Enantioselective synthesis of the ABC ring motif of norzoanthamine based on asymmetric robinson annulation reactions

Article abstract of DOI:10.1021/ol200966z

An enantioselective strategy for the synthesis of tetracyclic motif 5, representing the northern fragment of norzoanthamine, is presented. Key to the strategy is the use of two asymmetric Robinson annulation reactions that produce the tricyclic ABC ring system with excellent stereoselectivity. Further functionalization at the periphery of the C ring produces compound 5 containing six contiguous stereocenters of the natural product.

Full text of DOI:10.1021/ol200966z

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3308–3311
Enantioselective Synthesis of the ABC
Ring Motif of Norzoanthamine Based on
Asymmetric Robinson Annulation
Reactions
Thong X. Nguyen, Marianna Dakanali, Lynnie Trzoss, and
Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, University of California, San Diego,
9500 Gilman Drive, Mail Code 0358, La Jolla, California 92093-0358, United States
etheodor@ucsd.edu
Received April 12, 2011
ABSTRACT
An enantioselective strategy for the synthesis of tetracyclic motif 5, representing the northern fragment of norzoanthamine, is presented. Key to
the strategy is the use of two asymmetric Robinson annulation reactions that produce the tricyclic ABC ring system with excellent
stereoselectivity. Further functionalization at the periphery of the C ring produces compound 5 containing six contiguous stereocenters of
the natural product.
The zoanthamine alkaloids constitute a class of marine
natural products that have been isolated from colonial
zoanthids of the genus Zoanthus sp.1 These compounds are
structurally defined by a densely functionalized and stereo-
chemically rich scaffold, as shown with the structures of
zoanthamine (1),2 norzoanthamine (2)3 and zoanthamide
(3)4 (Figure 1).
biological activities. For instance, several family members
were found to inhibit thrombin-, collagen-, and arachidonic
acid-induced inflammation of platelets5 and exhibit potent
cytotoxicity against a number of cancer cell lines.4,6 In
addition, 1 and 3 inhibit inflammation induced by myristate
acetate in mouse ears,4,6a while 2, the demethylated version
of 1, has been found to exhibit promising antiosteoporotic
properties in vivo in ovariectomized mice.1,7
The combination of challenging structures and potent
bioactivities has prompted the design of various synthetic
approaches by several groups.8,9 These efforts led to two
total syntheses of norzoanthamine by the Miyashita10 and
In addition to their impressive chemical architecture, the
zoanthamines also display an attractive spectrum of
(1) For selected reviews on this topic, see: (a) Rahman, A. U.;
Choudhary, M. I. In Alkaloids; Academic Press: New York, 1999; Vol
52, pp 233ꢀ260. (b) Kuramoto, M.; Yamaguchi, K.; Tsuji, T.; Uemura,
D. Zoanthamines, Antiosteoporotic Alkaloids. In Drugs from the Sea;
Fusetani, N., Ed.; Karger: Basel, 2000; pp 98ꢀ106. (c) Yamada, K.;
Kuramoto, M.; Uemura, D. Rec. Res. Devel. Pure Appl. Chem. 1999,
3, 245–254. (d) Fernandez, J. J.; Souto, M. L.; Daranas, A. H.; Norte, M.
Curr. Top. Phytochem. 2000, 4, 105–119.
(5) Villar, R. M.; Gil-Longo, J.; Daranas, A. H.; Souto, M. L.;
Fernandez, J. J.; Peixinho, S.; Barral, M. A.; Santafe, G.; Rodriguez,
J.; Jimenez, C. Bioorg. Med. Chem. 2003, 11, 2301–2306.
(6) (a) Rao, C. B.; Rao, D. V.; Raju, V. S. N.; Sullivan, B. W.;
Faulkner, D. J. Heterocycles 1989, 28, 103–106. (b) Venkateswarlu, Y.;
Reddy, N. S.; Ramesh, P.; Reddy, P. S.; Jamil, K. Heterocycl. Commun.
1998, 4, 575–580.
(2) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.; Venkatateswarlu,
Y.; Rosser, R. M.; Faulkner, D. J.; Chen, M. H. M.; Clardy, J. J. Am.
Chem. Soc. 1984, 106, 7983–7984.
