Kinetic anomeric effects

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 role of the kinetic anomeric effect was demonstrated by the difference in diastereoselectivities observed for the addition of LiP03Me2 to IV-glycosylnitrone 51 and to the deoxy analogue 52. In TFIF, the difference in diastereoselectivities corresponds to a value of 1.1 kcal/mol while in CH2CI2 it gives a value of 0.6 kcal/mol. Moreover the deoxy derivative 52 undergoes a slower reaction than its parent glycosylnitrone 51. 

Scheme 5.—Enhanced Nucleophilicity of /J-Oxides (Kinetic Anomeric Effect).

Using a binary sensitizing system (phenanthrene P/DCNB /7-dicyanobenzene) in acetonitrile solution, O-aryl glycosides are transacetalized with alcohols after generation of aromatic radical cations [23], According to kinetic anomeric effects, the a-side attack of nucleophiles to cyclic oxocarbenium ions follows scheme 9. 

The results clearly show that the same kinetic anomeric effects governs these intramolecular cyclization reactions as well as the preceding anomeric hydrogen abstractions described in intermolecular photochemical substitutions. 

In a probe for the presence of stereoelectronic effects in nucleophilic addition to 12 sterically unbiased ketones, calculations have identified subtle bond length differences in the C-Nu bond of the diastereomeric alcohol products, where Nu- = H-or Me-.304 The calculated differences are weak (<1%) but consistent the bond is longer in the major product, acting as a fossil record of the TS. Using microscopic reversibility, the easier bond to cleave (the longer one) is the easier to form. The effect bears comparison with the kinetic anomeric effect in sugars, where such bond length differences in calculation are borne out in X-ray crystal structures. 

This review is an attempt to resolve the conceptual and experimental difficulties encountered in the application of ALPH as an axiom. A physical theory has only to fail once for it to be discredited as a fundamental explanation the electronic explanation of the data supporting ALPH in terms of a kinetic anomeric effect is therefore unlikely to be correct. Indeed, there are aspects of the operation of the ground-state anomeric effect itself which are not readily reconciled with the frontier-orbital view of its origin. 

Generally, the products derived from the open-chain form are insignificant in the reaction mixture and stereocontrol between the anomeric forms can be achieved. It was observed that the anomeric oxygen in the equatorial alkoxide 276 has enhanced nucleophilicity compared with the axial [284]. Often referred to as the kinetic anomeric effect, this phenomenon can govern the diastereoselective formations of the equatorial glycosides [579]. The anomeric effect, however, favors the formation of the thermodynamically more stable axial glycosides and chelation control can also play a role in determining anomeric stereoselectivity. 

The observed diastereoselectivity was rationalized on the basis of a kinetic anomeric effect increasing the reactivity of certain conformers, which control the direction of the attack [44]. Vasella also applied V-ribofuranosylnitrones in the 1,3-dipolar cycloaddition to alkenes [43]. However, the selectivities obtained from these nitrones proved to be lower than those obtained with 51. 

Huber, R, Vasella, A, The kinetic anomeric effect. Additions of nucleophiles and of dipolarophiles to A-glycosylnitrones and to A-pseudoglycosylnitrones, Tetrahedron, 46, 33-58, 1990. 

Stereochemical control in 0-alkylative /3-glycosylation relies on the kinetic anomeric effect [110] namely, that the oxyanion derived from a reducing sugar is more reactive in its 8-ori-ented form 71B than the corresponding a-anion 71A which should be more abundant. This tactic has met with partial success in cases of reactive substrate [111] (O Scheme 38). For example, reaction of 72 with a primary triflate in THF in the presence of NaH afforded the 8-glycoside in 62% yield. 

Scheme 17 Enhanced nucleophilicity of P-oxides (kinetic anomeric effect)...

The observed diastereoselectivity has been rationalized on the basis of a kinetic anomeric effect which increases the reactivity of some conformers. and on steric factors which determine conformer population and dictate the direction of attack. The fundamental role of the tetrahy-drofuran ring oxygen in the nitrone is confirmed by the sluggish and stereorandom cycloadditions of analogs which possess a methylene group instead of Ihe furan oxygen55. 

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