Transition state, anomeric effect

Reaction of 3-amino-1-propanol and 5-bromo-5-deoxy-D-furanoxylose (25) in D2O was monitored by NMR (Scheme 4). The a-anomer of trihydroxypyridoPd-f l-LbSloxazine 26 formed 20 times faster, but the /3-anomer 27 was more stable (A / 7.3). The faster formation of the Q -anomer is a consequence of a kinetic anomeric effect that destabilizes the transition state for equatorial A -alkylation and formation of the /3-anomer 27 (OOJOC889). 

The stereoselectivity of these reactions has been interpreted in terms of chair-like six-membered ring transition states in which the substituents a to tin adopt an axial position, possibly because of steric and anomeric effects. The cc-substituted (Z)-isomers are less reactive because the axial preference of the a-substituent would lead to severe 1,3-diaxial interactions17. 

The influence of the classical anomeric effect and quasi-anomeric effect on the reactivity of various radicals has been probed. The isomer distribution for the deu-teriation of radical (48) was found to be selective whereas allylation was non-selective (Scheme 37). The results were explained by invoking a later transition state in the allylation, thus increasing the significance of thermodynamic control in the later reactions. Radical addition to a range of o -(arylsulfonyl)enones has been reported to give unexpected Pummerer rearrangement products (49) (Scheme 38).A mechanism has been postulated proceeding via the boron enolate followed by elimination of EtaBO anion. 

In amines, dialkoxyl subsfilufion resulls in much higher barriers to inversion fhan in alky famines a fad that has also been explained in terms of an electronegativity effect increased p-character in the a bonds results in more s-character for the electron pair on nitrogen. The planar-inversion transition state is therefore destabilized since, in it, the lone pair must develop pure p-character. This transition state is also destabilized by a six-electron anti-bonding interaction between heteroatom lone pairs and, additionally, the better anomeric overlap that is possible in sp rather than sp systems may also play a role (Figure 4) . These phenomena have also been rationalized theoretically ... 

In addition to solvolysis and nitrenium ion formation, Af-aLkoxy-A-chloroamides (2) also undergo bimolecular reactions with nucleophiles at nitrogen. Not only is the configuration destabilized by the anomeric effect, it also parallels that of a-halo ketones, where halogen on an sp carbon is activated towards reactions by the adjacent carbonyl. This rate-enhancing effect on 8 /2 processes at carbon is well-known, and has been attributed to conjugation of the p-orbital on carbon with the carbonyl jr-bond in the S 2 transition state stabilization of ionic character at the central carbon as outlined by Pross as weU as electrostatic attraction to the carbonyl carbon. The transition states are also affected by the nature of the nucleophile. ... 

Recall that in the latter, certain types of substituents adjacent to oxygen in the ring actually prefer axial arrangements. This observation has been codified in what is commonly referred to as the anomeric effect and is responsible in part for the conformations of carbohydrates. Is it possible that conformational preferences seen in substituted tetrahydropyrans will carry over into preferences in transition-state geometries for Claisen rearrangements ... 

The hypothesis gained considerable plausibility by appearing to be a simple extension of what was already accepted. Thus, an antiperiplanar lone pair of electrons can be considered to play essentially the same role as the pair of electrons in the breaking C—H bond in an E2 elimination, and the strong preference for anti-stereochemistry in such reactions had long been known. Moreover, the frontier-orbital explanation of the anomeric effect was receiving support at the expense of the antecedent electrostatic explanation, and the ALPH merely applied the same ideas to transition states. 

In the second section of this review the failures of ALPH will be discussed these failures occur very largely in the heterolytic chemistry of acetals. Such reactions are characterised by late transition states. The theoretical basis of ALPH, and the closely related frontier-orbital rationalisation of the static anomeric effect, will be described and various difficulties in these interpretations pointed out. 

As was mentioned in the introduction, ALPH is an extension of the qualitative frontier-orbital explanation of the anomeric effect. Any difficulties with this explanation of the anomeric effect, therefore, will undermine the basis of ALPH, although even if the explanation is substantially correct it does not necessarily follow that it is legitimate to extend the same ideas to transition states. There are indeed difficulties, both of inadequate agreement with experiment and of conceptual confusion. A problem in this whole area is that experimental scientists have taken the formalisms and constructs of theoreticians and endowed them with a reality they do not possess, as can be illustrated by the case of the lone pair orbitals on oxygen. 

We have seen how ALPH, whilst it successfully rationalises a number of observations of reactivity of compounds at the acyl level of oxidation, nonetheless fails as a general principle, and that these failures are particularly frequent in the reactions of compounds at the aldehyde level of oxidation, such as acetals. Moreover, its theoretical foundation, the frontier orbital explanation of the anomeric effect, seems to be, at the very least, incomplete in its rationalisation of ground state effects, and therefore an insecure basis on which to found a dogma about transition states. 

The isothiocyanates are transformed into thiocarbamates by reaction with alcohols or into the acetamides by reaction with acetic acid or anhydride and sodium acetate. These transformations have also been applied to the preparation of unsaturated aminosugars73,74. Thus, suprafa-cial rearrangement of ethyl 2.3,4-trideoxy-6-0-methanesulfonyl-4-thiocyan ato-a-D-t/ireo-hex-2-enopyranoside to the 2-isothiocyanatc occurs in refluxing toluene (1 h), whereas the erythro-epimer needs to be heated in dimethylformamide for 6 hours73. This difference in reactivity might be due to an unfavorable anomeric effect and C-6 in an axial orientation in the transition state of the errr/iro-epimer, respectively. 

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