The synthesis and reactivity of allylic alcohols and their derivatives: The synthesis of (Z)-3beta,16alpha-dihydroxy-5,17(20)-pregnadiene 3-pivaloate; the Mitsunobu reaction of 2-cyclohexenols; the europium(III) -catalyzed rearrangement of allylic methoxyacetates.

Abstract

Allylic alcohols are an important functional group in organic chemistry. Their preparation and reactivity have long attracted the interest of synthetic organic chemists. This thesis describes the efficient stereoselective synthesis of an important allylic alcohol for the synthesis of unnatural steroid side chains, (Z)-3$\beta$,16$\alpha$-dihydroxy-5,17(20)-pregnadiene 3-pivaloate as well as its deoxygenated counterpart, (E)-3$\beta$-hydroxy-5,17-pregnadiene 3-pivaloate, achieved by the stereoselective reduction of 17$\alpha$-hydroxy-20-ketones to stereocally pure (20R)-17$\alpha$,20$\alpha$-diols. A review on the participation of unsaturation in the reaction of alcohols with a mixture of triphenylphosphine, diethyl azodicarboxylate (DEAD) and an acidic component (usually a carboxylic acid), known as the Mitsunobu reaction, is followed by a detailed study of this reaction on cyclic allylic alcohols. The results generated for the Mitsunobu reaction of (R)-3-deuterio-2-cyclohexen-1-ol and the cis and trans isomers of 5-methyl-2-cyclohexen-1-ol, 5-tert-butyl-2-cyclohexen-1-ol, and 5-isopropyl-2-methyl-2-cyclohexen-1-ol all give virtually identical product distributions with respect to inversion (75-90%) and retention (0-7%) at the carbinol center as well as syn (4-8%) and anti (3-13%) S$\sb{\rm N}$2$\sp\prime$ reaction when THF and benzene were used as solvent. The reaction in CH$\sb2$Cl$\sb2$ gives less selective product distributions. Since the quasi-equatorial and quasi-axial nature of the starting allylic alcohol did seem to affect the product distribution, it was concluded that the transition states for all these reactions are quite similar, with the axial/equatorial distinction largely lost. The Eu(fod)$\sb3$-catalyzed (3,3) -sigmatropic rearrangement of allylic methoxyacetates, a novel catalyst for the rearrangement of allylic esters is also presented. It was found that this stereospecific rearrangement has several advantages over existing methods for the rearrangement of allylic esters due to its chelation with the methoxyacetate system rather than association with the olefin as in other catalyst systems. Importantly, this rearrangement does not seem to be affected by the steric environment of the substrate and is specific to $\alpha$-alkoxy esters. Finally, preliminary study towards the synthesis of vitamin D$\sb3$ is discussed, as well as a related study on the catalytic Ni$\sb2$O$\sb3$ oxidation of acid-sensitive allylic alcohols to their respective enones.