Chemoselectivity and Unusual Internal Acetal Formation in the Synthesis of a Glycosidation Precursor

Abstract

Chemoselective deprotection of a tert-butyldimethyl (TBS) silyl ether group in the presence of an acetal moiety within an advanced iridoid precursor using scandium trifluoromethanesulfonate at 25 °C unexpectedly leads to internal acetal formation in high yield (70%). The same reaction at 0 °C resulted in spontaneous lactonisation of the diol intermediate, which was further elaborated to an iridoid glycosidation precursor.

iridoids - glycosidation - scandium triflate - chemoselective deprotection

References and Notes

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12 Martin VS. Carlsen PHJ. Katsuki T. Sharpless KB. J. Org. Chem.  1981,  46:  3936 

13

Methyl (3 R *,4 R *)-6-( tert -Butyldimethylsilanyloxy)-3-(2- tert -butyldimethylsilanyloxyethyl)-4-(1,3-dioxan-2-yl)hexanoate(14)
Sodium metaperiodate (10% solution in H₂O, 100 mL) and RuO₂ (60 mg, 0.5 mmol) were added sequentially to a vigorously stirred solution of 13 (21.32 g, 44.8 mmol) in CCl₄-MeCN (1:1, 100 mL) at 0 °C. Stirring was continued at this temperature for 18 h. The resulting mixture was poured into CH₂Cl₂-H₂O (1:1, 1000 mL) and the aqueous layer was extracted with CH₂Cl₂. The organic phase was dried (MgSO₄) and the solvent was removed under reduced pressure to give the acid (27.21 g), which was dissolved in MeCN (400 mL). N,N-Dimethylformamide (50 mL) was added, followed by K₂CO₃ (12.36 g, 89.6 mmol) and IMe (3.3 mL, 53.8 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure and the residual aqueous slurry was added to EtOAc (800 mL). The organic phase was washed with H₂O and brine, dried (MgSO₄), and the solvent was removed under reduced pressure to give a residue (29.32 g), which was purified by chromatography on silica gel (800 g) using EtOAc-hexane (1:9) as eluent, to yield the ester 14 (20.54 g, 91%) as a gum. IR (CHCl₃): ν_max = 1729 (CO) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.02 [6 H, s, Si(CH₃)₂], 0.04 [6 H, s, Si(CH₃)₂], 0.87 [9 H, s, SiC(CH₃)₃], 0.88 [9 H, s, SiC(CH₃)₃], 1.23-1.31 (1 H, m, 5′′-H_A), 1.38-1.80 (5 H, m, 4-H, 5-H₂, 1′-H₂), 1.93-2.07 (1 H, m, 5′′-H_B), 2.16 (1 H, dd, J = 15.6, 7.9 Hz, 2-H_A), 2.25-2.37 (1 H, m, 3-H), 2.57 (1 H, dd, J = 15.6, 5.7 Hz, 2-H_B), 3.63 (3 H, s, OCH₃), 3.55-3.79 (6 H, m, 6-H₂, 2′-H₂, 4′′-H_A, 6′′-H_A), 4.00-4.10 (2 H, m, 4′′-H_B, 6′′-H_B), 4.45 (1 H, d, J = 3.9 Hz, 2′′-H). ¹³C NMR (100 MHz, CDCl₃): δ = -5.1 and -5.1 [2 × Si(CH₃)₂], 18.4 and 18.5 [2 × SiC(CH₃)₃], 26.0 (C-5′′), 26.1 and 26.2 [2 × SiC(CH₃)₃], 29.4 (C-1′ or C-5), 32.6 (C-3), 35.7 (C-1′ or C-5), 36.8 (C-2), 42.1 (C-4), 51.5 (OCH₃), 61.8 and 62.9 (C-2′, C-6), 66.9 and 67.0 (C-4′′, C-6′′), 104.4 (C-2′′) and 174.2 (C-1). HRMS: m/z calcd for C₂₅H₅₂O₆Si₂ [M]: 504.3303; found [M⁺]: 504.3268.

