P-Lactams from imines

The first synthesis of (3-lactams bound to a soluble/insoluble polyethylene glycol monomethylether polymeric matrix has been realized by standard reactions carried out on immobilized imines. From the polymer, [3-lactams were removed under acidic and basic conditions [76, 77]. The reactivity of the immobilized reagent was tested by synthesizing p-lactam from imines and an enolate 8a and the... 

Scheme 5-176. p-Lactams from imines and allylic substrates. ... 

Condensation reactions of simple carboxylic acids with imines are of intense interest because of their applications to p-lactam synthesis. Activation of the carboxylic acid derivative is accomplished by preforming the enolate in situ or by using a silyl ketene acetal derivative with Lewis acid catalysis. The first example of an enolate-imine condensation of this type can be attributed to Gillman and Speeter, who in 1943 reported the synthesis of P-lactams from Reformatsky reagents and Schiff bases.87 Subsequently, other workers have investigated the mechanism and syn-anti selectivity of this reaction. A review of these studies by Evans et al. covering work through 1980 has appeared in their review, Stereoselective Aldol Condensations .10... 

An efficient and selective solid-phase synthesis of trans 3-alkyl-4-aryl-P-lactams from nonactivated acid chlorides has been accomplished <04TL4085>. The [2+2] cycloaddition between an aldehyde-derived resin-bound imine and a solution-generated ketene has been used to generate a variety of stereochemically pure cw-P-lactams <04JOC5439>. A new polymer-supported reagent has been used for the preparation of P-... 

Boyer, N. Gloanec, R De Nanteuil, G. Jubault, R Quirion, J.-C. Chemoselective and stereoselective synthesis of gcm-difluoro-P-aminoesters or gcm-difluoro-P-lactams from ethyl bromodifluoroacetate and imines during Reformatsky reaction. Tetrahedron 2007, 65(50), 12352-12366. 

A multistep solid phase synthesis of p-lactams with imines of benzaldehyde coming out from commercially available fluorinated a-amino acids has been reported in 2003 [77]. Using the Merrifield resin-bound imine [78, 79] in dichlor-omethane, the cycloaddition was carried out between 78°C and rt by addition of benzyloxyacetyl chloride in the presence of triethylamine. The resin cleavage using sodium methylate resulted in the two cis p-lactam derivatives (Scheme 20). 

SCHEME 2.7 A more general kinetic scheme for the formation of cis- and trawi -P-lactams from monosubstituted ketenes and ( )-imines. 

The ultrasoimd-assisted Reformatsky reaction was used in the preparations of diverse P-hydroxy esters326 (see p. 80). From imines, P-lactams are produced with the stereoselectivity imchanged with respect to the usual conditions (Eq. 74).327... 

In addition to the studies mentioned above, chiral alcohols have been used as H-bonding catalysts in a vinylogous aldol reaction of Chan s diene with aldehydes [73], in an enantioselective Strecker reaction [74], and in the enantioselective addition of aza-enamines to imines [75]. Taddol has also found use as a memory of chiraUty enhancer in the stereoselective synthesis of P-lactams from amino acid derivatives [76, 77]. 

The intramolecular cyclization route to p-lactams still provides interest. P-Amino esters (obtained by a Reformatsky-type reaction of an imine and bromoacetates derived from chiral alcohols) are cyclized by the action Grignard reagents to 4-substituted P-lactams with impressive e.e. <96TL4095>. A similar approach through a Reformatsky-type reaction uses tricarbonyl(Ti -benzaldimine)chromium complexes and ultrasound <96T4849>. 3-Methyl-azetidin-2-ones (obtained from 3-amino-2-methylpropionates) have been resolved and their... 

Azolium enolates such as 65 can be generated directly through addition of NHCs to symmetrical or unsymmetrical ketenes. For example, Smith and co-workers have shown that NHC promoted p-lactam formation from isobutylphenylketene 61 and AT-tosyl imines 63 proceeds with good yields and moderate levels of diastereoselec-tivity via enolate 65 (Scheme 12.12) [17]. 

