4-Acetoxy azetidinone, synthesis

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). 

In the early years of penem and carbapenem research, the easy preparation and commercial availability of azetidinone 10 prompted the devisal of several protocols for its conversion into an optically active equivalent (Scheme 1, F). Thus, acetate displacement with thioglycolic acid and resolution with d-( +)-ephedrine gave the 4/ -carboxymethylthio derivative 94, in turn elaborated to 95a [44], the 4R-enantiomer of the key intermediate of Woodward s first synthesis of racemic 6a-hydroxyethylpenems [45]. In another approach, analog 95b was obtained by diastereomer separation after displacement of 4-acetoxy-azetidinone with a chiral mercapto-alcohol [46]. Along a still different approach [43], optically active 93b was obtained from racemic 10 and thiophenol via asymmetric induction from the reaction medium (cinchonidine-containing benzene). 

The first application of silylimines in our laboratory is concerned with the synthesis of trans (3S,4/ )-3-hydroxyethyl-4-acetoxy-azetidinone with the natural R configuration of carbon bearing hydroxyl group (Scheme 4). This compound constitutes a most useful intermediate for the synthesis of both penems and carbapenems which can be easily obtained following the well established Merck and Farmitalia procedures respectively. ... 

The Beecham group found that thiols add readily to the double bond of C(2)-unsubstituted 1-carbapenems, and this approach has been used to synthesise racemic PS-5 130). The A -silylated 4-allylazetidinone (157) was alkylated with ethyl iodide and the product (158) transformed to the phosphorane (159). Cyclisation to (1 ) was followed by reaction with acetamidoethane thiol to form three isomers of the addition product (161). These could be converted to the carbapenem (162) on reaction with iodobenzene dichloride in the presence of pyridine. Isomerization to (163) and deprotection afforded the racemic natural product. The ester (163) has also been prepared via the diazo-intermediate (164) derived from the 4-acetoxy azetidinone (165) 131). A total synthesis of chiral PS-5 has been achieved using the resolved acid (166) (132). This was converted to (164) and then to optically pure PS-5. It has also been possible to synthesise PS-5 and PS-7 from the olivanic acid derivatives MM 17880 and MM 13902 133). The benzyl ester of ( )-MM 22381 was obtained from the azabicyc-loheptane (167) derived from the addition of acetamidoethane thiol to the appropriate C(2)-unsubstituted nucleus 108). 

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. 

Synthesis of selenopenams starts with commercially available 4-acetoxy-2-azetidinone derivatives which are reacted with sodium benzylselenoate, prepared by treatment of dibenzyl diselenide with sodium borohydride, to give 4-(benzylseleno)-2-azetidinones 97. The radical precursor 98 prepared from 97 was irradiated or heated, and the selenopenams 99 were thus obtained (Scheme 24) <20040BC2612, 2004MOL466, 2001TL4737>. 

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. 

Mori used the anodic decarboxylative acetoxylation for the synthesis of the valuable penem precursors 4-acetoxy-2-azetidinones. Thus, 4-carboxy-2-azetidinone was electrolyzed in acetonitrile/AcOH (3 1) in the presence of NaOAc (4.5 equivalents) to give the desired product in 76% yield. Starting from the enantiopure 4-carboxy-3-[l-(t-butyldi-methylsilyloxy)ethyl]-2-azetidinone, the enantiopure 4-acetoxy compound was obtained in 85% yield [Eq. (48)] [244]. 

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... 

Mori M, Kagechika K, Tohjima K, Shibasaki M (1988) New synthesis of 4-acetoxy-2-azetidinones by use of electrochemical oxidation. Tetrahedron Lett 29 1409-1412... 

The synthesis of PS-5 was achieved by treatment of silylimine of 0-protected (S) lactic aldehyde with the lithium enolate of /-butyl butanoate. The reaction is highly diastereoselective affording almost completely the trans a2etidinone with the natural configuration at C3. This azetidinone was converted, by sequential Jones and Baeyer-Villiger oxidation of hydroxyethyl side chain to the 4-acetoxy doivative that represents a most useful chiral building block fcv the synthesis of final carbapenem PS-5 via the Merck procedure (Scheme 8). 

Condensation of silylimine of (5)-lactic aldehyde with lithium enolate of t-butyl isovalerate affords the -lactam in 80% chemical yield and in a 97 3 diastereomeric ratio. The mixture was desilylated and treated with lead tetracetate to give, in one step, through a radical fragmentation reaction, the 4-acetoxy derivative as a 1 1 4(R) 4(S) imeric mixture. The lack oi stereospecificity is not easy to rationalize expecially if one considers that the analogous lead tetraacetate induced oxidative decarboxylation is completely trans stereoselective. Both reactions should have the same radical intermediate. However, this lack of stereospecificity is not important for the success of the synthesis since the mixture of diastereoisomers exclusively affords the trans 4-substituted azetidinone by the subsequent Merck procedure (Scheme 9). 

Di Fabio et al. reported synthesis of 3-alkoxy-substituted trinems from commercially available 4-acetoxy-3-[(R)-l-f-butyldimethylsilyloxyethyl]-2-azetidinone. Epoxide 20 was treated with ceric ammonium nitrate in acetonitrile to provide the intermediate nitrate ester 21 in 55% yield. Simultaneous protection of the secondary alcohol and the amide was accomplished using di-f-butylsilyl bis(trifluoromethanesulfonate) to provide the tricyclic /3-lactam 22. Removal of the nitro group by catalytic hydrogenation provided the desired secondary alcohol that was alkylated with allyl bromide to provide 23 in quantitative yield (eq 10). ... 

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