A New Oxidative Conversion of Carbohydrate Benzyl Ethers to Benzoyl Esters with RuCl3-NaIO

Abstract

The benzyl group is often used in organic synthesis, especially in carbohydrate chemistry, as one of the most useful of the hydroxyl protecting groups. Benzyl ethers are stable to basic conditions and the benzyl group is removed easily by hydrogenolysis or under Birch reduction conditions. Alternatively, the benzyl ether group is oxidized to benzoyl ester and removed under basic conditions. A few oxidation methods have been reported using more than a stoichiometric amount of chromium reagents such as CrO₃-H₂SO₄ (Jones reagent)¹ or CrO₃-AcOH₂. Here we report a new and mild oxidation of benzyl ether to benzoyl ester with a catalytic amount of RuO₄ derived from RuCl₃ and NaIO₄. This method has proved effective in removing benzyl ether groups chemoselectively in the presence of benzylidene acetal and benzyl glycosidic functions.     

Combinatorial Synthesis of Deoxyhexasaccharides Related to the Landomycin A Sugar Moiety,Based on an Orthogonal Deprotection Strategy

In this report, we describe the stereoselective synthesis of a combinatorial library comprised of 16 deoxyhexasaccharides that are related to a landomycin A sugar moiety, based on an orthogonal deprotection strategy. The use of an olivosyl donor containing a benzyl ether at the C3 position and benzoyl ester at the C4 position, and the olivosyl donor, a naphthylmethyl ether, and a p‐nitrobenzylethyl or benzyl sulfonyl ester enabled the synthesis of a set of four diolivosyl units containing a hydroxyl group at the C3 or C4 position by a simple glycosylation and deprotection procedure. Using a phenylthio 2,3,6‐trideoxyglycoside, α‐selective glycosidation proceeded without anomerization of the 2,6‐dideoxy‐β‐glycosides. In addition, alkylhydroquinone and levulinoyl groups were found to be an effective set of orthogonal protecting groups for the anomeric position and a hydroxyl group. The coupling of all combinations of trisaccharide units in a β‐selective manner was accomplished by activation of the glycosyl imidate with I₂ and Et₃SiH. No cleavage of the acid‐labile 2,3,6‐trideoxyglycoside was observed under the conditions used for the reactions. Finally, all of the protected hexasaccharides were deprotected by hydrolysis of the esters, microwave (MW) assisted cleavage of the 2‐trimethylsilylethoxymethoxy (SEM) ether, and a Birch reduction.     

Synthesis of glucuronic acid derivatives via the efficient and selective removal of a C6 methyl group

This investigation is related to the development of a general strategy for the synthesis of certain glucuronic acid derivatives. In particular, we report exceptionally selective conditions for removing the C6 methyl protecting group by potassium hydroxide without affecting the benzoyl protecting groups on the C2, C3 and C4 hydroxyl groups in high yields (95–99%). The present method proves to be efficient and environmentally friendly in terms of short reaction time, high yield and the single product.     

Benzylidene Acetal Protecting Group as Carboxylic Acid Surrogate: Synthesis of Functionalized Uronic Acids and Sugar Amino Acids

Direct oxidation of the 4,6‐O‐benzylidene acetal protecting group to C‐6 carboxylic acid has been developed that provides an easy access to a wide range of biologically important and synthetically challenging uronic acid and sugar amino acid derivatives in good yields. The RuCl₃–NaIO₄‐mediated oxidative cleavage method eliminates protection and deprotection steps and the reaction takes place under mild conditions. The dual role of the benzylidene acetal, as a protecting group and source of carboxylic acid, was exploited in the efficient synthesis of six‐carbon sialic acid analogues and disaccharides bearing uronic acids, including glycosaminoglycan analogues.     

2-(Prenyloxymethyl)benzoyl (POMB) as a new temporary protecting group for alcohols

The 2-(prenyloxymethyl)benzoyl (POMB) group was introduced in high yields to hydroxyl functions using the crystalline reagent, 2-(prenyloxymethyl)benzoic acid, in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). 2-(Prenyloxymethyl)benzoic acid is readily available, in two steps, from phthalide in 65% overall yield. The POMB group can be cleaved, in two steps, by treatment with 2,3-dichloro-5,6-dicyanoquinone (DDQ) followed by intramolecular lactonisation of the resulting hydroxy ester induced by a catalytic amount of Yb(OTf)₃·H₂O. The reaction conditions are compatible with the presence of a number of protecting groups such as isopropylidene, benzyl, acetyl, chloroacetyl, benzoyl, levulinoyl, Fmoc and Boc groups.     

