Total Synthesis of O-Methylmyxalamide D and (6E)-O- Methylmyxalamide D. Supplementary Information

Transcription

1 Total Synthesis of O-Methylmyxalamide D and (6E)-O- Methylmyxalamide D Robert S. Coleman,* Xiaoling Lu, and Isabelle Modolo Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH Supplementary Information General. 1 H (500 MHz) and 13 C (126 MHz) NMR spectra were recorded on a Bruker DRX-500 spectrometer in CDCl 3 using CHCl 3 ( 1 H δ 7.27) and CDCl ( 13 C δ 77.0) as internal standards. High resolution mass spectra were recorded on a Micromass Q-TOF2 instrument at The Ohio State University Chemistry Mass Spectrometry Facility. All reactions were conducted in either oven-dried (120 C) glassware or flame-dried glassware, under an Ar atmosphere when necessary. Tetrahydrofuran (THF) was distilled from benzophenone ketyl. Triethylamine and CH 2 Cl 2 were distilled from calcium hydride prior to use. All other chemicals were used as received. O 3-Pentyn-2-one (9). A mixture of racemic 3-pentyn-2-ol (4.28 g, mol), manganese dioxide (89.0 g, 1.02 mol), and CH 2 Cl 2 (400 ml) was stirred at 25 C for 24 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by distillation (bp C/55mm Hg) to afford 9 (3.21 g, 77%) as colorless oil: 1 H NMR (500 MHz, CDCl 3 ) δ 2.26 (s, 3H), 1.97 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) 184.7, 89.7, 80.6, 32.5, S1

2 OH (S)-3-Pentyn-2-ol. A solution of RuCl[(S,S)- NTsCH(C 6 H 5 )CH(C 6 H 5 )NH 2 ](η 6 -cymene) 1 (0.226 g, 0.38 mmol) in CH 2 Cl 2 (5 ml) was added to a solution of 3-pentyn-2-one (9) (2.84 g, 34.6 mol) in isopropanol (300 ml) via cannula. The reaction mixture was stirred at 25 C for 12 h and was concentrated. The residue was purified by distillation (bp C/50mm Hg) to afford the title compound (2.0 g, 69%) as colorless oil. The ratio of enantiomers (94:6) was determined by Chiral GC (Chira cyclodex B, isotemp 65 C, retention time: (R)-isomer 7.93 min, (S)-isomer 8.20 min). The spectroscopic data were identical with those reported. 2 OMs (S)-3-Pentyn-2-yl Methanesulfonate (10). Triethylamine (4.30 ml, 30.9 mmol) and methanesulfonyl chloride (1.84 ml, 23.8 mmol) were added successively to a solution of (S)-3-pentyn-2-ol (1.00 g, 11.9 mmol) in CH 2 Cl 2 (80 ml) at 78 C. The reaction mixture was stirred at 78 C for 2 h before it was quenched by the addition of 20 ml of saturated aqueous NaHCO 3 at 78 C. After the mixture was warmed to 25 C, the organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (2 x 20 ml). The combined organic extracts were washed with saturated aqueous NaHCO 3 (1 x 20 ml) and distilled water (3 x 50 ml), and were dried (Na 2 SO 4 ), filtered, and concentrated, to afford mesylate 10 (1.88 g, 97%) as pale yellow oil, which was used without further purification. 1 Kirkham, J. E. D.; Courtney, T. D. L.; Lee, V.; Baldwin, J. E. Tetrahedron 2005, 61, Lowe, J. T.; Panek, J. S. Organic Letters 2005, 7, S2

