The first tandem regioselective hydroformylation and enantioselective organocatalytic anti-Mannich reaction is reported. Starting from α-olefins, valuable functionalized amino acid derivatives were obtained in excellent yields and with high levels of diastereo-and enantioselectivities. The products represent valuable building blocks for biologically and pharmaceutically interesting targets.Functionalized α-amino acid derivatives are valuable building blocks for the synthesis of target structures of biological and medicinal interest. 1 As such, the development of methods for their preparation has drawn a lot of attention. 2-4 Among the many approaches used to achieve this goal, an elegant process is the organocatalytic Mannich reaction between enolizable aldehydes and imines. 5-7 However, enolizable aldehydes themselves are reactive substrates that may undergo side reactions such as aldol reactions and oligomerization, which can be obstructive for obtaining high yields. One strategy to avoid such undesired side reactions is to generate the aldehyde in a low stationary concentration by way of a catalytic reaction. As we have demonstrated recently, this can be efficiently achieved by generating an aldehyde in situ through the application of atom-economic hydroformylation of alkenes. By applying this strategy, we were able to develop an efficient enantioselective tandem regioselective hydroformylation and organocatalytic enantioselective aldol addition 8 as well as a tandem regioselective hydroformylation-Biginelli reaction. 9,10 We report herein on an extension of this concept with the development of the first tandem regio-, diastereo-and enantioselective hydroformylation-organocatalytic antiMannich reaction.Among the different known methods for organocatalytic Mannich reactions, we were attracted by the anti-selective Mannich methodology developed by Melchiore et al. 7 Central to this method is the generation of N-carbamatesubstituted imines in situ through base-initiated elimination of tolyl sulfinic acid from stable α-amidosulfones 2 (Scheme 1). An interesting aspect of this method is that NBoc or N-Cbz protected α-amino acids are obtained directly, which allows for follow-up peptide construction. Scheme 1 Design of a domino hydroformylation-aminocatalyticanti-Mannich reaction A crucial factor for success of the envisioned tandem hydroformylation-Mannich approach was the selection of the optimal catalyst system for the hydroformylation step. First, the catalyst has to be compatible with the substrates, reagents and the organocatalyst present at the same time. Second, it has to operate under mild conditions to allow for low reaction temperatures to ensure good enantioselectivities in the organocatalytic Mannich step. Finally the enolizable aldehyde reaction partner has to be generated through hydroformylation in high chemo-and regioselectivities.A catalyst system that has the potential to fulfill all these demands could be the self-assembling 6-diphenylphosphinopyridone/rhodium catalyst (6-DPPon see Scheme 1) de...

Tandem Regioselective Rhodium-Catalyzed Hydroformylation-Enantioselective Aminocatalytic anti-Mannich Reaction. -The enantioselective synthesis of -formyl amino acids from amidosulfones and olefins under high pressure is described. An alternative approach under milder conditions is also presented. -(DIEZEL, S.; BREIT*, B.; Synthesis 46 (2014) 10, 1311-1320, http://dx.