Bicyclic β-Lactones via Intramolecular NCAL Reactions with Cinchona Alkaloids: Effect of the C9-Substituent on Enantioselectivity and Catalyst Conformation

Abstract

C9-Acylated cinchona alkaloids promote an intramolecular, nucleophile-catalyzed aldol-lactonization (NCAL) reaction leading to optically active bicyclic β-lactones. A mechanistic scheme is proposed for this catalytic, asymmetric process. Only small variations in enantioselectivity were observed for a variety of esters, a carbamate, and a carbonate at the C9 position of quinidine. A combination of coupling constants (³ J _H8,H9) and nOe data was used to assign predominant solution conformations for these derivatives. Interestingly, a more rigid quinidine derivative gave a complete reversal in the sense of enantioselection.

Key words

asymmetric nucleophilic catalysis - aldol-lactonizations - 2-oxetanones - nuclear Overhauser effect - coupling constants

References

• 1a For a review of the chemistry of cinchona alkaloids, see: Grethe G. Uskokovic MR. In Heterocyclic Compounds, The Monoterpenoid Indole Alkaloids   Vol. 25:  Wiley; New York: 1983.  Part 4 Chap. XII. p.729 ; and references cited therein
• 1b Wynberg H. Top. Stereochem.  1986,  16:  87-130  
• 2a Wynberg H. Staring EGJ. J. Am. Chem. Soc.  1982,  104:  166 
• 2b Wynberg H. Staring EGJ. J. Chem. Soc., Chem. Commun.  1984,  1181 
• 3 Calter MA. Guo X. Liao W. Org. Lett.  2001,  3:  1499 ; and references cited therein
• 4 Taggi AE. Hafex AM. Wack H. Young B. Drury WJ. Lectka T. J. Am. Chem. Soc.  2000,  122:  7831 
• 5 Wack H. Taggi AE. Hafez AM. Drury WJ. Lectka T. J. Am. Chem. Soc.  2001,  123:  1531 
• 6 Chen Y. Tian S.-K. Deng L. J. Am. Chem. Soc.  2000,  122:  9542 ; and references cited therein
• 7 For a recent review of the Baylis-Hillman reaction including the use of cinchona alkaloids as catalysts, see: Langer P. Angew. Chem. Int. Ed.  2000,  39:  3049 
• 8 Yang HW. Romo D. Tetrahedron  1999,  51:  6401 
• 9 Tennyson RL. Romo D. J. Org. Chem.  2000,  65:  7248 
• 11 Floresca R. Kurihara M. Watt DS. Demir A. J. Org. Chem.  1993,  58:  2196 
• 12 Braje WM. Holzgrefe J. Wartchow R. Hoffmann HMR. Angew. Chem. Int. Ed.  2000,  39:  2085 
• 13a Hiratake J. Inagaki M. Yamamoto Y. Oda J. J. Chem. Soc., Perkin Trans. 1  1987,  1053 
• 13b Interestingly, the decrease in antimalarial activity of the epi-cinchona series has also been reported: Kowalik JT. Lipinska T. Oleksyn BJ. Sliwinski J. Enantiomer  1999,  4:  389 
• 13c Karle JM. Karle IL. Gerena L. Milhous WK. Antimicrob. Agents Chemother.  1992,  36:  1538 
• 14 Iwabuchi Y. Nakatani M. Yokoyama N. Hatakeyama S. J. Am. Chem. Soc.  1999,  121:  10219 
• 15a Dijkstra GDH. Kellogg RM. Wynberg H. Recl. Trav. Chim. Pays-Bas  1989,  108:  195 
• 15b Dijkstra GDH. Kellogg RM. Wynberg H. Svendsen JS. Marko I. Sharpless KB. J. Am. Chem. Soc.  1989,  111:  8069 
• 15c Dijkstra GDH. Kellogg RM. Wynberg H. J. Am. Chem. Soc.  1990,  112:  6121 
• 16 Shitangkoon A. Vigh G. J. Chromatogr., A  1996,  738:  31 
• 17a Langer P. Hoffmann HMR. Tetrahedron  1997,  53:  9145 
• 17b Blaser HU. Jalett HP. Lottenbach W. Studer M. J. Am. Chem. Soc.  2000,  122:  12675 
• 18 Stonehouse J. Adell P. Keeler J. Shaka AJ. J. Am. Chem. Soc.  1994,  116:  6037 
• 19 Waddell TG. Woods LA. Harrison W. Meyer GM. J. Tenn. Acad. Sci.  1984,  54:  48 
• 20 Pracejus H. Matje H. J. Prak. Chem.  1964,  24:  195 
• 21 Pinazzi CP. Menil A. Pleurdeau A. Bull. Soc. Chim. Fr.  1973,  4:  1345 
• 22 Iwabuchi Y. Nakatami M. Yokoyama N. Hakateyama S. J. Am. Chem. Soc.  1999,  121:  10219 

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Tennyson, R. L.; Cortez, G. S.; Romo, D. J. Am. Chem. Soc. 2001, accepted.