Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

An investigation on the stereoselective cascade sulfa-Michael/aldol reaction of nitroalkenes and commercially available 1,4-dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thiourea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-β-methyl-β-nitrostyrenes affording the heterocyclic products in good yields and moderate stereoselectivities.


General methods
All reactions requiring dry or inert conditions were conducted in flame-dried glassware under a positive pressure of nitrogen. THF and DCM were freshly distilled prior to use respectively over metallic Na and calcium hydride and stored under nitrogen, all other solvents were dried over molecular sieves. Molecular sieves (Aldrich Molecular Sieves, 3 Å, 1.6 mm pellets) were activated under vacuum at 200 °C overnight.
Reactions were monitored by thin layer chromatography (TLC) on Macherey-Nagel pre-coated silica gel plates (0.25 mm) and visualized by UV light and, when necessary, by phosphomolybdic acid and ninhydrin staining solutions. Flash chromatography was performed on Merck silica gel (60, particle size: 0.040-0.063 mm). 1 H NMR and 13 C NMR spectra were recorded on Bruker Avance-400, Bruker Avance-300 or Bruker Avance-250 spectrometers in CDCl 3 as solvent at room temperature. NOE and NOESY spectra were recorded on Bruker Avance III HD 600 spectrometer in CDCl 3 as solvent. Chemical shifts for protons are reported using residual solvent protons ( 1 H NMR: δ = 7.26 ppm for CDCl 3 ) as internal standard. Carbon spectra were referenced to the shift of the 13 C signal of CDCl 3 (δ =77.0 ppm).
Optical rotation of compounds was performed on a Jasco Dip-1000 digital polarimeter using the Na lamp (λ = 582 nm) and on a Jasco P-2000 digital polarimeter using WI (Tungsten-Halogen) lamp (λ = 589 nm). FTIR spectra were recorded as thin films on KBr plates using Bruker Vertex 70 spectrometer or Bruker Tensor 27 spectrometer and absorption maxima are reported in wavenumber (cm −1 ). ESIMS was performed using a Bio-Q triple quadrupole mass spectrometer (Micromass,  Subsequently, pivaladehyde (112 μL, 1.031 mmol) was added to the solution and the mixture was stirred for 1 h at room temperature. After this time, the reaction was cooled to 0 °C and NaBH 4 (143 mg, 3.77 mmol) was added. The resulting mixture was stirred at room temperature for 2 h.
The product was purified by flash chromatography (eluent 10-50% Et 2 O in PE) to give catalyst VIII (192 mg, 57% yield) as white solid.
10 The relative configuration of this compound has been assigned on the similarity of chemical shifts observed in the 1 H-NMR spectra with those of compound 7a.

MS (ESI
as the most stable diastereomer among compounds 7a, 8a, 9a and 14. Compounds 8a and 9a lie at slightly higher free energy, with 14 being the least accessible diastereomer. Although small free energy differences between diastereomers are predicted, theoretical results are in line with the experimental observation that 7a is the most abundant product and 14 is not obtained at all, thus suggesting that the reaction may proceed under thermodynamic control. For compound 4-ethyl-4nitro-5-phenyltetrahydrothiophen-3-ol 10, 11 and 12 isomers should be equally populated according to DFT computations, but relative free energies are too close to draw any realistic conclusion about relative stability. By contrast, it is sound and worth to note that the diastereomers of compound 4ethyl-4-nitro-5-phenyltetrahydrothiophen-3-ol span a narrower free energy range than that of 4methyl-4-nitro-5-phenyltetrahydrothiophen-3-ol , whichunder the hypothesis of thermodynamic controlis again in line with the lower diastereomeric ratio observed.

Computational details
DFT computations were carried out by using the Gaussian program. 11 The M06-2X functional in conjunction with the 6-31+G(d,p) basis set was used for geometry optimizations. Solvation effects