A divergent and concise total synthesis of (−)-lycoposerramine R and (+)-lycopladine A

Sheng Chen ab, Jinming Wang ab and Fayang G. Qiu *ab
aGuangzhou Institute of Biomedicine and Health, The Chinese Academy of Sciences, 190 Kaiyuan Ave., The Science Park of Guangzhou, Guangdong 510530, China. E-mail: qiu_fayang@gibh.ac.cn
bThe University of The Chinese Academy of Sciences, Beijing, 100049, China

Received 27th February 2018 , Accepted 8th March 2018

First published on 9th March 2018


Abstract

A concise, asymmetric and divergent synthesis of lycoposerramine R and lycopladine A is presented. The synthesis features the palladium-catalyzed cycloalkenylation of a silyl enol ether for assembling the 5/6-hydrindane system and generating a quaternary carbon center in one step.


Club mosses, such as Lycopodium complanatum and Lycopodium carinatum, are a rich source of structurally complex and biologically active alkaloids (Fig. 1).1–3 Lycoposerramine-R (1), isolated by Takayama and co-workers in 2009, was characterized to have a previously unknown skeleton consisting of a fused tetracyclic ring system with four chiral centers, a pyridone ring, and cis-fused hydrindane.4 Its simplified pyridine congener lycopladine A (2) was isolated from L. complanatum in 2006 and showed modest cytotoxicity against murine lymphoma cells.5 During the past decade, owing to their compact structures as well as their biological activities, these alkaloids have aroused the interest of a large number of research groups, whose studies have culminated in the completion of several elegant total syntheses of some lycopodium alkaloids and some new synthetic methodologies for assembling their core structures.6 To date, 4 total syntheses have been reported for lycoposerramine R (1)6h–k and 7 for lycopladine A (2), respectively.6l–r
image file: c8cc01626g-f1.tif
Fig. 1 The structures of lycoposerramine R, lycopladine A, and fawcettimine.

In this communication, we report a facile, alternative entry to these alkaloids that involves some novel chemistry involving the palladium-catalyzed cycloalkenylation of a silyl enol ether,7 a reaction that we believe will have general utility. As shown in the retrosynthetic analysis (Scheme 1), we reasoned that both lycoposerramine R (1) and lycopladine A (2) might be constructed from the common intermediate RS-1 through several different transformations. Intermediate RS-1 in turn might be accessed from silyl enol ether RS-2via a sequence of palladium-catalyzed cycloalkenylation of silyl enol ether followed by SeO2/TBHP oxidation. Silyl enol ether RS-2 might be obtained from the stereoselective conjugate addition of a Grignard reagent RS-4 prepared from commercial 4-bromo-1-butene8 to an α,β-unsaturated carbonyl compound RS-3, followed by trapping the enolate with TMSCl, while RS-3 could be derived from the readily accessible phenylsulfide 19via the introduction of a C3 unit.


image file: c8cc01626g-s1.tif
Scheme 1 Retrosynthetic analysis of (−)-lycoposerramine R (1) and (+)-lycopladine A (2).

Based on the above analysis, the synthetic strategy seemed feasible. Thus, alkylation of enolate of 1 (Scheme 2) with iodide 210 afforded phenylsulfenyl ketone 3 as a diastereomeric mixture (dr = 2.6[thin space (1/6-em)]:[thin space (1/6-em)]1) in 65% yield, oxidation of which with m-CPBA at −78 °C followed by warming to room temperature afforded enone 4.6q After the copper(I)-mediated conjugate addition of the Grignard reagent freshly prepared from 4-bromo-1-butene to enone 4 to generate an enolate, TMSCl was added at −20 °C to yield silyl enol ether 5 in 85% overall yield.


image file: c8cc01626g-s2.tif
Scheme 2 Synthesis of silyl enol ether 5.

