Azetidinone intermediate

A new efficient methodology for the preparation of a chiral 2-azetidinone intermediate applicable to the total synthesis of (+)-thienamycin and l)S-substituted carbapenems has been developed (86JAa673). This is based on the highly diastereoselective aldol-type reaction employing C4-chiral 3-acyl-l,3-thiazolidine-2-thiones and 4-acetoxy-2-azetidinones. 

The enthusiasm for the pharmaceutical potential of the monocyclic P-lactams was matched by renewed interest in the chemistry of these compounds both in industry and academe. This review will focus on recent developments in the chemistry of monocyclic P-lactam antibiotics, emphasizing new or improved methods for construction of the azetidinone ring as opposed to a discussion of the functional group manipulation of preformed P-lactams and the structure-activity relationships of the ultimate products. Emphasis will be placed on key advances in the preparation of true monocyclic antibiotics and intermediates for their synthesis and not on the voluminous chemistry dealing with the preparation of azetidinone intermediates for the synthesis of bicyclic compounds such as penems. The latter topic is covered elsewhere in this volume. The review is intended to cover the period from 1983 through early 1989 with an emphasis on more recent developments. Attention is drawn to previous reviews [4-14] which deal with the early phases of development of the monocyclic p-lactam antibiotics as well as those aspects of their chemistry not discussed in this work. 

The li -hydroxyethyl substituent at the 6a-position of penems and carbapenems imparts microbiological properties which have remained unrivalled through the last decade s research. Consequently, insertion of this essential group (when not present in the starting material, e.g. L-threonine) into penam or azetidinone intermediates is an integral part of penem synthesis today. 

Reaction of U-acetoxy-2-azetidinone (413) with siloxydienes (414), in the presence of zinc chloride, gives the displacement product (416) as the major component but low yields of cycloaddit ion products (415) are also obtained, making this a novel one-step synthesis of the carbacephalosporin framework from a monocyclic azetidinone precursor. Two other routes to the carbacepham system involving cyclization of monocyclic azetidinone intermediates have also appeared. Beckwith et al. have described a radical-induced ring closure of 4-phenylthioazetidinones (417) to afford cyclized... 

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

Na2S H20, H2O, THE, 68-90% yield DCC(—H2O), 67-97% yield hydrazine dil. HCl, 55-95% yield.This method is used to cleave N-phthalimido penicillins hydrazine attacks an intermediate phthalisoimide instead of the azetidinone ring. 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

The reaction of 4-(phenylsulfonyl)azetidin-2-one (128) with nucleophiles such as dialkylcopper lithium and Grignard reagents gives 4-alkyl, 4-allyl, 4-vinyl or 4-ethynyl-azetidinon-2-one (129) in good yields (equation 99)83. The yields of several azetidin-2-ones obtained by this method are given in Table 10. The reaction apparently proceeds through an intermediate azetin-2-one 131 derived from the five-membered coordination complex (equation 100). 

The anomalous behaviour observed in attempted 1-deprotection of certain 4-heteroarylmethyl-l-(4-methoxyphenyl)-2-azetidinones by the action of CAN has been investigated further <961771 > and evidence obtained to support the mechanism proposed, which involves the intermediate 47 when the 4-substituent is the tetrazolylmethyl group as in 46 <96T10169>. Use of the novel enzyme, o-phthalyl amidase, as a deprotection agent for P-lactams has been developed <96MI875>. 

Two variants of this method have been devised in which milder oxidants can be employed. Lead dioxide or silver oxide convert the free base of 8a into the azetidinone in good yield, perhaps34 via intermediate radical cations... 

The nonacarbonyldiiron-induced transformation of oxazabicyclo[2.2.2] octenes (12) into condensed azetidinones is intriguing mechanistically but will obviously have limited synthetic application (Scheme 15).37 The /(-lactam (14a), among other products, is isolated directly from the iron carbonyl reaction but the dimethyl analog (14b) is obtained by pyrolysis of an isolable intermediate <7-7r-allyl complex (13b). 

