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I. The synthesis of homoallylic amines via a 1,2-metalate rearrangement; II. The synthesis of bridged azabicyclic structures via ring-closing olefin metathesis
textA convergent, stereoselective route to homoallylic sulfonamides has been
described. Homoallylic sulfonamides with di- and trisubstituted double bonds were
prepared in good yields and with excellent control of alkene geometry via a cuprateinduced
1,2-metalate rearrangement of α-lithiated N-trisyl 2-pyrroline. Removal of
the N-trisyl group was achieved by sonication of the sulfonamides in the presence of
Li(0) wire and catalytic di-tert-butylbiphenyl. The utility of this method was
illustrated by its application toward the synthesis of a squalene synthetase inhibitor.
In other efforts, a versatile approach to bridged azabicyclic structures was
developed. This process involved the ring-closing metathesis (RCM) of cis-2,6-
dialkenyl N-acyl piperidines, which were prepared in six steps from glutarimide or in
three steps from 4-methoxypyridine. The N-acyl protecting group of these
piperidines played a crucial role in this sequence by stabilization of the C2,C6 bisaxial
conformers necessary for their RCM. In this manner, a diverse array of bridged
azabicyclic structures were obtained in excellent yields. Application of this RCM
strategy toward the synthesis of (±)-cocaine and compounds structurally related to
vellosimine has been reported.Chemistr
The Synthesis of Homoallylic Amines Utilizing a Cuprate-Based 1,2-Metalate Rearrangement
Indole Resin: A Versatile New Support for the Solid-Phase Synthesis of Organic Molecules
Design, Synthesis, and Structure−Activity Relationship of Tropane Muscarinic Acetylcholine Receptor Antagonists
Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>) Discovered through X‑ray Fragment Screening
Elevated levels of
human lipoprotein-associated phospholipase A2
(Lp-PLA<sub>2</sub>) are associated with cardiovascular disease and
dementia. A fragment screen was conducted against Lp-PLA<sub>2</sub> in order to identify novel inhibitors. Multiple fragment hits were
observed in different regions of the active site, including some hits
that bound in a pocket created by movement of a protein side chain
(approximately 13 Å from the catalytic residue Ser273). Using
structure guided design, we optimized a fragment that bound in this
pocket to generate a novel low nanomolar chemotype, which did not
interact with the catalytic residues
Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>) Discovered through X‑ray Fragment Screening
Elevated levels of
human lipoprotein-associated phospholipase A2
(Lp-PLA<sub>2</sub>) are associated with cardiovascular disease and
dementia. A fragment screen was conducted against Lp-PLA<sub>2</sub> in order to identify novel inhibitors. Multiple fragment hits were
observed in different regions of the active site, including some hits
that bound in a pocket created by movement of a protein side chain
(approximately 13 Å from the catalytic residue Ser273). Using
structure guided design, we optimized a fragment that bound in this
pocket to generate a novel low nanomolar chemotype, which did not
interact with the catalytic residues