A new synthesis of morphine-based analgesics

Total Synthesis of (±)-Thebainone A by Intramolecular Nitrone Cycloaddition

“…Gates succeeded in the first total synthesis of morphine ( 3 ) in 1952 . Since then, more than 30 total and formal syntheses have been published. − Due to our interest in the application of intramolecular nitrone cycloadditions toward the synthesis of morphine alkaloids, , we recently devised a novel access to thebainone A ( 1 ), which in turn is a known precursor for 2 and 3 . This was already shown by Gates in his pioneering work .…”

Chemoenzymatic Formal Total Synthesis of ent‐Codeine and Other Morphinans via Nitrone Cycloadditions and/or Radical Cyclizations. Comparison of Strategies for Control of C‐9/C‐14 Stereogenic Centers

“…One of the challenges in any design of the morphine skeleton is the relative stereochemistry at C‐9/C‐14 – this can be controlled by employing cycloadditions. In 1984 Parsons published a model study of an intramolecular nitrone cycloaddition, which produced the correct C‐9/C‐14 relationship,5 followed by a complete total synthesis of morphine by this strategy 6. In 2011 Metz reported a total synthesis of racemic codeine via a nitrone cycloaddition that yielded the correct relationship at C‐9/C‐14 7.…”

A new acylative cycloaddition reaction

“…In order to study the reaction a stable, readily available nitroalkene was required. We therefore chose to prepare l-(oallylphenyl)-2-nitroethene (5) as shown in Scheme 3.…”

“…112 "C at 0.25 mmHg (Kugelrohr) (Found: C, 63.7; H, 6.5; N, 6.4%; C, , H , ,NO, requires C, 63.7; H, 6.3; N, 6.8%); v,,,~(fiim) 3 540m, 3 450m sh, 1640m, 1565s, and 1380m cm-'; 6,(60 MHz) 7.1-7. (E)-o-AllJ~l-P-nitro~ryrene (5).-The nitro alcohol (3) (3.7 mmol, 0.76 g) and mesyl chloride (0.32 ml, 1.1 mol equiv.) were stirred undcr nitrogen in dichloromethane (10 ml).…”

“…-Citronellal(21) (9.1 ml, 0.05 mol) was treated with nitromethane as in the preparation of nitro alcohol (4). The resultant nitro alcohol was not purified but was dehydrated with mesyl chloride as in the preparation of compound (5). Purification by suction flash chromatography over silica with ether-light petroleum mixtures as eluant (0-30% ether; 15% polarity gradient) afforded the nitroalkene (22) (8.68 g, 88%).…”