Use Of Protecting Groups Research Articles

Chemical syntheses of inulin and levan structures.

A fructofuranosyl thiglycoside donor, ethyl 6-O-acetyl-3-O-benzyl-1,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-2-thio-beta-D-fructofuranoside (11), designed to yield stereospecifically beta-linkages and also to allow subsequent elongation in the 6- and/or 1-positions, was prepared and used in syntheses of levan and inulin structures. DMTST-promoted glycosylation between 11 (1.3 mol equiv) and methyl beta-D-fructofuranoside 6-OH and 1-OH acceptors (3 and 6) gave stereospecifically the protected methyl levanobioside 12 and inulinobioside 17 in excellent yields (80 and 86%), respectively. Protecting group manipulations on these afforded new disaccharide 6'-OH and 1'-OH acceptors (13 and 19), which were coupled again with donor 11 (1.0 mol equiv) to yield methyl levanotrioside 14 and inulinotrioside 20 in high yields, 65 and 67%, respectively. These were transformed into new acceptors and also fully deprotected to afford the methyl glycosides of levanotriose and inulinotriose, all structures that have earlier not been accessible by chemical synthesis.

Synthesis of a Small Repertoire of Non‐Racemic 5a‐Carbahexopyranoses and 1‐Thio‐5a‐carbahexopyranoses.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The synthesis of a carbohydrate-like dihydrooxazine and tetrahydrooxazine as putative inhibitors of glycoside hydrolases: A direct synthesis of isofagomine

The treatment of benzyl 2,3-O-isopropylidene-β-L-xylopyranoside with N-hydroxyphthalimide under Mitsunobu conditions, followed by protecting-group interchange, gave benzyl 4-O-[(tert-butoxycarbonyl)amino]-2,3- O-isopropylidene-α-D-arabinoside. Mild acid hydrolysis and catalytic hydrogenolysis afforded 4-O-[(tert-butoxycarbonyl)amino]-D-arabinose that, upon heating in water, gave the dihydrooxazine [(4R,5S,6R)-5,6-dihydro-4,5-dihydroxy-6-hydroxymethyl-4H-1,2-oxazine] as a crystalline solid. A single-crystal structure determination of this solid showed it to exist in the 5H6 conformation. Reduction of the dihydrooxazine gave the tetrahydrooxazine [(4R,5S,6R)-4,5-dihydroxy-6-hydroxymethyl-3,4,5,6-tetrahydro-2H-1,2-oxazine]. The dihydrooxazine was an effective inhibitor of two β-glucosidases (Ki = 27 and 35 µM). Benzyl 2,3-O-isopropylidene-β-L-xylopyranoside, via the derived imidazylate, was converted into a nitrile that, upon reduction and protecting-group manipulations, gave benzyl 4-C-aminomethyl-4-deoxy-α-D-arabinoside. Treatment of this amine with hydrogen and palladium-on-carbon gave isofagomine.Key words: dihydrooxazine, tetrahydrooxazine, isofagomine, iminosugars, glycosidase inhibitors.

Improved functional group compatibility in the palladium-catalyzed synthesis of aryl amines.

[reaction: see text] The use of Pd2dba3 with bulky, electron-rich ligands 1 or 2 and LiN(TMS)2 as the base for the coupling of amines with aryl halides containing hydroxyl, amide, or enolizable keto groups is described. This protocol expands the utility of palladium-catalyzed C-N bond formation by allowing for the use of aryl halides containing these functional groups, obviating the need for protecting group manipulations.

