Kinetic resolution of (±)-2,3-dihydro-3-methyl-4H-1,4-benzoxazines with (S)-naproxen

A very effective method for the preparation of the (S)-enantiomers of 2,3-dihydro-3-methyl- and 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazines (1a and 2a) was developed using (S)-(+)-naproxen acyl chloride as the chiral agent for kinetic resolution of racemates. This method enables one to obtain the (S)-enantiomers of benzoxazines 1a and 2a of high enantiomeric purity (99% ee) in nearly 50% yield, taking into account that the (R)-enantiomers are recycled after their racemisation.     

Nickel-Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin

Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug (R)-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75–92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with (R)- and (S)-1-phenylethylamines, the partially enantioenriched (R)- and (S)-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided >99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee, and has been reproduced in multiple batches.     

Synthèse énantiospécifique du (+)-(6S, 8R,E)-2,3-didéhydrononactate de méthyle

Enantiospecific Synthesis of (+)-(6S,8R,E)-Methyl 2,3-Didebydrononactate (+)-(6S,8R,E)-Methyl 2,3-didehydrononactate ( 7 ) has been synthesised from (?)-(3R)-methyl 3-hydroxy-butanoate with an enantiomeric excess ≥95%. The known stereoselective hydrogenation of 7 affords (?)-(2R,3R,6S,8R)-methyl nonactate ( 8 ) as the major isomer, a chiral synthon for the synthesis of nonactin.     

Synthesis of 1,11,11-trimethyl-3,6-diazotricyclo [6.2.1.0<Superscript>2,7</Superscript>]undeca-2,6-diene and 1,15,15-trimethyl-3,10-diazotetracyclo[10.2.1.0<Superscript>2,11</Superscript>.0<Superscript>4,9</Superscript>]pentadeca-2,4(9),5,7,10-pentaene from camphoroquinone enantiomers

Optically active camphordihydro-2,3-pyrazine and camphorquinoxaline were prepared from camphoroquinone enantiomers. It was shown that (1S,4R)-(+)-camphoroquinone was formed by oxidation of (1S,3R, 4R)-(−)-3-bromocamphor and (1R,4S)-(−)-camphoroquinone from (1R,3S, 4S)-(+)-3-bromocamphor, respectively. Camphor anhydride was a side product (6–10%) of the reaction. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 50–52, January–February, 2007.     

A simple method of synthesis of (+/-)-2,3-diarylpiperazines and a novel method of resolution of (+/-)-2,3-diphenylpiperazine

Intramolecular reductive coupling of diimines in the presence of Zn/Ti(O(i)Pr)2Cl2 gives the corresponding (+/-)-2,3-diarylpiperazines in 73-83% yields with dl/meso ratio >99%:<1%. The (+/-)-2,3-diphenylpiperazine obtained in this way was readily resolved partially using L-(+)-tartaric acid, and the enantiomeric purity was enhanced to >99% ee via preparation of hydrogen-bonded salt aggregates using oxalic acid.     

Highly Enantioselective Carbonyl–Ene Reactions of 2,3‐Diketoesters: Efficient and Atom‐Economical Process to Functionalized Chiral α‐Hydroxy‐β‐Ketoesters

Carbonyl–ene reactions of 2,3‐diketoesters catalyzed by [Cu{(S,S)‐tBu‐box}](SbF₆)₂ [box=bis(oxazoline)] generate chiral α‐functionalized α‐hydroxy‐β‐ketoesters in up to 94 % yield and 97 % ee. The 2,3‐diketoesters are conveniently accessed from the corresponding α‐diazo‐β‐ketoester, and a catalyst loading as low as 1.0 mol % can be achieved.     

Approaches to (R)- and (S)-1′-(1-aminoethyl)ferrocene-1-carboxylic acid derivatives

Lipase-catalyzed esterification of (±)-methyl 1′-(1-hydroxyethyl)ferrocene-1-carboxylate 4 afforded its (R)-acetate (−)-5 (ee = 99%) and (S)-(+)-4 (ee = 90%). Stereoretentive azidation/amination/acetylation of (R)-(−)-5 gave (R)-(+)-methyl 1′-(1-acetamidoethyl)ferrocene-1-carboxylate (R)-3 (ee = 98%). In a similar manner (S)-(+)-4 was converted into (S)-(−)-3 (ee = 84%). Both enantiomers of 3 were obtained in high chemical yields without a loss of enantiomeric purity. The title compounds can be coupled with natural amino acids and peptides on both C- and N-termini.     

Enantioselective synthesis of a key intermediate of Levofloxacin using microbial resolution

The important key intermediate in the synthesis of Levofloxacin, (S)-7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine, was prepared enantioselectively by microbial resolution. When lyophilized microorganism selected from soil was treated with the corresponding amide, the (S)-amine was obtained with high enantiomeric purity (99% ee).     

Enzymatic dissymmetrization of meso-2,3-dimethylbutane-1,4-diol and its diacetate. Synthesis of scalemic (–)-lasiol

Acylation of meso-2,3-dimethylbutane-1,4-diol with vinyl acetate in the presence of porcine pancreatic lipase (PPL) leads to the dextrorotatory monoacetate of the above diol with enatiomeric excess (ee) 58—64%. Absolute configuration of this scalemic specimen was determined by its sequential transformation to levorotatory lasiol, a metabolite of the Lasius ants. Partial hydrolysis of the corresponding meso-diacetate, mediated by PPL or by the Pseudomonas sp. lipase affords the monoacetate of opposite configuration with ee 72—86%, a formal intermediate in the synthesis of (3S,4R)-faranal. Other microbial lipases used are distinctive in low chemoselectivity.     

Enantiomerically pure 7-oxabicylo[2.2.1]hept-5-en-zyl derivatives as synthetic intermediates. Part III. Total synthesis of D- and L-ribose derivatives

Enantiomerically pure methyl 5-bromo-5-deoxy-2,3-O- isopropylidene-β-D - (D - 5b ) and -β-l-ribofuranoside (l- 5b ) have been derived from (?)-(1R,2S,4R)-2-exo-cyano-7-oxabicylo[2.2.1]hept-5-en-endo,-yl (1′S)-camphanate ( 1 ) and (+)-(1S,2R,4S)-2-exo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl(1′R)-camphanate ( 2 ), respectively, in 5 synthetic steps and 28% overall yield. Hydrolysis of D-5b and L - 5b afforded methyl 2,3-O isopropylidene-β-D -ribofuranoside (D -5a) and methyl 2,3-O-isopropylidene β-L-ribofuranoside (L-5a), respectively. The intermediate (+)-(1R,4R,5R,6R) 5-exo,6-exo-(isopropylidenedioxy)- 7 -oxabicyclo[2.2.1]heptan-2-one ((+)- 7 ) and its enantiomer(–)-7 were also obtained enantiomerically pure by resolution of (=)- 7 by the Johnson-Zeller method. In bothe approaches, the chiral auxiliaries ((–)- and (+)-camphanic acids, or (+)-(S)-N,S-dimethyl-S-phenylsulfoximide) were recovered at an early stage of the synthesis.