Palladium-catalyzed DYKAT of butadiene monoepoxide: enantioselective total synthesis of (+)-DMDP, (-)-bulgecinine, and (+)-broussonetine G

Palladium catalyzed asymmetric allylic alkylation reaction of an amine with two equivalents of butadiene monoxide allows for the expedient synthesis of trans- and cis-2,5-dihydropyrroles. The versatility of these chiral synthons towards the synthesis of a wide variety of iminosugar natural products was demonstrated with the short and high yielding asymmetric syntheses of (+)-DMDP, and (-)-bulgecinine. In addition, the first total synthesis of (+)-broussonetine G, a potent glycosidase inhibitor, is described along with the assignment of its relative and absolute stereochemical configuration.     

Enzymes in Organic Synthesis: Application to the Problems of Carbohydrate Recognition (Part 2)

Recognition of carbohydrates by proteins and nucleic acids is highly specific, but the dissociation constants are relatively high (generally in the mM to high μM range) because of the lack of hydrophobic groups in the carbohydrates. The high specificity of this weak binding often comes from many hydrogen bonds and the coordination of metal ions as bridge between sugars and receptors. Though weak hydrophobic interactions between sugars and proteins have also been identified, the unique shape of a complex carbohydrate under the influence of anomeric and exo anomeric effects (the glycosidic torsion angles are therefore often not flexible but are typically somewhat restricted) and the topographic orientation of the hydroxyl and charged groups contribute most significantly to the recognition process. Studies on the structure–function relationship of a complex carbohydrate therefore require deliberate manipulation of its shape and functional groups, and synthesis of oligosaccharide analogs from modified monosaccharides is often useful to address the problem. The availability of various monosaccharides and their analogs for the synthesis of complex carbohydrates together with the information resulting from structural studies (such a NMR or X-ray studies on sugar–protein complexes) will certainly provide a basic understanding of complex carbohydrate recognition. An ultimate goal is to develop simple and easy-to-make non-carbohydrate molecules that resemble the active structure involved in carbohydrate–receptor interaction or the transition-state of an enzyme-catalyzed transformation (for example, glycosidase or glycosyltransferase reactions) and have the approprite bioavailability to be used to control the carbohydrate function in a specific manner. In part one of this review we described various enzymatic approaches to the synthesis of monosaccharides, analogs, and related structures. We describe in this part enzymatic and chemoenzymatic approaches to the synthesis of oligosaccarides and analogs, including those involved in E-selectin recognition, and strategies to inhibit glycosidases and glycosyltransferases.     

Attempted synthesis of 2-acetamido and 2-amino derivatives of salacinol. Ring opening reactions

The attempted synthesis of the 2-acetamido and 2-amino derivatives of salacinol, a naturally occurring glycosidase inhibitor, is described. Reaction of the protected acetamidothioarabinitol unit with the cyclic sulfate derived from L-erythritol gave the corresponding sulfonium sulfate, which underwent ring opening to give an acyclic amido sulfate. The corresponding reaction of the protected azidothioarabinitol unit with the cyclic sulfate proceeded to give the sulfonium sulfate. However, upon reduction of the azido function to an amine it formed an acyclic ammonium sulfate.     

四环素C-2位Mannich反应的研究

报道了四环素C-2位与伯胺、仲胺反应形成Mannich碱的简便方法:四环素盐酸盐在甲醇和水溶液中与伯胺反应,生成二级Mannich碱;四环素在叔丁醇中与仲胺反应,生成三级Mannich碱。合成了10个化合物,其中8个未见报道,并对所合成化合物的结构进行了表征。     

Formal total synthesis of (+)-trehazolin. Application of an asymmetric aldol-olefin metathesis approach to the synthesis of functionalized cyclopentenes

An asymmetric synthesis of the aminocyclopentitol pseudosugar of trehazolin has been completed. The synthesis hinges on an asymmetric aldol-ring closing metathesis strategy to construct the five-membered ring with control of both the relative and absolute stereochemistry.     

A stereo-divergent route to aminocyclopentitol derivatives

A stereo-divergent synthetic strategy based on diastereoselective vinylation of an α-amino aldehyde, ring-closing metathesis reaction and diastereoselective dihydroxylation reaction as key steps has been developed for the synthesis of three aminocyclopentitol derivatives of chemical and biological relevance.     

Structural Basis of Outstanding Multivalent Effects in Jack Bean α‐Mannosidase Inhibition

Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic‐level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high‐resolution crystal structures of the Jack bean α‐mannosidase (JBα‐man) in apo and inhibited states. The three‐dimensional structure of JBα‐man in complex with the multimeric cyclopeptoid‐based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition.     

β-Lactams in synthesis: short syntheses of cobactin analogs

Mycobactins facilitate assimilation of iron by mycobacteria. Synthetic analogs with structural variation of the cobactin component have potent anti-TB activity. A new method for the synthesis of cobactin analogs is presented. The key process involves single-step coupling reactions between an amine of a cyclic (l)-lysine derived hydroxamic acid with cyanide activated β-lactams.     

