THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 34

cat. Pd

R 1 -M + R 2 -X R 1 -R 2 + M-X

R 1 , R 2 : carbon groups
M: metal or metal- containing
X : leaving group (halogen,...)
SCHEME 2.1

Cross-coupling reactions.

2.2. SYNTHESIS OF NATURAL PRODUCTS

2.2.1. Synthesis of Polyenes
2.2.1.1. Farnesol One of the first studies describing an efficient application of a
Negishi coupling in the synthesis of a natural product was published by Negishi and
coworkers and concerns the preparation of terpenoid farnesol

(Scheme 2.2) [4]. This
synthesis illustrated a more general problem in the area of cross-coupling reactions,
namely, the preparationof 1,5-diene unitswith a complete control of the stereochemical
outcome of the reaction. In addition, this procedure addressed the challenge of allyl-
allyl and allyl-propargyl coupling reactions in which, at some point of the process, an
organopalladium species bearing a hydrogen on the carbon located at the

1

b

position

4) 2

of the palladium is generated (cf. compound from the reaction of iodide with

3

propargylzinc bromide derivative in the presence of a palladium catalyst. Inter-

mediate 4 can then follow two different pathways: one yielding the expected coupling

product 5 by reductive elimination and the other leading to the b -hydride elimination

products 6 and 7 . In this study, it was shown that the reductive elimination was faster

than the -elimination, and therefore only traces of by-products were obtained.

Treatment of

b

2H 2 O followed by a zirconium-catalyzed carboalumination
and formylation eventually yielded the desired product ( E,E )-farnesol

5 with KF

1 in good yield

and with excellent regio- and stereochemical purity ( 98%).

>

2.2.1.2. ,

isolated from Eremophila freelingii [5], features three different palladium-catalyzed

Freelingyne The synthesis of the natural sesquiterpene freelingyne 8

Negishi coupling

Me 3 Si

+

I

OH

ZnCl

2 3 1

1. KF·2H 2 O, DMF
2. Me 3 Al (2 equiv)-Cl 2 ZrCp 2 (0.2 equiv), CH 2 Cl 2
3. n- BuLi (1 equiv), then (CH 2 O) n , THF

Pd(PPh 3 ) 4 (0.05 equiv)
THF

90% GLC yield 68% (2 steps)

SiMe 3

H

L

5

SiMe 3

Pd

L

4

SiMe 3

H

+

6 7

SCHEME 2.2 Synthesis of farnesol 1 .