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Access to Chiral HWE Reagents by Rhodium-Catalyzed Asymmetric. Arylation of γ ..... silica gel chromatography with CH2Cl2/EA (3:2) as the eluent to a...
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Access to Chiral HWE Reagents by Rhodium-Catalyzed Asymmetric Arylation of γ,δ-Unsaturated β‑Ketophosphonates Long Yin,§,† Dewei Zhang,§,‡ Junhao Xing,† Yuhan Wang,† Changhui Wu,† Tao Lu,†,# Yadong Chen,*,‡ Tamio Hayashi,*,¶ and Xiaowei Dou*,† †

Department of Organic Chemistry and ‡Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China # State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China ¶ Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore S Supporting Information *

ABSTRACT: Asymmetric arylation of γ,δ-unsaturated β-ketophosphonates with arylboronic acids is reported. By using the (R)diene* ligated rhodium(I) chloride complex as a catalyst under none basic conditions, the corresponding β-ketophosphonates bearing a δ-chiral center were obtained in high yields (up to 99%) with good to excellent enantioselectivities (up to >99% ee). The enantioenriched products can be readily converted to diverse chiral β′-aryl enones by the Horner−Wadsworth−Emmons reaction. Scheme 1. Asymmetric Conjugate Addition to γ,δUnsaturated β-Ketophosphonates

T

he Horner−Wadsworth−Emmons (HWE) reaction is one of the most useful methods for the preparation of olefins,1 and the HWE reagents (for example, β-carbonyl phosphonates) are versatile synthons and widely used in the synthesis of various building blocks, natural products, as well as pharmaceuticals.2 Despite the great successes achieved in the development of the HWE reaction, examples on the asymmetric synthesis of chiral HWE reagents are rare. Asymmetric conjugate addition to γ,δ-unsaturated β-ketophosphonates represents a convenient approach to those molecules:3 Kim and co-workers developed a Zn(II)-catalyzed asymmetric radical conjugate addition of γ,δ-unsaturated βketophosphonates, and alkyl groups could be introduced to the δ-position with high enantioselectivities.3a Besides, the asymmetric Friedel−Crafts reaction of indoles with γ,δunsaturated β-ketophosphonates was also studied.3b,c However, the available chiral HWE reagents accessed by this route are still greatly limited as a general method to introduce the aryl groups remains unknown. To address this challenge, we report herein a general asymmetric conjugate arylation of γ,δ-unsaturated βketophosphonates (Scheme 1). The rhodium-catalyzed conjugate arylation reactions of activated olefins with arylboronic acids have progressed remarkably since the seminal reports4 and have now become one of the most reliable methods to generate benzylic chiral centers.5 Despite the numerous reports on the rhodiumcatalyzed arylation reactions of α,β-unsaturated carbonyl © 2018 American Chemical Society

compounds,5,6 arylation of α,β-unsaturated ketones bearing an α′-electron-withdrawing group has not been studied. Such a transformation may be hampered by several challenges. First, the adjacent electron-withdrawing group helps stabilize the enol form of the ketone and thus may result in a low reactivity of the substrate toward the conjugate arylation reaction. Moreover, it is proved that the catalytically active hydroxorhodium catalyst can be immediately converted to the acetylacetonate rhodium complex in the presence of acetylacetone, resulting in a much less catalytically active rhodium species;7 similarly, α,βunsaturated ketones bearing an α′-electron-withdrawing group Received: April 16, 2018 Published: May 1, 2018 5869

DOI: 10.1021/acs.joc.8b00952 J. Org. Chem. 2018, 83, 5869−5875

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The Journal of Organic Chemistry

2). Chiral diene ligands have proved to be powerful in the rhodium-catalyzed asymmetric arylation reactions,8 and we then tested the effects of those privileged ligands. Although the (R,R)-Ph-bod9 ligand did not give a satisfactory ee value (entry 3, 54% ee), gratifyingly, the easily accessible (R)-diene*-ligated rhodium catalyst10 produced the product in a good yield with an excellent enantioselectivity (entry 4, 95% ee). A further screening of solvents showed that toluene was the best to give the product in 95% yield with the maintained ee value (entries 4−6). When the catalyst loading was reduced, the recently developed base-free condition11 was found to be slightly superior to the traditional condition (entries 7 and 8). Finally, the catalyst loading could be further reduced to 1 mol % Rh without erosion of the yield and enantioselectivity (entry 9). With the optimal reaction conditions, the scope of the reaction was then examined. As summarized in Table 2, diverse

may also deactivate the rhodium catalyst in the same manner (Scheme 2). Nevertheless, with an aim to address the Scheme 2. Rhodium-Catalyzed Arylation of α,β-Unsaturated Carbonyl Compounds