14 Boger DL. Borzilleri RM. Nukui S. Beresis RT. J. Org. Chem.  1997,  62:  4721 

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17

Methyl (4′ S *,4′a R *,7′aR*)-{Hexahydrofuro[2,3- b ]pyran-4-yl}acetate (15)
Water (0.22 mL, 12.6 mmol) followed by a solution of scandium trifluoromethanesufonate (6.2 mg, 0.013 mmol) in MeCN (5 mL) were added to a stirred solution of 14 (1.27 g, 2.52 mmol) in MeCN (20 mL). The reaction was stirred for 40 min at 25 °C after which sat. aq NH₄Cl was added. The resulting mixture was extracted with CH₂Cl₂, dried (MgSO₄), and the solvent was removed in vacuo. Chromatography of the residue (750 mg) on silica gel (70 g) using EtOAc-hexane (3:7) as eluent, yielded the acetal 15 (354 mg, 70%) as an oil. IR (CHCl₃): ν_max = 1732 (CO) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.26 (1 H, dtd, J = 13.7, 2 × 8.3, 3.6 Hz, 3′-H_A), 1.70-1.91 (3 H, m, 3′-H_B, 4′a-H, 5′-H_A), 1.96 (1 H, dtd, J = 12.1, 8.3, 2 × 7.2 Hz, 5′-H_B), 2.04-2.16 (1 H, m, 4′-H), 2.26 (1 H, dd, J = 15.1, 8.8 Hz, 2-H_A), 2.47 (1 H, dd, J = 15.1, 5.4 Hz, 2-H_B), 3.60 (1 H, ddd, J = 11.6, 6.2, 3.6 Hz, 2′-H_A), 3.65 (3 H, s, OCH₃), 3.76 (1 H, ddd, J = 11.6, 8.3, 3.5 Hz, 2′-H_B), 3.83 (1 H, td, J = 2 × 8.0, 5.2 Hz, 6′-H_A), 4.02 (1 H, q, J = 3 × 8.0 Hz, 6′-H_B), 5.12 (1 H, d, J = 3.6 Hz, 7′a-H). ¹³C NMR (75 MHz, CDCl₃): δ = 27.4 (C-3′), 27.8 (C-5′), 31.2 (C-4′), 39.2 (C-2), 41.1 (C-4′a), 51.5 (OCH₃), 60.2 (C-2′), 65.6 (C-6′), 100.2 (C-7′), 172.1 (C-1). HRMS: m/z calcd for C₁₀H₁₆O₄ [M]: 200.1049; found [M⁺]: 200.1061.

18 Oriyama T. Kobayashi Y. Noda K. Synlett  1998,  1047 

19

(2′ R *,4 R *)-4-[4- tert -Butyldiphenylsilanyloxy-1-(propan-1,3-dioxy)butan-2-yl]tetrahydropyran-2-one (17)
tert-Butyldiphenylsilyl chloride (0.13 mL, 0.49 mmol) and imidazole (33 mg, 0.49 mmol) were added to a stirred solution of 16 (40 mg, 0.16 mmol) in MeCN. The solution was stirred for 2 h, diluted with CH₂Cl₂, washed with H₂O, dried (MgSO₄), and the solvent was removed to give the crude product (280 mg). Chromatography on silica gel (20 g) using EtOAc-hexane (3:7) as eluent afforded the silyl ether 17 (75 mg, 97%). IR (CHCl₃): ν_max = 1731 (CO) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.05 [9 H, s, C(CH₃)₃], 1.24-1.31 (1 H, m, 2′′-H_A), 1.46-1.58 (1 H, m, 3′-H_A), 1.60-1.81 (4 H, m, 5-H₂, 2′-H, 3′-H_B), 1.97 (1 H, qt, J = 3 × 12.6, 2 × 4.9 Hz, 2′′-H_B), 2.26-2.40 (2 H, m, 3-H_A, 4-H), 2.61-2.73 (1 H, m, 3-H_B), 3.54-3.73 (3 H, m, 4′-H_A, 1′′-H_A, 3′′-H_A), 3.74-3.83 (1 H, m, 4′-H_B), 3.98-4.07 (2 H, m, 1′′-H_B, 3′′-H_B), 4.15 (1 H, td, J = 2 × 11.1, 3.7 Hz, 6-H_A), 4.32 (1 H, ddd, J = 11.1, 4.8, 3.7 Hz, 6-H_B), 4.43 (1 H, d, J = 3.5 Hz, 1′-H), 7.33-7.45 (6 H, m, ArH), 7.63-7.70 (4 H, m ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 17.1 [C(CH₃)₃], 23.7 (C-2′′), 24.9 [C(CH₃)₃], 25.0 (C-3′), 26.7 (C-5), 29.2 (C-4), 31.8 (C-3), 40.9 (C-2′), 60.5 (C-4′), 64.9 and 64.9 (C-1′′ and C-3′′) 66.7 (C-6), 100.9 (C-1′), 125.6 (0) and 125.6 (2), 127.6, 131.7 (6) and 131.8 (1), 133.5 (4) and 133.5 (9) (ArC), 170.0 (C-2). HRMS-FAB: m/z calcd for C₁₂H₁₉O₅Na [M]: 505.2386; found [M⁺ + Na]: 505.2372.