Synthesis of Muramyl Peptides Containing meso-Diaminopimelic Acid

Chain-extension of L-glutamate aldehyde 3 by means of the Wittig−Horner reaction furnished the desired C7 dicarboxylic acid derivative, which in turn, after C-C double bond hydrogenation and protecting group manipulation, afforded the 2,6-diaminopimelic acid derivatives (S,R)-9 and (S,S)-9, both with the desired orthogonal protecting group pattern. Synthesis of the muramic acid derivative 15 and attachment of an L-alanine residue furnished muramyl-L-alanine 18. The corresponding 1,6-anhydromuramic acid derivative 26 was obtained similarly. Treatment of these compounds with peptides 28−30 and with the 2,6-diaminopimelic acid containing di- and tripeptides 32a, 32b, and 35 gave the protected muramyl peptides 17, 37, 40, 42, 44, 46, and 49a and 49b, which, after deprotection, afforded the desired target molecules muramyl-L-alanine (38), muramyl-L-alanyl-D-glutamic acid (39), muramyl-L-alanyl-D-glutaminide (41), muramyl-L-alanyl-D-isoglutaminyl-L-lysine (43), muramyl-L-alanyl-D-isoglutaminyl-(2S,6R)-2,6-diaminopimelic acid (45), muramyl-L-alanylL-isoglutaminyl-(2S,6R)-2,6-diaminopimelinyl-D-alanine (47), 1,6-anhydromuramyl-L-alanyl-D-isoglutaminyl-(2S,6R)-2,6-diaminopimelic acid (50a), and 1,6-anhydromuramyl-L-alanyl-D-isoglutaminyl-(2S,6S)-2,6-diaminiopimelic acid (50b). (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of a Small Repertoire of Non-Racemic 5a-Carbahexopyranoses and 1-Thio-5a-carbahexopyranoses

A short and practical entry to optically pure 5a-carbahexopyranose and 1-thio-5a-carbahexopyranose representatives is described. Besides a few functional group and protecting group manipulations, the synthetic scheme counts on two fundamental carbon−carbon bond-forming reactions, namely (i) a regio- and stereoselective aldol addition between heterocyclic (silyloxy)diene donors (6 or 13) and D-glyceraldehyde as the acceptor (7) and (ii) a chemo- and stereoselective silylative cycloaldolization involving bifunctional aldehydes (10, 16, and 21). The 1H NMR based configurational and conformational assignment of target structures 1−5 and bicyclic intermediates 11, 12, 17, 18, and 22 is discussed. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of the TrifucosylatedN-Linked Hexasaccharide of a Glycoprotein fromHaemonchus contortus

The synthesis of a hexasaccharide from the inner part of an N-linked oligosaccharide portion of a glycoprotein from Haemonchus contortus is described. This hexasaccharide contains a novel fucosylation pattern with three α-linked fucosyl groups at O-3, O-6 and O-3′ of the two N-acetylglucosamine residues. In the synthesis two consecutive regioselective glycosylations were performed, thereby limiting protecting group manipulations, to yield a trisaccharide with β-(1⇄4) linkages. Subsequent trifucosylation in one step, followed by inversion of configuration via a displacement reaction at C-2′′ of the terminal glucosyl residue produced the resulting β-mannosyl linkage. The 2-acetamido-2-deoxy-glucosylamine residue was capped by an N-acetyl group and the hexasaccharide was deprotected. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Combined catalytic conversion involving an enzyme, a homogeneous and a heterogeneous catalyst: one-pot preparation of 4-deoxy- d-glucose derivatives from d-galactose

Consecutive catalytic oxidation (oxygen, d-galactose oxidase), dehydration ( l-proline) and reduction (hydrogen, palladium) of methyl β- d-galactoside in water at neutral pH yielded methyl 4-deoxy-6-aldehydo-β- d-glucoside without intermediate recovery steps demonstrating the potential power of a multi-catalytic approach, using both bio- and chemo-catalysts, for carbohydrate conversions without the use of protective groups or stoichiometric amounts of reagents.

Total synthesis of a stereoisomer of bistramide C and assignment of configuration of the natural product.

After the isolation of the bioactive polyether bistramide C from the marine ascidian Lissoclinum bistratum in 1988, NMR spectroscopic investigations over the next 12 years reduced the total number of possible stereoisomers of this compound from 1024 to 32. Based on the preparation of segments of the natural product as well as the total synthesis of a randomly selected stereoisomer of bistramide C, the stereochemical puzzle could be further simplified to eight possible stereoisomers. A convergent three-segment coupling strategy, the use of a common, D-glucose-derived intermediate for the preparation of pyran rings in two segments, a stereoselective photo-spiroketalization, and the use of azides to minimize protective group manipulations before segment couplings are highlights of the synthetic approach. The total synthesis also provided the key segments for a chiroptical analysis according to van't Hoff's principle of optical superposition, which was crucial for the assignment of a sole relative and absolute configuration of the natural product. Bistramide C represents therefore the first member of this class of structurally unusual marine polyethers whose configuration is known as a result of the combined use of synthetic and chiroptical tools.

