Formal Total Synthesis of (−)-Saliniketals

Formal Total Synthesis of (−)-Saliniketals J. S. Yadav,* Sk. Samad Hossain, Madasu Madhu, and Debendra K. Mohapatra Organic Chemistry Division-I, Indian Institute of Chemical Technology (CSIR), Hyderabad 500007, India [email protected]; [email protected] * Corresponding author. Tel.: +91-40-27193030; fax: +91-40-27160512 H2N O O O O O O 6 OBn O 3 OH O O O R OH OH 1. R = H; Saliniketal A 2. R = OH; Saliniketal B S1 Table of Contents: S. No Description Page 1 General Description and Experimental Details S4 S12 2 Spectral data of 10 S13 3 Spectral data of 11 S14 4 Spectral data of 12 S15 S16 5 Spectral data of keto S17 6 Spectra data of 13 S18 S19 7 Spectral data of 16 S20 S21 8 Spectral data of 14 S22 S23 9 Spectral data of alcohol S24 S25 10 Spectral data of 15 S26 S27 11 Spectral data of 16 S28 S29 12 Spectral data of 17 S30 S2 13 Spectral data of 18 S31 S32 S33 S34 S35 14 Spectral data of acetate derivative S36 S37 15 Spectral data of 5 S38 S39 16 Spectral data of 21 S40 S41 17 Spectral data of hydroxyl compound S42 S43 18 Spectral data of 22 S44 S45 S46 S47 S48 19 Spectral data of 23 S49 S50 20 Spectral data of 24 S51 S52 S53 21 Spectral data of 3 S54 S55 S3 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in an oven/flame-dried glassware. All anhydrous solvents were distilled prior to use: THF, benzene, toluene and diethyl ether from Na and benzophenone; CH2Cl2, N-methyl pyrolidinone from CaH2; MeOH, EtOH from Mg cake. Commercial reagents were used without purification. Column chromatography was carried out by using Spectrochem silica gel (60–120 mesh). Specific optical rotations [α]D are given in 10-1 degcm2g-1. Infrared spectra were recorded in CHCl3/neat (as mentioned) and reported in wave number (cm-1). 1H and 13 C NMR chemical shifts are reported in ppm downfield from tetramethylsilane and coupling constants (J) are reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Endo,endo-2,4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-en-3-one (9). A mixture of furan 8 (60 mL, 82.5 mmol), 1, 2-dimethoxy ethane (90 mL) and Zn-Cu couple (10 g) was taken and cooled to −10 oC. To this mixture, a solution of 2, 4-dibromo-3-pentanone 7 (30 g, 122.99 mmol) in DME (50 mL) was added drop-wise over the period of 30 min. Further four portions of Zn-Cu couple (10 g each) were added at 30 min intervals. The reaction was stirred at the same temperature for additional 4 h. The metallic Zn-Cu couple was filtered and washed with hexane. Solvent was removed until the solution became turbid; at this stage water (50 mL) was added to the reaction mixture. The white precipitate of zinc hydroxide thus formed was filtered off and washed with ethyl acetate (4 x 25 mL). The organic layer was separated, dried over anhydrous Na2SO4 and removal of the solvent furnished 9 along with two isomeric ketones (15.33 g, 82%) as a light yellow liquid. Endo-3-hydroxy-endo,endo-2, 4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-ene (10). To a solution of ketones 9 (15.7 g, 103.16 mmol) in dichloromethane (100 mL), was added DIBAL-H (17.57 g, 20% solution in toluene, 12.4 mmol) at – 10 oC over a period of 30 min. The reaction mixture was stirred for S4 4 h at the same temperature. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol followed by saturated aqueous potassium sodium tartarate solution (100 mL) at 0 oC and stirred for 1 h. The organic layer was separated, washed with brine, water, dried over Na2SO4 and solvent removed to obtain the mixture of alcohols from which the required isomer 10 was separated by silica gel column chromatography (11.77 g, 74%) as a colorless liquid. IR (neat) ν 3450, 1650 cm-1; 1H NMR (200 MHz, CDCl3) δ 6.50 (s, 2H), 4.47 (d, J = 2.3 Hz, 2H), 3.65 (t, J = 5.2 Hz, 1H), 2.28-2.15 (m, 2H), 1.48 (brs, 1H), 0.98 (d, J = 7.5 Hz, 6H). ESIMS for C9H14O2 m/z 154 [M]+. Endo-3-benzyloxy-endo,endo-2,4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-ene (11). To a stirred solution of NaH (5.18 g, 129.69 mmol) in THF (50 mL) was added the alcohol 10 (10 g, 64.84 mmol) in THF (50 mL) at 0 oC. The reaction mixture was heated to 50 oC for 30 min and allowed to attain room temperature. Then neat benzyl bromide (15.5 mL, 129.69 mmol) was added to it. The reaction mixture was then heated to 50 oC and stirring continued for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched using ice and extracted with tert-butyl methyl ether (TBME). The organic layer was separated, dried over anhydrous Na2SO4, evaporation under reduced pressure and purification by silica gel column chromatography afforded 11 (14.89 g, 94%) as a colorless liquid. IR (neat) ν 1650 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 6.27 (s, 2H), 4.40 (s, 2H), 4.394.26 (m, 2H), 3.50 (t, J = 5.2 Hz, 1H), 2.30-2.20 (m, 2H), 0.89 (d, J = 6.9 Hz, 6H); ESIMS for C16H20O2 m/z 244 [M]+. Endo-3-benzyloxy-endo,endo-2,4-dimethyl-exo-6-hydroxy-8-oxabicyclo-[3.2.1]-octan-6-ol (12). A 100 mL round bottomed flask equipped with a septum, a magnetic stirring bar, was charged with BH3.SMe2 (4.2 mL, 44 mmol) and THF (20 mL). The flask was cooled to 0 oC and (+)-α-pinene (15.5 mL, 98 mmol) was added drop-wise. The mixture was stirred at the same temperature for 2 h and the flask stored in a refrigerator at 0 oC for 7 days [(−)-Ipc2BH separated as a white solid during this time]. To the (−)-Ipc2BH (solid, 44 mmol), was added neat olefin 11 (10 g, 40.92 mmol) at −20 oC and stirred for 2 h. The reaction mixture was kept in the refrigerator at 0 oC for 4 days. The trialkyl borane was S5 treated with 3N NaOH (50 mL) and 30% H2O2 (30 mL) and stirred for 5 h at room temperature. The reaction mixture was extracted with tert-butyl methyl ether (TBME), dried over anhydrous Na2SO4, evaporation under reduced pressure and purification by silica gel column chromatography (ethyl acetate: hexane = 1:1) afforded 12 (10.02 g, 94%) as a colorless liquid. [α]D27 −3.6 (c 3.0 CHCl3); IR (neat) ν 3415, 2935, 1617, 1452 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.32-7.22 (m, 5H), 4.64-4.60 (m, 1H), 4.45 (s, 2H), 4.12 (dd, J = 10.5, 3.8 Hz, 1H), 3.80, (d, J = 3.8 Hz, 1H), 3.40 (t, J = 3.2 Hz, 1H), 2.85 (dd, J = 12.5, 6.6 Hz, 1H), 2.08-2.0 (m, 2H), 1.80 (br d, 1H), 1.56-1.52 (m, 1H), 1.07 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13 C NMR (75 MHz, CDCl3) δ 138.5, 128.0, 127.1, 126.7, 86.7, 79.9, 78.9, 75.6, 71.9, 40.7, 38.8, 38.2, 37.6, 13.0; ESIMS for C16H22O3 m/z 262 [M]+. Endo-3-benzyloxy-endo,endo-2,4-dimethyl-8-oxabicyclo-[3.2.1]-octan-6-one. To a stirred solution of alcohol 12 (10 g, 38.12mmol) in CH2Cl2 (50 mL), dipyridiniumchlorochromate (PCC) (24.6 g, 114.40 mmol) was added and the reaction mixture stirred for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with isopropanol (15mL). The residue was filtered and washed with diethyl ether (150mL). The organic layer was washed with 1N HCl (20mL), water (20mL), brine (15mL) and dried over Na2SO4. Removal of solvent under reduced pressure afforded a gummy material, which was crystallized from hexane and benzene (9:1) mixture to afford the ketone (9.03 g, 91%) as white solid. Mp. 62 oC; [α]D27 +23.4 (c 2.5 CHCl3); IR (neat) ν 2958, 1760, 1598, 1457 cm-1; 1 H NMR (200 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 4.55 (ABq J = 11.8 Hz, 2H), 4.31 (dd, J = 8.8, 3.7 Hz, 1H), 3.65 (d, J = 3.6 Hz, 1H), 3.58 (t, J = 3.4 Hz,1H), 2.75 (d, J = 15.9 Hz,1H), 2.40-2.20 (m, 3H), 1.08 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, H); ESIMS for C16H20O3 m/z 260 [M]+. Endo-3-benzyloxy-endo,endo-2,4-dimethyl-6,9-oxabicyclo-[3.2.1]-non-7-one (13). To a suspension of NaHCO3 (4.8 g, 57.69 mmol) in CH2Cl2 (30 mL), was added the ketone (10.0 g, 38.41 mmol) in CH2Cl2 under nitrogen atmosphere. Dry m-CPBA (6.3 g, 28.84 mmol) was added in lots to the reaction mixture and stirred for 10 h at room temperature. After completion reaction (monitored by TLC), the reaction mixture was diluted with CH2Cl2 (60 mL). The organic layer was washed with a saturated S6 solution of sodium metabisulfite (50 mL) followed by 5% aqueous NaHCO3 solution and water (50 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:4) as eluent to afford lactone 13 (9.6 g, 91%) as a colorless liquid. [α]D27 −46.5 (c 2.0 CHCl3); IR (neat) ν 1752, 1617, 1455 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 5.42 (d, J = 2.8 Hz, 1H), 4.55 (ABq, J = 11.5 Hz, 2H), 4.10-4.0 (m, 1H), 3.58 (t, J = 2.7 Hz, 1H), 2.73-2.70 (m, 2H), 2.27-2.20 (m, 1H), 2.102.0 (m, 1H), 1.15 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.5, 138.5, 128.0, 127.1, 100.1, 86.7, 79.9, 71.9, 40.7, 38.8, 37.6, 31.2,13.8, 13.0; ESIMS for C16H20O4 m/z 260 [M]+. Methyl-2-[4-benzyloxy-6-methoxy-3,5-dimethyl-(2R,3S,5S,6S)-tetrahydro-2H-2-pyranyl]acetate (6). To a stirred solution of lactone 13 (4.8 g, 17.4 mmol) in THF (30 mL) at −78 oC, was added LDA [prepared by the addition of n-butyl lithium (2.4 M solution in hexane, 8.6 mL, 20.0 mmol) to a −10 oC cooled solution of diisopropylamine (2.4 g, 24.0 mmol) in THF (30 mL)] and the reaction mixture was stirred for 30 min at the same temperature. The lithium enolate thus generated was alkylated with methyl iodide (3.2 mL, 52.0 mmol). The reaction mixture was stirred for additional 2 h and quenched with saturated aqueous NH4Cl (20 mL). The mixture was extracted with tert-butyl methyl ether (TBME) (3 x 30 mL), dried over anhydrous Na2SO4, evaporation under reduced pressure afforded the methylated lactone 6 as a yellow colored solid. Recrystallization with a mixture of hexane and benzene (5:1) gave 6 (4.6 g, 92%) as white solid. Mp. 91 oC; [α]D27 −23.4 (c 3.5 CHCl3); IR (neat) ν 2928, 1742, 1455, 1073 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 5.38 (d, J = 2.7 Hz, 1H, 4.58 (ABq, J = 11.8 Hz, 2H), 3.65 (d, J = 4.0 Hz, 1H), 3.60-3.52 (m, 1H), 2.75 (q, J = 7.0 Hz, 2H), 2.30-2.10 (m, 1H), 2.10-1.96 (m, 1H), 1.42 (d, J = 6.5 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, H); 13C NMR (75 MHz, CDCl3) δ 170.5, 138.0, 128.0, 127.0, 100.0, 79.0, 76.5, 76.0, 39.5, 37.5, 35.5, 31.0,20.0, 13.5, 13.0; FABMS for C17H22O4 m/z 291 [M + 1]+. S7 (2S)-2-(2S,3R,4S,5S)-4-(Benzyloxy-6-methyl-3,5-dimethyl-tetrahydro-2H-pyran-2-yl)propanoate (14). To a stirred solution of compound 6 (5.0 g, 17.24 mmol) in methanol (50 mL), catalytic amount of conc. H2SO4 (4 drops) was added slowly at 0 oC. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with solid NaHCO3 and filtered through a pad of Celite. The organic solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:19) as eluent to afford 14 (4.93 g, 85%) as a pale yellow oil. [α]D27 −49.0 (c 1.2, CHCl3); IR (neat) ν 2827, 1739, 1456, 1082 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.36-7.22 (m, 5H), 4.54 (s, 2H), 4.52 (s, 1H), 4.00-3.95 (m, 1H), 3.86 (t, J = 3.5 Hz, 1H), 3.72 (s, 3H), 3.28 (s, 3H), 2.68 (m, 1H), 2.25-2.10 (m, 2H), 1.14-1.05 (m, 6H), 1.02 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 176.0, 138.8, 128.2, 127.2, 127.1, 104.3, 74.9, 71.7, 69.5, 54.8, 51.6, 41.7, 36.5, 32.5, 13.1, 13.0, 7.6; HRMS calc. for C19H28O5 [M + Na]+ 359.1851 and Found 359.1842. (S)-2-((2S,3R,4S,5S)-4-(Benzyloxy)-6-methoxy-3,5-dimethyl-tetrahydro-2H-pyran-2-yl)propanal (15). To an ice cooled suspension of LAH (169 mg, 4.45 mmol) in THF (10 mL), was added a solution of ester 14 (1.0 g, 2.97 mmol) in dry THF (10 mL) under nitrogen atmosphere. The reaction mixture was stirred for 4 h at room temperature and quenched with saturated Na2SO4 solution. The precipitate formed was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was dried over anhydrous Na2SO4, concentrated to dryness under reduced pressure. The resulting crude product was purified by silica gel column chromatography utilizing ethyl acetate and hexane (1:9) as eluent to obtain alcohol (0.83 g, 90%) as colorless oil. [α]D27 +55.6 (c 1.0, CHCl3); IR (neat) ν 3450, 2970, 2920, 1718, 1457 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 4.51 (s, 1H), 4.49 (s, 