Metal-catalysed hydroformylation is successfully combined with an organocatalysed stereoselective Mannich reaction in a tandem reaction sequence. This novel type of "tandem catalysis" allows access to complex molecular systems with high levels of enantioselectivity, using simple starting materials and an amino acid as the chiral catalyst.Keywords: hydroformylation; Mannich reaction; organocatalysis; tandem reactions Recent syntheses of natural and drug-like compounds have clearly revealed the advantages of combining several reactions into a tandem reaction sequence to provide complex molecules in a clean and efficient manner.[1] We and others have demonstrated that tandem reactions under hydroformylation conditions are a useful strategy for the synthesis of complex molecular systems.[2] More recent attention has been focused on "tandem catalysis" [3] where a metal catalyst works together with a chiral organocatalyst affording highly functionalised molecules with excellent levels of enantioselectivity.[4] Here we now report the first use of this methodology in sequential hydroformylation and asymmetric Mannich reactions. The proposed sequential transformation involves hydroformylation of an alkene mediated by a triphenyl phosphite-modified Rh catalyst and l-proline-catalysed enantioselective Mannich reaction of the aldehyde formed in situ, an aromatic amine and a ketone (Scheme 1). Like the related tandem hydroformylation/enantioselective aldol reactions, [4d,e] this process leads to the generation of up to four new adjacent stereogenic centres in the product, and clearly, when high levels of control are observed, these approaches are of considerable importance.The synthetic plan relied on finding optimal conditions for both hydroformylation and enantioselective Mannich reactions and then combining these reactions into a tandem sequence.The hydroformylation reactions were performed using the previously reported protocol.[4d] The catalyst was readily prepared in situ from [RhA C H T U N G T R E N N U N G (acac)(CO) 2 ] and an excess of triphenyl phosphite. Cyclic olefins were used as substrates in order to avoid the regioselectivity problems of hydroformylation reactions. The hydroformylation experiments were performed in acetone, since in subsequent Mannich reactions acetone will serve both as the enamine component and as solvent (Table 1). As shown in Table 1, excellent converScheme 1. Hydroformylation/enantioselective Mannich reactions.
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