Carbapenames, synthesis

CO2 is well known to react with primary and secondary amines. In fact the white solid often found on the mouth of bottles containing these amines is the carbamate salt (R2NCO2HNR2) formed from the CO2 in the air. This type of salt has been used to advantage in a carbapenam synthesis during the hydrogenolysis of a 4-nitrobenzyl ester. Prereduction of the Pd-C was necessary to prevent the formation of colloidal... 

The Buchwald-Hartwig animation is not limited to aryl halides and sulfonates vinyl halides and sulfonates may participate as well. An early example of this process was shown in an intramolecular sense for a carbapenam synthesis in the laboratory of M. Mori.115 Pd/DPEphos catalyzed the cyclization of a vinyl bromide 79 giving 3-lactam 80 in 97% yield. 

This reaction has been applied to the synthesis of carbapenam skeletons [69] (Eq. 52). 

The synthesis of the carbapenam-3-carboxylic acid 36 <03JA15746> as well as a study on carbapenem biosynthesis have been documented <03JA8486>. The cephalosporin derivative 37 has been prepared and its use as a novel fluorogenic substrate for imaging P-lactamase gene expression demonstrated <03JA11146>. The nucleus of the carbacephem antibiotic loracarbef has been synthesized in a highly efficient and enantioselective fashion from 25,3iS-2-amino-3-hydroxy-6-heptenoic acid, which was derived from enzyme-catalyzed... 

A method for the enantioselective synthesis of the ftmctionalised carbapenam core 38 from D-serine-derived pyrrolidines has been reported <03JOC187>. Disubstituted pyrrolidines, obtained from the retro Dieckmann reaction of azabicyclo[2.2.1]heptan-2-one-1-carboxylic acid methyl esters, have been used as starting materials to develop concise syntheses of all four stereoisomers of carbapenam-3-carboxylic acid methyl esters <03JOC2889>. The synthesis of 1-methylcarbapenams 39 by intramolecular attack of lactam nitrogen on a 77 -propargylpalladium complex has been reported <03JOC8068>. 

Silyl methods of penicillin and cephalosporin modification 82KGS147. Synthesis of 1-carbapenems and 1-carbapenams 83YGK62. 

Kozawa and Mori reported the synthesis of different ring size heterocycles from the same propargyl ester 670 by a ligand effect on Pd(0) (Scheme 207).284 When the reaction was carried out using P(o-tolyl)3 as a ligand, the carbapenam 671 was obtained in 57% yield, while the reaction of 670 using DPPF gave the carbacepham 672 in 56% yield. 

Enol phosphates are used in the syntheses of various members of the carbapenam family of antibiotics. The azabicycloheptanedione 87 is enol-phosphorylated to 88, which reacts with thiol 89 to yield an intermediate ester. The ester is then hydrogenolyzed to yield carbapenam 90. Similar enol phosphates have been converted to useful intermediates for the synthesis of related carbapenam antibiotics.48,49... 

Borane reduces esters very slowly and ketones or aldehydes are selectively reduced in the presence of esters. The most widely used application of borane is for the selective reduction of carboxylic acids, even in the presence of halides, esters, nitriles, and ketones.200 since LiAlH4 reduces both acids and esters and NaBH4 does not reduce acids (and often reduces esters with difficulty), borane is the reagent of choice for selective reduction of carboxylic acids in the presence of an ester group. The reduction occurs without racemization of adjacent chiral centers, as in the borane reduction of (-)-malic acid to generate (5)-l,2,4-butanetriol in 92% yield.201 Seki and Kondo s reduction of the acid moiety in 173 to alcohol 174 (in a synthesis of orally active carbapenams), without reduction of the benzylthio or ester groups also demonstrates this selectivity.202 Borane can reduce imides to give an amine.203 Borane also reduces epoxides at the less hindered carbon when mixed with catalytic amounts of sodium borohydride.204... 

Because of the extraordinary interest of carbapenam antibiotics several other approaches have been described for their formal or total synthesis. For example, appropriately substituted 3-[(/ )-l-hydroxyethyl)] P-lactams have been synthesized from a 1,3-dipolar cycloaddition of nitrones with crotonates [103]. Formation of P-amino-8-lactones 261 (Fig. 8), and their transformation into carbapenems 259 have also been reported [104]. 

Since we were unable to obtain the succinaldehyde derivatives, e.g. 38 (ref. 26) that are needed for the above carbapenam derivatives, we confined ourselves to model experiments with malonaldehyde dimethyl acetal (ref. 23). In the meantime, we have found a convenient synthesis for succinal-dehyde diethyl acetal 38 (Scheme 8). Thus we now are able to continue our carbapenem syntheses via the cycloadducts 40. 

Insertion into N-H bond. Of major importance is the recently developped intramolecular carbene insertion into N-H bond, which is the key step in the Merck Synthesis of the 1-carbapenam ring system from diazo precursors. Yields are high, and the reaction is always very selective in one isomer. 

The synthesis of anti-MRSA carbapenam has been reported as a multigram scale synthesis involving Suzuki-Miyaura cross-coupling between carbapenam triflate 76 and the highly functionalized aryl boronate salt 77 as the key step by Merck scientists yielding polyfunctional product 78 in 60% yield over four steps. It highlights the versatility and effidency of the Suzuki-Miyaura cross<oupling reaction (Scheme 3.34) [53]. 

Schane 3.34 Synthesis of a carbapenam derivative via Suzuki-Miyaura cross-coupling. 

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