Enantiomeric and Diastereomeric Excesses

We have seen that a mixture of two enantiomers can exist in either an enantiopure (one single enantiomer present) or enriched form (two enantiomers present, but with one of them in excess over the other). The same is also true for diastereomers. In order to characterize such mixtures quantitatively, we will use the important terms of enantiomeric and diastereomeric excess, (ee) and (de) respectively. 

Diastereomeric ion pairs relevant to different types of chirality. 

The diastereomeric excess (de) of two diastereomers a and b is defined by the formula (de) = [a] — [b] / [a] + [b], where [a] [b]. Note that the diastereomeric excess tells us nothing about the enantiomeric purity of the diastereomers a and b. It is sometimes seen in the literamre that (ee) and (de) are considered as being equivalent, in particular when the ee) is determined by NMR with the use of a chiral shift reagent. This only makes sense if the ee) of the shift reagent itself is equal to one. 

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For this reaction, CALB catalyzes the amidation between a racemic P-hydroxyester and racemic amines, leading to the corresponding amide with very high enantiomeric and diastereomeric excesses. Besides, the remaining ester and amine are recovered from the reaction media, also showing good enantiomeric excesses. By this method, three enantioenriched interesting compounds are obtained from an easy one-step reaction. 

In this reactor the product could be synthesized with a space-time yield of 64 g d with an excellent enantiomeric and diastereomeric excess ee and de >99%). The biocatalyst consumption could be decreased 30-fold to 15 gproduct gwcw by using the membrane reactor as compared with a batch reactor. The corresponding (2S,5S)-hexanediol can also be obtained via biocatalysis [20]. 

As reported (J. Org. Chem. 68 6197,2003) by Yoshjii Takemoto of Kyoto University, a-amino acids can be prepared in high enantiomeric and diastereomeric excess by Ir-mediated two-carbon homologation of allylic phosphates such as 9 with the protected glycine 10. Either diastereomer can be made dominant by varying the reaction conditions. 

The oxazaborolidine-catalyzed reduction of 1,2-diketones (Equation (258)),1116-1120 1,2-keto-imines (Equation (259)),1121-1123 and 1,2-diimines (Equation (260))1124 provided optically active 1,2-diols, amino alcohols, and 1,2-diamines with both high enantiomeric and diastereomeric excess. The method can be also effective for (3- and y-analogs. 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

Besides the widely investigated proUne catalysis, other pyrrolidine derivatives have been considered in multicomponent Mannich reaction, as depicted in Scheme 2.4. In these works, the effects of either a carboxylic 17 or ester 18 moiety in position 5 on the pyrrolidine ring have been examined, achieving the desired class of products 19 with comparable enantiomeric and diastereomeric excesses (up to 98% ee, dr up to 94 6) [21]. 

The same cyclocarboUthiation reaction, using the corresponding A,A-diisopropylcarba-mate 60 and applying a five-fold excess of the chiral base, has been reported by Nakai and coworkers . Starting with the racemic 4-TBSO-hexenyl carbamate rac-61, a diastereomer resolution takes place The 1,3-cw-compound 62a remains stable until trapped by protonation (40% of 63, d.r. = 95 5), but from 62b the enantiomerically and diastereomerically pure bicyclo[3.1.0]hexane 64 (38%, > 95% ee) results (equation 14) . 

As depicted in Scheme 1.1.2, the silyl ketones (S)-ll of high enantiomeric purity were converted into the Z-configured silyl enol ethers (S) -12, which were used in the aminomethylation step by treatment with dibenzyl(methoxymethyl)amine in the presence of a Lewis acid. The silylated Mannich bases S,R)-13 were obtained in excellent yields and diastereomeric excesses (de = 92-96%). Finally,... 

The methyl group was introduced by a two-step procedure. Thus, the hydrazone Michael adducts 52 were converted into the enol pivaloates 53 in excellent yields and diastereomeric excesses de > 96%) by treatment with pivaloyl chloride and triethylamine. After treatment with lithium dimethylcuprate the chiral auxiliary was removed by addition of 6n HCl in order to obtain the 5-substituted 2-methylcyclopentene carboxylate 54 in good yields and with excellent stereoselectivity (de, ee > 96%). Finally, the asymmetric synthesis of dehydroiridodiol (55, R = Me, = H) and its analogues was accomplished by reduction of 54 with lithium aluminum hydride or L-selectride leading to the desired products in excellent yields, diastereo- and enantiomeric excesses (de, ee > 96%). 

Dess-Martin periodinane has a very low tendency to induce ot-epimer-ization of sensitive carbonyl compounds, being particularly useful in the obtention of epimerization-sensitive aldehydes and ketones without erosion of the enantiomeric or diastereomeric excess.71 Thus, in a detailed study aimed at finding the ideal oxidant for the obtention of racemization-prone TV-protected a-aminoaldehydes with a maximum of enantiomeric excess, Dess-Martin periodinane in wet CH2CI2 at room temperature was found to be the oxidant of choice. 

