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CH
2
OH
PCy
2
N
Me
PPh
2
PCy
2
Fe
Me
2
N
Fe
PPh
2
70
71
SL-T002-1
Figure 15.3
Structures of chiral ligands employed in the asymmetric synthesis of
(-)-huperzine A.
Pd(OAc)
2
(5 mol%)
dppp (7.5 mol%)
Et
2
Zn (1.0 M in hexane,
0.52 equiv)
L
-tryptophan (10 mol%)
THF,0ºCtort,3h
i.
CF
3
O
CF
3
CF
3
O
CF
3
O
HO
O
+
aqueous workup
Darco KB-B (50 wt%
per
72
)
concentration to an oil
ii.
iii.
CF
3
CF
3
CN
H
HN
O
F
H
CN
72
74
(39.8 g)
73
(1.0 equiv)
iv.
75
77%
NH
2
Scheme 15.15 Ether formation via Pd-catalyzed Tsuji-Trost allylation.
further stirred for a further 1 h. A solution of keto ester 66 and tetra-
methylguanidine (TMG) in acetone was added over 30 min and the resulting
mixture was stirred at 20-25 1C for 1 h. Upon completion of reaction, the
acetone was removed via vacuum distillation and the residue was passed
through a silica bed, eluting with hexane-EtOAc to remove Pd salts and
ligand. The eluate was concentrated and the residue (84% ee) was re-
crystallized from IPA to afford 385 g of bicyclic intermediate 68 in 45% yield
and 99% ee. It was mentioned that the level of residual Pd in 68 was not
determined but after converting (-)-huperzine to an imine derivative, the Pd
content was below 20 ppm.
The process group at Merck described the synthesis of hNK-1 receptor
antagonist 75, a drug candidate for the treatment of chemotherapy-induced
and postoperative nausea and vomiting (Scheme 15.15).
102e
Intermediate 72
was obtained via asymmetric enzymatic reduction of 3-cyanocyclopentenone
followed by treatment with 2-naphthoyl chloride. The next step involved a
Tsuji-Trost coupling between 72 and chiral benzylic alcohol 73 with
Pd(OAc)
2
and 1,3-diphenylphosphinopropane (dppp) as ligand in the pres-
ence of catalytic amounts of Et
2
Zn (reaction activator) and
L
-tryptophan (N,O-
chelator to increase the reaction rate)
104
to generate ether 74 via an Z
3
-
allylmetal species. The reaction proceeds through the formation of a Zn
alkoxide that adds to the Z
3
-allylpalladium complex.
105
After completion of
reaction, the mixture was filtered and the filtrates were subjected to an
aqueous work-up. The product-rich organic phase was treated with Darco
KB-B (50 wt% per 72) at room temperature for 18 h, filtered and concen-
trated to afford 39.8 g of 74 as an oil that was used in the next step without
further purification. It was mentioned that the acetate ester of 72 also
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