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Monday, June 27, 2005
Douglass Taber
University of Delaware

Enantioselective Construction of Arrays of Stereogenic Centers

Single enantiomer synthesis is of increasing importance in pharmaceutical production. It is essential that practical and scalable procedures be developed for controlling the absolute configuration of new stereogenic centers as they are formed. In the previous column, recent advances for the preparation of single stereogenic centers were covered. The construction of more extended arrays of stereogenic centers, which is also is important, is covered here.

One approach is to use enantioselective methods to establish a first stereogenic center, then use that center to control the relative configuration of additional centers as they are formed. Patrick Walsh of the University of Pennsylvania has found (J. Am. Chem. Soc. 2004, 126, 13608. DOI: 10.1021/ja046750g) that addition of a dialkyl zinc reagent to an aldehyde such as 1, using the high e.e. Nugent procedure, gives an intermediate that on exposure to molecular oxygen gives the epoxy alcohol 2 with high diastereomeric control. In a complementary approach, Guofu Zhong of the Scripps Institute, La Jolla has shown (Chem. Commun. 2004, 606. DOI: 10.1039/b314356b) that enantioselective aminoxylation of an aldehyde such as 3 can be followed in the same pot by the addition of an organometallic reagent, to give the monoprotected diol 4 in high enantiomeric excess. While the diastereomeric control is low in this case, one would expect this to improve if a bridging Lewis acid were included.

Enantioselective aldol reactions also can be used to create arrays of stereogenic centers. Two elegant α-amino anion approaches have recently been published. Fujie Tanaka and Carlos F. Barbas III of the Scripps Institute, La Jolla, have shown (Org. Lett. 2004, 6, 3541. DOI: 10.1021/ol0485417) that L-proline catalyzes the addition of the aldehyde 6 to other aldehydes with high enantio- and diastereocontrol. Keiji Maruoka of Kyoto University has developed (J. Am. Chem. Soc. 2004, 126, 9685. DOI: 10.1021/ja048865q) a chiral phase transfer catalyst that mediates the addition of the ester 9 to aldehydes, again with high enantio- and diastereocontrol.

Michael addition can also be used to establish arrays of stereogenic centers. Hiyoshuzi Kotsuki of Kochi University has shown (J. Am. Chem. Soc. 2004, 126, 9558. DOI: 10.1021/ja046871g) that the chiral DMAP derivative 13 mediates the addition of cyclic ketones such as 11 to nitrostyrene 12 with high enantio- and diastereocontrol. Acyclic aldehydes also add with high stereocontrol. Li Deng of Brandeis University has developed (Angew. Chem. Int. Ed. 2005, 44, 105. DOI: 10.1002/anie.200461923) a quinine-based catalyst 16 that directs the addition of 12 to a single face of the cyclic β-ketoester 15, establishing adjacent ternary and quaternary centers. For the conversion of the nitro group to a nitrile without epimerization, see Angew. Chem. Int. Ed. 2005, 44, 612, DOI: 10.1002/anie.200461879).

The construction of more extended arrays is also possible. Justin Du Bois of Stanford University has reported (Angew. Chem. Int. Ed. 2004, 43, 4349. DOI: 10.1002/anie.200460791) diastereoselective remote functionalization using C-H insertion of a sulfamate such as 18 to give the oxathiazinane 19, which on reaction with an allyl silane gives the alkylated product 20 with high diastereocontrol. Note that the oxygen of 20 is activated as a leaving group.


D. F. Taber, Org. Chem. Highlights 2005, June 27.