Concise and protective group-free syntheses of (±)-hamigeran B and (±)-4-bromohamigeran B

Article abstract of DOI:10.1021/ol102780s

Concise and protective group free syntheses of (±)-hamigeran B and (±)-4-bromohamigeran B are reported. The key reactions include an enone migration and a Diels-Alder cyclization to provide the requisite tricyclic skeleton.

Full text of DOI:10.1021/ol102780s

ORGANIC
LETTERS
2011
Vol. 13, No. 2
347-349
Concise and Protective Group-Free
Syntheses of (()-Hamigeran B and
(()-4-Bromohamigeran B†
Stephen Y. W. Lau*,‡
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, British Columbia, Canada V6T 1Z1
slau@exelixis.com
Received November 16, 2010
ABSTRACT
Concise and protective group free syntheses of (()-hamigeran B and (()-4-bromohamigeran B are reported. The key reactions include an
enone migration and a Diels-Alder cyclization to provide the requisite tricyclic skeleton.
Hamigeran B (1) and 4-bromohamigeran B (2) were first
isolated from the poecilosclerid sponge Hamigera tarangen-
sis Bergquist and Fromont (family Anchinoidae, syn. Phor-
basidae) and reported by Cambie and co-workers in 2000.1
While most members of the hamigeran family of natural
products, including 2, possess mild antitumor activity toward
P-388, hamigeran B also possesses potent antiviral activity.
The challenging nature of its unique structure has been
highlighted by recent syntheses of hamigeran B.2-7 Herein
we report an alternative synthesis to hamigeran B and also
to 4-bromohamigeran B that is extremely concise and does
not require the use of protective groups.
A similar feature of the previous syntheses is that the
aromatic A ring is already present as part of their respective
starting precursors, upon which the B and C rings are
incorporated (Figure 1). In contrast, we sought to first
† Dedicated to the memory of the late Professor Edward Piers.
‡ Current address: Exelixis, Inc., P.O. Box 511, So. San Francisco, CA
94083-0511.
(1) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P. R.
J. Nat. Prod. 2000, 63, 79.
(2) (a) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem., Int. Ed. 2001,
40, 3675. (b) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem., Int. Ed.
2001, 40, 3679. (c) Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem.
Soc. 2004, 126, 613
.
(3) (a) Clive, D. L. J.; Wang, J. Angew. Chem., Int. Ed. 2003, 42, 3406.
(b) Clive, D. L. J.; Wang, J. Tetrahedon Lett. 2003, 44, 7731. (c) Clive,
D. L. J.; Wang, J. J. Org. Chem. 2004, 69, 2773. (d) For a review of pre-
2005 syntheses, see: Clive, D. L. J.; Wang, J. Org. Prep. Proc. Int. 2005,
Figure 1. Hamigeran B and 4-bromohamigeran B listing the A-C rings.
37, 1
.
(4) (a) Trost, B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, G. M.
J. Am. Chem. Soc. 2004, 126, 4480. (b) Trost, B. M.; Pissot-Soldermann,
construct the B and C rings and envisaged an intermolecular
Diels-Alder cyclization as the key step in forming the A
ring toward the latter part of the synthesis (Scheme 1).
Although studies toward a direct route to 4 via cyclopen-
C.; Chen, I. Chem.sEur. J. 2005, 11, 951
.
(5) Taber, D. F.; Tain, W. J. Org. Chem. 2008, 73, 7560
.
(6) Miesch, L.; Welsch, T.; Rietsch, V.; Miesch, M. Chem.sEur. J. 2009,
15, 4394
.
10.1021/ol102780s  2011 American Chemical Society
Published on Web 12/02/2010

