Pattern Analysis in Complex Molecule Synthesis: Development of Methods for the Preparation of Iso-Diels- Alder Motifs

Transcription

1 Pattern Analysis in Complex Molecule Synthesis: Development of Methods for the Preparation of Iso-Diels- Alder Motifs Feng Peng 1, Robin Grote 1, Rebecca M. Wilson, 2 and Samuel J. Danishefsky 1,2 1. Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027; 2. Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY Supporting Information General information Unless otherwise noted, all reactions were performed under an argon atmosphere using flame-dried glassware. CH 2 Cl 2 (DCM) was distilled over CaH 2 under argon atmosphere. THF was distilled over sodium/benzophenone ketyl under argon atmosphere. Anhydrous toluene, hexane, ether were purchased and use without further purification. All reagents were commercially available and used without further purification unless indicated otherwise. Dienes 7, 16, and 17 were prepared according to literature procedure. 1, 2 Thin layer chromatography (TLC) was performed on Silica Gel 60 F254 plates and was visualized with UV light and KMnO 4 stain. Preparative thin layer chromatography was performed with Merck silica gel 60-F254 coated 0.50 mm plates. Flash chromatography

2 was performed with Sorbent Tech. silica gel 60. Yields reported are for isolated, spectroscopically pure compounds. NMR spectra were recorded on 300, 400 or 500 MHz instruments. The residual solvent protons ( 1 H) or the solvent carbons ( 13 C) were used as internal standards. 1 H NMR data are presented as follows: chemical shift in ppm downfield from tetramethylsilane (multiplicity, coupling constant, integration). The following abbreviations are used in reporting NMR data: s, singlet; br s, broad singlet; d, doublet; t, triplet; q, quartet; qt, quartet of triplets; dd, doublet of doublets; dt, doublet of triplets; AB, AB quartet; m, multiplet. High-resolution mass spectra were recorded by the Columbia University Mass Spectrometry Core facility on a JEOL HX110 spectrometer. Representative Experimental Procedure for the Diels-Alder Reaction of 2- phenylthio-3-methyl-butadiene: A solution of 2-methylcylopentenone (100 ul, 1.0 mmol) in dichloromethane (2.0 ml) under argon atmosphere was cooled to 0 C. A 1 M solution of methylaluminum dichloride in dichloromethane was added (1.0 ml, 1.0 mmol) and stirred for 10 minutes. A solution of diene (900 mg, 5.0 mmol) in dichloromethane (0.5 ml) was added and the ice bath removed. The reaction was allowed to stir for 15 hours at room temperature under argon. The reaction was then quenched with aqueous sodium potassium tartrate (4 ml) and diluted with dichloromethane (4 ml). The layers were separated and the aqueous layer was washed with dichloromethane (2 x 5 ml). The combined organic layers were then washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified via flash column chromatography (5% ethyl acetate in hexanes) to yield 240 mg desired product (88%).

3 O H SPh Compound 8: 88% yield. 1 H (CDCl 3, 400 MHz):! (m, 5H), (m, 2H), (m, 3H), (m, 6H), (m, 1H), 1.09 (s, 3H); 13 C (CDCl 3, 75 MHz)! 220.6, 137.7, 136.3, 129.2, 128.9, 128.6, 126.0, 121.8, 47.1, 41.8, 36.1, 35.3, 32.4, 24.8, 22.0, 20.7; IR (neat): cm , 2959, 2907, 1740, 1583, 1477, 1439, 1024; HRMS (FAB+, m/z) calcd for C 17 H 20 OS [M] , found ; TLC R f = 0.5 (10% ethyl acetate in pentanes). O H SPh Compound 9: 74% yield. 1 H (CDCl 3, 300 MHz):! (m, 5H), 2.69 (d, J = 18.0 Hz, 1H), (m, 1H), (m, 2H), (m, 5H), (m, 2H), (m, 3H), 1.18 (s, 3H); 13 C (CDCl 3, 75 MHz)! 214.6, 137.9, 136.6, 129.3, 128.8, 126.0, 121.4, 48.6, 42.9, 39.4, 37.5, 34.9, 27.5, 25.2, 21.9, 21.7; IR (neat): cm , 2931, 2866, 1704, 1583, 1477, 1438, 1140; HRMS (FAB+, m/z) calcd for C 18 H 22 OS [M] , found ; TLC R f = 0.3 (5% ethyl acetate in hexanes).

