Dimethyl (2R,3R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-dicarboxylate (4) Using a modification of a procedure reported16 by Maycock and co-workers, a magnetically stirred solution of L–tartaric acid (11.87 g, 79.09 mmol), 2,3-butanedione (7.25 mL, 80 mmol) and trimethyl orthoformate (50 mL, 466 mmol) in dry MeOH (100 mL) was treated with p-toluenesulfonic acid monohydrate (710 mg, 5 mol%). The resulting solution was heated under reflux for 24 h and the ensuing deep-red mixture then cooled to room temperature and neutralized with NaHCO3 (4.00 g). Stirring was continued for 0.5 h then the reaction mixture was concentrated under reduced pressure. The residue thus obtained was diluted with EtOAc (100 mL) then NaHCO3 (30 mL of a saturated aqueous solution) added and the separated organic phase washed with NaHCO3 (1 30 mL of a saturated aqueous solution) then (s, 6H), 1.36 (s, 6H); 13C NMR (CDCl3, 100 MHz) C 168.6, 99.4, 68.9, 52.7, 48.6, 17.5; IR (solid) max 2992, 1736, 1443, 1377, 1282, 1202, 1139, 1110, 1026, 898, 886, 810, 744 cm–1; MS (ESI, +ve) m/z 315 [(M + Na)+, 100%]. 1,1'-((2S,3S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-diyl)bis(prop-2-en-1-ol) (5) A magnetically stirred solution of bis-ester 4 (3.10 g, 10.63 mmol) in dry toluene (30 mL) was cooled to –78 ºC then DIBAl-H (22.3 mL of a 1 M solution in toluene, 22.3 mmol) added, via syringe-pump, over 0.75 h. The ensuing mixture was stirred at –78 ºC for 2 h then vinylmagnesium bromide (74.4 mL of a 1 M solution in THF, 74.4 mmol) was added dropwise over 0.5 h. The solution thus formed was stirred at –78 ºC for 0.5 h then allowed to warm to room temperature. After 16 h the reaction mixture was cooled to 0 ºC, quenched with Rochelle salt (100 mL of a saturated solution: CAUTION slow addition required) then re-warmed to room temperature and stirring continued for 3 h. The resulting biphasic mixture was transferred to a separating funnel and the organic layer separated then washed with water (1 100 mL). The combined aqueous layers were extracted with EtOAc (3 30 mL) and the combined organic phases then washed with brine (3 30 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure. The ensuing thick, orange oil was subjected to flash column chromatography (silica, hexane 1:1 v/v EtOAc/hexane gradient elution) and concentration of appropriate fractions (Rf = 0.5 in 1:1 v/v EtOAc/hexane) afforded bis-allylic alcohol 5 (2.69 g, 88%) as a clear, colorless oil and a mixture of diastereoisomers [Found: (M + Na)+, 311.1465. C14H24NaO6 requires (M + Na)+, 311.1471]. 1H NMR (CDCl3, 400 MHz) H (mixture of three diastereoisomers) 6.12–5.94 (complex m, 2H), 5.40–5.15 (series of m, 4H), 4.31–4.17 (complex m, 2H), 4.03–3.65 (series of m, 2H), 3.24–3.19 (4 s, 6H), 2.70–2.30 (series of m, 2H), 1.28–1.27 (3 s, 6H); 13C NMR (CDCl3, 100 MHz) C (mixture of three diastereoisomers) 138.1, 138.0, 136.7(2), 136.6(8), 117.2, 116.8, 116.1, 115.8, 99.0, 98.9, 98.8(1), 98.7(9), 72.6, 72.3, 72.1, 71.6, 71.3, 70.5, 48.1(0), 48.0(6), 17.6(1), 17.5(9), 17.5; IR (film) max 3407, 2991, 2949, 2833, 1375, 1121, 1036, 997, 921, 852 cm–1; MS (ESI, +ve) m/z 311 [(M + Na)+, 100%]. (2R,3R,4aS,8aS)-2,3-Dimethoxy-2,3-dimethyl-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxine-5,8-diol (6) (series of m, 2H), 4.51–4.20 (complex m, 2H), 4.10–3.57 (series of m, 2H), 3.49 (broad m, 1H), 3.36– 3.24 (4 s, 6H), 2.64–2.09 (series of broad m, 1H), 1.39–1.28 (4 s, 6H). 