Diastereoselective C-C bond formation at C-5 of vinyl sulfone-modified hex-5-enofuranosyl carbohydrates: diversity-oriented synthesis of branched-chain sugars and beyond

This is the first report on the diastereoselective addition of carbon nucleophiles to vinyl sulfone-modified hex-5-enofuranosides. The stereoelectronic properties of the substituents at the C-3 position and their interactions with the incoming carbon nucleophiles control the diastereoselectivity of addition at the C-5 position, favoring the formation of l-ido derivatives as major products in most of the cases studied. This new concept of stereocontrolled carbon-carbon bond formation in vinyl sulfone-modified carbohydrates is general in nature. The novel chirons generated by this diversity-oriented synthetic method have been implemented in the preparation of a wide range of hexofuranosyl C-5 branched-chain sugars, bicyclic derivatives, chirally pure enals, and densely functionalized carbocycles.     

The Role of the C-3 Substituent in the Asymmetric Dihydroxylation of Hexo-5-Enofuranosides

ABSTRACT

Asymmetric dihydroxylation of vinyl furanosides 1-6 by use of OsO₄, AD-mix-α® and β® is described yielding the corresponding hexofuranose sugars. Vinyl furanosides 2 and 3, with an ester group at C-3, and vinyl manno furanoside 5 on asymmetric dihydroxylation with AD-mix α® exhibited high R diastereoselectivity at C-5. Reversal in diastereoselectivity at C-5 was observed for the 3-deoxy vinyl furanoside 6 giving furanosaccharide 6S with the S configuration at C-5.     

Anomeric configuration-directed diastereoselective C-C bond formation in vinyl sulfone-modified carbohydrates: a general route to branched-chain sugars

[structure: see text] This is the first report on the diastereoselective addition of carbon nucleophiles to vinyl sulfone-modified hex-2-enopyranosides and pent-2-enofuranosides. Nucleophiles add to the C-2 position from a direction opposite to that of the disposition of the anomeric methoxy group. This novel concept of anomeric configuration-directed stereocontrolled carbon-carbon bond formation in vinyl sulfone-modified carbohydrates is general in nature and has been implemented in the synthesis of new hexopyranosyl and pentofuranosyl branched-chain sugars and densely functionalized carbohydrates.     

Vinyl sulfone- and vinyl sulfoxide-modified tetrahydrofurans: a preliminary account of the enantiomeric synthesis of and diastereoselectivity of addition to new classes of Michael acceptors

Enantiomerically pure 2-hydroxymethylene substituted-2,5-dihydro-3-(arylsulfonyl)- and 2-hydroxymethylene substituted-2,5-dihydro-3-(arylsulfinyl)-furans have been prepared from easily accessible carbohydrate derivatives for the first time. The strategy for accessing both these sulfones and sulfoxides is more efficient than the methods reported so far for the synthesis of this type of compounds. Hydroxymethylene group is sufficient to impose diastereoselectivity on the addition of a wide range of nucleophiles to vinyl sulfone-modified tetrahydrofurans. The benzyl protected hydroxymethylene group also suppresses the influence of chirally pure sulfoxides as two diastereomeric vinyl sulfoxide-modified tetrahydrofurans afforded the Michael adducts with same configurations at C-3 and C-4; this has been established by oxidizing the adducts, which were found to be identical to the products obtained by adding the same nucleophiles to the corresponding vinyl sulfones. These highly reactive Michael acceptors may be considered as a new addition to the arsenals of synthetic chemists interested in the functionalization of tetrahydrofurans.     

