Biocatalytic reductive amination
catalyzed by engineered imine
reductase (RedAms) is a new and powerful tool for the synthesis of
substituted chiral amines. Herein, we describe a streamlined synthesis
of compound 3, a key intermediate to a CDK 2/4/6 inhibitor 1, relying on the enzymatic reductive amination of a hydroxyketone
to introduce the chiral secondary amine with high diastereoselectivity.
The improved synthesis of the hydroxyketone precursor by a titanium-catalyzed
reductive cyclization and the process development for two SNAr reactions en route to 3 are also presented.
This
is the first in a series of three papers describing the identification
and development of a commercial synthesis of filibuvir (1). This contribution describes development of an Evans aldol reaction
to control the tertiary alcohol stereocenter, a challenging variant
of that strategy in that both reacting partners were nonstandard (acetate
enolate and ketone electrophile). A sequence consisting of Sonogashira
coupling, acylation and hydrogenation delivered acetate 24, and Dieckmann cyclization provided β-keto lactone 2.
Development of a reductive coupling
of a β-keto-lactone and an aldehyde is described, in which the
Hantzsch ester serves as an inexpensive and convenient reducing agent.
Structural features in the β-keto-lactone rendered standard
reductive coupling conditions ineffective, requiring development of
a specific addition and temperature protocol. Identification of one
of the reactants as Ames positive required a single-digit parts per
million control strategy for this impurity in the final active pharmaceutical
ingredient (API).
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