13C NMR (CDCl3, 100 MHz) C 132.9, 130.0, 129.3, 126.6, 100.0, 99.8, 99.3, 99.1, 72.5, 70.6, 70.3, 69.7, 67.9, 65.9, 65.5, 65.3, 48.3, 48.2, 48.1(3), 48.0(7), 17.9(4), 17.9(0), 17.8(2), 17.8(0); IR (solid) max 3313, 2948, 1465, 1373, 1204, 1117, 1030, 971, 915, 886, 847 cm–1; MS (ESI, +ve) m/z 283 [(M + Na)+, 100%]. (2R,3R,4aR,8aR)-2,3-Dimethoxy-2,3-dimethyl-2,3,4a,8a-tetrahydrobenzo[b][1,4]dioxine-5,8-dione (7) Dess-Martin periodane (23.80 g, 53.31 mmol) was added, in portions, to a magnetically stirred solution of compound 6 (4.63 g, 17.78 mmol) in CH2Cl2 (25 mL) maintained at 0 ºC. After addition was complete (0.25 h) the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h before being concentrated under reduced pressure at 20 ºC. The residue thus obtained was subjected to rapid flash chromatography (silica, 2:8 v/v pentane/Et2O elution) and concentration of the relevant fractions (Rf = 0.7 in 1:2 v/v CH2Cl2/Et2O) at 20 ºC afforded enedione 7 (4.01 g, 88%) as a bright yellow, crystalline solid, mp 115–117 ºC (dec.), []D –121.0 (c 0.9 in CHCl3) [Found: (M + Na)+, 279.0850. C12H16NaO6 requires (M + Na)+, 279.0845]. 1H NMR (CDCl3, 400 MHz) H 6.84 (s, 2H), 4.73 (s, 2H), 3.26 (s, 6H), 1.41 (s, 6H); 13C NMR (CDCl3, 100 MHz) C 192.1, 140.1, 100.6, 73.9, 48.7, 17.6; IR (solid) max 2954, 2849, 1699, 1380, 1133, 1113, 1027, 823, 543 cm–1; MS (ESI, +ve) m/z 343 [(M + 2 CH3OH + Na)+, 100%], 311 [(M + CH3OH + Na)+, 50], 279 [(M + Na)+, 10]. (2R,3R,4aR,8R,8aS)-8-Hydroxy-2,3-dimethoxy-2,3-dimethyl-2,3,8,8a-tetrahydrobenzo[b][1,4]dioxin- 5(4aH)-one (8) Sodium borohydride (770 mg, 20.35 mmol) was added, in portions over 0.08 h, to a magnetically stirred solution of CeCl3A2O (7.60 g, 20.40 mmol) in MeOH (50 mL) maintained at 0 ºC. The ensuing mixture was stirred at this temperature for 0.25 h then transferred to a pressure-equalized dropping funnel and added dropwise to a magnetically solution of endione 7 (4.01 g, 15.67 mmol) in MeOH (150 mL) that had been cooled to –78 ºC. After 1.5 h further portions of NaBH4 (5 10 mg, 1.32 mmol) were slowly added until the yellow reaction mixture became colorless and at which point it was quenched with acetone (20 mL). NH4Cl (100 mL of a saturated aqueous solution) was added to the reaction mixture so-formed that [Found: (M + Na)+, 281.1006. C12H18NaO6 requires (M + Na)+, 281.1001]. 1H NMR (CDCl3, 400 MHz) H 6.85 (dd, J = 10.5 and 2.0 Hz, 1H), 6.07 (dd, J = 10.5 and 2.6 Hz, 1H), 4.67 (m, 1H), 4.25 (d, J = 11.4 Hz, 1H), 3.96 (dd, J = 11.4 and 8.7 Hz, 1H), 3.31 (s, 3H), 3.28 (s, 3H), 2.55 (d, J = 3.9 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H); 13C NMR (CDCl3, 100 MHz) C 193.5, 148.6, 128.4, 100.3, 99.4, 74.3, 72.3, 70.1, 48.7, 48.2, 17.7(3), 17.6(6); IR (film) max 3452, 2958, 1683, 1379, 1118, 1028, 967, 947, 881, 806, 634, 585, 540 cm–1; MS (ESI, +ve) m/z 281 [(M + Na)+, 100%]. (2R,3R,4aR,8R,8aS)-6-Bromo-8-hydroxy-2,3-dimethoxy-2,3-dimethyl-2,3,8,8a-tetrahydrobenzo[b][1, 4]dioxin-5(4aH)-one (9) Molecular bromine (400 μL of a 10% v/v solution in CH2Cl2, 0.79 mmol) was added, dropwise, to a magnetically stirred solution of enone 8 (185 mg, 0.72 mmol) in CH2Cl2 maintained at –5 ºC. The resulting solution was stirred at this temperature for 1 h then triethylamine (300 μL, 2.15 mmol) added dropwise. The cooling bath was then removed and the reaction mixture stirred at room temperature for 16 h before being quenched with sodium sulfite (2 mL of a saturated aqueous solution). The separated organic layer was washed successively with sodium sulfite (3 5 mL of a saturated aqueous solution) and NH4Cl (3 5 mL of an aqueous solution) then the combined aqueous washings were extracted with EtOAc (3 10 mL). The combined organic phases were washed with brine (2 10 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure. The ensuing residue was subjected to flash column chromatography (silica, CH2Cl2 1:9 v/v Et2O/CH2Cl2 gradient elution) and concentration of appropriate fractions (Rf = 0.2 in 1:9 v/v Et2O/CH2Cl2) afforded bromoenone 9 (190 mg, 79 %) as a white, crystalline solid, mp 178–181 °C, []D –146.6 (c 0.5, CHCl3) [Found: (M + Na)+, 359.0100. C12H1779BrNaO6 requires (M + Na)+, 359.0106]. 