Reductive Dephthalimidation: A Mild and Efficient Method for The N-Phthaumido Deprotection During Ougosaccharide Synthesis

Abstract

Synthesis of biologically active oligosaccharides, haptens and their protein conjugates is a major area of interest because of their role in antigen-antibody interaction and receptor effects¹. A number of these molecules contain α-or β-linked 2-acetamido-2-deoxy-D-glucosamine (GlcNAc) moieties. Most commonly, during the oligosaccharide synthesis, introduction of the β-glycosidically linked GlcNAc residue is achieved by either the oxazoline² or the phthalimido method³. Of these, the latter is preferred because 2-N-phthalimido protected glycosamine units having a halogen or a thioalkyl group at C-1 have consistently proved to be more efficient donors than are the oxazolines. However, time and again, subsequent conversion of the N-phthalimido to amine by hydrazinolysis has proved inadequate. This has often resulted in a poor overall yield after an otherwise efficient synthesis. Recently it was shown that the phthalimido function could be removed under mild conditions from a number of amino acids⁴. We now report that this technique can be efficiently used for the deprotection of the phthalimido function in suitably protected carbohydrate compounds (2,3 and 5).     

Selective and Practical Synthesis of Penciclovir

Abstract

A selective and practical method has been developed for the synthesis of penciclovir (1) in gram quantities involving a highly N ⁹ selective alykylation of 2-amino-6-chloropurine (9) with 2-(2-phenyl-1,3-dioxane-5-yl)ethanol (12) as a key step.     

Synthetic Studies on Sialoglycoconjugates 50: Total Synthesis of Ganglioside GD2

Abstract

As more and more biological functions^1-10 of gangliosides are being revealed, their facile, stereocontrolled synthesis is strongly required. We have developed^11-l4 an α-stereoselective glycosylation of sialic acids, α-sialyl-(2→8)-sialic acid and α-sialyl-(2→8)-α-sialyl-(2→8)-sialic acid, by using their 2-thioglycosides as the glycosyl donor and suitably protected acceptors, and dimethyl(methy1thio)sulfonium triflate (DMTST) or N-iodosuccinimide (NIS)-trifluoromethanesufonic acid (or TMS triflate) as the glycosyl promoter in acetonitrile. In this way, we have synthesized a variety of gangliosides¹⁵ and their analogs.¹⁶ Previously,¹³ we synthesized Ganglioside GD3 containing α-sialyl-(2-8)-sialic acid residue in the molecule, in connection with a novel approach for systematic synthesis of polysialo-glycoconjugates. As a part of our continuing studies on the synthesis and elucidation of the functions of gangliosides, we describe here a facile, stereocontrolled, total synthesis of ganglioside GD2. Ganglioside GD2, which was first isolated from human brain by R. Kuhn et al.,¹⁷ is well known as a human melanoma associated antigen.¹⁸     

Synthetic Studies on Sialoglycoconjugates 60: α-Stereocontrolled,Glycoside Synthesis of Trimeric Sialic Acid with Galactose and Lactose Derivatives

Abstract

α-Stereocontrolled, glycoside synthesis of trimeric sialic acid is described toward a systematic approach to the synthesis of sialoglycoconjugates containing an α-sialyl-(2→8)-α-sialyl-(2→8)-sialic acid unit α-glycosidically linked to O-3 of a galactose residue in their oligosaccharide chains. Glycosylation of 2-(trimethylsilyl)ethyl 6-O-benzoyl-β-d-galactopyranoside (4) or 2-(trimethylsilyl)ethyl 2,3,6,2′,6′-penta-O-benzyl-β-lactoside (5), with methyl [phenyl 5-acetamido-8-O-[5-acetamido-8-O-(5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-d-glycero-α-d-galacto-2-nonulopyranosylono-1”, 9′-lactone)-4,7-di-O-acetyl-3,5-dideoxy-d-glycero-α-d-galacto-2-nonulopyranosylono-1′, 9-lactone]-4,7-di-O-acetyl-3,5-dideoxy-2-thio-d-glycero-d-galacto-2-nonulopyranosid]onate (3), using N-iodosuccinimide-trifluoromethanesulfonic acid as a promoter, gave the corresponding α-glycosides 6 and 8, respectively. The glycosyl donor 3 was prepared from trimeric sialic acid by treatment with Amberlite IR-120 (H⁺) resin in methanol, O-acetylation, and subsequent replacement of the anomeric acetoxy group with phenylthio. Compounds 6 and 8 were converted into the per-O-acyl derivatives 7 and 9, respectively.     

