Highly alpha- and beta-selective radical C-glycosylation reactions using a controlling anomeric effect based on the conformational restriction strategy. A study on the conformation-anomeric effect-stereoselectivity relationship in anomeric radical reactions.

We hypothesized that, because the stereoselectivity of anomeric radical reactions was significantly influenced by the anomeric effect, which can be controlled by restricting the conformation of the radical intermediate, the proper conformational restriction of the pyranose ring of the substrates would therefore make highly alpha- and beta-stereoselective anomeric radical reactions possible. Thus, the conformationally restricted 1-phenylseleno-D-xylose derivatives 9 and 10, restricted in a (4)C(1)-conformation, and 11 and 12, restricted in a (1)C(4)-conformation, were designed and synthesized by introducing the proper protecting groups on the hydroxyl groups on the pyranose ring as model substrates for the anomeric radical reactions. The radical deuterations with Bu(3)SnD and the C-glycosylation with Bu(3)SnCH(2)CH [double bond] CH(2) or CH(2) [double bond] CHCN, using the (4)C(1)-restricted substrates 9 and 10, afforded the corresponding alpha-products (alpha/beta = 97:3-85:15) highly stereoselectively, whereas the (1)C(4)-restricted substrates 11 and 12 selectively gave the beta-products (alpha/beta = 1:99-0:100). Thus, stereoselectivity was significantly increased by conformational restriction and was completely inverted by changing the substrate conformation from the (4)C(1)-form into the (1)C(4)-form. Ab initio calculations suggested that the radical intermediates produced from these substrates possessed the typical (4)C(1)- or (1)C(4)-conformation, which was similar to that of the substrates, and that the anomeric effect in these conformations would be the factor controlling the transition state of the reaction. Therefore, the highly alpha- and beta-selective reactions would occur because of the anomeric effect, which could be manipulated by conformational restriction of the substrates, as expected. This would be the first radical C-glycosylation reaction to provide both alpha- and beta-C-glycosides highly stereoselectively.     

An efficient synthesis of beta-C-glycosides based on the conformational restriction strategy: Lewis acid promoted silane reduction of the anomeric position with complete stereoselectivity

[reaction: see text] The reduction of glyconolactols having an anomeric carbon substituent by Et(3)SiH/TMSOTf proceeded with complete stereoselectivity to produce the corresponding beta-C-glycosides when the substrates were conformationally restricted in the (4)C(1)-chair form by a 3,4-O-cyclic diketal or a 4,6-O-benzylidene protecting group. Thus, the efficient construction of beta-C-glycosides was achieved on the basis of the conformation restriction strategy.     

Synthesis of 3,7-anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate as an IP(3) receptor ligand using a radical cyclization reaction with a vinylsilyl tether as the key step. Conformational restriction strategy using steric repulsion between adjacent bulky protecting groups on a pyranose ring

3,7-Anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate (5) was designed as a novel IP(3)-receptor ligand having a C-glycosidic structure and was synthesized via a radical cyclization reaction with a temporary connecting vinylsilyl tether as the key step. The phenyl 2-O-dimethylvinylsilyl-3,4, 6-tri-O-benzyl-1-seleno-beta-D-glucopyranoside (7), in the usual (4)C(1)-conformation, was successively treated with Bu(3)SnH/AIBN and under Tamao oxidation conditions to give a mixture of five C-glycosidic products. On the other hand, similar successive treatment of the corresponding 3,4-di-O-TBS-protected substrates 13 and 24, which were in an unusual (1)C(4)-conformaion due to the steric repulsion between the bulky silyl protecting groups, gave the desired 1alpha-C-glycosides 18 and 25, respectively, as the major products. Thus, the course of the radical cyclization was effectively controlled by a change in the conformation of the pyranose ring into a (1)C(4)-form due to steric repulsion between the adjacent bulky TBS-protecting groups at the 3- and 4-hydroxyl groups. From 25, the target 5 was synthesized via phosphorylation of the hydroxyls by the phosphoramidite method. The C-glycoside trisphosphate 5 has significant binding affinity for IP(3) receptor of calf cerebella.     

