Fast and Flexible Synthesis of Pantothenic Acid and CJ-15,801.

Fast and Flexible Synthesis of Pantothenic Acid and CJ-15,801. Alan L. Sewell a, Mathew V. J. Villa a, Mhairi Matheson a, William G. Whittingham b, Rodolfo Marquez a*. a) WestCHEM, School of Chemistry, University of Glasgow, G12 8QQ, UK. b) Syngenta, Jealott s Hill Research Station, Bracknell, Berkshire, RG42 6EY. r.marquez@chem.gla.ac.uk Supporting Information Experimental Details pg. 2 Spectra Data... pg.14 1

General Conditions. All reactions were performed in oven-dried glassware under an inert argon atmosphere unless otherwise stated. Tetrahydrofuran (THF), diethyl ether, and dichloromethane (DCM) were purified through a Pure Solv 400-5MD solvent purification system (Innovative Technology, Inc). All reagents were used as received, unless otherwise stated. Solvents were evaporated under reduced pressure at 40 C using a Buchi Rotavapor. IR spectra were recorded as thin films on NaCl plates using a JASCO FT/IR410 Fourier Transform spectrometer. Only diagnostic absorptions (ν max ) are reported in wavenumbers (cm -1 ). Proton magnetic resonance spectra ( 1 H NMR) and carbon magnetic resonance spectra ( 13 C NMR) were recorded at 400MHz and 100MHz or at 500MHz and 125MHz using either a Bruker DPX Avance400 instrument or a Bruker Avance III 500 instrument. Chemical shifts (δ) are reported in parts per million (ppm) and are referenced to the residual solvent peak. The order of citation in parentheses is (1) number of equivalent nuclei (by integration), (2) multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad, dm = double multiplet), and (3) coupling constant (J) quoted in Hertz to the nearest 0.1 Hz. High resolution mass spectra were recorded on a JEOL JMS-700 spectrometer by electrospray and chemical ionisation mass spectrometer operating at a resolution of 15000 full widths at half height. Flash chromatography was performed using silica gel (Fluorochem Silica Gel 60, 40-63 micron) as the stationary phase. TLC was performed on aluminium sheets pre-coated 2

with silica (Merck Silica Gel 60 F 254 ). The plates were visualised by the quenching of UV fluorescence (λ max 254nm) and/or by staining with anisaldehyde, potassium permanganate, iodine or cerium ammonium molybdate followed by heating. N-Formyl-(R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid amide, 9. A solution of the (D-) pantolactone derived amide 8 (591 mg) in anhydrous THF (10 ml) was cooled to 0 o C before being treated with n-buli (1.37 ml, 1.1 mmol, 1.6 M solution in hexanes). The reaction mixture was then stirred at 0 o C for 5 minutes before being treated with N-formylbenzotriazole (551 mg, 1.2 mmol). The resulting mixture was then allowed to warm up to room temperature and then stirred for a further 2 hours. The reaction mixture was diluted with t-butylmethyl ether (10 ml), and quenched with a satd. aq. NaHCO 3 solution (10 ml). The aqueous phase was then extracted with diethyl ether (3 x 20 ml) and the combined organic layers dried over Na 2 SO 4. The solvent was removed under vacuum to afford the crude product, which was then purified by flash column chromatography (silica gel, elution gradient 10% to 20% ethyl acetate in 40-60 petroleum ether) to afford 431 mg (64%) of the desired N-formyl imide 9 as a white solid. 1 H NMR (400MHz, CDCl 3 ) δ: 9.08 (1H, d, J = 10.4 Hz), 8.80 (1H, bs), 4.12 (1H, s), 3.65 (1H, d, J = 11.8 Hz), 3.27 (1H, d, J = 11.8 Hz), 1.41 (3H, s), 1.39 (3H, s), 0.99 (3H, s), 0.98 (3H, s). 13 C NMR (100MHz, CDCl 3 ) δ: 170.6, 161.4, 99.7, 77.0, 71.1, 33.3, 29.3, 21.7, 18.9, 18.6. IR ν max (film)/cm -1 3385, 3268, 2874, 1743, 1699. HRMS calcd for C 10 H 18 O 4 N (M+H + ): 216.1236. Found 216.1233. [α] D +48.0 (c = 1.4, CHCl 3 ). 3

