Racemization partial

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

Partial but not complete loss of optical activity m S l reactions probably results from the carbocation not being completely free when it is attacked by the nucleophile Ionization of the alkyl halide gives a carbocation-hahde ion pair as depicted m Figure 8 8 The halide ion shields one side of the carbocation and the nucleophile captures the carbocation faster from the opposite side More product of inverted configuration is formed than product of retained configuration In spite of the observation that the products of S l reactions are only partially racemic the fact that these reactions are not stereospecific is more consistent with a carbocation intermediate than a concerted bimolecular mechanism... 

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

Entry 4 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs wifii complete inversion. The results cited in entry 5 serve to illustrate the importance of solvation of ion-pair intermediates in reactions of secondary substrates. The data show fiiat partial racemization occurs in aqueous dioxane but that an added nucleophile (azide ion) results in complete inversion, both in the product resulting from reaction with azide ion and in the alcohol resulting from reaction with water. The alcohol of retained configuration is attributed to an intermediate oxonium ion resulting from reaction of the ion pair with the dioxane solvent. This would react until water to give product of retained configuratioiL When azide ion is present, dioxane does not efiTectively conqiete for tiie ion-p intermediate, and all of the alcohol arises from tiie inversion mechanism. ... 

The addition reaction requires the presence of 4 equivalents of HMPA, thus partial racemization of optically active aldehydes under these basic conditions is anticipated. Unfortunately, the addition of magnesium bromide, zinc chloride or cadmium iodide reverses the regioselectivity11 ... 

The low ee values probably derive from partial racemization of the 3-(4-methylphcnylsu finyl)-l-propene prior to reaction. b Temperature 21 °C. 

Preparation of the appropriate optically active sulfmate ester is initially required for reaction with a Grignard or other organometallic reagent. If the method is to produce homochiral sulfoxides, the precursor sulfmate ester must be optically pure. An exception to this statement occurs if the reaction yields a partially racemic sulfoxide which can be recrystallized to complete optical purity. 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

C. By Oxidation.—This year s literature has been notable for attempts to study the details of certain phosphine oxidation reactions. In one such investigation nitric acid was found to oxidize phosphines, or phosphine sulphides, to phosphine oxides with inversion of configuration at phosphorus, whereas dinitrogen tetroxide, in the absence of acid, was found to oxidize the same compounds with predominant retention. The partial racemization observed with the latter reagent was probably due to the racemization of the oxides, since methylphenyl-n-propylphosphine oxide... 

On the other hand, it is found that only partial racemization occurs on alkaline hydrolysis of optical active 198 in aqueous methanol136) and no racemization takes place in the hydrolysis of 199 in dioxane/water137). Moreover, the latter reaction is only ca. 80 times faster at 29 °C than that of the analogous morpholide 200, for which a metaphosphorimidate mechanism is precluded a priori by the absence of an NH function and whose hydrolysis is likewise stereospecific,37). Clearly a free metaphosphorimidothioate of type 191 cannot be involved in this case. The experimental findings are compatible, however, with the hypothesis that the nucleophile water attacks a metaphosphorothioimidate/phenolate associate 201. The question of how free metaphosphates occur in solution is of a general nature it has also been considered in the previous Section. 

The hydrogenation of 109 over palladium on charcoal in acidic methanol produced (l/ ,7aA)-l,3-diphenyl-5,6,7,7a-tetrahydro-1 //-pyrrolo[ 1,2-r]imidazolc 110 in 61% isolated yield (Equation 14). This reaction was totally unexpected and the authors proposed a mechanism that explains this transformation <2005JOC2368>. The mechanism is shown in Scheme 13. Many of the steps are interchangeable, but the end product is the same. The partial racemization observed could occur by epimerization of the phenyl-substituted carbon adjacent to the imine produced after the cleavage of the bicyclo-adduct. 

The a-selectivity for carbon radical addition to propadiene (la) is retained on substituting chlorine or fluorine for hydrogen in radicals of the type CX3 (X=F, Cl), no matter whether the reaction is conducted in the liquid or in the gas phase (Table 11.4) [14, 49-51]. /3-Selective addition to allenes becomes progressively more important for the CC13 radical with an increase in number of methyl substituents [14, 47]. For example, treatment of optically active (P)-(+)-2,4-dimethylpenta-2,3-diene [(P)-(lc)] with BrCCl3 affords a 59 41 mixture of a- and /3-monoadducts [47]. The a-addition product consists of a 20 80 mixture of E- and Z-stereoisomers, whereas the product of /3-addition exclusively exhibits the Z-configuration. The fraction of 2,4-dimethylpenta-2,3-diene (P)-(lc) that was recovered from this reaction mixture had completely retained its optical activity. These results indicate that the a-and the /3-CCl3 addition proceed under kinetic control. If one of the addition steps were reversible, at least partial racemization would inevitably have taken place. 

