Orthogonal protection of saccharide polyols through solvent-free one-pot sequences based on regioselective silylations

Abstract

tert-Butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS) are alcohol protecting groups widely employed in organic synthesis in view of their compatibility with a wide range of conditions. Their regioselective installation on polyols generally requires lengthy reactions and the use of high boiling solvents. In the first part of this paper we demonstrate that regioselective silylation of sugar polyols can be conducted in short times with the requisite silyl chloride and a very limited excess of pyridine (2–3 equivalents). Under these conditions, that can be regarded as solvent-free conditions in view of the insolubility of the polyol substrates, the reactions are faster than in most examples reported in the literature, and can even be further accelerated with a catalytic amount of tetrabutylammonium bromide (TBAB). The strategy proved also useful for either the selective TBDMS protection of secondary alcohols or the fast per-O-trimethylsilylation of saccharide polyols. In the second part of the paper the scope of the silylation approach was significantly extended with the development of unprecedented “one-pot” and “solvent-free” sequences allowing the regioselective silylation/alkylation (or the reverse sequence) of saccharide polyols in short times. The developed methodologies represent a very useful and experimentally simple tool for the straightforward access to saccharide building-blocks useful in organic synthesis.

Solvent-Free One-Pot Diversified Protection of Saccharide Polyols Via Regioselective Tritylations

“…The sequence terminating with the allylation protection gave satisfying yields when this latter step was conducted at 90 °C (as previously reported in the direct 3‐ O ‐allylation of 1 ) . The one‐pot sequence concluding with the silylation step could be conducted under tin‐free conditions with high regioselectivity (entry 5) in ca 5 hours. Interestingly, an analogous one‐pot sequence of 6‐ O ‐tritylation and 3‐ O ‐TBS protection was reported under standard conditions (with pyridine and DMF as the solvents) to take about 30 hours overall …”

“…In an attempt to give a contribution towards practical procedures for the synthetic manipulation of carbohydrates, often practiced by specialized groups, over the last years we have addressed our interest to solvent‐free protocols aimed at regioselective protection of highly functionalized saccharide substrates. In spite of the poor affinity of polar carbohydrates towards the much less polar reagents needed for their derivatization, several useful solvent‐free procedures were developed such as a simple protocol for the selective benzylation of primary saccharide alcohols, the first catalytic tin‐mediated procedure for regioselective benzylation/allylation of vicinal diols, three alternative acetalation protocols, and a silylation protocol which proved compatible in several cases with the one‐pot installation of further protecting groups in the same saccharide residue . More recently a solvent‐free approach also proved useful for the synthesis of glycosyl chlorides under conditions compatible with both acid‐ and base‐labile groups …”

“…Having recently realized that solvent‐free conditions can be usefully exploited for selective introduction of a variety of protecting groups on carbohydrates, we have now turned our interest into the feasible applicability of such a strategy for the tritylation reaction.…”

Solvent-Free Approaches in Carbohydrate Synthetic Chemistry: Role of Catalysis in Reactivity and Selectivity

“…Recently, a solvent-free version was also developed to achieve further regioselective protective etherifications on sugars. Primary positions can be preferentially protected with bulky electrophiles, and they can be tritylated [58] or silylated [59] in the presence of a slight stoichiometric excess of pyridine (2.2-3.0 equiv., not sufficient for dissolving the polyol substrate) and the requisite trityl (Tr) or silyl chloride (in particular, tert-butyldimethylsilyl or tert-butyldiphenylsilyl chloride, namely TBDMSCl or TBDPSCl, respectively) (Scheme 9). Scheme 9.…”

Developing cellulosic waste products as platform chemicals: protecting group chemistry of α-glucoisosaccharinic acid

“…The di-tert-butyldisilyl derivative 9b was synthesised using a method adapted from that described by Iadonisi et al [33] 1',1',3',3'-Tetraisopropyldisiloxane-1,3-diyl)…”