Total Synthesis of ( )-Xylogranatopyridine B via a Palladium-Catalyzed Oxidative Stannylation of Enones

Transcription

1 Supporting Information Total Synthesis of ( )-Xylogranatopyridine B via a Palladium-Catalyzed xidative Stannylation of Enones Alexander W. Schuppe, David uang, Yifeng Chen and Timothy R. ewhouse* Department of Chemistry, Yale University, 225 Prospect St., ew aven, Connecticut * timothy.newhouse@yale.edu Table of Contents General Experimental... SI2 Synthetic Scheme... SI3 Proposed Biosynthesis... SI4 Synthesis and spectroscopic data for SI-4... SI5 SI7 Synthesis and spectroscopic data for 8f... SI8 SI13 Synthesis and spectroscopic data for β-functionalized enones 5a 5m... SI14 SI53 Synthesis and spectroscopic data for SI-6... SI54 Synthesis and spectroscopic data for β-stannyl enone 5a... SI55 SI57 Synthesis and spectroscopic data for alcohol SI58 SI60 Synthesis and spectroscopic data for acetate (±)-15 and ( ) SI61 SI65 Recycling unreacted 15 to 5a... SI66 Synthesis and spectroscopic data for stannane SI67 SI69 Synthesis and spectroscopic data for oxime SI70 SI75 Synthesis and spectroscopic data for alkene SI76 SI79 Synthesis and spectroscopic data for Bz-xime 4... SI80 SI82 Synthesis and spectroscopic data for pyridine 3 and dienoate 8e... SI83 SI88 Synthesis and spectroscopic data for ketone SI89 SI91 Synthesis and spectroscopic data for enone SI92 SI94 Synthesis and spectroscopic data for enoxysilane SI-7... SI95 SI102 Synthesis and spectroscopic data for cyclopropanol SI103 SI108 Synthesis of ( )-xylogranatopyridine B (2)... SI109 Spectroscopic data for ( )-xylogranatopyridine B (2)... SI110 SI113 ptical rotation data for chiral intermediates in enantioselective route... SI114 SI115 References... SI116 SI1

2 General Experimental General Experimental Procedures: All reactions were carried out under an inert nitrogen atmosphere with dry solvents under anhydrous conditions unless otherwise stated. All reactions were capped with a rubber septum, or Teflon-coated silicon microwave cap unless otherwise stated. Stainless steel cannula or syringe were used to transfer solvent, and air- and moisturesensitive liquid reagents. Reactions were monitored by thin-layer chromatography (TLC) and carried out on 0.25 mm rck silica gel plates (60F-254) using UV light as the visualizing agent and potassium permanganate or an acidic solution of p-anisaldehyde as developing agents. Flash column chromatography employed SiliaFlash Ò P60 (40-60 µm, mesh) silica gel purchased from SiliCycle Inc. zonolysis reactions were conducted using an A2Z zone SP - 16G Swimming Pool zone Generator with a MG/ adjustable ozone concentration. Materials: All reaction solvents were purified using a Seca solvent purification system by Glass Contour.,-diisopropylamine, triethylamine, and chlorotrimethylsilane (TMSCl) were distilled over Ca 2. n-buli (2.5 M in hexanes), Zn(TMP) 2 (0.5 M in toluene), MgBr (3.0 M in Et 2 ), Et 2 Zn (15 wt% in toluene or 1.0 M in hexanes), 2 Zn (2.0 M in toluene), Li (1.6 M in Et 2 ), dicyclopentylzinc (0.4 M in Et 2 ), diisoproylzinc (1.0 M in toluene), cyclohexylmagnesium chloride (1.0 M in 2-TF) and LiTMP were purchased from Sigma- Aldrich. [Pd(allyl)Cl] 2, [PtCl 2 (C 2 4 )] 2, and Ag 2 were purchased from Strem Chemical Inc. The molarity of n-butyllithium solutions were determined by titration with -benzylbenzamide. All other reagents were used as received without further purification, unless otherwise stated. Instrumentation: All new compounds were characterized by means of 1 -MR, 13 C-MR, FT- IR (thin film), and R-MS. Copies of the 1 - and 13 C-MR spectra can be found at the end of each experimental procedure. MR spectra were recorded using a Varian 400 Mz MR spectrometer, Varian 500 Mz MR spectrometer, or a Varian 600 Mz MR spectrometer. All 1 -MR data are reported in δ units, parts per million (ppm), and were calibrated relative to the signals for residual chloroform (7.26 ppm) in deuterochloroform (CDCl 3 ) or residual benzene (7.16 ppm) in deuterobenzene (C 6 D 6 ). All 13 C-MR data are reported in ppm relative to CDCl 3 (77.16 ppm) and were obtained with 1 decoupling unless otherwise stated. The following abbreviations or combinations thereof were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet, and a = apparent. All IR spectra were taken on an FT-IR/Raman Thermo icolet igh resolution mass spectra (R-MS) were recorded on a Bruker microtf mass spectrometer using ESI-TF (electrospray ionization-time of flight). ptical rotation data was obtained using a Perkin-Elmer 341 polarimeter. PLC data was obtained using Agilent 1260 PLC. SI2

3 Synthetic Schemes Scheme SI-1: TMS a. MgBr, b. Ag 2, CuI, TMSCl TIPSCl c. Ph 3 P=C 2 d. Bz2, Et 3 (63% over (77%) (80%) two steps) :1 E:Z Bz then Cu(BF 4 ) 2, Fe(BF 4 ) 2 (55%) 2. Bu 3 SnLi, Bu 3 Sn [Pd(allyl)Cl] 2, 13 5a P()(Et) 2 (50%) C LDA (88%) 4. Ac 2, DMAP, py (94%) Bu 3 Sn Ac 5. LiTMP, then Burgess reagent Bu 3 Sn (67%) Cu(Ac) 2 quinuclidine Cr(V) 15-C-5 (56% + 27% 3) π then 2 (43%) 17 [1-g scale] 8. Zn(TMP) 2 [Pd(allyl)Cl] 2, P()(Et) 2 (67%) TBS Scheme SI-2: TBSTf (74%, 1:1 dr) 10. Et 2 Zn, C 2 I 2, then TBAT (75%, >20:1 dr) 2 C [PtCl 2 (C 2 4 )] 2 (69%) 2 C xylogranatopyridine B (2) (1) Bu 3 Sn (±) = Ph S 10 mol% (-)-Levamisole Ac 2 (59% after 1 recycle, 93:7 er) Bu 3 Sn (-)-15 Ac Scheme SI-3: Ts (0.03 equiv) LDA (1.15 equiv) I (2.0 equiv) Ph, Et, ºC Et Et 90 ºC,12 h 1 h, (63% over 6 SI-5 two steps) SI-6 Bu 3 Sn (1.2 equiv) LDA (1.1 equiv) ºC (41%) Bu 3 Sn 5a SI3

