Ester-enolate-imine condensation

The one-pot condensation of an ester enolate with an imine is a very powerful synthetic procedure toward azetidin-2-ones (Equation 183). Various types of esters and imines can be utilized. Although in the vast majority the reactions have been mediated by lithium, various other metals mediate the reaction as well. Some examples include zinc, aluminium, tin, boron, indium, and titanium 1996MI119 . Theoretical studies on these reactions have been reviewed 1998JCC1826 . 

The reaction of imines with 2-pyridyl thioesters in the presence of aluminium tribromide or ethylaluminium dichloride afforded /ra r-3,4-disubstituted azetidin-2-ones 1996T2583 . Similar stereoselective addition of silylketene thioacetals to imines is known in the presence of Lewis acids 1996T2573 . An indium-mediated reaction of ethyl bromoacetate with imines yielded 3-unsubstituted azetidin-2-ones in reasonable yields (Equation 195) 2000J(P1)2179 . 

Very recently, the reaction of the dianion-enolate of a Cbz-protected a-amino ester with a cyanomethylamine as an imine precursor toward several /3-lactam derivatives has been described 2007BML358 . 

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A stochiometric approach was applied by Van Koten and co-workers [29], who used chiral carbosilane dendrimers as soluble supports in the in situ ester enolate-imine condensation in the synthesis of /Mactams (e.g. 19, Scheme 20). The formation of the /Mactam products proceeded with high trans selectivity, and with the same level of stereoinduction as was earlier established in reactions without the dendritic supports, (i.e. the use of the enantiopure dendritic support did not affect the enantioselectivity of the C-C bond formation). After the reaction, the dendrimer species could be separated from the product by precipitation or GPC techniques and reused again. 

Lithium ester enolate-imine condensation has been used for the preparation of / -lactam rings via addition at the imine moiety <1996H(43)1057>. But treatment of imino derivatives of the pyridazine 293 with the lithium enolate of ethyl a,a-dimethylacetate 294 in THE led to the formation of the pyrido[3,4-r/ pyridazine 295 and its oxidized form 296. Compound 295 was obtained by nucleophilic attack of the carbanion species at C-5 of the pyridazine ring followed by cyclization (Equation 24) <1996JHC1731>. 

Scheme 49 Solid-phase synthesis of P-lactams via ester enolate-imine condensation...

The synthesis of monocyclic p-lactams via the ester-enolate imine condensation route has been reported to be carried out utilizing triazene esters (Scheme 54), [141], Esters were attached to benzylamine resin by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates were reacted with various imines to give polymer-bound p-lactams in different substitution patterns. Traceless cleavage from the triazene linker yielded the desired p-lactams. 

The ester enolate-imine condensation, also called Gilman-Speeter reaction, is another well-accepted method for (3-lactam synthesis (Scheme 4) [67-69]. In 1997, Tomioka reported the first example of a direct catalytic enantioselective synthesis of (3-lactam by using this method [70]. The active reagent is a ternary complex (comprising LDA, the ester enolate, and tridentate amino diether), which finally affords the (3-lactam compounds in high yields and good ee values. 

Schunk and Enders [134] disclosed the first solid-phase synthesis of (5-1 actants via ester enolate-imine condensation employing an immobilized ester enolate in a simple three-step procedure (Scheme 31). The protocol showed high purity, excellent diastereoselectivity, and good yields of the product. The substrates were attached to the polymer with a Tl-triazene linker, which was cleaved traceless. The... 

The possibility of the triazene linking system for the ester-enolate imine condensation was initially investigated on model compounds 110 and 111 (Scheme 35). Dibenzyltriazene 110 was used as a model compound for monobactam derivatives and prepared by diazotization of hippuric acid methyl ester. Dibenzyltriazene 111 was used as a model compound for 3-phenyl-substituted azetidin-2-ones and prepared by diazotization of 2-(4-aminophenyl)-propionic acid methyl ester and conversion with dibenzylamine in 64% overall yield. The low yields of /V-unsub-stituted lactams, during the model studies, hint at a problematic transfer to solid support. 

