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Synlett 2007(20): 3175-3179  
DOI: 10.1055/s-2007-990910
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Anne T. Stevensa, James R. Bulla, Kelly Chibale*a,b
a Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
b Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa
Fax: +27(21)6897499; e-Mail: Kelly.Chibale@uct.ac.za;
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Publication History

Received 18 October 2007
Publication Date:
21 November 2007 (online)

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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.

Key words

iridoids - glycosidation - scandium triflate - chemoselective deprotection

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): νmax = 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′′-HA), 1.38-1.80 (5 H, m, 4-H, 5-H2, 1′-H2), 1.93-2.07 (1 H, m, 5′′-HB), 2.16 (1 H, dd, J = 15.6, 7.9 Hz, 2-HA), 2.25-2.37 (1 H, m, 3-H), 2.57 (1 H, dd, J = 15.6, 5.7 Hz, 2-HB), 3.63 (3 H, s, OCH3), 3.55-3.79 (6 H, m, 6-H2, 2′-H2, 4′′-HA, 6′′-HA), 4.00-4.10 (2 H, m, 4′′-HB, 6′′-HB), 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.

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): νmax = 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′-HA), 1.70-1.91 (3 H, m, 3′-HB, 4′a-H, 5′-HA), 1.96 (1 H, dtd, J = 12.1, 8.3, 2 × 7.2 Hz, 5′-HB), 2.04-2.16 (1 H, m, 4′-H), 2.26 (1 H, dd, J = 15.1, 8.8 Hz, 2-HA), 2.47 (1 H, dd, J = 15.1, 5.4 Hz, 2-HB), 3.60 (1 H, ddd, J = 11.6, 6.2, 3.6 Hz, 2′-HA), 3.65 (3 H, s, OCH3), 3.76 (1 H, ddd, J = 11.6, 8.3, 3.5 Hz, 2′-HB), 3.83 (1 H, td, J = 2 × 8.0, 5.2 Hz, 6′-HA), 4.02 (1 H, q, J = 3 × 8.0 Hz, 6′-HB), 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.

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): νmax = 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′′-HA), 1.46-1.58 (1 H, m, 3′-HA), 1.60-1.81 (4 H, m, 5-H2, 2′-H, 3′-HB), 1.97 (1 H, qt, J = 3 × 12.6, 2 × 4.9 Hz, 2′′-HB), 2.26-2.40 (2 H, m, 3-HA, 4-H), 2.61-2.73 (1 H, m, 3-HB), 3.54-3.73 (3 H, m, 4′-HA, 1′′-HA, 3′′-HA), 3.74-3.83 (1 H, m, 4′-HB), 3.98-4.07 (2 H, m, 1′′-HB, 3′′-HB), 4.15 (1 H, td, J = 2 × 11.1, 3.7 Hz, 6-HA), 4.32 (1 H, ddd, J = 11.1, 4.8, 3.7 Hz, 6-HB), 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.

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): νmax = 1715, 1749 (CO) cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.27-1.34 (1 H, m, 2′′′-HA), 1.68-1.79 (1 H, m, 3′′-HA), 1.83-1.93 (1 H, m, 5-HA), 2.02 (1 H, qt, J = 3 × 12.4, 2 × 5.0 Hz, 2′′′-HB), 2.09-2.24 (2 H, m, 5-HB, 3′′-HB), 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′′′-HA, 3′′′-HA), 4.02-4.13 (3 H, m, 6-HA, 1′′′-HB, 3′′′-HB), 4.39 (1 H, ddd, J = 11.3, 6.2, 3.9 Hz, 6-HB), 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.

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′-HA), 1.56-1.82 (3 H, m, 4-H2 and 1′-HB), 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-HA), 4.35-4.47 (1 H, m, 3-HB), 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).