First,Highly Stereoselective Synthesis of Neotrehalosamines

ABSTRACT

Among the known non-symmetrical naturally occurring aminotrehaloses possessing antimicrobial activity, the stereoselective synthesis of α, α-linked D-glucosaminyl-D-glucoside as well as of D-glucosaminyl-D-mannoside has been reported.¹ In contrast, the synthesis of the α, β-isomer composed of two 2-amino sugar units occurring in tunicamycin antibiotics 1 has not been studied to the same extent and is not readily obtainable in pure form.     

Efficient Synthesis of Tosyl-aziridine-2-t-butyl Carboxylate

Tosyl-aziridine-2-t-butyl carboxylate is easily synthesized from Tos-Ser-O-tBu by use of Mitsunobu conditions.

Aziridine-2-carboxylates are valuable precursors to both α- and β-amino acids, as well as other useful synthetic targets,¹ and various approaches to these compounds have been reported.^2–18 Usually, aziridine-2-carboxylates are formed by cyclization of trityl protected mesylates or tosylates of serine and threonine, as originally described by Okawa et. al.,¹³ or by closely related procedures.^14–16 Recently we developed a versatile synthesis of α, β- diaminopropionic acid analogs from tosyl aziridine-2-t-butyl-carboxylate 1 and needed an efficient method to prepare this precursor.¹⁹     

Regioselective α(2→3)-Sialylation of LeX and Lea by Sialidase-Catalyzed Transglycosylation

Considerable effort has been devoted to the development of new methods for α-selective sialylation due to the growing importance of the synthetic sialoglycoconjugates in glycobiology³. The synthesis of α-sialoside has been establised by chemical routes,⁴ which often involve many steps and are complicated. The promising chemoenzymatic procedure through the use of sialyltransferases has already become a preparative technique.⁵ However, laborious isolation and the pronounced acceptor specificity of the transferases limit their synthetic potential. Recently, a novel procedure for α-sialylation has been reported, which uses sialosides of synthetic substrate as donors and is catalyzed by sialidase in place of sialyltransferase. Thiem et a1.⁶ have reported the enzymatic synthesis of α(2→6)-linked sialyl galactose, glucose, lactose and lactosamine in preference to the corresponding α(2→3)-linked derivatives employing sialidase from vibrio cholerae, while Ajisaka et al.⁷ have synthesized α(2→3)-linked sialyl lactose and lactosamine with sialidase from new castle disease virus.

     

Azlactone Synthesis. 2-Phenyl-2-Oxazolin-5-One

Abstract

2-Phenyl-2-oxazolin-5-one (3) has been used as an intermediate in the synthesis of α-amino acids¹, derivatives of α-amino acids,² and peptides.³ Procedures for the dehydration/cyclization of hippuric acid (1) leading to the isolation of azlactone 3, have been reported using acetic anhydride,⁴ phosphorus trihalides⁵, and N, N′-dicyclohexylcarbodiimide.⁶ We report herein an alternative, high yield procedure utilizing a water soluble carbodiimide.     

Preparation,Isolation and Characterization of all of the Regioisomeric 61, 6N-Bis-O-(Monomethoxytrityl) and-(Dimethoxytrityl) Derivatives of Cyclomalto-Olgosaccharides

Abstract

Regioisomeric 6¹, 6ⁿ-bis-O-(monomethoxytrityl) or 6¹, 6ⁿ-bis-O-(dimethoxytrityl) cyclomaltohexaose, -cyclomaltoheptaose (n = 2-4), and -cyclomaltooctaose derivatives (n = 2-5) were prepared by the reaction of cyclomaltohexaose (1, cG₆, αCD), cyclomaltoheptaose (11, cG₇, βCD) or cyclomaltooctaose (21, cG₈, γCD) and 4-monomethoxytrityl chloride or 4,4′-dimethoxytrityl chloride in pyridine. Products were isolated by HPLC. The regiochemical determination of these positional isomers was done by converting these compounds to the respective 6¹, 6ⁿ-bis-O-(tert-butyldimethylsilyl) derivatives¹ whose structures have been already established.     

