Tetrahedron Letters,Vo1.30,No.28,pp 3625-3628,1989 0040-4039/89 $3.00 + .
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Printed in Great Britain Maxwell Pergamon Macmillan plc
THE AZA-ROBINSON ANNULATION: AN APPLICATION
TO THE SYNTHESIS OF ISO-A58365A
Francis G. Fang, Maurizio Frato,l Guncheol Kim, and Samuel .I. Danishefsky*
Department of Chemistry, Yale University, New Haven CT 06511
Abstract. Annulation of diazomethylvinylketone (4a) with a variety of secondary thiolactams provides a novel
route to dihydro-y-pyridones. This approach has been applied to the synthesis of iso-A58365A (2), the y-pyridone
analog of the ACE inhibitor, A58365A (1).
We have recently described a novel route to 5-hydroxy-2pyridones in the context of the total synthesis of
the angiotensin converting enzyme (ACE) inhibitor, A58365A (1).2 In order to gain some insight into the
structural features of 1 which are pertinent to its biological activity, the synthesis of several variants was
undertaken. A particularly interesting target was the isomeric 4-pyridone (2). The biological evaluation of this
analog could provide information regarding the importance of the proximal lactam-dicarboxylate array in
determining the ACE inhibitory activity of 1. In this Letter we describe a new and general route to dihydro-y-
pyridones and the application of this methodology to the synthesis of 2.
“ooc-Jo 0 COOH COOH COOR
1 A58365A 2 iso-A58365A 3 4 I
Dihydropyridone 3 was seen to be a potentially useful intermediate for the synthesis of 2 via addition of a
propionate side chain and dehydrogenation. An aza-Robinson annulation type process for the construction of 3
(cf. 4 + 5 to 3) was pursued.3 Crucial to the successful realization of this strategy would be the feasibility of the
amide olefination reaction. A recent finding in our laboratories indicated that a diazo-thioamide coupling reaction
would be particularly well suited for achieving this process. 4 With this result in mind, diazomethylvinylketone(4,
X=N2) 5 and thiopyroglutamate (5, Y=S, R=t-Bu) 6 were selected as the annulation components.
Addition of a freshly prepared solution of 4 (O.lM in THF) to a solution of 5a (OSM in THF at room
temperature in the presence of a catalytic amount of solid sodium hydroxide followed by stirring for 1h produced a
95% yield of Michael adduct 6a. A solution of 6a (0.1 M in benzene) was added to a refluxing suspension of
rhodium(H) acetate dimer in benzene. The crude cyclization product (vi& infra) was taken up in acetone and
added to a stirred suspension of partially deactivated7 W-2 Raney nickel in acetone. Dihydropyridone 7a was
3625
3626
obtained in 65% yield following flash chromatography. The scope and limitations of this process were explored in
substrates 5b, c, d, and e. The results are shown in table 1.
4 a X=CHN, 5 a X=CO,tBu, n=l 6 a X=CO$Bu, n=l 7 a X=COatBu, n=l
4 b X=OMe 5 b X=C02Me, n=l 6 b X=C02Me, n=l 7 b X=CO,Me, n=l
5c X=H,n=l 6c X=H, n=l 7c X=H, n=l
5 d X=H, n=2 6d X=H, t-t=2 76X&i, n=2
5 e X=H, n=3 6e X=H, n=3 7 e X=H, n=3
Table 1 Aza-Robinson annulation of thiolactams
Michael acceptor Thiolactam Procedurea Michael adduct (%)b Dihydropyridone(%)b
4a Sa A 6a (9.5) 7a (68)
4b 5a B 6a (75)
4a 5b A 6b (85) 7b (65)
4b 5b B 6b (73)
4a SC A 6c (42) 7c (68)
4b SC B 6c (71)
4a Sd A 6d (28) 7d (70)
4b 5d B 6d (70)
4a 5e A 6e (12) 7e (73)
4b 5e B 6e (71)
a procedure A: NaOH (cat.), THF. procedure B: (i) NaOH (cat.), THF (ii) 1 N NaOH, MeOH (iii) ClCOzEt,
CH2C12 (iv) CH2N2, Et20. h isolated yields following flash column chromatography
With this series of substrates, the Michael addition of diazomethylvinylketone (4a) to thiolactams (giving
rise to 6) proceeds well in only two cases (5a and 5b). In the other examples (5~ d, and e) varying amounts of
starting material 5 are obtained in addition to product 6. Fortunately, a stepwise procedure using methyl acrylate
(4b) as the Michael acceptor (see proc. B), though longer proved to be more general8 The Michael adducts were
subjected to hydrolysis, mixed anhydride formation, and conversion to the diazoketone 6.The ring closure
process generates bicyclic dihydropyridones 7 in 65 to 73 % yield.