2H), 3.80 (t, J = 5.2 Hz, 1H), 3.63-3.54 (m, 3H), 3.35 (s, 3H), 3.20 (bs, 1H), 2.25-1.93 (m, 3H), 1.07 (d, J = 7.5 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 138.6, 128.0, 127.1, 126.9, 104.1, 75.1, 74.6, 69.1, 68.0, 54.5, 35.8, 33.2, 12.8, 12.4, 7.7; HRMS calc. for C18H28O4Na [M + Na]+ 331.1885 and Found 331.1875. S8 Iodoxybenzoic acid (6.3 g, 19.68 mmol) was taken in dry DMSO (15 mL) and stirred for 30 min. Alcohol (4.0 g, 13.12 mmol) in dry THF (30 mL) was added to the reaction mixture at room temperature and allowed to stir for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (40 mL) and the solid formed filtered through Celite. The organic layer was separated and aqueous layer extracted with ether (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography using ethyl acetate and hexane (1:19) as mobile phase to obtain aldehyde 15 (3.77 g, 95%) as a colorless liquid. [α]D27 −72.18 (c 1.0, CHCl3); IR (neat) ν 3442, 2975, 2913, 1715, 1457, 1371, 1273, 1207 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.82 (d, J = 2.9 Hz, 1H), 7.32 (s, 5H), 4.52 (s, 2H), 4.50 (s, 1H), 3.94 (dd, J = 11.1, 2.2 Hz, 1H), 3.85 (t, J = 5.2 Hz, 1H), 3.28 (s, 3H), 2.71 (dd, J = 6.6, 2.9 Hz, 1H), 2.30-2.07 (m, 2H), 1.09 (d, J = 7.4 Hz, 3H), 1.04 (d, J = 7.4 Hz, 3H), 1.00 (d, J = 7.4 Hz 3H); 13C NMR (75 MHz, CDCl3) δ 204.3, 138.7, 128.3, 127.3, 104.5, 74.7, 70.7, 69.5, 55.0, 47.2, 36.5, 32.9, 13.0, 9.8, 7.8; LCMS : m/z 345 [M + K]+. (2R′,3S′)-2-((2R,3R,4S,5S)-4-(Benzyloxy)-6-hydroxy-3,5-dimethyl-tetrahydro-2H-pyran-2-yl)hept6-en-3-yl acetate (19). To a stirred solution of alcohol 18 (1.0 g, 2.75 mmol) in CH2Cl2 (20 mL), Et3N (0.95 mL, 6.89 mmol), acetic anhydride (0.52 mL, 5.52 mmol) and catalytic amount of DMAP (50 mg) were added at 0 oC and stirred at room temperature for 7 h. The reaction mixture was quenched with H2O (20 mL) and the organic layer separated. The aqueous layer was extracted CH2Cl2 (2 x 40 mL). The combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography using ethyl acetate and hexane (1:19) as mobile phase to obtain the acetate derivative (1.05 g, 94%) as a colorless liquid. [α]D27 +33.4 (c 1.1, CHCl3); IR (neat) ν 3068, 2976, 2915, 1734 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.30 (d, J = 4.5 Hz, 4H), 7.24 (m, 1H), 7.24 (m, 1H), 5.79 (ddt, J = 16.6, 9.8, 6.8 Hz, 1H), 5.22 (m, 1H), 5.20-4.87 (m, 2H), 4.45 (s, 2H), 4.43 (s, 1H), 3.75 (t, J = 5.6 Hz, 1H), 3.49 (dd, J = 10.5, 2.2 Hz, 1H), 3.18 (s, 3H), 2.19-1.93 (m, 7H), 1.831.69 (m, 2H), 1.58 (m, 1H), 1.0 (d, J = 7.6 Hz, 3H,), 0.91 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H,); S9 13 C NMR (75 MHz, CDCl3) δ 170.8, 138.9, 137.8, 128.2, 127.2, 127.1, 114.7, 104.5, 75.4, 72.9, 69.9, 69.3, 55.1, 36.5, 33.3, 31.6, 30.0, 21.2, 13.2, 8.6, 7.6; HRMS calc. for C25H36O5 [M + Na]+ 427.2460 and Found 427.2455. A solution of acetate compound (1.0 g, 2.47 mmol) in 60% AcOH: H2O (15 mL), was added catalytic amount of conc. H2SO4 and stirred at 60 oC for 4 h. The reaction