4 Proposed Biosynthesis Scheme SI-4: 2 C R SI-1 retro-aldol, β-elimination, + 3 donor R 2 C SI-2 aza-michael, then aromatization 2 C xylogranatopyridine B (2) mexicanolidetype limonoid elimination 2 C R SI-3 It is postulated 1,2 that the biosynthesis of xylogranatopyridine B (2) may begin with a mexicanolide type limonoid containing a C9 hydroxyl group, such as SI-1 or a similar limonoid precursor at a different oxidation state. The alkoxide of SI-1 could undergo a retro-aldol reaction to cleave the C9-C10 linkage. SI-2 may be formed after protonation of the resulting enolate, β- elimination of the R group at C3, and condensation with an ammonia equivalent. The resulting imine could initiate an aza-michael reaction followed by loss of water and aromatization to from xylogranatopyridine B (2). Alternatively, a base could facilitate the elimination of water from SI-2 to generate azatriene SI-3, which may undergo a 6πelectrocyclization and aromatization to form xylogranatopyridine B (2). Aside from the proposed interconversions of mexicanolide type limonoids to xylogranatopyridine B depicted in Scheme SI-4 other biosynthetic proposals may be possible. 2 6π then aromatization SI4

5 Ketone SI equiv isoprene 5 mol % [AlCl 3 + 2TF] 30 o C, 24 h 8 SI-4 Compound SI-4 was prepared according to the literature procedure, 3 which produced the trans diastereomer (10:1 dr). 4 Rf: 0.41 (20 % Et 2 /hexanes) 1 MR (500 Mz, CDCl 3 ): δ 5.39 (s, 1), (m, 1), 2.36 (atd, J = 13.5, 6.0 z, 1), (m, 3), (m, 2), (m, 2), (m, 2), 1.64 (s, 3), (m, 1) 13 C MR (126 Mz, CDCl 3 ): δ 212.5, 132.5, 120.1, 50.5, 42.2, 40.7, 38.6, 32.9, 26.3, 24.0, 23.4 IR (cm -1 ): 2924, 1706, 1440, 1150, 825, 570 ESI-RMS (m/z): [M+] + calc d for C : ; found: SI5

6 SI-4 SI6

7 SI-4 SI7

8 Enone 8f 1.3 equiv Zn(TMP) 2, toluene, 0 o C, 10 min 2.5 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 120 o C, 2 h SI-4 8f To a flame-dried 20 ml microwave vial equipped with a magnetic stir bar and sealed with a Teflon-coated silicon microwave cap was added ketone SI-4 (500 mg, 3.0 mmol, 1.0 equiv) and toluene (5.0 ml, 0.6 M). The reaction vessel was moved to a 0 o C ice-water bath and stirred for 5 minutes before adding Zn(TMP) 2 (7.9 ml, 4.0 mmol, 1.3 equiv, 0.5 M in toluene). The reaction was stirred for 10 minutes before a solution of [Pd(allyl)Cl] 2 (27.8 mg, mmol, 2.5 mol %) and diethyl allyl phosphate (0.54 ml, 3.0 mmol, 1.0 equiv) in toluene (2.0 ml) was added to the reaction to give a mixture with a final concentration of 0.19 M. The reaction vessel was removed from the ice-water bath, sealed with parafilm, and moved to a preheated 120 o C oil bath. After stirring at 120 o C for 2 hours, the reaction was removed from the oil bath and cooled to room temperature. To the reaction mixture was added sat. aq. 4 Cl (20 ml). The mixture was diluted with Et 2 (20 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 20 ml) and the combined organic extracts were washed with brine (60 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded enone 8f (0.22 g, 46%) as a yellow oil. Enone 8f has previously been synthesized in the literature. 5 Rf: 0.36 (20% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ): δ 6.96 (ddd, J = 10.0, 6.0, 2.0 z, 1), 6.03 (dd, J = 12.0, 2.0 z, 1), (m, 1), (m, 2), (m, 6), 1.66 (s, 3) 1 MR (500 Mz, C 6 D 6 ): δ 6.21 (ddd, J = 10.0, 6.0, 2.0 z, 1), 5.97 (dd, J = 10.0, 3.0 z, 1), (m, 1), 2.68 (adt, J = 18.0, 5.0 z, 1), (m, 1), 1.86 (ddd, J = 13.0, 11.0, 5.8 z, 1), (m, 2), (m, 1), 1.50 (s, 3), (m, 2) 13 C MR (101 Mz, CDCl 3 ): δ 201.4, 149.0, 132.3, 130.0, 120.3, 46.5, 37.6, 35.9, 33.2, 25.6, 23.4 IR (cm -1 ): 2963, 2886, 1682, 1666, 1434, 1387, 1247, 1144, 926, 773, 433 ESI-RMS (m/z): [M+] + calc d for C : ; found: SI8

9 8f SI9

10 8f SI10

11 J = 13.0 z in C 6 D 6 8f SI11

12 8f SI12

13 8f SI13

14 Enone 5a 1.2 equiv Bu 3 SnLi, TF, 0 o C, 30 min 2.5 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 60 o C, 1 to 15 min SnBu 3 8a 5a To a flame-dried 1-L three-necked round-bottomed flask equipped with a magnetic stir bar and a dropping funnel was added TF (230 ml, 0.4 M) and diisopropylamine (20.0 ml, 143 mmol, 1.3 equiv). The reaction mixture was cooled to 0 o C by transferring the reaction apparatus to an ice-water bath. The reaction mixture was stirred for 10 minutes at 0 o C, before n-buli (44 ml, 109 mmol, 1.2 equiv, 2.5 M in hexanes) was added via a dropping funnel to the reaction mixture over 10 minutes. After stirring for 15 minutes at 0 o C, Bu 3 Sn (29.4 ml, 109 mmol, 1.2 equiv) was added to the mixture via syringe and stirred for 30 minutes at this temperature to give a yellow reaction mixture. To the reaction mixture was added enone 8a 6 (10.0 g, 91 mmol, 1.0 equiv) dropwise via syringe over 10 minutes, and the resulting mixture was stirred at 0 o C for 30 minutes. Following this, a solution of [Pd(allyl)Cl] 2 (830 mg, 2.3 mmol, 2.5 mol %) and diethyl allyl phosphate (16.2 ml, 91 mmol, 1.0 equiv) in TF (40 ml) was quickly added via syringe, resulting in a reddishbrown mixture with a final concentration of 0.37 M. The reaction vessel was then moved to a preheated 60 o C oil bath and stirred until palladium black precipitated out of the reaction (ca. 1 minute after heating). Upon formation of palladium precipitate, the reaction vessel was immediately removed from the oil bath and sat. aq. 4 Cl (500 ml) was added to the hot reaction mixture. The reaction mixture was diluted with Et 2 (300 ml) and filtered through Celite Ò. The organic phase was separated and the aqueous phase was extracted with Et 2 (2 x 300 ml). The combined organic extracts were washed with brine (800 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (100% hexanes to 5% Et 2 /hexanes) afforded enone 5a (18.3 g, 50%) as a pale-yellow oil. Preparation of Enone 5a on 35-g Scale To a flame-dried 3-L three-necked round-bottomed flask equipped with a magnetic stir bar and two dropping funnels was added TF (800 ml, 0.4 M) and diisopropylamine (58.0 ml, 413 mmol, 1.3 equiv). The reaction mixture was cooled to 0 o C by transferring the reaction apparatus to an ice-water bath. The reaction mixture was stirred for 10 minutes at 0 o C, before n- BuLi (153 ml, 382 mmol, 1.2 equiv, 2.5 M in hexanes) was added via a dropping funnel to the reaction mixture over 1 hour. After stirring for 15 minutes at 0 o C, Bu 3 Sn (103 ml, 382 mmol, 1.2 equiv) was added to the mixture via a dropping funnel over 30 minutes and the resulting mixture was stirred for 30 minutes at 0 o C to give a yellow reaction mixture. To the reaction mixture was added enone 8a 6 (35.0 g, 318 mmol, 1.0 equiv) dropwise via syringe over 20 minutes, and the resulting mixture was stirred at 0 o C for 30 minutes. Following this, a solution of [Pd(allyl)Cl] 2 (2.9 g, 8.0 mmol, 2.5 mol %) and diethyl allyl phosphate (57 ml, 318 mmol, 1.0 equiv) in TF (140 ml) was quickly added via cannula, resulting in a SI14

