Carbohydrate-Based Lactones:Synthesis and Applications 21 PPL Porcine pancreatic lipase Py Pyridine ROP Ring-opening polymerization TBAF Tetrabutylammonium fluoride TBDMS tert-Butyldimethylsilyl TE Trifluoromethanesulfonyl(triflyl) TEA Trifluoroacetic acid TMEDA etramethyl-1,2-ethylenediamine T TPAP Tetrapropylammonium perruthenate Ts Tosyl.4-toluenesulfonyl 1 Introduction Carbohydrate lactones have found broad applications as building blocks for the synthesis of important bioactive compounds and natural products,and constitute a valuable family of synthons for diverse types of transformations.Previous survey articles were published by De Lederkremer [1].Lundt [2-4].and Fleet [5].In this revision. phasis will begiven to nable aches involy limited of ronment tally friendly synthe meth ion of these m s into functional compounds. to m ep sequ the preparation of more complex targets.Starting with simple and available aldo nolactones,the chemistry of more elaborated carbohydrate-based lactones,such as aB-unsaturated 6-lactones as well as other types of bicyclic systems will then be presented and discussed.Allying the chirality inherent to the sugar to the reactivity of the lactone functionality turns these classes of compounds into useful chemical intermediates towards a variety of purposes. 2 Aldonolactone Synthesis 2.1 General Aspects Aldonolactones are commercially available at low cost,when compared to most of the common monosaccharides.They are typically synthesized by selective anomeric oxidation of unprotected aldoses with bromine [6].Usually the thermo- dynamically more stable five-membered lactone (y-lactone)predominates over the six-membered form,with the exception of D-gluconolactone,which crystal- lizes as the 1.5-pyranolactone(8-lactone)[7](Scheme 1).Another method for the preparation of sugar lactones is the dehydroger nation of u unprotected or partially
PPL Porcine pancreatic lipase Py Pyridine ROP Ring-opening polymerization TBAF Tetrabutylammonium fluoride TBDMS tert-Butyldimethylsilyl Tf Trifluoromethanesulfonyl (triflyl) TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride TMEDA N,N,N’,N’-Tetramethyl-1,2-ethylenediamine TMS Trimethylsilyl TPAP Tetrapropylammonium perruthenate Ts Tosyl, 4-toluenesulfonyl 1 Introduction Carbohydrate lactones have found broad applications as building blocks for the synthesis of important bioactive compounds and natural products, and constitute a valuable family of synthons for diverse types of transformations. Previous survey articles were published by De Lederkremer [1], Lundt [2–4], and Fleet [5]. In this revision, emphasis will be given to sustainable approaches involving a limited number of steps, to environmentally friendly synthetic methodologies for conversion of these molecules into functional compounds, and to multi-step sequences for the preparation of more complex targets. Starting with simple and available aldonolactones, the chemistry of more elaborated carbohydrate-based lactones, such as a,b-unsaturated d-lactones as well as other types of bicyclic systems will then be presented and discussed. Allying the chirality inherent to the sugar to the reactivity of the lactone functionality turns these classes of compounds into useful chemical intermediates towards a variety of purposes. 2 Aldonolactone Synthesis 2.1 General Aspects Aldonolactones are commercially available at low cost, when compared to most of the common monosaccharides. They are typically synthesized by selective anomeric oxidation of unprotected aldoses with bromine [6]. Usually the thermodynamically more stable five-membered lactone (g-lactone) predominates over the six-membered form, with the exception of D-gluconolactone, which crystallizes as the 1,5-pyranolactone (d-lactone) [7] (Scheme 1). Another method for the preparation of sugar lactones is the dehydrogenation of unprotected or partially Carbohydrate-Based Lactones: Synthesis and Applications 21
