Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine

Abstract

A concise and efficient total synthesis of the spermidine alkaloid (-)-isooncinotine (1) incorporating a 22-membered lactam ring is outlined. The approach is largely catalysis-based, involving a selective iron-catalyzed alkyl-aryl cross-coupling reaction of a difunctionalized pyridine substrate, a heterogeneous asymmetric hydrogenation step to set the chiral center of the target, and a highly integrated ring-closing metathesis/hydrogenation sequence to forge the saturated macrocyclic edifice in a single operation.

Fig. 1.

Structures of macrocyclic spermidine alkaloids.

Scheme 1.

Retrosynthetic analysis of (-)-isooncinotine 1.

Scheme 2.

Formation of optically active piperidine derivatives by asymmetric hydrogenation of pyridines with concomitant release of the chiral auxiliary (23).

Scheme 3.

[a] Fe(acac)₃ catalytic, THF/NMP, 0°C, 83%. [b] Oxazolidin-2-one 8, CuI catalytic, N,N′-dimethylethylenediamine, K₂CO₃, toluene, 140°C, 90%. [c] Pd(OH)₂/C catalytic, MeOH, HOAc, H₂ [120 atm (1 atm = 101.3 kPa)], 35°C, 78%, ee = 94%. [d] Bromide 18, K₂CO₃, NaI, EtOH, reflux, 73%. [e] Oxalyl chloride, DMSO, CH₂Cl₂, NEt₃, -60°C, 81%. [f] {Ph₃P-CH₃}⁺ Br^-, potassium hexamethyldisilazide, THF, HMPA, -78°C → room temperature, 82%. [g] HSCH₂COOH, LiOH, DMF, 84%. [h] (i) HCl/Et₂O, CH₂Cl₂; (ii) complex 14 catalytic, CH₂Cl₂, reflux; (iii) H₂ (50 bars), 70°C, 76%.

Scheme 4.

[a] 5-Hexenoic acid methyl ester, 60°C, 95%. [b] 2-Nitrobenzenesulfonyl chloride, pyridine, CH₂Cl₂, 73%. [c] 1,4-Dibromobutane, K₂CO₃, DMF, 60°C, 88%.