(R,E)-Benzyl-3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 10E and (R,Z)-Benzyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 10Z. A solution of n-formyl imide 9 (2.16 g, 9.9 mmol) in benzene (100 ml) was treated with benzyltriphenylphosphoranylidene (12.30 g, 30 mmol) and the resulting mixture heated to 95 o C for 19 h. Upon reaction completion as indicated by TLC analysis, the solvent was removed under vacuum. The crude residue was then purified by flash column chromatography (silica gel, elution gradient 10% to 30% EtOAc in 40-60 petroleum ether) to afford the desired enamides 10E and 10Z (2.99 g, 87%) as a mixture of E and Z isomers in a 3: 1 ratio (E: Z). 10E. 1 H NMR (500MHz, CDCl 3 ) δ: 8.44 (1H, bd, J = 12.1), 8.04 (1H, dd, J = 14.5, 12.1 Hz), 7.37 (5H, m), 5.68 (1H, d, J = 14.5 Hz), 5.22 (2H, s), 4.20 (1H, s), 3.72 (1H, d, J = 12.0 Hz), 3.32 (1H, d, J = 11.5 Hz), 1.52 (3H, s), 1.46 (3H, s), 1.06 (3H, s), 1.01 (3H, s). 13 C NMR (125MHz, CDCl 3 ) δ: 167.9, 166.9, 136.4, 136.2, 128.5, 128.2, 128.1, 102.7, 99.6, 77.2, 71.3, 66.0, 33.4, 29.5, 21.9, 18.8, 18.7. IR ν max (film)/cm -1 3332, 2992, 2959, 2872, 1716, 1637, 1496. HRMS calcd for C 19 H 26 O 5 N (M+H + ): 348.1811. Found 348.1812. [α] D +125.1 (c = 1.1, CHCl 3 ). 10Z. 1 H NMR (500MHz, CDCl 3 ) δ: 11.19 (1H, bd, J = 14.5 Hz), 7.39 (1H, dd, J = 14.5, 11.0 Hz), 7.31 (5H, m), 5.26 (1H, d, J = 11.5 Hz), 5.12 (2H, s), 4.15 (1H, s), 3.66 (1H, d, J = 15.0 Hz), 3.26 (1H, d, J = 14.5 Hz), 1.52 (3H, s), 1.40 (3H, s), 0.98 (3H, s), 0.97 (3H, s). 13 C NMR (100MHz, CDCl 3 ) δ: 168.8, 168.1, 136.6, 135.9, 128.6, 128.3, 128.2, 99.3, 97.6, 77.3, 71.3, 65.9, 33.3, 29.3, 21.9, 19.0, 18.6. 4

IR ν max (film)/cm -1 3329, 2992, 2957, 2872, 1712, 1692. HRMS calcd for C 19 H 26 O 5 N (M+H + ): 348.1811. Found 348.1809. [α] D +75.6 (c = 0.9, CHCl 3 ). (R)-3-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carboxamido)propanoic acid, 11. A solution of (R,Z)-benzyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate 10Z (220 mg, 6.3 mmol) in MeOH (5 ml) was treated with Pd/C (10% wt/wt). The heterogenous mixture was then stirred under a H 2 atmosphere for 24 h. Upon reaction completion as indicated by TLC analysis, the solvent was removed under vacuum. The crude residue (126 mg) was found by NMR to be the clean, desired acetonide 11 (85% yield) which required no further purification. 1 H NMR (400MHz, CDCl 3 ) δ: 7.07 (1H, t, J = 6.0 Hz), 4.13 (1H, s), 3.71 (1H, d, J = 11.7 Hz), 3.56 (2H, m), 3.30 (1H, d, J = 11.7 Hz), 2.63 (2H, t, J = 6.2 Hz), 1.48 (3H, s), 1.45 (3H, s), 1.05 (3H, s), 0.99 (3H, s). 13 C NMR (100MHz, CDCl 3 ) δ: 176.7, 170.2, 99.1, 77.1, 71.4, 34.1, 33.9, 32.9, 29.4, 22.0, 18.8, 18.7. IR ν max (film)/cm -1 3420, 2992, 1731, 1642. HRMS calcd for C 12 H 22 O 5 N (M+H + ): 260.1498. Found 260.1495. [α] D +104.0 (c = 1.2, MeOH). (R,E)-Benzyl 3-(2,4-dihydroxy-3,3-dimethylbutanamido)acrylate, 12. A solution of enamide 10E (1.01 g, 2.9 mmol) in MeCN (40 ml) was treated with Bi(III)Cl 3 (92 mg, 0.29 mmol) and H 2 O (6 drops) and stirred at room temperature for 3 h. Upon completion by TLC analysis, the reaction was quenched with sat. aq. NaHCO 3 soln. (7 ml) and stirred for a further 20 min. After this time, the mixture was filtered over Celite, dried over Na 2 SO 4 filtered a second time, and then the solvent removed under 5