15 reddish-brown mixture with a final concentration of 0.23 M. The reaction vessel was then moved to a preheated 60 o C heating mantle and stirred until palladium black precipitated out of the reaction (ca. 15 minutes after heating). Upon formation of palladium precipitate, the reaction vessel was immediately removed from the heating mantle and sat. aq. 4 Cl (1.5 L) was added to the hot reaction mixture. The reaction mixture was diluted with Et 2 (1 L) and filtered through Celite Ò. The organic phase was separated and the aqueous phase was extracted with Et 2 (2 x 1 L). The combined organic extracts were washed with brine (2 L), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (100% hexanes to 5% Et 2 /hexanes) afforded enone 5a (54.8 g, 43%) as a pale-yellow oil. Rf: 0.19 (5% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ): δ 6.19 (at, J Sn- = 28 z, 1), (m, 2), (m, 1), 2.03 (addt, J = 13.0, 8.0, 4.0 z, 1), 1.72 (dddd, 13.0, 12.0, 9.5, 5.0 z, 1), (m, 6), (m, 6), 1.13 (d, J = 8.0 z, 3), (m, 6), 0.89 (t, J = 8.0 z, 9) 13 C MR (151 Mz, CDCl 3 ): δ 200.0, 173.6, 138.5, 41.8, 32.8, 32.1, 29.2, 27.5, 15.4, 13.8, 9.5 IR (cm -1 ): 2956, 2923, 1673, 1458, 1375, 1195, 952, 876, 690, 666, 597, 500, 439 ESI-RMS (m/z): [M+] + calc d for C Sn + : ; found: The reaction mixture turns yellow upon the formation of Bu 3 SnLi. The reaction mixture turns reddish-brown after the addition of [Pd(allyl)Cl] 2 and diethyl allyl phosphate. After heating the reaction mixture at 60 o C, the mixture turns black upon the precipitation of palladium. SI15

16 SnBu 3 5a SI16

17 SnBu 3 5a SI17

18 Enone 5b 8b 1.2 equiv Bu 3 SnLi, TF, 23 o C, 30 min 2.5 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 60 o C, 1 min Bu 3 Sn 5b To a flame-dried microwave vial equipped with a magnetic stir bar was added TF (0.5 ml, 0.4 M) and diisopropylamine (36 µl, 0.26 mmol, 1.3 equiv). The reaction mixture was cooled to 0 o C by transferring the reaction apparatus to an ice-water bath. The reaction mixture was stirred for 10 minutes at 0 o C, before n-buli (0.10 ml, 0.24 mmol, 1.2 equiv, 2.5 M in hexanes) was added dropwise to the reaction. After stirring for 15 minutes at 0 o C, Bu 3 Sn (65 µl, 0.24 mmol, 1.2 equiv) was added to the mixture and the reaction mixture was stirred at 0 o C for an additional 30 minutes, resulting in a yellow solution. To the reaction mixture was added a solution of α-santonin (8b) (46.3 mg, 0.20 mmol, 1.0 equiv) in TF (0.5 ml) dropwise. The resulting red mixture was removed from the ice-water bath and stirred at room temperature for 30 minutes. Following this, a solution of [Pd(allyl)Cl] 2 (1.83 mg, mmol, 2.5 mol %) and diethyl allyl phosphate (35.6 µl, 0.20 mmol, 1.0 equiv) in TF (0.20 ml) was quickly added to give a mixture with a final concentration of 0.14 M. The resulting reddish-brown mixture was then moved to a preheated 60 o C oil bath and heated until palladium black precipitated out of the reaction (ca. 1 minute after heating). Upon formation of palladium precipitate, the reaction vessel was immediately removed from the oil bath and sat. aq. 4 Cl (5 ml) was added to the hot reaction mixture. The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (20% Et 2 /hexanes) afforded 5b (47.3 mg, 44%) as a pale-yellow oil. Rf: 0.24 (40% Et 2 /hexanes) [α] 20.0 D: 89.0 o (c 1.0, CCl 3 ) 1 MR (400 Mz, CDCl 3 ): δ 6.45 (at, J Sn- = 28.0 z, 1), 4.80 (d, J = 12.0 z, 1), 2.39 (dq, J = 20.0, 8.0 z, 1), 2.14 (s, 3), (m, 1), 1.88 (adt, J = 12.0, 4.0 z, 1), 1.80 (atd, J = 12.0, 4.0 z, 1), 1.67 (ddd, J = 24.0, 12.0, 4.0 z, 1), (m, 6), 1.32 (asept, J = 8.0 z, 6), (m, 6), (m, 6), 0.90 (t, J = 8.0 z, 9) 13 C MR (126 Mz, CDCl 3 ): δ 183.4, 177.8, 177.7, 154.1, 136.2, 128.7, 82.3, 53.3, 46.4, 41.3, 39.2, 29.1, 27.5, 26.3, 23.5, 13.8, 12.7, 11.6, 11.2 IR (cm -1 ): 2955, 2928, 1785, 1640, 1457, 1377, 1233, 1180, 1028, 984, 956, 656, 496 ESI-RMS (m/z): [M+] + calc d for C Sn + : ; found: SI18