3 OH (2E,4R,5R)-3,5-Dimethyl-2-octen-6-yn-4-ol (12). Triphenylphosphine (0.127 g, mmol) was added to a solution of palladium acetate (0.109 g, mmol) in THF (70 ml) at 78 C under Ar. After 20 min, a solution of (S)-3-pentyn-2-yl methanesulfonate (10) (1.88 g, 11.6 mmol) in THF (10 ml) and a solution of (E)-2-methyl-2-butenal (11) (0.814 g, 9.67 mmol) in THF (20 ml) were added successively via cannula. A solution of diethylzinc (1.0 M in THF, 29.0 ml, 29.0 mmol) was added dropwise via a syringe and the reaction mixture was warmed to 20 C and was stirred for 14 h at this temperature before it was allowed to warm to 25 C. The reaction was quenched by the addition of saturated aqueous NH 4 Cl (25 ml). The organic layer was separated, and the aqueous layer was extracted with Et 2 O (2 x 20 ml). The combined organic extracts were washed with saturated aqueous NaCl (3 x 50 ml), and were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (silica, 5:1 hexane/et 2 O) to afford alcohol 12 (0.938 g, 64%), as an inseparable 85:15 mixture of anti and syn diastereomers: anti isomer (major isomer): 1 H NMR (500 MHz, CDCl 3 ) δ 5.50 (qd, J = 6.5, 1.0 Hz, 1H), 3.71 (d, J = 8.5 Hz, 1H), (m, 1H), 1.81 (d, J = 2.5 Hz, 3H), (m, 3H), 1.57 (m, 3H), 1.00 (d, J = 7.0 Hz, 3H); syn isomer (minor isomer): 1 H NMR (500 MHz, CDCl 3 ) δ 5.53 (qd, J = 6.5, 1.0 Hz, 1H), 3.92 (d, J = 6.0 Hz, 1H), (m, 1H), 1.78 (d, J = 2.5 Hz, 3H), (m, 3H) 1.08 (d, J = 7.0 Hz, 3H). OTBS (2E,4R,5R)-4-(tert-Butyldimethylsilyloxy)-3,5-dimethyl-2-octen-6- yn (13). A solution of tert-butyldimethylsilyl trifluoromethanesulfonate (2.34 g, 2.04 ml, S3

4 8.88 mmol) in CH 2 Cl 2 (10 ml) was added dropwise to a solution of the diastereomeric mixture of alcohols 12 (0.900 g, 5.92 mmol), 2,6-lutidine (2.35 g, 2.56 ml, 21.9 mmol), and CH 2 Cl 2 (50 ml) at 0 C. The mixture was stirred at 0 C for 15 min and 25 C for 1 h. The reaction was quenched by the addition of saturated aqueous NaHCO 3 (30 ml) and the organic layer was separated. The aqueous layer was extracted with Et 2 O (2 x 20 ml) and the combined organic extracts were washed with 5% aqueous HCl (1 x 30 ml), saturated aqueous NaCl (1 x 30 ml), saturated NaHCO 3 (1 x 30 ml), and saturated aqueous NaCl (3 x 50 ml), and were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (silica, 100:2 hexane/et 2 O) to afford anti isomer 13 (1.16 g) along with the syn isomer (0.25 g) as colorless oils (total combined yield 89%). The anti isomer 13 was characterized: 1 H NMR (500 MHz, CDCl 3 ) δ 5.36 (qd, J = 6.5, 1.0 Hz, 1H), 3.76 (d, J = 9.0 Hz, 1H), (m, 1H), 1.78 (d, J = 2.5 Hz, 3H), 1.59 (dd, J = 6.5, 1.0 Hz, 3H), 1.53 (s, 3H), 0.92 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), (s, 3H), 0.00 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 136.4, 122.2, 83.2, 83.1, 75.8, 31.6, 25.8, 18.3,17.7, 12.9, 10.4, 3.56, 4.86, 4.97; IR (film) ν max 2957, 2857, 1075, 862, 836, 775 cm 1 ; HRMS (ESI) calcd for C 16 H 30 OSiNa: , found: OTBS I (2E,4R,5R,6E)-4-(tert-Butyldimethylsiloxy)-3,5-dimethyl-7-iodo- 2,6-octadiene (14). A solution of diisobutylaluminum hydride (1M in hexanes, 2.8 ml, 2.8 mmol) in THF (1.3 ml) was added over 15 min to a mixture of bis(cyclopentadienyl)zirconium dichloride (0.81 g, 2.78 mmol) and THF (7 ml) at 0 C. The mixture was stirred at 0 C for 30 min. Then a solution of alkyne 13 (0.370 g, mmol) in THF (3 ml) was added via cannula. The reaction mixture was stirred at 0 C S4

