Diastereoselective dynamic kinetic resolution

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

The dynamic kinetic resolution (DKR) of a-sulfur-substituted ketones such as 31 and 33 was investigated. When the MOM protected mercaptol ketone 31 was treated with the BINOL-LiAlH4 complex, a moderate diastereoselectivity of 5 1 favoring the desired anti isomer was observed. The major diastereomer had 70%... 

The sense of diastereoselectivity in the dynamic kinetic resolution of 2-substi-tuted / -keto esters depends on the structure of the keto ester. The ruthenium catalyst with atropisomeric diphosphine ligands (binap, MeO-biphep, synphos, etc.) induced syn-products in high diastereomeric and enantiomeric selectivity in the dynamic kinetic resolution of / -keto esters with an a-amido or carbamate moiety (Table 21.21) [119-121, 123, 125-127]. In contrast to the above examples of a-amido-/ -keto esters, the TsOH or HC1 salt of /l-keto esters with an a-amino unit were hydrogenated with excellent cwti-selectivity using ruthenium-atropiso-... 

The hydrogenation of a-amino ketones was also a key step for the synthesis of three more pharma actives (Fig. 37.25). Roche [95] divulged a pilot process involving the hydrogenation/dynamic kinetic resolution of a cyclic a-amino ketone using an optimized MeO-biphep ligand. The Ru-catalyzed reaction was carried out on a 9-kg scale with excellent enantio- and diastereoselectivities, and very... 

Enantioselective and Diastereoselective Enzyme-catalyzed Dynamic Kinetic Resolution of an Unsaturated Ketone... 

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

Dynamic kinetic resolution (chapter 28) of 123 with (+) -di-p -toluoyltar t aric acid equilibrated the easily enolisable chiral centre and precipitated a 90% yield of the salt of the (5) -amine having 80% ee. Reduction with NaBH4 in i-PrOH was very diastereoselective giving 99 1 syn anti-124. 

The quinine derived thiourea 12 was found to be the most efficient catalyst, in terms of conversion and enantioselectivity, in the Michael-Michael cascade process between tra y-3-(2-mercaptoaryl)-2-propenoic acid esters and /ra 5-nitroalkenes [39]. The thiochromanes, containing three new stereocenters, were obtained with excellent enantio- and diastereoselectivity irrespective of the electronic namre and substitution pattern of the aromatic ring in the nitroalkene and in the thiol. Although the first sulfa-Michael step of the process was poorly enantioselective, it was also reversible, so that the enantiomeric mixture of the adducts underwent an efficient dynamic kinetic resolution due to a retro-Michael-Michael-Michael sequence (Scheme 14.10). 

Such dynamic kinetic resolutions can also be conducted on cyclic jS-keto esters. Two examples are shown in Equations 15.59 and 15.60. Such cyclic substrates contain a stereocenter at the carbon between the two carbonyl groups. Again, a dynamic kinetic resolution of these substrates by hydrogenation occurs selectively to form predominantly a single stereoisomer. This reaction occurs to form a 99 1 ratio of diaste-reomers and 93% enantioselectivity of the major diastereomer in the presence of a ruthenium-BINAP catalyst. The positions of the keto and ester functionalities can also be reversed. Reduction of the cyclic p-keto ester in Equation 15.60 generates, in this case, the cis diastereomer with high diastereoselectivity and enantioselectivity. ... 

Fig. 22 Diastereoselective asymmetric transfer hydrogenation of cyclic substrates with dynamic kinetic resolution...

Dynamic kinetic resolution of racemic ketones can be achieved through asymmetric reduction. For example, baker s yeast reduction of (J /S)-2-(4-methoxyphenyl)-l,5-benzothiazepin-3,4(2H,5H)-dione gave only one out of four possible isomers as shown in Fig. 10.42(a).Only (S)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded diastereoselectively to give the enantiomericaUypure (2S.3S)-alcohol. The resulting product was used for the synthesis of (2S,3S)-diltiazem, a coronary vasodilator. 

The synthesis of -protected optically active a-amino esters from racemic a-halo esters via dynamic kinetic resolution has been described.The influence of the structure of the nucleophile and of the substrate on the diastereoselectivity was studied. 

Another example of this category is the first dynamic kinetic resolution of a racemic a-amino aldehyde [93]. It has been shown that the N-tosyl-protected aldehyde 149 reacts with a near equimolar amount of chiral phosphonate 27e to afford vinylogous amino acid esters (R, )-150 with excellent diastereoselectivity and chemical yield. Similarly, the N-tosyl-protected piperidine 151 was converted into the trisubstituted alkene 152 with good diastereoselectivity and in high chemical yield by reaction with chiral phosphonate 28. In several cases, it has been shown that the selectivity obtained under dynamic conditions exceeds that obtained by a traditional kinetic resolution. The HWE products obtained appear to be attractive precursors for non-proteinogenic amino acids [83] as well as various alkaloids. 

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