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

Abstract

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.

Regio‐ and Stereoselective Synthesis of Bicyclic Limonene‐Based Chiral Aminodiols and Spirooxazolidines

“…The results are presented in Table . The enantiomeric purities of propanols ( S )‐ 27 and ( R )‐ 27 were determined by GC on a CHIRASIL‐DEX CB column by using literature methods . Low‐to‐good enantioselectivities were observed.…”

“…The results obtained clearly show that the spirooxazolidine ring has poorer catalytic performance than the 1,3‐oxazine ring system. These results correlate well with those observed with pinane‐ and sabinane‐based spirooxazolidines and carane‐fused 1,3‐oxazines in our earlier studies …”

Stereoselective Synthesis of Limonene‐Based Chiral 1,3‐Amino Alcohols and Aminodiols

“…Cyclic chiral amino alcohols have many important applications in chiral catalysis, and as building blocks for the synthesis of biologically active compounds , . Many monoterpenes, such as (+)‐pulegone, (+)‐3‐carane,, as well as (+)‐ and (–)‐α‐pinene, have been widely used as starting materials for the synthesis of various amino alcohols, which are applied as chiral additives and catalysts in several chemical transformations . Monoterpene‐based 1,2‐ and 1,3‐amino alcohols, prepared stereoselectively from commercially available monoterpenes, have proved to be excellent catalysts in a wide range of stereoselective reactions, including catalytic asymmetric carbon–carbon‐bond formation, addition reactions of dialkylzinc to aldehydes, and asymmetric allylic alkylation reactions …”

“…Aminodiols have been shown to be excellent starting materials for the synthesis of both 1,3‐oxazines and spiro‐1,3‐heterocycles , , . Since the resulting heterocycles contain a free hydroxy group with coordinating ability, this may give rise to greater rigidity within a transition state, and hence to higher enantioselective induction in asymmetric transformations . Aminodiols also serve as substrates for the synthesis of biologically active natural compounds (cytoxazone, etc.…”

Chiral high‐performance liquid and supercritical fluid chromatographic enantioseparations of limonene‐based bicyclic aminoalcohols and aminodiols on polysaccharide‐based chiral stationary phases

“…1,3-Aminoalcohols and aminodiols and their heterocyclic derivatives are widely used as chiral auxiliaries or chiral ligands in enantioselective transformations, e.g. in asymmetric alkylation of aldehydes with organozinc compounds (Szakonyi, Csőr, Csámpai, & Fülöp, 2016). 1,3-Oxazines and oxazolines obtained by their regioselective ring closure may serve as catalysts in Pd-catalyzed allylic alkylation reactions (Popa et al, 2007).…”