SUPPLEMENTARY INFORMATION

Transcription

1 DOI: /NCHEM.2141 Catalytic, Stereospecific Syn-Dichlorination of Alkenes Alexander J. Cresswell, Stanley T.-C. Eey and Scott E. Denmark* Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, Illinois TABLE OF CONTENTS General Experimental Literature Preparations Preparation of Reagents Preparation of Alkenes Experimental Procedures Preparation of Alkenes Preparation of Diaryl Diselenides General Procedure I: Reaction Development with Cyclohexene (Table 1) General Procedure II: Survey of Lewis Base Additives with (E)-1-Benzyloxyl-4- hexene (17) (Table 2) General Procedure III: Survey of Diaryl Diselenides with (E)-1-Benzyloxyl-4- hexene (17) (Table 2) Table S1. Preliminary Survey of Reaction Generality General Procedure IV: Preliminary Survey of Reaction Generality (Table S1) General Procedure V: Control Experiments with (E)-1-Benzyloxyl-4-hexene (17) General Procedure VI: NMR Spectroscopic Studies on Catalytic, syn-dichlorination of Volatile Alkenes General Procedure VII: Catalytic, syn-dichlorination of Alkenes with 2,6-Lutidine N-Oxide as Additive (Table 3) General Procedure VIII: Catalytic, syn-dichlorination of Allylic Alcohols (Table 3) Determination of Relative Configurations Within Dichlorides (Table 3) PAGE S3 S6 S6 S6 S30 S33 S39 S45 S48 S49 S62 S64 S67 S101 S109 NATURE CHEMISTRY 1

2 General Procedure IX: anti-selective Dichlorination of Alkenes with Cl 2 Determination of Configurations Within Vinylic Chlorides (Figure 2) Table of Problematic Substrates References NMR Spectra S111 S117 S122 S124 S128 NATURE CHEMISTRY 2

3 General Experimental Reaction Setup: All reactions were performed in oven (160 C) and/or flamed-dried glassware under an atmosphere of dry argon, unless otherwise indicated. All reported reaction temperatures correspond to internal temperatures measured with a Teflon coated thermocouple. Room temperature (rt) was approximately 23 C. Brine refers to a saturated solution of sodium chloride in H 2 O. NMR Spectroscopy: 1 H and 13 C{ 1 H} NMR spectra were recorded on Varian Unity Inova 400 (400 MHz, 1 H; 100 MHz, 13 C) or 500 (500 MHz, 1 H; 126 MHz, 13 C) MHz spectrometers. Acquisition times were s for 1 H NMR, and s for 13 C NMR. Variable temperature (VT) NMR experiments were performed on a Varian Unity Inova 500 MHz spectrometer equipped with an external FTS cooling unit (set at 0 C) for temperature control. Spectra are referenced to residual chloroform (δ = 7.26 ppm, 1 H; ppm, 13 C) or residual acetonitrile (δ = 1.94 ppm, 1 H; 1.32 ppm, 13 C). Chemical shifts are reported in parts per million (ppm). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), pent (pentet), and m (multiplet). Coupling constants, J, are reported in Hertz. Integration is provided and assignments are indicated. 1 H and 13 C assignments are corroborated through 2-D NMR experiments (COSY, HSQC, HMBC). 1-D NOESY experiments were also used to assign relative configuration in certain cases. Infrared Spectroscopy: Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR system on NaCl plates. Peaks are reported in cm 1 with indicated relative intensities: s (strong, 0 33% T); m (medium, 34 66% T), w (weak, % T), and br (broad). Mass Spectrometry: Mass spectrometry (MS) was performed by the University of Illinois Mass Spectrometry Laboratory. Electron Impact (EI + ) spectra were performed at 70 ev using methane as the carrier gas, with either a double focusing sector field (DFSF) or time-of-flight (TOF) mass analyzer. Chemical Ionization (CI + ) spectra were performed with methane reagent gas, with either a double focusing sector field (DFSF) or time-of-flight (TOF) mass analyzer. Electrospray Ionization (ESI + ) spectra were performed using a time-of-flight (TOF) mass analyzer. Data are reported in the form of m/z (intensity relative to the base peak = 100). Melting Points: Melting points (mp) were determined on a Thomas-Hoover capillary melting point apparatus in vacuum-sealed capillary tubes and are corrected. Elemental Analysis: Elemental analysis was performed by the University of Illinois NATURE CHEMISTRY 3

4 Microanalysis Laboratory or Robertson Microlit Laboratories (1705 U.S. Highway 46, Suite 1D, Ledgewood, New Jersey 07852, U.S.A.). Reported data is the average of at least 2 runs. Distillation: Bulb-to-bulb distillation was performed on a Kugelrohr, with boiling points (bp) corresponding to uncorrected air-bath temperatures (ABT). A vacuum of 10 5 mm Hg was achieved using a BOC Edwards SI100 diffusion pump. Chromatography: Analytical thin-layer chromatography was performed on Merck silica gel 60 F 254 or Merck silica gel 60 RP-18 F 254s plates. Visualization was accomplished with UV light and/or potassium permanganate (KMnO 4 ) solution or ceric ammonium molybdate (CAM) solution. Retention factor (R f ) values reported were measured using a 10 2 cm TLC plate in a developing chamber containing the solvent system (10 ml) described. Flash column chromatography was performed using Silicycle SiliaFlash P60 (40-63 µm particle size, mesh) (SiO 2 ) or Woelm s high porosity grade silica. Unless otherwise specified, SiO 2 refers to P60 grade silica gel. Automated flash column chromatography was performed on a Teledyne Isco CombiFlash Rf 200 using pre-packed silica gel columns. Solvents: Reaction solvents tetrahydrofuran (THF) (Fisher, HPLC grade), ether (Et 2 O) (Fisher, BHT stabilized ACS grade), and dichloromethane (CH 2 Cl 2 ) (Fisher, unstabilized HPLC grade) were dried by percolation through two columns packed with neutral alumina under a positive pressure of argon. Reaction solvent toluene (ACS grade) was dried by percolation through a column packed with neutral alumina and a column packed with Q5 reactant (supported copper catalyst for scavenging oxygen) under a positive pressure of argon. Reaction solvent dimethylformamide (DMF) (Fischer, ACS grade) was dried by percolation through two columns of activated molecular sieves. Reaction solvent acetonitrile (CH 3 CN) (ACS grade, amylene stabilized) was distilled from CaH 2 prior to use. Reaction solvent ethanol (absolute, Decon Laboratories) was used as received. Solvents for filtration, transfers, chromatography, and recrystallization were benzene (PhH) (Fisher, ACS grade), dichloromethane (CH 2 Cl 2 ) (ACS grade, amylene stabilized), ether (Et 2 O) (Fisher, BHT stabilized ACS grade), ethyl acetate (EtOAc) (Fisher, ACS grade), hexane (Optima), methyl tert-butyl ether (MTBE) (ACS grade), methanol (MeOH) (ACS grade), pentane (ACS grade), and petroleum ether (35 60 C, ACS grade). Chemicals: Cyclohexene (Aldrich) and cycloheptene (Aldrich) were distilled prior to use. (Z)-4-Hexen-1-ol (Alfa), benzyl bromide (Eastman), chlorotrimethylsilane (Aldrich), 1,1,2,2- NATURE CHEMISTRY 4

