Regioselective O-Glycosylation of Nucleosides via the Temporary 2',3'-Diol Protection by a Boronic Ester for the Synthesis of Disaccharide Nucleosides

Summary

Here, we present protocols for the synthesis of disaccharide nucleosides by the regioselective O-glycosylation of ribonucleosides via a temporary protection of their 2',3'-diol moieties utilizing a cyclic boronic ester. This method applies to several unprotected nucleosides such as adenosine, guanosine, cytidine, uridine, 5-methyluridine, and 5-fluorouridine to give corresponding disaccharide nucleosides.

Abstract

Disaccharide nucleosides, which consist of disaccharide and nucleobase moieties, have been known as a valuable group of natural products having multifarious bioactivities. Although chemical O-glycosylation is a commonly beneficial strategy to synthesize disaccharide nucleosides, the preparation of substrates such as glycosyl donors and acceptors requires tedious protecting group manipulations and a purification at each synthetic step. Meanwhile, several research groups have reported that boronic and borinic esters serve as a protecting or activating group of carbohydrate derivatives to achieve the regio- and/or stereoselective acylation, alkylation, silylation, and glycosylation. In this article, we demonstrate the procedure for the regioselective O-glycosylation of unprotected ribonucleosides utilizing boronic acid. The esterification of 2',3'-diol of ribonucleosides with boronic acid makes the temporary protection of diol, and, following O-glycosylation with a glycosyl donor in the presence of p-toluenesulfenyl chloride and silver triflate, permits the regioselective reaction of the 5'-hydroxyl group to afford the disaccharide nucleosides. This method could be applied to various nucleosides, such as guanosine, adenosine, cytidine, uridine, 5-metyluridine, and 5-fluorouridine. This article and the accompanying video represent useful (visual) information for the O-glycosylation of unprotected nucleosides and their analogs for the synthesis of not only disaccharide nucleosides, but also a variety of biologically relevant derivatives.

Introduction

Disaccharide nucleosides, which are conjugates of a nucleoside and a carbohydrate moiety linked via an O-glycosidic bond, constitute a valuable class of naturally-occurring carbohydrate derivatives^{1,2,3,4,5,6,7}. For instance, they are incorporated in biological macromolecules such as tRNA (transfer ribonucleic acid) and poly(ADP-ribose) (ADP = adenosine diphosphate), as well as in some antibacterial agents and other biol....

Protocol

NOTE: All experimental data [NMR, infrared spectroscopies (IR), mass spectroscopies (MS), optical rotations, and elemental analyses data] of the synthesized compounds were reported in a previous paper⁵¹.

1. Procedure for O-Glycosylation Reactions

1. Synthesis of compound α/β-12 (Entry 12 in Table 1)
   NOTE: Entries 1 - 13 in Table 1 were carried out using a similar procedure.
   1. Temporary protection of 2',3'-diol of ribonucleoside⁴⁰
      1. In a 10 mL pear-shaped flask (flask 1), dissolve....

Results

The results of the O-glycosylation of uridine 10 with thiomannoside α-9 are summarized in Table 1^60,61. In Entry 1, the O-glycosylation of 10 with α-9 in the absence of boronic acid derivatives resulted in the formation of a complicated mixture. In Entry 2, 10 and phenylboronic acid 11a were mixe.......

Discussion

The purpose of this manuscript is to show a convenient synthetic method to prepare disaccharide nucleosides using unprotected ribonucleosides without tedious protecting group manipulations. We report herein on the regioselective O-glycosylations of nucleosides via the temporary 2',3'-diol protection by a cyclic boronic ester (Figure 1B)⁵¹.

