Carpanone has been stereoselectively synthesized in 55% yield and six steps from sesamol. The key step of the synthetic sequence is the direct introduction of the propenyl side chain via a Suzuki-Miyaura cross-coupling reaction. The subsequent Pd(II)-catalyzed oxidative coupling yields carpanone as a single diastereoisomer independently of the geometric configuration of the starting precursor. A new mechanism is proposed for this transformation.
The
hormone adrenomedullin has both physiological and pathological
roles in biology. As a potent vasodilator, adrenomedullin is critically
important in the regulation of blood pressure, but it also has several
roles in disease, of which its actions in cancer are becoming recognized
to have clinical importance. Reduced circulating adrenomedullin causes
increased blood pressure but also reduces tumor progression, so drugs
blocking all effects of adrenomedullin would be unacceptable clinically.
However, there are two distinct receptors for adrenomedullin, each
comprising the same G protein-coupled receptor (GPCR), the calcitonin
receptor-like receptor (CLR), together with a different accessory
protein known as a receptor activity-modifying protein (RAMP). The
CLR with RAMP2 forms an adrenomedullin-1 receptor, and the CLR with
RAMP3 forms an adrenomedullin-2 receptor. Recent research suggests
that a selective blockade of adrenomedullin-2 receptors would be therapeutically
valuable. Here we describe the design, synthesis, and characterization
of potent small-molecule adrenomedullin-2 receptor antagonists with
1000-fold selectivity over the adrenomedullin-1 receptor, although
retaining activity against the CGRP receptor. These molecules have
clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties, and inhibit
xenograft tumor growth and extend life in a mouse model of pancreatic
cancer. Taken together, our data support the promise of a new class
of anticancer therapeutics as well as improved understanding of the
pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers.
A palladium-catalyzed asymmetric decarboxylative allylic alkylation of allyl 2,2-diphenylglycinate imines using (S,S)-f-binaphane as a chiral supporting ligand has been developed. This transformation allows for decarboxylative generation and enantioselective allylation of nonenolate α-imino (2-azaallyl anions) to afford α-aryl homoallylic imines.
Class B G-protein-coupled
receptors (GPCRs) remain an underexploited
target for drug development. The calcitonin receptor (CTR) family
is particularly challenging, as its receptors are heteromers comprising
two distinct components: the calcitonin receptor-like receptor (CLR)
or calcitonin receptor (CTR) together with one of three accessory
proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1
forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM
1
) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM
2
) receptor. The CTR/RAMP complexes form three distinct amylin
receptors. While the selective blockade of AM
2
receptors
would be therapeutically valuable, inhibition of AM
1
receptors
would cause clinically unacceptable increased blood pressure. We report
here a systematic study of structure–activity relationships
that has led to the development of first-in-class AM
2
receptor
antagonists. These compounds exhibit therapeutically valuable properties
with 1000-fold selectivity over the AM
1
receptor. These
results highlight the therapeutic potential of AM
2
antagonists.
Functionalised cyclic enol ethers can be recovered with high levels of enantiocontrol after an asymmetric catalytic [1,3]-rearrangement reaction. These compounds can be further elaborated to a series of carbo- and heterocyclic products in good yield and with excellent levels of stereocontrol.
Palladium-Catalyzed Decarboxylative Generation and Asymmetric Allylation of -Imino Anions -[using (S,S)-f-binaphane (BPF) as chiral catalyst ligand]. -(QIAN, X.; JI, P.; HE, C.; ZIRIMWABAGABO, J.-O.; ARCHIBALD, M. M.; YEAGLEY, A. A.; CHRUMA*, J.
Enantioselective Route to Functionalized Pyrans. -The asymmetric Pd-catalyzed [1,3]-rearrangement of racemic cyclic enol ether (I) leads to enantioenriched cyclohexanone (II) and enantiopure enol ethers (I) (15 examples for analogues). Chiral compound (Ia) is used for the preparation of the optical antipode of cyclohexanone (IIa), as well as pyran (III), lactone (IV), and cyclooctenone (V). -(ZIRIMWABAGABO, J.-O.; HARRITY*, J. P. A.; Chem. Commun. (Cambridge) 50 (2014) 21, 2735-2737, http://dx.doi.org/10.1039/c4cc00109e ; Dep. Chem., Univ. Sheffield, Sheffield S3 7HF, UK; Eng.) -R. Staver 25-029
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