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Yamada, K.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207–214. (b)
Kuramoto, M.; Hayashi, K.; Fujitani, Y.; Yamaguchi, K.; Tsuji, T.;
Yamada, K.; Ijuin, Y.; Uemura, D. Tetrahedron Lett. 1997, 38, 5683–5686.
(4) Rao, C. B.; Anjaneyulu, A. S. R.; Sarma, N. S.; Venkatateswarlu,
Y.; Rosser, R. M.; Faulkner, D. J. J. Org. Chem. 1985, 50, 3757–3760.
(7) (a) Yamaguchi, K.; Yada, M.; Tsuji, T.; Kuramoto, M.; Uemura,
D. Biol. Pharm. Bull. 1999, 22, 920–928. (b) Kuramoto, M.; Hayashi, K.;
Yamaguchi, K.; Yada, M.; Tsuji, T.; Uemura, D. Bull. Chem. Soc. Jpn.
1998, 71, 771–779. (c) Kinugawa, M.; Fukuzawa, S.; Tachibana, K. J.
Bone Miner. Metab. 2009, 27, 303–314. (c) Kuramoto, M.; Arimoto, M.;
Uemura, D. Mar. Drugs 2004, 2, 39–54.
r
10.1021/ol200966z
Published on Web 05/26/2011
2011 American Chemical Society

Kobayashi11 groups. More recently, Miyashita and co-
workers also reported the total synthesis of zoanthenol via
oxidation of norzoanthamine hydrochloride.12
enantioselectively.13 It should be noted that in a previous
study we attempted the synthesis of the ABC ring fragment
of 1 using bicyclic motif 7b that was readily available from
condensation of 8 with 9b.14 However, implementation of
this strategy to an enantioselective synthesis of 7b proved
to be lengthy and inefficient.15
Figure 1. Structures of selected zoanthamine natural products.
Inspection of the polycyclic norzoanthamine framework
suggests that this compound can be dissected in two main
fragments: a rigid tricyclic ABC core and a bisaminal motif
that forms the DEFG part. Arguably, the most significant
challenges for the synthesis of 2 are the construction of the
AB trans decalin system and the functionalization of the
stereochemically rich C ring. In fact, both Miyashita and
Kobayashi have shown that the synthesis of 2 could be
achieved from condensation of compound 4 in which a
partially folded C1ꢀC8 side chain has been attached to a
fully functionalized ABC motif (Figure 2). With this in
mind, we focused our efforts on the development of an
enantioselective synthesis of the ABC ring fragment, re-
presented here by structure 5. In the retrosynthetic direc-
tion, 5 can derive from 6 after functionalization at the
periphery of the C ring and stereocontrolled installation of
the C9 methyl group. Construction of the carbon back-
bone of 6 could be accomplished with two Robinson
annulation reactions that would form rings A and C.
Along these lines, reaction between 8 and 9a promoted
by a chiral reagent would produce bicyclic motif 7a
Figure 2. Retrosynthetic analysis of norzoanthamine (2).
The synthesis of the BC ring system of 2 is shown in
Scheme 1. Compound 10, the required precursor for the
asymmetric Robinson annulation, was produced in high
yield after Michael addition of 2-methyl-1,3-cyclohexa-
dione (8) to enone 9a. The latter was synthesized from
butane-1,4-diol according to a reported protocol.16 Treat-
ment of 10 with D-Phe and R-CSA in DMF17 gave the
annulated product 7a, containing the C12 quaternary
center, in 75% yield. The enantioselectivity of this reaction
was 85% ee as determined by the chiral shift agent Eu-
(hfc)3.18 The C13 carbonyl group of 7a was selectively
(8) For a comprehensive review of the chemistry and biology of
zoanthamines, see: Behenna, D. C.; Stockdill, J. L.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2008, 47, 2365–2386.
(9) For representative publications from each group, see: (a) Juhl,
M.; Monrad, R.; Sotofte, I.; Tanner, D. J. Org. Chem. 2007, 72, 4644–
4654. (b) Irifune, T.; Ohashi, T.; Ichino, T.; Sakai, E.; Suenaga, K.;
Uemura, D. Chem. Lett. 2005, 34, 1058–1059. (c) Rivas, F.; Ghosh, S.;
Theodorakis, E. A. Tetrahedron Lett. 2005, 46, 5281–5284. (d) Williams,
D. R.; Patnaik, S.; Cortez, G. S. Heterocycles 2007, 72, 213–219. (h)
Hirai, G.; Oguri, H.; Hirama, M. Chem. Lett. 1999, 141–142. (i)
Behenna, D. C.; Stockdill, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed.
