Ester-imine condensation

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>. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

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. 

Keeping in view the biological and synthetic importance of the (3-lactams and the potential of solvent-free microwave chemistry, Kidwai et al. [148] prepared (3-lactams via an ester-imine based synthesis under solvent-free microwave irradiation. The //Y/n.v-4-aminocyclohexanol (128) was condensed with different aromatic aldehyde to give the respective Schiff base. The Schiff-base was then reacted with ethyl a-mercapto/a-cyano acetate, in the presence of basic alumina, to afford the required 3-mercapto/cyano (3-lactams respectively, outlined in Scheme 41. 

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]. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

Chiral silyl ketene acetals derived from (lS,2/ )-yV-methylephedrine (168), known to exhibit high levels of syn-anti and diastereofacial selectivities in the aldol condensation, have been used by Gennari et al. in TiCU-mediated imine condensations for the asymmetric synthesis of 3-lactams (Scheme 34) 32. 33 p.j mino esters (169) are produced in these reactions, and are characterized by their sub-... 

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. ... 

Murphy et al. [39] reported the synthesis of pyrrolidine 7 combinatorial libraries. Starting from polystyrene resin-bound amino acids, the a-amino ester was condensed with aromatic and heteroaromatic aldehydes in neat trimethylorthoformate to afford the resin-bound aryl imine. Pyrrolidine and pyrroline derivatives were obtained through cycloaddition of the 1,3-dipoles azomethine ylides to olefin and acetylene dipolarophiles. A library of 500 compounds was reported. The screening of this library for in vivo inhibition of angiotensin-converting enzyme (ACE) led to the identification of l-(3 -mercapto-2 -(S)-methyl-1 -oxopropyl)-5-phenyl-2,4-pyrrolidinedicarboxy-lic acid 4-methyl ester as a potent ACE inhibitor that incorporates the mer-captoisobutyryl side chain (Fig. 3e). 

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