Enzymatic Resolution of Tropinone Derivatives

Abstract

The lipase-mediated kinetic resolution of racemic scopoline [(±)-4] and 6-hydroxytropinone [(±)-7] is reported. Whereas (±)-4 is difficult to resolve due to steric hindrance of the hydroxy function, the resolution of (±)-7 with vinyl acetate as acyl donor gave alcohol (+)-7 and the corresponding acetate (-)-9 with high enantiomeric excess. In case of the optimal result of 99% ee for (+)-7 and 80% ee for (-)-9, an E-value of 35 was calculated. The preparative lipase-catalyzed resolution of (±)-7 resulted in almost enantiopure alcohol (+)-7 with >99% ee after one recrystallization.

enantioselectivity - lipase - resolution - tropinone

References

1a Singh S. Chem. Rev.  2000,  100:  925 

1b O’Hagan D. Nat. Prod. Rep.  2000,  17:  435 

1c Hemscheidt T. Top. Curr. Chem.  2000,  209:  175 

1d Newman AH. Agoston GE. Curr. Med. Chem.  1998,  5:  305 

1e Fodor G. In Rodd’s Chemistry of Carbon Compounds   2nd ed., Vol.:  Sainsbury M. Elsevier; Amsterdam: 1997.  p.4251-4276  

1f Lounasmaa M. Tamminen T. Alkaloids  1993,  44:  1 

Some recent examples:

2a Airaksinen AJ. Lipsonen J. Ahlgren M. Vainiotalo P. Bergstrom KA. Laatikainen R. Vepsäläinen J. Tetrahedron  2003,  59:  377 

2b Lazny R. Nodzewska A. Tetrahedron Lett.  2003,  44:  2441 

2c Airaksinen AJ. Ahlgren M. Vepsäläinen J. J. Org. Chem.  2002,  67:  5019 

2d Cheng J. Moore Z. Stevens ED. Trudell ML. J. Org. Chem.  2002,  67:  5433 

2e Armstrong A. Ahmed G. Dominguez-Fernandez B. Hayter BR. Wailes JS. J. Org. Chem.  2002,  67:  8610 

2f Zhao L. Johnson KM. Zhang M. Flippen-Anderson J. Kozikowski AP. J. Med. Chem.  2000,  43:  3283 

2g Petrović G. Saičić RN. Čeković Z. Synlett  1999,  635 

2h Bremner JB. Smith RJ. Tarrant GJ. Tetrahedron Lett.  1996,  37:  97 

2i Justice DE. Malpass JR. Tetrahedron Lett.  1995,  36:  4689 

3a Node M. Nakamura S. Nakamura D. Katoh T. Nishide K. Tetrahedron Lett.  1999,  40:  5357 

3b Johnson CR. Bis SJ. J. Org. Chem.  1995,  60:  615 

3c Werner G. Arzneim.-Forsch.  1967,  17:  1467 

4 Katoh T. Kakiya K. Nakai T. Nakamura S. Nishida K. Node M. Tetrahedron: Asymmetry  2002,  13:  2351 

5 Cramer N. Laschat S. Baro A. Frey W. Synlett  2003,  in press: 

6 Zeile K. Heusner A. Chem. Ber.  1957,  90:  2809 

7a Chen C.-S. Sih CJ. Angew. Chem., Int. Ed. Engl.  1989,  28:  695 ; Angew. Chem. 1989, 101, 711

7b Baumann M. Hauer BH. Bornscheuer UT. Tetrahedron: Asymmetry  2000,  11:  4781 

8

Screening Procedure for the Lipase-catalyzed Resolution. To a solution of the racemic substrate 4 or 7 (0.1 mmol) in the respective solvent was added vinyl acetate (13 µL, 0.30 mmol), molecular sieves 4 Å (4 pellets) and the respective enzyme (2000-10000 U; units according to the manufacturer’s information, respective 2-15 mg). The reaction mixture was shaken at 40 °C for 1 h. After sedimentation of the enzyme, an aliquot of 50 µL was taken from the supernatant, filtered through a plug of cotton wool, diluted with CH₂Cl₂ (300 µL) and directly analyzed by capillary GC. This procedure was repeated in time intervals from 0.5 to 4 h depending on the reaction rate (TLC control). The reaction was stopped after 48 h.

9

Capillary GC: Bondex unβ (20 m × 2.5 mm), carrier gas H₂ (0.4 bar), temperature program: 3 min at 100 °C, then 2.5 °C min^-1 gradient to 150 °C, t_R[(+)-8] = 15.09 min.

10

A solution of (±)-4 (230 mg, 1.49 mmol), vinyl acetate (300 µL), molecular sieves 4 Å (50 pellets) and Chirazyme l-1 (120 mg) in i-Pr₂O (25 mL) was shaken at 40 °C for 2.5 h. After filtration, the filtrate was concentrated and chromatographed on Al₂O₃ with a gradient of EtOAc to MeOH to yield (-)-4 (62 mg, 27%) and (+)-8 (161 mg, 51%). [α]_D ²⁰ -9.3 (c 1.00, CHCl₃), 33% ee for (-)-4 and [α]_D ²⁰ +48.7 (c 1.00, CHCl₃), 60% ee for (+)-8.

11

Capillary GC: Bondex unβ (20 m × 2.5 mm), carrier gas H₂ (0.4 bar), temperature program: 3 min at 80 °C, then 2.5 °C min^-1 gradient to 150 °C, t_R[(+)-7] = 28.66 min, t_R[(-)-9] = 25.29 min.

12

A solution of (±)-7 (180 mg, 1.16 mmol), vinyl acetate (250 µL), molecular sieves 4 Å (50 pellets) and Chirazyme l-6 (178 mg) in acetone (17 mL) was shaken at 40 °C for 90 min. After filtration, the filtrate was concentrated, taken up in CH₂Cl₂ and chromatographed on basic Al₂O₃ with EtOAc to EtOAc/MeOH (1:1) to give (+)-7 (63 mg, 35% after recrystallization from i-Pr₂O) and (-)-9 (89 mg, 39%). [α]_D ²⁰ +24.8 (c 1.00, CHCl₃), 99% ee for (+)-7 and [α]²⁰ -13.3
(c 1.00, CHCl₃), 80% ee for (-)-9.

13 Chen C.-S. Fujimoto Y. Girdaukas G. Sih CJ. J. Am. Chem. Soc.  1982,  104:  7294