Stereoselective and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

Transcription

1 Supporting information Stereoselective and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol Peter J.L.M. Quaedflieg,*, Bart R.R. Kesteleyn, Piet B.T.P. Wigerinck, Nicolaas M.F. Goyvaerts, Robert Jan Vijn, Constantinus S.M. Liebregts, Jaap H.M.H. Kooistra and Claudia Cusan DSM Pharma Chemicals, LS-ASC&D, P Box 18, 6160 MD Geleen, The Netherlands Tibotec BVBA, Generaal de Wittelaan L 11B 3, B-2800 Mechelen, Belgium S1

2 Materials and methods All reactions were performed under nitrogen atmosphere. Solvents and reagents were used as supplied without further purification. 1 H NMR spectra were recorded at 300 MHz in CDCl 3 or DMS-d 6 on a Bruker Avance Ultrashield TM 300 NMR spectrometer and chemical shifts are referred to the residual peak of CHCl 3 and DMS at δ 7.26 and 2.50 ppm, respectively. Quantitative 1 H NMR was performed with p-nitrotoluene as the internal standard. 13 C and DEPT NMR spectra were recorded at 75 MHz in CDCl 3 or DMS-d 6 on a Bruker Avance Ultrashield TM 300 NMR spectrometer and chemical shifts are referred to CHCl 3 and DMS at δ 77.0 and ppm, respectively. Specific optical rotations were determined in CHCl 3 at 20 o C on a Perkin-Elmer 241 polarimeter, using Na as source and filter at 589 nm using the equation [α] D = (100 α)/ (l c), where the concentration c is expressed in g/100 ml and the path length l in decimetres. Melting points were determined with a Büchi 535 apparatus using a temperature range of C. L-5,6--isopropylidene-gulono-1,4-lactone was prepared according to the method described by C. Hubschwerlen, Synthesis, 1986, 962. The 1 H NMR spectrum, melting point and optical rotation of the resulting product corresponded to the data as reported by Hubschwerlen. Its purity (97 wt%) was assessed by quantitative 1 H NMR. The GC assay and e.e. determination of S-2,3--isopropylidene-glyceraldehyde (4) in reaction mixtures was performed with an Agilent 6890 GC (EPC) and a Betadex column (part number 24305, Supelco or equivalent) of 60 m and with a film thickness of 0.25 µm using a column head pressure of 26.4 kpa, a column flow of 1.4 ml/min, a split flow of 37.5 ml/min and an injection temperature of 150 C. The used ramp was: initial temperature 60 C (3 min), rate 5 C/min, intermediate temperature 130 C (1 min), rate 25 C/min, final temperature 230 C (8 min). Detection was performed with an FID detector at a temperature of 250 C. The retention times were as follows: chlorobenzene (internal standard) 13.9 min, S-2,3- -isopropylidene-glyceraldehyde 15.9 min, R-2,3--isopropylidene-glyceraldehyde 16.2 min. A reference sample of S-2,3- -isopropylidene-glyceraldehyde was prepared and purified according to the method described by C. Hubschwerlen, Synthesis, 1986, 962. The boiling point and optical rotation of the resulting product corresponded to the reported data; the peak area on GC was 98%. Racemic R,S-2,3--isopropylidene-glyceraldehyde required for the e.e. determination was prepared according to the method described in patent W 2005/040149, example 2.1: to a solution of R,S-solketal (Acros, 5.46 g, 40.0 mmol) in acetone (25.9 g) was added sodium acetate (3.95 g, 48.2 mmol), trichloroisocyanuric acid (3.72 g, 16.0 mmol) and the resulting suspension was stirred at 25 o C. A solution of 2,2,6,6-tetramethylpiperidinyloxy radical (TEMP, 15.7 mg, 0.10 mmol) in acetone (11.3 g) was added over 8 min, allowing the reaction mixture to warm up to 60 o C. After another 30 min of stirring the solids were filtered off and washed with acetone (25 g). The resulting filtrate (containing 4.2 g, 32.2 mmol R,S-2,3--isopropylidene-glyceraldehyde) was used as such as racemic reference in the e.e. determination. S2

