Stereoselective total synthesis of (–)-pumiliotoxin C by an aqueous intramolecular acylnitroso Diels–Alder approach

Abstract

A chiral approach to (–)-pumiliotoxin C based on an aqueous intramolecular acylnitroso Diels–Alder reaction is described. Upon treatment of the (S)-1,3-diene hydroxamic acid 19, available from L-malic acid, with Pr₄NIO₄ under the aqueous conditions, the in situ generated acylnitroso compound 19 was subjected to intramolecular [4 + 2] cycloaddition to yield the trans-1,2-oxazino lactam 21 with significantly increased diastereoselectivity in comparison with the same cycloaddition conducted in a chloroform solution. Subsequent addition of the propyl side chain was achieved by means of a tandem Grignard reaction–NaBH₃CN reduction in a completely stereocontrolled manner. The bicyclic 1,2-oxazine 26 thus obtained was converted into the all-cis-decahydroquinoline 34 by sequential reductive N–O bond cleavage, aldol condensation of the diketone 31 and hydrogenation of the octahydroquinolone 33. Clemmensen reduction of 34, followed by LiAlH₄ reduction, provided a ca. 2 : 1 epimeric mixture of α-methyl and β-methyl isomers 36 and 37, and subsequent debenzylation converted the major isomer 36 into 5-epi-pumiliotoxin C 2. On the other hand, 34 underwent LiAlH₄ reduction followed by Swern oxidation to afford a 1.2 : 1 epimeric mixture of the decahydroquinolones 39 and 41. Equilibrium control of this epimeric mixture by prolonged heating with Zn(OTf)₂ followed by treatment with ethane-1,2-dithiol resulted in the exclusive formation of the thermodynamically more stable β-methyl epimer 43 as a single isomer, which was converted into (–)-pumiliotoxin C 1 by desulfurization and debenzylation.