vacuum. The crude residue was then purified by flash column chromatography (silica gel, elution gradient 10% to 50% EtOAc in 40-60 petroleum ether) to afford 760 mg (88%) of the desired diol 12 as a clear oil. 1 H NMR (500MHz, CDCl 3 ) δ: 8.87 (1H, bd, J = 12.0 Hz), 8.04 (1H, dd, J = 14.0, 12.0 Hz), 7.34 (5H, m), 5.63 (1H, d, J = 14.0 Hz), 5.19 (2H, s), 4.19 (2H, bs), 3.63 (1H, dd, J = 10.5, 4.5 Hz), 3.56 (1H, dd, J = 10.5, 4.5 Hz), 2.38 (1H, t, J = 5.0 Hz), 1.05 (3H, s), 0.98 (3H, s). 13 C NMR (125MHz, CDCl 3 ) δ: 170.7, 167.1, 136.7, 136.1, 128.5, 128.2, 128.1, 102.5, 78.4, 72.0, 66.0, 39.2, 20.9, 20.2. IR ν max (film)/cm -1 3327, 2962, 1698, 1634. HRMS calcd for C 16 H 22 O 5 N (M+H + ): 308.1498. Found 308.1501. [α] D +75.0 (c = 1.8, CHCl 3 ). (R)-3-(2,4-Dihydroxy-3,3-dimethyl butanamido)propanoic acid [(R)-pantothenic acid], 1. A solution of (R,Z)-benzyl 3-(2,4-dihydroxy-3,3-dimethyl butanamido)acrylate 12 (218 mg, 0.7 mmol) in MeOH (5 ml) was treated with Pd/C (10% wt/wt). The heterogenous mixture was then stirred under a H 2 atmosphere for 24h. Upon reaction completion as indicated by TLC analysis, the solvent was removed under vacuum. The crude residue was found by NMR to be the desired pantothenic acid 1 in 83% yield (135 mg), which required no further purification. 1 H NMR (400MHz, MeOD) δ: 3.92 (1H, s), 3.46 (4H, m), 2.56 (2H, t, J = 6.4 Hz), 0.94 (6H, s). 13 C NMR (100MHz, CDCl 3 ) δ: 176.1, 175.5, 77.3, 70.4, 40.4, 35.8, 34.8, 21.3, 20.9. 6

