the influence of protecting 
 groups on the reactivity and selectivity 
 of glycosyl donors is a widely recognized and exploited phenomenon . the corresponding influence of protecting groups on the anomeric 
 equilibrium , while evident for many years , is less widely studied and exploited . recent examples of the latter 
 include the recognition that 2n,3o - oxazolidinones both facilitate anomerization in the 2-amino-2-deoxyhexopyranosides 
 and stabilize the axial over the equatorial anomer , with similar effects being apparent in hexopyranosides carrying 
 a 2,3-o - cyclic carbonate group , and the realization that cyclic 4,6-o - acetals modulate 
 the anomeric effect in the hexopyranoses . our interest in the use of the n - acetyl-4o,5n - oxazolidinone protected 
 sialyl donors , and their n - desacetyl 
 counterparts , which have emerged as some of 
 the most powerful and equatorially selective systems for the preparation 
 of sialyl o - glycosides , as well as their c- and s - counterparts , prompted us 
 to examine the effect of these systems on the anomeric equilibrium 
 of sialyl glycosides . the magnitude of the anomeric effect is typically 
 assessed either by mutarotation of anomeric hemiacetals or by the 
 brnsted or lewis acid - mediated equilibration of glycosides , 
 and such methods have been used to determine the position of the anomeric 
 equilibrium in both n - acetyl neuraminic acid itself 
 and its methyl glycoside , leading to the conclusion that the axial glycoside is significantly 
 more strongly favored in the sialic acids ( figure 1 ) than in glucose and that mutarotation of the hemiacetal 
 takes place via a ring - opening mechanism . the attempted synthesis of a n - acetyl-4o,5n - protected sialyl 
 hemiacetal 2 by hydrolysis of the corresponding thioglycoside 3 resulted in the formation of a complex mixture of the two 
 anomers 
 of 2 and of the acyclic form 4 , and its 
 hydrate 5 , as determined by nmr spectroscopy , in which 
 the latter two species predominated ( figure 2 ) . the complexity of the spectra together with the predominance of 
 the open - chain forms revealed the strain placed on the pyranose forms 
 by the presence of the trans - fused oxazolidinone 
 ring , even if no distortion of the pyranose ring is evident from x - ray 
 structures , and precluded use of the standard 
 methods in this investigation . compounds employed in and arising from 
 the mutarotation of an oxazolidinone - protected 
 sialose derivative . accordingly , we turned 
 our attention to the use of neutral methods 
 for the equilibration of sialic acid glycosides such as would not 
 involve the intermediacy of the anomeric hemiacetal and would be compatible 
 with the readily cleaved activated oxazolidinone 
 ring . precedent for the equilibration of anomeric stereochemistry 
 through the reversible homolytic cleavage and reformation of anomeric 
 c  h , c  co , and c  te bonds , suggested 
 that the answer might lie in radical reactions . the need to approximate 
 as closely as possible the properties of o - glycosidic 
 bonds suggested the synthesis and equilibration of o - glycosyl derivatives of sterically hindered n , n - disubstituted hydroxylamines by the fischer albeit less substituted than 
 the systems required for the radical equilibration process , glycosyl 
 hydroxylamines are found in nature in the enediyne antibiotics calicheamicin 
 16 and esperamicin 7 , and simple hydroxylamines have been employed as glycosidic bond 
 surrogates in neoglycoconjugates ( figure 3 ) . moreover , the distinct conformational preferences of the o - glycosyl hydroxylamine linkage have been advanced as a 
 design element used by nature to assist in the binding of calicheamicin 
 to the minor groove of dna.o - glycosyl hydroxylamines have been identified as metabolites of various 
 drugs , including glucosides and glucuronides 
 of the antioxidant 2,2,6,6-tetramethylpiperidin-1-ol . natural products featuring the o - glycosyl hydroxylamine 
 moiety . in a preliminary communication 
 we established the concept with 
 sialyl glycosides of 2,2,4,4-tetramethylpiperidin-1-ol in a single 
 solvent . in this article we report in 
 full on the synthesis of the o - sialyl glycosides 
 of two further hydroxylamines of differing steric bulk and conduct 
 equilibration studies in three solvents spanning a broad range of 
