A Stable, Commercially Available Sulfenyl Chloride for the Activation of Thioglycosides in Conjunction with Silver Trifluoromethanesulfonate

Abstract

p-Nitrobenzenesulfenyl chloride is a stable commercially available sulfenyl chloride that, in conjunction with silver triflate, cleanly activates a wide range of thioglycosides for glycosylation at −78 °C in CH₂Cl₂.

Thioglycosides¹ are some of the most popular glycosyl donors because they are easily prepared and are stable to most functional group modifications. Although many other thiophilic reageants, including NIS–TfOH,² iodonium dicollidine perchlorate (IDCP),³ methyl trifluoromethanesulfonate (MeOTf)⁴ are known for the activation of thioglycosides, the sulfenyl/sulfonium class of thiophiles have gained considerable popularity since the discovery of dimethyl(methylthio)sulfonium triflate⁵ (DMTST) as a promoter. Methanesulfenyl triflate (MeSOTf, MeSBr–AgOTf),⁶ benzenesulfenyl triflate (PhSOTf, PhSCl–AgOTf)^7,8 and p-toluenesulfenyl triflate (p-TolSOTf, p-TolSCl–AgOTf)⁹ have been investigated as powerful promoters capable of activating thioglycosides rapidly and cleanly at −78 °C with the formation of glycosyl triflates⁸ as intermediates and stable disulfide byproducts. However, methanesulfenyl bromide (MeSBr), benzenesulfenyl chloride (PhSCl), and p-toluenesulfenyl chloride (p-TolSCl) are not commercially available owing to their limited shelf-life, and must be prepared and distilled prior to use. The 1-benzenesulfinyl piperidine (BSP)/trifluoromethanesulfonic anhydride (Tf₂O),¹⁰ diphenyl sulfoxide (DPSO)–Tf₂O, ^11,12 benzenesulfinyl morpholine–Tf₂O¹³ and dimethyl disulfide–Tf₂O¹⁴ protocols have been developed as shelf-stable substitutes for this sulfenyl halide-based chemistry and have been employed widely in oligosaccharide synthesis. Herein, we report on the use of a stable, commercially available p-nitrobenzenesulfenyl chloride (p-NO₂PhSCl) as an activator for glycosylation in conjunction with silver trifluoromethanesulfonate (AgOTf). p-Nitrobenzenesulfenyl chloride is an orange solid that has been previously employed as the precursor to photolabile sulfenate esters and, thus, as a source of alkoxy radicals.^15,16

As a first demonstration of the method, the coupling of mannopyranoside donor 1 and an amino acid 2 was conducted using 1 eq p-NO₂PhSCl–2.5 eq AgOTf as promoter in CH₂Cl₂. This reaction was complete in 30 min at −78 °C and gave the α-anomeric product in 80% yield. As expected, the disulfide 4 was also obtained in 83% yield (Scheme 1).

Scheme 1.

A number of other examples were then conducted employing 1.2 eq p-NO₂PhSCl, 2.5 eq AgOTf and 1.5 eq acceptor in CH₂Cl₂, occasionally in admixture with acetonitrile^17,18 or 2,4,6-tri-tert-butylpyrimidine (TTBP)¹⁹ as additive. The acetate glucose donor 5 and acceptor 6 were pre-mixed and then activated to give disaccharide 7 in 95% yield (Table 1, entry 1). The formation of the β-isomer in this example relies on the neighboring group participation effect. The coupling of 5 with a primary alcohol 8, the acetyl-transfer product 9 predominated (Table 1, entry 2). Preactivation of the 4,6-O-benzylidene mannopyranoside 10 followed by addition of acceptor 6 gave a 13:1 (β:α) anomeric mixture of disaccharides in 72% yield; When 6 and 10 were pre-mixed before activation in the presence of 20% acetonitrile, only a 5:1 (β:α) selectivity was obtained (Table 1, entry 3, 4). The pre-activated 4,6-O-benzylidene glucopyranosyl donor 12 gave a 3:1 (α:β) anomeric mixture of disaccharides after preactivation and then the addition of acceptor 13 as expected on the basis of earlier work (Table 1, entry 5). ^6,20 The tetra-O-benzyl glucosyl donor 15 exhibited a β-selective coupling with a primary alcohol (Table 1, entry 6) in keeping with the observation of Hashimoto²¹ for a related coupling. However, with a less reactive partner 17 the more typical α-selectivity reasserted itself (Table 1, entry 7).

Table 1.

