Structure–sweetness relationships for fructose analogs. Part I. Synthesis and evaluation of sweetness of 5-deoxy-<scp>D</scp>-<i>threo</i>-hexulose

Martin, Olivier R.; Korppi-Tommola, Sirkka-Liisa; Szarek, Walter A.

doi:10.1139/v82-258

Cited by 26 publications

(11 citation statements)

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“…While the keto form is hardly detectable in D-fructose (0.5-0.8%) (26), its highly deoxygenated analogs exist completely (e.g., 6-hydroxy-2-hexanone (27)) or largely (e.g., 1,6-dihydroxy-2-hexanone (28)) in the open-chain form in aqueous solution. It is remarkable that we had not observed the keto form in the spectra of the 5-deoxy isomer of 1, namely 5-deoxy-D-threohexulose, in our previous studies of this compound (4). This can be explained by the fact that the P-pyranose form of 5-Can.…”

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confidence: 77%

Structure–sweetness relationships for fructose analogs. Part III. 3-Deoxy-D-erythro-hexulose (3-deoxy-D-fructose): composition in solution and evaluation of sweetness

Szarek¹,

Rafka²,

Yang³

et al. 1995

Can. J. Chem.

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Abstract:As part of continuing studies on the structural features responsible for the intense sweetness of D-fructose, 3-deoxy-D-erythro-hexulose (3-deoxy-D-fructose, 1) was prepared, its solution composition was determined, and its taste was evaluated. In aqueous solution, 3-deoxy-D-fructose exists as a complex mixture of five tautomeric forms in which the P-D-pyranose form is preponderant (52.5% at 22OC) and the a-D-pyranose form is the least abundant (5%). Quite remarkable is the behavior of the open-chain keto form of 1: its content increases from 7.5% at 22"C, to 36% at 82OC, and to 47% at 97OC, making this form the preponderant one at high temperatures. 3-Deoxy-D-fructose was found to be sweet, albeit probably not as sweet as D-fructose. The hydroxyl group at C-3 is thus not an essential function of the glycophore of D-fructose. The significance of this result is discussed in relation to the evidence already available and the divergent theories that have been proposed to explain the origin of the sweet taste of D-fructose.Key words: 3-deoxy-D-erythro-hexulose (3-deoxy-D-fructose), sweetness, solution composition.Resume : La poursuite d'ttudes sur les attributs structuraux responsables pour la douceur intense du D-fructose nous a conduit B prCparer le 3-dCsoxy-D-Prythro-hexulose (3-dCsoxy-D-fructose, I), B determiner sa composition en solution et h Cvaluer son gotit. En solution aqueuse, le 3-dCsoxy-D-fructose existe sous forme d'un mClange complexe de cinq formes tautomkres dans lequel la forme P-D-pyranose est prtpondtrante (52.5% j. 22°C) et la forme a-D-pyranose est la moins abondante (5%). Le comportement de la forme a chalne ouverte ce'to est tout-i-fait remarquable : prtsente i 7.5% i 22"C, sa concentration augmente i 36% i 82°C et i 47% B 97"C, ce qui en fait la forme la plus abondante i haute tempkrature. Le 3-dCsoxy-D-fructose est doux, cependant probablement pas aussi doux que le D-fructose. Le groupement hydroxyle en C-3 apparait ainsi ne pas &tre une fonction essentielle du glycophore du D-fructose. L'importance de ce rtsultat est discutC en relation avec les donnCes dCji disponibles et les thCories divergentes qui ont Ct C proposCes pour expliquer l'origine de la douceur du D-fructose.Mots clPs : 3-dtsoxy-D-e'rythro-hexulose (3-dtsoxy-D-fructose), caractkre sucrt, composition d'une solution.The origin of the intense sweetness of D-fructose, the sweetest of the natural sugars (I), has been the object of much debate (2). While the lipophilic component X of the presumed tripartite AH-B-X glycophore (3) can be attributed to one of the methylene groups (2), the assignment of the hydrogen bond donor (AH) and acceptor (B)-couple remains unresolved. As part of continuing studies on deoxy ketohexoses designed to probe the role of individual hydroxyl groups in the glycophore of D-fructose, we have already shown (4) that the 5-OH group is not essential for the sweet response since 5-deoxy-D-threohexulose (5-deoxy-D-fructose) is nearly as sweet as D-fructose. We have now completed studies on 3-and 4-deoxy...

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confidence: 77%

Structure–sweetness relationships for fructose analogs. Part III. 3-Deoxy-D-erythro-hexulose (3-deoxy-D-fructose): composition in solution and evaluation of sweetness

Szarek¹,

Rafka²,

Yang³

et al. 1995

Can. J. Chem.