3 Wittig route E-R-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid ethylester (5a) Et Synthesis To a well-stirred slurry of KI 4 (530 g, 2.3 mol, 2.3 eq), KHC 3 (230 g, 2.3 mol, 2.3 equiv) in water (1200 g) was added dropwise a solution of L-5,6--isopropylidene-gulono-1,4-lactone (218.5 g, 1 mol) in water (135 g) and THF (1145 g) during 3 h at C. The reaction mixture was stirred for 4.5 h at 32 C. According to GC analysis (see Materials and methods) the oxidation was complete since the S-2,3--isopropylidene-glyceraldehyde 8 (4) content was 4.38 wt% and did not increase any further. The reaction mixture was cooled to 5 C and kept at this temperature for 14 h. The solids (mainly consisting of KI 3 ) were removed by filtration and the cake was washed with THF (115 ml) and with another portion of THF (215 ml) by reslurrying. A sample was taken from the filtrate (2975 g) and analyzed by GC showing that the content of 4 in the filtrate was 3.69 wt% corresponding to g (0.843 mol) and a yield of 84% based on L-5,6--isopropylidene-gulono-1,4- lactone. To 2953 g of the obtained filtrate (containing g = mol 4) at 13 C was added dropwise under stirring triethyl phosphonoacetate (TEPA, g, 97% pure, mol, 1.01 equiv) during 25 min at C. Subsequently, K 2 C 3 (838 g, 6.07 mol, 7.26 equiv) was added portionwise during 30 min at C. The final ph of the reaction mixture was The reaction mixture was stirred for another 17 h at 20 C. The aqueous and THF phases were separated and the aqueous phase extracted twice with 660 ml of toluene. The combined THF and toluene phases were concentrated in vacuo ( mbar, temperature C) giving g of a light yellow liquid. Quantitative 1 H NMR indicated the presence of 78 wt% E-R-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid ethylester (5a), 2.5 wt% Z-R-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)- acrylic acid ethylester, 4.4 wt% TEPA and 15 wt% toluene. GC (see below) indicated that the e.e. of 5a was 98%. Thus, the crude yield of 5a was g (0.685 mol) corresponding to 82% yield based on 4. f above residue, 0.50 g was purified by flash chromatography on silica gel using 3/7 (v/v) ethyl acetate/n-heptane as the eluent (R f = 0.61). This gave 0.37 g of 5a with a purity of 96 wt% (as assessed by quantitative 1 H NMR) which corresponds to 78% yield based on 4. Identity and purity Colorless oil. [α] D = (c = 1.096, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ = 6.79 (1H, dd, J = 16.0, 5.3 Hz), 6.01 (1H, dd, J = 16.0, 0.9 Hz), 4.58 (1H, q, J = 6.0 Hz), (3H, m), 3.58 (1H, t, J = 7.6 Hz), 1.35 (3H, s), 1.31 (3H, s), 1.20 (3H, t, J = 7.0 Hz). 