Synthesis of (±)-presqualene alcohol, (±)-prephytoene alcohol, and structurally related compounds

Abstract

The stereochemistry of the base-catalysed addition–elimination method for cyclopropane ring synthesis, employing a βγ-unsaturated phenyl sulphone and an αβ-unsaturated ester, has been examined. The olefinic geometry of the βγ-unsaturated sulphone is retained in the product, and the unsaturated side chain and the ester function emerge trans about the ring, with substantial stereoselectivity. On the other hand, the geometry of the double bond of the αβ-unsaturated ester becomes equilibrated in the anion addition product. Thus the resulting cyclopropanes are produced without a stereoselective preference based on the geometry of the original αβ-unsaturated ester. This work has led to the synthesis of ethyl 2,2-dimethyl-trans-3-[(1E,5E)-2,6,10-trimethylundeca-1,5,9-trienyl]cyclopropanecarboxylate (40) and the corresponding cyclopropylmethanol (42), representing one side of the presqualene molecule, and to the pair of C-2 epimeric diterpenoid ethyl 2-[(E)-4,8-dimethylnona-3,7-dienyl]-2-methyl-trans-3-(2-methylprop-1-enyl)cyclopropanecarboxylates (44) and (45) and the corresponding alcohols (47) and (48), representing the other side of the presqualene molecule. Lower prenylogues were also studied.

By using phenyl 3,7,11-trimethyldodeca-2,6,10-trienyl sulphone (37) and ethyl (2E,6E)-3,7,11-trimethyl-dodeca-2,6,10-trienoate (39; R = Et), the stereochemically controlled synthesis was developed to give two stereoisomers of presqualene esters (49) and (50), which were separated and reduced to give (±)-natural presqualene alcohol (53) and the C-2 epimer (54); tritiated samples were also prepared. Chemical and biological comparison with natural presqualene alcohol, the C₃₀ compound involved in squalene biosynthesis, confirmed the identification. An n.m.r. study with shift reagents was used to investigate the stereochemistry of these and related subsituted cyclopropanes.

Condensation of the C₂₀ sulphone (64) with the C₂₀ ester (62) led, in a similar synthesis, to the C₄₀ cyclopropane carotenoid precursor (±)-prephytoene alcohol (68) and its C-2 epimer (69).