Preparation of Conformationally Constrained α₂ Antagonists:The Bicyclo[3.1.0]hexane Approach

Abstract

The aim of the research was to discover antagonists at α 2 receptor subtypes potentially more selective than known compounds. We focused on new, conformationally restricted analogues of atipamezole. The key step in the synthetic sequences leading to target compounds relied on a rhodiumcatalyzed intramolecular cyclopropanation reaction, the outcome of which varied with the nature of the diazo styrene precursor. Thus, depending on the substitution pattern of the double bond and the electronic properties of the diazo pre-

Preparation of Conformationally Constrained α2‐Antagonists: The Bicyclo[3.2.0]heptane Approach

“…Chain extension of styrene 4 1a with diethyl malonate afforded the diester 5 . Saponification and treatment of the monosodium salt 6 with acetyl chloride provided the mixed anhydride 7 which was utilized directly in the next step.…”

“…Initially, we focused on cyclopropyl analogues of atipamezole, and reported on the derivatives of the type bicyclo[3.1.0]hexane (Figure 1). 1a Such compounds, in particular those bearing a 2‐imidazoline pharmacophore, exhibit improved selectivity at the α 2A ‐sites compared to the α 2B ‐ and α 2C ‐sites 1b. Pursuing this promising vein, we have now extended our investigations to include derivatives of the bicyclo[3.2.0]heptane type, homologues of the compounds described previously.…”

A rapid and convergent synthesis of the integrastatin core

“…Commercially obtained reagents were used as received. Styrene 8 was prepared according to the method of Seijas, et al 6 Benzylic alcohol 10 was prepared according to the method of Bonnaud, et al 7 Ketone 5 was prepared according to the method of Murata, et al 9 Reaction temperatures were controlled by an IKAmag temperature modulator. Thinlayer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, potassium permanganate, or CAM staining.…”

Synthesis of 1-indanones with a broad range of biological activity

“…Vacher et al synthesized α 2 -adrenergic receptor antagonists, potentially more selective than known compounds [87]. Transformation of diazo compounds 209 into 1-indanone derivatives 210 , catalyzed by rhodium acetate, has been one of the steps in the total synthesis of atipamezole analogues 211 (Scheme 58).…”

“…Atipamezole is a synthetic α 2 -adrenergic receptor antagonist used in veterinary for reversal of the sedative and analgesic effects induced by α 2 -adrenergic receptor agonists. Vacher et al synthesized α 2 -adrenergic receptor antagonists, potentially more selective than known compounds [ 87 ]. Transformation of diazo compounds 209 into 1-indanone derivatives 210 , catalyzed by rhodium acetate, has been one of the steps in the total synthesis of atipamezole analogues 211 ( Scheme 58 ).…”