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Communication

A One-Pot Tandem Strategy in Catalytic Asymmetric Vinylogous Aldol Reaction of Homoallylic Alcohols

1
School of Chemistry and Chemical Engineering, Xuchang University, Xuchang 461000, China
2
Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng 475004, Henan, China
*
Author to whom correspondence should be addressed.
Academic Editor: Bartolo Gabriele
Molecules 2016, 21(7), 842; https://doi.org/10.3390/molecules21070842
Received: 14 May 2016 / Revised: 21 June 2016 / Accepted: 22 June 2016 / Published: 27 June 2016
(This article belongs to the Special Issue Cascade Catalysis)

Abstract

Reported is a rationally-designed one-pot sequential strategy that allows homoallylic alcohols to be employed in a catalytic, asymmetric, direct vinylogous aldol reaction with a series of activated acyclic ketones, including trifluoromethyl ketones, γ-ketoesters, and α-keto phosphonates, in high yields (up to 95%) with excellent regio- and enantio-selectivity (up to 99% ee). This modular combination, including Jones oxidation and asymmetric organocatalysis, has satisfactory compatibility and reliability even at a 20 mmol scale, albeit without intermediary purification.
Keywords: asymmetric organocatalysis; vinylogous aldol reactions; oxidation; cascade; homoallylic alcohols asymmetric organocatalysis; vinylogous aldol reactions; oxidation; cascade; homoallylic alcohols

1. Introduction

Asymmetric vinylogous aldol (AVA) reaction allows expedient generation of chiral multifunctional alcohols with an extended carbon skeleton and α,β-unsaturated group, which is easily further transformed into structurally complex molecules with divergent synthetic targets [1,2,3,4,5]. As such, the development of the AVA reaction has spurred research in this field in the past few decades [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. Inspired by the atom economy philosophy, the AVA variant in which direct employment of unmasked nucleophiles to facilitate the generation of dienolates is our current focus [6,7,8,9,10,11,12,13,14,15,16,17,18,19].
We disclosed a direct AVA reaction of allyl ketones to isatins back in 2013, leading to the divergent synthesis of biologically-important 3-hydroxy-2-oxindoles derivatives [14]. Since then, a series of direct asymmetric vinylogous reactions using allyl ketones as nucleophiles have been carried out successfully with excellent γ-selectivity and enantioselectivity [17,18,19]. For example, Chen and co-workers developed a catalytic asymmetric vinylogous Michael addition of allyl ketones to maleimides through dienamine catalysis [17]. Xu et al. reported another efficient asymmetric vinylogous Michael addition between allyl ketones and α,β-unsaturated aldehydes by employing a multifunctional supramolecular iminium catalyst [18]. Very recently, our group introduced a highly-enantioselective vinylogous aldol reaction of allyl ketones to activated acyclic ketones, such as trifluoromethyl ketones, α-ketoesters, and α-keto phosphonates, developing expedient and divergent methods to access valuable chiral electron-withdrawing group-substituted tertiary hydroxyl-based carboxylic acids [19]. These progressive contributions highlight the versatility of allyl ketone nucleophiles in asymmetric synthesis.
The oxidation of homoallylic alcohols is known as the most direct and efficient method to synthesize allyl ketones. However, previous works revealed that yields of allyl ketones were non-quantitative (less than 70%; most gave poor conversions) through Jones oxidation or Dess-Martin oxidation [20,21,22]. In the course of our studies, allyl ketones were observed to easily isomerize to the more stable activated α,β-alkenes during of purification and storage [14,19]. The relative instability of allyl ketones means a major fraction of it forms the more stable precursor before vinylogous reactions, and complicating the process for large-scale synthesis.
The “one-pot” tandem strategy is known to sequentially perform multiple chemical transformations in a single reaction vessel without intermediary purification steps [23,24,25,26,27,28]. Owing to the significant potential in scale-up production, as well as saving costs, time, and waste generation, it has been recognized as one of the most promising paradigms in both industry and pharmaceuticals [23,24,25,26,27,28]. As an extension of our work towards direct asymmetric vinylogous reactions, we envisaged developing a tandem one-pot protocol involving both oxidation and asymmetric organocatalysis. The in situ generation of allyl ketone from homoallylic alcohol is fed directly into AVA, thus skipping intermediate purification.

2. Results and Discussion

To probe the feasibility of this one-pot asymmetric method, we initiated our study with the model reaction of homoallylic alcohol 1a with trifluoromethyl acetophenone 2a (Table 1). The Dess-Martin oxidation of homoallylic alcohol 1a in CH2Cl2 at 25 °C completed within 20 min, affording the corresponding allyl ketone 3a with full conversion. However there was no reaction after adding 2a under the AVA reaction conditions: 10 mol % of catalyst 4, 2.0 equiv. of Na3PO4 in tBuPh at −10 °C [19]. Subsequent Jones oxidation gave a cloudy reaction mixture requiring extraction and flash chromatography purification. After careful selection of diverse benzenes (such as benzene, toluene, chlorobenzene, and so on) as the solvent, only tert-butylbenzene was found to present a clear separation between the organic and aqueous phases, and the tandem Jones oxidation and direct AVA reaction of 1a can provide 5a in 80% yield and 95% ee after 38 h.
With optimized reaction conditions, we began assessing the potential of this one-pot sequential protocol in the reaction between homoallylic alcohols 1 and trifluoromethyl ketones 2. As shown in Table 2, the corresponding adduct 5 was obtained in 44%–95% yields with ee of 73%–99%. It should be noted that allyl ketones 1 with ortho-substituted phenyl groups gave deteriorated enantiomeric excesses (Table 2, entries 18 and 23), whereas allyl 2-thienyl ketone presented 5y with outstanding 98% ee (Table 2, entry 25). This is in contrast with the results of the AVA reaction between allyl ketones and trifluoromethyl ketones as reported [19], and overall yields were increased dramatically. A plausible mechanism for this asymmetric vinylogous aldol reaction is proposed via the transition-state model in the Supplementary Materials.
The established protocol was also used in vinylogous aldol reactions of vinyl ketones with α-ketoesters and α-keto phosphonates. Representative methyl benzoylformate 6a was selected to react with homoallylic alcohol 1a under the established reaction conditions. After the complete oxidation of 1a, asymmetric reaction was performed in the presence of 10 mol % of catalyst 4 and 2.0 equiv. of K2HPO4 as the acid-capturer in tBuPh at −20 °C (Scheme 1, (1)) It was found that the reaction was done in 48 h, affording the desired vinylogous aldol adduct 7a in 72% yield with 89% ee. Another activated acyclic ketones, diethyl benzoylphosphonate 8a was also attempted (Scheme 1, (2)) and the γ-selective adduct 9a was isolated in 67% yield with 92% ee after 50 h.
To demonstrate the synthetic value of this work, the sequential Jones oxidation/AVA reaction of homoallylic alcohol 1a with trifluoromethyl acetophenone 2a was conducted in 20 mmol or gram-scale (Scheme 2). Due to the scale-up, a longer reaction time of 54 h was necessary to fully oxidize 1a with Jones reagent. After removal of the aqueous phase, the AVA reaction with 2a was completed within 60 h, affording the product 5a in 79% yield with 95% ee after flash chromatography. During the course of reaction, the product 5a precipitated out; thus, a convenient filtration approach [20] could be carried out. Enantiopure 5a (>99% ee) as a white powder was obtained in 66% yield after filtration and rinsing with cold hexane (IMG-7, Scheme 2). This protocol, thus, has good potential in industry.

