THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 60

Negishi coupling

MeO

Macrolactonization

N

O

O O

OH

O
HO

O H

P

OH

O

Witting olefination

Hetero-Diels-Alder

Enigmazole A 154

FIGURE 2.10 Retrosynthetic analysis of enigmazole A 154 .

EtO 2 C EtO 2 C EtO 2 C

N N N

2 steps

Zn, LiCl
THF, rt, 10 min

ZnI · LiCl I NH 2

O O O

157 156 155

I OMe I

3 steps
40%

Pd(PPh 3 ) 4
THF, rt, 1h
86%

HO

OMe

158 159

EtO 2 C

N

O

160

SCHEME 2.40 Negishi cross-coupling using the organozinc oxazole derivative 157 .

ring. Other key steps included a hetero Diels-Alder cycloaddition to access the
2,6- syn -pyrane ring, a Wittig olefination to assemble the southern fragment with the
eastern fragment, and a macrolactamization to afford enigmazole A

in 22 steps
(longest linear sequence) and 0.41% overall yield [83] (Scheme 2.40). The ethyl 2-
amino-4-carboxy oxazole

154

, easily obtained in one step from urea and ethylbro-
mopyruvate [84], has a double nature since it displays an electrophilic character at C4
position and a latent nucleophilicity at C2 after derivatization in ametalated form. The
ethyl 2-iodo-4-carboxy oxazole

155

was prepared on a multigram scale after
diazotation and I 2 exchange reactions, and then directly metalated with Zn(0) [85]
to afford oxazol-2-yl zincate

156

157

(Scheme 2.40). Interestingly, if the 2-bromo
derivative was used instead of the iodide

, the insertion of zinc was not efficient.
The Negishi cross-coupling was eventually achieved in the presence of vinyl iodide
159 , affording multigram quantity of coupled product 160 (Scheme 2.40).

156

2.2.3.5. Borrelidin Borrelidin is a 18-membered macrolide extracted from

S. rochei in 1949 [86] (Figure 2.11). Its anticancer activity (angiogenesis inhibitor
with IC 50 ¼

161

0.8 nM) coupled with its unique macrolide structure containing a con-
jugated cyanodiene made its enantioselective total synthesis a particularly interesting
challenge [87].
The alkyl iodide

162 and the ( E )-vinyl iodide 163 involved in the construction of

the northern fragment of borrelidin under Negishi coupling conditions were

prepared according to a common iridium-catalyzed large-scale procedure for the

161