4 O CN H SPh Compound 10: 56% yield. 1 H (CDCl 3, 400 MHz):! (m, 2H), (m, 3H), 2.95 (d, J = 18.2 Hz, 1H), (m, 1H), (m, 4H), (1H), (m, 2H), (m, 4H), (m, 1H), (m, 1H); 13 C (CDCl 3, 75 MHz)! 201.9, 135.2, 135.0, 129.1, 128.7, 126.0, 121.9, 119.9, 50.4, 40.9, 37.2, 35.3, 32.7, 25.9, 23.8, 21.0; IR (neat): cm , 2245, 1720, 1582, 1477, 1438, 1023; HRMS (FAB+, m/z) calcd for C 18 H 19 ONS [M] , found ; TLC R f = 0.4 (25% ethyl acetate in hexanes). O H SPh Compound 11: 61% yield. 1 H (CDCl 3, 300 MHz):! (m, 5H), (m, 1H), 5.05 (d, J = 5.1 Hz, 1H), 5.00 (s, 1H), (m, 3H), (m, 3H), (m, 6H), 1.86 (d, J = 18.5 Hz, 1H), (m, 3H); 13 C (CDCl 3, 75 MHz)! 213.1, 137.6, 136.2, 134.1, 128.9, 128.4, 125.6, 121.2, 117.8, 51.1, 38.9, 38.6, 38.0, 37.5, 33.7, 26.5, 24.2, 21.5; IR (neat): cm , 2930, 1704, 1639, 1583, 1477, 1439, 915; HRMS (FAB+, m/z) calcd for C 20 H 24 OS [M] , found ; TLC R f = 0.4 (5% ethyl acetate in hexanes).

5 O H SPh Compound 12: 76% yield. 1 H (CDCl 3, 300 MHz):! (m, 2H), (m, 3H), 2.74 (d, J = 17.9 Hz, 1H), 2.42 (t, J = 6.9 Hz, 2H), (m, 1H), (m, 2H), 1.97 (s, 3H), (m, 7H), (m, 1H), (m, 1H), 0.91 (t, J = 7.2 Hz, 3H); 13 C (CDCl 3, 75 MHz)! 213.7, 138.9, 136.5, 128.9, 128.0, 125.4, 120.6, 51.8, 39.3, 38.5, 38.1, 37.5, 34.1, 25.7, 23.7, 21.4, 17.1, 14.8; IR (neat): cm , 2957, 2931, 2871, 1704, 1582, 1477, 1454, 1439, 999; HRMS (FAB+, m/z) calcd for C 20 H 26 OS [M] , found ; TLC R f = 0.4 (5% ethyl acetate in hexanes). General Experimental Procedure for the Reduction of Vinyl Sulfides: To a solution of vinyl sulfide (0.1 mmol) in acetone (10 ml) was added unwashed Raney nickel (excess). The reaction was monitored by TLC for completion (aprox. 2-4 hours). Upon completion the mixture was filtered carefully through a pad of silica, concentrated, and purified via flash column chromatography (2% ethyl acetate in hexanes). O H

6 Compound 13: 62% yield. 1 H (CDCl 3, 400 MHz):! 5.39 (m, 1H), 2.48 (ddd, J = 19.3, 9.1, 2.1 Hz, 1H), (m, 1H), (m, 1H), (m, 4H), (m, 4H), 1.49 (d, J = 17.7 Hz, 1H), 1.05 (s, 3H); 13 C (CDCl 3, 75 MHz)! 221.4, 129.7, 118.2, 46.8, 39.7, 35.4, 32.4, 25.5, 24.7, 23.9, 19.8; IR (neat): cm , 2910, 2880, 2835, 1740, 1442, 1047; HRMS (FAB+, m/z) calcd for C 11 H 16 O [M] , found ; TLC R f = 0.3 (5% ethyl acetate in hexanes). O H Compound 14: 60% yield. 1 H (CDCl 3, 400 MHz):! 5.37 (m, 1H), (m, 1H), (m, 3H), (m, 1H), 1.87 (d, J = 20.1 Hz, 1H), (m, 4H), (m, 4H), 1.12 (s, 3H); 13 C (CDCl 3, 75 MHz)! 215.3, 129.7, 118.1, 48.3, 40.7, 37.2, 36.0, 28.4, 27.7, 25.2, 23.7, 20.6; IR (neat): cm , 2929, 2889, 2865, 1705, 1441, 1097; HRMS (FAB+, m/z) calcd for C 12 H 18 O [M] , found ; TLC R f = 0.4 (5% ethyl acetate in hexanes). O H Compound 15: 72% yield. 1 H (CDCl 3, 400 MHz):! 5.34 (m, 1H), (m, 3H), (m, 1H), (m, 2H), (m, 3H), (m, 6H), 1.51 (d, J =

