonist for the treatment of COPD.111 In their first synthetic route,
desired compound 218 was prepared in six synthetic steps (Scheme 46).
Even though starting material 211 is readily available, the inefficiency
of the dealkylation/alkylation steps encouraged the group to develop a
more efficient synthetic route (Scheme 47). The synthesis is based on an
epoxidation/reduction sequence and gives compound 218 using only using
two silica-gel column chromatography purification steps (Scheme 47).

Scheme 45 Synthesis of nojiristegine (208) and manno-nojiristegine (210) starting

from 207 and 209 in 21 synthetic steps.
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The Chemical Synthesis and Applications of Tropane Alkaloids 73

Scheme 46 Synthetic route 1 for the preparation of muscarinic antagonist 218.

Reagents and conditions: (i) PhLi, dibutyl ether, 0°C, 89%; (ii) TMSCN, SnCl4, CH2Cl2,
0°C; (iii) HCl, isopropyl alcohol (IPA), methyl isobutyl ketone, 75%; (iv) 1. NaOH (aq.),
tert-butyl methyl ether; 2. 1-chloroethylchloroformate, NaHCO3, toluene, 50°C; 3. HCl,
IPA, 85% yield, over three steps; (v) K2CO3, acetone, BrCH2CH2OBn; (vi) MeI, acetone,
0–20°C, then MeOH, 40–20°C, 75%, two steps, dr: 99:1; (vii) MeOH, H2O, 60–20°C,
85%, >99.5:0.5.

Scheme 47 Synthetic route 2 for the preparation of muscarinic antagonist 218.

Reagents and conditions: (i) NaOAc, HCl, H2O, 5–45°C, pH 4.6–5.3; (ii) KOtBu, tBuOH,
2-methyltetrahydrofuran (2-MTHF), Me3S(O)I, 60°C; (iii) DIBAL-H, toluene, 75°C, then
HCl/IPA; (iv) MsCl, Et3N, THF, 46% (three steps); (v) Ph2CHCN, THF, KOtBu, tBuOH, 65°C;
(vi) MeI, methyl isobutyl ketone, MeOH, 0–60°C, 82% over three steps, dr: 22:1.

In 2013, Janda and coworkers disclosed the synthesis and evaluation of

halogenated cocaine haptens as potential anticocaine vaccines.112 Met-
hylecgonine 226 was obtained in two steps from cocaine (35), and subse-
quent benzoylation, demethylation, and N-acylation with succinic
anhydride afforded cocaine haptens (GN) 229 containing halogens (GNF,
GNCl, GNCF, and GN5F) after five synthetic steps. Next, coupling to key-
hole limpet hemocyanin (KLH) protein gave corresponding hapten carrier
 ARTICLE IN PRESS

74 Samson Afewerki et al.

Scheme 48 Synthesis of halogenated cocaine haptens. DMAP:

4-dimethylaminopyridine; DMF: dimethylformamide; EDC, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide; GNF, cocaine hapten; KLH, keyhole limpet hemocy-
anin; PBS, phosphate-buffered saline; Sulfo-NHS, N-hydroxysulfosuccinimide; Troc,
trichloroethyl chloroformate.

Figure 3 The structures of succinyl norcocaine (SNC) and SNC-KLH.

adducts 230 (Scheme 48). The immunological properties of these com-

pounds were evaluated and compared to succinyl norcocaine (SNC) and
SNC-KLH, a drug that currently undergoes clinical trials (Fig. 3). The
investigation confirmed GNF to be the best candidate, as it also produced
antibodies in higher concentration than SNC. From these studies, Janda’s
group concluded the importance of having a fluorine atom at the para-
position of the benzoyl ester group of the cocaine hapten. These findings
are very important since the clinical drug SNC could be further improved
based on this knowledge.
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The Chemical Synthesis and Applications of Tropane Alkaloids 75

