THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 44

1. Me 3 Al, Cp 2 ZrCl 2 , CH 2 Cl 2

OH

2. n- BuLi, THF
3. (CHO) n

61 Vitamin A ( 55 )

67%

SCHEME 2.22 Synthesis of vitamin A 55 .

It is worth noting that for both these syntheses, not only the yields were high,
but also the two polyenes 54 and 55 were obtained in very high isomeric purity

( 99%).

>

2.2.1.9. Anguinomycins C and D Natural polyketide anguinomycins C and D
(Figure 2.2) were shown to selectively induce apoptosis of inactivated tumor cells and
growth arrest on normal cells [22]. This selectivity prompted the synthesis of the
natural products by Gademann and coworkers [23] especially to study the role of
the polyketide chain.
The key intermediate for the synthesis of both anguinomycin C 62 and

anguinomycin D ), which could be obtained by two

successive Negishi couplings starting from compounds

63 was dihydropyran ( 64

(Scheme 2.23).
For the first coupling, the organozinc species was generated from alkyne

65 and 66

via
a hydrozirconation with Schwartz's reagent, followed by transmetalation with ZnCl 2 .
Reaction with dibromo derivative

65

in the presence of a catalytic amount of
palladium resulted in the efficient and selective formation of the monobromo
derivative

66

as a single isomer in high yield (Scheme 2.24).
The next step also consisted of a Negishi coupling, known to occur in this case
with either an inversion or a retention of configuration depending on the ligands
present on the Pd [24,25]. Inversion was required in the present case to bring the
correct stereochemical arrangement present in anguinomycin C or D. As a first
experiment, 67 was reacted with dimethylzinc and Pd(PPh 3 ) 4 (Scheme 2.25). The use
of this catalytic system afforded the expected compound 64a as the cis product as
assigned by NOE experiments.

67

R

H

O O

CH 3 CH 3 CH 3 CH 3 CH 3

CH 3

H 3 C

O OH

Anguinomycin C ( 62 ; R = CH 3 )
Anguinomycin D ( 63 ; R = C 2 H 5 )
FIGURE 2.2

Anguinomycins C and D.

Negishi coupling

R Br

H

H

i- Pr-O O

i- Pr-O O

Br

+

OTIPS

OTIPS

H 3 C H 3 C

64a (R = CH 3 )
64b (R = C 2 H 5 )

65 66

SCHEME 2.23 Retrosynthesis of the key intermediate of anguinomycins C 62 and D 63 .