IR ν max (film)/cm -1 3700, 2948, 1721, 1650. HRMS calcd for C 9 H 17 O 5 N (M+ ): 219.1107. Found 219.1110. [α] D +82.4 (c = 1.3, MeOH). (R,E)-Methyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 13E and (R,Z)-Methyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 13Z. A solution of N-formyl imide 9 (193 mg, 0.89 mmol) in benzene (10 ml) was treated with methyltriphenylphosphoranylidene acetate (888 mg, 2.7 mmol) and the resulting mixture heated to 95 o C for 19 h. Upon reaction completion as indicated by TLC analysis, the solvent was removed under vacuum. The crude residue was then purified by flash column chromatography (silica gel, elution gradient, 10% to 30% EtOAc in 40-60 petroleum ether) to afford the desired enamide 13 (220 mg, 91%) as a mixture of E and Z isomers in a 2:1 E: Z ratio. 13E 1 H NMR (500MHz, CDCl 3 ) δ: 8.40 (1H, bd, J = 11.5 Hz), 8.99 (1H, dd, J = 14.5, 12.0 Hz), 5.61 (1H, d, J = 14.0 Hz), 4.20 (1H, s), 3.73 (3H, s), 3.71 (1H, d, J = 11.5 Hz), 3.32 (1H, d, J = 11.5 Hz), 1.52 (3H, s), 1.46 (3H, s), 1.06 (3H, s), 1.01 (3H, s). 13 C NMR (125MHz, CDCl 3 ) δ: 167.9, 167.6, 136.2, 102.5, 99.6, 77.2, 71.2, 51.4, 33.4, 29.5, 21.9, 18.8, 18.7. IR ν max (film)/cm -1 3330, 2992, 2954, 1720, 1640. HRMS calcd for C 13 H 22 O 5 N (M+H + ): 272.1498. Found 272.1494. [α] D +137.6 (c = 1.0, CHCl 3 ). 13Z 1 H NMR (400MHz, CDCl 3 ) δ: 11.02 (1H, bd, J = 11.7 Hz), 7.37 (1H, dd, J = 11.7, 9.0 Hz), 5.11 (1H, d, J = 8.9 Hz), 4.15 (1H, s), 3.67 (4H, m), 3.26 (1H, d, J = 11.7 Hz), 1.53 (3H, s), 1.41 (3H, s), 0.98 (3H, s), 0.97 (3H, s). 13 C NMR (100MHz, CDCl 3 ) δ: 168.8, 168.6, 136.1, 99.3, 97.6, 77.3, 71.3, 51.3, 33.3, 29.4, 21.9, 19.0, 18.6. 7

IR ν max (film)/cm -1 3325, 2955, 1696, 1629. HRMS calcd for C 13 H 22 O 5 N (M+H + ): 272.1498. Found 272.1501. [α] D +108.0 (c = 1.1, CHCl 3 ). (R,E)-Methyl 3-(2,4-dihydroxy-3,3-dimethyl butanamido)acrylate, 14E. A solution of enamide 13E (391 mg, 1.44 mmol) in MeCN (12 ml) was treated with Bi (III)Cl 3 (45 mg, 0.14 mmol) and H 2 O (4 drops) and stirred at room temperature for 3h. Upon completion by TLC analysis, the reaction was quenched with sat. NaHCO 3 (2 ml) and stirred for a further 20min. After this time, the mixture was filtered through Celite, dried over Na 2 SO 4, filtered a second time, and then the solvent removed under vacuum. The crude residue was then purified by flash column chromatography (silica gel, elution gradient 10% to 30% EtOAc in 40-60 petroleum ether) to afford 73 mg of the desired diol 14E (50%) as a colourless oil. 1 H NMR (500MHz, MeOD) δ: 7.94 (1H, d, J = 14.0 Hz), 5.78 (1H, d, J = 14.5 Hz), 4.01 (1H, s), 3.70 (3H, s), 3.48 (1H, d, J = 11.0 Hz), 3.37 (1H, d, J = 11.0 Hz), 0.93 (3H, s), 0.92 (3H, s). 13 C NMR (125MHz, MeOD) δ: 175.0, 170.2, 138.9, 102.5, 77.1, 69.8, 51.8, 40.8, 21.5, 20.4. IR ν max (film)/cm -1 3291, 2992, 1721, 1670, 1169. HRMS calcd for C 10 H 18 O 5 N (M+H + ): 232.1185. Found 232.1184. [α] D +131.7 (c = 1.4, CHCl 3 ). (R,E)-tert-Butyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 15E and (R,Z)-tert-Butyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 15Z. A solution of n-formyl imide 9 (500 mg, 2.3 mmol) in benzene (20 ml) was treated with t-butoxycarbonylmethylene triphenylphosphorane (2.59 g, 6.9 mmol) and the resulting 8

