thus allowing for a moderately effective kinetic resolu-
tion.7d Rh-catalyzed 1,4-additions to racemic 5-TMS- or
5-phenylcyclohex-2-enone proceeded with high enantio-
selectivity but low diastereoselectivity, thus revealing the
predominance of catalyst control.8 Substrate control,
however, can prevail under Cu-catalysis resulting in only
one diastereomer, but with low ee.8c With a different Cu-
catalyst, however, Feringa et al. achieved very impressive
kinetic resolutions of various 5-substituted derivatives.7d
Finally, 6-substituted cyclohex-2-enones exerted very low
substrate control in both Cu- and Rh-catalyzed 1,4-additions,
and mixtures of diastereomers were obtained which, via
their enolates, could be epimerized into enantiopure trans-
2,5-disubstituted cyclohexanones.9,10 Herein, we report on
kinetic resolutions of 4- and 5-substituted cyclohex-2-
enones by Rh/binap-catalyzed 1,2-addition of AlMe3 or
1,4-addition of boron and zinc organyls.
First, addition reactions to geminal dimethylated cyclo-
hex-2-enones were studied to determine whether substitu-
ents in the respective positions would interfere with the
catalyst. As already reported,4 1,2-addition of AlMe3 to
the 4,4-dimethylated 1b occurred in the same high yield as
in the case of the unsubstituted 1a (Table 1, entries 1, 2).
The 5,5-dimethylated 1c furnished only a moderate yield,
while the 6,6-disubstituted 1d showed again a very high
reactivity (entries 3, 4). In contrast, 1b did not undergo a
1,4-addition of PhB(OH)2 but slowly decomposed, while
1c smoothly reacted to cyclohexanone 3cm (entries 5, 6).
These results led to the hypothesis that the 1,2-addition
is most promising for kinetic resolutions of 5-substituted
cyclohex-2-enones whereas the 1,4-addition might be sui-
table for those with substituents in the 4-position. There-
fore, racemic 5-methylcyclohex-2-enone (1e) was reacted
with AlMe3 (1.2 equiv) and GC analysis revealed the
formation of the 1,2-adduct cis-(R,R)-2e in 50% yield with
79% ee, together with the 1,4-adduct (S,S)-4e (15% yield,
96% ee) and traces of trans-2e (Table 2, entry 1). Enantio-
pure (R)-1ewas then treated withthe Rh-catalysts contain-
ing (S)- and (R)-binap, respectively, and the former turned
out to be the matched pair furnishing only cis-2e in an
excellent yield (entry 2). In the case of the mismatched pair,
however, both diastereomers of the 1,2-adduct 2e were
obtained in 9% combined yield and, additionally, the 1,4-
adduct (R,R)-4e wasformedasasinglediastereomer in 16%
yield, most likely the consequence of a trans-selectivity
Table 1. Addition to Geminal Dimethylated Cyclohex-2-enones
a A: [Rh(cod)OMe]2 (2.5 mol %), (S)-binap (6.0 mol %), THF, rt,
15 min, then enone, AlMe3 (1.0 equiv), temp, time. B: [Rh(cod)OH]2
(1.5 mol %), (R)-binap (3.6 mol %), dioxane/H2O (10:1), rt, 1 h, then
enone, PhB(OH)2 (2.5 equiv), temp, time. b Yield of isolated product,
GC yield in parentheses. c Determined by chiral GC. d See ref 4. e [Rh-
(cod)Cl]2 and 1.2 equiv of AlMe3 were used. f Slow decomposition.
under substrate control (entry 3).11 Obviously, steric inter-
actions hampered the regular coordination of (R)-1e to the
(R)-catalyst, but some sort of unspecific activation must
have occurred. These results elucidate that, under the
conditions of entry 1, (S)-1e is transformed unspecifically
leading to the moderate 79% ee in the formation of cis-2e.
