Synthesis azetidinones

Cationic Fp (olefin) complexes [Fp = f/5-C5H5Fe(CO)2] undergo regio-specific addition of heteroatomic nucleophiles.32 Subsequent ligand transfer (carbonyl insertion) occurs with retention of configuration at the migrating center (R—Fe—CO -> RCOFe).33 A combination of these processes has provided a novel stereospecific azetidinone synthesis which can also be applied to condensed systems.34... 

Azetidinones, synthesis, 56, 214 Azetidin-2-ones, /V-phenyl-, nitration, 58, 259... 

Intramolecular nucleophilic substitution by an active methylene linked to the nitrogen atom of a-substituted carboxamides was first utilized in azetidinone synthesis by Sheehan and Bose in 1950 [27]. When 3-hydroxyethylazetidinones became an important research target, it was realized that L-threonine or D-allo-treonine, easily converted to bromohydrins 57,61 or to epoxyacid 64, are by this method one of the most convenient natural chiral source for penem and carbapenem synthesis. Shiozaki et al. [28] at Sankyo s laid down the fundaments of the threonine route . Early works from D-a//o-threonine-derived 2R-bromo-3R-hydroxybutyric acid 57 were run using malonate anions as the nucleophilic moiety, as shown in amide 58, which in presence of DBN cyclized to azetidinone 59a with complete inversion of configuration [28a, c]. 

Extension of the Phosphorane Route. Ample evidence of the versatihty of the phosphorane synthesis strategy is provided by the proliferation of penems that followed. Nucleophilic displacement of the acetate function of the acetoxy-azetidinone (51, R = OCOCH ) [28562-53-0] (86) provided azetidinones where R = SCOCH, SCSSC2H, and SCSOC2H, which on elaboration gave the penems (52, R = CH ) (87), (52, R = SC2H ) (88), (52, R = 0C2H ) (89). Similar treatment of 3-substituted (or disubstituted) acetoxyazetidinones allowed the synthesis of a number of 2-substituted- 6-alkyl-and 6,6-dialkylpenems (90). 

Azetidin-2-one, l-benzyl-3,3,4-triphenyl-, 7, 249 Azetidin-2-one, l-(2-bromophenyl)-X-ray crystallography, 7, 247 Azetidin-2-one, 3-carboxy-synthesis, 7, 262 Azetidin-2-one, 3-halo-synthesis, 7, 77 ring contraction, 7, 81-82 Azetidin-2-one, 4-imino-IR spectroscopy, 7, 248 Azetidin-2-one, 1-phenyl-irradiation, 7, 255 Azetidin-2-one, 4-phenyl-reductive ring cleavage, 7, 252 Azetidin-2-one, 4-thio-IR spectroscopy, 7, 248 Azetidinones bicyclic, 7, 348-356 C NMR, 7, 348 H NMR, 7, 348 reactivity, 7, 356-358 spectroscopy, 7, 357 structure, 7, 349 synthesis, 7, 358-359 fused ring... 

Merck s thienamycin synthesis commences with mono (V-silylation of dibenzyl aspartate (13, Scheme 2), the bis(benzyl) ester of aspartic acid (12). Thus, treatment of a cooled (0°C) solution of 13 in ether with trimethylsilyl chloride and triethylamine, followed by filtration to remove the triethylamine hydrochloride by-product, provides 11. When 11 is exposed to the action of one equivalent of tm-butylmagnesium chloride, the active hydrogen attached to nitrogen is removed, and the resultant anion spontaneously condenses with the electrophilic ester carbonyl four atoms away. After hydrolysis of the reaction mixture with 2 n HC1 saturated with ammonium chloride, enantiomerically pure azetidinone ester 10 is formed in 65-70% yield from 13. Although it is conceivable that... 

Aryl vinyl sulphones, reactions of 646 Aryl vinyl sulphoxides 620 optical resolution of 287 reactions of 354, 355, 360, 361, 621 Asscher-Vofsi reaction 189 Asymmetric induction 625 Asymmetric oxidation 72-78 Asymmetric reduction 78, 79 Asymmetric synthesis 824-846 Atomic orbitals 2, 3 Azetidinones 790, 791 ot-Azidoaldehydes, synthesis of 811 Azidosulphones, photolysis of 883, 884 Azosulphones, photolysis of 879 Azoxysulphones, photolysis of 879 1-Azulyl sulphoxides, synthesis of 265... 

Although dirhodium(II) carboxamidates are less reactive toward diazo decomposition than are dirhodium carboxylates, and this has limited their uses with diazomalonates and phenyldiazoacetates, the azetidinone-ligated catalysts 11 cause rapid diazo decomposition, and this methodology has been used for the synthesis of the cyclopropane-NMDA receptor antagonist milnacipran (17) and its analogs (Eq. 2) [10,58]. In the case of R=Me the turnover number with Rh2(45-MEAZ)4 was 10,000 with a stereochemical outcome of 95% ee. 

Interesting developments in simple azetidine chemistry continue to be reported. The apparently general acetylative dealkylation of Af-tert-butyl-3-substituted azetidines 6 (R = Bu ) in the presence of boron trifluoride provides a two-step route to azabicyclobutane 7 from 6 (R = Bu, R = Cl). An aqueous solution of 7 reacts with ethyl chloroformate to give 8. Relatively unexplored 3-azetidinones 9 (R = Ac or NO2) are available from 3-acetoxya2Ktidine 6 (R = Ac, R = OAc) which is obtained by acetylative dealkyation of 6 (R = Bu , R = OAc) <96JOC5453>. 3-Substituted azetidines can be utilized in the synthesis of polyfunctional y- and S-aminophosphonic acid derivatives <95TL9201>. 

The mild conditions of the base-catalyzed sulfonate synthesis are particularly apparent in the case of two reactions in which the reacting OH groups are present in an azetidinone system 155... 

Scheme 11). Alternatively the quaternary salts can be converted thermally into acyliron chelate complexes which can then be oxidized to azetidinones (Scheme 12). Extension of the method to the synthesis of a condensed azetidinone is illustrated in Scheme 13, but the scope of the procedure has not been evaluated. It will also be of interest to assess the utility of other cationic organometallic complexes preliminary studies have shown that molybdenum complexes behave in an analogous manner but the oxidative cyclization is inefficient (Scheme 14). 

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