13 C NMR (75 MHz, CDCl 3 ) δ = (C), (CH), (CH), (C), 75.0 (CH), 68.8 (CH 2 ), 60.6 (CH 2 ), 26.5 (CH 3 ), 25.8 (CH 3 ), 14.2 (CH 3 ). HRMS (CI) calculated for C 10 H 17 4 (M+H + ) , found E.e. = 98% (as determined by GC, see below). The optical rotation and 1 H NMR data are consistent with those as reported by Hubschwerlen 8 and by Takano et al. Synthesis 1986, 403. The 13 C NMR data correspond with those of D. Díez Martin et al. 7 Determination of e.e. The e.e. determination of 5a was performed with the equipment as used for the GC analysis of 4 (see Materials and methods). The injection temperature was 250 C. The used ramp was: initial temperature 80 C (1 min), rate 5 C/min, final temperature 225 C (10 min). Detection was performed with a FID detector at a temperature of 250 C. The retention times were as follows: toluene 7.3 min, chlorobenzene (internal standard) 9.4 min, S min, R min, Z-3-(2,2-dimethyl- [1,3]dioxolan-4-yl)-acrylic acid ethyl ester 20.4 min, 5a 22.6 min, the S-enantiomer of 5a 22.9 min, TEPA 25.5 min. Racemic 5a required for the e.e. determination was prepared according to patent W 2005/040149, example 2.23: the ph of a solution of K 2 C 3 (32.0 g, mmol) in water (120 ml) was adjusted to 11.5 by adding aq. 4 M HCl. The resulting solution was cooled to 3 C and TEPA (8.0 g, 34.6 mmol) was added. While maintaining the temperature of the reaction mixture below 5 C, 73.5 g of a solution containing 4.2 g (32.0 mmol) R,S-2,3--isopropylidene-glyceraldehyde in acetone (as obtained by the procedure described above in Materials and methods ) was added over 70 min. The ph of the reaction mixture was meanwhile kept in the range by adding small portions of K 2 C 3. The resulting mixture was stirred during 4 h between 0 and 5 C and subsequently during 16 h between 5 and 15 C. The acetone was evaporated in vacuo at ambient temperature and the resulting aqueous phase extracted with toluene (3 x 150 ml). After concentrating the combined organic phase in vacuo, the resulting residue was purified by flash chromatography on silica gel using 3/7 (v/v) ethyl acetate/n-heptane as the eluent (R f = 0.61). The resulting racemic 5a was used as a reference in the e.e. determination. S3

4 Et Chemical Shift (ppm) S4

5 (3aS,4S,6aR)-4-Methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one (α-8a) CH 3 Synthesis To g of non-chromatographed 5a (78 wt% pure, g, 0.68 mol) was added nitromethane (88.6 g of a 51.7 wt% solution in methanol, 0.75 mol, 1.1 equiv) and the solution was cooled to 10 C. Subsequently, DBU (103.4 g, 0.68 mol, 1 equiv) was added dropwise during 35 min at C and the funnel was rinsed with methanol (7 g). After stirring for 18 h at 20 C the resulting dark-red solution was cooled to 0 C and NaMe (134.6 g of a 30 wt% solution in methanol, mol, 1.1 equiv) was added dropwise during 35 min at 0 C and the funnel was rinsed with methanol (10 g) [CAUTIN: the experiment as described here is safe but in general reaction mixtures containing salts of nitromethane should be treated with care since some of them (e.g., the sodium salt of nitromethane) in the precipitated form may be explosive. In the present experiment (where such precipitation did not occur) we therefore made sure that high concentrations of nitromethane and sodium methoxide could not be present simultaneously, for instance, by carefully adding the prescribed amounts and by taking care that no significant amount of methanol could evaporate]. After 30 min stirring at 0 C the reaction mixture was quenched into a solution of H 2 S 4 (243 g, 96 wt%, 2.38 mol, 3.5 equiv) in methanol (243 g) at 0-5 C by dropwise addition during 3 h under vigorous stirring and the funnel was rinsed with cold (0 C) methanol (2 x 15 g). After 2 h stirring at 0-2 C the reaction mixture was quenched into a stirred slurry of KHC 3 (353 g) in water (680 ml) at 0 6 C by dropwise addition during 1 h. The ph was 7 at the end of the quench and