Sulfoxide method

The problem of the nucleophilicity of amides in glycosylation reactions is not limited to the sulfoxide method and has been shown to result in the formation of glycosyl imidates from intermolecular reaction with activated donors. It appears that this problem may be suppressed by the prior silylation of the amide [348,349]. Accordingly, it may be sufficient to operate the sulfoxide method with an excess of triflic anhydride when amides are present so as to convert all amides into O-triflyl imidates, which are then hydrolyzed on work-up. Despite these problems, several examples have been published of successful sulfoxide glycosylation reactions with acceptors carrying remote peptide bonds [344,345] and with donors coupled to resins via amide-based linkages [346,347], with no apparent problems reported. Sulfonamides and tertiary amides appear to be well tolerated by the sulfoxide method [340,350],... 

In addition to the examples laid out in the above schemes, the sulfoxide method has been employed in the synthesis of numerous natural products. The examples presented below are chosen to illustrate the power of the method and the broad functional group compatibility. 

A remarkable example of the compatibility of the sulfoxide method with polyene functionality is taken from a key step in the synthesis of apoptolidin (Scheme 4.59) [361],... 

The sulfoxide method was employed in the direct synthesis of a P-l,2-man-nooctaose (Scheme 4.60) [362-364]. The synthesis of a p-mannosyl phosphoiso-prenoid illustrates the possibility of employing even such weak nucleophiles as phosphates (Scheme 4.61) [365]. Both syntheses rely on the presence of 4,6-0-benzylidene acetal, and its effect on the covalent triflate-contact ion-pair equilibrium [366,367], to influence the stereochemistry of the glycosylation process [295,323],... 

In the furanoside field, the introduction of the last two P-arabino units of a hexasaccharide motif from a bacterial cell wall arabinogalactan was achieved by the sulfoxide method with stereocontrol achieved because of the presence of the 2,3-anhydro group (Scheme 4.62) [368], More recently, the direct stereocontrolled synthesis of arabinofuranosides has been achieved by the sulfoxide method with the aid of a 3,5-0-(di-tert-butylsilylene)-protected donor [369]. 

Related 2,3-anhydrogulofuranosyl sulfoxides have been employed in the stereo-controlled synthesis of P-arabinofuranosides [370]. The epimeric a-arabinofurano-sides have also been synthesized by the sulfoxide method, with the aid of the neighboring-group participation [371,372]. 

The crown jewel in the application of the sulfoxide method to the assembly of natural products is the synthesis of a pentasaccharide from the antibiotic moeno-mycin A, wherein each glycosidic bond was formed in a stereocontrolled manner by one variant or another by the sulfoxide method (Scheme 4.63) [373],... 

The sulfoxide method has been applied to the concept [319,374] of intramolecular aglycone delivery for the formation of [1-mannosidcs by means of a silylene linker. In the original work, the acceptor and a thioglycoside donor were joined by means of a silylene group before the oxidation to the sulfoxide [141]. However, it was later found that the preformed sulfoxide was tolerated by the chemistry for the introduction of the linker [286,375]. The intramolecular aglycone delivery step was shown to function effectively for the transfer of the donor to the 2-, 3- and 6-position of glucopyr-anosides, as exemplified in Scheme 4.64. 

A soluble aminomethylated polyethylene glycol and a succinoyl linker were used to support a 9-fluorenylmethyl group for solution-phase glycosylation by the sulfoxide method. With the help of temporary protection by a 6-O-triphenylmethyl ether, the method could be carried out iteratively to form disaccharides (Scheme 4.69) [379],... 

The sulfoxide method was introduced by Kahne and coworkers,1 and was heralded as a new method for rapid glycosylation of unreactive substrates in high yield under mild conditions. The reaction involves the sulfoxide donor [sulfoxide (I)], an activating agent (usually triflic anhydride), a hindered, nonnucleophilic base (2,6-di-tert-butyl-4-mcthylpyridine, DTBMP) and a nucleophilic acceptor (most often an alcohol) (Scheme 3.1). The glycosylation of sterically hindered steroidal alcohols, phenols and the /V-glycosylation of an acetamide was reported (Table 3.1). 

Since 1989, the sulfoxide method has been investigated extensively by the laboratories of Kahne and Crich and employed by many others. 

Crich, D. Sun, S. X., Formation of beta-mannopyranosides of primary alcohols using the sulfoxide method. J Org. Chem. 1996,61, 4506-4507. 

As mentioned in Section 2, isopropyl phenyl sulfoxide was included in the crystals of 1 with a high enantioselectivity of its (.S )-form. Generally, the inclusion compound of a sulfoxide was prepared by two methods (1) insoluble 1 was simply stirred in the presence of an alkyl phenyl sulfoxide and water (Method A sorption ) and (2) 1 was recrystallized in the presence of the sulfoxide (Method B ... 

The practicahty of direct glycosylation methodology was demonstrated in the context of the synthesis of -mannan [55,56] and )6-rhamnoside (6-deoxy-)6-mannoside) [57,58,59]. In the latter case, a construction of the )6-mannoside by the sulfoxide method was followed by... 

It has been observed that the incorporation of lipophilic chains into vancomycin can increase the potency of the dmg [159,160,161,162]. This is best exemplified by the observation that teicoplanin retains activity against some vancomycin-resistant bacterial strains. In one early study directed at improving the efficacy of these antibiotics, Ge et al. investigated the mechanism of action of a chloro-biphenyl derivative of vancomycin that showed activity against resistant bacteria [163]. The sulfoxide method of glycosylation was utilized to achieve the desired modification of the gluco-vancomycin precursor (O Scheme 28). 

The glycosyl sulfoxide method has proven very efficient and flexible in constructing a variety of glycosidic linkages on the solid support. Combinatorial carbohydrate libraries prepared by this strategy hold great potential for the identification... 

Scheme 8 Solid phase synthesis of a trisaccharide by the glycosyl sulfoxide method.

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