Catalytic Enantioselective Synthesis

The saga of efficient enantioselective catalysis by the amino acid proline continues. Nearly simultaneously, Dave MacMillan of Caltech and Yujiro Hayashi of the Tokyo University of Science reported (J. Am. Chem. Soc. 2003, 124, 10808, DOI: 10.1021/ja037096s; Tetrahedron Lett. 2003, 44, 8293, DOI: 10.1016/j.tetlet.2003.09.057) that exposure of an aldehyde 1 or ketone 4 to nitrosobenzene and catalytic proline gives the oxamination products 2 and 5 in excellent yield and ee. Reduction of 2 is reported to give the terminal diol 3 in 98% ee. The N-O bond can also be reduced with CuSO₄. The importance of prompt submission is underlined by these two publications - the MacMillan paper was submitted in July, and the Hayashi paper in August.

Many methods have been developed for asymmetric allylation. One of the best is the procedure reported by Masahisa Nakada of Waseda University (J. Am. Chem. Soc. 2003, 125, 1140. DOI: 10.1021/ja021243p) . This uses the inexpensive allyl or methallyl chlorides directly. The reduction of the chloride with Mn metal is catalyzed by CrCl₂. When the addition is carried out in the presence of 10 mol % of the enantiomerically-pure ligand 7, the product is formed in high yield and ee.

One of the severest challenges of asymmetric synthesis is the direct enantioselective construction of quaternary stereogenic centers. Brian Pagenkopf of the University of Texas has reported (Chem. Communications 2003, 2592. DOI: 10.1039/b308204k) that alkynyl aluminum reagents will open a trisubstituted epoxide such as 10 at the more substituted center, with inversion of absolute configuration. As the epoxide 10 is available in high ee from 9 by the method of Yian Shi of Colorado State (J. Am. Chem. Soc. 1997, 119, 11224. DOI: 10.1021/ja972272g) , this opens a direct route to quaternary cyclic stereogenic centers.