was adjusted to 4.1 with H 2 S 4 (96 wt%) at 0 C. After heating up to 20 C the salts were removed by filtration and washed with ethyl acetate (3 x 375 ml). The wash liquor was used later on in the extractions. The mother liquor of the filtration (1380 g), according to GC (see below) containing 3.08 wt% α-8a and 0.82 wt% β-8a (corresponding to a total yield of 50% based on 5a and an α-8a:β-8a ratio of 3.75:1) was concentrated in vacuo to remove the methanol. To the resulting residue (760 g) was added water (80 g) and the ph was adjusted to 4.1 with H 2 S 4 (96 wt%). The resulting aqueous solution was extracted with ethyl acetate (700 ml, 4 x 500 ml). The combined organic phases were concentrated in vacuo at C to 181 g of a residue. The volatiles were coevaporated 3 x with isopropanol (2 x 140 g and 90 g) giving a residue (146 g) consisting of a crude mixture of α-8a and β-8a, which was dissolved in isopropanol (202 g) at 70 C. Insoluble material was removed by filtration and washed with isopropanol (5 ml); the weight after drying was 0.33 g. The filtrate (346 g) was cooled to 50 C resulting in spontaneous crystallization of α-8a. The slurry was further cooled to 1 C during 4 h and the crystals were isolated by filtration, washed with isopropanol (2 x 100 ml, 0 C) and dried in vacuo at 40 C until constant weight giving α-8a as an off-white crystalline product (39.7 g, 37% yield based on 5a). According to quantitative 1 H NMR the purity was > 99 wt%. The mother liquor and wash liquors of the first α-8a crystallization (totally 374 g) were concentrated in vacuo to 90.8 g, methanol (120 ml) was added and the resulting mixture concentrated in vacuo to 83 g. Methanol (120 ml) was added once more and the mixture concentrated in vacuo to 83 g. To the residue was added methanol (45 g) and methanesulfonic acid (MeS 3 H, 2.66 g, mol, 0.2 equiv based on total α-8a + β-8a present in the mother liquor and wash liquors) and the solution was heated up to reflux. After 1 h at reflux (60-65 C) GC indicated that the epimerization was complete (the α-8a:β-8a ratio was 3.1:1) and the solution was cooled to 33 C, neutralized with triethyl amine (2.94 g, 1.05 equiv based on MeS 3 H) and concentrated in vacuo. To the resulting residue was added isopropanol (120 ml) and the mixture was concentrated in vacuo to give 88 g of a residue. The residue was dissolved in isopropanol (37 g) at 47 C. The resulting solution was cooled down to 2 C during 2.5 h; crystallization started spontaneously at 30 C. The crystalline product was isolated by filtration, washed with isopropanol (3 x 20 ml, 0 C) and dried in vacuo at 40 C until constant weight giving a second crop of α-8a as an off-white crystalline product (9.8 g, 9% yield based on 5a). According to quantitative 1 H NMR the purity was > 99 wt%. Thus, the total yield of the first and second crop of α-8a based on 5a was 46%. The GC assay for compounds α-8a and β-8a was performed with an Agilent 6890 GC (EPC) and a CP-Sil 5 CB column (part number CP7680 (Varian) or equivalent) of 25 m and with a film thickness of 5 µm using a column head pressure of 5.1 kpa, a split flow of 40 ml/min and an injection temperature of 250 C. The used ramp was: initial temperature 50 C (5 min), rate 10 C/min, final temperature 250 C (15 min). Detection was performed with an FID detector at a temperature of 250 C. The retention times were as follows: chlorobenzene (internal standard) 17.0 min, α-8a 24.9 min, β-8a 25.5 min. The retention time of β-8a was determined by epimerizing pure α-8a (as prepared above) to an approximately 3:1 mixture of α- 8a and β-8a in methanol using 0.2 equiv MeS 3 H at ambient temperature during 16 h ( 1 H NMR and GC-MS confirmed that only β-8a had been formed). For the quantification of β-8a it was assumed that the response factor of β-8a was identical to that of α-8a. S5

