Total synthesis of (2S,3s,4R)-plakoridine A

Article abstract of DOI:10.1016/S0040-4039(00)00096-4

The β-amino ester 6 is synthesized via the diastereoselective Michael addition of the lithium amide derived from amine 5 to methyl (E)-2-hexenoate. This ester is converted to the pyrrolidinone 8 via an aldol condensation/deprotection/cyclization. Transformation of the lactam 8 into thiolactam 11 followed by Eschenmoser sulfide contraction provides (2S,3S,4R)-plakoridine A. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00096-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1947–1950
Total synthesis of (2S,3S,4R)-plakoridine A
Dawei Ma ∗ and Haiying Sun
State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 25 August 1999; revised 5 January 2000; accepted 11 January 2000
Abstract
The β-amino ester 6 is synthesized via the diastereoselective Michael addition of the lithium amide derived
from amine 5 to methyl (E)-2-hexenoate. This ester is converted to the pyrrolidinone 8 via an aldol condensa-
tion/deprotection/cyclization. Transformation of the lactam 8 into thiolactam 11 followed by Eschenmoser sulfide
contraction provides (2S,3S,4R)-plakoridine A. © 2000 Elsevier Science Ltd. All rights reserved.
Plakoridine A (1)1 and plakoridine B (2)2 are two novel tyramine-containing pyrrolidine alkaloids
that possess a fully substituted, functionally diverse pyrrolidine ring system. Both compounds were
isolated from the extracts of an Okinawan sponge of the genus Plakortis. Preliminary studies showed
that plakoridine A is cytotoxic against the murine lymphoma L1210 cell line. Their structures were
established largely by extensive NMR studies and the absolute configurations of both compounds
remained undetermined.1,2 In order to verify further the length of the aliphatic chain of plakoridine
A, Kobayashi and co-workers ozonolyzed this compound and obtained two fragments corresponding
to lactam 3 and heptadecanoic acid.1 Plakoridine A may be available from the lactam 3 through the
Eschenmoser sulfide contraction.3,7,8 In 1995, Stafford reported his studies on a racemic synthesis of 3
using nitrone cycloaddition chemistry.4 Since then no reports concerning its synthesis have appeared.
Herein we wish to report the first total synthesis of (2S,3S,4R)-plakoridine A.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00096-4
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Scheme 1.
As outlined in Scheme 1, the desired pyrrolidinone 8 was synthesized from ethyl 4-
hydroxyphenylacetate. This ester was converted into 4-benzyloxyphenylacetic acid 4 by treatment
with benzyl bromide and potassium carbonate in DMF followed by hydrolysis with 2N NaOH in
methanol. After the chiral auxiliary was introduced by coupling 4 with (S)-α-methylbenzylamine, the
amide was reduced with LAH to afford the secondary amine 5. Next, treatment of this amine with
n-BuLi followed by trapping the anion with methyl (E)-2-hexenoate provided the Michael addition
product 6. The diastereoselectivity of this step was higher than 97% because only one isomer was
observed in its 1H NMR spectrum. According to Davies’ studies,5 the configuration of the newly created
chiral center should be S. With β-amino ester 6 in hand, we planned to condense it with ethyl glyoxalate
to set up the polysubstituted pyrrolidinone ring system.6 Accordingly, the ester 6 was treated with 3
equiv. of LDA and the anion was reacted with ethyl glyoxalate to give 7 in 51% yield together with other
isomers. Attempts to improve the selectivity by using trimethyl borate as an additive failed. Finally,
hydrogenation of 7 followed by heating the deprotected product in ethyl acetate at reflux afforded

