Tandem Enyne Metathesis and Claisen Rearrangement: A Versatile Approach to Conjugated Dienes of Variable Substitution Patterns.

Abstract

All reactions were conducted under an argon atmosphere unless otherwise noted. Dichloromethane (CH 2 Cl 2 ) (alumina), benzene and toluene (alumina + Q5) were drawn from a solvent purifier immediately prior to use. Dry tetrahydrofuran (THF) was obtained from a still (Na/benzophenone). Reagent S2 grade methanol was used for trituration and the cycloaddition reaction. Ruthenium [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidine]dichloro (phenylmethylene)(tricyclohexylphosphine) (Grubbs' second generation catalyst) was obtained from Materia Inc. (Pasadena, CA). 1,5-Cyclooctadiene (COD) was distilled from sodium prior to use. Amines were purchased from Aldrich and distilled from CaH 2 and stored over KOH. Polymer grade ethylene gas was obtained from Matheson Tri-gas. Triethylchlorosilane was obtained from Gelest, Inc. and distilled under reduced pressure prior to use. N,N-dimethylaminopyridine was obtained from Acros. The remaining reagents were purchased from Aldrich and distilled when applicable. Column chromatography was carried out on Bodman industries silica gel 60 (230 -400 mesh). Thin layer chromatography was developed on glass-backed EM science F254 silica plates and made visible with UV light, iodine, 1.7% KMnO 4 solution in water or Hanessian's stain (5 % w/v cerium molybdate in 0.72 M H 2 SO 4 ). 1 H-NMR spectra were recorded at 500 MHz and 13 C-NMR spectra at 125 MHz in CDCl 3 . 1 H-NMR spectra were referenced on the TMS signal for CDCl 3 . The 13 C-NMR spectra were referenced at 77.0 ppm for CDCl 3 . High resolution mass spectra were obtained using a ThermoFinnigan MAT95XL. Gas chromatography was performed on a Shimadzu GC-17A FID Gas chromatograph (thermal program: 40 °C, 4 min; 25 °C/min to 280 °C; 280 °C, 16.4 min) using an Agilent Technologies 19091J-433 capillary column (30m X 0.250 mm, 0.25 micron). FT-IR spectra were recorded on a Nicolet Impact series 420 IR. Optical rotations were measured on a Jasco DIP-370 polarimeter using the sodium D line at 589 nm in a 50 mm cell held at 25 °C. S3Table 1 Acyclic Diene/Ireland Claisen Rearrangement (E)-2-Methylene-1-phenyl-oct-3-enyl acetate (2B, metathesis step, entry 1). As reported in the literature: 1 To an oven-dried 50 mL Schlenk tube was added 500 mg of alkyne 2A (2.87 mmol), 3.2 mL of 1-hexene (9 equiv, 25.86 mmol), and 3 mL of dichloromethane. The clear solution was stirred for 5 min and 122 mg Grubbs' catalyst 1 (0.14 mmol, 5 mol%) was added as a single portion. Then reaction was heated at reflux for 18 h, cooled to room temperature, concentrated in vacuo (rotary evaporator), and loaded directly onto a silica gel column (3 X 15 cm). Elution with 5% ethyl acetate/hexane gave 500 mg of 2B (68%) as a clear oil. Analytical TLC (10% ethyl acetate/hexane) R f 0.36. 1

Recent advances in the total synthesis of cytochalasan natural products using bioinspired strategies

“…The desired Ireland-Claisen substrate 104 was obtained from 102 through a Suzuki-Miyaura cross-coupling reaction of triflate 102 with dienyl boronate 103 in 71% yield. The key Ireland-Claisen rearrangement proceeded well under the optimized Diver's condition 24 (LDA/TBSCl/TPPA) to afford carboxylic acid 105 in 71% yield after treatment with TBAF. The next step was the coupling of carboxylic acid 105 with γ-lactam 30, 4 which was achieved by the addition of the anion of 30 to the activated pivaloyl anhydride of 105.…”

Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins and Formal Synthesis of Trichoderone A

“…In 2006, Diver and co-workers were able to perform tandem enyne metatheses giving products with the branched 2-vinylallylic acetate topology like ours, which were engaged in the Ireland-Claisen rearrangement. 37 We first attempted this rearrangement on simplified substrate 18 previously obtained in a racemic form from enyne metathesis 38 (Scheme 3, see also Scheme S3 in the Supporting information). Rearranged product 19 was successfully obtained in 59% yield after deprotonation by LiHMDS in toluene, followed by the addition of TMSCl/Et3N and increasing the temperature to reflux.…”

“…The cross coupling performed well in the presence of Pd(OAc) 2 (10 mol %) and K 3 PO 4 in a 7:3 dioxane/water mixture at 0 °C without ligand, providing triene 10 in 71% yield after 1 h. In fact, the absence of ligand allowed us to perform the reaction on a 1.6 g scale, providing 10 as a 4:1 mixture of E and Z isomers, respectively, supposedly formed through triene isomerization under the reaction conditions (the undesired Z isomer was eliminated during the next step, possibly due to lower reactivity attributed to a steric clash during the Ireland−Claisen rearrangement). Although electron-rich ligands like PCy 3 , P(2-furyl) 3 , or bis(diphenylphosphino)ferrocene (dppf) allowed the reaction to proceed in good yields (75−80%) and selectivities, these 37 We first attempted this rearrangement on simplified substrate 18 previously obtained in a racemic form from enyne metathesis 38 (Scheme 3, see also Scheme S3). Rearranged product 19 was successfully obtained in 59% yield after deprotonation by LiHMDS in toluene, followed by the addition of TMSCl/Et 3 N and increasing the temperature to reflux.…”