1H NMR (CDCl3, 400 MHz) H 7.29 (d, J = 2.3 Hz, 1H), 4.63 (ddd, J = 8.6, 4.1 and 2.3 Hz, 1H), 4.28 (d, J = 11.4 Hz, 1H), 3.98 (dd, J = 11.4 and 8.6 Hz, 1H), 3.31 (s, 3H), 3.28 (s, 3H), 2.57 (d, J = 4.1 Hz, 1H), 1.42 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3, 100 MHz) C 186.3, 148.6, 123.2, 100.5, 99.3, 73.6, 71.6, 70.5, 48.8, 48.3, 17.6(3), 17.5(9); IR (solid) max 3480, 2945, 1712, 1601, 1450, 1373, 1334, 1279, 1205, 1141, 1110, 1023, 907, 888, 870, 858, 606, 782, 663, 606, 517, 440 cm–1; MS (ESI, +ve) m/z 361 and 359 [(M + Na)+, 98 and 100%, respectively]. 4.39 (d, J = 11.2 Hz, 1H), 4.18 (dd, J = 11.2 and 8.9 Hz, 1H), 3.29 (s, 3H), 3.25 (s, 3H), 2.16 (s, 3H), 1.40 (s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 100 MHz) C 185.9, 170.1, 144.8, 124.3, 100.5, 99.3, 71.7, 71.0, 70.6, 48.7, 48.1, 20.9, 17.6, 17.5; IR (solid) max 2952, 1751, 1720, 1377, 1220, 1135, 1113, 1028, 979, 918, 886, 853, 786, 662 cm–1; MS (ESI, +ve) m/z 467 and 465[(M + 2 CH3OH + Na), 98 and 100%, respectively], 403 and 401 [(M + Na)+, 30 and 29, respectively]. (2R,3R,4aS,5R,8aR)-7-Bromo-2,3-dimethoxy-2,3-dimethyl-8-oxo-2,3,4a,5,8,8a-hexahydrobenzo[b][1, 4]dioxin-5-yl acetate (11) and (2R,3R,4aS,5R,8S,8aS)-7-Bromo-8-hydroxy-2,3-dimethoxy-2,3- dimethyl-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxin-5-yl acetate (12) Sodium borohydride (211 mg, 5.59 mmol) was added, in portions over 0.08 h, to a magnetically stirred solution of CeCl3T 2O (1.09 g, 2.93 mmol) in MeOH (20 mL) maintained at 0 ºC. The ensuing mixture was stirred at this temperature for 0.25 h then transferred to a pressure-equalized dropping funnel and added dropwise to a magnetically solution of acetate 10 (1.06 g, 2.79 mmol) in MeOH (100 mL) maintained at –78 ºC. After 1 h the reaction mixture was allowed to warm to room temperature, quenched with water (5 mL) and concentrated under reduced pressure. The residue thus obtained was diluted with EtOAc (100 mL) and NH4Cl (50 mL of a saturated aqueous solution). The separated aqueous layer was extracted with EtOAc (3 50 mL) and the combined organic phases then washed with brine (2 50 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica, 1:19 v/v Et2O/CH2Cl2) to afford two fractions, A and B. Concentration of fraction A (Rf = 0.3 in 1:19 v/v Et2O/CH2Cl2) afforded compound 11 (76 mg, 7%) as a clear, colorless oil, []D –160.0 (c 0.9, CHCl3) [Found: (M + Na)+, 403.0373. C14H2179BrNaO7 requires (M + Na)+, 403.0368]. 1H NMR (CDCl3, 400 MHz) H 6.12 (d, J = 2.5 Hz, 1H), 5.30 (dd, J = 8.4 and 2.5 Hz, 1H), 4.35 (d, J = 4.0 Hz, 1H), 4.16 (dd, J = 11.0 and 8.4 Hz, 1H), 3.78 (dd, J = 11.0 and 4.0 Hz, 1H), 3.27 (s, 3H), 3.26 (s, 3H), 2.74 (broad s, 1H), 2.09 (s, 3H), 1.33 (s, 3H), 1.29 (s, 3H); 13C NMR (CDCl3, 100 MHz) C 170.5, 130.6, 123.8, 100.1, 99.3, 72.2, 72.1, 67.6, 65.1, 48.4, 48.0, 21.1, 17.8, 17.7; IR (film) max 3475, 2950, 1750, 1733, 1371, 1230, 1135, 1116, 1033, 970, 933, 886, 851, 732 cm–1; MS (ESI, +ve) m/z 405 and 403 [(M + Na)+, 100 and 98%, respectively]. 100 and 98%, respectively]. (2R,3R,4aR,5R,8R,8aS)-8-Acetoxy-6-bromo-2,3-dimethoxy-2,3-dimethyl-2,3,4a,5,8,8a-hexahydro- benzo[b][1,4]dioxin-5-yl 4-methoxybenzoate (13) Tri-n-butylphosphine (520 μL, 2.08 mmol) was added to a magnetically stirred solution of allylic alcohol In document Stereoselective Syntheses of Certain Natural Products and their Analogues from Chiral-pool and Enzymatically-derived Building Blocks (Page 190-195)
