Total Synthesis of (8 S ) and (8 R ) Methyl 8-β- d -Glucopyranosyl-Helianthenate B and Their Application for Other Derivatives

Abstract

The first total synthesis of (8R) and (8S) methyl β-d-glucopyranosyl helianthenate B was accomplished using the Cadiot-Chodkiewicz coupling reaction as a key step. Significant differences were observed in the resonances between the ¹H-NMR and ¹³C-NMR spectra of the diastereomers. Based on these results, the absolute configurations of glucopyranosyloxymethine in methyl β-d-glucopyranosyl helianthenate A to E (1 -5) were reconfirmed to be the (R) configuration.

The isolation and structural determination of methyl β-d-glucopyranosyl helianthenate A to E (1 -5, Figure 1) from leaves of Jerusalem artichoke (Helianthus tuberosus L.) were reported in previous papers. ^1,2 The absolute configuration of glucopyranosyloxymethine in methyl β-d-glucopyranosyl helianthenate B (2) was determined to be in the (R) configuration, and those of methyl β-d-glucopyranosyl helianthenate A (1) and C to E (3-5) were also determined to be in the (R) configuration by comparing the ¹H- and ¹³C-NMR data with those of methyl (8R) 8-β-d-glucopyranosyl helianthenate B (2). However, there is a remote possibility that there are no sufficient differences in the ¹H- and ¹³C-NMR chemical shift data between the (8R) and (8S) methyl 8-β-d-glucopyranosyl helianthenate B diastereomers. In this paper, we accomplished the total synthesis of (8R) and (8S) methyl 8-β-d-glucopyranosyl helianthenate B (6a, 6b), revealing that there were distinguishable differences in the chemical shifts, especially in the terminal olefin and anomeric proton of glucose moiety in ¹H-NMR and the terminal olefin and glucopyranosyloxymethine carbon in ¹³C-NMR.

Figure 1

Chemical structures of methyl 8-β-d-glucopyranosyl helianthenate B (2) and its related compounds.

We anticipated that synthesis of (8R) and (8S) methyl 8-β-d-glucopyranosyl helianthenate B (6a and 6b, respectively) could be accomplished using the Cadiot-Chodkiewicz coupling reaction ³ as a key step. First, compound 9, 1-trimethylsilylpent-4-en-1-yn-3-ol, was synthesized according to Scheme 1, coupling trimethylsilyl acetylene (7) with acrolein (8). The key compounds, (3R)- and (3S)-3-tetra-O-acetyl-β-d-glucopyranosyloxy-1-trimethylsilylpent-4-en-1-yn (11a and 11b, respectively), were obtained by coupling 9 with 2,3,4,6-tetra-O-acetyl-1-bromo-β-d-glucopyranoside (10) and separable using silica gel chromatography (Et₂O:n-hexane, 8:92, v/v). The protective groups, trimethylsilyl and acetyl moieties, of 11a and 11b were removed by treatment with NaOMe in MeOH to give 12a and 12b, respectively. The β configurations of the d-glucose moiety were confirmed from coupling constants of the anomeric proton (δ 4.36, J = 7.8 Hz for 12a and δ 4.65, J = 7.9 Hz for 12b) in the ¹H-NMR spectra and the resonances (δ 100.8 for 12a and δ 100.9 for 12b) in the ¹³C-NMR spectra. Compounds 12a and 12b were subjected to a Cadiot-Chodkiewicz coupling reaction ³ with 5-bromopent-4-yn-1-oic acid (14) to afford (8R) and (8S) methyl 8-β-d-glucopyranosyl helianthenate B (6a, [α]_D: −55.8 and 6b, [α]_D: −61.2), respectively. Because the ¹H- and ¹³C-NMR spectra of 6a had good accordance with those of (8R) methyl 8-β-d-glucopyranosyl helianthenate B ² ([α]_D: −50.0), ¹ the absolute configurations of glucosyloxymethine in 11a and 12a were determined to be (3R), and therefore those of 11b and 12b were determined to be (3S).