3. Materials and Methods

Experiments involving moisture and/or air sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet. Dried solvents and liquid reagents were transferred by oven-dried syringes or hypodermic syringe cooled to ambient temperature in a desiccator. Reaction mixtures were stirred in 10 mL sample vials with Teflon-coated magnetic stirring bars unless otherwise stated. Moisture in non-volatile reagents/compounds was removed in high vacuum by means of an oil pump and subsequent purging with nitrogen. Solvents were removed in vacuo under ~30 mmHg and heated with a water bath at 30–35 °C using a rotary evaporator with an aspirator. The condenser was cooled with running water at 0 °C.
All experiments were monitored by analytical thin layer chromatography (TLC). TLC was performed on pre-coated plates, 60 F254. After elution, each plate was visualized under UV illumination at 254 nm for UV-active material. Further visualization was achieved by staining with KMnO4, ceric molybdate, or anisaldehyde solution. For those using the aqueous stains, the TLC plates were heated on a hot plate.
Columns for flash chromatography (FC) contained 200–300 mesh silica gel. Columns were packed as slurry of silica gel in petroleum ether and equilibrated solution using the appropriate solvent system. The elution was assisted by applying pressure of about 2 atm with an air pump.
Proton nuclear magnetic resonance (1H-NMR) and carbon NMR (13C-NMR) spectra were recorded in CDCl3, unless otherwise stated. Chemical shifts are reported in parts per million (ppm), using the residual solvent signal as an internal standard: CDCl3 (1H-NMR: δ 7.26, singlet; 13C-NMR: δ 77.0, triplet). Multiplicities were given as: s (singlet), d (doublet), t (triplet), q (quartet), quintet, m (multiplets), dd (doublet of doublets), dt (doublet of triplets), and br (broad). Coupling constants (J) were recorded in Hertz (Hz). The number of proton atoms (n) for a given resonance was indicated by nH. The number of carbon atoms (n) for a given resonance was indicated by nC. HRMS was reported in units of mass of charge ratio (m/z). Mass samples were dissolved in CH3CN (HPLC grade) unless otherwise stated. Melting points were determined on a melting point apparatus.
Enantiomeric excesses were determined by chiral high-performance liquid chromatography (HPLC) analysis. UV detection was monitored at 254 nm, 230 nm, and 210 nm at the same time. HPLC samples were dissolved in HPLC grade isopropanol (IPA), unless otherwise stated.
All commercial reagents were purchased with the highest purity grade. They were used without further purification unless specified. All solvents used, mainly petroleum ether (PE) and ethyl acetate (EtOAc), were distilled. Anhydrous DCM was freshly distilled from CaH2 and stored under N2 atmosphere. tert-butylbenzene was freshly distilled from sodium/benzophenone before use. All compounds synthesized were stored in a −20 °C freezer and light-sensitive compounds were protected with aluminum foil.

3.1. General Experimental Procedure for the One-Pot Tandem Direct Asymmetric Vinylogous Aldol Reaction of Allyl Ketones 1 to Trifluoromethyl Ketones 2

Jones reagent (0.25 mL) was added dropwise to a solution of homoallic alcohols 1 (0.4 mmol, 4.0 equiv.) in tert-butylbenzene (1.0 mL) at 0 °C over a period of 3.5–7 h. When the reaction was completed (monitored by TLC), the sample was stewed for a moment until a clear separation between the organic and aqueous phase was formed, and the aqueous phase was released. Then the trifluoromethyl ketone 2 (0.1 mmol, 1.0 equiv.) was added, the reaction mixture was stirred at −10 °C for 10 min. Sodium phosphate (0.2 mmol, 2.0 equiv.) and catalyst 4 (0.01 mmol, 0.1 equiv.) were added sequentially (10 min interval). The reaction mixture was stirred at −10 °C and monitored by TLC. Upon complete consumption of trifluoromethyl ketone 2, the reaction mixture was directly loaded onto a short silica column, followed by gradient elution with PE/EA mixture (20/1–5/1 ratio). Removing the solvent in vacuum afforded products 5ay.

3.2. General Experimental Procedure for the One-Pot Tandem Direct Asymmetric Vinylogous Aldol Reaction of Homoallylic Alcohol 1a to Acyclic Activated Ketones (6a and 8a)

