Nonbonding interactions and stereoselection in the Corey-Bakshi-Shibata reduction

Article abstract of DOI:10.1021/ol901707h

Deuterium kinetic isotope effect measurements upon enantiotopic methyl groups for the Corey-Bakshi-Shibata reduction of 2',5'-dimethylphenyl isopropyl ketone suggest a complex role for nonbonding Interactions In the mediation of stereoselectlon.

Full text of DOI:10.1021/ol901707h

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4338-4341
Nonbonding Interactions and
Stereoselection in the
Corey-Bakshi-Shibata Reduction
Matthew P. Meyer*
UniVersity of California, Merced, School of Natural Sciences, P.O. Box 2039,
Merced, California 95344
mmeyer@ucmerced.edu
Received July 24, 2009
ABSTRACT
Deuterium kinetic isotope effect measurements upon enantiotopic methyl groups for the Corey-Bakshi-Shibata reduction of 2′,5′-dimethylphenyl
isopropyl ketone suggest a complex role for nonbonding interactions in the mediation of stereoselection.
Asymmetric catalysis has established a firm foothold in
natural product synthesis1 and is of growing importance in
industrial processes.2 Qualitative transition-structure models
are capable of explaining product distributions in a number
of stereoselective reactions and reaction classes. Comparative
estimates of steric repulsion play a key role in these models.
Unfortunately, it is often difficult to quantitatively measure
nonbonding interactions that arise in the transition state.
Methods relying upon linear free energy relationships have been
somewhat successful in elucidating the role of steric interactions
in determining reactivity;3 however, it is often difficult to
extricate the role of steric interactions in these studies from
spurious orbital interaction and solvation effects.4,5
that develops at the transition state.6 Similarly, other research
groups have performed elegant steric equilibrium isotope effect
measurements that illustrate the influence of isotopic perturba-
tion upon processes ranging from conformational equilibria to
enzyme-substrate binding. Until recently, however, a general
approach to measuring steric interactions that develop in the
transition states of asymmetric reactions was lacking. The new
methodology uses two isotopic competition experiments to
arrive at an estimate of the 2H KIEs upon chemically innocuous
prochiral groups (Scheme 1). In asymmetric reactions, the
symmetry element that makes these prochiral groups chemically
equivalent is broken in a deterministic way in the transition
state. If these enantiotopic probe groups are close to the reaction
center, then they can be used to interrogate nonbonding forces
that contribute to symmetry breaking at the transition state.
Pioneered by Carter and Melander, steric kinetic isotope
effects (KIEs) offer a less perturbative probe of steric repulsion
The CBS reduction is of interest in its own right and as a
point of comparison with results obtained recently for the
B-chlorodiisopinocampheylborane (DIP-Cl) reduction of 4′-
methylisobutyrophenone.7 The DIP-Cl reduction is somewhat
limited in its substrate range, being primarily used for the
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10.1021/ol901707h CCC: $40.75
Published on Web 09/04/2009
 2009 American Chemical Society

