Carbohydrate-based oxepines: ring expanded glycals for the synthesis of septanose saccharides

A ring-closing metathesis (RCM) approach to a family of carbohydrate-based oxepines is described. A variety of readily accessible, protected monosaccharide derived dienes were used to demonstrate the utility of the synthetic sequence and to investigate how factors such as rigidification and deoxygenation mediate RCM using the Grubbs or Schrock catalyst. The seven-membered cyclic enol ethers are ring expanded glycals to be used in the synthesis of septanose carbohydrates.     

Stereoselectivity in the epoxidation of carbohydrate-based oxepines

The facial selectivity in the DMDO epoxidation of carbohydrate-based oxepines derived from glucose, galactose, and mannose has been determined by product analysis and density functional theory (DFT, B3LYP/6-31+G**//B3LYP/6-31G*) calculations. Oxepines 3 and 4, derived from d-galactose and d-mannose, largely favor alpha- over beta-epoxidation. The results reported here, along with selectivities in the DMDO-mediated epoxidation of d-xylose-based oxepine 1 and d-glucose-based oxepines 2 and 5 reported earlier, support a model in which electronic effects, guided by the stereochemistry of the oxygens on the oxepine ring, largely determine the stereoselectivity of epoxidation. Other contributing factors included conformational issues in the oxepine's transition state relative to the reactant, the asynchronicity in bond formation of the epoxide, and the overall steric bulk on the alpha- and beta-faces of the oxepine. Considered together, these factors should generally predict facial selectivity in the DMDO-epoxidation of cyclic enol ethers.     

Synthesis of a Glyoxalase I Inhibitor from Streptomyces griseosporeus NIIDAet OGASAWARA

The pseudolactones 6 and 12 were prepared in a straightforward way from methyl α-D -glucopyranoside and methyl α-D -mannopyranoside, respectively. The pseudolactone 6 reacted with tert-butyl lithioacetate to give the protected, trihydroxylated cyclohexenone carboxylate 7 (51 %). The sterically hindered, L-ribo-configurated pseudolactone 12 reacted with diethyl ethylphosphonate and dimethyl methylphosphonate to give the protected trihydroxycyclohexenones 17 (49 %) and 18 (62 %), respectively. The hydroxymethylated cyclohexenone 21 was obtained from 18 by treatment with Me₂AlSPh and then formaldehyde, oxidation of the product 19 , and elimination. Deprotection of 21 gave 2 , identical with KD16-Ul. Esterification of 2 gave 1 , identical with the title compound. Alternatively, 1 was obtained in higher yields by esterification of 21 , followed by deprotection of the hydroxy groups. This synthesis gave 1 and 2 from methyl α-D -mannopyranoside in an overall yield of 18 and 20 %, respectively, confirming their absolute configuration.     

Gold-catalyzed ketene dual functionalization and mechanistic insights: divergent synthesis of indenes and benzo[d]oxepines

An unprecedented gold-catalyzed ketene C=O/C=C bifunctionalization method has been developed. Mechanistic studies and density function theory(DFT) calculations indicate that the reaction is initiated by gold-catalyzed Wolff rearrangement of diazoketone to form the ketene intermediate, followed by intermolecular nucleophilic addition and terminated with two divergent cyclization processes via enol intermediates. In the case with alcohols as the nucleophiles, the reaction goes through a C-5-endodig carbocyclization to give the indene products; whereas, O-7-endo-dig cyclization occurs dominantly when indoles/pyrroles are used as the nucleophiles, delivering the 7-membered benzo[d]oxepines. In comparison with the well-documented cycloaddition and nucleophilic addition reactions, this cascade reaction features a novel reaction pattern for the ketene dual functionalization through addition with nucleophile and electrophile in sequence.     