22 N.M.Xavier et al. protected alditols and aldoses catalyzed by a transition metal complex in the presence of a hydrogen acceptor [8-10].Protected aldoses with a free anomeric hydroxyl group can be converted into the corresponding aldonolactones by xidation protocols.such as those empl ng chromium(VD re [11]or DMSO-based oxidizin ystems [1213 o protected aldo scatalysts combination of Bi-P/C.haveaso been developed (1 processes for the synthesis of aldonolactones/aldonic acids are preferred on the industrial scale. 2.2 Glucono-1,5-Lactone Gn-acucolactone )is the cyclic ester ofcond which is pro uced eindustrial scale by enzymatic oxi eview of the production,properties,and applications ofccidnd derivatives see [18)).This process is mediated by enzymes from selected micro organisms,including bacteria such as Pseudomonas or Gluconobacter oxydans and fungi such as Aspergillus niger.The method involving A.niger is widely used and is based on glucose oxidase.The oxidation pathway consists in the oxidation of glucose to 8-D-gluconolactone.which is mediated by the latter enzyme,followed by hydrolysis to gluconic acid.which may occur spontaneously or be promoted by the lactonase e enzyme(Scheme 2).After the fermentation process,the lactone can simply OH HO OH HO O HO. HO Ho..08 0 OH OH OH Lactonase/ SpontaneousH0 OH HO OH HO O -OH LOH D-Glucose 1 D-Glu Scheme 2 Oxidation of p-glucose by Aspergillus niger
protected alditols and aldoses catalyzed by a transition metal complex in the presence of a hydrogen acceptor [8–10]. Protected aldoses with a free anomeric hydroxyl group can be converted into the corresponding aldonolactones by common oxidation protocols, such as those employing chromium(VI) reagents [11] or DMSO-based oxidizing systems [12, 13]. Methods for aerobic oxidation of unprotected aldoses over heterogeneous catalysts, including Pd/C, Au/C, or a combination of Bi-Pd/C, have also been developed [14–17]. However enzymatic processes for the synthesis of aldonolactones/aldonic acids are preferred on the industrial scale. 2.2 Glucono-1,5-Lactone Glucono-1,5-lactone (d-D-gluconolactone, 1) is the cyclic ester of D-gluconic acid, which is produced on the industrial scale by enzymatic oxidation of glucose (for a review of the production, properties, and applications of gluconic acid and its derivatives see [18]). This process is mediated by enzymes from selected microorganisms, including bacteria such as Pseudomonas or Gluconobacter oxydans and fungi such as Aspergillus niger. The method involving A. niger is widely used and is based on glucose oxidase. The oxidation pathway consists in the oxidation of glucose to d-D-gluconolactone, which is mediated by the latter enzyme, followed by hydrolysis to gluconic acid, which may occur spontaneously or be promoted by the lactonase enzyme (Scheme 2). After the fermentation process, the lactone can simply O OH O OH [O] [O] OH HO HO HO O O OH HO HO HO OH HO OH HO O O OH HO OH HO Scheme 1 Formation of 1,4 and 1,5-lactone from D-glucose HO HO HO HO HO OH CO2H OH OH OH HO HO OH OH OH Lactonase/ O Spontaneous O O Glucose oxidase D-Glucose 1 D-Gluconic acid (quant.) Scheme 2 Oxidation of D-glucose by Aspergillus niger 22 N.M. Xavier et al
