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Monday, October 11, 2004
Douglass Taber
University of Delaware

Enantioselective Ring Construction: Part One of Two

As new drug entities must be usually be prepared as single enantiomers, and as many contain one or more heterocyclic or carbocyclic rings, there is an increased emphasis on the development of practical methods for the construction of enantiomerically pure cyclic systems. In this three-part series, we will cover the most important recent advances. (Part Two)

One of the most powerful strategies for asymmetric ring construction is to desymmetrize a preformed ring. Yasamusa Hamada of Chiba University in Japan has reported (J. Am. Chem. Soc. 2004, 126, 3690. ) that the inexpensive diaminophosphine oxide 2 nicely catalyzes the asymmetric alkylation of the cyclohexanone carboxylate 1 to give 3. Although no examples were given, this asymmetric alkylation would probably work as well with heterocyclic β-ketoesters.

While enantioselective transition metal catalysis continues to be important, several useful all-organic catalysts have been developed over the past few years. Tomislav Rovis of Colorado State University has reported (J. Am. Chem. Soc. 2004, 126, 8876. ) that the triazolium salt 5 catalyzes the enantioselective Stetter-type cyclization of 4 to 6. The cyclization also works well for the enantioselective construction of azacyclic, thiacyclic and carbocyclic rings.

Another example of organic catalysis was reported (J. Am. Chem. Soc. 2004, 126, 450. ) by Benjamin List of the Max Planck Institute, Mülheim. The amino acid 8 cyclizes 7 to 9 efficiently and with high enantioselectivity. This is particularly remarkable given the ease with which 9 would be expected to racemize under acidic or alkaline conditions.

D. F. Taber, Org. Chem. Highlights 2004, October 11.