Application of the Cleavable Isocyanide in Efficient Approach to Pyroglutamic Acid Analogues with Potential Biological Activity

Two efficient procedures have been developed for the synthesis of pyroglutamic acid analogues 28, 29, and 34. According to the first method the Ugi (4C3C) reaction is followed by a post-transformation reaction, and the second method involves the Michael addition reaction. The present methodologies demonstrate the applicability of 1-(2,2-dimethoxyethyl)-2-isocyanobenzene (15) as a cleavable isocyanide in the Ugi/ post-transformation reaction and a strong nucleophile in the Michael addition reaction. The framework of pyroglutamic acid analogues has been constructed by the selective cleavage of the C-terminal amide bond and nucleophilic addition to the activated α,β-unsaturated carbonyl group.

     

Synthesis of LeX and LeY Oligosaccharides with Azido-Type Spacer-Arms. Comparison of 3- and 4-Methoxybenzyl Groups as Key Temporary Protective Groups

Abstract

5-Azido-3-oxa-l-pentanol was prepared from 2-(2-chloroethoxy)ethanol and used as a spacer in the chemical synthesis of the trisaccharide β-D-Gal-(1→4)-[α-L-Fuc-(1→3)]-GlcNAc and the tetrasaccharide α-L-Fuc-α-(1→2)-β-D-Gal-(1→4)-[α-L-Fuc-(1→3)]-GlcNAc that represent the epitopes defining the human blood groups Le^x and Le^y. The classical 4-methoxybenzyl group and the remarably acid-stable 3-methoxybenzyl group were compared as temporary protective groups for position 3 at the glucosamine unit to circumvent the problems associated with the simultaneous presence of allyl and azido groups. The resulting oligosaccharides were coupled to proteins with high efficiency.

     

Chemical-Enzymatic Synthesis of A Branched Hexasaccharide Fragment of Type Ia Group B Streptococcus Capsular Polysaccharide

ABSTRACT

A branched hexasaccharide fragment of type Ia group B streptococcal polysaccharide, α-NeuAc(2→3)-β-D-Gal(1→4)-β-D-GlcNAc(1→3)-[β-D-Glc(1→4)]-β-D-Gal(1→4)-β-D-Glc-OMe (13), has been synthesized by chemical-enzymatic procedures. Chemical synthesis of a pentasaccharide, β-D-Gal(1→4)-β-D-GlcNAc(1→3)-[β-D-Glc(1→4)]-β-D-Gal(1→4)-β-D-Glc-OMe (12), was achieved from glycosyl donor, 4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-3,6-di-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl trichloroacetimidate (9), and acceptor, methyl O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-(1→4)-O-(2,6-di-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside (6), by block condensation in 41% yield. Following enzymatic sialylation of 12 at the 3-O-position of its terminal galactopyranosyl residue using recombinant α-(2→3)-sialyltransferase and CMP-NeuAc afforded 13 in 59% yield.     

Expeditious Synthesis of a Trisubstrate Analogue for α(1→3)Fucosyltransferase

Abstract

The synthesis of cyclohexyl 2-acetamido-2-deoxy-3-O-{2-O-[2-(guanosine 5′-O-phosphate)ethyl]-α-L-fucopyranosyl}-β-D-glucopyranoside (1), a potential inhibitor of α(1→3)fucosyltransferases, is described. Target compound 1 was assembled via fucosylation of cyclohexyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside (6) with ethyl 2-O-[2-(benzoylhydroxy)ethyl]-3,4-O-isopropylidene-1-thio-β-L-fucopyranoside (5) followed by debenzoylation, subsequent condensation of the resulting compound with 3′,4′ -di-O-benzoyl-5′ -O-(2-cyanoethyl-N,N-diisopropylphosphoramidite)-2-N-diphenylacetylguanosine (10) and deprotection.     

