Deoxygenation of carbohydrates by thiol-catalysed radical-chain redox rearrangement of the derived benzylidene acetals

Five- or six-membered cyclic benzylidene acetals, derived from 1,2- or 1,3-diol functionality in carbohydrates, undergo an efficient thiol-catalysed radical-chain redox rearrangement resulting in deoxygenation at one of the diol termini and formation of a benzoate ester function at the other. The role of the thiol is to act as a protic polarity-reversal catalyst to promote the overall abstraction of the acetal hydrogen atom by a nucleophilic alkyl radical. The redox rearrangement is carried out in refluxing octane and/or chlorobenzene as solvent at ca. 130 degrees C and is initiated by thermal decomposition of di-tert-butyl peroxide (DTBP) or 2,2-bis(tert-butylperoxy)butane. The silanethiols (Bu(t)O)3SiSH and Pr(i)3SiSH (TIPST) are particularly efficient catalysts and the use of DTBP in conjunction with TIPST is generally the most effective and convenient combination. The reaction has been applied to the mono-deoxygenation of a variety of monosaccharides by way of 1,2-, 3,4- and 4,6-O-benzylidene pyranoses and a 5,6-O-benzylidene furanose. It has also been applied to bring about the dideoxygenation of mannose and of the disaccharide alpha,alpha-trehalose. The use of p-methoxybenzylidene acetals offers no great advantage and ethylene acetals do not undergo significant redox rearrangement under similar conditions. Functional group compatibility is good and tosylate, epoxide and ketone functions do not interfere; it is not necessary to protect free OH groups. Because of the different mechanisms of the ring-opening step (homolytic versus heterolytic), the regioselectivity of the redox rearrangement can differ usefully from that resulting from the Hanessian-Hullar (H.-H.) and Collins reactions for brominative ring opening of benzylidene acetals. When simple deoxygenation of a carbohydrate is desired, the one-pot redox rearrangement offers an advantage over H.-H./Collins-based procedures in that the reductive debromination step (which often involves the use of toxic tin hydrides) required by the latter methodology is avoided.     

Studies on DMDO-mediated benzylidene acetal oxidation

We have shown that dimethyldioxirane (DMDO) can be used to effect an oxidative partial deprotection of benzylidene acetals derived from both 1,2- and 1,3-diols to afford hydroxy benzoate products. A wide range of functional groups are tolerated, and good to excellent yields are usually observed. The reactions are easy to perform and produce little waste other than acetone.     

A two-step synthesis of allylic syn 1,3-diols via an intramolecular oxa-Michael reaction followed by a modified Julia olefination

A two-step process for the synthesis of allylic syn 1,3-diols is developed. An intramolecular oxa-Michael reaction onto vinyl heteroaromatic sulfones allows the diastereoselective formation of 1-sulfonyl 2,4-diols protected as benzylidene acetals. These sulfones are then engaged in a modified Julia olefination to furnish the olefins contiguous to the benzylidene acetal ring with good E/Z selectivity.     

(Triisopropylsilyl)acetaldehyde acetal as a novel protective group for 1,2-diols

(Triisopropylsilyl)acetaldehyde dimethyl acetal (TIPS-ADMA) was synthesized from chlorotriisopropylsilane in three steps. Cyclic and acyclic 1,2-diols can be transformed to (triisopropylsilyl)ethylidene acetals (TIPS-AA). Removal of the acetal by LiBF₄ regenerates the starting diol in excellent yield even in the presence of an acetonide of 1,2-diol. The TIPS-AA group can survive under the deprotection conditions of the acetonide in acetic acid at 80 °C. Selective protection of 2,3- and 4,6-diols for O-methyl d-mannoside with TIPS-ADMA and selective deprotection of the acetals have been achieved.     

NMR determination of the absolute configuration of chiral 1,2- and 1,3-diols

Each of the chiral 1,2- and 1,3-diols examined was derivatized exclusively to a single diastereomeric acetal by the use of a new axially chiral reagent, 2′-methoxy-1,1′-binaphthalene-8-carbaldehyde (MBC). The absolute configuration of the original 1,2- and 1,3-diols was determined by the NOE correlation between the proton signals of the reagent moiety and those of the diol moiety in the acetals.     

Stripping off water at ambient temperature: direct atom-efficient acetal formation between aldehydes and diols catalyzed by water-tolerant and recoverable vanadyl triflate

[reaction: see text]. Aromatic aldehydes can be readily protected as acetals with 1,2- and 1,3-diols by using vanadyl triflate as a catalyst in CH(3)CN at ambient temperature. Carbohydrate-based 1,2- and 1,3-diols can similarly be protected in good to excellent yields. The catalyst can be readily recovered from the aqueous layer. In combination with vanadyl triflate-catalyzed sequential regioselective, reductive acetal opening and chemoselective acylations, the title method allows for differential functionalization of all four hydroxyl units in a given glucopyranoside.     

