Lactams stereocontrol

Ikota, N., O. Yoshino, and K. Koga Synthetic Studies on Optically Active p-Lactams. Stereocontrolled Synthesis of Chiral Thienamycin Intermediates from D-Glucose. Chem. Pharm. Bull. 30, 1929 (1982). 

Regio- and stereocontrolled radical cyclizations in syntheses of (3-lactams 97YZ973. 

Stereocontrolled synthesis of oxabicyclic (3-lactam antibiotics via [2- -2] cycloaddition of isocyanates to sugar vinyl ethers 96CC2689. 

The same authors also studied recently the preparation of substituted vinyl -lactams 14, with efficient stereocontrol [11], by use of limited amounts of solvent (chlorobenzene) (Scheme 8.7). Microwave oven-induced reaction enhancement (MORE) chemistry techniques have been used to reduce pollution at the source and to increase atom economy. 

Several eco-friendly approaches to vinyl-/i-lactams (219-221) bearing a vinyl substituent at various positions on the ring (Scheme 9.71) have recently been described by Manhas [122]. Vinyl-/i-lactams are efficient synthons for a variety of compounds of biomedical interest, e. g. isocephalosporins, carbapenem intermediates and pyrrolidine alkaloids. MORE chemistry techniques allow highly accelerated syntheses using limited amounts of solvent and with efficient stereocontrol, thus achieving high atom economy . 

The Baylis-Hillman reaction of TV-protected 3-substituted 4-formylazetidin-2-ones with methyl vinyl ketone has been used to prepare intermediates from which highly functionalised P-lactams fused to medium rings were obtained by radical, stereocontrolled methods <99CC1913>. 

Environmentally Benign Chemistry—Microwave-Induced Stereocontrolled Synthesis of Beta-Lactam Synthons (Banik et al., 1997)... 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

In cell culture, 1 is by far the most active of these three natural products. The challenge in the synthesis of 1 is not closing the (1-lactone, but rather the stereocontrolled assembly of the y-lactam 9. 

A major method for the preparation of y-amino-()-hydroxy adds of syn configuration is the stereocontrolled reduction of enantiomerically pure tetramic acids 32, followed by alkaline or acid hydrolysis of the resulting N-protected 4-hydroxy lactams 33 (Scheme 9))53-571... 

The synthesis of spirocyclic and fused unusual (3-lactam derivatives has been discussed. The 2-azetidinone skeleton has been extensively used as a template on which to build the carbo(hetero)cyclic structure joined to the four-membered ring, using the chirality and functionalization of the (3-lactam ring as a stereocontrolling element. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found. 

Microwave-induced organic reaction enhancement chemistry techniques have been reported to allow highly accelerated synthesis of variously substituted vinyl-(3-lactams, using limited amounts of solvents and with efficient stereocontrol [3]. 

A stereocontrolled Staudinger cycloaddition reaction has been reported to be performed on vinylketenes, possessing a y-heteroatom, and imines to produce frans-vinyl-(3-lactams [112]. The vinyl side chain adopted stereoselectively the (Z) configuration in the transition state, stabilizing the vinyl ketene and leading, exclusively, to the frans-3-vinyl-(3-lactam (Scheme 37). 

A general approach towards the asymmetric synthesis of amino acid derived 4-alkyl-4-carboxy-2-azetidinones has been described [192], The (+)- or (-)-lO-(N, Af-dicyclohexylsulfamoyl)isobomeol was used as chiral auxiliary in the intramolecular cyclization of /V-(/>methoxybenzyI)-/V-chloroacetyl Phe and Ala derivatives for the stereocontrolled base-catalyzed construction of the (1-lactam ring (Scheme 85). 

The group of Palomo has reported in 2003 the preparation of short pseudopeptides containing enantiopure a-substituted a-amino-fS-lactam fragments (II, Fig. 11) by a-alkylation of suitable V-[bis(trimethylsilyl)methyl]-(3-lactams through a totally stereocontrolled way [270]. 

More recently, we have found that the role of the isomerization pathways in the reaction between ketenes and imines can be extended to the (E)/(Z) isomerization of imines themselves [68]. Thus, the stereocontrol observed in the reaction between methoxyketene 41 and (E)-imines (62a,b) was attributed to the competition between the energy barriers associated with the formation of intermediates (63a,b) and (65a,b) and the energies of activation corresponding to the isomerisation of (E)-imines (62a,b). Inclusion of isomerisation processes involving both imines (62a,b) and zwitterionic intermediates (63a,b) and (65a,b) led to a more complex kinetic analysis. As the final steps leading to (3-lactams (64) can be considered irreversible, the formation of both cis- and trans-(64) can be described by (3) and (4) ... 

In a complementary approach, the stereocontrolled [4-exo-tet] cyclization of enolates (71) in which the nucleophilic species attack from the C4-position of the p-lactam ring to be formed has been reported [77] (Scheme 17). B3LYP/6-311+ +G calculations showed that the enolates (71) are preferred with respect to enolates (72) thus resulting in the formation of (3-lactams (3S,4)-(73). 

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition-elimination reaction yields the (5-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

Allylation of organic halides. T wo laboratories2 have reported briefly that in the presence of a radical initiator organic halides undergo allylic substitution reactions with allyltrialkyltin compounds in moderate yield. This reaction was used in a recent Synthesis of the neurotoxin (+ )-perhydrohistrionicotoxin (7) to introduce the n-butyl tide chain.3 AI BN-catalyzed reaction of the bromide 2 with 1 proceeds in unexpectedly igh yield and with complete stereocontrol to give a single product 3. It is the tndesired isomer, but the desired stereochemistry is obtained by epimerization of the Intermediate ketone 5. The hydroxy lactam (6) had previously been used for the Synthesis of 7. 

The stereocontrolled synthesis of functionalized lactams has been achieved via sulfur-stabilized enolates.36 Thio-substituted enolates were the reagents of choice as these proved to be more generally applicable than the corresponding sulfoxide-substituted enolates. 

M. Chmielewski, Z. Kaluza, and B. Furman, Stereocontrolled synthesis of 1-oxabicyclic /1-lactam antibiotics via [2 + 2]cycloaddition of isocyanates to sugar vinyl ethers, Chem. Commun. (Cambridge), (1996) 2689-2696. 

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