Chiral Amine Synthesis Nugent

523 Pages·2010·4.64 MB·English

Chiral Amine Synthesis
Methods, Developments and Applications
Edited by
Thomas C. Nugent

Chiral Amine Synthesis
Edited by
Thomas C. Nugent
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Chiral Amine Synthesis
Methods, Developments and Applications
Edited by
Thomas C. Nugent
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This book is dedicated to my twins, Kian and Helen,
and their wonderful mother Elisa.

VII
Foreword
A vast majority of drugs are amines or contain functional groups derived from
amines, and an increasing number of these molecules are chiral and nonrace
mic. Thus, the development of many biologically active molecules, whether
derived from natural or synthetic sources, relies on the development of general
and efficient methods to prepare chiral amines. With this need in mind, many
researchers made the enantioselective synthesis of amines a focus of their
research during the past decade. During the early 1990s, several groups illu
strated that the asymmetric hydrogenation of imines was possible and that the
asymmetric hydrogenation of enamides without the accompanying ester func
tionality present in the reagent for the classic hydrogenation to form LDOPA
could be achieved. However, this work also revealed many of the challenges
faced by these types of hydrogenation. Further work on hydrogenation of
heteroarenes illustrated both progress and additional challenges. Finally, meth
ods to form chiral amines by C C and C N bond formation began to emerge.
Again, progress was made, but this chemistry confronted many challenges.
The asymmetric synthesis of amines is a difficult problem for many reasons
describedinthismonograph.Althoughacomprehensivelistofchallengescannotbe
provided here, I outline a few of them. First, acyclic imines can adopt E and Z
isomers, and these isomers often lead to opposite enantiomers of the addition
product, thereby reducing enanioselectivity. Second, both imines and amines can
beligandsforatransitionmetal,andaminesoramidescanformmetal amideor
metal amidatecomplexesinwhichtheproductbecomesapartofthestructureof
the active or deactivated catalyst. Third, nitrogen protective groups are a
particularly thorny component of any synthetic endeavor, and the most useful
protectivegroupsforasyntheticsequence,duetotheirabilitytoberemovedunder
mild conditions, need not be the substituents on nitrogen that lead to highly
enantioselectivechemistrytoformaminederivatives.
However, the creativity of a large number of synthetic chemists has led to
tremendousprogresstowardaddressingthesechallengesandthedevelopmentof
trulypracticalmethodstopreparechiralamines.Perhapsthebestillustrationofhow
anopenmindcanleadtosignificantadvancestowardtheasymmetricsynthesisof
aminesisthedevelopmentoftheprocesstomanufacturetheblockbusterdiabetes
drugJanuviabytheasymmetrichydrogenationofanunstabilizedN Himine.
ChiralAmineSynthesis:Methods,DevelopmentsandApplications.EditedbyThomasC.Nugent
Copyright(cid:1)2010WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:978-3-527-32509-2