Insights into the Mechanism of the Asymmetric Reduction of Ketones with Diisopinocampheyl Boron Chloride

Mark Mackey and Jonathan Goodman

Department of Chemistry
Cambridge University
Lensfield Rd, 
Cambridge CB2 1EW

Abstract

The structures and properties of complexes of a range of carbonyl compounds with dihydro- and dialkylboron fluorides and chlorides were examined by ab initio methods. Based on these results it is suggested that the observed enantioselectivity of reduction of ketones with diisopinocampheyl boron chloride can be directly related to which group on the ketone prefers to be coordinated syn to the boron.

Introduction

In the past few decades numerous chiral reagents for the asymmetric reduction of carbonyl compounds have been developed. Although many of the earlier reagents exhibited only a poor optical induction in the reduction of prochiral ketones, a number of recently developed reagents have shown excellent success in this regard. One such successful reagent is diisopinocampheyl boron chloride.

(Ipc)2BCl

The mechanism of reduction is postulated to involve the formation of a Lewis acid-carbonyl complex complex between the reagent and the carbonyl compound, followed by transfer of a beta-hydrogen, liberating alpha-pinene. The hydrogen transfer is usually depicted as proceeding through a six-membered cyclic 'boatlike' transition state. The asymmetric induction is ascribed by this model to an unfavourable steric interaction between the larger of the two groups on the carbonyl and the beta methyl group on the isopinocampheyl unit:

However, this transition state model is incomplete in a number of respects. Firstly, (Ipc)2BCl reduces acetophenone in 98% ee, but reduces cyclohexyl methyl ketone in only 26% ee (Acc. Chem. Res 1992, 25, 17). This large difference in selectivity seems difficult to rationalise on simply steric grounds.

More recently, the following results from the reduction of fluorinated ketones with (Ipc)2BCl have been reported:

Based on the proposed mechanism for the reduction as given above, these results give a 'bulk' for the ketone substituents in the following order:

CF3 >> CHF2 > CH3 ~= n-hex > CH2F

which does not correlate well to the steric bulk of these substituents. A better understanding of the structure and electronic nature of the intermediate Lewis acid complex formed in this reaction is obviously necessary if predictions of the enetioselectivity of this reagent are to be made.

Results and Discussion

In an attempt to understand the factors affecting the stereoselectivity of this reagent, the structures of a number of dihydro- and dialkyl boron chloride complexes to various aldehydes and ketones were calculated using the 4-31G basis set, and some single point energies were obtained at the MP2/6-31G*//4-31G level. A selection of the structures calculated is shown below:

The short Cl-H distances observed in most of these structures is ascribed to a hydrogen bonding interaction. This interaction appears to have a reasonably large effect on the relative energies of the E and Z isomers of these adducts. A systematic study was performed examining the E / Z energy differences of complexes of H2BCl to various ketones.

E / Z Energetic differences (kJ/mol)

Functional Group      Relative to H      Relative to Me

Me                      15.4 (11.6)           0.00
Et                      18.2                  2.25
C=C                     17.0 (12.3)          11.56
C%C (alkynyl)           21.1 (14.6)           4.80
t-butyl                 27.2 
CH2F                                         -5.30
CHF2                                          0.40
CF3                                           8.00

(Bracketed energies are MP2/6-31G*//4-31G, others are 4-31G//4-31G. The energy refers to the energetic penalty of making the indicated functional group syn to the boron.)

The E / Z energy differences that are observed for aliphatic ketones indicate an possible alternative explanation for the source of stereochemistry in (Ipc)2BCl reductions. If one of the two Ipc groups is much more likely to transfer a hydrogen to the carbonyl group than the other, then the enantiomeric excess of the product will be directly related to the E / Z energetic preference of coordination:

Work is currently proceeding on developing an extension to the MM2 force field to allow molecular modelling of these complexes and establish whether one of the two diastereomeric isopinocampheyl groups is indeed significantly more likely to transfer a hydrogen than the other.

This model explains the previously discussed results of reduction of fluorinated ketones: the order of preference of the chlorine to be syn to a group is CH2F >> CH3 ~= CHF2 >> CF3, which accords well with the observed enantioselectivity.
Some other experimental evidence in support of this model exists. Reduction of o-hydroxyacetophenones with (-)-(Ipc)2BCl gives the opposite stereochemistry to that expected by analogy to the reduction of o-methoxyacetophenones:

Conclusions

The E / Z energy difference in R2BCl adducts to ketones and aldehydes is not simply dependent on steric effects.
A Cl-H hydrogen bond is often present in these complexes and has a strong influence on their conformational preferences.
The enantioselectivity of the asymmetric reduction reagent (Ipc)2BCl can be directly related to the E / Z energetic preference of coordination.

Mark Mackey / Cambridge University / mdm1004@cus.cam.ac.uk
Jonathan Goodman / Cambridge University / jmg11@cus.cam.ac.uk