Synthetic studies toward the construction of the cis-decalin portion of superstolides A and B. Application of a sequential double Michael reaction and an anionic oxy-Cope rearrangement

Article abstract of DOI:10.1021/ol050339w

(Chemical Equation Presented) A highly convergent strategy for the asymmetric synthesis of the cis-decalin portion of the antitumor macrolide superstolide A was developed. The key reactions in our approach involve a sequential double Michael reaction and

Full text of DOI:10.1021/ol050339w

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1939-1942
Synthetic Studies toward the
Construction of the cis-Decalin Portion
of Superstolides A and B. Application of
a Sequential Double Michael Reaction
and an Anionic Oxy-Cope
Rearrangement
Zhengmao Hua, Wensheng Yu, Mei Su, and Zhendong Jin*
DiVision of Medicinal and Natural Products Chemistry, College of Pharmacy,
The UniVersity of Iowa, Iowa City, Iowa 52242
zhendong-jin@uiowa.edu
Received February 17, 2005
ABSTRACT
A highly convergent strategy for the asymmetric synthesis of the cis-decalin portion of the antitumor macrolide superstolide A was developed.
The key reactions in our approach involve a sequential double Michael reaction and an anionic oxy-Cope rearrangement.
As part of our program studying the chemistry and biology
of antitumor natural products, we initiated a project directed
toward the total synthesis of Superstolides A (1) and B (2)
that were isolated from the deep-water marine sponge
Neosiphonia superstes collected off New Caledonia.1 The
structural novelty of these two molecules is characterized
by a unique 16-membered macrolactone attached to a highly
functionalized cis-decalin (Figure 1).
expressing resistance toward doxorubicine P388 Dox, with
an IC50 of 20 ng/mL.1 These factors make both molecules
Superstolides A (1) and B (2) are highly cytotoxic against
human NSCLC-N6-L16 cells, with IC50 values of 40 and
39 ng/mL, respectively.1 They exhibited potent cytotoxicity
against murine leukemia P388 cells, with an IC50 of 3 ng/
mL, and human nasopharyngeal carcinoma KB cells, with
IC50 values of 20 and 5 ng/mL, respectively.1 In addition,
superstolide A is also highly cytotoxic against HT29 cells,
with an IC50 of 40 ng/mL, and murine leukemia cells
(1) (a) D’Auria, M. V.; Debitus, C.; Paloma, L. G.; Minale, L.; Zam-
pella, A. J. Am. Chem. Soc. 1994, 116, 6658. (b) D’Auria, M. V.;
Debitus, C.; Paloma, L. G.; Minale, L.; Zampella, A. J. Nat. Prod. 1994,
57, 1595.
Figure 1. Antitumor marine macrolide superstolildes A and B.
10.1021/ol050339w CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/12/2005