In 2014, Ablordeppey and coworkers designed and evaluated tropane

analogues of haloperidol with the purpose of synthesizing compounds that
would have lower binding activity to the D2 receptor than haloperidol.113
Haloperidol is an antipsychotic agent that has side effects (e.g., catalepsy). It
is believed that decreasing the binding affinity to the D2 receptor could
reduce effects such as catalepsy. The synthesized and evaluated compounds
are shown in Fig. 4. All of these haloperidol analogues showed antipsychotic
activity, and encouragingly, they also showed decreased inhibition affinity to
the D2 receptor. Thus, they produced lower levels of catalepsy. Compound
238 was shown to be the best candidate, as it showed the lowest binding
affinity and concomitantly induced the least catalepsy.
In 2015, Sunden et al. reported the synthesis and biological evaluation of
tropanol-based androgen receptor modulators, which are closely associated
with prostate cancer.114 The group first performed a molecular topology
investigation, which showed that 241 with a methyl group on the 30 -
position has agonist properties on the androgen receptor, while compound
240, which lacks the methyl group, has antagonist properties (Fig. 5). Based
on these findings, Sunden et al. decided to expand the scope of these antag-
onist compounds and synthesized a library of compounds lacking the methyl
group. The biological properties of these compounds were compared with
bicalutamide, a clinically available nonsteroidal antiandrogen. Overall, these
compounds showed a potency similar to that of bicalutamide, and they did
not show agonist properties for the mutant W741L as bicalutamide did. The
most promising compounds were 246 and 240, which displayed similar and
stronger antagonist activity compared to bicalutamide, respectively.
In 2015, Kato et al. reported the design and synthesis of a new class of
nortropane-type iminosugars such as labystegines which are hybrid
iminosugars from LAB (1α-1-C-alkylated 1,4-dideoxy-1,4-imino-L-
arabinitol) and calystegine.115 These specific compounds were selected
based on molecular dynamics and molecular docking studies. The
labystegines 247–252 were prepared starting from sugar-derived cyclic

Figure 4 Structures of haloperidol analogues.

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76 Samson Afewerki et al.

Figure 5 Structure of the synthesized androgen receptor antagonists.

nitrones via intramolecular-1,3-dipolar-cycloaddition or samarium iodide-

catalyzed reductive coupling reactions.52,116 They were then evaluated for
their biological activity, and their properties were compared to natural cal-
ystegines and miglitol (Fig. 6). The biological study indicated that labystegine
(247) had selectivity against intestinal α-glucosidases from LAB, and com-
pared to miglitol, it was a more potent inhibitor by a factor of 10. From this
study, the group concluded that this family of alkaloids could serve as potential
compounds for improving postprandial hyperglycemia.
Liu and coworkers synthesized a wide range of acetamido- and
carbamido-substituted 3-(1H-indazol-3-yl)benzenesulfonamides.117 They
next investigated the inhibitory activities on threonine tyrosine kinase
(TTK), which is essential for the alignment of chromosomes to the meta-
phase plate and genomic integrity during cell division through establishment
and maintenance of the spindle assembly checkpoint (SAC). Inhibitor mol-
ecules such as 253, containing the bicyclic 3-hydroxy-8-azabicyclo[3.2.1]
octan-8-yl structural motif, were potent inhibitors (TTK IC50 < 10 nM),
displayed low off-target activity (>500 ), and showed microsomal stability
(T1/2 > 30 min) (Fig. 7). Compound 253 recapitulated the phenotype of
TTK RNAi and demonstrated in vivo tumor growth inhibition upon oral
dosing. It was therefore selected for preclinical evaluation.
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The Chemical Synthesis and Applications of Tropane Alkaloids 77

Figure 6 The structures of labystegines, calystegines, and miglitol.

Figure 7 TTK inhibitor 253.

In 2013, there were 35.3 million people worldwide living with human
immunodeficiency virus (HIV), and 2 million new infections were acquired
that year.118 At the same time, approximately 1.5 million individuals died
from acquired immunodeficiency syndrome (AIDS). Today, new drugs
have appeared, and HIV infection is more manageable but is still growing.
Maraviroc (254), which has a bicyclic 8-azabicyclo[3.2.1]octan-8-yl struc-
tural motif, was discovered and developed by Pfizer. It is a potent antagonist
for the CCR5 receptor and is used for the treatment of human immune
deficiency virus (HIV).119,120 In 2007, Maraviroc became the first small-
molecule CCR5 antagonist to be approved by the FDA, and it is sold
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78 Samson Afewerki et al.

