Bis-p-lactams

Scheme 5 Synthesis and subsequent cleavage of azetidin-2-one ring of bis-P-lactams...

In a similar way, formation and subsequent hydrolysis of bis-p-lactams provide a route to peripheral functionalization of macrocyclic imines. For example, racemic bis-p-lactam 15, Scheme 5, which is formed upon Staudinger reaction of imine 14 and the ketene originated from phenoxyacetyl chloride and triethylamine, led to C2 symmetric amino acid 16 in high yield [59]. 

Bisketenes can provide different reaction paths in the reaction with imines (Scheme 18). For example, bisketene (74) does not form p-lactam species like (76). Instead, DFT computations [78] indicate that zwitterionic intermediate (75) leads to the furane intermediate (77) whose cyclization yields aziridine (78). 1,2-, 1,3- and 1,4-bisketenyl benzene react normally to yield mainly bis (p-lactams) [78],... 

Antifungal and antibacterial activity have also been reported for bile acid dimers linked through 1,2,3-triazole and bis-p-lactam [336]. 

Groups, like 6-oxo-l,6-dihydropyrimidin-3-ium -oleates, are light-sensitive and undergo intramolecular photo-cyclization to bis-p-lactams when irradiated with UV light between 320 and 490 nm [189]. 

Preparation of bis-P-lactams by ketene—imine cycloadditions 13THC (30)111. 

The preparation of bis(P-lactams) has been a more recent aspect of the study of ketene-imine reactions, and in one example ketenes generated by dehydrochlorination react with bisimines to form bis(P-lactams) 144 as... 

The bis(acyl chloride) from adipic acid reacts with imines generated in situ from 2-aminobenzothiazole and aryl aldehydes in the presence of zeohtes as acid catalysts resulting in formation of bis(p-lactams) (Scheme 4.31). The reactions were found to be enhanced by the use of ultrasound, and while the reactions were presumably largely stepwise bisketenes can be formed under these conditions. The preparation of bis- and poly(p-lactams) by ketene cycloadditions has been reviewed. 

Translactamization occurs when the bis-P-lactam (258) is heated the product (259) can then be methylated at nitrogen to give the natural product homalin (Scheme 131). ... 

An interesting preparation of alkyl carboxylates in high yield (Table 3.14) from the sodium salt of the carboxylic acids under mild phase-transfer catalytic conditions involves their reaction with alkyl chlorosulphate [50] and has been used with success in the preparation of alkyl esters derived from p-lactam antibiotics. The procedure is also excellent for the production of chloromethyl esters, particularly where the carboxylic acids will not withstand the classical Lewis acid-catalysed procedure using an acid chloride and formaldehyde, or where the use of iodochloromethane [51] results in the formation of the bis(acyloxy)methane. The procedure has been applied with some success to the synthesis of chloromethyl A-protected a-amino carboxylates [52],... 

The above reagents serve as condensing reagents and have different reactivities for peptides 279, p-lactams 281, esters, thioesters, and mixed phosphates, as well as for the direct preparation of 3-acyl-2(3F/)-oxazolones. The bis(2-oxo-3-oxazohnyl)phosphinate 282 is useful for Zr(IV)-catalyzed phosphorylation of alcohols, leading to the general synthesis of acid- and base-labile mixed phosphate esters 284 (Fig. 5.67). ... 

A/-Phenylazetidin-2-ones are prepared by reaction of a P-lactam with bromobenzenes in the presence of palladium(II) acetate and l,l-bis(diphenylphosphino)ferrocene <99TL2035>. 

Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spiro-[S-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-p-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-p-lactams 231 was established by X-ray crystallographic studies. These spiro-p-lactams will be studied as precursors of modified p-amino acids, (3-peptides and monobactam analogues. 

Analogously, in 2004, it has been reported that the treatment of bis-spirocy-clopropanated isoxazolidines [202-207] with TFA in acetonitrile furnished the 3-spirocyclopropanated p-lactams in 75-96% yields [208]. 

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]. 

Regio- and stereoselective metal-mediated l,3-butadien-2-ylation reactions between 1,4-dibromo-2-butyne or l,4-bis(methanesulfonyl)-2-butyne and optically pure azetidine-2,3-diones in aqueous media offers a convenient asymmetric entry to potentially bioactive 3-substituted-3-hydroxy-p-lactams 19 <02JOC1925>. In addition, 2-azetidinone-tethered 1,3-butadienes can easily be transformed into other functionalities via Diels-Alder reaction. 

The 4,4 dimethoxydiphenylmethyl (Ddm) group, or to be more precise bis(4-methoxypheny])methyl, is another activated arylmethyl group that is labile towards oxidative and acidic cleavage. It has been used to protect p-lactams and in the example shown in Scheme 8.195, cleavage was effected with... 

The reaction of ketene silyl acetals with 1 catalyzed by trimethylsilyl triflate affords N,N-bis(trimethylsilyl)-P-amino esters (2), which undergo desilylation to P-amino acids (3). These products are convertible into p-lactams on treatment with base. ... 

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