Organic Chemistry Portal
Organic Chemistry Highlights

Monday, July 30, 2007
Douglass F. Taber
University of Delaware

Enantioselective Construction of Arrays of Stereogenic Centers

A classic strategy for controlling relative stereocontrol is to imbed the stereogenic centers in a ring. Hisashi Yamamoto of the University of Chicago has developed (J. Am. Chem. Soc. 2006, 128, 16482. DOI: 10.1021/ja066726y) a silver catalyst that directs the absolute sense of the Diels-Alder cyclization of the dienophile 2. The adduct 3 was easily unraveled to the 1,4-diamine 4.

The enzyme-mediated addition of 1,3-dihydroxy acetone (6) to an aldehyde is an attractive strategy for the rapid elaboration of carbohydrates. This approach has been limited, however, by the requirement that 6 first be converted to the phosphate. Jesús Joglar and Pere Clapés of the Institute for Chemical and Environmental Research, Barcelona, have found (Org. Lett. 2006, 8, 6067. DOI: 10.1021/ol0625482) that crude recombidant fructose-6-phospate aldolase works well with 6, adding it to 5 to give 7 in high ee. The triol 7 was reduced to D-fagomine (8), N-alkyl derivatives of which are inhibitors of α-D-glucosidase.

Several years ago (J. Am. Chem. Soc. 1998, 120, 11798. DOI: 10.1021/ja981075u), Nicos A. Petasis of the University of Southern California described a borono-Mannich homologation of chiral α-hydroxy aldehydes such as 11. The limitation on this was the difficulty of preparing the α-hydroxy aldehydes. Stephen G. Pyne of the University of Wollongong has now devised (J. Org. Chem. 2006, 71, 7097. DOI: 10.1021/jo0610661) a scheme for the enantioselective homologation of a terminal alkene 9 using the Petasis procedure. The alkene was converted into the unsaturated sulfone 10 either by Ru-catalyzed metathesis or, more economically, by iodosulfonylation followed by elimination. Exposure of the unsaturated sulfone to AD-mix-β (or α) gave the crude α-hydroxy aldehyde 11, which as carried on directly via the Petasis protocol to give 14.

Viresh H. Rawal, also of the University of Chicago, has made (Angew. Chem. Int. Ed. 2006, 45, 6130. DOI: 10.1002/anie.200601638) the remarkable observation that the taddol 16, originally designed as a ligand for early transition metals, is an effective organocatalyst for the Mukaiyama aldol reaction of 17 with aldehydes. Professor Rawal has also found that the product tertiary amides can be reduced with Cp2Zr(H)Cl to the aldehydes with little or no epimerization.

A powerful strategy for the assembly of enantiomerically-pure fragements is the desymmetrization of meso precursors. Masakatsu Shibasaki of the University of Tokyo has designed (J. Am. Chem. Soc. 2006, 128, 16438. DOI: 10.1021/ja067003h) a chiral Gd catalyst for the opening of meso aziridines such as 19 to the amido nitrile 20 in high ee.

Much good work has been reported recently on the enantioselective construction of contiguous alkylated stereogenic centers. One of the most powerful approachs is the organocatalyst-mediated hetero Diels-Alder condensation developed (J. Am. Chem. Soc. 2006, 128, 8418. DOI: 10.1021/ja062707c) by Jeffrey W. Bode of the University of California, Santa Barbara. More recently, Professor Bode reported (J. Am. Chem. Soc. 2006, 128, 15088. DOI: 10.1021/ja066380r) that the analogous oxa reaction, to make cyclic ethers, also works well.

Attention has been focused by several groups on the chiral organocatalyst-mediated conjugate addition of aldehydes to unsaturated nitroalkenes. Claudio Palomo of the Universidad del País Vasco has optimized (Angew. Chem. Int. Ed. 2006, 45, 5984. DOI: 10.1002/anie.200602207) additions such as that of 15 to 24. Eric N. Jacobsen of Harvard University has used (Angew. Chem. Int. Ed. 2006, 45, 6366. DOI: 10.1002/anie.200602221) a related approach to prepare quaternary alkylated stereogenic centers in high ee.

D. F. Taber, Org. Chem. Highlights 2007, July 30.