5 tetrachloroethane, and triethylamine (Aldrich) were distilled from CaH 2 prior to use. Sulfolane (Aldrich) was distilled from 4Å molecular sieves (powder) prior to use. Dimethyl sulfoxide (DMSO) (Fischer) was dried over 4Å molecular sieves (pellets) prior to use. N-Fluoropyridinium tetrafluoroborate (11) (TCI), 3-buten-1-ol (Aldrich), 4-N,N -dimethylaminopyridine (DMAP) (Aldrich), acetic anhydride (Fisher), benzyltriethylammonium chloride (Oakwood), diphenyl diselenide (TCI), bis(2-nitrophenyl) diselenide (Acros), selenium powder (Aldrich), imidazole (Aldrich), (E)-4-octene (GFS Organic), tri-iso-propylsilyl chloride (TIPSCl) (Gelest), tertbutyldiphenylsilyl chloride (TBDPSCl) (Gelest), m-chloroperbenzoic acid (m-cpba) (Acros), cyclopropanecarboxylic acid (Aldrich), N,N -dicyclohexylcarbodiimide (DCC) (Alfa), 1,1 - carbonyldiimidazole (CDI) (Aldrich), benzylmagnesium chloride (Aldrich), N,Odimethylhydroxylamine hydrochloride (Alfa), ethylene glycol (Aldrich), p-toluenesulfonic acid (PTSA) monohydrate (Aldrich), oxalyl chloride (Alfa), benzylamine (TCI), sodium hydride (Aldrich), di-tert-butyl dicarbonate (Boc 2 O) (Alfa), potassium phthalimide (Aldrich), Red-Al (Aldrich), 4-bromoanisole (Aldrich), 2-bromoanisole (Alfa), tert-butyllithium (Aldrich), N- chlorosuccinimide (NCS) (Aldrich), and triphenylphosphine (Aldrich) were used as received. NATURE CHEMISTRY 5

6 Literature Preparations Preparation of Reagents The following compounds were prepared according to literature procedures: 2,6-lutidine N-oxide (23), 1 and bis[3,5-bis(trifluoromethyl)phenyl] diselenide (24). 2,3,4 Preparation of Alkenes The following compounds were prepared according to literature procedures: (E)-4-hexen- 1-ol, 5 ethyl (E)-4-hexenoate (28k), 5 3-cyclopenten-1-ylmethanol, 6 (E)-7-phenylhept-4-en-1-ol, 7 4-(but-3-en-1-yl)-2,2-dimethyl-1,3-dioxolane (28e), 8 (E)-[(hex-4-en-1-yloxy)methyl]benzene (17), 5 (E)-5-phenylpent-2-en-1-ol (28u), 9 (Z)-5-phenylpent-2-en-1-ol (28v), 10 (Z)-4- (benzyloxy)but-2-en-1-ol (28x), 11 and (Z)-6-iodo-2-hexene. 12 Experimental Procedures Preparation of Alkenes Preparation of Cyclopent-3-en-1-ylmethyl acetate (28b) A 100-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with 4-N,N-dimethylaminopyridine (61.7 mg, 0.50 mmol, 10 mol %) and 3-cyclopenten-1-ylmethanol (491 mg, 5.00 mmol, 1.0 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (25 ml) and triethylamine (1.01 g, 1.39 ml, 10.0 mmol, 2.0 equiv) were then added sequentially and stirring was commenced. The mixture was cooled in an ice-water bath and acetic anhydride (1.02 g, 945 µl, 10.0 mmol, 2.0 equiv) was added dropwise via syringe over ca. 1 min, then the resultant mixture was allowed to warm to rt over 2 h. The reaction mixture was then transferred to a separatory funnel and brine (10 ml) and H 2 O (10 ml) were added. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (2 10 NATURE CHEMISTRY 6

7 ml). The combined organic extracts were washed sequentially with sat. aq. NaHCO 3 (40 ml) and sat. aq. CuSO 4 (40 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (45 C, 120 mm Hg) to give a colorless oil (1.03 g). Purification via flash column chromatography (40 g SiO 2, 30 mm Ø, wet loaded, 97:3 hexane/mtbe, ca. 5 ml fractions) gave a colorless oil (750 mg). Further purification via Kugelrohr distillation at reduced pressure (20 mm Hg) gave 28b as a clear, colorless oil (488 mg, 70%). Data for 28b: bp: 80 C (ABT) (20 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) (m, 2 H, HC(1,5)), 3.97 (d, J = 7.3 Hz, 2 H, C(3)CH 2 OAc), (m, 1 H, HC(3)), (m, 2 H, HC(2,4)), (m, 5 H, HC(2,4), COMe) 13 C NMR: (126 MHz, CDCl 3 ) (COMe), (C(1,5)), 68.1 (C(3)CH 2 OAc), 35.8 (C(3)), 35.6 (C(2,4)), 20.9 (COMe) IR: (neat) 3056 (w), 2937 (m), 2850 (m), 1743 (s), 1616 (w), 1467 (w), 1443 (m), 1385 (m), 1365 (m), 1237 (s), 1079 (w), 1036 (m), 978 (w), 952 (w), 905 (w), 828 (w), 773 (w), 679 (m), 632 (w), 773 (w), 679 (m), 632 (w), 605 (w) MS: (CI +, DFSF) ([M+H] +, 0.6), 81.1 ([M OAc] +, 100) TLC: R f 0.13 (95:5 hexane/mtbe) [KMnO 4 ] HRMS: (CI +, DFSF) calcd for C 8 H 13 O 2 ([M+H] + ): , found: NATURE CHEMISTRY 7

8 Preparation of tert-butyl(cyclopent-3-en-1-ylmethoxy)diphenylsilane (28c) A flame-dried, 50-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with 3-cyclopenten-1-ylmethanol (491 mg, 5.00 mmol, 1.0 equiv) and imidazole (518 mg, 7.61 mmol, 1.5 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (12.5 ml) was then added and stirring was commenced. tert- Butyldiphenylsilyl chloride (1.51 g, 1.43 ml, 5.50 mmol, 1.1 equiv) was added dropwise via syringe and the resultant cloudy mixture was stirred under argon at rt for 16 h. The reaction mixture was quenched with H 2 O (20 ml), diluted with CH 2 Cl 2 (10 ml), then was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2 20 ml) and the combined organic extracts were washed with brine (20 ml), dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a colourless oil. Purification via flash column chromatography [72 g high porosity grade SiO 2, 34 mm Ø, wet loaded, petroleum ether (900 ml), ca. 20 ml fractions] gave 28c as a clear, colorless oil (1.61 g, 96%). The 1 H and 13 C NMR spectroscopic data matched that for alternative preparations. 13 Data for 28c: 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 4 H, HC(2,2 )), (m, 6 H, HC(3,3,4,4 )), (m, 2 H, HC(3,4)), 3.59 (d, J = 7.1 Hz, 2 H, HC(6)), (m, 1 H, HC(1)), (m, 2 H, HC(2,5)), (m, 2 H, HC(2,5)), 1.07 (s, 9 H, Sit-Bu) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(2,2 )), (C(1,1 )), (C(4,4 )), (C(3,4)), (C(3,3 )), 67.7 (C(6)), 39.4 (C(1)), 35.5 (C(2,5)), 26.9 (SiCMe 3 ), 19.3 (SiCMe 3 ) NATURE CHEMISTRY 8

