THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 36

TMS

H H

Br

H H

H TMS H

TMS ZnBr
Pd(PPh 3 ) 4
THF, 0°C
80%

C

C C

H PdCl 2 (PPh 3 ) 2

CuI/ i- Pr 2 NH
EtOAc, 0°C
77%

OO OO OO TMS

18 16 17

SCHEME 2.5 Model studies for the alkyne-allene coupling.

CO 2 MOM CO 2 MOM CO 2 MOM

CBS reduction TBAF

THF 0°C
99%

4 4 4

-40°C
94%

TMS TMS H

O HO HO

19 14 20

TsCl, Et 3 N
DMAP
0°C

n -Pr

95%

22

CO 2 MOM

1. MeLi
2. ZnBr 2
Pd(PPh 3 ) 4 (5 mol%)
THF 0°C
92%

4

CO 2 MOM

CO 2 MOM

TFA CuBr·Me 2 S, LiBr

H

4

13

4

C

Br

CH 2 Cl 2
92%

THF
86%

H

C H

H H

TsO

23 15 21

2

n -Pr

SCHEME 2.6 Synthesis of phomallenic acid C 13 .

formation of easily detectable diastereoisomers. Interestingly, the reaction of

trimethylsilyl acetylene with bromoallene in the presence of palladium and

copper salts resulted in a scrambling of the stereocenter, as confirmed by the presence
of a mixture of diastereoisomers by 1 H NMR. On the other hand, when trimethylsilyl
acetylene was converted to the corresponding organozinc species and reacted with
16

16

was formed as a
single diastereoisomer. The optical rotation confirmed the inversion of the stereo-
genic center.
Consequently, the Negishi coupling was used as the method of choice for the
synthesis of phomallenic acid C

together with a catalytic amount of Pd(PPh 3 ) 4 , product 18

13 19

(Scheme 2.6). Hence, ketone was first reduced

14

to the corresponding chiral alcohol under CBS (Corey-Bakshi-Shibata) [11]

conditions. Deprotection of the TMS group followed by tosylation of the resulting
alcohol provided with a slight

erosion of the enantiomeric excess from 96% ee for 21 to 90% ee for 15 . The reaction
conditions developed in the model study were next used for the preparation of 23 .
Diyne

21 . A copper-mediated bromination then afforded 15

was thus initially subjected to n -BuLi and zinc bromide and then cross-
coupled with bromoallene

22

15 in the presence of 5mol% of Pd(PPh 3 ) 4 . The corre-

sponding allene was obtained in excellent yield but once again with a slight erosion

of the enantiomeric purity (ee

23

88%). Deprotection of the MOM group with
trifluoroacetic acid finally yielded phomallenic acid C

¼

13 .

2.2.1.4. Discodermolide ( is an antitumor agent that

was isolated from the marine sponge Discodermia dissoluta [12,13]. Its wide mode of
antitumoral action and the small amounts that were isolated from the sponge
prompted intense activity toward its total synthesis [14]. The synthesis published by
Smith and coworkers [15] is based on three key disconnections unveiling three main

þ )-Discodermolide 24