Asymmetric Synthesis of β-Substituted α-Methylenebutyro- lactones via TRIP-Catalyzed Allylation: Mechanistic Studies and Application to the Synthesis of (S)-(−)-Hydroxymatairesinol

Asymmetric allylation of (hetero)aromatic aldehydes by a zinc(II)-allylbutyrolactone species catalyzed by a chiral BINOL-type phosphoric acid gave β-substituted α-methylenebutyrolactones in 68 to >99% ee and 52–91% isolated yield. DFT studies on the intermediate Zn2+-complex – crucial for chiral induction – suggest a six-membered ring intermediate, which allows the phosphoric acid moiety to activate the aldehyde. The methodology was applied to the synthesis of the antitumour natural product (S)-(−)-hydroxymatairesinol.


Experimental Procedures
General. All chemicals were purchased from Sigma Aldrich, Acros Organics or Alfa Aesar and used as received, solvents were obtained from Roth. Zinc dust was from Sigma Aldrich (< 10 µm, ≥98% purity, catalog number 209988). All moisture-or air-sensitive operations were conducted under dry argon in heat-dried glassware. NMR-spectra were recorded on a Bruker NMR unit at 300 ( 1 H) and 75 ( 13 C) MHz, shifts are given in ppm and coupling constants (J) are given in Hz. GC-MS measurements were performed on an Agilent 7890A GC system, equipped with an Agilent 5975C mass-selective detector (EI 70 eV) and a HP-5-MS column (30 m x 0.25 mm x 0.25 µm film) using He at a flow rate of 0.55 mL/min. Temperature program: 100 °C, hold 0.5 min, 10 °C/min 300 °C, inlet temperature 250 °C.
Low resolution mass spectra were recorded on an Agilent Technologies 6120 Quadrupole LC/MS detector in combination with an Agilent Technologies 1260 Infinity HPLC system, equipped with a Zorbax SB-18 column (2.1 x 50mm, 1.8 micron). High resolution mass spectra were recorded on a Waters Synapt HDMS Q-TOF mass spectrometer (ESI ion source, S5 positive mode, capillary voltage 2.6 kV) using a syringe pump to directly inject the sample dissolved in MeCN. Chiral HPLC analysis was performed on a Shimadzu HPLC system using columns and methods as specified below. Optical rotation values were measured on a Perkin Elmer Polarimeter 341. CD-spectra were recorded in MeOH using a 0.1 cm quartz cuvette on a Jasco J-715 spectropolarimeter (concentrations are given in mg/mL). IR-spectra were recorded neat on a Burker Alpha-P (ATR) instrument. Flash chromatography was performed using Merck silica gel 60 (mesh size 40-63 µm). Petroleum ether had a boiling range of 60-95 °C. Compounds 4 [1] and 5 [2] were prepared according to slightly modified literature protocols as outlined below.
The physical data were identical for enantiopure (R,S)-6 as described below.

4-(Dimethylamino)pyridine
• The absolute configuration of compound 6 was determined via asymmetric total synthesis of (S)-(-)-hydroxymatairesinol (1) and comparison of the optical rotation with literature data. [4] • The absolute configurations of compounds 7-13 were determined via CD-spectroscopy (vide infra) and correlated to that of compound 6; in addition, the elution order of enantiomers of compounds 6-13 on a chiral stationary phase (Daicel Chiralpak AD) was consistent, i.e. the (S)-alcohol eluted first. S13

Additional Computational Details
All computations were carried out with the Gaussian suite of programs (G09 Rev. C.01) [5] using a triple-ζ basis set (6-311G**) and the Minnesota M06 functional. [6] Optimized structures were determined to be true minima by inspection of their vibrational frequencies.
Solvent effects were mimicked using the Polarizable Continuum Model (IEF-PCM). [7]  In addition to the coordination of protonated phosphoric acid as described in the manuscript ( Fig. 1), we also considered a single coordination of Zn 2+ salt of the deprotonated phosphoric acid of both isomers with the TRIP-catalyst. The relative energies of the intermediates would favour the S ax S alc R isomer (D) over the desired S ax R alc S isomer (C) by 10 kcal/mol ( Figure   S02). A linear arrangement of the TRIP-Zn-O(aldehyde)-allyl chain with elongated distances between the chirality-inducing iPr-groups and the lactone moiety was observed due to steric repulsion in case of isomer D, which therefore lacks catalytic significance.
S40 Figure S01. Intramolecular distances of isomers A (top, S ax R alc S lac ) and B (bottom, S ax S alc R lac ) used for the calculation the mean distances between the phenyl substituent of the catalyst and the lactone moiety.