An oxepinone route to carbohydrate based oxepines

Oxepines are ring expanded analogs of glycals that can be used to prepare septanose carbohydrates. A route to carbohydrate based oxepines that utilizes oxepinones as a key intermediate has been developed. The oxepinone intermediates were prepared via an amine catalyzed cycloisomerization of furanose hemi-ketals. 1,2-Reduction of the oxepinones followed by acetylation provided the novel ring expanded enol ether products. Moderate diastereoselectivity was observed for the reduction based on the starting oxepinone. 1,4-Addition onto the oxepinones was also demonstrated. Overall, the syntheses reported here will allow for ready access to novel ring expanded carbohydrate analogs.     

Synthesis of sulfonium sulfate analogues of disaccharides and their conversion to chain-extended homologues of salacinol: new glycosidase inhibitors

Four chain extended homologues of salacinol, a naturally occurring glycosidase inhibitor, were prepared for evaluation as inhibitors of glucosidase enzymes involved in the breakdown of carbohydrates. The syntheses involved the reactions of 1,4-anhydro-2,3,5-tri-O-benzyl-4-thio-D-arabinitol with cyclic sulfate derivatives of different monosaccharides. Debenzylation of the products afforded the novel sulfonium sulfate derivatives of D-glucose, D-galactose, D-arabinose, and D-xylose that are of interest in their own right as glycosidase inhibitors. Reduction to the corresponding alditols then afforded the homologues of salacinol containing polyhydroxylated, acyclic chains of 5- and 6-carbons, differing in stereochemistry at the stereogenic centers. Three of the chain-extended homologues inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the low micromolar range, of approximately the same magnitude as salacinol, thus providing lead candidates for the treatment of Type 2 diabetes.     

New amino-functionalized 1,3-alternate calix[4]arene bis- and mono-(benzo-crown-6 ethers) for pH-switched cesium nitrate extraction

Four calix[4]arene benzo-crown-6 ethers functionalized with primary amine groups in various positions have been synthesized. The cesium extraction behavior under alkaline and acidic conditions has been measured for these compounds and compared with that of non-amine containing analogs. Extraction strength when the amine group is neutral is not affected by the amino substituent, but protonation causes a marked decrease in extraction strength, permitting pH-switched back-extraction.     

Allylic Amines as Key Building Blocks in the Synthesis of (E)-Alkene Peptide Isosteres

Nucleophilic imine additions with vinyl organometallics have developed into efficient, high yielding, and robust methodologies to generate structurally diverse allylic amines. We have used the hydrozirconation-transmetalation-imine addition protocol in the synthesis of allylic amine intermediates for peptide bond isosteres, phosphatase inhibitors, and mitochondria-targeted peptide mimetics. The gramicidin S-derived XJB-5-131 and JP4-039 and their analogs have been prepared on up to 160 g scale for preclinical studies. These (E)-alkene peptide isosteres adopt type II' β-turn secondary structures and display impressive biological properties, including selective reactions with reactive oxygen species (ROS) and prevention of apoptosis.     

Functional group requirements within the peptide H-Pro-Pro-Asp-NH2 as a catalyst for aldol reactions

H-Pro-Pro-Asp-NH₂1 is a versatile catalyst for asymmetric aldol reactions. In this work, the functional group tolerance within the catalyst structure has been examined. Several analogs of H-Pro-Pro-Asp-NH₂ in which the N-terminal secondary amine or the carboxylic acid in the side chain of the aspartic acid residue is replaced by different functional groups were prepared. Evaluation of their catalytic properties revealed that both the N-terminal secondary amine and the carboxylic acid are important for catalysis. The implications for the reaction mechanism are discussed.     

Suppression of racemization in the carbonylation of amino acid-derived aryl triflates

The carbonylation of enantiopure phenylglycine-derived aryl triflates was achieved to afford 4-carboxyphenylglycine analogs with high enantiomeric excesses (88 to >99% ee). Amide analogs of phenylglycine were well-tolerated in the hydroxy- and methoxycarbonylation processes, providing efficient access to benzoic acid and ester building blocks. The % ee of the product was dependent on the relative steric bulk of both the amino acid substrate and the requisite amine base, with ⁱPr₂NEt proving optimal in minimizing product racemization.     

Investigation of the sunscreen octocrylene's interaction with amino acid analogs in the presence of UV radiation

Octocrylene is an organic UV filter, commonly used in sunscreens and cosmetics, which can give rise to both contact and photocontact allergy. Our aim was to investigate octocrylene's interaction with amino acid analogs in the presence of UV radiation to better understand the reason for octocrylene's photoallergenic capacity. The amino acid analogs were photolysed in presence and absence of octocrylene for 1 h in cyclohexane. The rate of degradation was considerably slower for all amino acid analogs when octocrylene was present in the mixture. Benzylamine, the lysine analog, did react with octocrylene during the photolysis and the corresponding amide was formed in an acylation reaction. By varying the benzylamine concentration and keeping the octocrylene concentration fixed the reaction rate was shown to be independent of the amine concentration. The same type of acylation reaction took place when octocrylene alone was photolysed in ethanol in which the ethyl ester was formed from octocrylene and ethanol. Our results suggest that octocrylene's ability to cause photocontact allergy could be due to its photoinduced reactivity toward primary amines and alcohols.     