Stereoselective synthesis of highly enantioenriched 3-methyl-2-cyclohexen-1-ones possessing an asymmetric quaternary carbon as C-4 or C-6: a sugar template approach

The 1,4-addition of the enolate generated from α-methylated acetoacetate incorporated at C-4 of methyl 6-deoxy-2,3-di-O-(tert-butyldimethylsilyl)-α-d-glucopyranoside to methyl vinyl ketone, followed by aldol condensation of the resulting 1,4-addition product under two base-mediated conditions, provided 4-O-functionalized d-glucose derivatives with high diastereoselectivity. These products install a 3-methyl-2-cyclohexen-1-one-4- (or -6-) carboxylic acid as the O-4 ester, in which C-4 or C-6 is an asymmetric quaternary carbon. Removal of the sugar template from those aldol condensation products provided synthetically useful 3,6-dimethyl-2-cyclohexen-1-one-6-carboxylic acid and 3,4-dimethyl-2-cyclohexen-1-one-4-carboxylic acid derivatives both in high enantioenriched forms.     

Synthesis of C-5 substituted nucleosides via palladium-catalyzed coupling of dienes and amines

The palladium-catalyzed coupling of C-5 iodopyrimidine nucleosides; 1,2-, 1,3-, or 1,ω-dienes; and amines provides a novel and efficient method for the preparation of a wide variety of C-5 aminoalkyl-substituted nucleosides. Adding certain Lewis acids, particularly zinc salts, improves the yields significantly. Secondary amines are the most effective amines for this process. Acyclic and cyclic dienes have been successfully employed. Protection of the 3′- and 5′-hydroxyl groups of iodouridine is required in order to obtain good yields when the coupling process is carried out on 1,3-dienes or long chain or branched non-conjugated dienes.     

Synthesis of anomerically pure vinyl sulfone-modified pent-2-enofuranosides and hex-2-enopyranosides: a group of highly reactive Michael acceptors for accessing carbohydrate based synthons

Syntheses of the benzyl or the trityl protected α- and β-anomers of vinyl sulfone-modified pent-2-enofuranosides have been initiated by the ring opening of the suitably masked methyl α-lyxofuranosyl-epoxide or methyl β-ribofuranosyl-epoxide or by the nucleophilic displacement of the leaving groups in benzyl protected 3-O-tosyl xylofuranoside and 3-O-mesyl ribofuranoside by p-thiocresol. In case of the latter set of starting materials, α- and β-methyl glycosides formed in almost equal ratio only from the derivatives of d-xylose. For the synthesis of α- and β-anomers of vinyl sulfone-modified hex-2-enopyranosides, a d-glucose derivative was selected over a d-allose derivative as the starting material because the former almost exclusively produced the required methyl pyranosides whereas the latter produced a mixture. All sulfides were converted to vinyl sulfone-modified carbohydrates by the sequential application of oxidation, mesylation and base induced elimination reactions.     

Diastereoselective addition of planar N-heterocycles to vinyl sulfone-modified carbohydrates: a new route to isonucleosides

Michael-type addition reactions of planar N-heterocycles at the C-2 positions of vinyl sulfone-modified carbohydrates provide an efficient and general route for the carbon-N-heterocycle bond formation. Therefore, the addition pattern of planar heterocycles, such as imidazole, triazole, thymine, and adenine to 3-C-phenylsulfonyl-hex-2-enopyranosides (1α/1β) and 3-C-p-toluenesulfonyl-pent-2-enofuranosides (2α/2β) was studied for developing a general methodology for the synthesis of new classes of isonucleosides possessing a carbon-N-heterocycle linkage at C-2 positions of furanosyl and pyranosyl sugars. To a great extent, the anomeric configurations of the starting vinyl sulfones play crucial roles in deciding the diastereoselectivity of addition of heterocycles. However, the trityl protected 3-C-p-toluenesulfonyl-hex-2-enopyranosides (33α/33β) were judged to be more practical starting materials for desulfonylation and deprotection for the synthesis of a new class of thymine and adenine deoxyisonucleosides.     