Alpha- and beta-thujone radical rearrangements and isomerizations. A new radical clock

Radical clocks have been extensively used in chemical and biochemical mechanistic studies. The C4 radicals of alpha- and beta-thujone can undergo two distinct rearrangement reactions that could, in principle, serve as simultaneous but independent radical clocks. We have therefore generated these C4 radicals by photolysis of the corresponding N-hydroxypyridine-2-thione ester precursors and have investigated their fates and lifetimes. Photolysis of either alpha- or beta-thujone generates the same 6:100 mixture of alpha- and beta-thujone when the radicals are quenched by thiophenol. Hydrogen atom transfer from thiophenol to the radical thus occurs preferentially from the less sterically hindered alpha-face to give beta-thujone. The third product formed in the photolysis via opening of the cyclopropyl ring is 2-methyl-5-isopropylcyclopent-2-enone. The ratio of ring opened to unopened products gives very similar values of kralpha = 4.4 x 10(7) s(-1) and krbeta = 1.0 x 10(8) s(-1) for ring opening of the radicals generated from alpha- and beta-thujone, respectively. If the C4 cation rather than radical is generated, it is converted to carvacrol, a phenol that is not obtained in the radical reactions. Thujone therefore differentiates between radical and cation pathways and provides a measure of the radical lifetime.     

Regio- and stereoselective synthesis of tetrahydroindolysines,tetrahydropyridin-6-olates,and cyclopropanes from pyridinium ylides and unsaturated nitriles

The regio- and stereoselectivity of the reactions of pyridinium ylides with unsaturated nitriles are dependent on the electronic nature of the substituent in position 3 of the pyridine ring. The reaction of 1-carbamoylmethylide-3-cyanopyridinium with arylmethylenemalononitriles or arylmethylcyanoacetic esters proceeds regio- and stereoselectively with the formation of substituted 2-aryl-3-carbamoyl-6-cyano-2,3-trans- or 2,3-cis-1,2,3,8a-tetrahydroindolysines. The condensation of pyridinium 1-carbamoylmethylide with arylmethylenecyanoacetic ether leads to 4-aryl-2-oxo-3-(1-pyridinio)-5-cyano-3,4-trans-1,2,3,4-tetrahydropyridin-6-olates. The reaction of pyridinium (3-methylpyridinium) 1-carbamoylmethylide with arylmethylenemalononitriles results in the formation of 2-aryl-1,1-dicyano-3-carbamoyl-3-(1-pyridinio)- or (3-methyl-1-pyridinio)-1-propanides, which undergo stereoselective 1,3-transelimination with the formation of 3-aryl-1,1-dicyano-2-carbamoylcyclopropanes.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 146–155. January, 1991.     

Hydrogen-bonding catalysis and inhibition by simple solvents in the stereoselective kinetic epoxide-opening spirocyclization of glycal epoxides to form spiroketals

Mechanistic investigations of a MeOH-induced kinetic epoxide-opening spirocyclization of glycal epoxides have revealed dramatic, specific roles for simple solvents in hydrogen-bonding catalysis of this reaction to form spiroketal products stereoselectively with inversion of configuration at the anomeric carbon. A series of electronically tuned C1-aryl glycal epoxides was used to study the mechanism of this reaction based on differential reaction rates and inherent preferences for S(N)2 versus S(N)1 reaction manifolds. Hammett analysis of reaction kinetics with these substrates is consistent with an S(N)2 or S(N)2-like mechanism (ρ = -1.3 vs ρ = -5.1 for corresponding S(N)1 reactions of these substrates). Notably, the spirocyclization reaction is second-order dependent on MeOH, and the glycal ring oxygen is required for second-order MeOH catalysis. However, acetone cosolvent is a first-order inhibitor of the reaction. A transition state consistent with the experimental data is proposed in which one equivalent of MeOH activates the epoxide electrophile via a hydrogen bond while a second equivalent of MeOH chelates the side-chain nucleophile and glycal ring oxygen. A paradoxical previous observation that decreased MeOH concentration leads to increased competing intermolecular methyl glycoside formation is resolved by the finding that this side reaction is only first-order dependent on MeOH. This study highlights the unusual abilities of simple solvents to act as hydrogen-bonding catalysts and inhibitors in epoxide-opening reactions, providing both stereoselectivity and discrimination between competing reaction manifolds. This spirocyclization reaction provides efficient, stereocontrolled access to spiroketals that are key structural motifs in natural products.     

