Lactams asymmetric reactions

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

Reactions with imines also occur under similar conditions leading to the formation of difluorinated /1-lactams [196,197]. Formally, this reaction corresponds to a [2+ 2]-cycloaddition across an imine there is also an isolated report of a difluoroketene reaction, shown in Eq. (63) [198]. Useful chemistry of a silyl difluoroketene acetal was reported recently Eq. (64) shows the efficient asymmetric reaction between this reactive carbon nucleophile and aldehydes catalysed by chiral Lewis acids [199]. 

Stoichiometric and catalytic asymmetric reactions of lithium enolate esters with imines have been developed using an external chiral ether ligand that links the components to form a ternary complex.36 The method affords /i-lactams in high enantiomeric excess. 

Groaning, M. D. Meyers, A. I. Chiral Non-Racemic Bicyclic Lactams. Auxiliary-Based, Asymmetric Reactions, Tetrahedron... 

Imines derived from optically active amines have also been used in asymmetric Staudinger syntheses of p-lactams. Georg et al. [32] employed O-acetylated galactosylamine as the chiral auxiliary for the synthesis of P-lactams. The reaction between imines 41 and aryloxyacetyl chlorides 42 in the presence of Et3N afforded c/ -configurated A -galactosyl-P-lactams 43 in diastereomeric ratios not exceeding 66 34 (Scheme 10.11). 

The examples outlined in this chapter show that carbohydrates are efficient stereodifferentiating auxiliaries, which offer possibilities for stereochemical discrimination in a wide variety of chemical reactions. Interesting chiral products are accessible, including chiral carbo- and heterocycles, a- and 3-amino acid derivatives, 3-lactams, branched carbonyl compounds and amines. Owing to the immense material published since the time of the earlier review articles on carbohydrates in asymmetric synthesis [9,10], the examples discussed in this chapter necessarily focused on the use of carbohydrates as auxiliaries covalently linked to and cleavable from the substrate. Given the scope of this chapter, a discussion of other interesting asymmetric reactions has not been permitted — for example, reactions in which carbohydrate-derived Lewis acids, such as cyclopentadienyl titanium carbohydrate complexes, exhibit stereocontrol in aldol reactions [180]. Similarly, processes in which in situ glycosylation induces reactivity and stereodifferentiation — for example, in Mannich reactions of imines [181] — have also been excluded from this discussion. 

Miura and coworkers showed that the reaction could also be carried out using catalytic amounts of Cul in the presence of pyridine (95JOC4999). Asymmetric reactions were reported to occur with chiral bisoxazoline ligands producing p-lactams with moderate (40-68%) enantiomeric excesses. Use of an oxazolidinone with a chiral auxiliary appended to the alkyne also provided enantiomerically pure products (02TL5499). In all of these latter reports, mixtures of cis and irons lactam isomers were obtained in which the trans-product predominates. It was also shown that the c/s-isomer could easily be converted to the trans-product when exposed to base. 

For the synthesis of bis-3-lactam (JJ) (Scheme 14), the synthetic equivalent of a tripeptide, a quite effective asymmetric reaction in the formation of 3-lactam was found The azidoketene cycloaddition to a diastereomerically pure 3-benzylideneamino-3-lactam or proceeds in a completely stereoselective manner... 

The preparation of optically pure carbocycles from bicylic lactam templates has been described in a review looking at the use of chiral bicyclic lactams in auxiliary-based asymmetric reactions. ... 

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

Groaning MD, Meyers AI. Chiral non-racemic bicyclic lactams, auxiliary-based asymmetric reactions. Tetrahedron 2000 56(51) 9843-9873. 

Asymmetric synthesis of 3-amino (3-lactams via Staudinger ketene-imine cycloaddition reaction 98KGS1448. 

Whereas there are numerous examples of the application of the products from diastereoselective 1,3-dipolar cycloaddition reaction in synthesis [7, 8], there are only very few examples on the application of the products from metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction in the synthesis of potential target molecules. The reason for this may be due to the fact that most metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction have been carried out on model systems that have not been optimized for further derivatization. One exception of this is the synthesis of a / -lactam by Kobayashi and Kawamura [84]. The isoxazoli-dine endo-21h, which was obtained in 96% ee from the Yb(OTf)3-BINOL-catalyzed... 

Intermolecular Schmidt reactions of alkyl azides and hydroxyalkyl azides with cycloketones in the presence of a Lewis acid, lead to formation of iV-alkyl lactams and A-hydroxyalkyl lactams respectively in good yield. The synthesis of chiral lactams by an asymmetric Schmidt reaction has also been reported. ... 

Reaction of p-nitrophenyl 2-(p-tolylsulfinyl)acetate 161 with aryl aldimines in the presence of imidazole was found to give /j-lactams 162 and amides 163206. In the cyclization, only the two 3,4-trans derivatives were formed out of a possible four diastereomeric pairs and, interestingly, the ratio of two diastereomeric pairs went up to 6.7 1. This means not only that internal asymmetric induction207 affords the trans derivative, but that also a relatively high asymmetric induction took place during the reaction. 

Fig. 40 Formation of (3-lactams via asymmetric Staudinger-type reactions, catalyzed by 64c...

Taggi AE, Hafez AM, Wack H, Young B, Ferraris D, Lectka T (2002) The development of the first catalyzed reaction of ketenes and imines catalytic, asymmetric synthesis of P-lactams. J Am Chem Soc 124 6626-6635... 

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