对苯二酚的氨基酸缀合物的合成、表征及美白活性

以新药设计原理中的拼合原理为指导,将对苯二酚一侧酚羟基与具有生物活性的氨基酸进行偶联,以期得到活性更好、毒性更低的对苯二酚氨基酸缀合物。 将对苯二酚的一侧酚羟基进行保护得到对苄氧基苯酚,将氨基被保护的氨基酸与其酚羟基进行偶联,去掉保护基后得到8种对苯二酚的氨基酸缀合物。 在对苄氧基苯酚的酚羟基上引入乙酸连接片段,与氨基酸甲酯盐酸盐进行偶联,去掉保护基后得到8种对苯二酚的氨基酸缀合物。 通过IR、¹H NMR、¹³C NMR和ESI-MS等技术手段对所合成的16种氨基酸缀合物进行了结构表征。 对目标产物进行了美白活性研究。 结果表明,化合物HQ-3b、HQ-3c、HQ-4a、HQ-4b、HQ-7c和HQ-8a对酪氨酸酶的抑制作用优于阳性对照物α-熊果苷(IC₅₀=3.60),其中HQ-4b的IC₅₀值低至0.15,有望成为新型化妆品美白剂。     

Selective hydrogenolysis of benzyl ethers in the presence of benzylidene acetals with Raney nickel

A simple method to remove selectively a benzyl group protecting a hydroxyl function in the presence of a benzylidene acetal by catalytic hydrogenolysis with Raney nickel is reported. This method was successfully applied to the synthesis of the C1-C14 fragment of dolabelides.     

The dioxanone approach to (2S,3R)-2-C-methylerythritol 4-phosphate and 2,4-cyclodiphosphate, and various MEP analogues

Efficient syntheses of the non-mevalonate pathway intermediates 2-C-methylerythritol 4-phosphate (MEP) and 2-C-methylerythritol 2,4-cyclodiphosphate (ME-2,4-cycloPP), as well as the parent tetrol 2-C-methylerythritol, in enantiopure form from (2S,4R)-cis-2-phenyl-4-tert-butyldimethylsilyloxy-1,3-dioxan-5-one are reported. The 2S configuration of the C-methyl group was installed by highly axial-face selective addition of CH3MgBr (20:1) to the chiral dioxanone carbonyl group. Primary selective mono-phosphorylation and 2,4-bis-phosphorylation, followed by desilation and hydrogenolysis to the free mono- and diphosphates, and, in the latter case, cyclization to form the eight-membered phosphoryl anhydride, afforded MEP and ME-2,4-cycloPP in good yields. The C2 epimeric analogues, 2-C-methylthreitol and its 4-phosphate, were accessed by LiAlH4 reduction of the cis,cis epoxide of (2S,4R)-4-tert-butyldimethylsilyloxymethyl-5-methylene-2-phenyl-1,3-dioxane, primary-selective phosphorylation, and cleavage of the silyl, benzylidene, and benzyl protecting groups. Regioselective cleavage of the acetal ring of 1,3-benzylidene 2-C-methylerythritol silyl ether by ozonolysis afforded a 1,2,3-triol 3-monobenzoate intermediate that was converted to the novel amino sugar, 1-amino-1-deoxy-2-C-methylerythritol.     

Linear synthesis of a protected H-type II pentasaccharide using glycosyl phosphate building blocks.

A linear synthesis of a fully protected H-type II blood group determinant pentasaccharide utilizing glycosyl phosphate and glycosyl trichloroacetimidate building blocks is reported. Envisioning an automated solid-phase synthesis of blood group determinants, the utility of glycosyl phosphates in the stepwise construction of complex oligosaccharides, such as the H-type II antigen, is demonstrated. Installation of the central glucosamine building block required the screening of a variety of nitrogen protecting groups to ensure good glucosamine donor reactivity and protecting group compatibility. The challenge to differentiate C2 of the terminal galactose in the presence of other hydroxyl and amine protecting groups prompted us to introduce the 2-(azidomethyl)benzoyl group as a novel mode of protection for carbohydrate synthesis. The compatibility of this group with traditionally employed protecting groups was examined, as well as its use as a C2 stereodirecting group in glycosylations. The application of the 2-(azidomethyl)benzoyl group along with a systematic evaluation of glycosyl donors allowed for the completion of the pentasaccharide and provides a synthetic strategy that is expected to be generally amenable to the solid support synthesis of blood group determinants.     

Synthesis of dinucleoside phosphates and their analogs by the boranophosphotriester method using azido-based protecting groups

Oligodeoxyribonucleotides and their backbone-modified analogs were synthesized in good yields by the boranophosphotriester method in solution. The oligodeoxyriobonucleoside boranophosphates, fully protected with 2-(azidomethyl)benzoyl groups, were converted to the various backbone-modified DNA analogs via the corresponding H-phosphonate intermediates. A new efficient protecting group for the O⁶-position of 2′-deoxyguanosine, 4-[(2-azidomethyl)benzoyloxy]benzyl (AZBn) group, was also developed. The AZBn group was found to be quickly removed by treatment with MePPh₂ in dioxane-2-mercaptoethanol-H₂O.     