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“…We synthesized four additional N-substituted compounds, 22-25, to further define the SAR of 1. 14 Treatment of alcohol 4 with sulfuryl chloride in the presence of pyridine (toluene, 0-10 °C) afforded a reasonably stable chlorosulfate 2a (26) in 95% yield. Reaction of 26 with excess ethylamine, butylamine, or benzylamine provided 22-24 (yields: 59, 67, and 76%).…”

Section: Structural Alterations and Synthetic Chemistrymentioning

confidence: 99%

“…Hexafluoroacetone was reacted with 28 to generate a 1:1 adduct that was subjected to dehydration with dicyclohexylcarbodiimide (DCC) at 90 °C; however, target 47 was not formed. 24 Cyclic carbonate 52 (vide infra) also failed to react with hexafluoroacetone ethyl hemiacetal at 100 °C for 18 h. 25 The successful synthesis started with diol 40, which was converted 26 to chlorohydrin 48 in 47% yield (eq 4). Formation of epoxide 49 occurred in 100% yield, and condensation with hexafluoroacetone in the presence of iodide in a sealed vessel for 38 h provided ketal 50 in 89% yield.…”

Section: Structural Alterations and Synthetic Chemistrymentioning

confidence: 99%

Structure−Activity Studies on Anticonvulsant Sugar Sulfamates Related to Topiramate. Enhanced Potency with Cyclic Sulfate Derivatives

et al. 1998

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We have explored the structure-activity relationship (SAR) surrounding the clinically efficacious antiepileptic drug topiramate (1), a unique sugar sulfamate anticonvulsant that was discovered in our laboratories. Systematic structural modification of the parent compound was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacological importance of several molecular features: (1) the sulfamate group (6-8, 22-25, 27, 84), (2) the linker between the sulfamate group and the pyran ring (9, 10, 21a,b), (3) the substituents on the 2,3- (58-60, 85, 86) and 4, 5-fused (30-38, 43, 45-47, 52, 53) 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84-87, 90a, 91a, 93a), (5) the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106 and 107). We established the C1 configuration as R for the predominant alcohol diastereomer from the highly selective addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by single-crystal X-ray analysis of the major diastereomer of sulfamate 21a. Details for the stereoselective syntheses of the hydrindane carbocyclic analogues 95, 96, 100, and 104 are presented. We also report the synthesis of cyclic imidosulfites 90a and 93a, and imidosulfate 91a, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite 93a required the preparation and use of the novel sulfur dichloride reagent, BocN=SCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analogue 2 (RWJ-37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than 1 in mice at 4 h, ED50 = 6.3 mg/kg; ca. 15 times greater than 1 in rats at 8 h, ED50 = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate 2, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, 2 was not active in diverse in vitro receptor binding and uptake assays. However, 2 turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e. g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examination of several analogues of 2 (83a-r, 85-87, 90a, 91a, 93a) indicated that potent anticonvulsant activity is associated with relatively small alkyl substituents on nitrogen (Me/H, 83a; Me/Me, 83m; Et/H, 83b; allyl/H, 83e; c-Pr/H, 83j; c-Bu/H, 83k) and with limited changes in the cyclic sulfate group, such as 4,5-cyclic sulfite 87a/b. The potent anticonvulsants 83a and 83j had greatly diminished carbonic anhydrase inhibitory activity; thus, inhibition of this enzyme may not be a significant factor in the anticonvulsant activity. The alpha-L-sorbopyranoses 67, 68, and 80, which mainly possess a skew conformation (ref 29...

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“…It is worth mentioning that TalB F178Y demonstrated excellent conversion of 3‐hydroxypropanal and DHA to afford 5‐deoxy‐ D ‐fructose ( 6 , Scheme ) as a single product in 83 % isolated yield 43. This reaction constitutes the first efficient one‐step preparation of 6 , which has been discussed as a potential artificial sweetener,95–97 from inexpensive starting materials. Analogously, 1‐deoxy‐fructose ( 5 ) and 1,5‐dideoxy‐fructose ( 7 ) can be obtained by simple substrate variation.…”

Section: Preparative Applicationsmentioning

confidence: 89%

The Transaldolase Family: New Synthetic Opportunities from an Ancient Enzyme Scaffold

et al. 2011

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Aldol reactions constitute a powerful methodology for carbon-carbon bond formation in synthetic organic chemistry. Biocatalytic carboligation by aldolases offers a green, uniquely regio- and stereoselective tool with which to perform these transformations. Recent advances in the field, fueled by both discovery and protein engineering, have greatly improved the synthetic opportunities for the atom-economic asymmetric synthesis of chiral molecules with potential pharmaceutical relevance. New aldolases derived from the transaldolase scaffold (based on transaldolase B and fructose-6-phosphate aldolase from Escherichia coli) have been shown to be unusually flexible in their substrate scope; this makes them particularly valuable for addressing an expanded molecular range of complex polyfunctional targets. Extensive knowledge arising from structural and molecular biochemical studies makes it possible to address the remaining limitations of the methodology by engineering tailored biocatalysts.

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Structure–sweetness relationships for fructose analogs. Part I. Synthesis and evaluation of sweetness of 5-deoxy-D-threo-hexulose

Cited by 26 publications

References 4 publications

Structure–sweetness relationships for fructose analogs. Part III. 3-Deoxy-D-erythro-hexulose (3-deoxy-D-fructose): composition in solution and evaluation of sweetness

Structure–sweetness relationships for fructose analogs. Part III. 3-Deoxy-D-erythro-hexulose (3-deoxy-D-fructose): composition in solution and evaluation of sweetness

Structure−Activity Studies on Anticonvulsant Sugar Sulfamates Related to Topiramate. Enhanced Potency with Cyclic Sulfate Derivatives

The Transaldolase Family: New Synthetic Opportunities from an Ancient Enzyme Scaffold

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