THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 57

OMOM OMOM OMOM

TBDPSO TBDPSO TBDPSO

12 12 12

Zn/Cu couple
SET

Zn/Cu couple
SET

Pd(0)
135

I I ZnI

137

O O O

(12 R )- 134 A B

(Me 3 Sn) 2 (0.3 equiv)
AIBN (0.1 equiv)
Benzene, reflux

I

OMOM OMOM OMOM

TBDPSO TBDPSO TBDPSO

Pd(0)
135

138

H

O O O

I ZnI

139 C F

Zn/Cu couple
SET

1-6-H shift

I

OMOM OMOM

TBDPSO TBDPSO

5- exo - trig

O O

D E

SCHEME 2.37 Radical mechanism proposed [66] to explain the formation of 138 .

coupling with (Scheme 2.37). The indirect

proof came from a control experiment under radical-free conditions [72], where the
iodinated alcohol (12 R )-

135 , affording the bicyclic compound 138

was treated with hexamethylditin in the presence of
AIBN, affording bicyclic iodide

134

as an equimolar mixture of the two epimers at
equilibrium with the starting iodinated alcohol

139

(12 R )- 134 ( 134 : 139¼ 3:1)

(Scheme 2.37).

2.2.3.2. )-Kendomycin The preparation of a highly functionalized pyran

ring systemwas reported in the synthesis of the 16-membered constrainedmacrocycle
( )-kendomycin 140 [73], originally isolated in 1996 from Streptomyces vio-
laceoruber [74,75] (Figure 2.8). The macrocycle 140 finds application in many
therapeutic areas exerting its activity as an endothelin receptor antagonist [74,75], an
antibacterial and cytotoxic agent toward several tumor cell lines (average IG 50
<

(

0.10 m M) [76,77], and a proteasome inhibitor [78]. A [4 þ 2]-annulation between

( E )- syn -crotylsilane 141 and the aldehyde 142 allowed to access the corresponding

2,5- syn -dihydropyran in 87% yield (dr 20:1). Wittig olefination, Corey-Fuchs

synthesis of the internal alkyne, and Pd(0)-catalyzed hydrostannylation were the key
steps in the synthesis of ( E )-vinyl iodide

>

, which is the key for the introduction of
the ANSA system (Scheme 2.38). The trisubstituted ( E )-alkene moiety of compound
145

143

was obtained in 92% yield through a Pd(0)-catalyzed cross-coupling reaction
between the organozinc species, prepared in situ from the alkyl iodide 144 , and

the ( E )-vinyl iodide 143 . The synthesis was eventually completed through a