protected as its p-methoxyphenyl acetal 12 by exposure to
PPTS and 4-methoxybenzaldehyde dimethylacetal. The
carbon chain was next elongated via a cross metathesis
reaction with ethyl acrylate (Table 1). The cyclic acetal was
Scheme 1
Table 1. Optimization of the Terminal Olefin 12/Ethyl
Acrylate Cross Metathesisa
ethyl acrylate
entry
catalyst
temperature
(equiv)
yield (%)
1
G2
G2
G2
G1
G1
G2
G2
rt
40 °C
rt
40 °C
40 °C
rt
2
2
2
5
4
61
37
53
20
0
2b
3c
4d,e
5
the superior ability of C35 (relative to C36) to stabilize the
developing positive charge in the transition state. Treating
the resulting diol 4 with base was expected to produce
epoxide 5 via a displacement of the tosylate. Upon acidifica-
tion, epoxide 5 was projected to cyclize to the desired bridged
bicyclic diether 6, again based on the better trajectory for
attack and the greater positive charge stabilization at C36
relative to C37.
The synthesis of epoxide 2 began with the known Evans
anti-aldol reaction between (E)-cinnamaldehyde (8) and
N-propionylthiazolidinethione 7, which delivered the aldol
adduct 9 in 83% yield (91:9 dr, Scheme 2).5 The chiral
auxiliary was reductively removed with i-Bu2AlH,6 and the
resultant aldehyde 10 was immediately subjected to Brown’s
asymmetric allylation protocol (>95:5 dr).7 Diol 11 was
6
7
10
20
71
95
rt
a Reactions run in degassed methylene chloride (0.1 M) for 14 h using
5 mol % catalyst. b Reaction was run for 3 h. c 7.5 mol % catalyst was
used. d Reaction was run for 4 h. e 10 mol % catalyst was used.
chosen as the diol protecting group since the six-membered
acetal orients the two alkenyl substituents in equatorial
positions strongly disfavoring ring-closing metathesis to give
a six-membered bridged bicyclic structure.
Several conditions for the cross metathesis8 were explored.
Treatment of terminal alkene 12 and 2 equiv of ethyl acrylate
with the Grubbs second generation catalyst [Cl2(Cy3P)(IMes)-
RudCHPh] at room temperature for 14 h produced unsatur-
ated ester 13 in 61% yield (Table 1). In addition to ester 13,
other metathesis byproducts (15%) as well as alkene 12 (7%)
were recovered. Increasing temperature or catalyst loading
had no favorable effect on the yield (entries 2 and 3,
respectively). The Grubbs first generation catalyst [Cl2(Cy3P)2-
RudCHPh] produced mostly the dimer of 12. The best
results were realized when olefin 12 and 20 equiv of ethyl
acrylate were treated with 5 mol % of the Grubbs second
generation catalyst (entry 7). The desired enoate 13 was
isolated in 95% yield after 14 h at room temperature.
Ester 13 was converted to the desired epoxide 2, as
illustrated in Scheme 3. Reduction of ester 13 to allylic
alcohol 14 was accomplished in 93% yield by exposure
to i-Bu2AlH (Scheme 3). Allylic alcohol 14 was treated un-
der Sharpless asymmetric epoxidation conditions providing
Scheme 2
(4) Baldwin, J. J. Chem. Soc., Chem. Commun. 1976, 734.
(5) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett.
2002, 4, 1127.
(6) (a) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama,
S.; Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097. (b) Crimmins,
M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. (c) Crimmins, M. T.; King,
B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894.
(7) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(8) Chatterjee, A. K.; Choi, T.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
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Org. Lett., Vol. 8, No. 19, 2006