6 Identity and purity ff-white crystalline material. Melting point: C. [α] D = (c = 1.22, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ = 5.15 (1H, dd, J = 7.4, 3.8 Hz), 4.88 (1H, s), 4.10 (1H, d, J = 11.1 Hz), 3.96 (1H, dd, J = 10.9, 3.8 Hz), 3.33 (3H, s), (1H, m), 2.84 (1H, dd, J = 18.2, 11.0 Hz), 2.51 (1H, dd, J = 18.3, 3.7 Hz). 13 C NMR (75 MHz, CDCl 3 ) δ = (C), (CH), 83.0 (CH), 70.6 (CH 2 ), 54.5 (CH 3 ), 45.1 (CH), 31.7 (CH 2 ). HRMS (CI) calculated for C 7 H 11 4 (M+H + ) , found E.e. > 99% (as determined by GC, see below). Determination of e.e. The e.e. determination of α-8a was performed with an Agilent 6890 GC (EPC) and a Betadex 120 column of 60 m and an internal diameter of 0.25 mm and with a film thickness of 0.25 µm using a column head pressure of 195 kpa, a column flow of 1.0 ml/min, a split flow of 50 ml/min and an injection temperature of 200 C. The used ramp was: initial temperature 150 C (40 min), rate 20 C/min, final temperature 220 C (6 min). Detection was performed with an FID detector at a temperature of 250 C. The retention times were as follows: (3aR,4R,6aS)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one (the enantiomer of α-8a) 26.4 min, α-8a 27.0 min. Racemic α-8a required for the e.e. determination was prepared according to the same procedure as described above for optically active α-8a except that racemic 5a was used as the starting material. CH Chemical Shift (ppm) S6

7 (3R,3aS,6aR)-Hexahydro-furo[2,3-b]furan-3-ol (2) H Synthesis To a solution of α-8a (14.2 g, 90.0 mmol) in THF (80 g) was added dropwise during 30 min a 10 wt% solution of LiBH 4 (21.55 g, 1.1 equiv) and the reaction mixture was stirred at 50 o C for 2½ h. The obtained suspension was cooled to 10 o C and a 32 wt% aq. HCl solution (13.6 g, mol, 1.3 equiv based on LiBH 4 ) was added dropwise over a period of 4 h keeping the temperature < - 5 o C. After stirring for an additional 2 h at 10 o C, triethyl amine (13.25 g, mol, 1.1 equiv based on HCl) was added dropwise over 1 h keeping the temperature < 0 o C. The reaction mixture was warmed up and concentrated at atmospheric pressure to a residual weight of approximately 50 g, the residue taken up in ethyl acetate (180 g) and concentrated once more at atmospheric pressure to a residual weight of approximately 50 g. The residue was taken up in ethyl acetate (180 g), stirred at reflux for 15 min and cooled to 0 o C. The salts were removed by filtration and washed with cold (0 o C) ethyl acetate (2 x 15 g). The combined filtrates were concentrated in vacuo at < 40 o C to a colorless oil containing 9.4 g of 2 (72.3 mmol, 80% based on α-8a, purity 87 wt% based on quantitative 1 H NMR). The oil was purified by flash chromatography on silica gel using ethyl acetate as the eluent (R f = 0.56). This gave 8.9 g (68.5 mmol) of 2 with a purity of > 99 wt% (as assessed by quantitative 1 H NMR) which corresponds to 76% yield based on α-8a. Identity and purity Colorless oil. [α] D = (c = 1.744, CHCl 3 ) and (c = 1.3, CH 3 H). 