Table 2. Substrate Scope for the Conjugate Arylation of γ,δUnsaturated β-Ketophosphonatesa aforementioned issue in the synthesis of chiral HWE reagents, as well as to study the rhodium-catalyzed arylation of α,βunsaturated ketones bearing an α′-electron-withdrawing group, we embarked on a project to investigate the rhodium-catalyzed asymmetric arylation of γ,δ-unsaturated β-ketophosphonates. We commenced our investigation with the model reaction between γ,δ-unsaturated β-ketophosphonate 1a and 3-methoxyphenylboronic acid 2a, and the results are summarized in Table 1. In the first set of the experiments, chiral bisphosphine ligands (R)-binap and (R)-segphos-coordinated rhodium catalysts were found to catalyze the reaction efficiently, furnishing the conjugate addition product 3a in a high yield, but the enantioselectivities were only moderate (entries 1 and Table 1. Rhodium-Catalyzed Asymmetric Conjugate Arylation of γ,δ-Unsaturated β-Ketophosphonate 1aa

entry 1 2 3 4 5 6 7f 8f,g 9g,h

Rh catalyst [Rh(OH)((R)-binap)]2d [Rh(OH)((R)-segphos)]2d [RhCl((R,R)-Ph-bod)]2e [RhCl((R)-diene*)]2e [RhCl((R)-diene*)]2e [RhCl((R)-diene*)]2e [RhCl((R)-diene*)]2e [RhCl((R)-diene*)]2 [RhCl((R)-diene*)]2

solvent

yield (%)b

ee (%)c

dioxane dioxane dioxane dioxane DCE toluene toluene toluene toluene

95 92 91 88 83 95 90 95 95

76 74 54 95 95 95 95 95 95

entry

3 (R, Ar)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

3a (C6H5, 3-OMe-C6H4) 3b (C6H5, 2-Me-C6H4)d 3c (C6H5, 3-Me-C6H4) 3d (C6H5, 4-Me-C6H4) 3e (C6H5, 4-OMe-C6H4) 3f (C6H5, 3-Cl-C6H4)d 3g (C6H5, 3-Br-C6H4) 3h (C6H5, 4-Br-C6H4)d 3i (C6H5, 4-Ac-C6H4)d 3j (C6H5, 4-CO2Me-C6H4)d 3k (C6H5, 1-naphthyl)d 3l (C6H5, 2-naphthyl)d 3m (C6H5, 3-thienyl)e 3n (2-Cl-C6H4, C6H5) 3o (3-F-C6H4, C6H5) 3p (4-Cl-C6H4, C6H5) 3q (3,4-Cl2−C6H3, C6H5) 3r (3,4-OCH2O−C6H4, C6H5) 3s (Me, C6H5) 3t (Et, C6H5) 3u (Me, 4-Me-C6H4) 3v (Et, 3-thienyl)e 3w (Et, 2-furyl)e

95 99 98 91 94 91 97 99 88 98 84 95 88 90 82 85 94 90 91 93 92 92 49

95 99 93 93 93 96 95 96 97 96 >99 95 98 95 94 95 92 92 92 96 92 97 95

a

Reactions were performed with 1 (0.15 mmol), 2 (1.5 equiv to 1), and [RhCl((R)-diene*)]2 (1 mol % Rh) in toluene/H2O (1.0/0.5 mL) at 60 °C for 14 h. bYield of the isolated product 3. cThe ee value was determined by HPLC analysis on a chiral stationary phase column. d 0.30 mmol of 2 (2 equiv to 1) was used. e0.45 mmol of 2 (3 equiv to 1) was used.

