Synthesis of pseudaminic acid, a unique nonulopyranoside derived from pathogenic bacteria through 6-deoxy-AltdiNAc

Chemical synthesis of pseudaminic acid is described. Starting from N-acetylglucosamine, deoxygenation and deoxyamination with stereo-inversion afforded 6-deoxy-AltdiNAc, which is the key intermediate for the biosynthesis of pseudaminic acid. Subsequently, the elongation reaction via In-mediated allylation of 6-deoxy-AltdiNAc with bromomethacrylate ester derivative followed by ozonolysis and hydrolysis gave the desired pseudaminic acid. Furthermore, we demonstrated glycosylation with dibenzyl phosphite derivative of pseudaminic acid as the glycosyl donor to afford disaccharide.     

Stereochemical assignment and first synthesis of the core of miharamycin antibiotics

The relative configuration at C-6' of nucleoside antibiotic miharamycin A has been elucidated by NMR spectroscopy and proved to be S. The total synthesis of miharamycin B has also been investigated, which has led to the unprecedented construction of its core. The bicyclic sugar moiety has been elaborated by means of a SmI(2)-based keto-alkyne coupling. Elongation of its C-6 position towards a bicyclic sugar amino acid and conversion into a suitable glycosyl donor enabled efficient N-glycosylation with 2-aminopurine to take place to afford the nucleosidic part of miharamycin B. Final peptide coupling with arginine afforded the skeleton of miharamycin B. Unfortunately, attempts to deprotect this scaffold failed to afford the complex nucleoside antibiotic.     

Synthesis of the non-reducing end trisaccharide of the antithrombin-binding domain of heparin and its bioisosteric sulfonic acid analogues

A glucoronic acid-containing trisaccharide related to the antithrombin-binding DEFGH domain of heparin and its methanesulfonic acid analogues were synthesized. Trisaccharides without sulfonic acid content or possessing a sulfonatomethyl moiety at position 2 or 6 of unit F were prepared in high yields by [DE+F] couplings using the same disaccharide uronate donor, respectively. Synthesis of the trisaccharide with a 3-deoxy-3-sulfonatomethyl function was accomplished in three different pathways, from which a [D+EF] coupling and applying a non-oxidized precursor of the glucuronic acid afforded the trisaccharide in the highest yield.     

Novel ester linked glycosyl amino acids: convenient building blocks for the synthesis of glycopeptide libraries

The completely orthogonally protected aspartic acid derivative FmocAsp(OBn)O^tBu is readily synthesized on a large scale. Deprotection of the β-carboxylic acid allows coupling to various sugar derivatives via free hydroxyl groups to produce novel glycosyl amino acids. Subsequent deprotection of either the α-acid or nitrogen is achieved cleanly to allow elaboration into an oligopeptide, whilst selective deprotection of PMB protected sugar hydroxyls is also readily achievable. Such novel glycosyl amino acid building blocks may be useful for the combinatorial synthesis of novel glycopeptide libraries.     

Heck-type arylation of 2-cycloalken-1-ones with arylpalladium intermediates formed by decarboxylative palladation and by aryl iodide insertion

[reaction: see text] A palladium-catalyzed decarboxylative arylation reaction was shown to produce Heck-type coupling products using a number of different arene carboxylic acid and 2-cycloalken-1-one substrates. The more conventional Heck coupling of an aryl iodide and a 2-cycloalken-1-one reactant was also briefly explored for comparison, where it was found that phosphine-free (Jeffery) conditions afforded the highest yield of product.     

Stereoselective synthesis of 2-C-branched (acetylmethyl) oligosaccharides and glycoconjugates: Lewis acid-catalyzed glycosylation from 1,2-cyclopropaneacetylated sugars

1,2-Cyclopropaneacetylated sugars as glycosyl donors reacted with a series of glycosyl acceptors (monosaccharides, amino acids, and other alcohols) in the presence of Lewis acid to produce oligosaccharides and glycoconjugates containing 2-C-acetylmethylsugars. Galactosyl donor gave good to excellent α-selectivities with TMSOTf as a catalyst, whereas galactosyl donor offered moderate to good β-selectivities when BF(3)·Et(2)O was used as a catalyst. However, glucosyl donors produced β-exclusive selectivity under both conditions. The stereoselectivities of glycosylation depend on the reactivity of donor sugars and Lewis acid catalyst, which effectively dictated the glycosylation pathways. The evidence suggests that galactosyl donors (e.g., 7) can undergo S(N)1 pathway with a strong Lewis acid (TMSOTf) and S(N)2 pathway under BF(3)·Et(2)O, whereas the glucosyl donors (e.g., 8 and 10) followed S(N)2 pathway. The stereoselectivity was also consequential to the formation of a C2'-acetal intermediate formed via the 2-C-acetylmethyl group and the anomeric carbonium intermediate in glycosylation.     