 polarities . the influence of the sialyl protecting groups , solvent 
 polarity , and hydroxylamine steric bulk on the thermal equilibration 
 reactions of the sialyl hydroxylamines are presented and afford insight 
 into the influence of the trans - fused oxazolidinone 
 group in sialic acid chemistry . the lack of kinetic selectivity of 
 sialyl anomeric radicals is discussed from the viewpoint of their 
 conformation , which is based on literature electron spin resonance 
 data of cognate radicals . despite the presence of o - glycosyl hydroxylamines 
 in various enediyne antibiotics and their use in neoglycoconjugates , 
 literature methods for their synthesis are limited to the glycosylation 
 of ( i ) various n - acylated hydroxylamines , e.g. , n - hydroxyphthalimide and n - carboethoxy 
 hydroxylamine , ( ii ) oximes , and ( iii ) nitrones , each with subsequent manipulation of the functionality at nitrogen . these methods are , however , not suitable for the synthesis of the 
 sterically hindered o - glycosyl n , n - dialkylhydroxylamines required for this investigation , 
 and we therefore turned to the design of alternative routes . a brief 
 investigation of the direct glycosylation of n - hydroxy-2,2,6,6-tetramethylpiperidine 
 with efficient sialyl donors such as developed previously in our laboratory was unfruitful , perhaps for reasons of steric 
 hindrance , and we turned therefore to radical reactions and their 
 relative indifference to steric constraints . previous workers have generated sialyl anomeric radicals for the 
 purposes of c - sialoside formation by the action of 
 stannyl radicals on sialyl chlorides , but we have 
 preferred simple photolysis of a readily available s - sialyl xanthate ester 8 . we note in passing that attempted photochemical equilibration of 
 xanthate 8 resulted , in a process reminiscent of the 
 barton fortunately , 254 nm 
 photolysis of 8 through pyrex 
 in a rayonnet photoreactor in the presence of the stable nitroxyl 
 radicals tempo ( 10 ) , tmio ( 11 ) , and sg1 ( 12 ) resulted in the formation of the desired o - glycosyl hydroxylamines 1416 as 
 reported in scheme 2 . attempted application 
 of this method to dbno 13(107 ) resulted only in the formation of the glycal 9 . that 
 the photolysis of 8 can be interrupted with appropriate 
 radical traps before the formation of glycal 9 indicates 
 that it takes place via a two - step process giving an initial radical 
 pair followed by disproportionation ( scheme 1 ) . this observation , which is critical to the success of the project , 
 differs from the original conclusion of the barton and porter laboratories 
 regarding the photoelimination of thiobenzoate esters . those workers 
 preferred a concerted elimination from a photochemically excited state 
 of the thiocarbonyl ester on the basis of ( i ) the observation of a 
 short - lived transient on irradiation of the thiobenzoate , and ( ii ) 
 the inability to trap radical intermediates with ( unspecified ) radical 
 traps . we also note , however , and more 
 in line with the results observed here , that the photolysis of s - acyl xanthate esters is known to proceed with homolytic 
 scission of the s - acyl bond resulting in acyl radical 
 formation . returning to the synthesis of the o - glycosyl hydroxylamines , 
 when the photolysis of 8 was conducted in the presence 
 of tempo ( 10 ) the product 14 was obtained 
 as an approximately 1:2 mixture , favoring the isomer ( - ) with 
 the axial hydroxylamino residue , in 69% yield together with 10% of 
 the glycal . with tmio ( 11 ) , the adduct 15 was obtained in 72% yield as an approximate 1:2.2 : 
 mixture . photolysis in dichloroethane in the presence of racemic sg1 
 ( 12 ) gave only the glycal 9 , but the anomeric 
 radical could be intercepted in 45% yield when neat sg1 ( 12 equiv ) 
 was used as solvent . finally , photolysis in the presence of di(t - butyl)nitroxide in dichloroethane afforded only the glycal 9 . given the use of racemic sg1 , there are four potential 
 diastereomers of 16 , but the product was isolated as 
 a mixture of two predominant but inseparable isomers , the major one 
 of which we tentatively assign as an equatorial ( - ) adduct 
 and the minor as an axial ( - ) adduct without commenting 
 on the configuration at the stereogenic 
 center adjacent to the phosphoryl group . the anomeric stereochemistry 