Jones reagent (0.45 mL) was added dropwise to a solution of homoallic alcohol 1a (0.4 mmol, 4 equiv.) in tert-butylbenzene (800 μL) at 0 °C over a period of 4 h. When the reaction was completed (monitored by TLC), the sample was stilled for a moment, and the aqueous phase was released. The reaction mixture was stirred at −20 °C for 10 min. Potassium phosphate anhydrous (0.2 mmol, 2.0 equiv.), catalyst 4 (0.01 mmol, 0.1 equiv.), and 6a/8a (0.1 mmol, 1.0 equiv.) were added sequentially (10 min interval). The reaction mixture was stirred at −20 °C and monitored by TLC. Upon complete consumption of acyclic activated ketones 6a/8a, the reaction mixture was directly loaded onto a short silica column, followed by gradient elution with PE/EA mixture (20/1–1/1 ratio). Removing the solvent in vacuum afforded products 7a/9a.
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-1,5-diphenylhex-2-en-1-one (5a): White solid, Mp 133.7–135.2 °C; 25.6 mg (0.1 mmol), 80% yield; 95% ee; [ α ] D 26 −36.4 (c 2.47, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.75 (d, J = 7.4 Hz, 2H), 7.59–7.51 (m, 3H), 7.46–7.33 (m, 5H), 6.91 (d, J = 15.5 Hz, 1H), 6.76–6.66 (m, 1H), 3.25–3.05 (m, 2H), 3.16 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 190.4, 140.6, 137.1, 135.8, 133.0, 130.7, 128.9, 128.6 (two peaks), 128.5, 126.3, 125.2 (q, J = 284.0 Hz), 77.7 (q, J = 28.2 Hz), 39.0; 19F-NMR (376 MHz, CDCl3) δ −79.55; HRMS (ESI) m/z 343.0928 [M + Na+], calc. for C18H15F3O2Na 343.0922. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 10.2 min (minor) and 11.2 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-1-phenyl-5-(4-(trifluoromethyl)phenyl)hex-2-en-1-one (5b): White solid, Mp 88.2–90.9 °C; 33.8 mg (0.1 mml), 87% yield; 92% ee; [ α ] D 26 –26.3 (c 2.47, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.75–7.66 (m, 6H), 7.51 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.8Hz, 2H), 6.92 (d, J = 15.5 Hz, 1H), 6.75–6.65 (m, 1H), 3.59 (s, 1H), 3.17 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 190.3, 140.0, 139.7, 136.9, 133.3, 131.8, 131.3, 130.9, 130.6, 130.4, 129.2 (two peaks), 128.6, 128.2, 127.0, 126.8, 125.6 (two peaks), 125.5 (two peaks), 125.4, 123.0, 122.0, 118.4, 77.2, 76.8, 76.4, 76.0, 39.0; 19F-NMR (376 MHz, CDCl3) δ −62.77, −79.37; HRMS (ESI) m/z 411.0797 [M + Na+], calc. for C19H14F6O2Na 411.0796. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 10.9 min (minor) and 15.4 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-(4-fluorophenyl)-5-hydroxy-1-phenylhex-2-en-1-one (5c): White solid, Mp 107.0–108.3 °C; 24.0 mg (0.1 mmol), 71% yield; 94% ee; [ α ] D 26 −31.0 (c 2.42, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.77 (d, 2H), 7.78–7.52 (m, 3H), 7.41 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 8.64 Hz, 2H), 6.92 (d, J = 15.5 Hz, 1H), 6.76–6.66 (m, 1H), 3.47 (s, 1H), 3.22–3.04 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 190.3, 164.5 , 161.2, 140.3, 137.0, 133.2, 131.8, 131.7, 130.7, 128.6 (two peaks), 128.5 (two peaks), 128.4 (two peaks), 125.1 (q, J = 283.4 Hz), 123.2, 115.6, 115.4, 76.4 (q, J = 28.4 Hz), 38.9; 19F-NMR (376 MHz, CDCl3) δ −79.80, −112.84; HRMS (ESI) m/z 361.0829 [M + Na+], calc. for C18H14F4O2Na 361.0828. The ee was determined by HPLC analysis. CHIRALPAK IB-3 (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 11.2 min (major) and 12.6 min (minor).
(−)-(S,E)-5-(4-Chlorophenyl)-6,6,6-trifluoro-5-hydroxy-1-phenylhex-2-en-1-one (5d): White solid, Mp 110.4–111.6 °C; 34.8 mg (0.1 mmol), 98% yield; 94% ee; [ α ] D 26 −46.6 (c 3.41, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.76 (d, J = 7.32 Hz, 2H), 7.53–7.50 (m, 3H), 7.44–7.37 (m, 4H), 6.91 (d, J = 15.51 Hz, 1H), 6.75–6.65 (m, 2H), 3.51 (s, 1H), 3.21–3.04 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 190.3, 140.1, 137.0, 135.0, 134.5, 133.2, 130.8, 128.8, 128.6 (two peaks), 127.9, 125.0 (q, J = 284.3 Hz), 76.5 (q, J = 28.5 Hz ), 38.9; 19F-NMR (376 MHz, CDCl3) δ −79.66; HRMS (ESI) m/z 377.0531 [M + Na+], calc. for C18H14ClF3O2Na 377.0532. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 6.8 min (minor) and 9.1 min (major).
(−)-(S,E)-5-(4-Bromophenyl)-6,6,6-trifluoro-5-hydroxy-1-phenylhex-2-en-1-one (5e): White solid, Mp 114.2–115.3 °C; 31.9 mg (0.1 mmol); 80% yield; 95% ee; [ α ] D 26 −54.5 (c 1.42, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.75 (d, J = 7.4 Hz, 2H), 7.56–7.53 (m, 3H), 7.47–7.39 (m, 4H), 6.90 (d, J = 15.5 Hz, 1H), 6.74–6.65 (m, 1H), 3.50 (s, 1H), 3.20–3.03 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 190.3, 140.1, 137.0, 135.1, 133.2, 131.7, 130.8, 128.6 (two peaks), 128.2 (two peaks), 126.8, 124.9 (q, J = 284.2 Hz), 123.3, 76.5 (q, J = 28.4 Hz), 38.9; 19F-NMR (376 MHz, CDCl3) δ −79.64; HRMS (ESI) m/z 423.0009 [M + Na+], calc. for C18H14BrF3O2Na 423.0006. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 7.0 min (minor) and 12.3 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-(3-fluorophenyl)-5-hydroxy-1-phenylhex-2-en-1-one (5f): Colorless oil; 32.1 mg (0.1 mmol), 95% yield; 91% ee; [ α ] D 26 −41.5 (c 2.56, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.78 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 2H), 7.45–7.32 (m, 5H), 7.08 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 15.5 Hz, 1H), 6.75–6.65 (m, 1H), 3.25 (s, 1H), 3.21–3.04 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 190.3 (two peaks), 164.5, 161.2, 140.1, 140.0, 138.6, 138.5, 137.0, 133.2, 130.8, 130.2, 130.1, 128.6 (two peaks), 125.0 (q, J = 284.0 Hz), 122.0 (two peaks), 116.0, 115.7, 114.2, 113.8 (two peaks), 76.2 (two peaks), 75.8 (two peaks), 39.0; 19F-NMR (376 MHz, CDCl3) δ −79.51, −111.68; HRMS (ESI) m/z 339.1004 [M + H+], calc. for C18H15F4O2 339.1008. The ee was determined by HPLC analysis. CHIRALPAK IB-3 (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 11.3 min (major) and 13.2 min (minor).