Optimising stereoselectivity in intramolecular Diels-Alder reactions of pentadienyl acrylates: synthetic and computational investigations into the "steric directing group" approach

Experimental conditions for the intramolecular cycloaddition of four related pentadienyl acrylates 3, 4, 5 and 6 are reported. In contrast with several previous reports, pentadienyl acrylates do undergo synthetically useful intramolecular Diels-Alder reactions: 3, 4, 5 and 6 cyclise at reasonable rates at temperatures of 132-180 degrees C at atmospheric pressure in moderate to good yields. The stereochemical outcome of each of these reactions was accurately measured and the results are in good agreement with transition structure populations predicted using B3LYP/6-31+G(d) theory. The parent system 3 cyclises with moderate endo selectivity; the presence of either a C5-methyl substituent or a C3-bromine atom results in a slight shift towards the trans-fused exo stereoisomer but--overall--a less selective reaction. The presence of both C3-Br and C5-CH3 substituents results in a marked improvement in stereoselectivity with the exo,lk-product predominating. Interpretation of B3LYP/6-31+G(d) transition structures allows insights into the improvement in stereoselectivity obtained by incorporating a removable "steric directing group" into a 5-methyl-1,3,8-nonatriene precursor.     

Highly stereoselective grignard addition to cis-substituted C-cyclopropylaldonitrones. The bisected s-trans transition state can be stabilized effectively by the Lewis acid-coordination

We previously found that Grignard addition to a C-cyclopropylaldonitrone, C-[cis-2-(N,N-diethylcarbamoyl)-trans-2-phenylcyclopropyl]-N-benzylaldonitrone (1), stereoselectively gave the anti-product 3, in which the stereoselectivity was particularly high when MgBr(2) was the additive. In this study, the reaction pathway was investigated in detail. The stereoselective addition was initially thought to occur via either a 1,5-chelation-controlled or a bisected s-trans conformation-controlled pathway. However, Grignard addition to a nonchelating silyl ether-type substrate, C-[cis-2-(tert-butyldiphenylsilyloxymethyl)-trans-2-phenylcyclopropyl]-N-benzylaldonitrone (7), also gave the anti-product 9 with high stereoselectivity suggesting that chelation is not important in the reaction. Theoretical calculations of C-cyclopropylaldonitrones showed that the coordination of Mg(2+) at the nitrone oxygen significantly stabilizes the bisected s-trans conformer due to the effective hyperconjugation between the pi* of the nitrone C=N bond and the electron-donating cyclopropane orbitals. This kind of orbital interaction is able to stabilize the transition state of the nucleophilic addition and is maximized in the bisected conformation, in which the orbitals of the forming bond and the cyclopropane C-C bond are in an almost planar arrangement. Thus, the high stereoselectivity can be explained by nucleophilic attack on the less hindered side of the C=N bond of the substrates in the Mg(2+)-coordinated bisected s-trans conformation.     

