Total Synthesis of Huperzine Q

Article abstract of DOI:10.1021/acs.orglett.7b01633

The total synthesis of huperzine Q was accomplished. The synthesis features the construction of the cis-hydrindane skeleton via a Diels-Alder reaction and a ring contraction reaction of an epoxyketone.

Full text of DOI:10.1021/acs.orglett.7b01633

Letter
pubs.acs.org/OrgLett
Total Synthesis of Huperzine Q
Shun Tanimura,†,‡ Satoshi Yokoshima,*,† and Tohru Fukuyama*,†
†Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan
‡Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
S
* Supporting Information
ABSTRACT: The total synthesis of huperzine Q was accomplished. The synthesis features the construction of the cis-
hydrindane skeleton via a Diels−Alder reaction and a ring contraction reaction of an epoxyketone.
uperzine Q (1, Figure 1) is an alkaloid isolated from
Lycopodium serratum by Zhu and co-workers in 2002.1,2
Scheme 1. Construction of the cis-Hydrindane Core via a
Diels−Alder Reaction
H
Figure 1. Structures of huperzine Q and fawcettimine.
It is classified as a fawcettimine-type Lycopodium alkaloid.
Although the core structure, cis-hydrindane, is identical to that
of fawcettimine (2), the presence of an additional N,O-acetal
moiety at C13 distinguished itself from 2. The formation of the
N,O-acetal moiety in huperzine Q was first achieved by
Takayama and co-workers in 2011 via dehydration of the
corresponding hemiaminal by treatment with CSA in refluxing
toluene, leading to the total synthesis of huperzine Q.3 Lei and
co-workers reported the formation of the N,O-acetal moiety via
bromination of an enamine in their synthesis of huperzine Q.4
The construction of the cis-hydrindane core of the
Lycopodium alkaloids, which contains a quaternary carbon,
has received significant attention, and a variety of synthetic
strategies have been explored.2i−m A Diels−Alder reaction was
employed to construct the cis-fused bicyclic system in one such
strategy. Diels−Alder reactions between a diene and cyclo-
pentene derivative 3 can directly provide cis-hydrindane 4
(Scheme 1).5 Inubushi and co-workers carried out a Diels−
Alder reaction of cyclohexenone 5 with 1,3-butadiene to
produce a cis-decaline 6, which was converted into the cis-
hydrindane skeleton 8 via oxidative cleavage of the cyclohexene
moiety in a later step, followed by the intramolecular aldol
condensation of the resulting dialdehyde 7.6 Although
Inubushi’s strategy required a subsequent ring contraction to
form the cis-hydrindane skeleton, the carbonyl group at C13
and the stereogenic center at C15, both of which originated
from the cyclohexenone, could be directly used for the
synthesis of fawcettimine and related molecules. We envisioned
that the side chain on the cis-hydrindane core might be installed
as a part of the diene unit.7 Herein, we disclose our total
Received: May 31, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01633
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Total Synthesis of Huperzine Q
synthesis of huperzine Q by means of a Diels−Alder reaction
between 9 and 10 and a subsequent ring contraction reaction.
Our synthesis commenced with the benzylation of the
known hydroxyketone 138 according to Dudley’s protocol by
using the reagent A (Scheme 2).9 α-Iodination, followed by
Suzuki−Miyaura coupling10 with alkylborane B, afforded the
coupling product 16. The crucial Diels−Alder reaction of 16
with diene C11 in the presence of zinc chloride occurred at the
opposite side of the benzyloxymethyl group on the cyclo-
hexenone ring to furnish cis-decaline 17 as an inseparable
mixture of the endo- and exo-isomers (dr = 1.5:1).12,13
of the ketone moiety in 24 were simultaneously achieved via
the Birch reduction, leaving the hemiaminal moiety intact.
Finally, the formation of the N,O-acetal moiety was carried out
according to Takayama’s procedure to furnish huperzine Q
(1).3a
In summary, we have achieved a total synthesis of huperzine
Q in the racemic form. The Diels−Alder reaction constructed
the cis-decaline system, which was converted into the cis-
hydrindane core of the natural product via a ring contraction
reaction of the epoxyketone.
Having constructed the cis-decaline system, we next focused
on the conversion into the cis-hydrindane core. We found that a
ring contraction reaction of an epoxyketone was effective for
this purpose.14 The silyl enolate moiety in 17 was oxidized with
DDQ to afford enone 18.15 Sequential cleavage of the Boc and
TBDPS groups gave hydroxy nosylamide 19, which, upon
subjection to the Mitsunobu reaction conditions16 with di(2-
methoxyethyl) azodicarboxylate (DMEAD),17 underwent cyc-
lization to produce the tricyclic compound 20.18 Nucleophilic
epoxidation of the enone moiety in 20 afforded epoxyketone 21
under standard conditions.14a,19 Upon treatment with TMSOTf
in dichloromethane at −78 °C, 21 underwent a selective
cleavage of the epoxide, followed by a 1,2-shift of the carbonyl
group, to give a ring-contracted product 23 in 91% yield.
Transformation of ketoaldehyde 23 into huperzine Q (1)
proceeded uneventfully. Under the conditions for removal of
the nosyl group, cleavage of the formyl group occurred
concomitantly by the addition of methanol to afford hemi-
aminal 24. The stereochemistry at C4 was thermodynamically
controlled during the formation of the hemiaminal moiety.20
Cleavage of the benzyl group and the stereoselective reduction
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01633.
Experimental procedures, spectroscopic data, and 1H and
13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: yokosima@ps.nagoya-u.ac.jp.
*E-mail: fukuyama@ps.nagoya-u.ac.jp.
ORCID
Satoshi Yokoshima: 0000-0003-4036-0062
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.7b01633
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(14) (a) House, H. O.; Wasson, R. L. J. Am. Chem. Soc. 1957, 79,
1488. (b) Ryerson, G. D.; Wasson, R. L.; House, H. O. Org. Synth.
1959, 39, 70. For recent examples, see: (c) Guerrab, Z.; Daou, B.;
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ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI (Grant
Numbers 25221301, 26713001, and 16H01141) and by the
Platform Project for Supporting Drug Discovery and Life
Science Research (Platform for Drug Discovery, Informatics,
and Structural Life Science) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (MEXT) and
the Japan Agency for Medical Research and Development
(AMED).
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C
DOI: 10.1021/acs.orglett.7b01633
Org. Lett. XXXX, XXX, XXX−XXX