5 for 4 h before it was cooled to 78 C. A solution of iodine (0.564 g, 2.22 mmol) in THF (8 ml) was added dropwise. The reaction mixture was stirred at 78 C for 12 h before it was allowed to warm to 25 C. The reaction was quenched by the addition of saturated NH 4 Cl (25 ml). The organic layer was separated, and the aqueous layer was extracted with Et 2 O (2 x 20 ml). The combined organic extracts were washed with 5% aqueous HCl (1 x 30 ml), saturated aqueous sodium thiosulfite (1 x 30 ml), saturated aqueous NaHCO 3 (1 x 30 ml), and saturated aqueous NaCl (2 x 50 ml), and were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (silica, hexane) to afford 14 (0.293 g, 53%) as colorless oil: 1 H NMR (500 MHz, CDCl 3 ) δ 5.94 (dd, J = 10.5, 1.5 Hz, 1H), 5.33 (qd, J = 6.5, 0.5 Hz, 1H), 3.61 (d, J = 8.0 Hz, 1H), (m, 1H), 2.38 (d, J = 1.0 Hz, 3H), 1.59 (d, J = 6.5 Hz, 3H), 1.55 (s, 3H), 0.87 (s, 9H), 0.76 (d, J = 6.5 Hz, 3H), (s, 3H), (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 145.2, 136.5, 121.9, 93.8, 82.8, 40.2, 28.0, 25.8, 18.0, 16.8, 12.9, 10.6, 4.83, 4.89; IR (film) ν max 2957, 2857, 1472, 1250, 1059, 860, 836, 775 cm 1 ; HRMS (ESI) calcd for C 16 H 31 IOSiNa: , found: OH I (2E,4R,5R,6E)-3,5-Dimethyl-7-iodo-2,6-octadien-4-ol (7). A mixture of compound 14 (0.227 g, mmol) and tetrabutylammonium fluoride (1M solution in THF, 9 ml) was stirred at 25 C for 12 h. Ether (10 ml) and distilled water (10 ml) were added, the organic layer was separated, and the aqueous layer was extracted with Et 2 O (5 x 20 ml). The combined organic extracts were washed with saturated aqueous NaCl (2 x 50 ml), and were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (silica, 10:3 hexane/et 2 O) to afford S5

6 compound 7 (0.162 g, 87%) as colorless oil: 1 H NMR (500 MHz, CDCl 3 ) δ 6.06 (dd, J = 10, 1.5 Hz, 1H), 5.48 (qd, J = 6.5, 0.5 Hz, 1H), 3.67 (d, J = 8.5 Hz, 1H), (m, 1H), 2.44 (d, J = 1.5 Hz, 3H), 1.63 (d, J = 7.0 Hz, 3H), 1.62 (s, 3H), 0.83 (d, J = 6.5 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 143.9, 135.4, 123.5, 95.4, 81.9, 39.7, 28.1, 16.8, 13.1, 10.7; IR (film) ν max 3453 (br), 2966, 2925, 1454, 1377, 1008, 827 cm 1 ; HRMS (ESI) calcd for C 10 H 17 IONa: , found: I O N H OMe (S,E)-3-Iodo-N-(1-methoxypropan-2-yl)-2-methylacrylamide (8). Oxalyl chloride (0.975 g, 0.66 ml, 7.68 mmol) was added to a solution of (E)-3- iodo-2-methylacrylic acid (1.48 g, 6.98 mmol) in CH 2 Cl 2 (3 ml). Three drops of anhydrous DMF were added to the mixture, which was stirred at 25 C for 3 h before it was concentrated. The residue was purified by distillation (bp C, 18 mm Hg) to afford (E)-3-iodo-2-methylacryloyl chloride (1.04 g, 4.51 mmol) as pale yellow oil. A solution of the acryloyl chloride in THF (5 ml) was added via cannula to a mixture of (S)-1-methoxypropan-2-amine (0.348 g, 3.91 mmol), triethylamine (1.97 g, 2.70 ml, 19.6 mmol), 4-dimethylaminopyridine (47 mg, 0.39 mmol) and THF (5 ml) at 0 C. The reaction mixture was stirred at 25 C for 12 h before it was quenched by the addition of Et 2 O (10 ml) and distilled water (10 ml). The organic layer was separated, and the aqueous layer was extracted with Et 2 O (2 x 20 ml). The combined organic extracts were washed with 1 N aqueous HCl (1 x 10 ml), saturated aqueous NaHCO 3 (1 x 10 ml), and saturated aqueous NaCl (2 x 20 ml), and was dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by crystallization from a mixture of hexanes and Et 2 O (2:1) to afford 8 (0.99 g, 90%) as a white solid: mp C; 1 H NMR (500 MHz, CDCl 3 ) δ 7.23 S6

