Ip-Methylcarbapenem

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). 

Studies of the intramolecular cyclization of P-amino acids have included the use of camphor-derived oxazoline A-oxide 66 and a [3+2] cycloaddition reaction as a step in the formation of the amino acid with the required stereochemistry <00OL1053, OOEJOC1595>. A diastereoselective synthesis of a ip-methylcarbapenem intermediate utilises a cyclization of a P-amino acid <99CC2365>. 

A convenient, one-pot, two-step synthesis of l-azabicyclo[1.1.0]butane (5, R = H) from f -chlorosuccinimide is reported and its application to the synthesis of 133-tnnitroazetidine (TNAZ) is discussed <98SC3949>. Another novel and efficient synthesis of 1-aza-bicyclo[1.1.0]butane (5, R = H) and its derivatives is from 23-dibromopropylamine. The bicyclic 5 (R = H) is also useful in the synthesis of the pendant group of a ip-methylcarbapenem antibiotic <99TL3761>. The reaction of 5 (R = Et and Ph) with tosyl chloride and tosyl azide are described <98T15127,99H131>. 

The 2-formyl-ip-methylcarbapenem 62 has been obtained in five steps from a readily available P-lactam in 23-26% overall yield <98MI1294>. Suzuki-Miyaura cross-coupling of aiylboronic acids and vinyl triflates is a convenient route to 2-aiylcarbapenems on a small scale but may present problems on a large scale. Vinyl phosphates, mesylates or tosylates are convenient alternatives to triflates <9981471>. Radical cyclizations of readily available enyne-2-azetidinones (e.g., 63) with a tin hydride, RjSnH, provides a route to the... 

Geraniol or nerol can be converted to citronellol in 96-99% ee in quantitative yield without saturation of the C(6)-C(7) double bond (eq 6). The S C ratio approaches 50000. The use of alcoholic solvents such as methanol or ethanol and initial H2 pressure greater than 30 atm is required to obtain high enantioselectivity. Diastereoselective hydrogenation of the enantiomerically pure al-lylic alcohol with an azetidinone skeleton proceeds at atmospheric pressure in the presence of an (i )-BINAP-Ru complex to afford the (3-methyl product, a precursor of ip-methylcarbapenem antibiotics (eq 7). Racemic allylic alcohols such as 3-methyl-2-cyclohexenol and 4-hydroxy-2-cyclopentenone can be effectively resolved by the BINAP-Ru-catalyzed hydrogenation (eq 8). ... 

Development of efficient synthetic methods for ip-methylcarbapenems 98YZ353. 

Regioselective techniques were developed to direct the cyclization of unsymmetrical esters. An interesting example of this aspect of the Dieckmann condensation is the synthesis of ip-methylcarbapenems by Tanabe and co-workers, ip-methylcarbapenems is a structure that exists in potent and broad antibacterial compounds, such as meropenem and biapenem, which renders it synthetically interesting for the synthesis of some close analogues 30a-d. Thioesters 29 was subjected to cyclization under dehydration type Ti-Dieckmann condensation conditions 3.0 equivalents of the TiCU and 3.3 equivalents of the base BusN were used to give the vinyl... 

Amlnation of branched-chain hexop3n anosidulose (54) via reaction of its enolate with diben2yl azodicarboxylate led ultimately to the 5-lactone (55), a key intermediate for chiral synthesis of Ip-methylcarbapenems of type (56).53... 

Wildonger KJ, Leanza WJ, Ratcliffe RW, Springer JP. The syntheses of 1 a-fluoro-ip-methylcarbapenem esters. Heterocycles 1995 41 1891-1900. 

Iso Y, Me T, Nishino Y, Motokawa K, Nishitani Y. (1996) A novel 1 3-methylcarbapenem antibiotic, S-4661. Synthesis and structure-activity relationships of 2-(5-substituted pyrroldin-3-ylthio)-ip-methylcarbapen-ems. J Antibiot 49 199-209. 

The intermediates for 1 -methylcarbapenems have also been synthesized using methyl (5)-P-hydroxyisobutyrate as a starting material (Fig. 8) [82-84]. In these syntheses, the ip-methyl moieties of the target molecules come from the corresponding parts of the (S)-P-hydroxyisobutyric acid derivatives. 

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