(−)-(S,E)-5-(3-Chlorophenyl)-6,6,6-trifluoro-5-hydroxy-1-phenylhex-2-en-1-one (5g): Colorless oil; 33.3 mg (0.1 mmol), 94% yield; 90% ee; [ α ] D 26 −35.6 (c 3.04, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.77 (d, J = 7.3 Hz, 2H), 7.62 (s, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.47–7.32 (m, 5H), 6.92 (d, J = 15.5 Hz, 1H), 6.74–6.64 (m, 1H), 3.54 (s, 1H), 3.21–3.05 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 190.4, 140.0, 138.1, 137.0, 134.7, 133.2, 130.9, 129.8, 129.1, 128.7, 128.6, 126.9, 126.8, 124.9 (q, J = 284.1 Hz), 124.6 (two peaks), 76.4 (q, J = 28.4 Hz), 39.0; 19F-NMR (376 MHz, CDCl3) δ −79.48; HRMS (ESI) m/z 377.0533 [M + Na+], calc. for C18H14ClF3O2 377.0532. The ee was determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 95/05; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 9.8 min (major) and 11.8 min (minor).
(−)-(S,E)-6,6,6-Trifluoro-5-(2-fluorophenyl)-5-hydroxy-1-phenylhex-2-en-1-one (5h): White solid, Mp 106.9–107.2 °C; 24.0 mg (0.1 mmol), 71% yield; 99% ee; [ α ] D 26 −26.5 (c 2.25, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.77–7.74 (m, 2H), 7.70–7.64 (m, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.42–7.34 (m, 3H), 7.21 (td, J = 7.9, 1.1 Hz, 1H), 7.13–7.06 (m, 1H), 7.00 (d, J = 15.5 Hz, 1H), 6.85–6.75 (m, 1H), 3.76 (d, J = 5.0 Hz, 1H), 3.60–3.52 (m, 1H), 3.08–3.00 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 190.5, 161.7, 158.4, 141.0, 137.2, 133.0, 131.4, 131.3, 130.4, 130 (two peaks), 128.6, 128.5, 124.9 (qd, J = 284.4, 1.7 Hz), 124.5 (two peaks), 122.4, 122.3, 116.8, 116.4, 76.2 (qd, J = 30, 3.6 Hz), 37.5, 37.4; 19F-NMR (376 MHz, CDCl3) δ −80.65, −80.69, −111.46, −111.50; HRMS (ESI) m/z 339.1004 [M + H+], calc. for C18H15F4O2 339.1008. The ee was determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 95/05; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 9.4 min (major) and 11.9 min (minor).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-1-phenyl-5-(p-tolyl)hex-2-en-1-one (5i): White solid, Mp 109.2–110.6 °C; 20.1 mg (0.1 mmol), 60% yield; 95% ee; [ α ] D 26 −51.2 (c 1.32, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.78–7.75 (m, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.46–7.38 (m, 4H), 7.22 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 15.5 Hz, 1H), 6.76–6.66 (m, 1H), 3.23–3.02 (m, 2H), 2.97 (d, J = 5.9 Hz, 1H), 2.37 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 190.3, 140.6, 138.8, 137.2, 133.0, 132.9, 130.7, 129.3, 128.6, 128.5, 127.1, 125.2 (q, J = 284.2 Hz), 76.7 (q, J = 28.2 Hz), 39.0, 21.0; 19F-NMR (376 MHz, CDCl3) δ −79.74; HRMS (ESI) m/z 357.1077 [(M + Na+], calc. for C19H17F3O2Na 357.1078. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 6.7 min (minor) and 10.8 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-1-phenyl-5-(m-tolyl)hex-2-en-1-one (5j): White solid, Mp 78.5–80.4 °C; 22.4 mg (0.1 mmol), 67% yield; 94% ee; [ α ] D 26 −45.8 (c 1.84, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.78–7.74 (m, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43–7.28 (m, 5H), 7.19 (d, J = 7.2 Hz, 1H), 6.92 (d, J = 15.5 Hz, 1H), 6.76–6.66 (m, 1H), 3.24–3.06 (m, 2H), 3.02, (s, 1H) 2.38 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 190.4, 140.7, 138.3, 137.2, 135.8, 133.0, 130.8, 129.7, 128.7, 128.6, 128.5, 127.0 (two peaks), 125.2 (q, J = 284.0 Hz), 123.4 (two peaks), 77.7 (q, J = 28.2 Hz), 39.1, 21.6; 19F-NMR (376 MHz, CDCl3) δ −79.99; HRMS (ESI) m/z 357.1087 [M + Na+], calc. for C19H17F3O2Na 357.1078. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 9.5 min (minor) and 11.0 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-5-(naphthalen-2-yl)-1-phenylhex-2-en-1-one (5k): White solid, Mp 163.1–164.9 °C; 25.9 mg (0.1 mmol), 70% yield; 91% ee; [ α ] D 26 −40.1 (c 0.87, CHCl3); 1H-NMR (300 MHz, acetone-d6) δ 8.30 (s, 1H), 8.00–7.92 (m, 3H), 7.83 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.58–7.51 (m, 3H), 7.36 (t, J = 7.7 Hz, 2H), 7.15 (d, J = 15.5 Hz, 1H), 6.76–6.67 (m, 1H), 6.13 (s, 1H), 3.63–3.56 (m, 1H), 3.31–3.24 (m, 1H); 13C-NMR (75 MHz, acetone-d6) δ 190.1, 141.7, 138.4, 135.2, 134.0, 133.9, 133.6, 131.1, 129.4, 129.3, 129.2, 128.8, 128.4, 127.8, 127.6, 127.3, 126.9 (q, J = 284.2 Hz), 77.5 (q, J = 27.5 Hz), 38.8; 19F-NMR (376 MHz, CDCl3) δ −79.23; HRMS (ESI) m/z 371.1257 [M + H+], calc. for C22H18F3O2 371.1259. The ee was determined by HPLC analysis. CHIRALPAK IE (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 95/05; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 11.8 min (minor) and 12.7 min (major).
(−)-(R,E)-6,6,6-Trifluoro-5-hydroxy-1-phenyl-5-(thiophen-2-yl)hex-2-en-1-one (5l): White solid, Mp 77.2–82.2 °C; 27.1 mg (0.1 mmol), 83% yield; 92% ee; [ α ] D 26 −26.6 (c 2.26, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.81 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 3.4 Hz, 1H), 7.04 (dd, J = 4.9, 3.9 Hz, 1H), 6.94 (d, J = 15.5 Hz, 1H), 6.87–6.78 (m, 1H), 3.58 (s, 1H), 3.13 (s, 1H), 3.10 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 190.4, 140.2, 140.0, 137.1, 133.1, 130.8, 128.7, 128.6, 127.3, 126.6, 126.1, 124.6 (q, J = 283.9 Hz), 76.4 (q, J = 29.7 Hz), 40.0; 19F-NMR (376 MHz, CDCl3) δ −80.58; HRMS (ESI) m/z 349.0493 [M + Na+], calc. for C16H13F3O2SNa 349.0486. The ee was determined by HPLC analysis. CHIRALPAK IB-3 (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 10.4 min (major) and 11.8 min (minor).
