Organic Chemistry Portal
Organic Chemistry Highlights

Monday, May 9, 2005
Douglass Taber
University of Delaware

Diastereoselective and Enantioselective Construction of Aza-Heterocycles

Five- and six-membered azacyclic rings are the basic building blocks of pharmaceutical synthesis. Several powerful methods for the construction of such rings that recently have been developed are highlighted here.

Continuing the theme of small molecules as catalysts for organic reactions, Eric Jacobsen of Harvard has reported (J. Am. Chem. Soc. 2004, 126, 10558. DOI: 10.1021/ja046259p) the design of a peptide thiourea that mediates enantioselective Pictet-Spengler cyclization, e.g. of 1 to 2.

Günter Helmchen of the Universität Heidelberg took advantage (Chem. Comm. 2004, 896. DOI: 10.1039/b400023d) of the substitutional flexibility of π-allyl iridium complexes to develop enantioselective cyclizations such as 3 to 4. Six-membered rings are also formed efficiently (88% ee).

In a related approach, John Wolfe of the University of Michigan has demonstrated (Angew. Chem. Int.Ed. 2004, 43, 3605. DOI: 10.1002/anie.200460060) that Heck addition of an aryl halide 5 to an amino alkene 6 can be terminated by C-N bond formation. The reaction proceeds with high diastereoselectivity, to give 7.

Azacycles can also be constructed by C-C bond construction. The enantiomerically-pure amide 8 is easily prepared by photolysis of pyridine followed by acetylation and enzymatic desymmetrization. Patrick Mariano of the University of New Mexico has shown (J. Org. Chem. 2004, 69, 7284. DOI: 10.1021/jo040226a) that the second generation Grubbs Ru catalyst converts the derived 9 into 10 with high regioselectivity.

Jeff Aubé of the University of Kansas has reported (Org. Lett. 2004, 6, 4993. DOI: 10.1021/ol047809r) a cascade strategy of C-C and C-N bond formation. Thus, Diels-Alder cyclization of 11 and 12 gives 13, which in situ undergoes azido-Schmidt ring expansion to give 14. In a complementary approach, 15 and 16 combine to give 17 and then 18.

There is a continuing interest in the diastereoselective and enantioselective hydrogenation of inexpensive pyridine derivatives. Frank Glorius of the Max-Planck-Institut, Mülheim, has coupled (Angew. Chem. Int. Ed. 2004, 43, 2850. DOI: 10.1002/anie.200453942) 2-chloropyridines such as 19 with the inexpensive chiral auxiliary 20. Hydrogenation of 21 then proceeded with high diastereocontrol, to give the reduced product 22 and recovered 20.

New catalyst systems for intramolecular alkene hydroamination have also been developed (Chem. Comm. 2004, 894, DOI: 10.1039/b401493f and Angew. Chem. Int. Ed. 2004, 43, 5542, DOI: 10.1002/anie.200460880).

D. F. Taber, Org. Chem. Highlights 2005, May 9.