Kinetic resolutions: Evaluation of a one dimensional E value calculation method using a computer and statistical software

Tetrahedron Asymmetry

Volumn 8, Issue 8, 1997, Pages 1153-1156

  Zmijewski, Milton J ^a   Sullivan, Gary ^a   Persichetti, Rose ^b   Lalonde, Jim ^b  

^a ELI LILLY AND COMPANY   (United States)

^b Altus Pharmaceuticals Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANALYTICAL ERROR; ARTICLE; COMPUTER ANALYSIS; COMPUTER PROGRAM; DRUG SYNTHESIS; ENANTIOMER; INFORMATION PROCESSING; METHODOLOGY; PRIORITY JOURNAL; STATISTICS; THEORY;

EID: 0031001327     PISSN: 09574166     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0957-4166(97)00112-2     Document Type: Article

References (11)

1. s)]]. E is the enantiomeric ratio; c is the conversion and ee is the enantiomeric excess of the substrate (S) or product (P).
2. p))].
3. Rakels, J. L. L.; Romein, B.; Straathof, A. J. J.; Heijnen, J. J. Biotech. Bioeng. 1994, 43, 411.
4. Fourneron, J. D.; Combemorel, A.; Buc, J.; Pieroni, G. Tetrahedron Lett. 1992, 33, 2469.
5. Lu, Y.; Zhao, X.; Chen, Z. N. Tetrahedron Asymm. 1995, 6, 1093.
6. Draper, N. R.; Smith, H. Applied Regression Analysis Wiley, New York, 1981.
7. JMP® Statistics and Graphics Guide Version 3.1, SAS Institute, Inc., 1995. For this application, equation (1) is entered as the 'formula' for one of the columns of the spread sheet. This becomes the F(x) column. 'Time' and the '% substrate remaining' are then entered into separate data columns. The non-linear curve fitting application is selected, the F(x) column is entered into the 'X' field and the '% substrate remaining' is entered into the 'Y' field. The 'go' button is selected and the iterative process begins. The method is little more complicated then graphing data in a simple graphing program.
8. Zmijewski, M. J.; Briggs, B. unpublished data.
9. Methyl bromopropionate (0.736g, 4.4 mmol) in 50 ml of 20 mM pH 5 phosphate buffer cooled to 5°C. Candida rugosa esterase (20 mg/ml) was added and the pH maintained with base addition. Progress curve determined by amount of based added. Reaction was complete after 120 minutes. Chiral GC conditons: Cyclodex B 25 m capillary GC column; He flow 1 ml/min; initial temperature=50°C, gradient rate=5°C/min, final temp.= 130°C. Retention times for the methyl ester enantiomers were 12.6 and 13.25 min.
10. (R,S)-Sulcatol (50 mg) and vinyl acetate (100 μl) were added to 5 ml of toluene. ChiroCLEC-PC (Altus Biologics) (5.2 mg) was added to start the reaction. Progress curves were generated by following the reaction using chiral GC. Chiral GC conditions: Cyclodex B capillary GC 25 m column; He flow=1 ml/min; initial temperature=90°C, gradient=5°C/min, final temp.= 130°C. Retention times; (S)-sulcatol, 12.5 min; (R)-sulcatol, 12.32 min; (S)-sulcatol acetate, 14.43 min; (R)-sulcatol acetate, 15.12 min. The ee of the remaining starting material and product alcohol was 99% and 69.1% respectively at 59% conversion.
11. ChiroCLEC-CR (Altus Biologics) (2 mg) was added to a solution of (±)-trans-2-methyl cyclohexanol (0.2 mmol) in 1 ml of toluene containing 1 μl water. Vinyl butyrate (0.2 mmol) was added after a 1 minute stir. Progress curves at 25°C were generated using capillary GC. GC conditions: DB1701 column; He flow rate=25 cm/sec; initial temp.=60°C, gradient=10°C/min, final temp.=170°C. Retention times: alcohol, 4.6 min; ester, 8.43 min. Chiral GC was similar to above method.