Biomedical Engineering Reference
In-Depth Information
8
1.
G-II
(3 mol%), CH
2
Cl
2
, reflux, 2 h
2.
HG-II
(10 mol%), 1-undecene
CH
2
Cl
2
, reflux, 2 h
O
OH
OH
O
O
O
O
P
O
O
O
O
P
P
O
then
o
-NBSH, Et
3
N, CH
2
Cl
2
, rt, 24 h
O
O
97
40%
98
99
100
NHCHO
8
O
O
N
-formyl-
L
-leucine
DIAD, PPh
3
, THF
0°C to RT, 12 h
O
O
O
OH
O
O
6 steps
O
O
P
C
6
H
13
C
6
H
13
O
94%
102
101
(
−
)-Tetrahydrolipstatin
SCHEME 5.27
Phosphate-tethered ring-closing metathesis in the total synthesis of
(
)-tetrahydrolipstatin by Hanson and coworkers.
forming events. Furthermore, the metathesis events were followed by a one-pot
chemoselective diimide reduction, which further streamlined the overall synthetic
strategy. Therefore, desymmetrization of phosphate-tethered triene
in the
presence of Grubbs second generation catalyst yielded bicyclic phosphate
98
,
which underwent further olefin cross-metathesis upon treatment with Hoveyda-
Grubbs second generation catalyst and 1-undecene to afford intermediate
99
100
.
Without isolation, diene
participated in a chemoselective diimide reduction
with
o
-nitrobenzenesulfonyl hydrazine (
o
-NBSH, Et
3
N), in the same reaction
vessel, to give bicyclic phosphate
100
101
in 40% yield over three steps. Bicyclic
phosphate
was further elaborated to (-)-tetrahydrolipstatin, culminating in a
highly efficient strategy that required only nine linear synthetic steps from diol
101
97
(Scheme 5.27) [50].
5.7. RELAY METATHESIS
The evolving design of new metal carbene catalysts continues to elevate the
metathesis technology to achieve greater substrate scope and efficiency. However,
an alternative strategy bymodifying the metathesis substratewith a “relay” tether also
enabled sterically demanding and electronically deactivated alkenes to participate in a
metathesis reaction that otherwise would not have taken place by conventional
means [51]. This concept was first demonstrated in the pioneering work of Hoye
and Lee [52] and subsequently found widespread application in the synthesis of
bioactive natural products. In 2004, Porco and coworkers reported the total synthesis
of (
to achieve site-
specific triggering of the metathesis event. In this instance, the conjugated diene
moiety was substituted at the terminus to circumvent the formation of the nonpro-
ductive metal carbene species
)-oximidine III with a strategically designed substrate
103
and a relay tether was installed at the epoxy-alkene
domain to ensure site-specific initiation. With this optimized metathesis precursor
in hand, ring-closing alkene metathesis took place smoothly in the presence of
Hoveyda-Grubbs second generation catalyst to furnish diene macrolactone
104
106
in
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