Allylic compounds, lithium aluminum hydride

The synthesis of the right-wing sector, compound 4, commences with the prochiral diol 26 (see Scheme 4). The latter substance is known and can be conveniently prepared in two steps from diethyl malonate via C-allylation, followed by reduction of the two ethoxy-carbonyl functions. Exposure of 26 to benzaldehyde and a catalytic amount of camphorsulfonic acid (CSA) under dehydrating conditions accomplishes the simultaneous protection of both hydroxyl groups in the form of a benzylidene acetal (see intermediate 32, Scheme 4). Interestingly, when benzylidene acetal 32 is treated with lithium aluminum hydride and aluminum trichloride (1 4) in ether at 25 °C, a Lewis acid induced reduction takes place to give... 

The rest of the synthesis (Scheme 13) is completely stereospecific and most of the steps are known (20). The bicyclic acid was oxidatively decarboxylated with lead tetraacetate and copper acetate (21). The resulting enone was alkylated with methyllithium giving a single crystalline allylic tertiary alcohol. This compound was cleaved with osmium tetroxide and sodium periodate. Inverse addition of the Wittig reagent effected methylenation in 85% yield. Finally, the acid was reduced with lithium aluminum hydride to grandisol. 

However, a source of the non-natural 9S isomer (2) was first required. The ready availability of natural crinitol made a racemization/resolution route, as illustrated in Scheme 1, attractive. Racemization was accomplished by Collins oxidation (16,25) to the dicarbonyl compound (14), followed by lithium aluminum hydride (LAH) reduction to give the racemic mixture (1 + 2). Resolution via diastereomeric derivatives seemed plausible. Esterification with enantiomerically pure a-methoxy-a-(trifluoromethyl) phenylacetic acid (MTPA) (17), followed by separation of diastereomers by recycle-HPLC (R-HPLC), had earlier been used to purify enantiomers of ipsenol and ipsdienol (26). A model system, the resolution of -3-nonen-2-ol, a secondary allylic alcohol naturally occurring in Rooibos tea (16,27), also worked satisfactorily. Therefore, the route using the bis-(MTPA) esters was selected for crinitol. 

Both enantiomers of binaphthol have found many uses as chiral reagents and catalysts. Thus, they modify reducing agents (e.g., lithium aluminum hydride) for the reduction of ketones to chiral secondary alcohols (Section D.2.3.3.2.) or react with aluminum, titanium or boron compounds to give chiral Lewis acids for asymmetric Diels-Alder reactions (Section D. 1.6.1.1.1.3.) and ene reactions (Section D.I.6.2.). They have also been used as chiral leaving groups in the rearrangement of allyl ethers (Section D.l.1.2.2.) and for the formation of chiral esters with a-oxo acids (Section D. 1.3.1.4.1, and many other purposes. 

The acetylenic side chain of (58) has been hydrogenated in the presence of Lindler catalyst to give the Z-allylic alcohol (70). This olefin was stereoselectively epoxidized at -78° with t-butyl hydroperoxide and a catalytic amount of vanadyl acetoacetate to give an 85 15 mixture of products (71) and (72). The major isomer (71) was separated and converted to 24(R),25-dihydroxycholesterol (73) by the subsequent steps of lithium aluminum hydride reduction and A-ring depfotection (143). These steps provide the means for selectively preparing 24,25-dihydroxy-vitamin D compounds with the natural configuration at the 24-position. 

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