Carbohydrate-Based Lactones:Synthesis and Applications 23 be recovered from the broth by crystallization.Under appropriate conditions.glucose can be quantitatively converted into gluconic acid.About 100,000 tons of D-gluconic acid,mainly used in the food industry,are produced annually worldwide [19]. Glucono-1.5-lactone (1)has widespread application as a food additive,particularly in dairy products,confectionery,and meat. 2.3 Other Aldono-1,5-Lactones Glycosyl azides have been shown to be useful precursors for the synthesis o aldonolactones.A viable one-pot procedure for the conversion of per-O-alkylated glycopyranosides into the corresponding aldono-1,5-lactones is based on the formation of glycosyl azide intermediates by treatment of the substrates with trimethylsilyl (TMS)azide in the presence of tin(IV)chloride,followed by hydro- lysis [20].In other work,aldono-1,4-lactones and aldono-1.5-lactones could be prepared from glycosyl azides via a two-step methodology consisting in the N-brom corre ng Nh de (NBS)mediated bromi and subsequent hydrolysis of nd Schlaf [22]were a toprepare and isolate for the first time the les catalyti system,which is based on the dimeric ruthenium complex [(CaPh CO)(CO)Ru]2 The transformation led to the 8-galactonolactone in 93%yield,against 7%of the isolated y-lactone isomer.This procedure also allowed the preparation of 8-D-man- nonolactone in a much better yield(94%)than that reported in an early procedure [23] based on crystallization from a solution of calcium mannonate in aqueous oxalic acid. O'Dohe and co-workers have explored the use of 2.4-dien ates as pr for galac 24,25 Th eti droxylation steps of the es d Dy AD-mi reagent systems(Scheme 3).After the first enantioselective dihydroxylat on ste】 the resulting Y.8-dihydroxyenoate intermediates (3a-c)were protected at the Y-hydroxyl group as cyclic carbonates,which were then treated with p-methoxy phenol (PMPOH)in the presence of a pd(o)catalyst.The resulting 4-0-protected derivatives(4a-c)were submitted to diastereoselective dihydroxylation affording triols possessing galacto configuration.which were then lactonized to give the no-1.5-lacto nes(5a-c)or their enantiomers,depending on the orde arpless reagents were applied [24]. 2.4 Aldono-1,4-Lactones An efficient method for preparing aldono-1.4-lactones(y-aldonolactones)as the single products from oxidation of unprotected or partially protected monosacchar ides was reported [9].It consisted in treatment of the latter by catalytic amounts of [RuH(PPh3).in the presence of an excess of benzalacetone(frans-4-phenylbut-3- en-2-one)as the hydrogen acceptor,in DMF.The corresponding y-lactones were
be recovered from the broth by crystallization. Under appropriate conditions, glucose can be quantitatively converted into gluconic acid. About 100,000 tons of D-gluconic acid, mainly used in the food industry, are produced annually worldwide [19]. Glucono-1,5-lactone (1) has widespread application as a food additive, particularly in dairy products, confectionery, and meat. 2.3 Other Aldono-1,5-Lactones Glycosyl azides have been shown to be useful precursors for the synthesis of aldonolactones. A viable one-pot procedure for the conversion of per-O-alkylated glycopyranosides into the corresponding aldono-1,5-lactones is based on the formation of glycosyl azide intermediates by treatment of the substrates with trimethylsilyl (TMS) azide in the presence of tin(IV) chloride, followed by hydrolysis [20]. In other work, aldono-1,4-lactones and aldono-1,5-lactones could be prepared from glycosyl azides via a two-step methodology consisting in the N-bromosuccinimide (NBS) mediated bromination and subsequent hydrolysis of corresponding N-bromoiminolactone intermediates [21]. Bierenstiel and Schlaf [22] were able to prepare and isolate for the first time the less stable d-D-galactonolactone by oxidation of galactose with the Schvo’s catalytic system, which is based on the dimeric ruthenium complex [(C4Ph4CO)(CO)2Ru]2. The transformation led to the d-galactonolactone in 93% yield, against 7% of the isolated g-lactone isomer. This procedure also allowed the preparation of d-D-mannonolactone in a much better yield (94%) than that reported in an early procedure [23] based on crystallization from a solution