Organic Chemistry of Drug Synthesis. Volume 7

a consequence been focused on finding inhibitors of that enzyme. The first
step in the convergent synthesis starts by protection of the chiral hydroxy
acid ( 123 ) as its benzyl ester ( 124 ). The hydroxyl is activated toward dis-
placement by conversion to its triflate 125. Reaction of 125 with the anion
from the unsymmetrical malonate leads to triester 126.
Thea-aminonitrile ( 127 ) from acetone and methylamine comprises
starting material for the heterocyclic moiety. Reaction of 127 with chloro-
sulfonyl isocyanate and hydrochloric acid gives hydantoin ( 128 ).
Treatment of intermediate 128 with formaldehyde leads to a carbinol
from addition to the free amino group on the imidazole dione. The
hydroxyl group is then converted to the bromo derivative ( 129 ) with phos-
phorus tribromide.^19 Use of this intermediate ( 129 ) to alkylate the enolate
from 126 yields 130. Catalytic hydrogenation of this product leads to the
formation of the corresponding ester-diacid by loss the benzyl protection
groups on two of the esters. Heating this last intermediate in the presence
ofN-methylmorpholine causes the free acid on the carbon bearing thetert-
butyl ester to decarboxylate ( 131 ). The desired stereoisomer ( 131 ) predomi-
nates, in effect reflecting the selectivity of alkylation step ( 126! 130 )

NH

CN

123

NH

N O

O

124

1. CH 2 =O


2. PBr 3

N

N O

O

125

Br

HO CO 2 H HO CO 2 CH 2 C 6 H 5 CF 3 SO (^3) CO 2 CH 2 C 6 H 5
C 6 H 5 O 2 C
ButO 2 C
ButO 2 C
ButO 2 C ButO^2 C
C CO^2 CH^2 C^6 H^5
6 H 5 CH 2 O 2 C
NaH
126
127 128 129
CO 2 CH 2 C 6 H 5
C 6 H 5 CH 2 O 2 C
CO 2 tBu
N
N O
O
130
NaH
H 2
N
N O
O
131
N – CO 2
N O
O
132
N CO^2 H
O
HO 2 C
N
N O
O N
O N
N O
O N
O
O
HOHN
133 134

1. C 6 H 5 CH 2 ONH 2


2. H 2

ClSO 3 N=C=O

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