Scheme 49 Pfizer’s retrosynthesis of Maraviroc and key intermediates for its synthesis.

under the brand-names Selzentry® (the United States) and Celsentri® (outside
the United States). The pioneering and elegant syntheses of Maraviroc
by Pfizer utilized an intermolecular Mannich/enantiomer resolution
process to produce β-amino ester 255 (Scheme 49),121–123 a key intermediate
that was subsequently employed in coupling reactions with 4,4-
difluorocyclohexane-1-carboxylic acid (256) and tropane triazole 257124 to
complete the synthesis. The Pfizer method has also been the basis for efficient
Maraviroc syntheses by the groups of Schaus,125 Córdova,126 and Sorensen,127
respectively. In these cases, key intermediates 258–260 were constructed
by novel catalytic methods (Scheme 49).
Biologically active 2β-substituted-β-aryltropanes 261 have been gener-
ally synthesized from cocaine (35) and evaluated for binding at monoamine
transporters (Fig. 8).128

Figure 8 2β-Substituted-β-aryltropanes 261 are usually made from 35.

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The Chemical Synthesis and Applications of Tropane Alkaloids 79

Some analogues are better at inhibiting the dopamine (DA) transporter

(DAT) and the norepinephrine (NE) transporter (NET) than the serotonin
(5HT) transporter (SERT). Others were selective for DAT over NET and
SERT, whereas others showed similar inhibition of all three transporters.
This approach is an alternative cocaine dependence therapy to the above
described strategy used by Janda (Scheme 48). β-Aryltropanes 261 also
shows promising activity for future possible treatments of nicotine
dependence.129

REFERENCES
1. (a) Lounasmaa, M.; Tamminen, T. In: The Alkaloids, Vol. 44, Cordell, G. A. Ed.;
Academic Press: London, 1993; pp 1–114; (b) Fodor, G.; Dharanipragada, R. Nat.
Prod. Rep. 1994, 11, 443–450.
2. (a) The Angiosperm Phylogeny Group. Bot. J. Linn. Soc. 2009, 161, 105–121; (b) The
Angiosperm Phylogeny Group. Bot. J Linn. Soc. 2003, 141, 399–436; (c) The Angio-
sperm Phylogeny Group. Ann. Missouri Bot. Gard. 1998, 85, 531–553.
3. Sena-Filho, J. G.; da Silva, M. S.; Tavares, J. F.; Oliveira, S. L.; Romero, M. A.;
Xavier, H. S.; Barbosa-Filho, J. M.; Braz-Filho, R. Helv. Chim. Acta 2010, 93,
1742–1744.
4. Philipov, S.; Berkov, S. Z. Naturforsch. C 2002, 57, 559–561.
5. Khattak, K. F.; Atta-ur-Rahman; Choudhary, M. I.; Hemalal, K. D.;
Tillekeratne, L. M. J. Nat. Prod. 2002, 65, 929–931.
6. El Bazaoui, A.; Bellimam, M. A.; Soulaymani, A. Fitoterapia 2011, 82, 193–197.
7. Jordan, M.; Humam, M.; Bieri, S.; Christen, P.; Poblete, E.; Muñoz, O. Phytochemistry
2006, 67, 570–578.
8. (a) Weigl, R.; Kaloga, M.; Eich, E. E. Planta Med. 1992, 58 (Suppl. A), 705; (b) Jenett-
Siems, K.; Weigl, R.; B€ ohm, A.; Mann, P.; Tofern-Reblin, B.; Ott, S. C.;
Ghomian, A.; Kaloga, M.; Siems, K.; Witte, L.; Hilker, M.; M€ uller, F.; Eich, E.
Phytochemistry 2005, 66, 1448–1464.
9. Gapparov, A. M.; Razzakov, N. A.; Aripova, S. F. Chem. Nat. Compd. 2007, 43,
291–292.
10. Humam, M.; Muñoz, O.; Christen, P.; Hostettmann, K. Nat. Prod. Commun. 2007, 2,
743–747.
11. Gapparov, A. M.; Aripova, S. F.; Tashkhodzhaev, B.; Levkovich, M. G.; Aripov, O.
Chem. Nat. Comp. 2010, 46, 590–592.
12. Razzakov, N. A.; Aripova, S. F. Chem. Nat. Comp. 2004, 40, 54–55.
13. Doerk-Schmitz, K.; Witte, L.; Alfermann, W. Phytochemistry 1994, 35, 107–110.
14. Christen, P.; Roberts, M. F.; Phillipson, J. D.; Evans, W. C. Phytochemistry 1995, 38,
1053–1056.
15. Doncheva, T.; Philipov, S.; Kostova, N. C. R. Acad. Bulg. Sci. 2004, 57, 41–44.
16. (a) Aripova, S. F. Chem. Nat. Comp. 1996, 32, 677–679; (b) Aripova, S. F. Khim.
Prirodnykh Soedinenii 1985, 2, 275.
17. Jenett-Siems, K.; Mann, P.; Kaloga, M.; Siems, K.; Jakupovic, J.; Witte, L.; Eich, E.
Phytochemistry 1998, 49, 1449–1451.
18. Khattak, K. F.; Atta-ur-Rahman; Choudhary, M. I. Heterocycles 2003, 60, 917–924.
19. (a) Doncheva, T.; Berkov, S.; Philipov, S. Biochem. Syst. Ecol. 2006, 34, 478–488;
(b) Berkov, S.; Doncheva, T.; Philipov, S.; Alexandrov, K. Biochem. Syst. Ecol.
2005, 33, 1017–1029.
 ARTICLE IN PRESS