mixture was diluted with ethyl acetate (25 mL) and solid NaHCO3 added. After the effervescence stops, the organic layer was separated and the aqueous layer extracted with ethyl acetate (3 x 40 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was passed through a small pad of silica gel to give compound 19 (0.83 g, 86%) as a colorless viscous liquid. (2R,3R,4S,5R,6R,7S)-3-Benzyloxy-2,4,6-trimethylundec-10-ene-1,5,7-triol (20). To a stirred solution of compound 19 (0.081 g, 2.03 mmol) in dry THF (15 mL), lithium borohydride (0.13 g, 6.38 mmol) was added at 0 oC followed by two drops of H2O and allowed stir at room temperature for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched at 0 oC with saturated aqueous NH4Cl solution. The organic layer was separated and aqueous layer extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure to give triol 20 (0.64 g, 89%) as a colorless viscous liquid. (5S,6R,7R,8S,9R,10R)-9-(Benzyloxy)-11-(tert-butyldiphenylsilyloxy)-6,8,10-trimethylundec-1-ene5,7-diol (5). To an ice cooled solution of triol 20 (630 mg, 1.87 mmol) and imidazole (257 mg, 3.78 mmol) was added TBDPSCl (0.74 mL, 2.84 mmol) in CH2Cl2. The reaction mixture was stirred at 0 oC for 1 h and quenched with aqueous NH4Cl solution and extracted with dichloromethane (2 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure and purified by silica gel chromatography using ethyl acetate and hexane (1:9) as mobile phase to afford compound 5 (826 mg, 94%) as a colorless viscous liquid. [α]D27 +4.9 (c 1.8, CHCl3); IR (neat) ν 3450, 3068, 2962, 2932, 2860, 1639, 1461, 1426; 1H NMR (300 MHz, CDCl3) δ 7.64 (m, 4H), 7.46-7.30 (m, S10 6H), 7.26 (m, 3H), 7.06 (m, 2H), 5.85 (ddt, J = 16.9, 10.1, 6.6 Hz, 1H), 5.09-4.9 (m, 2H), 4.52 (dd, J = 21.7, 10.5 Hz, 2H), 3.93 (t, J = 4.5 Hz, 2H), 3.85 (dd, J = 9.8, 4.7 Hz, 1H), 3.75 (dd, J = 9.8, 3.2 Hz 1H), 3.54 (m, 1H), 3.57 (dd, J = 9.6, 1.7 Hz, 1H), 3.1 (d, J = 7.9 Hz, 1H), 2.35 (m, 1H), 2.18-1.95 (m, 2H), 1.85 (m, 2H), 1.57 (m, 1H), 1.46 (m, 1H), 1.14 (d, J = 7.1 Hz, 3H), 1.10 (s, 9H), 0.96 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.9 Hz, 3H); 13C NMR (75 Hz, CDCl3) δ 139.0, 137.6, 135.7, 135.6, 133.5, 133.4, 129.6 , 128.4, 127.8, 127.7, 127.7, 127.6, 114.4, 87.2, 76.0, 74.0, 72.7, 65.4, 39.7, 38.5, 34.4, 31.8, 31.0, 27.0, 19.3, 14.5, 12.2, 11.8; ESIMS for C37H52O4Si m/z 589 [M+H]+. (2S,3S,4R)-3-(Benzyloxy)-4-((1S,3R,4R,5S)-1,4-dimethyl-2,8-dioxa-bicyclo[3.2.1]octan-3-yl)-2-methylpentanal (4). To an ice cooled solution of silyl ether 21 (1.0 g, 1.7 mmol) in dry THF (5 ml) was added TBAF (3.4 mL, 1 M solution in THF, 3.4 mmol). After 1 h, the reaction mixture was brought to room temperature and stirred for another 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and quenched with aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (3 x 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography utilizing ethyl acetate and hexane (1:6) as mobile phase to afford alcohol (569 mg, 95%) as a colorless