19 Bu 3 Sn 5b SI19

20 Bu 3 Sn 5b SI20

21 Enone 5c 1.2 equiv Bu 3 SnZnEt 2 Li, TF, 0 o C, 30 min 2.5 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 60 o C, 15 min SnBu 3 8c 5c To a flame-dried microwave vial equipped with a magnetic stir bar was added TF (0.5 ml 0.4 M) and diisopropylamine (36 µl, 0.26 mmol, 1.3 equiv). The reaction mixture was cooled to 0 ºC by transferring the reaction apparatus to an ice-water bath. The reaction mixture was stirred for 10 minutes at 0 ºC, before n-buli (0.10 ml, 0.24 mmol, 1.2 equiv, 2.5 M in hexanes) was added dropwise to the reaction. After stirring for 15 minutes at 0 ºC, Bu 3 Sn (65 µl, 0.24 mmol, 1.2 equiv) was added to the reaction mixture and the reaction mixture was stirred at 0 o C for an additional 30 minutes to give a yellow solution. To this mixture was added Et 2 Zn (0.20 ml, 0.20 mmol, 1.0 equiv, 1.0 M in hexanes) dropwise at 0 o C and the reaction mixture was stirred for an additional 30 minutes. To the reaction mixture was added ( )-carvone (8c) (31 µl, 0.20 mmol, 1.0 equiv) dropwise and the resulting mixture was stirred at 0 o C for 30 minutes before a solution of [Pd(allyl)Cl] 2 (1.8 mg, mmol, 2.5 mol %) and diethyl allyl phosphate (82 µl, 0.46 mmol, 2.3 equiv) in TF (0.20 ml) was quickly added to give a mixture with a final concentration of 0.28 M. The reaction vessel was then moved to a preheated 60 o C oil bath until palladium black precipitated out of the reaction (ca.15 minutes after heating). Upon formation of palladium precipitate, the reaction vessel was immediately removed from the oil bath and sat. aq. 4 Cl (5 ml) was added to the hot reaction mixture. The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (5% Et 2 /hexanes) afforded 5c (26.5 mg, 30%) as a pale-yellow oil. Rf: 0.19 (5% Et 2 /hexanes) [α] 20.0 D: 51.0 o (c 1.0, CCl 3 ) 1 MR (400 Mz, CDCl 3 ): δ 4.80 (s, 1), 4.73 (s, 1), (m, 3), (m, 1), 2.32 (dd, J = 16.0, 12.0 z, 1), 1.87 (dd, J = 2.4, 1.0 z, 3), 1.75 (s, 3), (m, 6), 1.32 (sext, J = 8.0 z, 6), (m, 6), 0.90 (t, J = 8.0 z, 9) 13 C MR (151 Mz, CDCl 3 ): δ 197.2, 166.8, 147.2, 143.1, 110.4, 43.3, 39.3, 29.3, 27.5, 20.7, 18.8, 13.8, 10.5 IR (cm -1 ): 2955, 2921, 1668, 1456, 1376, 1288, 1107, 890, 689, 665, 498 ESI-RMS (m/z): [M+] + calc d for C Sn + : ; found: SI21

22 SnBu 3 5c SI22

23 SnBu 3 5c SI23

24 Enone 5d 1.2 equiv Ph 2 SiLi, TF, 0 o C, 30 min 2.5 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 23 o C, 30 min Si 2 Ph 8a 5d To a flame-dried microwave vial equipped with a magnetic stir bar was added 1,2 diphenyltetramethyldisilane (65 mg, 0.24 mmol, 1.2 equiv) and MPA (0.10 ml, 0.57 mmol, 2.87 equiv). The reaction vessel was moved to a 78 o C dry ice-acetone bath until the reaction mixture became frozen. To the frozen mixture was added Li (0.15 ml, 0.24 mmol, 1.2 equiv, 1.6 M in Et 2 ) and TF (0.5 ml, 0.4 M) and the reaction vessel was moved to a 0 o C ice-bath and stirred until a dark red solution was formed (5 minutes). To the reaction mixture was added enone 8a 6 (22.0 mg, 0.20 mmol, 1.0 equiv) dropwise and the resulting mixture was stirred at 0 o C for 30 minutes. Following this, a solution of [Pd(allyl)Cl] 2 (1.8 mg, mmol, 2.5 mol %) and diethyl allyl phosphate (36 µl, 0.20 mmol, 1.0 equiv) in TF (0.20 ml) was quickly added to give a mixture with a final concentration of 0.2 M. The reaction vessel was then removed from the ice-water bath and allowed to warm to room temperature. After the reaction mixture was stirred at room temperature for 30 minutes, sat. aq. 4 Cl (5 ml) and Et 2 (5 ml) were added to the reaction mixture and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (5% Et 2 /hexanes) afforded 5d (38.6 mg, 79%) as a clear oil. The characterization data matches those reported in the literature. 7 Rf: 0.50 (20% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ): δ (m, 2), (m, 3), 6.26 (s, 1), (m, 3), 2.03 (ddd, J = 16.0, 8.0, 4.0 z, 1), (m, 1), 1.12 (d, J = 4.0 z, 3), 0.43 (s, 3), 0.43 (s, 3) 13 C MR (151 Mz, CDCl 3 ): δ 201.6, 164.9, 136.6, 135.9, 134.0, 129.8, 128.2, 41.8, 31.8, 27.9, 15.3, 3.9, 4.1 IR (cm -1 ): 2959, 2929, 1672, 1428, 1249, 1200, 1037, 957, 810, 699, 476 ESI-RMS (m/z): [M+] + calc d for C Si + : ; found: SI24

25 Si 2 Ph 5d SI25

26 Si 2 Ph 5d SI26

27 Enone 5e 8d To a flame-dried microwave vial equipped with a magnetic stir bar was added 1,2 diphenyltetramethyldisilane (65 mg, 0.24 mmol, 1.2 equiv) and MPA (0.10 ml, 0.57 mmol, 2.87 equiv). The reaction vessel was moved to a 78 o C dry ice-acetone bath until the reaction mixture became frozen. To the frozen mixture was added Li (0.15 ml, 0.24 mmol, 1.2 equiv, 1.6 M in Et 2 ) and TF (0.5 ml, 0.4 M) and the reaction vessel was moved to a 0 o C ice-water bath and stirred until a dark red solution was formed (5 minutes). To the reaction mixture was added a solution of enone 8d 8 (93.3 mg, 0.20 mmol, 1.0 equiv) in TF (0.5 ml, 0.4 M) dropwise and the resulting mixture was stirred at 0 o C for 30 minutes. Following this, a solution of [Pd(allyl)Cl] 2 (1.8 mg, mmol, 2.5 mol %) and diethyl allyl phosphate (36 µl, 0.20 mmol, 1.0 equiv) in TF (0.20 ml) was quickly added to give a mixture with a final concentration of 0.13 M. The reaction vessel was then removed from the ice-water bath and moved to a preheated 60 o C oil bath. After the reaction was stirred at 60 o C for 30 minutes, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded enone 5e (105.3 mg, 88%) as a colorless solid. Rf: 0.43 (Et 2 /hexanes = 4:1) [α] 20.0 D: +76 o (c 1.0, CCl 3 ) 1.2 equiv Ph 2 SiLi, TF, 0 o C, 30 min 2.5 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 60 o C, 30 min 1 MR (500 Mz, CDCl3): δ (m, 2), (m, 3), 6.38 (s, 1), 5.16 (dd, J = 3.5, 1.2 z, 1), 3.57 (s, 3), 2.81 (dd, J = 10.0, 5.0 z, 1), 2.01 (dd, J = 15.0, 5.0 z, 1), 1.91 (td, J = 15.0, 5.0 z, 1), (m, 2), 1.67 (atd, J = 15.0, 5.0 z, 1), (m, 3), (m, 9), 1.19 (s, 3), 1.11 (s, 3), (m, 1), 0.97 (s, 3), 0.95 (s, 3), 0.94 (s, 3), 0.94 (s, 3), 0.81 (s, 3), 0.50 (s, 3), 0.42 (s, 3) 13 C MR (151 Mz, CDCl3): δ 206.1, 178.3, 174.0, 144.3, 138.8, 138.7, 133.6, 129.2, 128.1, 122.1, 53.1, 51.7, 47.3, 45.8, 45.2, 44.7, 42.9, 42.3, 41.0, 40.0, 34.1, 33.3, 32.8, 32.4, 30.8, 29.7, 27.8, 27.5, 23.7, 23.3, 22.1, 21.9, 20.2, 19.0, 1.7, 0.1 IR (cm -1 ): 2949, 1725, 1667, 1461, 1383, 1196, 909, 818, 472 Ph 2 Si ESI-RMS (m/z): [M+] + calc d for C Si + : ; found: e SI27