Entry	Donor	Acceptor	Coupling Product	Yield(α:β)e
1	5	6	7	95%b,d(β only)
2	5	8	9	75%b.
3	10		11	72%a,c(1:13)
4		6		80%b,c,d(1:5)
5	12	13	14	88%a,c(3:1)
6	15	8	16	85%a,c(1:3)
7	15	17	18	82%a,c(7:3)
8	19	8	20	20%b,d(β only)
9	21	8	22	60%b,c, d(1.5:1)
10	23	24	25	77%a,d(3:1)

^apreactivation;

^bpre-mixed;

^c1.2 eq TTBP;

^d20% (v/v) acetonitrile;

^edetermined by ¹H NMR analysis on the crude reaction mixture.

With the N-acetylglucosamine based thioglycoside 19 (Table 1, entry 8), oxazoline ring formation could not be suppressed; nevertheless, the glycosylation product 20 was formed in 20% yield. In the coupling of phenyl thiosialoside donor 21 and acceptor 8, the anomeric ratio of the products was formed to be 1.5:1 (α:β) for a coupling conducted in the presence of acetonitrile, comparable to the result achieved with the DPSO/Tf₂O²² promotion system. Encouragingly, the p-NO₂PhSOTf promoter could activate even the relatively inert phenyl thiosialoside donor 23 at −78 °C. Thus, premixing of donor 23 and acceptor 24 at −78 °C with acetonitrile as additive before activation afforded the α-sialoside (3:1) in good yield (Table 1, entry 10). This result is comparable to the NIS–TfOH²³ activated reaction using the more reactive 1-adamantanyl thiosialoside donor and the same acceptor.

In summary, the shelf stable, commercially available p-NO₂PhSCl–AgOTf promoter works well with different kinds of donors. Both 1,2-trans and 1,2-cis products are formed as major products according to the choice of protecting group.

1. Experimental

1.1. General methods

Optical rotations were determined with an Autopol III polarimeter. ¹H and ¹³C NMR spectra were recorded at 500 and 125 MHz, respectively, with chemical shifts reported downfield from tetramethylsilane. All solvents were dried by standard procedures. Commercial reagents were used without purification. Air and/or moisture-sensitive reactions were carried out under an atmosphere of argon or nitrogen using oven-dried glassware.

1.2. Typical procedure for coupling of pre-mixed donors and acceptors: α-tert-Butyl γ-{3,4,6-tri-O-benzyl-2-O-[3′-(2″-benzyloxy-4″,6″-dimethylphenyl) -3′,3′-dimethylpropanoyl]-α-D-mannopyranosyl}-N-tert-butyloxycarbonyl-L-glutamate (3) and 1-ethyl-2-(p-nitrophenyl)disulfane (4)

A suspension of 1 (88 mg, 0.11 mmol), 2 (51 mg, 0.17 mmol), silver triflate (72 mg, 0.28 mmol) and 5 Å molecular sieves in anhydrous CH₂Cl₂ (1 mL) was stirred, with the exclusion of light, for 10 min at room temperature under N₂ before it was cooled to −78 °C. A solution of p-nitrobenzenesulfenyl chloride (22.3 mg, 0.11 mmol, 95% purity) in anhydrous CH₂Cl₂ (0.5 mL) was dropped into the above suspension at −78 °C. TLC analysis showed the reaction to be finished after stirring for 30 min at −78 °C after which a satd aq NaHCO₃ solution (0.2 mL) was added. The reaction mixture was diluted with CH₂Cl₂ (5 mL) to give a suspension, which was filtered through Celite and the Celite pad was washed with CH₂Cl₂ (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (10:1→3:1, hexane–EtOAc) to give first 4 (20 mg, 0.09 mmol, 83%) as a light yellow color oil, and then 3 (92 mg, 0.09 mmol, 80%) in the form of a viscous oil. Compound 3: [α]¹⁸D +22.5 (c, 1.0, CHCl₃); lit.²⁴ [α]¹⁶D +22.2 (c, 1.0, CHCl₃); ¹H and ¹³C NMR spectral data matched that reported.²⁴ Compound 4: ¹H NMR (500 MHz, CDCl₃): δ: 1.33 (t, J = 7.5 Hz, 3H), 2.80 (q, J = 7.5 Hz, 2H), 7.60 (m, 2H), 8.11 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 14.5, 33.1, 124.2, 126.0, 146.4, 147.5; HRMS(EI): calcd for C₈H₉NO₂S₂[M⁺]: 215.0075. Found: 215.0079.