Scheme 1

(a) EtMgBr/THF (76%); (b) HgO, HgBr₂, drierite/CHCl₃, 1-bromo-2,3,4,6- tetraacetylglucose (10) (19% for 11a, 16% for 11b); (c) NaOMe/Me0H (89% for 12a, 95% for 12b); (d) CuI (I), 35% aq. C₂H₅NH₂, NHOH-HCl, 5-bromo-pent-4-yn-1-oic acid (14) (54% for 6a, 34% for 6b).

The partial ¹H- and ¹³C-NMR spectral data for methyl β-d-glucopyranosyl helianthenate A (1), B (2), C (3), D (4), and E (5) and (8S) methyl 8-β-d-glucopyranosyl helianthenate B (6b) are given in Tables 1 and 2. By surveying those data, differences between 1 to 5 and 6b are clearly observed, especially between the chemical shifts for the terminal olefin cis protons (Hb in Table 1) and anomeric protons (He in Table 1) in the ¹H-NMR spectra. In ¹³C-NMR spectra (Table 2), the differences were observed at terminal olefin and glucopyranosyloxymethine carbons.

Table 1

¹ H-NMR Chemical Shift for the Partial Structure.

			Chemical shift (ppm)
Compound		Ha	Hb	Hc	Hd	He
1		5.44	5.32	5.87	5.12	4.34
2	(=6a)	5.43	5.31	5.85	5.11	4.33
3		5.44	5.35	5.85	5.21	4.34
4		5.44	5.32	5.86	5.12	4.34
5		5.46	5.32	5.87	5.18	4.33
6b		5.48	5.26	5.93	5.26	4.60

Table 2

¹³C-NMR Chemical Shift for the Partial Structuure.

		Chemical shift (ppm)
Compound	Ca	Cb	Cc	Cd
1	119.8	135.4	70.1	101.1
2(=6a)	119.9	135.3	70.0	101.1
3	119.8	135.4	70.1	101.1
4	119.8	135.4	70.1	101.1
5	120.1	135.2	70.1	101.1
6b	118.2	135.7	71.6	101.1

The first total syntheses of (8R) and (8S) methyl 8-β-d-glucopyranosyl helianthenate B (6a and 6b, respectively) were accomplished; this result confirmed that the conformational differences in glucosyloxymethine, (R) or (S), gave sufficient differences in the ¹H- and ¹³C-NMR spectral data for the methyl β-d-glucosyloxy-helianthenate A to E (1-5) series. However, the absolute configurations of the hydroxyl methine C-3 in methyl β-d-glucopyranosyl helianthenate C (3) and E (5) still remain unclear. Therefore, further study is needed to determine these configurations.

Experimental

General

Spectra were obtained with the following instruments: IR, Hitachi 285 spectrometer; optical rotation values, JASCO DIP-4 polarimeter; NMR, Brucker AM-500 FT-NMR spectrometer and JEOL JNM-EX 270 FT-NMR system; and FD- and EI-MS, JEOL JMS-O1SG-2 and JMS-DX-300 mass spectrometers, respectively.

Preparation of Methyl ( 8 R ) and ( 8 S ) Methyl 8-β- d-Glucopyranosyloxydec-9-Ene-6,4-Diyn-1-Oate (6a, 6b)

1-Trimethylsilylpent-4-En-1-Yn-3-Ol (9)

EtMgBr in THF was prepared from Mg (864 mg, 36 mmol) and EtBr (4.2 g, 2.9 mL, 38 mmol) in THF (40 mL) using a general method. Trimethylsilylacetylene (7, 1.78 g, 2.5 mL, 18 mmol) in THF (20 mL) was added to the EtMgBr solution over 20 minutes and the reaction mixture was stirred for 1 hour at 50°C. Acrolein (8) (1.68 g, 2.5 mL, 30 mmol) in THF (2.5 mL) was added to the stirred mixture over 30 minutes at room temperature, and this solution was further stirred for 45 minutes. A solution of saturated aqueous NH₄Cl (40 mL) was added to the reaction mixture and the organic layers were then dissolved in Et₂O (80 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 3) and dried over Na₂SO₄. The volatile component was removed under reduced pressure to give a pale yellow oil, which was purified by flash chromatography (Et₂O-n-hexane = 2 : 8, v/v) to give 9 (2.1 g, 13 mmol, 76%).

