Enantioselective cyanosilylation of ketones catalyzed by a chiral oxazaborolidinium ion

Article abstract of DOI:10.1021/ja050543e

The chiral oxazaborolidinium salt 1 (X = TfO) is an excellent catalyst for the cyanosilylation of methyl ketones promoted by trimethylsilyl cyanide and diphenylmethyl phosphine oxide as co-reactants (to generate Ph ₂MePOTMS(N=C:) as a reactive

Full text of DOI:10.1021/ja050543e

Published on Web 03/26/2005
Enantioselective Cyanosilylation of Ketones Catalyzed by a
Chiral Oxazaborolidinium Ion
Do Hyun Ryu† and E. J. Corey*
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138, and Department of Chemistry, Sungkyunkwan UniVersity,
Suwon 440-746, Korea
Received January 27, 2005; E-mail: corey@chemistry.harvard.edu
Abstract: The chiral oxazaborolidinium salt 1 (X ) TfO) is an excellent catalyst for the cyanosilylation of
methyl ketones promoted by trimethylsilyl cyanide and diphenylmethyl phosphine oxide as co-reactants
(to generate Ph2MePOTMS(NdC:) as a reactive intermediate). The face selectivity of this reaction parallels
that previously observed for the corresponding reaction of aldehydes. A unifying and rational mechanistic
explanation is provided for these enantioselective reactions. Evidence is presented to support the importance
of R-C-H‚‚‚O hydrogen bonding, π,π-interaction of the complexed ketonic carbonyl with the mexyl group
of 1, and an early transition state for high enantioselectivity. The cyanosilylation reaction described herein
provides access to many useful chiral compounds.
Chiral oxazaborolidinium salts such as 1 and 2 have been
shown to be remarkably effective catalysts for a broad range of
enantioselective Diels-Alder reactions.1 The absolute stereo-
chemical course of each of these reactions can be predicted by
a logical and clear mechanistic rationale.1,2 The face selectivity
of the enantioselective Diels-Alder reaction depends on the
structural type of the dienophile component. For 2-substituted
R,â-enals, formyl C-H‚‚‚O hydrogen bonding2 leads to a
preferred pathway via 3,1a,b,2 whereas for R,â-unsaturated
carbonyl compounds having an R-C-H substituent (e.g. esters,
ketones, quinones) R-C-H‚‚‚O hydrogen bonding favors reac-
tion via complex 4.1b,c Two aspects of these catalytic pathways
are critical to the success of this new and powerful methodol-
ogy: (1) the oxazaborolidinium ions 1 and 2 are strong Lewis
acids that are capable of promoting Diels-Alder reactions
between components of only modest reactivity, and (2) the
complexed dienophilic carbonyl group retains its positive charge
even in the Diels-Alder transition state, which preserves the
strong attractive interaction between the coordinated carbonyl
group of the dienophile and the proximal π-electron-rich Ar
group of 1 or 2.3 We recently investigated the question of
whether catalysts such as 1 and 2 could function effectively in
Lewis acid-catalyzed enantioselective 1,2-additions to the formyl
group of aldehydes. In principle, the same factors that operate
to ensure face-selectivity in Diels-Alder reactions of R,â-enals
with dienes could serve to promote highly selective 1,2-addition
to aldehydes, e.g. cyanosilylation to form chiral cyanohydrin
derivatives.4 We were able, in fact, to find conditions for
effecting highly enantioselective cyanosilylation of a variety of
aldehydes.4 For instance, the reaction of benzaldehyde with
trimethylsilyl cyanide (TMSCN) using 10 mol % of the
oxazaborolidinium salt 1 and 20 mol % of triphenylphosphine
oxide in toluene at 0 °C proceeded in 94% isolated yield to
form the TMS derivative of mandelonitrile of 95% ee.4 In this
reaction a reactive cyanide donor, Ph3P(OTMS)(NdC:), is
generated from TMSCN and Ph3PO which then adds to the
complex 5 (from coordination of 1 to benzaldehyde) to form
† Sungkyunkwan University.
(1) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808-3809. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc.
2002, 124, 9992-9993. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc.
2003, 125, 6388-6390. (d) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett.
2003, 5, 3979-3982. (e) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem.
Soc. 2004, 126, 4800-4802. (f) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J.
Am. Chem. Soc. 2004, 126, 5984-5986. (g) Hu, Q.-Y.; Zhou, G.; Corey,
E. J. J. Am. Chem. Soc. 2004, 126, 13708-13713.
(2) Corey, E. J.; Lee, T. W. J. Chem. Soc., Chem. Commun. 2001, 1321-
1329.
(3) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650-1667.
(4) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8106-8107.
