β-Lactams from Carbohydrates

Top Heterocycl Chem (2007) 7: 101–132 DOI 10.1007/7081_2006_046 © Springer-Verlag Berlin Heidelberg Published online: 28 February 2007 β-Lactams from Carbohydrates Bartłomiej Furman · Zbigniew Kałuz˙a · Agnieszka Stencel · Barbara Grzeszczyk · Marek Chmielewski (�) Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland chmiel@icho.edu.pl 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 2 Syntheses Based on [2+ 2]Cycloaddition of Sugar-Derived Imines with Ketenes or their Equivalents . . . . . . . . . . . . . . . . . . . . . . . 102 3 Synthesis of β-Lactams by Cyclization Methods . . . . . . . . . . . . . . . 113 4 Synthesis of β-Lactams via [2 + 2]Cycloaddition of Isocyanates to Chiral Vinyl Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 5 [2+ 2]Cycloaddition of CSI to Alkoxyallenes . . . . . . . . . . . . . . . . . 121 6 Synthesis of 5-Oxacephams using 4-Vinyloxy-Azetidin-2-one . . . . . . . . 123 7 Solid-Phase Synthesis of β-Lactams . . . . . . . . . . . . . . . . . . . . . . 125 8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Abstract Since more then thirty years carbohydrates have gained much attention as chiral starting materials in stereocontrolled target oriented synthesis. Among variety of applica- tions, synthesis of β-lactam antibiotics from carbohydrate precursors played a special role owing to the importance of these class of compounds in modern chemotherapy. In 1994 we published a review article on the synthesis of β-lactams from carbohydrate precursors. The present survey reports literature published after that date. The streaking feature of the syntheses performed during the last decade is domination of the highly stereoselect- ive direct formation of a four-membered β-lactam ring via [2 + 2]cycloaddition of ketenes to imines and of chlorosulfonyl isocyanate to olefins. Particularly attractive substrates are: in former method, imines derived from glyceraldehyde and in latter one, vinyl ethers of acetal protected sugars. 1 Introduction Since the early 1970s, the tendency to use low molecular weight carbohydrates as convenient enantiomerically pure substrates for stereocontrolled target- oriented organic synthesis became a world trend often seen in the chemical 102 B. Furman et al. literature [1–5]. Despite spectacular achievements of contemporary organic synthesis in the field of catalytic enantioselective organic reactions [6–16], carbohydrates still remain very attractive, renewable, starting organic materi- als, simply because they are very cheap and available in many structural and configurational forms [17, 18]. In 1994 we published a review article on the synthesis of β-lactams from carbohydrate precursors [19]. Carbohydrates were used either as a chiral pool or chiral auxiliaries. Transformations of carbohydrates offered full stereo- control in the formation of the desired structure but showed the potency of modern organic synthesis rather than practical value. Great effort has been made to select the appropriate sugar synthons since simple carbohydrates dis- play some shortcomings such as overfunctionalization with hydroxyl groups, too many stereogenic centers, the lack of double bonds, and a configuration that is not fixed at the anomeric center. Although the search for new, more active β-lactam antibiotics, or for new methods of their synthesis does not represent contemporary world research trends, a variety of compounds having β-lactam fragments have been found to display very interesting, but not antibacterial activities [20]. This prompted us to update the report on the synthesis of β-lactams from carbohydrates. The present survey comprises literature published after 1994. Over the last 12 years direct formation of a four-membered β-lactam ring via [2 + 2]cycloaddition of ketenes to imines and of isocyanates to olefins dominated over other methods. Because of the well-defined transition states, both cycloadditions usually offer an excellent stereoselectivity. In the case of cycloaddition of ketenes or their equivalents to imines, the cycloadducts were used not only for the synthesis of β-lactam antibiotics, but also as intermedi- ates for the preparation of other biologically active compounds. 