Synthesis of pyrene and benzo[a]pyrene adducts at the exocyclic amino groups of 2'-deoxyadenosine and 2'-deoxyguanosine by a palladium-mediated C-N bond-formation strategy

Single-electron oxidation of the carcinogenic hydrocarbon benzo[a]pyrene (BaP) is thought to result in a radical cation intermediate and this species has been proposed to cause alkylation at the nitrogens of the purine nucleobases. Although several different nucleoside adducts have been isolated as arising from this mode of metabolic activation, there are no selective, total syntheses of the stable exocyclic amino group adducts formed by the single-electron oxidation of any hydrocarbon with the purine 2'-deoxynucleosides to date. In this paper we disclose the synthesis of the model adducts N(6)-(1-pyrenyl)-2'-deoxyadenosine and N(2)-(1-pyrenyl)-2'-deoxyguanosine as well as the first synthesis of the carcinogen-linked nucleoside derivatives N(6)-(6-benzo[a]pyrenyl)-2'-deoxyadenosine and N(2)-(6-benzo[a]pyrenyl)-2'-deoxyguanosine via a palladium-mediated C-N bond formation. Two different coupling strategies were attempted: coupling of an aryl bromide with a suitably protected nucleoside and the coupling of an arylamine with a suitable halonucleoside. The former had somewhat limited applicability in that only N(6)-(1-pyrenyl)-2'-deoxyadenosine was prepared by this method; on the other hand, the latter was more general. However, there are noteworthy differences in the amination reactions at the C-6 and C-2 positions. Reactions at the C-6 resulted in the competing formation of a 1:2 amine-nucleoside adduct in addition to the desired monoaryl nucleoside. Such a dimer formation was not observed at the C-2. The C-2 adducts, however, displayed an interesting conformational behavior.     

A novel bornane synthesis by an old idea

Aiming at a synthesis of spiro[2.4]hepta-4,6-dienes with a carbon substituent at C-4, we investigated solvolysis reactions of the thiatricycle 2, obtained from spiro[2.4]hepta-4,6-diene (1) and thiophosgene by [4 + 2] cycloaddition. With methanol or ethanol a mixture of the esters 7 and 8 was formed. Desulfurization of the thionoesters 8 gave methyl and ethyl spiro[2.4]hepta-4,6-diene-4-carboxylate (10a,b). The corresponding alcohol (11) was prepared from 10b by LiAlH(4) reduction. Ethenetetracarbonitrile combined with the 4-substituted spiro[2.4]hepta-4,6-dienes to give the [4 + 2] cycloadducts 12a-c. Diels-Alder reaction between 11 and 2-chloroacrylonitrile afforded the spiro(bicyclo[2.2.1]hept-5-ene-7,1'-cyclopropane) derivative 14a that was transformed in three steps to rac-10-hydroxycamphor (17). This synthesis of a bornane derivative opens opportunity for variations and thus may find further applications.     

Uses of adsorbed reagents in the synthesis of reactive molecules via elimination reactions

The synthesis of reactive molecules (in vacuo) using reagents adsorbed on inert surfaces to effect elimination reactions has been investigated. Potassium t-butoxide adsorbed on Chromosorb W can be used to generate methylenecyclopropene from 2-chloromethylenecyclopropane and 1-vinylcyclopropene from either 1,4-dichlorospiropentane or 1-chloro-2-vinylcyclopropane. Both compounds can be characterized at low temperature using NMR and IR spectroscopy. Methyllithium on glass helices has been used in the reductive elimination of halogen from vicinal cyclopropyl dihalides to yield cyclopropenes. β-Halocyclopropylsilanes can be converted in high yield to the corresponding cyclopropene using tetra-n-butylammonium fluoride deposited on glass helices. The fluoride route has been used to generate bicyclo[4.1.0]hept-(1,6)-ene and bicyclo[4.1.0]hept-(1,7)-ene in the gas phase under conditions which allow either spectroscopic characterization or trapping as Diels-Alder adducts.     

A stereodivergent approach to 1-deoxynojirimycin, 1-deoxygalactonojirimycin and 1-deoxymannojirimycin derivatives

A stereodivergent synthesis of N-alkylated 1-deoxygalactonojirimycin and 1-deoxymannojirimycin derivatives has been achieved from a protected 1-deoxynojirimycin intermediate having two free OH groups tactically positioned at C-2 and C-4. The inversion of configuration of the secondary alcohols was performed by way of a Swern oxidation followed by a highly diastereoselective reduction using NaBH₄ or L-Selectride.     

