Organic Chemistry of Drug Synthesis. Volume 7

the product with butyllithium generates an anion on carbon next to nitro-
gen. Treatment of this compound with triethyl borate displaces one of
the ethoxy groups in the reagent to form a carbon–boron bond. The
product is comprised of a 1 : 1 mixture of enantiomers. Hydrolysis of
this intermediate then affords the corresponding boronic acid ( 10 ). A key
step involves formation of the acetal-like compound of 12 with naturally
occurring (þ) pinanediol ( 11 ). The initial product is comprised of two dia-
stereomers due to the fact that the starting boronic acid ( 10 ) consists of two
enantiomers. The pair of diastereomers of 13 are then separated by recrys-
tallization. In the next step, the desired isomer is coupled with the tot-BOC
derivative from valine to give amide 16. The pinane diol group is then
removed by exchange with excess phenyl boronic acid. The final com-
pound is converted to a salt ( 18 ) in order to avoid the formation of a
stable zwitterion between the amine and the boronic acid function. Thus,
18 is obtained.^2

HN t-BOC N t-BOC

t-BOC

t-BOC

t-BOC

t-BOC

1. BuLi


2. B(OC 2 H 5 ) 3

9

N

B(OH) 2

10

3. H+

HO HO

N

OB O

11

NH NH

NH

CO 2 H

14

COCl

15

8

HN

O B O

N

OB O

12

13

16

H 3 O+

N

OB O

H 2 N

17

+H 2 N N

18

O 1. C O O

6 H 5 B(OH) 2

2. HCl

B(OH) 2

(t-BuO) 2 CO

(t-BuO) 2 CO

As noted in Chapter 3, endothelins rank among the most potent
known vasoconstricting agents; they have been implicated in a number
of diseases including cerebral vasospasm and pulmonary hypertension.
The stereoselective synthesis of an endothelin antagonist begins with the

1. COMPOUNDS WITH ONE HETEROATOM 85