 in each of the adducts 1416 is assigned 
 on the basis of the j heteronuclear coupling 
 constant between the anomeric carboxyl carbon and the axial methylene 
 proton at c3 in the pyranose ring , which is diagnostic in the sialic 
 acid glycosides . these assignments are also supported by noe measurements for the 
 axial ( - ) anomer of 14 and subsequent members 
 of the same series ( vide infra ) , which reveal the spatial proximity 
 of the axial h6 in the pyranose ring and one or more of the methyl 
 singlets in the hydroxylamine moiety . resubmission of 14 to the photolysis conditions did not result in any change in the 
 anomeric ratio consistent with the lack of a suitable chromophore , 
 and indicating the products 1416 to be kinetic mixtures . rate constants for the trapping of 
 alkyl radicals by nitroxyl radicals , while high ( 10 to 
 10 s ) , are nevertheless below the 
 diffusion controlled limit for stabilized alkyl radicals and are dependent 
 on steric bulk in both the radical and the trap . the stereoselectivities observed in the formation of 1416 therefore must factor in the inherent face 
 selectivity of the intermediate radical 18 ( figure 4 ) and the steric bulk of the trap , which according 
 to bowry and ingold , follows the trend dbno > tempo > tmio on 
 the 
 basis of kinetic trapping data ( sg1 not being included in the study ) . we conclude therefore that radical 18 shows a modest axial selectivity that can be overridden by the use 
 of the presumably more bulky trap sg1 . this modest axial selectivity 
 is consistent with the work of paulsen and matschulat , who recorded 
 an axial / equatorial trapping preference of 1.8:1 for the reaction 
 of 18 with allyltributylstannane at 60 c in thf , but not with the work of nagy and bednarski , 
 who reported an approximate axial / equatorial ratio of 1:1 for the 
 same reaction conducted at room temperature under photochemical conditions . we depict radical 18 as a 
 close to planar -radical 
 with extensive delocalization onto the carboxyl oxygen resulting in 
 two distinct conformers about the exocyclic c1c2 bond ( figure 4 ) on the basis of literature esr data for simple 
 model radicals . thus , esr studies of the tri - o - acetyl-2-deoxy-1-glucosyl 
 radical 19 show it to adopt a chair conformation with 
 an out of plane bend of 6 for the anomeric carbon consistent 
 with a radical that is 90% sp hybridized . the methoxycarbonylmethyl radical 20 is a planar 
 -radical with extensive delocalization onto the carboxyl oxygen 
 and a barrier to rotation about the ch2co2me bond of 11 kcal mol , and the methoxy(methoxycarbonyl)methyl radical 21 displays esr parameters that closely mirror those of 20 , including the hyperfine splitting ah indicative of coupling to the ester methyl hydrogens , which is diagnostic 
 of extensive delocalization . finally , 
 the close model radicals 22 and 23 also 
 show esr spectral parameters consistent with those for 20 , including hyperfine splitting by the ester methyl hydrogens and 
 two distinct rotamers about the c5co2me bond . the two radicals 22 and 23 , isomeric at 
 the -position , adopt different conformations so as in each 
 case to maximize the overlap of the -acetoxy group with the 
 singly filled orbital , a phenomenon known as quasi - homoanomeric stabilization . it follows that when the -position is unsubstituted as in 
 radicals 18 and 19 , and the constraint of 
 the quasi - homoanomeric interaction absent , the chair conformation 
 will be retained . predicted structure of the intermediate 
 radical 18 and literature structures of the model radicals 1923 with key esr parameters ( hyperfine 
 splitting constants a in mt ) . presumably , it is the close to -type , approximately 
 planar 
 structure of radical 18 and the presence of the anomeric 
 carboxyl group that accounts for the low kinetic stereoselectivities 
 in its reactions with radical traps , which contrast with the high 
 axial selectivity seen in the chemistry of simple per acetylated glycosyl 
 radicals , including 19 , and their 1-alkoxy derivatives . thus , trapping of radical 18 along the axial direction , 
 while favored on stereoelectronic grounds and leading directly to 
 the chair conformation of the product , involves a 1,3-diaxial interaction 
 between the axial h4 and h6 and the partially formed c2o bond , 
