Epimers synthesis

The chemical syntheses of l,24(R),25-trihydroxy-vitamiQ [56142-94-0] and l,24(3),25-trihydroxy-vitamiQ D [56142-95-1] were reported (131,132) ki 1975. The chemical synthesis of 25,26-dihydroxy-vitamin [29261 -12-9] has also been described, and it has been determined that the biologically occurring epimer is 25(R),26-dihydroxy-vitamin (117,133—135). The 23,25-dihydroxy-24-oxo metabohte has been isolated (136) as well. 1 a-Hydroxycalcitroic acid (l-hydroxy-24-nor-9,10-secochola-5,7-10(19)-ttien-23-oic acid) [71204-89-2], 25-hydroxy-26,23-lactone vitamin [71203-34-6],... 

Scientists at Merck developed a cephalosporin synthesis based on the addition of azidoacetyl chloride to 1,3-thiazines (56). Although this gives the incorrect 7a -epimer (57), it could be equilibrated to a mixture of 7-amino epimers (see Section 5.10.3.3) from which the desired 7/3-isomer could be separated and further elaborated to cephalosporins (B-82MI51001). 

During the course of a mass spectrometric study of D-homo-14-hydroxy steroids, it was necessary to prepare the corresponding C-8 deuterium labeled analogs. The preparation of these uncommon steroid derivatives has been achieved by repeating the Torgov total synthesis [(257) (262)] with a deuterium-labeled bicyclic starting material (258). Both of the resulting 14-hydroxy epimers, (261) and (262), exhibited better than 90% isotopic purity. ... 

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

The issue of stereochemistry, on the other hand, is more ambiguous. A priori, an aldol condensation between compounds 3 and 4 could proceed with little or no selectivity for a particular aldol dia-stereoisomer. For the desired C-7 epimer (compound 2) to be produced preferentially, the crucial aldol condensation between compounds 3 and 4 would have to exhibit Cram-Felkin-Anh selectivity22 23 (see 3 + 4 - 2, Scheme 9). In light of observations made during the course of Kishi s lasalocid A synthesis,12 there was good reason to believe that the preferred stereochemical course for the projected aldol reaction between intermediates 3 and 4 would be consistent with a Cram-Felkin-Anh model. Thus, on the basis of the lasalocid A precedent, it was anticipated that compound 2 would emerge as the major product from an aldol coupling of intermediates 3 and 4. 

An important stereochemical issue presents itself here. A priori, an aldol condensation between intermediates 2 and 3 could result in the formation of a mixture of diastereomeric aldol adducts, epi-meric at C-7, with little or no preference for a particular stereoisomer. Cram s rule2,4 predicts the formation of aldol adduct 43. This intermediate possesses the correct absolute configuration at C-7, and it should be noted that Kishi et al. had demonstrated during the course of their monensin synthesis that a similar aldol condensation produced the desired C-7 epimer as the major product.12... 

Ueno and coworkers49 have developed a procedure for the synthesis of chiral sulfinic acids. Treatment of (R)-( + )-23 with disulfide 24 and tributylphosphine in THF gave (S)-( — )-25. Compound 25 was oxidized with potassium permanganate to the sulfone, which was then reduced to the sulfinic acid, (S)-( — )-26, by treatment with sodium borohydride. Conversion of 26 or an analog to an ester would lead to diastereomers. If these epimers could be separated, then they would offer a path to homochiral sulfoxides with stereogenic carbon and sulfur atoms. 

RCM was also used in Yamamoto s total synthesis of the marine neurotoxin gambierol (81) [62], to close the central seven-membered E ring, thereby completing the octacyclic polyether core 80 (Scheme 15). Following previously developed methodology [63], metathesis precursor 79 was produced as the major epimer, by boron trifluoride etherate-mediated intramolecular allylation of a-chloroacetoxy ether 78. Subsequent treatment of 79 with catalyst C produced the octacyclic ether 80 in 88% yield. 

This section is completed with a brief review of the synthesis and properties of this epimer (20) of the precursor of thiazole in bacteria. This pentulose is conveniently accessible by an unconventional route (Scheme 19). Methyl 2,3 4,6-di-O-isopropylidene-a-D-mannopyranoside, readily available from methyl ot-D-mannopyranoside, is converted to the ketonic glycoside by butyllithium in 91% yield, following a method first published by Klemer and Rodemeyer43 and scaled up by Horton and Weckerle.44 This was converted by means of lithium hydroxide in a water-ether mixture into 3,5-0-benzylidene-l-deoxy-D-eryf/iro-2-pen-tulose in 55% yield. Hydrolysis to the free pentulose (20) proceeded in 73% yield in aqueous acetic acid. This product was obtained as a syrup with a characteristic absorption band at 1705 cm 1 as a film. Thus, there is a fair proportion of the open-chain ketone under these conditions, as with the D-threo epimer.45... 

Scheme 26 Diastereoselective synthesis of C2-epimers of 2,3-diamino-4-hydroxybutanal and 2,3-diamino-4-hydroxybutanoic acid...

Searching for a method of synthesis of enantiopure lamivudine 1, the compound having a monothioacetal stereogenic centre, Rayner et al. investigated a lipase-catalysed hydrolysis of various racemic a-acetoxysulfides 2. They found out that the reaction was both chemoselective (only the acetate group was hydrolysed with no detectable hydrolysis of the other ester moieties) and stereoselective. As a result of the kinetic resolution, enantiomerically enriched unreacted starting compounds were obtained. However, the hydrolysis products 3 were lost due to decomposition." In this way, the product yields could not exceed 50% (Equation 1). The product 2 (R = CH2CH(OEt)2) was finally transformed into lamivudine 1 and its 4-epimer. ... 

A major problem with the sulfoxide synthesis using menthyl sulfmates is its failure to produce optically pure dialkyl sulfoxides. The prerequisite menthyl alkanesulfinates are oils which have resisted separation into the individual epimers. The menthyl phenyl methanesulfmates are an exception the R epimer is crystalline . One solution to this problem, at least for preparing methyl alkyl sulfoxides, was achieved using cholesteryl methanesulfmates (27) . Both epimers were crystalline and could be separated by fractional crystallization, although in poor yield. Treatment of the epimers with n-propyl, n-butyl, isobutyl, p-tolyl and benzyl magnesium halides yielded the respective methyl alkyl sulfoxides (28) in greater than 95% e.e. and in 32 to 53% yields. 

Griehl, C. and Merkel, S., Synthesis and separation of pprotected tripeptide epimers by RP-HPLC, Inti. J. Peptide Protein Res., 45, 217, 1995. 

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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