THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 69

Negishi coupling

CN

F

O

H H N

OH

O

MIV-150 210

FIGURE 2.18 Retrosynthetic analysis of MIV-150 210 .

F

F

4 steps

OMe

F

73%

OH

O

1. n -BuLi, THF, -78°C
2. ZnBr 2 , THF, -65°C then rt
3. (+)- 212 , 10 mol% Pd(OAc) 2
P(OAr) 3 (5 mol%), reflux
85%

CO 2 Et

O

7 steps
27% overall yield from 211

210

OMe

211

O

O

213 8 steps

I

CO 2 H CO 2 Et

(+)- 212

32%

SCHEME 2.50 Multigram synthesis of MIV-150 210 .

while keeping the stereochemical integrity of the a and the b position of the

cyclopropyl ring (Scheme 2.50).

2.3.4. B-Raf Kinase Inhibitors
Previously described optimization studies on large-scale Negishi reaction [101] were
applied to the multikilogram scale of diisoquinoline derivatives [103] 214 and 215 ,
identified as potent inhibitors of B-Raf kinase, responsible of survival and prolifer-
ation in various cancer models (Figure 2.19). ANegishi coupling was thus involved in
the assembly of the southern isoquinoline fragment, with the central isoquinoline
core, while the introduction of the northern segment was achieved by a Buchwald
amination. Starting from the previously reported laboratory-scale studies [101] in
which Negishi conditions proved to be more suitable for time-critical preparation and
endowed with a easier purification of the crude with respect to Suzuki conditions, the
bis-isoquinoline core was built up using organozinc chemistry.

N

Buchwald
amination

N

HN HN

N N

Negishi coupling

N N

214 215

FIGURE 2.19 Retrosynthesis of diisoquinoline derivatives.