Dual Catalysis DOI: 10.1002/anie.201307295 An Iron/Amine-Catalyzed Cascade Process for the Enantioselective Functionalization of Allylic Alcohols** Adrien Quintard,* Thierry Constantieux, and Jean Rodriguez* The development of transformations that allow the fast and environmentally compatible generation of enantiopure com- plex products directly from simple and readily available starting materials is at the forefront of modern synthetic chemistry, and it entails a strong potential for industrial developments. [1] To achieve these ambitious goals, mainly asymmetric transformations that are catalyzed by a single catalyst have been realized, but more recently, the develop- ment of multicatalytic approaches has allowed access to new chemical transformations that are otherwise difficult or even impossible to accomplish. [2] In this context, we intended to combine a hydrogen autotransfer process with an organocatalytic cycle in a dual manner (Scheme 1 a). As a result, the reactive carbonyl functionality that is required for an enantioselective amino- catalyzed process would be catalytically generated from the alcohol oxidation level (an unactivated functional group), and then transformed in situ. The strategy should rely on the use of a metal catalyst that is suitable for borrowing-hydrogen processes; if possible, this catalyst should be based on cheap and abundant iron, [3] and it should catalytically and reversibly enable hydrogen transfer without the requirement for a stoi- chiometric redox reagent. [4] The proposed one-pot relay cascade would be a fully atom-economic and waste-free transformation of simple allylic alcohols into b-chiral satu- rated alcohols (Scheme 1 c), as this process would bypass the three distinct waste-producing steps that are otherwise required (oxidation, organocatalytic nucleophilic addition, reduction; Scheme 1 b). Recently, hydrogen-transfer processes that are promoted by well-defined metal catalysts have been extensively studied, which led to the development of several applications, includ- ing hydrogen production or storage and the development of more sustainable chemical transformations. [4] Indeed, these catalysts may induce the transient formation of reactive intermediates from unactivated substrates, and they have thus been applied for so-called borrowing-hydrogen methods. To date, such processes remain largely limited to a small set of reactions, such as alcohol amination or racemic C ÀC bond- formation, [5] as exemplified by an early example of allylic alcohol substitution, which was reported by Williams and co- workers in 2001. [5d] Unfortunately, the need for relatively harsh reactions conditions (> 70 8C) [6] hampers the develop- ment of enantioselective versions of this reaction. [7] In sharp contrast, chiral iminium activation has estab- lished itself as a cornerstone of organocatalytic Michael additions to unsaturated carbonyl compounds, as it enables efficient access to enantiopure complex products. [8] Pivotal to this reactivity is the use of highly reactive carbonyl substrates, namely ketones or aldehydes, that entail severe drawbacks, such as tedious substrate preparation, toxicity, or possible decomposition or product racemization. To avoid such issues, the combination of the in situ formation of the carbonyl functional group with an aminocatalytic step is a promising approach. [9] Furthermore, we anticipated that combining the two orthogonal catalytic cycles (iminium activation and borrow- ing-hydrogen catalysis) would enhance the hydrogen-transfer activity of easily accessible iron complexes. A directed thermodynamic displacement by catalytic in situ formation of a chiral conjugated iminium intermediate followed by Scheme 1. Concept of the dual iron-/organocatalyzed process and its application to the asymmetric functionalization of allylic alcohols. [*] Dr. A. Quintard, Prof. T. Constantieux, Prof. J. Rodriguez Aix-Marseille UniversitØ, Centrale Marseille, CNRS iSm2 UMR 7313, 13397, Marseille (France) E-mail: adrien.quintard-inv@univ-amu.fr jean.rodriguez@univ-amu.fr Homepage: http://ism2.univ-amu.fr/pages-bleues/index2.htm [**] Financial support from the Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille UniversitØ is gratefully acknowledged. The authors gratefully thank Marion Jean and Nicolas Vanthuyne (Aix-Marseille UniversitØ) for chiral-phase HPLC analysis of all compounds. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201307295. A ngewandte Chemi e 12883 Angew. Chem. Int. Ed. 2013, 52, 12883 –12887  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim