Organic Chemistry of Drug Synthesis. Volume 7

stereochemistry of the newly formed olefin follows from the normal course
of this reaction. Reduction of the side-chain carbonyl group with zinc bor-
ohydride gives the alcohol 5 after separation of the isomers. Reaction with
mild base results in hydrolysis of the diphenyl ester protecting group ( 6 ).
The newly revealed alcohol, as well as that on the side chain, are then pro-
tected as their tetrahydropyranyl ethers by reaction with dihydropyran in
the presence of acid ( 7 ). Controlled reduction of the lactone ring with dii-
sobutylaluminum hydride (DIBAL-H) stops at the lactol stage ( 8 ).
Condensation with the zwitterionic salt-free ylide, 4-triphenylphosphino-
butyrate, results in condensation with the open aldehyde form of the
lactol. The “salt free” conditions of this reaction account for the
formation of the new olefin with cis stereochemistry. The acid is then
converted to its isopropyl ester by reaction of the carboxylate salt with
isopropyl iodide. There is thus obtained travaprost ( 9 ).^2

O

CF 3

1

(CH 3 O) 2 POCH 3

BuLi

2

O

HH 3 C^3 COO O

O

O CH=O

O

O

O

O

CF 3

Cl

O

O

CF 3

O

P

O

O

O

O

O

CF 3

OH

Separate

C 6 H 5 C 6 H 4

O

C 6 H 5 C 6 H 4

O

C 6 H 5 C 6 H 4

O

K 2 CO 3

5 4

O

O

HO

O

CF 3

OH

6

ZnBH 4

DihydropyranTsOH

O

O

THPO

O

CF 3

OTHP

7

DIBAL-H

O

OH

THPO

O

CF 3

OTHP

1. (C 6 H 5 ) 3 P+(CH 2 ) 3 CO 2 –
   2. (CH 3 ) 2 CHI

HO

HO

O

CF 3

3. H+ OH

CO 2 CH(CH 3 ) 2

8 9

3

The rather simpler ophthalmic prostaglandinlatanoprost( 10 ),^3 carries a
simple benzene ring directly at the end of the side chain. The amide of this
drug is said to be better tolerated because of the absence of an acidic
carboxyl group. Reaction of 10 with 1,8-diazobicyclo[5.4.0]undec-7-ene

1. MONOCYCLIC COMPOUNDS 23