Selective cleavage of acetals with ZnBr2 in dichloromethane

A selective cleavage of acetals of 1,2- and 1,3-diols has been achieved under mild conditions using ZnBr₂ in dichloromethane at room temperature. Acetal types cleavable by this procedure include benzylidene, isopropylidene and cyclohexylidene acetals. This method is compatible with several other types of hydroxyl protecting groups such as Bn, Bz, TBDPS, TIPS and TBDMS.     

Asymmetric Desymmetrization of Saturated and Unsaturated meso-1,2-Diols

An asymmetric desymmetrization of saturated and unsaturated cyclic and acyclic meso-1,2-diols has been developed from the ene acetals, prepared from the norbornene carboxyaldehyde and meso-1,2-diols. The intramolecular haloetherification of the ene acetals as a key step afforded 8-membered acetals in a stereoselective manner just by the reaction of norbornene olefin even when the ene acetals from unsaturated meso-1,2-diols having olefins in the same molecule were used. Subsequent reductive elimination, followed by protecting the hydroxy group and transacetalization, gave optically active 1,2-diol derivatives and the starting ene acetals in good yields.     

Azide/oxygen photocatalysis with homogeneous and heterogeneous photocatalysts for 1,2-aminohydroxylation of acyclic/cyclic alkenes and Michael acceptors

Homogeneous as well as heterogeneous photocatalysts that are able to oxidize the azide anion with low competitive singlet oxygen quantum yields are used to generate azidyl radicals. These radicals add to electron-rich as well as electron-poor (Michael acceptors) alkenes, and carbon radicals are formed regioselectively. Trapping with triplet oxygen (type I photooxygenation) is diffusion controlled, and the initially formed peroxy radicals are reduced with regeneration of the photocatalyst. Fluorescence quenching studies reveal rapid photoinduced electron transfer in the first catalysis step. The lack of rearrangement products in the bicyclic terpene series (pinenes, limonene) accounts for rapid subsequent oxygen trapping and back electron transfer steps. The 1,2-azidohydroperoxidation enables synthesis of 1,2-azidoalcohols and 1,2-aminoalcohols by different reduction protocols. Substrate modification and combination of type II photooxygenation with electron transfer photocatalysis allows the synthesis of 1-amino-2,3-diols and 2-amino-1,3-diols.     

Syntheses of (-)-Cryptocaryolone and (-)-Cryptocaryolone Diacetate via a Diastereoselective Oxy-Michael Addition and Oxocarbenium Allylation

The total syntheses of both (-)-cryptocaryolone and (-)-cryptocaryolone diacetate is presented herein. The usage of a diastereoselective oxy-Michael addition/benzylidene acetal formation coupled with a selective axial oxocarbenium allylation allowed for the preparation of the α-C-glycoside moiety present in the bicyclic bridged structure. In addition, the syn-1,3-diol of the linear portion was installed via a Wacker oxidation followed by a subsequent directed reduction of the appropriate homoallylic alcohol precursor.     

Total synthesis of 6-epiprelactone-V via a syn-selective oxygen tethered intramolecular Michael reaction

The intramolecular protective group (benzylidene acetal) assisted syn-1,3-diol synthesis has been efficiently utilized in a short synthesis of 6-epiprelactone-V starting from (S)-malic acid.     

Serendipitous synthesis of 3-hydroxy tetrahydrofurans from tin catalyzed sulfonylation of acyclic 1,2,4-triols

The reaction of syn-1,2,4-triols under sulfonylation conditions catalyzed by Bu₂SnO (5 mol %) results in cyclization and the formation of 3-hydroxy tetrahydrofurans (56-85%) while the anti-1,2,4-triols react to give C1-O-sulfonyl derivatives in good yields (66-83%) and the cyclization product in poor yield (5-12%). A mechanism that justifies these observations is proposed to occur via the tosylation of the primary hydroxyl followed by an intramolecular tin acetal rearrangement to a 1,3-stannylene which then undergoes a 5-exo-tet-cyclization. The difference in rates of cyclization reactivity is due to the energetically more stable tin acetals of syn-1,3-diols compared to those of anti-1,3-diols.     

C(2)-Symmetric bis-sulfoxide: A novel chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols

A new heterocyclic compound, C(2)-symmetric bis-sulfoxide 1, has been found to be an efficient chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal fission. Both (R,R)- and (S,S)-1 are readily synthesized with high optical purity via asymmetric oxidation of 1, 5-benzodithiepan-3-one (2). After acetalization of meso-1,2-diols 6a-e and a mono-TMS ether 6f with this chiral auxiliary 1, the resulting acetals 7a-f were subjected to base-promoted acetal fission upon treatment with potassium hexamethyldisilazide (KHMDS) followed by acetylation or benzylation to give the desymmetrized diol derivatives 8a-f with high diastereoselectivity. The chiral auxiliary 1 is readily removed by acid-promoted hydrolysis and can be recovered without a loss in enantiomeric excess.     

