Epimers, alcohol

In reductions with NaBH4 the proportions of epimers are generally of the same order as with Li AIH4, but usually more of the axial alcohol is produced. This is especially true of reductions done in methanol. " A summary of the... 

Reduction of a 16a-bromo-17-ketone (but not the 16 -epimer) is a little less stereospecific than reduction of the 17-keto compound. When a 2a-bromo-3-keto steroid is reduced, at least 78 % of the 3/ -alcohol is obtained. 

The facile and selective oxidation of both primary and secondary hydroxy groups with certain nucleotides led Pfitzner and Moffatt (48) to explore the scope of the carbodiimide-methyl sulfoxide reagent with steroid and alkaloid alcohols. Relatively minor differences were apparent in the rate of oxidation of epimeric pairs of 3- and 17- hydroxy steroids whereas the equatorial lLx-hydroxyl group in several steroids was readily oxidized under conditions where the axial epimer was unreactive [cf. chromic oxide oxidation (51)]. 

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

Another version of the double [2,3]-sigmatropic rearrangement, involving the sequence sulfenate - sulfoxide - sulfenate, has also been observed. For example, an effective one-pot epimerization procedure of 17a-vinyl-l 7/i-hydroxysteroids to the rather inaccessible 17-epimers has been achieved by the use of such a rearrangement (equation 35)137. Thus treatment of alcohol 76a with benzenesulfenyl chloride afforded the sulfoxide 77 as a single isomer and E-geometry of the olefinic double bond. Exposure of 77 to trimethyl phosphite in refluxing methanol produced a mixture of 76b and 76a in a 73 27 ratio. 

More recently, Brown and Fallis138 have described a similar epimerization of bicyclic and allylic tertiary alcohols, such as, for example, the epimerization of the endo alcohol 78 to its exo epimer 79 (equation 36). An exo-to-endo ratio of 8 to 1 was obtained in this case. 

Similarly, the oxazoHdine (it,S)-147, obtained as a mixture of epimers at C2 from N,N-dibenzyl (it)-phenylalaninal and hl-benzyl (S)-valinol, reacted with Grignard reagents to form in situ the iminium ion 148, from which the diamino alcohols 149 were produced as a single diastereomer [71 ] (Scheme 23). On the other hand, when the oxazoHdine derived from the (S)-aldehyde was used, the diamino alcohol was obtained as a 70 30 mixture of diastereomers. Alhough the preparation of the primary 1,2-diamines was not explored in that paper, compoimds 149 would be the precursors of the syn 1,2-diamine... 

Arenesulfinate esters are usually prepared from an arenesulfinyl chloride and an alcohol in ether and pyridine. The arenesulfinyl chloride is usually prepared from the sodium arenesulfinate which is made by reduction of the arenesulfonyl chloride, preferably by aqueous sodium sulfite. After the crystalline sulfinate epimer has been removed by filtration, the equilibrium between the epimers remaining in the mother liquor may be reestablished by the addition of hydrogen chloride as shown by Herbrandson and Cusano . In this way the yield of the least soluble diastereomer may be increased beyond that which exists in the original reaction mixture (Scheme 1). Solladie prepared sulfinate ester 19 in 90% yield using this technique and published the details of his procedure. Estep and Tavares also published a convenient recipe for this method, although their yields were somewhat lower than Solladie s. 

Although menthyl esters, especially 19, are most often used to prepare sulfoxides, esters derived from optically active alcohols other than menthol have been prepared . Ridley and Smal prepared arenesulfmic esters of 1,2 5,6-di-O-cyclohexylidene-a-D-glucofuranose. Unfortunately, these diastereomers were oils, except for the mesityl derivative, with the major epimer having configuration R at sulfur and so they offered no advantage over the menthyl esters. Separation of the epimers by chromatography failed. 

In the particular case studied in this paper, it is not worth carrying out the reaction under hydrogen transfer conditions to increase the amount of axial epimer, as up to 65% of the thermodynamically unfavoured alcohol can be obtained over Cu/Si02 at 60°C and 1 atm of H2 (5). However, this work shows that the use of secondary alcohols as donors is possible under very mild conditions over the same catalyst. This can be useful both for safety reasons and for operating under mild experimental conditions in order to convert sensitive molecules (such as the ones used in the synthesis of speciality chemicals that can not withstand gas phase conditions). 

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