IR υ _max (film) cm⁻¹: 3290, 2930, 2140, 1400, 1240, 1220, 1020, 980, 840, 760.

¹H-NMR (270 MHz, CDCl₃) ppm: 5.95 (1H, ddd, J = 16.8, 10.2, 5.6 Hz), 5.45 (1H, d, J = 16.8 Hz), 5.19 (1H, d, J = 10.2 Hz), 4.87 (1H, br.t, J = 5.6 Hz), 0.18 (9H, s).

¹³C-NMR (67.8 MHz, CDCl₃) ppm: 137.0, 116.5, 104.7, 90.8, 63.4, 0.2.

EI-MS m/z (rel. int.): 99 (8), 91 (10), 83 (100), 73 (38), 55 (25).

(3R) and (3S) 3-Tetra-O-Acetyl-β-d-Glucopyranosyloxy-1-Trimethylsilylpent-4-En-1-Yne (11a, 11b)

A CHCl₃ (50 mL) solution containing HgO (II) (yellow) (5.6 g), HgBr₂ (468 mg, 1.3 mmol), and drierite (14 g) was placed in a 500 mL three-necked, round-bottom flask equipped with a stirring bar, septum cap, and N₂ balloon. Compound 9 (1.8 g, 11.6 mmol) in CHCl₃ (50 mL) was added to the stirred mixture and the reaction mixture was further stirred for 30 minutes at room temperature. Next, 1-bromo-2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (10, 21 g, 52 mmol) in CHCl₃ (50 mL) was added to the stirred mixture. The reaction mixture was stirred for an additional 48 hours at 30°C to 35°C and filtered off with celite. The organic layers were washed with saturated aqueous NaCl (80 mL × 2) and dried over Na₂SO₄. The volatile component was removed under reduced pressure to give an oil, which was purified by flash chromatography (Et₂O-n-hexane = 8 : 92, v/v) to give 11a (2.1 g, 4.7 mmol, 37%) and 11b (0.85 g, 1.8 mmol, 16%).

(3R) 3-Tetra-O-Acetyl-β-d-Glucopyranosyloxy-1-Trimethylsilylpent-4-En-1-Yne (11a)

IR υ _max (KBr) cm⁻¹: 2900, 2200, 1750, 1370, 1260, 1230, 1090, 1060, 980, 840, 760.

¹H-NMR (500 MHz, CDCl₃) ppm: 5.86 (1H, ddd, J = 16.9, 10.4, 6.4 Hz), 5.42 (1H, dt, J = 16.9, 1.3 Hz), 5.29 (1H, dt, J = 10.4, 1.3 Hz), 5.20 (1H, t, J = 9.5 Hz), 5.09 (1H, t, J = 9.5 Hz), 5.04 (1H, dd, J = 9.5, 8.0 Hz), 4.95 (1H, d, J = 6.4 Hz), 4.70 (1H, d, J = 8.0 Hz), 4.24 (1H, dd, J = 12.2, 4.6 Hz), 4.12 (1H, dd, J = 12.2, 2.1 Hz), 3.66 (1H, ddd, J = 9.5, 4.6, 2.1 Hz), 2.09 (3H, s), 2.05 (3H, s), 2.02 (3H, s), 2.01 (3H, s), 0.19 (9H, s).

¹³C-NMR (125.8 MHz, CDCl₃) ppm: 170.7, 170.3, 169.4, 169.3, 134.2, 118.8, 100.6, 97.5, 93.2, 73.0, 71.8, 71.1, 70.5, 68.4, 62.0, 20.7, 20.6, -0.2.

EI-MS m/z (rel. int.): 469 (0.1), 259 (3), 245 (6), 169 (9), 139 (20), 109 (12), 97 (16), 59 (16), 43 (100).

FDHRMS m/z [M]⁺ calculated for C₂₂H₃₃O₁₀Si: 485.1843, found 485.1867.