7 17.6 Hz, 1H), (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13 C (CDCl 3, 75 MHz)! 214.5, 130.4, 118.4, 51.8, 37.6, 37.3, 37.0, 35.9, 28.1, 26.5, 24.1, 23.5, 17.1, 14.9; IR (neat): cm , 2957, 2890, 2872, 1704, 1454, 1378, 1214; HRMS (FAB+, m/z) calcd for C 14 H 22 O [M] , found ; TLC R f = 0.4 (5% ethyl acetate in hexanes). O Me SPh OMe H Me Compound 18: 83% yield. 1 H NMR (500 MHz, CDCl 3 )! (m, 2H), (m, 3H), 3.43 (s, 3H), 3.30 (s, 1H), (m, 1H), (m, 1H), 2.27 (ddd, J = 20.5, 11.2, 8.1 Hz, 1H), (m, 1H), (m, 3H), 1.76 (d, J = 1.1 Hz, 3H), 1.20 (s, 3H); 13 C NMR (126 MHz, CDCl 3 )! 218.9, 145.8, 137.8, 131.5, 128.9, 127.2, 115.6, 57.9, 52.4, 50.3, 40.6, 39.1, 31.5, 26.4, 22.8, 16.3; IR (neat): cm , 2890, 1744, 1650, 1452, 1216; HRMS (FAB+, m/z) calcd for C 18 H 22 O 2 S [M] , found O Me OMe H Me Compound 21: 65% yield. 1 H NMR (500 MHz, CDCl 3 )! 3.48 (s, 3H), 2.50 (ddd, J = 19.4, 9.0, 2.2 Hz, 1H), (m, 1H), (m, 1H), 2.13 (dd, J = 17.1, 2.7 Hz, 1H), (m, 3H), 1.76 (d, J = 9.5 Hz, 1H), 1.69 (d, J = 9.6 Hz, 1H), 1.67 (d, J =

8 1.3 Hz, 3H), 1.10 (s, 3H). 13 C NMR (126 MHz, CDCl 3 )! 220.2, 145.8, 115.6, 57.9, 52.4, 50.3, 40.6, 39.1, 31.5, 26.4, 22.8, 16.3; IR (neat): cm , 1740, 1644, 1210; HRMS (FAB+, m/z) calcd for C 12 H 18 O 2 [M] , found O O CN CN 1) Allylsilane, TiCl 4 2) Pd(OAc) 2, PPh 3, H R 4 OAc 27 R 1, 4 addition reaction: To a reaction mixture of "-cyano cyclohexenone (1g, 8.2 mmol) and allylsilane(1.9g, 16.8 mmol) in DCM at -78 o C was added TiCl 4 (0.9 ml, 8.2 mmol). 3 The reaction was aged at this temperature for about 5 min and quenched with NaHCO 3 solution. Then the mixture was warmed up to room temperature and extracted with ether and concentrated. The residue was purified via flash chromatography(1.04g, 78%). Compound 27: In a 100 ml flame-dried round-bottom flask, Pd(OAc) 2 (45 mg, 0.2 mmol), triphenylphospine (210 mg, 0.4 mmol) were dissolved in 20 ml of THF under argon. The mixture was stirred for 10 min at room temperature. To this solution methallyl acetae (275mg, 2.4 mmol) in 2 ml of TFH was injected and 5 min later, a solution of freshly prepared sodium enolate (Prepared from 320 mg of 1 and 88 mg of NaH) in THF (10 ml) was added. The reaction mixture was stirred for 1 h at 60 o C, then quenched by addition of saturated NH 4 Cl solution, extracted with diethyl ether and dried over

