Chemical Science EDGE ARTICLE Cite this: Chem. Sci., 2013, 4, 3198 Received 17th April 2013 Accepted 20th May 2013 DOI: 10.1039/c3sc51027a www.rsc.org/chemicalscience Asymmetric synthesis of propargylic alcohols via aldol reaction of aldehydes with ynals promoted by prolinol ether–transition metal–Brønsted acid cooperative catalysis† Enrique G´ us M. Garcıa, enez, a Irati Lapuerta,‡ a omez-Bengoa, a Jes´ ´ b Sandra Jim´ Antonia Mielgo, a Jos´ us Razkin, b I ~ e M. Odriozola, b Itziar Otazo,‡ a Jes´ naki Urruzuno, a Silvia Vera,‡ a Mikel Oiarbide a and Claudio Palomo * a 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. Introduction Propargylic alcohols constitute small but densely functionalized units that, owing to the rich chemistry of the carbon–carbon triple bond, may serve as building blocks in the construction of molecular complexity. 1 Despite their synthetic value, there are few catalytic entries to propargylic alcohols of stereodened structure, namely: (a) the reduction of ynones, (b) the addition of terminal alkynes to aldehydes, and (c) the 1,2-addition of nucleophiles to a,b-ynals (Fig. 1). 2 Although the rst two methods have been studied extensively, efforts for exploring the latter approach have been essentially limited to the use of organometallic reagents, which usually allow for the generation of a sole stereocenter and do not readily permit concomitant introduction of additional functionality. The aldol addition 3 of an enolate or equivalent to an a,b-ynal can be viewed as an attractive means for accessing propargylic alcohols because two contiguous stereocenters may be gener- ated at once, with concomitant formation of a new carbon– carbon bond between them, and a b-carbonyl group is also installed, all under rather mild reaction conditions. However, a Departamento de Qu´ ımica Org´ ımica, Universidad del Pa´ anica I, Facultad de Qu´ ıs Vasco UPV/EHU, Apdo. 1072, 20080 San an, Spain. E-mail: Sebasti´ claudio. palomo@ehu.es b Departamento de Qu´ ımica Aplicada, Universidad P´ ublica de Navarra, Campus de Arrosad´ ıa, 31006 Pamplona, Spain † Electronic supplementary information (ESI) available: Experimental procedures, structural proofs, and spectral data for all new compounds are provided. See DOI: 10.1039/c3sc51027a ‡ These authors contributed equally to this work. realizing such a transformation in a catalytic and asymmetric manner from readily available substrates remains poorly addressed, if at all. Here we report a cross aldol reaction between aldehydes and ynals promoted by prolinol ether– transition metal–Brønsted acid cooperative catalysis that enables a straightforward and highly stereocontrolled synthesis of functionalized propargylic alcohols. Results and discussion Background and reaction design Despite the fact that the aldol reaction stands among the most amply investigated chemical transformations, examples of Fig. 1 Fundamental routes to propargylic alcohols and our strategy. 3198 | Chem. Sci., 2013, 4, 3198–3204 This journal is ª The Royal Society of Chemistry 2013