28 Ph 2 Si 5e SI28

29 Ph 2 Si 5e SI29

30 Dienoate 5f 1.2 equiv Ph 2 SiLi, TF, 0 o C, 30 min 2.5 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 60 o C, 30 min Ph 2 Si (±)-8e (±)-5f To a flame-dried microwave vial equipped with a magnetic stir bar was added 1,2 diphenyltetramethyldisilane (65 mg, 0.24 mmol, 1.2 equiv) and MPA (0.10 ml, 0.57 mmol, 2.87 equiv). The reaction vessel was moved to 78 o C dry ice-acetone bath until the reaction mixture became frozen. To the frozen mixture was added Li (0.15 ml, 0.24 mmol, 1.2 equiv, 1.6 M in Et 2 ) and TF (0.5 ml, 0.4 M) and the reaction vessel was moved to a 0 o C ice-water bath and stirred until a dark red solution was formed (5 minutes). To the reaction mixture was added a solution of dienoate 8e (46.1 mg, 0.20 mmol, 1.0 equiv) in TF (0.5 ml) dropwise and the resulting mixture was stirred at 0 o C for 30 minutes. Following this, a solution of [Pd(allyl)Cl] 2 (1.8 mg, mmol, 2.5 mol %) and diethyl allyl phosphate (36 µl, 0.20 mmol, 1.0 equiv) in TF (0.20 ml) was quickly added to give a mixture with a final concentration of 0.13 M. The reaction vessel was then removed from the ice-water bath and moved to a preheated 60 o C oil bath. After the reaction was stirred at 60 o C for 30 minutes, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded dienoate 5f (28.0 mg, 38%) as a colorless solid. Rf: 0.15 (10% EtAc/hexanes) 1 MR (400 Mz, CDCl 3 ): δ (m, 3), (m, 4), 6.49 (d, J = 2.5 z, 1), 6.42 (d, J = 1.1 z, 1), 5.70 (s, 1), 5.09 (s, 1), 2.37 (dd, J = 20.0, 4.0 z, 1), (m, 1), 1.49 (ddd, 12.0, 4.0, 1.6 z, 1), 1.37 (td, J = 12.0, 4.0 z, 1), 1.00 (s, 3), 0.43 (s, 3), 0.43 (s, 3) 13 C MR (101 Mz, CDCl 3 ): δ 166.2, 157.9, 153.5, 143.1, 141.1, 136.4, 134.0, 133.3, 129.7, 128.2, 120.2, 113.0, 110.1, 81.0, 36.9, 30.3, 24.9, 16.2, 3.8, 3.9 IR (cm -1 ): 2955, 1708, 1503, 1427, 1255, 1233, 1026, 983, 812, 493 ESI-RMS (m/z): [M+] + calc d for C Si + : ; found: SI30

31 Ph 2 Si (±)-5f SI31

32 Ph 2 Si (±)-5f SI32

33 Enone 5g 1.0 equiv 3 ZnLi, TF, -40 o C, 30 min 5.0 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 80 o C, 2 h 8f 5g A flame-dried microwave vial equipped with a magnetic stir bar was sealed with a Teflon-coated silicon microwave cap and placed in a 0 o C ice-water bath. To the reaction vessel was added TF (0.5 ml, 0.4 M), 2 Zn (0.10 ml, 0.20 mmol, 1.0 equiv, 2.0 M in toluene), and Li (0.13 ml, 0.20 mmol, 1.0 equiv, 1.6 M in Et 2 ). The reaction mixture was stirred for 30 minutes at 0 o C. The reaction vessel was then moved to a 40 o C dry ice-acetonitrile bath and stirred for 5 minutes before the dropwise addition of enone 8f (32.4 mg, 0.20 mmol, 1.0 equiv). The reaction mixture was then stirred for 30 minutes at this temperature. Following this, a solution of [Pd(allyl)Cl] 2 (3.7 mg, mmol, 5.0 mol %) and diethyl allyl phosphate (0.11 ml, 0.60 mmol, 3.0 equiv) in TF (0.2 ml) was quickly added to give a mixture with a final concentration of 0.19 M. The reaction vessel was removed from the dry ice-acetonitrile bath, sealed with parafilm, and moved to a preheated 80 o C oil bath. After the reaction mixture had stirred at 80 o C for 2 hours, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded enone 5g (19.1 mg, 54%) as a yellow oil. Rf: 0.33 (20% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ): δ 5.88 (s, 1), 5.44 (s, 1), 2.51 (dt, J = 16.0, 4.0 z, 1), 2.35 (dd, J = 16.0, 4.0 z, 1), (m, 5), (m, 1), 1.95 (s, 3), 1.66 (s, 3) 13 C MR (101 Mz, CDCl 3 ): δ 201.2, 160.9, 132.3, 126.7, 120.5, 45.4, 38.5, 37.7, 35.8, 25.8, 24.4, 23.4 IR (cm -1 ): 2908, 1659, 1433, 1381, 1247, 1190, 925, 845, 796, 444 ESI-RMS (m/z): [M+] + calc d for C : ; found: SI33

34 5g SI34

35 5g SI35

36 Enone 5h 1.0 equiv Et 2 ZnLi, TF, 23 o C, 30 min TBS 5.0 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 80 o C, 2 h TBS Et 8g 5h A flame-dried microwave vial equipped with a magnetic stir bar was sealed with a Teflon-coated silicon microwave cap and placed in a 0 o C ice-water bath. To the reaction vessel was added TF (0.5 ml, 0.4 M), Et 2 Zn (0.20 ml, 0.20 mmol, 1.0 equiv, 1.0 M in hexanes), and Li (0.13 ml, 0.20 mmol, 1.0 equiv, 1.6 M in Et 2 ). After stirring for 30 minutes at 0 o C, a solution of enone 8g 9 (80.1 mg, 0.20 mmol, 1.0 equiv) in TF (0.5 ml) was added dropwise to the reaction mixture. The reaction vessel was removed from the ice-water bath and stirred at room temperature for 30 minutes. Following this, a solution of [Pd(allyl)Cl] 2 (3.7 mg, mmol, 5.0 mol %) and diethyl allyl phosphate (0.11 ml, 0.60 mmol, 3.0 equiv) in TF (0.2 ml) was quickly added to give a mixture with a final concentration of 0.12 M. The reaction vessel was removed from the dry ice-acetonitrile bath, sealed with parafilm, and moved to a preheated 80 o C oil bath. After the mixture was stirred at 80 o C for 2 hours, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded enone 5h (40.3 mg, 47%) as a colorless solid. Rf: 0.33 (20% Et 2 /hexanes) [α] 20.0 D: 74 o (c 1.0, CCl 3 ) 1 MR (400 Mz, CDCl 3 ): δ 5.75 (s, 1), (m, 1), 3.48 (tt, J = 12.0, 4.0 z, 1), (m, 3), (m, 3), 2.04 (ddd, J = 24.0, 12.0, 4.0 z, 1), (m, 2), 1.81 (dt, J = 12.0, 4.0 z, 1), (m, 2), (m, 1), (m, 2), 1.16 (t, J = 8.0 z, 3), (m, 2), 1.08 (s, 3), 1.07 (s, 3), 0.89 (s, 9), 0.06 (s, 6) 13 C MR (101 Mz, CDCl 3 ): δ 212.6, 181.5, 142.1, 125.6, 120.1, 72.5, 58.4, 52.2, 51.3, 42.7, 37.4, 37.1, 33.0, 32.2, 30.3, 29.1, 27.1, 26.1, 20.8, 20.1, 19.4, 18.4, 11.7, 4.4, 4.4 IR (cm -1 ): 2931, 2855, 1704, 1591, 1462, 1371, 1250, 1089, 869, 773, 613 ESI-RMS (m/z): [M+] + calc d for C Si + : ; found: SI36