Asymmetric synthesis of rubiginones A(2) and C(2) and their 11-methoxy regioisomers

Convergent enantioselective syntheses of angucyclinone-type natural products rubiginones A(2) (2) and C(2) (1) and their 11-methoxy regioisomers 3 a and 3 b have been achieved by using two domino processes from a common enantiomerically pure 1-vinylcyclohexene 4. Key steps in the synthesis of this diene were the stereoselective conjugate addition of AlMe(3) on (SS)-[(p-tolylsulfinyl)methyl]-p-quinol (9) and the elimination of the beta-hydroxy sulfoxide fragment, after oxidation to sulfone, to recover a carbonyl group. The first domino sequence comprised Diels-Alder reaction with a sulfinyl naphthoquinone followed by sulfoxide elimination. An efficient opposite regioselection in the cycloaddition step was achieved in the convergent construction of the tetracyclic skeleton using a sulfoxide at C-2 or C-3 of the dienophiles 5 or 6, derived from 5-methoxy-1,4-naphthoquinone. The second domino process, triggered by oxygen and sunlight, allowed the transformation of the initial tetracyclic adducts into the final products after B ring aromatization, silyl deprotection and C-1 oxidation.     

2,3-Anhydro sugars in glycoside bond synthesis. Highly stereoselective syntheses of oligosaccharides containing alpha- and beta-arabinofuranosyl linkages

The ever-increasing discovery of biologically important events mediated by carbohydrates has generated great interest in the synthesis of oligosaccharides and the development of new methods for glycosidic bond formation. In this paper, we report that 2,3-anhydrofuranose thioglycosides (1, 5) and glycosyl sulfoxides (2, 6), in which the hydroxyl groups C-2 and C-3 are "protected" as an epoxide, glycosylate alcohols with an exceptionally high degree of stereocontrol. The predominant or exclusive product of reactions with this fundamentally new class of glycosylating agent is that in which the newly formed glycosidic bond is cis to the epoxide moiety. We further demonstrate that subsequent nucleophilic opening of the epoxide moiety proceeds under basic conditions to give products in high yield and with good to excellent regioselectivity. The major ring-opened products possess the arabino stereochemistry, and thus this methodology constitutes a new approach for the synthesis of arabinofuranosides. In the epoxide opening reactions of glycosides with the 2,3-anhydro-beta-D-lyxo stereochemistry (e.g., 73), the addition of (-)-sparteine (78) to the reaction mixture dramatically enhanced the regioselectivity in favor of the arabino product. This represents the first example of the use of 78 to influence the regioselectivity of an epoxide ring opening reaction with a non-carbon nucleophile. We have demonstrated the utility of this methodology through the efficient synthesis of an arabinofuranosyl hexasaccharide, 7, which is a key structural motif in two mycobacterial cell wall polysaccharides.     

Deoxygenation at C-4 and Stereospecific Branched-Chain Construction at C-3 of a Methyl Hexopyranuloside. Synthetic Approach to the Amipurimycin Sugar Moiety

A five-step synthesis from 3 leading to a partially protected amipurimycin sugar moiety 14 in an overall yield of 47% is described and includes deoxygenation at C-4 and regio- and stereoselective construction of the branched chain. Deoxygenation at C-4 of 3 was possible by three different methods. Radical reduction with tri-n-butyltin hydride of the appropriate phenoxythiocarbonyl derivative afforded the desired deoxysugar 5 in 47% overall yield together with the secondary products 6 and 7 due to depivaloylation at C-2 and elimination of methanol. The most adequate deoxygenation procedure used the system Ph(3)P/I(2)/imidazole which led to the preparation of 5 in one step in 61% yield. When the system Ph(3)PBr(2)/Ph(3)P was tried, only 8 was formed due to elimination of methanol. The synthesis of 5 was then accomplished by reaction of 8 with methanol in the presence of triphenylphosphine hydrobromide in 37% overall yield. Branched-chain construction was accomplished by Wittig reaction of 5 with [(ethoxycarbonyl)methylene]triphenylphosphorane, followed by osmilation and reduction with lithium aluminum hydride. Isopropylidenation of 14 afforded 16 with a free hydroxy group at C-6 for chain elongation and further synthesis of amipurimycin.     

