Models for the Asymmetric Enol borinate reduction of a ketone

Source: 2nd Year Organic Problems, 1999, Set 1.

Background:

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, vol 46, p 4663; 1991, Vol.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. We need to 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 1). Ab initio programs can also be used, but they take much longer, and yield very similar results. These calculations reveal that both chair and boat forms of the transition state are possible.
Prototypic Chair transition statePrototypic Boat transition state
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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 ( ) is formed with the methyl group equatorial ( ), thus avoiding steric congestion from the chiral auxilliary X ( ) This particular steric interaction in effect defines which p face of the carbonyl group is used to form the new C-C bond.
  3. The alternative relative stereochemistry ( ) would place the methyl group axial ( ). It is about 3 kcal/mol higher in energy, and hence is not formed. In effect, this particular interaction defines which p face of the carbonyl group forms the new C-C bond.
  4. Another way of avoiding steric congestion is for the boat comformation to form. The most stable boat isomer is also 3 kcal/mol higher, eliminating this possibility as well.
Chair transition stateChair transition state isomerBoat transition state
-103.1 kcal/mol-100.3 kcal/mol-100.1 kcal/mol
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The Absolute Stereochemistry

The methyl group X () must now be replaced with a chiral auxilliary. Many such auxilliaries 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)
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A "natural" chiral group can now be inserted to form the final models.
Chiral S, RS (-149.55) Chiral S, SR (-152.43)
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Modelling Details: All models were calculated using the semo-empirical AM Hamiltonian, with full location of the transition states. The energies where quoted correspond to the computed enthalpies of formation of the transition states. Software used included CAChe and Chem3D Pro, and MacMolPlt/GAMESS for ab initio calculations (on the naked chair and boat).
(c) Sonsoles Martín-Santamaría and Henry S. Rzepa, 1999.