Experimental Procedures

General Procedures. All reactions were performed under an atmosphere of dry nitrogen using oven dried or flame dried glassware. Reaction solvents were purchased from Aldrich or Fluka and were purified as follows: Tetrahydrofuran (THF) was distilled from benzophenone ketyl or passed over activated alumina; dichloromethane (CH2Ch) was distilled from CaH or passed over activated alumina; diethyl ether (Et20) was distilled from benzophenone ketyl or passed over activated alumina; acetonitrile (CH3CN) was passed over activated alumina; toluene (PhMe) was passed over activated alumina; benzene (PhH) was distilled from sodium pellets; dimethylformamide (DMF) was stored over

4A

molecular sieves prior to use; dimethylsulfoxide (DMSO) was stored over

4A

molecular sieves prior to use; methanol (MeOH) was distilled from magnesium methoxide. Carbon tetrachloride (CC14) was percolated through silica gel, distilled under dry N2, then sparged with Ar for 30 min with sonication before use. Ethyl acetate, hexanes, pentane and dichloromethane used for work up and chromatography were obtained as technical grade and flash distilled prior to use or were purchased as reagent grade or higher from Aldrich or Fluka. All reagents were purchased from Aldrich or Fluka as reagent grade or better and used without further purification with the following exceptions: Tributyltinhydride was distilled at reduced pressure (<I torr); triethylamine (TEA), diisopropylamine, pyridine, and ethyldiisopropylamine (Hiinig's base) were distilled from KOH; benzyl alcohol was stored over

4A

molecular sieves prior to use;

propane- I ,3-diol was distilled at reduced pressure (<I torr) from K2C03; meta- chloroperbenzoic acid (m-CPBA) was washed with pH=7.4 buffer then crystallized twice

65 from dichloromethane; triphenylphosphone was crystallized from 95% EtOH.

Chromatographic purification of products was performed on Baker 7024-R silica gel, EM Science Geduran silica gel 60, or Fluka Silica Gel 60 using a forced flow of EtOAc/hexanes eluant (unless noted otherwise) at 0.1-0.15 bar. Thin layer chromatography was performed using Merck Silica Gel 60 F2s4 TLC plates and visualized by fluorescence quenching under UY light. In addition, all TLC plates were stained using either eerie ammonium molybdate (CAM), ethanolic anisaldehyde, or aqueous potassium permanganate stain. NMR spectra were recorded on a General Electric QE Plus or Varian Mercury 300 operating at 300 MHz and 75 MHz for ¹H and

13C, respectively, and are referenced to the internal solvent signals. Data for 1 H-NMR spectra are reported as follows: chemical shift relative to tetramethylsilane (o in ppm), multiplicity (s, singlet; d, doublet; dd, doublet of doublets; m, multiplet), integration, coupling constant (J in Hz). Measurements of nuclear Overhauser enhancement (nOe) were performed at 500 MHz by the Laboratorium fi.ir Organische Chemie NMR service at ETH in Zurich. IR spectra were recorded on a Perkin Elmer Spectrum RXI FT-IR spectrometer or paragon 1000 FTIR spectrometer using NaCl salt plates and are reported in tenns of frequency of absorption (v, cm-1). Optical rotations were measured on a Jasco DIP-1 000 digital polarimeter operating at the sodium D line. Gas chromatographic analyses were performed on a Hewlett-Packard 6890 gas chromatograph with a flame ionization detector and a 30m J&W Cyclodex-B capillary column. High-resolution mass spectra were obtained from the UC Irvine Mass Spectral facility or the Laboratorium fUr Organische Chemie mass spectrometry lab at ETH in Zurich. Combustion analyses were perfonned by the Mikroelementaranalysches Laboratorium at the ETH in Zurich. X-ray

crystallography was performed by Professor Volker Gramlich of the Laboratory of Crystallography at ETH in Zurich.

The term "in vacuo" refers to rotary flash distillative removal of bulk solvent at<

40 °C under reduced pressure (25-1 00 torr) followed by further evaporation of the residue at high vacuum ( < 1 torr) to remove trace solvent. Unless otherwise noted, reactions are presumed to be at equilibrium temperature with the external environment and are reported in terms of the composition of the external bath as follows: "-78 °C" indicates acetone/dry ice suspension; "-1 0 °C" indicates ice/salt melt; "0 °C" indicates water/ice melt; "23 °C" indicates ambient air temperature. Temperatures greater than 23

o c

^were

measured in the external heating bath.