of calcium mannonate in aqueous oxalic acid. O‘Doherty and co-workers have explored the use of 2,4-dienoates as precursors for d-galactonolactones [24, 25]. The synthetic approach involved sequential dihydroxylation steps of the dienoates (2a–c) double bonds by Sharpless AD-mix reagent systems (Scheme 3). After the first enantioselective dihydroxylation step, the resulting g,d-dihydroxyenoate intermediates (3a–c) were protected at the g-hydroxyl group as cyclic carbonates, which were then treated with p-methoxyphenol (PMPOH) in the presence of a Pd(0) catalyst. The resulting 4-O-protected derivatives (4a–c) were submitted to diastereoselective dihydroxylation affording triols possessing galacto configuration, which were then lactonized to give the target L-galactono-1,5-lactones (5a–c) or their enantiomers, depending on the order in which the Sharpless reagents were applied [24]. 2.4 Aldono-1,4-Lactones An efficient method for preparing aldono-1,4-lactones (g-aldonolactones) as the single products from oxidation of unprotected or partially protected monosaccharides was reported [9]. It consisted in treatment of the latter by catalytic amounts of [RuH2(PPh3)4], in the presence of an excess of benzalacetone (trans-4-phenylbut-3- en-2-one) as the hydrogen acceptor, in DMF. The corresponding g-lactones were Carbohydrate-Based Lactones: Synthesis and Applications 23
24 N.M.Xavier et al. obtained in excellent yields,even in the case of D-glucose,for which no 1.5-lactone was observed.The results suggested that the oxidation step is followed by a ring contraction mechanism,probably promoted by coordination of the catalyst to the endocyclic oxygen and to the carbonyl gr facilitating ring opening and its closune into the mo thermody molecular targets of interest.Stereoselective approaches involving few steps lead- ing to 2,3-0-isopropylidene-L-ribono-lactones and L-lyxono-1.4-lactones were reported by Rao and Lahiri [26].The L-ribono derivative could be synthesized in three steps starting from the easily available isopropylidene-D-erythrose (6) (Scheme 4).It was converted into the unsaturated acid 7 by Wittig olefination and further oxidation.Epoxidation of the latter afforded the desired 1.4-lactone Eo人久人R AD-a' OH EtO人 R 180-89%1 OH 2a-c 80-90%0) 3a-c R=OBn,CH H a)(Clco)co,py (77-6%))DBA),CHCL 2%PPha 1)AD-B OH PMPO OH 5a-c AD-a"=2%Os04.4%(DHO).PHAL.3 eg K.Fe Scheme 3 Synthesis of L-galactono-1.5-lactones from 2.4-hexadienoates Scheme 4 Synthesis of 2.3-0 isopropylidene L-ribono-and L-lyxono-1.4-lacto
obtained in excellent yields, even in the case of D-glucose, for which no 1,5-lactone was observed. The results suggested that the oxidation step is followed by a ring contraction mechanism, probably promoted by coordination of the catalyst to the endocyclic oxygen and to the carbonyl group, facilitating ring opening and its closure into the more thermodynamically stable five-membered form. L-Aldonolactones are much less available than their D-enantiomers. Their potential to serve as chiral building blocks for L-sugar derivatives also makes them molecular targets of interest. Stereoselective approaches involving few steps leading to 2,3-O-isopropylidene-L-ribono-lactones and L-lyxono-1,4-lactones were reported by Rao and Lahiri [26]. The L-ribono derivative could be synthesized in three steps starting from the easily available isopropylidene-D-erythrose (6) (Scheme 4). It was converted into the unsaturated acid 7 by Wittig olefination and further oxidation. Epoxidation of the latter afforded the desired 1,4-lactone O OH O O OH O O O O O H O O O O O O OH O O O O HO O TsCl O O O TsO O BnOH KH O O OBn O O O O O HO O 1) PPh3= CH2 2) PCC 3) NaClO2 m-CPBA 6 7 8 H2, Pd/C 9 10 11 12 (79%) (40%) (42%) (44%) Scheme 4 Synthesis of 2,3-O-isopropylidene L-ribono- and L-lyxono-1,4-lactones EtO O R EtO O R OH OH AD−α∗ 1) AD-β∗ 2) py⋅TsOH 2a–c 3a–c 4a–c R = OBn, CH3, H EtO O R OH OPMP a) (Cl3CO)2CO, py b) PMPOH, 0.5 % Pd2(DBA)3.CHCl3 2% PPh3 O O R OH OH 5a–c (80–89%) (80–90% ee) PMPO (77-86%) (66–73%) AD−α∗ = 2% OsO4, 4% (DHQ)2PHAL, 3 eq K3Fe(CN)6, 3 eq K2CO3, 1 eq MeSO2NH2 AD-β∗ = 2% OsO4, 4% (DHQD)2PHAL, 3 eq K3Fe(CN)6, 3 eq K2CO3, 1 eq MeSO2NH2 Scheme 3 Synthesis of L-galactono-1,5-lactones from 2,4-hexadienoates 24 N.M. Xavier et al