Gram scale synthesis of the glucuronide metabolite of ABT-724

A gram scale synthesis of the glucuronide metabolite of ABT-724 is reported. Glycosidic coupling between a trichloroacetimidate glucuronyl donor and a Cbz-protected hydroxypyridylpiperazine glycosyl acceptor is the key step in the synthesis, since attempts to directly glucuronidate the aglycon, aglycon derivatives, and other truncated glycosyl acceptors were unsuccessful. The route was used to produce 2.1 g of metabolite in eight steps from 2-chloro-5-hydroxypyridine in 21% overall yield.     

Synthesis of s-linked glycoconjugates and s-disaccharides by thiol-ene coupling reaction of enoses

Free-radical hydrothiolation of the endocyclic double bond of enoses is reported. Reaction between 2-acetoxy-d-glucal and a range of thiols including amino acid, peptide, glycosyl thiols, and sugars with primary or secondary thiol functions gave S-linked α-glucoconjugates and S-disaccharides with full regio- and stereoselectivity. Addition of glycosyl thiols to a 2,3-unsaturated glycoside also proceeded with good selectivity and afforded a series of 3-deoxy-S-disaccharides.     

TCP Building Blocks for Oligosaccharide Synthesis: Progress Towards the Synthesis of Nodulation Factors

Abstract

The ability of tetrachlorphthaloyl (TCP) sugars to act as glycosyl acceptors as well as the viability of TCP as a global amine protecting group in the syntheis of polyglucosamine natural products such as N-methyl-N-lipid nodulation factors have been examined. Disaccharides corresponding to the reducing end segments and the core region of the target nodulation factors were assembled from n-pentenlyl glycosides. TCP acceptors were successfully coupled with a variety of pentenyl glycosyl donors to produce β-(1→4) oligosaccharides in good yields. Model coupling reactions to produce trisaccharides provided clear evidence for the disarming effect of an ester at O3 on a C4-OH in the glycosyl acceptor. Also, a unique pentenyl donor, which contained the desired N-metyl-N-lipid moiety of the non-reducing end segments of the target compounds, was synthesized and its efficacy in a coupling reaction was tested.     

Efficient synthesis of core 2 class glycosyl amino acids by one-pot glycosylation approach

We describe the one-pot synthesis of core 2 class branched oligosaccharides initiated by chemo-selective glycosylation of silyl ether. Glycosylation of 6-O-silyl-4-benzyl-2-azido-thiogalactoside with glycosyl fluoride provided selectively 6-glycosylated thioglycoside without both O-glycosylation at the 3 position and S-glycosylation. Subsequent coupling of galactosyl fluoride and amino acids afforded the protected branched oligosaccharides in good yields.     

Spectrophotometric determination of advanced products of non-enzymatic glycosylation of lysine by means of their reaction with diazonium salts

A typical product (glycosyl lysine) formed by reaction of lysine with glyceraldehyde is measured at 490 nm after coupling with diazotized sulfanilic acid. Reaction with 4-dimethylaminobenzaldehyde was less satisfactory.     

Combinatorial synthesis of an oligosaccharide library by using beta-bromoglycoside-mediated iterative glycosylation of selenoglycosides: rapid expansion of molecular diversity with simple building blocks

A new method for constructing an oligosaccharide library composed of structurally defined oligosaccharides is presented based on an iterative glycosylation of selenoglycosides. Treatment of 2-acyl-protected selenoglycosides with bromine selectively generates beta-bromoglycosides, which serve as glycosyl cation equivalents in the oligosaccharide synthesis. Thus, the coupling of the bromoglycosides with another selenoglycoside affords the corresponding glycosylated selenoglycosides, which can be directly used to next glycosylation. The iteration of this sequence allows the synthesis of a variety of oligosaccharides including an elicitor active heptasaccharide. A characteristic feature of the iterative glycosylation is that glycosyl donors and acceptors with the same anomeric reactivity can be selectively coupled by activation of the glycosyl donor prior to coupling with the glycosyl acceptor. Therefore, same selenoglycosides can be used for both the glycosyl donors and the acceptors. This feature has been exemplified by a construction of an oligosaccharide library directed to elicitor-active oligosaccharides. The library composed of stereochemically defined oligoglucosides with considerable structural diversity can be constructed starting from simple selenoglycosides.     

The Suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues.

The thallium-accelerated Suzuki coupling reaction of tetraenyl iodide 19 and cyclohexenyl boronate 18 afforded ethyl 9-cis-retinoate (12) in high yield. Both coupling partners of the Suzuki reaction are better reacted immediately after generation from their precursors, tetraenylstannane 10 and cyclohexenyl iodide 13. The geometrically homogeneous tetraenylstannane 10, comprising the polyenic side chain of ethyl 9-cis-retinoate and its ring-demethylated analogues, was synthesized by a stereoselective Horner-Wadsworth-Emmons reaction. On the other hand, easily available cyclohexanones are ideal starting materials for preparation of the cyclohexenyl boronates required for the synthesis of the ring-modified 9-cis-retinoic acid analogues. For hindered cyclohexanones, hydrazones were converted to cyclohexenyl iodides. Iodine-lithium exchange and trapping with B(OMe)(3) then afforded the cyclohexenyl boronates. If the precursor cyclohexanone has secondary carbons, the alkenyllithium species was conveniently formed by elimination of the C,N-dilithiated intermediate obtained upon treating the trisylhydrazone with n-BuLi (Shapiro reaction). None of the above procedures allowed the generation of the more substituted organolithium from 2-methylcyclohexanone. However, the alternative Stille cross-coupling of 34 and 10 afforded 9-cis-1,1-bisdemethylretinoic acid 7. Both Suzuki and Stille coupling reactions took place under mild conditions, and the preservation of the retinoid side-chain geometry was therefore secured.     

Design and synthesis of novel sugar‐based nitrogen‐containing heterocycles as potential anticancer agents under microwave in water

A series of novel glycosyl nitrogen‐containing heterocycles derivatives were designed and synthesized. With the help of microwave, the reaction was carried out in water rapidly and afforded the target compounds in good yields. The acid catalysts that were essential for this kind of reaction under traditional heating method were avoided through this strategy. Preliminary biological evaluation showed that most of the compounds could inhibit the growth of A549 cells, but the inhibition of HepG‐2 cells was relatively poor. Notably, compound 2i displayed the best potency with an IC₅₀ value of 3.42 μM against A549 cell lines, which is comparable with the common anticarcinogen paclitaxel (5.12 μM). Molecular modeling studies suggested that 2i may bind to the ATP‐binding site of epidermal growth factor receptor (EGFR), indicating a rational design strategy. These results provide a starting point for designing glycosyl nitrogen‐containing heterocycles as the potential drugs in lung cancer therapy.     

Synthesis of 10-thia-5-deazafolic acid and 2-desamino-2-oxo-10-thia-5-deazafolic acid

The folate analogue, 10-thia-5-deazafolic acid, was obtained via a multistep synthetic sequence beginning with the known intermediate, 2,4-diaminopyrido[2,3-d]pyrirnidine-6-carboxaldehyde. Reduction of this aldehyde with sodium borohydride gave 2,4-diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine, which when heated in base gave 2-amino-3,4-dihydro-6-(hydroxymethyl)-4-oxopyrido[2,3-d]pyrimidine. Treatment of the latter compound with phosphorus tribromide in tetrahydrofuran afforded 2-amino-6-(bromomethyl)-3,4-dihydro-4-oxopyrido[2,3-d]pyrimidine, thus constituting the first successful synthesis of this elusive intermediate. The aforementioned bromomethyl compound reacted smoothly with the sodium salt of ethyl 4-mercaptobenzoate, and the resulting ester was saponified to give 10-thia-5-deazapteroic acid. Conventional peptide bond coupling to di-tert-butyl L-glutamate followed by treatment with trifluoroacetic acid afforded the target compound in respectable yield. Attempts to prepare its 5,6,7,8-tetrahydro derivative by catalytic hydrogenation were unsuccessful.     