With enone 5 in hand, a Reusch enone migration15
protocol was performed (Scheme 3).16 Enone 5 was treated
Scheme 1. Retrosynthetic Analysis of Hamigeran B
Scheme 3. Enone Migration Protocol
tenone annulation chemistry developed in the Piers labora-
tory8 showed limited success, we were able to take advantage
of some previously reported work in order to build the
desired enone 4 through an enone migration protocol on
enone 5.9
Enone 5 was synthesized on the basis of work performed
by Snider and co-workers10 and by Corey and Engler11 in
order to obtain bicyclic ketone 9 stereospecifically, containing
the requisite relative stereochemistry of the three contiguous
chirality centers in hamigeran B (Scheme 2). Introduction
with 30% hydrogen peroxide and catalytic sodium hydroxide
in methanol to furnish epoxide 10. Without purification, the
epoxide was opened with sodium methoxide in methanol,
providing the R-methoxy enone 11 in 87% yield over two
steps. Enone 11 was then treated with tosyl hydrazide in
ethanol to furnish the hydrazone 12 as a mixture of geometric
isomers. Again without purification, hydrazone 12 was
subjected to Shapiro conditions17 using 4 equiv of methyl-
lithium at -78 °C and then warming from -78 to 0 °C. An
in situ hydrolysis of the resulting methyl enol ether with
refluxing aqueous acetic acid afforded the desired enone 4
in 79% yield from 11.
Surprisingly, enone 4 was a poorly reactive dienophile and
required the use of ketene acetal 13 as the reactive diene.
Acetal 13 was synthesized from 3,3-dimethylacrylic acid in
77% yield following a procedure developed by Boehler and
Konopelski (Scheme 4).18
Scheme 2. Synthesis of Enone 5
Diene 13 and dienophile 4 were mixed in a 4:1 ratio,
respectively, with 10 mol % of K2CO3 (as a proton
scavenger) and heated to 150 °C in a sealed vial for 4 days
(9) Enone 5 had been previously reported as a minor byproduct: Attah-
Poku, S. K.; Chau, F.; Yadav, V. K.; Fallis, A. G. J. Org. Chem. 1985, 50,
3418.
(10) Snider, B. B.; Rodini, D. J.; van Straten, J. J. Am. Chem. Soc. 1980,
102, 5872.
(11) Corey, E. J.; Engler, T. A. Tetrahedron Lett. 1984, 25, 149.
(12) Devanathan, V. C.; Bhagan, V. U.; Arumugam, N. Indian J. Chem.
1983, 22B, 766.
(13) Ando, M.; Wada, T.; Kusaka, H.; Takase, K.; Hirata, N.; Yanagi,
Y. J. Org. Chem. 1987, 52, 4792.
(14) For a similar application, see: Paquette, L. A.; Wang, X. J. Org.
Chem. 1994, 59, 2052.
of the unsaturation was accomplished by the regioselective
R-bromination of 9 using pyridinium tribromide in acetic
acid,12 followed by elimination of HBr with lithium carbon-
ate and lithium bromide in hot dimethylformamide,13 to
provide the desired enone 5 in 88% yield.14
(15) Patel, K. M.; Reusch, W. Synth. Commun. 1975, 5, 27. For a
modification, see: Paquette, L. A.; Wang, T.-Z.; Vo, N. H. J. Am. Chem.
Soc. 1993, 115, 1676.
(16) Each of the intermediates 10 and 12 were used in the following
transformation without purification and were not fully characterized. All
other compounds were isolated, purified, and exhibited spectra in accord
with assigned structures and gave satifactory elemental analyses or molecular
mass determinations.
(7) For approaches to hamigeran B, see: (a) Mehta, G.; Shinde, H. M.
Tetrahedron Lett. 2003, 44, 7049. (b) Cai, Z.; Harmata, M. Org. Lett. 2010,
12, 5668.
(17) For reviews, see: (a) Adlington, R. M.; Barrett, A. G. M. Acc. Chem.
Res. 1983, 16, 55. (b) Shapiro, R. H. Org. React. 1986, 23, 405.
(18) (a) Konopelski, J. P.; Boehler, M. A. J. Am. Chem. Soc. 1989, 111,
4515. (b) Boehler, M. A.; Konopelski, J. P. Tetrahedron 1991, 47, 4519.
(8) Piers, E.; Cook, K. L.; Rogers, C. Tetrahedron Lett. 1994, 35, 8573.
348
Org. Lett., Vol. 13, No. 2, 2011

dienophile 4 were mixed in a 2:1 ratio, respectively, for 4 d
at 150 °C, only 23% conversion was observed.
Scheme 4. Preparation of Ketene Acetal 13
With the cyclized compound 16 in hand, hydrolysis of
the ketal functionality20 using sulfuric acid in wet acetone
gave enol 17 quantitatively. Compound 17 was then aroma-
tized using DDQ21 in benzene at rt to give ketone 3 also in
high yield. The 1,2-diketone functionality was introduced
using selenium dioxide22 with catalytic acetic acid in
refluxing wet dioxane to form 18 in 92% yield.
to afford the Diels-Alder adduct 16 as primarily a single
Careful o-bromination of the phenol using NBS with
diisopropylamine in methylene chloride23 afforded hamigeran
B, whose spectral data were in agreement with reported data.1
Use of an excess of NBS with rapid addition to the phenol
resulted in the dibromination of phenol 18 to form 4-bro-
mohamigeran B, whose spectral data were also in agreement
with reported data.1
diastereomer (Scheme 5),19 with yields ranging from 61%
Scheme 5. Diels-Alder Cyclization and End Game
In summary, we report a novel, concise, and stereospecific
synthesis of (()-hamigeran B and of (()-4-bromohamigeran
B that does not require the use of any protective groups.
Acknowledgment. We thank NSERC and AHFMR for
funding.
Supporting Information Available: Full experimental
details and spectroscopic data for compounds 1-5, 7-13,
and 15-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL102780S
(19) Approximate 10:1 ratio by 1H NMR. As the stereochemistry of
the newly formed stereogenic centers of 16 were to be destroyed through
subsequent aromatization, no attempt was made to determine their config-
uration.
(20) Note that the use of the acetal functionality in 13 was to both
activate the diene and to provide the enol functionality in the cyclized
product. Consequently, the ketal formed in 16 as a result of the Diels-Alder
cyclization does not actually serve as a protective group.
(21) For a review, see: Walker, D.; Hiebert, J. D. Chem. ReV. 1967, 67,
153.
(83% based on recovered starting material) to 77% (complete
consumption of the enone). Heating of the reaction for longer
periods in order to completely consume the enone tended to
lower the yield. Furthermore, use of fewer equivalents of
diene resulted in a sluggish reaction. For example, when 13:
(22) For a review, see: Rabjohn, N. Org. React. 1976, 24, 261.
(23) Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida, A. Bull.
Chem. Soc. Jpn. 1993, 66, 1576.
Org. Lett., Vol. 13, No. 2, 2011
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