OTIPS

~ _(J

^CN

24

O-triisopropylsilylspiro[2.4]hcpta-4,6-diene-1-methanol-4-nitrile 24. To a solution of 19 (8.4g, 30 mmol) in 210 mL THF cooled to -78

o c

^{was add}ed chlorosulfonyl isocyanate (2.9 mL, 32 mmol) dropwise over 30 min. The mixture was stirred an additional 30 min then poured into stirring water (1.5 L), EtOAc (1 L), and TEA (15.5 mL, 111 mmol). The resulting suspension was adjusted to pH=6 by adding 1 N HCl or TEA as indicated by pH paper. The mixture was stirred for 56 h. The organic layer was then separated, washed I x 200 mL sat. NaCl and dried over sodium sulfate. Solvent was removed in vacuo to give intermediate amide 23 as a viscous orange oil (9.37g, 97%

mass balance; I 0: I mixture of diastereomers). The unpurified material was then taken up in 200 mL THF and cooled to -78 °C, and pyridine (23 mL, 0.28 mol) was added

67 followed by freshly distilled TFAA (4.1 mL, 29 mmol) dropwise over 20 min. The resulting orange reaction was quenched immediately with 200 mL water and extracted 2 x 300 mL pentane. The combined extracts were washed I x 200 mL water, 2 x 200 mL 1N HCl, I x 200 mL pJ-1=7 phosphate buffer (1.25 M), I x 200 mL saturated aqueous NaCI, then dried over Na2S0^{4 .} Solvent was removed in vacuo to give a brown oil that was purified by chromatography on silica gel (20: I hexanes/EtOAc) to give 24 as an oil (4.09g, 46%, 2 steps).

1H-NMR (C₆0₆, 300 MHz)8 6.68 (dd, lH, J=2.6, 1.5), 6.49 (dd, 1H, J=5.2, 1.5), 6.14 (dd, IH, J=5.2, 2.6), 3.55 (dd, IH, J=11.2, 4.1), 3.42 (dd, 1H, J=11.2, 5.6), 2.36 (dddd, I H, J=9.0, 8.1, 5.6, 4.1), 1.72 (dd, I H, J=J2.0, 9.0), 1.68 (dd, 1 H, J=12.0, 8.1), 1.07-0.88 (m,21H).

13C-NMR (CDCh, 75 MHz)8 142.84, 142.16, 129.18, 119.07, 115.56, 62.58, 44.48, 32.51' 18.93, 18.07, 11.98.

IR (thin film) v 2945,2867,2210, 1729, 1467, 1384, 1259, 1138, 1110, 1013,882,783. HRMS(CI) calc'd for CtsH29NOSi: [Mt 303.2018; found 303.2010.

1H-NMR 300 MHz C6D6

13C-NMR 75 MHz C6D6

FTTR

thin film

0

-B.:::;·.

6

J

160 140

I~

.f

f

j

120

-'·- '-r .

'!

N '

\j-~OTIPS

NC ,_/'<

'U

100 80

I

, - - -1 2

60

0

I -

r-1---, ---, --,-·r·-¥,----1-

4C 2C c

--,--- -,----·--------·----,-----------.,.--------

:))0() (!!>l)O ZOUO tSHO H)ill) ern ..

69

General procedure for cuprate additions To a solution of alkyl, alkenyl, or aryl magnesium bromide or lithium (3.66 mmol) inTI-IF (12 ml) cooled to 0 OC was added Cui (1.83 mmol, 348 mg). The resulting dark suspension was stirred for 30 min then cooled to -78 OC and 24 (0.608 mmol, 0.194 ml of 100 mg/ml sol in THF) was added dropwise. The reaction was stirred for 1.5 h then warmed to 0 °C and quenched with saturated aqueous NH4CI (15 ml). The mixture was diluted with water (I 0 ml) and extracted with pentane (3 x 30 ml). The combined extracts were dried over anhydrous MgS04. Solvent removal in vacuo afforded an oil that was purified by chromatography on silica gel (hexanes: EtOAc 20: I).

(+)-25a: R = Methyl Obtained as a colorless oil (76%).

TLC: Rr= 0.47 (20:1 hexanes/EtOAc).

Optical rotation [a]Na +60.2° (c

=

1.37, CHCI3).

11-1 NMR (C₆D_{6 ,} 300 MHz): 8 6.29 (dd, I H, J = 5.3, 1.0), 5.95 (d br., I H, J = 5.3), 3.72- 3.60 (m, 2H,), 3.05-2.93 (m, 1 H), 2.60 (s br., 2H), 1.67-1.33 (m, 2H), 1.08-0.92 (m, 21 TI), 0.76 (dd, 3H, J = 7.5, 7.5).

13C NMR (C6D6, 75 MHz): 165.4, 138.3, 132.9, 65.8, 45.0, 43.5, 29.7, 23.2, 17.9, 11.9.

IR (thin film): 2943, 2867,2210, 1463, 1382, 1368, 1248, 1119, 1067, 1010, 996, 882, 786.

HRMS (FAB+): calculated for C19ll)₃0NSi: (M+I-I)+ 320.2409, found 320.2412.

1H-NMR 300 MHz C6D6

13

C-NMR