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