(+)-(R,E)-5-Hydroxy-1-phenyl-5-(trifluoromethyl)hept-2-en-1-one (5m): Colorless oil; 16.3 mg (0.1 mmol), 60% yield; 91% ee; [ α ] D 26 +12.4 (c 0.74, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.94–7.92 (m, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.08–6.93 (m, 2H), 2.72 (d, J = 5.07 Hz, 2H), 2.36 (s, 1H), 1.81 (q, J = 7.6 Hz, 2H), 1.04 (t, J = 7.6 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 190.2, 141.2, 137.4, 133.0, 129.8, 128.6 (two peaks), 126.2 (q, J = 284.9 Hz), 75.4 (q, J = 26.9 Hz), 36.5, 27.0, 7.2; 19F-NMR (376 MHz, CDCl3) δ −79.51; HRMS (ESI) m/z 273.1103 [M + H+], calc. for C14H16F3O2 273.1102. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 7.0 min (major) and 7.7 min (minor).
(−)-(S,E)-6,6,6-Trifluoro-1-(4-fluorophenyl)-5-hydroxy-5-phenylhex-2-en-1-one (5n): White solid, Mp 106.7–108.0 °C; 27.7 mg (0.1 mmol), 82% yield; 95% ee; [ α ] D 26 −30.2 (c 2.30, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.79–7.72 (m, 2H), 7.57 (d, J = 7.0 Hz, 2H), 7.45–7.36 (m, 3H), 7.10–7.03 (m, 2H), 6.86 (d, J = 15.5 Hz, 1H), 6.75–6.65 (m, 1H), 3.27 (s, 1H), 3.25–3.17 (m, 1H), 3.12–3.04 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 188.89, 167.4, 164.0, 140.9, 135.9, 133.5, 133.4, 131.3, 131.2, 130.3, 128.9, 128.6, 126.3, 125.2 (q, J = 284.1 Hz), 115.8, 115.5, 76.7 (q, J = 28.1 Hz), 39.0; 19F-NMR (376 MHz, CDCl3) δ −79.56, −105.09; HRMS (ESI) m/z 339.1015 [M + H+], calc. for C18H15F4O2 339.1008. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 8.0 min (minor) and 9.9 min (major).
(−)-(S,E)-1-(4-Chlorophenyl)-6,6,6-trifluoro-5-hydroxy-5-phenylhex-2-en-1-one (5o): White solid, Mp 90.1–91.5 °C; 30.5 mg (0.1 mmol), 86% yield; 96% ee; [ α ] D 26 −37.2 (c 2.60, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.67–7.63 (m, 2H), 7.57 (d, J = 6.8 Hz, 2H), 7.47–7.34 (m, 5H), 6.83 (d, J = 15.5 Hz, 1H), 6.75–6.65 (m, 1H), 3.34 (s, 1H), 3.24–3.17 (m, 1H), 3.12–3.04 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 189.3, 141.3, 139.5, 135.8, 135.4, 130.2, 130.0, 128.9, 128.8, 128.6, 126.30 (two peaks), 125.2 (q, J = 284.2 Hz), 76.7 (q, J = 28.2 Hz), 39.0; HRMS (ESI) m/z 355.0720[M + H+], calc. for C18H15ClF3O2 355.0713. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 11.0 min (minor) and 16.7 min (major).
(−)-(S,E)-6,6,6-Trifluoro-1-(3-fluorophenyl)-5-hydroxy-5-phenylhex-2-en-1-one (5p): White solid, Mp 87.1–88.9 °C; 31.1 mg (0.1 mmol), 92% yield; 96% ee; [ α ] D 26 −27.5 (c 1.32, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.58–7.50 (m, 3H), 7.46–7.35 (m, 5H), 7.23–7.20 (m, 1H), 6.84 (d, J = 15.6 Hz, 1H), 6.77–6.70 (m, 1H), 3.22 (m, 1H), 3.08 (m, 1H), 2.87 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 189.0, 164.4, 161.1, 141.3, 139.4, 139.3, 135.8, 130.4, 130.3, 130.2, 129.0, 128.7, 126.3, 125.2 (q, J = 283.9 Hz), 124.3 (two peaks), 120.2, 119.9, 115.6, 115.3, 39.1; HRMS (ESI) m/z 339.1010 [M + H+], calc. for C18H15F4O2 339.1008. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 7.6 min (minor) and 8.6 min (major).
(−)-(S,E)-1-(3-Chlorophenyl)-6,6,6-trifluoro-5-hydroxy-5-phenylhex-2-en-1-one (5q): Colorless oil; 28.4 mg (0.1 mmol), 80% yield; 95% ee; [ α ] D 26 −38.2 (c 1.82, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.70 (t, J = 1.8 Hz, 1H), 7.59 (t, J = 8.2 Hz, 3H), 7.51–7.31 (m, 5H), 6.83 (d, J = 15.6 Hz, 1H), 6.76–6.66 (m, 1H), 3.25–3.18 (m, 1H), 3.12–3.05 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 189.0, 141.5, 138.7, 135.7, 134.8, 132.9, 130.3, 129.8, 129.0, 128.6, 126.6, 126.2 (two peaks), 125.2 (q, J = 284.0 Hz), 76.2, 39.0; HRMS (ESI) m/z 355.0703 [M + H+], calc. for C18H15ClF3O2 355.0713. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 7.7 min (minor) and 8.8 min (major).
(−)-(S,E)-6,6,6-Trifluoro-1-(2-fluorophenyl)-5-hydroxy-5-phenylhex-2-en-1-one (5r): White solid, Mp 74.0–75.9 °C; 22.0 mg (0.1 mmol), 65% yield; 88% ee; [ α ] D 26 −40.5 (c 1.86, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.64–7.55 (m, 3H), 7.52–7.35 (m, 4H), 7.20–7.05 (m, 2H), 6.83 (dd, J = 15.5, 3.0 Hz, 1H), 6.73–6.64 (m, 1H), 3.23–3.16 (m, 1H), 3.07–3.03 (m, 1H), 2.96 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 188.4, 162.9, 159.5, 140.6, 135.8, 134.3, 134.2, 134.0, 133.9, 131.0, 130.9, 128.9, 128.5, 126.3 (two peaks), 125.1 (q, J = 284.2 Hz), 124.5, 124.4, 116.6, 116.3, 76.6 (q, J = 28.3 Hz), 38.9; HRMS (ESI) m/z 339.1009 [M + H+], calc. for C18H15F4O2 339.1008. The ee was determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 95/05; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 9.3 min (major) and 11.1 min (minor).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-5-phenyl-1-(p-tolyl)hex-2-en-1-one (5s): White solid, Mp 106.2–107.7 °C; 30.8 mg (0.1 mmol), 92% yield; 95% ee; [ α ] D 26 −33.2 (c 1.69, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.45–7.38 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 6.74–6.64 (m, 1H), 6.78–6.61 (m, 1H), 3.24–3.04 (m, 3H), 2.39 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 189.8, 143.9, 140.0, 136.0, 134.6, 130.8, 129.2, 128.8 (two peaks), 126.3 (two peaks), 125.2 (q, J = 284.1 Hz), 76.7, 39.0, 21.6; HRMS (ESI) m/z 335.1261 [(M + H+], calc. for C19H18F3O2 335.1259. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 13.6 min (minor) and 19.3 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-5-phenyl-1-(m-tolyl)hex-2-en-1-one (5t): Colorless oil; 30.4 mg (0.1 mmol), 91% yield; 94% ee; [ α ] D 26 −40.7 (c 2.46, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.59–7.53 (m, 4H), 7.45–7.28 (m, 5H), 6.89 (d, J = 15.5 Hz, 1H), 6.74–6.64 (m, 1H), 3.25–3.18 (m, 1H), 3.15 (s, 1H), 3.12–3.04 (m, 1H), 2.36 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 190.6, 140.2, 138.4, 137.2, 135.9, 133.8, 131.0, 130.9, 129.2, 128.8, 128.6, 128.4, 126.3 (two peaks), 125.8, 125.2 (q, J = 284.0 Hz), 76.7 (q, J = 28.2 Hz), 39.0, 21.3; HRMS (ESI) m/z 335.1257 [M + H+], calc. for C19H18F3O2 335.1259. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 10.5 min (minor) and 11.9 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-1-(4-methoxyphenyl)-5-phenylhex-2-en-1-one (5u): White solid, Mp 107.7–109.2 °C; 25.9 mg (0.1 mmol), 74% yield; 95% ee; [ α ] D 26 −39.6 (c 2.20, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 7.0 Hz, 2H), 7.43–7.35 (m, 3H), 6.93–6.86 (m, 3H), 6.73–6.63 (m, 1H), 3.85 (s, 3H), 3.33 (s, 1H), 3.23–3.16 (m, 1H), 3.11–3.04 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 188.6, 163.6, 139.4, 136.0, 131.0, 130.6, 130.0, 128.8, 128.5, 127.1, 126.4 (two, peaks), 125.2 (q, J = 284.0 Hz), 113.8, 76.7 (q, J = 28.1 Hz), 55.4, 38.9; HRMS (ESI) m/z 351.1212 [M + H+], calc. for C19H18F3O2 351.1208. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 12.1 min (minor) and 15.0 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-1-(3-methoxyphenyl)-5-phenylhex-2-en-1-one (5v): Colorless oil; 27.7 mg (0.1 mmol), 79% yield; 94% ee; [ α ] D 26 −36.3 (c 2.76, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.57 (d, J = 7.1 Hz, 2H), 7.45–7.38 (m, 3H), 7.33–7.31 (m, 3H), 7.11–7.06 (m, 1H), 6.89 (d, J = 15.5 Hz, 1H), 6.77–6.67 (m, 1H), 3.81 (s, 3H), 3.25–3.18 (m, 1H), 3.12–3.04 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 190.0, 159.8, 140.5, 138.6, 135.9, 130.8, 129.5, 128.9, 128.6, 126.3, 125.2 (q, J = 284.2 Hz), 121.3, 119.7, 112.8, 76.7 (q, J = 28.2 Hz), 55.4, 39.0; HRMS (ESI) m/z 351.1211 [M + H+], calc. for C19H18F3O3 351.1208. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 17.7 min (minor) and 19.8 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-1-(2-methoxyphenyl)-5-phenylhex-2-en-1-one (5w): Colorless oil; 15.4 mg (0.1 mmol), 44% yield; 73% ee; [ α ] D 26 −38.3 (c 1.17, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.57 (d, J = 7.0 Hz, 2H), 7.48–7.34 (m, 5H), 7.00–6.91 (m, 2H), 6.83 (d, J = 15.6 Hz, 1H), 6.59–6.48 (m, 1H), 3.83 (s, 3H), 3.18–3.11 (m, 1H), 3.08–3.01 (m, 1H), 2.93 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 192.0, 158.1, 137.8, 136.2, 136.1, 133.3, 130.5, 128.8, 128.5, 128.2, 126.3, 125.1 (q, J = 283.9 Hz), 120.8, 111.5, 76.4 (q, J = 28.1 Hz), 55.7, 38.8; HRMS (ESI) m/z 351.1204 [M + H+], calc. for C19H18F3O3 351.1208. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 95/05; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 19.3 min (minor) and 22.1 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-1-(naphthalen-2-yl)-5-phenylhex-2-en-1-one (5x): White solid, Mp 91.4–93.2 °C; 29.6 mg (0.1 mmol), 80% yield; 93% ee; [ α ] D 26 −28.0 (c 3.13, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 8.20 (s, 1H), 7.87–7.80 (m, 4H), 7.63–7.37 (m, 7H), 7.04 (d, J = 15.5 Hz, 1H), 6.83–6.73 (m, 1H), 3.43 (d, J = 3.3 Hz, 1H), 3.30–3.22 (m, 1H), 3.17–3.10 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 190.3, 140.5, 136.0, 135.5, 134.4, 132.3, 130.8, 130.4, 129.5, 128.9, 128.6, 128.5 (two peaks), 126.7, 126.4 (two peaks), 125.2 (q, J = 283.9 Hz), 76.7 (q, J = 28.1 Hz), 38.9; HRMS (ESI) m/z 371.1258 [M + H+], calc. for C22H18F3O2 371.1259. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 12.5 min (minor) and 20.9 min (major).
(−)-(S,E)-6,6,6-Trifluoro-5-hydroxy-5-phenyl-1-(thiophen-2-yl)hex-2-en-1-one (5y): White solid, Mp 126.3–128.0 °C; 27.1 mg (0.1 mmol), 83% yield; 98% ee; [ α ] D 26 −44.6 (c 2.46, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.64–7.56 (m, 4H), 7.44–7.34 (m, 3H), 7.11–7.08 (m, 1H), 6.84 (d, J = 15.3 Hz, 1H), 6.80–6.73 (m, 1H), 3.26–3.18 (m, 2H), 3.11–3.05 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 181.7, 144.4, 139.9, 135.9, 134.4, 132.5, 130.1, 128.9, 128.5, 128.2, 126.3, 125.2 (q, J = 284.1 Hz), 76.6 (q, J = 28.3 Hz), 38.8; HRMS (ESI) m/z 327.0666 [M + H+], calc. for C16H14F3O2S 327.0667. The ee was determined by HPLC analysis. CHIRALPAK IB (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 30.6 min (minor) and 31.5 min (major).
(+)-(S,E)-Methyl 2-hydroxy-6-oxo-2,6-diphenylhex-4-enoate (7a): Colorless oil; 24.2 mg (0.1 mmol), 78% yield; 89% ee; [ α ] D 26 +5.8 (c 1.27, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.85–7.82 (m, 2H), 7.63–7.52 (m, 3H), 7.46–7.30 (m, 5H), 6.92–6.90 (m, 2H), 3.82 (s, 4H), 3.22–3.15 (m, 1H), 3.06–3.00 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 190.7, 174.5, 142.6, 140.8, 137.6, 132.7, 129.9, 128.6, 128.5 (two peaks), 128.2, 125.3, 78.0, 53.5, 43.0; HRMS (ESI) m/z 333.1092 [M + H+], calc. for C19H18O4Na 333.1103. The ee was determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 20.7 min (minor) and 23.6 min (major).
(−)-(R,E)-Diethyl (1-hydroxy-5-oxo-1,5-diphenylpent-3-en-1-yl)phosphonate (9a): White solid; Mp 130.1‒131.9 °C; 26.0 mg (0.1 mmol), 67% yield; 92% ee; [ α ] D 26 −16.1 (c 1.13, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.73–7.70 (m, 2H), 7.76–7.59 (m, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.5 Hz, 4H), 7.31 (dd, J = 7.2, 1.6 Hz, 1H), 6.86–6.70 (m, 2H), 4.17–4.07 (m, 2H), 4.04–3.89 (m, 1H), 3.87–3.76 (m, 1H), 3.63 (d, J = 6.7 Hz, 1H), 3.21 (t, J = 7.1 Hz, 2H), 3.21 (t, J = 7.1 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 190.8, 142.4, 142.2, 138.1, 137.5, 132.6, 130.3, 128.6, 128.4, 128.3, 128.2, 127.7, 127.6, 126.1 (two peaks), 76.6, 74.5, 63.7, 63.6, 63.5, 63.4, 41.4, 41.3, 16.4, 16.3 (two peaks), 16.2; HRMS (ESI) m/z 411.1336 [M + Na+], calc. for C21H25O5P 411.1337. The ee was determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time: 19.2 min (minor) and 22.4 min (major).