1 H NMR (300 MHz, DMS-d 6 ) δ = 5.52 (1H, d, J = 4.8 Hz), 5.14 (1H, d, J = 4.5 Hz), (1H, m), (2H, m), (1H, m), 3.33 (1H, dd, J = 22.6, 14.1 Hz), (1H, m), (1H, m), (1H, m). 13 C NMR (75 MHz, DMS-d 6 ) δ = (CH), 72.1 (CH 2 ), 69.4 (CH), 68.8 (CH 2 ), 45.8 (CH), 24.6 (CH 2 ). 1 H NMR (300 MHz, CDCl 3 ) δ = 5.62 (1H, d, J = 4.9 Hz), 4.36 (1H, q, J = 7.2 Hz), (3H, m), 3.52 (1H, dd, J = 8.9, 7.1 Hz), 3.20 (1H, s), (1H, m), (1H, m), (1H, m). 13 C NMR (75 MHz, CDCl 3 ) δ = (CH), 72.7 (CH 2 ), 70.4 (CH), 69.7 (CH 2 ), 46.3 (CH), 24.7 (CH 2 ). HRMS (CI) calculated for C 6 H 11 3 (M+H + ) , found E.e. > 99% (as determined by GC, see below). All optical data are consistent with the data reported by Ghosh et al. 5,6 Determination of e.e. The e.e. determination of 2 was performed with an HP 5890 GC and a Supelco Betadex column of 60 m and an internal diameter of 0.25 mm and with a film thickness of 0.25 µm using a column head pressure of 30 psi, a column flow of 1.4 ml/min, a split flow of 37.5 ml/min and an injection temperature of 250 C. The used ramp was: initial temperature 80 C (1 min), rate 4 C/min, final temperature 180 C (5 min). Detection was performed with an FID detector at a temperature of 250 C. The retention times were as follows: min, (3S,3aR,6aS)-hexahydro-furo[2,3-b]furan-3-ol (the enantiomer of 2) 27.3 min. Racemic 2 required for the e.e. determination was prepared according to the same procedure as described above for optically active 2 except that racemic α-8a was used as the starting material. S7

8 H (DMS-d 6 ) Chemical Shift (ppm) S8

9 Dimethyl malonate based route 2-((4R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethylene)-malonic acid dimethylester (5b) Me Me Synthesis Fresh S-2,3--isopropylidene-glyceraldehyde (4) was prepared according to the method as described by Hubschwerlen 8 (see Materials and methods), except that the crude product was not distilled. To g of a 20 wt% solution of 4 in THF (as determined by GC, 0.83 mol) having a water content of 1.2 wt% (as determined by Karl-Fischer titration, corresponding to 0.43 equiv based on 4) was added dimethyl malonate (109.0 g, 0.83 mol, 1.0 equiv) and the reaction mixture was stirred for 3 h at 20 o C. After adding 32.8 g pyridine (0.415 mol, 0.5 equiv) the mixture was heated to 45 o C and g of a 50 wt% solution of acetic anhydride (2.49 mol, 3.0 equiv) in THF was added over a period of 4 h. After stirring for another 12 h at 45 o C the reaction mixture was concentrated in vacuo at < 35 o C. The resulting residue was taken up in 1250 g toluene and added over a period of 30 min to a vigorously stirred mixture of solid NaHC 3 (95 g) and 1 N (8.4 wt%) aq. NaHC 3 (880 g) at a temperature of 20 o C. The toluene phase was washed with an additional portion of 880 g 1 N aq. NaHC 3, dried (NaS 4 ) and concentrated in vacuo giving a yellow residue containing g 5b (0.64 mol, 77% yield based on 4, purity 83 wt% based on quantitative 1 H NMR). Part of this residue (10.0 g) was purified by flash chromatography on silica gel using 4/6 (v/v) ethyl acetate/n-heptane as the eluent (R f = 0.54). This gave 7.9 g of 5b with a purity of 97 wt% (as assessed by quantitative 1 H NMR) which corresponds to 71% yield based on 4. Identity and purity Colorless oil. [α] D = (c = 1.640, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ = 6.97 (1H, d, J = 6.7 Hz), 4.86 (1H, q, J = 6.9 Hz), 4.22 (1H, dd, J = 8.4, 6.9 Hz), 3.77 (3H, s), 3.74 (3H, s), 3.66 (1H, dd, J = 8.3, 6.9 Hz), 1.39 (3H, s), 1.32 (3H, s). 13 C NMR (75 MHz, CDCl 3 ) δ = (C), (C), (CH), (C), (C), 73.4 (CH), 69.0 (CH 2 ), 52.6 (CH 3 ), 52.5 (CH 3 ), 26.3 (CH 3 ), 25.5 (CH 3 ). HRMS (CI) calculated for C 11 H 17 6 (M+H + ) , found S9

