An approach to the skeleton of aspidophylline A

Article abstract of DOI:10.1021/ol4007713

An approach to the pentacyclic core of aspidophylline A is described. The strategy features CAN-mediated intramolecular azidoalkoxylation of enecarbamate and ruthenium-catalyzed atom transfer cyclization.

Full text of DOI:10.1021/ol4007713

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
An Approach to the Skeleton
of Aspidophylline A
Qi Li,† Guang Li,† Shaobo Ma,† Pengju Feng,† and Yian Shi*,†,‡
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China, and Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523, United States
yian@lamar.colostate.edu
Received March 21, 2013
ABSTRACT
An approach to the pentacyclic core of aspidophylline A is described. The strategy features CAN-mediated intramolecular azidoalkoxylation
of enecarbamate and ruthenium-catalyzed atom transfer cyclization.
Aspidophylline A (1), a monoterpene indole alkaloid
isolated by Kam and co-workers from K. singapurensis in
2007, has displayed the ability to reverse drug resistance
Scheme 1. Retrosynthetic Analysis of Aspidophylline A Skeleton
in drug-resistant KB cells (Figure 1).1 Aspidophylline A
contains an indoline fused with a tetrahydrofuran ring and
five contiguous chiral centers within a cyclohexane ring.
The unique structure and its interesting biological activity
make aspidophylline A an attractive synthetic target.
During our studies toward this compound, a total
synthesis of (()-aspidophylline A was recently reported
by Garg and his colleagues, involving an elegant interrupted
Fischer indole cyclization.2 Herein, we wish to report our
own efforts to assemble the skeleton of aspidophylline A.
The retrosynthetic analysis of aspidophylline A skeleton
(2) is outlined in Scheme 1. The aza-bicycle [3,3,1] moiety
of compound 2 could be constructed by ruthenium-
catalyzed atom transfer cyclization from trichloroaceta-
mide 3, which was envisioned to be derived from azide 4.
Figure 1. Structure of aspidophylline A.
† Chinese Academy of Sciences.
‡ Colorado State Untiversity.
(1) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama,
(2) Zu, L.; Boal, B. W.; Garg, N. K. J. Am. Chem. Soc. 2011, 133,
K.; Kam, T. S. J. Nat. Prod. 2007, 70, 1783.
8877.
r
10.1021/ol4007713
XXXX American Chemical Society

Compound 4 was conceived to be obtained by cerium
ammonium nitrate (CAN) mediated azidoalkoxylation of
enecarbamate 5, which could be prepared from 6 through
Heck cyclization and functional manipulations. Com-
pound 6 could be synthesized from two known compounds
N-tosyl-2-bromoaniline (7) and 2-allyl-2-cyclohexenol (8).
the Ts group by sodium naphthalenide (93% yield),6c,7
Swern oxidation (69% yield),8 the formation of enecarba-
mate with ClCO2Et and Et3N (64% yield),9 and subse-
quent desilylation by TBAF (91% yield).
Scheme 3. Synthesis of Compound 2
Scheme 2. Synthesis of Compound 5
With enecarbamate 5 in hand, azidoalkoxylation was
subsequently investigated. While the intermolecular azi-
doalkoxylation has been reported,10À13 the intramolecular
The synthesis of enecarbamate 5 is outlined in Scheme 2.
Readily available compounds 73 and 84 were coupled via a
Mitsunobu reaction to give compound 6 in 95% yield.5
The terminal alkene of 6 was selectively dihydroxylated
with OsO4/NMO and oxidatively cleaved by NaIO4 to
afford aldehyde 9 in 72% yield over two steps.5 Upon
reduction by NaBH4 and silylation with TBSCl, aldehyde
9 was converted to compound 10, which was subjected to
Mori’s conditions [10 mol % Pd(OAc)2, 20 mol %
Me2PhP, and 2 equiv of Ag2CO3 in DMSO at 105 °C]
for the Heck cyclization to afford indoline 11 in 73%
yield.6 The choice of Me2PhP is crucial to the suppression
of the olefin isomerization during the Heck reaction. Indo-
line 11 was converted to enecarbamate 5 via the removal of
Figure 2. X-ray structure of compound 4a.
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Org. Lett., Vol. XX, No. XX, XXXX

Figure 3. X-ray structure of compound 4b.
process is less explored. Treating 5 with NaN3 and CAN in
acetone at 0 °C gave azides 4a and 4b in 36% and 31%
yield, respectively (Scheme 3). The X-ray structures of 4a
and 4b are shown in Figures 2 and 3. Compound 4b was
readily reduced to amine 15 with Ph3P in quantitative
yield.14 Acylation of 15 with trichloroacetyl chloride and
Et3N gavetrichloroacetamide3in97%yield. Treatment of
3 with 6 mol % RuCl2(PPh3)3 in xylene at 150 °C yielded
the skeleton of aspidophylline A (2) in 52% yield (for the
X-ray structure see: Figure 4).15,16
Figure 4. X-ray structure of compound 2.
involve CAN-mediated intramolecular azidoalkoxylation
of an enecarbamate to construct the fused tetrahydrofuran
ring and ruthenium-catalyzed intramolecular atom trans-
fer cyclization to form the aza-bicycle [3,3,1] fragment. The
synthesis of aspidophylline A and its analogues using this
strategy will be pursued.
In summary, we have developed a rapid synthetic route
to the pentacyclic core of aspidophylline A. The key steps
Acknowledgment. We gratefully acknowledge the
National Basic Research Program of China (973 program,
2011CB808600) and the Chinese Academy of Sciences for
the financial support.
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Supporting Information Available. Experimental pro-
cedures, characterization data, and X-ray data of 4a, 4b,
and 2 along with NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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