THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 38

the potentially more reactive vinyl iodide was also investigated. Finally, the

best results were obtained when using a Negishi coupling between the organozinc
species derived from 25 and the vinyl iodide 26b . This strategy allowed the synthesis
of 9.3 g of

26b

29 that were eventually used to complete the gram-scale synthesis of

discodermolide 24 .

2.2.1.5. Xerulinic Acid The Pd-catalyzed coupling of tin derivatives has been
widely used in the synthesis of complex molecules (Stille coupling). Unfortunately,
in certain cases, the organotin species is not reactive enough and needs to be
transmetalated to a more reactive intermediate such as an organozinc derivative.
Another way to circumvent this issue is to interchange the role of the two coupling
partners by performing a metal-halogen exchange, where the organotin derivative is
converted to the corresponding vinyl bromide or iodide. This was typically the case in
the synthesis of xerulinic acid

30 published by Sorg and Br € uckner [16] that involved

the preparation and coupling of key fragments 31 , 32 , and 33 (Scheme 2.9).

from 1,4-dichlorobut-2-
yne. The same numbers of steps were needed to prepare building block

Four steps were needed to prepare bromo derivative 31

33 starting

from levulinic acid. Finally, distannane was synthesized in five steps starting from

propargyl alcohol (Scheme 2.10). Hence, a cuprostannylation/protonolysis provided
34

32

35

by bromination. The latter was then transformed to
the corresponding sulfide and oxidized in sulfone

[17], which was converted to

36

before a Ramber-Backlund

. 1 H NMR showed that

rearrangement provided triene was obtained as a 96:4

mixture of the ( trans,trans,trans ) and ( trans,cis,trans ) isomers.

32 32

Br

HO

O

31

SnBu 3

Bu 3 Sn

32

30

O

O

O

OH

Br

O

33

O

SCHEME 2.9 Retrosynthetic analysis of xerulinic acid 30 .

Bu 3 Sn(Bu)CuCNLi 2
THF, reflux

CBr 4 , PPh 3

OH Bu 3 Sn OH Bu 3 Sn Br

CH 2 Cl 2
82%

34

35

1. Na 2 S, Bu 4 NHSO 4
H 2 O, THF (90%)
2. (NH 4 )Mo 7 O 24
H 2 O 2 , EtOH (88%)

SnBu 3 KOH/Al 2 O 3 , CBr 2 F 2

Bu 3 Sn Bu 3 Sn S SnBu 3

THF
73%

O O

32 36

SCHEME 2.10 Synthesis of distannane 32 .