Reaction Steps
A solution of sodium carbonate (459 mg, 4.33 mmol) in water (20 mL) was added whilst stirring to a solution of (3R,3aR,6R,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol in 1,4-dioxane (20 mL). A solution of 9-fluorenylmethoxycarbonyl chloride (614 mg, 2.37 mmol) in 1,4-dioxane (3 mL) was added then the mixture stirred for 1.5 hours then water (30 mL) was added and the product extracted into dichloromethane (3×50 mL). The organic layer was washed with brine (70 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 80:20 gave (in order of elution) syn-epoxide (9H-fluoren-9-yl)methyl (R)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethyl carbamate (111 mg, 14%) as a colourless oil and bicyclic alcohol (5b) (453 mg, 58%) as a white solid. Data for syn-epoxide; TLC (Rf=0.22, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=17.108 min.; HPLC-MS 382.2 [M+H]+, 404.2 [2M+Na]+; [α]D19−24.5° (c=6.120, CHCl3); δH (500 MHz, CDCl3) 3.37-3.56 (3H, m, CHOCH3 and CH2NH), 3.49 (3H, s, OCH3 major), 3.71 (1H, d, J=10.63 Hz, OCH2CH), 3.75 (1H, d, J=7.48 Hz, OCHCHOCH3), 3.79-3.84 (2H, m, OCH2CHCH), 4.04 (1H, d, J=10.67 Hz, OCH2CH), 4.23 (1H, t, J=6.97 Hz, Fmoc CH), 4.38 (2H, d, J=7.12 Hz, Fmoc CH2), 5.16 (1H brs, NH), 7.29-7.76 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3) 40.837 (CH2NHFmoc), 47.259 (Fmoc CH), 56.424/56.648 (OCH2CHCH), 58.047 (OCH3), 66.688 (Fmoc CH2), 67.700 (OCH2CH), 77.573 (OCHCHOCH3), 78.238 (CHOCH3), 119.932, 125.088, 126.998 and 127.617 (Fmoc aromatic CH), 141.277, 143.021 and 144.021 (Fmoc quaternary), 156.521 (Cbz C═O). Data for bicyclic alcohol (5b); TLC (Rf=0.05, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=15.004 min., HPLC-MS 382.2 [M+H]+, 404.2 [M+Na]+, 785.3 [2M+Na]+; [α]D16−10.0° (c=4.016, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 4:3; 0.96 (0.57H, d, J=3.54 Hz, OH major), 2.51 (0.43H, d, J=3.50 Hz, OH minor), 2.93 (0.57H, t, J=10.12 Hz, FmocNCH2 major), 3.07-3.15 (0.43H, m, FmocNCH2 minor), 3.36 (1.71H, s, OCH3 major), 3.41 (1H, brd, J=4.63 Hz, FmocNCH major), 3.46 (1.29H, s, OCH3 minor), 3.48-3.52 (0.57H, m, OCH2CHOH major), 3.56-3.64 (1.14H, m, CHOCH3 major and OCH2CHOH major), 3.73-3.86 (2.43H, m, OCH2CHOH, FmocNCH2 and CHOCH3 minor), 4.00 (0.43H, dd, J=4.65 and 9.90 Hz, OCH2CHOH minor), 4.16 (1H, dd, J=4.85 and 1.09 Hz, FmocNCH minor), 4.20-4.25 (1H, m, Fmoc CH), 4.38-4.43 (0.86H, m, OCHOH minor and 1×Fmoc CH2 minor), 4.45 (0.57H, t, J=4.29 Hz, CHCHOCH3 major), 4.49 (0.43H, dd, J=10.64 and 6.82 Hz, Fmoc CH2 minor), 4.69-4.73 (0.43H, m, OCHCHOCH3 minor), 4.75 (0.57H, dd, J=10.83 and 3.74 Hz, Fmoc CH2 major), 4.81 (0.57H, dd, J=10.83 and 4.01 Hz, Fmoc CH2 major), 7.28-7.81 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3) 47.276/47.369 (Fmoc CH), 47.504/47.898 (FmocNCH2), 57.788/57.839 (OCH3), 65.761/67.333 (Fmoc CH2), 68.812/69.338 (FmocNCH), 74.940/75.145 (OCH2CHOH), 76.276/76.746 (OCH2CHOH), 78.834/79.335 (OCHiCHOCH3), 78.994/79.507 (OCHCHOCH3), 119.859, 119.895, 120.036, 124.389, 124.442, 124.877, 124.960, 127.035, 127.059, 127.451, 127.494, 127.803, 127.89 and 127.941 (Fmoc aromatic CH), 141.348, 141.373, 141.434, 143.585, 143.585, 143.729, 143.911 and 143.947 (Fmoc quaternary), 153.937/154.896 (Fmoc C═O).
