4-(2′-Phenylethynylphenyl)phenyl glycosides as glycosylation donors

Introduction

In 2019, we disclosed an effective and versatile glycosylation protocol, which employed 3,5-dimethyl-4-(2′-phenylethynylphenyl)phenyl (EPP) glycosides as donors and NIS/TMSOTf as promoter (Fig. 1) [1]. The EPP aglycone could proceed a dearomative cyclization initiated by activation of the triple bond with I⁺, leading to the glycosyl oxocarbenium species, which underwent glycosylation, and the spiroindene (A1) as a side-product. A plausible competing reaction would be an intramolecular Friedel-Crafts-type addition, converting the EPP glycoside to a phenanthrene glycoside (e.g., B). To avoid this competing pathway, methyl groups were installed at the 3,5-positions involving in the Friedel-Crafts-type addition. Here, we report the glycosylation reactions of EPP glycosides without the 3,5-dimethyl groups, which are easier to prepare than the previous 4-(2′-phenylethynylphenyl)phenyl glycosides.

Fig. 1:

Glycosylation reaction with 4-(2′-ethynylphenyl)phenyl (EPP) glycosides as donors.

Results and discussion

An effective procedure was developed for the convenient synthesis of the new EPP glycosides (Scheme 1). Taking l-rhamnopyranoside 4 and d-glucopyranoside 7 as examples, the preparation involved: (1) Lewis acid-promoted glycosylation of the peracyl glycosides 1/5 with p-bromophenol to give the corresponding p-bromophenyl glycosides 2 (92 %, α only) and 6 (92 %, β/α = 3/1); (2) installation of the 2′-phenylethynylphenyl moiety onto the aglycone of 2 and 6β via a Suzuki-Miyaura cross-coupling reaction with pinacol boronic ester 3 [2]. The resultant EPP glycosides 4 and 7 were crystalline compounds, which could stay inert on shelf for at least six months.

Scheme 1:

Preparation of 4-(2′-phenylethynylphenyl)phenyl glycosides 4 and 7.

The glycosylation capability of the new EPP glycosides 4 and 7 was then examined (Scheme 2). Under the promotion of NIS (3.0 eq.) and triflic acid (0.4 eq.) in CH₂Cl₂ at 0 °C to RT, the reaction of EPP rhamnoside 4 with diacetone-d-galactose acceptor 8 proceeded smoothly, providing the coupled disaccharide 13 in a good yield (68 %). The side-product derived from the aglycone, i.e., spiro[4.5]-cyclohexadienone 14 [3], was isolated in 81 % yield, while the phenanthrene glycoside 15 derived from the intramolecular Friedel-Crafts-type addition was isolated in a low 5 % yield [4].

Scheme 2:

Glycosylation reactions of EPP glycosides 4 and 7 with a panel of complex alcohols (8–12).

The construction of aryltetralin 4-O-glycosidic linkage is a challenging task, due to the acid and base sensitivity of the podophyllotoxin skeleton [5]. Indeed, the glycosylation of podophyllotoxin 9 with EPP rhamnoside 4 led to the desired rhamnoside 16 in a moderate 35 % yield. A small amounts of 15 was isolated, testifying that the Friedel-Crafts-type addition was not the major side-reaction. With 2-aminoglucoside 4-OH 10 as acceptor, the glycosylation of EPP rhamnoside 4 afforded the coupled disaccharide 17 in a satisfactory 69 % yield. Taking tetraacetylglucoside 7 as donor, the coupling with diacetone-d-galactose acceptor 8 under the action of NIS and TMSOTf proceeded smoothly to deliver disaccharide 18 in 78 % yield. With benzyl ursolate 9 as acceptor, the glycosylation led to the coupled glycoside 19 in a low 33 % yield. In this case, migration of acetyl groups in the donor to the acceptor became a major reaction [6], leading to 20 in 52 % yield. EPP glucoside donor 7 could couple with azidoglucoside 4-OH acceptor 12 to provide disaccharide 21 in 71 % yield.