37 TBS Et 5h SI37

38 TBS Et 5h SI38

39 Enone 5i 1.0 equiv i-pr 2 ZnLi, TF, -40 o C, 30 min 5.0 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 80 o C, 2 h 8h 5i A flame-dried microwave vial equipped with a magnetic stir bar was sealed with a Teflon-coated silicon microwave cap and placed in a 0 o C ice-water bath. To the reaction vessel was added TF (0.5 ml, 0.4 M), i-pr 2 Zn (0.20 ml, 0.20 mmol, 1.0 equiv, 1.0 M in toluene), and Li (0.13 ml, 0.20 mmol, 1.0 equiv, 1.6 M in Et 2 ) and the reaction mixture was stirred for 30 minutes at 0 o C. The reaction vessel was then moved to a 40 o C dry ice-acetonitrile bath and stirred for 5 minutes before the dropwise addition of enone 8h 10 (22.0 mg, 0.20 mmol, 1.0 equiv). The reaction mixture was then stirred for 30 minutes at this temperature. Following this, a solution of [Pd(allyl)Cl] 2 (3.7 mg, mmol, 5.0 mol %) and diethyl allyl phosphate (0.11 ml, 0.60 mmol, 3.0 equiv) in TF (0.2 ml) was quickly added to give a mixture with a final concentration of 0.17 M. The reaction vessel was removed from the dry ice-acetonitrile bath, sealed with parafilm, and moved to a preheated 80 o C oil bath. After the reaction mixture was stirred at 80 o C for 2 hours, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded enone 5i (14.4 mg, 47%) as a colorless oil. Rf: 0.30 (20% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ): δ 5.86 (s, 1), (m, 1), 2.43 (dd, J = 16.0, 4.0 z, 1), 2.33 (dd, J = 20.0, 4.0 z, 1), (m, 1), 2.03 (dd, J = 16.0, 12.0 z, 1), 2.00 (dd, J = 8.0, 2.0 z, 1), 1.10 (d, J = 1.2 z, 3), 1.08 (d, J = 1.2 z, 3), 1.07 (d, J = 8.0 z, 3) 13 C MR (101 Mz, CDCl 3 ): δ 200.8, 171.2, 123.4, 45.9, 36.3, 35.8, 30.5, 21.3, 20.9, 20.5 IR (cm -1 ): 2961, 2874, 1660, 1428, 1293, 891 ESI-RMS (m/z): [M+] + calc d for C : ; found: SI39

40 5i SI40

41 5i SI41

42 Enone 5j 1.0 equiv n-buzn 2 Li, TF, -78 o C, 30 min 5.0 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 80 o C, 2 h n-bu 8i 5j A flame-dried microwave vial equipped with a magnetic stir bar was sealed with a Teflon-coated silicon microwave cap and placed in a 0 o C ice-water bath. To the reaction vessel was added TF (0.5 ml, 0.4 M), 2 Zn (0.20 ml, 0.20 mmol, 1.0 equiv, 1.0 M in toluene), and n-buli (0.08 ml, 0.20 mmol, 1.0 equiv, 2.5 M in hexanes) and the reaction mixture was stirred for 30 minutes at 0 o C. The reaction vessel was then moved to a 78 o C dry ice-acetone bath and stirred for 5 minutes before the dropwise addition of enone 8i (19 µl, 0.20 mmol, 1.0 equiv). The reaction mixture was then stirred for 30 minutes at this temperature. Following this, a solution of [Pd(allyl)Cl] 2 (3.7 mg, mmol, 5.0 mol %) and diethyl allyl phosphate (0.11 ml, 0.60 mmol, 3.0 equiv) in TF (0.2 ml) was quickly added to give a mixture with a final concentration of 0.18 M. The reaction vessel was removed from the dry ice-acetone bath, sealed with parafilm, and moved to a preheated 80 o C oil bath. After the mixture was stirred at 80 o C for 2 hours, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (20% Et 2 /hexanes) afforded enone 5j (19.0 mg, 62%) as a colorless oil. The characterization data matches those reported in the literature. 11 Rf: 0.20 (20% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ): δ 5.87 (at, J = 1.2 z, 1), 2.36 (dd, J = 6.8, 6.4 z, 2), 2.28 (t, J = 8.0 z, 2), 2.21 (t, J = 8.0 z, 2), 1.98 (adq, J = 6.8, 6.3 z, 2), (m, 2), 1.33 (adq, J = 16.0, 8.0 z, 2), 0.92 (t, J = 8.0 z, 3) 13 C MR (151 Mz, CDCl 3 ): δ 200.2, 166.9, 125.8, 37.9, 37.5, 29.8, 29.2, 22.9, 22.5, 14.0 IR (cm -1 ): 2930, 1665, 1253, 1191, 908, 501 ESI-RMS (m/z): [M+] + calc d for C : ; found: SI42

43 n-bu 5j SI43

44 n-bu 5j SI44

45 Enone 5k 1.0 equiv (C 5 9 ) 2 ZnLi, TF, -40 o C, 30 min 5.0 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 80 o C, 2 h 8a 5k A flame-dried microwave vial equipped with a magnetic stir bar was sealed with a Teflon-coated silicon microwave cap and placed in a 0 o C ice-water bath. To the reaction vessel was added TF (0.5 ml, 0.4 M), dicyclopentylzinc (0.20 ml, 0.20 mmol, 1.0 equiv, 0.4 M in Et 2 ), and Li (0.13 ml, 0.20 mmol, 1.0 equiv, 1.6 M in Et 2 ) and the reaction mixture was stirred for 30 minutes at 0 o C. The reaction vessel was then moved to a 40 o C dry ice-acetonitrile bath and stirred for 5 minutes before the dropwise addition of enone 8a 6 (22.0 mg, 0.20 mmol, 1.0 equiv). The reaction mixture was then stirred for 30 minutes at this temperature. Following this, a solution of [Pd(allyl)Cl] 2 (3.7 mg, mmol, 5.0 mol %) and diethyl allyl phosphate (0.11 ml, 0.60 mmol, 3.0 equiv) in TF (0.2 ml) was quickly added to give a mixture with a final concentration of 0.17 M. The reaction vessel was removed from the dry ice-acetonitrile bath, sealed with parafilm, and moved to a preheated 80 o C oil bath. After the reaction mixture was stirred at 80 o C for 2 hours, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded enone 5k (19.5 mg, 55%) as a colorless oil. Rf: 0.40 (20% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ): δ 5.87 (s, 1), 2.56 (quint, J = 8.0 z, 1), (m, 3), 2.06 (addt, J = 12.0, 8.0, 4.0 z, 1), (m, 2), (m, 3), (m, 2), (m, 2), 1.13 (d, J = 4.0 z, 3) 13 C MR (101 Mz, CDCl 3 ): δ 202.9, 168.8, 123.5, 47.6, 41.2, 31.2, 31.2, 30.9, 28.3, 25.4, 25.4, 15.3 IR (cm -1 ): 2955, 2868, 1666, 1453, 1373, 1209, 1109, 876 ESI-RMS (m/z): [M+] + calc d for C : ; found: SI45

