Improved Methodology for the Preparation of Chiral Amines

1.8. α-Chiral Amine Synthesis Different Methodologies
As mentioned previously chiral amines are key components of different pharmaceutical and
agrochemical compounds. Over the last fifty years different methodologies have been
developed for their synthesis. Some of the methodologies are industrially viable and others
are better suited for pilot studies. Of course for a methodology to be applicable on industrial;
scale it must fulfil certain features e.g. should be cost effective and waste generation should
be low. Some processes are highly efficient in preparing chiral amines in high yield and
stereoselectivity. Despite their efficiency they suffer mainly from major drawbacks as lengthy
multistep procedures which hinder their applications on industrial scale. Among the versatile
strategies employed is the hydrogenation of enamine esters (diastereo and
enantioselective), [61] hydrogenation of α- or β-N-acetylenamide esters, [62] 1,4-addition of
amines to enones, [63] Chemical, [64] and enzymatic [65] reductive amination of α- ketoacids,
remote amination via C-H insertion [66] and hydroamination of olefins. [67]
Reduction of unfunctionalized ketones and aldehydes is one of the major strategies for the
synthesis of chiral amines. This strategy can be subdivided into various subdivisions which
includes the following.
1) N-acetylenamide reduction.
2).Transfer hydrogenation or hydrogenation of imines
3). Reductive amination of ketones
4) Carbanion addition to aldimine and ketimine derivatives.
5) Sequential aminationalkylation of aldehydes.
The first three methodologies are closely related as they use hydrogen from different hydride
sources for the reduction of prochiral carbonyl compounds. The asymmetric version of these
methodologies has been developed extensively over the past few years. N-acetylenamide
reduction and transfer hydrogenation or hydrogenation of imines will be discussed in details
trying to shed light on their advantages and disadvantages and their applications. Reductive
amination as the core of my work will be discussed showing its historical development over
the last century and the major breakthroughs in the field during the last two decades. The
application of reductive amination in pharmaceutical industry will be summarized in the
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