80 Samson Afewerki et al.

20. Cretton, S.; Glauser, G.; Humam, M.; Jeannerat, D.; Muñoz, O.; Maes, L.;
Christen, P.; Hostettmann, K. J. Nat. Prod. 2010, 73, 844–847.
21. Humam, M.; Kehrli, T.; Jeannerat, D.; Muñoz, O.; Hostettmann, K.; Christen, P.
J. Nat. Prod. 2011, 74, 50–53.
22. Bringmann, G.; G€ unther, C. G. È.; G€ uhlbacher, J.; Gunathilake, M. D. L. P.;
Wickramasinghe, A. Phytochemistry 2000, 53, 409–416.
23. de Oliveira, S. L.; Tavares, J. F.; Castello Branco, M. V. S.; Lucena, H. F. S.; Barbosa-
Filho, J. M.; Gra, M. d. F.; do Nascimento, S. C.; Aguiar, J. d. S.; da Silva, T. G.; de
Simone, C. A.; de Araujo-Junior, J. X.; da Silva, M. S. Chem. Biodivers. 2011, 8, 155–165.
24. Muñoz, O.; Piovano, M.; Garbarino, J.; Hellwig, V.; Breitmaier, E. Phytochemistry
1996, 43, 709–713.
25. Silva, G. L.; Cui, B.; Chávez, D.; You, M.; Chai, H.-B.; Rasoanaivo, P.; Lynn, S. M.;
O’Neill, M. J.; Lewis, J. A.; Besterman, J. M.; Monks, A.; Farnsworth, N. R.;
Cordell, G. A.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 2001, 64, 1514–1520.
26. Chávez, D.; Cui, B.; Chai, H.-B.; Garcı́a, R.; Mejı́a, M.; Farnsworth, N. R.;
Cordell, G. A.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 2002, 65, 606–610.
27. Zanolari, B.; Guilet, D.; Marston, A.; Queiroz, E. F.; Paulo, M. Q.; Hostettmann, K.
J. Nat. Prod. 2003, 66, 497–502.
28. Zanolari, B.; Guilet, D.; Marston, A.; Queiroz, E. F.; Paulo, M. Q.; Hostettmann, K.
J. Nat. Prod. 2005, 68, 1153–1158.
29. Chin, Y.-W.; Jones, W. P.; Waybright, T. J.; McCloud, T. G.; Rasoanaivo, P.;
Cragg, G. M.; Cassady, J. M.; Kinghorn, A. D. J. Nat. Prod. 2006, 69, 414–417.
30. (a) Berkov, S.; Zayed, R. Z. Naturforsch. C 2004, 59, 184–186; (b) Berkov, S.; Pavlov, A.;
Kovatcheva, P.; Stanimirova, P.; Philipov, S. Z. Naturforsch. C 2003, 58, 42–46.
31. Vitale, A. A.; Acher, A.; Pomilio, A. B. J. Ethnopharmacol. 1995, 49, 81–89.