fractional conversion of the reaction to arrive at rate constant
ratios. The first competition reaction (Scheme 1A) is used to
measure the product of isotope effects resulting from H-
2
Scheme 1. Two Competition Reactions by which H KIEs at
2
Enantiotopic Methyl Groups Are Determined
substitution upon the enantiotopic groups (eq 1). Inherent in
this assumption is the rule of the geometric mean.14 This
assumption is likely to be exceptionally good in the current
context because the enantiotopic methyl groups under consid-
eration do not appear to participate significantly in the reaction
coordinate mode at the transition state.13 The second competi-
tion reaction is used to measure the ratio of isotope effects
resulting from 2H-substitution upon each enantiotopic group (eq
2). Together, these measurements can be used to compute the
2
isotope effects resulting from H-substitution upon both the
pro-S and pro-R methyl groups (eqs 3a and 3b).
k1
k2
k1 k1
)
×
(1)
(2)
kR-3 kS-3
kS-3
kR-3
k1 kS-3
)
×
kR-3 k1
reduction of aralkyl ketones.8 By contrast, the most com-
monly used CBS catalyst, employing a B-methyl substituent
(Scheme 2), has an unusually broad substrate range.9,10
k1
k1 kS-3
)
)
×
(3a)
(3b)
kR-3
k
kR-3
ꢀ
ꢀ
2
k1
k1 kS-3
/
Scheme 2. CBS Reduction Studied Here
kS-3
k k
2
R-3
The rate ratios in eqs 1 and 2 are computed from
fractionation observed in reisolated reactant in reactions taken
to high (∼80-95%) conversion. Measurements of the
relative amounts of R-3 and S-3 reisolated in the second
competition experiment are performed following a desym-
metrization step that converts the enantiotopic methyl groups
into diastereotopic groups. The measurements presented here
utilize the CBS reduction as the desymmetrization method.
Reduction of 2′,5′-dimethylphenyl isopropyl ketone by
BH3·DMS catalyzed by (S)-Me-CBS proceeds with es-
sentially quantitative conversion and greater than 98% ee.
Quantitative conversion ensures that the desymmetrization
step does not introduce spurious isotopic fractionation. High
stereoselectivity ensures that isotopic fractionation in the
prochiral methyl groups (Scheme 1B) results almost exclu-
sively from the Si-facial reduction channel.
Qualitative11 and precise12 transition-structure models il-
lustrate a clear and distinct role for steric repulsion in the
DIP-Cl reduction. The determinants of stereoselection in (S)-
Me-CBS-catalyzed reductions and other analogues are not
immediately obvious from qualitative transition structures.
In this paper, we interpret the 2H KIEs measured at prochiral
groups (Scheme 2) in the context of similar experiments upon
the DIP-Cl reduction7 and 13C KIEs recently measured for
the CBS reduction of 2′,5′-dimethylisobutyrophenone.13
The methodology employed in the current studies (Scheme
1) utilizes two competition reactions. Both competition reactions
use the fractionation in unreacted starting material and the
All measurements of isotopolog (1 vs 2) or isotopomer
(R-3 vs S-3) ratios utilize quantitative H NMR employing
1
calibrated 90° pulses separated by delays of greater than 5T1
for the methyl doublets of interest. The relative NMR
assignments of the diastereotopic methyl groups in the
product were accomplished using the CSGT15 methodology
and the IGAIM16 variation upon a fully optimized B3LYP/
6-31+G(d,p) model of the anticipated R enantiomer of the
benzylic alcohol product.
(8) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16–
24.
(9) Corey, E. j.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 7925–7926
.
(10) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012
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(11) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.
Chem. Soc. 1988, 110, 1539–1546.
(12) Stafford, S. E.; Meyer, M. P. Tetrahedron Lett. 2009, 50, 3027–
3030.
(13) Saavedra, J.; Stafford, S. E.; Meyer, M. P. Tetrahedron Lett. 2009,
50, 1324–1327.
(14) Decius, J. C.; Wilson, E. B., Jr. J. Chem. Phys. 1951, 19, 1409–
1412.
Org. Lett., Vol. 11, No. 19, 2009
4339

