Epimers formation

The analogous N-thiocarboxyanhydrides have now been investigated. It was hoped that these thiocarbamates would be more stable to side reactions below pH 11 (decarboxylation) and those above pH 11 (NCA hydrolysis and hydantoic acid formation). While the His-NTA and those of Gly and Ala did prove more useful than the corresponding NCA in each case, the usefulness of the NTA derivatives was found limited by epimer formation of up to 20%. "... 

Although when epimerisation of active substances occurs, it will be during synthesis and during preparation of the finished product as well. The manufacturer will set different specifications for active substance and finished product, but always as low as possible. Unless it appears that epimer formation is a major (more than 10 %) metabolic pathway in the body making an impurity specification of less than 0.4 % rather improper. 

The problem of epimer formation depends on the reaction time and reaction conditions as well as the components employed. Heyns investigated the ratio of the two possible epimers as well as the fraction of the corresponding Amadori product in the reaction of D-fructose with glycine. In this particular case, the product of kinetic control was the D-manno-configured 2-aminosugar, but the proportion of the more stable D-gluco epimer increased upon extended reaction times. The analysis of the products from the reaction of D-fructose with alanine and valine provided a similar picture [115]. 

Reactions with Imines. In some cases, BSF can react with imines to provide AA -acetal derivatives. For example, treatment of the quinone methide-substituted imine 3 (R = t-Bu, X = OAc, formed via lead(IV) oxide-mediated oxidation of Schiff base 2) provides the corresponding iV-formyl-lV-imino-lV,)V-acetal 4, with concurrent rearomatization of the quinone unit (eq 13). However, when this procedure was adapted for multigram scale, the yield of desired product was very low, with 9% epimer formation. Changing of the oxidant to DDQ allowed smoother reactions... 

According to the lUPAC definition, any diastereo-mer that has the opposite configuration at only one or two tetrahedral stereogenic centers is called an epimer, and the process of epimer formation by changing one of the asymmetric centers in the molecule is known as epimerization. The positions in two diastereomers that have different configurations are called epimeric. For example, for 2-(methylamino)-l-phenylpropan-l-ol (ephedrine), the IR,2R- and 1/ ,25-stereoisomers have the same configuration at Cl, but they are epimeric at the C2 atom (Figure 1.20). 

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

Crude tetrahydropyranyl ethers are usually a mixture of epimers due to formation of an additional asymmetric center. Consequently these derivatives are sometimes difficult to characterize. 

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... 

Ketone 13 possesses the requisite structural features for an a-chelation-controlled carbonyl addition reaction.9-11 Treatment of 13 with 3-methyl-3-butenylmagnesium bromide leads, through the intermediacy of a five-membered chelate, to the formation of intermediate 12 together with a small amount of the C-12 epimer. The degree of stereoselectivity (ca. 50 1 in favor of the desired compound 12) exhibited in this substrate-stereocontrolled addition reaction is exceptional. It is instructive to note that sequential treatment of lactone 14 with 3-methyl-3-butenylmagnesium bromide and tert-butyldimethylsilyl chloride, followed by exposure of the resultant ketone to methylmagnesium bromide, produces the C-12 epimer of intermediate 12 with the same 50 1 stereoselectivity. 

The rate-determining step in the formation of the x-lithio ethers is the formation of a carbon radical as a precursor to the anion. The intermediate radical in the tetrahydropyranyl system is expected to be nonplanar, to be capable of rapid equilibration between the quasiequatorial and quasiaxial epimers, and to exist largely or entirely in the axial configuration at — 78 °C. However, treatment of the a-phenylthio ether 4 with LDMAN at higher temperature in the presence of A, A, lV, ./V -tetramethylethylenediamine leads to the more stable equatorial epimer of the lithio ether 5 and, after addition to benzaldehyde, the axial- and equatorial-substituted products were obtained in a ratio of 13 87. 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

Imine 214 (R = H) gave a 3 1 mixture of ot/(3 chloro epimers of 215 (R = H) when a mixture of Lewis acids, TiCl4, and Ti(OiPr)4 was used. The stereoselectivity of the formation of 215 is rationalized by a chair-like transition state 217 with equatorial attack of chloride ion <1998TL7239, 2000JOC655>. 

As has been described for allyl bromide (see preceding paragraph), allyl sulfides and allyl phenyl selenide react with 6-diazopenicillanates 134 under Cu(acac)2 catalysis to give the products of ylide formation and subsequent [2,3] rearrangement 155-159). Both C-6 epimers are formed. The yields are better than with BF3 Et20 catalysis, and, in contrast to the Lewis acid case, no 6[Pg.139]

Successive treatments of chiral acylsultam 50 with -BuLi or NaHMDS and primary alkyl halides, followed by crystallization, give the pure a,a-alkylation product 52 (Scheme 2-28). Under these conditions, the formation of C-10-alkylated by-product is inevitable. It is worth mentioning, however, that product 52 can readily be separated from the C(a)-epimers by crystallization. In fact,... 

Increasing the steric hindrance of the ester was found to suppress completely the undesired lactamization. Thus, C-5-/-butoxycarbonyl cycloadducts 54a-e were reduced in near quantitative yield (NaBH3CN, 2M HC1, THF) to the A-substituted pyrrolidines 55a-e with, in some cases, the formation of the C-4 epimers 56c and 56d in low yield (Equation 6) <1996TL1711>. 

A different approach involving cyanohydrin formation from the 3-keto sugar was also explored in the D-Fru series (Scheme 17). A mixture of epimeric cyanohydrins was quantitatively formed by reaction with sodium cyanide in methanol, albeit without stereoselectivity. Chromatographic separation of (R)- and (A)-isomers was straightforward and the former epimer was selected to exemplify the two-step transformation into an OZT. Reduction of this nitrile by lithium aluminum hydride led to the corresponding aminoalcohol, which was further condensed with thiophosgene to afford the (3i )-spiro-OZT in ca. 30% overall yield. Despite its shorter pathway, the cyanohydrin route to the OZT was not exploited further, mainly because of the disappointing yields in the last two steps. 

The endo-spiro-OZT could be prepared through a reaction sequence similar to that applied for the exo-epimer, with spiro-aziridine intermediates replacing the key spiro-epoxides (Scheme 18). Cyanohydrin formation from ketones was tried under kinetic or thermodynamic conditions, and only reaction with the d-gluco derived keto sugar offered efficient stereoselectivity, while no selectivity was observed for reaction with the keto sugar obtained from protected D-fructose. The (R) -cyanohydrin was prepared in excellent yield under kinetic conditions (KCN, NaHC03, 0 °C, 10 min) a modified thermodynamic procedure was applied to produce the (S)-epimer in 85% yield (Scheme 18). 

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