aryl boronic acids could be employed in this reaction system, and generally high yields and excellent enantioselectivities were attainable. Aryl boronic acids bearing electron-donating groups (entries 1−5), halogen substitutions (entries 6−8), as well as electron-withdrawing groups (entries 9 and 10) at different positions were all well-tolerated. Other aryl boronic acids such as naphthyl boronic acids and 3-thienyl boronic acid worked equally well under optimal reaction conditions, and a perfect ee value was obtained when 1-naphthyl boronic acid was

a

Reactions were performed with 1a (0.15 mmol), 2a (1.5 equiv to 1a), and Rh catalyst (5 mol % Rh) in solvent/H2O (1.0/0.1 mL) at 60 °C for 5 h. bYield of the isolated 3a. cThe ee value was determined by HPLC analysis on a chiral stationary phase column. dGenerated in situ from [Rh(OH)(cod)2]2 (5 mol % Rh) and ligand (6 mol %). eKOH (10 mol %) was added. f[RhCl((R)-diene*)]2 (2 mol % Rh) was used. g 0.5 mL of H2O was added, and the reaction time was 14 h. h [RhCl((R)-diene*)]2 (1 mol % Rh) was used. 5870

DOI: 10.1021/acs.joc.8b00952 J. Org. Chem. 2018, 83, 5869−5875

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The Journal of Organic Chemistry

In summary, we have developed the first asymmetric conjugate arylation reaction of γ,δ-unsaturated β-ketophosphonates. The strategy developed here features a broad substrate scope, low catalyst loading, high yield, and good to excellent enantiocontrol, which provides a practical method for preparing the useful enantioenriched HWE reagents. We hope the current method will find broad applications in organic synthesis.

employed (entries 11−13). In addition, γ,δ-unsaturated βketophosphonates bearing different δ-substitutions were also verified. For instance, reactions employing substrates 1 bearing diversely substituted δ-aryl groups proceeded smoothly to yield the desired products with good results (entries 14−18); those substrates bearing δ-alkyl substitutions were also suitable to afford the corresponding arylation products in high yields with good to excellent enantioselectivities (entries 19−23). Notably, 3-thienyl boronic acid worked well for both the δ-aryl and δalkyl substrates, producing the products in a high yield with an excellent enantiocontrol (entries 13 and 22). Other heteroaryl boronic acids like the 2-furyl one also produced the product with a high ee value, but the yield was only moderate due to the fast protodeboronation under the reaction conditions (entry 23). To demonstrate the practicality of this transformation, a gram-scale synthesis was carried out. As shown in Scheme 3A,