mixture heated to 95 o C for 19 h. Upon reaction completion as indicated by TLC analysis, the solvent was removed under vacuum. The crude residue was then purified by flash column chromatography (silica gel, elution gradient 10% to 30% EtOAc in 40-60 petroleum ether) to afford the desired enamides 15E and 15Z (614 mg, 85%) as a mixture of E and Z isomers in a 4:1 E: Z ratio. 15E 1 H NMR (500MHz, CDCl 3 ) δ: 8.46 (1H, bd, J = 11.5 Hz), 7.86 (1H, dd, J = 14.5, 12.0 Hz), 5.52 (1H, d, J = 14.0 Hz), 4.19 (1H, s), 3.71 (1H, d, J = 12.0 Hz), 3.31 (1H, d, J = 11.5 Hz), 1.51 (3H, s), 1.48 (9H, s), 1.45 (3H, s), 1.05 (3H, s), 1.00 (3H, s). 13 C NMR (125MHz, CDCl 3 ) δ: 167.9, 166.4, 134.9, 105.1, 99.5, 80.2, 77.2, 71.2, 33.4, 29.4, 28.2, 21.9, 20.2, 18.8, 18.7. IR ν max (film)/cm -1 3336, 2976, 1709, 1638, 1499. HRMS calcd for C 16 H 28 O 5 N (M+H + ): 314.1967. Found 314.1971. [α] D +105.9 (c = 1.5, CHCl 3 ). 15Z 1 H NMR (500MHz, CDCl 3 ) δ: 11.22 (1H, bd, J = 15.0 Hz), 7.37 (1H, dd, J = 14.5, 11.5 Hz), 5.11 (1H, d, J = 11.0 Hz), 4.23 (1H, s), 3.75 (1H, d, J = 14.5 Hz), 3.32 (1H, d, J = 14.5 Hz), 1.61 (3H, s), 1.52 (9H, s), 1.50 (3H, s), 1.08 (6H, s). 13 C NMR (100MHz, CDCl 3 ) δ:. 168.8, 167.8, 135.1, 99.9, 99.2, 80.5, 77.3, 71.4, 33.2, 29.3, 28.3 (2C), 21.9, 19.1, 18.7. IR ν max (film)/cm -1 3320, 2980, 2872, 1686, 1628. HRMS calcd for C 16 H 28 O 5 N (M+H + ): 314.1967. Found 314.1965. [α] D +85.5 (c = 1.9, CHCl 3 ). (R,E)-3-(2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-acrylic acid tert-butyl ester, 16E. 9

A solution of enamide 15E (280 mg, 0.89 mmol) in MeCN (6.0 ml) was treated with H 2 O (200 μl) and Bi(III)Cl 3 (28 mg, 0.09 mmol) and the resulting mixture was stirred at room temperature overnight. Upon completion by TLC analysis (20 h), the reaction was filtered over Celite and dried over Na 2 SO 4. The solvent was removed under vacuum and the crude residue was then purified by flash column chromatography (silica gel, elution gradient 10% to 50% EtOAc in 40-60 petroleum ether) to afford 196 mg (80%) of the desired diol, 16E as a clear oil. 1 H NMR (500MHz, CDCl 3 ) δ: 8.76 (1H, bd, J = 11.5 Hz), 7.90 (1H, dd, J = 14.5, 12.0 Hz), 5.50 (1H, d, J = 14.5 Hz), 4.19 (1H, d, J = 4.0 Hz), 4.12 (1H, d, J = 3.5 Hz), 3.64 (1H, dd, J = 11.0, 5.0 Hz), 3.56 (1H, dd, J = 11.0, 5.0 Hz), 2.36 (1H, t, J = 5.0 Hz), 1.49 (9H, s), 1.06 (3H, s), 0.98 (3H, s). 13 C NMR (125MHz, CDCl 3 ) δ: 170.6, 166.5, 135.3, 104.9, 80.3, 78.3, 72.0, 39.3, 28.2, 20.8, 20.2. IR ν max (film)/cm -1 3336, 2976, 1709, 1638, 1499. HRMS calcd for C 13 H 24 O 5 N (M+H + ): 274.1654, Found 274.1646. (E)-2-(Trimethylsilyl)ethyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4- carboxamido)acrylate, 17E and (Z)-2-(Trimethylsilyl)ethyl 3-(2,2,5,5-tetramethyl- 1,3-dioxane-4-carboxamido)acrylate, 17Z. A solution of N-formyl imide 9 (200 mg, 0.9 mmol) in benzene (7 ml) was treated with trimethylsilylethylphosphoranylidene acetate (950 mg, 2.25 mmol) and the resulting mixture heated to 80 o C for 19 h. Upon reaction completion as indicated by TLC analysis, the solvent was removed under vacuum. The crude residue was then purified by flash column chromatography (silica gel, elution gradient, 5% to 15% EtOAc in 40-60 10