At this stage, we began to investigate the key cycloalkenylation (Table 1). Surprisingly, treatment of the silyl enol ether 5 with stoichiometric amounts of palladium acetate in dry THF yielded exo-olefin 6 along with endo-olefin 6a in 35% and 17% yields, respectively. After many unfruitful attempts, it was found that when treated with 10 mol% of palladium acetate in dry DMSO under a balloon pressure of oxygen at 45 °C, silyl enol ether 5 underwent cycloalkenylation and exo-olefin 6 was obtained in 48% yield together with endo-olefin 6a in 26% yield. Allylic oxidation of 6 using SeO2/TBHP, followed by Dess–Martin oxidation yielded the desired key intermediate 7 in 63% yield. Treatment of the endo-olefin 6a with m-CPBA, followed by Al(Oi-Pr)3 and oxidation by the Dess–Martin reagent yielded 7 in 58% yield (Scheme 3).

Table 1 Palladium-catalyzed cycloalkenylation of 5

image file: c8cc01626g-u1.tif

Entry Catalyst (equiv.) Solvent Temp. Additives (equiv.) 6 (%) 6a (%)
1 PdCl2(PPh3)2 (1.0) THF RT 0 0
2 Pd(CF2COOH)2 (1.0) THF RT Trace Trace
3 PdCl2 (1.0) THF RT 23 10
4 Pd(OAc)2 (1.0) THF RT 35 17
5 Pd(OAc)2 (0.1) THF RT Cu(OAc)2·H2O (1.0) 6 2
6 Pd(OAc)2 (0.1) THF RT Ag2CO3 (1.0) 6 2
7 Pd(OAc)2 (0.1) THF RT Benzoquinone (1.0) 6 2
8 Pd(OAc)2 (0.1) DMSO RT O2 33 16
9 Pd(OAc)2 (0.1) DMSO 45 °C O2 48 26



image file: c8cc01626g-s3.tif
Scheme 3 Synthesis of key intermediate 7.

Addition of 2-(phenylsulfonyl)acetamide11 to intermediate 7 in the presence of sodium hydride, followed by treatment with methanolic hydrogen chloride, resulted in the formation of intermediate 8 in 62% yield (Scheme 4). Removal of the benzyl group by treatment with 10% Pd/C in EtOH under a hydrogen atmosphere gave intermediate 9 (85%). Dess–Martin oxidation of this alcohol yielded ketoaldehyde 10 (92%), which when treated with ammonium acetate in the presence of NaBH3CN in methanol at room temperature for 24 h afforded (−)-lycoposerramine R (1) in 65% yield. Synthetic (−)-lycoposerramine R (1) was identical in all respects to the natural product.


image file: c8cc01626g-s4.tif
Scheme 4 Total synthesis of (−)-lycoposerramine R (1).

With intermediate 7 in hand, the synthesis of (+)-lycopladine A (2) was investigated (Scheme 5). When treated with (N-vinylimino)phosphorene12 in dry benzene at 90 °C in a sealed tube, intermediate 7 underwent cyclization to afford intermediate 11 in 65% yield. Finally, removal of the benzyl group in 11 gave (+)-lycopladine A (2) (70%). The synthetic (+)-lycopladine A (2) showed identical spectroscopic properties in all respects to the natural product.


image file: c8cc01626g-s5.tif
Scheme 5 Total synthesis of (+)-lycopladine A (2).

In summary, by using a divergent strategy we have developed a concise, asymmetric total synthesis of both (−)-lycoposerramine-R (1) and (+)-lycopladine A (2) from known phenylsulfide 1 in 9 and 7 steps, respectively. The key features of the current synthesis include a palladium-catalyzed cycloalkenylation of silyl enol ether 5 for assembling the 6,5-fused hydrindane and generating a quaternary carbon center in one step. The application of these synthetic studies to an enantioselective synthesis of the related fawcettimine-type alkaloid 3 will be reported in due course.

We are grateful to the National Natural Science Foundation of China for the financial support of this work (Grant #21372221 and #21572228).

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc01626g

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