32. Payo-Hill, A. L.; Dominguez, R. S.; Suarez, M. O.; Batista-Baez, M.; Castro, H. T. V.;
Rastrelli, L.; Aquino, R. Phytochemistry 2000, 54, 927–932.
33. Cruz, R. A. S.; Almeida, H.; Fernandes, C. P.; Joseph-Nathan, P.; Rocha, L.;
Leitao, G. G. J. Sep. Sci. 2016, 39, 1273–1277.
34. Zuanazzi, J. A. S.; Tremea, V.; Limberger, R. P.; Sobral, M.; Henriques, A. T. Biochem.
Syst. Ecol. 2001, 29, 819–825.
35. (a) El Bazaoui, A.; Bellimam, M. A.; Lançar, I. T.; Soulaymani, A. Z. Naturforsch. C
2012, 67, 461–465; (b) El Bazaoui, A.; Bellimam, M. A.; Soulaymani, A. Z. Naturforsch.
C 2012, 67, 8–14.
36. Ott, S. C.; Jenett-Siems, K.; Siems, K.; Muller, F.; Hilker, M.; Eich, E. Sci. Pharm.
2013, 81, 543–548.
37. Kusano, G.; Orihara, S.; Tsukamoto, D.; Shibano, M.; Coskun, M.; Guvenc, A.;
Erdurak, C. S. Chem. Pharm. Bull. 2002, 50, 185–192.
38. Asano, N.; Yamashita, T.; Yasuda, K.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.;
Nash, R. J.; Lee, H. S.; Ryu, K. S. J. Agric. Food Chem. 2001, 49, 4208–4213.
39. Ribeiro, E. M. d. O.; Lima, L. S.; David, J. M.; Vale, A. E. d.; Lopes, L. M. X.;
David, J. P. Phytochem. Lett. 2013, 6, 232–235.
40. Casale, J. F.; Moore, J. M. J. Chromatogr. A 1996, 749, 173–180.
41. Moore, J. M.; Hays, P. A.; Cooper, D. A.; Casale, J. F.; Lydon, J. Phytochemistry 1994,
36, 357–360.
42. (a) Kato, A.; Asano, N.; Kizu, H.; Matsui, K.; Suzuki, S.; Arisawa, M. Phytochemistry
1997, 45, 425–429; (b) Asano, N.; Oseki, K.; Tomioka, R.; Kizu, H.; Matsui, K. Car-
bohydr. Res. 1994, 259, 243.
43. Moore, J. M.; Casale, J. F. J. Forensic Sci. 1997, 42, 246–255.
44. (a) Fandino, A. S.; Karas, M.; Toennes, S. W.; Kauert, G. J. Mass Spectrom. 2002, 37,
525; (b) Nishiyama, Y.; Moriyasu, M.; Ichimaru, M.; Sonoda, M.; Iwasa, K.; Kato, A.;
Juma, F. D.; Mathenge, S. G.; Mutiso, P. B. C. J. Nat. Med. 2007, 61, 56–58.
 ARTICLE IN PRESS

