We attribute this excellent regioselectivity to a kinetic pathway
involving a six-membered chelative intermediate.14
Scheme 1. Three Possible Aldol Pathways for Dienolborinates
The initial success in obtaining both diastereoisomers
prompted the development and optimization of protocols
for the selective formation of either one. A systematic
screening of reaction conditionsÀchoice of amine, solvent,
boron ligand and leaving group, concentration, time, and
temperatureÀwas performed using 6 as the electrophile.
The full optimization studies, which will be detailed at a
later date, improved the syn- and anti-selectivity for the
methyl and tert-butyl ester enolates to excellent levels in
both cases. Unlike the case of methyl phenylacetate, wherein
unusual solvent and temperature effects were demonstrated
to exist,15 no unexpected effects were noted. Ultimately, it
was discovered that Et3N, in combination with Chx2BCl,
provided the anti-tert-butyl isomers in excellent selectivities
and yields, whereas the use of di(bicyclo[2.2.1]heptan-2-yl)-
chloroborane (Nrb2BCl) and ethyl-N,N-diisopropylamine
(DIPEA) furnished the syn-methyl isomers in excellent
selectivities but with slightly decreased yields. Deleteriously,
it was discovered that the syn/anti ratio of these compounds
could be readily degraded when the conditions were not
carefully controlled, especially during the workup stage
involving methanolic hydrogen peroxide oxidation. This is
possibly due to the inherent instability of these compounds.6b,j
While it is perhaps not surprising that Chx2BCl pro-
moted anti-selectity, the syn-selective aldolization seen with
Nrb2BCl is entirely unprecedented. We recently showed
that Nrb2BOTf16 was more anti-selective than Chx2BOTf
in enolizing trifluoropropionates.17 Knowing this, we were
astounded bythe selectivity reversal, especially considering
the fact that dialkylchloroboranes are usually considered
E-selective enolization reagents.18
Careful studies of ketone substrates by Brown showed
that larger boron ligands favor the formation of anti-aldol
products. The large sterics of the cyclohexyl ligands,
when combined with the bulkiness of the tert-butyl ester,
are likely the source of anti-selectivity in these reactions.
As the steric comparison between norbornane and cy-
clohexane is unclear at this time, the former’s effects are
obscure. One possibile explanation is that the methyl
ester is mimicking the selectivity expected for hexan-
3-one. This is an important consideration, as smaller
ketones (such as pentan-3-one) were shown by Brown
to give high Z-selectivity during enolization with all
screened dialkylchloroboranes. Although unlikely, the
possibility that the reaction furnishes the observed syn-
stereochemistry19 by way of either a closed boat or an open
transition state cannot be ruled out. At this time, the exact
methodology could solve this long-standing synthetic prob-
lem. Specifically, we envisaged that the reaction of the boron
enolates of either alkyl but-(2 or 3)-enoates with aldehydes
could provide the desired adducts (Scheme 1). Our addi-
tional goal was to demonstrate that the enhanced allylic
acidity could allow for enolization with chloroboranes,
which, unlike bromoboranes8 and boron triflates,9 are con-
sidered incapable of enolizing simple esters.10 However, we
were hopeful, as we had recently shown that certain dialkyl-
chloroboranes could affect the enolizationÀaldolization
sequence of 3,3,3-trifluoropropionates.11
We first screened several classes of esters and boranes and
found that some dialkylchloroboranes, such as dicyclohex-
ylchloroborane (Chx2BCl), and triflates affected the stereo-
selective enolization of but-(2 and 3)-enoates. The former
reagent, which was first introduced for aldol reactions by
Brown,12 had previously been shown to be highly effective in
enolizing aldehydes, ketones, and thioesters. We also found
that certain triflates functioned, but their instability and
cumbersome synthesis encouraged the use of the former.
After confirming that both esters provided identical dr
(Scheme 1), we chose to focus on the use of but-3-enoates,
which are readily accessible from crotonic acid. Reports of
boron enolates of esters have revealed a trend in which the
smaller methyl esters provide Z-enolates13 (syn-aldol products)
and that larger groups such as tert-butyl provide E-enolates
(anti-products), a trend similar to that seen with ketones.12 We
anticipated a similar effect in this case and, after initially
screening the methyl (1), ethyl (2), isopropyl (3), benzyl (4),
and tert-butyl (5) but-3-enoate esters, felt great satisfaction
when we reaffirmed this trend: the initial reaction of 1 with
benzaldehyde 6provided methyl 2-(hydroxy(phenyl)methyl)-
but-3-enoate in an approximately 1:1 dr with Chx2BCl and
triethylamine (Et3N). The same conditions with 5 provided 7
in an initial ratio of 24:76. In these and all further reactions
performed in this study, exclusive R-alkylation took place.
ꢀ
(14) Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett.
1994, 35, 9083.
(8) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976.
(9) Abiko, A. Acc. Chem. Res. 2004, 37, 387.
(15) Ramachandran, P. V.; Chanda, P. B. Org. Lett. 2012, 14, 4346.
(16) Ramachandran, P. V.; Parthasarathy, G.; Gagare, P. D. Org.
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(10) (a) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B.
J. Org. Chem. 1992, 57, 499. (b) Evans, D. A.; Nelson, J. V.; Vogel, E.;
Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099.
(11) Ramachandran, P. V.; Gagare, P. D.; Parthasarathy, G. Tetra-
hedron Lett. 2011, 52, 6055.
(12) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.;
Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441.
(17) It was initially thought (ref 10b) that R2BOTf could not function
as an enolization agent. This was disproved by Abiko et al. See ref 9.
(18) Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993,
58, 147.
(13) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, Ch. 1.
(19) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Am. Chem. Soc.
1988, 110, 3684.
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