4.2: Syntheses of Loganin

Total syntheses of loganin, that invole polar connection as the first step in the retrosynthetic analysis, have been described. Thus, dislocation of the monocyclic target to a bicyclic target recognizes the potential of retroaldol cleavage of a cyclobutane ring for generation of the required vicinal cis relationship of the malonyl and carboxaldehyde substituents of the target. The cyclobutane can be generated in a two bond-forming cycloaddition process, which, owing to the strain expected for the alternative trans-fused bicyclic product, can be expected to favor the required cis-fused bicyclic intermediate.

Loganin was synthesized in the laboratory by an ingenious scheme involving photochemical cycloaddition to a preformed symmetrical cyclopentene synthon 16.¹ The desired cis ring fusion is assured by a temporary bridge in the intermediate 17.

An asymmetric total synthesis of loganin was achieved² by an overall strategy for skeletal construction which is similar to, although shorter than, the previous approach. The asymmetric intermediate 18 was produced in high optical purity (at least 98%) by hydroboration of the prochiral symmetrical substrate, 5-methyl-cyclopentadiene, with (+)- or (-)-di-e-pinanylborane.

Since this involves stereospecific addition of the borane to the least hindered face of 18, the configuration at the carbinol carbon had to be inverted during the preparation of the acetate 19. The regioselective formation of the isomer 20 results from the steric approach control during the photoannealation. The enol (21) attacks the less hindered face of 19.