Carbohydrate-Based Lactones:Synthesis and Applications 25 (8)in40%yield,due tocyclization of the intermediate epoxide promoted by silica gel when attempting product separation by column chromatography.The synthesis of the L-lyxono-1,4-lactone derivative (12)was accomplished starting from D-ribono-1,4-lactone (9).of which the 5-0-tosyl derivative 10 was treated with the potassium salt of benzyl alcohol to give the epoxy benzyl ester 11,furnishing directly on catalytic hydrogenation the target compound in 44%yield. More recently,a simple synthetic route for a large scale production of 12 (2,3-0- pylidene-L-lyxonolact tone)was described [.The derivative which was then mesylated at H5.Treatment of the c mesylate 15 with potassium hydroxide led to 12 according to the mechanism proposed in Scheme 5. L-Galactono-1,4-lactone (16)is prepared in three steps (51%,overall yield) from 2a applying two successive asymmetric dihydroxylations (ADs)[25] (Scheme 6). L-Aldono-1,4-lactones can be of aldx on (Sche 7.The resutin5-0-mesyl glyconitrile d vatives(19)are then submitted to acid-catalyzed hydrolysis giving the corresponding 1,4-lactones 20a-c. OH Br2 Acetone Mscl 0 KOH 12 H.SO. H20 H0OH(65%.13-g到 (59%,9→12 14 +HO 12 Scheme 5 Proces sfor a large scale production of 23-0-isopropylidene-L-yxono-14-actone OBn OH OBn 1)AD-B HO、 2)py-TsOH OH (57%,2 steps)OH 3a 16 Scheme 6L-Galactono-1.5-lactones from 2.4-hexadienoates
(8) in 40% yield, due to cyclization of the intermediate epoxide promoted by silica gel when attempting product separation by column chromatography. The synthesis of the L-lyxono-1,4-lactone derivative (12) was accomplished starting from D-ribono-1,4-lactone (9), of which the 5-O-tosyl derivative 10 was treated with the potassium salt of benzyl alcohol to give the epoxy benzyl ester 11, furnishing directly on catalytic hydrogenation the target compound in 44% yield. More recently, a simple synthetic route for a large scale production of 12 (2,3-Oisopropylidene-L-lyxonolactone) was described [27]. The chosen starting material was D-ribose (13), which was oxidized to the corresponding lactone 14 (Scheme 5). The latter was submitted in situ to acetonation to provide the 2,3-O-isopropylidene derivative 9, which was then mesylated at OH-5. Treatment of the crude 5-Omesylate 15 with potassium hydroxide led to 12 according to the mechanism proposed in Scheme 5. L-Galactono-1,4-lactone (16) is prepared in three steps (51%, overall yield) from 2a applying two successive asymmetric dihydroxylations (ADs) [25] (Scheme 6). L-Aldono-1,4-lactones can be prepared from D-aldose perpivaloates and peracetates (compounds of type 17) [28]. The method implies formation of aldoximes (18), followed by mesylation (Scheme 7). The resulting 5-O-mesyl glyconitrile derivatives (19) are then submitted to acid-catalyzed hydrolysis giving the corresponding 1,4-lactones 20a–c. EtO O OBn EtO O OBn OH OH O O HO OH OH OBn AD-α∗ 1) AD-β∗ 2) py⋅TsOH 2a 3a 16 (89%) (57%, 2 steps) Scheme 6 L-Galactono-1,5-lactones from 2,4-hexadienoates O HO OH HO OH O HO OH HO O MsCl O MsO O O O KOH H2O Br2 K2CO3 H2SO4 O MsO OH O O O O O O O O 9 12 Acetone 13 14 15 15 12 + HO + HO – MsO (65%, 13 9) (59%, 9 12) Scheme 5 Process for a large scale production of 2,3-O-isopropylidene-L-lyxono-1,4-lactone Carbohydrate-Based Lactones: Synthesis and Applications 25