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). 

Development of efficient synthetic methods for l(3-methylcarbapenems 98YZ353. 

Considerable efforts have been devoted to the stereoselective introduction of a /(-methyl function in intermediates for the synthesis of 1 jS-methylcarbapenems. While the trimethylsilyl trifluoromethanesulfonate catalyzed reaction of a 4-acetoxyazetidinone derivative with ketene acetals shows no selectivity, ketene thioacetals lead to stereoselective formation of the a-methyl isomer108. The zirconium enolate, however, shows high /(-methyl selectivity. 

Bitha, P., Lin, Y. I., Testa, T., In vivo activities of peptide prodrugs of novel aminomethyl tetrahydrofuranyl-1 beta-methylcarbapenems, Antimicrob. 

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>. 

INAC reactions have also led to enantioselective syntheses of key intermediates in the synthesis of antibiotic l 3-Methylcarbapenem (724), to optically pure derivatives of tetrahydropyrano[2,3] cyclohexane (725a) to novel terahydro-isoxazolo-fused pyrano 2,3-/ quinolines (725b) and to a novel heterocyclic system, isoxazolo[3,4-d]thieno[2,3-b]pyridine (Scheme 2.229) (221). 

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. 

Stereoselective aldol condensation. The stereoselectivity of the reaction of 1 with the ester 2 can be controlled by the choice of the metal enolate. The products are intermediates to 1-methylcarbapenems. 

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. 

Stereoselective Reformatsky reaction. The Reformatsky reaction of the chiral 2-azetidinone 1 with 3-(2-bromopropionyl)-2-oxazolidone (2a) gives essentially a 1 1 mixture of the diastereomers 3a(3 and 3aa. However, introduction of two methyl groups at C4 in 2 markedly improves the (i-diastereoselectivity, as does an increase in the temperature from 0 to 67° (reflux, THF). The highest diastereoselectivity (95 5) is observed with the derivative of 4,4-dibutyl-5,5-pentamethylene-2-oxa-zolidone. The 3p-diastereomer is a useful intermediate to lp-methylcarbapenems.1... 

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. 

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... 

Takasago group and Nozaki reported the synthesis of the 1-methylcarbapenem intermediate 78 by hydroformylation of the 4-vinyl / -lactam, (3BINAPHOS system followed by oxidation (Scheme 8, Table 13, entry Slightly better selectivities are... 

U. E. Udodong and B. Fraser-Reid, Electrophilic amination as a route to deoxyamino sugars Synthesis of the key intermediate for 1-p-methylcarbapenem, J. Org. Chem. 53 2132 (1988). 

A synthesis of l-/l-methylcarbapenems has been described28 in which TMSC1 acts both as a Lewis acid in accelerating the Dieckmann-type cyclization and as a trapping agent... 

Alcoxycarbonyl-l (3-methylcarbapenem and 3-alcoxycarbonyl-la-methylcar-bapenem (HI and IV, respectively, Fig. 11) have been reported to be prepared by using a palladium-catalyzed C-N bond-forming coupling of vinyl halide and p-lactam nitrogen [271]. 

Using a similar methodology but starting from a (3-lactam having a propargyl moiety, the synthesis of 1 (3-methylcarbapenem and la-methylcarbapenem (V and VI, respectively, Fig. 11) has also been reported [272],... 

The asymmetric hydroformylation of //-substituted 4-vinyl (3-lactams, catalyzed by rhodium(I) complexes, leading to l-(3-methylcarbapenem precursors (VI, Fig. 16) has been reported [285]. 

These reactions have been applied to synthetic studies on biologically active compounds such as l/ -methylcarbapenem (87), the antileukemic principle, pareitropone (88), and the potentially antiinflammatory marine alkaloid, halichlorine (89). 

A similar cyclization strategy has been used for the synthesis of a key methylcarbapenem intermediate 10 [95SL915], The note worthy aspect of this work is the establishment of three contiguous chiral centers during the radical reaction. 

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