Cyclobutanone mimics of penicillins: effects of substitution on conformation and hemiketal stability

The tendency for carbocyclic analogues of penicillins to undergo hydrate and hemiketal formation is central to their ability to function as beta-lactamase inhibitors. 2-Thiabicyclo[3.2.0]heptan-6-one-4-carboxylates with alkoxy functionality at C3 have been prepared through two complementary diastereoselective substitution reactions following a highly stereoselective chlorination with sulfuryl chloride. We have found that carbocyclic analogues with 3beta substituents favor an endo envelope conformation in solution, the solid state, and the gas phase, whereas those with 3alpha substituents adopt an exo envelope. Evidence from X-ray crystal structures and ab initio calculations suggests that an anomeric effect contributes to the large conformational preference of the tetrahydrothiophene ring that favors the C3 substituent in an axial orientation. In addition, the envelope conformation of the bicycle, which is determined by the stereochemistry of the C3 substituent, has a dramatic effect on the ability of the cyclobutanone to undergo hemiketal formation in methanol-d4.     

Stereoelectronic factors in the stereoselective epoxidation of glycals and 4-deoxypentenosides

Glycals and 4-deoxypentenosides (4-DPs), unsaturated pyranosides with similar structures and reactivity profiles, can exhibit a high degree of stereoselectivity upon epoxidation with dimethyldioxirane (DMDO). In most cases, the glycals and their corresponding 4-DP isosteres share the same facioselectivity, implying that the pyran substituents are largely responsible for the stereodirecting effect. Fully substituted dihydropyrans are subject to a "majority rule", in which the epoxidation is directed toward the face opposite to two of the three groups. Removing one of the substituents has a variable effect on the epoxidation outcome, depending on its position and also on the relative stereochemistry of the remaining two groups. Overall, we observe that the greatest loss in facioselectivity for glycals and 4-DPs is caused by removal of the C3 oxygen, followed by the C5/anomeric substituent, and least of all by the C4/C2 oxygen. DFT calculations based on polarized-π frontier molecular orbital (PPFMO) theory support a stereoelectronic role for the oxygen substituents in 4-DP facioselectivity, but less clearly so in the case of glycals. We conclude that the anomeric oxygen in 4-DPs contributes toward a stereoelectronic bias in facioselectivity whereas the C5 alkoxymethyl in glycals imparts a steric bias, which at times can compete with the stereodirecting effects from the other oxygen substituents.     

Synthesis of Conformationally Restricted Carbocyclic Nucleosides: The Role of the O(4′)-Atom in the Key Hydration Step of Adenosine Deaminase

Conformationally restricted carbocyclic nucleosides with either a northern(N)-type conformation, i.e., N-type 2′-deoxy-methanocarba-adenosine 8 ((N)MCdAdo), or a southern(S)-type conformation, i.e. S-type 2′-deoxy-methanocarba-adenosine 9 , ((S)MCdAdo), were used as substrates for adenosine deaminase (ADA) to assess the enzyme's preference for a fixed conformation relative to the flexible conformation represented by the carbocyclic nucleoside aristeromycin ( 10 ). Further comparison between the rates of deamination of these compounds with those of the two natural substrates adenosine (Ado; 1 ) and 2′-deoxyadenosine (dAdo; 2 ), as well as with that of the conformationally locked nucleoside LNA-Ado ( 11 ), which, like the natural substrates, has a furanose O(4′) atom, helped differentiate between the roles of the O(4′) anomeric effect and sugar conformation in controlling the rates of deamination by ADA. Differences in rates of deamination as large as 10000 can be attributed to the combined effect of the O(4′) atom and the enzyme's preference for an N-type conformation. The hypothesis proposed is that ADA's preference for N-type substrates is not arbitrary; it is rather the direct consequence of the conformationally dependent O(4′) anomeric effect, which is more efficient in N-type conformers in promoting the formation of a covalent hydrate at the active site of the enzyme. The formation of a covalent hydrate at the active site of ADA precedes deamination. A new and efficient synthesis of the important carbobicyclic template 14a , a useful intermediate for the synthesis of (N)MCdAdo ( 8 ) and other conformationally restricted nucleosides, is also reported.     