attractive synthetic targets.2 However, a complete total
synthesis has not yet been reported.
Our retrosynthetic analysis of superstolide A (1) is shown
in Scheme 1. Disconnections at C2-C3, C6-C7, and C19-
fragment 3. Compound 7 was envisaged to be formed via
an asymmetric double Michael reaction between 9 and the
cross-conjugated dienolate 10 derived from compound 11.
The major advantage of this double Michael approach might
be that it could take place at low temperature and give a
product with predominately endo selectivity as well as
excellent diastereofacial selectivity.3
Scheme 1. Retrosynthetic Analysis of Superstolide A
(R)-4-tert-Butyldimethyl-silyloxy-2-cyclohexen-one 11 is
a very useful building block that has been used in organic
synthesis on a number of occasions.4 The advantage of using
this compound as a starting material resides in the excellent
diastereoselectivity often observed in its conjugate additions
since all stereochemistry is introduced by communication
from the stereogenic center at the C-4 position of compound
11. However, to the best of our knowledge, asymmetric
double Michael reactions employing cross-conjugated di-
enolate 10 derived from compound 11 have never been
reported previously.
An enzymatic literature procedure was modified to prepare
compound 11 (Scheme 2).5 Bromination of cis-1,4-diacetoxy-
Scheme 2. Asymmetric Synthesis of
(R)-4-tert-Butyldimethyl-silyloxy-2-cyclohexen-one
2-cyclohex-ene 126 gave the trans-dibromo compounds 13a
and 13b in 95% yield. Asymmetric hydrolysis of 13 by
C20 reveal three key fragments 3-5 with intramolecular
Horner-Wadsworth-Emmons olefination, Julia-Kocienski
olefination, and Suzuki (or Stille) coupling playing crucial
roles in the synthetic strategy. Fragment 4 (C20-C26) of
superstolide A was successfully synthesized employing
Brown’s asymmetric crotylboronate methodology.2b Herein,
we report our synthetic studies toward the construction of
fragment 3, the cis-decalin portion of the molecule.
Fragment 3 is the core structure of the molecule. It is
highly functionalized with six stereogenic carbons, including
one quaternary carbon (Scheme 1). Disconnection at C13-
C14 would be a crucial step. An anionic oxy-Cope rear-
rangement of 7 was expected to give the cis-fused bicyclic
6, which after functional group manipulation would lead to
(3) (a) Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. Engl. 1993, 32,
1010 and references therein. (b) Ihara, M.; Makita, K.; Tokunaga, Y.;
Fukumoto, K. J. Org. Chem. 1994, 59, 6008 and references therein. (c)
Lee, R. A. Tetrahedron Lett. 1973, 14, 3333. (d) Nagaoka, H.; Kaoru, K.;
Okamura, T.; Yamada, Y. Tetrahedron Lett. 1987, 28, 6641. (e) Nagaoka,
H.; Shibuya, K.; Kobayashi, K.; Miura, I.; Muramatsu, M.; Yamada, Y.
Tetrahedron Lett. 1993, 34, 4039. (f) Maiti, S.; Bhaduri, S.; Achari, B.;
Banerjee, A. K.; Nayak, N. P.; Mukherjee, A. K. Tetrahedron Lett. 1996,
37, 8061. (g) Hagiwara, H.; Yamada, Y.; Sakai, H.; Suzuki, T.; Ando, M.
Tetrahedron 1998, 54, 10999. (h) Hagiwara, H.; Endou, S.; Fukushima,
M.; Hoshi, T.; Suzuki, T. Org. Lett. 2004, 6, 1115.
(4) (a) Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989, 111,
2599. (b) Jones, A. B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J.;
Ragan, J. A.; Smith, D. B.; Schreiber, S. L. J. Org. Chem. 1989, 54, 17.
(5) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia.
L. A. J. Org. Chem. 1991, 56, 2656. For asymmetric synthesis of 4-hydroxy-
2-cyclohexenone, see also: (a) Audia, J. E.; Boisvert, L.; Patten, A. D.;
Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738. (b) Gebauer,
O.; Bruckner, R. Liebigs Ann. 1996, 1559. (c) Carren˜o, M. C.; Garc´ıa Ruano,
J. L.; Garrido, M.; Ruiz, M. P.; Solladie´, G. Tetrahedron Lett. 1990, 31,
6653. (d) Brunjes, R.; Tilstam, U.; Winterfeldt, E. Chem. Ber. 1991, 124,
1677. (e) Evarts, J. B, Jr.; Fuchs, P. L. Tetrahedron Lett. 2001, 42, 3673.
(f) Demir, A. S.; Ozge, S. Org. Lett. 2002, 4, 2021. (g) Morgan, B. S.;
Hoenner, D.; Evans, P.; Roberts, S. M. Tetrahedron: Asymmetry 2004,
15, 2807.
(2) (a) Roush, W. R.; Champoux, J. A.; Peterson, B. C. Tetrahedron
Lett. 1996, 37, 8989. (b) Yu, W.; Zhang, Y.; Jin, Z. Org. Lett. 2001,
3, 1447. (c) Zampella, A.; D’Auria, M. V. Tetrahedron: Asymmetry
2001, 12, 1543. (d) Roush, W.; Hertel, L.; Schnaderbeck, M. J.; Yakelis,
N. A. Tetrahedron Lett. 2002, 43, 4885. (e) Yakelis, N.; Roush, W. R.
J. Org. Chem. 2003, 68, 3838. (f) Solsona, J. G.; Romea, P.; Urpi, F.
Org. Lett. 2003, 5, 4681. (g) Paterson, I.; Mackay, A. C. Synlett 2004,
1359. (h) Marshall, J. A.; Mulhearn, J. J. Org. Lett. 2005, 7, 1593-1596.
(6) Ba¨ckvall, J. E.; Gatti, R.; Schink, H. E. Synthesis 1993, 343.
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Org. Lett., Vol. 7, No. 10, 2005