7 (d, J = 1.0 Hz, 1H), 5.97 (s, 1H), (m, 1H), 3.43 (dd, J = 9.5, 4.0 Hz, 1H), 3.38 (s, 3H), 3.36 (dd, J = 9.5, 4.0 Hz, 1H), 2.06 (d, J = 1.0 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 165.2, 143.9, 90.4, 75.2, 59.1, 45.3, 20.9, 17.6; IR (film) ν max 3294, 2970, 1645, 1109, 729 cm 1 ; HRMS (ESI) calcd for C 8 H 14 INO 2 Na: , found: O n-bu 3 Sn B O 2-((1E,3E,5E)-6-(Tri-n-butylstannyl)hexa-1,3,5- trienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5). The following process was conducted in the dark or the reaction flask was wrapped with aluminum foil. A solution of (2E,4E)-5-(tri-n-butylstannyl)penta-2,4-dienal (16) (3.20 g, 8.62 mmol) and 2- (dichloromethyl-4,4,5,5-tetramethyl-1,3,2,dioxaborolane (3.64 g, 17.2 mmol) in THF (40 ml) was added via cannula to a mixture of anhydrous chromium dichloride (8.48 g, 69.0 mmol) in THF (80 ml). A solution of lithium iodide (4.61 g, 34.5 mmol) in THF (40 ml) was added via cannula and the reaction mixture was stirred at 25 C for 12 h. The reaction was quenched by the addition of water. The mixture was passed through a pad of Celite. Additional 20 ml of distilled water was added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with Et 2 O (2 x 30 ml). The combined organic extracts were washed with saturated aqueous NaCl (2 x 50 ml), then dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (short silica column, 100:5 hexane/et 2 O) to afford triene 5 (3.00 g, 70%) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 7.03 (dd, J = 17.5, 10.0 Hz, 1H), 6.59 (dd, J = 18.5, 9.5 Hz, 1H), 6.42 (d, J = 19.0 Hz, 1H), 6.31 (dd, J = 15.5, 10.0 Hz, 1H), 6.23 (dd, J = 15.0, 10.5 Hz, 1H), 5.59 (d, J = 18.0 Hz, 1H), (m, 6H), (m, 6H), S7

