THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 59

Ru-catalyzed tandem
tetrahydropyran formation

Northern fragment

MeO

MeO 2 C

HO

OAc

Macro
cyclization
(RCM)

MeO 2 C OAc

O

O

O O

O

O

OH H

OH H OH

O

O O

HO

O

Esterification

Negishi
coupling

OH

OH

O

AcO

Southern fragment

n-Pr

CO 2 Me

O

CO 2 Me

Pd(II)-catalyzed
tandem dihydropyran formation

Bryostatin 146 Analogue of bryostatin 147

FIGURE 2.9 Bryostatin 146 and its ring-expanded analogue 147 .

n -BuLi
Et 2 O, -78°C
then ZnCl 2
THF, -78°C to rt

I

ZnCl Br

OMe

H

Pd(PPh 3 ) 4
(10 mol%)
THF, rt

151 150

O

9 steps O

O

O

O

4.3%

O

AcO

CO 2 Me

148 149

OMe OMe

H H

O O

O O

5 steps
8.8%

147

O O

AcO AcO

CO 2 Me CO 2 Me

152 153 68% (combined mixture)

SCHEME 2.39 Synthesis of the southern fragment of ring-expanded analogue of

bryostatin 147 .

(Figure 2.9). The total synthesis of the ring-expanded bryostatin involved a

ruthenium- and a palladium-catalyzed tandem reaction to access, respectively, the
tetrahydropyran and dihydropyran rings, as well as a macrocyclization via a RCM.
The Negishi cross-coupling [80] was theway to the ring-expanded analogue, allowing
the synthesis of the southern fragment functionalized with the terminal alkene to be
used in the RCM.
The ( E )-vinyl iodide

147

149 was reacted with the organozinc derivative 151 ,

generated in situ from5-bromo-1-pentene (

150 153

), to afford the triene together with

the dehalogenated product 152 in a combined yield of 68% ( 152 : 153¼ 1:5)

(Scheme 2.39).

2.2.3.4. Enigmazole A Enigmazole A ( 154 ) is a cytotoxic 18-membered
macrolide isolated from the sponge Cinachyrella enigmatica that targets a type III
transmembrane protein tyrosine kinase [81,82] (Figure 2.10).
ANegishi cross-coupling was used at the early stage of the synthesis in order to
deploy a bidirectional C-C bond construction using a 2,4-disubstituted oxazole