Diastereoselective addition of amines to vinyl sulfone modified carbohydrates: a highly flexible methodology for the synthesis of new classes of deoxyaminosugars

Methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-phenylsulfonyl-alpha- D-erythro-hex-2-enopyranoside (5 alpha) and methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-phenylsulfonyl- beta-D-erythro-hex-2-enopyranoside (5 beta) have been subjected to Michael addition reaction with various amines to develop a new methodology for the synthesis of new classes of aminosugars. Compound 5 alpha reacted with primary amines to generate gluco- derivatives, but secondary amines produced both gluco- (major) and manno- (minor) isomers. Compound 5 beta, on the other hand, produced only gluco- isomers with both primary and secondary amines. The stereochemical course of addition of some of the amines to 5 alpha and 5 beta are significantly different from that of the addition of amines to 3-nitroenopyranoses. The present route to the syntheses of various aminosugars with gluco- configurations from 5 alpha and 5 beta constitutes a novel method for the introduction of N-monoalkylated and N,N-dialkylated amines to the C-2 carbon of pyranoses in equatorial configurations.     

Stereoselective |2+2| photocycloaddition of chiral 2(5H)-furanones to alkenes

The steric and stereoelectronic dependence of the diastereoselectivity in the photochemical |2+2| cycloaddition of chiral 2(5H)-furanones to alkenes is investigated to prepare eventually cyclobutanic natural products. It is shown that the alkenes approach to different chiral 5-substituted 2(5H)-furanones mainly by the less hindered side.     

Versatile routes to C-2- and C-6-functionalized glucose derivatives of iminodiacetic acid

A series of novel d-glucose derivatives, functionalized at the C-2 or the C-6 position with an iminodiacetic acid moiety for transition-metal complexation, has been prepared. The sugar and the metal-chelating parts are separated by either propyl or octyl chains and were introduced by the reaction of bromoalkylamine. Either N-1-Boc-3-bromopropylamine (17) or N-(8-bromooctyl)phthalimide (19) reacted with methyl 3,5,6-tri-O-benzyl-alpha-beta-d-glucofuranoside (4) (C-2 position) and 1,2:3,5-(O-methylene)-alpha-d-glucose (11) (C-6 position), respectively, in the presence of sodium hydride in DMF at room temperature, affording the desired intermediates. For aminopropyl derivatives, yields varied between 57% and 65%, and for aminooctyl derivatives, yields varied between 40% and 71%. After deprotection of the amine functionality, the metal chelate was built up by dialkylation (6a-c and 13a,b) with methyl bromoacetate in the presence of triethylamine under reflux in THF. Yields varied between 56% and 69% for the glucose modified at the C-2 position and between 58% and 62% for the one modified at the C-6 position. All compounds were characterized by 1H or 13C NMR or both, IR, and mass spectroscopy. Final products were isolated as a mixture of alpha and beta anomers.     

A C-13 study of the reaction of 2,4,6-triarylpyrylium cations with amines

The reaction of primary and secondary amines with 2,4,6-triarylpyryliums is shown by C-13 NMR to proceed by fast ring opening to a vinylogous amide; in the case of primary amines this closes slowly to a pyridinium salt. The reaction in DMSO gives the pyridinium salt quantitatively when 2 moles of amines are used, with less amine significant quantities of a diketone intermediate are produced which results in slower conversion.     

Free radical addition of trichloromethyl to caffeine access to C-8 polyhalogenoalkane derivatives and to unexpected 5-trichloromethyl-1,3,7 trimethyl-5,7-dihydrouric acid

The “Electrophilic” trichloromethyl radical was introduced directly into the model purine compound, caffeine, leading to products 2 and 3 (the former being smoothly converted to the corresponding carboxy ester derivative) and to the unexpected C-5 substituted title compound 4.     

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.     