When there is a KR of the racemic mixture, it can be evaluated by measuring ee jjj = eej (ee j = enantiomeric excess of the recovered starting material) and by calculating the conversion C as a function of the enantiomeric excess and diastereomeric excess of the products. Then, from C and ee, one can get the... 

A related situation is found in the case of P-substituted cycloketones here, the electronic difference between the two a-carbons is almost insignificant, resulting in unselective migration upon chemical oxidation. BVMOs have a particularly different behavior, as they can influence the stereo- and/or regioselectivity of the biooxidation. In the latter case, the distribution of proximal and distal lactones is affected by directing the oxygen insertion process either into the bond close or remote to the position of the P-substituent. Consequently, a regioisomeric excess (re) can be defined for this biotransformation, similar to enantiomeric excess or diastereomeric excess values [143]. 

When dealing with reactions leading to stereoisomeric products we have the additional complication that descriptors such as enantiomeric (diastereomeric) excess and enantiomeric (diastereomeric) ratio are used to describe product purities. The evaluation of RME for a specific stereoisomer, say the R enantiomer, is exactly as above using the connecting relationships for the fraction of each product shown below. 

The diastereomeric excess (de) and enantiomeric excess (ee) were determined by first converting the methyl ester to the diastereomeric acetal by acid-catalysed reaction with (2R,3 )-2,3-butanediol. The acetals were then analysed on a capillary GC HP5 column (30 m X 0.32 mm x 0.25 pm) injector 250 °C 320 °C column 130 °C isothermal. The de was calculated to be 82 % and the ee >95 %. ... 

The same group also demonstrated an efficient, two-step asymmetric synthesis of (S)-2-phenylpiperidine as an extension of the N-heterocycUzation of primary amines with diols the results are illustrated in Scheme 5.25. First, the reaction of enantiomerically pure (R)-l-phenylethylamine and 1-phenyl-1,5-pentanediol was conducted to produce a diastereomeric mixture of the corresponding N-(l-phenyl-ethyl)-2-phenylpiperidines 32 and 33 with 92% diastereomeric excess (de). Hydrogenation of this diastereomeric mixture of 32 and 33 with Pd/C catalyst then gave (S)-2-phenylpiperidine in 96% yield (78% ee). 

The reaction has been applied to many systems an impressive example is the enantiomeric differentiation and kinetic resolution of a-pinene 199 (Tab. 14.15) [135]. The Rh2(S-DOSP)4-catalyzed reaction with (-t)-a-pinene is the matched reaction, in which 200 is formed in 93% yield and with 96% diastereomeric excess. The corresponding re-... 

Unsymmetrical 3,6-dialkoxy-2,5-dihydropyrazines (e.g., 3 and 4), derived from L-valine and either glycine11 or alanine12, respectively, have been more extensively studied. These reagents are commercially available in both enantiomeric forms6. In general, considering diastereomeric excess, alkylation yield and hydrolysis, the best results are obtained with these unsymmetrical derivatives. 

An alternative access was achieved by alkylation of the a-diphenylphosphino acetaldehyde SAMP hydrazone 95, yielding the hydrazone products 96 in good yields (60-63%) and good diastereomeric excesses (die = 68-71%) as EjZ mixtures, from which the major diastereomer was separated and purified by preparative HPLC. Ozonolysis and in-situ reduction with the borane-dimethyl sulfide complex of the aldehydes generated gave the air-stable borane-protected 2-diphenylphosphino alcohols 97 in good yields (67-83%). Reaction with DABCO afforded the unprotected 2-phosphino alcohols 98 in very good yields (85-91%) and excellent enantiomeric excesses (ee > 96%) (Scheme 1.1.27). 

The mixture of the crude product hydrazone 138 and the excess of hydrazone 129 was used directly in an acidic acetalization reaction utilizing aqueous 3n HCl in a biphasic system and gave a diastereomeric mixture of sordidin (126) and 7-epi-sordidin (7-epi-126) in 84% yield over two steps in a 1.5 1 ratio. Gratifyingly, we succeeded in separating the desired sordidin epimers by preparative gas chromatography. As a result, both could be obtained in diasteromerically pure form (sordidin de > 99% 7-epi-sordidin de > 97%) and with a high enantiomeric excess for each epimer (ee > 98%). 

Intramolecular cycloaddilion of kctcnc iminium salts possessing a chiral pyrrolidine auxiliary group gives bicyclic cyclobutanone 7 with good to excellent enantioselectivity. The enantiomeric enrichment was determined by conversion to the diastereomeric acetals 8 with (2R, >R)-bu-tane-2,3-diol and determination of the diastereomeric excesses.16... 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

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