9 magnesium sulfate. The drying agent was filtered and the solution was concentrated. The residue was purified by flash-column chromatography to give product as a colorless oil. O CN H Me Compound 27a: 78% yield. 1 H NMR (CDCl 3, 300 MHz):! 6.03 (ddd, J = 10.4, 3.2, 3.2 Hz, 2H), 5.91 (s, 1H), 5.51 (ddd, J = 10.4, 2.0, 2.0 Hz, 2H), 3.65 (d, J = 5.6 Hz, 2H), 2.70 (dd, J = 3.2, 3.2 Hz, 2H), (m, 4H), (m, 3H); 13 C NMR (CDCl 3, 75 MHz):! 202.7, 139.6, 134.9, 118.7, 117.8, 116.4, 56.3, 45.8, 39.3, 38.3, 35.3, 25.4, 24.2, 23.7; IR (neat): cm , 2280, 1718, 1642, 1442; HRMS (FAB, m/z) calcd for C 14 H 20 NO [M+H] , found O CN H Et Compound 27b: 89% yield. 1 H NMR (500 MHz, CDCl 3 )! (m, 1H), (m, 2H), 5.00 (s, 1H), 4.92 (s, 1H), (m, 5H), (m, 4H), (m, 2H), 1.07 (t, J = 5.0 Hz, 3H), 1.00 (ddd, J = 7.9, 5.5, 2.3 Hz, 1H), 0.90 (td, J = 7.8, 2.7 Hz, 1H); 13 C NMR (126 MHz, CDCl 3 )! 203.1, 145.2, 134.9, 118.8, 117.8, 113.7, 56.70,

10 46.1, 38.4, 38.0, 35.3, 29.5, 25.4, 24.3, 12.2; IR (neat): cm , 2878, 2240, 1731, 1667, 1642, 1458, 1235; HRMS (FAB, m/z) calcd for C 15 H 22 NO [M+H] , found O CN H Bu Compound 27d: 85% yield. 1 H NMR (500 MHz, CDCl 3 )! 5.69 (dddd, J = 16.4, 10.1, 8.5, 5.5 Hz, 1H), (m, 2H), 4.96 (d, J = 1.5 Hz, 1H), 4.88 (s, 1H), (m, 2H), (m, 2H), (m, 1H), 2.12 (ddd, J = 14.0, 10.7, 8.6 Hz, 1H), (m, 5H), (m, 2H), 1.43 (ddd, J = 13.1, 8.3, 6.3 Hz, 2H), 1.31 (h, J = 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 )! 202.9, 143.7, 134.9, 118.7, 117.7, 114.7, 56.6, 45.9, 38.3, 37.6, 36.4, 35.3, 29.9, 25.3, 24.2, 22.2, 13.9; IR (neat): cm , 2879, 2240, 1730, 1668, 1642, 1458, 1235; HRMS (FAB, m/z) calcd for C 17 H 25 NO [M] , found O CN H OEt Compound 27e: 65% yield. 1 H NMR (500 MHz, CDCl 3 )! (m, 1H), (m, 2H), 4.11 (s, 1H), 4.06 (s, 1H), (m, 2H), 2.95 (d, J = 14.4 Hz, 1H), 2.78 (d,

11 J = 14.4 Hz, 1H), (m, 3H), (m, 4H), (m, 2H), 1.23 (t, J = 7.0 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 )! , , , , , 86.05, 63.16, 56.62, 44.74, 38.54, 37.94, 35.09, 24.38, 23.15, 14.05; IR (neat): cm , 2942, 2241, 1722, 1641, 1067; HRMS (FAB, m/z) calcd for C 15 H 22 NO 2 [M+H] , found O CN H Ph Compound 27c: 75% yield. 1 H NMR (500 MHz, CDCl 3 )! (m, 5H), 5.56 (dddd, J = 16.8, 10.3, 8.4, 5.5 Hz, 1H), 5.41 (d, J = 0.9 Hz, 1H), 5.33 (d, J = 1.0 Hz, 1H), 5.13? 4.96 (m, 2H), 3.26 (dd, J = 14.7, 1.0 Hz, 1H), 3.16 (dd, J = 14.7, 1.1 Hz, 1H), (m, 1H), 2.53 (dddd, J = 13.9, 5.0, 3.3, 1.6 Hz, 1H), 2.41 (dddd, J = 13.6, 6.4, 5.3, 1.3 Hz, 1H), (m, 1H), (m, 2H), (m, 3H); 13 C NMR (126 MHz, CDCl 3 )! 202.5, 143.2, 141.6, 134.8, 128.3, 127.8, 126.7, 118.8, 118.2, 117.7, 57.3, 45.6, 38.2, 36.9, 35.4, 25.3, 23.9; IR (neat): cm , 2242, 1722, 1680, 1067; HRMS (FAB, m/z) calcd for C 19 H 21 NO [M] , found O CN H R 3) Grubbs's 2 nd generation catalyst O CN H R