ChemInform Abstract: Rapid Carbohydrate Protecting Group Manipulations Assisted by Microwave Dielectric Heating.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Biosynthetic studies on the α-glucosidase inhibitor acarbose: the chemical synthesis of dTDP-4-amino-4,6-dideoxy-α- d-glucose

To study the biosynthesis of the pseudotetrasaccharide acarbose, dTDP-4-amino-4,6-dideoxy-α- d-glucose ( 3) was prepared from galactose in 16 steps. After initial protecting-group manipulations, the 6-position of galactose was deoxygenated by hydride displacement of a tosylate. Similarly a tosyl group at the 4-position was displaced upon reaction with sodium azide. Conversion of the resulting glycoside to a glycosyl phosphate was accomplished by reaction of a glycosyl trichloroacetimidate with dibenzyl phosphate. Subsequent removal of the benzyl protecting groups and reduction of the azide by hydrogenation and coupling with an activated nucleoside phosphate gave dTDP-4-amino-4,6-dideoxy-α- d-glucose.

Indium-Mediated Stereoselective Synthesis of Truncated, 6- and 7-Carbon Sialic Acids

Several 6- and 7-carbon sialic acid derivatives were synthesized, without tedious protecting group manipulations, in high overall yields. A key step of the synthesis was the chain extension of suitable α-amino aldehyde derivatives by an indium-mediated addition of ethyl 2-(bromomethyl)acrylate. Under acidic reaction conditions, the corresponding extended enoates were obtained with high trans-stereoselectivity. Ozonolysis furnished the desired 4-acylamino-substituted hexulosonic and heptulosonic acids in free form for biochemical studies.

2′-Ethynyl-DNA: Synthesis and Pairing Properties

2-Ethynyl-DNA was developed as a potential DNA-selective oligonucleotide analog. The synthesis of 2′-arabino-ethynyl-modified nucleosides was achieved starting from properly protected 2′-ketonucleosides by addition of lithium (trimethylsilyl)acetylide followed by reduction of the tertiary alcohol. After a series of protecting-group manipulations, phosphoramidite building blocks suitable for solid-phase synthesis were obtained. The synthesis of oligonucleotides from these building blocks was successful when a fast deprotection scheme was used. The pairing properties of 2′-arabino-ethynyl-modified oligonucleotides can be summarized as follows: 1) The 2′-arabino-ethynyl modification of pyrimidine nucleosides leads to a strong destabilization in duplexes with DNA as well as with RNA. The likely reason is that the ethynyl group sterically influences the torsional preferences around the glycosidic bond leading to a conformation not suitable for duplex formation. 2) If the modification is introduced in purine nucleosides, no such influence is observed. The pairing properties are not or only slightly changed, and, in some cases (deoxyadenosine homo-polymers), the desired stabilization of the pairing with a DNA complementary strand and destabilization with an RNA complement is observed. 3) In oligonucleotides of alternating deoxycytidine-deoxyguanosine sequence, the incorporation of 2′-arabino-ethynyl deoxyguanosine surprisingly leads to the formation of a left-handed double helix, irrespective of salt concentration. The rationalization for this behavior is that the ethynyl group locks such duplexes in a left-handed conformation through steric blockade.

A Concise Synthesis of Fumagillol

A concise synthesis of fumagillol was accomplished in twelve steps starting from cyclohexadiene, proceeding by way of ring-opening of a symmetrical protected epoxydiol with a cuprate reagent and subsequent protecting group manipulation to give a key ketone intermediate. Installation of the required epoxide functions was achieved by addition of chloromethyllithium to the ketone and by directed epoxidation of the unsaturated side-chain.

Formation of a W(CO) 5–furanosylidene complex from ribose without the use of protective groups

