Benzylic anomeric effect

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

These results clearly indicate that barriers to all isomerisation processes are at least less than about 8kcalmol 1. In /V-benzyloxy-7V-chlorobenzamide 44 the amide isomerisation was not observable but the anomeric overlap resulted in diastereotopic benzylic hydrogens, which at coalescence afforded a barrier for rotation about the N-OBn bond of around 10.3 kcalmol-1.32 Like its /V-chloro analogue, the amide isomerisation barrier in 43 is too low to be observed by 3H NMR and even though there is definitive X-ray and theoretical evidence for anomeric effects in /V-acyloxy-/Y-alkoxyamidcs, the barrier to isomerisation about the N-OBn bond must be lower than 10.3 kcalmol-1. The n0-CN ci anomeric interaction in 44 is predicted to be stronger than the n0-CN OAc interaction in 43 on purturbation arguments.32... 

Anomeric effects are evident from dynamic NMR studies on at least one substrate, N-benzyloxy-Af-chlorobenzamide (2c) ". In acetone-de the benzyl aromatic signal (S 7.85) de-coalesced into two signals (ratio 2 1) close to 200 K, corresponding to a free energy barrier of ca 10-11 kcalmoH Amide isomerization appeared to be faster than N—0 rotation since benzoyl resonances were largely unaffected. 

A detailed study of trichloroacetonitrile addition to 2,3,4,6-tetra-O-benzyl-D-glucose showed that from the 1-oxide the -trichloroacetimidate is formed preferentially or even exclusively in a very rapid and reversible addition reaction (Scheme 16). However, this product anomerizes in a slow, base-catalyzed reaction via retroreaction, 1-oxide anomerization and renewed addition) practically completely to the a-trichloroacetimidate, with the electron-withdrawing 1-substituent in an axial position as favored by the thermodynamically efficient anomeric effect. Thus with different bases, for instance K2CO3 and... 

A 2-(trimethylsilyl)ethyl glycoside is convertible into a glycosyl chloride by treatment with 1,1-dichloromethyl methyl ether in the presence of zinc(II) chloride, tin(IV) chloride, or iron(III) chloride. Normally an a-chloro sugar is the product. If a (3-chloro product is formed first (kinetic product) by participation from a 2-O-substituent, this is rapidly equilibrated into the thermodynamically more stable a product (anomeric effect, Section VI). The transformation is compatible with acetyl, benzoyl, and benzyl protecting groups and most importandy, also with the presence of inter-residue glycosidic bonds 229,230... 

The generalized anomeric effect has been invoked to explain the preference of benzyl mercaptan, benzyl methyl sulphide, benzyl methyl sulphoxide and benzyl methyl sulphone for an orientation of the C—SR bond in a plane perpendicular to the nodal plane of the 7i-system [27] (Penner et al.,... 

It was now time to test the regiochemistry of epoxide cleavage, as discussed above with respect to compound Fllla and Flllb (Scheme 19). Clearly, the approach to C-6 of compound Fll (which has the benefit of the anomeric effect) was hindered by interactions with the functional groups at C-4 and C-8. Indeed, epoxide cleavage proved to be sensitive to the protecting group at 0-8. Failure was experienced with benzyl, but fortunately, with a-ethoxyethyl, acetolysis occurred smoothly. 

Aebischer et al. [85] reported in 1983 results of their studies on the anomeric effect of nitro group. They studied the anomeric effect of nitro group in two sugars 1-deoxy-l-nitro-tetra-O-benzyl-D-mannopyranose 106 and 3,4,6-tri-(9-benzyl-l,2-dideoxy-l-nitro-D-arabino-hexopyranose 108 (Fig. 2.35). 

Hashimoto found that low-temperature activation of mannosyl chlorides with silver triflate in the presence of alcohols leads to varying ratios of a- and P-linked mannosides [45, 126, 127]. A study of the factors controlling stereoselectivity in silver triflate-mediated mannosylation has been published [128]. Activation of O-benzyl-protected mannosyl fluorides by a combination of Sn(OTf)2 and La(C104)3 has been reported by Shibasaki to afford mixtures of a- and P-mannosides [129]. The large proportions of a-mannosides formed in the homogeneous reactions outlined in this section indicate the involvement of oxocarbonium-ions enabling the anomeric effect to dictate the steric outcome. Because the stereoselectivity of these approaches is crucially dependent on the reacting partners and conditions their scope remains limited. 

Conformational analyses by n.m.r. and computational methods have been reported for the following compounds l,2-anhydro-3,4,6-tri-0-benzyl-P-D-talopyranose, anhydro sugars 13 and similar hexopyranose derivatives, methyl 3,4-0-isopropylidene-a- and P-D-galactopyranoside and their di-O-acetates and di-O-methyl ethers, 3,4-0-(/ )-benzylidene-D-ribono-1,5-lactone (see Chapter 6), and 6-deoxy-6-phosphonoyl-D-fructopyranoses (see Chapter 17 for synthesis). D-Glucospyranosylamine, its tetra-O-acetate and 4,6-0-benzylidene acetal and several N-acylated derivatives, together with D-[l- C]glucopyranosylamine, have been used in a conformational study by n.m.r. spectroscopy aimed at probing the existence of the reverse anomeric effect. ... 

---