Synthesis of di-branched heptasaccharide by one-pot glycosylation using seven independent building blocks

[reaction: see text] We describe an efficient synthesis of di-branched heptasaccharide 1 having phytoalexin elicitor activity in soybeans by one-pot glycosylation. The synthesis involves chemo- and regioselective sequential six-step glycosylations using seven independent building blocks and sequential removal of acyl- and benzyl ether-type protecting groups. The coupling of seven building blocks requires only four chemoselective activitable leaving groups of glycosyl donors. Both the glycosylation and deprotection reactions can be achieved utilizing a parallel manual synthesizer.     

Clavaminols G-N, six new marine sphingoids from the Mediterranean ascidian Clavelina phlegraea

An exhaustive examination of the chemical constituents of the Mediterranean ascidian Clavelina phlegraea led to the isolation of clavaminols G-N (1-6), a new series of amino alcohols, which expand the family of modified marine sphingoids. Structures of the novel compounds 1-6 have been elucidated by spectroscopic analysis and chemical derivatization; bioactivities of compounds 1-6 have also been investigated and comparison of their pharmacological properties with those of previously isolated clavaminols A-F allowed us to perform an assessment of simple structure-activity relationships.     

Nordehydrocyclodercitin, a hexacyclic pyridoacridine alkaloid from the marine ascidian, Aplidium sp

A new hexacyclic pyridoacridine alkaloid, nordehydrocyclodercitin (1), from an ascidian, Aplidium sp., cf. Aplidium cratiferum collected at Arab Reef, Great Barrier Reef, Australia is reported. Nordehydrocyclodercitin is structurally related to stellettamine (2) and cyclodercitin (3), which are sponge metabolites, and cycloshermilamine D (4) which was isolated from the marine tunicate Cystodytes violatinctus. The structure of nordehydrocyclodercitin was determined by interpretation of spectroscopic data, particularly those obtained from HMBC correlations, and by comparison with reported data for known related pyridoacridine alkaloids.     

Synthesis of a non-natural T-antigen containing glycosphingolipid

A non natural glycosphingolipid containing the mucin derived, cancer associated disaccharide moiety Galbeta1-->3GalNAc, the T-antigen, alpha linked to a ceramide, has been synthesised via the protected disaccharide glycosyl trichloroacetimidate. The product has potential as a cancer vaccine.     

Synthesis, inhibitory effects on nitric oxide and structure-activity relationships of a glycosphingolipid from the marine sponge Aplysinella rhax and its analogues

The novel glycosphingolipid, β-D-GalNAcp(1-->4)[α-D-Fucp(1-->3)]-β-D-GlcNAcp(1-->)Cer (A), isolated from the marine sponge Aplysinella rhax has a unique structure, with D-fucose and N-acetyl-D-galactosamine moieties attached to a reducing-end N-acetyl-D-glucosamine through an α1-->3 and β1-->4 linkage, respectively. We synthesized glycolipid 1 and some non-natural di- and trisaccharide analogues 2-6 containing a D-fucose residue. Among these compounds, the natural type showed the most potent nitric oxide (NO) production inhibitory activity against LPS-induced J774.1 cells. Our results indicate that both the presence of a D-Fucα1-3GlcNAc-linkage and the ceramide aglycon portion are crucial for optimal NO inhibition.     

一锅法合成新型木犀草素衍生物

以木犀草素为母体,保留B环邻苯二酚结构或C’3-OH,在无水碳酸钾作用下,RBr选择性的与木犀草素结构中的其他酚羟基反应,一锅法合成了7个新型木犀草素衍生物,通过1H NMR、MS等手段对其进行了结构表征。这类新型化合物的合成,为开发抗氧化和血管并发症的新药提供了理想中间体。一锅法设计路线短、成本低、用时少,是制备该类中间体的优选方法。     

An approach to the total synthesis of the marine ascidian metabolite perophoramidine via a halogen-selective tandem Heck/carbonylation strategy

A halogen-selective tandem intramolecular Heck/carbonylation reaction has been developed for the construction of the C,E,F-ring system and the C20 quaternary center found in perophoramidine (1). This process can be effected in good yields in the presence of both the chlorine and bromine atoms found in the natural product. In addition, it is possible to introduce the quaternary center at C4 in a stereoselective manner by a lactone enolate alkylation, using NaH and allyl bromide. [reaction: see text]     

A modular strategy toward the synthesis of heparin-like oligosaccharides using monomeric building blocks in a sequential glycosylation strategy

A novel flexible assembly strategy is described for the modular synthesis of heparin and heparan sulfates. The reported strategy uses monomeric building blocks to construct the oligosaccharide chain to attain a maximum degree of flexibility. In the assembly, 1-hydroxyl glucosazido- and 1-thio uronic acid donors are combined in a sequential glycosylation protocol using sulfonium triflate activator systems. The key 1-thio uronic acids were obtained in an efficient manner from diacetone glucose employing a chemo- and regioselective oxidation of partially protected glucose and idose thioglycosides.     