[W(CO) 5(acetone)], formed by photolysis of W(CO) 6, undergoes a spontaneous reaction at the C-1 position of d-ribose in d 6-acetone in 24 h in quantitative yield to form water and the W(CO) 5–furanosylidene complex, exhibiting a characteristic carbene 13C resonance at 427 ppm. The reaction proceeds without protection of any of the ribose hydroxyl groups, and occurs only at the C-1 position. The same reaction does not occur for fructose, d(+)-ribonic γ-lactone, or 2-deoxy- d-ribose. No reaction occurred with the pyranose sugars, d-glucose or d-galactose. A pathway via oxidative addition to CH of the open chain aldehyde form of ribose is proposed. Insertion of W(CO) 5 into the CH bond, followed by rearrangement of the W(II)(CO) 5–acyl hydride to a hydroxy carbene that recyclizes to the coordinated furanosylidene accounts for the reactivity of d-ribose and the absence of reactivity for the other sugars. Molecular mechanics calculations were carried out using spartan and mmff94 programs for the free sugars d-ribose and d-glucose and their C-1-coordinated carbenes of W(CO) 5. The carbene complexes are energetically uphill of the free sugars by 54.8 and 63.3 kcal mol −1 for ribose and glucose, respectively. Therefore, elimination of water is a key factor in the net driving force to form the coordinated carbene of d-ribose. The structures reveal a useful planarity at C-1 which places the filled p-orbital on the O atom alpha to the carbene in the proper perpendicular arrangement to maximize resonance with the carbene carbon. The theoretical structure for the d-glucose analogue adopts sufficient puckering of the chair arrangement of the glucose to cause a misalignment of the alpha O p-orbital, which would decrease the inherent stablity, consistent with the absence of forming such a species.

Synthesis of di- to hexasaccharide 1,2-linked beta-mannopyranan oligomers, a terminal S-linked tetrasaccharide congener and the corresponding BSA glycoconjugates.

Homo oligomers of (1-->2)-beta-D-mannopyranosyl residues have been synthesized in order to study the unique immunological properties of the cell wall mannan of C. albicans. p-Chlorobenzyl-protected ulosyl bromide (2) in combination with the sterically hindered, participating solvent, pivaloyl nitrile, facilitated a new approach for the synthesis of these unique homooligomers ranging from disaccharide up to hexasaccharide. The glycosyl donor 2 demonstrates high diastereoselectivity over both the glycosylation and subsequent reduction step and minimizes the number of protecting group manipulations necessary for the synthesis. Congeners of the (1-->2)-beta-D-mannotetraose were synthesized containing a terminal S-linked (1-->2)-beta-D-mannopyranosyl residue. Deprotection of these compounds afforded the propyl glycosides as well as oligomers with amino terminated aglyconic tethers. The tethers were generated from the oligosaccharide allyl glycosides by photoaddition with 2-aminoethanethiol. The functionalized haptens were coupled to BSA via squarate conjugation, and the degree of incorporation was established by TOF mass spectrometry.

Complex Structures of Antennary Human Milk Oligosaccharides − Synthesis of a Branched Octasaccharide

We have developed a highly convergent synthetic route for the synthesis of the branched structure of human milk octasaccharide β-D-galactopyranosyl-(1→3)-2-acetamido-2-de oxy-β-D-glucopyranosyl-(1→3)-β-D-galactopyranosyl)-(1→4)-2-acetamido-2-deoxy-β-D-glucopyranosyl-(1→6)-[β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-glucopyranosyl-(1→3)]-β-D-galactopyranosyl-(1→4)-α,β-Dglucopyranose (1). In the retrosynthetic analysis, target structure 1 was disconnected into building blocks 2−6. Starting from only four known building blocks − 4, 7, 8, and 12 − the required three disaccharide units were obtained, resulting after further protecting group manipulation and glycoside bond formation in the desired tetrasaccharides 13 and 16. Cleavage of the TBDMS group of 13 afforded tetrasaccharide 14, which was transformed into isolactosamine-β-(1→3)-lactosamine trichloroacetimidate 15. Removal of the 4b,6b-O-benzylidene group of tetrasaccharide 16 gave the lacto-N-tetraose acceptor 17, to afford the protected octasaccharide 18 on glycosylation with donor 15. Complete deprotection of the octasaccharide by way of 19 afforded target human milk oligosaccharide 1 in a short and efficient route.

Oligosaccharide synthesis with glycosyl phosphate and dithiophosphate triesters as glycosylating agents.