(3S) 3-Tetra-O-Acetyl-β-d-Glucopyranosyloxy-1-Trimethylsilyl-Pent-4-En-1-Yne (11b)

IR υ _max (KBr) cm⁻¹: 2900, 2100, 1750, 1560, 1220, 1040.

¹H-NMR (500 MHz, CDCl₃) ppm: 5.85 (1H, ddd, J = 17.0, 10.1, 5.1 Hz), 5.49 (1H, dd, J = 17.0, 1.2 Hz), 5.26 (2H, m), 5.11 (1H, t, J = 9.9 Hz), 5.02 (2H, m), 4.89 (1H, d, J = 8.0 Hz), 4.29 (1H, dd, J = 12.3, 4.6 Hz), 4.13 (1H, br.d, J = 12.3 Hz), 3.73 (1H, m), 2.09 (3H, s), 2.04 (3H, s), 2.03 (3H, s), 2.02 (3H, s), 0.21 (9H, s).

¹³C-NMR (125.8 MHz, CDCl₃) ppm: 170.6, 170.3, 169.3, 133.6, 118.0, 100.4, 97.4, 93.4, 72.6, 71.8, 70.9, 68.6, 68.4, 61.8, 20.7, 20.6, 20.5, −0.3.

EI-MS m/z (rel. int.): 469 (0.1), 259 (6), 245 (15), 169 (26), 139 (43), 97 (22), 59 (24), 43 (100).

FDHRMS m/z [M]⁺ calculated for C₂₂H₃₃O₁₀Si: 485.1843, found 485.1824.

(3R) 3-β-d-Glucopyranosyloxypent-4-En-1-Yne (12a)

NaOMe (4 mmol) in MeOH was added to a stirred mixture of 11a (170 mg, 0.31 mmol) and MeOH (10 mL) at 0°C and the reaction mixture was stirred for 30 minutes at the same temperature. An excess of IR-120B beads (Organo Corporation) were added to this stirred mixture, and then the beads were filtered off. The volatile component in the organic layer was removed under reduced pressure to give 12a (76 mg, 0.31 mmol, 89%).

IR υ _max (film) cm^-−1: 3300, 2900, 2100, 1400, 1250, 1060.

¹H-NMR (500 MHz, CD₃OD) ppm: 5.89 (1H, ddd, J = 17.1, 10.1, 7.3 Hz), 5.46 (1H, br.d, J = 17.1 Hz), 5.36 (1H, br.d, J = 10.1 Hz), 5.07 (1H, br.dt, J = 7.3, 2.1 Hz), 4.36 (1H, d, J = 7.8 Hz), 3.76 (1H, dd, J = 11.9, 2.1 Hz), 3.66 (1H, dd, J = 11.9, 5.9 Hz), 3.34-3.19 (4H, m), 2.97 (1H, d, J = 2.1 Hz).

¹³C-NMR (125.8 MHz, CD₃OD) ppm: 135.9, 119.5, 100.8, 82.1, 78.1, 76.2, 74.9, 71.6, 69.6, 62.8.

EI-MS m/z (rel. int.): 97 (14), 81 (41), 73 (43), 65 (81), 60 (49), 55 (60), 39 (100).

FDHRMS m/z [M+H]⁺ calculated for C₁₁H₁₇O₆: 245.1025, found 245.1015.

(3S) 3-β-d-Glucopyranosyloxypent-4-En-1-Yne (12b)

The deprotection of 11b (500 mg, 1.03 mmol) was performed according to the same method used for 11a, affording 12b (240 mg, 0.98 mmol, 95%).

IR υ _max (film) cm^–1: 3300, 2900, 2100, 1400-1220, 1080.

¹H-NMR (500 MHz, CD₃OD) ppm: 5.96 (1H, ddd, J = 17.0, 10.2, 5.4 Hz), 5.53 (1H, dt, J = 17.0, 1.4 Hz), 5.24 (1H, dt, J = 10.2, 1.4 Hz), 5.20 (1H, m), 4.65 (1H, d, J = 7.9 Hz), 3.87 (1H, dd, J = 11.8, 1.3 Hz), 3.66 (1H, dd, J = 11.8, 1.6 Hz), 3.03 (1H, d, J = 2.2 Hz).