46 5k SI46

47 5k SI47

48 Enone 5l 1.0 equiv CyZn 2 MgCl, TF, -40 o C, 30 min 5.0 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 80 o C, 2 h 8a 5l A flame-dried microwave vial equipped with a magnetic stir bar was sealed with a Teflon-coated silicon microwave cap and placed in a 0 o C ice-water bath. To the reaction vessel was added TF (0.5 ml, 0.4 M), 2 Zn (0.10 ml, 0.20 mmol, 1.0 equiv, 2.0 M in toluene), and cyclohexylmagnesium chloride (0.20 ml, 0.20 mmol, 1.0 equiv, 1.0 M in 2-TF) and the reaction mixture was stirred for 30 minutes at 0 o C. The reaction vessel was then moved to a 40 o C dry ice-acetonitrile bath and stirred for 5 minutes before the dropwise addition of enone 8a 6 (22.0 mg, 0.20 mmol, 1.0 equiv). The reaction mixture was then stirred for 30 minutes at this temperature. Following this, a solution of [Pd(allyl)Cl] 2 (3.7 mg, mmol, 5.0 mol %) and diethyl allyl phosphate (0.11 ml, 0.60 mmol, 3.0 equiv) in TF (0.2 ml) was quickly added to give a mixture with a final concentration of 0.18 M The reaction vessel was removed from the dry ice-acetonitrile bath, sealed with parafilm, moved to a preheated 80 o C oil bath. After the reaction mixture was stirred at 80 o C for 2 hours, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The reaction mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded enone 5l (20.1 mg, 52%) as a yellow oil. Rf: 0.46 (20% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ): δ 5.83 (s, 1), (m, 3), (m, 2), (m, 4), (m, 2), (m, 5), 1.13 (d, J = 8.0 z, 3) 13 C MR (101 Mz, CDCl 3 ): δ 203.0, 170.2, 123.6, 46.1, 41.2, 31.4, 31.2, 31.1, 28.1, 26.5, 26.4, 26.2, 15.3 IR (cm -1 ): 2925, 2853, 1667, 1449, 1208, 870, 559 ESI-RMS (m/z): [M+] + calc d for C : ; found: SI48

49 5l SI49

50 5l SI50

51 Enone 5m 1.0 equiv CyZn 2 MgCl, TF, -78 o C, 30 min 5.0 mol % [Pd(allyl)Cl] equiv diethyl allyl phosphate, 80 o C, 4 h 8j 5m A flame-dried microwave vial equipped with a magnetic stir bar was sealed with a Teflon-coated silicon microwave cap and placed in a 0 o C ice-water bath. To the reaction vessel was added TF (0.5 ml, 0.4 M), 2 Zn (0.10 ml, 0.20 mmol, 1.0 equiv, 2.0 M in toluene), and cyclohexylmagnesium chloride (0.20 ml, 0.20 mmol, 1.0 equiv, 1.0 M in 2-TF) and the reaction mixture was stirred for 30 minutes at 0 o C. The reaction vessel was then moved to a 78 o C dry ice-acetone bath and stirred for 5 minutes before the dropwise addition of enone 8j (22.3 µl, 0.20 mmol, 1.0 equiv). The reaction mixture was then stirred for 30 minutes at this temperature. Following this, a solution of [Pd(allyl)Cl] 2 (3.7 mg, mmol, 5.0 mol %) and diethyl allyl phosphate (0.11 ml, 0.60 mmol, 3.0 equiv) in TF (0.2 ml) was quickly added to give a mixture with a final ceoncentration of 0.18 M. The reaction vessel was removed from the dry ice-acetone bath, sealed with parafilm, and moved to a preheated 80 o C oil bath. After the reaction mixture was stirred at 80 o C for 4 hours, the reaction vessel was removed from the oil bath and cooled to room temperature before the addition of sat. aq. 4 Cl (5 ml). The mixture was diluted with Et 2 (5 ml) and the organic phase was separated. The aqueous phase was extracted with Et 2 (2 x 5 ml) and the combined organic extracts were washed with brine (15 ml), dried with a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et 2 /hexanes) afforded enone 5m (15.8 mg, 41%) as a yellow oil. Rf: 0.30 (20% Et 2 /hexanes) 1 MR (400 Mz, CDCl 3 ) δ 5.87 (s, 1), (m, 2), (m, 2), 2.01 (att, J = 12.0, 4.0 z, 1), (m, 8), (m, 6) 13 C MR (101 Mz, CDCl 3 ): δ 205.2, 166.7, 127.5, 48.9, 42.0, 31.4, 31.0, 26.5, 26.2, 25.3, 21.1 IR (cm -1 ): 2925, 2852, 1657, 1449, 1258, 874, 530 ESI-RMS (m/z): [M+] + calc d for C : ; found: SI51

52 5m SI52

53 5m SI53

54 Synthesis of SI-6: Ph, Et, ºC Et Et 90 ºC,12 h 1 h, (63% over 6 SI-5 two steps) SI-6 To a flame-dried 1-L round-bottomed flask equipped with a magnetic stir bar was added 1,3-cyclohexanedione (25 g, 220 mmol, 1.0 equiv), Ph (360 ml, 0.6 M) and ethanol (100 ml, 2.3 M). To the stirred reaction mixture was added p-toluenesulfonic acid monohydrate (1.0 g, 5.6 mmol, 0.03 equiv) at room temperature. After stirring for 5 minutes at room temperature the reaction vessel was moved to a 90 ºC preheated oil bath. After stirring at 90 ºC for 12 hours, the reaction vessel was removed from the oil bath and cooled to room temperature, and the reaction mixture was concentrated under reduced pressure by rotary evaporation until ca. 100 ml remained. To this mixture was added water (200 ml), and the layers were separated. The aqueous layer was extracted with Et 2 (3 x 150 ml) and the combined organic extracts were washed with sat. aq. ac 3 (100 ml), brine (500 ml), dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation to provide the title compound (SI-5) 12 as a crude orange oil (27.6 g, 89%), which was greater than >95% purity and used without further purification. Ts (0.03 equiv) LDA (1.15 equiv) I (2.0 equiv) To a flame-dried 2-L three-necked round-bottomed flask equipped with a magnetic stir bar and a dropping funnel was added TF (710 ml, 0.5 M), and diisopropylamine (62 ml, 445 mmol, 1.25 equiv). The reaction mixture was cooled to 0 ºC by transferring the reaction apparatus to an ice-water bath. The reaction mixture was allowed to stir for 10 minutes at 0 ºC before n-buli (170 ml, 409 mmol, 1.15 equiv, 2.5 M in hexanes) was added via a dropping funnel to the stirred reaction mixture over 10 minutes. After the addition was complete the reaction mixture was allowed to stir for 25 minutes at 0 ºC. The reaction vessel was then transferred to a 78 ºC saturated dry-ice acetone bath and stirred for 10 minutes before 3-ethoxy-2-cyclohexenone (SI-6) (50 g, 356 mmol, 1.0 equiv) was added dropwise over 5 minutes, resulting in an orange reaction mixture. After stirring at 78 ºC for 30 minutes, iodomethane (44.2 ml, 714 mmol, 2.0 equiv) was added dropwise to the reaction mixture over 5 minutes, resulting in a pale-yellow solution. nce the reaction mixture had stirred at 78 ºC for 10 minutes, the reaction vessel was transferred to a room temperature water bath and allowed to stir for 1 hour. To the reaction mixture was added sat. aq. 4 Cl (700 ml), and the layers were separated. The aqueous layer was extracted with Et 2 (3 x 500 ml). The combined organic extracts were washed with brine (700 ml), dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation to provide a crude orange oil. Purification by flash column chromatography on silica gel (5% Et 2 /hexanes to 20% Et 2 /hexanes) afforded the title compound (39.0 g, 71%) as a colorless oil. The spectral data collected matched those previously reported. 12 SI54