9 Preparation of (But-3-en-1-yloxy)(tert-butyl)diphenylsilane (28d) A 25-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with imidazole (309 mg, 4.50 mmol, 1.5 equiv) and 3-buten-1-ol (225 mg, 3.00 mmol, 1.0 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (6.0 ml) was then added and stirring was commenced. tert-butyldiphenylsilyl chloride (922 mg, 872 µl, 3.30 mmol, 1.1 equiv) was added via syringe in one portion and the resultant mixture was stirred under argon at rt for 22 h. The reaction mixture was then transferred to a separatory funnel and diluted with CH 2 Cl 2 (25 ml), washed sequentially with H 2 O (10 ml) and brine (10 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (45 C, ca. 5 mm Hg) to give a colorless oil (1.14 g). Purification via flash column chromatography (40 g SiO 2, 30 mm Ø, wet loaded, 98:2 hexane/mtbe, ca. 5 ml fractions) gave a colorless oil (975 mg). Further purification via Kugelrohr distillation at reduced pressure (10 5 mm Hg) gave 28d as a clear, colorless oil (931 mg, quant). The 1 H and 13 C NMR spectroscopic data matched that for alternative preparations. 14 Data for 28d: bp: 125 C (ABT) (10 5 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 4 H, HC(4,4 )), (m, 6 H, HC(3,3,4,4 )), 5.87 (ddt, J = 17.1, 10.2, 6.9 Hz, 1 H, HC(3)), (m, 2 H, HC(4)), 3.75 (t, J = 6.7 Hz, 2 H, HC(1)), 2.36 (qt, J = 6.7, 1.3 Hz, 2 H, HC(2)), 1.09 (s, 9 H, Sit-Bu) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(2,2 )), (C(3)), (C(1,1 )), (C(4,4 )), (C(3,3 )), (C(4)), 63.5 (C(1)), 37.2 (C(2)), 26.8 (SiCMe 3 ), 19.2 (SiCMe 3 ) NATURE CHEMISTRY 9

10 Preparation of (Z)-[(Hex-4-en-1-yloxy)methyl]benzene (28h) A flame-dried, 25-mL, Schlenk flask equipped with a magnetic stirrer bar and waterjacketed reflux condensor was charged sequentially with (Z)-4-hexen-1-ol (620 mg, 723 µl, 6.00 mmol, 1.0 equiv) and THF (10 ml). The solution was cooled in an ice-water bath and NaH (washed, 158 mg, 6.60 mmol, 1.1 equiv) was added against a backflow of argon, and the resultant mixture was stirred in the ice-water bath for 15 min. Benzyl bromide (1.13 g, 785 µl, 6.60 mmol, 1.1 equiv) was then added via syringe in one portion and the resultant mixture was stirred at reflux for 14 h. After being allowed to cool to rt, the reaction was quenched by addition of sat. aq. NH 4 Cl (2.0 ml). H 2 O (20 ml) and EtOAc (20 ml) were then added and the layers were separated. The aqueous layer was extracted with EtOAc (2 20 ml) and the combined organic extracts were washed with brine (30 ml) then dried (MgSO 4 ), filtered, and concentrated in vacuo (45 C, ca. 5 mm Hg) to give a colorless oil (733 mg). Purification via flash column chromatography (40 g SiO 2, 30 mm Ø, wet loaded, 98:2 hexane/mtbe, ca. 5 ml fractions) gave a clear, colorless oil (1.13 g). Further purification via Kugelrohr distillation at reduced pressure (0.01 mm Hg) gave 28h as a clear, colorless oil (1.06 g, 93%, >99:1 dr, contaminated with 2% regioisomeric terminal alkene impurity). The 1 H and 13 C NMR spectroscopic data matched that for alternative preparations. 15 Data for 28h: bp: 100 C (ABT) (0.01 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 4 H, HC(2,3 )), (m, 1 H, HC(4 )), (m, 1 H, HC(5)), (m, 1 H, HC(4)), 4.52 (s, 2 H, HC(5 )), 3.49 (t, J = 6.5 Hz, 2 H, HC(1)), 2.15 (app q, J = 7.4 Hz, 2 H, HC(3)), (m, 2 H, HC(2)), 1.62 (ddt, J = 6.7, 1.9, 0.9 Hz, 3 H, HC(6)) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(1 )), (C(4)), (C(3 )), (C(2 )), (C(4 )), (C(5)), 72.9 (C(5 )), 69.8 (C(1)), 29.5 (C(2)), 23.4 (C(3)), 12.7 (C(6)) NATURE CHEMISTRY 10

11 Preparation of (E)-tert-Butyl(hex-4-en-1-yloxy)diphenylsilane (13) A 25-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with imidazole (309 mg, 4.50 mmol, 1.5 equiv) and (E)-4-hexen-1-ol (300 mg, 353 µl, 3.00 mmol, 1.0 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (6.0 ml) was then added and stirring was commenced. tert-butyldiphenylsilyl chloride (922 mg, 872 µl, 3.30 mmol, 1.1 equiv) was added via syringe in one portion and the resultant mixture was stirred under argon at rt for 18.5 h. The reaction mixture was then transferred to a separatory funnel and diluted with CH 2 Cl 2 (25 ml), washed sequentially with H 2 O (10 ml) and brine (10 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (45 C, ca. 5 mm Hg) to give a colorless oil (1.15 g). Purification via flash column chromatography (40 g SiO 2, 30 mm Ø, 99:1 hexane/mtbe, ca. 5 ml fractions) gave a colorless oil (1.00 g). Further purification via Kugelrohr distillation at reduced pressure (10 5 mm Hg) gave 13 as a clear, colorless oil (985 mg, 97%, >99:1 dr). Data for 13: bp: 125 C (ABT) (10 5 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) (m, 4 H, HC(2,2 )), (m, 6 H, HC(3,3,4,4 ), (m, 2 H, HC(4,5)), 3.67 (t, J = 6.4 Hz, 2 H, HC(1)), (m, 2 H, HC(3)), (m, 5 H, HC(2,6)), 1.06 (s, 9 H, Sit-Bu) 13 C NMR: (125 MHz, CDCl 3 ) IR: (C(2,2 )), (C(1,1 )), (C(4)), (C(4,4 )), (C(3,3 )), (C(5)), 63.3 (C(1)), 32.4 (C(2)), 28.8 (C(3)), 26.8 (SiCMe 3 ), 19.2 (SiCMe 3 ), 17.9 (C(6)) (neat) 3134 (w), 3070 (m), 3049 (m), 3016 (m), 2998 (w), 2931 (s), 2857 (s), 2736 (w), 1958 (w), 1888 (w), 1823 (w), 1654 (w), 1589 (w), 1486 (w), 1472 (m), 1462 (w), 1448 (w), 1427 (m), 1389 (w), 1361 (w), 1305 (w), 1260 (w), 1225 (w), 1188 (w), NATURE CHEMISTRY 11

12 1111 (s), 1042 (w), 1007 (w), 998 (w), 964 (m), 939 (w), 911 (w), 823 (m), 739 (m), 701 (s), 687 (m), 613 (m) MS: (CI +, DFSF) ([M+H] +, 4), (24), ([M t-bu] +, 100), (14), (16), ([M Ph] +, 72), (27), (12), (14), (10), (15), (10), 91.1 (23), 83.1 (22), 59.1 (33) TLC: R f 0.49 (95:5 hexane/mtbe) [KMnO 4 ] HRMS: (CI +, DFSF) calcd for C 22 H 31 OSi ([M+H] + ): , found: Preparation of (Z)-tert-Butyl(hex-4-en-1-yloxy)diphenylsilane (28i) A 25-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with imidazole (309 mg, 4.50 mmol, 1.5 equiv) and (Z)-4-hexen-1-ol (310 mg, 361 µl, 3.00 mmol, 1.0 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (6.0 ml) was then added and stirring was commenced. tert-butyldiphenylsilyl chloride (922 mg, 872 µl, 3.30 mmol, 1.1 equiv) was added via syringe in one portion and the resultant mixture was stirred under argon at rt for 18.5 h. The reaction mixture was then transferred to a separatory funnel and diluted with CH 2 Cl 2 (25 ml), washed sequentially with H 2 O (10 ml) and brine (10 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (45 C, ca. 5 mm Hg) to give a colorless oil (1.19 g). Purification via flash column chromatography (40 g SiO 2, 30 mm Ø, wet loaded, 99:1 hexane/mtbe, ca. 5 ml fractions) gave a colorless oil (1.06 g). Further purification via Kugelrohr distillation at reduced pressure (10 5 mm Hg) gave 28i as a clear, colorless oil (1.02 g, quant, >99:1 dr). Data for 28i: bp: 125 C (ABT) (10 5 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) (m, 4 H, HC(2,2 )), (m, 6 H, HC(3,4 )), (m, 2 H, NATURE CHEMISTRY 12