2 Syntheses Based on [2 + 2]Cycloaddition of Sugar-Derived Imines with Ketenes or their Equivalents The discovery that E-imines obtained from a variety of isopropylidene pro- tected sugar open-chain aldehydes and ketenes, or ketene equivalents afford cis-substituted β-lactam adducts usually with a high asymmetric induction and definite relative geometry depending on the absolute configuration of the stereogenic center next to the imine carbon atom (Scheme 1) [21–24], prompted many laboratories to exploit this reaction in a number of synthe- ses. Imines derived from both easily available enantiomeric forms of 2,3-O- isopropylidene-glyceraldehyde are particularly attractive. The search for high biological activity prompted Hassan and Soliman to synthesize compounds that were a combination of β-lactam with sul- fonamide fragments. A series of potential antibacterial and antiviral agents β-Lactams from Carbohydrates 103 Scheme 1 were prepared by [2 + 2]cycloaddition of imines derived from isopropylidene d-glyceraldehyde and p-aminophenyl-sulfonamides N-linked to heterocycles with benzyloxyacetyl chloride [25]. An easy deprotection of the isopropylidene residue in 1 and glycolic cleav- age of the diol 2 to the aldehyde 3, or glycolic cleavage followed by the oxidation to the carboxylic function and formation of the ester 4, provide par- ticularly attractive synthons (Scheme 2). Dirhodium complexes derived from difluoro-azetidinones, obtained in this way, were used as chiral catalysts for enantioselective decomposition of diazocompounds and cyclopropanation, to show, however, a moderate selectivity (Scheme 3) [26]. Scheme 2 Scheme 3 104 B. Furman et al. The Bose group continued their studies on the cycloaddition of ketenes to imines directed at target-oriented organic synthesis [23] and the application of microwave methodology [27, 28]. Recently, highly stereoselective synthesis of α-hydroxy-β-lactams readily available from carbohydrates has been de- veloped [29, 30]. It has been shown [27–30] that the reaction of acetoxyacetyl chloride and N-methylmorpholine with Schiff bases having aromatic sub- stituents gives mostly cis β-lactams at low energy of microwave irradiation, whereas at higher energy levels more than 90% of the β-lactam formed may be the trans isomer. Interestingly, with Schiff bases derived from carbohy- drate precursors 5–8 the cis β-lactams are formed at all levels of microwave irradiation. Stereocontrolled approaches and microwave-assisted chemical reactions have been utilized for the preparation of the corresponding hydrox- yazetidinones and this was followed by their conversion to intermediates for the synthesis of gentosamine (9), 6-epilincosamine (10), γ -hydroxythreonine (11), and polyoxamic acid (12) [29, 30]. Chart 1 An intramolecular opening of β-lactams with amines as a strategy for the formation of larger heterocyclic compounds was reported by two groups [31, 32]. Banik et al. [31] transformed β-lactam 13, which was obtained by cycloaddition of a glyceraldehyde-derived imine with o-nitrophenoxyacetyl chloride, into oxazine 14 by a sequence of reactions involving reduction of the nitro group in the presence of indium/ammonium chloride, followed by in- tramolecular transamidation. The same reaction sequence performed in the presence of zinc stopped at the stage of o-anisidine derivative 15 (Scheme 4). Similar transamidation leading to the enlargement of the four-membered ring has been reported by Banfi et al. [32]. In that case, the amino function in 17 was introduced to the end of the 4-allyloxy substituent of the azetidi- none 16 by a