The Cyanopivaloyl Ester: A Protecting Group in the Assembly of Oligorhamnans

Abstract

Protecting groups play a vital role in the assembly of oligosaccharides. The pivaloyl (Piv) ester is commonly used to ensure 1,2‐trans‐selective glycosylation reactions. A significant drawback of the Piv ester is its stability, necessitating strong alkaline conditions for its removal. We here present the cyanopivaloyl (CNPiv) group, a modified pivaloyl group having a cyano group appended to the tert‐butyl moiety. The CNPiv group benefits from the profitable features of the Piv group (stability and effective neighboring‐group participation with minimal orthoester formation during glycosylation reactions), but can be removed under mild conditions (reduction of the cyano function followed by mild base treatment). The applicability of the CNPiv group is demonstrated in the assembly of two rhamnose oligosaccharides, a hexarhamnan that represents a fragment of the capsular polysaccharide of Enterococcus faecium and a tetrarhamnan that is part of the polyrhamnose backbone of the Lancefield Group A carbohydrate (GAC).

Cyanopivaloyl Ester in the Automated Solid-Phase Synthesis of Oligorhamnans

“…The synthesis of the required dirhamnosyl building blocks is depicted in Scheme 2 and started by coupling imidate donor 14 (12) and acceptor 15 (26)/ 16 12 using a catalytic amount of TfOH. This led to disaccharides 17 and 18 , which could both be purified by crystallization from hot ethanol.…”

“…The organic layer was dried over MgSO 4 and concentrated in vacuo. A quick column purification (PE/EtOAc, 6:1 → 1:1) followed by crystallization from hot EtOH yielded the target disaccharide as a white powder (4.57 g, 5.19 mmol, 88%): 12 mp 106 °C.…”

“…12 It features the favorable characteristics of the pivaloyl ester—stability, effective neighboring group participation, minimal othoester formation, and migratory aptitude—while it circumvents the drawbacks of the parent pivaloyl group—its problematic removal at the end of the synthesis—as it can be removed by reduction of the cyano group to the corresponding amine, which can engage in an effective intramolecular ring closure to cleave the ester function. Thus, removal of the cyanopivaloyl group can be effected in tandem with the removal of benzyl ethers, commonly used as permanent protecting groups.…”

Advances in Protecting Groups for Oligosaccharide Synthesis

“…Wide use of pivaloyl ester group for ensuring 1,2‐ trans stereoselectivity in glycosylation reaction suffers from its deprotection condition, as it requires strong alkaline conditions, which accounts for its significant drawback . Codée and his group developed cyanopivaloyl ester (CNPiv) as a new hydroxy protecting group which renders effective anchimeric assistance by obviating orthoester formation during glycosylation reactions and also with ameliorated deprotection condition . By employing cyanopivaloyl ester Codée et al.…”

“…[3b] CodØea nd his group developed cyanopivaloyl ester (CNPiv) as an ew hydroxy protecting group which renders effective anchimeric assistance by obviating orthoester formationd uring glycosylation reac-tions and also with ameliorated deprotection condition. [26] By employing cyanopivaloyl ester CodØee tal. reporteds ynthesis of hexa-oligorhamnana nd tetra-oligorhamnan (Scheme 11).…”