P-mannoside formation

Treatment of the less reactive secondary galacto triflate 45 with stannylene 39 also resulted in P-mannoside formation. Once again yields with DMF as a solvent were low and the long reaction time led to unwanted decomposition of starting materials. Optimum yields were obtained by changing the solvent to DMSO, which resulted in the stereoselective formation of p-mannoside 46 in a very good yield of 59% (Method 4) [52]. 

Consideration of Scheme 6 and of (1) leads directly to the hypothesis that the explanation of any factors affecting the stereochemistry of glycosylation reactions can be found in the manner in which these factors influence the equilibrium between the contact and solvent separated ion pairs. For example, polar solvents support charge separation better than nonpolar solvents and so are likely to shift the equilibrium toward the solvent separated ion pair and increase the proportion of a-glycoside formation. The difference in selectivity noted earlier between the use of diethyl ether and dichloromethane as solvent [14], as well as the increased p-selectivity with weaker nucleophiles in toluene solution (see Sect. 2.1) [80, 81], are thus readily understood. The importance of the concentration of the alcohol on selectivity is also apparent from (1) as is the expected influence of the concentration of the triflate counterion. To favor p-mannoside formation it is necessary to shift the contact ion pair-solvent separated ion pair equilibrium as far as possible toward the contact ion pair. However, any factors favoring the contact ion pair over the solvent separated ion pair are also likely to favor the covalent glycosyl triflate over the... 

The potential of the mannuronate ester donors in the formation of the p-mannosidic linkage has been demonstrated with the construction of a mannuronic acid alginate pentamer using a convergent orthogonal glycosylation.64... 

Scheme 6.9 Formation of P-mannosides using glycosyl phosphates...

Another interesting approach was developed by Ikegami and coworkers, who used an anomeric orthoester as the key intermediate (Scheme 7.14).59 Formation of orthoester 16 from lactone was effected by TMSOTf and TMSOMe. Subsequent Lewis acid mediated reduction afforded p-mannoside in high selectivity, presumably because of the stereoelectronically controlled hydride delivery from the a face. 

David Crich and coworkers found that preactivation of 4,6-O-benzylidene-protected mannosyl sulfoxide donors at low temperature, followed by addition of a glycosyl acceptor, leads to the stereoselective formation of p-mannosides (Scheme 4.12). The necessity for preactivation at low temperature to obtain good p selectivity led to the notion that a stable intermediate is first formed, which then reacts in a stereoselective manner with the nucleophile to generate p-mannosides. In addition to preactivation, the 4,6-0-benzylidene acetal was found to be indispensable for high... 

P selectivity. Crich and coworkers proposed that, under preactivation conditions, the oxocarbenium ion is trapped by a triflate anion to form the more stable a-triflate 65. After addition of the acceptor, the a-triflate intermediate can then be displaced in an SN2-like manner to afford a p-mannoside product (68). The formation of a-glycosyl triflates was confirmed by II, 13C, and 19F NMR analyses of the activated mannosyl donor recorded at low temperature [37], The experimentally determined KIE is approximately 1.12, which is consistent with an oxocarbenium-like TS [38], It was hypothesized that the a-triflate converts into the contact ion pair 66 in which the triflate anion remains at the a face or that an exploded TS is formed where the nucleophile is loosely associated with the oxocarbenium ion as the triflate departs [39,40], The a product 69 can be explained by the formation of the solvent-separated ion pair 67 where the counterion is solvated and facial selectivity is lost. 

Nagai, H, Matsumura, S, Toshima, K, Environmentally benign and stereoselective formation of p-mannosidic linkages utilizing 2,3-di-0-benzyl-4,6-0-benzylidene-protected mannopyranosyl phosphite and montmorillonite K-10, Carbohydr. Res., 338, 1531-1534, 2003. 

Figure 6.32 Successes and failure of carbonate protection in an attempt to make aryl P-mannobiosides. The formation of the cyclic orthocarbonate must be entirely due to the complex phosphine oxide leaving group in the Mitsunobu reaction, since 4,6-di-O-acetyl-a-D-mannopyranosyl bromide 2,3-carbonate gave the expected aryl P-mannosides on reaction -with phenoxides. ...

El Badri MH, Willenbring D, Tantillo DJ, Garvay-Hague J (2007) Meehanistic studies rai the stereoselective formation of p-mannosides from mannosyl iodides using o-deuterium kinetic isotope effects. J Org Chem 72 4663-4672... 

---