Dynamic kinetic resolution stereoselection

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

Interestingly, for the transformation of both the racemic 1-hydroxyalkanephosphonates 41 and 2-hydroxyalkanephosphonates 43 into almost enantiopure acetyl derivatives 42 and 44, respectively, a dynamic kinetic resolution procedure was applied. Pamies and BackvalP used the enzymatic kinetic resolution in combination with a ruthenium-catalysed alcohol racemization and obtained the appropriate O-acetyl derivatives in high yields and with almost full stereoselectivity (Equation 25, Table 5). It should be mentioned that lowering... 

The stereoselective hydrogenation of a-substituted / -keto carboxylates and phosphonates via dynamic kinetic resolution catalyzed by a BINAP-Ru com-... 

If kepi, k-epi are much larger than the rates k, ki of substitution, the enantiomeric ratio Hepi-1 is similar to kxjk (path C, dynamic kinetic resolution . Both mechanisms are performing when the rates of the two steps are similar. Since rates and equilibrium are temperature-dependent, enhancement of stereoselectivities can be achieved by sophisticated protocols (see Section m.E). The equilibrium 6/epi-6 is determined by the difference of free energy A AG. This effective energy difference is enlarged if it can be coupled with a second order transformation such as the selective crystallization of one diastere-omer dynamic thermodynamic resolution ). In fact, this applies to the first successful (—)-sparteine-mediated deprotonation (Section FV.C.l). 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

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. 

These results, obtained with chiral substrates, agree with the general sense of enantioselective hydrogenation of prochiral 3-oxo carboxylic esters. Obviously, the chirality of the BINAP ligand controls the facial selectivity at the carbonyl function, whereas cyclic constraints determine the relative reactivities of the enantiomeric substrates. Sterically restricted transition states that lead to the major stereoisomers are shown in Scheme 66. Overall, one of four possible diastereomeric transition states is selected to afford high stereoselectivity by dynamic kinetic resolution that involves in situ racemization of the substrates. 

Highly stereoselective hydrogenation of racemic a-substituted P-keto esters via dynamic kinetic resolution [14,17] has been reported. Hydrogenation of a racemic a-amidomethyl substrate with the (-)-DTBM-SEGPHOS/Ru catalyst resulted in the 2S,3R alcohol in 99.4% ee (syn anti=99.3 0.7) (Scheme 22) [36]. The product was a key compound for an industrial synthesis of carbapenem antibi-... 

The stereoselective hydrogenation of a-monosubstituted (3-keto carboxylates and phosphonates through dynamic kinetic resolution has been applied to the synthesis of a wide variety of useful bioactive compounds as well as some chiral diphosphines (Figure 1.16) [lc,20,162b,c,179,243,246,250,252], The stereogenic center determined by the BINAP-Ru... 

Notz W, Tanaka F, Watanabe S, Chaudari NS, Turner JM, Thayumanavan R, Barbas CF 3rd (2003) The direct organocatalytic asymmetric mannich reaction unmodified aldehydes as nucleophiles. J Org Chem 68 9624-9634 Noyori R (2002) Asymmetric catalysis science and opportunities (Nobel lecture). Angew Chem Int Ed Engl 41 2008-2022 Noyori R, Tokunaga M, Kitamura M (1995) Stereoselective organic synthesis via dynamic kinetic resolution. Bull Chem Soc Jpn 68 36-55 Ohkuma T, Kitamura M, Noyori R (2000) Asymmetric hydrogenation. In Ojima I (ed) Catalytic asymmetric synthesis, 2nd edn. Wiley-VCH, New York, p 1-110... 

The enzymes of the nucleic acid metabolism are used for several industrial processes. Related to the nucleobase metabolism is the breakdown of hydantoins. The application of these enzymes on a large scale has recently been reviewed [85]. The first step in the breakdown of hydantoins is the hydrolysis of the imide bond. Most of the hydantoinases that catalyse this step are D-selective and they accept many non-natural substrates [78, 86]. The removal of the carbamoyl group can also be catalysed by an enzyme a carbamoylase. The D-selective carbamoylases show wide substrate specificity [85] and their stereoselectivity helps improving the overall enantioselectivity of the process [34, 78, 85]. Genetic modifications have made them industrially applicable [87]. Fortunately hydantoins racemise readily at pH >8 and additionally several racemases are known that can catalyze this process [85, 88]. This means that the hydrolysis of hydantoins is always a dynamic kinetic resolution with yields of up to 100% (Scheme 6.25). Since most hydantoinases are D-selective the industrial application has so far concentrated on D-amino acids. Since 1995 Kaneka Corporation has produced 2000 tons/year of D-p-hydroxyphenylglycine with a D-hydantoinase, a d-carbamoylase [87] and a base-catalysed racemisation [85, 89]. 

A synthetic entry to enantiopure cis- and frans-3,5-disubstituted piperidines was reported. The key steps are a cyclocondensation, which involves a dynamic kinetic resolution, and a stereoselective alkylation of the resulting bicyclic 6-lactam <03OL3139>. 

A dynamic kinetic resolution was utilized for the highly stereoselective Gabriel synthesis of -amino acids by K. Nunami and co-workers. The substrate, f-butyl-(4S)-1-methyl-3-2-(bromoalkanoyl)-2-oxoimidazolidine-4-carboxylate, smoothly reacted with potassium phthalimide at room temperature to give only one diastereomer in good yield. The removal of the chiral auxiliary afforded an A/-phthaloyl-L- -amino acid. 

Kubo, A., Kubota, H., Takahashi, M., Nunami, K.-i. Dynamic kinetic resolution utilizing 2-oxoimidazolidine-4-carboxylate as a chiral auxiliary stereoselective synthesis of a-amino acids by Gabriel reaction. Tetrahedron Lett. 1996, 37, 4957-4960. 

Makino, K., Goto, T., Hiroki, Y., Hamada, Y. Stereoselective synthesis of anti-P-hydroxy-a-amino acids through dynamic kinetic resolution. Angew. Chem., Int. Ed. Engl. 2004,43, 882-884. 

Kitamura, M., Tokunaga, M., Noyori, R. Quantitative expression of dynamic kinetic resolution of chirally labile enantiomers stereoselective hydrogenation of 2-substituted 3-oxo carboxylic esters catalyzed by BINAP-ruthenium(ll) complexes. J. Am. Chem. Soc. 1993,115, 144-152. 

Reaction of racemic aldehyde 245 with chiral 246 resulted in formation of the lactam 247 with 9 1 stereoselectivity in 78% yield. A dynamic kinetic resolution with epimerization of the labile stereocenter in 245 was proposed (Scheme 73) <05CC1327>. 

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