THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 48

1. Pd(OAc) 2 (5 mol%)

Q-phos, THF

N
NN

N N

HN

N

N

Ph 3 C

75°C, 2 h (80%)
2. 3 M NaOH, MeOH
reflux, 6 h
then 2 N HCl (90%)

HCl

N CO 2 H N CO 2 H

+

ZnCl

Br O

O

86 87 Valsartan 88

SCHEME 2.31 Synthesis of angiotensin II inhibitor valsartan 86 .

conditions and low yields. The advantages related to the use of organozinc reagents
are their chemoselectivity toward most common functional groups and enhanced
transmetalation activity with respect to that observed with organoboron reagents used
in Suzuki-Miyaura couplings.

2.2.2.3. , isolated

in 1992 from the marine sponge Theonela swinhoei Gray in Papua New Guinea [36],
is one of the most potent inhibitors of protein phosphatase 1 (PP1) (IC 50 <

( )-Motuporin The cyclic pentapeptide ( )-motuporin 89

1.0 nM),
showing also a potent in vitro cytotoxicity toward a variety of cancer cells.
( [37,38] is a 19-memberedmacrocyclewhose structure can be

obtained by a convergent and enantioselective synthesis involving the advanced
coupling of two main fragments, an N- Boc-Valine-Adda residue

)-motuporin 89

and a tripeptide
(Figure 2.3), by anchoring the tripeptide from its N- terminal side to the HATU-
activated N- Boc-Valine-Adda residue

94

94

, followed by the macrocyclization in the

89

last step of the synthesis. Hence, ( was obtained in 31 steps (with a

longest linear sequence of 16 steps) and 15.8% overall yield.
On the basis of the retrosynthetic analysis, the two fragments

)-motuporin

91a , 91b and 92a ,

92b needed to be synthesized and coupled in order to introduce the ( E , E )-diene of

N- Boc-Valine-Adda . The Pd(0)-mediated cross-coupling was studied using

Stille [38] (method A) or Negishi [37,38] (method B) conditions and the results
were compared (Scheme 2.32). The syn -homopropargylic ether

94

was syn- hydro-
zirconated using the Schwartz's reagent [39] Cp 2 Zr(H)Cl to afford the corresponding
( E )-trisubstituted zirconate as a single regioisomer and with complete conversion of
the starting unsymmetrical acetylene

90

. The vinyl zirconium intermediate was then
iodinated to the corresponding ( E )-vinyl iodide

90

(method A, Scheme 2.32) or
transmetalated in situ with anhydrous ZnCl 2 to afford the ( E )-vinyl zinc species

91a

91b

(method B, Scheme 2.32). The ( E )-vinyl iodide ( 91a ) was reacted with the ( E )-vinyl

stannane ( 92a ) for the subsequent Stille coupling (method A). However, despite the

D -glutamate

HO 2 C

Fragment
coupling

Valine-Adda

NH O

O

N

N-Me But

OMe HN O

O HN O

Negishi
coupling

H CO 2 H

erythro-( D )- -Me-Asp

(-)-Motuporin 89

Macrocyclization

FIGURE 2.3

Retrosynthetic analysis of ( )-motuporin 89 .