sequence of reactions involving hydroxylation, introduction of an azide, and its reduction (Scheme 5) [32]. β-Lactams from Carbohydrates 105 Scheme 4 Scheme 5 Azetidinones derived from glyceraldehyde imines and acetoxy-, phenoxy-, or alkoxy-acetyl chlorides have been investigated as intermediates for the synthesis of a variety of β-lactam antibiotics by the Alcaide group [33–35]. Easy hydrolysis of the dioxolane ring in 18 followed by deoxygenation af- forded 4-vinyl azetidinone 19. Alternatively, hydrolysis of 20 and a glycolic cleavage of the resulting diol provided the corresponding optically pure alde- hyde 21 which after nucleophilic addition of lithium TMS-acetylide afforded compounds 22, as diastereomeric mixtures. Both 4-substituted azetidinones 19 and 22 constitute starting materials for a variety of syntheses. Both enyne azetidinones 19 and 22 were used for the synthesis of fused tricyclic β-lactam 23 and diastereomeric tricyclic system 24 by the Pauson–Khand reaction (Scheme 6) [33, 34]. In a similar way, highly functionalized medium-sized rings fused to β-lactams 25–27 were obtained from the aldehyde 21 using radical cyclization of Baylis–Hillman adducts (Scheme 7) [35]. The Wittig–Horner olefination of the aldehyde 28 provided alkenes 29 which were subjected to radical cyclization leading to benzofused tricyclic β-lactams 30, obtained as single diastereomers (Scheme 8) [36]. A convenient, direct regio- and stereoselective route to optically pure unusually fused or bridged tricyclic β-lactams has been developed by the use of intramolecu- lar nitrone-alkene cycloaddition reactions. For example, the aldehyde 21 can be transformed into nitrone 31 which subsequently was used for a variety 106 B. Furman et al. Scheme 6 Scheme 7 Scheme 8 of cycloaddition reactions providing unusual fused polycyclic β-lactam 32 (Scheme 9) [37]. A thorough investigation of allylation reactions of the adducts 33 and the aldehydes 34 under a variety of conditions was reported. Mesylates of the homoallylic alcohols obtained, having an extra alkene or alkyne at position β-Lactams from Carbohydrates 107 Scheme 9 1 or 3 of the lactam ring, were transformed into fused tricyclic β-lactams 35–38 via tandem one-pot elimination-intramolecular Diels–Alder reactions (Scheme 10) [38]. Scheme 10 The Alcaide group [39, 40] continued investigations leading to un- usual fused tricyclic β-lactams 39–42 via aza-cycloadditions/ring closing metathesis. The diolefinic precursors were obtained, like before, from [2 + 2]cycloadducts of imines derived from glyceraldehydes [39]. A similar strat- egy has been applied to the synthesis of other unusual β-lactams having a seven-membered ring fused to the azetidinone 43 and 44 via tin-promoted radical cyclization [40]. 108 B. Furman et al. Chart 2 An introduction of an alkyl substituent, bearing a double bond, to the β-lactam nitrogen atom and subsequent transformation of the dioxolane ring stemming from glyceraldehyde into the aldehyde group opened an interest- ing access to carbacephams. Lewis acid-promoted carbonyl-ene cyclizations of azetidinone-tethered alkenylaldehydes led to a rapid, highly diastereo- selective formation of polyfunctionalized compounds having carbacepham skeletons (Scheme 11) [41]. Scheme 11 Azetidinone having a N-dehydroamino acid side chain, structurally re- lated to the active penem and cephem antibiotics, was obtained by the stan- dard phenylselenylation-oxidation-elimination reaction sequence [42]. C-4- substituted aldehydes can also be subjected to a novel N-1–C-4 β-lactam bond cleavage in the presence of 2-(trimethylsilyl)thiazole (TMST) to give enan- tiopure α-alkoxy-γ -keto amides (Scheme 12) as the major products [43]. Deprotection of the C-3 hydroxy group and subsequent oxidation gave reactive dicarbonyl compounds 45. Addition of a variety of nucleophilic reagents to the keto group led to C-3 functionalized compounds [44–47]. Using this path, 3-hydroxy-3-allyl-46 [44], allenyl-47, propargyl-48 [45], β-Lactams from Carbohydrates 109 Scheme 12 butadienyl-49 [46], and methoxycarbonyl-vinyl 50 [47] substituted azetidi- nones were obtained, and they were used for further transformations leading to 3-functionalized β-lactams (Scheme 13). Scheme 13 The dicarbonyl compound 51 was oxidized to the anhydride 52, which sub- sequently reacted with primary or secondary amines to form α-amino acids, α-amino amides and dipeptides 53 (Scheme 14) [48]. 