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

Article abstract of DOI:10.1039/c8cc01626g

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

Full text of DOI:10.1039/c8cc01626g

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DOI: 10.1039/C8CC01626G
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ARTICLE
A Divergent and Concise Total Synthesis of (-)-Lycoposerramine R
and (+)-Lycopladine A
Received 00th January 20xx,
Accepted 00th January 20xx
Sheng Chen, Jinming Wang and Fayang G. Qiu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
concise, asymmetric and divergent synthesis of
In this paper, we report a facile, alternative entry to these
alkaloids that involves some novel chemistry involving a 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 lycoposserramine 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-2 via a sequence of a palladium-catalyzed cycloalkenylation of
silyl enol ether followed by a SeO2/TBHP oxidation. Silyl enol ether
RS-2 might be obtained from a 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 19 via the introduction of a
C3 unit.
lycoposerramine R and lycopladine A is presented. The synthesis
features a 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
(Figure 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 the 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-
kand 7 for lycopladine A (2), respectively.6l-r
Figure 1 The structures of lycoposerramine R, lycopladine A,
and fawcettimine
Scheme 1. Retrosynthetic analysis of (-)-lycoposerramine R (1)
and (+)-lycopladine A (2).
*
Guangzhou Institute of Biomedicine and Health, The University of the Chinese
Academy of Sciences, 190 Kaiyuan Avenue, The Science Park of Guangzhou,
Guangdong, 510530, China, and the University of Chinese Academy of Sciences,
Beijing, 100049, China. E-mail: qiu_fayang@gibh.ac.cn
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 =
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2.6:1) in 65% yield, oxidation of which with m-CPBA at -78oC the endo-olefin 6a with m-CPBA, followed by Al(Oi-Pr)3 and
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followed by warming to room temperature afforded enone 46q. oxidation by Dess-Martin reagent yielded 7 in 58% yield (Scheme 3).
DOI: 10.1039/C8CC01626G
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 oC to yield silyl enol
ether 5 in 85% overall yield.
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% yileds,
respectively. After many unfruitful attempts, it was found that
when treated with 10 mol% of palladium acetate in dry DMSO
Scheme 3. Synthesis of key intermediate 7.
Addition of 2-(phenylsufinyl)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
Scheme 2. Synthesis of silyl enol ether 5.
65% yield. Synthetic (-)-lycoposerramine R (1) was identical in all
respects to the natural product.
Table 1. Palladium-Catalyzed Cycloalkenylation of 5.
Entry
Catalyst (equiv)
Solvent
Temp
Additives (equiv)
6 (%)
6a (%)
1
2
PdCl2(PPh3)2 (1.0 )
Pd(CF2COOH)2
(1.0 )
THF
THF
RT
RT
-
-
0
0
trace
trace
3
4
5
PdCl2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (0.1)
THF
THF
THF
RT
RT
RT
-
-
23
35
6
10
17
2
.
Cu(OAc)2 H2O (1.0 )
6
7
8
9
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
THF
RT
Ag2CO3 (1.0 )
6
2
THF
RT
benzoquinone (1.0)
6
2
DMSO
DMSO
RT
O2
O2
33
48
16
26
45oC
Scheme 4. Total synthesis of (-)-lycoposerramine R (1).
under a balloon pressure of oxygen at 45oC, silyl enol ether 5
With intermediate 7 in hand, the synthesis of (+)-lycopladine A
underwent the cycloalkenylation and exo-olefin 6 was obtained in (2) was investigated (Scheme 5). When treated with (N-
48% yield together with endo-olefin 6a in 26% yield. Allylic vinylimino)phosphorene12 in dry benzene at 90oC in a sealed tube,
oxidation of 6 using SeO2/TBHP, followed by Dess–Martin oxidation intermediate 7 underwent cyclization to afford intermediate 11 in
yielded the desired key intermediate 7 in 63% yield. Treatment of 65% yield. Finally, removal of the benzyl group in 11 gave (+)-
lycopladine A (2) (70%). The synthetic (+)-lycopladine A (2) showed
2 | J. Name., 2012, 00, 1-3
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M. Kitajima and H. Takayama, Org. Biomol. Chem., 2015, 13
,
identical spectroscopic properties in all respects to the natural
product.
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7762; (k) W. W. Felix, T. F. Hartrampf and D. Trauner, Angew.
DOI: 10.1039/C8CC01626G
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,
Scheme 5. Total synthesis of (+)-lycopladine A (2).
10 B. Guillaume, St. O. Miguel and B. C. Andre, Org. Lett., 2008,
10, 5497.
11 T. Nishimura, A. K. Unni, S. Yokoshima, T. Fukuyama, J. Am.
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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.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China for the financial support of this work (Grant #21372221
and #21572228).
Notes and references
1
2
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