Enantiomerically Pure Bithiophene Diphosphine Oxides as Catalysts for Direct Double Aldol Reactions ANDREA GENONI, 1 MAURIZIO BENAGLIA, 1 * SERGIO ROSSI, 1 AND GIUSEPPE CELENTANO 2 1 Dipartimento di Chimica, Universita’ degli Studi di Milano, Milano, Italy 2 Dipartimento di Scienze Farmaceutiche, Universita’ degli Studi di Milano, Milano, Italy ABSTRACT The direct aldol reaction between aryl methyl ketones with aromatic aldehydes in the presence of tetrachlorosilane and a catalytic amount of a chiral bithiophene diphosphine oxide was studied; the product of double aldol addition was isolated as diacetate in good diastereoselectivity (up to 95:5) and enantioselectivities up to 91%. The reaction with heteroaromatic aldehydes was also investigated leading to the corresponding 1,3 diols, in some cases with excellent stereoselectivities. Chirality 00:000–000, 2013. © 2013 Wiley Periodicals, Inc. KEY WORDS: aldol reaction; Lewis bases; organocatalysis; stereoselectivity; tetrachlorosilane INTRODUCTION The use of tetrachlorosilane in combination with catalytic amount of chiral Lewis bases to promote stereoselective reactions nowadays is a well-established methodology. 1–3 Seminal works by Denmark and colleagues 4–6 with chiral phosphoroamides have shown the versatility of the catalytic system that opened avenues to several different synthetic ap- plications. 7 Soon after, Nakajima and colleagues 8–14 and we 15–17 demonstrated that phosphine oxides could also coordinate SiCl 4 and generate hypervalent cationic silicon species in situ as chiral Lewis acids able to promote stereoselective direct aldol reactions. Recently, it was reported 18 that the binaphthyl-based phos- phine oxide BINAPO catalyzed the double aldol reaction 19,20 of acetophenone with benzaldehyde, leading to the formation of the corresponding products as a mixture of two diastereo- isomers and 60% e.e for the major isomer. By looking for the best experimental conditions it was found that a mixture of DCM and propionitrile as reaction solvent in combination with the use of dicyclohexylmethylamine allowed an increase in the stereoselectivity up to 70% enantiomeric excess (e.e.) Only with 2-furyl and 2-cyclopropyl methyl ketones was 90% of enantioselectivity reached. We were interested in applying our catalytic methodologies to the transformation; in our previous studies of Lewis-based catalyzed reactions in the presence of silicon tetrachloride the use of biheteroaromatic diphosphine oxides, more electron- rich than the commonly used binaphthyl diphosphine deriva- tives, has often led to the formation of the desired products with enantioselectivities higher than those obtained with BINAPO 21 ; therefore we decided to investigate the behavior of (S)- tetramethyl-bithiophene phosphine oxide, (S)-TetraMe- BITIOPO, in the direct double aldol reaction between aryl methyl ketones and aromatic aldehydes. MATERIALS AND METHODS General TLC was performed on Merck silica gel 60 TLC plates F254 and visual- ized using UV or phosphomolibdic acid. Flash chromatography was car- ried out on silica gel (230–400 mesh). 1 H NMRs were recorded at 300 MHz (Bruker Fourier 300 or AMX 300) with the indicated solvent. 13 C NMRs were obtained at 75 MHz with complete proton decoupling. Chemical shifts were determined relative to tetramethylsilane (for hydro- gen atoms) and residual solvent peaks (for carbon atoms). HPLC for e.e. determination was performed on an Agilent 1100 or 1200 instrument un- der the conditions reported below. Mass spectra (MS) were performed at CIGA (Centro Interdipartimentale Grandi Apparecchiature), with mass spectrometer APEX II and Xmass software (Bruker Daltonics).All reac- tants were freshly distilled (if liquid) or crystallized (if solid) before use. Double Aldol Reaction: Typical Procedure To a stirred solution of (S)-tetra-Me-BITIOPO (0.016 mmol, 0.1 equiv) in CH 2 Cl 2 (2 mL), DIPEA (diisopropylethylamine) (0.8 mmol, 5 equiv.) and the ketone (0.16 mmol, 1 equiv.) were added. The mixture was cooled to –40  C, then freshly distilled tetrachlorosilane (0.64 mmol, 4 equiv.) was added dropwise with a syringe. After 15 min, aldehyde (0.352 mmol, 2.2 equiv.) was added. The mixture was stirred for 20 h. After this time, the reaction was quenched by the addition of a saturated aqueous solution of NH 4 Cl (2 mL). The mixture was allowed to warm to room temperature and stirred for 30 min, then CH 2 Cl 2 (15 mL) was added. The two-layer mixture was separated and the aqueous layer was extracted with CH 2 Cl 2 (15 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under vacuum at room tempera- ture to give the crude 1,3-diols, as confirmed by 1 H-NMR. The crude products were then treated with acetic anhydride (1.76 mmol, 11 equiv) in 2 mL of pyridine at room temperature (RT). After stirring for 20 h, the mixture was quenched with H 2 O (10 mL) and extracted with CH 2 Cl 2 (2 x 15 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under vacuum at RT. The diastereoisomeric ratio was calculated by 1 H-NMR spettroscopy. Yields were determined after chromatographic purification on silica gel with dif- ferent hexane/ethyl acetate mixtures as eluent (see below). The e.e. was determined by high-performance liquid chromatography (HPLC) on a chiral stationary phase. Attributions were performed using racemic mixtures as references. (S)-tetra-Me-BITIOPO was quantitatively recov- ered by further elution with 10% MeOH in CH 2 Cl 2 without any loss of optical purity. (3-acetoxy-2-(1 0 -acetoxy(phenyl)methyl)-1,3-diphenylpropan- 1-one (3). This product was purified by flash column chromatography on silica gel with a 8:2 hexane/ethyl acetate mixture as eluent. The purification afforded a mixture of chiral and meso adducts. Additional Supporting Information may be found in the online version of this article. *Correspondence to: Maurizio Benaglia, Dipartimento di Chimica, via C. Golgi 19, I-20133 Milano, Italy. E-mail: maurizo.benaglia@unimi.it Received for publication 11 February 2013; Accepted 25 April 2013 DOI: 10.1002/chir.22190 Published online in Wiley Online Library (wileyonlinelibrary.com). © 2013 Wiley Periodicals, Inc. CHIRALITY (2013)