 while equatorial trapping results in 1,3-diaxial interaction of h4 
 and h6 with the fully formed c2-co2me bond albeit while 
 placing the incoming bulky hydroxylamine in the sterically more accessible 
 equatorial position ( figure 5 ) . this latter 
 mode only begins to predominate with the most bulky nitroxide trap , 
 sg1 ( 12 ) and the formation of 16 ( scheme 2 ) . a similar rationale has been previously invoked 
 for exo  endo - selectivity , 
 with competing steric interactions between a full covalent bond to 
 a substituent at the radical center and partially formed covalent 
 bond to an incoming trap for the bicyclic radical 24 . competing transition states for the trapping of radical 18 showing 1,3-diaxial interactions with h4 and h6 , and structure 
 of 
 the radical 24 . with a series of glycosyl hydroxylamines in hand , and with 
 a view 
 to examining the influence of protecting groups on the anomeric equilibrium , a set of standard protecting group manipulations were applied to 14 and 15 , as illustrated in scheme 3 , giving a number of derivatives for subsequent 
 equilibration studies . a series of equilibration 
 reactions were then conducted by heating 
 individually ( 0.050.1 m ) solutions of substances 14 , 15 , and 3033 to 
 90 c in each of deuteriobenzene , deuterio-1,2-dichloroethane , 
 and deuterioacetonitrile , with periodic monitoring by nmr spectroscopy 
 until no further change was observed ( table 1 ) . attempted equilibration of the sg1 derivative 16 resulted 
 only in the formation of the elimination product 9 , for 
 which reason , coupled with the problem of extra diastereomers arising 
 from the stereogenic center in the aglycone , the sg1 series was not 
 pursued further . a further compound , the n , n - diacetyl tempo glycoside 25 was also subjected 
 to equilibration in deuterio-1,2-dichloroethane ( table 1 ) ; however , further work with this compound was not conducted 
 in other solvents , nor was the tmio analogue prepared . the mechanism 
 of the equilibration process involves reversible homolytic scission 
 of the glycosyl - hydroxylamine c  o bond to an anomeric radical 
 and a persistent aminoxyl radical ( scheme 4 ) . ingold radical effect that the recombination is intermolecular 
 rather than intramolecular within the confines of the initial radical 
 pair . the intermolecular nature of the process enables its use in 
 combinatorial library generation , and 
 for the present purposes it was readily demonstrated by a simple crossover 
 experiment . thus , heating of 15 in the presence of an 
 equimolar amount of tempo in 1,2-dichloroethane to 90 c for 
 nine days , after which no further change was observed , resulted in 
 the formation of an approximately 1:2 mixture of 14 and 15 , both as a mixture of anomers favoring the -anomers . the predominace of the tmio sialosides 15 over the tempo 
 sialosides 14 in this equilibrated mixture indicates 
 the greater thermodynamic stability of 15 over 14 , which is consistent with the less hindered , more tied 
 back nature and therefore less persistent 
 nature of the tmio radical 11 in comparison to the tempo 
 radical 10 . successful achievement of the 
 equilibration process required rigorous 
 exclusion of oxygen , which was achieved by copious sparring with argon , 
 and possibly moisture , as with some batches of deuterioacetonitrile 
 a further type of byproduct exemplified by 34 was observed 
 ( scheme 5 ) . while this thermal oxidative decarboxylation 
 process of a sialic acid glycoside is certainly interesting in view 
 of other sialic acid decarboxylation processes , both oxidative and reductive , we have not pursed 
 it further at present , especially as it could be avoided by degassing 
 and use of fresh deuterioacetonitrile . first , as compared to sialic acid itself ( figure 1 ) and to simple methyl sialosides the o - sialyl hydroxylamines studied 
 all show an inverted preference for the equatorial over the axial 
 glycosides . second , there is a solvent effect on the position of the 
 anomeric equilibrium with the equatorial ( - ) anomers generally 
 being more highly favored in the higher polarity solvents . third , 
 the magnitude of this solvent effect is on the whole greater in the 
 tmio series ( table 1 , entries 2 , 5 , and 7 ) 
 than in the tempo series ( table 1 , entries 
