Carbapenems, chiral synthesis

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)... 

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... 

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. 

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. 

Jacobi and co-workers have applied the above Schreiber/Evans chiral boron enolate methodology to afford stereoselective routes to precursors of biologically important tetrapyr-roles [187], pyrromethanenones (114) (Scheme 4-59) [188], phycocyanin and phytochrome precursors, and P-amino acids [189], versatile intermediates for P-lactams of the carbapenem class. Generally, reaction of achiral or matched enolates with racemic cobalt complexes gave excellent selectivity. With a careful choice of mis-matched chiral enolate, moderate to good anti selectivity could also be achieved, leading to a formal total synthesis of thienamycin [190]. 

Silylimine 749 has also been used as a chiral template in the synthesis of the carbapenem (+ )-PS-5 (758), an antibiotic isolated from the fermentation broth of soil microorganisms [215,216] (Scheme 99). The crucial ring-forming step (749753) is accomplished by reaction of 749 with the lithium enolate of tert-h xty butanoate. The resulting )5-lactam is... 

Novel chiral auxiliary, 2 -isopropyl-5 -methylbenzoxazine-spiro-[2.1 ]cyclo-hexan-4-one, and its application to the synthesis of carbapenem antibiotics ... 

Through this approach formation of chiral P-hydroxy carboxylic acids with appropriate carbon frameworks is the key step of the method. Evans [92] reported an asymmetric synthesis of the carbapenem PS-5 in which the two stereocenters of the P-lactam ring were efficiently established via an asymmetric aldol addition reaction (Scheme 34). In this approach, the boron enolate 214 was... 

Intramolecular nucleophilic substitution by an active methylene linked to the nitrogen atom of a-substituted carboxamides was first utilized in azetidinone synthesis by Sheehan and Bose in 1950 [27]. When 3-hydroxyethylazetidinones became an important research target, it was realized that L-threonine or D-allo-treonine, easily converted to bromohydrins 57,61 or to epoxyacid 64, are by this method one of the most convenient natural chiral source for penem and carbapenem synthesis. Shiozaki et al. [28] at Sankyo s laid down the fundaments of the threonine route . Early works from D-a//o-threonine-derived 2R-bromo-3R-hydroxybutyric acid 57 were run using malonate anions as the nucleophilic moiety, as shown in amide 58, which in presence of DBN cyclized to azetidinone 59a with complete inversion of configuration [28a, c]. 

In the early years of penem and carbapenem research, the easy preparation and commercial availability of azetidinone 10 prompted the devisal of several protocols for its conversion into an optically active equivalent (Scheme 1, F). Thus, acetate displacement with thioglycolic acid and resolution with d-( +)-ephedrine gave the 4/ -carboxymethylthio derivative 94, in turn elaborated to 95a [44], the 4R-enantiomer of the key intermediate of Woodward s first synthesis of racemic 6a-hydroxyethylpenems [45]. In another approach, analog 95b was obtained by diastereomer separation after displacement of 4-acetoxy-azetidinone with a chiral mercapto-alcohol [46]. Along a still different approach [43], optically active 93b was obtained from racemic 10 and thiophenol via asymmetric induction from the reaction medium (cinchonidine-containing benzene). 

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