3- Azetidinone, 4 + 2-cycloaddition

Density functional theory calculations (B3LYP/6-31G level) have provided an explanation for the stereodivergent outcome of the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (/3-lactams). When ketene is formed prior to cycloaddition, preferential or exclusive formation of ct5-j6-lactam (50) is predicted. If, however, the imine reacts directly with the acid chloride, the step that determines the stereochemical outcome is an intramolecular 5n2 displacement, and preferential or exclusive formation of trans isomer (51) is predicted. These predictions agree well with the experimental evidence regarding the stereochemical outcome for various reactants and reaction conditions. 

Azetidinones on a solid support 49 have been prepared in high yield by Staudinger reaction of a supported imine with an acid chloride in the presence of a base. The liberated p-lactams were of high purity <99TL1249>. Cycloaddition of a ketene intermediate, derived fi"om an azo compound, to an imine having an oxidatively cleavable chiral auxiliary N-substituent was used to obtain p-lactams 50. The trans. cis ratio which varied between 69 31 and 93 7, depended on the nature of the substituents R and R <99S650>. 

Lactams.1 The ketene derived from (S)-phenyloxazolidylacetyl chloride (1), prepared from (S)-phenylglycine, undergoes cycloaddition with N-benzyl al-dimines to give two as-azetidinones with high stereochemical control (equation I). The chiral auxiliary and the benzyl group are cleaved by Birch reduction to provide enantiomerically pure azetidinones (3). 

Other 1,2-cycloadditions have been accomplishedphotochemically. The photolytic decomposition of diazoketones in the presence of imines to give azetidinones [see, for example, Eq. (80)] is sometimes preferable310 to the direct chemical addition of ketene to imine. Diazetidinones of general structure (291) can be prepared311 either by thermal or photochemical addition of ketenes to azobenzenes, or by photolysis of diazoketones in azobenzene. 

This procedure illustrates a general method for preparing aliphatic and, in certain cases, aromatic /3-lactarns containing a free NH group and substituted in either the 4 position or in both the-3 and 4 positions of the 2-azetidinone ring. The major byproduct of the cycloaddition step is a /3,7-unsaturated carbox-amide-N-sulfonyl chloride which, in the case of certain aromatic olefins, may predominate. Reactions of both /3-lactam-N-sulfonyl chlorides and the /3,y-unsaturated carboxamide-N-sulfonyl chlorides have been tabulated.3... 

Boedeker and Courault215 reacted Schiff bases (151) derived from 2-aminopyridine and aromatic aldehydes with diphenylketene. In benzene at room temperature 4-oxopyrido[l,2-a]pyrimidines (152) were obtained in a reversible [4 + 2] cycloaddition reaction, whereas upon boiling mesitylene, irreversible [2 + 2] cycloaddition yielded azetidinones (150). Previously Sakamoto et al.216 prepared the azetidinones (150) in boiling xylene. 

In 2006, the palladium-catalyzed carbonylative [2+2] cycloaddition of allyl bromide with heteroaryliden anilines was reported to afford 2-azetidinones... 

Alcaide and coworkers have reported in 2002 the synthesis of various types of racemic and homochiral 1,3,4-trisubstituted- or fused polycyclic (3-lactams (III and IV, respectively, Fig. 9) via intermolecular 1,3-dipolar cycloaddition reaction of 2-azetidinone-tethered nitrones with a variety of alkenes or alkynes [264]. 

They have also reported a direct route to optically pure, fused, or bridged tricyclic (3-lactams (III and IV, Fig. 18) as further advances in the intramolecular nitrone-alkene cycloaddition reactions of monocyclic 2-azetidinone-tethered alkenyl-aldehydes [289]. 

The preparation of novel, strained tricyclic (3-lactams (Fig. 22) containing a cyclobutane ring has been developed to be performed by intramolecular [2+2] cycloaddition reactions of 2-azetidinone-tethered enallenols [299],... 

The Diels-Alder cycloaddition reaction of both cis- and trans-dienyl-2-azetidi-nones with unsymmetrical dienophiles in the presence of Lewis acid catalysts has been reported to give in regio-, stereo-, and remarkably high 7i-facial selectivity novel l,3,4-trisubstituted-2-azetidinone derivatives in good yields (I and II, Fig. 26), [306],... 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

Azetidinones. CSI and allyl iodide undergo [2 + 2]cycloaddition to form the zctidine-2-one (1), which can be converted into 3, a potential precursor to carbapenams. 

The 2 + 2-cycloaddition of chlorosulfonyl isocyanate with chiral alkoxyallenes, derived from ethylidene and benzylidene L-erythritol and D-threitol, produces azetidi-nones that are readily converted into the corresponding tricyclic cephams. NMR and CD spectroscopy were used to assign the absolute configurations of the azetidinones... 

The silver acetate-promoted 1,3-dipolar cycloaddition of nitrilimines with 3(/f )-pheny]-4(A )-cinnamoyl-2-azetidinone produced the major adduct, 4-(4,5-dihydro- (g) pyrazol-5-yl)carbonyl-2-azetidinones, with high stereoselectivity.70 The 1,3-dipolar cycloadditions of substituted 2,7-dime(liyl-3-thioxo-3,4,5,6-ici.rahydro-2//- 1,2,41 triazepin-5-one with iV-aryl-C-ethoxycarbonylnitrilimines are highly chemoselective, where the sulfur atom of the dipolarophile interacts with the carbon atom of the dipole.71 The enantioselective 1,3-dipolar cycloaddition of nitrile imines with electron deficient acceptors produces dihydropyrazoles in the presence of 10 mol% of chiral Lewis acid catalyst.72... 

The synthesis of carbacephems 183 and 186 involving C(4)-N(5) bond formation has been described. Carbacephem 183 has been prepared through aza-Achmatowicz rearrangement of 4-(2-furyl) azetidinones (Scheme 32) <1996CC881, 1998SL105>. Azetidinone 175 was obtained by the formal cycloaddition of suitable ketenes with iV-/>-anisyl-2-furylimines. 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

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