 1 , 4 , and 6 ) . fourth , the anomeric ratio at equilibrium is a function 
 of the protecting groups employed with the same trends being seen 
 for the both the tempo and tmio series of compounds . the general 
 preference of the equatorial over the axial glycosides 
 seen in table 1 , which contrasts sharply with 
 the strong anomeric effect in simple sialosides , reflects the significant 
 steric bulk of the hindered hydroxylamine aglycones and the attendant 
 destabilization of the axial glycosides through classical 1,3-diaxial 
 interactions . this reversal of the anomeric preference between simple 
 sialosides and those of hindered hydroxylamines does not detract from 
 the validity of comparisons within the later series of compounds that 
 form the core of this article . the observed solvent effect , which 
 is consistent with the well - known general 
 trend whereby the anomeric effect is greatest in less polar solvents , 
 simply reflects the more polar nature of equatorial versus axial glycosides . the greater solvent dependence of the tmio series as compared to the 
 tempo series of compounds presumably arises from the more polar nature 
 of the tmio group relative to the tempo group , which is a function 
 of the presence of the electron - withdrawing arene in the tmio moiety . the most consistent trend , which holds for 
 both the tempo and tmio series of compounds and for all three solvents 
 assayed , involves the change in anomeric ratio as a function of protecting 
 groups at the o4 and n5 positions . thus , there is generally a greater 
 preference for the equatorial glycoside , or a smaller anomeric effect , 
 in the 4o,5n - oxazolidinone series 
 ( table 1 , entries 4 and 5 ) , than in the n - acetyl-4o,5n - oxazolidinone 
 series ( table 1 , entries 6 and 7 ) , which in 
 turn show a greater equatorial preference than the 4o,5n - diacetyl series ( table 1 , entries 1 and 2 ) . although less data is available , the 4o,5n,5n - triacetyl compounds 
 ( table 1 , entry 3 ) appear to fall between the 
 diacetyl and the n - acetyloxazolidinones . decreasing preference 
 for the axial ( - ) sialoside as a function 
 of protecting group . turning to the reasons underlying the general greater preference 
 for the equatorial glycosides ( figure 6 ) in 
 the oxazolidinone series , we discount steric arguments based on a 
 smaller steric clash between the aglycone and the o4 protecting group 
 in the oxazolidinones because the usual exoanomeric effect conformation about the glycosidic 
 bond will orient the aglycone toward the rear of the molecule and 
 away from o4 ( figure 7 ) . indeed , the typical 
 exoanomeric effect conformation with an n  o  anomeric 
 c  ring oxygen torsion angle of -60 is evident 
 in the x - ray crystal structure of a calicheamicin derivative , in the x - ray structures of a simple o - glycosyl 
 hydroxylamine , and of various o - glycosyl oximes and hydroxyimides , albeit a molecular mechanics - based computational 
 paper appears to suggest a n  o  anomeric c  ring 
 oxygen torsion angle of 170. newman 
 projection about the hydroxylamine n  o bond showing 
 the typical exoanomeric effect conformation of the o - glycosyl hydroxylamines . rather we suggest that the influence 
 of the oxazolidinone on the 
 anomeric effect is rooted in the highly polar nature of the oxazolidinone 
 system with its strong dipole moment aligned with the axis of the 
 carbonyl bond ( figure 8) . thus , as illustrated in figure 9 , the oxazolidinone 
 moiety exhibits a powerful electron - withdrawing effect in the mean 
 plane of the pyranose ring due to the alignment of the carbonyl dipole 
 with the polar c4o4 and c5n5 bonds . this is to be 
 contrasted with the 4o,5n - diacetyl 
 system in which , assuming the standard minimum energy conformations 
 of the ester and amide groups with the latter apparent from 
 the 180 h5c5n5nh torsion angle with jnh , h5 = 10 hz , the two carbonyl 
 dipoles are oriented in opposite directions and approximately perpendicular 
 to the c4o4 and c5n5 bonds resulting overall in a 
 smaller electron - withdrawing effect . the electron - withdrawing effect 
 of the n - acetyloxazolidinone system , while still 
 powerful because of the alignment of the oxazolidinone carbonyl with 
 the c4o4 and c5n5 bonds in the mean plane of the pyranose 
 ring , is moderated by the orientation of the acetyl group , which , 