Synthesis of New Phosphonate Derivatives of Naphtho[2,1-b[Pyran]3,2-e][1,2,4]Triazolo [1,5-c]Pyrimidines

Abstract

The synthesis of new naphthopyranotriazolopyrimidines phosphonates 4a–i in good yields (74%–93%) has been accomplished via Michaelis–Arbusov rearrangement by the reaction of trialkyl phosphite with naphthopyranotriazolopyrimidines chloride 3a–e, which were obtained from α-functionalized iminoethers 1 in two steps. The synthesized compounds 4a–i were completely characterized by IR, ¹H, ¹³C, and ³¹P NMR and HRMS.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

PHOSPHORORGANISCHE VERBINDUNGEN 851 SYNTHESE UND ANWENDUNG OPTISCH AKTIVER TERTIÄRER PHOSPHINE ALS CO-KATALYSATOREN DER HOMOGENHYDRIERUNG MIT RHODIUM-PHOSPHIN-KOMPLEXEN

Abstract

Die Darstellung der optisch aktiven Methyl-n-propyl(bzw.-isopropyl)arylphosphine 1 bis 8 wird beschrieben. Hierbei ist Aryl: p-Methoxyphenyl (1 und 2), p-Dimethylaminophenyl (3 und 4), o-Methoxyphenyl (5 und 6), o-Dimethyl-aminophenyl (7) und o-Aminophenyl (8).

Die Phosphine 1 bis 8 werden als optisch aktive Co-Katalysatoren bei der Homogenhydrierung von α- und ß-Methylzimtsäureethylester, der α-Acetaminoacrylsäure und der α-Acetaminozimtsäure mit Rhodium-Phosphinkomplexen eingesetzt und jeweils die optische Induktion bestimmt. Folgende Ergebnisse (Vgl. die Tabellen 1 bis 4) wurden erhalten:

1) Die CH₃O-Gruppe und N(CH₃)₂-Gruppe verändern unabhängig von ihrer Stellung die optische Induktion bei der Homogenhydrierung von α- und ß-Methylzimtsäureethylester nur unwesentlich im Vergleich zu den entsprechenden Methyl-n-propyl (bzw.-isopropyl)-phenylphosphinen.

2) Bei der Homogenhy drierung von α-Acetaminoacrylsäure und α-Acetaminozimtsäure üben para-ständige OCH₃- und (CH₃)₂N-Gruppen in den optisch aktiven Co-Katalysatoren (Verbindungen 1 bis 4) keinen Einfluß auf die Höhe der optischen Induktion aus.

3) In ortho-Stellung verknüpfte OCH₃- und (CH₃)₂N-Gruppen (Verbindungen 5 bis 7) führen jedoch bei der Homogenhydrierung von α-Acetaminoacrylsäure und α-Acetaminozimtsäure zu einer beachtlichen Erhöhung der optischen Induktion. Bei α-Acetaminozimtsäure und 7 als Co-Katalysator beträgt die optische Induktion 80%! Hierbei übertrifft die (CH₃)₂N-Gruppe die CH₃O-Gruppe an Wirksamkeit.

4) Methyl-n-propyl-o-aminophenylphosphin 8 ist als Co-Katalysator unbrauchbar, da es offenbar durch Wechsel-wirkung der NH₂-Gruppe mit Rhodium die Koordinierung des prochiralen Olefins mit dem Komplex unterdrückt.

5) Eine experimentell begründete Deutung für das Zusammenwirken der am Aufbau der Homogenkatalysatoren beteiligten Komponenten konnte nicht gegeben werden.

Tabelle 5 zeigt die Abhängigkeit der Hydriergeschwindigkeit von Art und Stellung der Substituenten im Phenylrest. Die Hydriergeschwindigkeit ist bei den induktionsstarken Co-Katalysatoren 5 bis 7 deutlich vermindert.

The preparation of the optically active methyl-n-propyl(isopropy) aryl phosphines 1 ± 8 is described, whereby the aryl group is p-methoxyphenyl (1, 2), p-dimethylaminophenyl (3, 4), o-methoxyphenyl (5, 6), o-dimethylaminophenyl (7) and o-aminophenyl (8).

The phosphines 1–8 were used as chiral co-catalysts at the rhodium complex in the homogeneous hydrogenation of α- and ß-methyl cinnamic acids, α-acetaminoacrylic acid and α-acetaminocinnamic acid. The optical induction in the products was measured. The following results (see Tables 1–4) were obtained:

1) The methoxy and dimethylamino groups, independent of their site, have only negligible influence on the optical yield in the reduction of α- and ß-methylcinnamic acids compared with the parent methyl-propylphenylphosphine.

