Azetidinones 4-0-keto

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... 

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

Carbacephalosporins The ketene-imine cyclization described above has been extended to a synthesis of a chiral carbacepham (4). This synthesis uses a dihy-droanisole group as the equivalent of a p-keto ester. Thus the azetidinone 1, obtained in 80% yield by the above route, was reduced and acylated in situ to provide 2. Ozonization followed by a rhodium-catalyzed cyclization of an a-diazo-P-keto ester provides 3, which is a useful intermediate to various substituted car-bacephams such as 4. 

A protocol has been reported based on a cyclization procedure followed by hydrolysis and oxidation, which allowed the preparation of a-keto-(3-lactams (Scheme 11), [59]. The cyclization of imines with acetylglyoxylic acid, in the presence of POCI3 and Et3N, gave 3-acetoxy-(3-lactams in good yields as cis-isomers, prevalently. These latter were hydrolyzed to alcohols in excellent yields under very mild conditions. Subsequent oxidations were performed by treatment with dimethyl sulfoxide (DMSO) in the presence of phosphorous pentoxide to give a-keto-(3-lactams. More 2-azetidinones were synthesized varying the substituent of the acetyl moiety. 

Oxidative methanolysis of azetidinone 176 followed by hydrogenolysis of compound 177 afforded /3-lactam 178, which was protected to obtain the protected amine 179. The best conditions for rearrangement of 179 were found using TFA. Conversion of compound 180 to carbacephem 183 was accomplished by ketone reduction, alcohol protection, and elimination of methanol. Synthesis of carbacephem derivative 186 has been performed by rhodium(n)-catalyzed cycliza-tion of iodonium ylide 185 <1997TL6981> (Scheme 33). The iodonium ylide 185 was easily prepared from the corresponding /3-keto ester 184 and [(diacetoxy)iodo]benzene in good yield. 

Carbapenem antibiotics (29) can be manufactured from intermediates obtained by Ru(BINAP)-catalyzed reduction of a-substituted P-keto esters by a dynamic kinetic resolution (Scheme 12.8). 4-Acetoxy azetidinone (30) is prepared by a regioselective RuCl3-catalyzed acetoxylation reaction of 31 with peracetic acid 46 This process has been successful in the industrial preparation of the azetidinone 30 in a scale of 120 tons per year.47 The current process has changed ligands to 3,5-Xyl-BINAP (3c), and 31 is obtained in 98% ee and >94% de (substrate-to-catalyst ratio, or S/C ratio = 1,000).23... 

The photochemical behavior of aminocyclohexenones depends on the substituents on nitrogen. Cyclization of iV-arylketoenamines to 2-carbazolones is achieved photochemic-ally332 (equation 251). However JV-benzyl-jV-tosyl-a-ketoenamines yield stereospecific-ally on irradiation a-keto azetidinones. Branched N-alkyl substituents suffer desulphona-tion and intramolecular aryl migration to give 2-amino-3-aryl-2-cyclohexenones333 (equation 252). 

Variations on the same theme were explored in the preparation of polycyclic P-lactams from the Sml2-promoted cyclization of C4-keto-functionaliz-ed l-[(benzoyloxy)(ethoxycarbonyl)methyl]-2-azetidinones (Scheme 11) [13]. Cyclization of the azetidinone 18 afforded stereoselectively the tricyclic [4.5.6] core structure of the potent antibiotic sanfetrinem as the major compound, whereas in many of the other cases tested (e.g., with 19), cyclization... 

It can also be named as an azetidine derivative (e.g., 2-azetidinone, or 2-keto-azetidine). 

Azetidinone having a N-dehydroamino acid side chain, structurally related to the active penem and cephem antibiotics, was obtained by the standard phenylselenylation-oxidation-elimination reaction sequence [42], C-4-substituted aldehydes can also be subjected to a novel N- l-C-4 /S-lactam bond cleavage in the presence of 2-(trimethylsilyl)thiazole (TMST) to give enan-tiopure a-aUcoxy-y-keto amides (Scheme 12) as the major products [43]. 

In another penem building block synthesis, a functionalised azetidinone is reacted with benzyl 2-bromopropionate in the presence of diethylaluminium chloride in hexane/THF. A mixture of epimers is obtained, which has to be separated chromatographically. Afterwards, the lactam nitrogen is protected, and the benzyl residue reductively cleaved. The next steps bear a close resemblance to those of the thienamycin synthesis construction of a jS-ketoester, diazo transfer and rhodium-catalysed insertion of a carbenoid into the lactam N-H bond. Finally, the jS-keto-ester is activated with diphenyl chlorophos-phonate. [60]... 

R = CH3 or Ac) bearing a 3-kctam moiety. The use of microwave irradiation on 2-azetidinone-tethered bis(allene) retains the reactivity pattern, but suppresses the keto—enol isomerization while maintaining the same regioselectivity of the cyclization step affording exclusive formation of the bicyclic enol ether 98 in reasonable yields (Scheme 27). 

A semi-synthetic approach by the Merck group (775) makes use of the 4-chloro-azetidinone (153) which can be obtained from 6-aminopenicillanic acid. Reaction with the silylated diazo-intermediate (154) in the presence of silver tetrafluoroborate followed by desilylation provides a one-step process to (148) from (153). A similar displacement with a 4-acetoxy substituted azetidinone derived from aspartic acid provides another route (776) to (148). The amidine derivative (155) of thienamycin is chemically more stable than the amine and a direct introduction of this side-chain by way of the keto-ester has also been achieved (777). It is this amidine (MK 0787) that is undergoing clinical investigation rather than thienamycin itself... 

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