Origin of enantioselectivity in CF3-PIP-catalyzed kinetic resolution of secondary benzylic alcohols

Article abstract of DOI:10.1021/ja805275s

Computational studies provide support for the involvement of intermolecular π-interactions in the chiral recognition of secondary benzylic alcohols by the enantioselective acyl transfer catalyst CF₃-PIP. Copyright

Full text of DOI:10.1021/ja805275s

Published on Web 09/26/2008
Origin of Enantioselectivity in CF
3
-PIP-Catalyzed Kinetic Resolution of
Secondary Benzylic Alcohols
†
‡
,‡
,†
Ximin Li, Peng Liu, K. N. Houk,* and Vladimir B. Birman*
Department of Chemistry, Washington UniVersity, One Brookings DriVe, St. Louis, Missouri 63130, and Department
of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
Received July 8, 2008; E-mail: houk@chem.ucla.edu; birman@wustl.edu
Nonenzymatic enantioselective acyl transfer catalysis has been
an active area of research for over a decade. Many of the catalysts
which was in accord with the expected conformation. However,
the involvement of π-interactions in the transition state is inherently
difficult to verify by direct experimental observation. Therefore,
we initiated a computational study aimed at elucidating the origin
of the enantioselectivity. To the best of our knowledge, the role of
intermolecular π-interactions in chiral recognition has not been
1
developed to date have demonstrated varying degrees of enanti-
2
oselectivity in kinetic resolution of secondary alcohols. Secondary
benzylic alcohols have enjoyed particular popularity as substrates
3
,4a-c
in this reaction.
However, the origin of enantioselectivity in
6
,7
this process has not been elucidated. In this communication, we
present the results of our computational studies, which support the
involvement of π-interactions in the chiral recognition of this class
previously investigated by computational methods.
The energy-minimized geometry of N-acetyl-(R)-CF
+
3
-PIP (5,
8,9
X omitted) obtained at the B3LYP/6-31G* level of theory was
consistent with the X-ray structure of 5a, the acyl carbonyl being
nearly coplanar with the pyridine ring. Transition state geometries
for reactions of 5b and the R- and S-enantiomers of 1-phenylethanol
5
of substrates.
In 2004, we introduced a new class of enantioselective acyl
transfer catalysts. Among the first-generation catalysts, CF
3
-PIP
1
1
proved to be particularly effective in the kinetic resolution of
(2, R ) Me) were investigated next. The acetate anion hydrogen-
secondary benzylic alcohols (2). Structure-selectivity trends
observed in this initial study led us to hypothesize that the chiral
recognition depends on π-π and cation-π interactions between
the pyridinium ring of the N-acylated catalyst and the benzene ring
of the substrate, as shown in the proposed transition state model 4
bound to the hydroxyl group of the substrate was included in the
calculations, as suggested by the recent computational studies on
10
achiral acyl transfer catalysis. Each enantiomer of 1-phenylethanol
was attached to the unencumbered ꢀ-face of 5b, and all accessible
conformations were explored.
4
a
(
Scheme 1). Later, this hypothesis proved to be valuable as a
guide in the development of subsequent generations of related
4
b,c,f
4a-c,f
4b
catalysts.
Their application to benzylic,
allylic, and
4
d
4e
propargylic alcohols, 4-aryl-oxazolidinones, and 2-aryl-cyclo-
4
f
alkanols produced results that were also consistent with the
π-stacking mechanism.
Scheme 1. CF3-PIP-Catalyzed Kinetic Resolution
Figure 1. Transition states for reactions of (R)- and (S)-phenylethanol with
5
b.
(
R)-1-Phenylethanol, which is the fast-reacting enantiomer in
kinetic resolutions with (R)-1, preferred the slipped-stacked geom-
etry, with the phenyl of the substrate centered approximately over
the pyridinium N. In conformer 7a, representing the global energy
minimum, the distance between the center of the phenyl ring and
the pyridinium N is 3.74 Å, and the planes of the pyridinium and
the benzene rings are at an 8.5° dihedral angle. The lowest-energy
splayed conformer 7b was 7.6 kcal/mol less stable than 7a. For
the diastereomeric transition states with the slow-reacting (S)-1-
phenylethanol, the situation was reversed. The stacked conformer
Recently, we were able to obtain an X-ray structure of the
11
N-acetylated CF -PIP in the form of hexafluoroantimonate 5a,
3
†
Washington University.
University of California.
‡
1
3836 9 J. AM. CHEM. SOC. 2008, 130, 13836–13837
10.1021/ja805275s CCC: $40.75  2008 American Chemical Society

C O M M U N I C A T I O N S
8a was less energetically favorable than the splayed conformer 8b,
In summary, our computational study lends theoretical support
presumably due to the A1,3-strain introduced by the methyl group
virtually coplanar with the benzene ring in the former.
to the π-interaction hypothesis of chiral recognition in the KR of
secondary benzylic alcohols catalyzed by CF -PIP and provides a
3
Finally, we confirmed that the approach of either the R- or the
S-enantiomer of the substrate to the R-face of the N-acylated catalyst
encumbered by the phenyl substituent at C2 is disfavored relative
to the aforementioned ꢀ-face conformers 7a and 8b (by 6.6 and
more accurate and detailed description of the transition state. The
enantioselectivity depends upon two factors: steric repulsion
between the methyl and the ortho-hydrogen (7a , 7b; 8b , 8a)),
and the electrostatic attraction between the phenyl and pyridinium
in the slipped-parallel geometry (7a < 8a). The results of this
investigation are expected to be applicable to our more advanced
catalysts and may also shed light on the mechanism of chiral
recognition achieved by enantioselective acylation catalysts devel-
oped by other groups.
1
0.1 kcal/mol, respectively).
The energy difference between the lowest-energy conformers for
the R- and S-enantiomers of the substrate (7a and 8b) is 1.9 kcal/
mol. This value was adjusted to 1.6 kcal/mol by introducing solvent
3
correction (CHCl , CPCM model (UFF radii)), which is in excellent
agreement with the experimental data (selectivity factor s ) 12
obtained in chloroform at room temperature corresponds to ∆Grel
Acknowledgment. We thank Prof. Glaser (University of Mis-
souri-Columbia) for collaboration and helpful discussions during
the early phase of this project. X-ray analysis was performed by
Dr. Rath (University of Missouri-St. Louis). The financial support
of this study by NIGMS (GM072682 for V.B.B. and X.L.; GM
)
1.5 kcal/mol) (Table 1, column 1, entries 1 and 5). Encouraged
by these findings, we examined the transition states of the R- and
S-enantiomers of 1-phenylethanol with N-propionyl-(R)-CF -PIP
3
2
propionate 6 (R ) Et), operating in kinetic resolutions with
propionic anhydride (Figure 2). The computed increase in the free
energy difference between the energy minimized diastereomeric
transition states 9a and 10b (∆Grel ) 3.5 kcal/mol in gas phase, or
3
6700 for K.N.H. and P.L.) is gratefully acknowledged.
Supporting Information Available: Kinetic resolution, computa-
tional and X-ray data, and complete ref 9. These materials are available
free of charge via the Internet at http://pubs.acs.org.
2
.8 kcal/mol in chloroform) is qualitatively consistent with the
experimentally observed enhanced enantioselectivity (s ) 26, ∆Grel
1.9 kcal/mol)(column 2, entries 1 and 5). Apparently, it reflects
)
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B3LYP/6-31G*
(
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3
4
3.7 (4.5)
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1.5
5.4 (5.7)
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5
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a
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JA805275S
J. AM. CHEM. SOC. 9 VOL. 130, NO. 42, 2008 13837