13 HC(4,5)), 3.71 (t, J = 6.4 Hz, 2 H, HC(1)), 2.17 (q, J = 7.3 Hz, 2 H, HC(3)), (m, 5 H, HC(2,6)), 1.09 (s, 9 H, Sit-Bu) 13 C NMR: (125 MHz, CDCl 3 ) (C(2,2 )), (C(1,1 )), (C(4)), (C(4,4 )), (C(3,3 )), (C(5)), 63.4 (C(1)), 32.4 (C(2)), 26.8 (SiCMe 3 ), 23.1 (C(3)), 19.2 (SiCMe 3 ), 12.7 (C(6)) IR: (neat) 3135 (w), 3070 (m), 3049 (w), 3013 (m), 2931 (s), 2858 (s), 2739 (w), 1957 (w), 1886 (w), 1824 (w), 1655 (w), 1589 (w), 1486 (w), 1472 (m), 1462 (w), 1446 (w), 1403 (w), 1389 (w), 1361 (w), 1305 (w), 1259 (w), 1222 (w), 1189 (w), 1111 (s), 1043 (w), 1006 (w), 998 (w), 960 (w), 940 (w), 823 (m), 739 (m), 701 (s), 688 (m), 613 (m) MS: (CI +, DFSF) ([M+H] +, 5), (23), ([M t-bu] +, 100), (17), ([M Ph] +, 80), (12), (15), 83.1 (30) TLC: R f 0.50 (95:5 hexane/mtbe) [KMnO 4 ] HRMS: (FAB +, DFSF) calcd for C 22 H 31 OSi ([M+H] + ): , found: Preparation of (E)-Tri-iso-propyl[(7-phenylhept-4-en-1-yl)oxy]silane (28j) A flame-dried, 50-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with (E)-7-phenylhept-4-en-1-ol (951 mg, 5.00 mmol, 1.0 equiv) and imidazole (515 mg, 7.56 mmol, 1.5 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (12.5 ml) was then added and stirring was commenced. Tri-iso-propylsilyl chloride (1.08 g, 1.20 ml, 5.61 mmol, 1.1 equiv) was added dropwise via syringe and the resultant mixture was stirred under argon at rt for 16 h. The reaction mixture was quenched with H 2 O (20 ml), diluted with CH 2 Cl 2 (10 ml), then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2 20 ml) and the combined NATURE CHEMISTRY 13

14 organic extracts were washed with brine (20 ml), dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a pale yellow oil. Purification via flash column chromatography [71 g high porosity grade SiO 2, 34 mm Ø, wet loaded, 100:0 98:2 hexane/etoac (200 and 900 ml, respectively), ca. 20 ml fractions] gave 28j as a clear, colorless oil (1.69 g, 98%, >99:1 dr). An analytically pure sample was obtained by further purification of 28j (219 mg) via flash column chromatography [27 g SiO 2, 24 mm Ø, wet loaded with hexane, 98:2 hexane/etoac (400 ml), ca. 10 ml fractions], followed by Kugelrohr distillation at reduced pressure (0.05 mm Hg), to give 28j as a clear, colorless oil (214 mg, 98% mass return). Data for 28j: bp: 158 C (ABT) (0.05 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 2 H, HC(2 )), (m, 3 H, HC(3,4 )), (m, 2 H, HC(4,5)), 3.67 (t, J = 6.5 Hz, 2 H, HC(1)), (m, 2 H, HC(7)), (m, 2 H, HC(6)), 2.06 (q, J = 7.0, 6.3 Hz, 2 H, HC(3)), 1.59 (app pent, J = 6.6 Hz, 2 H, HC(2)), (m, 21 H, Sii-Pr 3 ) 13 C NMR: (126 MHz, CDCl 3 ) IR: MS: HRMS: δ (C(1 )), & (C(4,5)), (C(2 )), (C(3 )), (C(4 )), 62.8 (C(1)), 36.1 (C(7)), 34.5 (C(6)), 32.8 (C(2)), 28.8 (C(3)), 18.0 (SiCH(CH 3 ) 2 ), 12.0 (SiCH(CH 3 ) 2 ) (neat) 3086 (w), 3063 (w), 3028 (w), 2941 (s), 2893 (m), 2865 (s), 2726 (w), 1605 (w), 1497 (w), 1463 (m), 1455 (w), 1383 (w), 1366 (w), 1247 (w), 1108 (m), 1070 (w), 1031 (w), 1013 (w), 996 (w), 967 (m), 919 (w), 883 (w), 785 (w), 744 (w), 698 (m), 681 (m), 659 (w) (ESI +, TOF) (14), (32), (75), ([M+H] +, 4), (11), (34), (100), (21), (12), (29), (53), (91), (21), (17) (ESI +, TOF) calcd for C 22 H 39 OSi ([M+H] + ): , found: NATURE CHEMISTRY 14

15 TLC: R f 0.56 (99:1 hexane/mtbe) [UV/KMnO 4 ] Analysis: C 22 H 38 OSi (346.63) Calcd: C, 76.23; H, 11.05% Found: C, 76.38; H, 11.22% Preparation of (E)-Hex-4-en-1-yl cyclopropanecarboxylate (28l) A flame-dried, 50-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with 4-N,N-dimethylaminopyridine (74 mg, 0.61 mmol, 10 mol %) then was sealed with a rubber septum and purged with argon via an inlet needle. Et 2 O (6 ml), cyclopropanecarboxylic acid (519 mg, 0.48 ml, 6.03 mmol, 1.0 equiv), and (E)-4-hexen-1-ol (639 mg, 0.75 ml, 6.37 mmol, 1.05 equiv) were sequentially added via syringe. The mixture was then cooled in an icewater bath and stirring was commenced. N,N -Dicyclohexylcarbodiimide (1.36 g, 6.60 mmol, 1.1 equiv) was added in one portion against a backflow of argon and the resultant mixture was stirred in the ice-water bath and allowed to gradually warm to rt over 18 h to give a thick, white slurry. The reaction mixture was filtered through a pad of Celite (10 g, 35 mm) under house vacuum to remove the urea by-product, which was rinsed with Et 2 O (50 ml). The filtrate was concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a pale yellow oil. Caution: the product is volatile and should not be left on the rotary evaporator for an extended period. Purification via flash column chromatography [90 g SiO 2, 42 mm Ø, wet loaded with hexane, 96:4 hexane/etoac (1 L), ca. 20 ml fractions] gave a clear, pale yellow oil (1.03 g). Further purification via Kugelrohr distillation at reduced pressure (10 mm Hg) gave 28l as a clear, colorless oil (994 mg, 98%, >99:1 dr). Data for 28l: bp: 81 C (ABT) (10 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 2 H, HC(4,5)), 4.06 (t, J = 6.7 Hz, 2 H, HC(1)), 2.05 (dt, J = 7.5, 6.7 Hz, 2 H, HC(3)), (m, 5 H, HC(2,6)), 1.59 (ddd, J = 12.7, 8.1, 4.6 Hz, NATURE CHEMISTRY 15

