THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 52

formation with the eastern fragment (second step), an intramolecular non-
regioselective Stille cross-coupling reaction, and a Negishi cross-coupling with
2-zincated methyl thiazole-5-carboxylate under the same reaction conditions as
previously described.

2.2.2.5. Kapakahines E and F The Negishi cross-coupling reaction has also
been successfully applied to the synthesis of tryptophan-containing natural
products [52] such as the kapakahines, a family of cyclic peptides isolated in 1995
from the marine sponge Cribrochalina olemda [53-55]. Even though the bio-
logical properties of this family of compounds still remain unknown mostly due to
the limited supply, preliminary cytotoxicity studies showed that kapakahine E
(Figure 2.5), together with a few other members of the family, were active against
P388 murine leukemia cells (IC 50 about 5.0

g/mL in vitro ). The key steps in the
synthesis of the western fragment of kapakahines E

m

[52] were
the heterodimerization reaction of bromoindoline to the corresponding pyrro-
loindoline, its rearrangement to

110 [52] and F 111

-carboline, and a Negishi cross-coupling to
generate the appropriate tryptophan derivative (Figure 2.5). The western fragment
was then coupled with the appropriate eastern fragment (second step), the tetra-
(Phe-Pro-Tyr-Ala) or dipeptide (Ala-Leu), and macrocyclized (third step) through
an amide bond formation to afford the 22-membered ring kapakahine E

a

110

(3.9%
overall yield, 17 steps for the longest linear sequence) and the 16-membered
kapakahine F

111 (6.8% overall yield, 17 steps for the longest linear sequence)

(Figure 2.5).
The key intermediate to access kapakahine natural products is the tryptophan
C(3)-N(1 0 ) heterodimer 114 . Any attempts to functionalize a -carboline 113 incor-
porating the alanine side chain on the C(3 0 ) position of a tryptophan using aziridine
ring openings were unsuccessful, resulting in either the recovery of unreacted starting
material or its decomposition (Scheme 2.34). The breakthrough was achieved when
the zincated protected alanine under

Negishi cross-coupling conditions, affording the functionalized bis-tryptophane core
114

117 [56] was reacted with the iodoindole 115

in good yield (74%) (Scheme 2.34).

(1st step)

(2nd step)

(1st step)

Negishi
coupling

Fragment
coupling

Negishi
coupling

(2nd step)

Western fragment Western fragment

Fragment
coupling

O

-Carboline O -Carboline

N

NH

NH

N

N

NH

O TFA

N

O

Eastern fragment
TFA , H-Ala-Leu-OBn

N
H

O

H
N

N

NH

NH

O O

N

H N

Eastern fragment
TFA , H-Phe-Pro-Tyr-Ala-OBn

NH

O

TFA

O O N

H

O O

Macrocyclization

(3rd step) Macrocyclization

(3rd step)

OH

Kapakahine E 110 Kapakahine F 111

FIGURE 2.5 Retrosynthetic analysis of kapakahines E 110 and F 111 .