Mannosyl triflates

The most common activator for the glycosyl sulfoxides is trifluoromethanesulfonic anhydride (triflic anhydride), which, in the absence of nucleophiles, rapidly and cleanly converts most sulfoxides into the corresponding glycosyl triflates in a matter of minutes at —78 °C in dichloromethane solution [86,280,315,316]. In the more extensively studied mannopyranose series, only the a-mannosyl triflate is observed by low-temperature NMR spectroscopy (Scheme 4.35) [280]. In the glucopyranose series, mixtures of a- and (1-triflates are observed, in which the a-anomer nevertheless predominates (Scheme 4.36) [280],... 

In the critical area of (1-mannoside synthesis [317-321], the evidence strongly suggests that a-mannosyl triflate serves as a reservoir for a transient contact ion pair (CIP), which is the glycosylating species (Scheme 4.37), although the possibility of an SN2-like mechanism with an exploded transition state cannot be completely excluded [135]. In view of the probable operation of the contact ion-pair mechanism... 

III. MANNOSYL TRIFLATES FROM MANNOSYL SULFOXIDES AND THIOGLYCOSIDES THE /3-MANNOSYLATION REACTION... 

Deoxy-2-[ F]fluoro-D-glucose (FDG) has been used as a probe in positron emission tomography (PET). FDG has been synthesized by the nucleophilic substitution of mannosyl triflate with [ F]fluoride ion, which is produced by irradiation of [ 0]water with 10-18 MeV protons in a cyclotron (Scheme 3.2). Because the half-life of i F is 110 min, the synthesis of FDG should be carried out very quickly. Therefore, the use of a microflow system was examined for the FDG synthesis and a microfluidic chip reactor was found to be effective for the purpose [2]. 

The subsequent seminal studies of Crich and Sun [73] relating to the synthesis of p-mannosides are summarized in Scheme 9b. Their work showed that the 4,6-0-benzylidene ring is a compulsory requirement for p-glycosylation, and extensive mechanistic scrutiny has revealed that the a mannosyl triflate, 57, is a key intermediate, isolable with caution, which is displaced by acceptor, ROH, in a SN2-like process [74]. 

They reasoned that the electron-withdrawing effect of the 0-2 sulfonyl group would destabilize the oxocarbenium ion, thereby shifting the equilibrium toward a covalent ot-mannosyl triflate, which would react with an acceptor in an SN2-like fashion to generate the p-mannoside [19]. 

To a first approximation the stability of the covalent glycosyl triflate with respect to the oxocarbenium ion (pairs) will be reflected in the decomposition temperature of the triflate (Table 1). Thus, the tetra-O-methyl a-mannosyl triflate (Table 1, entry 2) has a decomposition temperature of 30 °C whereas the corresponding 4,6-0-benzylidene protected system decomposes at —10 °C (Table 1, entry 1) [29]. The equilibrium constant K is therefore smaller for the benzylidene protected system than for a similar all-ether protected one. In agreement with this observation, the benzylidene protected system is more p-selective than the per-ether protected one. When an extra electron-withdrawing group is added to the 2-position of the benzylidene protected system, for example a sulfonate ester, the equilibrium constants Ki and K2 necessarily decrease further, leading to an observed decomposition temperature for the covalent triflate of 25 °C and a general lack of reactivity (Table 1, entry 31) [50]. 

While it is usually considered most efficient to conduct polymer-supported glycosylation by an acceptor-bound strategy [132, 133], consideration of the hydrolytic and thermal instability of the mannosyl triflate intermediates initially led to the development of a donor-bound strategy for the supported synthesis of the p-mannopyranosides. Thus, a polystyrylboronate resin was employed to capture a 4,6-diol leading to a resin bound donor that was activated and coupled under the standard BSP conditions. Excellent p-selectivities were obtained and the products cleaved from the resin with aqueous acetone (Scheme 11) [88]. 

Scheme 4.1 The equilibrium of benzylidene mannosyl triflates, contact ion pairs (CIPs), and solvent-separated ion pairs (SSIPs).

The synthesis of 1,2-cis linkages, such as those found in /3-D-mannopyranosides, has proven a problem to carbohydrate chemists over the years. Treatment of a D-manno thioglyco-side and the appropriate acceptor with AgOTf in the presence of PhSCl results in the formation of the )3-D-mannopyranoside in excellent yield (eq 38). It has been confirmed that the reaction proceeds through an a-D-mannosyl triflate. AgOTf has also been used to prepare a-D-mannopyranosides in good yields (eqs 39 and... 

Hindered secondary and tertiary alcohols are also suitable acceptors [51, 103-107]. Mannosyl triflates can also be prepared from thiomannosides and mannosyl bromides by reaction with PhSOTf, or silver triflate, respectively. As in Schuerch s method [100], the order of the addition of the reactants is critical for the success. The intermediate triflates should be prepared first before addition of the alcohol to prevent attack by the latter at the initially formed oxocarbonium ion. Additional requirements are the presence in the mannosyl donors of non-participating (benzyl) groups at 0-2 and 3 and a benzylidene-acetal moiety at 0-4 and 0-6. Crich s method is likely to enjoy widespread popularity because of its simple experimental protocol combined with high yields and excellent P-stereoselectivity. 

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