16 1 H, HC(8)), (m, 2 H, HC(9,10)), (m, 2 H, HC(9,10)) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(7)), & (C(4,5)), 64.0 (C(1)), 28.8 (C(3)), 28.5 (C(2)), 17.9 (C(6)), 12.9 (C(8)), 8.3 (C(9,10)) IR: (neat) 3387 (w), 3021 (w), 2938 (w), 2853 (w), 1729 (m), 1451 (w), 1403 (w), 1372 (w), 1266 (w), 1172 (m), 1135 (s), 1106 (m), 996 (w), 967 (w), 914 (w), 615 (m) MS: (CI +, DFSF) ([M+H] +, 2), (11), 83.1 (39), 82.1 (26), 69.0 (22), 67.0 (16), 65.0 (32), 63.0 (100), 62.0 (25), 61.0 (13), 59.0 (57) HRMS: (EI +, DFSF) calcd for C 10 H 17 O 2 ([M+H] + ): , found: TLC: R f 0.45 (96:4 hexane/etoac) [KMnO 4 ] Preparation of (E)-2-Benzyl-2-(pent-3-en-1-yl)-1,3-dioxolane (28m) Preparation of (E)-4-hexenoic acid (S1). An oven-dried, 50-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged sequentially with ethyl (E)-4-hexenoate (28k) (1.42 g, 10.0 mmol, 1.0 equiv), EtOH (6.0 ml), H 2 O (6.0 ml), and NaOH (2.31 g, 57.8 mmol, 5.8 equiv) then was fitted with a water-jacketed condenser (sealed with a rubber septum at the top) and purged with argon via an inlet needle. Stirring was commenced and the reaction mixture was refluxed at C (oil bath temperature) for 3 h, then was allowed to cool to rt. The reaction mixture was diluted with H 2 O (20 ml) and transferred to a separatory funnel, then extracted with Et 2 O (3 10 ml). The combined organic extracts were discarded and the aqueous NATURE CHEMISTRY 16

17 layer was then cooled in an ice-water bath, acidified with 2 M HCl to ph 2 (with stirring), transferred to a separatory funnel, and extracted with CH 2 Cl 2 (3 20 ml). The combined organic extracts were washed with H 2 O (20 ml) and brine (20 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a colorless oil. Purification via Kugelrohr distillation at reduced pressure (10 mm Hg) gave S1 as a clear, colorless oil (1.12 g, 98%, >99:1 dr). The 1 H NMR spectroscopic data matched that reported in the literature. 16 Data for S1: bp: 145 C (ABT) (10 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ (br s, 1 H, COOH), (m, 2 H, HC(4,5)), 2.41 (ddd, J = 7.9, 7.1, 1.0 Hz, 2 H, HC(2)), (m, 2 H, HC(3)), 1.64 (dq, J = 6.3, 1.3 Hz, 3 H, HC(6)) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(1)), (C(4)), (C(5)), 34.1 (C(2)), 27.5 (C(3)), 17.8 (C(6)) Preparation of (E)-N-Methoxy-N-methylhex-4-enamide (S2). A flame-dried, 50-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with (E)-4-hexenoic acid (S10) (572 mg, 5.01 mmol, 1.0 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (14 ml) was added and stirring was commenced. The mixture was cooled in an ice-water bath and 1,1 -carbonyldiimidazole (977 mg, 6.02 mmol, 1.2 equiv) was added in one portion against a backflow of argon, and the resultant mixture was stirred in the ice-water bath for 30 min. N,O-Dimethylhydroxylamine hydrochloride (1.22 g, 12.5 mmol, 2.5 equiv) was then added in one portion against a backflow of argon. The reaction flask was removed from the ice-water bath and the resultant mixture was allowed to warm to rt over 7 h. The reaction mixture was then filtered through a sintered funnel under house vacuum to remove the amine salt, which was rinsed with CH 2 Cl 2 (50 ml). The filtrate was transferred to a separatory funnel and the organic layer was washed sequentially with 2 M HCl (30 ml), 2 M NaOH (30 ml), and brine (30 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a colorless oil. Purification via Kugelrohr distillation at reduced pressure (130 C, 5 mm Hg) gave S2 as a clear, colorless oil (782 mg, 99%, >99:1 dr). The 1 H and 13 C NMR spectroscopic data matched that for alternative preparations. 17 NATURE CHEMISTRY 17

18 Data for S2: bp: 130 C (ABT) (5 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 2 H, HC(4,5)), 3.65 (s, 3 H, N(Me)OMe), 3.15 (s, 3 H, N(Me)OMe), 2.45 (t, J = 7.4 Hz, 2 H, HC(4)), (m, 2 H, HC(3)), (m, 3 H, HC(6)) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(1)), (C(4)), (C(5)), 61.1 (N(Me)OMe), 32.0 (N(Me)OMe)), 31.8 (C(2)), 27.4 (C(3)), 17.9 (C(6)) Preparation of (E)-1-Phenylhept-5-en-2-one (S3). A flame-dried, 50-mL, roundbottomed flask equipped with a magnetic stirrer bar was charged with (E)-N-methoxy-Nmethylhex-4-enamide (S2) (629 mg, 4.00 mmol, 1.0 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. THF (14 ml) was added and stirring was commenced. The mixture was cooled in an ice-water bath (bath temperature ca. 0 C) and benzylmagnesium chloride (2.0 M in THF, 4.2 ml, 8.40 mmol, 2.1 equiv) was slowly added via syringe under an argon atmosphere over 5 min. The resultant yellow-brown mixture was allowed to stir in the icewater bath and gradually warm to rt over 20 h, then was re-cooled in an ice-water bath and carefully quenched with 2 M HCl (20 ml). The mixture was transferred to a separatory funnel and the aqueous layer was extracted with Et 2 O (3 20 ml). The combined organic extracts were washed with brine (20 ml) then dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a yellow oil. Purification via flash column chromatography [37 g SiO 2, 30 mm Ø, dry loaded with 2 g SiO 2, 100:0 98:2 95:5 hexane/et 2 O (200 ml, 300 ml, and 300 ml, respectively), ca. 10 ml fractions], followed by further purification via flash column chromatography under the same conditions, gave S3 as a clear, pale yellow oil (455 mg, 60%, >99:1 dr). Caution: the product is volatile at ca mm Hg some material was lost as a result. Data for S3: 1 H NMR: (500 MHz, CDCl 3 ) δ , & (m, 5 H, HC(2,3,4 )), (m, 2 H, HC(5,6)), 3.68 (s, 2 H), 2.50 (t, J = 7.4 Hz, 2 H, HC(3)), (m, 2 H, HC(4)), NATURE CHEMISTRY 18