12 Compound 27 (217mg, 1 mmol) was dissolved in 50 ml of DCM under argon. The solution was heated to 46 o C and a solution of Grubbs s 2 nd generation catalyst (20 mg, 0.03 mmol) in 2 ml of DCM was injected. The reaction mixture was stirred at this temperature for about 6 hours. Then the solution was concentrated and the residue was purified with flash chromatography to give pure compound 28 as a colorless oil. O CN Me H Compound 28a: 93% yield. 1 H NMR (CDCl 3, 300 MHz):! 6.03 (ddd, J = 10.4, 3.2, 3.2 Hz, 2H), 5.91 (s, 1H), 5.51 (ddd, J = 10.4, 2.0, 2.0 Hz, 2H), 3.65 (d, J = 5.6 Hz, 2H), 2.70 (dd, J = 3.2, 3.2 Hz, 2H), (m, 4H), (m, 3H); 13 C NMR (CDCl 3, 75 MHz):! 202.6, 129.9, 119.4, 118.5, 50.3, 42.9, 38.9, 33.5, 30.3, 29.1, 26.3, 23.2; IR (neat): cm , 2280, 1728, 1448; HRMS (FAB, m/z) calcd for C 12 H 15 ON [M] , found O CN Et H Compound 28b: 95% yield. 1 H NMR (400 MHz, CDCl 3 )! 5.41 (br s 1H), 2.94 (td, J = 13.6, 6.2 Hz, 1H), (m, 2H), (m, 3H), 2.17 (ddt, J = 12.2, 6.1, 2.9 Hz, 1H), (m, 2H), (m, 3H), (m, 1H), 1.00 (t, J = 7.4 Hz, 3H);

13 13 C NMR (101 MHz, CDCl 3 )! 202.9, 135.5, 118.6, 117.8, 50.4, 43.3, 39.1, 32.2, 30.4, 29.9, 29.2, 26.4, 12.0; IR (neat): cm , 2229, 1728, 1220; HRMS (FAB, m/z) calcd for C 13 H 17 ON [M] , found O CN Ph H Compound 28c: 85% yield. 1 H NMR (500 MHz, CDCl 3 )! (m, 5H), 6.15 (dt, J = 5.5, 3.0 Hz, 1H), (m, 2H), 2.90 (d, J = 17.9 Hz, 1H), (m, 1H), (m, 2H), 2.28 (ddt, J = 12.1, 5.9, 2.9 Hz, 1H), (m, 3H), 1.83 (tdd, J = 13.6, 10.1, 6.7 Hz, 1H); 13 C NMR (126 MHz, CDCl 3 )! 202.4, 140.6, 133.2, 128.4, 127.4, 125.2, 122.2, 118.3, 50.4, 42.9, 39.0, 31.5, 30.9, 29.1, 26.4; IR (neat): cm , 2230, 1729, 1680, 1449; HRMS (FAB, m/z) calcd for C 17 H 17 ON [M] , found O CN Bu H Compound 28d: 95% yield. 1 H NMR (500 MHz, CDCl 3 )! 5.40 (dt, J = 5.2, 2.8 Hz, 1H), 2.93 (td, J = 13.7, 6.2 Hz, 1H), 2.51 (dtt, J = 13.2, 3.9, 2.4 Hz, 1H), (m, 4H), 2.00 (t, J = 7.6 Hz, 2H), (m, 4H), 1.69 (tdd, J = 11.9, 9.1, 6.1 Hz, 1H), 1.38 (qd, J = 7.5, 6.8, 5.1 Hz, 2H), (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13 C NMR

14 (126 MHz, C 6 D 6 )! , , , , 50.42, 43.27, 39.06, 36.87, 32.09, 30.44, 29.53, 29.21, 26.35, 22.20, 13.87; IR (neat): cm , 2228, 1728, 1448; HRMS (FAB, m/z) calcd for C 15 H 21 ON [M] , found O CN OEt H Compound 28e: 80% yield. 1 H NMR (400 MHz, CDCl 3 )! 4.59 (td, J = 4.7, 4.0, 2.2 Hz, 1H), (m, 2H), 2.92 (td, J = 13.7, 6.2 Hz, 1H), 2.70 (dd, J = 17.6, 2.6 Hz, 1H), (m, 1H), 2.37 (dd, J = 17.6, 1.1 Hz, 1H), (m, 2H), 2.17 (ddd, J = 13.3, 6.1, 3.0 Hz, 1H), (m, 4H), 1.71 (dddd, J = 21.0, 13.5, 7.3, 4.3 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 )! 201.9, 150.5, 118.2, 91.7, 62.3, 50.6, 43.7, 38.7, 31.6, 28.9, 28.7, 26.3, 14.5; IR (neat): cm , 2233, 1731, 1671, 1225, 1185; HRMS (FAB, m/z) calcd for C 13 H 17 O 2 N [M] , found O CN 1) LN, THF, -50 o C to -20 o C O SPh 2) HMPA (20 eq), -78 o C dr = 4:1 28a 3) PhSCH 2 I (8 eq), -78 o C to rt 12 h H 30 Compound 30: Under an atmosphere of argon, a flame-dried long-neck flask equipped with a magnetic stirring bar was charged with lithium (31 mg, 4.4 mmol), naphthalene (576 mg, 4.5 mmol), and 20 ml of THF. The mixture was stirred at room temperature for about 3 hour. The resulting dark green mixture was cooled to -50 o C and a solution of