Polymer-bound P-lactams have been prepared via the ester enolate imine condensation route <02JOC8034>. On the other hand, an efficient asymmetric synthesis of 2-azetidinones was accomplished when chiral acid chlorides or chiral aldehydes were used in the polymer-supported Staudinger reaction <02TA905>. 

Electrochemical transformations of /3-lactams 90YZ463. Ester-enolate-imine condensation in the synthesis of /3-lactams 89CRV1447, 89H(29)2225. 

This method can be effectively applied to the preparation of /S-lactam compounds. The ester enolate-imine condensation approach to j8-lactam formation has been developed over the past decade. Thienamycin and related carbapenems have been the focus of particular attention because of their structural uniqueness and potent antibacterial activity. 

Enders [273] reported a solid-phase ester-enolate imine condensation for the preparation of [i-lactams. The easy access to a number of imines and imine precursors is the advantage of this procedure. Ester enolate precursors were attached to a triazene linker, notably stable under the basic conditions required in order to generate the enolate species. The main limitation concerning this linker is the ability to immobihze only aromatic diazonium salts, due to the intrinsic instability of the aliphatic ones. 

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]. 

A comprehensive review article on 3-lactam formation via the ester enolate-imine condensation has been written by Hart and Ha. Achiwa and coworkers have published a full paper detailing their work on the synthesis of N-benzyloxy-3-lactams utilizing the reaction of N-benzyloxyimines with silylketene acetals in the presence of TMS-OTf, or with lithium ester enolates. ... 

Among the most suitable methods for the synthesis of appropriately substituted monocyclic P-lactams [16], the chlorosulphonylisocyanate-alkene approach, the acid chloride-imine method, the ester enolate-imine condensation and the hydroxamate approach have received considerable attention in P-lactam synthesis. 

The first report on the synthesis of P-lactams through an ester enolate-imine condensation was reported by Gilman and Specter close to 45 years ago [68]. The method involved reaction between an a-bromoester and an imine in the presence of zinc and iodine as catalyst to give P-aminoesters or P-lactams, depending on the reaction conditions employed. The mechanistic and stereochemical features of this reaction have been widely studied [69], however its utility in the preparation of valuable P-lactams for carbapenem synthesis has received very little attention. Recently we [70a] demonstrated the utility of this reaction for the preparation of 3-alkyl-4-acetoxyazetidin-2-ones as precursors for the synthesis of ( ) PS-5 and ( ) PS-6 antibiotics. 

Shimizu M, Ishida T, Fujisawa T (1994) Highly Stereocontrolled Construction of 3-Alkoxyazetidin-2-ones Using Ester Enolate-Imine Condensation. Chem Lett 1403... 

If the ester enolate reaction involves reversible addition while the cyclisation remains irreversible, it should be possible to use weaker bases than the generally used lithium amides for the condensation reaction. A situation of this type results when potassium enolates are used. In this case, the highly ionized oxygen-potassium bond renders the addition of the enolate to the imine reversible. As a result, we were able to prepare P-lactams via ester enolate imine condensation using potassium r-butoxide that has a pK of 16.5 (Scheme 16). ... 

Scheme 4.80 Synthesis of the cholesterol absorption inhibitor SCH48461 by ester enolate-imine condensation.

A substoichiometric version of this ester enolate-imine condensation could be developed shortly later the tridentate ligand 383 catalyzed the condensation of lithium enolate 378 with imines 381 derived from aromatic and aliphatic aldehydes to give P-lactams 382 in excellent chemical yield and substantial. 

Scheme 5.99 Enantioselective ester enolate-imine condensation mediated by the stoichiometric additive 379.

Hart DJ, Ha DC. The ester enolate-imine condensation route to beta lactams. Chem. Rev. 1989 89(7) 1447 1465. 

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