In line with our efforts on the synthesis of heparin oligosaccharides [7, 8], we examined the construction of the challenging α-GlcN-(1→4)-GlcA linkage with an EPP glycoside donor. Thus, the requisite EPP 2-azidoglucoside 27 was prepared (Scheme 3). Treatment of 2-azido-d-glucose tetraacetate 22 with p-bromophenol in the presence of stoichiometric amounts of TfOH led to the desired p-bromophenyl glycoside 23 (86 %, α/β = 5.2/1). Subjection of 23 to deacylation, selective protection of the resulting 4,6-di-OH with a benzylidene group, and subsequent benzylation of the remaining 3-OH delivered 24 (61 % over 3 steps). Regioselective opening of the 4,6-O-benzylidene acetal in 24 with BH₃·THF and Bu₂B·OTf provided 6-ol 25 (90 %) [9]. The primary hydroxyl group in 25 was then subjected to silylation with TBDPSCl in the presence of triethylamine and DMAP to afford 26 in 74 % yield. Finally, installation of the 2′-phenylethynylphenyl moiety on the aglycone via Suzuki-Miyaura coupling with pinacol boronic ester 3 furnished the desired EPP glycoside 27 in excellent yield (84 %).

Scheme 3:

Synthesis of EPP glycoside 27.

To our delight, the coupling of EPP glycoside 27 with disaccharide 28 [8b, 10] proceeded smoothly under the promotion of NIS and triflic acid, giving trisaccharide 29 in a satisfactory 57 % yield and excellent stereoselectivity (α only) (Scheme 4). It was worth noting that the exclusive α selectivity was partially benefited from the steric effect of the hindered 6-O-TBDPS group [11]. Subsequently, the 6-O-TBDPS group in trisaccharide 29 was selectively removed with HF-pyridine at 50 °C to provide 30 (88 %). The benzyl esters were removed completely with KOH in THF/MeOH, furnishing trisaccharide 31 in 95 % yield [8]. Trisaccharide 31 had been readily converted into heparin trisaccharides bearing a variety of N-sulfonate/acetate and O-sulfonate substituents.

Scheme 4:

Synthesis of heparin trisaccharides precursor 31.

Given the consistent presence of spiro[4.5]-cyclohexadienone 14 and the minor phenanthrene glycoside (e.g., 15), the present EPP glycosides proceed glycosylation via the expected mechanism (Scheme 5). The activation with NIS/TfOH resulted in the formation of iodonium species, which coordinated and activated the alkyne C–C triple bond (II/III), resulting in the generation of dearomatic intermediate IV or the competitive Friedel-Crafts-type glycoside V (e.g., 15). The ready cleavage of the anomeric C-O bond in IV generated oxocarbenium ion VI and spiro[4.5]-cyclohexadienone 14. Subsequently, the oxocarbenium VI accepted the approach of nucleophiles to afford glycoside VII and H⁺, which could participate in the next catalytic cycle.

Scheme 5:

The plausible mechanism of the glycosylation of 4-(2′-phenylethynylphenyl)phenyl glycosides.

Conclusion

Here we studied 4-(2′-phenylethynylphenyl)phenyl (EPP) glycosides (i.e., 4, 7, 27) which could undergo glycosylation effectively via the dearomative activation mechanism. Employing EPP 2-azidoglucoside 27 as donor, the construction of the challenging α-GlcN-(1→4)-GlcA linkage has been realized to furnish a heparin trisaccharides precursor (i.e., 31). Compared to the previous 3,5-dimethyl-4-(2′-phenylethynylphenyl)phenyl (EPP) glycosides, the absence of the 3,5-dimethyl groups in the present EPP donors could result in a competitive intramolecular Friedel-Crafts-type addition, leading to the phenanthrene glycoside (i.e., 15) as side products.