8 1.28 (s, 12H), (m, 15H); 13 C NMR (126 MHz, CDCl 3 ) δ 149.8, 146.6, 138.9, 138.5, 133.0, 83.2, 29.1, 27.2, 24.8, 13.7, 9.56, [note: the carbon bonded to boron was not observed due to quadrupole broadening caused by the 11 B nucleus]; IR (film) ν max 2956, 2926, 1614, 1354, 1144, 1012, 967 cm 1 ; HRMS (ESI) calcd for C 24 H 45 BO 2 SnNa: , found: (n-bu) 3 Sn O B O 2-((1E, 3Z,5E)-6-(Tri-n-butylstannyl)hexa-1,3,5- trienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6). The following process was conducted in the dark or the reaction flask was wrapped with aluminum foil. A solution of sulfone 18 (0.479 g, mmol) and aldehyde 19 (0.137 g, mmol) in THF (9 ml) was cooled to 78 C. The flask was purged by evacuating for 1 min and then flushing with Ar. The de-gas process was repeated three times. A solution of potassium hexamethyldisilazide (0.50 M in toluene, 1.96 ml, mmol) in THF (10 ml) was added via a syringe pump over 2 h. The reaction mixture was stirred at 78 C for 16 h, and was quenched by the addition of water. The cold bath was removed and the reaction mixture was allowed to warm to room temperature. Distilled water (20 ml) and Et 2 O (20 ml) were added. The organic layer was separated, and the aqueous layer was extracted with Et 2 O (2 x 30 ml). The combined organic extracts were washed with saturated aqueous NaCl (2 x 50 ml), and were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (short silica column, 100:5 hexanes/et 2 O) to afford triene 6 (0.100 g, 41% based on the recovered sulfone) as yellow oil, recovered sulfone 18 (0.221g), and isomerized sulfone (32 mg). Triene 6 was characterized: 1 H S8

9 NMR (500 MHz, CDCl 3 ) δ 7.53 (dd, J = 17.5, 11.0 Hz, 1H), 7.14 (dd, J = 18.5, 10.5 Hz, 1H), 6.41 (d, J = 18.5 Hz, 1H), 6.07 (t, J = 10.5 Hz, 1H), 5.98 (t, J = 10.5 Hz, 1H), 5.59 (d, J = 17.5 Hz, 1H), (m, 6H), 1.35 (sextet, J = 7.4 Hz, 6H), 1.30 (s, 12H), (m, 15H); 13 C NMR (126 MHz, CDCl 3 ) δ 144.4, 141.9, 138.9, 135.6, 129.6, 83.2, 29.1, 27.3, 24.8, 13.7, 9.68, [note: the carbon attached to boron was not observed due to quadrupole broadening caused by the 11 B nucleus]; IR (film) ν max 2920, 2852, 1614, 1337, 1144, 988, 850 cm 1 ; HRMS (ESI) calcd for C 24 H 45 BO 2 SnNa: , found: O B O O NH OMe (S,2E,4E,6E,8E)-N-(1-Methoxypropan- 2-yl)-2-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nona-2,4,6,8-tetraenamide (17). The following process was conducted in the dark or the reaction flask was wrapped with aluminum foil. A flame dried flask was loaded with tris(dibenzylideneacetone)dipalladium (8.0 mg, 8.9 μmol), triphenylarsine (7.0 mg, 22 μmol), all-trans triene 5 (0.175 g, mmol), vinyl iodide 8 (0.050 g, mmol), and anhydrous DMF (1.5 ml). The flask was purged by evacuating for 1 min and then flushing with Ar. The de-gas process was repeated three times. The reaction mixture was stirred at 25 C for 2 h. Ethyl acetate (20 ml) and distilled water (20 ml) were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with saturated aqueous NaCl (2 x 50 ml), and were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (silica, 2:1 hexane/etoac) to afford tetraene 17 (0.054g, 84%) as yellow S9