The Chemical Synthesis and Applications of Tropane Alkaloids 81

45. Atta-ur-Rahman; Khattak, K. F.; Nighat, F.; Shabbir, M.; Hemalal, K. D.;
Tillekeratne, L. M. Phytochemistry 1998, 48, 377–383.
46. Geng, C.-A.; Ma, Y.-B.; Chen, J.-J. Chin. Chem. Lett. 2013, 24, 236–238.
47. Cretton, S.; Bartholomeusz, T. A.; Humam, M.; Marcourt, L.; Allenbach, Y.;
Jeannerat, D.; Muñoz, O.; Christen, P. J. Nat. Prod. 2011, 74, 2388–2394.
48. Muñoz, O.; Cortes, S. Pharm. Biol. 1998, 36, 162–166.
49. Rigby, J. H.; Pigge, F. C. J. Org. Chem. 1995, 60, 7392–7393.
50. Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem. In. Ed. 2008, 47, 7040–7043.
51. Ishii, K.; Kido, M.; Noji, M.; Sugiyama, S. Org. Biomol. Chem. 2008, 6,
3186–3195.
52. Delso, I.; Tejero, T.; Goti, A.; Merino, P. J. Org. Chem. 2011, 76, 4139–4143.
53. Bai, Y.; Tao, W.; Ren, J.; Wang, Z. Angew. Chem. In. Ed. 2012, 51, 4112–4116.
54. Davis, F. A.; Gaddiraju, N. V.; Theddu, N.; Hummel, J. R.; Kondaveeti, S. K.;
Zdilla, M. J. J. Org. Chem. 2012, 77, 2345–2359.
55. Córdova, A.; Lin, S.; Tseggai, A. Adv. Synth. Catal. 2012, 354, 1363–1372.
56. He, S.; Hsung, R. P.; Presser, W. R.; Ma, Z. X.; Haugen, B. J. Org. Lett. 2014, 16,
2180–2183.
57. Hernández, A. S.; Thaler, A.; Castells, J.; Rapoport, H. J. Org. Chem. 1996, 61,
314–323.
58. Gauthier, I.; Royer, J.; Husson, H.-P. J. Org. Chem. 1997, 62, 6704–6705.
59. Ikeda, M.; Kugo, Y.; Kondo, Y.; Yamazaki, T.; Sato, T. J. Chem. Soc., Perkin Trans.
1997, 1, 3339–3344.
60. Yu, P.; Cook, J. M. Tetrahedron Lett. 1997, 38, 8799–8802.
61. Peng, Y.; Wang, T.; Fuxiang, Y.; Cook, J. M. Tetrahedron Lett. 1997, 38, 6819–6822.
62. Mans, D. M.; Pearson, W. H. Org. Lett. 2004, 6, 3305–3308.
63. Miller, K. A.; Shanahan, C. S.; Martin, S. F. Tetrahedron 2008, 64, 6884–6900.
64. Davis, F. A.; Theddu, N.; Gaspari, P. M. Org. Lett. 2009, 11, 1647–1650.
65. Lin, G.-J.; Zheng, X.; Huang, P.-Q. Chem. Commun. 2011, 47, 1545–1547.
66. Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2012,
14, 4278–4281.
67. Mao, Z.; Huang, S.; Gao, L.; Wang, A.; Huang, P. Sci. China Chem. 2013, 57, 252–264.
68. Huang, S.-Y.; Chang, Z.; Tuo, S.-C.; Gao, L.-H.; Wang, A.-E.; Huang, P.-Q. Chem.
Commun. 2013, 49, 7088–7090.
69. Hiroya, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1995, 2205–2206.
70. Ham, W.-H.; Jung, Y. H.; Lee, K.; Oh, C.-Y.; Lee, K.-Y. Tetrahedron Lett. 1997, 38,
3247–3248.
71. Schultz, D. M.; Wolfe, J. P. Org. Lett. 2011, 13, 2962–2965.
72. Monn, J. A.; Rice, K. C. Tetrahedron Lett. 1989, 30, 911–914.
73. Monn, J. A.; Thurkauf, A.; Mattson, M. V.; Jacobson, A. E.; Rice, K. C. J. Med. Chem.
1990, 33, 1069–1076.
74. Brawn, R. A.; Guimarães, C. R. W.; McClure, K. F.; Liras, S. Org. Lett. 2012, 14,
4802–4805.
75. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y. L. J. Am. Chem. Soc. 2002,
124, 2245–2258.
76. Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2001, 42, 1275–1277.
77. Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651–2654.
78. Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.; Huby, N. J. S.; Thornley, C.; Kong, N.;
Houser, J. H. J. Org. Chem. 1997, 62, 1095–1105.
79. Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10312–10313.
80. Nocquet, P.-A.; Opatz, T. Eur. J. Org. Chem. 2016, 1156–1164.
81. Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.; Zanirato, V.
Tetrahedron 1999, 55, 5923–5930.
 ARTICLE IN PRESS

