Biomedical Engineering Reference
In-Depth Information
N
N
S-SO
2
Tol
S-SO
2
Tol
PhO
PhO
CuMgBr
Me
O
O
2
THF, -100°C
N
N
•
O
O
CO
2
Bn
Cu
O
OBn
73
74
75%
NH
2
N
H
N
S
S
PhO
Me
Me
steps
O
O
N
N
HO
O
O
CO
2
Bn
COOH
Cefzil
76
75
SCHEME 9.14
Synthesis of cefzil
76
by Kant and coworkers.
chiral amine used during the process (45-100%). In the illustrated case, the highest ee
(64%) was achieved using the cinchona alkaloid
72
as determined through compound
69
. Several groups have taken
this advanced intermediate through to the desired anti-Alzheimer's compound
following the elimination of the mesylate to form
70
.
The
b
-lactamclass of
N
-heterocycles has long been associatedwith treatment of
bacterial infections. Kant and coworkers targeted cefzil
(76)
, a C3 alkene containing
cephalosporin, based on a domino reaction initiated by an organocuprate-mediated
Michael reaction [26]. In the latter stage of this synthesis, copper dienolate
71
74
,
100
C from
initially formed at
73
via a Michael addition, then underwent a S
N
0
reaction to generate
containing a thiazinane ring (Scheme 9.14). The final steps of
the synthesis were carried out according to the previously known literature proce-
dures [27]. Hence, by applying this method using a broad range of organocuprates,
the authors could productively construct a variety of differently C3-substituted
cephalosporins with yields ranging from 68% to 95%.
In pursuit of a rapid and cost-effective synthesis of the anti-influenza drug
75
(
, Tamiflu TM) Hayashi and coworkers developed an
innovative synthesis involving three one-pot processes (Scheme 9.15) [28]. This
large-scale synthesis of
)-oseltamivir phosphate (
82
is considered profoundly important today, with the
outbreak of the bird flu (H5N1) in several countries as well as the probable pending
mutation of the H5N1 virus into a strain capable of human-to-human transmission.
Initially, the enantiopure precursor
82
containing two stereogenic centers was
prepared from cheap starting materials. Indeed, by treating aldehyde
77
77
with
78
vinylphosphonate
, a domino Michael/Wittig-Horner reaction afforded a 5:1
mixture of (5
R
)-
80
and (5
S
)-
80
79
presumably as an intermediate.
Unfortunately, in this domino reaction, the undesired (5
R
)-diastereomer predomi-
nated. However, Hayashi and coworkers overcame this imbalance in the next step that
involved an equilibration of this C5 stereogenic center via a Michael reaction with
p
-toluene thiol to give
81
. Following two more single-pot processes, the desired
(
, with compound
)-oseltamivir
was obtained in a remarkable overall yield of 57%.
In a quite recent approach, Ma and coworkers prepared (
(82)
)-oseltamivir
(82)
using a domino Michael addition/Wittig reaction [29].
Search WWH ::
Custom Search