2007, 46, 4077–4080.
(14) Ghosh, S.; Rivas, F.; Fischer, D.; Gonzalez, M. A.; Theodorakis,
E. A. Org. Lett. 2004, 6, 941–944.
(10) (a) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K.
Science 2004, 305, 495–499. (b) Miyashita, M. Pure Appl. Chem. 2007,
79, 651–665. (c) Yoshimura, F.; Sasaki, M.; Hattori, I.; Komatsu, K.;
Sakai, M.; Tanino, K.; Miyashita, M. Chem.;Eur. J. 2009, 15, 6626–
6644.
(11) (a) Murata, Y.; Yamashita, D.; Kitahara, K.; Minasako, Y.;
Nakazaki, A.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 1400–
1403. (b) Yamashita, D.; Murata, Y.; Hikage, N.; Takao, K. I.; Nakazaki,
A.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 1404–1406.
(12) Takahashi, Y.; Yoshimutra, F.; Tanino, K.; Miyashita, M.
Angew. Chem., Int. Ed. 2009, 48, 8905–8908.
(15) (a) Ling, T.; Kramer, B. A.; Palladino, M. A.; Theodorakis,
E. A. Org. Lett. 2000, 2, 2073–2076. (b) Ling, T.; Chowdhury, C;
Kramer, B. A.; Vong, B. G.; Palladino, M. A.; Theodorakis, E. A. J.
Org. Chem. 2001, 66, 8843–8853.
(16) Iyengar, R.; Schildknegt, K.; Morton, M.; Aube, J. J. Org.
Chem. 2005, 70, 10645–10652.
(17) (a) Tamai, Y.; Mizutani, Y.; Hagiwara, H.; Uda, H.; Harada, N.
J. Chem. Res., Synop. 1985, 148–149. (b) Hagiwara, H.; Uda, H. J. Org.
Chem. 1988, 53, 2308–2311.
(18) (a) Goering, H. L.; Eikenberry, J. N.; Koermer, G. S. J. Am.
Chem. Soc. 1971, 93, 5913–5914. (b) Corey, E. J.; Virgil, S. C. J. Am.
Chem. Soc. 1990, 112, 6429–6431. (c) Calmes, M.; Daunis, J.; Jacquier,
R.; Verducci, J. Tetrahedron 1987, 43, 2285–2292.
(13) For a review of annulation chemistry, see: Jung, M. E. Tetra-
hedron 1976, 32, 3–31.
Org. Lett., Vol. 13, No. 13, 2011
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reduced with sodium borohydride, and the resulting alco-
hol was protected as a silyl ether to afford enone 11 (67%
overall yield). The second quaternary center at C22 was
then installed. Methylation of 11 with t-BuOK produced
12 as a single stereoisomer. Reduction of the carbonyl
group of 12 gave an alcohol, which was protected as a
benzyl ether. Stereoselective hydroboration of the C20ꢀ
C21 alkene occurred at 0 °C over the course of 72 h to give
alcohol 13 (55% yield over three steps).
The chemical structure and stereochemistry of compound
17 were unambiguously confirmed via single-crystal X-ray
analysis.20
Scheme 2. Stereoselective Synthesis of trans,anti,trans-Fused
Perhydrophenanthrene Fragment 6
Scheme 1. Enantioselective Synthesis of Fragment 13
Conversion of diol 17 to the corresponding di-TIPS
ether 6 was achieved in two steps: (a) exhaustive silylation
of both ketone and diol functionalities of 17 and (b)
deprotection of the silyl enol ether using TFA (80% yield
overall). This two-step strategy was necessary because the
C15 ketone was shown to be more reactive over the C9
secondary alcohol.
The next task was the complete functionalization of the
C ring including the installation of the last quaternary
center at C9 (Scheme 3). To this end, the C15 carbonyl
group of 6 was stereoselectively reduced at ꢀ78 °C,21 and
the resulting equatorial alcohol was protected as the p-
methoxybenzyl ether. The two silyl ether groups were then
removed using TBAF to provide diol 18 (42% yield over
three steps). Selective TBDPS monoprotection of the
primary alcohol followed by DMP oxidation of the C9
hydroxyl group afforded ketone 19 in excellent yield (82%
yield over two steps).