10 oil: 1 H NMR (500 MHz, CDCl 3 ) δ 7.06 (dd, J = 17.5, 10.0 Hz, 1H), 6.94 (d, J = 9.5 Hz, 1H), (m, 4H), 5.98 (d, J = 7.5 Hz, 1H), 5.64 (t, J = 18.0 Hz, 1H), (m, 1H), 3.43 (dd, J = 9.5, 4.0 Hz, 1H), 3.39 (dd, J = 9.5, 4.0 Hz, 1H), 3.38 (s, 3H), 2.00 (s, 3H), 1.29 (s, 12H), 1.23 (d, J = 7.0 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 168.1, 149.0, 137.4, 136.6, 135.8, 133.2, 131.1, 129.7, 83.3, 75.5, 59.1, 45.1, 24.8, 17.7, 13.1, [note: the carbon attached to boron was not observed due to quadrupole broadening caused by the 11 B nucleus]; IR (film) ν max 3381 (br), 2980, 1681, 1643, 1453, 1145, 1009 cm 1 ; HRMS (ESI) calcd for C 20 H 32 BNO 4 Na: , found: O OMe HO 1 N 6 H (6E)-O-Methylmyxalamide D (2). The following process was conducted in the dark or the reaction flask was wrapped with aluminum foil. A flame dried flask was loaded with tetraene 17 (27 mg, mmol), vinyl iodide 7 (15 mg, mmol), bis(diphenylphosphino)ferrocene palladium dichloride (2.0 mg, 5.5 μmol), triphenylarsine (2 mg, 13.2 μmol), K 3 PO 4 (3 M in water, degassed with Ar, 0.11 ml, 0.33 mmol), and anhydrous DMF (2.0 ml). The flask was purged by evacuating for 1 min and then flushing with Ar. The de-gas process was repeated three times. The reaction mixture was stirred at 25 C for 2 h. Ethyl acetate (20 ml) and distilled water (20 ml) were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with saturated aqueous NaCl (2 x 50 ml), then dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (silica, 1:1 hexane/etoac) to afford (6E)-methylmyxalamide D (2) (15 mg, 71%) as yellow oil: 1 H S10

11 NMR (500 MHz, CDCl 3 ) δ 6.96 (dd, J = 11.0, 1.0 Hz, 1H), 6.54 (dd, J = 14.5, 9.5 Hz, 1H), 6.46 (dd, J = 14.5, 11 Hz, 1H), 6.41 (dd, J = 14.5, 9.5 Hz, 1H), 6.37 (d, J = 10.0 Hz, 1H), 6.36 (dd, J = 14.5, 9.5 Hz, 1H), 6.27 (dd, J = 15.0, 10.0 Hz, 1H), 5.97 (d, J = 7.5 Hz, 1H), 5.50 (qd, J = 7.0, 2.0 Hz, 1H), 5.44 (d, J = 10 Hz, 1H), (m, 1H), 3.69 (d, J = 9.0 Hz, 1H), 3.42 (dd, J = 9.5, 4.0 Hz, 1H), 3.39 (dd, J = 9.5, 4.0 Hz, 1H), 3.38 (s, 3H), (m, 1H), 1.98 (s, 3H), 1.86 (d, J = 0.5 Hz, 3H), 1.65 (s, 3H), 1.64 (d, J = 5.5 Hz, 3H), 1.23 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 168.3, 139.2, 138.2, 137.1, , , 135.6, 133.7, 132.0, 129.6, 127.3, 127.2, 123.5, 82.7, 75.6, 59.1, 45.0, 37.2, 17.8, 17.3, 13.1, 13.0, 12.9, 10.6; IR (film) ν max 3361 (br), 2976, 2927, 1651, 1520, 1453, 1108, 998 cm 1 ; HRMS (ESI) calcd for C 24 H 37 NO 3 +H: , found: HO O NH OMe O-Methylmyxalamide D (3). The following process was conducted in the dark or the reaction flask was wrapped with aluminum foil. A flame dried flask was loaded with triene 6 (22 mg, mmol), vinyl iodide 8 (10 mg, mmol), tris(dibenzylideneacetone)dipalladium (2.0 mg, 2.3 μmol), triphenylarsine (1.7 mg, 5.6 μmol), and anhydrous DMF (0.5 ml). The flask was purged by evacuating for 1 min and then flushing with Ar. The de-gas process was repeated three times. The reaction mixture was stirred at 25 C for 2 h. A solution of vinyl iodide 7 (10 mg, mmol) in DMF (0.5 ml) was added via cannula followed by a solution of K 3 PO 4 (3 M in water, degassed with Ar, 0.11 ml, 0.33 mmol) via a syringe. The reaction mixture was degassed again and stirred at 25 C for 1 h. Dichloromethane (10 ml) and S11

