A concise asymmetric total synthesis of (+)-fawcettimine

Article abstract of DOI:10.1016/j.tetlet.2020.152329

A straightforward and stereocontrolled total synthesis of (+)-fawcettimine was accomplished from the known (R)-5-methyl-2-cyclohexen-one in 11 steps. The synthesis features a palladium mediated cycloalkenylation of a silyl enol ether for assembling the 6/

Full text of DOI:10.1016/j.tetlet.2020.152329

Tetrahedron Letters 61 (2020) 152329
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Tetrahedron Letters
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A concise asymmetric total synthesis of (+)-fawcettimine
⇑
Xin Zeng, Zhuqing Jia, Fayang G. Qiu
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China
University of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward and stereocontrolled total synthesis of (+)-fawcettimine was accomplished from the
Received 31 May 2020
Revised 24 July 2020
Accepted 2 August 2020
Available online 28 August 2020
known (R)-5-methyl-2-cyclohexen-one in 11 steps. The synthesis features
a palladium mediated
cycloalkenylation of a silyl enol ether for assembling the 6/5-hydrindane system and generating a qua-
ternary carbon center in one step; an oxa-Diels-Alder reaction followed by a Mitsunobu reaction to con-
struct the Heathecock intermediate, i.e., the 6–5-9 tricycle skeleton.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Lycopodium alkaloids
Fawcettimine
Total synthesis
Introduction
cycloalkenylation of a silyl enol ether to synthesize the cis-fused
6–5 bicycle and the oxa-Diels-Alder reaction of the
a,b-unsatu-
The Lycopodium alkaloids have attracted great interest from
researchers because these compounds are both structurally inter-
esting and biologically active [1–4]. This class of alkaloids includes
some 300 natural products isolated from over 50 of the 500 extant
species in the Lycopodium genus of club mosses [5]. Since 1959,
over 80 members of the fawcettimine class of the Lycopodium alka-
loids have been discovered. The fawcettimine (1) subclass pos-
sesses a cis-fused 6,5-hydrindane framework with an all-carbon
quaternary center and an azonane ring (Fig. 1). Fawcettimine was
the first member of this type isolated from Lycopodium fawcetti
by Burnell in 1959 [6]. It has attracted considerable attention from
synthetic chemists. Inubushi completed the first synthesis of faw-
cettimine in 1979 via 6–5-9 tricycle (Scheme 1) which had a mix-
ture of diastereomers at the C4 center [7]. Heathcock pioneered
conformational studies through the construction of 6–5-9 tricycle
(called Heathcock intermediate) to the synthesis of fawcettimine
in 1986 [8]. Many elegant total syntheses of fawcettimine-type
alkaloids have been reported in the past decade [9]. One of the
big challenge of the synthesis of the tricycle intermediate was to
install the quaternary center of the 6/5-hydrindane moiety. So
far, the syntheses of fawcettimine and related molecules shared
the initial innovative construction of the cis-fused 6–5 bicycle,
and completion via the Heathcock intermediate (6–5-9 tricycle).
Herein we report a new synthesis of fawcettimine via a stereo-
rated ketone for the construction of the 6–5-9 tricycle.
Results and discussion
The retrosynthetic analysis
The retrosynthetic analysis is detailed in Scheme 1. Based on
Heathcock’s finding [8], fawcettimine could be formed via isomer-
ization to the thermodynamically favored b-diastereomer at the
C4 position under basic conditions. The 6–5-9 tricycle precursor
6 could be assembled via a Mitsunobu reaction from 7, which
in turn could be derived from the oxa-Diels-Alder reaction, selec-
tive reduction and amination of 8. The cis-fused 6/5 bicycle 9 may
be constructed via a Pd-mediated intramolecular cycloalkenyla-
tion [10,11] from silyl enol ether 10. Thus the total synthesis
may be achieved by employing enone 11 in enantiomerically pure
form.
Syntheses of (+)-Fawcettimine
Based on the above analysis, the synthesis was commenced
from the known (R)-5-methyl-2-cyclohexen-one 11 which was
readily prepared from commercially available (R)-(+)-pulegone
according to a previously reported procedure [12].
a-Iodination
controlled strategy involving
a
novel palladium-catalyzed
under K2CO3/DMAP/I2 conditions followed by Suzuki À Miyaura
coupling with alkylborane 13 afforded the coupling product 14
(Scheme 2). After the Michael addition of the Grignard reagent
15 freshly prepared from 4-bromo-1-butene [13] to enone 14 to
⇑
Corresponding author.
E-mail address: qiu_fayang@gibh.ac.cn (F.G. Qiu).
https://doi.org/10.1016/j.tetlet.2020.152329
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

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X. Zeng et al. / Tetrahedron Letters 61 (2020) 152329
Fig. 1. The structures of fawcettimine and related molecules.
Scheme 1. Restrosynthetic analysis of (+) fawcettimine.
generate an enolate, TMSCl was added to trap the enolate to yield
silyl enol ether 16 in a one-pot fashion in 89% overall yield [6e].
The key cycloalkenylation usually generates 5-exo-olefin along
with 6-endo-olefin in a certain ratio [14]. Delightfully, good selec-
tivity (17:18) was achieved when tert-butylchlorodiphenyl-silane
was chosen as a protecting group of 3-hydroxypropane side chain.
Stoichiometric Riley oxidation of the allylic position with sele-
nium dioxide, followed by the addition of Martin reagent furnished
the desired intermediate 19 in 69% yield. The following oxa-Diels-
Alder reaction catalyzed by EuFOD proceeded smoothly [15] and
the resulting mixture was treated with p-toluene sulfonic acid in
acetone to generate aldehyde 21 in 93% yield.
With aldehyde 21 in hand, the global reduction was conducted
with NaBH4. Considering the high water solubility of 22, the result-
ing mixture was then treated with methanesulfonyl chloride to
give mesylate 23 under À20℃. The amination with p-NH2Ns pro-
ceeded smoothly. Without purification, the following Dess-Martin
oxidation of the product furnished intermediate 24 in 72% yield
over two steps.
The efficient formation of the azonane ring is a critical step for
this synthesis. Since the application of the Mitsunobu reaction for
the formation of the azonane framework in total synthesis was
reported previously [9c,16], thus, after the cleavage of the silyl pro-
tecting group of compound 24 under acidic conditions, the closure

X. Zeng et al. / Tetrahedron Letters 61 (2020) 152329
3
Scheme 2. Total systhesis of (+) -fawcettimine.
of the key Heathcock-type 6–5-9 tricycle 25 was accomplished fol-
Appendix A. Supplementary data
lowing treatment with DEAD/Ph3P.
Upon desulfonation of precursor 25, the (+)-fawcettimine free
base was obtained in 81% yield after C-4 epimerization and aminal
formation [9i,9n]. After treatment with aqueous HBr (1 M) the cor-
responding HBr salt was obtained. The spectral data of the syn-
thetic (+)-fawcettimine as well as its HBr salt were identical to
those reported [8,9a], including 1H NMR, 13C NMR data, mass spec-
tra and optical rotation.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152329.
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In summary, we have developed a concise, asymmetric total
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Highlights of the synthesis include
a palladium-catalyzed
cycloalkenylation of silyl enol ether to assemble the 6,5-fused
hydrindane and generate a quaternary carbon center in one step,
and a facile construction of the key Heathecock intermediate- 6–
5-9 tricycle via an oxa-Diels-Alder reaction followed by a Mit-
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We gratefully acknowledge the financial support from the NSFC
(grant #21772200, 21971243).
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