Finally, rac-1e was treated with the racemic catalyst, which
furnished almost exclusively cis-2e (entry 4). Thus, the
inherent 1,2-selectivity of the Rh-catalyzed AlMe3 addition
is maintained and combined with strong substrate control,
leading to a highly selective approach of the methyl group
from the face opposite to the substituent in the 5-position.
Under the conditions for a kinetic resolution with 0.5 equiv
of AlMe3, rac-1e reacted extraordinarily well furnishing
almost exclusively the expected cis-(R,R)-2e in 46% yield
with 95% ee together with unreacted (S)-1e in 32% yield with
97% ee (entry 5). Similar results were obtained at a lower
temperature, with the air-stable Lewis acidÀbase pair
DABCO 2AlMe3 (DABCO = 1,4-diazabicyclo[2.2.2]-
3
octane)12 or with the bulkier 5-isopropylcyclohexenone
1f(entries 6À8). Comparedtotheknown kineticresolution
of 5-substituted cyclohex-2-enones by Cu-catalyzed 1,4-
additions,7d this procedure furnishes synthetically interest-
ing allylic alcohols in high yield and optical purity while the
amount of recovered starting material is lower due to
unspecific side reactions.
(8) Rh-catalysis: (a) Chen, Q.; Kuriyama, M.; Soeta, T.; Hao, X.;
Yamada, K.-i.; Tomioka, K. Org. Lett. 2005, 7, 4439–4441. (b) Tomioka,
K. Pure Appl. Chem. 2006, 78, 2029–2034. Cu-catalysis: (c) Soeta, T.; Selim,
K.; Kuriyama, M.; Tomioka, K. Tetrahedron 2007, 63, 6573–6576.
(9) Rh-catalysis: (a) Mediavilla Urbaneja, L.; Krause, N. Tetrahe-
dron: Asymmetry 2006, 17, 494–496. (b) Chen, Q.; Soeta, T.; Kuriyama,
M.; Yamada, K.-i.; Tomioka, K. Adv. Synth. Catal. 2006, 348, 2604–
2608. Cu-catalysis: (c) Mediavilla Urbaneja, L.; Alexakis, A.; Krause,
N. Tetrahedron Lett. 2002, 43, 7887–7890. (d) Selim, K.; Soeta, T.;
Yamada, K.-i.; Tomioka, K. Chem.;Asian J. 2008, 3, 342–350.
(10) For Cu-catalyzed asymmetric 1,4-additions to other chiral
cyclohex-2-enones, see: (a) Imbos, R.; Minnaard, A. J.; Feringa, B. L.
Tetrahedron 2001, 57, 2485–2489. (b) Jagt, R. B. C.; Imbos, R.; Naasz,
R.; Minnaard, A. J.; Feringa, B. L. Isr. J. Chem. 2001, 41, 221–230. For
1,4-additions to chiral cyclic substrates catalyzed by achiral Rh-com-
plexes, see ref 2f and (c) Ramnauth, J.; Poulin, O.; Bratovanov, S. S.;
Rakhit, S.; Maddaford, S. P. Org. Lett. 2001, 3, 2571–2573.
Besides the possibility of a kinetic resolution, the Rh-
catalyzed addition of AlMe3 to 1e is an unprecedented
example of a regiodivergent reaction on a racemic mixture
(regiodivergent RRM)6 due to the formation of the
(11) For a discussion on the origin of trans-selectivity in cuprate
additions, see: Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1990, 31,
1393–1396.
(12) Biswas, K.; Prieto, O.; Goldsmith, P. J.; Woodward, S. Angew.
Chem., Int. Ed. 2005, 44, 2232–2234.
(13) For asymmetric 1,2-additions of mixed aluminum-zinc organyls
to aldehydes, see: Shannon, J.; Bernier, D.; Rawson, D.; Woodward, S.
Chem. Commun. 2007, 3945–3947.
(14) See Supporting Information for details.
Org. Lett., Vol. 14, No. 8, 2012
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