Azetidines, conformation

Cremer, D. 1981. Theoretical Determination of Molecular Structure and Conformation Part X. Geometry and puckering potential of azetidine, (CH2)3NH, combination of electron diffraction and ab initio studies. J. Mol. Struct. 75, 225-240. 

The origins of the observed conformations of azetidine, oxetane and thielane... 

Azetidine, a liquid, has been known since 1899 it smells of ammonia and is a strong base. For azetidine and its derivatives the ring is puckered to reduce eclipsing interactions, the extent depending upon the substituents. The barrier to inversion is low, which helps equilibration between the two conformers (Scheme 8.4). 

The spatial requirement of the hetero atom reduced forms determines the conformation of the ring. 

N-Acyl derivatives of azetidine have been studied (72CC788 720MRI45 78JCS(P2)1157) as derivatives of azetidine-2-carboxylic acid (87), since conformational properties of these compounds have been compared to those of N-acylprolines (90). 

In D O solution, the cyclic trimeric derivative of azetidine-2-carboxylic acid [cyclo(Aze)3] displayed (78MI2) more than one interconverting conformation, with peptide bonds slightly deviated from planarity. Circular di-chroism in methanol showed (78MI3) absorption very similar to that of... 

Introduction of one azetidine unit in proline peptides reduces the conformational mobility (78MI2). 

The discovery of the norcardicins and monobactams demonstrated for the first time that a conformationally constrained bicyclic structure was not necessary for antibacterial activity of (3-lactams [12, 13]. In recent years, various natural and unnatural monocyclic-(3-lactams have been shown to exhibit high biological activity, suggesting that the biological activity of the particular ring is influenced by the type of substitution attached to the azetidin-2-one ring (Fig. 2). 

Several H and 13C NMR data of azetidines and azetidin-3-ones have been reported. A significant variation is observed in geminal coupling constants of the methylene group attached to nitrogen of different classes of azetidines. The substituents at the nitrogen atom and the conformations of the compounds appear to affect the J values. 

Diphenylsilane is compatible with the ester group at C-4 in azetidin-2-ones 203 and reduces only the amide carbonyl group affording azetidin-2-carboxylates 204 (Equation 55) <2004TL2193>. Removal of the />-methoxy-benzyl group from azetidin-2-carboxylates 204 allowed the preparation of conformationally strained amino ester hydrochlorides. 

The classical reaction with chlorosulfonyl isocyanate has been extended to it-vinyl sulfide 449 to give a 2.5 1 diastereomeric mixture of 4-(phenylthio)azetidin-2-ones 343 and 450 (Equation 180) <2000MI935>. The facial selectivity in the cycloaddition has been explained by the conformational preference of the allylic groups in the transition structure. A similar reaction with styrene resulted into synthesis of the racemic 4-aryl-azetidin-2-one (Equation 181) <2000TA2351>. The divinyl ether 451 reacted with acid-free chlorosulfonylisocyanate to form 4-vinyloxyazetidin-2-one 452 (Equation 182) <1996SL895, 1997TA2553, 1998TL8349>. Most of the results in the reactions of isocyanate with vinyl ethers could be rationalized by a -conformational preference of the ether in... 

The ease of racemization of chiral a-amino aldehydes under MBH conditions is undoubtedly a major difficulty in studying diastereoselective reactions [53]. Epi-merization can be essentially avoided by conducting the reaction at low temperature [54, 67], or it can be minimized at room temperature when a conformation-ally restricted amino aldehyde, such or N-trityl-azetidine 2-(S)-carboxyaldehyde is used [54]. The use of ultrasound also increases the rate of the MBH reaction, avoiding racemization almost completely, even at room temperature [55]. When adding various a-amino acid-derived aldehydes to methyl acrylate using DABCO... 

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