High 1,3-trans stereoselectivity in nucleophilic substitution at the anomeric position and β-fragmentation of the primary alkoxyl radical in 3-amino-3-deoxy-ribofuranose derivatives: application to the synthesis of 2-epi-(-)-jaspine B

The high inverse stereoselectivity in the nucleophilic substitution at the anomeric position of 3-amino-3-deoxy-ribofuranose derivatives is reported. This unprecedented stereoselectivity is explained in terms of preferential nucleophilic attack on the "inside face" of the respective five-membered ring oxocarbenium ion that orients pseudoequatorially to the benzylamine group placed at the C-3 position. In addition, an unusual β-fragmentation of a primary alkoxyl radical generated from its corresponding N-phthalimide derivative was achieved, and thus taking advantages of both reactions, the total synthesis of 2-epi-(-)-jaspine B was completed.     

Zirconium complexes incorporated with asymmetrical tridentate pincer type mono- and di-anionic pyrrolyl ligands: mechanism and reactivity as catalytic precursors

The reactions of Zr(NR(2))(4) (1, R = Me; 2, R = Et) with an asymmetrical tridentate pincer type pyrrole ligand precursor [C(4)H(2)NH(2-CH(2)NH(t)Bu)(5-CH(2)NMe(2))] and treatment of the derivatives with either PhNCS or PhNCO have been carried out and characterized. Reacting Zr(NR(2))(4) (1, R = Me; 2, R = Et) with [C(4)H(2)NH(2-CH(2)NH(t)Bu)(5-CH(2)NMe(2))] generates Zr[C(4)H(2)N(2-CH(2)N(t)Bu)(5-CH(2)NMe(2))](NR(2))(2) (3, R = Me; 4, R = Et) in high yield along with the elimination of 2 equiv of dimethylamine or diethylamine, respectively. Interestingly, while changing the solvent from Et(2)O to CH(2)Cl(2), the complex Zr[C(4)H(2)N(2-CH(2)N(t)Bu)(5-CH(2)NMe(2))][C(4)H(2)N(2-CH(2)NH(t)Bu)(5-CH(2)NMe(2))]Cl (5) is produced by undergoing C-Cl bond cleavage. Furthermore, reaction of either 3 or 4 with 1 or 2 equiv of PhNCS or PhNCO yields Zr[C(4)H(2)N(2-CH(2)N(t)Bu)(5-CH(2)NMe(2))](NMe(2))[PhNC(NMe(2))S] (6), Zr[C(4)H(2)N(2-CH(2)N(t)Bu)(5-CH(2)NMe(2))](NEt(2))[PhNC(NEt(2))O] (7) and Zr[C(4)H(2)N(2-CH(2)NH(t)Bu)(5-CH(2)NMe(2))][PhNC(NEt(2))O](3) (8), respectively. All the aforementioned complexes were characterized by (1)H and (13)C NMR spectrometry and the molecular structures of 5, 6, and 8 have been determined by single-crystal X-ray diffractometry. Complexes 4, 5, and 7 initiated the ethylene polymerization in the presence of MAO as the co-catalyst.     

Etudes configurationnelles et conformationnelles de quelques chlorures de désoxy-6 β-L-héxopyrannosyle chlorosulfonyles et de leurs glycosides de méthyle

A total analysis of the NMR spectra of 6-deoxy-L -hexopyranoses in the α-configuration and of the corresponding β-anomers was carried out. The parameters obtained are characteristic of a 1C (L ) chair conformation, having the anomeric substituent in an axial orientation for the methyl α-fuco-, α-rhamno- and α-chinovopyranosides and for the α-fuco- and α-rhamnopyranosyl chlorides. The structure is also of a 1C (L ) chair type for the methyl β-fuco- and β-chinovopyranosides; the geometry is the same for the β-fuco- and β-rhamnopyranosyl chlorides despite the anomeric effect of a chlorine atom. However, the NMR parameters of the β-chinovopyranosyl chloride are not explicable on the basis of a chair conformation with an equatorial chlorine or a boat structure.     