15 compound 28a (170 mg, 0.9 mmol) in 5 ml of THF was injected dropwise. The mixture was allowed to slowly warm up to -20 o C in about 50 mins and re-cooled to -78 o C. Anhydrous HMPA (3.2 ml) was injected dropwise and the mixture was stirred at this temperature for 10 mins. At this stage, a solution of iodomethyl phenyl sulfide (2.2g, 9 mmol) in 5 ml of THF was added via inside glassware wall slowly and the mixture was allowed to warm up to room temperature via 12 hours. The reaction was then quenched by addition of water, extracted with ether, and dried over anhydrous MgSO 4. After filtration of the drying agent, the solution was concentrated and the residue was purified using flash chromatography to give compound 30 (170 mg, 67%) as diastereoisomer. (dr = 4:1) 1 H NMR (CDCl 3, 300 MHz):! 6.03 (ddd, J = 10.4, 3.2, 3.2 Hz, 2H), 5.91 (s, 1H), 5.51 (ddd, J = 10.4, 2.0, 2.0 Hz, 2H), 3.65 (d, J = 5.6 Hz, 2H), 2.70 (dd, J = 3.2, 3.2 Hz, 2H), (m, 4H), (m, 3H); 13 C NMR (CDCl 3, 75 MHz):! 212.9, 136.7, 132.8, 130.2, 128.9, 126.4, 118.4, 51.8, 43.2, 38.9, 34.0, 33.9, 29.7, 27.4, 26.6, 23.6; IR (neat): cm , 1707, 1438; HRMS (FAB, m/z) calcd for C 18 H 22 OS [M] , found O SPh 1) m-cpba O SPh O H 30 2) TFAA (3 eq) 0 o C, 30 min, rt, 30min 50% H 31 Compound 31: This compound was prepared according to literature 4 (50% yield). 1 H NMR (CDCl 3, 300 MHz):! 6.03 (ddd, J = 10.4, 3.2, 3.2 Hz, 2H), 5.91 (s, 1H), 5.51 (ddd,

16 J = 10.4, 2.0, 2.0 Hz, 2H), 3.65 (d, J = 5.6 Hz, 2H), 2.70 (dd, J = 3.2, 3.2 Hz, 2H), (m, 4H), (m, 3H); 13 C NMR (CDCl 3, 75 MHz):! 211.4, 136.1, 131.1, 129.1, 127.1, 58.4, 56.2, 50.2, 38.9, 37.9, 35.9, 33.1, 28.9, 27.1, 26.2, 25.0; IR (neat): cm , 2860, 1707, 1438, 1025; HRMS (FAB, m/z) calcd for C 18 H 23 O 2 S [M] , found O 1 H NMR (400 MHz, CDCl 3 )! 6.74 (dd, J = 4.8, 3.6 Hz, 1H), 4.79 (t, J = 1.8 Hz, 1H), (m, 1H), 2.90 (s, 2H), (m, 2H), 2.38 (dtt, J = 5.9, 4.0, 1.6 Hz, 2H), 2.00 (dq, J = 8.1, 6.2 Hz, 2H), 1.68 (t, J = 1.0 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 )! 198.9, 146.3, 143.7, 137.4, 111.8, 38.4, 36.8, 26.1, 23.1, 22.3: HRMS (FAB, m/z) calcd for C 10 H 14 O [M] , found O 1) allyl magnesium bromide, CuI, TMSCl O Me 2) MeLi, MeI, HMPA H R 67%, 8:1 Compound 34: To a RBF was charged with anhydrous LiBr(2.6g, 30 mmol), CuI(5.7g, 30 mmol), and THF under argon. To this mixture was injected allylbrominde Grignard

