2,4-cyclohexadienones are often not stable to isolation,
undergoing rapid Diels-Alder dimerization, and, to our
knowledge, have not been prepared practically in optically
active form before. Dimerization of 7 did occur slowly at
23 °C (t1/2 ) 4 h, initial concentration 0.6 M, CDCl3),
forming a single Diels-Alder adduct (X-ray analysis, see
Supporting Information), consistent with the proposal that 7
was of high optical purity.
into an alternative allylic epoxide series. Thus, exposure of
14 to anhydrous sodium methoxide in methanol at 23 °C
furnished the epoxide 15 in 81% yield. By contrast, osmy-
lation of the diene system of the acetonide methyl ester 4
(catalytic osmium tetroxide, stoichiometric NMO) proceeded
with predominant attack upon the less hindered olefin and
with complete selectivity for the â-face (regioselectivity 5:1,
major isomer 16, 90% isolated yield).
Virtually any position of the 1,3-cyclohexadiene nucleus
of 1 and its protected forms can be oxidized stereoselectively
in simple one- and two-step procedures. The products, allylic
epoxides, bromides, lactones, etc. (Figure 1), are well
disposed for further facile synthetic elaboration. Epoxidation
can be conducted either before or after protection of the diol
and carboxylic acid groups, with the ordering determining
the stereoselectivity of the reaction. Thus, hydroxyl-directed
epoxidation of 1 with m-CPBA (1.2 equiv) in ethyl acetate
at 23 °C provided the R-oriented allylic epoxide 8 exclusively
(91%, after washing with CH2Cl2), whereas epoxidation of
the acetonide methyl ester 4 produced the stereoisomeric,
â-epoxide 9 as a crystalline solid (m-CPBA, 1.5 equiv, CH2-
Cl2, 23 °C, 91% of a 3:1 mixture of 9 and 15). Both products
8 and 9 are activated toward invertive 1,2-addition of
nucleophiles to the allylic position of the epoxide. For
example, perchloric acid-mediated hydrolysis of the methyl
ester derived from 8 (CH2N2) in aqueous acetonitrile at 23
°C followed by acetonide formation provided the crystalline
diol acetonide 10 in 79% yield, whereas 9 produced the
stereoisomeric diol acetonide 11 under similar conditions
(76%, structure confirmed by X-ray analysis). Epoxide
opening followed an intramolecular pathway when 8 was
treated with perchloric acid in anhydrous acetone at reflux;
acetonide formation occurred concomitantly and with a
different regiochemistry than before, providing the lactone
acetonide 12 in 64% yield. Because the epoxy acid 8 was
sensitive to acid-catalyzed aromatization (and the corre-
sponding methyl ester 20 more so), to protect the diol it was
necessary to use neutral conditions. This was achieved by
ketalization using 2,4-dimethoxybenzyl methyl ether (1.5
equiv) and DDQ (2.0 equiv) in dichloromethane at 23 °C
for 24 h, furnishing a 1.5:1 mixture of the diastereomeric
acetals 13 (75%, major stereoisomer (â) depicted).9 The 2,4-
dimethoxyphenyl acetal was useful not only as a protective
group but also for its ability to promote nucleophilic addition
of organometallic reagents (e.g., vinyllithium intermediates)
to the adjacent ester group, an observation of some interest,
should it prove to be general.
One of the more interesting and useful transformations
we developed in this study was discovered serendipitously,
arising from an effort to produce the cyclohexenone 17 by
the rearrangement of the bis-trimethylsilyl ether 18 (BSTFA,
83%) in the presence of a palladium catalyst.11 In the event,
only trace quantities of 17 were formed (5 mol % of Pd-
(PPh3)4, THF, 23 °C, 16 h); the rearranged, isomeric allylic
epoxide 19 was produced instead, in 68-79% yield after
chromatographic isolation (Scheme 2). We believe that this
Scheme 2
rearrangement, which did not occur in the absence of the
palladium catalyst or with triphenylphosphine alone, is novel.
Speculation upon the mechanism of this transformation
should take into account the fact that essentially the same
rearrangement occurs, and more efficiently, within the methyl
ester 20, in the presence of tert-butyldimethylsilyl triflate
(3 equiv) and triethylamine (10 equiv) in dichloromethane
at -40 f 23 °C, forming the epoxide 21 (80-91%). We
defer mechanistic conjecture at this point, other than to offer
that the system is well disposed for intramolecular 1,3-
transfer of a silyl group, be this promoted by a Lewis acid
(silyl triflate) or in a nucleophilic process (alkoxy π-allylpal-
ladium intermediate). Evidently, and not surprisingly, the
more substituted epoxide (21) is favored thermodynamically.
Resubjection of 21 to the reaction conditions did not lead to
detectable levels of the regiosiomeric epoxide. The great
advantage of the transformation is that it transfers the position
of the allylic epoxide so as to allow for nucleophilic additions
to C6, of potential utility in tetracycline synthetic studies.
Selective functionalization of the more hindered olefin of
the diene system was accomplished by bromolactonization
of 3 with NBS (2 equiv) in a mixture of toluene and
dichloromethane (1:20) at 23 °C for 2 h. The crystalline
bromo â-lactone 14 was obtained in 69% yield after
purification by column chromatography. This regiochemical
outcome in the halolactonization reaction, although not
unprecedented,10 was useful here, for it provided an entry
In summary, practical, large-scale microbial hydroxylation
of benzoic acid provides convenient access to the diol 1 in
high optical purity. Apart from simplification of the original
fermentation procedure of Reiner and Hegeman, we have
shown that an extraordinarily wide array of highly function-
(9) Oikawa, Y.; Nishi, T.; Yonemitsu, O. Tetrahedron Lett. 1983, 24,
4037.
(10) Barnett, W. E.; McKenna, J. C. J. Chem. Soc., Chem. Commun.
1971, 551.
(11) Suzuki, M.; Oda, Y.; Noyori, R. J. Am. Chem. Soc. 1979, 101, 1623.
Org. Lett., Vol. 3, No. 18, 2001
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