Organic Chemistry of Drug Synthesis. Volume 7

with 2-chloropyrimidine ( 157 ) to afford 158. Yet another hydrogenation
reduces the heterocyclic ring to a tetrahydropyrimidine ( 159 ). The three
terminal nitrogen atoms in the productalniditan( 159 )^23 in effect comprise
a cyclized guanidine.

O

CO 2 H 1. SO 2 Cl

2. H 2

152

O

CH=O

153

C 6 H 5 CH 2 NH 2

O

154

NH

H 2

CN

CH 2 C 6 H 5

O CH^2 C^6 H^5

N CN

O

N NH NH 2 H 2

Cl N

O

NH

N

NH N H^2

O

N

NH NH NH

157 156 155

158 159

B. Miscellaneous Six-Membered Heterocycles

The proteasome is an enzyme complex found in all cells that is responsible
for the turnover of the proteins regulating the cell cycle, as well as other
cellular processes. This complex becomes unregulated in tumor cells and
leads to excessive degradation of cycle regulatory proteins and tumor sup-
pression genes. The absence of these factors leads to run-away cell proli-
feration. An unusual short peptide-like compound in which a boronic
acid replaces the usual terminal carboxylic acid has proven to be an effec-
tive blocker of the proteasome. The first step in preparing that compound
comprises amide formation between the aminoboronic acid ( 161 ), where
the boron is protected as the cyclic pinanediol ester, and the tert-
butyloxycarbonyl (t-BOC) protected phenylalanine ( 160 ) using standard
peptide chemistry to afford 162. Removal of the protecting group on the
N-terminal nitrogen followed by acylation with pyrazine carboxylic acid
163 gives the amide ( 164 ). Reaction of intermediate 164 with excess
isobutyl boronic acid leads to the free acid by transfer of the pinanediol
protecting group to the reagent. Thus,bortezomib( 165 ) is obtained,^24
which is a drug recently approved for treatment of multiple myeloma.

2. COMPOUNDS WITH TWO HETEROATOMS 133