Modification of both the electrophilic center and substituents on the nonleaving group in pyridinolysis of O-4-nitrophenyl benzoate and thionobenzoates

A kinetic study is reported for reactions of 4-nitrophenyl benzoate (1c) and O-4-nitrophenyl X-substituted thionobenzoates (2a-e) with a series of pyridines in 80 mol % H2O/20 mol % dimethyl sulfoxide (DMSO) at 25.0 +/- 0.1 degrees C. O-4-Nitrophenyl thionobenzoate (2c) is more reactive than its oxygen analogue 1c toward all the pyridines studied. The Br?nsted-type plot is linear with beta(nuc)=1.06 for reactions of 1c but curved for the corresponding reactions of 2c with beta(nu)c decreasing from 1.38 to 0.38 as the pyridine basicity increases, indicating that the reaction mechanism is also influenced on changing the electrophilic center from C=O to C=S. The curvature center of the curved Br?nsted-type plots (defined as pK(a)(o)) occurs at pKa = 9.3 regardless of the electronic nature of the substituent X in the nonleaving group. The Hammett plot for reactions of 2a-e with 4-aminopyridine is nonlinear, i.e., the substrates having an electron-donating substituent exhibit negative deviations from the Hammett plot. However, the Yukawa-Tsuno plot for the same reactions exhibits good linear correlation, indicating that the negative deviations shown by these substrates arise from stabilization of the ground state through resonance interaction between the electron-donating substituent X and the C=S bond.     

Mechanistic studies on the stereoselective formation of beta-mannosides from mannosyl iodides using alpha-deuterium kinetic isotope effects

Stereoselective synthesis of beta-mannosides is one of the most challenging linkages to achieve in carbohydrate chemistry. Both the anomeric effect and the C2 axial substituent favor the formation of the axial glycoside (alpha-product). Herein, we describe mechanistic studies on the beta-selective glycosidation of trimethylene oxide (TMO) using mannosyl iodides. Density functional calculations (at the B3LYP/6-31+G(d,p):LANL2DZ level) suggest that formation of both alpha- and beta-mannosides involve loose S(N)2-like transition-state structures with significant oxacarbenium character, although the transition structure for formation of the alpha-mannoside is significantly looser. alpha-Deuterium kinetic isotope effects (alpha-DKIEs) based upon these computed transition state geometries match reasonably well with the experimentally measured values: 1.16 +/- 0.02 for the beta-linkage (computed to be 1.15) and 1.19 +/- 0.05, see table 2 for the alpha-analogue (computed to be 1.26). Since it was unclear if beta-selectivity resulted from a conformational constraint induced by the anomeric iodide, a 4,6-O-benzylidine acetal was used to lock the iodide into a chairlike conformation. Both experiments and calculations on this analogue suggest that it does not mirror the behavior of mannosyl iodides lacking bridging acetal protecting groups.     

A new reaction manifold for the Barton radical intermediates: synthesis of N-heterocyclic furanosides and pyranosides via the formation of the C(1)-C(2) bond

The first radical intermediate in the thiourethane-mediated deoxygenation of an alcohol (Barton-McCombie reaction) can participate in an exo-hex-5-enyl- or exo-hept-6-enyl-type radical cyclization when a suitable radical acceptor (e.g., alpha,beta-unsaturated ester, oxime ether, or hydrazone) is appropriately placed. Carbohydrate-derived imidazolyl and triazolyl thiourethanes with such acceptors, upon addition to excess of a good hydride donor (reverse addition), undergo efficient cyclization reactions to give N-heterocyclic furanosides, and, surprisingly even N-pyranosides. Depending on the acceptor, glycosides with either a C(2)()-amino or a C(2)()-carbon substituent are formed.     

