Enol Borinates in Stereospecific C-C bond formation. Studying Asymmetric Induction

A key stage in the reaction sequence shown as part of the problem is the following step involving C-C bond formation to an aldehyde, mediated by the chiral auxilliary X=di-isopinocampheyl (see I. Paterson et al, Tetrahedron, 1990, 46, p 4663; 1991, 47, pp. 3471-3484)
Enol borinate reaction with an aldehyde
Other than the chiral auxiliary, all the reagent components are achiral. However, two entirely new chiral centres are formed in the product. Modelling can help us understand two features of these new chiral centres and why they form so specifically.
  1. their relative stereochemistry
  2. their absolute stereochemistry.

The Relative Stereochemistry

A 3D model for the basic framework (i.e. replacing all substituents with H) of the transition state must be constructed. Since this involves bond formation and cleavage, a QM (Quantum Mechanics) based model must be used, in this case the AM1 semi-empirical method (Table). The transition state can be located using a variety of methods. Since the reaction involves two bonds making and one breaking, its difficult to construct a 1D or 2D grid as in the example 13 above. The easiest way is to guess the approximate lengths of the breaking/making bonds (about 1.9 - 2.1A), and insert this guessed geometry into an appropriate transition state location algorithm, such as the eigenvector following method. Whilst rather hit and miss, after a few attempts, the algorithm should result in transition state location. A little trick to help it do so is to define the coordinates in internals (ie bond lengths etc) and to ensure that the three changing bonds are defined. Next, freeze their values at 1.9 - 2.1A and optimise the remainder of the molecule (to remove all gradients associated with non reacting centres). Then, release the transition state bonds and let the TS optimiser do the rest!

These calculations reveal that both chair and boat forms of the transition state are possible. A full calculation of the 2nd derivative matrix, followed by appropriate mass weighting, will give the frequencies of the various normal modes of the molecule. One is shown as -ve (imaginary), being the transition state normal mode. A program such as JMol can be used to animate the form of this normal mode.

Prototypic Chair transition state Prototypic Boat transition state
One next needs to understand how the various substitution sites interact sterically. To do this, methyl groups are inserted into the various positions (including one for the chiral auxilliary X) and the energies of some of the various possible isomers are calculated. Note the following:
  1. The chair form ( ) is the most stable
  2. The chiral centre on the aldehyde ( ) is formed with the methyl group equatorial ( ), thus avoiding steric congestion from the chiral auxilliary X ( ) This particular steric interaction in effect defines which π face of the carbonyl group is used to form the new C-C bond.
  3. The alternative relative stereochemistry of the chiral centre ( ) would place the methyl group axial ( ). It is about 3 kcal/mol higher in energy, and hence is not formed.
Chair transition state Chair transition state isomer
-103.1 kcal/mol -100.3 kcal/mol


Another way of avoiding steric congestion is for the boat conformation ( ) to form. The methyl ( ) adopts an equatorial position, but it is eclipsed rather than staggered with the adjacent C-H and hence the most stable boat isomer is 3 kcal/mol higher than the chair.
Boat transition state
-100.1 kcal/mol

The Absolute Stereochemistry

The methyl group X must now be replaced with a chiral auxilliary. Many such auxiliaries can be used (most derived from natural products that are enantiomerically pure). To start with a simple model, will use the (un-natural) chiral group -CHClI ( ), which contains three ligands of quite different size. Its chirality is defined in these models as S. When inserted into the model, two diastereoisomers with carbon chirality of S,R ( ) or R,S > can be formed. The calculations reveal that one of these is about 3 kcal/mol more stable than the other, which is the correct order of magnitude to result in a high degree of chiral induction.
Chiral S, Carbon R,S (-84.9) Chiral S, Carbon S,R (-87.6)
A "natural" chiral group can now be inserted ( ) to form the final models.
Chiral S, RS (-149.55) Chiral S, SR (-152.43)