Lactam formation cycloaddition

Staudinger reaction of imine 8 derived from 7-oxanorbomenone with 2-alkoxy-acetyl chlorides in the presence of Et3N (toluene, RT), afforded (3-lactams 9 (Scheme 3). These were obtained as single diastereomers, and no traces of the corresponding isomeric exo-(3-lactams were detected in the crude reaction products [50]. It is worth mentioning that this stereochemical outcome of (3-lactam formation with acid chlorides under Staudinger reaction conditions was opposite to the one expected from a simple [2+2]-cycloaddition reaction, which should have taken place from the exo face of compound 8. 

Sordo et al. [144] explained the stereoselectivity on the basis of torquoelectronic effects. Low-temperature infrared spectroscopy was also used to identify the reactive intermediates [145]. Two mechanisms were proposed to explain the product distribution in the (3-lactam formation reaction. The ketene mechanism was observed in a low temperature infrared spectroscopy study [145], while the acylation of imine mechanism was believed to be involved in some [122]. Both mechanisms were supported by evidences. It had been hypothesized that cycloaddition of the imine occurs from the least hindered side of the ketene, and this process generates zwitterionic intermediates conrotatory cyclization of these intermediates then produce cis- and //Y/ .v-[S-lactanis. Acylation of the imine by the acid chloride to form /V-acyliminium chloride also produced zwitterionic intermediates (Scheme 10). 

In a similar manner, imines 50 with various ancillary groups X, such as ethoxy-carbonyl, 2-pyridyl, or 2-thiazolyl, are also converted into lactams 51 in mod-erate-to-good yields (Eq. 24) [38]. The [2+2+1] lactam formation using a chiral substrate 52, ethylene, and CO quantitatively furnished the spiro lactam 53 (Eq. 25) [39]. The cycloaddition exclusively took place at the carbon-nitrogen double bond next to the oxazine oxygen atom, although 53 was obtained as a diastereomeric mixture. 

The main principles of lactam, especially 3-lactam, formation by cycloaddition, exemplified by equation (49), are described in Volume 5, Part 2 of this series. 

Cycloadditions. The scope of the Evans asymmetric aziridination is broadened by the ready availability of nitrene precursor 4-02NCjH S02N=IPh. The oxazolidinone-Af-acetic acid derived from (+)-cw-2-amino-l,2-diphenylethanol participates in p-lactam formation with imines. The predominant products (>99 1) have the (3/f,45)-configuration. The intramolecular [2+2]photocycloaddition involving a chiral allenylsilane moiety is an excellent method for accessing optically active methylenecyclobutane derivatives. ... 

The mechanism of 3-lactam formation in enolate-imine condensations proceeds by the stepwise pathway depicted in Scheme 19, in which diastereomeric 3-lactams (100) and (101) are formed by cycliza-tion of intermediate, metalated amine adducts (98) and (99), respectively. The possibility of a less likely [2 -I- 2] cycloaddition mechanism has been discussed. - Equilibration between 3-lactams (100) and (101) via epimerization at C-3 does not normally occur. The stepwise mechanism is supported by the fact that trans 3-lactam (101 R = Pr R = R = Ph) is formed from (99 M = MgBr) without loss of... 

The synthesis of tabtoxinine /3-lactam is briefly outlined in Scheme 3-XII. The initial nitroso formate cycloaddition was totally regioselective and provided the basic functionality needed to ultimately prepare 18. 

Menthol [(—)-l] has been used as a chiral ligand for aluminum in Lewis acid catalyzed Diels-Alder reactions with surprising success2 (Section D.l.6.1.1.1.2.2.1). The major part of its application is as a chiral auxiliary, by the formation of esters or ethers. Esters with carboxylic acids may be formed by any convenient esterification technique. Esters with saturated carboxylic acids have been used for the formation of enolates by deprotonation and subsequent addition or alkylation reactions (Sections D.l.1.1.3.1. and D.l.5.2.3.), and with unsaturated acids as chiral dienes or dienophiles in Diels-Alder reactions (Section D. 1.6.1.1.1.), as chiral dipolarophiles in 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), as chiral partners in /(-lactam formation by [2 + 2] cycloaddition with chlorosulfonyl isocyanate (SectionD.l.6.1.3.), as sources for chiral alkenes in cyclopropanations (Section D.l.6.1.5.). and in the synthesis of chiral allenes (Section B.I.). Several esters have also been prepared by indirect techniques, e.g.,... 

This method is an extension of the known ketene—imine procedure, which has been in use for -lactam formation since the beginning of the century [51]. Examples of this acid chloride - ketene route up to the end of 1971 have been reviewed by Mukerjee and Srivastava [52]. It is interesting to note that, depending upon the experimental conditions, both the concerted 1,2-cycloaddition path and another involving an acylation step and salt formation can be operative [53,54], The former is supported by the formation of by-products of dioxo-piperidine type [55,56]. Use of this procedure has provided a number of azaoctams of type (92) [46]. 

Mandai G2 (2009) plan for oseltamivir phosphate p-lactam formation in step 3 via [2 + 2] cycloaddition and opened in step 9. 

In a recent example of p-lactam formation dehydration ofphenoxyacetic acid with 2-fluoro-l-methylpyridinium p-toluenesulfbnate in the presence of diaryhmines is proposed to proceed thorough the pyridinium intermediate 142 which leads to phenoxyketene, which reacts by [2 + 2] cycloaddition with the imine forming the product ds-P-lactam (Eqn (4.87)). Similahly propylphosphonic anhydride (T3P) was also successful in carboxylic acid activation (Eqn (4.88)). 

Phenylketene generated from phenylacetyl chloride with triethylamine gives [2 + 2] imine cycloaddition with catalysis by the N-heterocyclic carbene prepared by partial electrochemical reduction of 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM-BF4) as solvent gives iraws-p-lactam formation (Eqn (4.92)). The zwitterionic intermediate formed in the reaction is stabiHzed by the highly ionic solvent, which also allows isomerization to form the trans product. The use of such N-heterocyclic carbenes in the catalysis of [2 + 2] cycloadditions of ketenes has been reviewed. ... 

The lactam is an important class of heterocycles and has been investigated due to its potent anti-bacterial activity. Among the multiple synthetic approaches, a [2 -i- 2] cycloaddition of a ketene with an imine, is one method to provide quick access to cis P lactams. The typical prerequisite for these protocols involves the generation of the ketene from an activated carboxylic acid derivative (often an acyl chloride), which limits the scope of this pathway. Lee and coworkers developed a rhodium-catalyzed oxygenative addition reaction that furnishes the acyl chloride equivalent from a more stable terminal alkyne 41. An intermediate rhodium vinylidene then undergoes a [2 -i- 2] cyclization with imines (42) to provide the P-lactam 4. This reaction pathway enables more easily accessible alkynes to be employed as substrates for tran -P-lactam formation. 

The reaction is a reversible stereospecific process which most likely proceeds via a concerted mechanism. An ab-initio study of the [2+2] cycloaddition reaction predicts that /3-lactam formation is a concerted suprafacial process . The stereospecificity of the [2+2] cycloaddition reaction is evidenced by the fact that cis- and trans- mieat-2 give the respective cycloadducts in high yields, indicating that the life of the ionic 1 1 adduct is shorter than the rotational time about the developing carbonium ion . The kinetics of the reaction were studied by Clauss , who found that CSI (chlorosulfonyl isocyanate) reacts... 

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

---