Organic Chemistry Portal
Organic Chemistry Highlights

Monday, March 10, 2008
Douglass F. Taber
University of Delaware

Stereocontrolled Construction of Arrays of Stereogenic Centers

Complex natural products and even some complex pharmaceuticals contain arrays of stereogenic centers. Sometimes, the desired array is readily available from a natural product, but usually, such arrays of multiple stereogenic centers must be assembled. Armando Córdova of Stockholm University has reported (Angew. Chem. Int. Ed. 2007, 46, 778. DOI: 10.1002/anie.200603810) a simple procedure for the organocatalyst-mediated addition of the nitrene equivalent 2 to an α,β-unsaturated aldehyde to give the protected aziridine 4 in high ee. Organocatalysis was also used (Org. Lett. 2007, 9, 1001. DOI: 10.1021/ol063012j) by Arumugam Sudalai of the National Chemical Laboratory, Pune, to effect coupling of the aldehyde 5 with dibenzylazodicarboxylate 6 to give, following the List procedure, the aldehyde 7. Osmylation of the derived unsaturated ester 8 proceeded with high diastereocontrol, to give 9.

Products 4 and 9 have adjacent stereogenic centers. Hisashi Yamamoto of the University of Chicago has introduced (J. Am. Chem. Soc. 2007, 129, 2762. DOI: 10.1021/ja0693542) the linchpin reagent acetaldehyde “super”silyl enol ether 11. Diastereoselective addition of 11 to the enantiomerically-pure aldehyde 10, with concomitant silyl transfer, followed by the addition of allyl magnesium bromide delivered the protected triol 12 in high de and ee.

Arrays that combine alkylated and oxygenated or aminated centers are also important. Akio Kamimura of Yamaguchi University took (J. Org. Chem. 2007, 72, 3569. DOI: 10.1021/jo062251h) a Baylis-Hillman like approach, adding thiophenoxide to t-butyl acrylate in the presence of an enantiomerically-pure aldehyde N-sulfinimine such as 13 to give the adduct 14 with high diastereocontrol. Keiji Maruoka of Kyoto University has designed (Angew. Chem. Int. Ed. 2007, 46, 1738. DOI: 10.1002/anie.200604640) the chiral amine 17, that catalyzed the condensation of an aldehyde with ethyl glyoxylate 16 with high enantiocontrol. In a very thoughtful approach, Liu-Zhu Gong of the University of Science and Technology of China in Hefei extended (Chem. Commun. 2007, 736. DOI: 10.1039/b615043h) the now-classic aldol condensation of cyclohexanone to 4-substituted cyclohexanones such as 19. The product 21 could be carried in many directions, including to the Baeyer-Villiger product 22.

Arrays of alkylated and polyalkylated centers have been among the most challenging to prepare. Professor Córdova has established conditions (Chem. Commun. 2007, 734. DOI: 10.1039/b614962f) under which 3 will catalyze the addition of aliphatic aldehydes such as 23 to imides such as 24 with high enantio- and diastereocontrol. The two carbonyls of the imide would be easily distinguishable by reduction of the aldehyde followed by selective formation of the γ-lactone. Using the same catalyst, Wei Wang of the University of New Mexico effected (Org. Lett. 2007, 9, 1833. DOI: 10.1021/ol070581y) the addition of the mercapto ester 27 to unsaturated aldehydes such as 26. The product 28 has three new stereogenic centers. In what may be a very general approach to this problem, Hiroki Hamada of the Okayama University of Science has observed (Tetrahedron Lett. 2007, 48, 1345. DOI: 10.1016/j.tetlet.2006.12.126) that crude purified p51 and p83 reductases from Glycine max showed showed complementary selectivity, leading to 30 and 31 respectively.

D. F. Taber, Org. Chem. Highlights 2008, March 10.