Synthesis of the pentasaccharide repeating unit of the O-specific polysaccharide from salmonella strasbourg

The pentasaccharide α - Tyv - (1→3) - β - d - Man - (1→4) - α - l - Rha - (1→3) - d - Gal - (4←1) -α - d - Glc 1, the repeating unit of the O-specific polysaccharide chain of the lipopolysaccharide from S. Strasbourg, was obtained by glycosylation of benzyl - 2,6 - di - O - benzyl - 4 - O - (2,3,4 - tri - O - benzyl - 6 - O - benzoyl - α - d - glucopyranosyl) - β - d - galactopyranoside with 1,2 - methylorthoacetyl - 3 - O - acetyl - 4- O - [3 - O - (2,4 - di - O - acetyl - 3, 6 - dideoxy,- α - d - arabino - hexopyranosyl) - 2,4,6 - tri - O - acetyl - β - d - mannopyranosyl] - β - l - rhamnopyranose 3 followed by removal of protecting groups. The structure of the synthetic pentasaccharide was proved by methylation analysis and ¹³C NMR.     

Synthesis of antifols related to 2,4-diamino-6,7-dihydro-5H-pyrrolo[3,4-d] pyrimidine. Enhancement of antiparasitic selectivity by nitrogen-linked mono- and dichlorobenzoyl groups or the 3,4–dichlorophenylthiocarbamoyl group

Improved procedures have been developed for the synthesis of 2,4-diamino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine ( 2a ), its 7-mcthyl derivative ( 2b ), and 6-(chloro-substituted phenyl) derivatives of 2,4-diamino-6,7-dihydro-5H-pyrrolo[3,4-d]pyritnidine ( 4 ). Direct acylation of compounds 2a or 2b with acid chlorides or mixed anhydrides derived from chloro-substituted benzoic or cinnamic acids gave 6-(chloro-substituted benzoyl or cinnamoyl) derivatives. Lithium aluminum hydride reduction of 6-(chloro-substituted benzoyl) derivatives under controlled conditions permitted preparation of 6-(chloro-substituted benzyl) derivatives (3). Compound 2a also reacted with aryl isothiocyanates to yield 6-arylthiocarbamoyl derivatives. Antimalarial assays for in vivo activity against murine malaria (P. berghei) and avian malaria (P. gallinaceum) revealed that a somewhat enhanced in vivo antiparasitic effect above that of parent compound 2a without any evident increase in host toxicity was conferred by introduction of certain of the 6-chloro-substituted benzoyl groups or the 6-(3,4-dichlorophenylthiocarbamoyl) group. Corresponding 6-(chloro-substituted benzyl) derivatives more frequently displayed host toxicity.     

Oligosaccharide Analogues of Polysaccharides. Part 7. Synthesis of a monosaccharide-derived monomer for amylose and cyclodextrin analogues

The synthesis of monomers of type C (Scheme 1) is described. In a first approach, chloro-acetyl-addition to the dioxolane 2 (Scheme 2), followed by treatment of the resulting chlorides 3 (α-D /β-D 1:3) with excess AgOTf and Bu₃SnC?CSiMe₃ gave the axial C-alkynyl-glycoside 4 (31%) and the C-arylglycoside 5 (29%). The structure of the dialkyne 6 , obtained by deacetylation of 4 , was established by X-ray analysis. The yield of the C-alkynyl-glycoside was slightly improved by protecting the C(4)-ethynyl group as the triethysilyl derivative, but not by substituting the benzyl by allyl or 2,6-difluorobenzyl groups. Silylation of the diol 1 with (chloro)diethyl[2-(trimethylsilyl)ethynyl]silane ( 19 ) resulted in 90% of the monosilyl ether 20 . HO? C(3) of 20 should favor coordination of a Lewis acid to O? C(6), and intramolecular, inverting acetal opening should lead to the product of axial alkynylation. Indeed, treatment of 20 with in situ generated BuAlCl₂, followed by treatment of the crude product with 0.1M HCl in MeOH, gave the dialkynylated triol 22 in yields of 85 to 90%. Under similar conditions, the disilyl ether 21 reacted more slowly to 22 (75%). The slower reaction correlates with the assumed intramolecular interaction of the precoordinated Lewis acid with O? C(6) in 20 .     

A new oligosaccharide synthesis using special hydroxy protecting group

A new hydroxy protecting group for convenient preparation of oligosaccharide was developed using uni-chemo protection (UCP) concept. The UCP group was comprised of polymerized amino acid derivatives and protecting each hydroxyl groups by ester linkage. Depending on the polymerization degree, the hydroxyl groups were characterized and controlled. Using this protecting group, two kinds of sialyl-T analogues were successfully synthesized from same sugar parts merely by repeating Edman degradation and coupling.     

