Total synthesis of (-)-isoschizogamine

Article abstract of DOI:10.1021/ja305856q

A first asymmetric total synthesis of (-)-isoschizogamine has been accomplished. Our synthesis features the facile construction of the carbon framework of the natural product through a Wagner-Meerwein rearrangement, a tandem metathesis, a stereoselective rhodium-mediated 1,4-addition of an arylboronic acid, and a ring-closing metathesis via a hemiaminal ether.

Full text of DOI:10.1021/ja305856q

Communication
pubs.acs.org/JACS
Total Synthesis of (−)-Isoschizogamine
Yusuke Miura, Noriyuki Hayashi,‡ Satoshi Yokoshima,† and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
Scheme 1. Retrosynthesis
ABSTRACT: A first asymmetric total synthesis of
(−)-isoschizogamine has been accomplished. Our syn-
thesis features the facile construction of the carbon
framework of the natural product through a Wagner−
Meerwein rearrangement, a tandem metathesis, a stereo-
selective rhodium-mediated 1,4-addition of an arylboronic
acid, and a ring-closing metathesis via a hemiaminal ether.
soschizogamine (1, Figure 1) was isolated in 1963 from
I
Schizozygia caffaeoides,1 whose structure was initially
Figure 1. Isoschizogamine and schizogamine.
assigned as an epimer at the C-7 position of the related indole
alkaloid, schizogamine (2).2 Intensive NMR studies led to the
revision of the structure of 1 as a highly fused hexacyclic
compound containing tetrahydroquinoline, hexahydroquinoli-
zine, and pyrrolidinone moieties.3 The two nitrogen atoms of
these heterocycles form an aminal that is adjacent to a
quaternary carbon. These fascinating structural features have
attracted the attention of synthetic chemists, and one racemic
total synthesis by Heathcock4 and two synthetic studies5 have
been reported to date. Herein we disclose a novel total
synthesis of isoschizogamine that features a unique approach to
the construction of the carbon framework.
As shown in our retrosynthesis (Scheme 1), the aminal
moiety would be constructed from diaminoketone 3. The
stereochemistry at C-2 could be controlled by enolization of the
ketone at a later stage of the synthesis.4 The double bond in 3
would be constructed by a ring-closing metathesis of diene 4.
An aromatic moiety of 4 could be incorporated via a 1,4-
addition to the α,β-unsaturated lactone 6. The cis-fused bicyclic
lactone 6 is expected to control the stereoselectivity of the 1,4-
addition. The bicyclic lactone 6 could be prepared by a tandem
metathesis of bicyclo[2.2.1]heptene 7, which would in turn be
derived from norbornene oxide 8 via a Wagner−Meerwein
rearrangement.6
with s-butyllithium, 10 underwent the Shapiro reaction9 to give
an alkenyllithium species, which was treated sequentially with
ethylene oxide and TBDPSCl to afford 11 in 79% yield.
Epoxidation of 11 with mCPBA proceeded stereoselectively to
furnish norbornene oxide 12.
With the requisite norbornene oxide in hand, we next
attempted the key Wagner−Meerwein rearrangement. Accord-
ing to Kleinfelter’s procedure,6 12 was treated with phenyl-
magnesium bromide in refluxing ether. While the reaction of 2-
phenylnorbornene oxide with phenylmagnesium bromide was
reported to form the gem-diphenyl product,6 12 underwent the
desired rearrangement to give 13 in 40% yield. The yield was
further optimized by careful selection of the substituent on the
aryl group and the halide ion in the Grignard reagent. The
optimal conditions were achieved when 12 was treated with o-
tolylmagnesium iodide in refluxing ether, giving 13 in 68%
yield. The hydroxy group in 13 was acylated with acryloyl
chloride to give 14 in 96% yield.
The crucial tandem metathesis to construct bicyclic lactone
16 required an extensive investigation of the reaction
conditions. The literature precedents suggested that the syn-
substitution to the double bond at the C7 position of the
norbornene would lower the reactivity of the double bond in
metathesis reactions.10 Indeed, treatment of 14 with the
Our synthesis commenced with the preparation of
norbornene oxide 12 by means of the Shapiro reaction
(Scheme 2). Oxidation of (+)-exo-norborneol7 9 by treatment
with TPAP and NMO8 afforded a ketone, which was converted
into the corresponding trisyl hydrazone 10. Upon treatment
Received: June 16, 2012
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja305856q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
moiety (Scheme 3). Treatment of 18 with allylamine resulted
in the ring opening of the lactone to give an amide. The
hydroxy group of this amide intermediate was oxidized with
Dess-Martin periodinane14 to furnish ketone 19. Attempted
ring-closing metathesis of 19, however, did not yield the desired
