Biomedical Engineering Reference
In-Depth Information
i
-Pr
i
-Pr
i
-Pr
i
-Pr
Cl
N
Me
Me
N
Me
Me
OH
Me
M
Ph
Mo
TBSO
N
O
N
Mo
Ph
Cl
+
Me
Me
Me
N
Cl
Cl
Me
TBSO
184
185
183
(1 mol%)
N
N
N
5 mol% PtO
2
, H
2
(1 atm
)
EtOH, 22°C, 1 h
97%
Et
PhH, 22°C, 1 h
N
H
N
H
H
84%
182
186
(
+
)-Quebrachamine
(96% ee)
SCHEME 5.41
Enantioselective ring-closing metathesis in the total synthesis of (
þ
)-queb-
rachamine by Hoveyda, Schrock, and coworkers.
mechanistic principles, to achieve a highly efficient and enantioselective synthesis of
the tetracyclic indole intermediate
through an asymmetric ring-
closing metathesis [74]. Their studies commenced with achiral metal carbenoid
initiators to probe the reactivity of the sterically demanding triene
186
from triene
182
182
and the influence
of the Lewis basic amine, a functionality that had been shown to deactivate both
molybdenum- and ruthenium-based carbene catalysts. Subsequently, asymmetric ring-
closing metathesis in the presence of ruthenium- or molybdenum-based catalysts with
chiral
N
-heterocyclic carbenes (NHCs) and bidentate bisaryloxide ligands, respec-
tively, were examined. Unfortunately, under a variety of reaction conditions, including
prolonged heating at elevated temperatures and high catalyst loading, asymmetric ring-
closing metathesis of
proceeded in disappointing yields with decimal enantios-
electivities. Through intelligence gathering the most significant breakthrough came
with the discovery of a “stereogenic-at-molybdenum” complex, where the preparation
of this new generation of asymmetric metathesis catalysts also featured an un-
precedented diastereoselective desymmetrization of molybdenum-based bispyrrolide
precatalyst
182
through a selective protonation of one of the two nitrogen-molybdenum
bonds and chelation with monodentate ligand
185
184
. Thus, in the presence of the
in situ
generated catalyst
183
,triene
182
underwent asymmetric ring-closing metathesis to
afford tetracyclic indole
in an astonishing 84% yield and 96% ee, a remarkable
improvement over the conventional chiral metathesis catalysts. Final hydrogenation of
186
186
over PtO
2
completed a highly efficient and enantioselective synthesis of the natural
product (
)-quebrachamine in 97% yield (Scheme 5.41).
Application of the metathesis reaction in desymmetrization also extends
beyond the context of enantioselective processes. Metathesis substrates with pre-
existing stereogenic center(s) and diastereotopic sites available for metathesis
reaction could undergo desymmetrization under metathesis conditions, thereby
generating a diastereomerically enriched product. This concept was elegantly illus-
trated in Nicolaou's synthesis of coleophomones B and C, two structurally intriguing
natural products found to exhibit antifungal activity, inhibition of human heart
chymase, and antibiotic properties. On close inspection, coleophomones B and C
differs only in the configuration of their
D
þ
16,17
double bond, a structural motif that
could be conceived from a ring-closing olefin metathesis reaction. Indeed, Nicolaou
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