Cyclic sulfamidates as versatile lactam precursors. An evaluation of synthetic strategies towards (−)-aphanorphine

Abstract

A full account of studies which led to the efficient asymmetric synthesis of (-)-aphanorphine is reported. Two routes to the key cyclic sulfamidate intermediate are described, the first was based on a chiral auxiliary approach and the second utilised asymmetric hydrogenation methodology. A range of C(3)-substituted lactams (, and ) were synthesised and evaluated as precursors for Pd(0) catalysed entries (based on (i) alpha-arylation of a lactam enolate and (ii) reductive Heck reaction) to the 3-benzazepine core of . These approaches were less effective than an aryl radical cyclisation which allowed the completion of a synthesis of in 12 steps from anisaldehyde.

Magnolol dimer-derived fragments as PPARγ-selective probes

“…Mp 59.0–60.5 °C (lit. : 26 59–60 °C); 1 H NMR (200 MHz, CDCl 3 ) δ 7.36 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.6 Hz, 1H), 6.84 (dd, J = 8.5, 2.6 Hz, 1H), 4.60 (s, 2H), 3.80 (s, 3H) ppm; 13 C NMR (50 MHz, CDCl 3 ) δ 160.4, 132.0, 129.2, 125.2, 118.6, 114.2, 55.8, 33.9 ppm.…”

Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors

“…[79a] A similar cyclization leading to the fused isoindolobenzazepine alkaloid lennoxamine (not shown) is also reported. [79b] b) The tricyclic structure of aphanorphine was achieved from aryl bromides through 6‐ exo radical cyclizations either upon a methylene acceptor with a thiophenyl group in 94 or an α‐methylene lactam moiety in 95 in an enantioselective synthesis . c) The alkaloid rosettacin of the aromathecin family was synthesized using lactam N ‐alkylation followed by an aryl radical cyclization ( 96 → 97 ) of an enamide tether with a 2‐chloroquinoline acting as a radical precursor .…”

Stereoselective Hydrogenation ofCCBonds: Application to Drug and Natural Product Synthesis

“…206 In 2006, Gallagher and group proposed asymmetric synthesis of (À)-aphanorphine via asymmetric hydrogenation of N-Boc-protected a-amino-cynnamate derivative 138 to create one of the stereogenic centers in the molecule (Scheme 29.8). 207 Asymmetric hydrogenation was carried out in methanol under 5 bar of hydrogen pressure using {Rh [(R,R)-Et-DuPHOS](COD)}BF 4 precatalyst affording NBoc-protected amino acid 139 in quantitative yield and asymmetric induction >98% ee.…”