Candida rugosa lipase (CRL) provided 14a and 14b in 88%
yield. Debromination followed by protection and hydrolysis
gave compound 16 in 92% yield. Oxidation of compound
16 afforded enantiomerically pure 11 in 98% yield. This
approach is highly reproducible and can easily be scaled up
(100 g scale) to give excellent overall yield with >98% ee.
Moreover, the approach can also be easily adapted to the
synthesis of the (S)-isomer of compound 11 through protect-
ing group manipulation.
The key reaction in our approach is a highly controlled
double Michael reaction for the asymmetric construction of
bicyclo[2.2.2]octanone 8 employing the cross-conjugated
dienolate 10 derived from compound 11. A model study has
been conducted to examine the feasibility of this key reaction.
Several R,â-unsaturated esters have been prepared and
carefully examined as partners in this double Michael
reaction. Scheme 3 shows the preparation of three represen-
tative R,â-unsaturated esters.
process occurred during the double Michael reaction since
two configurationally defined components reacted and four
new stereogenic centers were created in a controlled manner.
The stereochemical course was initially defined by the first
Michael addition that occurred from the endo approach of
the dienolate 10, anti to the bulky OTBS substituent, to the
re-face of the conjugate position of the Michael acceptor
23. The following two stereogenic centers in the second
Michael addition were imposed by the initial step. To the
best of our knowledge, this is the first successful application
of asymmetric double Michael reactions employing cross-
conjugated dienolate 10 derived from compound 11.
Treatment of compound 24 with an excess of DIBAL
provided diol 25 in 86% yield (Scheme 5). Regioselective
Scheme 5. Synthesis of Compound 30
Scheme 3. Preparation of R,â-Unsaturated Esters
We found that both compounds 9 and 21 were poor
partners in our double Michael reaction, and no desired
reaction was observed. However, compound 23 underwent
the requisite asymmetric double Michael reaction with 10
(Scheme 4).7 The reaction was highly facial- and stereo-
protection of the primary alcohol with a pivaloyl ester
followed by Dess-Martin oxidation of the secondary alcohol
gave compound 26 in 92% yield for two steps. Deprotection
of the TBS group followed by the conversion of the resulting
secondary alcohol to olefin afforded compound 27, which
underwent protecting group exchange to furnish ketone 28
in excellent yield. 1,2-Addition of vinyllithium reagent 29b8
to ketone 28 gave the tertiary alcohol 30 with complete
stereoselectivity, but the yield was only 35%. The low yield
was due to the extensive enolization of the ketone moiety
of compound 28 by vinyllithium 29b. Compound 31 was
isolated in 61% yield after the reaction was quenched with
Scheme 4. Asymmetric Double Michael Reaction Employing
Cross-Conjugated Dienolate 10 Derived from 11
(7) Cross-conjugated dienolate 10 was prepared by the addition of a
solution of 11 in THF to 1 equiv of LDA at -78 °C. The reaction mixture
was warmed to -40 °C in 30 min.
selective and afforded only one of the eight possible
diastereomers. An efficient double asymmetric induction
(8) Kraihanzel, C. S.; Losee, M. L. J. Orgnomet. Chem. 1967, 10, 427.
Org. Lett., Vol. 7, No. 10, 2005
1941

D2O. No improvement was observed when vinyl cerium
reagent 29c was employed in this reaction.
Now the stage was set for the proposed anionic oxy-Cope
rearrangement.9 Treatment of compound 30 with excess
KHMDS in DME at 115 °C in a sealed tube furnished the
cis-decalin 34 in 76% yield. Unfortunately, the acetonide
protecting group underwent a base-promoted â-elimination
after the desired anionic oxy-Cope rearrangement. Limiting
the amount of base KHMDS to 1 equiv did not prevent the
â-elimination, and a large amount of starting material 30
was also recovered. To solve this problem, we decided to
first remove the acetonide protecting group to give the free
diol, which was subjected to the anionic oxy-Cope rear-
rangement to afford the requisite compound 35 in 51% yield
(unoptimized).10 It should be noted that four stereogenic
centers in compound 35 have been set in their requisite forms
and two more stereogenic centers can be easily installed late
in the process. Currently, the conversion of compound 35
to fragment 3 is underway and will be reported in due course.
In conclusion, we have shown for the first time that cross-
conjugated dienolate 10 derived from compound 11 can be
employed in the double Michael reaction for the asymmetric
synthesis of highly functionalized bicyclo[2.2.2]octanone.
Furthermore, we have demonstrated that the combination of
our asymmetric double Michael reaction and an anionic oxy-
Cope rearrangement is a powerful approach for the synthesis
of the cis-decalin portion of the antitumor marine natural
products superstolides A and B.
We speculated that increased steric hindrance might
prevent the facile enolization of the ketone moiety of bicyclo-
[2.2.2]octanone. Therefore, we decided to investigate the
requisite 1,2-addition on a different substrate such as
compound 32 (Scheme 6). Hydrolysis of the pivaloyl ester
Scheme 6. Synthesis of cis-Decalin 35 via an Anionic
Oxy-Cope Rearrangement
Acknowledgment. This work was financially supported
by Research Project Grant RPG-00-030-01-CDD from the
American Cancer Society and a fellowship from the Center
for Biocatalysis and Bioprocessing at the University of Iowa
(to W. Yu).
Supporting Information Available: Experimental pro-
1
cedures and copies of H and 13C NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
26 followed by the protection of the primary alcohol with a
PMB group gave ketone 32. As expected, 1,2-addition of
vinyllithium reagent 29b to ketone 32 provided tertiary
alcohol 33 in 89% yield with complete stereoselectivity.
Deprotection of the TBS group followed by the conversion
of the resulting secondary alcohol to olefin afforded com-
pound 30 in excellent yield.
OL050339W
(9) (a) Paquette, L. A. Chem. Soc. ReV. 1995, 9 and references therein.
(b) Polniaszek, R. P.; Dillard, L. W. J. Org. Chem. 1992, 57, 4103.
(10) All compounds were fully characterized. The stereochemistry was
determined by extensive two-dimensional NMR analysis.
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Org. Lett., Vol. 7, No. 10, 2005