An unequivocal synthesis of 1-benzyl-3-ethyl-1,6-dihydropyridine and its use for a biogenetically modelled synthesis of (±)-catharanthine

Abstract

The first unambiguous synthesis of an Nsubstituted 3-ethyl-1,6-dihydropyridine (2) and its use for a biomimetic synthesis of ( &)-catharanthine (4) are described.

Synthesis of Isoquinuclidines from Highly Substituted Dihydropyridines via the Diels–Alder Reaction

“…Isoquinuclidines have been used as intermediates in the preparation of tetrahydroisoquinoline alkaloids, 6 piperidines, 7 Iboga alkaloids 8 and the related Cantharanthus alkaloids, 9 which have been developed as cancer therapeutics. Isoquinuclidines are most often prepared by Diels-Alder reaction of 1,2-dihydropyridines generated by N -acylation followed by nucleophilic addition to pyridines.…”

“…In our efforts to further harness the 1,2-dihydropyridine intermediates generated through Rh-catalyzed C–H activation, we became interested in the potential of generating isoquinuclidines utilizing a Diels–Alder reaction (Scheme B). Isoquinuclidines have been used as intermediates in the preparation of tetrahydroisoquinoline alkaloids, piperidines, Iboga alkaloids, and the related Cantharanthus alkaloids, which have been developed as cancer therapeutics. Isoquinuclidines are most often prepared by a Diels–Alder reaction of 1,2-dihydropyridines generated by N -acylation followed by nucleophilic addition to pyridines. − However, the incorporation of an acyl protecting group attenuates the nucleophilicity of the dihydropyridine substrates .…”

Progress in the Synthesis of Iboga-alkaloids and their Congeners

“…Using the Diels-Alder approach reported earlier by Sundberg 85 (Scheme 28), Das et al 96 have synthesized key intermediate 197 from a reaction between indole-2-acrylate 196 and 3-ethyl-1,6-dihydropyridine (Scheme 40). Prior to the synthesis of catharanthine, these authors reported the synthesis of 20-deethycathernathine by the same route using unsubstituted dihydropyridine.…”

“…Prior to the synthesis of catharanthine, these authors reported the synthesis of 20-deethycathernathine by the same route using unsubstituted dihydropyridine. 97 Kutney and coworkers used Cr(CO) 3 complexes of dihydropyridine as the precursor of catharnathine. 98 Compound 198 was synthesized by Fisher indole synthesis of levulinic acid with phenylhydrazine followed by reduction with LiAlH 4 and the resultant alcohol was protected with benzyl chloride.…”

A concise synthesis of (±)-vincadifformine and related Aspidosperma alkaloids (±)-desethylvincadifformine, (±)-ibophyllidine, (±)-20-epi-ibophyllidine, and (±)-desethylibophyllidine

“…As part of a programme oriented towards devising a concise general synthetic route to such alkaloids we previously demonstrated the utility of the readily accessible indole derivative (1)3 leading to the synthesis of secodine,3 (5)-de~ethylcatharanthine,~ and (+)-catharanthine. 5 We now illustrate that the compound (1) can also serve as a useful building block for the facile production of (k)vincadifformine (9) and the structurally related Aspidosperma alkaloids such as (+)-desethylvincadifformine (lo), (+)ibophyllidine ( l l ) , (*)-2O-epi-ibophyllidine (12), and (+)desethylibophyllidine (13).…”