19 1.61 (dd, J = 6.0, 1.2 Hz, 3 H, HC(7)) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(2)), (C(1 )), (C(2 )), (C(5)), (C(3 )), (C(4 )), (C(6)), 50.2 (C(1)), 41.8 (C(3)), 26.7 (C(4)), 17.8 (C(7)) IR: (neat) 3063 (w), 3028 (m), 2959 (w), 2918 (m), 2855 (w), 1714 (s), 1603 (w), 1585 (w), 1496 (m), 1454 (m), 1408 (w), 1361 (w), 1315 (w), 1189 (w), 1113 (w), 1075 (w), 1031 (w), 967 (m), 732 (w), 699 (m) MS: (ESI +, TOF) (12), (34), ([M+Na] +, 29), (85), (12), (14), ([M+H] +, 100), (19), (21), (15), 91.1 ([CH 2 Ph] +, 45) HRMS: (ESI +, TOF) calcd for C 13 H 17 O ([M+H] + ): , found: TLC: R f 0.28 (96:4 hexane/etoac) [UV/KMnO 4 ] Preparation of (E)-2-Benzyl-2-(pent-3-en-1-yl)-1,3-dioxolane (28m). A flame-dried, 50-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with (E)-1- phenylhept-5-en-2-one (S3) (390 mg, 2.07 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (8.2 mg, 0.04 mmol, 2 mol %) then was sealed with a rubber septum and purged with argon via an inlet needle. Toluene (20 ml) and ethylene glycol (1.11 g, 1.0 ml, 17.9 mmol, 8.6 equiv) were added sequentially, then the rubber septum was replaced with a Dean-Stark trap fitted with a condenser (sealed at the top with a rubber septum), and the apparatus was purged with argon via an inlet needle. The resultant mixture was refluxed at C (oil bath temperature) for 24 h (N.B. ca. 0.9 ml H 2 O was collected in the receiver of the Dean-Stark trap at the end of the reaction). The reaction mixture was then allowed to cool to rt and was transferred to a separatory funnel and diluted with Et 2 O (20 ml). The organic phase was washed sequentially with sat. aq. NaHCO 3 (2 10 ml) and brine (10 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a pale yellow oil. Purification via flash column chromatography [26 g SiO 2, 24 mm Ø, dry loaded with 1.9 g SiO 2, 97:3 hexane/etoac (400 ml), ca. 10 ml fractions)], followed by further purification via flash column NATURE CHEMISTRY 19

20 chromatography under the same conditions, gave 28m as a clear, colourless oil (461 mg, 96%, >99:1 dr). An analytically pure sample was obtained by further purification of 28m (216 mg) via Kugelrohr distillation at reduced pressure (0.05 mm Hg) to give 28m as a clear, colourless oil (211 mg, 98% mass return). Data for 28m: bp: 100 C (ABT) (0.05 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ & (m, 5 H, HC(2,3,4 )), (m, 2 H, HC(5,6)), (m, 2 H, HC(8,9)), (m, 2 H, HC(8,9)), 2.89 (s, 2 H, HC(1)), (m, 2 H, HC(4)), (m, 2 H, HC(3)), (m, 3 H, HC(7)) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(1 )), (C(5)), (C(2 )), (C(3 )), (C(4 )), (C(6)), (C(2)), 65.3 (C(8,9)), 43.9 (C(1)), 37.8 (C(3)), 26.6 (C(4)), 17.9 (C(7)) IR: (neat) 3086 (w), 3063 (w), 3029 (m), 2953 (m), 2922 (m), 2884 (m), 2856 (m), 1605 (w), 1496 (m), 1475 (m), 1454 (w), 1377 (w), 1324 (w), 1258 (w), 1198 (m), 1124 (m), 1077 (m), 1048 (m), 967 (m), 950 (m), 851 (w), 751 (m), 700 (m), 671 (w), 640 (w), 617 (w) MS: (ESI +, TOF) (34), (24), (26), (13), ([M+H] +, 35), (11), (13), ([M (CH 2 CH 2 O)+H] +, 84), (18), (32), ([M (CH 3 CH=CHCH 2 CH 2 )] +, 59), ([M (CH 2 Ph)] +, 20), (20), (24), (30), 99.1 (12), 91.1 ([CH 2 Ph] +, 100) HRMS: (ESI +, TOF) calcd for C 15 H 21 O 2 ([M+H] + ): , found: TLC: R f 0.36 (96:4 hexane/etoac) [UV/KMnO 4 ] Analysis: C 15 H 20 O 2 (232.32) Calcd: C, 77.55; H, 8.68% Found: C, 77.97; H, 8.67% NATURE CHEMISTRY 20

21 Preparation of Methyl (2E,6E)-Octa-2,6-dienoate (28n) A flame-dried, 100-mL, round-bottomed flask equipped with a magnetic stirrer bar and rubber septum was purged with argon via an inlet needle then was charged sequentially with CH 2 Cl 2 (25 ml) and oxalyl chloride (1.14 g, 0.76 ml, 8.98 mmol, 1.5 equiv) via syringe, and stirring was commenced. The solution was cooled at 78 C in a dry ice-acetone bath under an argon atmosphere, then anhydrous DMSO (1.43 g, 1.3 ml, 18.3 mmol, 3.0 equiv) was added dropwise via syringe over 5 min, and the resultant mixture was allowed to stir at 78 C for a further 5 min. (E)-4-Hexen-1-ol (604 mg, 0.71 ml, 6.03 mmol, 1.0 equiv) was then added via cannula transfer over 10 min using two portions of CH 2 Cl 2 (4 ml and 2 ml), and the resultant white suspension was stirred at 78 C for 30 min. Triethylamine (3.66 g, 5.0 ml, 36.1 mmol, 6.0 equiv) was then added via syringe and the mixture was allowed to warm to 5 C with stirring over 2 h, then the dry ice-acetone bath was replaced with an ice-water bath. A solution of methyl(triphenylphosphoranylidene)acetate (4.02 g, 12.0 mmol, 2.0 equiv) in CH 2 Cl 2 (10 ml) was then transferred into the reaction mixture via cannula, and the resultant mixture was allowed to stir in the ice-water bath and gradually warm to rt over 20 h. The mixture was then transferred to a separatory funnel containing H 2 O (50 ml) and the aqueous layer was extracted with Et 2 O (3 30 ml). The combined organic layers were washed with brine (30 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a thick, yellow paste (95:5 E/Z). Caution: the product is volatile and should not be left on the rotary evaporator for an extended period. Purification via flash column chromatography [66 g SiO 2, 34 mm Ø, dry loaded, 99:1 hexane/et 2 O (1.2 L), ca. 20 ml fractions then 28 g SiO 2, 24 mm Ø, wet loaded, 100:0 99:1 hexane/etoac (100 ml and 500 ml, respectively), ca. 10 ml fractions] gave a colourless oil (785 mg). Further purification via Kugelrohr distillation at reduced pressure (5 mm Hg) gave 28n as a clear, colourless oil (772 mg, 83%, >99:1 dr). Data for 28n: bp: 81 C (ABT) (5 mm Hg) NATURE CHEMISTRY 21

22 1 H NMR: (500 MHz, CDCl 3 ) δ 6.96 (dt, J = 15.7, 6.8 Hz, 1 H, HC(3)), 5.82 (dt, J = 15.7, 1.6 Hz, 1 H, HC(2)), (m, 2 H, HC(6,7)), 3.72 (s, 3 H, CO 2 Me), 2.25 (q, J = 7.5 Hz, 2 H, HC(4)), 2.13 (q, J = 6.7 Hz, 2 H, HC(5)), 1.64 (dt, J = 6.2, 1.3 Hz, 3 H, HC(8)) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(1)), (C(3)), (C(6)), (C(7)), (C(2)), 51.4 (CO 2 Me), 32.2 (C(4)), 31.0 (C(5)), 17.9 (C(8)) IR: (neat) 3027 (w), 2993 (w), 2950 (m), 2855 (w), 1727 (s), 1659 (m), 1436 (m), 1378 (w), 1324 (w), 1271 (m), 1203 (m), 1164 (m), 1126 (w), 1041 (m), 967 (m), 852 (w), 718 (w) MS: (EI +, DFSF) (M +, 13), ([M OMe] +, 50), (28), (100), 95.1 ([M CO 2 Me] +, 46), 94.1 (25), 69.0 ([CH 3 CH=CHCH 2 CH 2 ] +, 60), 68.0 (54), 67.0 (23), 55.1 ([CH 3 CH=CHCH 2 ] +, 100), 53.1 (29) HRMS: (EI +, DFSF) calcd for C 9 H 14 O 2 (M + ): , found: TLC: R f 0.53 (92:8 hexane/etoac) [UV/KMnO 4 ] Preparation of tert-butyl (Z)-benzyl(hex-4-en-1-yl)carbamate (28o) Preparation of tert-butyl Benzylcarbamate (S5). A flame-dried, 50-mL, roundbottomed flask equipped with a magnetic stirrer bar and rubber septum was purged with argon via an inlet needle, then was charged sequentially with CH 2 Cl 2 (15 ml), benzylamine (647 mg, 660 µl, 6.04 mmol, 1.0 equiv), and triethylamine (944 mg, 1.3 ml, 9.33 mmol, 1.5 equiv) via syringe, and stirring was commenced. The resultant mixture was cooled in an ice-water bath then NATURE CHEMISTRY 22