■

EXPERIMENTAL SECTION

General Information. All air-sensitive manipulations were carried out with standard Schlenk techniques under nitrogen or argon. NMR spectra were recorded on a Bruker AVANCE AV-500 spectrometer (500 MHz for 1H, 125 MHz for 13C) or Bruker AVANCE AV-300 spectrometer (300 MHz for 1H, 75 MHz for 13C). Chemical shifts were reported in δ (ppm) referenced to the residual solvent peak of CDCl3 (δ 7.26) for 1H NMR and CDCl3 (δ 77.0) for 13C NMR. Coupling constants were reported in hertz (Hz). Optical rotations were measured on a RUDOLPH AUTOPOL IV automatic polarimeter. High resolution mass spectra (HRMS) were obtained on a Thermo Scientific LTQ Orbitrap XL (ESI) unit. For thin layer chromatography (TLC), Yantai precoated TLC plates (HSGF 254) were used, and compounds were visualized with a UV light at 254 nm. Further visualization was achieved by staining with KMnO4 followed by heating. Column chromatography separations were performed on silica gel (300−400 mesh). Enantiomeric excesses (ee) were determined by HPLC analysis on a SHIMADZU HPLC system with Daicel chiral columns. General Procedure for the Synthesis of 3. [RhCl((R)diene*)]2 (0.8 mg, 0.75 μmol, 1 mol % Rh) and arylboronic acid 2 (0.225 or 0.3 mmol) were placed in an oven-dried Schlenk tube under nitrogen. Toluene (0.4 mL), substrate 1 (0.15 mmol), H2O (0.5 mL), and another portion of toluene (0.6 mL) were added successively, and the mixture was stirred at 60 °C for 14 h. Upon completion, the reaction mixture was passed through a short column of silica gel with EtOAc as an eluent. The solvent was removed on a rotary evaporator, and the crude product was subjected to silica gel chromatography with CH2Cl2/EA (3:2) as the eluent to afford product 3. Gram-Scale Synthesis of 3e. [RhCl((R)-diene*)]2 (15.1 mg, 15 μmol, 1 mol % Rh) and 2e (683.8 mg, 4.5 mmol) were placed in an oven-dried Schlenk tube under nitrogen. Toluene (10 mL), substrate 1a (762.7 mg, 3.0 mmol), H2O (10 mL) and another portion of toluene (10 mL) were added successively, and the mixture was stirred at 60 °C for 20 h. Upon completion, the reaction mixture was passed through a short column of silica gel with EtOAc as eluent. The solvent was removed on a rotary evaporator, and the crude product was subjected to silica gel chromatography with CH2Cl2/EA (3:2) as the eluent to afford product 3e (1.01 g, 93% yield, 93% ee). Procedure for the Synthesis of 4. To a solution of 3e (54.4 mg, 0.15 mmol) in EtOH (2 mL) were added K2CO3 (41.5 mg, 0.3 mmol) and the corresponding aldehyde (0.3 mmol), and the mixture was stirred at room temperature. After completion of the reaction as indicated by TLC analysis, the mixture was extracted with CH2Cl2, washed with H2O, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography with PE/EA (10/1) as the eluent to afford product 4. Procedure for the Synthesis of 5. To a solution of 3e (54.4 mg, 0.15 mmol) in EtOH (2 mL) were added K2CO3 (41.5 mg, 0.3 mmol) and acetone (3.0 mmol), and the mixture was stirred at 50 °C for 12 h. After completion, the mixture was extracted with CH2Cl2, washed with H2O, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography with PE/EA (50/1) as the eluent to afford product 5. Characterization of the Products. Dimethyl (R)-(4-(3-Methoxyphenyl)-2-oxo-4-phenylbutyl)phosphonate (3a): 95% yield, 95% ee (R), pale yellow oil, 51.8 mg at 0.15 mmol scale; HPLC analysis Chiralcel IA column, 1.0 mL/min, hexane/2-propanol = 70.0/30.0, 254 nm, tmajor = 7.4 min (R), tminor = 8.5 min (S); [α]25 D −2.3 (c 0.3, CHCl3) for 95% ee (R); 1H NMR (300 MHz, CDCl3) δ 3.04 (d, JP−H = 22.6 Hz, 2H), 3.41 (d, J = 7.6 Hz, 2H), 3.71 (dt, JP−H = 11.3, 2.0 Hz,

Scheme 3. Gram-Scale Synthesis and Derivatization of the Product

when the reaction was scaled up to 3.0 mmol, product 3e could be obtained with almost no change in chemical yield and stereoselectivity. The asymmetric arylation products 3 obtained here with a high % ee are readily converted into enones bearing a β′-chiral center by the HWE reaction. For instance, 3e was allowed to react with aryl and alkyl aldehydes under mild conditions to produce the corresponding chiral β′-aryl enones in high yields with the maintained ee value (Scheme 3B). The enantioenriched β′-aryl enones are versatile building blocks in organic synthesis, and their asymmetric synthesis has been a continuous research interest.12 Our protocol provides an alternative approach to that reported by Willis.12a The arylation product also reacted with ketones to give the β′-aryl-β,βdisubstituted enones. For example, (S)-ar-turmerone 5 was synthesized from the arylation product 3u and acetone (Scheme 3C), which represents one of the most efficient asymmetric synthesis routes to this sesquiterpene.13 The absolute configurations of 4a and 5 were determined by comparison of their specific rotation with that reported,14 and the absolute configurations of products 3e and 3u were accordingly assigned. 5871

DOI: 10.1021/acs.joc.8b00952 J. Org. Chem. 2018, 83, 5869−5875

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The Journal of Organic Chemistry