Enantioselective conjugate addition of nitro compounds to α,β-unsaturated ketones: an experimental and computational study

A series of chiral thioureas derived from easily available diamines, prepared from α-amino acids, have been tested as catalysts in the enantioselective Michael additions of nitroalkanes to α,β-unsaturated ketones. The best results are obtained with the bifunctional catalyst prepared from L-valine. This thiourea promotes the reaction with high enantioselectivities and chemical yields for aryl/vinyl ketones, but the enantiomeric ratio for alkyl/vinyl derivatives is very modest. The addition of substituted nitromethanes led to the corresponding adducts with excellent enantioselectivity but very poor diastereoselectivity. Evidence for the isomerization of the addition products has been obtained from the reaction of chalcone with [D(3)]nitromethane, which shows that the final addition products epimerize under the reaction conditions. The epimerization explains the low diastereoselectivity observed in the formation of adducts with two adjacent tertiary stereocenters. Density functional studies of the transition structures corresponding to two alternative activation modes of the nitroalkanes and α,β-unsaturated ketones by the bifunctional organocatalyst have been carried out at the B3LYP/3-21G* level. The computations are consistent with a reaction model involving the Michael addition of the thiourea-activated nitronate to the ketone activated by the protonated amine of the organocatalyst. The enantioselectivities predicted by the computations are consistent with the experimental values obtained for aryl- and alkyl-substituted α,β-unsaturated ketones.     

Factors affecting the efficiency and stereoselectivity of α-amino acid synthesis by the Petasis reaction

The use of chiral secondary amines containing only one branched substituent has been shown to give optimal yields and stereoselectivities in the preparation of α-amino acids using the Petasis reaction. While the use of chiral primary amines generally gives products in low to moderate diastereoselectivity, chiral secondary amines generally give products in >95:5 diastereoselectivity. Additionally, the use of amines with two chiral (and by definition, branched) N-alkyl substituents results in significantly reduced yields with respect to to secondary amines with one or no branched N-alkyl substituents.     

Stereochemistry of the Palladium(II) Promoted Carbocyclization of Hex-5-Enopyranosides

Abstract

Palladium(II) promoted carbocyclization of hex-5-enopyranosides proceeds with high stereoselectivity, but accompanying elimination is observed when the substituent is an ester on C-3.     

Modular Synthesis of 1,2-Diamine Derivatives via Palladium-Catalyzed Aerobic Oxidative Cyclization of Allylic Sulfamides

Allylic sulfamides undergo efficient aerobic oxidative cyclization at room temperature, mediated by a new Pd catalyst system consisting of 5% Pd(TFA)(2)/10% DMSO in THF. The synthetic utility of these reactions is enhanced by several features: (1) the sulfamide substrates are accessible in multi-gram scale from the corresponding allylic and primary amines, (2) the cyclic sulfamide products are readily converted to the corresponding 1,2-diamines upon treatment with LiAlH(4), and (3) substrates derived from chiral allylic amines cyclize with very high levels of diastereoselectivity.     

Origin of diastereocontrol in the oxy-Michael reactions of delta-lactol anions: a computational and experimental study

The diastereoselectivity in the alkylation and Michael addition of "naked" 6-substituted delta-lactolates has been studied by density functional (B3LYP) calculations with ab initio (MP2) energy refinements. The resulting proposed model for the origins of stereocontrol in this reaction has been tested by experiment. The reactions lead to a high cis diastereoselectivity across the THP ring due to the preference for both the alkoxide and the 6-substituent to sit equatorial in the alkylation transition structure. In the oxy-Michael addition of these lactolates to beta-substituted nitroolefins, we propose that the high diastereoselectivity beta- to the nitro group is a result of a combination of steric, stereoelectronic and solvation factors.     

Diastereoselective synthesis of pyrrolidines via the Yb(OTf)3 catalyzed three-component reaction of aldehydes, amines, and 1,1-cyclopropanediesters

[Chemical reaction: see text] Aldimines, generated in situ by the reaction of primary amines or anilines with aldehydes, undergo smooth reaction with various 1,1-cyclopropanediesters in the presence of catalytic Yb(OTf)3. The products are pyrrolidines in which the major diastereomer bears a cis relationship between substituents at the 2- and 5-positions. In most cases the diastereoselectivity is greater than 10:1.