The partial racemization of isolated 2-octanol suggests that the hydrolysis may proceed via ionization of optically active substrates as in the Sjjl hydrolysis in homogeneous solution. The hydrolysis via ionization may be suppressed in media with low dielectric constant like micelles (Okamoto and Kinoshita, 1972), resulting in net retention. The ineffectiveness of the stereochemical influence of the CTAB micelle may be interpreted as a consequence of the mutual repulsion of the positively charged head groups of [46] and CTAB, so there is need for molecules of solvent to be incorporated between surfactant head groups (Sukenik et al., 1975). An appreciable increase in retention was also observed in a reversed micellar system (Kinoshita and Okamoto, 1977). 

Related to the NMR use of CLSRs is the application of chiral solvating agents (CSAs), so-called because the first report of the determination of enantiomeric excess by NMR was that of a partially racemic sample of 2,2,2-trifluro-l-phenylethanol (98),... 

A two-step sequence to prepare di-O-acetyl-3-deoxy-D-arabino-l, 4-lactone from tri-O-acetyl-D-ribono-1,4-lactone has also been reported, but in a low yield of 46% because ol the difficulty of controlling the elimination of the 3-acetoxy group, since the 2,3-unsaturated lactone also undergoes further elimination.5 Furthermore, partial racemization of the enolizable 2,3-unsaturated lactone could occur during treatment with DBU.6... 

The behavior of chiral phenyl /-butyl sulfoxide 219 and a-phenyl-ethyl phenyl sulfoxide 220 is completely different in strongly acidic media and in the presence of halide ions. Two reactions were found (266) to occur in parallel. One results in the loss of optical activity, and the second leads to the decomposition of the sulfoxide. It was observed that the racemization process is not accompanied by [ 0] oxygen exchange. In the case of sulfoxide 220 the complete loss of optical activity at chiral sulfur is accompanied by partial racemization at the chiral carbon center. These results are consistent with a sulfenic acid-ion-pair mechanism formulated by Modena and co-workers (266) as follows (it is obvious that the formation of achiral sulfenic acid is responsible for racemization). 

The sample thus contains 43.8% of laevorotatory enantiomer and 100 — 43.8% = 56.2% of racemate, the latter contributing no overall optical activity. The racemate contains equal amounts of laevorotatory and dextrorotatory enantiomers, i.e. it contributes 28.1% of each isomer to the overall mixture. Therefore, we have 43.8 + 28.1 = 71.9% of laevorotatory enantiomer, and 28.1% of dextrorotatory enantiomer in the partially racemized mixture. 

Comparison of the configuration of the stannane with the prodncts of reaction reveals that primary alkyl halides that are not benzyhc or a to a carbonyl react with inversion at the lithium-bearing carbon atom. In the piperidine series, the best data are for the 3-phenylpropyl compound, which was shown to be >99 1 er. In the pyrrolidine series, the er of the analogous compound indicates 21-22% retention and 78-79% inversion of configuration. Activated alkyl halides such as benzyl bromide and teri-butyl bromoacetate afford racemic adducts. In both the pyrrolidine and piperidine series, most carbonyl electrophiles (i.e. carbon dioxide, dimethyl carbonate, methyl chloroformate, pivaloyl chloride, cyclohexanone, acetone and benzaldehyde) react with virtually complete retention of configuration at the lithium-bearing carbon atom. The only exceptions are benzophenone, which affords racemic adduct, and pivaloyl chloride, which shows some inversion. The inversion observed with pivaloyl chloride may be due to partial racemization of the ketone product during work-up. 

Electrophiles, which lead to high yields, are methyl iodide, trialkyltin- and trialkylsUyl chlorides, diphenylphosphinyl chloride, acid chlorides, aldehydes and carbon dioxide. Remarkably, though highly acidic ketones are formed on acylation, no deprotonation or racemization by excess of carbanionic species occurs. Other alkyl halides than methyl iodide react very sluggishly with low yields. Benzylic and aUylic halides lead to partial racemization, presumably due to single-electron transfer (SET) in the alkylation step. As very recently found by Papillon and Taylor, racemization of 42 can be suppressed by copper-zinc-lithium exchange before alkylation to 43 via the Knochel cuprates (equation 7) °. 

The (2R,3R,4R) diastereomer results from partial racemization of one or both of the allenylmetal intermediates. This point was confirmed by comparison to authentic material as the (S)-MPA ((S)-(2-methoxy)phenylacetic acid-Mosher s acid) derivative. The optical rotations of these compounds are small, and thus correlation by comparison of [ajp... 

In an effort to synthesize the chiral alkaloid, optically active 37 was prepared by chemical resolution, but both enantimoers were partially racemized when reacted with potassium amide in ammonia. Efforts to resolve ( )-39 failed to give the desired enantiomer. 

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