Abstract
A general, scalable two-step regio- and diastereoselective method has been described for the synthesis of versatile alkaloid-type azetidines from simple building blocks with excellent overall yields. In the kinetically controlled reaction, only the formation of the strained four-membered ring can be achieved instead of the thermodynamically favorable five-membered rings under appropriate conditions. Remarkable functional group tolerance has also been demonstrated. In this paper, we give a new scope of Baldwin’s rules by density functional theory (DFT) calculations with an explicit solvent model, confirming the proposed reaction mechanisms and the role of kinetic controls in the stereochemical outcome of the reported transition-metal-free carbon–carbon bond formation reactions.
Highlights
Despite the irrefutable importance of azetidines as bioactive compounds and pharmaceutical building blocks, they have received moderate attention compared to larger-ring-sized pyrrolidines and piperidines.1−3 The most important strategy for the synthesis of saturated N-heterocycles relies on unimolecular cyclization reactions by nucleophilic substitution
It has been demonstrated, that the introduction of these strained rings improves enormously the fluorescent properties of rhodamines30−32 and coumarins33 and the efficacy of homogenous catalysts as ligands,34,35 which makes them an attractive and challenging synthetic topic for chemists nowadays. Compared to their widespread uses, there are relatively few synthetic methods available, they cover a wide range of structural variability.3,36−38 In conclusion, there are no general methods for the synthesis of azetidines, with a wide variety of functional groups
The key intermediates 2 were synthesized from N-substituted benzylamines (3) and epichlorohydrin (4) or readily prepared 2-substituted-(oxiran-2-yl)methyl 4-toluenesulfonates (5−7) (Scheme 2)
Summary
Despite the irrefutable importance of azetidines as bioactive compounds and pharmaceutical building blocks, they have received moderate attention compared to larger-ring-sized pyrrolidines and piperidines.− The most important strategy for the synthesis of saturated N-heterocycles relies on unimolecular cyclization reactions by nucleophilic substitution. Azetidines have excellent physicochemical properties, bioavailability and metabolic stability.− A wide variety of antibiotics,− numerous anticancer agents containing azetidines, and other drug molecules have been developed over the last decade.− They have a significant role as synthetic building blocks of foldamers, N-heterocycles,− and polymers.29 It has been demonstrated, that the introduction of these strained rings improves enormously the fluorescent properties of rhodamines− and coumarins and the efficacy of homogenous catalysts as ligands, which makes them an attractive and challenging synthetic topic for chemists nowadays. Compared to their widespread uses, there are relatively few synthetic methods available, they cover a wide range of structural variability.− In conclusion, there are no general methods for the synthesis of azetidines, with a wide variety of functional groups. Only a few methods for the preparation of druglike azetidines have been reported.−
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