Synthetic studies on quassimarin and simalikalactone D: Functionalization of ring C

Article abstract of DOI:10.1016/S0040-4039(01)00964-9

The tricycle 18 containing the oxygenated ring C is constructed from (S)-carvone in 14 steps involving a Shapiro reaction and a selective acylation as the key steps.

Full text of DOI:10.1016/S0040-4039(01)00964-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5271–5273
Synthetic studies on quassimarin and simalikalactone D:
functionalization of ring C
Qin Jiang and Tony K. M. Shing*
Department of Chemistry, The Chinese University of Hong Kong, Hong Kong, China
Received 3 April 2001; accepted 1 June 2001
Abstract—The tricycle 18 containing the oxygenated ring C is constructed from (S)-carvone in 14 steps involving a Shapiro
reaction and a selective acylation as the key steps. © 2001 Elsevier Science Ltd. All rights reserved.
Among the pentacyclic quassinoids,1 quassimarin (1)
and simalikalactone D (2) are important synthetic
targets because of their potent activity in vivo against
the P-388 lymphocytic leukemia in mice and in vitro
against human carcinoma of the nasopharynx at the
10−3 mg/mL level.2 They have also been shown to
possess marked differential solid tumor selectivity.3
Both quassimarin (1) and simalikalactone D (2) pos-
sess a C20 picrasane carbon framework, but have a
different butyrate ester at C(15).
Functionalization of ring C in 6 by installing a trans-
diaxial diol at C(11) and C(12) has been unsuccessful,
attributable to the sensitive lactone D ring. We rea-
soned that construction of the diol moiety at an early
stage should solve the problem. This letter describes
our endeavors in the preparation of a functionalized
ring C intermediate that could be transformed into the
target molecules.
In our quest for the first enantiospecific entry to quas-
simarin 1 and simalikalactone D 2, we have reported
that (S)-(+)-carvone 3 could be transformed into diol
5, and then into a pentacyclic quassinoid skeleton 6 in
18 steps with an overall yield of 22%.4
Our initial attempt was to protect the isopropenyl
group and the primary alcohol in 5 in one-pot so that
the remaining secondary alcohol could be eliminated.
Towards this end, bromocyclization of diol 5 with
N-bromosuccinimide (NBS) caused the formation of
Keywords: quassinoids; antitumour compounds; elimination reactions.
* Corresponding author. Tel.: +852 2609 6367; fax: +852 2603 5057; e-mail: tonyshing@cuhk.edu.hk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00964-9

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Q. Jiang, T. K. M. Shing / Tetrahedron Letters 42 (2001) 5271–5273
Scheme 1.
bromo-tetrahydrofuran 7 in a good yield (Scheme 1).
However, the free secondary alcohol could not be elim-
inated to give the corresponding alkene 8 under a
number of reaction conditions. We speculated that the
rigid tricycle 8 might not be flexible enough to accom-
modate three sp2 carbons in ring C.
followed by protection of the diol at C(7) and C(14)
(quassimarin numbering) with 2,2-dimethoxypropane
afforded the acetonide 10 in a moderate yield. The
constitution of the acetonide 10, especially the stereo-
chemistry of the a-proton at C(14) and the epoxy
bridge between C(13) and C(20), was confirmed by an
X-ray crystallographic analysis.5 Oxidation of the ace-
tonide 10 with Dess–Martin periodinane6 yielded
ketone 11 in an excellent yield. Exposure of ketone 11
to tosylhydrazine in the presence of a catalytic amount
of tosic acid afforded a quantitative yield of hydrazone
12. Shapiro reaction7 of the hydrazone 12 with tert-
butyllithium in THF resulted in a 73% yield of alkene
13 (86% conversion). Stereoselective dihydroxylation of
alkene 13 with a catalytic amount of OsO4 furnished
cis-diol 14 in 86% yield. The stereochemistry of the
b-protons at C(11) and C(12) in diol 14 was confirmed
by 1H NMR spectral analysis of its corresponding
In view of these failures, we revised our approach by
reducing the ketone moiety first before attempting the
elimination of the secondary alcohol. Hence, stereo-
selective reduction of the ketone group in 4 with NaBH4
in the presence of CeCl3·7H2O gave a quantitative yield
of b-alcohol 9 (Scheme 2). Exposure of b-alcohol 9 to
trifluoroacetic acid (TFA) in ethanol at about 50°C
1
diacetate 15. The H NMR spectrum of 15 showed that
H12 appeared at l 5.19 ppm as a doublet (J12,11=4.5
Hz), H11 appeared at l 5.48 ppm as a doublet of
doublets (J11,12=4.5 Hz and J11,9=12 Hz), and H9
appeared at l 2.44 ppm as a doublet (J9,11=12 Hz).
The small coupling constant of 4.5 Hz was consistent
with H12 occupying the equatorial position (b-face) and
the large coupling constant of 12 Hz was consistent
with both H11 and H9 being in the axial position which
supported our assignment of the stereochemistry of the
C(11a) and C(12a) diacetate unit in 15 (Fig. 1).
Regioselective protection of the C(12a) hydroxy group
with phosgene iminium chloride in the presence of
triethylamine produced the a-hydroxy carbamate 16 in
82% yield.8 A plausible mechanism is shown in Fig. 2.
The favorable protonation of the less hindered equato-
rial alkoxy moiety in the cyclic intermediate led to the
selective protection of the axial hydroxy group at the
C(12) position.
Inversion of configuration of the C(11a) hydroxy group
in 16 was accomplished via a two-step oxidation–reduc-
tion sequence. Swern oxidation9 of the free alcohol in
carbamate 16 followed by reduction with NaBH4
yielded the desired b-hydroxy carbamate 17 and the
a-hydroxy carbamate 16. The ratio of 17 to 16 was
Scheme 2. (a) NaBH4, CeCl3·7H2O, MeOH, 0°C (100%); (b)
TFA, EtOH, 50°C; (c) (MeO)2CMe2, pTsOH (cat.), CH2Cl2,
rt (40% overall yield); (d) Dess–Martin periodinane, CH2Cl2,
rt (93%); (e) pTsNHNH2, pTsOH (cat.), MgSO4, THF, rt
(100%); (f) t-BuLi, THF 0°C to rt (73%, 86% conversion); (g)
NMO·H2O, OsO4 (cat.), acetone/H2O (5:1, v/v), rt (86%); (h)
DMAP, Ac2O, CH2Cl2, rt (94%); (i) phosgene iminium chlo-
ride, Et3N, CH2Cl2, reflux (82%); (j) DMSO, TFAA, CH2Cl2,
−78°C then Et3N −78°C to rt; (k) NaBH4, MeOH, rt (overall
90%).
Figure 1.

Q. Jiang, T. K. M. Shing / Tetrahedron Letters 42 (2001) 5271–5273
5273
Acknowledgements
Financial support from Hong Kong RGC (Ref. No.
CUHK 4185/97P) is gratefully acknowledged.
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Figure 2.
2.3:1. Acetylation of 17 provided the b-acetate 18.
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H11 at l 5.14 ppm as a doublet of doublets (J11,12=1.2
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ring C in quassimarin and simalikalactone D. Starting
from (S)(+)-carvone, the tricycle 18 comprising the
functionalized CE ring has been constructed in 14
steps with an overall yield of 12%. Conversion of
tricycle 18 into the target molecules quassimarin and
simalikalactone D is under investigation.
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