 as is clear from the available x - ray crystal structures and literature data with simple models , is oriented so as to minimize the overall dipole ( figure 8) at least in weakly polar environments . dipole moments 
 ( debye units ) of open chain and cyclic carbonyl 
 functionalities in nonpolar solvents . orientations of the key o4 and n5 protecting group carbonyl dipole 
 moments in the o - sialyl hydroxylamines ( side chains 
 omitted for clarity ) . if the anomeric effect is understood in terms of donation 
 of electron 
 density from a lone pair ( n ) on the ring oxygen into 
 the synperiplanar c  o  * orbital of the axial glycosidic 
 bond , the influence of the oxazolidinone can be 
 attributed to the lowering of the energy of the lone pair due to the 
 presence of the strongly electron - withdrawing group , which in turn 
 reduces the n * interaction and so 
 diminishes the anomeric effect . in valence bond terms this equates 
 to the destabilization of the double bond  no bond resonance 
 form owing to the increased energy of the oxocarbenium ion arising 
 from the presence of the strongly electron - withdrawing protecting 
 group ( figure 10 ) . it can also be argued in 
 view of the high dipole moment of the oxazolidinone group that there 
 is a dipolar component to the stabilization of the equatorial glycosides . thus , in the axial glycosides the vectors of the oxazolidinone dipole 
 and the anomeric carbon oxygen bond dipole subtend an angle of approximately 
 90 , whereas in the equatorial glycoside the angle subtended 
 is approximately 60 , suggesting that the equatorial glycosides 
 will be more highly stabilized in less polar media , as is the case 
 ( table 1 ) . a new method of equilibration of sialyl anomeric 
 c  o bonds 
 has been developed on the basis of the fischer  ingold persistent 
 radical effect . this method enables the investigation of protecting 
 groups on the anomeric equilibrium and is compatible with acid and 
 base sensitive functionality . the trans - fused oxazolidinone 
 moiety is found by this method to stabilize equatorial glycosides 
 over their axial counterparts , i.e. , to reduce the magnitude of the 
 anomeric effect . this effect , which adds to a series of recent observations 
 on the influence of cyclic protecting groups on the anomeric effect , is a manifestation of the strongly electron - withdrawing nature of 
 the trans - fused oxazolidinone , ( and by extrapolation trans - fused cyclic carbonates ) , which is a direct consequence 
 of the highly dipolar nature of such heterocycles . the strongly electron - withdrawing 
 nature of these groups manifest by the present study more than likely 
 also plays an important role in the high kinetic selectivity observed 
 in the trans - fused oxazolidinone ( and cyclic carbonate)-directed 
 -sialoside synthesis methods . the unusually poor kinetic diastereoselectivity 
 of anomeric radicals in the sialic acid series is a function of the 
 -type planar nature of these radicals coupled with the existence 
 of competing 1,3-diaxial interactions in the diastereomeric transition 
 states for the formation of both anomers .
a method 
 for the investigation of the influence of protecting groups 
 on the anomeric equilibrium in the sialic acid glycosides has been 
 developed on the basis of the equilibration of o - sialyl 
 hydroxylamines by reversible homolytic scission of the glycosidic 
 bond following the dictates of the fischer 
 ingold persistent 
 radical effect . 
 it is found that a trans - fused 4o,5n - oxazolidinone group stabilizes the 
 equatorial glycoside , i.e. , reduces the anomeric effect , when compared 
 to the 4o,5n - diacetyl protected 
 systems . 
 this effect is discussed in terms of the powerful electron - withdrawing 
 nature of the oxazolidinone system , which in turn is a function of 
 its strong dipole moment in the mean plane of the pyranose ring system . 
 the new equilibration method displays a small solvent effect and is 
 most pronounced in less polar media consistent with the anomeric effect 
 in general . 
 the unusual ( for anomeric radicals ) poor kinetic selectivity 
 of anomeric sialyl radicals is discussed in terms of the planar -type 
 structure of these radicals and of competing 1,3-diaxial interactions 
 in the diastereomeric transition states for trapping on the - 
 and -faces of the radical .