The first observation of the uncommon phenomenon of desmotropy in seven-membered heterocycles was reported for the prototropic annular tautomers 128 and 129. These dihydro-4,1-benzothiazepines, which were prepared (via the non-isolated intermediates 130 and 131 from the fused azetidinone 127 on treatment with NaOEt), could be isolated in pure form by column... 

The same group has developed the enantiospecffic synthesis of a-hydroxy [5-lactams 224 from readily available carbohydrates (Scheme 9.72) [123]. Microwave-assisted chemical reactions have been utilized for the preparation of these 3-hydroxy-2-azetidinones 224 and their subsequent conversion to enantiomeric forms of intermediates for natural products. 

This asymmetric alkylation of cyclic acylimines can provide optically active precursors to carbapenems.2 Thus reaction of the 4-acetoxy-2-azetidinone 5 with the chiral 3-acyl-(4S)-ethyl-l,3-thiazolidine-2-thione 6 provides the substituted aze-tidinone 7, an intermediate in a total synthesis of (- )-l-(3-methylcarbapenem. 

Stereoselective Reformatsky reaction. The Reformatsky reaction of the chiral 2-azetidinone 1 with 3-(2-bromopropionyl)-2-oxazolidone (2a) gives essentially a 1 1 mixture of the diastereomers 3a(3 and 3aa. However, introduction of two methyl groups at C4 in 2 markedly improves the (i-diastereoselectivity, as does an increase in the temperature from 0 to 67° (reflux, THF). The highest diastereoselectivity (95 5) is observed with the derivative of 4,4-dibutyl-5,5-pentamethylene-2-oxa-zolidone. The 3p-diastereomer is a useful intermediate to lp-methylcarbapenems.1... 

For the cis azetidinones 315, the first step is the formation of an amidine intermediate, followed by ring enlargement with transamidation [96-H(42)625]. The preceding amidine structure was revealed by TLC on silica gel when the formation of derivatives 316 was investigated (89MI1). 

The diazo ketones that are synthesized as intermediates are not only useful for the preparation of p-amino acids but may serve as versatile starting materials in different reactions, e.g. preparation of 3-azetidinones or 2-aminocyclopentanones. ... 

Alternative syntheses of ezetimibe (1) have been demonstrated. The three approaches outlined below proceed through penultimate intermediate 10a and differ with respect to the number of carbons and functionality on the side-chain before attachment to the 2-azetidinone fragment. These alternative strategies illustrate the remarkable stability of A-aryl 2-azetidinones to a wide variety of conditions and allowed access to a wide variety of ezetimibe analogs. 

Wu and co-workers (Wu et al., 1999) have demonstrated a novel chiral lactone enolate-imine process to access 2-azetidinone diols such as 35 (Scheme 13.10). Treatment of 34 with LDA at — 25°C in THF followed by addition of imine 3, afforded only trace product. Addition of HMPA or the less toxic DMPU during the lithium enolate formation step improved the yield and the trans cis diastereoselectivity ( 90 10). Recrystallization improved the purity to >95 5 trans cis 2-azetidinone. Addition of an equivalent of lithium bromide accelerates the rate of ring closure, presumably by destabilizing the intermediate lithium aggregates. Side-chain manipulation of 35 was accomplished by sodium... 

Azetidinones on a solid support 49 have been prepared in high yield by Staudinger reaction of a supported imine with an acid chloride in the presence of a base. The liberated p-lactams were of high purity <99TL1249>. Cycloaddition of a ketene intermediate, derived fi"om an azo compound, to an imine having an oxidatively cleavable chiral auxiliary N-substituent was used to obtain p-lactams 50. The trans. cis ratio which varied between 69 31 and 93 7, depended on the nature of the substituents R and R <99S650>. 

Takasago group and Nozaki reported the synthesis of the 1-methylcarbapenem intermediate 78 by hydroformylation of the 4-vinyl / -lactam, (3BINAPHOS system followed by oxidation (Scheme 8, Table 13, entry Slightly better selectivities are... 

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