55 β-stannyl enone (5a) via β-ethoxy enone (SI-6): Et SI-6 Bu 3 Sn (1.2 equiv) LDA (1.1 equiv) ºC (41%) Bu 3 Sn To a flame-dried 3-L three-necked round-bottomed flask equipped with a magnetic stir bar and a dropping funnel, was added TF (630 ml, 0.5 M) and diisopropylamine (54 ml, 381 mmol, 1.2 equiv). The reaction mixture was cooled to 0 ºC by transferring the reaction apparatus to an ice-water bath. The reaction mixture was allowed to stir for 10 minutes at 0 ºC, before n- BuLi (144 ml, 350 mmol, 1.1 equiv, 2.5 M in hexanes) was added via a dropping funnel to the stirred reaction mixture over 10 minutes. After stirring for 25 minutes at 0 ºC, Bu 3 Sn (101 ml, 381 mmol, 1.2 equiv) was added dropwise over 25 minutes at 0 ºC, resulting in a yellow reaction mixture. nce the reaction mixture had stirred for an additional 10 minutes at 0 ºC, the reaction apparatus was transferred to a 78 ºC saturated dry-ice acetone bath, and the reaction mixture was allowed to stir for another 10 minutes at 78 ºC. To the reaction mixture was added a solution of ethoxy-enone SI-6 (49.0 g, 318 mmol, 1.0 equiv) in TF (50 ml, 6.4 M) dropwise over 5 minutes, which resulted in a red reaction mixture. After stirring at 78 ºC for 30 minutes, the dry-ice acetone bath was replaced with a room temperature water bath, and the reaction mixture was allowed to stir at room temperature for 2 hours. To the reaction mixture was added sat. aq. 4 Cl (1 L) and Et 2 (500 ml). The layers were separated, and the aqueous layer was extracted with Et 2 (3 x 500 ml). The combined organic extracts were washed with brine (500 ml), dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation to provide a crude yellow oil. Purification by flash column chromatography on silica gel (100% hexanes to 10% Et 2 /hexanes) afforded the title compound (52.3 g, 41%) as a colorless oil. 5a R f : 0.19 (5% Et 2 /hexanes, p-anisaldehyde) 1 MR (500 Mz, CDCl 3 ): δ 6.19 (at, J -Sn = 30.0 z, 1), (m, 2), (m, 1), 2.04 (addt, J = 13.5, 9.0, 4.5 z, 1), 1.72 (dddd, J = 13.0, 11.5, 10.0, 5.0 z, 1), (m, 6), 1.31 (asept., J = 8.0 z, 6), 1.13 (d, J = 8.0 z, 3), (m, 6), 0.89 (t, J = 8.0 z, 9) 13 C MR (126 Mz, CDCl 3 ): δ 200.0, 173.6, 138.5, 41.8, 32.8, 32.1, 29.2, 27.4, 15.4, 13.8, 9.5 IR (cm -1 ): 2956, 2923, 2871, 1673, 1458, 1375, 1194, 875, 664, 595, 500, 439 ESI-RMS (m/z): [M+] + calc d for C Sn + : ; found: SI55

56 Bu 3 Sn 5a SI56

57 Bu 3 Sn 5a SI57

58 Synthesis of Alcohol 21: Bu 3 Sn To a flame-dried 500-mL three-necked round-bottomed flask equipped with a magnetic stir bar and a dropping funnel, was added TF (240 ml, 0.5 M) and diisopropylamine (19.8 ml, 141 mmol, 1.2 equiv). The reaction mixture was cooled to 0 ºC by transferring the reaction apparatus to an ice-water bath. The reaction mixture was allowed to stir for 10 minutes at 0 ºC before n-buli (54 ml, 130 mmol, 1.1 equiv, 2.5 M in hexanes) was added via a dropping funnel to the stirred reaction mixture over 10 minutes. After stirring for 25 minutes at 0 ºC, the reaction vessel was transferred to a 78 ºC saturated dry-ice acetone bath and stirred for 10 minutes before the dropwise addition of β- stannyl enone 5a (47.0 g, 118 mmol, 1.0 equiv) over 5 minutes, resulting in a pale-yellow reaction mixture. The reaction mixture was stirred for 30 minutes at 78 ºC, before 3- furaldehyde (12.2 ml, 141 mmol, 1.2 equiv), freshly distilled at 30 ºC (200 mtorr) over 7% (w/v) a 2 C 3, was added dropwise over 5 minutes. After stirring at 78 ºC for 30 minutes, sat. aq. 4 Cl (100 ml) and Et 2 (100 ml) were added to the reaction mixture, and the reaction vessel was removed from the dry-ice acetone bath. After warming to room temperature, the layers were separated and the aqueous layer was extracted with Et 2 (3 x 250 ml). The combined organic extracts were washed with brine (500 ml), dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure by rotary evaporation to provide a crude yellow oil. Purification by flash column chromatography on silica gel (5% Et 2 /hexanes to 10% Et 2 /hexanes) afforded the title compound (63.4 g, 88%) as a colorless oil. R f : 0.10 (10% Et 2 /hexanes p-anisaldehyde) 5a 1 MR (500 Mz, CDCl 3 ): δ 7.37 (s, 1), 7.36 (s, 1), 6.37 (s, 1), 6.16 (at, J -Sn = 26.5 z, 1), 4.88 (s, 1), 4.68 (s, 1), (m, 2), (m, 1), (m, 7), 1.30 (asept., J = 7.3 z, 6), 1.16 (s, 3), 0.99 (dd, J = 8.5, 8.5 z, 6), 0.88 (t, J = 7.0 z, 9) 13 C MR (126 Mz, CDCl 3 ): δ 204.1, 176.0, 142.6, 140.7, 137.1, 123.9, 110.4, 71.7, 47.1, 32.2, 30.2, 29.1, 27.4, 14.6, 13.8, 9.5 IR (cm -1 ): 3456, 2956, 2925, 2871, 1645, 1501, 1420, 1206, 1072, 1048, 957, 874, 601, 537, 507, 415 ESI-RMS (m/z): [M+] + calc d for C Sn + : ; found: C 14 LDA (1.1 equiv), TF -78 ºC, 30 min (88%) Bu 3 Sn (±)-21 SI58