P-Lactams. Diketene can function as an equivalent to acetylketene, CH3C0CH=C=0, to provide 3-acetyl-p-lactams by [2 + 2]cycloaddition with imines.1 A stereoselective cycloaddition of this type can furnish a useful precursor (2) to lp-methylcarbapenems. Thus reaction of diketene with the chiral imine 1, prepared in a few steps from the readily available methyl (S)-3-hydroxy-2-meth-ylpropionate (Aldrich), can provide the desired 3,4-frpreviously developed for synthesis of the antibacterial carbapenem 4. 

Monosubstituted-5(4//)-oxazolones behave differently upon reaction with imines. Here, 4-methyl-2-phenyl-5(4/7)-oxazolone 196 (Ri = Ph, R2 = Me) reacts with imines derived from 2-furancarboxaldehyde or 2-thiophenecarboxaldehyde to give 3-amino-p-lactams 197. On the other hand, 196 reacts with chlorosul-fonyl isocyanate in a [2 + 2] cycloaddition to give dioxazabicycloheptanones 198 as shown in Scheme 7.60. ... 

Monobactams have been investigated as p-lactamase inhibitors <98CHE1308, 98CHE1319>. The ketene-imine route to P-lactams was used to obtain 1,3,4-trisubstituted derivatives with high trans selectivity. The enolate from 4-hydroxy-y-lactone reacted with the imine (Ar CH NAr ) to give 59, vdiich cyclized in the presence of lithium chloride at low temperature to yield 60. The compounds were assayed for cholesterol absorption inhibition and 61 (R = = OH, R = F) was found to be a potent inhibitor of 3-hydroxy-3-... 

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. 

In 2000, the group of Banik et al. reported the enantiospecific synthesis of 3-hydroxy-2-azetidinones by microwave assisted Staudinger reaction [51]. Chiral imines, derived from chiral aldehydes and achiral amines, reacted with methoxy- or acet-oxy-acetyl chloride to afford a single, optically pure c/s-p-lactam, (Scheme 7). 

In 2001, p-lactams have been reported to be obtained via Staudinger reaction with complete m-diastereoselection starting from prochiral imine chromium complexes (Scheme 14), [63]. 

Enantioselective synthesis of analogous p-lactams has been also reported [63]. If the starting imine complex was prepared from the corresponding chiral amine in enantiomerically pure form (Fig. 1), two separable diastereomers were obtained. Using, then, one of the two diastereomers, ck-p-lactams were isolated as single enantiomers. 

Rink resin derived imines have been reported to give cycloaddition reactions with acetyl chlorides (or equivalent) using triethylamine as the base and dichloro-methane as the solvent at temperature ranging from 0°C to room temperature [70], The resin-bound p-lactam could be cleaved by using 50% trifluoroacetic acid (TFA) in dichloromethane, to afford the /V-unsubstituted p-lactam. 

Chiral imines derived from D-(+)-glucose have allowed an asymmetric synthesis of p-lactams by the [2+2] cycloaddition with ketenes [85]. c/A-p-Lac tarns were formed with very high diastereoselectivity and the stereochemistry at the C-3 and the C-4 was established as 3S and 4R from the known absolute configuration of the sugar moiety (Scheme 24). 

Scheme 24 Asymmetric synthesis of cw-P-lactams starting from chiral imines derived from D-(+)-glucose...

The synthesis of monocyclic p-lactams via the ester-enolate imine condensation route has been reported to be carried out utilizing triazene esters (Scheme 54), [141], Esters were attached to benzylamine resin by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates were reacted with various imines to give polymer-bound p-lactams in different substitution patterns. Traceless cleavage from the triazene linker yielded the desired p-lactams. 

Iridium-catalyzed reductive coupling of acrilates and imines has been reported to provide trans (3-lactams with high diastereoselection [142], The use of electron-deficient aryl acrylates resulted in improved product yields. The mechanism, proposed by the authors, started from an in situ generated iridium hydride reacting with the acrilate to provide an iridium enolate that, then, reacted with the imine to give a (3-amido ester. Subsequent cyclization furnished the p-lactam and an iridium alcoxide. 

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]. 

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