The first enantioselective Brønsted acid catalyzed reduction of imines has been developed. This new organocatalytic transfer hydrogenation of ketimines with Hantzsch dihydropyridine as the hydrogen source offers a mild method to various chiral amines with high enantioselectivity. The stereochemistry of the chiral amines can be rationalized by a stereochemical model derived from an X-ray crystal structure of a chiral BINOL phosphate catalyst. [reaction: see text]

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Although known for more than 50 years the rubromycin family still constitutes a fascinating class of antitumour antibiotics. They are characterized by a challenging molecular architecture with the central spiroketal unit as the key feature and possess highly attractive biological properties. After a short treatment of the history of their isolation, structural elucidation and biosynthesis, their biological activities will briefly be summarized. This review strongly emphasizes the synthetic efforts aimed at these complex hexacyclic spiroketals. Reactions leading to simple spiroketal model compounds are described, followed by the synthetic approaches to the fully functionalized naphthalene and isocoumarin “wings”. The coupling of these units and their transformations into more advanced spiroketals demonstrate “the state of the art” in this research field. Only Danishefsky and co‐workers have so far completed the total synthesis of a fully functionalized rubromycin derivative; however, their product heliquinomycinone (103) is still only the aglycon of the natural product heliquinomycin (7), and it was prepared as the racemic compound. All these achievements and pitfalls reveal that increased engagement of synthetic organic chemists is required to develop new methods to make rubromycins and their analogues available by a modular approach and with reasonable efficacy. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The application of Brønsted acids in chemical syntheses continues to rise. As well as inorganic Brønsted acids, more and more achiral and chiral organic Brønsted acids are being applied.[1] The main function of Brønsted acids is the activation of the electrophile or nucleophile. On the one hand, the transfer of a proton from the Brønsted acid to the electrophile can lead to a lowering of the energy of the LUMO, which results in activation of the electrophile and enables it to react with a nucleophile. On the other hand, the addition of Brønsted acids can lead to activation of a nucleophile, as demonstrated by the acid-catalyzed ketoenol tautomerism. In most cases only catalytic amounts of Brønsted acid are required for complete product formation. Recently, chiral Brønsted acids (*BH) enabled enantioselective transformations with aldimines and ketimines for the first time [Eq. (1)]. [2][3][4] In the first step of these reactions a proton is transferred from the Brønsted acid to the substrate to form a chiral ion pair that contains an iminium ion, which subsequently reacts with a nucleophile to form the corresponding amine and the regenerated Brønsted acid. We recently used this concept of chiral ion pair catalysis to develop highly enantioselective reactions, such as transfer hydrogenations [3] and hydrocyanations.[4]Herein we report the development of a new, double Brønsted acid catalyzed reaction in which both the electrophile and the nucleophile are activated and which provides a straightforward and effective route to isoquinuclidines in remarkably high enantioselectivities. Isoquinuclidines (5, azabicyclo[2.2.2]octanes) have N-bicyclic structures, which are the structural element of numerous naturally occurring alkaloids with interesting biological properties.[5] Furthermore, these products can be readily converted into the biologically active pipecolic acids.[6] A retrosynthetic analysis shows that these isoquinuclidines (5) can be prepared from imines (3) and cyclohexenone (4) [Eq. (2)]. [7] On the basis of our previous work we assumed that an asymmetric Brønsted acid catalyzed reaction should enable the formation of these valuable products. Our concept, based on the direct reaction between 3 and 4, provides the simultaneous, double Brønsted acid catalyzed activation of an electrophile (by a chiral Brønsted acid *BH, 1) and a nucleophile (by an achiral Brønsted acid BH, 2), whereby both activation processes behave cooperatively (Scheme 1). The fundamental requirement for a successful reaction process must be that the achiral Brønsted acid BH 2 is not able to activate the imine 3.

A new Brønsted acid catalysed hydrogenation of imines with Hantzsch dihydropyridine as the hydrogen source has been developed. Diphenyl phosphate (DPP) and various other acids catalyse this first metal-free hydrogen transfer to give various amines under mild reaction conditions. The development of catalysts for the asymmetric hydrogenation of imines is a topic of ongoing interest. Current methods include transition-metal-catalysed high-pressure hydrogenations, 1 hydro-silylations, 2 or transfer hydrogenations using ammonium formate. 3 Additionally, metalcatalysed reductions using chiral biomimetic NADH models have been reported. 4 Among these, Hantzsch 1,4-dihydropyridine is a widely used model compound with application in the reduction of a,b-unsaturated carbonyl compounds, 5 conjugated olefins 6 and metal-catalysed reductive aminations. 7 However, to date no metal-free transfer hydrogenation of imines has been reported.