Methylcarbapenem synthesis

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). 

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. 

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. 

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. 

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>. 

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... 

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],... 

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. 

Intramolecular acid- or rhodium [II]-cataIysed carbene nitrogen-hydrogen insertion from iodonium ylide intermediates was used in an efficient synthesis of 1-/1-methylcarbapenems the cyclization products had different stereoselectivity, depending on the catalyst [11] ... 

Deprotection of a sensitive TBS ether was required in a synthesis of the orally active 1-p-methylcarbapenem antibiotic TA-949 [Scheme 4.47].70 A slow but efficient and mild method entailed treatment of TBS ether 47,1 with ammonium bifluoride (NH4F HF) in a mixture of DMF and JV-methyl-2-pyrrolidinone (NMP) at room temperature. The desired product 47 2 was obtained in 90% yield. 

Enantioseiective Hydrofomiylation. Enantioseiective hy-droformylation of a 4-vinyl-3-lactam, i.e., (3S,4R)-3-[(R)-l-(/er/-butyl-dimethylsilyloxy)ethyl]-4-vinyl-2-azetidinone,has been achieved by using an Rh(l)-NORPHOS catalyst system (eq 17). The optically active hydroformylation products thereby obtained are of interest as intermediates in the synthesis of 1-methylcarbapenem antibiotics. 

S-methylcarbapenems (e.g., 76). In fact, compound 73b was transformed to the known key intermediate 75 (84H29), which had already been employed by Shih et al. for the synthesis of 76 (84H29). 

Compound 82 was readily converted to the known key intermediate 75, which is useful for synthesis of l/ -methylcarbapenems (Scheme 15). Other alkylated azetidinones 81, 83, and 84 were also similarly converted to 75. 

Udodong, U E, Fraser-Reid, B, Formal total synthesis of l 3-methylcarbapenem via a novel route to deoxyamino sugars, J. Org. Chem., 54, 2103-2112, 1989. 

Scheme 5 Synthesis of l- 8-methylcarbapenems with an isothiazoloethenyl side chain...

---