Stereoselective Synthesis and Modelling-Driven Optimisation of Carane-Based Aminodiols and 1,3-Oxazines as Catalysts for the Enantioselective Addition of Diethylzinc to Benzaldehyde

The reductive amination of (−)‐2‐carene‐3‐aldehyde, prepared in two steps from (−)‐perillaldehyde, furnished 2‐carene‐based allylamines. tert‐Butyloxycarbonyl (Boc) or carbobenzyloxy (Cbz) protection of the resulting amines, followed by stereoselective dihydroxylation in highly stereospecific reactions with OsO4 and subsequent deprotection, resulted in N‐benzylaminodiols, which were transformed to primary and tertiary aminodiols. The reactions of the N‐benzyl‐ and N‐(1‐phenylethyl)‐substituted derivatives with formaldehyde led to highly regioselective ring closure, resulting in carane‐fused 1,3‐oxazines. The aminodiols and their 1,3‐oxazine derivatives were applied as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. The best (R) enantioselectivity was observed in the case of the N‐((R)‐1‐phenylethyl)‐substituted aminodiol, whereas the opposite chiral direction was preferred when the 1,3‐oxazines were applied. Through the use of molecular modelling at an ab initio level, this phenomenon was interpreted in terms of competing reaction pathways. Molecular modelling at the RHF/LANL2DZ level of theory was successfully applied for a mechanism‐based interpretation of the stereochemical outcome of the reactions leading to the development of further 1,3‐oxazine‐based ligands, which display excellent (S) enantioselectivity (95 and 98 % ee) in the examined transformation. Being selective: A carane‐based 3‐amino‐1,2‐diol library was created by stereoselective dihydroxylation. The reactions of aminodiols with formaldehyde resulted in carane‐fused 1,3‐oxazines in regioselective ring closures (see scheme). The chiral catalysts were applied in the enantioselective addition of diethylzinc to aldehydes. N‐Substituent‐dependent catalytic activity was observed and molecular modelling was devised to predict and explain this phenomenon.