epoxy alcohol opening, and brominative cyclization, respec-
tively. Broka innovated the use of intramolecular oxymer-
curations to sequentially close the C and B rings, followed
by bromoetherification to access the A ring. The combined
yields for the three key etherification steps in each of these
approaches range from 4 to 16%. This is largely due to the
low yielding formation of the desired bromotetrahydropy-
ranyl A ring via intramolecular bromoetherification (22-
36% yield).13-15 Here, the problematic A ring is constructed
independently and at the outset, and then joined in the form
of C1-C7 aldehyde 6 to a fragment containing the preformed
C ring and representing C8-C15 (7). Subsequent annulation
to close the B ring completes the synthetic sequence.
The synthesis of aldehyde 6 began with (S)-(+)-linalool
(8) which was prepared from geraniol in 95% ee (Mosher
ester analysis) by sequential Sharpless asymmetric epoxi-
dation,16 tosylation, and Te-assisted reduction (Scheme 2).17
Figure 2. X-ray conformation of the C1-C15 domain of thyrsiferyl
18-acetate, highlighting the C10-C14 twist-boat.1
angular methyl group at C10 and the C15 side chain (Figure
2). The distinct structural features of the A-B-C ring system
have motivated the synthetic strategies that have been devised
toward these natural products.9-15 Reported here is a novel
assembly of the A-B-C ring system of thyrsiferol and
venustatriol.
A convergent synthetic approach to these natural products
involves the separate construction of two fragments repre-
senting C1-C15 (5) and C16-C24 domains (Scheme 1).
Scheme 2. Synthesis of the C1-C7 A-Ring (6)
Scheme 1. Retrosynthesis of the C1-C15 Domain of the
Thyrsiferol and Venustatriol Natural Products
Tertiary alcohol 8 was treated with TBCO18 in CH3NO2 at
0 °C to give a mixture of bromotetrahydrofurans 9 (17%
yield) and tetrahydropyrans 10 (38%) and 11 (24%).19
Although the direct yield of the desired tetrahydropyran 11
was comparable to those reported for similar bromoetheri-
fications,13-15 far less of the 5-exo tetrahydrofuran products
(9) were obtained. The mild diastereoselectivity reflects the
preferential axial orientation of the terminal alkene in the
transition state leading to 10. Isomers 9 and 10 could be
reverted to 8 by treatment with Zn in AcOH-EtOH,14,15 but
separation of 10 and 11 was difficult. Subjection of the
mixture of 10 and 11 to alkene oxidation allowed facile
chromatographic separation to provide epimeric bromo
The aldehyde corresponding to 5 was an advanced interme-
diate used in Corey’s total synthesis of 4,14 whereas Shira-
hama9 and Broka15 have also prepared A-B-C ring
constructs related to 5. In the total syntheses of 1, 2, and 4,
Shirahama assembled these rings in the order B-C-A,
highlighting the use of epoxy alcohol opening/ring expansion
strategies for the B and C rings, and a brominative cyclization
to close the A ring. Corey’s concise synthesis of 4 featured
a C-B-A ring closure sequence involving cyanohydrin
formation, distal hydroxyl-directed asymmetric epoxidation-
(9) Hashimoto, M.; Kan, T.; Yanagiya, M.; Shirahama, H.; Matsumoto,
T. Tetrahedron Lett. 1987, 28, 5665-5668.
(10) Broka, C. A.; Hu, L.; Lee, W. J.; Shen, T. Tetrahedron Lett. 1987,
28, 4993-4996.
(11) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.;
Matsumoto, T. Tetrahedron Lett. 1988, 29, 1143-1144.
(12) Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama, H. Tetrahedron
Lett. 1988, 29, 5417-5418.
(13) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.;
Matsumoto, T. J. Org. Chem. 1990, 55, 5088-5107.
(14) Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171-3174.
(15) Broka, C. A.; Lin, Y.-T. J. Org. Chem. 1988, 53, 5876-5885.
(16) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masumune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(17) Dittmer, D. C.; Discordia, R. P.; Zhang, Y.; Murphy, C. K.; Kumar,
A.; Pepito, A. S.; Wang, Y. J. Org. Chem. 1993, 58, 718-731.
(18) 2,4,4,6-Tetrabromocyclohexa-2,5-dienone: Kato, T.; Ichinose, I.;
Hosogai, T.; Kitahara, Y. Chem. Lett. 1976, 1187-1190. Also see: Jung,
M. E., D’Amico, D. C.; Lew, W. Tetrahedron Lett. 1993, 34, 923.
(19) All new compounds gave satisfactory characterization data (1H
NMR, IR, MS) consistent with the structures assigned.
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Org. Lett., Vol. 1, No. 2, 1999