Carbapenam carboxylic acids

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>. 

Fig. 10. Analytical and semipreparative HPLC of p-lactams from Serratia marcescens ATCC39006. (A) Analytical HPLC chromatogram of the P-lactam free acids. (B) Semipreparative HPLC chromatogram of the p-nitrobenzyl esters. HPLC conditions Column Spherisorb 5 pm ODS2 (CIS) 25 x 1 cm. Mobile Phases (A) 0 1 M KH2PO4 in water pH 7.0. (B) 40% v/v acetonitrile/water. Flow rate 2 mL/min. Detection wavelength (A) 210 nm. (B) 254 nm. The peaks corresponding to (35,55)-l-carbapenam-3-carboxylic acid, (55)-l-carbapen-2-em-3-carboxylic acid, and (55, 5J )-l-carbapenam-3-carboxylic acid are labeled as peaks 1—3, respectively (see Fig. 11 for structures). Sample loading for the semipreparative experiment 5 mg containing 2 mg total products, dissolved in 0.5 mL mobile phase.

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... 

In the chemistry of (3-lactam antibiotics, isolations of carboxylic acid derivatives are successfully achieved by formation of amidinium salts [56]. Lewis acid catalysed reaction of 4-substituted 1-trimethylsilyloxyfurans with 4-acetoxyazetidinone chiron leads to highly enantioselective construction of tricyclic carbapenam and penems, in which DBU (1) and Eshenmoser amidine (4) were used for the introduction of the exo double bond on the (3-lactam skeleton by demesylation (A route) and the isolation of carboxylic acids as... 

The conversion of the amide group in 34 into the carboxy group via 35 seems to be a promising way to solve the "cunide problem" of B-lactam syntheses by 4CC (refs. 2,21). The conversion of B-lactam amides into the carboxylic acids via the esters was very successful in the hands of Hofheinz and Isenring (ref. 22) who worked with the N-benzhydryl amides of nocardicin derivatives. The stereoselective and regiose-lective 1,3-dipolar cycloaddition of chiral nitrones to benzyl crotonate is a key step in our approach to thienamy-cine (ref. 23) and related carbapenam derivatives. Besides chiral 2-phenylethyl hydroxylamine (ref. 24) the 1-hydro-xylamino derivative of 2,3-5,6-diacetone mannose (ref. 25) is a promising source of chiral nitrones for such enantiose-lective cycloadditions. 

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