Chemistry Reference
In-Depth Information
Ph
Ph
O
O
O
HOOC
N
HOOC
N
HOOC
NH
2
O
98.7% ee
98% ee
96% ee
Ph
O
MeO
t
BuOOC
t
BuOOC
>99%ee
COOH
COONa
96% ee
Figure 7.23.
Asymmetric hydrogenation of other itaconic acid derivatives.
P - Phos [129] , TetraMe - BITIANP [195] , and TetraMe - BITIOP [196] , are also effective
for this transformation. Taking tigic acid as the standard substrate, Table 7.7 summarizes
some examples of the hydrogenation of α , β-unsaturated acids. Generally over 90% ee
can be achieved under relatively mild reaction conditions. Ligands with large dihedron
angles such as H
8
-BINAP and BIPHEMP have produced notably higher enantioselec-
tivities compared with other ligands.
The hydrogenation approach to two anti-infl ammatory drugs (
S
) - naproxen and (
S
) -
ibuprofen have been investigated using Ru complexes of BINAP [17d,198], H
8
-
BINAP [193], or P-Phos [132] (Fig. 7.24). In the case of hydrogenation of
2-arylpropionic acids, high hydrogenation pressure and low temperature are required
to achieve good enantioselectivity. A key intermediate (
S
) - 2 - (4 - fl uorophenyl) - 3 - meth-
ylbutanoic acid for the synthesis of calcium antagonist Mibefradil was prepared in
94% ee through hydrogenation of the corresponding unsaturated acid using an (
R
) -
BIPHEMP - Ru catalyst (Eq. 7.11 ) [199] . Using Rh - (
R
) -
47
as catalyst, the asymmetric
hydrogenation of
tert
- butylammonium (
Z
) - 3 - cyano - 5 - methyl - 3 - hexenoate led to the
precursor to CI-1008 (pregabalin), a compound for psychotic disorder, seizure disor-
der, and pain. Both good selectivity (98% ee) and high turnover numbers of 27,000
were achieved (Eq. 7.12) [49]. An Rh-Me-DuPhos complex also provides high enanti-
oselectivity (97.7% ee) although from high catalyst loading (
S
/
C
= 100) [200] . An
isomeric mixture (
E
/
Z
= 19:1) of 4,4 ′ - diaryl - 3 - butenoate has been successfully hydro-
genated to produce a chiral intermediate for an antidepressant agent sertraline. Using
Rh-PhanePhos complex as the catalyst, 90% ee was obtained [201] (Eq. 7.13).
Walphos was applied to the Rh-catalyzed hydrogenation of unsaturated carboxylic
acid to yield a key synthon for renin inhibtor aliskiren with 95% ee and turnover
numbers of 5700 [202] (Scheme 7.4). de Vries and others also developed a hydrogena-
tion process of a mixed-ligand approach for the same target, producing a turnover
number of over 5000 and an ee up to 95% [203]. It was found that the combination
of a chiral monodentate phosphoramidite ligand and a nonchiral trialkylphosphine
provided the best reaction rate and selectivity. This approach also generated a virtu-
ally unlimited ligand library for parallel screening of the best catalyst.