Aerobic oxidation of benzyl alcohols catalyzed by aryl substituted N-hydroxyphthalimides. Possible involvement of a charge-transfer complex

A series of aryl-substituted N-hydroxyphthalimides (X-NHPIs) containing either electron-withdrawing groups (4-CH(3)OCO, 3-F) or electron-donating groups (4-CH(3), 4-CH(3)O, 3-CH(3)O, 3,6-(CH(3)O)(2)) have been used as catalysts in the aerobic oxidation of primary and secondary benzylic alcohols. The selective formation of aromatic aldehydes was observed in the oxidation of primary alcohols; aromatic ketones were the exclusive products in the oxidation of secondary alcohols. O-H bond dissociation enthalpies (BDEs) of X-NHPIs have been determined by using the EPR radical equilibration technique. BDEs increase with increasing the electron-withdrawing properties of the aryl substituent. Kinetic isotope effect studies and the increase of the substrate oxidation rate by increasing the electron-withdrawing power of the NHPI aryl substituent indicate a rate-determining benzylic hydrogen atom transfer (HAT) from the alcohol to the aryl-substituted phthalimide-N-oxyl radical (X-PINO). Besides enthalpic effects, polar effects also play a role in the HAT process, as shown by the negative rho values of the Hammett correlation with sigma(+) and by the decrease of the rho values (from -0.54 to -0.70) by increasing the electron-withdrawing properties of the NHPI aryl substituent. The relative reactivity of 3-CH(3)O-C(6)H(4)CH(2)OH and 3,4-(CH(3)O)(2)-C(6)H(3)CH(2)OH, which is higher than expected on the basis of the sigma(+) values, the small values of relative reactivity of primary vs secondary benzylic alcohols, and the decrease of the rho values by increasing the electron-withdrawing properties of the NHPI aryl substituent, suggest that the HAT process takes place inside a charge-transfer (CT) complex formed by the X-PINO and the benzylic alcohol.     

Substituent effects on the SmI2/Pd(0)-promoted carbohydrate ring-contraction of 5-alkynylpyranosides

The effect of substituents on the reactivity and stereoselectivity of the SmI₂/Pd(0)-promoted ring-contraction of 5-alkynylpyranosides has been examined using substrates substituted only at selected positions. While formation of 2-ethynylcyclopentanols takes place efficiently, an internal alkyne did not afford the expected product. The presence of peripheral alkoxy substituents leads to variable stereoselectivities that depend on the number and orientation of such groups. Thus, an isolated OBn substituent at C(3) (carbohydrate numbering) exerts a significant stereochemical control while additional substitution with the same group at C(4) either enhances or drastically reduces stereoselectivity depending on its orientation (α or β, respectively).     

Stereoselective Triplet‐Sensitised Radical Reactions of Furanone Derivatives

The stereo‐ and regioselectivity of triplet‐sensitised radical reactions of furanone derivatives have been investigated. Furanones 7 a , b were excited to the ³ππ* state by triplet energy transfer from acetone. Intramolecular hydrogen abstraction then occurred such that hydrogen was transferred from the tetrahydropyran to the β position of the furanone moiety. Radical combination of the tetrahydropyranyl and the oxoallyl radicals led to the final products 8 a , b . In the intramolecular reaction, overall, a pyranyl group adds to the α position of the furanone. The effect of conformation was first investigated with compounds 9 a , b carrying an additional substituent on the tether between the furanone and pyranyl moiety. Further information on the effect of conformation and the relative configuration at the pyranyl anomeric centre and the furanone moiety was obtained from the transformations of the glucose derivatives 12 , 14 , 17 and 18 . Radical abstraction occurred at the anomeric centre and at the 5′‐position of the glucosyl moiety. Computational studies of the hydrogen‐abstraction step were carried out with model structures. The activation barriers of this step for different stereoisomers and the abstraction at the anomeric centre and at the 6‘‐position of the tetrahydropyranyl moiety were calculated. The results of this investigation are in accordance with experimental observations. Furthermore, they reveal that the reactivity and regioselectivity are mainly determined in the hydrogen‐abstraction step. Intramolecular hydrogen abstraction (almost simultaneous electron and proton transfer) in ³ππ* excited furanones only takes place under restricted structural conditions in a limited number of conformations that are defined by the relative configuration of the substrates. It is observed that in the biradical intermediate, back‐hydrogen transfer occurs leading to the starting compound. In the case of glucose derivatives, this reaction led to epimerisation at the anomeric centre.