Organic Chemistry of Drug Synthesis. Volume 7

activates liver enzymes that metabolize fatty acids thus lowering serum tri-
glyceride levels. Reaction of the lithio reagent from 2,3-dimethylthiophene
( 7 ) with benzaldehyde leads to the carbonyl addition product ( 9 ). The
benzylic hydroxyl is next removed by hydrogenation over palladium to
yield 10. This intermediate is then treated with the substituted benzoyl
chloride ( 11 ) in the presence of stannic chloride to afford the product
from acylation on the carbon with highest electron density, thus yielding
the thiophene ( 12 ). Exposure of 12 to boron tribromide in the cold leads
to formation of a new ring; the methyl ether on the pendant benzene ring
is cleaved to the corresponding phenol in the process ( 13 ). The enolate
from treatment of that phenol with potassium carbonate with thea-bromo
ester ( 14 ), affords the corresponding alkylation product as a mixture of
enantiomers. Saponification of the ester affords corresponding carboxylic
acid. Resolution as its salt completes the synthesis ofertiprotafib( 15 ).^2

S

+O=HC

8

BuLi

S OH

9

H 2

S

10

OCH 3

COCl

11

SnCl 4

S

O

H 3 CO

12

BBr 3

S

OH

13

CO 2 H

Br

1. CO^2 CH^3
   2. LiOH
   S 3. Resolve

O

15

14

7

A compound whose structure bears some slight resemblance to 15 , based
on a phenoxazine nucleus, also shows PPAR activity and increases sensi-
tivity to insulin as well. The synthesis of the side chain begins with
Emmons–Smith condensation of benzaldehyde 16 with the ylide from
phosphonate 17 and base to afford the enol ether 18 as a mixture of
isomers. Hydrogenation of the resulting intermediate reduces the double
bond and at the same time removes the benzyl group to afford the free
phenol ( 19 ). Reaction of this compound with a hydrolase enzyme leads to
selective hydrolysis of the ester, which leads to the (S) enantiomer ( 20 ).
This kinetic resolution affords the acid as a virtually single stereoisomer.
The carboxyl group is then protected for the next step as its isopropyl ester
( 21 ). In a convergent scheme, the anion on nitrogen from phenoxazine

1. COMPOUNDS WITH THREE FUSED RINGS 219