petroleum ether) to afford 241 mg of the desired enamides 17E and 17Z (76%) as a 1.5:1 mixture of E: Z isomers. 17E 1 H NMR (400MHz, CDCl 3 ) δ: 8.31 (1H, d, J = 12.0 Hz), 7.90 (1H, m), 5.52 (1H, d, J = 14.3 Hz), 4.18 (2H, m), 4.14 (1H, s), 3.66 (1H, d, J = 12.0 Hz), 3.26 (1H, d, J = 12.3 Hz), 1.46 (3H, s), 1.40 (3H, s), 1.00 (3H, s), 0.96 (5H, m), 0.00 (9H, s). 13 C NMR (100MHz, CDCl 3 ) δ: 169.4, 168.7, 137.2, 104.7, 101.0, 78.7, 72.7, 63.9, 34.9, 30.9, 23.3, 20.3, 20.1, 18.8, 0.0. IR ν max (film)/cm -1 3318, 2955, 2878, 1670, 1628, 1188, 1095. HRMS calcd for C 17 H 32 O 5 NSi (M+H + ): 358.2050. Found 358.2051. 17Z 1 H NMR (CDCl 3, 400 MHz): 11.02 (1H, d, J =10.8 Hz), 7.35 (1H, dd, J = 11.6, 8.9 Hz), 5.09 (1H, d, J = 11.0 Hz), 4.18 (3H, m), 3.66 (1H, d, J = 11.7 Hz), 3.27 (1H, d, J = 11.7 Hz), 1.54 (3H, s), 1.41 (3H, s), 0.99 (3H, s), 0.98 (3H, s), 0.96 (2H, m), 0.00 (9H, s). IR ν max (film)/cm -1 3402, 2955, 2878, 1697, 1636, 1195. HRMS calcd for C 17 H 32 O 5 NSi (M+H + ): 358.2050. Found 358.2060. (E)-3-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carboxamido)acrylic acid, 18E. A solution of enamide 17E (110mg, 0.31 mmol) was treated with a 1M solution of tetrabutylammoniumfluoride in THF (0.37ml, 0.37 mmol) and the resulting mixture left to stir at RT for 19 h. Upon reaction completion as indicated by TLC analysis, solvent was removed under vacuum and the crude residue was purified by flash column chromatography (silica gel, elution gradient 0% to 5% methanol in dichloromethane) to afford 15 mg of the desired acid 18E. 11

The combined impure factions were reduced under vacuum and dissolved in ethyl acetate. 1M sodium hydroxide solution was added, and the solution was left to stir for 0.5 h. The phases were separated and the organic layer was extracted with water (2 x 15 ml). The combined aqueous layers were acidified with 1M hydrochloric acid to ph 2 and the resulting solution was extracted with ethyl acetate (2 x 15 ml). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated under vacuum to give 48 mg (63 mg total, 79%) of the desired acid 18E as a white solid. Mp. 165-167 o C. 1 H NMR (400MHz, CDCl 3 ) δ: 7.95 (1H, d, J = 14 Hz), 5.86 (1H, d, J = 14 Hz), 4.31 (1H, s), 3.80 (1H, d, J = 11.6 Hz), 3.32 (1H, d, J = 11.6 Hz), 2.10 (3H, s), 1.51 (3H, s), 1.03 (3H, s), 1.02 (3H, s). 13 C NMR (100MHz, CDCl 3 ) δ: 170.9, 138.5, 104.0, 100.8, 78.6, 72.2, 34.3, 29.5, 22.2, 19.3, 19.0. IR ν max (film)/cm -1 3318, 3140, 3094, 2963, 2878, 1720, 1670, 1636, 1474, 1389. (R,E)-3-(2,4-Dihydroxy-3,3-dimethylbutanamido)acrylic acid [CJ-15,801], 3. From Diol 16E. A solution of tert-butyl ester 16E (59 mg, 0.21 mmol) in formic acid (1 ml) was stirred at room temperature for 120 min. After this time, the excess formic acid was removed under vacuum to afford 38 mg (83%) of CJ-15,801 3 which was clean by 1H NMR with the exception of formic acid traces. Purification by flash column chromatography (elution gradient 0 to 10% MeOH in DCM) afforded a yellow oil which upon azeotroping with chloroform yielded 22 mg (48%) of CJ-15,801 3 as a fine white powder. From Acetonide 15E. 12