Photolabile protection of 1,2- and 1,3-diols with salicylaldehyde derivatives

1,2- and 1,3-diols, including carbohydrates, can be readily caged as acetals of 5-methoxy- or 5-hydroxysalicylaldehydes. Irradiation of these acetals with 300 nm light results in their efficient (Phi = 0.2-0.3) cleavage, regenerating an aldehyde and a glycol in excellent chemical yield. Photoreactive 5-hydroxysalicylaldehyde acetals can be produced by mild in situ reduction of photostable p-quinone precursors.     

Contrast effect of hydrogen bonding on the acceptor and donor OH groups of intramolecularly hydrogen-bonded OH pairs in diols

We studied the influence of hydrogen bonding on the fundamental and overtone bands of the OH-stretching vibration of each OH group in the intramolecularly hydrogen-bonded OH(I)::OH(II) pair in 1,2-, 1,3- and 1,4-diols. The hydrogen bonding between the two OH groups significantly increases in strength from the five-membered ring of a 1,2-diol to the seven-membered ring of a 1,4-diol. Although the hydrogen bonding does not affect the vibrational property of the OH(II) (or acceptor), it significantly influences the OH(I) (or donor). As the hydrogen bonding becomes stronger from a 1,2- to a 1,4-diol, the fundamental band of the OH-stretching shifts downwards by from about 50 to 140 cm(-1), and the overtone band markedly decreases in intensity, although the effect on the intensity and bandwidth of the fundamental band varies among 1,2-, 1,3- and 1,4-diols. The quantum-mechanically calculated normal frequencies of the acceptor and donor OH groups in the hydrogen-bonded ring are in good agreement with the observed frequencies. The calculated interatomic distance between the O of an acceptor OH and the H of a donor OH is the shortest for a 1,4-diol, which is consistent with the largest frequency shift caused by the hydrogen bonding.     

New protecting groups for 1,2-diols (boc- and moc-ethylidene). Cleavage of acetals with bases

[reaction: see text] 1,2-Diols react at rt with alkyl propynoates, in the presence of 4-dimethylaminopyridine, to give cyclic acetals which are quite stable to acid-catalyzed hydrolysis or methanolysis. 1,3-Diols and 1, 4-diols do not form acetals with alkyl propynoates under the same conditions. Deprotection is accomplished with bases (via elimination and addition/elimination steps).     

Utilization of 1-oxa-2,2-(dimesityl)silacyclopentane acetals in the stereoselective synthesis of polyols

We have developed a route for the stereoselective synthesis of 1-oxa-2,2-(dimesityl)silacyclopentane acetals, intermediates in the synthesis of highly functionalized 1,3-diols. This route involves a diastereoselective conjugate addition reaction of a hydrosilyl anion, a subsequent diastereoselective enolate alkylation, and a fluoride-catalyzed intramolecular hydrosilylation reaction to afford the oxasilacyclopentane acetal. A highly selective nucleophilic substitution reaction, followed by oxidation of the C-Si bond, leads to the desired polyol.     

Synthesis and some properties of cyclic acetals of malonaldehyde

The Lewis acid-catalyzed addition of cyclic orthoformates to vinyl ethyl ether, which leads to the formation of malonaldehyde acetals, was studied. It is shown that of the linear-cyclic malonaldehyde acetals, 2-(2,2-diethoxyethyl)- and 5,5-dimethyl-2-(2,2-diethoxyethyl)-1,3-dioxanes are stable. The transacetalization of 1,1,3,3-tetraethoxypropane with 1,2- and 1,3-diols, which leads to the formation of cyclic malonaldehyde acetals, was studied. The physicochemical constants of the acetals were determined, and their ¹H and ¹³C NMR spectra are described.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 459–463, April, 1983.     

Synthesis of eight-membered aminocyclitol analogues

The first syntheses of four stereoisomeric diaminocyclooctane diols, as well as a chlorocyclooctane aminodiol, are reported. In the first part, photooxygenation of cis,cis-1,3-cyclooctadiene gave a bicyclic endoperoxide, which was reduced with zinc followed by mesylation of the hydroxyl groups. Treatment with sodium azide afforded 1,4- and 1,2-cyclooctene diazides. Oxidation of the double bonds in the isomeric diazides with OsO₄, followed by hydrogenation of the azide groups, led to 3,8-diaminocyclooctane-1,2-diol and 3,4-diaminocyclooctane-1,2-diols. In the second part, cis-3,8-diazidocyclooctene was converted into the corresponding epoxide. Stereospecific hydrolysis of the epoxide ring with HCl_(g) in methanol, and hydrogenation of the azide groups gave 3,8-diamino-2-chloro-cyclooctan-1-ol. Bromination of the double bond in cyclooctene diacetate, followed by acetate deprotection, azidolysis of the bromides, and hydrogenation of the azide groups resulted in the formation of 2,3-diaminocyclooctane-1,4-diol.     

Selective mono-fluorination of diols via a cyclic acetal of N,N-diethyl-4-methoxybenzamide

Selective mono-fluorination of 1,2- and 1,3-diols was achieved using N,N-diethyl-4-methoxybenzamide diethyl acetal and Et₃N-3HF. The reaction proceeds through a cyclic acetal of the benzamide, and only one hydroxy group was fluorinated and another one was acylated.