Total Synthesis of Petrosin, Petrosin A, and Petrosin B
journal contributionposted on 1998-06-26, 00:00 authored by Robert W. Scott, James Epperson, Clayton H. Heathcock
The petrosins are a family of marine alkaloids that includes the chiral, racemic isomer petrosin (1), the meso isomer petrosin A (2), and the chiral, scalemic isomer petrosin B (3). Monte Carlo molecular mechanics calculations indicated that petrosin (1) is the most stable isomer of the group, suggesting that it might be synthesized by a route that utilizes thermodynamic control for establishing the relative configurations of the eight stereocenters. The model synthesis summarized in Scheme 1 showed that intramolecular Mannich condensation is a viable route to the quinolizidone subunit of the petrosins and that this synthesis gives isomer 5, having the relative configuration found in petrosin and petrosin A, as the kinetic product. Equilibration studies with this isomer afforded an approximate equimolar mixture of 5 and diastereomer 6, having the relative configuration found in one of the two quinolizidone units of petrosin B. On the basis of this model study, a “stereo-uncontrolled” synthesis of petrosin was carried out, as summarized in Schemes 3−5. The key step of this synthesis is a “double-barrelled” intramolecular Mannich condensation of a diamino keto dialdehyde. This transformation provides crystalline petrosin in 23% yield, along with about 37% of a mixture of petrosin diastereomers. Although simple acid- and Lewis acid-mediated equilibrations of this mixture of diastereomers were not successful, the derived mixture of bis-butylimines undergoes equilibration upon treatment with protic acid to give a mixture that is greatly enriched in petrosin, relative to the other isomers. Crystallization of this equilibration mixture provided another 10% of petrosin, bringing the overall yield of petrosin to 33%. In the course of the equilibration studies, pure samples of petrosin A (2), petrosin B (3), and petrosin B‘ (7) were isolated and characterized.
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petrosin diastereomersmarine alkaloidsmodel studyScheme 1diamino keto dialdehydePetrosin BTotal SynthesisMonte Carlomodel synthesisEquilibration studiesintramolecular Mannich condensationracemic isomer petrosinprotic acidquinolizidone unitsequimolar mixturescalemic isomer petrosin Bequilibration studiespetrosin Bmeso isomer petrosindiastereomer 6equilibration mixtureisomer 5mechanics calculationsquinolizidone subunit