Improved Methodology for the Preparation of Chiral Amines

Chapter 7
Stereochemical Considerations of
Proposed Mechanistic Models
7.1. Introduction.
The outstanding diastereoselectivities reported for different amines using stoichiometric
quantities of Yb(OAc) 3 and the application of catalytic quantities of Lewis acids for first time
in reductive amination of prochiral ketones were the driving force for investigating the
mechanistic aspects behind this effect. It is known historically that the imine conformation
plays the major role in determining the stereochemical outcome of reductive amination.
Analyzing transition state structures for trans-and cis imines which controls the facial
selectivity during addition of hydrogen to the imine allows the prediction of which
diastereomer will be formed in excess (figure 7.1). Diastereomeric excess of the amine
product depends on which enantiomer of α-MBA is used, the well known concept of allylic
1,3-strain [1] and on the earlier proposed models. [2]
Although predictions obtained from this model agree with the reaction outcome, other models
were also introduced aiming to describe the reason behind the improved diastereoselectivity.
It was suggested previously that the reductive amination of an α-ketoester with α-MBA may
involve a rotamer (about the nitrogen-benzylic carbon bond) with the phenyl ring of α-MBA
coplanar to the imine double bond. [3] This proposed idea agrees with the known fact of π
bonds affinity for heterogeneous hydrogenation catalyst surfaces. [4]
Despite this fact, close examination of other two possible trans-ketimine rotamers, having
phenyl group in a coplanar conformation with the imine double bond reveals that one rotamer
suffers from high allylic 1,3-strain resulting from steric crowding of phenyl group with
methyl group connected to imine carbonyl carbon the other rotamor is less sterically
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