Each type of competition experiment shown in Scheme 1
was performed in triplicate. The rate constant ratios from the
competition experiments in Scheme 1 (k1/k2 and kS-D3/kR-D3) were
computed using equations reported recently.7 The 2H KIE upon
each enantiotopic group was computed using the weighted
average values of the two rate constant ratios measured in
triplicate (Figure 1). The relative amounts of 1 and 2 in the
the comparatively more inverse 13C KIE measured at the
pro-R group for this reaction.13
To date, quantitative measurements of steric interactions
arising in asymmetric reactions have been limited to a recent
report from our laboratory.7 Other examples of unequivocal
2
steric H KIEs have been limited to systems in which the
sterically impacted atoms participate substantially in the
reaction coordinate at the transition state. These reactions,
none of which involve bond breaking or bond forming, can
be characterized as inversions18 or internal rotations19 within
molecules with rigid aromatic frameworks. Another notable
example is the deslipping reaction of rotaxanes.20 As might
be expected, these reactions, in which the free energy of
reaction results from steric interaction, yield steric 2H KIEs
(kH/kD ) 0.85-0.82) well in excess of those measured in
the current study.
2
The relative magnitudes of the inverse H KIEs can be
Figure 1. Relative rate constants computed from fractionation in
reisolated reactant and resulting KIEs upon the prochiral methyl
groups in the substrate. Errors in the last digit are in parentheses.
understood in terms of individual pairwise interactions
between neighboring groups. Figure 3 shows that the
stock ketone mixture and reisolated samples were computed in
the following way: The methyl doublet integration was used
as a measure of the amount of 1 present, while the total amount
of 1 and 2 could be estimated from the integration of the septet
corresponding to the aliphatic methyne proton. The errors on
the isotope effects at each position are propagated from the error
estimates taken from the single value estimates computed from
the competition experiments.17
The computed transition structure in Figure 2 reproduces
13C KIEs measured for the BH3-DMS reduction of 2′,5′-
dimethylphenyl isopropyl ketone catalyzed by (S)-Me-CBS.13
In light of this transition structure and the 13C KIE measure-
ments reported in the previous study, the 2H KIEs shown in
Figure 1 have a simple and satisfying explanation. In the
transition state, significant steric repulsion develops at each
prochiral methyl group, with more steric repulsion occurring
at the pro-R group. These values agree qualitatively with
Figure 3. Nearest neighbor nonbonding interactions in the computed
transition structure for the (A) pro-S and (B) pro-R methyl groups.
Distances are nearest H-H contact distances between the groups
indicated.
immediate environment of the pro-R methyl group residing
on the isopropyl moiety experiences closer nonbonding
contacts than the pro-S methyl group. What is perhaps
surprising is that each of the prochiral methyl groups has
nonbonding interactions with the aryl group on the substrate.
Judging from the high stereoselectivity observed in (S)-Me-
CBS/BH3 reductions of acetophenone, self-interaction is not
requisite for high selectivity but is rather simply an artifact
of having a tertiary R-carbon on the alkyl substituent of the
aralkyl ketone.9,10
In contrast to earlier semiempirical computational stud-
ies,21,22 we find that the cyclic arrangement of the reactive
(15) Keith, T. A.; Bader, R. F. W. Chem. Phys. Lett. 1992, 194, 1–8.
(16) Keith, T. A.; Bader, R. F. W. Chem. Phys. Lett. 1993, 210, 223–
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(17) Mandel, J. The Statistical Analysis of Experimental Data; Dover
Press: New York, 1984.
(18) (a) Mislow, K.; Graeve, R.; Gordon, A. J.; Wahl, G. H. J. Am.
Chem. Soc. 1964, 86, 1733–1741. (b) Hayama, T.; Baldridge, K. K.; Wu,
Y.-T.; Linden, A.; Siegel, J. S. J. Am. Chem. Soc. 2008, 130, 1583–1591.
(19) (a) Melander, L.; Carter, R. E. J. Am. Chem. Soc. 1964, 86, 295–
296. (b) Carter, R. E.; Dahlgren, L. Acta Chem. Scand. 1969, 23, 504–514.
(c) Sherrod, S. A.; da Costa, R. L.; Barnes, R. A.; Boekelheide, V. J. Am.
Chem. Soc. 1974, 96, 1565–1577.
Figure 2. Computed transition structure [B3LYP/6-31+G(d,p)]for
Re attack of hydride upon 2′,5′-dimethylphenyl isopropyl ketone.
The two phenyl groups on the CBS catalyst are denoted by gold
spheres.
(20) Felder, T.; Schalley, C. A. Angew. Chem., Int. Ed. 2003, 42, 2258–
2260.
4340
Org. Lett., Vol. 11, No. 19, 2009