With the fully functionalized BC ring system in hand, we
shifted our attention to the stereoselective construction of
the trans,anti,trans-fused perhydrophenanthrene skeleton
of norzoanthamine (Scheme 2). Alcohol 13 was protected
as the corresponding MOM ether in 98% yield. The C13
silyl ether of 14 was then deprotected using TBAF under
microwave (MW) radiation at 130 °C for 1 h. It is worth
noting that conventional heating in THF under reflux gave
only a 50% conversion after 5 days. The resulting C13
alcohol was oxidized using DessꢀMartin periodinane
(DMP) to provide compound 15 in 97% yield over two
steps. Our initial attempts to react 15 with methyl vinyl
ketone (MVK) using a strong base led to a complex
mixture of products. To circumvent this problem, we
converted 15 to a β-keto aldehyde that underwent a
smooth Michael addition with MVK and triethylamine.19
The Robinson cyclization proceeded cleanly with t-BuOK
to provide the tricyclic motif 16 in 75% yield over three
steps. The final trans,anti,trans-decalin 17 was synthesized
after stereoselective reduction of 16 using lithiumꢀ
ammonia conditions. Under these reductive conditions,
both benzyl ethers were cleaved, producing diol 17.
Conversion of 19 to ketone 22 was accomplished via a
sequence of five steps that included (a) triflation of the C9
(20) CCDC-820554 (17) and CCDC-820555 (5) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/const/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge, CB21EZ, UK; fax: (þ44)1223-336-033; or deposit@ccdc.
cam.ac.uk).
(19) Spencer, T. A.; Smith, R. A. J.; Storm, D. L.; Villarica, R. M. J.
Am. Chem. Soc. 1971, 93, 4856–4864.
(21) Alcaide, B.; Tarazona, M. P.; Fernandez, F. J. Chem. Soc.,
Perkin Trans. 1 1982, 2117–2122.
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Org. Lett., Vol. 13, No. 13, 2011

the C22 quaternary carbon center would lead to a regio-
selective hydroboration reaction in favor of the desired
product (hydroxylation at C10). Indeed, this hydroxyla-
tion produced, after further oxidation, a 2:1 mixture of
ketones 21 and 19 (34% and 17% yield, respectively). The
undesired ketone 19 can be recycled to yield the desired
product 21. Treatment of 22 with t-BuOLi as base,
dimethyl carbonate, and iodomethane yielded methyl enol
ether 23 that, upon alkylation with LiHMDS and iodo-
methane, formed the desired compound 5 (two steps, 62%
yield).10a The absolute stereochemistry of 5 was confirmed
by single-crystal X-ray analysis.20
Scheme 3. Stereoselective Synthesis of the ABC Ring System 5
In conclusion, we have described an enantioselective
approach to the fully functionalized ABC ring system of
norzoanthamine, represented by compound 5. Key to the
strategy is a double Robinson annulation reaction that
installs the C and A rings of this motif. The initial
Robinson annulation (formation of the BC ring) proceeds
with excellent enantioselectivity, setting the desired stereo-
chemistry at the C12 quaternary group. A sequence of
stereoselective transformations was then developed to
install the five remaining stereocenters. The C8 lactone
functionality could serve as an attachment point for the
remaining side chain of norzoanthamine.
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (NIH) for financial support of
this work through Grant No. R01 GM081484. We thank the
National Science Foundation for instrumentation grants
CHE9709183 and CHE0741968. We also thank Dr. An-
thony Mrse (UCSD NMR Facility), Dr. Yongxuan Su
(UCSD MS Facility), and Dr. Arnold L. Rheingold and
Dr. Curtis E. Moore (UCSD X-ray facility). We also thank
Sanne Bouwman and Weng K. Chang (UCSD) for technical
assistance.
ketone; (b) reduction of the resulting vinyl triflate using
formic acid and palladium(II) acetate to give alkene 20; (c)
hydroboration/oxidation of the C9ꢀC10 alkene; (d) oxi-
dation of the resulting alcohol to ketone 21; and (e)
deprotection of the primary silyl ether (23% yield over five
steps). We anticipated that, by virtue of steric hindrance,
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of the 1H and
13C NMR of all new compounds, as well as X-ray data of
compounds 5 and 17. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
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