Chemistry Reference
In-Depth Information
chemistry for the synthesis of pharmaceuticals.
82
Natural product syn-
thesis
83
and other industrial applications
84
have also benefited from this
reaction. Many types of substrates can now undergo Heck coupling (triflates,
carbonyl and sulfonyl chlorides, diazonium salts, iodonium salts),
85
but only
aryl halides (chlorides, bromides and iodides) have been used on a large
scale for the synthesis of drug candidates. The asymmetric version
86
has also
been developed but no examples on scale have been found. Numerous re-
views on the Heck reaction
87
and its mechanistic aspects
88
have been
published.
The process group at Merck reported the synthesis of hepatitis C virus
(HCV) NS3/4a protease inhibitor vaniprevir (57, MK-7009). Two approaches
to this macrocyclic structure were devised. The first involves a Heck reaction
that brings together two advanced intermediates to give a substrate that then
undergoes macrolactamization to afford the 20-membered macrocycle
(Scheme 15.11).
80v
The second approach generates the macrocycle via ring-
closing metathesis (see Section 15.2.11).
The Heck approach to vaniprevir (57) is shown in Scheme 15.11 and in-
volves the coupling of aryl bromide 53 and unactivated, terminal olefin 54.
A Pd source and ligand screen revealed that this transformation could be
carried out under a variety of conditions (485% assay yield) but, at the same
time, 10-12% of undesired exo regioisomer 56 was produced. The fact that a
wide variety of Pd-ligand combinations gave similar yields of 56 suggested
that the ligand does not intervene in the step where the regioselectivity is
determined. As a result, the Heck coupling was tested under ligandless
conditions and comparable yield and regioselectivity were then observed.
Further optimization showed that the Pd(OAc)
2
loading could be reduced to
O
N
O
Br
O
O
CO
2
Me
53
(50 g)
N
Cbz
N
N
Pd(OAc)
2
(1 mol%)
NMP, 100 ºC, 2 h
O
O
+
+
CO
2
Me
CO
2
Me
100%
N
Cbz
N
Cbz
O
O
O
O
O
N
H
CO
2
H
Cy
2
NH
N
H
O
H
CO
2
H
CO
2
H
56
(exo, undesired)
10
55
54
(1.2 equiv)
−
12%
Isomer mixture isolated as NMP solution
O
N
O
O
H
N
O
O
S
N
H
N
N
O
O
O
57
vaniprevir (MK-7009)
O
Scheme 15.11 Pd-catalyzed Heck approach to vaniprevir (57).
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