Prepatellamide A, a new cyclic peptide from the ascidian Lissoclinum patella

A new cyclic peptide, prepatellamide A (1), along with three known cyclic peptides (2)-(4), was isolated from the ascidian Lissodinum patella. The structure of prepatellamide A was determined from one- and two-dimensional H and 13C NMR spectra. The known cyclic peptides were identified as patellamides A (2), B (3) and C (4).     

Synthesis of 2'-amino-LNA: a new strategy

In this paper we present revised and significantly improved synthetic routes to 2'-amino-LNA (locked nucleic acid). The optimal route is convergent with the synthesis of LNA monomers ("2'-oxy-LNA") via a common intermediate obtained by a mild deacetylation for the liberation of the 2'-hydroxy group to give compound 23 without the concomitant ring closure that affords the 2'-oxy-LNA skeleton. After inversion of the stereochemistry at C2' and triflate formation at the 2'-hydroxy group a new common intermediate 16 is obtained which gives easy access to a range of other analogues exemplified by the introduction of a sulfur nucleophile leading to the 2'-thio-LNA structure. After substitution of the triflate with azide a basic reduction affords the desired 2'-amino-LNA structure, i.e., compound 18. This new synthesis strategy towards 2'-amino-LNA improves the overall yield significantly and converges the syntheses of 2'-oxy-LNA and LNA analogues.     

Exploratory studies toward a total synthesis of the marine ascidian metabolite perophoramidine

A strategy for a total synthesis of the marine alkaloid perophoramidine has been investigated. Key steps which have been tested include a tandem intramolecular Heck/carbonylation reaction and a stereoselective allylation of a pentacyclic δ-lactam to produce the C-4/20 vicinal quaternary centers having the requisite relative configuration of the metabolite.     

Preparation of nonsymmetrically substituted stilbenes in a one-pot two-step heck strategy using ethene as a reagent

We present here a strategy for the preparation of nonsymmetrically substituted stilbenes using a one-pot two-step double Heck strategy. First a protocol is developed for the selective preparation of a range of styrenes using ethene as the alkene coupling partner. Then conditions are found for the effective coupling of the styrenes with aryl halides using a 1:1 stoichiometric ratio of the two components. The use of the microwave apparatus to perform the reactions offers a convenient method for synthesis as well as for safely, easily, and accurately loading vessels with gaseous reagents.     

Synthesis of biphenyl anilines using iodo phenylformamides via a one-pot Suzuki coupling reaction

We have developed a novel and economical synthesis of biphenyl anilines via a one-pot Suzuki coupling reaction with iodo phenylformamides. This literature is an unprecedented approach to biphenyl anilines replacing costly aminophenylboronic acids with economical iodo anilines for the preparation of biphenyl anilines. It also provides a viable synthesis toward substituted biphenyl anilines where the required aminophenylboronic acids are not readily available.     

Prepatellamide A, a new cyclic peptide from the ascidian Lissoclinum patella

A new cyclic peptide, prepatellamide A (1), along with three known cyclic peptides (2)— (4), was isolated from the ascidianLissoclinum patella. The structure of prepatellamide A was determined from one- and two-dimensional¹H and¹³C NMR spectra. The known cyclic peptides were identified as patellamides A (2), B (3) and C (4).     

Kingamide A, a new indole alkaloid from the ascidian Leptoclinides kingi

Chemical investigation of the CH₂Cl₂/MeOH extract from the Australian ascidian Leptoclinideskingi led to the isolation of a new brominated indole alkaloid, kingamide A (1). The planar structure of kingamide A was elucidated following the interpretation of 1D/2D NMR and MS data, and the absolute configuration was determined using Marfey’s method. This is the first report of a natural product from L. kingi.     