10 Me Me Chemical Shift (ppm) S10

11 (3R,S,3aS,4R,S,6aR)-4-Methoxy-2-oxo-hexahydro-furo[3,4-b]furan-3-carboxylic acid methylester (8b) CH 3 CH 3 Synthesis To a 23.6 wt% solution of non-chromatographed 5b in methanol (520 g, containing g of 5b, mol) was added 61 g of a 55 wt% solution of nitromethane in methanol (0.55 mol, 1.1 equiv). Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 7.6 g, 0.05 mol, 0.1 equiv) was added dropwise over a period of 30 min while cooling with an ice-bath to such an extent that the temperature was kept < 25 o C. After an additional 3 h stirring at 20 o C the reaction mixture was cooled to 0 o C and a 30 wt% solution of NaMe in methanol (100.0 g, containing mol NaMe, 1.1 equiv) was added dropwise, keeping the temperature at 0-3 o C) [CAUTIN: the experiment as described here is safe but in general reaction mixtures containing salts of nitromethane should be treated with care since some of them (e.g., the sodium salt of nitromethane) in the precipitated form may be explosive. In the present experiment (where such precipitation did not occur) we therefore made sure that high concentrations of nitromethane and sodium methoxide could not be present simultaneously, for instance, by carefully adding the prescribed amounts and by taking care that no significant amount of methanol could evaporate]. The dropping funnel was rinsed with cold (0 o C) methanol (60 g) and the solution stirred for 30 min at 0-3 o C. Subsequently, the mixture was added during 1 h under vigorous stirring to a freshly prepared solution of H 2 S 4 (128 g, 96 wt%, 2.5 equiv) in methanol (200 g) while keeping the temperature at 0-3 o C. The dropping funnel was rinsed with cold (0 o C) methanol (40 g) and the resulting reaction mixture stirred for 4 h at 0-3 o C and quenched by dropwise addition over a period of 1 h into a cold (0-3 o C) and vigorously stirred mixture of ethyl acetate (450 g) and 1 N (8.4 wt%) aq. NaHC 3 (1905 g, 1.9 equiv) while keeping the temperature below 15 o C using an ice bath. During this quench the ph of the aqueous phase was continuously monitored and kept > 5; the final ph was The mixture was filtrated to remove the Na 2 S 4 precipitate and the aqueous phase was extracted with ethyl acetate (4 x 560 g). The combined organic phase was washed with aq. 23 wt% NaCl solution (300 g), dried (Na 2 S 4 ) and concentrated in vacuo at < 40 o C giving 101 g of a residue. Quantitative 1 H NMR in DMS-d 6 indicated the presence of 51.8 wt% of the (3R,4S)-diastereomer (1H, dd, δ = 5.31 ppm; 1H, s, 5.13 ppm) and 13.7 wt% of the (3R,4R)-diastereomer (1H, ddd, δ = 5.20 ppm; 1H, d, 5.09 ppm). This corresponds to 52.3 g (48% yield based on 5b) of the (3R,4S)-diastereomer and 13.8 g (13% yield based on 5b) of the (3R,4R)-diastereomer. 