Straightforward synthesis of thiodisaccharides by ring-opening of sugar epoxides

3,4-Anhydro hexopyranosides have been prepared by diastereoselective epoxidation of derivatives of 2-propyl 3,4-dideoxy-alpha-D-erythro-hex-3-enopyranoside (5), selectively protected at HO-2 and HO-6. The allylic group at C-2, in 5 and derivatives, plays a critical role in the facial selectivity of the epoxidation reaction. Thus, the free HO-2 in 3 (the 6-O-acetyl derivative of 5) directs the attack of m-chloroperbenzoic acid from the more hindered alpha face of the molecule to give 2-propyl 6-O-acetyl-3,4-anhydro-alpha-D-allopyranoside (7) accompanied by the beta epoxide 6 as a very minor product. Reverse diastereoselectivity has been obtained when the HO-2 in 3 was substituted by a bulky tert-butyldimethylsilyl (TBS) group. In this case, the major isomer was the 2-O-TBS derivative of 6 (alpha-D-galacto configuration). The ring-opening of sugar epoxides by nucleophilic per-O-acetyl-1-thio-beta-D-glucopyranose (11) was employed as a convenient approach to the synthesis of (1-->3)- and (1-->4)-thiodisaccharides. For example, ring-opening of the oxirane 7 by 11 led to the expected regioisomeric per-O-acetyl thiodisaccharides beta-D-Glc-S-(1-->3)-4-thio-alpha-D-Glc-O-iPr (12) and beta-D-Glc-S-(1-->4)-4-thio-alpha-D-Gul-O-iPr (13). Regioselectivity in the construction of the (1-->4)-thioglycosidic linkage could be achieved by hindering C-3 of the 3,4-anhydro sugar with a bulky silyloxy group at the vicinal C-2. For instance, coupling of the 2-O-TBS derivative of 7 with 11 led regioselectively to the protected thiodisaccharide beta-D-Glc-S-(1-->4)-4-thio-alpha-D-Glc-O-iPr (27). The utility of the approach was demonstrated through the synthesis of sulfur-linked analogues of naturally occurring (laminarabiose and cellobiose) and non-natural disaccharides (i.e., beta-D-Glc-(1-->4)-alpha-D-Gul).     

Total synthesis of natural dysidiolide

Dysidiolide (1), a novel sesterterpenoid previously isolated from the Caribbean sponge Dysidea etheria de Laubenfels, inhibits the action of the protein phosphatase, cdc25A. The authors establish a novel total synthesis of natural dysidiolide (1) using intramolecular Diels-Alder reaction as the key step from optically active cyclohexenone 3. Decalin, the core structure of 1, was constructed by intramolecular Diels-Alder reaction of the diene ester generated by elimination of the phenyl sulfoxide group from sulfoxide ester 6 prepared from cyclohexenone 3. Diastereoselective methylation at C-7, alkylation at C-6, and deoxygenation of C-12 and C-24 positions gave the fully substituted bicyclic core of 1. The two side chains of the bicyclic core were further extended so as to afford natural dysidiolide (1). The total yield of this synthesis exceeds that of previous syntheses of 1.     

Convenient synthesis of 2,4-disubstituted pyrido[2,3-d]pyrimidines via regioselective palladium-catalyzed reactions

A novel and effective route for the synthesis of 2,4-disubstituted pyrido[2,3-d]pyrimidines III is reported starting from the corresponding 2,4-dichloropyridopyrimidine 1 through regioselective functionalization palladium-catalyzed C–C coupling reactions, by two successive palladium-catalyzed reactions involving an original regioselective chlorine discrimination. Alternatively, type III compounds were elaborated from 2 by C-2 chlorine further displacement of the C-4 isopropylsulfanyl group, which acted as a temporary C-4 protecting group. Further Suzuki–Miyaura cross-coupling reactions led to C-2 and C-4 disubstituted compounds.     

