to produce adduct 12a in 83% yield. Similarly, adduct 12b
was obtained from 11b in 90% yield. After Swern oxidation
Scheme 2. Synthesis of R-Keto Ester 87
Scheme 4. Cr(II)/Ni(II)-Mediated Coupling
Scheme 3. Synthesis of Triflate 98
of 12a followed by desilylation, treatment of 14a with 3 M
HClO4 in THF at room temperature gave spiroketal 15a as
a diastereoisomeric mixture in good yield. When dilute
HCl or p-TsOH was used as an acid catalyst, the spiroketal-
formation required higher temperature and longer reaction
time, leading to moderate yields of 15a (30-60%). Treat-
ment of 15a with methanesulfonyl chloride in pyridine
afforded diene 20a as a 4:1 epimeric mixture, NOE mea-
surement of which allowed us to determine the stereochem-
istry of the spirocenter of the major isomer to be S*.
Interestingly, dehydration of 15b obtained from 12b also
produced 20b as a major constituent of a 4:1 epimeric
mixture. The predominant formation of the S*-spirocenter
observed in both cases can be interpreted by assuming
oxonium ion intermediate 21 where the cyclization would
occur from the less-hindered top face regardless of the C3-
stereochemistry.
Upon acetylation and oxidative removal of the p-meth-
oxybenzyl protecting group, 15a gave alcohol 16a, which
was then converted to carboxylic acid 17a by Dess-Martin
oxidation11 followed by NaClO2-oxidation.12 Finally, ozo-
nolysis of 17a and exposure of the resulting ketone to TFA
furnished tricarboxylic acid 18a. Similarly, tricarboxylic acid
18b was synthesized from 15b via 16b and 17b. At this stage,
we found that 18a was identical with trachyspic acid2 by 1H
and 13C NMR comparison. The trimethyl ester of 18a also
exhibited spectral properties in accord with those reported2
for the trimethyl ester of natural trachyspic acid. Furthermore,
Aldol reaction of 8 and the lithium enolate generated from
tert-butyl 4-pentenoate gave a 2:3 mixture of (3S*,4S*)-10a
and (3R*,4S*)-10b, which were separated by column chro-
matography on silica gel. The stereochemistry of 10a and
10b was determined by 1H NMR analysis and NOE experi-
ments of the corresponding γ-lactones 13a and 13b pre-
pared via osmylation, NaIO4-oxidation, and PDC-oxidation.
Upon silylation and oxidative cleavage of the olefin, 10a
and 10b were converted to key aldehydes 11a and 11b,
respectively. After experimentation under various condi-
tions,9,10 the optimum conditions to achieve the crucial
Cr(II)/Ni(II)-mediated coupling reaction were found. Thus,
when 11a was reacted with triflate 9 in the presence of 4
equiv of CrCl2 and 0.1 equiv of NiCl2 in DMF at room
temperature, the coupling reaction occurred very successfully
(3) (a) Takai, K.; Kimura, K.; Kuroda, T. Hiyama, T.; Nozaki, H.
Tetrahedron. Lett. 1983, 24, 5281-5284. (b) Takai, K.; Tagashira, M.;
Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986,
108, 6048-6050. (c) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am.
Chem. Soc. 1986, 108, 5644-5646.
(4) For a review see: Saccomano, N. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, UK, 1991; Vol. 1, Chapter
1.6.4, pp 193-201.
(5) After aldol reaction with acetone, dehydration gave â,γ-unsaturated
ester almost exclusively.
(6) The triflation reaction proceeded with perfect regioselectivity.
(7) For the esterification step see: Santini, C.; Ball, R. G.; Berger, G.
D. J. Org. Chem. 1994, 59, 2261-2266.
(8) For the triflation step see: Commins, D. L.; Dehghani, A. Tetrahedron
Lett. 1992, 33, 6299-6302.
(9) In this particular case, use of 4-tert-butylpyridine as an additive turned
out to decrease the yield of the coupling product (<60%). For the procedure
with 4-tert-butylpyridine see: Sheng, D. P. X. C.; Chen, S. S.; Kishi, Y.
Tetrahedron Lett. 1997, 38, 6355-6358.
(10) When DMSO was used as a solvent, the coupling reaction became
very sluggish.
(11) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(12) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567-569.
858
Org. Lett., Vol. 5, No. 6, 2003