Described is an efficient one-pot synthesis of alpha- and beta-glycosyl phosphate and dithiophosphate triesters from glycals via 1,2-anhydrosugars. Glycosyl phosphates function as versatile glycosylating agents for the synthesis of beta-glucosidic, beta-galactosidic, alpha-fucosidic, alpha-mannosidic, beta-glucuronic acid, and beta-glucosamine linkages upon activation with trimethylsilyl trifluoromethanesulfonate (TMSOTf). In addition to serving as efficient donors for O-glycosylations, glycosyl phosphates are effective in the preparation of S-glycosides and C-glycosides. Furthermore, the acid-catalyzed coupling of glycosyl phosphates with silylated acceptors is also discussed. Glycosyl dithiophosphates are synthesized and are also used as glycosyl donors. This alternate method offers compatibility with acceptors containing glycals to form beta-glycosides. To minimize protecting group manipulations, orthogonal and regioselective glycosylation strategies with glycosyl phosphates are reported. An orthogonal glycosylation method involving the activation of a glycosyl phosphate donor in the presence of a thioglycoside acceptor is described, as is an acceptor-mediated regioselective glycosylation strategy. Additionally, a unique glycosylation strategy exploiting the difference in reactivity of alpha- and beta-glycosyl phosphates is disclosed. The procedures outlined here provide the basis for the assembly of complex oligosaccharides in solution and by automated solid-phase synthesis with glycosyl phosphate building blocks exclusively or in concert with other donors.

Orthogonal, convergent syntheses of dendrimers based on melamine with one or two unique surface sites for manipulation.

An orthogonal, convergent route for the introduction of substoichiometric numbers of latent surface sites into dendrimers based on melamine is used to prepare targets that display one or two Boc-protected amines on the periphery. Asymmetry is the result of the stepwise incorporation of functionalized and unfunctionalized dendrons onto the triazine cores, a highly selective process due to the different reactivities of the substituted triazines. The routes to the dendrons rely on iterative reactions of the growing dendrons with triazine cores and diamine linkers. p-Aminobenzylamine is used as a linking group to avoid functional group interconversions or protecting group manipulations. Addition of the benzylamine group to the monochlorotriazine of the dendron proceeds cleanly leaving a less reactive aniline for subsequent reaction with trichlorotriazine. The routes to these targets proceed in 5 or 6 linear steps (11 or 12 total steps) in 40% overall yield. The unique surface sites can be deprotected and subjected to additional chemistries. Reaction of the monofunctionalized dendrimer with trichlorotriazine yields the desired dimer, a molecule whose increased size is evident from light scattering and tapping mode atomic force microscopy, and corroborated with computation.

1-Methyl 1′-cyclopropylmethyl: an acid labile O-protecting group for polymer-supported oligosaccharide synthesis

R, S-1-Methyl 1′-cyclopropylmethanol can be converted to its trichloroacetimidate derivative. Lewis acid catalyzed etherification can then be used to prepare methyl cyclopropylmethyl (MCPM) ethers. Thus, ethyl 2,3,4-tri- O-benzyl-6- O-( R, S-1-methyl 1′-cyclopropylmethyl)-1-thio-α/β- d-glucopyranoside was prepared and the linker polymer combination (MPEG)(DOX)OH glycosylated. The MCPM group was cleaved with 10% trifluoroacetic acid in CH 2Cl 2 and the resulting alcohol glycosylated. After protecting group manipulations and cleavage the peracetylated disaccharide GlcNAc(β1→6)GlcOAc was isolated. Similarly the 4,6- O-phenylboronate diester of ethyl 1-thio-β- d-galactopyranoside was regioselectively etherified at O-3 and after boronate cleavage the sugar benzoylated to give ethyl 2,4,6-tri- O-benzoyl-3- O-( R, S-1-methyl 1′-cyclopropylmethyl)-1-thio-β- d-galactopyranoside. Through a similar sequence of glycosylation of (MPEG)(DOX)OH, MCPM deprotection, glycosylation, functional group manipulation and cleavage the peracylated disaccharide GlcNAc(β1→3)Gal(β1→)DOXOAc was prepared. Finally, the donor 2,6-di- O-benzoyl-4- O-levulinoyl-3- O-( R, S-1-methyl 1′-cyclopropylmethyl)-1-thio-β- d-galactopyranoside was prepared and elaborated into the trisaccharide GlcNAc(β1→3)[Glc(β1→4)]Gal(β1→)DOXOH. This trisaccharide was elaborated into the pentasaccharide Neu5Ac(α2→3)Gal(β1→4)GlcNAc(β1→3) [Glc(β1→4)]Gal(β1→)DOXOH using GalE-LgtB fusion and CMP-Neu5Ac synthetase/sialyltransferase fusion enzymes. This pentasaccharide is a single repeat unit of the capsular polysaccharide of Group B Streptococcus type 1A.