Trans 3 Alkyl /? lactams

Trisubstituted (3-lactams have been reported to be obtained through oxidative removal of the /V-alkyl group from more complex (3-lactams by treatment with cerium ammonium nitrate [260], Anologous methodology was employed for a general synthesis of cis- and trans-(3-lactams bearing a quinone moiety at the N-l, the C-3, or the C-4 position (I, II and III, respectively, Fig. 8), [261]. 

Rearrangement of (3-lactams, bearing a bromo-iso-alkyl group at C4, to y-lactams via A-acyliminium intermediates has been described by De Kimpe [142-144]. Besides the major trans y-lactam product 187 and 188, respectively, traces of the corresponding cis diastereomer and minor quantities of the dehydro-halogenated (3-lactam, are also obtained (Scheme 57). Application to the synthesis of bicyclic y-lactams from monocyclic (3-lactams has been described [144]. 

The reaction of imines with Reformatsky reagents was first examined by Gilman and S pee ter82 in 1943 with benzalaniline. The product of the reaction was a (3-lactam, formed by cyclization of an intermediate zinc salt (Scheme IS). The stereoselectivity of the reaction of a-alkyl-substituted bromo esters with a variety of benzalanilines was examined by both Luche and Kagan,83 and Gaudemar and coworkers.84 Condensations conducted at reflux temperatures gave a mixture of cis and trans 3-lactams (equation 41). 

The study of [2 + 2]cycloaddition of chlorosulfonyl isocyanate (CSI) to a variety of l,2-0-isopropylidene-3-0-vinyl-D-glycofuranoses (Scheme 32) showed that the observed high selectivity of these reactions was steri-cally controlled and depended on the size of the substituent at C-5 of the sugar [89]. The /3-lactams 113 and 114, obtained from vinyl ethers 112, were transformed into the corresponding cephams 115-118 by the intramolecular alkylation of the j6-lactam nitrogen atom [89,90]. [2 -I- 2]Cycloaddition of CSI to (Z) and (E) vinyl ethers proceeds stereospecifically with asymmetric induction in the range reported for simple vinyl ethers to afford corresponding cis and trans /3-lactams [91,92]. 

Lactam 299 was prepared from tryptamine and cyano diester 298 by reductive alkylation in about 12% yield. Phosphorus oxychloride cyclization of 299, followed by catalytic reduction, resulted in the corresponding trans disubstituted indolo[2,3-a]quinolizine 300. After transesterification, formylation and methyla-tion were carried out in two subsequent steps with ethyl formate in the presence of triphenylmethylsodium and with an excess of diazomethane to supply ( )-dihydrocorynantheine (163). 

Methyl esters undergo trans-esterification with the quaternary ammonium salts at high temperature and the reaction has been used with some effect for the preparation of, for example, n-butyl esters by heating the methyl ester with tetra-n-butylammo-nium chloride at 140°C [31]. Optimum yields (>75%) are obtained in HMPA or in the absence of a solvent. A two-step (one-pot) trans-esterification under phase-transfer catalysed conditions in which the carboxylate anion generated by initially hydrolysis of the ester is alkylated has been reported for Schiff s bases of a-amino acids [32] and for A-alkoxycarbonylmethyl [1-lactams [33]. Direct trans-esterification of methyl and ethyl esters with alcohols under basic catalytic conditions occurs in good yield in the presence of Aliquat [34, 35]. 

Cyanogen Iodide (ICN) has been used extensively for the cyanation of alkenes and aromatic compounds [12], iodination of aromatic compounds [13], formation of disulfide bonds in peptides [14], conversion of dithioacetals to cyanothioacetals [15], formation of trans-olefins from dialkylvinylboranes [16], lactonization of alkene esters [17], formation of guanidines [18], lactamization [19], formation of a-thioethter nitriles [20], iodocyanation of alkenes [21], conversion of alkynes to alkyl-iodo alkenes [22], cyanation/iodination of P-diketones [23], and formation of alkynyl iodides [24]. The products obtained from the reaction of ICN with MFA in refluxing chloroform were rrans-16-iodo-17-cyanomarcfortine A (14)... 

Solid-phase preparation of trans 3-alkyl (3-lactams was reported by Mata et al. recently (Scheme 14) [103]. The synthetic sequence involved the start from Fmoc-glycine tethered to Wang resin, followed by addition of a controlled excess of 43 (4 equiv) and triethylamine (8 equiv) to the resin bound imine 42 in refluxing toluene. Cleavage form resin surface and esterification afforded the 3-alkyl (3-lactams, 45, as a single product with excellent trans-selectivity. 

The alkylation of y-acetoxy or y,y-difluoro-o ,/3-unsaturated-5-lactams (2) with Me3CuLi2.LiI.3LiBr and an alkyl halide2 gave mainly the 3,6-cis isomer (3) when the alkyl halide was small (Mel), but mainly the 3,6-trans isomer (4) when a bulky (g) alkyl halide was used. Calculations at the B3LYP/6-31G(d) level of theory suggested the mechanism in Scheme 1 where the intermediate is stabilized by an interaction... 

However, cycloaddition involving aryl a-amido sulfone afforded modestly attenuated yields due to competing formation of the P-lactam adducts, possessing the unanticipated trans diastereoselection that was not observed for alkyl imine electrophiles (Eq. (10.1)). 

The reaction of ester enolates with imines is a general method for the preparation of /5-lactams. This reaction is clearly not a concerted cycloaddition. The enolate adds to the imine generating an arnido ester intermediate. This intermediate, which is usually not isolated, cyclizes to give the /3-lactam. Since this subject has been recently reviewed81, only the stereochemical aspects of this reaction will be discussed here. In this reaction there are four possible sites for the chiral auxiliary. As in ketene imine cycloadditions, stereogenic centers can be introduced into the substituent on the imine carbon (R1), the substituent on the imine nitrogen (R2) or the substituent on the acyl portion of the ester (R3). There is a fourth possibility in these cycloadditions since the stereogenic center can also be introduced into the alkyl portion of the ester (R4), In some cases /r K-/ -lactams are obtained exclusively, while in other cases, mixtures of cis- and trans-isomers are isolated. 

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