Professor Franklin Davis Research Interests

Asymmetric Synthesis using Sulfur–Nitrogen Reagents

With the realization that biological activity often critically depends on molecular shape and absolute stereochemistry, the synthesis of enantiomerically pure compounds and the elucidation of the underlying principles of molecular recognition have emerged as increasingly important objectives.   The focus of our research programs at Temple is the development of new reagents and methodologies for the asymmetric synthesis of biologically and pharmacologically active amine derivatives (amino acids, amino phosphonates, and alkaloids).  

Asymmetric Synthesis of Bioactive Amines .   Our studies at Temple have demonstrated that sulfinimines ( 1 N -sulfinyl imines) offer a general solution to the problem of addition of organometallic reagents to imines because the N -sulfinyl group activates the C=N bond for addition, is highly stereodirecting and easily removed in the sulfinamide 2 without epimerization of the amine product 3 . 1   The most direct and reliable method for the asymmetric synthesis of diverse amines is the addition of   an organometallic reagent to an enantiopure sulfinimines.   In this regard sulfinimines have been utilized in the asymmetric synthesis of amines; a - and b -amino acids; a - and b -amino phosphonates; nitrogen heterocycles including aziridine 2-carboxylated and 2-phosphonates; isoquinolines; 2 H -azirine carboxylates and phosphonates; pyrrolidines and piperidines.

Currently efforts are aimed at the design and synthesis of a series of sulfinimine-derived polyfunctionalized chiral building blocks for the synthesis of polysubstituted amines.   We require these building blocks to be easily prepared in both enantiomerically pure forms and provide efficient access to classes of amines with a minimum of chemical manipulation.   For example, d -amino b -ketoesters provide access to enantiopure, densely substituted pyrrolidine 2 and piperidine alkaloids. 3   The regio- and stereoselective ring-opening reactions of aziridine 2-carboxylates 4 and phosphonates 5 afford novel a - and b -amino acids and a - and b -amino phosphonates, respectively.   2 H -Azirine 2-phosphonates are a new class of chiral iminodienophiles for the asymmetric construction of bicyclic aziridine phosphonates and quaternary piperidine phosphonates. 6   The difficult to prepared b -amino carbonyl moiety is now readily available from our recently introduced N -sulfinyl b -amino Weinreb amides. 7    b -Amino ketones have recently been employed in the asymmetric synthesis of the toxic frog indolizidine alkaloids (-)-209B 8 and (-)-223A. 9

References

1.            For a review on the chemistry of sulfinimines see Zhou, P.; Chen, B.-C.; Davis,   F. A., "Recent advances in asymmetric reaction using sulfinimines ( N -sulfinyl imines)," Tetrahedron 2004 , 60 , 8003.

3.            (a)   Davis, F. A.; Zhang, Y.; Anilkumar, G., "Asymmetric Synthesis of the Quinolizidine Alkaloid (-)-Epimyrtine with Intramolecular Mannich Cyclization and N -Sulfinyl d -Amino b -Ketoesters," J. Org. Chem . 2003 , 68 , 8061.   (b) Davis, F. A.; Rao, A.; Carroll, P. J., "Asymmetric Synthesis of Functionalized trans -2,6-Disubstituted Piperidines using N -Sulfinyl d -Amino b -Ketoesters," Org. Lett . 2003 , 5 , 3855.

2.           (a)   Davis, F. A.; Yang, B.; Deng, J., "Asymmetric   Synthesis of cis -5- tert -Butylproline using Metal Carbenoid NH Insertion, J. Org. Chem . 2003 , 68 , 5147.   (b) (i)   Davis, F. A.; Deng, J., "Asymmetric synthesis of (+)-preussin from N -sulfinyl d -amino b -ketoesters," Tetrahedron 2004 , 60 , 5111.

4.            McCoull, W.; Davis, F. A., "Recent Synthetic Applications of Chiral Aziridines," Synthesis 2000 , 1347.

5.            Davis, F. A.; Ramachandar, T.; Wu, Y., "Improved Asymmetric   Synthesis of Aziridine 2-Phosphonates using ( S )-(+)-2,4,6-Trimethylphenylsulfinimide," J. Org. Chem . 2003 , 68 , 6894.

6.            Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.; McCoull, W., "2 H -Azirine 3-Phosphonates: A New Class of Chiral Iminodienophiles. Asymmetric Synthesis of Quaternary Piperidine Phosphonates," Org, Lett . 2002 , 4 , 655.

7.            Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.; Bowen, K.; Lee, S. H.; Eardley, J. H., "Asymmetric Synthesis of b -Amino Carbonyl Compounds with N -Sulfinyl b -Amino Weinreb Amides," J. Org. Chem . 2005 , 70 , 2184.

8.           Davis, F. A.; Yang, B., "Direct Asymmetric Synthesis of b -Amino Ketones from Sulfinimines ( N -Sulfinylimines). Synthesis of (-)-Indolizidine 209B," Org. Lett . 2003, 5, 5011.  

9.            Davis, F. A.; Yang, B., "Asymmetric Synthesis of a -Substituted b -Amino Ketones from Sulfinimines ( N -Sulfinyl Imines).   Synthesis of the Indolizidine Alkaloid (-)-223A," J. Am. Chem. Soc . 2005 , 127 , 8398.

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