82 Samson Afewerki et al.

82. Demizu, Y.; Shiigi, H.; Mori, H.; Matsumoto, K.; Onomura, O. Tetrahedron: Asym-
metry 2008, 19, 2659–2665.
83. Beniazza, R.; Desvergnes, V.; Mehta, G.; Blanchard, N.; Robert, F.; Landais, Y. J. Org.
Chem. 2011, 76, 791–799.
84. Olivo, H. F.; Colby, D. A.; Hemenway, M. S. J. Org. Chem. 1999, 64, 4966–4968.
85. Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2007, 46,
4534–4538.
86. Willand, N.; Folleas, B.; Boutillon, C.; Verbraeken, L.; Gesquière, J.-C.; Tartar, A.;
Deprez, B. Tetrahedron Lett. 2007, 48, 5007–5011.
87. Tsarev, V. N.; Morioka, Y.; Caner, J.; Wang, Q.; Ushimaru, R.; Kudo, A.; Naka, H.;
Saito, S. Org. Lett. 2015, 17, 2530–2533.
88. Carroll, R. J.; Leisch, H.; Scocchera, E.; Hudlicky, T.; Cox, D. P. Adv. Synth. Catal.
2008, 350, 2984–2992.
89. Karlsen, M.; Liu, H. L.; Johansen, J. E.; Hoff, B. H. Molecules 2015, 20, 5329–5345.
90. Yu, Y.; Yang, X.-F.; Xu, C.-F.; Ding, C.-H.; Hou, X.-L. Org. Lett. 2013, 15,
3880–3883.
91. Majewski, M.; Lazny, R. J. Org. Chem. 1995, 60, 5825–5830.
92. Lazny, R.; Wolosewicz, K.; Ratkiewicz, A.; Pioro, D.; Stocki, M. Tetrahedron 2014,
70, 597–607.
93. Nodzewska, A.; Bokina, A.; Romanowska, K.; Lazny, R. RSC Adv. 2014, 4,
29668–29681.
94. Lyapkalo, I. M.; H€ ogermeier, J.; Reissig, H.-U. Tetrahedron 2004, 60, 7721–7729.
95. Bai, D.; Xu, R.; Chu, G.; Zhu, X. J. Org. Chem. 1996, 61, 4600–4606.
96. Xu, R.; Chu, G.; Bai, D. Tetrahedron Lett. 1996, 37, 1463–1466.
97. Chen, Z.; Gonzalez, M. D.; Blundell, P.; Meltzer, P. C. Tetrahedron Lett. 1997, 38,
6823–6824.
98. Jonsson, S. Y.; L€ om, C. M. G.; B€ackvall, J.-E. J. Org. Chem. 2000, 65, 8454.
ofstr€
99. Gunes, Y.; Arcelik, N.; Sahin, E.; Fleming, F. F.; Altundas, R. Eur. J. Org. Chem.
2015, 23, 6679–6686.
100. Zhang, Z.-L.; Nakagawa, S.; Kato, A.; Jia, Y.-M.; Hu, X.-G.; Yu, C.-Y. Org. Biomol.
Chem. 2011, 9, 7713–7719.
101. Shiigi, H.; Mori, H.; Tanaka, T.; Demizu, Y.; Onomura, O. Tetrahedron Lett. 2008,
49, 5247–5251.
102. Cramer, N.; Laschat, S.; Baro, A. Organometallics 2006, 25, 2284–2291.
103. Vlahovic, S.; Sch€adel, N.; Tussetschl€ager, S.; Laschat, S. Eur. J. Org. Chem. 2013,
1580–1590.
104. Humphrey, A. J.; O’Hagan, D. Nat. Prod. Rep. 2001, 18, 494–502.
105. Robins, R. J.; Walton, N. J. In: The Alkaloids; Cordell, G. A. Ed.; Vol. 44; Academic
Press: London, 1993; pp 115–187.
106. Huettner, J. E.; Bean, B. P. Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 1307–1311.
107. Thompson, W. J.; Anderson, P. S.; Britcher, S. F.; Lyle, T. A.; Thies, J. E.;
Magill, C. A.; Varga, S. L.; Schwering, J. E.; Lyle, P. A.; Christy, M. E.;
Evans, B. E.; Colton, D.; Holloway, M. K.; Springer, J. P.; Hirshfield, J. M.;
Ball, R. G.; Amato, J. S.; Larsen, R. D.; Wong, E. H. F.; Kemp, J. A.;
Tricklebank, M. D.; Singh, L.; Oles, R.; Priestly, T.; Marshall, G. R.;
Knight, A. R.; Middlemiss, D. N.; Woodruff, G. N.; Iversen, L. L. J. Med. Chem.
1990, 33, 789–808.
108. Rasmussen, T. S.; Jensen, H. H. Org. Biomol. Chem. 2010, 8, 433–441.
109. Viuff, A. H.; Besenbacher, L. M.; Kamori, A.; Jensen, M. T.; Kilian, M.; Kato, A.;
Jensen, H. H. Org. Biomol. Chem. 2015, 13, 9637–9658.
110. Rasmussen, T. S.; Jensen, H. H. Carbohydr. Res. 2011, 346, 2855–2861.
 ARTICLE IN PRESS