几种齐墩果酸糖缀合物的合成

报道了齐墩果酸与四种单糖和二糖（葡萄糖、半乳糖、乳糖及葡萄糖醛酸）进 行糖苷化制备糖缀合物的方法。在合成过程中首先将葡萄糖、半乳糖及乳糖转化成 相应的全苯甲酰三氯亚胺酯糖基供体（10a-10c），将葡萄糖醛酸转化成为1-溴代 乙酰葡萄糖醛酸甲酯糖基供体（10d）；在齐墩果酸的28-位羧基上进行酰胺化引入 ω-氨基羧酸甲酯得到其衍生物6。然后10a-10c在TMSOTf的催化下与化合物6的3-位 羟基进行β-糖苷化；10d在AgOTf的催化下与6进行β-糖苷化，最后脱掉保护基得 到相应的糖缀合物13a-13d，所有目的化合物均为新化合物，其结构经IR，^1H NMR，^13C NMR，2D-COSY，HMQC，DEPT及HRMS进行了确证。     

Amino acid derivatives,part 2: Synthesis,antiviral, and antitumor activity of simple protected amino acids functionalized at N‐terminus with naphthalene side chain

Coupling of various acylated amino acid derivatives with (naphthalen‐2‐lyloxy)acetic acid ( 3 ) in the presence of 1‐hydroxy‐benzoteriazole (HOBt) and DCC afforded the new amides 6–12 . Alternatively, the latter compounds were prepared from reaction of the corresponding hydrazide 5 , via the azide‐coupling method, with the acylated amino acid derivatives. Treatment of 6, 10–12 with N₂H₄ċH₂O afforded the hydrazides 13–16 , respectively, as key intermediates for the synthesis of peptide derivatives. Reaction of 12 , as a acceptor, with the glycosyl‐trichloroimidate 18 , as donors in the presence of TMSOTf gave the new glycoside 19 . The new compounds were evaluated for their anti‐HIV‐1, antibovine viral diarrhea virus (BVDV), and antitumor activity. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:148–222, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20082     

Design and Synthesis of Glycosylated Aromatic Nitrogen Mustard Derivatives

Antibody-directed enzyme prodrug therapy(ADEPT) is a new strategy for the treatment of cancer that has arisen in recent twenty years, the main merits of which are that it can improve the selectivity of anticancer drugs and reduce the side effects in remote tissue. In the present study, two prodrugs-glycosylated aromatic nitrogen mustard derivatives were synthesized. Glucose and lactose were converted into glycosyl donors-trichloroacetimidate; the obtained glycosyl donors were glycosylated with p-nitrophenol(glycosyl donors) to form β-glucosyl p-nitrobenzene and β-lactosyl p-nitrobenzene that were protected by acetyl in a stereoselective manner; the two products were reduced by zinc dust and then treated with ethylene oxide, afforded two glycosylated nitrogen mustard derivatives that were protected by acetyl; the last step was to deacetylate and then afforded the two target compounds that could be used as prodrugs of ADEPT for further Anti-tumor research.     

Incorporation of a molecular hinge into molecular tweezers by using tandem cycloadditions onto 5,6-dimethylenenorbornene

Site-selective 1,3-dipolar coupling at the norbornene pi-bond of 5,6-dimethylenenorbornene 1 yields cycloadducts with an end-fused 1,3-diene system which have been reacted with N=N (or C=C) dienophiles to produce ribbon molecules, in which the internal diazacyclohexene (or cyclohexene) subunits are capable of acting as conformational hinges. Direct coupling of 5,6-dimethylenenorbornene with 1,3,4-oxadiazoles or dual coupling with bis(cyclobutene epoxides) afforded bis(1,3-dienes) that diastereoselectively react with dienophiles to produce new, conformationally mobile, molecular tweezers.     

Total synthesis of everninomicin 13,384-1--Part 1: retrosynthetic analysis and synthesis of the A1B(A)C fragment

In this first of a series of four articles we introduce everninomicin 13,384-1 (1), a powerful antibiotic effective against drug resistant bacteria, as a target for total synthesis and discuss its retrosynthetic analysis. From the three defined fragments required for the synthesis (2: A1B(A)C fragment; 4: DE fragment; 5: FGHA2 fragment), we describe herein two approaches to the A1B(A)C block. The first strategy relied on an olefin metathesis reaction to construct a common intermediate for rings B and C, but was faced with final protecting group problems. The second, and successful approach, involved a 1,2-phenylsulfeno migration and a sulfur directed glycosidation procedure to link rings B and C, as well as an acyl fluoride intermediate to install the sterically hindered aryl ester moiety (ring A1). The final stages of the synthesis of the required 2-phenylseleno glycosyl fluoride 2 required introduction of a phenylseleno group at C-1 of ring C followed by a novel, DAST-promoted 1,2-migration to produce the desired 2-beta-phenylseleno glycosyl fluoride moiety.