12 distilled water (10 ml) were added. The organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (2 x 10 ml). The combined organic extracts were washed with saturated aqueous NaCl (3 x 20 ml), then dried over (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by flash chromatography (short basic alumina column, 2:1 hexane/etoac) to afford a mixture of title compound and (n-bu) 3 SnI as yellow oil. Hexane (10 ml) was added to the mixture. A yellow solid was precipitated after the solution was kept at 30 C for 12 h. The supernatent hexane layer was separated from the solid by using a pipette, and the solid was washed with cold hexanes (3 x 5 ml). O-Methylmyxalamide D (3) was obtained (4.1 mg) as a yellow solid. The combined hexane washes and supernatent were concentrated to dryness. Hexane (1 ml) was added and the same process was performed to yield an additional 2.3 mg of title compound (total 6.4 mg, 46%): mp C; 1 H NMR (500 MHz, CDCl 3 pretreated with basic alumina) δ 7.00 (d, J = 10.5 Hz, 1H), (dd, J = 15.0, 11.5 Hz, 1H), 6.70 (dd, J = 15.0, 11.0 Hz, 1H), 6.49 (dd, J = 14.5, 11.5 Hz, 1H), 6.37 (d, J = 15.5 Hz, 1H), 6.17 (t, J = 11.0 Hz, 1H), 6.10 (t, J = 11 Hz, 1H), 5.98 (d, J = 8.0 Hz, 1H), 5.50 (q, J = 6.5 Hz, 1H), 5.47 (d, J = 10.5 Hz, 1H), (m. 1H), 3.70 (d, J = 8.5 Hz, 1H), 3.45 (dd, J = 9.5, 4.0 Hz, 1H), 3.40 (dd, J = 9.5, 4.0 Hz, 1H), 3.39 (s, 3H), (m, 1H), 1.99 (d, J = 1.0 Hz, 3H), 1.92 (d, J = 1.0 Hz, 3H), 1.66 (s, 3H), 1.65 (d, J = 6.5 Hz, 3H), 1.24, (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 pretreated with basic alumina) δ 168.2, 139.8, 137.6, 136.0, 135.7, 133.6, 133.2, 132.5, 130.3, 128.4, 128.0, 123.5, 122.3, 82.7, 75.6, 59.1, 45.0, 37.2, 17.8, 17.3, 13.1, 13.07, 13.05, 10.7; IR (film) ν max 3344 (br), 2956, 2870, 1634, 1520, 1455, 1371, 964 cm 1 ; HRMS (ESI) calcd for C 24 H 37 NO 3 Na: , found: S12

13 N.B. The optical rotation of synthetic 2 and 3 were not in agreement with those reported for the naturally occurring compounds. Obviously, this measurement is only useful if the reported specific rotation for a compound is known with certainty. For the title compounds this is not the case. We came to the conclusion that the reported values are erroneous from several angles. Most importantly, in this family of pentaene natural products, as one goes from a mono-cis isomer to an all-trans isomer, the optical rotation becomes more positive. For example, in the myxalamide B series, the mono-cis isomer has an [α] 20 D 61.6 (c 0.25, MeOH) whereas the all-trans myxalamide B has an [α]20 D 4.5 (c 0.53, MeOH), for a difference of +57 between the isomers. 3 For the di-acetate of myxalamide B, the numbers are 92.0 (c 0.40, MeOH) and 36.3 (c 0.5, CHCl 3 ) for a difference of Similarly, for stipiamide, the mono-cis isomer has an [α] 25 D 189 (c 1.0, MeOH), whereas the all-trans isomer has an [α] 25 D +3.0 (c 1.0, MeOH) for a difference of +192 between the isomers. 4 The reported values for the O-methylmyxalamide D series are [α] 21 D 27 (c 0.04, MeOH) and [α] 21 D 31 (c 0.017, MeOH) for the mono-cis and all-trans (6E)-isomer, respectively. 5 These numbers are simply not reasonable based on what is known in this natural product family and based on the low concentration at which the measurements were made (the actual rotations measured would be nearly within the margin of error of making the measurement). Since it is well established that large changes in [α] D are 3 Jansen, R.; Reifenstahl, G.; Gerth, K.; Reichenbach, H.; Höfle, G. Liebigs Ann. Chem. 1983, Trowitzsch-Kienast, W.; Forche, E.; Wray, V.; Riechenbach, H.; Hunsmann, G.; Höfle, G. Liebigs Ann. Chem. 1992, Kundim, B. A.; Itou, Y.; Sakagami, Y.; Fudou, R.; Yamanaka, S.; Ojika, M. Tetrahedron 2004, 60, S13

