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Monday, February 26, 2007
Douglass F. Taber
University of Delaware

Enantioselective Construction of Arrays of Stereogenic Centers

The controlled construction of extended arrays of stereogenic centers is one of the central challenges of organic synthesis. One of the earliest methods to become available, and still one of the most valuable, is Sharpless asymmetric epoxidation. Karl Anker Jørgensen of Aarhus University, Denmark, devised (J. Am. Chem. Soc. 2005, 127, 6964. ) ( 2006 Feb 13) an elegant alternative, the direct epoxidation of α,β-unsaturated aldehydes such as 1. Armando Córdova of Stockholm University has now shown (Tetrahedron Lett. 2006, 47, 99. ) that the simple catalyst 2 works at least as well in this application as does the more expensive Jørgensen catalyst.

Motomu Kanai and Masakatsu Shibasaki of the University of Tokyo have developed (J. Am. Chem. Soc. 2006, 128, 6312. ) an enantioselective lanthanide-catalyzed opening of prochiral aziridines such as 4 to the amido azide 5. Acyclic aziridines work equally well. They carried the inexpensive 5 on the important antiviral agent Tamiflu 6.

Construction of alkylated centers is also important. Both Professor Córdova (Chem. Commun. 2006, 1760. ) and Carlos F. Barbas, III of Scripps / La Jolla (J. Am. Chem. Soc. 2006, 128, 1040. ) have found that organocatalysts can effect smooth anti-selective Mannich condensation of imines such as 8 with aldehydes such as 7. Professor Córdova found that the simple catalyst 2 also worked well in this application.

Convergent synthesis strategies are inherently the most efficient. The key to a convergent approach is a protocol for coupling the two highly-functionalized intermediates so as to control relative and absolute configuration. Andrew J. Phillips of the University of Colorado has illustrated the coupling protocol they developed by a synthesis (J. Am. Chem. Soc. 2006, 128, 408. ) of the pyridine antibiotic 7-demethylpiericidin A1 (14). Sonagashira coupling of 10 and 11 gave 12. Ti-mediated reductive coupling then proceeded with high regio- and diastereocontrol, to give 13, which was carried on to 14.

Another approach for the convergent coupling of two fragments is to use a third fragment as a linchpin. In particular, there is a need for chiral linchpins, that can set absolute configuration as bonds are formed. Glenn A. Micalizio of Yale University has reported (Org. Lett. 2006, 8, 2409. ) work in this direction, using the chiral linchpin 16, based on the work of James A. Marshall. Condensation of enantiomerically-pure 16 with the aldehyde 15 gave, after protection, the alkyne 17. Ti-mediated reductive coupling of 17 with 18 to give 19 proceeded with 5:1 regiocontrol and 3:1 diastereocontrol.

The establishment of arrays of alkylated stereogenic centers is particularly challenging. Dolores Badía of the Universidad del País Vasco in Bilbao has found (Org. Lett. 2006, 8, 2535. ) that the pseudoephedrine chiral auxiliary of Andrew G. Meyers works particularly well for conjugate addition followed by enolate trapping, delivering the product 21 in high de and ee. In a complementary approach, Scott G. Nelson of the University of Pittsburgh has shown (J. Am. Chem. Soc. 2006, 128, 4232. ) that the ether 23 is readily prepared in high ee by the addition, using the amino alcohol developed by William A. Nugent, of diethylzinc to the aldehyde 22, followed by Pd-mediated coupling of the Zn alkoxide with allyl acetate. Ir-catalyzed bond shift then proceeded selectively on the terminal alkene to give, after Claisen rearrangement, the aldehyde 24.

D. F. Taber, Org. Chem. Highlights 2007, February 26.