Diastereomers, mixtures

Conventional kinetic resolution of diastereomer mixtures by retroaldolization for preparation of enantiopure arylserines and for a synthetic intermediate of an antiparkinsonism drug (b). 

Preparative chromatographic resolution procedures have overall freed chemists from the constraint of dependency on crystallization. They are most often performed with covalent diastereomer mixtures but ionic salts can also be separated. Recently, it was found that the lipophilicity of TRISPHAT anion 8 profoundly modifies the chromatographic properties of the cations associated with it and the resulting ion pairs are usually poorly retained on polar chromatographic phases (Si02, AI2O3) [131]. Using enantiopure TRISPHAT anion. 

Thus, (1 A S Hra/7.v-chrysanthemic acid was condensed with 1,1 -binaphthol derivative using the TsCb/V-methylimidazole reagent to give the corresponding two sets of diastereomers (26) and (27). From the solution, only the (l/ )-trans-chrysanthemic acid ester (26) crystallized from the diastereomer mixtures. The ester was readily... 

While the complexation of ( )-BIPHEP-Pd 32 with (1 ,1 )-DPEN is in a nonse-lective manner even with 0.5 equiv. of (1 ,1 )-DPEN, a highly selective (9 1) complexation of one enantiomer of ( )-32 is observed by addition of 0.5 equiv of (/ )-DABN (/ )-32/(/i)-DABN is formed as the major diastereomer. With 1.0 equiv of (7 )-DABN, however, a 1 1 ratio of a diastereomeric mixture of (/f)-32/(/ )-DABN and (5)-32/(7 )-DABN is observed (Scheme 8.27). The diastereomer mixture of 32/ (7 )-DABN does not isomerize at room temparature over 3 days. But tropo-inversion of the BIPHEP moiety at 80°C after 8h leads to the favorable (/ )-32/(/f)-DABN exclusively (Scheme 8.27). This shows that the BIPHEP moiety in 32/DABN complex isomerizes at 80 C but not at room temperature. 

In a similar manner, the enantiopure BIPHEP-Pt complex-catalyzed enantiose-lective Diels-Alder and carbonyl-ene reactions are also reported by Gagne (Scheme 8.29)." Racemic BIPHEP-Pt(C03) 34 with (5)-BINOL gives a 1 1 diastereomer mixture 34/(5)-BINOL complexes. The (S)/(S) isomer can be seen in a 96 4 ratio at 92-122°C. The (R)/(5) isomer can be converted to a 95 5 ratio of the (S)/(S) major isomer in pyridine at lower temperature (40°C). On the other hand, the thermodynamically less favorable (R)/(5) isomer can be by recrystallization from CH2CI2. 

The synthetic viability of this protocol was demonstrated by the efficient synthesis of an isoindole alkaloid from the Mexican sponge Reniera. a-Cyanosi-lylamine (9) was treated with AgF, in the presence of dipolarophile 10 to furnish the requisite cycloadduct in 68%. An advanced intermediate in the synthesis of nicotine was also prepared by cycloaddition of 11 with phenylvinylsulfone giving the requisite adduct 12 in a 3 1 diastereomic mixture (Schem 3.3). 

Not much is currently known concerning diastereoselective addition of metal enolates to ketones 48,108), but selectivities are expected to be lower. In case of titanium enolates, several examples have been studied 77). The reaction shown in Equation 67 involves an ester-enolate21 and proceeds strictly in a 1,2 manner with 90% diastereoselectivity. The observation is significant because similar reactions with aldehydes are essentially stereo-random77). Also, the lithium analog of 203 affords a 1 1 mixture of diastereomers. Diastereoface-selectivity in Equation 67 is not an exception, because 203 adds to acetophenone and pinacolone to afford 85 15 and >76 24 diastereomer mixtures, respectively 77). Although stereochemical assignments have not been made in all cases, the acetophenone adduct was converted stereospecifically into the p-lactone which was decarboxylated to yield an 85 15 mixture of Z- and E-2-phenyi-2-butene 77). 

For convenience, a phase diagram of a pair of diastereomeric crystals is ordinarily studied in detail, and the mechanism of the diastereomeric resolution is interpreted in terms of the thermodynamic and physical properties of the bulk of the diastereomeric crystals.4,7-10 Such studies reveal the importance for diastereomeric resolution of the type of mixture of diastereomers in a target system. There are three types of diastereomer mixtures an eutectic mixture, a 1 1 addition compound, and a solid solution. To achieve successful resolution, it is essential that the mixture of the diastereomeric crystals of a target racemate with a resolving agent be an eutectic mixture. The classic studies are thoroughly reviewed by Collet and co-workers.4,12... 

Preparation of 2-(3,4-dichlorophenyl)tetrahydropyran-2-yl acetic acid methyl ester diastereomer mixture... 

The reactivity of achiral Ru compounds for the hydrogenation of functionalized ketones has not been extensively studied. RuCl2 P(C6H5)3 3 reduces y-keto carboxylic acid at 180 °C to the corresponding y-lactone (Eq. 2.15) [115]. Heterogeneous Ru/C catalyzes the atmospheric pressure hydrogenation of furfural in water at 25 °C [86]. Under such mild conditions, glucose is industrially converted to sorbitol (Eq. 2.16) [116]. At elevated temperature and pressure, tetramethyl-l,3-cyclobutanedione can be converted to a 98 2 diastereomer mixture of the diol (Eq. 2.17) [117]. 

