Carbapenem antibiotics synthesis

Manefield M, Welch M, Givskov M, Salmond GPC, Kjelleberg S (2001) Halogenated Furanones from the Red Alga, Delisea pulchra, Inhibit Carbapenem Antibiotic Synthesis and Exoenzyme Virulence Factor Production in the Phytopathogen Erivinia carotovora. FEMS Microbiol Lett 205 131... 

A key intermediate in carbapenem antibiotic synthesis has been prepared through a highly stereoselective [2 + 2] cycloaddition of chlorosulfonyl isocyanate with an optically pure 1,3-dioxin... 

Ketene has also been used on a large scale for C-acetylation in the synthesis of the carbapenem antibiotic thienamycin [59995-64-1] (86,87). 

Chiral 2,2-disubstituted l,3-benzoxazin-4-ones as auxiliaries in the synthesis of carbapenem antibiotics 97YGK858. 

The enantioselective synthesis of the V-benzyl-substituted /3-lactam 274a (NR2 = PhCH2NH), a precursor for carbapenem antibiotics, was described starting from the chiral synthon 5(R)-menthyloxy-2(5//)-furanone 170 (Scheme 71)... 

Additions of organometallic compounds to 2-azelidinones such as 1 or 4 bearing a leaving group in the 4-position preferentially or exclusively afford tram-3,4-substituted /(-lactams 3 or 6. Therefore, the participation of an A -acylinline intermediate such as 2 or 5 which is attacked from the less hindered side is probable14-16. This has been exploited for the synthesis of carbapenem antibiotics, e.g., thienamycin (7)16. 

Takasago International Co. commercialized this hydrogenation method for the production of a chiral intermediate for the synthesis of carbapenem antibiotics (Equation (8)).29... 

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... 

Pharmacology Meropenem is a broad-spectrum carbapenem antibiotic. The bactericidal activity of meropenem results from the inhibition of cell-wall synthesis. Meropenem readily penetrates the cell wall of most gram-positive and gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. 

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. 

This insertion reaction has provided a stereocontrolled synthesis of ( + > thienamycin (3), an important carbapenem antibiotic.5... 

Hakimelahi, G. H. Moosavi-Movahedi, A. A. Tsay, S.-C. Tsai, F.-Y. Wright, J. D. Dudev, T. Hakimelahi, S. Lim, C. Design, synthesis, and SAR of novel carbapenem antibiotics with high stability to xanthomonas maltophilia oxy-iminocephalosporinase type II./. Med. Chem. 2000, 43, 3632-3640. 

A formal total synthesis of the early carbapenem antibiotics thienamycin 217 and PS-5 218 from an acyclic amino acid derivative has been reported <1996JOC2413>. For a cycloaddition process from acyclic compounds, see Section... 

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

A convenient biocatalytic process has been developed using a novel whole-cell biocatalyst for the preparation of (R)-l,3-butanediol (BDO) by stereo-specific oxidoreduction on an industrial scale. (R)-l,3-BDO is an important chiral synthon for the synthesis of various optically active compounds, such as azetidinone derivatives, which are used to prepare penem and carbapenem antibiotics for industrial usage. 

The nucleophilic addition of anions derived from the enantiomerically pure 2-methyloxazoline (73) to the )V-methoxycarbonylimines generated in situ from (72) provides adducts that may be readily converted into 3-aniino acid derivatives (74) in good overall chemical yield (40-65%) and 72-90% enantiomeric excess (Scheme 27). This transformation has been featured as a key step in the enantioselective synthesis of carbapenem antibiotics. 

In the field of the carbapenem syntheses Hatanaka et a/. have set new standards by their elegant syntheses of the carbapenem (179) and the synthesis of the carbapenem antibiotic PS-5 (180) and its 6-epi analog in remarkably few steps. ... 

A stereoselective synthesis of 6-amino acid derivatives by an aldol-type condensation of tin(II) carboxylic thioester enolates with imines has been reported (Scheme 90) the method was used to synthesize an intermediate of the carbapenem antibiotic... 

Benzyloxy derivative 764a can be transformed to the carbapenem antibiotic ( + )-PS-5 (758) as shown in Scheme 101. The first required manipulation is removal of the benzyloxy group in the 3-position, which is accomplished by reductive debenzylation, conversion of the resultant hydroxy group to a xanthate, and Barton deoxygenation. Next, enolate formation with LDA followed by alkylation with four equivalents of ethyl iodode gives the trans-3,4-disubstituted j5-lactam 766. Removal of the PMP group with CAN furnishes intermediate 753, which is required for completion of the synthesis of ( + )-PS-5. 

---