17 reagent(25 ml, 1M in ether) slowly at -78 o C. The reaction mixture was aged for about 30 min at this temperature and then substituted enones(10 mmol) and TMSCl(3.8 ml, 30 mmol) was injected sequentially. The reaction was aged for 1 h and at this temperature Et 3 N(6.3 ml, 45 mmol) was injected. The reaction mixture was then warmed up to rt and diluted with hexane. The solution was decanted from the mixture and washed with NaHCO 3 solution and concentrated. The residue was directly purified via flash chromatography. To a solution of silyl enol ether in THF was added MeLi and aged for 30 mins at -78 o C. HMPA was injected to the mixture and aged for 5 mins. Then RI was injected and aged at -78 o C for 6 h. The the reaction mixture was slowly warmed up to rt and quenched with water. The organic layer was concentrated and purified via chromatography. O Me H Me Compound 34: 1 H NMR (400 MHz, CDCl 3 )! (m, 1H), (m, 2H), 4.83 (br s, 1H), 4.76 (br s, 1H), 2.91 (d, J = 14.4 Hz, 1H), (m, 1H), 2.41 (ddd, J = 15.5, 10.1, 5.8 Hz, 1H), (m, 2H), (m, 2H), 1.79 (tt, J = 8.0, 7.4, 1.9 Hz, 2H), (m, 1H), 1.60 (br s, 3H), (m, 1H), 1.03 (s, 3H); 13 C NMR (101 MHz, CDCl 3 )! 215.2, 142.8, 137.4, 116.1, 114.8, 51.8, 43.7, 42.5, 38.5, 34.2, 24.8, 24.2, 23.3, 20.4; IR (neat): cm , 2860, 1723, 1640, 1438, 1025; HRMS (FAB, m/z) calcd for C 14 H 22 O [M] , found

18 O Me H R Grubbs's 2 nd Catalyst DCM, reflux O Me H Compound 29: To a solution of 1 in DCM was added Grubbs s catalyst under argon. The reaction mixture was then reflux at 45 o C for 12 h. Then the reaction mixture was cooled down to rt and concentrated. The residue was then purified via flash chromatography. Compound 29: 82% yield. 1 H NMR (500 MHz, CDCl 3 )! 5.28 (br s, 1H), 2.60 (td, J = 14.0, 6.4 Hz, 1H), (m, 2H), 2.26 (dddd, J = 14.3, 4.1, 2.3, 1.6 Hz, 1H), (m, 2H), 1.90 (dddt, J = 17.5, 8.6, 4.3, 2.2 Hz, 1H), 1.76 (d, J = 18 Hz, 1H), (m, 1H), 1.67 (br s, 3H), (m, 3H), 1.04 (d, J = 0.9 Hz, 3H); 13 C (CDCl 3, 75 MHz)! 215.8, 130.5, 120.2, 47.4, 40.7, 37.6, 35.3, 34.2, 27.7, 26.2, 23.2, 18.3; IR (neat): cm , 1701, 1441, 1097; HRMS (FAB+, m/z) calcd for C 12 H 18 O [M] , found O Me Ketone 38 was prepared via a modified procedure from Forsyth et al. 5 A solution of silylenol ether 37 (45 mg, 0.20 mmol) in dimethoxyethane (2.0 ml) was cooled to 0 C

19 and a 1.6 M solution of methyl lithium in ether (125 ul, 0.20 mmol) was added dropwise and allowed to stir for 30 minutes. The reaction mixture was then cooled to -78 C and propargyl bromide was added as an 80% by weight solution in toluene (179 mg, 1.20 mmol). The reaction was allowed to slowly warm to room temperature over 12 hours and was then quenched with water (3 ml) and diluted with ether (3 ml). The layers were separated and the aqueous layer was washed with ether (2 x 5 ml). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified via flash column chromatography (5% ethyl acetate in hexanes) to yield 15 mg of the desired product as a 9:1 mixture of diastereomers (40%) and carried forward as is. Major diastereomer is assumed trans given litereature precedent. 5 1 H (CDCl 3, 400 MHz):! (m, 1H major diastereomer), (m, 1H minor diastereomer), (m, 2H), 2.93 (dd, J = 16.7, 2.6 Hz, 1 H minor diastereomer), (m), (m), (m), (m), (m), (m), (m), (m); 13 C (CDCl 3, 75 MHz, only major diastereomer reported):! 213.1, 137.2, 116.4, 81.4, 70.4, 52.1, 43.0, 38.0, 34.4, 25.4, 25.2, 24.3, 18.8; IR (neat): cm , 3076, 2972, 2936, 2868, 2117, 1708, 1641, 1444, 1424, 915; HRMS (EI+, m/z) calcd for C 13 H 18 O [M] , found ; TLC R f = 0.3 (5% ethyl acetate in hexanes). O H Experimental Procedure for Eneyne Metathesis: Diene 39 was prepared according the procedure of Mori et al. 6 and was purified via flash column chromatography (2% ethyl acetate in hexanes) to give 35 mg of desired product