The preparation of the cyclic boronic ester intermediate is.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Silver trifluoromethanesulfonate	Nacalai Tesque	34945-61
Phenylboronic acid (contains varying amounts of anhydride)	Tokyo Chemical Industry	B0857
p-Methoxyphenylboronic acid	Wako Pure Chemical Industries	321-69201
4-(Trifluoromethyl)phenylboronic acid (contains varying amounts of anhydride)	Tokyo Chemical Industry	T1788
2,4-Difluorophenylboronic acid (contains varying amounts of anhydride)	Tokyo Chemical Industry	D3391
Cyclopentylboronic acid (contains varying amounts of Anhydride)	Tokyo Chemical Industry	C2442
4-Nitrophenylboronic acid (contains varying amounts of anhydride)	Tokyo Chemical Industry	N0812
4-Hexylphenylboronic acid (contains varying amounts of anhydride)	Tokyo Chemical Industry	H1489
Adenosine	Merck KGaA	862.
Guanosine	Acros Organics	411130050
Cytidine	Tokyo Chemical Industry	C0522
Uridine	Tokyo Chemical Industry	U0020
5-Fluorouridine	Tokyo Chemical Industry	F0636
5-Methyluridine	Sigma	M-9885
Methylamine (40% in Methanol, ca. 9.8mol/L)	Tokyo Chemical Industry	M1016
N,N-dimethyl-4-aminopyridine	Wako Pure Chemical Industries	044-19211
Acetic anhydride	Nacalai Tesque	00226-15
Pyridine, Dehydrated	Wako Pure Chemical Industries	161-18453
Acetonitrile	Kanto Chemical	01031-96
1,4-Dioxane	Nacalai Tesque	13622-73
Dichloromethane	Wako Pure Chemical Industries	130-02457
Propionitrile	Wako Pure Chemical Industries	164-04756
Molecular sieves 4A powder	Nacalai Tesque	04168-65
Molecular sieves 3A powder	Nacalai Tesque	04176-55
Celite 545RVS	Nacalai Tesque	08034-85
Acetonitrile-D3 (D,99.8%)	Cambridge Isotope Laboratories	DLM-21-10
Trifluoroacetic acid	Nacalai Tesque	34831-25
TLC Silica gel 60 F254	Merck KGaA	1.05715.0001
Chromatorex	Fuji Silysia Chemical	FL100D
Sodium hydrogen carbonate	Wako Pure Chemical Industries	191-01305
Hydrochloric acid	Wako Pure Chemical Industries	080-01061
Sodium sulfate	Nacalai Tesque	31915-96
Chloroform	Kanto Chemical	07278-81
Sodium chloride	Wako Pure Chemical Industries	194-01677
Methanol	Nacalai Tesque	21914-74
JEOL Always 300	JEOL		Measurement of NMR
Lamda 400	JEOL		Measurement of NMR
PerkinElmer Spectrum 100 FT-IR Spectrometer	Perkin Elmer		Measurement of IR
JEOL JMS-700	JEOL		Measurement of MS
PerkinElmer CHN 2400 analyzer	Perkin Elmer		Measurement of elemental analysis
JASCO P-1030 digital polarimeter	JASCO		Measurement of optical rotation
JASCO PU-2089 Plus intelligent HPLC pump	JASCO		For HPLC
Jasco UV-2075 Plus Intelligent UV/Vis Detector	JASCO		For HPLC
Rheodyne Model 7125 Injector	Sigma-Aldrich	58826	For HPLC
Chromatopac C-R8A	Shimadzu		For HPLC
Senshu Pak Pegasil ODS	Senshu Scientific		For HPLC
p-Toluenesulfenyl chloride			Prepared  Ref. 38
Phenyl 6-O-acetyl-2,3,4-tri-O-benzyl-1-thio-a-D-mannopyranoside (a-9)			Prepared  Ref. 52
4-Metylphenyl 2,3,4,6-tetra-O-benzoyl-1-thio-b-D-galactopyranoside (b-21)			Prepared  Ref. 53
4-Metylphenyl 2,3,4,6-tetra-O-benzoyl-1-thio-b-D-glucopyranoside (b-31)			Prepared  Ref. 57
4-Metylphenyl 2,3,4,6-tetra-O-benzoyl-1-thio-a-D-Mannopyranoside (a-32)			Prepared  Ref. 67
6-N-Benzoyladenosine (14)			Prepared  Ref. 54
2-N-Isobutyrylguanosine (16)			Prepared  Ref. 55
4-N-Benzoylcytidine (20)			Prepared  Ref. 56