1.3. Typical procedure for glycosylation with preactivation of the donor: Methyl 2,3,6-tri-O-benzyl-4-O-(2,3-di-O-benzyl-4,6-O-benzylidene-β-D-mannopyranosyl)-α-D-glucopyranoside (11)

A suspension of 10 (73 mg, 0.15 mmol), TTBP (44.0 mg, 0.18 mmol, 1.2 eq), silver triflate (95 mg, 0.37 mmol, 2.5 eq) and 5Å molecular sieves in anhydrous CH₂Cl₂ (1 mL) was stirred, with the exclusion of light, for 10 min at room temperature under N₂ before it was cooled to −78 °C. A solution of p-nitrobenzenesulfenyl chloride (35.5 mg, 0.18 mmol, 1.2 eq, 95% purity) in anhydrous CH₂Cl₂ (0.5 mL) was dropped into the above suspension at −78 °C. After 5 min, A solution of 6 (103 mg, 0.22 mmol, 1.5 eq) in anhydrous CH₂Cl₂ (1 mL) was dropped into this suspension. TLC analysis showed the reaction to be finished after stirring for 1 h at −78 °C after which a satd aq NaHCO₃ solution (0.2 mL) was added. The reaction mixture was diluted with CH₂Cl₂ (5 mL) to give a suspension, which was filtered through Celite and the Celite pad was washed with CH₂Cl₂ (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (9:1, toluene–EtOAc) to give 11 (95 mg, 0.11 mmol, 72%) in the form of a viscous oil. Compound 11: [α]²⁰D −26.3 (c, 1.0, CHCl₃); lit.²⁵ [α]²⁸D −26.4 (c, 1.5, CHCl₃); ¹H and ¹³C NMR spectral data matched that reported.²⁵

1.4 Methyl 2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-α-D-glucopyranoside (7)

Colourless syrup; [α]²⁰D −5.1 (c, 1.1, CHCl₃); lit.²⁶ [α]²⁰D −5.0 (c, 1.0, CHCl₃); ¹³C NMR spectral data matched that reported.²⁷

1.5 3-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranosyl)-1,2;5,6-di-O-isopropylidene-α-D-glucofuranose (14α)

[α]¹⁸D +5.9 (c, 1.0, CHCl₃); lit.²⁰ [α]D +5.8 (c, 0.8, CHCl₃); ¹H and ¹³C NMR spectral data matched that reported.²⁰

1.6 Methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-α-D-glucopyranoside (16β)

Colourless syrup; [α]²⁰D +19.8° (c, 1.0, CHCl₃); lit.²⁸ [α]²⁴D +19.3° (c, 0.2, CHCl₃); ¹H and ¹³C NMR spectral data matched that reported.²⁸

1.7 2,6-Dimethylphenyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside (18α)

Colourless syrup; [α]¹⁸D +36.5 (c, 1.0, CHCl₃); lit.⁸ [α]²⁰D +36.7 (c, 4.2, CHCl₃); ¹H and ¹³C NMR spectral data matched that reported.⁸ 18β was isolated as a mixture together with 18α, the ¹H and ¹³C NMR spectral data matched that reported.⁸

1.8 Methyl 6-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-2,3,4-tri-O- benzyl-α-D-glucopyranoside (20)

Colourless syrup; [α]²⁰D −19.9 (c, 1.0, CHCl₃); lit.²⁹ [α]²⁵D −20.1 (c, 1.0, CHCl₃); ¹H and ¹³C NMR spectral data matched that reported.²⁹

1.9 Methyl [methyl 5-(N-acetylacetamido)-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-non-2-ulopyranosylonate]-2,3,4-tri-O-benzyl-α-D-glucopyr anoside (22α) and Methyl [methyl 5-(N-acetylacetamido)-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-non-2-ulopyranosylonate]-2,3,4-tri-O-benzyl-α-D-glucopyranoside (22β)

22α and 22β was isolated as an anomeric mixture, the ¹H and ¹³C NMR spectral data matched that reported.²²

1.10 Methyl [methyl 5-acetamido-7,8,9-tri-O-acetyl--5-N, 4-O-carbonyl-3,5-dideoxy-D-glycero-α-D-galacto-non-2-ulopyranosylonate]-2,4,6-tri-O-benzyl-β-D-galactopyranoside (25α) and Methyl [methyl 5-acetamido-7,8,9-tri-O-acetyl-5-N, 4-O-carbonyl-3,5-dideoxy-D-glycero-β-D-galacto-non-2-ulopyranosylonate]-2,4,6-tri-O-benzyl-β-D-galactopyranoside (25β)

25α and 25β was isolated as an anomeric mixture, the ¹H and ¹³C NMR spectral data matched that reported.²³