Biomedical Engineering Reference
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CHO
H
107
CO
2
Me
N
1. [RhCl(coe)
2
]
2
(10 mol%)
FcPCy
2
(30 mol%)
Toluene, 75°C, 20 h
2. aq HCl, 75°C, 20 h
88%
(56% after recrystallization)
O
CHO
CO
2
Me
OMe
CHO
NH
2
OMe
3 steps
H
4 Å MS
CO
2
Me
OMe
Benzene, reflux, 14 h
48%
O
O
OMe
OMe
99%
OMe
OMe
OMe
OMe
106
108
109
(ee = 73%)
(ee = 99% after recrystallization)
Veratraldehyde
OMe
OMe
4 steps
22%
CO
2
H
Aux
Aux
Aux
Aux
O
O
N
N
HO
N
reductive
elimination
N
Rh(I)
R
OH
Rh
Rh
H
H
R
ligand-assisted
oxidative addition
migratory
insertion
CO
2
H
OH
R
H
H
OH
O
OH
Rh(I)
(+)-Lithospermic Acid
105
(dr = 10:1)
SCHEME 1.27
Synthesis of (
þ
)-lithospermic acid by Bergman, Ellman, and coworkers.
unprecedented diastereoselective Rh(I)-catalyzed intramolecular alkylation of an
arene C-H bond (Scheme 1.27). Starting from veratraldehyde, alkene
was
obtained in three steps and with 55% yield. The transformation of this intermediate
to enantioenriched dihydrobenzofuran
106
was investigated using both chiral
catalysts and chiral auxiliaries. Unfortunately, inadequate yields and enantioselec-
tivities were obtained with the wide range of chiral catalytic systems that were
tested. However, optically pure aminoindane
109
was identified as optimal for
inducing diastereoselective olefin insertion during a screen of potential chiral imine
auxiliary directing groups. Accordingly, imine
108
waspreparedbyrefluxing
106
and (
R
)-aminoindane
107
in benzene for 14 h in the presence of 4A
107
molecular
sieves. Subsequent treatment of
with [RhCl(coe)
2
]
2
(10mol%) and (dicyclo-
hexylphosphinyl)ferrocene (FcPCy
2
) (30mol%) yielded dihydrobenzofuran
108
in
88% yield and 73% ee after hydrolysis. The product was further purified by
recrystallization in benzene/pentane mixtures to obtain
109
109
in 56% yield as a
single enantiomer. The synthesis of (
was completed in
four additional synthetic steps. Themechanismof this transformation is proposed to
occur via a three-step process involving: (i) auxiliary-directed oxidative addition of
the C-H bond to the rhodium(I) catalyst, (ii) diastereoselective
syn
-olefin insertion,
and (iii) reductive elimination of the new carbon-carbon bond with concomitant
regeneration of Rh(I) (Scheme 1.27).
With the development of new catalysts for the intramolecular alkylation of
olefin C-H bonds [92b], Tsai and coworkers were able to apply this strategy toward
the asymmetric synthesis of (
þ
)-lithospermic acid
105
) (Scheme 1.28) [95]. This
monoterpene alkaloid, which exhibits analgesic properties [96], presents an inter-
esting synthetic challenge due to the five contiguous stereocenters found in the
bicyclic piperidine moieties it contains. The intramolecular alkylation precursor
)-incarvillateine (
110
112
111
was prepared from commercially available
in 85% yield using an asymmetric
allylation, TBS protection, and cross-metathesis sequence, followed by imine for-
mation. Treatment of imine
with [RhCl(coe)
2
]
2
(2.5mol%) in the presence
of phosphine ligand
113
(5mol%) provided the desired cyclized product
114
as a
112
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