Combined a,a-dialkylprolinol ether/Brønsted acid promotes Mannich reactions of aldehydes with unactivated imines. An entry to anti-configured propargylic amino alcohols† Enrique G omez-Bengoa, Jacqueline Jim enez,‡ Irati Lapuerta, Antonia Mielgo, Mikel Oiarbide, Itziar Otazo, Irene Velilla, Silvia Vera and Claudio Palomo * Received 10th May 2012, Accepted 25th June 2012 DOI: 10.1039/c2sc20590d The first enamine mediated anti-selective and highly enantioselective Mannich reaction of aldehydes and unactivated imines is reported. The key for success is the combined use of a Brønsted acid with an a,a-dialkylprolinol ether catalyst that leads to adducts with good yields (typically 70–75%), anti : syn ratios greater than 90 : 10, and ee values usually above 95%. The method works particularly well with propargylic imines and, unlike previous catalytic routes to optically active propargylamines, provides adducts featuring two contiguous stereocenters and a functionalized side chain amenable for ulterior synthetic applications. Introduction The Mannich reaction, that is the reaction between a nucleo- philic enolate or equivalent and an electrophilic azomethine group, stands as one of the most powerful methods for the production of b-amino carbonyl compounds. This reaction has experienced impressive advances in recent years 1 because the resulting b-amino carbonyl compounds may be transformed into b-amino acids, 1,3-amino alcohols, and 1,3-diamines, structural units often present in natural products and medicinal agents. However, catalytic asymmetric Mannich methodologies that encompass both wide substrate scope for carbonyls and imines, and effective stereocontrol, are uncommon. Two major problems are the inherently low electrophilicity of the azomethine func- tion, which is best exemplified in the simplest imines, or Schiff bases, and the preference of enolizable azomethines to undergo a-deprotonation rather than addition. These problems remain poorly resolved even beyond the realm of catalytic methodolo- gies. A few years ago we reported an efficient asymmetric acetate Mannich methodology which was also suitable for enolizable imines, 2 thus contributing to the solution of the above problems. The method relied on the use of N-Boc imines, generated in situ from a-amidosulfones, in conjunction with a chiral lithium acetate enolate equivalent. To date, the use of N-Boc, or related N-acyl, N-sulfonyl, N-sulfinyl, and N-phosphonyl imines has indeed become customary for the majority of asymmetric Mannich methodologies. With the seminal, independent, reports from the groups of Barbas III 3 and List, 4 on the proline-catalyzed Mannich reaction of aldehydes and ketones as unmodified donor carbonyls, an important step was made. 5 Besides proline, other proline congeners have subsequently emerged, 6 constituting a powerful arsenal for performing syn-selective Mannich reactions with a variety of imines enantioselectively. Unfortunately, proline and the related catalysts are unable to preferentially produce adducts of anti relative configuration. 7 Alternative amine catalysts, among them the a,a-diarylprolinol ethers, 8 have been found capable of promoting the Mannich reaction of unmodified aldehydes and ketones with anti-selectivity, thus helping to fill this gap. However, once again, these catalysts are generally suitable for reactions involving reactive imines only, 9 that is, imines equipped with electron withdrawing groups (EWG) at either C or N atom, or both, of the azomethine function (Fig. 1). For instance, Barbas III and C ordova, 10 using (S)-2-methoxy- methylpyrrolidine as the catalyst, and Jørgensen et al., 11 using Fig. 1 A classification of imines based on their reactivity (arbitrary scale) 20 in Mannich-type reactions. Departamento de Qu ımica Org anica I, Facultad de Qu ımica, Universidad del Pa ıs Vasco UPV/EHU, Apdo. 1072, 20080 San Sebasti  an, Spain. E-mail: claudio.palomo@ehu.es † Electronic supplementary information (ESI) available: Experimental procedures, structural proofs, and spectral data for all new compounds (119 pages) (PDF). CCDC 871606. For ESI and crystallographic data in CIF or other electronic format DOI: 10.1039/c2sc20590d ‡ Present address: Centro de Investigaci on, Facultad de Ciencias Qu  ımicas, Benem erita Universidad Aut onoma de Puebla, M exico. This journal is ª The Royal Society of Chemistry 2012 Chem. Sci., 2012, 3, 2949–2957 | 2949 Dynamic Article Links C < Chemical Science Cite this: Chem. Sci., 2012, 3, 2949 www.rsc.org/chemicalscience EDGE ARTICLE