Potassium carbonate-mediated β-selective anomeric O-alkylation with primary electrophiles: Application to the synthesis of glycosphingolipids

Abstract

Stereoselective construction of a variety of β-glycosides can be achieved using abundant and inexpensive K₂CO₃-mediated stereoselective anomeric O-alkylation of sugar lactols with primary electrophiles. In addition, application of this methodology to the synthesis of various azido-modified glycosphingolipids has been accomplished in good yields and excellent anomeric selectivity using sphingosine-derived primary triflate.

Introduction

It has been well recognized that glycans and glycoconjugates play essential roles in numerous biological and cellular processes.[1] Structurally, glycans consist of monosaccharides linked to one another via either α or β-glycosidic bonds. From synthetic perspective, those glycosidic bonds can be formed by chemical or enzymatic reactions. Despite advances in the development of modern chemical glycosylation methods,[2,3,4] stereoselective construction of glycosidic linkages, especially 1,2-cis-glycosides,[5] remains challenging. In addition, strategically assembling monosaccharides into complex oligosaccharides or polysaccharides is certainly a non-trivial process. Therefore, development of efficient approaches, especially easily operable and cost-effective synthetic methods, is desirable in order to access good quantities of pure and structurally well-defined complex carbohydrate molecules for studying their biological functions and manufacturing effective therapeutics.

Since first reported by Schmidt,[6] anomeric O-alkylation has been proven as a viable method for stereoselective construction of glycosidic linkages.[7,8,9,10,11,12,13,14] This approach affords glycosides under basic conditions, complementing the traditional glycosylation methods involving Lewis acidic catalysts or promoters. Among reported synthesis of glycosides by anomeric O-alkylation, strong bases, such as NaH or KH were mostly employed.

Recently, we reported the use of Cs₂CO₃, a relatively weaker base than NaH, for efficient stereoselective synthesis of β-mannosides via anomeric O-alkylation (a, Scheme 1).[15] This method tolerates both primary and secondary triflate electrophiles and affords desired β-mannosides in good yields and excellent anomeric selectivity. Since then, our efforts in carbohydrate synthesis via stereoselective anomeric O-alkylation have been limited to β-d-mannosides[16,17,18,19] or related β-d-mannoheptopyranoside[20] and 2-azido-2-deoxy β-d-mannosides.[21]

Scheme 1.

Synthesis of β-glycosides via stereoselective anomeric O-alkylation.

During our studies on β-selective anomeric O-alkylation of mannose-type lactols involving secondary triflates as electrophiles, Cs₂CO₃ was found to be the optimal base and other alkaline metal carbonates were found to be less effective or ineffective.[22] Since primary electrophiles are obviously more reactive than secondary ones, we speculated that other more abundant and less costly alkaline metal bases may be sufficient for anomeric O-alkylation of mannoses or other types of sugar lactols involving primary electrophiles. In this Communication, we would like to report our findings in the discovery of less basic and inexpensive potassium carbonate (K₂CO₃) for β-selective anomeric O-alkylation of various sugars with primary triflate electrophiles (b, Scheme 1). In addition, this method has been utilized in the synthesis of various carbohydrate-derived glycosphingolipids (GSLs).

Previously, we reported that Cs₂CO₃-mediated anomeric O-alkylation of partially protected d-mannose 1 with C6-primary triflate 5 afforded β-d-mannoside 6 in 93% yield (β only) (entry 1, Table 1).[15] Use of K₂CO₃ instead of Cs₂CO₃ under the same reaction condition afforded desired β-d-mannoside 6 in slightly lower yield (83%, β only, entry 2). The less basic Na₂CO₃ was found to be ineffective (entry 3). In addition, it was found that use of powdered KOH or NaOH, obtained by grinding the pellets, afforded desired β-d-mannoside 6 in 80% and 71% yields, respectively (β only, entries 4 and 5). Other bases, including Ba(OH)₂, magnesium oxide (MgO) and organic bases, e.g. N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), were found to be ineffective (entries 6 – 9). When benzyl bromide was used as the electrophile, corresponding desired β-d-mannoside 7 was produced in comparable yields employing Cs₂CO₃[17] or K₂CO₃ (entries 10 and 11). These studies indicated that cost-effective K₂CO₃ may be used to replace Cs₂CO₃ for stereoselective anomeric O-alkylation of partially protected d-mannose 1 with primary electrophiles. However, it is worth noting that K₂CO₃ was not effective in the anomeric O-alkylation of partially protected d-mannose 1 with secondary electrophiles.[22]

Table 1.

