Dynamic kinetic asymmetric esters

Silylated amino acid esters have been prepared by a dynamic kinetic asymmetric transformation of this type. Slow addition (by syringe pump) of (R,R) DPEC maintained insertion slow relative to interconversion and afforded the silyl-substituted amino acid esters in Eq. 36 with ee values of 80, 68, and 83%. The ester 38c (R=TMS) was too base-sensitive to permit removal of the chiral diol, but transesterification of the other /J-hydroxyethyl esters 38 to the corresponding methyl esters was straightforward [22]. 

The current review is of necessity selective. Over the two year period covered, there has been impressive advances in several areas of P(V) chemistry. For example, biological aspects of quinquevalent phosphorus acids chemistry continue to increase in importance. A wide variety of natural and unnatural phosphates including inositols, lipids, some carbohydrates and their phospho-nates, phosphinates and fluorinated analogues has been synthesized. Special attention has been paid to the synthesis of phosphorus analogues of all types of amino acids and some peptides. Numerous investigations of phosphate ester hydrolysis and related reactions continue to be reported. Interest in approaches to easier detoxification of insecticides continues. A number of new and improved stereoselective synthetic procedures have been elaborated. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications. 

Scheme 7.9 NHC-catalyzed dynamic kinetic asymmetric cross-benzoin reaction of P-stereogenic a-keto esters reported by Johnson.

The stereogenic centers were then introduced by palladium-catalyzed dynamic kinetic asymmetric transformatitHi. ITierefore, 41 was coupled with lactone 42 in the presence of chiral ligand (RJt)-43 and gave 44 in 89% yield. The synthesis of 42 is shown below in Scheme 2.6. Compound 44 was subjected to an intramolecular Heck reaction followed by acidic cleavage of the ester function 45). The intramolecular Heck reaction only produced one diastereomer, because the c/s-annelated rings are favored. Scandium(lll)-mediated cyclizatitMi and reduction of the lactone with DIB ALII yielded (-)-aflatoxin Baa (46). It was acetoxylated and then pyiolyzed to give (-)-aflatoxin Bi (1) in 1.6% overall yield and nine linear steps from catechol (40). 

Among asymmetric version of barium-catalyzed aldol reactions, the direct aldol reaction of y3,y-unsaturated esters with aldehydes is promising due to the DYKAT (dynamic kinetic asymmetric transformation). Shibasaki and coworkers (147) established an optimized catalyst system for the DYKAT involving aldol/retro-aldol reaction, that a Ba(0-iPr)2/BIN0L mixture gave excellent enan-tioinduction and conversion (Scheme 32). a-Alkylidene-y3-hydroxy esters were obtained under proton-transfer conditions via DYKAT in 87-99% ee. 

Scheme 9.31 Gold(l)-catalyzed dynamic kinetic asymmetric transformation of propargyl esters according to Toste and coworkers [58].

Toste s group made several modifications of bis(HBHC)-digold complex 40 by placing differently substituted aryl groups at the binaphthyl 3,3 -positions of the diamine synthon and examined them in catalytic dynamic kinetic asymmetric transformations of propargyl esters (Scheme 16.14) [29b]. Drastic substituent effects on enantioselectivity were observed, with j -trifluoromethylphenyl-... 

Scheme 16.14 Dynamic kinetic asymmetric transformation of propargyi esters with a chiral bis(HBHC)-digold catalyst.

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

Makino, K., Hiroki, Y. and Hamada, Y. Dynamic Kinetic Resolution Catalyzed by Ir Axially Chiral Phosphine Catalyst Asymmetric S3mthesis of anti-Aromatic -Hydroxy-ot-amino Acid Esters. J. Am. Chem. Soc. 2005, 127, 5784—5785. 

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. 

Ruthenium catalysts that contain Cl-MeO-BIPHEMP have been used in the asymmetric hydrogenation of P-keto esters (99% ee)126 and the dynamic kinetic resolution of substituted P-keto esters (Scheme 12.33).121 The asymmetric hydrogenation of methyl 3,3-dimethyl-2-oxobutyrate to the corresponding a-hydroxy ester has been reported with ruthenium catalyst, RuBr2[(-)-Cl-MeO-BIPHEMP] 2 (Scheme 12.34).121... 

Rhodium and ruthenium complexes of CHIRAPHOS are also useful for the asymmetric hydrogenation of p-keto esters. Dynamic kinetic resolution of racemic 2-acylamino-3-oxobutyrates was performed by hydrogenation using ((5,5)-CHIRAPHOS)RuBr2 (eq 3). The product yields and enantiomeric excesses were dependent upon solvent, ligand, and the ratio of substrate to catalyst. Under optimum conditions a 97 3 mixture of syn and anti p-hydroxy esters was formed, which was converted to o-threonine (85% ee) and D-allothreonine (99% ee) by hydrolysis and reaction with propylene oxide. 

Scheme 7.8. Asymmetric reduction of chiral P-keto esters may be used in an asymmetric transformation of the first kind (dynamic kinetic resolution) [78],...

The first example of asymmetric synthesis of allenic esters by a samarium(ii)-mediated reduction of propargylic compounds through dynamic kinetic protonation performed in the presence of a palladium catalyst was reported by Mikami and colleagues. Various chiral proton sources were involved and furnished enantio-enriched allenic esters, as shown in Scheme 2.47. 

Liu, Shultz, et al. recently reported on an efficient synthesis of enantiomerically enriched aryl (3-hydroxy a-amino esters 183 using an asymmetric transfer hydrogenation of a-amino (3-keto esters 182 accompanied by dynamic kinetic resolution (Scheme 30.34). 

Steward KM, Gentry EC, Johnson JS. Dynamic kinetic resolution of a-keto esters via asymmetric transfer hydrogenation. J. Am. Chem. Soc. 2012 134(17) 7329-7332. 

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