THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 43

β -Carotene 54

OH

Vitamin A 55

FIGURE 2.1 Carotenoid derivatives.

TMS ZnBr
Pd(PPh 3 ) 4 (2 mol%)
THF
81%

Br

TMS

I

Br

56 57

SCHEME 2.19 Preparation of the C4 synthon.

1. LDA

O

2. ClPO(OEt) 2
3. LDA
85%

58 59

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

1. 57 , Pd 2 (dba) 3 (2.5 mol%)
tri(2-furyl)phosphine (10 mol%)

ZnCl

2. K 2 CO 3 , MeOH
70%

61 60

SCHEME 2.20 Synthesis of the tetraenyne.

Tetraenyne 61 , on the other hand, was prepared starting from b -ionone 58 ,

whichwas first converted to the corresponding terminal alkyne by elimination of an

enol phosphate intermediately formed (Scheme 2.20). Carboalumination, ZnCl 2
addition, Negishi coupling, and deprotection of the trimethylsilyl group finally
yielded the desired compound

59

.
The carboalumination and transmetalation were performed on synthon

61

61 ,

followed by a Negishi coupling with 0.5 equiv of 56 to provide b -carotene 54

(Scheme 2.21).
Compound

was also involved in the preparation vitamin A. It was first
subjected to a carboalumination reaction, followed by a metal-metal exchange with
n- BuLi and a final formylation (Scheme 2.22).

61

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

2. ZnCl 2 , THF
3. 56 , Pd 2 (dba) 3 (2.5 mol%)
tri(2-furyl)phosphine (10 mol%)
68%
SCHEME 2.21

61 -Carotene ( 54 ) β

Synthesis of b -carotene.