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J. AM. CHEM. SOC. 2005, 127, 5384-5387
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Cyanosilylation Catalyzed by Oxazaborolidinium Ion
A R T I C L E S
the R cyanosilylation product by attack at the si face; see
transition-state assembly 6.
summarizes the most significant experiments of this study with
a variety of substrates. Using optimized conditions, good yields
and enantioselectivities were obtained with the (S)-catalyst 1
(X ) TfO) and a range of different methyl ketones. The
reactions were generally faster with aliphatic methyl ketones
than with aryl methyl ketones. As shown in entries 1-6 of Table
1, the predominating enantiomer from the (S)-catalyst 1 is the
(R)-cyanosilylation product which is formed by addition of CN
to the si face of the coordinated methyl ketone.12 This is the
same face selectivity that has been observed for the cyanosi-
lylation of aldehydes4 and can be rationalized by the transition-
state assembly (TSA) 7. This is analogous to the TSA (6) for
The meta xylyl (mexyl) catalyst 1 effected cyanosilylation with
greater enantioselectivity than the phenyl analogue 2, indicating
clearly the importance of π-electron basicity in the neighboring
aromatic group of the catalyst.3,4 Enantioselectivities were
superior with Ph3P(OTMS) (NdC:) as cyanide donor than with
TMSCN alone, probably due to the greater reactivity of the
former and the advantage of an earlier transition state.4,5
In this study we investigated the possibility of extending the
catalytic enantioselective cyanosilylation using TMSCN to
methyl ketones. CAUTION! TMSCN is Volatile and toxic and
must be used in a well-Ventilated hood. Until recently, the
cyanosilylation of ketones had not been achieved. At present
only the titanium6 and lanthanide7 systems of Shibasaki and
co-workers, the aluminum-peptide complexes of Hoveyda,8 and
basic cinchona alkaloid catalysts9 have been used for this
purpose. We describe herein the development of a successful
enantioselective cyanosilylation of methyl ketones, the critical
conditions for optimal enantioselectivity, the dependence of the
process on the structure of the ketonic substrate, and the
mechanistic implications of this study.
Cyclohexyl methyl ketone was selected as the substrate for
screening experiments to optimize the following parameters:
(1) substituent on boron of the oxazaborolidine ring, (2) the
gem-diaryl substituent on that ring, (3) the counterion (i.e., the
acid for oxazaborolidine activation), (4) phosphine co-reactant,
(5) solvent, and (6) temperature. As a result of this evaluation
it emerged that the o-tolyl group was the optimal boron
appendage, as had been found previously in studies of Diels-
Alder reactions catalyzed by 1, 2, and analogues.1,10 The mexyl
group was superior to phenyl as gem-diaryl substituents on the
oxazaborolidine ring. The triflate counterion afforded somewhat
better results than Tf2N-, as phosphine oxide co-reactant Ph2-
MePO appeared superior to Ph3PO, PhMe2PO, p-tol3PO, or (p-
MeOC6H4)3PO.11 Toluene was definitely better in terms of yield
and ee of product than CH2Cl2 or CH3CN. Optimal temperatures
were in the range 25-45 °C, depending on substrate. Table 1
the cyanosilylation of aldehydes but involves R-C-H‚‚‚O
hydrogen bonding as an organizing element instead of formyl
C-H‚‚‚O hydrogen bonding. Table 1 also reveals a very
significant and surprising effect of para substituents in the
acetophenone series on enantioselectivity of cyanosilylation.
First of all, it is clear that the enantioselectivity is greater with
4-nitro- and 4-triflyloxyacetophenone (95-96% ee) than with
acetophenone itself (Table 1, entries 3, 5, and 6). Because of
their very high enantioselectivities the reactions of entries 5 and
6 are especially valuable synthetically. As shown below,
(5) The earlier the transition state in the 1,2-addition to the complexed carbonyl,
the greater the attractive interaction between carbonyl and neighboring
mexyl groups and the greater the degree of organization of the reactants as
shown in Table 1, entry 6.
(6) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
7412-7413.
the product of entry 5 can be converted easily and efficiently
into (R)-4-nitroatrolactic acid (8) of 100% ee. This process
represents the best route to this useful chiral acid. Since the
4-triflyloxy group in the product of entry 6 is easily replaced
by a large variety of other substituents using Pd(0) catalysis,
the enantioselective silylation of entry 6 in Table 1 represents
(7) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du,
W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908-
9909.
(8) Tian, S.-K.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900-
9901.
(9) Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2002, 41, 1009-1012.
(10) Higher enantioselectivities were observed with an o-tolyl substituent on
boron relative to phenyl, methyl, or n-alkyl.
(11) In the absence of phosphine oxide as co-reactant the enantioselectivities
were considerably lower.
(12) Data on the determination of enantioselectivities and absolute configurations
of the cyanosilylation products are provided in the Supporting Information.
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A R T I C L E S
Ryu and Corey
Table 1. Oxazaborolidinium-Catalyzed Cyanosilylation of Methyl
Ketones
Figure 1. X-ray structures of BF3‚4-nitroacetophenone (9) and BF3‚4-
methoxyacetophenone (10).
positive charge on the para methoxy substituent and diminished
charge on the carbonyl carbon. This fact and the displacement
of the transition state to a later point along the reaction
coordinate serve to severely negate the interaction between the
not-so-positive carbonyl carbon and the π-electron-rich mexyl
substituent leading to a disorganization of the transition state
(i.e., B-OCO rotomers) and low enantioselection.