1 H NMR revealed the presence of trace amounts of other components, amongst which most probably also the two other ((3S,4S)- and (3S,4R)-) diastereomers of 8b. The identified crude yield of 8b (i.e. the yield of the (3R,4S) + (3R,4R)-diastereomers) is therefore 66.1 g (61% based on 5b). The crude residue could be used as such in the conversion to α-8a. Alternatively, the residue could be purified by flash chromatography on silica gel using 1/1 (v/v) ethyl acetate/n-heptane as the eluent. This gave 49.1 g of the major (3R,4S)-diastereomer (R f = 0.53) with a purity of 96 wt% according to quantitative 1 H NMR in DMS-d 6 corresponding to a yield of 43% based on 5b. CH 3 CH 3 CH 3 (3R,4S) diastereomer (major) CH 3 (3R,4R) diastereomer (minor) Identity and purity of the (3R,4S)-diastereomer Colorless oil. [α] D = (c = 1.056, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ = 5.19 (1H, dd, J = 7.1, 3.8 Hz), 4.91 (1H, s), 4.06 (1H, d, J = 11.0 Hz), 3.93 (1H, dd, J = 11.1, 3.8 Hz), 3.78 (3H, s), 3.53 (1H, d, J = 4.1 Hz), 3.35 (1H, dd, J = 6.8, 4.1 Hz), 3.28 (3H, s). 13 C NMR (75 MHz, CDCl 3 ) δ = (C), (C), (CH), 82.6 (CH), 70.3 (CH 2 ), 54.7 (CH 3 ), 53.5 (CH 3 ), 50.0 (CH), 49.8 (CH). HRMS (CI) calculated for C 9 H 13 6 (M+H + ) , found S11

12 CH 3 CH Chemical Shift (ppm) S12

13 (3aS,4S,6aR)-4-Methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one (α-8a) CH 3 Synthesis The 101 g non-chromatographed residue of 8b (containing 66.1 g of the (3R,4S) + (3R,4R) diastereomers, mol) was dissolved in 200 g methanol and the mixture was concentrated in vacuo at < 40 o C to a total weight of 100 g. The resulting residue was redissolved in 800 g methanol and after the addition of water (38 g) and 45 wt% aq. KH solution (68 g, 1.1 equiv based on 5b) the reaction mixture was refluxed for 2 h leading to complete ester hydrolysis, decarboxylation and lactone hydrolysis to give 10. After cooling the mixture to 35 o C, acetic acid (46 g, 1.5 equiv based on KH) was added dropwise and the reaction mixture was concentrated in vacuo at < 35 o C to a residual weight of approximately 200 g. To the resulting oil was added acetic acid (350 g) and the mixture was stirred for 3 h at ambient temperature leading to almost complete lactone formation giving 8a. The solution was concentrated in vacuo at < 45 o C to a residual weight of approximately 250 g which was partitioned between water (800 g) and ethyl acetate (700 g) at ambient temperature. The aqueous phase was extracted with ethyl acetate (2 x 700 g) and the combined organic phase was washed with 1 N (8.4 wt%) aq. NaHC 3 (2 x 586 g) leading to a ph value of the aqueous phases of approximately 5.2 and 5.8. To the stirred organic phase was subsequently added dropwise 1 N (8.4 wt%) aq. NaHC 3 (approximately 410 g) until the ph of the aqueous phase was The resulting organic phase was concentrated in vacuo at < 40 o C to a residual weight of approximately 200 g. The residue was taken up in 350 g isopropanol and concentrated in vacuo at < 40 o C to a residual weight of approximately 200 g. After adding another 350 g isopropanol and concentrating in vacuo to a residual weight of 144 g using a water bath of o C, the solution was filtrated and warmed up to 60 o C. After cooling to 48 o C during 30 min the solution was seeded with crystalline α-8a (0.2 g), stirred for another 30 min at o C, cooled to 30 o C during 1½ h, cooled to 0-5 o C during 1½ h and stirred for another 1 h at 0-5 o C. The crystals of α-8a were collected by filtration, washed with 50 g cold (0 o C) isopropanol and dried in vacuo at 40 o C. This furnished 26.0 g of brownish crystals of α-8a with a purity of 98 wt%, as assessed by quantitative 1 H NMR, corresponding to 52% yield based on 8b. Identity and purity See the data of α-8a from the Wittig route, except that the crystals are brownish in stead of off-white. S13