THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 65

(R = H)
Pd(DPEphos)Cl 2 (10 mol%)
DMF/THF (1:1)

O OMe O

O O OMe O

6 steps
20%

N

N

AcO H
H 2 O
85%

O

O O

OH

193

NH

NH

Zn( i -Pr) 2 , rt
67%

OH O

OR O

194

I I

195

P(PPh 3 ) 4 (10 mol%)

(R = TBS)
Pd(DPEphos)Cl 2 (10 mol%)
ZnC(CH 3 ) 3 Br

(R = TBS)

ZnBr O OMe O

80% N

O

THF, rt, 1h

NH

THF, rt
67%

OTBS O

O OMe O

196

N

O

NH

OTBS O

197

SCHEME 2.46 Synthesis of bengamide analogues.

the construction of the main backbone via an asymmetric epoxidation with a chiral
sulfur ylide and an amide bond formation to anchor the -caprolactam. In a diversity-

oriented synthetic approach, the Negishi cross-coupling reaction was used in the last
key step in order to deliver a library of analogues.
In order to achieve this target, olefin metathesis was chosen as the means to
access bengamide E

e

and its analogues. The synthesis of the corresponding
isopropyl derivative of bengamide E

193

was obtained in 89% yield with complete
conversion of the starting material; however, for other analogues, the chemical yields
were low and the conversions were moderate to poor. Owing to the failure to
synthesize 2-C-alkyl analogues and the obtention of trisubstituted olefin derivatives,
it appeared that the method could not be considered as a general approach for
synthesizing a large variety of bengamide analogues.
The attention was therefore turned toward the use of a Pd(0)-catalyzed cross-
coupling reaction and vinyl iodide

193

as the intermediate to incorporate various alkyl
groups (Scheme 2.46). The isopropyl group was thus introduced by a Negishi reaction
using diisopropyl zinc, affording the bengamide E precursor

194

in 67% yield. The
use of alkylzinc bromide derivatives [99] was, however, unsuccessful in the presence
of unprotected alcohols. Nonetheless, after masking the alcohol moiety by protecting
it as a silyl ether, the reaction with tert -butyl- and cyclopropylzinc bromide afforded
the corresponding bengamide analogues 196 and 197 in satisfying to good yields
(Scheme 2.46).

195

2.3. LARGE-SCALE SYNTHESIS OF BIOLOGICALLY
ACTIVE MOLECULES

2.3.1. Nonsteroidal Ligand A-224817.0 1A
A-224817.0 is a potent nonsteroidal ligand for the glucocorticoid receptor.

However, to support initial biological studies and assess its effectiveness, a large-scale
chromatography-free process was developed that allowed to synthesize A-224817.0
198

198

in seven steps and 25% overall yield [100] (Figure 2.16).