4. Conclusions

In summary, we have developed an elaborate one-pot tandem strategy, which allowed homoallyic alcohols to be successfully employed in the direct AVA reaction with a series of activated acyclic ketones, such as trifluoromethyl ketones, α-ketoesters, and α-keto phosphonates, in high yields, γ-selectivity, and stereoselectivity. This modular combination, including Jones oxidation and asymmetric hydrogen bonding catalysis, features satisfactory compatibility and reliability, albeit without an intermediary purification step. This methodology also presents effective in large-scale synthesis. We anticipate that this efficient one-pot tandem paradigm will find application in more types of direct vinylogous reactions using homoallylic alcohols as pro-nucleophiles.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/21/7/842/s1.

Acknowledgments

We are grateful for the grants from NSFC (21072044) and Henan province (14IRTSTHN006, 152300410057, 162300410002 and 162300410209).

Author Contributions

Xufeng Hou and Zhenzhong Jing contributed equally to this paper. Zhiyong Jiang conceived the idea of this piece of research; Xufeng Hou, Zhenzhong Jing and Xiangbin Bai designed the experiments; Xufeng Hou and Zhenzhong Jing performed the chemical experiments; Zhenzhong Jing and Xiangbin Bai performed the spectra analyses; Zhiyong Jiang wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Chinchilla, R.; Nájera, C. Acylvinyl and vinylogous synthons. Chem. Rev. 2000, 100, 1891–1928. [Google Scholar] [CrossRef] [PubMed]
  2. Casiraghi, G.; Zanardi, F. The vinylogous aldol reaction: A valuable, yet understated carbon-carbon bond-forming maneuver. Chem. Rev. 2000, 100, 1929–1972. [Google Scholar] [CrossRef] [PubMed]
  3. Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. The vinylogous aldol and related addition reactions: Ten years of progress. Chem. Rev. 2011, 111, 3076–3154. [Google Scholar] [CrossRef] [PubMed]
  4. Yan, L.; Wu, X.; Liu, H.; Xie, L.; Jiang, Z. Catalytic asymmetric synthesis of γ-butenolides by direct vinylogous reactions. Mini-Rev. Med. Chem. 2013, 13, 845–853. [Google Scholar] [CrossRef] [PubMed]
  5. Zhang, Q.; Liu, X.; Feng, X. Recent advances in enantioselective synthesis of γ-substituted butenolides via the catalytic asymmetric vinylogous reactions. Curr. Org. Synth. 2013, 10, 764–785. [Google Scholar] [CrossRef]
  6. Das Sarma, K.; Zhang, J.; Curran, T.T. Novel synthons from mucochloric acid: The first use of α,β-dichloro-γ-butenolides and γ-butyrolactams for direct vinylogous aldol addition. J. Org. Chem. 2007, 72, 3311–3318. [Google Scholar] [CrossRef] [PubMed]
  7. Ube, H.; Shimada, N.; Terada, M. Asymmetric direct vinylogous aldol reaction of furanone derivatives catalyzed by an axially chiral guanidine base. Angew. Chem. Int. Ed. 2010, 49, 1858–1861. [Google Scholar] [CrossRef] [PubMed]
  8. Yang, Y.; Zheng, K.; Zhao, J.; Shi, J.; Lin, L.; Liu, X.; Feng, X. Asymmetric direct vinylogous aldol reaction of unactivated γ-butenolide to aldehydes. J. Org. Chem. 2010, 75, 5382–5384. [Google Scholar] [CrossRef] [PubMed]
  9. Pansare, S.V.; Paul, E.K. Organocatalytic asymmetric direct vinylogous aldol reactions of γ-crotonolactone with aromatic aldehydes. Chem. Commun. 2011, 47, 1027–1029. [Google Scholar] [CrossRef] [PubMed]
  10. Bastida, D.; Liu, Y.; Tian, X.; Escudero-Adán, E.; Melchiorre, P. Asymmetric vinylogous aldol reaction via H-bond-directing dienamine catalysis. Org. Lett. 2013, 15, 220–223. [Google Scholar] [CrossRef] [PubMed]
  11. Luo, J.; Wang, H.; Han, X.; Xu, L.W.; Kwiatkowski, J.; Huang, K.W.; Lu, Y. The Direct asymmetric vinylogous aldol reaction of furanones with α-ketoesters: Access to chiral γ-butenolides and glycerol derivatives. Angew. Chem. Int. Ed. 2011, 50, 1861–1864. [Google Scholar] [CrossRef] [PubMed]
  12. Yazaki, R.; Kumagai, N.; Shibasaki, M. Direct catalytic asymmetric addition of allyl cyanide to ketones. J. Am. Chem. Soc. 2009, 131, 3195–3197. [Google Scholar] [CrossRef] [PubMed]
  13. Yazaki, R.; Kumagai, N.; Shibasaki, M. Direct catalytic asymmetric addition of allyl cyanide to ketones via soft Lewis acid/hard Brønsted base/hard Lewis base catalysis. J. Am. Chem. Soc. 2010, 132, 5522–5531. [Google Scholar] [CrossRef] [PubMed]
  14. Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.; Tan, D.; Jiang, Z. Direct asymmetric vinylogous aldol reaction of allyl ketones with isatins: Divergent synthesis of 3-hydroxy-2-oxindole derivatives. Angew. Chem. Int. Ed. 2013, 52, 6666–6670. [Google Scholar] [CrossRef] [PubMed]
  15. Li, T.Z.; Jiang, Y.; Guan, Y.Q.; Sha, F.; Wu, X.Y. Direct enantioselective vinylogous aldol-yclization cascade reaction of allyl pyrazoleamides with isatins: Asymmetric construction of spirocyclic oxindole-dihydropyranones. Chem. Commun. 2014, 50, 10790–10792. [Google Scholar] [CrossRef] [PubMed]
  16. Jiang, L.; Lei, Q.; Huang, X.; Cui, H.L.; Zhou, X.; Chen, Y.C. Lewis base assisted Brønsted base catalysis: Direct regioselective asymmetric vinylogous alkylation of allylic sulfones. Chem. Eur. J. 2011, 17, 9489–9493. [Google Scholar] [CrossRef] [PubMed]
  17. Zhan, G.; He, Q.; Yuan, X.; Chen, Y.C. Asymmetric direct vinylogous Michael additions of allyl alkyl ketones to maleimides through dienamine catalysis. Org. Lett. 2014, 16, 6000–6603. [Google Scholar] [CrossRef] [PubMed]
  18. Gu, Y.; Wang, Y.; Yu, T.Y.; Liang, Y.M.; Xu, P.F. Rationally designed multifunctional supramolecular iminium catalysis: Direct vinylogous Michael addition of unmodified linear dienol substrates. Angew. Chem. Int. Ed. 2014, 53, 14128–14131. [Google Scholar] [CrossRef] [PubMed]