20 Grieco PA. Gilman S. Nishizawa M. J. Org. Chem.  1976,  41:  1485 

21

(2′ R *,3 E ,4 S *)-4-[4-Phenylselanyl-1-(propan-1,3-dioxy)butan-2-yl]-3-benzoyloxymethylenetetrahydro­-pyran-2-one (20)
Formyl lactone 19 (80 mg, 0.19 mmol) was dissolved in CH₂Cl₂-pyridine (2:1, 3 mL). Benzoyl chloride (0.05 mL, 0.43 mmol) was added and the solution was stirred at 25 °C for 90 min. The pyridine was removed under reduced pressure by azeotrope formation with toluene (3 × 30 mL). The resulting material was dissolved in CH₂Cl₂, washed with brine, and the aqueous phase was extracted with CH₂Cl₂. The organic extract was dried (MgSO₄) to give the benzoylated product (270 mg) which was purified by chromatography on silica gel (20 g) using EtOAc-hexane (1:9) to elute excess benzoyl chloride followed by elution with EtOAc-hexane (3:2) to yield the enol benzoate 20 (85 mg, 86%). IR (CHCl₃): ν_max = 1715, 1749 (CO) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.27-1.34 (1 H, m, 2′′′-H_A), 1.68-1.79 (1 H, m, 3′′-H_A), 1.83-1.93 (1 H, m, 5-H_A), 2.02 (1 H, qt, J = 3 × 12.4, 2 × 5.0 Hz, 2′′′-H_B), 2.09-2.24 (2 H, m, 5-H_B, 3′′-H_B), 2.24-2.33 (1 H, m, 2′′-H), 2.98-3.13 (2 H, m, 4′′-H₂), 3.32-3.41 (1 H, m, 4-H), 3.63-3.74 (2 H, m, 1′′′-H_A, 3′′′-H_A), 4.02-4.13 (3 H, m, 6-H_A, 1′′′-H_B, 3′′′-H_B), 4.39 (1 H, ddd, J = 11.3, 6.2, 3.9 Hz, 6-H_B), 4.57 (1 H, d, J = 3.3 Hz, 1′′-H), 7.16-8.14 (10 H, m, ArH), 8.36 (1 H, d, J = 1.7 Hz, 1′-H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.3 (C-5), 25.6 (C-2′′′), 26.6 (C-4′′), 28.6 (C-3′′), 33.0 (C-4), 45.1 (C-2′′), 66.4 (C-6), 66.8 and 66.9 (C-1′′′, C-3′′′), 102.5 (C-1′′), 116.7 (C-3), 126.8, 127.8, 128.4, 128.8, 129.0, 130.1, 130.2, 130.3, 132.5, 133.5 and 134.2 (ArC), 144.1 (C-1′), 162.0 (ArC=O), 167.4 (C-2). HRMS: m/z calcd for C₂₆H₂₈O₆ ⁸⁰Se [M]: 516.1051; found [M⁺]: 516.1053.

22 Mazal C. Jonas J. Collect. Czech. Chem. Commun.  1993,  58:  1607 

23 Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   John Wiley and Sons; New York: 1999.  p.317 

24 Marko IE. Gautier A. Ates A. Leroy B. Angew. Chem. Int. Ed.  1999,  38:  3207 

25

(4a S *,5 R *,6 R *)-6-Hydroxy-5-(2-phenylselanylethyl)-4,4a,5,6-tetrahydro-3 H -pyrano[3,4- c ]-pyran-1-one ( 21)
Borate-HCl buffer (pH 8, 2 mL) followed by CAN (18 mg, 0.03 mmol) were added to a stirred solution of 19 (150 mg, 0.36 mmol) in MeCN (2 mL). The resulting mixture was stirred at 60 °C for 24 h and then cooled and diluted with CH₂Cl₂ (10 mL). The aqueous phase was extracted with CH₂Cl₂, the combined organic phases were dried (MgSO₄), and the solvent was removed under reduced pressure to give an oil (140 mg). Flash chromatography on silica gel (12 g) using EtOAc-hexane (1:1) as eluent afforded the hemiacetal 21 (82 mg, 65%). ¹H NMR (400 MHz, CDCl₃): δ = 1.34-1.55 (1 H, m, 1′-H_A), 1.56-1.82 (3 H, m, 4-H₂ and 1′-H_B), 2.06-2.18 (1 H, m, 5-H), 2.70-3.20 (3 H, m, 4a-H, 2′-H₂), 4.18-4.32 (1 H, m, 3-H_A), 4.35-4.47 (1 H, m, 3-H_B), 5.46 (1 H, d, J = 1.8 Hz, 6-H), 7.20-7.29 (3 H, m, ArH), 7.43-7.50 (2 H, m, ArH), 7.55 (1 H, d, J = 2.2 Hz, 8-H). ¹³C NMR (75 MHz, CDCl₃): δ = 24.2 (C-4), 25.1 (C-1′), 25.6 (C-2′), 27.8 (C-4a), 36.9 (C-5), 68.2 (C-3), 94.1 (C-6), 103.5 (C-8a) 127.2, 129.2 and 132.9 (ArC), 153.3 (C-8), 166.3 (C-1).