Chemistry Reference
In-Depth Information
catalyst and 2.5 equiv. boronic acid 63 at 35 1C in the presence of 0.5 equiv.
NaHCO
3
(no list of additives was provided), which afforded Michael addition
product 64 in 96% yield with the same 93:7 dr on a 60 g scale. This tech-
nology was further implemented on a 2 kg scale (no detailed experi-
mental protocol was provided). No information was given on the level of
residual Pd in 64.
15.2.8 Tsuji-Trost Allylation
The Tsuji-Trost reaction was originally discovered by Tsuji et al.
96
in the
mid-1960s and represented the first example of a Pd-mediated C-C bond
formation.
97
Following this seminal discovery that employed stoichiometric
Pd, conditions were developed that were substoichiometric in metal.
98
Trost
and co-workers further developed this reaction to convert it into an asym-
metric process.
99
In addition to Pd, examples of Ir-
100
and Fe-catalyzed
101
Tsuji-Trost reactions have been reported. The application of the Tsuji-Trost
reaction in process chemistry is limited, but several examples have been
published, mostly since the early 2000s.
102
The large-scale preparation of the naturally occurring quinolizidine al-
kaloid (-)-huperzine A (69), a potent acetylcholinesterase inhibitor for the
potential treatment of Alzheimer's disease, has been reported thanks to a
collaboration between Shasun Pharma Solutions, Rhodia Pharma Solutions
and Debiopharm SA Forum ''apr´s-demain'' (Scheme 15.14).
102f
The bicyclic
core on the molecule was installed via an asymmetric Pd-catalyzed annu-
lation originally developed by Terashima's group in Japan between b-keto
ester 66 and diacetate 67.
103
Since Terashima's asymmetric synthesis em-
ploying Pd(OAc)
2
(20 mol%) and chiral ferrocenyl ligand 70 (40 mol%,
Figure 15.3) gave 68 with modest enantioselectivity (64% ee) under a variety
of reaction conditions, a screen of 33 mono- and diphosphine ligands was
carried out in collaboration with Solvias. As a result, Taniaphos ligand SL-
T002-1 (71, Figure 15.3) was selected as the ligand of choice. Further opti-
mization of the reaction conditions (catalyst loading, solvent, concentration
and temperature) allowed for a 20-fold reduction in the amount of Pd source
and ligand. In the laboratory, the large-scale preparation of 68 involved
stirring a mixture of ligand 71 and [PdCl(p-allyl)]
2
in acetone at 25 1C for 1 h
to form the active catalyst. Diacetate 67 was then added and the mixture was
i. [PdCl(
π
-allyl)]
2
(1 mol%
)
71
(2 mol%)
TMG, acetone
20
−
25 ºC, 1.5 h
H
N
N
OMe
N
OMe
O
+
AcO
OA c
O
ii. filtration through silica
iii. concentration
iv. recrystallization from IPA
CO
2
Me
CO
2
Me
NH
2
69
O
66
67
(1.0 equi v)
68
(385 g)
99% ee
45%
(
−
)-huperzine A
Scheme 15.14 Large-scale preparation of the bicyclic core of (-)-huperzine A via
Tsuji-Trost coupling.
Search WWH ::
Custom Search