  19. Jing, Z.; Bai, X.; Chen, W.; Zhang, G.; Zhu, B.; Jiang, Z. Organocatalytic enantioselective vinylogous aldol reaction of allyl aryl ketones to activated acyclic ketones. Org. Lett. 2016, 18, 260–263. [Google Scholar] [CrossRef] [PubMed]
  20. Jiang, D.; Peng, J.; Chen, Y. Pd-catalyzed carboetherification of β,γ-unsaturated oximes: A novel approach to Δ2-isoxazolines. Org. Lett. 2008, 10, 1695–1698. [Google Scholar] [CrossRef] [PubMed]
  21. Zhuo, L.G.; Yao, Z.K.; Yu, Z.X. Synthesis of Z-alkenes from Rh (I)-catalyzed olefin isomerization of β,γ-unsaturated ketones. Org. Lett. 2013, 15, 4634–4637. [Google Scholar] [CrossRef] [PubMed]
  22. Qiao, B.; Huang, Y.J.; Nie, J.; Ma, J.A. Highly regio-, diastereo-, and enantioselective Mannich reaction of allylic ketones and cyclic ketimines: Access to chiral benzosultam. Org. Lett. 2015, 17, 4608–4611. [Google Scholar] [CrossRef] [PubMed]
  23. Enders, D.; Grondal, C.; Huettl, M.R. Asymmetric organocatalytic domino reactions. Angew. Chem. Int. Ed. 2007, 46, 1570–1581. [Google Scholar] [CrossRef] [PubMed]
  24. Walji, A.M.; MacMillan, D.W. Strategies to bypass the taxol problem. Enantioselective cascade catalysis, a new approach for the efficient construction of molecular complexity. Synlett 2007, 10, 1477–1489. [Google Scholar] [CrossRef]
  25. Gaunt, M.J.; Johansson, C.C.; McNally, A.; Vo, N.T. Enantioselective organocatalysis. Drug Discov. Today 2007, 12, 8–27. [Google Scholar] [CrossRef] [PubMed]
  26. Dondoni, A.; Massi, A. Asymmetric organocatalysis: From infancy to adolescence. Angew. Chem. Int. Ed. 2008, 47, 4638–4660. [Google Scholar] [CrossRef] [PubMed]
  27. Albrecht, Ł.; Jiang, H.; Jørgensen, K.A. A Simple recipe for sophisticated cocktails: Organocatalytic one-pot reactions-concept, nomenclature, and future perspectives. Angew. Chem. Int. Ed. 2011, 50, 8492–8509. [Google Scholar] [CrossRef] [PubMed]
  28. Bernardi, L.; Fochi, M.; Franchini, M.C.; Ricci, A. Bioinspired organocatalytic asymmetric reactions. Org. Biomol. Chem. 2012, 10, 2911–2922. [Google Scholar] [CrossRef] [PubMed]
  • Sample Availability: All samples are available from the authors.
Scheme 1. Expansion of substrate scope: (1) the reaction of 1a to methyl benzoylformate 6a; (2) the reaction of 1a to diethyl benzoylphosphonate 8a.
Scheme 1. Expansion of substrate scope: (1) the reaction of 1a to methyl benzoylformate 6a; (2) the reaction of 1a to diethyl benzoylphosphonate 8a.
Molecules 21 00842 sch001
Scheme 2. The one-pot tandem synthesis of 5a from 1a and 2a in a 20 mmol scale: flash chromatography: 79% yield (5.07 g), 95% ee; filtration and wash: 66% yield (4.23 g), >99% ee. Images (IMG): (1) 5a in tBuPh (500 mL container); (2): initiation of Jones oxidation; (3): duration of oxidation; (4): after oxidation (a clear stratification between organic and aqueous phase); (5): after aqueous phase was released; (6): after AVA reaction of 2a (white precipitant is 5a); (7): product 5a with >99% ee (after filtrated and washed with cool hexane, white solid).
Scheme 2. The one-pot tandem synthesis of 5a from 1a and 2a in a 20 mmol scale: flash chromatography: 79% yield (5.07 g), 95% ee; filtration and wash: 66% yield (4.23 g), >99% ee. Images (IMG): (1) 5a in tBuPh (500 mL container); (2): initiation of Jones oxidation; (3): duration of oxidation; (4): after oxidation (a clear stratification between organic and aqueous phase); (5): after aqueous phase was released; (6): after AVA reaction of 2a (white precipitant is 5a); (7): product 5a with >99% ee (after filtrated and washed with cool hexane, white solid).
Molecules 21 00842 sch002
Table 1. Investigation of reaction conditions a.
Table 1. Investigation of reaction conditions a.
Molecules 21 00842 i001
EntryOxidation ConditionsConversion of 3a bYield of 5a cee of 5a d
1DMP (2.0 equiv.), CH2Cl2, 25 °C, 20 min>99%0 (N.R.)N.D.
2Jones reagent (1.5 equiv.), CH2Cl2, 25 °C, 10 min>99%0 (N.R.)N.D.
3Jones reagent (1.5 equiv.), tBuPh, 0 °C, 4.0 h, then aqueous phase released>99%8095
a Reaction conditions: 1a (0.4 mmol), 2a (0.1 mmol), 2.0 equiv. of Na3PO4, 0.8 mL solvent; b the conversion was determined by the crude 1H-NMR; c yield of isolated product; d Ees were determined by HPLC analysis on a chiral stationary phase. DMP = Dess-Martin Periodinane.
Table 2. One-pot tandem reactions between homoallylic alcohols 1 and trifluoromethyl ketones 2 a.
Table 2. One-pot tandem reactions between homoallylic alcohols 1 and trifluoromethyl ketones 2 a.
Molecules 21 00842 i002
EntryR1R2t (h)5Yield (%) bee (%) c
1PhC6H4385a8095
2Ph4-CF3-C6H4395b8792
3Ph4-F-C6H4395c7194
4Ph4-Cl-C6H4605d9894
5Ph4-Br-C6H4415e8095
6Ph3-F-C6H4385f9591
7Ph3-Cl-C6H4615g9490
8Ph2-F-C6H4785h7199 d
9Ph4-Me-C6H4625i6095
10Ph3-Me-C6H4605j6794
11Ph2-naphthyl665k7091
12Ph2-thienyl635l8392
13PhEt805m6091
144-FC6H4Ph615n8295
154-ClC6H4Ph705o8696
163-FC6H4Ph595p9296
173-ClC6H4Ph705q8095
182-FC6H4Ph645r6588
194-MeC6H4Ph645s9295
203-MeC6H4Ph615t9194
214-MeOC6H4Ph345u7495
223-MeOC6H4Ph615v7994
232-MeOC6H4Ph645w4473
242-napthylPh705x8093
252-thienylPh655y8398
a Reaction conditions: 1 (0.4 mmol), Jones reagent (1.5 equiv.), 1.0 mL tBuPh, 0 °C, then 2 (0.1 mmol), catalyst IV (0.01 mmol), Na3PO4 (0.2 mmol), −10 °C. In all reactions, the ratio of E/Z was >20:1 determined by crude 1H-NMR; b Yield of isolated product; c determined by HPLC analysis on a chiral stationary phase; d the ee value and yield were obtained after a single recrystallization. Initial data: 80% yield, 85% ee.
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