Azetidines, 3-acyl

N-Inversion in azetidine and azetidin-2-one is rapid, even at —77 and -40 °C, respectively (B-73NMR144). Again, halo substituents on nitrogen drastically slow the inversion rate, so that Af-chloro-2-methylazetidine can be separated into two diastereomers (b-77SH(1)54). Substituent effects on N-inversion are much the same as in the aziridines Af-aryl and N- acyl... 

A number of examples of acid catalyzed ring expansion of acyl and thioacyl azetidines to sbc-membered rings have been reported (B-73MI50903). This type of rearrangement (Scheme 2) is similar to the more general vinylaziridine to pyrroline ring expansion. 

Azete, trisdimethylamino-isolation, 7, 278 Azetes, 7, 237-284, 278-284 benzo fused, 7, 278 benzodiazepine fused applications, 7, 284 fused ring, 7, 341-362 structure, 7, 360 2,3-naphtho fusion, 7, 278 reactivity, 7, 279 structure, 7, 278 synthesis, 7, 282-283 Azetidine, acylring expansion, 7, 241 synthesis, 7, 246 Azetidine, 3-acyl-irradiation, 7, 239 synthesis, 7, 246 Azetidine, N-acyl-synthesis, 7, 245 Azetidine, alkyl-synthesis, 7, 246 Azetidine, 3-alkylthio-synthesis, 7, 246 Azetidine, 3-amino-synthesis, 7, 246 Azetidine, N-amino-oxidation, 7, 241 synthesis, 7, 246 Azetidine, aryl-synthesis, 7, 246... 

The main interest in azacyclobutanes is reserved for azetidin-2-ones ( 3-lactams), as this ring system is found in penicillin and cephalosporin antibiotics (Box 8.2). These compounds are effective because the (3-lactam ring is strained and readily reacts with the enzyme transpepidase, responsible for the development of the bacterial cell wall. The ring of the lactam is cleaved by this enzyme, which becomes 0-acylated in the process (Scheme 8.6). Once this occurs the enzyme s normal cross-linking function is lost and the cell wall is ruptured. 

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). 

A-(tert-Butoxycarbonyl)azetidine-2-carboxylic acid is obtained by reaction of azetidine-2-carboxylic acid with Boc-N3, m 112 Boc20, 113-"4 or 2-(fert-butoxycarbonyloxyimino)-2-phe-nylacetonitrile. 115 In a similar manner, the Fmoc derivative is prepared by the standard procedure using Fmoc-OSu as acylating agent.1"6 For derivatives of azetidine-2-carboxylic acid, see Table 4. 

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

In 2005 highly potent and selective inhibitors of cathepsin K were reported based on the 3,4-disubstituted azetidin-2-one which seemed to transiently acylate the sulfhydrile of cathepsin K [365]. 

Nitration of I-substituted azetidines with N2Os often gives ring-opened products similar to those found for aziridines (95T5073). However, V-acyl azetidines undergo nitrolysis of the substituent to yield /V-nitroazetidines in good yields. 

Chiral azetidines have been synthesized by lipase-catalyzed selective acylation of the hydroxyl group in 2,4-bis(hydroxymethyl)azetidine 112 (Scheme 24) <2001TA605>. The resulting alcohol 113 was then transformed into an amino alcohol 114 (Equation 29), which represents an interesting precursor for the chiral catalyst 115. 

Reduction of an azide functionality at C-3 of azetidin-2-one 355 followed by acylation afforded 3-amidoazetidin-2-one 356 (Scheme 50). O-Debenzylation, followed by treatment with the Jones reagent, afforded a m-3,4-disubsti-tuted azetidin-2-one 357, which is a precursor of the antibiotic loracarbef <2001TL4519>. The reduction of an ethoxycarbonyl group and an acetoxy group at C-3 to a hydroxyl group has been accomplished by sodium borohydride (Equation 134) <2001T10155>. 

A new reaction of iV-acyl thiazolidinethione enolates with enolizable aldoxime ethers has been reported to give 2-(thiazolidine-2-thione)-l-azetines 608 with excellent diastereoselectivity (Equation 235) <2003JA3690>. The absence of either a methoxy or a carbonyl group in the 1-azetines indicated a complex mechanism rather than a simple addition reaction. The formation of azetines has been rationalized by combination of the oxime and TiCh to give a highly electrophilic trichlorotitanium iminium intermediate 609, which adds onto enolate 610 to form intermediate 611, which cyclizes to azetidines 612 (Scheme 81). An irreversible elimination of bis-trichlorotitanium oxide provides the ultimate driving force to produce azetines. 

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