Ester-enolate cycloaddition

Ester-Enolate Cycloaddition The ester enolate-imine cyclocondensation method (Scheme 3.13) provides fS-lactams in good yields with higher stereoselectivity. Various types of esters and imines can be utilized. Some recent reactions have been mediated by zinc [47], rhodium [48], indium [49], and diethylzinc [50]. 

The reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

N-Metalated azomethine ylides generated from a-(alkylideneamino) esters can exist as tautomeric forms of the chelated ester enolate (Scheme 11.8). On the basis of the reliable stereochemical and regiochemical selectivities described below, it is clear that the N-metalated tautomeric contributor of these azomethine ylides is important. Simple extension of the above irreversible lithiation method to a-(alkylideneamino) esters is not very effective, and cycloadditions of the resulting lithiated ylides to a,(3-unsaturated carbonyl compounds are not always clean reactions. When the a-(alkylideneamino) esters bear a less bulky methyl ester moiety, or when a,(3-unsaturated carbonyl compounds are sterically less hindered, these species suffer from nucleophihc attack by the organometalhcs, or the metalated cycloadducts undergo further condensation reactions (81-85). 

After examining the feasibility of an asymmetric [2 + 2] ketene-imine cycloaddition route and an asymmetric ester enolate-imine cyclocondensation route, we chose the latter route for the efficient asymmetric synthesis of (3/ ,4Sj-3-hydroxy-4-phenylazetidin-2-one and (2R,35)-/V-benzoyl-3-phenylisoserine. The cyclocondensation of the lithium enolate of (-)-(1 / ,2S)-2-phenyl-1 -cyclohexyltriiso-propylsiloxyacetate (5a P = (i-Pr)3Si (TIPS) and R = (-)-(lR,2S)-2-phenyl-1 -cyclohexyl) with A-trimethylsilylbenzaldimine (6a R1 = Ph) in THF at -78 °C gives (3/ ,4S)-3-triisopropylsiloxy-4-phenylazetidin-2-one (7a P = TIPS and R1 = Ph)... 

In the same way, electrophilic reactions can be applied to the tandem reaction. The ynolate-initiated tandem [2 + 2] cycloaddition-Michael reaction followed by decarboxylation furnished the polysubstituted five-, six- and seven-membered cycloalkenes in good overall yield (equation 33) . The ester enolate intermediates 77 are nucleophilic, and further bond formation is possible. 

Asymmetric cycloadditions of the chiral non-racemic nitrones 101 and 103 afford the isoxazolidinones 102 and 104 respectively, with high diastereoselectivity. This process can lead to an efficient asymmetric synthesis of /3-amino acids (equations 42 and 43) . This is the first example of asymmetric reactions with ynolates. It is noteworthy that the ynolates show higher reactivity and stereoselectivity than the corresponding lithium ester enolates and demonstrate the high potential of lithium ynolates in asymmetric reactions. 

For the preparation of optically active P-lactams (154) with relative trans configuration (e.g. for the synthesis of (+)-PS-5 ), the [2 -i- 2] cycloaddition of ester enolates such as (152) and A -trialkylsilyl-imines (153) is an appropriate strategy (Scheme 70).In this case, chirality is introduced by the imino moiety. 

A convenient synthesis of zirconocene cyclic ester enolates such as complex 866 is the direct [2 + 4]-type cycloaddition reaction between the zirconocene imido complex and methyl methacrylate666 (Equation (52)). The resulting cyclic ester enolate can be activated by the Lewis acid A1(C6F5)3 for efficient polymerization of methyl methacrylate. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

Alcohol derivatives 1.155 (Y = CHOHR) are useful as auxiliaries in a-keto-ester reductions [540] or [4+2] cycloadditions of aciylates [548]. 6-Lactams are obtained from imines 1.155 (Y = CH=NAr) with a high enantiomeric excess after reaction with ester enolates and decomplexation [549]. Alkylations of benzylimine 1.155 (Y = Ph2N=CH) give interesting results [539], and some 1,3-dipdar cycloaddition reactions with nitrones have been described [550],... 

Several other examples of this [2 + 2 + 2] procedure with chiral nitriles have been reported32. Highly stereocontrolled construction of 3-alkoxy-2-azctidinones are obtained via formal [2 + 2] cycloaddition of imincs and ester enolates in the presence of chirally modified titanium(IV) salts33-34. 

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. 

The cycloaddition of ester enolates with imines is of continuing interest and potassium rert-butoxide may be used to generate the enolate (94S805) but more usually tin, titanium or zinc enolates are employed. When enolates are generated from 2-pyridylthioesters, the stereochemistry of the tin enolate may be greater than and, in some cases, opposite to that for titanium enolates (94T5821). The effect of the lithium, zinc or titanium on the diastereoselectivity in addition reactions of the enolates of a-... 

The synthesis of p-lactams by the condensation of ester enolates with imines, followed by ring closure, utilizes the same starting materials as the [2 + 2]-cycloaddition, but offers added flexibility and new opportunities for stereocontrol. While most often used for the preparation of penem synthons in which the relative stereochemistry of the C-3-hydroxyethyl group and ring substituents... 

Also, ester enolates undergo the [4+2] cycloaddition reaction with vinyl isocyanate 503... 

Deoxy-D-erythro-pentose (2 1) has been elaborated from 2,3-0-isopropylldene-D-glyceraldehyde (25) either by a stereoselective dipolar cycloaddition reaction (Scheme 6, route a)" or by a stereoselective aldol condensation involving a boronated ester enolate reagent (route b). The DL-analogue of (24) has been synthesized from 1,3 2,4-di- -benzylidene-erythrltol by mono-bromination (Hanessian s procedure with NBS) to give a l-bromo-3- -benzoate,... 

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. 

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