A Simple and Efficient Synthetic Route to Chiral Isopavines. Synthesis of (−)-O-Methylthalisopavine and (−)-Amurensinine

Abstract

The isopavinan alkaloids (−)-O-methylthalisopavine (7a) and (−)-amurensinine (7d) have been synthesized in good yield and high ee from the appropriate 1,2-diarylethylamine derivatives using optically active β-amino alcohols as chiral support. This synthetic route employs as key steps the alkylation reaction of the azomethine derivatives 2 with Grignard reagents 1 and a novel one-pot double-intramolecular cyclization of the adequately functionalized 1,2-diarylethylamines 5 to afford a series of optically active isopavines 6a−d and 7a−d.

A Convergent and Enantioselective Synthesis of (+)‐Amurensinine via Selective C—H and C—C Bond Insertion Reactions.

“…Purification by flash chromatography (4:1 hexanes/EtOAc eluent) provided diazoketoester 11 (487 mg, 99% yield) as a clear oil: R f 0.50 (1:1 hexanes/EtOAc); 1 H NMR (300 MHz, C 6 D 6 ): δ 7.00-6.94 (comp. m, 2H), 6.62 (d, J = 8.0 Hz, 1H), 4.12 (s, 2H), 3.89 (q, J = 7.1 Hz, 2H), 3.51 (s, 3H), 3.43 (s, 3H), 0.89 (t, J = 7.2 Hz, 3H); 13 β-Ketoester 9. A flask equipped with an addition funnel and an N 2 inlet was charged with a catalytic amount of Rh 2 (OAc) 4 (138 mg, 0.31 mmol) and CH 2 Cl 2 (140 mL).…”

Highly Diastereoselective Intramolecular [1,2]-Stevens Rearrangements—Asymmetric Syntheses of Functionalized Isopavines as Morphinomimetics

“…[7] A very recent method developed by Miller et al employs a gel, covalently bonded to a fluorescent indicator, formed by polymerization around the library beads. [8] Herein we report an alternative gel-based protocol for screening for bead-bound catalytic activity in aqueous media.…”

“…[6] Natural O-methylthalisopavine was first prepared by Meyers and co-workers, [7] by utilizing chiral nonracemic formamidines as substrates in an asymmetric synthesis. Dominguez and co-workers [8] relied on b-amino alcohols as chiral auxiliaries in their synthesis of the same alkaloid.…”

“…. [8] The isopavines A and B have interesting topologies, particularly when viewed in the context of constrained piperidine analogues. As such, they are closely related to morphine, [14] with a quasi-ideal convergence of their carbon skeleton and the strategic location of the tertiary nitrogen atom.…”

“…[6] Natural O-methylthalisopavine was first prepared by Meyers and co-workers, [7] by utilizing chiral nonracemic formamidines as substrates in an asymmetric synthesis. Dominguez and co-workers [8] relied on b-amino alcohols as chiral auxiliaries in their synthesis of the same alkaloid.In view of the pharmacological importance of the isopavines, and the paucity of methods to access enantiopure analogues that would be useful to study selective interactions with designated receptors, we investigated various routes to their stereocontrolled synthesis. We report herein examples of highly stereocontrolled, diastereoselective [1,2]-Stevens rearrangements [9, 10] of 13-substituted dihydro methanodiarylazocines, which are readily available from a-amino acids, [11] to give 6-substituted enantiopure isopavines.…”