THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 47

1. t -BuLi, (2.1 equiv)
ZnCl 2 (0.6 equiv)

Me 3 Al
(+)-(NMI) 2 ZrCl 2 ( 76 ) (1 mol%)

Me Me Me Me

I OTBS OTBS HO OTBS

2. PdCl 2 (DPEphos) (1 mol%) O 2

45%

74

Br

75 77 (ee > 98%)

84%

1. t -BuLi, (2.1 equiv)
ZnCl 2 (0.6 equiv)

Me Me Me Me Me Me

I 2 (1.2 equiv)

ZrCl 2

OTBS OTBS

2. Pd(PPh 3 ) 4 (1 mol%)

2

PPh 3 (1.2 equiv)
imidazole (1.3 equiv)
CH 2 Cl 2
95%

78 (ee > 98%) 80

Me Me

79

Negishi coupling

I

(+)-(NMI) 2 ZrCl 2 ( 76 )

SCHEME 2.29 Synthesis of the key intermediate 80 of scyphostatin 68 .

In both approaches, the key intermediates eventually led to the synthesis of
scyphostatin.

2.2.2. Synthesis of Amino Acids and Macrocyclic Peptides
2.2.2.1. Excitatory Amino Acid Analogues Excitatory amino acids (EAAs)
are valuable tools for the study of neurophysiology of higher organisms by triggering
synaptic excitation and consequently neural transmission. The Negishi coupling
opens up a general route to the synthesis of modified amino acids. As the glutamic acid
motif is often present in naturally occurring EAAs, the synthesis (eight steps from a
common intermediate

) [30] and the biological evaluation [31] of two aromatic
analogues of glutamic acids 81 and 82 were envisioned and eventually performed.
The two compounds were prepared via a palladium-catalyzed direct coupling
between vinyl bromide

83

84 and Jackson's organozinc reagent [32,33] 85 derived from

L -serine (Scheme 2.30).

2.2.2.2. Valsartan The potentially scalable method [34] for the synthesis of the
nonpeptide angiotensin II (AT-II) inhibitor valsartan [35] 34] is based on a Negishi

coupling between the methyl N -(4-bromobenzyl)- N -pentanoyl- L -valinate

88 [

87 and the

ortho -metalated zinc chloride 5-phenyl-1-trityl-1 H -tetrazole prepared in situ

(Scheme 2.31). The final product was recovered after simple crystallization from
ethyl acetate.
The published methods for the formation of the aryl-aryl bond in valsartan
derivatives make use of multistep sequences characterized by tedious reaction

86

H

CO 2 H
NH 2 Negishi coupling

O

CO 2 H

OTBS

OTBS

[( o -Tol) 3 P] 2 PdCl 2
THF/DMA (3:1)

81

H

H

Br

8 steps

CO 2 Bn

IZn CO 2 Bn

+

or

NHBoc

NHBoc

H

CO 2 H
NH 2

84

83 85

90%

O

CO 2 H

82

SCHEME 2.30 Synthesis of excitatory amino acids analogues.