The First Supported N-Pyridinyl Proline-derived Chiral Catalyst for the Kinetic Resolution of Racemic Alcohols

Abstract

A family of polymer-supported chiral acylation catalysts derived from N-4′-pyridinyl-α-methyl-proline has been synthesised and screened in the kinetic resolution of racemic alcohol 1. The best supported catalyst 4 behaves in most cases as its solution phase analog 13 in the enantioselective acylation of a range of alcohols and can be recycled without loss of activity or selectivity.

asymmetric catalysis - kinetic resolution - alcohols - supported catalysts - enantioselective acylations

References

Reviews:

1a Shuttleworth SJ. Allin SM. Sharma PK. Synthesis  1997,  1217 

1b Fodor K. Kolmschot SGA. Sheldon RA. Enantiomer  1999,  4:  497 

1c Bein T. Curr. Opin. Solid State Mater. Sci.  1999,  4:  85 

1d Shuttleworth SJ. Allin SM. Wilson RD. Nasturica D. Synthesis  2000,  1035 

Reviews:

2a Spivey AC. Maddaford A. Redgrave AJ. Org. Prep. Proc. Int.  2000,  32:  333 

2b Long YO. Paquette LA. Chemtracts  2000,  13:  1 

Reviews:

3a Höfle G. Steglich W. Vorbrüggen H. Angew. Chem., Int. Ed. Engl.  1978,  17:  569 

3b Scriven EFV. Chem. Soc. Rev.  1983,  12:  129 

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4b Tao B. Ruble JC. Hoic DA. Fu GC. J. Am. Chem. Soc.  1999,  121:  5091 

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6 Spivey AC. Fekner T. Spey SE. J. Org. Chem.  2000,  65:  3154 

7

Priem, G.; Pelotier, B.; Macdonald, S. J. F.; Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003, in press.

8 Kagan HB. Fiaud JC. Top. Stereochem.  1988,  18:  249 

9 For the only other example of chiral polymer-supported catalyst for the kinetic resolution of alcohols, see: Clapham B. Cho C.-W. Janda KD. J. Org. Chem.  2001,  66:  868 

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12

General Procedure for the Coupling of Acid 2 with Aminoresins: To a solution of acid 2 (5 equiv) in DMF (7 mL/mmol) was added HATU (4.9 equiv). The mixture was warmed to 65 °C and stirred until all the reagents had dissolved. Diisopropylethylamine (10 equiv) was added, followed by the aminoresin (1 equiv) and the resulting suspension was stirred at that temperature overnight. The resin was then filtered into an Alltech tube, washed thoroughly with DMF (3¥) and CH₂Cl₂ (5¥) and dried in a vacuum oven at 50 °C. A negative TNBS test indicated all amine sites had reacted.

13

Aminoresin 11: A solution of 4-(Fmoc-aminomethyl)benz-oic acid (6 equiv, 4.5 mmol, 1.68 g) in DMF (8 mL) was cooled to 0 °C and diisopropylcarbodiimide (5.3 equiv, 4.0 mmol, 660 µL) was added. After 45 min stirring at that temperature, the ice bath was removed and Wang resin (1.13 mmol/g, 1 equiv, 0.75 mmol, 664 mg) followed by 4-dimethylaminopyridine (0.1 equiv, 0.075 mmol, 10 mg) were added. After 16 h stirring at r.t., the resin was filtered and thoroughly washed with DMF (3 ¥) and CH₂Cl₂ (5 ¥). The resin was dried overnight at 50 °C in a vacuum oven (946 mg). A loading of 0.81 mmol/g was calculated from the mass increase of the polymer. The dry resin was treated with a solution of 20% piperidine in DMF (5 mL) for 20 min and filtered and washed with DMF. The operation was repeated twice and resin 11 was finally washed with CH₂Cl₂ (5 ¥) and dried in a vacuum oven at 50 °C.

14

Aminoresin 12: A solution of 8-(Fmoc-amino)octanoic acid (5 equiv, 0.36 mmol, 137 mg) in DMF (2 mL) was cooled to 0 °C and HATU (4.9 equiv, 0.35 mmol, 133 mg) was added. The solution was stirred for 1 h under nitrogen and amino-Merrifield resin (0.36 mmol/g, 1 equiv, 0.072 mmol, 200 mg) was added, followed by diisopropylethylamine (10 equiv, 0.72 mmol, 93 mg). The resulting suspension was stirred at r.t. overnight. The resin was filtered, washed with DMF (3 ¥) and CH₂Cl₂ (5 ¥) and dried in a vacuum oven at 50 °C (231 mg). A loading of 0.31 mmol/g was calculated from the mass increase of the polymer. The dry resin was treated with a solution of 20% piperidine in DMF (4 mL) for 20 min and filtered and washed with DMF. The operation was repeated twice and resin 12 was finally washed with CH₂Cl₂ (5¥) and dried in a vacuum oven at 50 °C.

15

Typical Procedure for the Kinetic Resolution of Alcohols with Supported Catalysts: The supported catalyst (5 mol%) was weighed in an Alltech tube and swollen in CH₂Cl₂ for 1 h. The solvent was then filtered and a solution of alcohol (1 equiv) in CH₂Cl₂ or CHCl₃ (10 mL/mmol) was added, followed by isobutyric anhydride (1.2 equiv). The resulting mixture was shaken at r.t.