3-Hydroxy β-lactams obtained from imines derived from carbohydrates [49, 50] or prepared via the Sharpless AD reaction [51–53] were directly oxidized to anhydrides by treatment with NaOCl and TEMPO. Anhydrides 54–56 were used for the syn- thesis of compounds related to the family of polyoxins represented by 57 (Scheme 15) [49–53]. Scheme 14 110 B. Furman et al. Scheme 15 Cyclohexylidene-protected glyceraldehyde imines were used by Annunzi- ata et al. [54, 55] for the synthesis of a β-lactam precursor of thrombin and tryptase inhibitors [54], as well as for the inhibitor of serine protease [55]. Glucosamine-derived imines 58 were used for the synthesis of carbapenem and carbacephem antibiotics. [2 + 2]Cycloaddition with methoxyacetyl chlo- ride provided diastereomeric β-lactams with low asymmetric induction [56]. Radical cyclization and oxidation reactions of diastereoisomer 59 led to car- bapenems 60 and 61 (Scheme 16) [57]. The same research group continued the transformation of β-lactams derived from d-glucosamine. In particular, a tandem elimination-conjugate addition performed on 62 provided the sec- ond ring of the carbacephem, for example 63 (Scheme 17) [58]. Scheme 16 β-Lactams obtained from glucosamine were used also for other trans- formations leading to a variety of carbacephams. The formation of epoxides β-Lactams from Carbohydrates 111 Scheme 17 64–66, their chromatographic separation into pure diastereomers, followed by cyclization in the presence of titanocene monochloride afforded bicyclic and tricyclic β-lactams with high regio- and stereoselectivity [59–61]. Chart 3 Readily available 3-deoxy-3-iodo-sugar aldehydes derived from d-glu- cose [62, 63] and d-galactose [29, 30, 49, 50] provide imines attractive for reaction with a variety of ketenes. [2 + 2]Cycloaddition of benzyloxy- or phenoxyacetyl chloride to d-ribo compound 67 proceeded with a low asym- metric induction to afford two cis β-lactams 68 and 69 in the ratio of about 1 : 1 [63]; the same observation was also made by another group [64]. On the other hand, d-xylo imines 70 under the same conditions gave only one cis diastereomer 71. The intramolecular radical cyclization in 68, 69, and 71 pro- ceeded with high stereoselectivity providing in all cases d-xylo configuration in the sugar part of the bicyclic β-lactam products 72 and 73, respectively (Scheme 18) [63]. The Vasella group [65] reported the synthesis of carboxylic acid 77 and the corresponding phosphonic-acid isoster 78 from d-erythrose derived imines 74–76 (Scheme 19). Despite expectations, none of the synthesized compounds exhibited a significant inhibitory in vitro activity against the sialidases of Vib- rio cholerae, Salmonella typhimurium, Influenza A, and Influenza B virus. Oxazolidinone auxiliaries based on d-xylose [66] and d-mannitol [67] residues were converted into corresponding carboxylic acids 79 and 80 which after activation were used for stereoselective Staudinger reaction with di- aryl, or aryl-styryl imines. In the first case, an excellent diastereoselectivity was obtained to afford 81 with high preponderance [66]. In the second case, 112 B. Furman et al. Scheme 18 Scheme 19 β-Lactams from Carbohydrates 113 Scheme 20 a mixture of cis and trans adducts 82 was obtained with high predominance of the cis isomer; the cyclohexylidene protection was shown to display a better selectivity than the isopropylidene one (Scheme 20) [67]. 