Typical examples of bis-cyclization anion capture processes forming fused and spirocyclic rings, triggered by aryliodide species, are shown in Scheme 5.6.16. Thus, enamide 50 reacts with Af-SEM-indolyl stannane in the presence of Pd(0) to afford a 5 1 diastereomer mixture of 51 and 52 in 74% yield, whilst 53 reacts with 2-pyridyltri- -butyltin in the presence of Pd(0) to afford 54a as a single diastereoisomer. ... 

Some p-hydroxyamides (246) in different diastereomic mixtures were cyclized to tetrahydrofurane derivatives (247) in the presence of Ph-SeCl, and subsequently, their diastereomeric ratios could be determined by Se NMR analysis.Some arylseleninic acids (Ar-SeO2H S = 1200-1276) were optically resolved by chiral columns and their racemization studied. 

Sulfoxide-magnesium exchange on the a-chloroalkyl sulfoxide 42 was performed with ethylmagnesium bromide followed by trapping with benzaldehyde-dimethyl-aluminum chloride, to furnish 99% of the sulfoxide 43 with 99% ee. Chlorohydrins 44 were obtained in 56% yield as a 94 6 diastereomer mixture. After conversion to the epoxide 45, the latter had an ee of >98% (Scheme 3.18). 

Deprotonation of one a-methylthio ester is reported to give a 75 25 diastereomer mixture, but it is not known if the ( )- or (Z)-isomer is the major product (equation 1) ... 

Diastereomers mixtures (Figure 1) of 2-amino-3-methyl-4-pentenoic acid (2), 2-amino-2-methyl-4-pentynoic acid (21), 2-amino-3-dimethyl-4-pentenoic acid (22), 2-amino-2,3-dimethyl-4-pentenoic acid (23), 2-amino-3-methyl-4-pentynoic acid (3), 2-amino-3-dimethyl-4-pentynoic acid (31), 2-amino-2,3-dimethyl-4-pen-tynoic acid (32) were prepared according to Aidene et al.tl The regioselective reaction between a-unsaturated organozincs and A-(phenylsulfanyl)iminoesters was used as a starting step to obtain the a-aminoesters.11... 

Danishefsky has looked at chiral induction in [4 + 2] cycloadditions of aldehydes to oxygenated dienes bearing chiral auxiliaries.44 1 Optically inactive europium(III) catalysts proved effective in promoting the cycloaddition reaction but did not give favorable diastereomer mixtures (Scheme 4-XII). However, combination of the appropriate chiral diene... 

The new diphenylalanine-derived oxazolidinone, 15, is particularly effective when used as an auxiliary on radical 29. The auxiliary can be used in a propagation sequence that involves radical addition followed by trapping of the addition radical with allylstannane or allylsilanes, Eq. (21). Excellent yield and diastereoselectivity are observed if the reaction is carried out in the presence of Lewis acids such as magnesium bromide or lanthanide triflates at —78°C. The reaction promoted by magnesium bromide, for example, provides a diastereomer mixture in excess of 100 1 with a yield of 85%. Sc, Yb, Y, La, or Sm triflates provide similar results in reactions usually carried out in ether. 

The observations summarized in Table 8 have important preparative consequences. To achieve the highest possible ( )-alkene selectivity in a system that is capable of stereochemical equilibration, it is essential to provide sufficient time for oxaphosphetane equilibration below the decomposition temperature. This is best done by monitoring the diastereomer mixture using NMR methods to establish the temperature thresholds for diastereomer equilibration as well as for alkene formation from the more reactive cis-diastereomer. Once these temperatures are known, equilibration can be allowed to proceed below the temperature for (Z)-alkene formation until the optimum ratio of trans-cis oxaphosphetanes is obtained. Subsequent warming completes the optimized E-selective alkene synthesis in an equilibrating system (Table 7). 

The clue to the rationalization of these results came from theoretical calculations at the DPT level of theory. These calculations showed that the two most stable dienamine conformers were the E-s-trans-2>E and the E-s-trans-3Z, which differed in energy by 1.4kcal/mol. Assuming that these two isomers were readily interconvertible by reprotonation to the iminium ion followed by deprotonation, the experimentally observed diastereomer mixture could be explained. However, the calculations showed that the "y-amination of these two intermediates was endothermic. On the other hand, the less stable s-cis conformers were predicted to react in an exothermic fashion with diethyl azodicarboxylate via a Diels-Alder cycloaddition. The reaction of the E-s-cis-3E conformer was the more exothermic one, and it showed an activation energy lower than that of the E-s-cis-3Z conformer by 6.5 kcal/mol. Hydrolysis of this adduct would then lead to the observed "y-amination product, with (R) configuration (Scheme 2.18). 

Nozaki and co-workers reported -phospha[7]helicene 99 via palladium-catalyzed C—P bond formation (Scheme 23.39) [47], The cross-coupling of 3,3 -t>iphenanthlyl-2,2 -ylene disulfonate 97 with ethyl phenylphosphinate gave monophosphorus compound 98 as a diastereomer mixture. Reduction of 98, the subsequent palladium-catalyzed intramolecular P-arylation, and oxidation provided X -phospha[7]helicene 99 with a phosphole-oxide moiety. 

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