liquid. [α]D27−32.4 (c 0.9, CHCl3); IR (neat) ν 3449, 3030, 2961, 2880, 1608, 1459 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.41-7.25 (m, 5H), 4.67 (dd, J = 20.5, 11.5 Hz, 2H), 4.20 (dd, J = 6.6, 3.5 Hz, 1H), 3.90 (dd, J = 11.1, 3.3 Hz, 1H), 3.82 (dd, J = 12.5, 1.3 Hz, 1H), 3.56 (dd, J = 10.3, 2.4 Hz, 1H), 3.49 (dd, J = 10.0, 2.0 Hz, 1H), 2.91 (bs, 1H), 2.09-1.67 (m, 7H), 1.47 (s, 3H), 1.22 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 138.4, 128.4, 127.5, 126.9, 104.7, 85.8, 80.0, 75.6, 72.8, 64.0, 36.9, 35.9, 34.2, 33.8, 24.1, 23.8, 16.3, 12.7, 9.9; HRMS calc. for C21H32O4Na [M+Na]+ 371.2198 and Found 371.2198. To solution of solution of IBX (920 mg, 2.87 mmol) in dry DMSO (3.0 mL), was added above alcohol (500 mg, 1.44 mmol) in dry THF (10 mL) at room temperature and allowed to stirr for 3 h at room temperature. The reaction mixture was diluted with Et2O (20 mL), stirred for 15 min., the solid S11 precipitate was filtered off and washed with ether (20 mL). The organic layer was washed with H2O (20 mL), dried over anhydrous Na2SO4, concentrated to dryness under reduced pressure and filtered through a small pad of silica gel to give aldehyde 4 (452 mg, 91%) as a colorless liquid. S12 1 H NMR of Compound 10 (CDCl3, 200 MHz) S13 1 H NMR of Compound 11 (CDCl3, 200 MHz) S14 1 H NMR of Compound 12 (CDCl3, 200 MHz) S15 13 C NMR of Compound 12 (CDCl3, 75 MHz) S16 1 H NMR of Keto Compound (CDCl3, 200 MHz) S17 1 H NMR of Compound 13 (CDCl3, 200 MHz) S18 13 C NMR of Compound 13 (CDCl3, 75 MHz) S19 1 H NMR of Compound 6 (CDCl3, 200 MHz) S20 13 C NMR of Compound 6 (CDCl3, 75 MHz) S21 1 H NMR of Compound 14 (CDCl3, 200 MHz) S22 13 C NMR of Compound 14 (CDCl3, 75 MHz) S23 1 H NMR of Alcohol (CDCl3, 200 MHz) S24 13 C NMR of Alcohol (CDCl3, 50 MHz) S25 1 H NMR of Compound 15 (CDCl3, 300 MHz) S26 13 C NMR of Compound 15 (CDCl3, 75 MHz) S27 1 H NMR of Compound 16 (CDCl3, 300 MHz) S28 S29 1 H NMR of Compound 17 (CDCl3, 300 MHz) S30 1 H NMR of Compound 18 (CDCl3, 300 MHz) S31 13 C NMR of Compound 18 (CDCl3, 75 MHz) S32 nOe Spectrum of Compound 18 S33 HPLC Chromatogram of Compound 18 S34 LCMS Chromatogram of Compound 18 S35 1 H NMR of Acetate Derivative (CDCl3, 300 MHz) S36 13 C NMR of Acetate Derivative (CDCl3, 75 MHz) S37 1 H NMR of Compound 5 (CDCl3, 300 MHz) S38 13 C NMR of Compound 5 (CDCl3, 75 MHz) S39 1 H NMR of Compound 21 (CDCl3, 300 MHz) S40 13 C NMR of Compound 21 (CDCl3, 75 MHz) S41 1 H NMR of Hydroxyl Compound (CDCl3, 300 MHz) S42 13 C NMR of Hydroxyl Compound (CDCl3, 75 MHz) S43 1 H NMR of Compound 22 (CDCl3, 300 MHz) S44 13 C NMR of Compound 22 (CDCl3, 75 MHz) S45 HPLC Chromatogram of 22 S46 LCMS Chromatogram of 22 S47 LCMS Chromatogram of 22 S48 1 H NMR of Compound 23 (CDCl3, 300 MHz) S49 13 C NMR of Compound 23 (CDCl3, 75 MHz) S50 1 H NMR of Compound 24 (CDCl3, 300 MHz) S51 13 C NMR of Compound 24 (CDCl3, 75 MHz) S52 nOe Spectrum of Compound 24 S53 1 H NMR of Compound 3 (CDCl3, 400 MHz) S54 13 C NMR of Compound 3 (CDCl3, 100 MHz) S55