23 di-tert-butyl dicarbonate (1.61 g, 1.7 ml, 7.40 mmol, 1.2 equiv) was added via syringe over 2 3 min, and the resultant mixture was allowed to warm to rt over 4 h. The reaction mixture was then transferred to a separatory funnel, diluted with CH 2 Cl 2 (30 ml), and washed sequentially with H 2 O (2 20 ml) and brine (20 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a colourless, viscous oil. Purification via flash column chromatography [75 g SiO 2, 42 mm Ø, dry loaded, 92:8 hexane/etoac (1.2 L), ca. 20 ml fractions] gave S5 as a clear, colourless, viscous oil, which solidified to a white solid on standing in a 20 C freezer for ca. 1 day (1.25 g, quant.). The 1 H and 13 C NMR spectroscopic data matched that for alternative preparations. 18 Data for S5: 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 5 H, HC(2,3,4 )), 4.98 (br s, 1 H, NH), 4.30 (d, J = 5.4 Hz, 2 H, HC(5 )), 1.46 (s, 9 H, Ot-Bu) 13 C NMR: (126 MHz, CDCl 3 ) δ (NCO 2 CMe 3 ), (C(1 )), (C(3 )), (C(4 )), (C(2 )), 79.3 (NCO 2 CMe 3 ), 44.5 (C(5 )), 28.3 (NCO 2 CMe 3 ) Preparation of tert-butyl (Z)-Benzyl(hex-4-en-1-yl)carbamate (28o). An oven-dried, 25-mL, Schlenk flask equipped with a magnetic stirrer bar was charged with NaH (washed, 108 mg, 4.50 mmol, 1.5 equiv) in the glovebox, and was then sealed with a rubber septum and removed from the box. DMF (7.5 ml) was then added via syringe under an atmosphere of argon and stirring was commenced. The suspension was cooled in an ice-water bath then tert-butyl benzylcarbamate S5 (622 mg, 3.00 mmol, 1.0 equiv) was added via cannula transfer using two portions of DMF (2 2.0 ml), and the resultant mixture was stirred in the ice-water bath for 10 min, then was allowed to warm to rt over 30 min at rt (N.B. generation of H 2 gas was only observed when the temperature was elevated). (Z)-6-Iodo-2-hexene (662 mg, 3.15 mmol, 1.05 equiv) was added via syringe using two portions of DMF (2 1.0 ml), then the rubber septum was replaced with a water-jacketed reflux condenser (sealed at the top with a rubber septum). The mixture was allowed to stir at rt for 30 min then was heated at C (oil bath temperature) for a further 18 h. Once the reaction had been allowed to cool to rt, it was carefully quenched with H 2 O (2 ml), transferred to a separatory funnel, and diluted with H 2 O (20 ml). NATURE CHEMISTRY 23

24 The aqueous layer was extracted with Et 2 O (3 20 ml) and the combined organic extracts were washed sequentially with H 2 O (20 ml) and brine (20 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a pale yellow oil. Purification via flash column chromatography [88 g SiO 2, 42 mm Ø, dry loaded, 97:3 hexane/etoac (1 L), ca. 20 ml fractions] gave 28o as a clear, colourless oil (718 mg, 83%, >99:1 dr). An analytically pure sample was obtained by further purification of 28o (279 mg) via flash column chromatography [28 g SiO 2, 24 mm Ø, wet loaded with CH 2 Cl 2, 97:3 hexane/etoac (400 ml), ca. 10 ml fractions] followed by Kugelrohr distillation at reduced pressure (0.05 mm Hg) to give 28o as a clear, colorless oil (275 mg, >99:1 dr, 99% mass return). Data for 28o: bp: 158 C (ABT) (0.05 mm Hg) 1 H NMR: (500 MHz, MeCN-d 3, VT at 53 C, calibrated with ethylene glycol) δ (m, 2 H, HC(2 )), (m, 3 H, HC(3,4 )), (m, 2 H, HC(4,5)), 4.42 (s, 2 H, HC(5 )), 3.19 (t, J = 7.4 Hz, 2 H, HC(1)), 2.00 (q, J = 7.3 Hz, 2 H, HC(3)), (m, 5 H, HC(2,6)), 1.45 (s, 3 H, Ot-Bu) 13 C NMR: (126 MHz, MeCN-d 3, VT at 53 C, calibrated with ethylene glycol) [N.B. partial isomerization (ca. 1%) of the (Z)-olefin was observed after heating at 53 C for 1 h whilst collecting the 13 C NMR spectroscopic data] δ (NCO 2 CMe 3 ), (C(1 )), (C(4)), (C(3 )), (C(4 )), (C(2 )), (C(5)), 80.1 (NCO 2 CMe 3 ), 51.4 (C(5 )), 47.7 (C(1)), 29.1 & 29.0 (C(2), NCO 2 CMe 3 ), 25.1 (C(3)), 13.1 (C(6)) IR: (neat) 3011 (w), 2975 (m), 2931 (m), 1696 (s), 1605 (w), 1496 (w), 1453 (m), 1415 (m), 1391 (w), 1365 (m), 1241 (m), 1165 (m), 1134 (m), 1029 (w), 987 (w), 878 (w), 770 (w), 733 (w), 699 (m) MS: (ESI +, TOF) ([M+Na] +, 28), (12), ([M+H] +, 57), (20), (100), (40), 91.1 ([CH 2 Ph] +, 30) HRMS: (ESI +, TOF) calcd for C 18 H 28 NO 2 ([M+H] + ): , found: TLC: R f 0.24 (96:4 hexane/etoac) [UV/KMnO 4 ] NATURE CHEMISTRY 24

25 Analysis: C 18 H 27 NO 2 (289.42) Calcd: C, 74.70; H, 9.40; N, 4.84% Found: C, 74.92; H, 9.44; N, 5.11% Preparation of (Z)-2-(Hex-4-en-1-yl)isoindoline-1,3-dione (28p) A flame-dried, 25-mL, Schlenk flask equipped with a magnetic stirrer bar and waterjacketed reflux condenser was charged with (Z)-6-iodo-2-hexene (630 mg, 3.00 mmol, 1.0 equiv) and DMF (15 ml) under an argon atmosphere, then stirring was commenced. Potassium phthalimide (680 mg, 3.60 mmol, 1.2 equiv) was added against a backflow of argon and the resultant mixture was heated at 90 C for 14.5 h. The reaction mixture was then allowed to cool to rt and was transferred to a separatory funnel, then diluted with H 2 O (75 ml) and EtOAc (50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2 50 ml). The combined organic extracts were then washed with H 2 O (5 50 ml), dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a yellow oil (730 mg). Purification via flash column chromatography (40 g SiO 2, 30 mm Ø, 90:10 hexanes/mtbe, ca. 5 ml fractions) gave a colourless oil (684 mg). Further purification via Kugelrohr distillation at reduced pressure (0.01 mm Hg) gave 28p as a clear, colorless oil, which solidified to a white semi-solid on standing in a 20 C freezer for ca. 1 day (650 mg, 94%, >99:1 dr, ca. 97% purity, contaminated with a regioisomeric terminal alkene impurity and an unidentified hydrocarbon impurity). The 1 H NMR spectroscopic data matched that for alternative preparations. 19 Data for 28p: bp: 120 C (ABT) (0.01 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 2 H, HC(3 )), (m, 2 H, HC(4 )), (m, 2 H, HC(4,5)), 3.69 (dd, J = 8.1, 6.8 Hz, 2 H, HC(1)), 2.11 (q, J = 7.4 Hz, 2 H, HC(3)), (m, 2 H, HC(2)), 1.60 (ddd, J = 6.6, 1.5, 0.7 Hz, 3 H, HC(6)) NATURE CHEMISTRY 25