3627
The intermediate in the transformation of 6 to 7 prior to treatment with W-2 Raney nickel was identified as
enethio18 for two of the substrates (6b and 6~). These unstable species @a, 8b) could be methylated (methyl
iodide, n-iethylamine) or oxidatively dimerized (methanol, sodium carbonate, air) to produce thiomethyl ethers
9a,b (S8%, 60%) or disulfides 10a,b (48%,51%).
SMW
\
~“&E$-$$
N
ti
X X X
9a X=QMe aa X=CC$Me 1 Oa X=CO*Me
9b X=H 8bX=H lObX=H
Treatment of 7a with osmium tetroxide in pyridine followed by reductive workup afforded hydroxy
dihydropyridone 11 in 51% yield. Protection of the hydroxyl group as a t-butyl dimethylsilyl ether gave 12 in
92% yield. Regioselective deprotonation of 12 with lithium isopropylcyclohexylamide (LICA) in THF at -78
followed by addition of t-butyl propiolate and quenching with glacial acetic acid gave a crude reaction mixture
containing Michael adduct 13 along with several regio- and stereoisomers. Direct treatment of the crude mixture
with W-2 Raney nickel in acetone provided pyridone 14 in 35 % overall yield in a process which apparently
involves migration of the acrylate double bond into the pyridone ring.’ Removal of the protecting groups by
treatment of 14 with formic acid provided iso-A58365A (2) in quantitative yield. Evaluation of iso-A583fiSA (2)
showed it to be virtually inactive as an ACE inhibitor in protocols where 1 showed strong activity. lo This result,
although of a negative sort, suggests that the proximity of the lactam carbonyl group with both carboxyl functions
might be an important source of activity. Experiments to probe this point are being readied.
OR
1. OsO,, pyridine 0
1. LICA, THF. -78%
2. H,S, MeOH N
ti 2. t-butyl propiolate, -7fC
CO,tBu CO&Bu 3. AcOH, -78%
7a 11 f&H TBSCI,
NEt,. CH$&
12 R=TB. J
OR’
OTBS
N
QC &
t B.,&
CO,tBu
cog
14 R=tBu, R’=TBS
HCOQH
13 2 R=R’=H _J
3628
In summary, the utility of diazomethylvinylketone or a synthetically equivalent scheme for an annulation of
thiolactams leading to y-dihydropyridones has been demonstrated. Using this chemistry, a synthesis of iso-
A58365A (2) was achieved. Further applications of this methodology towards the synthesis of other biologically
interesting alkaloids will be described in due course.
Acknowledgements. This research was supported by PHS Grant CA 28824. A Kent Fellowship (Yale
University) to FGF is gratefully acknowledged. NMR spectra were obtained through the auspices of the Northeast
Regional NSF/NMR facility at Yale University, which was supported by NSF Chemistry Division Grant CHE
7916210.
Notes and References
1 Present Address: Universita Degli Studi Di Padova, Dipartimento di Chimica Grganica via Marzolo l-
35 13 1 Padova Italy.
Fang, F. G.; Danishefsky, S. J. Tetrahedron Let?. preceding publication
Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. Reunions 1959,10, 179.
A variety of vinylogous amides have been prepared in this fashion. G Kim, unpublished results.
Rosenquist, N. R.; Chapman, 0. L. J. Org. Chem. 1976,41, 3326.
Andersen, T, P.; Rasmussen, P. B.; Thomsen, I.; Lawesson, S.-O.; Jorgensen, P.; Lindhardt, P. Liebigs
Ann. Chem. 1986, (2), 269.