A solution of (R,E)-tert-butyl 3-(2,4-dihydroxy-3,3-dimethylbutanamido)acrylate 15E (195 mg, 0.62 mmol) in formic acid (7 ml) was stirred at room temperature for 90 min. After this time, the excess formic acid was removed under vacuum. The crude residue was then taken up into MeOH (7 ml) and p-toluenesulfonic acid added (11 mg, 62 μmol) and the resulting mixture stirred for 75 min. After this time, the solvent was removed under vacuum, and the crude residue purified by flash column chromatography (silica gel, 50% EtOAc in 40-60 petroleum ether) to afford CJ-15,801 3 in 20% yield over the two steps. From Acetonide 18E. A solution of (E)-3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylic acid 18E (60 mg, 0.23 mmol) in MeCN (1 ml) was treated with Bi(III)Cl 3 (7 mg, 23 μmol) and H 2 O (50 μl) and stirred at room temperature for 19 h. Upon completion by TLC analysis, the mixture was filtered over Celite, and dried over Na 2 SO 4. The solution was filtered a second time, and then the solvent removed under vacuum. The crude residue was then purified by flash column chromatography (silica gel, elution gradient 5% to 10% methanol in dichloromethane) to afford 28 mg (56%) of CJ-15,801 3 as a white solid. 1 H NMR (500MHz, MeOD) δ: 7.94 (1H, d, J = 14.2 Hz), 5.69 (1H, d, J = 14.2 Hz), 4.02 (1H, s), 3.50 (1H, d, J = 10.9 Hz), 3.38 (1H, d, J = 10.9 Hz), 0.94 (3H, s), 0.93 (3H, s). 13 C NMR (125MHz, MeOD) δ: 173.4, 170.4, 137.1, 102.1, 75.6, 68.2, 39.2, 19.9, 18.8. IR ν max (film)/cm -1 3398, 2952, 2841, 1774, 1639. HRMS calcd for C 9 H 15 O 5 N (M+H + ): 218.1028 Found 218.1025. [α] D +58.0 (c = 0.6, MeOH). 13

(R,E)-Benzyl-3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 10E 14

(R,Z)-Benzyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 10Z. 15

(R,E)-Benzyl 3-(2,4-dihydroxy-3,3-dimethylbutanamido)acrylate, 12. 16

(R,E)-Methyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 13E 17

(R,Z)-Methyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 13Z. 18

(R,E)-Methyl 3-(2,4-dihydroxy-3,3-dimethyl butanamido)acrylate, 14E. 19

(R,E)-tert-Butyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 15E 20

(R,Z)-tert-Butyl 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido)acrylate, 15Z. 21

(R,E)-3-(2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-acrylic acid tert-butyl ester, 16E. 22

(E)-2-(Trimethylsilyl)ethyl3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido) acrylate, 17E 23

(Z)-2-(Trimethylsilyl)ethyl acrylate, 17Z. 3-(2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamido) 24

(E)-3-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carboxamido)acrylic acid, 18E. 25

(R,E)-3-(2,4-Dihydroxy-3,3-dimethylbutanamido)acrylic acid [CJ-15,801], 3. 26