26 13 C NMR: (126 MHz, CDCl 3 ) δ (C(1 )), (C(4 )), (C(2 )), (C(4)), (C(5)), (C(3 )), 37.6 (C(1)), 28.2 (C(2)), 24.2 (C(3)), 12.7 (C(6)) Preparation of (E)-tert-Butyl(hex-2-en-1-yloxy)diphenylsilane (28q) A 25-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with imidazole (309 mg, 4.50 mmol, 1.5 equiv) and trans-2-hexen-1-ol (313 mg, 371 µl, 3.00 mmol, 1.0 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (6.0 ml) was then added and stirring was commenced. tert-butyldiphenylsilyl chloride (922 mg, 872 µl, 3.30 mmol, 1.1 equiv) was added via syringe in one portion and the resultant mixture was stirred under argon at rt for 16 h. The reaction mixture was then transferred to a separatory funnel and diluted with CH 2 Cl 2 (25-mL), washed sequentially with H 2 O (10 ml) and brine (10 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (45 C, ca. 5 mm Hg) to give a colorless oil (1.17 g). Purification via flash column chromatography (40 g SiO 2, 30 mm Ø, wet loaded, 99:1 hexane/mtbe, ca. 5 ml fractions) gave 28q as a clear, colorless oil (900 mg, 89%, >99:1 dr, contaminated with ca. 4% regioisomeric alkene contaminants). Data for 28q: 1 H NMR: (500 MHz, CDCl 3 ) (m, 4 H, HC(2,2 )), (m, 6 H, HC(3,3,4,4 ), & (m, 2 H, HC(2,3)), (m, 2 H, HC(1)), (m, 2 H, HC(4)), 1.40 (sextet, J = 7.4 Hz, 2 H, HC(5)), 1.08 (s, 9 H, Sit-Bu), 0.92 (t, J = 7.4 Hz, 3 H, HC(6)). 13 C NMR: (126 MHz, CDCl 3 ) (C(2,2 )), (C(1,1 )), (C(2)), (C(4,4 )), (C(3)), (C(3,3 ), 64.7 (C(1)), 34.3 (C(4)), 26.9 (SiCMe 3 ), 22.4, (C(5)), 19.2 (SiCMe 3 ), 13.7 (C(6)) NATURE CHEMISTRY 26

27 IR: (neat) 3071 (w), 3051 (w), 2956 (m), 2931 (m), 2895 (w), 2858 (m), 1591 (w), 1473 (w), 1462 (w), 1428 (m), 1379 (w), 1362 (w), 1112 (s), 1058 (m), 1009 (w), 969 (m), 823 (m), 739 (m), 701 (s) MS: (EI +, TOF) (M +, 29), (13), (14), ([M-CH 3 ] +, 18), (17), ([M-CH 3 CH 2 CH 2 ] +, 69), ([M-CH 3 CH 2 CH 2 CH] +, 22), (98), (29), (17), (100), (13), (13), (16) TLC: R f 0.38 (99:1 hexane/mtbe) [UV/KMnO 4 ] HRMS: (EI +, TOF) calcd for C 22 H 30 OSi (M + ): , found: Preparation of (E)-tert-Butyldimethyl[(5-phenylpent-2-en-1-yl)oxy]silane (28s) A 25-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with (E)-5-phenylpent-2-en-1-ol 28u (487 mg, 3.00 mmol, 1.0 equiv) and imidazole (309 mg, 4.50 mmol, 1.5 equiv) then was sealed with a rubber septum and purged with argon via an inlet needle. CH 2 Cl 2 (6 ml) was then added and stirring was commenced. tert-butyldimethylsilyl chloride (497 mg, 3.30 mmol, 1.1 equiv) was added in one portion against a backflow of argon and the resultant mixture was stirred at rt for 22 h. The reaction mixture was then transferred to a separatory funnel and diluted with CH 2 Cl 2 (25 ml), then was washed sequentially with H 2 O (10 ml) and brine (10 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (45 C, ca. 5 mm Hg) to give a colorless oil (886 mg). Purification via flash column chromatography (40 g SiO 2, 30 mm Ø, wet loaded, 98:2 hexane/mtbe, ca. 5 ml fractions) gave a colorless oil (785 mg). Further purification via Kugelrohr distillation at reduced pressure (10 5 mm Hg) gave 28s as a clear, colorless oil (758 mg, 91%, >99:1 dr). The 1 H and 13 C NMR spectroscopic data matched that for alternative preparations. 20 NATURE CHEMISTRY 27

28 Data for 28s: bp: 100 C (ABT) (10 5 mm Hg) 1 H NMR: (500 MHz, CDCl 3 ) δ (m, 2 H, HC(2 )), (m, 3 H, HC(3,4 )), 5.71 (dt, J = 15.4, 6.5 Hz, 1 H, HC(2)), (m, 1 H, HC(3)), 4.14 (d, J = 5.2 Hz, 1 H, HC(1)), 2.71 (t, J = 7.9 Hz, 2 H, HC(5)), (m, 2 H, HC(4)), 0.93 (s, 9 H, Sit-Bu), 0.08 (s, 6 H, SiMe 2 ) 13 C NMR: (126 MHz, CDCl 3 ) δ (C(1 )), (C(2)), (C(2 )), & (C(3,3 )), (C(4 )), 63.9 (C(1)), 35.6 (C(5)), 34.0 (C(4)), 26.0 (SiCMe 3 ), 18.4 (SiCMe 3 ), 5.1 (SiMe 2 ) Preparation of (E)-4-(Benzyloxy)but-2-en-1-ol (28w) Preparation of 4-(benzyloxy)but-2-yn-1-ol (S6). Following a literature procedure, 20 an oven-dried, 100-mL, round-bottomed flask equipped with a magnetic stirrer bar was charged with 2-butyne-1,4-diol (3.47 g, 40.3 mmol, 4.0 equiv) and an aqueous solution (30 ml) of KOH (2.26 g, 40.3 mmol, 4.0 equiv), then was sealed with a glass stopper and stirred at rt for 5 min. Benzyl bromide (1.72 g, 1.2 ml, 10.0 mmol, 1.0 equiv) was added dropwise via syringe over 2 3 min and the resultant mixture was allowed to stir at rt for 48 h. The reaction mixture was then transferred to a separatory funnel and extracted with CH 2 Cl 2 (3 30 ml), and the combined organic extracts were washed with brine (20 ml), then dried (MgSO 4 ), filtered, and concentrated in vacuo (20 23 C, ca. 20 mm Hg) to give a pale yellow oil. Purification via flash column chromatography [40 g SiO 2, 30 mm Ø, dry loaded, 95:5 90:10 80:20 70:30 hexane/etoac (100 ml, 100 ml, 300 ml, and 300 ml, respectively), ca. 20 ml fractions] gave S6 as a colorless oil (1.56 g, 89%). The 1 H NMR spectroscopic data matched that reported in the literature. 21 NATURE CHEMISTRY 28