product. Because steric repulsion between the amide side chain
and the ketone moiety appeared to inhibit the approach of the
two double bonds, we decided to bring these double bonds
close together by connecting the nitrogen atom and the ketone
moiety. While formation of an enamide from 19 via
condensation between the ketone and the amide moieties
could not be achieved, acid-mediated cleavage of the TBDPS
group, followed by treatment with PPTS in refluxing toluene,
afforded hemiaminal ether 20. As expected, the ring-closing
metathesis of 20 using the second-generation Hoveyda−
Grubbs catalyst11 proceeded smoothly to give 21 in 97% yield.
The remaining tasks primarily involved introduction of the
nitrogen atom on the aromatic ring and construction of the
aminal moiety. Nitration of 21 by treatment with Cu(NO3)2 in
acetic anhydride proceeded smoothly. Reduction of the
resulting nitro group followed by protection with an Fmoc
group afforded 22. Treatment of 22 with TMSOTf induced
cleavage of the hemiaminal ether moiety to furnish, after
treatment with TBAF, alcohol 23. Oxidation of 23 followed by
protection of the resulting aldehyde15 afforded acetal 24.
Cleavage of the Fmoc group of 24 with piperidine in DMF
afforded amine 25, a known intermediate in Heathcock’s
racemic synthesis, which was converted to the natural product
according to the published protocol.4 Thus, reduction with
LiAlH4, cleavage of the ethylene acetal moiety in refluxing
acetic acid, and oxidation with PDC in methylene chloride
afforded (−)-isoschizogamine (1).
Scheme 2
a
Reagents and conditions: (a) TPAP, NMO, MS4A, CH2Cl2, rt; (b)
TrisNHNH2, conc HCl, MeCN, rt, 96% (2 steps); (c) s-BuLi, THF,
−78 to 0 °C; ethylene oxide in THF (1.2 M), −78 to 0 °C; TBDPSCl,
rt, 79%; (d) mCPBA, NaHCO3, CH2Cl2, 93%; (e) o-tolMgI, Et2O,
reflux, 68%; (f) acryloyl chloride, i-Pr2NEt, CH2Cl2, 96%; (g) Ru
catalyst 15, 1,6-heptadiene, benzene, 60 °C, 73%; (h) 3,4-
(MeO)2C6H3B(OH)2 (17), [RhCl(cod)]2, Et3N, aq dioxane, rt, 93%.
second-generation Hoveyda−Grubbs catalyst11 in refluxing
benzene afforded 16 in only 24% yield. Gratifyingly, we
found that the use of the highly reactive catalyst 1512 in the
presence of 1,6-heptadiene improved the yield of 16 to 73%
yield. A subsequent rhodium-catalyzed 1,4-addition of arylbor-
onic acid 17 to 16 proceeded smoothly with complete
stereoselectivity to furnish 18.13
In conclusion, we have achieved the first asymmetric total
synthesis of (−)-isoschizogamine. Key features of our synthesis
include a facile construction of the carbon framework of the
natural product using a Wagner−Meerwein rearrangement, a
tandem metathesis, a stereoselective rhodium-mediated 1,4-
Having established an efficient route to the key intermediate
18, we next focused on construction of the cis-double bond
a
Scheme 3
a
Reagents and conditions: (a) allylamine, 2-pyridone, THF, 50 °C, 84%; (b) Dess-Martin periodinane, CH2Cl2, rt, 99%; (c) conc HCl, MeOH, 0 °C,
98%; (d) PPTS, toluene, reflux, 72%; (e) the second-generation Hoveyda−Grubbs catalyst, toluene, 70 °C, 97%; (f) Cu(NO3)2·3H2O, Ac2O,
CH2Cl2, 0 °C, 97%; (g) NaBH4, Cu(acac)2, EtOH, rt; (h) FmocCl, i-Pr2NEt, CH2Cl2, 86% (2 steps); (i) TMSOTf, 2,6-lutidine, CH2Cl2, rt; (j)
TBAF, AcOH, THF, rt, 85% (2 steps); (k) Dess-Martin periodinane, CH2Cl2, rt; (l) (TMSOCH2)2, TMSOTf, CH2Cl2, −78 °C, 96% (2 steps); (m)
piperidine, DMF, rt; (n) LiAlH4, THF, reflux; (o) aq AcOH, reflux; (p) PDC, CH2Cl2, rt, 23% (4 steps).
B
dx.doi.org/10.1021/ja305856q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
addition of an arylboronic acid, and a ring-closing metathesis
via hemiaminal ether 20. The absolute configuration of natural
isoschizogamine, which was determined through comparison of
the observed and calculated VCD, ECD, and optical rotation,16
has been unambiguously confirmed by our synthesis.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization data, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
fukuyama@mol.f.u-tokyo.ac.jp
■
Present Address
†Graduate School of Pharmaceutical Sciences, Nagoya Uni-
versity, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
Notes
The authors declare no competing financial interest.
‡Visiting researcher from Daiichi Sankyo Co., Ltd.
ACKNOWLEDGMENTS
■
This work was financially supported by Grants-in-Aid for
Scientific Research (20002004, 22590002) from the Japan
Society for the Promotion of Science (JSPS), the Research
Foundation for Pharmaceutical Sciences, the Mochida Memo-
rial Foundation for Medical and Pharmaceutical Research, and
the Uehara Memorial Foundation. We also thank Dr. S.
Higashibayashi at the Institute for Molecular Science for helpful
discussions.
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