¹³C-NMR (125.8 MHz, CD₃OD) ppm: 135.2, 117.9, 100.9, 80.9, 78.1, 77.6, 74.8, 71.6, 66.5, 62.7.

EI-MS m/z (rel. int.): 97 (18), 85 (19), 73 (72), 65 (100), 57 (51), 39 (46).

FDHRMS m/z [M+H]⁺ calculated for C₁₁H₁₇O₆: 245.1025, found 245.1036.

5-Bromopent-4-Yn-1-Oic Acid (14):

Compound 14 was prepared according to a reported method using pent-4-yn-1-oic acid (13) as a starting material.

( 8 R ) Methyl 8-β- d-Glucopyranosyloxydec-9-Ene-6,4-Diyn-1-Oate (6a):

CuI (0.5 mg) and NHOH-HCl (5 mg) were placed in a three-necked, round-bottom flask equipped with a stirring bar, septum cap, and N₂ balloon. The mixture was then suspended in 35% aqueous EtNH₂ (0.5 mL). Compound 11a (76 mg, 0.31 mmol) in MeOH (1 mL) was added to this solution, and then the reaction mixture was heated to 30-40°C. 5-Bromo-4-pentyn-1-oic acid (14) (98 mg, 0.55 mmol) in MeOH (0.75 mL) was added to this reaction mixture over 10 minutes, and the reaction mixture was further stirred for 3 hours. Six drops of 6 M HCl and an excess of IR-120B beads were added to the stirred mixture. The IR-120B beads were filtered off and the volatile components in the organic layers were removed under reduced pressure to afford an oil. This oil was dissolved into EtOH, excess CH₂N₂ (Et₂O solution) was added, and the reaction mixture was stirred for 60 minutes at 0°C. The volatile components were removed under reduced pressure and the residue was purified by flash chromatography to give 6a (58.8 mg, 0.17 mmol, 54%).

[α]_D ²⁵: −55.8 (c 1.18 MeOH).

¹H-NMR (500 MHz, CD₃OD) ppm: 5.86 (1H, ddd, J = 17.2, 10.2, 7.1 Hz), 5.44 (1H, dd, J = 17.2, 0.9 Hz), 5.32 (1H, dd, J = 10.2, 0.9 Hz), 5.11 (1H, br.d, J = 5.1 Hz), 4.33 (1H, d, J = 7.8 Hz), 3.86 (1H, dd, J = 11.9, 2.1 Hz), 3.69 (3H, s), 3.66 (1H, m), 3.31 (1H, m), 3.22 (1H, m), 2.57 (4H, m).

¹³C-NMR (125.8 MHz, CD₃OD) ppm: 173.7, 135.3, 120.0, 101.0, 81.0, 78.1, 78.0, 74.9, 74.3, 71.2, 71.5, 70.0, 65.6, 62.7, 52.4, 33.5, 15.7.

(8S) Methyl 8-β - d-Glucopyranosyloxydec-9-Ene-6,4-Diyn-1-Oate (6b):

The coupling reaction of 12b (20 mg, 0.08 mmol) with 14 was performed according to the same method used for 6a, affording 6b (10.0 mg, 0.03 mmol, 38%).

[α]_D ²⁵: −61.2 (c 0.50 MeOH).

¹H-NMR (500 MHz, CD₃OD) ppm: 5.93 (1H, m), 5.48 (1H, d, J = 17.0 Hz), 5.26 (2H, m), 5.20 (1H, m), 4.58 (1H, d, J = 7.8 Hz), 3.87 (1H, br.d, J = 12.2 Hz), 3.69 (3H, s), 3.66 (2H, m), 3.20 (2H, m), 2.57 (4H, m).

¹³C-NMR (125.8 MHz, CD₃OD) ppm: 173.6, 135.7, 118.2, 101.0, 80.8, 78.2, 78.0, 74.9, 73.4, 73.0, 71.6, 65.5, 62.7, 52.4, 33.4, 15.7.