Enantiopure 4‐oxazolin‐2‐ones and 4‐methylene‐2‐oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles

Abstract

Enantiopure 3‐((R)‐ and 3‐((S)‐1‐phenylethyl)‐4‐oxazoline‐2‐ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N‐(R)‐ or N‐(S)‐1‐phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4‐ and 5‐positions of the 4‐oxazolin‐2‐one ring through thermal and MW‐promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six‐membered carbo‐ and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4‐methylene‐2‐oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero‐Diels‐Alder cycloaddition.

Synthesis of Diarylamines and Methylcarbazoles and Formal Total Synthesis of Alkaloids Ellipticine and Olivacine

“…The latter compounds reacted with acrolein ( 6 a ) under MW irradiation to furnish the 3‐aryl‐3a,7a‐dimethyl‐3,3a,7,7a‐tetrahydro‐2 H ‐pyrano[2,3‐ d ]oxazol‐2‐ones 18 a – g in good yields (Table 1). Based on DFT calculations, [28] this process appears to take place through a concerted hetero‐Diels‐Alder cycloaddition, which was highly efficient and regioselective regardless of the electronic effect of the functional group or its position in the aryl ring. This is probably due to the quasi‐orthogonal conformation of the aromatic ring attached to the nitrogen atom with respect to the 4‐oxazolidin‐2‐one ring (as established by X‐ray diffraction of derivative 11 c [29] and analogous heterocycles [23a,29,30] ), thus avoiding the perturbance of the electronic density of the endocyclic double bond.…”

“…According to the most recent report, [28] the first step of the reaction mechanism for this transformation involves the formation of the corresponding bicyclic tetrahydro‐2 H ‐pyrano[2,3‐ d ]oxazol‐2‐ones 18 , followed by the opening of the hemiaminal moiety to provide intermediates 20 . The latter undergo cyclization to species 21 and then dehydration, resulting in the observed products 19 (Scheme 3).…”

Divergent Pd-catalyzed Functionalization of 4-Oxazolin-2-ones and 4-Methylene-2-oxazolidinones and Synthesis of Heterocyclic-Fused Indoles

“…This suggests the possible effect of the N-substituent in the heterocycle on the polarization of the enamide double bond . Interestingly, the N -chiral auxiliary of the latter compounds attached to similar 4-oxazolin-2-ones has been shown to efficiently furnish a highly diastereoselective series of products . Therefore, the series 10j–10o is a source of potential building blocks for asymmetric synthesis.…”

“…A straightforward and regioselective method was developed by our group to obtain 4-methylidene-2-oxazolidinones and 4-oxazolin-2-ones . Both heterocycles have been used as building blocks for the divergent synthesis of α-hydroxyamides, propellane compounds, aza-polycyclic compounds, and enantiopure heterocyclic frameworks . The aim of the current contribution was to explore the synthetic potential of subjecting 4-oxazolin-2-ones and 4-alkylidene oxazolidine-2-ones to a palladium-catalyzed coupling for intermolecular Heck arylation and dimerization, as well as for the intramolecular construction of oxazolo­[3,4- a ]­indol-3­(1 H )-ones and functionalized indoles.…”

New Advances in the Synthetic Application of Enantiomeric 1-Phenylethylamine (α-PEA): Privileged Chiral Inducer and Auxiliary

“…Recently, chiral 1,3-oxazolidin-2-ones have been devised as an efficient chiral auxiliary to synthesize carboxylic compounds [ 60 ]. Consequently, ( R )- or ( S )-α-PEA fragment was used for the diastereoselective induction in the 4-oxazolin-2-one scaffold at the C-4 and C-5 stereocenters ( Scheme 37 ).…”