(16S)-diastereomer.12 The alcohol 12 was then esterified with
PMB protected glycolic acid 13 to give the glycolate ester
in 91% yield. At this stage, the two diastereomers resulting
from the preceding Grignard addition were easily separable
by HPLC to afford ester 14 (76%) as a single diastereomer.
The Ireland-Claisen [3,3] sigmatropic rearrangement13 of
ester 14 afforded polar carboxylic acid 15, which was not
isolated but immediately reduced to give the primary alcohol
16 (80%) as a single diastereomer. Protection of primary
alcohol 16 as the TBS ether and removal of the PMB group
provided alcohol 4 (74%). In this sequence, the (16S)-
configuration of the starting ester 1411 and the chelation-
controlled generation of the (Z)-ketene silyl acetal interme-
diate 1714 (see box, Scheme 3) leads ultimately, Via a
chairlike transition state, to the formation of tetrahydropyran
4 with the (19R,16E)-configuration depicted.15,16
Scheme 5
A concise synthesis of the C1-C9 coupling fragment,
trienoic acid 3, was completed from acrylate ester 18, as
shown in Scheme 4, with the trisubstituted Z-alkene estab-
Scheme 4
20,18 using the RCM protocol of Buchwald,19 afforded
lactone 19 in excellent yield (95%). Partial reduction of the
lactone 19 gave the corresponding lactol as a latent hydroxy-
aldehyde, and direct reaction of this intermediate with
stabilized ylide 21 afforded the desired (2E,4Z)-diene ester
22 in 86% yield (over two steps) after chromatographic
separation of the 94:6 2E/Z mixture. Oxidation of the
primary alcohol 22 with Dess-Martin periodinane20 afforded
the aldehyde, but its elaboration to trienol 23 with vinyl
Grignard reagent proved problematic due to the acidity of
the R-proton in the â,γ-unsaturated aldehyde, a finding also
reported by Jennings et al.5b In an attempt to reduce any
competing enolization of the aldehyde, advantage was taken
of the reduced basicity of organocerium reagents.21 Genera-
tion of the vinylcerium reagent Via transmetalation at
-78 °C and addition of the aldehyde gave the desired trienol
23 in 56% yield. Finally, protection of the allylic alcohol 23
as the TBS ether and hydrolysis of the methyl ester afforded
lished Via a six-membered lactone intermediate 19. Treatment
of the ester 1817 with Grubbs’ second-generation catalyst
(12) Assigned by analogy to the literature (ref 11). Confirmation of this
stereochemical assignment was obtained on the synthesis of pyran 4 (see
below, refs 15 and 16).
(13) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868. (b) Martin-Castro, A. M. Chem ReV. 2004, 104, 2939.
(14) (a) Rozners, E.; Xu, Q. Org. Lett. 2003, 5, 3999. (b) Hong, J. H.;
Oh, C.-H.; Cho, J.-H. Tetrahedron 2003, 59, 6103. (c) Mulzer, J.; Mohr,
J.-T. J. Org. Chem. 1994, 59, 1160. (d) Burke, S. D.; Pacofsky, G. J.;
Piscopio, A. D. J. Org. Chem. 1992, 57, 2228. (e) Burke, S. D.; Pacofsky,
G. J. Tetrahedron Lett. 1986, 27, 445. (f) Burke, S. D.; Fobare, W. F.;
Pacofsky, G. J. J. Org. Chem. 1983, 48, 5221.
(17) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S.
P. J. Org. Chem. 2000, 65, 2204.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(19) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 11253.
(15) The (19R)-configuration of the secondary alcohol 4 was confirmed
using the modified Mosher method: Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(16) The (16E)-configuration of the alkene 16 was confirmed by the
presence of a strong 1H NMR NOESY cross-peak between the C16 alkene
proton and the C18 allylic protons.
(20) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(21) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
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