7 W-2 Raney nickel was partially deactivated by stirring in refluxing acetone for 1h.
8 The adducts of methyl acrylate (4a) with thiolactams 5a-e were obtained in greater than 95% yield in all
cases. These products were fully characterized ( lH NMR, IR, MS, HRMS and or elemental analysis).
9 The dihydro version of 13 (the adduct of 12 and 4a) failed to give 14 upon treatment with W-2 Ra-Ni.
10 Descriptions of the protocols and test results for the biological evaluations of compounds 1 and 2 and
derivatives of these systems will be disclosed separately.
11 All new compounds were fully characterized. The data for selected compounds is: 1Oa (mp 208-210°C):
[a]~ -1-165.2’ (MeOH, c 0.37); IR vmax (CHzClz) 1739, 1627, 1542,1460, 1163 cm-l; *H NMR (250
MHz, CDC13) 6 4.37 (dd, J=8.8, 4.7 Hz, 2H, 2(NCH)), 3.79 (s, 6H, 2(OCH3)), 3.67-3.27 and 3.16
3.02 (m, 8H, 4(CH2)), 2.62 (t, J=7.6 Hz, 4H, 2(CH2)), 2.56-2.45 and 2.25.2.13 (m, 4H, 2(CH2)). MS
m/e (%) 454 (l.Y), 453 (3.8), 241 (16.9), 228 (24.4), 227 (5.7), 226 (loo), 196 (11.5),184 (16.8), 182
(45.1), 168 (66.8); HRMS Calcd. for C~OH~~N~O&: 452.1077, obsd 452.1064. 9a (mp 115-116°C);
[a]~ -99.1” (MeOH, c 0.32); IR vmax (CDC13) 1735,1627, 1549, 1460, 1160 cm-l; ‘H NMR (250 MHz,
CDC13) 6 4.28 (dd, J=8.7, 4.4 Hz, lH, NCH), 3.80 (s, 3H, OCH3), 3.69-3.57 and 3.46-3.35 (m, 2H,
CH2). 3.07 (t, J=8.6 Hz, CH2). 2.69-2.61 (m, 2H, CH2), 2.52-2.37 and 2.24-2.11 (m, 2H, CHz), 2.14
(s, 3H, SCH3). MS m/e (%) 243 (6.1), 242 (13.0), 241 (loo), 208 (17.6), 184 (10.9), 183 (11.5), 182
(99.4). 7b (mp 75-77°C); 10l]~ -147.4” (EtOAc, c 0.77); IR Vmau (CDC13) 1738, 1623,1578 cm-l; 1H
NMR (250 MHz, CDCl3) 6 5.04 (s, lH, C=CH), 4.18 (dd, J=8.5, 4.3 Hz, lH, NCH), 3.79 (s, 3H,
OCH3), 3.78-3.58 and 3.46-3.36 (m, 2H, CH2), 2.X6-2.12 (m, 6H, 3(CH2)); MS m/e (%) 196 (3.7),
195 (26.8), 137 (8.7) 136 (loo), 109 (1.8) 108 (25.5); HRMS Calcd. for CtoHl3NO3: 195.0896, bbsd
195.0890. 6b [a]D +100.3” (CHC13, c 3.35); IR vmax (CDC13) 2100, 1735, 1635, 1480, 1375, 1325,
1210, 1170 cm-l; 1H NMR (250 MHz, CDC13) 6 5.34 (bs, lH, N2CH), 4.78 (dd, J=9.4, 2.9 Hz, lH,
NCH), 4.24-4.14 and 3.87-3.76 (m, 2H, CH2), 3.79 (s, 3H, OCH3), 3.13-2.99 and 2.75-2.67 (m. 4H,
2(CH2)), 2.46-2.10 (m, 2H, CH2); MS m/e (%) 229 (l.O), 228 (2.9), 227 (10.9), 196 (2.0), 195 (12.3),
194 (loo), 184 (27.6), 168 (60.1), 166 (12.8), 140 (52.8), 136 (12.4). 134 (21.7), 126 (28.1), 114
(27.4), 112 (19.4)..
(Received in USA 20 April 1989)
