Chiral carbapenems

In common with the naturally occurring carbapenem thienamycin (2), the introduction of the /n j -6-[l-(R)-hydroxyethyi] group had a profound effect on the biological properties of the penems. This, together with an indication from an early study (93) that, as with other P-lactams, the 5(R)-enantiomer was solely responsible for antibacterial activity, provided impetus for the development of methods for the synthesis of chiral penems. 

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)... 

A second route was devised using chiral /3-keto ester 14, which was identified as our precursor for 2 [7]. This idea was in analogy with the carbapenem chemistry [8], as depicted in Scheme 2.4, where Masamune reaction [9] for carbon elongation, diazo-transfer, and transition metal-mediated carbene insertion reaction [10] were employed as key steps sequentially. 

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... 

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. 

The continued importance of 3-lactam ring systems in medicine has encouraged a number of research groups to investigate their synthesis via a nitrone cycloaddition protocol. Kametani et al. (60-62) reported the preparation of advanced intermediates of penems and carbapenems including (+)-thienamycin (29) and its enantiomer (Scheme 1.7). They prepared the chiral nitrone 30 from (—)-menthyl... 

Closely related to penicillin is the antibiotic cephalosporin C. It contains a D-a-aminoadipoyl side chain, which can be replaced to form various semisynthetic cephalosporins. Carbapenems have similar structures but with CH2 replacing S and often a different chirality in the lactam ring. 

Nowadays, all the therapeutically relevant penems are equipped with the lf/ 3-hydroxyethyl side chain, characteristic of the thienamycin (carbapenem) family (see Table 1). Accordingly, they are prepared by hemisynthesis from the chiral acetoxyazetidinone 76, which is industrially produced on a large scale by chemical methods (see Section 2.03.9). This chiron plays a similar role as 6-APA for the synthesis of semisynthetic penicillins, but here for the synthesis of non-natural penems and carbapenems <1996T331>. 

A new efficient methodology for the preparation of a chiral 2-azetidinone intermediate applicable to the total synthesis of (+)-thienamycin and l)S-substituted carbapenems has been developed (86JAa673). This is based on the highly diastereoselective aldol-type reaction employing C4-chiral 3-acyl-l,3-thiazolidine-2-thiones and 4-acetoxy-2-azetidinones. 

A highly diastereo-controlled alkylation at the C4 position of 60, employing chiral tin(II) enolates 6Sa-e of heteroatom-substituted acetyl derivatives 64a-e, provided 66a-e, new synthetic intermediates for l) -heteroatom-substituted carbapenems (see Scheme 13 and Table III) (87CC602). 

Carbapenems are regarded as hopeful candidates for new-generation /S-lactam antibiotics (78JA6491 84H29). Thus, we applied our new chiral alkylation method to the synthesis of chiral / -substituted carbapenems and of the key intermediates for carbapenem syntheses. 

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-... 

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 aldol-type condensation can be extended to carbonyl equivalents such as the 4-acetoxy-2-azetid-inone (93) or similar a-acetoxylactams. The condensation of (93) with the chiral tin(II) enol ether (94) has been used in a highly diastereoselective synthesis of chiral carbapenems. 

Induced stereoselectivity can also be obtained with chiral ketenes. Since most studies have been directed toward the synthesis of /1-lactam antibiotics, cycloadditions of protected aminoketenes have been extensively explored to produce intermediates for penicillin and cephalosporin synthesis and cycloadditions of protected hydroxyethylketenes have been used to produce intermediates for carbapenem synthesis. 

Addition of imine 2a to the zinc enolate prepared by treatment of 1 with lithium diisopropyl-amide in tetrahydrofuran followed by addition of zinc(II) chloride at —78 °C gives trans-fi-lactam 3a in 98% yield and d.r. [(37 ,4i )/(35,45)] >97 <3. Similar reaction with imine 2b with chiral substituents on both the carbon and nitrogen affords j3-lactam 3b in 90% yield and d.r. [(3/ ,4/ )/(35,45)] 93 782. Reaction of the lithium enolate 4 with imine 5 gives the trans-ji-lactam 6, a precursor of the carbapenem antibiotic PS-5, with d.r. [(3jR,4S)/(3S,4jR)1 96 483. 

---