Screening bases for β-mannosylation via O-alkylation with primary electrophiles.^a,b

Entry	Electrophile	Base	Product, Yield(α/β ratio)
1	5	Cs2CO3	6, 93% (β only)
2	5	K2CO3	6, 83% (β only)
3	5	Na2CO3	NDc
4	5	KOH	6, 80% (β only)
5	5	NaOH	6, 71% (β only)
6	5	Ba(OH)2	6, 24% (β only)
7	5	MgO	NDc
8	5	DIEA	6, trace
9	5	DBU	6, trace
10	BnBr	Cs2CO3	7, 64% (β only)
11	BnBr	K2CO3	7, 68% (β only)

^aReaction condition: 1 (1.0 eq.), 5 or benzyl bromide (1.5 eq.), base (2.0 eq.), ClCH₂CH₂Cl, 40 °C, 24 h.

^bIsolated yield.

^cNot detected.

Next, we turned to investigate the substrate scope of this K₂CO₃-mediated β-selective anomeric O-alkylation. As shown in Table 2, anomeric O-alkylation of various sugar lactols (8-13) with C6-primary triflate 5 in the presence of K₂CO₃ afforded corresponding β-linked disaccharides 14-19 in good yields and excellent anomeric selectivity, respectively. Similar to d-mannose 1 bearing a free C2-OH, triflate 5 (1.5 eq.) and K₂CO₃ (2.0 eq.) are needed for efficient anomeric O-alkylation of d-glucose 9 and d-galactose 11 bearing a free C2-OH. However, when C2-OH was protected as the benzyl ether or replaced with an azide group, such as lactols 8, 10, 12 and 13, triflate 5 (2.0 eq.) and K₂CO₃ (2.5 eq.) are required for efficient anomeric O-alkylation, probably due to the steric effect and electronic effect (for azide). It is also worth noting that use of Cs₂CO₃[21] or K₂CO₃ for anomeric O-alkylation of 2-azido-2-deoxy-d-mannose 13 afforded comparable yields.

Table 2.

K₂CO₃-mediated β-selective anomeric O-alkylation of various sugar lactols with C6-primary triflate 5.^a,b

^aUnless otherwise noted, all reactions were carried out employing lactols (1.0 eq.), triflate 5 (1.5 eq.), K₂CO₃ (2.0 eq.), ClCH₂CH₂Cl, 40 °C, 24 h.

^bIsolated yield.

^cTriflate 5 (2.0 eq.) and K₂CO₃ (2.5 eq.) were used.

^dTriflate 5 (2.0 eq.) and Cs₂CO₃ (2.5 eq.) were used.

With these results in hand, we attempted the synthesis of various sugar-derived glycosphingolipids using this K₂CO₃-mediated β-selective anomeric O-alkylation. Glycosphingolipids (GSLs) are one type of structurally diverse and complex glycolipids found in the cell membranes of organisms including bacteria and animals. Consisting of a hydrophilic carbohydrate moiety and a hydrophobic lipid group, GSLs are known to play significant biological roles in membrane structure, cell–cell recognition, host–pathogen interactions as well as modulation of membrane protein function.[23] Even with the availability of numerous chemical, enzymatic, and chemo-enzymatic protocols, efficient synthesis of diverse and structurally complex glycosphingolipids, especially in homogenous form and large scale, remain as a challenge.[23] This certainly impedes their biological studies and the development of GSL-based vaccines and related therapeutics. In previously reported syntheses of GSLs, the key glycosidic bond between the sugar moiety and the partially protected sphingosine derivatives was constructed by conventional glycosylation involving electrophilic glycosyl donors and nucleophile alcohol acceptors. Herein, we demonstrate that synthesis of glycosphingolipids can be efficiently achieved via K₂CO₃-mediated stereoselective anomeric O-alkylation.

As shown in Table 3, synthesis of various monosaccharides containing glycosphingolipids (23-28) via K₂CO₃-mediated β-selective anomeric O-alkylation was accomplished in good yields and excellent anomeric selectivity. In addition, a disaccharide, lactose, derived glycosphingolipid 29 was obtained. In comparison, use of Cs₂CO₃-mediated β-selective anomeric O-alkylation afforded the same glycosphingolipids in comparable yields, which demonstrate that K₂CO₃ was as efficient as Cs₂CO₃ in anomeric O-alkylation involving primary electrophiles. These molecules can be deprotected and acylated to afford free glycosphingolipids following the procedures reported in the literature.[24,25,26]

Table 3.

Synthesis of azido-modified glycosphingolipids via K₂CO₃-mediated β-selective anomeric O-alkylation.^a,b

^aUnless otherwise noted, all reactions were carried out employing lactols (1.0 eq.), triflate 22 (2.0 eq.), base (2.5 eq.), ClCH₂CH₂Cl, 40 °C, 24 h.

^bIsolated yield.

In conclusion, an approach for stereoselective synthesis of β-glycosides has been developed involving K₂CO₃-mediated β-selective anomeric O-alkylation of diverse sugar lactols with primary electrophiles. Under these conditions, use of Cs₂CO₃ or less costly K₂CO₃ afforded desired β-glycosides in comparable yields. In addition, this methodology has been utilized in the synthesis of various glycosphingolipids in good yields and excellent anomeric selectivity.

Data availability

Data will be made available on request.