20 (46%). 1 H (CDCl 3, 400 MHz):! 6.38 (dd, J = 17.5, 10.8 Hz, 1H), 5.67 (m, 1H), 5.23 (d, J = 17.5 Hz, 1H), 4.96 (d, J = 10.8 Hz, 1H), (m, 1 H), (m, 2H), (m, 2H), (m, 4H), 1.07 (s, 3H); 13 C (CDCl 3, 75 MHz)! 215.8, 139.8, 134.7, 126.6, 110.8, 46.7, 41.5, 38.1, 32.0, 29.9, 27.5, 26.0, 16.3; IR (neat): cm , 2928, 2867, 1706, 1641, 1606, 1429, 1147; HRMS (EI+, m/z) calcd for C 13 H 18 O [M] , found ; TLC R f = 0.4 (5% ether in pentatnes). O CO 2 Me H compound 41: this compound was prepared using same procedure as preparation of compound H NMR (400 MHz, Chloroform-d)! (m, 1H), (m, 1H), 5.00 (br s, 1H), 4.84 (q, J = 1.3 Hz, 1H), 4.73 (br s, 1H), 3.67 (s, 3H), 3.10 (d, J = 14.5 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 4H), (m, 2H), 1.54 (s, 3H); 13 C NMR (101 MHz, CDCl 3 )! 207.8, 171.0, 141.6, 136.7, 116.5, 115.9, 63.2, 52.1, 41.4, 39.9, 38.5, 35.8, 25.7, 24.2, 23.2, 23.2; HRMS (EI+, m/z) calcd for C 15 H 22 O 3 [M] , found O CO 2 Me H Compound 42: this compound was prepared using same procedure as preparation of compound H NMR (400 MHz, Chloroform-d)! (m, 1H), 3.66 (s, 3H), (m, 6H), (m, 3H), (m, 2H), 1.67 (dt, J = 2.4, 1.4 Hz, 3H);

21 13 C NMR (101 MHz, CDCl 3 )! 207.2, 170.7, 131.2, 119.9, 60.1, 52.1, 42.9, 40.23, 34.7, 30.4, 27.9, 26.4, HRMS (EI+, m/z) calcd for C 13 H 18 O 3 [M] , found References: 1) Baeckvall JE, EricssonA (1994) Palladium-Catalyzed Regioselective Addition of Thiophenol to Conjugated Enynes. Efficient Syntheses of 2-(Phenylsulfinyl) and 2-(Phenylsulfonyl) 1,3-Dienes. J. Org. Chem 59: ) Cohen T, Kosarych Z (1980) Preparative methods for (Z)-2-methoxy-1- phenylthio-1,3-butadienes. Rearrangement during copper(i)-induced elimination of thiophenol from some!,"-unsaturated thioacetals. Tetrahedron Letter 41: ) Ruel R, Deslongchamps P (1990) Synthesis of 14-hydroxy steroids. Total synthesis of methyl 14#-hydroxy-1,7,17-trioxo-5#,8-androstene-10#-oate and related compounds. Can. J. Chem. 68: ) Zhang Y, Lee J, Danishefsky S J (2011) Antarafacial Mediation of Oxygen Delivery by a Phenylsulfinyl Group in the Epoxidation of Proximal Double Bonds: Intramolecular Trapping of an Early Pummerer Intermediate with Stereoelectronic Control. J. Am. Chem. Soc. 133: ) Huang H, Forsyth C J (1995) Synthesis of the Sesquiterpenes Trifarienols A and B via Anti-Selective.alpha.'-Intramolecular Carbomercuration. J. Org. Chem. 60:

22 6) Mori M, Sakakibara N, Kinoshita A (1998) Remarkable Effect of Ethylene Gas in the Intramolecular Enyne Metathesis of Terminal Alkynes J. Org. Chem. 63:

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