Molecular requirements of imino sugars for the selective control of N-linked glycosylation and glycosphingolipid biosynthesis

N-Butyl-deoxynojirimycin (NB-DNJ) has been approved for clinical trials as a potential therapy for Gaucher disease, a glycolipid lysosomal storage disorder. As this compound has both glycoprotein processing α-glucosidase and ceramide glucosyltransferase inhibitory activity, we have sought to determine the molecular basis for these two activities. NB-DNJ is known to resemble the positively charged oxocarbonium-like transition state for α-glucosidase I and the structure–function relationships we present now help to define the recognition epitope for the enzyme. Inhibition of ceramide glucosyltransferase by NB-DNJ was competitive for ceramide (K_i=7.4 μM) and non-competitive for UDP-glucose, indicating inhibitory activity is by ceramide mimicry. The presence of an N-alkyl chain was obligatory for transferase inhibition and increases in alkyl chain length provided a modest increase in inhibitory potency.By contrast, α-glucosidase inhibition was independent of the N-alkyl chain and changes in chain length. The effects of ring substitutions identified the C₃ hydroxyl group as being critical for both enzymes but C₁ and C₆ modifications led to a loss of transferase inhibition only. Attempts to rationalise these data for transferase inhibition using an energy minimised molecular model of NB-DNJ and ceramide predicted structural homology of three stereogenic centres and the N-alkyl chain of NB-DNJ, with the trans-alkenyl and N-acyl chain of ceramide. On the basis of these studies, modifications to imino sugar inhibitors can be suggested that allow a more selective approach for molecular inhibition of both ceramide glucosyltransferase and α-glucosidase I, leading to improved compounds for the potential treatment of lysosomal glycosphingolipid storage disorders and viral infections, respectively.     

Haouamines A and B: a new class of alkaloids from the ascidian Aplidium haouarianum

The chemical study of the ascidian Aplidium haouarianum has led to the isolation of the new metabolites haouamines A (1) and B (2) which belong to a novel class of alkaloids. The structure of 1 was established by interpretation of its spectroscopic data and those of the N-methyl derivative 3, and confirmed by X-ray crystallographic analysis. The structure of 2 was deduced by spectroscopic study of its peracetyl derivative 2a. In solution each haouamine exists as an unseparable mixture of two interconverting isomers derived by the presence of a highly strained 3-aza-[7]-paracyclophane moiety in their structures. Compound 1 exhibits a selective cytotoxic activity against the HT-29 human colon carcinoma cell line.     

A strategy for the identification of site-specific glycosylation in glycoproteins using MALDI TOF MS

A strategy for investigation of site-specific glycosylation of glycoproteins has been developed, based on peptide mass fingerprinting using matrix assisted laser desorption ionisation time of flight mass spectrometry (MALDI TOF MS). The glycoprotein is subjected to sequential digestion with a protease and glycan-specific endoglycosidases or with the glycan-specific endoglycosidases followed by the protease. Peptides with characteristic masses are detected for sequences containing glycosylated asparagine residues. By using a panel of three proteases, chymotrypsin, protease V8 and trypsin, and endoglycosidases F3 and H and peptide N-glycanase F, it was possible to monitor the state of glycosylation of all putative N-glycosylation sites on three glycoproteins. It was deduced that all potential N-glycosylation sites in human serum transferrin (two) and α1-antitrypsin (three) were occupied by non-fucosylated, biantennary, disialylated, complex glycans. In contrast, only four (asparagines 19, 59, 146 and 270) out of the five potential sites were glycosylated in recombinant human β-glucosylceramidase, with the site nearest the C-terminal (asparagine 462) being unoccupied. The glycans at each site consisted of a mixture of non-fucosylated and core α1–6 fucosylated oligomannose glycans (Man₃ GlcNAc₂), derived from the enzymic truncation of complex glycans.     

Synthesis of a vinylchlorine-containing 1,3-diol from a marine cyanophyte

Using epoxy chiral building blocks readily derived from d-gluconolactone as the source of the stereogenic centers, both (6R,8R)- and (6R,8S)-isomers of (E)-1-chlorotridec-1-ene-6,8-diol were synthesized. The vinylchloro unit was installed onto the substrate carbon chain in an approximately 9:1 (E)/(Z) ratio via a condensation of CrCl₂/CHCl₃ with a terminal aldehyde. A tosylation protocol featuring addition of H₂O was also developed for a highly polar tetraol. The synthetic products allowed for re-acquisition of the NMR spectra of better quality and revealed some delicate yet unignorable discrepancies in the ¹³C NMR for the natural isomer obtained by synthesis and that isolated some 30 years ago from the marine cyanophyte. The puzzling discrepancies were eventually shown to be caused by deuteration of the hydroxyl groups.