3 Synthesis of β-Lactams by Cyclization Methods Cyclization methods of β-lactam formation shown in Scheme 21 have not been recently widely reported. The most common cyclization of chiral β-amino acids is represented by a few reports only. Imino aldol reaction of ketene silyl acetals with the chiral imine derived from tartaric acid 83 in the presence of a cation-exchange resin provided the corresponding β-amino esters 84 in a good yield and high diastereose- lectivity [68]. The esters 84, thus obtained, were subjected to the Grignard reagent which promoted β-lactam formation. After a sequence of reactions compound 84 was transformed into the ester 85 [68] which in the past was Scheme 21 114 B. Furman et al. the key intermediate for 2-isocephem and 2-oxaisocephem antibiotics 86 (Scheme 22) [69]. Scheme 22 β-Amino acid 88 obtained from methyl 3-deoxy-3-amino-altropyranoside 87 was treated with methanesulfonyl chloride in the presence of sodium bicarbonate and gave the β-lactam 89. Compound 89 was subsequently sub- jected to ring-opening polymerization to afford optically active polyamide 90 (Scheme 23) [70]. Scheme 23 The Miller group [71] continued investigation on the cyclization of β-hydroxy-O-benzyl hydroxamates in the presence of the Mitsunobu reagent leading to N-benzyloxy-β-lactams. The Ferrier rearrangement of d-glucal 91 followed by formation of hydroxamate and deacetylation provided a sub- strate 92 suitable for cyclization. In the Mitsunobu reaction conditions 92 was converted into the β-lactam 93, which was oxidized to the lactone 94 (Scheme 24). Scheme 24 β-Lactams from Carbohydrates 115 Compounds having a four-membered β-lactam ring fused to the pyra- noid ring were synthesized with intention to find a new entry to carbapen- ems and -cephems. N-Tosyl-2-C-carbamoyl glycosides with α-l-arabino- and β-d-xylo-configuration provided, under Mitsunobu reaction conditions, the corresponding bicyclic β-lactams, even in the presence of a neighboring trans-vic-diol fragment. The preference of β-lactam formation over γ -lactam was noticed (Scheme 25) [72]. Scheme 25 An interesting stereoselective formation of the β-lactam ring was reported by Izquierdo et al. (Scheme 26) [73]. Protected aldehydes 95 and 96 were transformed into the corresponding epoxides 97 and 98 by the method re- ported earlier by Lopez-Herera et al. [74–76] Cyclization involving carban- ions generated from the N,N-dibenzylamino group provided a single isomer 99 in the case of the fructopyranose auxiliary (97), whereas a mixture of β-lactams 100 was obtained in the case of the glyceraldehyde (96). Scheme 26 Tri-O-acetyl-d-glucal 101 was used for resolving racemic hydroxy β-lactam 102 into two diastereomeric glycosides 103 and 104 in the presence of iodine in THF (Scheme 27). Compounds 103 and 104 were subjected to catalytic transfer hydrogenation under microwave irradiation [77–80]. Carbohydrates or carbohydrate-derived compounds were used to pro- mote asymmetric induction in the crystalline state. In particular, enantio- selective photocyclization of α-ketoamide 105 in the clathrate crystalline environment with chiral hosts 106 and 107 derived from tartaric acid pro- vided the β-lactam 108 with high enantiomeric purity (Scheme 28) [81]. 116 B. Furman et al. Scheme 27 Scheme 28 The other report describes irradiation of achiral and chiral α-ketoamides as crystalline complexes with α-, β-, and γ -cyclodextrins leading to 3-hydroxy- β-lactams [82]. 4 Synthesis of β-Lactams via [2 + 2]Cycloaddition of Isocyanates to Chiral Vinyl Ethers Owing to the interesting antibacterial, antifungal, and β-lactamase inhibitory activity, oxygen analogs of penicillins and cephalosporins have attracted the attention of many research laboratories [82]. Among the variety of possible methods of construction of 4-alkoxy-substituted azetidinones [83], [2 + 2]cycloaddition of isocyanates to vinyl ethers p