Synthesis of an immunomodulator (+)-conagenin and its analogs

Stereoselective synthesis of an immunomodulator (+)-conagenin was achieved. Both amine and carboxylic acid moieties were prepared from commercially available optically active methyl 3-hydroxy-2-methylpropanoate using dirhodium(II)-catalyzed C-H amination and chelation-controlled reductions as key steps. In addition, demethyl analogs of conagenin were synthesized using similar procedures.     

Synthesis of sterically hindered 3,5,5-trimethyl 2,6-dioxo tetrahydro pyrimidine as HCV protease inhibitors

An efficient route for the synthesis of sterically hindered substituted and unsubstituted 2,6-dioxo tetrahydropyrimidines from amine 1 is described. These analogs are active against HCV NS3 serine protease. The biological data for some of the representative examples are also reported.     

New cyclobutyl analogs of adenosine and guanosine. Part 1. Synthesis of the 9-[3,3-bis(hydroxymethyl)cyclobutyl]purine nucleoside analogs

The synthesis of 1-amino-3,3-bis(benzyloxymethyl)cyclobutane has been performed from 3,3-bis(benzyloxymethyl)cyclobutanone, via the corresponding oxime which was reduced with lithium aluminum hydride. The amine thus obtained led to two new cyclobutyl analogs of adenosine and guanosine which were devoid of antiviral activity against HSV-1, HCMV and HIV in cell culture.     

Inhibition of mitochondrial respiratory chain by arylthiolated 2,3-ethylenedioxy-1,4-benzoquinones

A series of arylthiolated 2,3-ethylenedioxy-1,4-benzoquinones as a coenzyme Q (CoQ) antagonist was tested for inhibition of succinate oxidase and reduced nicotinamide adenine dinucleotide (NADH) oxidase systems in the mitochondrial respiratory chain. The following characteristics were revealed: (1) 2,3-ethylenedioxy, 5-arylthio and 5,6-diarylthio groups were confirmed to be favorable for inhibition of both systems; (2) these analogs were more effective in the succinate oxidase system than in the NADH oxidase system; (3) 4' substituents on the benzene side ring had little effect on inhibitory activity; (4) the acting sites of these analogs had no strict stereospecificity. The reduced minus oxidized difference spectra revealed that these analogs inhibited the succinate oxidase system at the site between succinate and CoQ, and the NADH oxidase system at the site after cytochrome a + a3, suggesting these analogs might act as antagonists of CoQ in the succinate oxidase system. However, 5-(4'-nitrophenylthio)-2,3-ethylenedioxy-1,4-benzoquinone (If) strongly inhibited only the succinate oxidase system at the site after cytochrome a + a3.     

New synthetic routes to chain-extended selenium, sulfur, and nitrogen analogues of the naturally occurring glucosidase inhibitor salacinol and their inhibitory activities against recombinant human maltase glucoamylase

Six heteroanalogues (X = S, Se, NH) of the naturally occurring glucosidase inhibitor salacinol, containing polyhydroxylated, acyclic chains of 6-carbons, were synthesized for structure-activity studies with different glycosidase enzymes. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the PMB-protected 1,4-anhydro-4-seleno-, 1,4-anhydro-4-thio-, and 1,4-anhydro-4-imino-D-arabinitols at the least hindered carbon atom of 1,3-cyclic sulfates. These 1,3-cyclic sulfates were derived from D-glucose and D-galactose, and significantly, they utilized butane diacetal as the protecting groups for the trans 2,3-diequatorial positions. Deprotection of the coupled products proceeded smoothly, unlike in previous attempts with different protecting groups, and afforded the target selenonium, sulfonium, and ammonium sulfates with different stereochemistry at the stereogenic centers. The four new heterosubstituted compounds (X = Se, NH) inhibited recombinant human maltase glucoamylase (MGA), one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine. The two selenium derivatives each had Ki values of 0.10 microM, giving the most active compounds to date in this general series of zwitterionic glycosidase inhibitors. The two nitrogen compounds also inhibited MGA but were less active, with Ki values of 0.8 and 35 microM. The compounds in which X = S showed Ki values of 0.25 and 0.17 microM. Comparison of these data with those reported previously for related compounds reinforces the requirements for an effective inhibitor of MGA. With respect to chain extension, the configurations at C-2' and C-4' are critical for activity, the configuration at C-3', bearing the sulfate moiety, being unimportant. It would also appear that the configuration at C-5' is important but the relationship is dependent on the heteroatom.