Synthesis of Fasicularin

Article abstract of DOI:10.1021/acs.orglett.6b01669

The synthesis of a tricyclic marine alkaloid, fasicularin, was accomplished. Stereoselective synthesis of the aza-spirocyclic BC-ring precursor and ensuing construction of the A-ring with stereocontrolled installation of the C2 hexyl group feature prominently in the synthesis.

Full text of DOI:10.1021/acs.orglett.6b01669

Letter
pubs.acs.org/OrgLett
Synthesis of Fasicularin
Atsushi Kaga, Ya Lin Tnay, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: The synthesis of a tricyclic marine alkaloid,
fasicularin, was accomplished. Stereoselective synthesis of the
aza-spirocyclic BC-ring precursor and ensuing construction of
the A-ring with stereocontrolled installation of the C2 hexyl
group feature prominently in the synthesis.
asicularin (1) is a marine tricyclic alkaloid isolated from
ascidian Nephteis fasicularis1 and exhibits cytotoxicity
Scheme 1. Retrosynthesis
F
through alkylation of the cellular DNA (Figure 1).2 The
Figure 1. Fasicularin and lepadiformines.
structure of fasicularin (1) is based on the trans-1-azadecalin
AB-ring of chair−chair conformation, which is connected with
the piperidine C-ring having a thiocyanate unit. There is
another class of marine tricyclic alkaloids, lepadiformines (2),3
which contain the twist boat−chair trans-1-azadecalin AB-ring
fused with the hydroxymethyl pyrrolidine C-ring. The differ-
ence of the AB-ring conformation between fasicularin (1) and
lepadiformines (2) is attributed to the stereochemistry of C2
with the alkyl chain; fasicularin (1) bears a β-hexyl group, while
the C2-alkyl group of lepadiformines (2) is oriented α. Their
unique chemical structures and biological activities have
stimulated many groups to be engaged in synthetic studies of
these classes of alkaloids.4−6 Our group has been independently
engaged in synthetic studies of them. We herein report a new
approach for the stereoselective synthesis of fasicularin (1) that
takes advantage of the characteristic structure of the spirocyclic
BC-ring precursor.
Our retrosynthetic analysis is illustrated in Scheme 1. It was
reported by Kibayashi that fasicularin (1) could be approached
from C2-epi-lepadiformine A (3).5c It is envisaged that C2-epi-
lepadiformine A (3) would be derived from the spirocyclic
iminoester 4 having a bromo substituent at C5 trans to the
C10−N bond through A-ring construction. Azaspirocycle 4
would be constructed by aminobromination of α-azido ester 5,
which could be synthesized from 1-(2-bromoethyl)cyclohexene
(6)7 and diethyl oxalate (7).
Our synthesis commenced with the reaction of the Grignard
reagent prepared from bromide 6 with diethyl oxalate (7) to
afford α-keto ester 8, which was subsequently converted into α-
azido ester 5 in a three-step sequence involving reduction of the
keto carbonyl group by NaBH3CN, mesylation of the resulting
hydroxyl group, and azidation through nucleophilic substitution
with NaN3 (Scheme 2). Treatment of α-azido ester 5 with NBS
in the presence of NaHCO3 could induce denitrogenative
spirocyclization through trans-aminobromination of alkene,
forming desired spirocyclic iminoester 4 in good yield.
We next focused on the introduction of carbon functionality
at C5 for construction of the A-ring. Reduction of the CN
bond of 4 by NaBH4 resulted in formation of tricyclic aziridine
9 in a diastereoselective fashion (Scheme 3).8 In this process,
the hydride reduction occurred from the sterically less hindered
β-face, which was followed by an intramolecular nucleophilic
substitution reaction at C5 to form the aziridine ring.
Treatment of aziridine 9 with benzyl iodide (prepared in situ
Received: June 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of 4
Scheme 4. Synthesis of Fasicularin (1)
Scheme 3. Synthesis of 10
In summary, we have achieved the synthesis of fasicularin
(1). The characteristic feature of the synthesis includes
construction of the azaspirocyclic BC-ring intermediate through
spirocyclizing aminobromination of α-azido ester and stereo-
selective installation of the cyano group at C5 via ring opening
of the aziridine ring as well as A-ring construction with
stereocontrolled installation of the β-hexyl group.14
from BnBr and NaI) followed by addition of Bu4NCN to the
resulting N-benzyl aziridinium ion successfully opened the
aziridine ring with installation of a cyano group at C5 in a regio-
and stereoselective manner, affording azaspirocycle 10.9
Chemoselective reduction of the ethoxy carbonyl group of 10
by Red-Al provided alcohol 11 (Scheme 4).10,11 Without
protection of the hydroxyl group of 11, the cyano group was
reduced with DIBAL to form the corresponding aldehyde,
which was subsequently converted into α,β-unsaturated ester
12 by the reaction with triethyl phosphonoacetate under the
Masamune−Roush protocol.12 Hydrogenation to reduce the
CC bond and remove N-benzyl protection followed by
DIBAL reduction of the ethoxy carbonyl group produced
tetracyclic N,O-acetal 13. The reaction of 13 with hexylmagne-
sium bromide enabled stereoselective ring opening of the N,O-
acetal with inversion of the configuration to afford alcohol 14
having a β-hexyl group at C2.13 Alcohol 14 was converted into
methyl ester 15 through Jones oxidation followed by
esterification of the resulting carboxylic acid with trimethylsilyl
diazomethane. Subsequent treatment of ester 15 with NaOMe
enabled epimerization of C13, and ensuing LiAlH4 reduction
delivered C2-epi-lepadiformine A (3). Finally, installation of the
thiocyanate unit and ring expansion of 3 were conducted
according to the Kobayashi’s method to complete the synthesis
of fasicularin (1), which was obtained as a mixture with its
structural isomer 16. The synthetic sample was identical to the
natural product by comparison with the reported spectroscopic
data (1H and 13C NMR, MS).5c
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01669.
Experimental procedures, spectral data (PDF)
Crystallographic data for compound 10 (CIF)
Crystallographic data for compound 19 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shunsuke@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funding from Nanyang
Technological University and the Singapore Ministry of
Education and Singapore Ministry of Education (Academic
B
DOI: 10.1021/acs.orglett.6b01669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
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Research Fund Tier 1: RG4/13). We acknowledge Dr. Yongxin
Li and Dr. Rakesh Ganguly (Division of Chemistry and
Biological Chemistry, Nanyang Technological University) for
assistance in X-ray crystallographic analysis. We thank Dr. Wei
Ren and Yan Zhu (Division of Chemistry and Biological
Chemistry, Nanyang Technological University) for their
assistance in carrying out several experiments in the initial
study.
(13) Craig demonstrated in the synthesis of lepadiformine A that ring
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interestingly, the reaction of hemiaminal 13 with the hexynyl Grignard
reagent resulted in inversion of the configuration to form β-alkynyl 19
as a single isomer, the stereochemistry of which was confirmed by X-
ray single crystallographic analysis (see the Supporting Information).
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C
DOI: 10.1021/acs.orglett.6b01669
Org. Lett. XXXX, XXX, XXX−XXX