Carbapenem precursors synthesis

Since the first report by Bergbreiter and Newcomb in 1980 [72] on the utilization of lithium enolates of esters in place of Reformatsky reagents for the construction of the azetidinone ring (Fig. 4), several research groups have applied such approach to the synthesis of carbapenem compounds. Most notably, the recent review by Georg [5g] on the synthesis of thienamycin and related P-lactams delineated the most recent advances in the P-lactam field and focuses great attention on the utilization of optically active esters of 3-hydroxy-butyric acid for an effective control of the relative and absolute stereochemistry at the carbon atoms T and 3 of the 3-(l -hydroxyethyl)azetidin-2-one 132. Inversion of the configuration at the hydroxyethyl side chain by Mitsunobu s reaction [42] and further elaboration of the peripheral functionalities leads to the formation of a variety of carbapenem precursors. 

Cycloadducts 88 (from glycals and isocyanates) undergo a two-stage oxidation (NaI04 followed by NaOCl) to provide i-lactams 89 and this chemistry has been used in clavam synthesis. Full details of synthesis of carbapenem precursors from aldono-1,5-lactones have also appeared. N-Aryl Schiff bases (derived from D-glyceraldehyde) undergo efficient [2+2] cycloaddition to ketenes (e.g. BnOCH=C=0) to afford P-lactams 90. This process, which has been carried out on 100-500 g scale, was shown to benefit greatly firom exposure to microwave radiation. ... 

Racemic acyldiiron complexes bearing an olefin moiety can be kinetically resolved in the [3+2] cycloaddition reaction with enantiopure nitrones. The recovered starting material is highly enantiomerically enriched. The cycloaddition product can be oxidatively demetalated using CAN. After reductive cleavage of the N-0 bond with zinc in acetic acid and thioester cleavage with mercury(II) acetate, spontaneous cyclization to the P-lactams occurs. This procedure was applied to the synthesis of carbapeneme precursors (Scheme 4-50). 

Formal syntheses of thienamycin (2) from precursors such as carbohydrates (43—45), amino acids (46,47), isoxa2ohdines (48), and tricarbonyliron lactam complexes (49) have also been reported. Many other methods for carbapenem synthesis have been widely reviewed (10,50—52). 

A number of highly potent DHP-I stable iP-methylcarbapenems having a variety of C-2 substituents have now been described (60,66—69) including SM 7338 [96036-03-2] (42), C yH25N20 S. An acylamiao compound (66) and a iP-methoxy analogue (70) provide other variations. The pyrroHdine substituted iP-methyl-carbapenem SM 7338 (42) is being developed as a broad-spectmm parenteral antibiotic under the name meropenem the synthesis of (42) is by way of the lactone (43) derived by a novel Diels-Alder approach to dihydropyran precursors of (43) (71). 

The enantioselective synthesis of the V-benzyl-substituted /3-lactam 274a (NR2 = PhCH2NH), a precursor for carbapenem antibiotics, was described starting from the chiral synthon 5(R)-menthyloxy-2(5//)-furanone 170 (Scheme 71)... 

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. 

P-Lactams. Diketene can function as an equivalent to acetylketene, CH3C0CH=C=0, to provide 3-acetyl-p-lactams by [2 + 2]cycloaddition with imines.1 A stereoselective cycloaddition of this type can furnish a useful precursor (2) to lp-methylcarbapenems. Thus reaction of diketene with the chiral imine 1, prepared in a few steps from the readily available methyl (S)-3-hydroxy-2-meth-ylpropionate (Aldrich), can provide the desired 3,4-frpreviously developed for synthesis of the antibacterial carbapenem 4. 

In a series of reports, Gallagher and co-workers (51,52) outlined the use of azomethine ylide technology in the construction of the bicyclic core of p-lactams. Initially the synthesis of carbapenems was studied. The oxazolidine-based ylide precursor 185 was prepared by a literature precedent and submitted to thermolytic... 

Ready availability of cycloalkenyl triflates from ketone precursors often renders them superior to the corresponding halides in synthesis. The syntheses of arylated cycloalkenes [164] and 2-substituted carbapenems (Scheme 2-59) [165] have been achieved in excellent yields by the reaction with triflates. 

Researchers at Merck have studied the synthesis of the simple carbapenem system (94) through Wittig cyclization of the keto ylide (93). This interesting precursor was prepared directly from the thiol ester... 

Jacobi and co-workers have applied the above Schreiber/Evans chiral boron enolate methodology to afford stereoselective routes to precursors of biologically important tetrapyr-roles [187], pyrromethanenones (114) (Scheme 4-59) [188], phycocyanin and phytochrome precursors, and P-amino acids [189], versatile intermediates for P-lactams of the carbapenem class. Generally, reaction of achiral or matched enolates with racemic cobalt complexes gave excellent selectivity. With a careful choice of mis-matched chiral enolate, moderate to good anti selectivity could also be achieved, leading to a formal total synthesis of thienamycin [190]. 

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. 

Lactone L is a synthetic equivalent of amino acid K its homo-analog has gained popularity in carbapenem synthesis as Melillo s lactone [36]. Its precursor, butenolide 82a, easily accessible by condensation (LDA) of methyl... 

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