The Chemical Synthesis and Applications of Tropane Alkaloids 83

111. Bream, R. N.; Hayes, D.; Hulcoop, D. G.; Whiteman, A. J. Org. Process Res. Dev.
2013, 17, 641–650.
112. Cai, X.; Tsuchikama, K. T.; Janda, K. M. J. Am. Chem. Soc. 2013, 135, 2971–2974.
113. Sampson, D.; Bricker, B.; Zhu, X. Y.; Peprah, K.; Lamango, N. S.; Setola, V.;
Roth, B. L.; Ablordeppey, S. Y. Bioorg. Med. Chem. Lett. 2014, 24, 4294–4297.
114. Sunden, H.; Holland, M. C.; Poutiainen, P. K.; J€a€askel€ainen, T.; Pulkkinen, J. T.;
Palvimo, J. J.; Olsson, R. J. Med. Chem. 2015, 58, 1569–1574.
115. Kato, A.; Zhang, Z.-L.; Wang, H.-Y.; Jia, Y.-M.; Yu, C.-Y.; Kinami, K.;
Hirokami, Y.; Tsuji, Y.; Adachi, I.; Nash, R. J.; Fleet, G. W. J.; Koseki, J.;
Nakagome, I.; Hirono, S. J. Org. Chem. 2015, 80, 4501–4514.
116. Zhang, Z.-L.; Nakagawa, S.; Kato, A.; Jia, Y.-M.; Yu, C.-Y. Biomol. Chem. 2011, 9,
7713–7719.
117. Liu, Y.; Lang, Y. H.; Patel, N. K.; Ng, G.; Laufer, R.; Li, S.-W.; Edwards, L.;
Forrest, B.; Sampson, P. B.; Feher, M.; Ban, F. Q.; Awrey, D. E.; Beletskaya, I.;
Mao, G. D.; Hodgson, R.; Plotnikova, O.; Qiu, W.; Chirgadze, N. Y.;
Mason, J. M.; Wei, X.; Lin, D. C.-C.; Che, Y.; Kiarash, R.; Madeira, B.;
Fletcher, G. C.; Mak, T. W.; Bray, M. R.; Pauls, H. W. J. Med. Chem. 2015, 58,
3366–3392.
118. UNAIDS, 2013, Global Report, 1–116.
119. Lederman, M. M.; Penn-Nicholson, A.; Cho, M.; Mosier, D. J. Am. Med. Assoc. 2006,
296, 815–826.
120. MacArthur, R. D.; Novak, R. M. Clin. Infect. Dis. 2008, 47, 236–241.
121. Price, D. A.; Gayton, S.; Selby, M. D.; Ahman, J.; Haycock-Lewandowski, S.;
Stammen, B. L.; Warren, A. Tetrahedron Lett. 2005, 46, 5005–5007.
122. Haycock-Lewandowski, S. J.; Wilder, A.; Ahman, J. Org. Proc. Res. Dev. 2008, 12,
1094–1103.
123. Åhman, J.; Birch, M.; Haycock-Lewandowski, S. J.; Long, J.; Wilder, A. Org. Proc. Res.
Dev. 2008, 12, 1104–1113.
124. Price, D. A.; Gayton, S.; Selby, M. D.; Ahman, J.; Haycock-Lewandowski, S. Synlett
2005, 1133–1134.
125. Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398–15404.
126. Zhao, G. L.; Lin, S.; Korotvicka, A.; Deiana, L.; Kullberg, M.; Córdova, A. Adv. Synth.
Catal. 2010, 352, 2291–2298.
127. Bedell, T. A.; Hone, A. B.; Du Bois, J.; Sorensen, E. J. Tetrahedron Lett. 2015, 56,
3620–3623.
128. (a) Riss, P. J.; Hummerich, P.; Schloss, P. Org. Biomol. Chem. 2009, 7, 2688;
(b) Carroll, F. I.; Tyagi, S.; Blough, B. E.; Kuhar, M. J.; Navarro, H. A. J. Med. Chem.
2005, 48, 3852–3857; (c) Xu, L.; Kulkarni, S. S.; Izenwasser, S.; Katz, J. L.;
Kopajtic, T.; Lomenzo, S. A.; Newman, A. H.; Trudell, M. L. J. Med. Chem.
2004, 47, 1676–1682; (d) Kline, R. H., Jr.; Wright, J.; Fox, K. M.;
Eldefrawi, M. E. J. Med. Chem. 1990, 33, 2024–2027; (e) Clarke, R. L.;
Daum, S. J.; Gambino, A. J.; Aceto, M. D.; Pearl, J.; Levitt, M.; Cumiskey, W. R.;
Bogado, E. F. J. Med. Chem. 1973, 16, 1260.
129. Carroll, F. I.; Blough, B. E.; Mascarella, S. W.; Navarro, H. A.; Eaton, J. B.;
Lukas, R. J.; Damaj, M. I. J. Med. Chem. 2010, 53, 8345–8353.