No abstract

A catalytic and highly stereoselective entry to propargylic alcohols and products derived thereof is reported based on an unprecedented cross-aldol coupling between unmodified aldehydes and ynals. The method requires an amine-metal salt-Brønsted acid ternary catalyst system and implies synergistic activation of the donor aldehyde via enamine and of the acceptor carbonyl via unique and reversible metal-alkyne complexation. Specifically, by using a combined a,a-dialkylprolinol silyl ether-CuI-PhCO 2 H catalyst system, remarkably high levels of diastereo-and enantioselectivity (anti/syn up to >20 : 1, ee up to >99%) are achieved.

Direct coupling of enolizable aldehydes with C-alkynyl imines is realized affording the corresponding propargylic Mannich adducts of syn configuration, thus complementing previous methods that gave access to the anti-isomers. The combination of proline and a urea Brønsted base cocatalyst is key for the reactions to proceed under very mild conditions (3-10 mol % catalyst loading, dichloromethane as solvent, -20 °C, 1.2 molar equivalents of aldehyde) and with virtually total stereocontrol (syn/anti ratio up to 99:1; ee up to 99 %). Some possibilities of further chemical elaboration of adducts are also briefly illustrated.

An effective asymmetric route to functionalized 1,6- and 1,7-enynes has been developed based on a direct cross-aldol reaction between ω-unsaturated aldehydes and propargylic aldehydes (α,β-ynals) promoted by combined α,α-dialkylprolinol ether/Brønsted acid catalysis. This synergistic activation strategy is key to accessing the corresponding aldol adducts with high stereoselectivity, both enantio- and diastereoselectivity. The aldol reaction also proceeds well with propargylic ketones (α,β-ynones) thus enabling a stereocontrolled access to the corresponding tertiary alcohols. The utility of these adducts, which are difficult to prepare through standard methodology, is demonstrated by their transformation into trisubstituted bicyclic enones using standard Pauson-Khand conditions.

Combined α,α-Dialkylprolinol Ether/Broensted Acid Promotes Mannich Reactions of Aldehydes with Unactivated Imines. An Entry to anti-Configured Propargylic Amino Alcohols. -A series of amino alcohols (III) and (IX) is prepared with 80-98% diastereomeric excess using a hitherto not reported enamine-mediated antiselective Mannich reaction of corresponding imines with aldehydes (II). -(GOMEZ-BENGOA, E.; JIMENEZ, J.; LAPUERTA, I.; MIELGO, A.; OIARBIDE, M.; OTAZO, I.; VELILLA, I.; VERA, S.; PALOMO*, C.; Chem. Sci. 3 (2012) 10, 2949-2957, http://dx.doi.org/10.1039/c2sc20590d ; Dep. Quim. Org., Fac. Quim., Univ. Pais Vasco, E-20080 San Sebastian, Spain; Eng.) -R. Staver 12-058