Biomedical Engineering Reference
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Me
N
Me
H
H
Me
Me
Me
N
Me
N
O
O
[RhCl(coe)
2
]
2
(2.5 mol%)
Ligand
113
(5 mol%)
N
MeO
NaBH
4
(4 equiv)
MeOH, rt, 6 h
reflux, 40 h
49% (2 steps)
CO
2
Et
Me
O
Me
5 steps
42%
H
CO
2
Et
Me
H
HO
OH
PhMe, 45°C, 6 h
Me
OTBS
Me
OTBS
112
Me
OMe
O
O
OTBS
Et
Me
P
N
Me
H
114
(dr = 5:1)
115
(obtained in pure
diastereomeric form
after purification)
Et
Me
4 steps
85%
H
113
Me
N
CO
2
Et
Me
H
(
−
)-Incarvillateine
110
Me
111
O
SCHEME 1.28
Synthesis of (
)-incarvillateine by Tsai, Bergman and Ellman.
5:1 mixture of diastereomers. A screen of ferrocenyl dialkyl phosphines and
4-(dimethylamino)phenyl dialkyl phosphines led to the choice of ligand
113
for this
transformation as it provided
in the greatest diastereomeric ratio. Crucial to the
success of this strategy was the development of a highly active catalyst system that
enabled the reaction to occur at 45
C and avoided olefin isomerization, whichwould
have led to erosion of the diastereo isomeric ratio. Since
114
readily isomerizes to
the ester-conjugated alkene, the crude product was directly reduced using NaBH
4
and transformed into lactam
114
115
. The synthesis was completed using a short five-
110
step sequence, providing (
)-incarvillateine
in 15% overall yield.
1.11. RHODIUM(III)-CATALYZED SYNTHESIS
OF NITROGEN-CONTAINING HETEROCYCLES
Compared to Pd(II)/Pd(0) processes for oxidative carbon-carbon bond formation (see
Section 1.5), the equivalent Rh(III)/Rh(I) catalytic systems have remained relatively
unexplored until recently. Indeed, in the past 5 years, there has been a flurry of reports
on the oxidative coupling of (hetero)arenes containing chelating functional groups
with alkynes and alkenes under rhodium catalysis [90c]. Carboxylic acids, alcohols,
imines, and amides have all been used to direct selective C-H bond cleavage, yielding
a wide range of heterocyclic products when reacted with an alkyne (Scheme 1.29a).
These reactions are proposed to occur through a Rh(III)-catalyzed ligand-directed
C-H bond cleavage to produce rhodacycle
(Scheme 1.29b). Following alkyne
insertion into the rhodium-carbon bond, reductive elimination delivers the desired
116
(a)
Rh(III)-catalyzed heterocycle synthesis
(b)
Rh(III)-catalyzed heterocycle synthesis (catalytic cycle)
H
[o]
Rh(III)
H
R
Y
catalyst
regeneration
ligand-assisted
C-H bond cleavage
R
Rh(I)
R'
cat Rh(III)
H
+
H
X
Y
H
[o]
reductive
elimination
Y
R
R'
Rh
R
R'
R'
alkyne
insertion
(Y = Lewis basic functional group)
Y
H
Rh
Y
116
117
Y
R
R'
SCHEME 1.29
Rh(III)-catalyzed heterocycle synthesis.
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