Synthetic study on L-755,807: Asymmetric synthesis of the epoxy-γ- lactam moiety

Article abstract of DOI:10.1016/S0957-4166(99)00041-5

The optically active epoxy-γ-lactam moiety (-)-4 of the B₂ selective bradykinin inhibitor L-755,807 1 was prepared from (S)-aldehyde 7 via an anti selective aldol reaction as the key step.

Full text of DOI:10.1016/S0957-4166(99)00041-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 675–678
Synthetic study on L-755,807: asymmetric synthesis of the
epoxy-γ-lactam moiety
Shinji Marumoto, Hiroshi Kogen ∗ and Shunji Naruto
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku Tokyo,
140-8710 Japan
Received 11 January 1999; accepted 28 January 1999
Abstract
The optically active epoxy-γ-lactam moiety (−)-4 of the B2 selective bradykinin inhibitor L-755,807 1 was
prepared from (S)-aldehyde 7 via an anti selective aldol reaction as the key step. © 1999 Published by Elsevier
Science Ltd. All rights reserved.
There has been increasing interest in naturally occurring epoxy-γ-lactam compounds due to their
important biological activities.1–3 For example, L-755,807 1 was isolated by a Merck research group1
from the endophytic Microsphaeropsis sp. as a new non-peptide bradykinin binding inhibitor4,5 to bind
to a cloned human B2 receptor (Fig. 1).
Figure 1.
∗
Corresponding author. E-mail: hkogen@shina.sankyo.co.jp
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00041-5

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S. Marumoto et al. / Tetrahedron: Asymmetry 10 (1999) 675–678
Epolactaene 2 was isolated from the culture broth of a marine microbe and showed potent neurite
outgrowth activity,2 and fusarin C 3 was isolated from fungus as a mutagenic agent.3a Additionally,
fusarin-related compounds were used to show neurite outgrowth activity similar to that shown in 2.3b
Among these compounds, epolactaene 2 was the only one to be synthesized and for which absolute
stereochemistry was determined.6 Extensive spectroscopic studies elucidated every aspect of the structure
of 1 except for the absolute stereochemistry of the epoxy-γ-lactam part and the relative configuration of
two methyl groups on the side chain (C23 and C24).1 Recently, Clark and Ellard synthesized the syn-
and anti-5 corresponding C12–C25 fragments of the side chain of 1.7 By comparing the calculated8
and observed NMR spectra between syn-5, anti-5, and 1, they deduced that the relative configuration
of the C23 and C24 methyl groups is syn. However, construction of the optically active epoxy-γ-lactam
moiety still remains to be performed. In this paper we wish to report on the asymmetric synthesis of the
epoxy-γ-lactam part 4 as a model compound.
We postulated that both 1 and 2 have the same absolute configuration for the epoxy-γ-lactam part since
both may be biosynthesized through the same pathway starting from amino acid precursors. Therefore,
(3R,4R)-epoxy lactam 4a (R=Ph) was selected for the target model of 1. According to our previously
reported asymmetric total synthesis of 2 via a syn selective aldol reaction,6a 4a was synthesized in 12
steps from the known (S)-aldehyde 7 as shown in Scheme 1. This time, the anti selective aldol reaction9
between racemic α-alkoxy aldehyde and malonate ester enolate was applied to optically active aldehyde
(S)-7.
Scheme 1. Reagents and conditions: i, ZnCl2, LiCH(CO2But)2, THF, −78°C (75%); ii, Me3SiOTf, 2,6-lutidine, CH2Cl2, 0°C
(70%); iii, LiHMDS, THF, −46°C to room temp. then I2, THF, −46°C; iv, TBAF, THF, −46°C to room temp. (64% from 9); v,
Pd(OH)2, H2, MeOH, 50°C (93%); vi, HCO2H, room temp.; vii, Me(MeO)NH·HCl, PyBOP®, i-Pr2EtN, CH2Cl2, 0°C (84%
from 12); viii, NH3, MeOH, room temp.; ix, Me3SiOTf, 2,6-lutidine, CH2Cl2, room temp. (73% from 14); x, (E)-BrCH_CHPh,
t-BuLi, THF, −78°C (80%); xi, 3HF·Et3N, DMF, room temp. (82%); xii, Dess–Martin reagent, CH2Cl2, room temp. then SiO2,
room temp. (89%)
The aldehyde (S)-710 was readily prepared from commercially available (S)-(+)-6 {[α]D +18 (c
22
1, CHCl3)} in four steps according to the reported procedure.11 An aldol reaction between aldehyde

S. Marumoto et al. / Tetrahedron: Asymmetry 10 (1999) 675–678
677
(S)-7 and lithium enolate of di-tert-butyl malonate in the presence of zinc chloride in THF at −78°C
proceeded with high diastereoselectivity (75% yield as a 97:3 ratio of isomers) to give desired isomer
anti-8, which was easily separable by silica gel flash column chromatography. The pure anti-8 was
treated with trimethylsilyltriflate (TMSOTf) in CH2Cl2 to give 9 in 70% yield. The O-TMS derivative 9
was converted to the anion by treatment with lithium hexamethyldisilazide (LiHMDS) in THF followed
by iodination to give α-iodo malonate derivative 10. Desilylation of iodide 10 with tetrabutylammonium
fluoride (TBAF) resulted in cyclization to produce epoxide 11 in 64% yield (from 9). Cleavage of the
O-benzyl group by Pd(OH)2 catalyzed hydration provided epoxyalcohol 12 in 93% yield. Treatment
of 12 with formic acid afforded lactone carboxylic acid 13, which was transformed to the Weinreb
amide 14 using (1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP®)12
and N,O-dimethylhydroxylamine in 84% yield from 12. Ammonolysis of 14 with concentrated ammonia
in methanol yielded amide 15 followed by protection of the generated secondary alcohol with the
trimethylsilyl group to give 16 (73% yield from 14). Reaction of the Weinreb amide 16 with 5 equiv.
of vinyllithium generated in situ by lithiation of commercially available 2-bromostyrene (E:Z=ca. 5:1)
with tert-butyllithium afforded (E)-α,β-unsaturated ketone 17 in 80% yield. The stereochemistry of the
1
double bond of 17 was confirmed by the large coupling constant (J=16 Hz) observed in the H NMR
spectrum. Deprotection of the silyl group with triethylamine trihydrofluoride furnished alcohol 18 in
82% yield. Finally, Dess–Martin oxidation of 18 provided the ketone which underwent lactamization
with silica gel to afford (−)-4a {[α]D22=−200 (c 0.60, MeOH)} in 89% yield, as an inseparable ca. 3:1
diastereomeric mixture at C5.
Table 1 shows a comparison of the 1H and 13C NMR spectra of (−)-4a with that of L-755,807 1 for the
lactam moiety. There is good agreement between them. This result suggests that the major isomer of (−)-
4a has the same relative configuration with L-755,807 1. The antipode of (−)-4a could be synthesized
from commercially available (R)-(−)-6 through the same procedure. The obtained result suggests that
fusarin C 3 and its related compounds belonging to the epoxy-γ-lactam family could be synthesized
from the appropriate starting materials. Further work towards the total synthesis of 1 is underway.
Table 1
13C (100 MHz) and 1H (400 MHz) chemical shifts for 1 and 4a in CH2Cl2

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