THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 61

(1st step)

Negishi coupling

OH

OH O

O

(3rd step)

NC

H Macrocyclization

H

CO 2 H

Sonogashira

(2nd step)

Borrelidin 161

FIGURE 2.11 Retrosynthetic analysis of borrelidin.

OTBS OTBS

ZnCl 2 , Et 2 O
then t -BuLi, rt

BnO BnO

I Zn

O O

162 164

7 steps

RO +

H OMe

62% (R = Bn)
42% (R = PMB) 58%

OTBS OTBS

Pd(PPh 3 ) 4 (5 mol%)
dark, rt

I

PMBO

OTBS

OPMB

OBn 165
SCHEME 2.41 Construction of the northern fragment of borrelidin 161 via a modified
Negishi cross-coupling.

163

asymmetric reductive aldol reaction between the suitable protected aldehyde and the
methylacrylate (Scheme 2.41). The alkyl iodide 162 was thus converted to the
corresponding dialkylzinc reagent 164 to afford the advanced precursor 165 in which

all the stereogenic centers were preserved.

2.2.4. Synthesis of Small Heterocycles
2.2.4.1. Brevisamide Brevisamide is a cyclic ether recently isolated from

the red tide dinoflagellate Karenia brevis [88]. Although it belongs to the same family
of the brevetoxins that are known for their neurotoxic activity, its biological properties
still remain unknown (Figure 2.12).
The convergent approach to the total synthesis of brevisamide

166

166 is based

on the construction of the advanced tetrahydropyrane intermediate 169 starting from

( Z )- anti -crotylsilane 2]-annulation, a

diastereoselective hydroboration, and a hydrozirconation. The side chain presents
a conjugated trisubstituted ( E , E )-diene, introduced through a modified Negishi

167 and aldehyde 168 and features a [4 þ

Negishi coupling

OH

N

H

O

O O

Brevisamide 166

FIGURE 2.12 Retrosynthetic analysis of brevisamide.