2) In the hydrogenation of acetaminoacrylic acid and α-acetaminocinnamic acid, para methoxy- or dimethylamino groups (compounds 1–4) show likewise no special influence on the optical yield.

3) Ortho methoxy or dimethylamino groups (compounds 5–7), however, result in a measurable increase in optical yield in the reduction of α-acetaminoacrylic- and α-acetaminocinnamic acids. In the case of compound 7 with α-acetaminocinnamic acid, an optical purity of 80% was obtained! The dimethylamino group is in this case more effective than the methoxy group.     

Mono-Glycosylated 3-N-Alkylcatechols: Direct Synthesis from Glycosylacetates, 1H Nmr Analysis and Conformational Studies

ABSTRACT

The direct coupling of 3-n-alkyl catechols to the acetate or trichloroacetimidate derivatives of β-D- or α-D-glycosides (glucose, galactose, xylose, mannose and maltose) catalyzed by BF₃Ot₂ has been studied. β-Glycosides with an equatorial acetate group at position 2 formed exclusively β adducts with yields of 60–80%. α-Glycosides with an equatorial acetate group at position 2 formed β adducts, while β-glycosides with an axial acetate group formed α adducts when activated as trichloroacetimidates, with yields of 70–85%. This was applied to the coupling of 3-n-alkylcatechols of increasing chain length (up to C15) to sugar derivatives. The coupling position of glycosides on the catechol was determined either by differential NOE experiments and by the regioselective synthesis of 1-(O-β-D-glucopyranosyl)-3-pentadecylcatechol, a water soluble analogue of the poison ivy skin allergen. ¹H NMR of acetylated and deprotected compounds were investigated and the conformational preferences of the C₆ side chain determined using molecular modeling.     

Per-O-Benzylated Ethyl 5-N-Acetyl-α-thiosialoside as a Glycosyl Donor for α-Silylation

Abstract

Per-O-benzylated ethyl 5-N-acetyl-α-thiosialoside 1 was synthesized and its reactivity as a sialyl donor was investigated. It was demonstrated that the reactions of 1 with various primary and secondary alcohol acceptors, including monosaccharides, gave good to excellent yields (53-92%) and acceptable to excellent α-selectivity (α:β?=?2?～?10:1) , showing its promise for application to sialoglycan synthesis.     

Synthesis of SE- and TE-Containing Amino Acids: Useful Probes for Structural Studies of Proteins

ABSTRACT

The synthesis of (l)-Se-cystine, (l)-[⁷⁷Se]-cystine and (l)-Te-cystine in 4 steps from commercially available 2(S)-[(tert-butoxycarbonyl)amino]-3-hydroxy-propionate has been accomplished. [4-¹³C]Te-Met has been synthesized in a one pot reaction.     

Large Scale Synthesis of A Derivative of An α-Galactosyl Trisaccharide Epitope Involved in the Hyperacute Rejection of Xenotransplantation

ABSTRACT

A derivative of an α-galactosyl trisaccharide xenoactive antigen, (2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)-(1→3)-(2,4,6-tri-O-acetyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranosyl azide (5), was synthesized on a large scale (50 gram). The synthesis involved a high yielding and highly stereoselective (α/β>20:1) glycosylation reaction utilizing a thiogalactoside as the donor and a selectively protected lactose azide as the acceptor. This derivative serves as a versatile intermediate that can be transformed into a variety of α-Gal containing glycoconjugates highly desired in xenotransplantation research and pharmaceutical development.     

Functionalized C-Glycosyl Compounds. III. Reaction of Tertiary Nucleophiles with Unsaturated Carbohydrates. Mechanism of the Anomerization

Abstract

Phenyl 2, 3-dideoxy-4, 6-di-O-benzyl-D-erythro-hex-2-enopyranoside 1α (or 1β) is alkylated regio- and stereospecifically at the anomeric center by stabilized tertiary nucleo-philes in the presence of Pd(0) as a catalyst, leading to the C-glycoside of α- (or β-) configuration. The observed loss of stereoselectivity using secondary stabilized nucleophiles is mainly due to a retro Michael reaction. The assignment of the α- (or β-) configuration at the anomeric center was accomplished using ¹³C NMR and NOE experiments.