14 observed between the geometric isomers in this family, we conclude that the reported specific rotations are wrong in sign and/or magnitude. Not surprisingly, and despite considerable effort, we were unable to duplicate the reported specific rotations. Our value for the mono-cis isomer 3 was [α] 25 D 54 (c 0.21, MeOH), whereas that for the all-trans isomer 2 was positive in sign and highly concentration dependent: [α] 25 D +22 /+25 /+31 (c 0.11/0.27/0.41, MeOH). S14

15 NAME P3 pentyone d Date_ Time 9.48 PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 64 DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm S15

16 NAME P3 pentyone d EXPNO 2 Date_ Time 9.52 PULPROG zgpg30 NS 75 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S16

17 ppm NAME P3 RR Alkyne OH 1 c Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 57 DW usec TE K D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm ppm ppm ppm ppm S17

18 ppm NAME P3 RR TBS Alkyne 1 c EXPNO 2 Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 80.6 DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm ppm ppm ppm 0.1 ppm S18

19 NAME P3 RR TBS Alkyne 1 C13 Date_ Time PULPROG zgpg30 NS 354 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S19

20 6.0 ppm NAME P3 RR Hzr1 H Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec TE K D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm ppm 3.6 ppm 2.5 ppm ppm ppm S20

21 NAME P3 RR Hzr1 C Date_ Time PULPROG zgpg30 NS 226 DS 4 SWH Hz FIDRES Hz AQ sec RG 6502 DW usec TE K D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S21

22 6.05 ppm NAME P3 RR OH Iodide H Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm ppm 3.7 ppm ppm ppm ppm 0.85 ppm S22

23 NAME P3 RR OH Iodide C Date_ Time PULPROG zgpg30 NS 408 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S23

24 NAME P3 R Iodoamide rec1 Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm S24

25 NAME P3 R Iodoamide C Date_ Time PULPROG zgpg30 NS 487 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S25

26 ppm ppm ppm NAME P3 M B Tin H Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 64 DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm S

27 NAME P3 M B Tin C ppm ppm Date_ Time PULPROG zgpg30 NS 194 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ppm ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S27

28 ppm ppm ppm NAME P3 JO16 column EXPNO 2 Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm S

29 ppm NAME P3 JO16 C13 Date_ Time PULPROG zgpg30 NS 280 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S29

30 ppm ppm ppm 4.3 ppm NAME P3 C4 stille4 check Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm S

31 NAME P3 C4 stille4 C13 Date_ Time PULPROG zgpg30 NS 880 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S31

32 ppm NAME P3 RR 6EMMD H Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm ppm ppm ppm ppm ppm ppm S32

33 ppm NAME P3 RR 6EMMD C Date_ Time PULPROG zgpg30 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz ppm SF MHz LB 1.00 Hz PC ppm S33

34 ppm NAME P3 cis MMD H4 Date_ Time PULPROG zg30 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 512 DW usec D sec NUC1 1H P usec PL db SFO MHz SF MHz LB 0.30 Hz PC ppm ppm 4.25 ppm 3.7 ppm ppm ppm ppm S34

35 ppm ppm NAME P3 cis MMD3 C13 Date_ Time 9.57 PULPROG zgpg30 NS 2847 DS 4 SWH Hz FIDRES Hz AQ sec RG 4096 DW usec D sec d sec DELTA sec NUC1 13C P usec PL db SFO MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db PL db SFO MHz SF MHz LB 1.00 Hz PC ppm S35