Catalytic Oxidation of Cyclohexene by Dendrimer-bond Metal Catalysts

Since Tomalia and Dovornic discussed the promising outlook of surface-functionalized dendrimer catalysts in 1994, [1] dendritic catalysts have been proposed to many kinds of catalysis.These well-defined macromolecular structures enable the construction of precisely controlled catalyst structures. The large number of the peripheral functionalities enhanced their activity in many processes. [2,3] We report herein a new method of using the dendritic catalysts in the oxidation of cyclohexene. The reactions give some interesting results.In short, the synthesis of the dendritic catalysts was initiated from the well-known PAMAM dendrimers by using their peripheral ammonia groups. The condensation reactions of these ammonia groups and salicyaldehyde (SA) offer the ligands PAMAMSA with different generation (G) numbers.dendrimer-bond PAMAMSA-Ni(Ⅱ) complexes.In the presence of the dendritic PAMAMSA-Ni(Ⅱ) catalysts, cyclohexene was fully oxidized under 1 atm of molecular oxygen at 70℃. All the oxidations give 7-oxabicyclo[4.1.0]heptane 1,2-cyclohexen-l-ol 2, 2-cyclohexen-1-one 3 and 7-oxabicyclo [4.1.0]heptan-2-one 4 as the major products. The results of the oxidation are shown in the table below (table 1):Table 1 Oxidation of cvclohexene bv PAMAMSA-Ni2+ catalysts** Reaction condition: cat. 2mg, cyclohexene 5mL, 1atm O2, 6hat 70℃.**Oxygen absorption (mL) per mol catalyst.It can be seen from table that the oxidations give a new product 7-oxabicyclo[4.1.0]heptan-2-one 4, which is the first reported product in this oxidation. Meanwhile, product 4possesses relatively high selectivity in the six oxidation processes. It will arise much more emphasison the optimizing of these reactions.     

Transformations of lignans. Part 11: Oxidation of diphyllin with hypervalent iodine reagents and reductive reactions of a resulting 1-methoxy-1-aryl-4-oxonaphthalene lactone

Treatment of diphyllin 4 with phenyliodonium diacetate (PIDA) in methanol affords a 1-methoxy-1-aryl-4-oxonaphthalene lactone 6. Reduction of 6 with lithium aluminium hydride yields, inter alia, 3,4-dihydrodiphyllin 13, while reaction with sodium in ethanol yields 8 as a major product. These reactions illustrate that selective oxidation followed by reduction provides a facile route for the conversion of a 1-arylnaphthalene lactone to novel functionalised naphthalene and dihydronaphthalene derivatives. Of particular interest is that the oxidation indirectly activates the methylene position (C-10) of the γ-lactone, which may then potentially be substituted to give a new series of lignans. Reaction of 6 with hydroxylamine and benzyloxyamine also proceeds by way of initial attack at C-10.     

Synthesis and diels-alder reactions of 5,5-dicyanocyclopentadiene: regioselective synthesis of 1,5-disubstituted-1,3-cyclohexadienes

5,5-Dicyanocyclopentadiene, readily prepared in three steps from commercially available cis-1,4-dichloro-2-butene, undergoes Diels-Alder reactions with a number of dienophiles to give 5-substituted 7,7-dicyanobicyclo[2.2.1]hept-2-enes with high endo-selectivity. The adduct produced with methyl acrylate undergoes base-induced retro-Michael reactions to give 1-carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene.     

Preparation of 2-deoxy-2-C-p-tolylsulfonyl-beta-D-glucopyranosyl p-tolylsulfones having non-chair conformation and their elimination reactions

When the title sulfones, which have non-chair conformations, were stirred with silica gel, elimination of sulfinic acid occurred to give a 1-enitol derivative, if the hydroxyl group at C-6 was protected, whereas such an elimination did not proceed if the hydroxy group was free.     

Versatile route to centro-substituted triquinacene derivatives: synthesis of 10-phenyltriquinacene

[reaction: see text] A versatile route to prepare centro-substituted triquinacene derivatives (1, R = various substituents), as exemplified by the preparation of 10-phenyltriquinacene (1, R = Ph), is reported. The quaternary, centro substituent (C-10) was installed by a trimethylsilyl chloride-promoted conjugate addition reaction of an organocuprate, derived from phenylmagnesium bromide, and the protected bicyclic enone (11). The resultant trimethylsilyl enol ether was then converted regioselectively to the C-2-allylated conjugate addition products (13, R = Ph). The allyl moiety, following oxidative cleavage of the carbon-carbon double bond, was used to elaborate the tricyclic ring system by an intramolecular aldol/acetal deprotection reaction. The product of this reaction was then converted to the target compound using a standard series of functional group transformation reactions.     

A short formal synthesis of squalamine from a microbial metabolite

A short formal synthesis of squalamine is described, utilizing the biotransformation product 2, which is available in one step from commercially available 3-keto-23,24-bisnorchol-4-en-22-ol (1). Regioselective C-22 oxidation and C-24 sulfation of the corresponding alcohols in the presence of a free C-7 alcohol make for an efficient preparation of squalamine intermediate 11.