Solvent-modulated Pd/C-catalyzed deprotection of silyl ethers and chemoselective hydrogenation

Recently we have reported undesirable and frequent deprotection of the TBDMS protective group of a variety of hydroxyl functions occurred under neutral and mild hydrogenation conditions using 10% Pd/C in MeOH. The deprotection of silyl ethers is susceptible to significant solvent effect. TBDMS and TES protecting groups were selectively cleaved in the presence of acid-sensitive functional groups such as TIPS ether, TBDPS ether and dimethyl acetal under hydrogenation condition using 10% Pd/C in MeOH. In contrast, chemoselective hydrogenation of reducible functional groups such as acetylene, olefin and benzyl ether, proceeds in the presence of TBDMS or TES ethers in AcOEt or MeCN.     

新型熊果酸单糖苷的简便合成

以熊果酸为原料,经苄基化反应制得熊果酸苄酯(2); 2与三氯乙酰亚胺酯经糖苷化反应制得酯保护的熊果酸-3-糖苷（4a~4d）;4a~4d依次脱去苄基和苯甲酰基合成了4个熊果酸-3-糖苷(6a～6d,其中6c为新化合物),其结构经¹H NMR, ¹³C NMR和MS(ESI)表征。     

Synthesis of cyclopropene analogues of ceramide and their effect on dihydroceramide desaturase

The synthesis of several analogues of the N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first reported inhibitor of dihydroceramide desaturase, as well as their effects on this enzyme, are described. Modifications of the parent structure include variations on the cyclopropene ring, the N-acyl chain length, the configuration of the stereocenters, and the hydroxyl group at C1. The key intermediates for the synthesis are the products resulting from the addition of suitable organolithium compounds to either Garner's aldehyde or its enantiomer. The final products are obtained by TMSTf-induced cleavage of the protecting groups and N-acylation, both under specific conditions. An alternative method for N-Boc deprotection is also reported that allows us to obtain the cyclopropene analogue of sphingosine 12a, which can be transformed into GT11 upon acylation. The procedure consists of the conversion of the Garner aldehyde addition products into the bicyclic dihydrooxazolo[3,4,0]oxazol-3-ones 19 by transesterification in basic medium of the tert-butyl group with the hydroxyl function at C3. Mild cleavage of the N,O-isopropylidene cyclic acetal present in 19 affords the oxazolidin-2-one 20, which gives 12a upon saponification. Furthermore, compound 20 is also the key intermediate in the synthesis of the terminal deoxy, methoxy, and fluoro derivatives 9, 10, and 11, respectively. Determination of dihydroceramide desaturase activity in vitro showed that GT11 was a competitive inhibitor (Ki = 6 microM) and that its analogues with N-hexanoyl (6) and N-decanoyl (7) moieties inhibited the enzyme with similar potencies (IC50 = 13 and 31 microM, respectively). No decrease in dihydroceramide desaturase activity was observed with any of the other compounds tested.     

Semisynthesis of Some 7-Deoxypaclitaxel Analogs from Taxine B

Taxine B (3), isolated from the dried needles of Taxus baccata, was converted into six novel 7-deoxypaclitaxel analogs, 20, 21a,b, and 23-25, that have structural changes at C1, C2, and C4. A method for the introduction of the benzoyl function at C2, via a benzylidene acetal at C1-C2, will be revealed. All compounds showed very little or no measurable cytotoxic activity against some well-characterized human tumor cell lines, probably due to the nonacylated hydroxyl group at C4.     

Synthesis of New Regioselectively Sulfated Hyaluronans for Biomedical Application

Sulfated glycosaminoglycans (GAGs) display various biological effects which are strongly influenced by the degree of sulfation and the position of sulfate groups within the polymer. Hyaluronan, a non-sulfated GAG, represents a readily accessible educt to synthesize structural analogues of sulfated GAGs mimicking their biological activity. Different strategies were developed and evaluated to synthesize hyaluronan sulfates with a free primary hydroxyl group at C-6' and sulfated secondary hydroxyl groups. Applying selective desulfation methods of high-sulfated hyaluronan by means of silylating agents, products regioselectively desulfated at the primary C-6' but also partly the C-4' position were obtained. A pathway using benzoyl ester protecting groups to block the primary hydroxyl function of Hya during the sulfation resulted in a high-sulfated product, functionalized only at the secondary hydroxyl groups.     

Solid-Phase Synthesis of Thio-oligosaccharides

No protecting groups are present in the highly reactive polymer-bound sugar 1-thiolates 1 , which undergo reactions with sugar triflates 2 to give thio-oligosaccharides 3 in high yield. Tr=trityl=triphenylmethyl, Tf=trifluoromethylsulfonyl, Bz=benzoyl.