portion of the transition structure, including the borane
reductant and the carbonyl of the ketone, is arrayed in a boat
conformation as predicted by Evans.23 This difference may
be due to the presence of R-branching present on the
isopropyl group of 2′,5′-dimethylisobutyrophenone. In con-
trast, the earlier semiempirical studies utilized acetone and
acetophenone as model substrates.
2′,5′-dimethylisobutyrophenone. These measurements indi-
cate that significant steric interactions develop at each
prochiral group in the transition structure. Computed transi-
tion structures identify internal interactions within the ketone
substrate as the origin of some of the steric occlusion that is
2
indicated by the inverse H KIEs measured. The primary
steric interaction between the substrate and catalyst appears
to be repulsion that develops between the B-Me substituent
and the pro-S methyl group. Minimization of the interaction
between the B-Me group residing on the (S)-Me-CBS catalyst
and the isopropyl group residing upon the substrate seems a
likely origin of at least some stereoselectivity in the (S)-Me-
CBS catalyzed reduction of 2′,5′-dimethylisobutyrophenone.
This finding contrasts with previous studies that explored
the effect of B-alkyl group identity upon stereoselection in
the reduction of acetophenone.10,24,25 However, computed
transition structures for acetophenone reduction using the (S)-
Me-CBS catalyst exhibit a chairlike conformation of the
reacting atoms in the transition state as compared to the
boatlike transition state computed here.
As can be seen in Figure 3, the only neighboring group
on the CBS catalyst to come into close proximity with the
prochiral methyl groups is the B-Me group. This may infer
that stereoselection is primarily determined by the B-alkyl
group when the boat conformer of the transition state
predominates. This finding is in contrast to what is observed
in reductions of acetophenone with a series of oxazaboro-
lidine catalysts bearing different B-alkyl groups. Analogues
of the CBS catalyst bearing boron substituents of H, Me,
Et, and n-Bu catalyze the borane reduction of acetophenone
in nearly quantitative yields and with selectivities greater
than or equal to 96% ee.10,24,25 This indicates that the steric
presence of the B-alkyl group on the CBS catalyst has little
impact upon stereoselection in the reduction of acetophenone.
This may simply reflect a preference for the chair conformer
of the transition state for acetophenone reduction.
In light of the exceedingly broad substrate range of (S)-
Me-CBS, these findings suggest that there may be two
avenues for stereoselection. In prochiral ketones having small
substituents that are sterically unobtrusive, it may be that
the chair conformer predominates, in which case the prolinol
substituents enforce stereoselection. Conversely, in prochiral
ketones bearing small substituents with greater steric pres-
ence, it may be that the boat conformer predominates,
resulting in stereoselection mediated by the B-alkyl substitu-
ent. It is also possible that the transition state is best
represented by an admixture of the chair and boat conform-
ers. We are currently exploring this possibility by measuring
2H KIEs upon the 2′- and 5′-methyl substituents of 2′,5′-
dimethyisobutyrophenone.
While previously measured 13C KIEs correspond exceed-
ingly well with those computed from the boat-like structure
2
in Figure 2, the H KIEs computed (B3LYP/6-31+G**) at
the pro-S and pro-R groups are 0.964 and 0.934, respectively.
This represents a substantial overestimation of the inverse
steric isotope effect. Computed estimates of the 2H KIEs on
the prochiral methyl groups in the DIP-Cl reduction of 4′-
methylisobutyrophenone also significantly overestimate the
inverse isotope effect. It is doubtful that conformational
uncertainty is the cause of the discrepancy in the DIP-Cl
reduction, as the boat conformation for the transition structure
is mandated by severe 1,3-interactions that would develop
in a chair conformer.8,12 We are currently developing a
computational methodology that incorporates anharmonicity
Acknowledgment. M.P.M. thanks the ACS Petroleum
Research Fund (No. 48064-G4) for support of this research
and Prof. Michael Colvin (UCM) for the use of his Linux
cluster.
2
into estimations of steric H KIEs in order to reconcile
experiment and theory.
We have presented 2H KIE measurements at the prochiral
methyl groups in the (S)-Me-CBS-catalyzed reduction of
Supporting Information Available: Detailed experimen-
tal procedures, derivation of equations for computing kinetic
isotope effects from NMR measurements, and tables of
integrations from quantitative NMR measurements.This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Linney, L. P.; Self, C. R.; Williams, I. H. J. Chem. Soc., Chem.
Commun. 1994, 1651–1652.
(22) Jones, D. K.; Liotta, D. C.; Shinkai, I.; Mathre, D. J. J. Org. Chem.
1993, 58, 799–801.
(23) Evans, D. A. Science 1988, 240, 420–426.
(24) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551–5553
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(25) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33, 4141–4144
.
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