THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 54

HO

OMe

CO 2 H ZnI Zn

TMSCl
DMF, rt

I

BocHN Fragment

coupling

O

5 steps

NHZ

NHZ

90%
over three steps

55%

CO 2 - t -Bu

CO 2 - t -Bu

CHO

I

F

CO 2 Me

BocHN

120 122 121

OMe

OMe

69%
over two steps

Fragment
coupling

O

O Pd 2 dba 3 (3 mol%)

P( o -Tol) 3 (12 mol%)
DMF, 50°C
75%

I

I

CO 2 Me

HN

I O

NHBoc

O

BocHN

OMe

O

NH

MeO 2 C N

H

O

CONH 2

123

125

ZNH

OMe

OMe

CO 2 Me

HN

O

CO 2 -t-Bu

BocHN

O

1. Zn*, I 2 cat, DMF
rt, 30 min

124

CO 2 Me

CONH 2

NHBoc

O

2. Pd 2 dba 3 (3 mol%)
P( o -Tol) 3 (12 mol%)
THF, 60°C, 16 h
35%

O

3 steps
73%

4 steps
54%

HN

Macrocyclization

NH

126

K-13 119 OF4949-III 118

OMe

SCHEME 2.35 Intermolecular and intramolecular Negishi cross-couplings to cyclic pep-
tides OF4949-III 118 and K-13 119 .

N -terminal group that was used to construct the peptide backbone in the synthesis of
OF4949-III 118 ,itisthe C -terminal group that was used in the case of K-13 119 .

was constructed in a sequential fashion
by anchoring the second amino acid Boc-Asn-ONp (Np

Cyclic tripeptide OF4949-III 118

¼ nitrophenylester) to the

O -aryltyrosine derivative by classic peptide chemistry. The third amino acid was

then introduced via an intramolecular Negishi cross-coupling between the aryl iodide
and the zincated iodoalanine

120

122 (Figure 2.6 and Scheme 2.35). In an alternative

approach, iodoalanine [56] could have been anchored to the growing peptide

chain and then converted to the zincated derivative; however, previous work had
shown that the stability of a carbon-zinc bond at the N -terminus of a dipeptide was
lower than that of the corresponding bond at the C -terminus [60]. The modified
dipeptide

121

was then reacted under Negishi cross-coupling condition with the
organozinc species

123

[61], prepared in two steps after side chain iodination and
zincation of the corresponding protected serine [62] (Scheme 2.35). It is worth
mentioning that the preparation of the zincated species was carried out in DMF, which
was able to stabilize the organozinc reagents, thus promoting the partial ionization of
the zinc-iodine bond and reducing its tendency to protonate [63]. The cross-coupled
product

122

124

was obtained in high yield (75%), showing the high functional group
tolerance of the organozinc iodide with respect to the unprotected asparagine side