Chemistry Reference
In-Depth Information
1.7 SAR Optimization Leading to the Discovery of
Saxagliptin
Building upon the cis-4,5-methano-2-nitrilopyrrolidine core, a wide variety of
substituents, represented generically in 31, were explored (Figure 1.7). As
highlighted earlier, greater potency and stability were realized via introduction
of highly b-branched P2 side-chains. Due to the very limited commercial
availability of b-quaternary a-amino acids, the team devised an e
cient
strategy to generate novel P2 units by several complementary paths, each
deriving from cyclic and/or symmetrical ketones to avoid unnecessary intro-
duction of additional stereocenters.
6,43
In one arm of this approach, ketones
underwent Knoevenagel condensation with a malonate diester, and the
resulting Michael acceptor was subjected to conjugate addition to introduce
the alkyl-substituted quaternary center. Mono-hydrolysis and subsequent
Curtius rearrangement yielded the desired b-branched amino acids. A parallel
approach began with Horner-Emmons condensation of the ketone to give an
a,b-unsaturated ester. Reduction of the ester to the primary allylic alcohol
and esterification with Boc-Gly set up a zinc-mediated ester enolate Claisen
rearrangement, which provided the desired amino acids with a vinyl functional
handle at the b-position. Alternatively, a standard Strecker synthesis could
be used on available aldehydes to ultimately afford the desired amino acid
building blocks. In all cases, the racemic amino acids were then coupled to the
R
1
R
3
R
1
R
3
R
1
R
3
R
1
R
3
CO
2
R
PG
O
PG
N
H
OH
H
CO
2
H
O
R
1
R
3
O
R
2
R
2
R
1
R
3
R
1
R
3
R
2
R
1
R
3
R
1
R
3
PG
H
CO
2
H
HO
2
C
CO
2
H
RO
2
C
CO
2
R
CHO
HN
R
2
R
3
R
1
CONH
2
R
N
N
H
CN
O
31
Figure 1.7
Various synthetic routes for the generation of highly b-branched amino
acids.
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