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(2S,3R,4R)-8 in 91% yield. Its stereochemistry was confirmed by NOESY spectra in which significant
NOEs were observed between 2-H and 3-H, 2-H and 4-H, and 3-H and 4-H.
Treatment of the pyrrolidinone 8 with tert-butyldimethylsilyl chloride followed by reaction with
phosphorus pentasulfide produced the thiolactam 9 in 75% yield. At this time we decided to try to
use the thiolactam 11 with a free hydroxyl group to carry out the Eschenmoser sulfide contraction.
Accordingly, the silyl protecting groups were removed from 9 under the action of TsOH in methanol,
and the phenol hydroxy group was reprotected with TBDPS to provide 10. The compound 10 was
isomerized to 11 by treatment with potassium carbonate in methanol for 30 min. It was observed that
S-alkylation of 11 with 1-bromo-2-octadecanone in methylene chloride and subsequent Eschenmoser
sulfide contraction mediated by triphenylphosphine and triethylamine worked well to afford the olefin
12 in 75% yield. Finally, deprotection of 12 with TBAF/HOAc in THF furnished (2S,3S,4R)-plakoridine
A in 71% yield. Its spectral data were the same as those of the natural product except for its optical
rotation (lit.1 [α]D20=−0.4 (c 0.5, CHCl3), our observed: ([α]D22=−43.0 (c 0.5, CHCl3)).9 Although the
reason for this difference is not clear, one possible explanation is that the natural plakoridine A isolated
by Kobayashi’s group may be racemic.
Initially, an acetyl group was chosen for protecting the two hydroxy groups in 8 because of its small
steric hindrance and easy deprotection. However, we found that S-alkylation8 of the thiolactam 13 with
1-bromo-2-octadecanone in methylene chloride with the assistance of silver triflate followed by treatment
with triphenylphosphine and triethylamine did not give the desired olefin but delivered a polysubstituted
pyrrole 14. This product might result from the elimination of the 4-OAc. When the thiolactam 10 was
used for the Eschenmoser transformation, a similar elimination product (involving the 4-hydroxy as a
leaving group) was obtained. No S-alkylation occurred when the thiolactam 9 reacted with 1-bromo-2-
octadecanone, perhaps because of the larger steric hindrance of the silyloxy group. When the thiolactam
11 was used as a substrate in which the 4-OH is cis to 3-H, the elimination was depressed thereby giving
the desired olefin.
In conclusion, we have developed a stereoselective route to (2S,3S,4R)-plakoridine A from the
conveniently available β-amino ester 6. The overall yield for the 14 steps is about 3%. It is notable
that the present synthesis also provides an unusual example of an Eschenmoser sulfide contraction of a
fully substituted thiolactam, which will be a guide for synthesizing other polysubstituted pyrrolidines or
piperidines.
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences and National Natural Science Foundation
of China (grant 29725205) for their financial support. We thank Professor Kobayashi for providing NMR
spectrum of natural plakoridine A.
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9. Selected data for 1: IR (KBr) 3166, 2853, 1740, 1606 cm−1; 1H NMR (300 MHz, CHCl3) δ 7.03 (d, J=8.5 Hz, 2H), 6.99 (br
s, 1H), 6.81 (d, J=8.5 Hz, 2H), 5.40 (br s, 1H), 5.21 (d, J=5.5 Hz, 1H), 5.09 (s, 1H), 3.74 (s, 3H), 3.71 (m, 1H), 3.44 (m, 1H),
3.28 (m, 1H), 2.90 (t, J=5.5 Hz, 1H), 2.83–2.71 (m, 2H), 2.37 (t, J=6.6 Hz, 2H), 1.69 (m, 1H), 1.54 (m, 1H), 1.50 (m, 30H),
0.93 (t, J=7.1 Hz, 3H), 0.88 (t, J=6.9 Hz, 3H); FABMS m/z 572 (M++H+); 13C NMR (75 MHz, CDCl3) δ 199.9, 172.8, 165.8,
154.8, 129.9, 129.8, 115.7, 90.2, 75.9, 65.4, 52.6, 52.2, 46.2, 43.5, 35.3, 31.2, 29.7, 29.6, 29.4, 26.4, 22.7, 17.7, 14.1, 13.9.