Although it might be argued that the large difference in the
cyanosilylation reactions of 4-nitroacetophenone and 4-meth-
oxyacetophenone could be due to a different geometry of
coordination of ketone to catalyst 1, for instance very different
B-O-CCO angles, we have obtained strong evidence against
this possibility. Crystalline complexes of 4-nitroacetophenone
and 4-methoxyacetophenone with boron trifluoride were pre-
pared and structurally examined by single-crystal X-ray dif-
fraction analysis. The structures of these complexes, 9 and 10
respectively, are shown in Figure 1.
The structures found for these complexes, 9 and 10, each
involve coordination of BF3 to the lone pair on the carbonyl
group syn to the methyl group, as shown in the proposed TSA
7. In addition, the shortest distances between the methyl
hydrogen and the nearest fluorine are 2.38 and 2.41 Å. These
distances are appreciably shorter than the sum of the van der
Waals radii for H and F, 2.67 Å, which points to the attractive
H-F interaction. A similar H-O interaction may help organize
the TSA 7. There are small, but interesting, differences in the
X-ray-determined structures of the boron trifluoride complexes
9 and 10. The bond between boron and the coordinated carbonyl
oxygen is longer in the p-nitro complex 9 (1.588(3) Å), than in
the p-methoxy complex 10 (1.531(12) Å), as expected from the
greater basicity of 4-methoxyacetophenone relative to that of
4-nitroacetophenone. There is a small difference, in the expected
direction, between the formyl CdO bond distance in 9 (1.251
Å) and that in 10 (1.266 Å). Differences in the B-O-CCO
angles are clearly insufficient to account for the divergent
enantioselectivities observed in the cyanosilylation of 4-nitro-
and 4-methoxyacetophenones, those angles being 126.3° for 9
and 129.3° for 10. The detailed X-ray crystallographic data for
9 and 10 are provided in the Supporting Information.
a Absolute configuration of the product is S. b The absolute configuration
of the major product is S, i.e. in contrast to the results of entries 3-6.
a practical link to a large number of other interesting 4-substi-
tuted atrolactic acids.
The beneficial effect of electron-withdrawing para substituents
on the enantioselectivity of the cyanosilylation of acetophenones
with catalysis by 1 can be rationalized in a logical way. Although
an electron-withdrawing para substituent can be expected to
diminish the basicity of the acetophenone carbonyl group and
thus the degree of complexation to catalyst 1, the transition state
for the cyanosilylation would occur at an earlier stage along
the reaction coordinate than would be the case for more basic
acetophenones. Consequently, the interaction of the partially
positive complexed carbonyl carbon and the neighboring mexyl
group would be greater for the less basic substrates, and the
enantioselectivity should be higher, as it in fact is. As
documented in entry 7 in Table 1, the strongly electron-
supplying para methoxy group of 4-methoxyacetophenone
causes a drastic reduction in enantioselectivity as compared to
the other acetophenones of Table 1 (entries 3-6). Remarkably,
the predominating absolute stereochemical course of the catalytic
cyanosilylation of 4-methoxyacetophenone is opposite to that
of the other acetophenones. We think that this large difference
is a consequence of the transition-state argument that is
summarized above. The complex between catalyst 1 and
4-methoxyacetophenone is especially stable with substantial
Conclusions
This research has shown that the chiral catalyst 1 is highly
effective for the enantioselective cyanosilylation of a range of
methyl ketones. The absolute stereochemical course of these
carbonyl additions can be rationalized in a logical way using
mechanistic considerations that have proved highly successful
in predicting many Diels-Alder reactions in previous work.1
The reactive intermediate Ph2MePOTMS(NdC), generated from
Ph2MePO and TMSCN, leads to considerably higher enantio-
selectivity in cyanosilylation than does TMSCN. As demon-
strated from comparative experiments with 4-substituted aceto-
phenones, higher enantioselectivities result with the more
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Cyanosilylation Catalyzed by Oxazaborolidinium Ion
A R T I C L E S
electron-withdrawing substituents because these favor early
transition states and a stronger attractive interaction between
the coordinated methyl ketone carbonyl and the neighboring
π-electron-rich mexyl group of 1. Electron-supplying groups
have the opposite effect, leading to stereochemically variable
pathways possibly involving B-OCO rotamers, and low, in fact
opposite, enantioselectivity. The face selectivity in the cyanosi-
lylation of methyl ketones under catalysis by 1 (si face) parallels
that established for aldehydes. It is proposed that the former
process involves R-C-H‚‚‚O hydrogen bonding as an organizing
element, whereas the latter involves formyl C-H‚‚‚O hydrogen
bonding. The highly enantioselective cyanosilylations described
herein are synthetically valuable since they open pathways for
the synthesis of many useful chiral compounds, for example,
chiral atrolactic acids.
Supporting Information Available: General procedure for
the enantioselective cyanosilylation of methyl ketones using
catalyst 1 and characterization data for each product. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA050543E
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