1/9-Methyl carbapenem

Chemists from the Sankyo Co. reported the use of 6-bromopenicillanate 28, easily obtained from 6-aminopenicillanic acid, in a multistep synthesis of (3RAR)-4-acetoxy-3- (R)- -((/-hutyldimethylsilyl)oxy)ethyl]-2-azctidinonc (31)97, a pivotal intermediate for the synthesis of 1-/9-methyl carbapenem antibiotics (equation 23)98. After cleavage of the thiazolidine ring of 28 with trimethyloxonium tetralluoroborate, the intermediate 29 was subjected to a Reformatsky condensation with acetaldehyde, catalysed by diethyla-luminium chloride. The 8-(S) stereocentre in 30, formed in 50% d.e., was inverted under Mitsunobo conditions to approach the target molecule 31. 

A number of highly potent DHP-I stable iP-methylcarbapenems having a variety of C-2 substituents have now been described (60,66—69) including SM 7338 [96036-03-2] (42), C yH25N20 S. An acylamiao compound (66) and a iP-methoxy analogue (70) provide other variations. The pyrroHdine substituted iP-methyl-carbapenem SM 7338 (42) is being developed as a broad-spectmm parenteral antibiotic under the name meropenem the synthesis of (42) is by way of the lactone (43) derived by a novel Diels-Alder approach to dihydropyran precursors of (43) (71). 

En route to 1 -/J-methyl carbapenem antibiotics, the reaction of 31 with Reformatsky reagents 78 has been explored it likely involves preliminary formation of the intermediate 79, which then undergoes nucleophilic addition to give 2-(4-oxoazetidin-2-yl)-propanoic acid derivatives 80 (equation 48). 

In the route to BO-2727 (18), a broad-spectrum P-methyl carbapenem being developed by Merck, a bioreduction catalyzed by the fungus Mortierella alpina MF 5534 is used to form a precursor (7 )-P-hydroxy ester 19 (Scheme 19.12).102 This fungal culture was a result of screening approximately 260 strains of microorganisms and resulted in the production of gram quantities of product with a de of >98%. 

The Tadano group extended the use of the sugar-based chiral templates for the l 8-methyl carbapenem synthesis. As concerns the chemical synthesis of 1/3-methyl carbapenems such as 1 /S-methyl thienamycin, the most common approach is a late-stage ring closure for bicyclic skeleton construction using a C-4 functionalized azetidin-2-one, such as 113, namely (35, 45)-3-[(R)-l-(r-butyldimethylsilyloxy)ethyl]-4-[(R)-l-carboxyethyl]azetidin-2-one, which may be constructed via the Mannich-like reaction of commercial (3R,4R)-4-acetoxy-3-[(R)-l-(r-... 

Berks AH (1996) Preparations of two pivotal intermediates for the synthesis of 1-P-methyl carbapenem antibiotics. Tetrahedron 52 331-375, and references therein... 

The postulated intermediate azetinone 21 (Scheme 3), has recently been trapped in a hetero Diels-Alder reaction [12c] providing a novel access to thienamycin [12g] (R = H) and P-methyl-carbapenems [12h] (R = Me), which should be readily extended to the synthesis of PS-5 and PS-6 carbapenems. Although preparation of protected 3-(l-hydroxyethyl)azetidin-2-ones directly... 

Activated sulfonamides and other activated amines were used in a series of Mitsunobu reactions to prepare analogs of 2-(sulfanamido)methyl carbapenems (124) as potential anti-MRSA compounds. The basic reaction scheme and some of the activated amines that were used are shown in the figure below. Additional examples can be found in the original paper. 

Through the ester enolate-imine route, we have been able to prepare with high diastereo-and enantio-selectivity carbapenems such as PS-5 and PS-6 as well as ip-methyl carbapenems and monobactams. A promising application is represented by the stereospecific synthesis of chiral aziridines, potential starting materials for the preparation of a- and P-amino acids. Metallo imines also undergo reaction with a number of organometallic compounds to give primary amines and chiral 1,2-aminols. 

Park HS, Alberico E, Alper H. Regio- and stereoselective synthesis of key 1-methyl carbapenem intermediates via hydroformylation using a zwitterionic rhodium catalyst. J. Am. Chem. Soc. 1999 121 11697 11703. 

ANTTBIOTTCS - BETA-LACTAMS - CARBAPENEMS AND PENEMS] (Vol 3) 2-Methyl-4-hydroxyphenylarsomc acid [26738-23-8]... 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

P-Lactams. Diketene can function as an equivalent to acetylketene, CH3C0CH=C=0, to provide 3-acetyl-p-lactams by [2 + 2]cycloaddition with imines.1 A stereoselective cycloaddition of this type can furnish a useful precursor (2) to lp-methylcarbapenems. Thus reaction of diketene with the chiral imine 1, prepared in a few steps from the readily available methyl (S)-3-hydroxy-2-meth-ylpropionate (Aldrich), can provide the desired 3,4-frpreviously developed for synthesis of the antibacterial carbapenem 4. 

Like carbapenems, several penems have also been found to be susceptible to renal dehydropeptidase degradation [165-167], 6-Substituted methyl-idene-penems 5.56 are very potent broad-spectrum inhibitors of bacterial /3-lactamase, with the inhibitory activity residing predominantly in the (5R)-enantiomers. As a rule, the (5S)-enantiomers are less stable than the (5R)-enantiomers toward DHP-I [168],... 

Meropenem (Merrem) is another carbapenem antibiotic with a broad spectrum of activity comparable to that of imipenem. A methyl group attached at the one-position on the five-member ring confers stability to dehydropeptidase 1. Consequently, meropenem does not require administration with cilastatin. When compared in human trials, imipenem-cilastatin and meropenem achieve similar clinical outcomes in patients with serious intraabdominal and soft tissue infections. Both imipenem-cilastatin and meropenem are used to treat infections caused by highly resistant Klebsiella pneumoniae producing ESBLs.The major cUnicaUy relevant distinction between imipenem-cilastatin and meropenem... 

The differences in nephrotoxicity of carbapenems are due to the different structural features, especially the physicochemical properties. The structure of meropenem differs from the structure of imipenem and panipenem due to the presence of a ip-methyl group and the lesser basicity of the amino group in the C-2 side chain. The basicity of meropenem is much lower than that of imipenem and panipenem [70]. The reduced meropenem nephrotoxicity is not related to the presence of the ip-methyl group. However, the basicity of the C-2 side chain of carbapenems is important for... 

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