1 16.1 min (S); [α]25 D −9.6 (c 0.4, CHCl3) for 95% ee (R); H NMR (300 MHz, CDCl3) δ 3.03 (d, JP−H = 22.9 Hz, 2H), 3.39 (m, 2H), 3.69 (dd, JP−H = 11.3, 5.0 Hz, 6H), 4.56 (t, J = 7.5 Hz, 1H), 7.09−7.33 (m, 8H), 7.39 (d, J = 1.9 Hz, 1H); 31P NMR (CDCl3, 121 MHz) δ 21.9; 13 C NMR (125 MHz, CDCl3) δ 41.4, 42.4, 45.2, 49.6, 53.0, 53.1, 122.6, 126.6, 126.8, 127.7, 128.7, 129.6, 130.1, 130.8, 142.8, 146.0, 199.20, 199.24; HRMS (ESI) calcd for C18H2179BrO4P+ [M + H]+ 411.0355, found 411.0351; HRMS (ESI) calcd for C18H2181BrO4P+ [M + H]+ 413.0335, found 413.0333. Dimethyl (R)-(4-(4-Bromophenyl)-2-oxo-4-phenylbutyl)-phosphonate (3h): 99% yield, 96% ee (R), pale yellow oil, 61.2 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 40.0/60.0, 254 nm, tmajor = 17.1 min (R), tminor = 1 14.0 min (S); [α]25 D −7.3 (c 0.3, CHCl3) for 96% ee (R); H NMR (300 MHz, CDCl3) δ 3.03 (d, JP−H = 22.9 Hz, 2H), 3.39 (m, 2H), 3.68 (dd, JP−H = 11.2, 1.5 Hz, 6H), 4.56 (t, J = 7.4 Hz, 1H), 7.09−7.31 (m, 7H), 7.35−7.42 (m, 2H); 31P NMR (CDCl3, 121 MHz) δ 22.0; 13C NMR (125 MHz, CDCl3) δ 41.4, 42.4, 45.0, 49.7, 52.98, 53.03, 120.3, 126.7, 127.7, 128.7, 129.6, 131.6, 142.6, 143.0, 199.3; HRMS (ESI) calcd for C18H2179BrO4P+ [M + H]+ 411.0355, found 411.0351; calcd for C18H2181BrO4P+ [M + H]+ 413.0335, found 413.0333. Dimethyl (R)-(4-(4-Acetylphenyl)-2-oxo-4-phenylbutyl)-phosphonate (3i): 88% yield, 97% ee (R), pale yellow oil, 49.4 mg at 0.15 mmol scale; HPLC analysis Chiralcel IF column, 1.0 mL/min, hexane/2propanol = 80.0/20.0, 254 nm, tmajor = 57.4 min (R), tminor = 54.6 min 1 (S); [α]25 D −15 (c 0.3, CHCl3) for 97% ee (R); H NMR (300 MHz, CDCl3) δ 2.56 (d, J = 1.5 Hz, 3H), 3.06 (d, JP−H = 23.4 Hz, 2H), 3.47 (m, 2H), 3.70 (dd, JP−H = 11.3, 1.4 Hz, 6H), 4.67 (t, J = 7.4 Hz, 1H), 7.16−7.33 (m, 5H), 7.34−7.40 (m, 2H), 7.88 (dd, J = 8.3, 1.5 Hz, 2H); 31P NMR (CDCl3, 121 MHz) δ 22.0; 13C NMR (125 MHz, CDCl3) δ 26.5, 41.3, 42.4, 45.5, 49.5, 52.96, 53.02, 126.8, 127.7, 128.0, 128.6, 128.7, 135.5, 142.7, 149.0, 197.5, 199.2, 199.3; HRMS (ESI) calcd for C20H24O5P+ [M + H]+ 375.1356, found 375.1354. Dimethyl (R)-4-(4-(Dimethoxyphosphoryl)-3-oxo-1-phenylbutyl)benzoate (3j): 98% yield, 96% ee (R), pale yellow oil, 57.6 mg at 0.15 mmol scale; HPLC analysis Chiralcel IB column, 1.0 mL/min, hexane/ 2-propanol = 70.0/30.0, 254 nm, tmajor = 32.4 min (R), tminor = 30.2 1 min (S); [α]25 D −12 (c 0.4, CHCl3) for 96% ee (R); H NMR (300 MHz, CDCl3) δ 3.04 (d, JP−H = 22.9 Hz, 2H), 3.44 (m, 2H), 3.68 (d, JP−H = 11.2 Hz, 6H), 3.87 (s, 3H), 4.66 (t, J = 7.4 Hz, 1H), 7.14−7.24 (m, 3H), 7.28 (d, J = 1.6 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.90−7.99 (m, 2H); 31P NMR (CDCl3, 121 MHz) δ 21.9; 13C NMR (125 MHz, CDCl3) δ 41.4, 42.4, 45.6, 49.5, 52.0, 53.98, 53.03, 126.8, 127.8, 127.9, 128.5, 128.7, 130.0, 142.8, 148.8, 166.8, 199.25, 199.30; HRMS (ESI) calcd for C20H24O6P+ [M + H]+ 391.1305, found 391.1303. Dimethyl (R)-(4-(Naphthalen-1-yl)-2-oxo-4-phenylbutyl)-phosphonate (3k): 84% yield, > 99% ee (R), pale yellow oil, 48.3 mg at 0.15 mmol scale; HPLC analysis Chiralcel IA column, 1.0 mL/min, hexane/2-propanol = 70.0/30.0, 254 nm, tmajor = 7.1 min (R), tminor = 1 10.2 min (S); [α]25 D −14 (c 0.3, CHCl3) for >99% ee (R); H NMR (300 MHz, CDCl3) δ 3.02 (d, JP−H = 22.9 Hz, 2H), 3.43−3.61 (m, 2H), 3.68 (dd, JP−H = 11.2, 8.9 Hz, 6H), 5.43 (t, J = 7.3 Hz, 1H), 7.08−7.19 (m, 1H), 7.20−7.26 (m, 2H), 7.27−7.32 (m, 2H), 7.35− 7.52 (m, 4H), 7.73 (dd, J = 7.1, 2.3 Hz, 1H), 7.80−7.84 (m, 1H), 8.08−8.19 (m, 1H); 31P NMR (CDCl3, 121 MHz) δ 22.2; 13C NMR (125 MHz, CDCl3) δ 41.2, 41.3, 42.3, 50.5, 52.9, 53.98, 53.04, 123.7, 124.5, 125.2, 125.5, 126.2, 126.5, 127.4, 128.0, 128.5, 128.8, 131.5, 134.1, 138.9, 143.4, 199.7, 199.8; HRMS (ESI) calcd for C22H24O4P+ [M + H]+ 383.1407, found 383.1402. Dimethyl (R)-(4-(Naphthalen-2-yl)-2-oxo-4-phenylbutyl)-phosphonate (3l): 95% yield, 95% ee (R), pale yellow oil, 54.7 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 60.0/40.0, 254 nm, tmajor = 22.9 min (R), tminor = 1 21.1 min (S); [α]25 D −27 (c 0.5, CHCl3) for 95% ee (R); H NMR (300 MHz, CDCl3) δ 3.05 (d, JP−H = 22.8 Hz, 2H), 3.45−3.62 (m, 2H), 3.69 (dd, JP−H = 11.2, 4.2 Hz, 6H), 4.80 (t, J = 7.4 Hz, 1H), 7.17−7.25 (m, 1H), 7.28−7.32 (m, 4H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.40−7.51 (m, 2H), 7.69−7.86 (m, 4H); 31P NMR (CDCl3, 121 MHz) δ 22.2; 13C NMR (125 MHz, CDCl3) δ 41.4, 42.5, 45.8, 49.8, 52.96, 53.02, 125.6, 125.8, 126.1, 126.6, 126.7, 127.6, 127.8, 128.0,

6H), 3.78 (d, J = 1.4 Hz, 3H), 4.58 (t, J = 7.4 Hz, 1H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 7.13−7.35 (m, 6H); 31P NMR (CDCl3, 121 MHz) δ 22.2; 13C NMR (125 MHz, CDCl3) δ 41.4, 42.4, 45.8, 49.9, 52.9, 53.0, 55.2, 111.6, 114.0, 120.1, 126.5, 127.7, 128.6, 129.5, 143.4, 145.1, 159.8, 199.69, 199.74; HRMS (ESI) calcd for C19H24O5P+ [M + H]+ 363.1356, found 363.1352. Dimethyl (R)-(2-Oxo-4-phenyl-4-(o-tolyl)butyl)phosphonate (3b): 99% yield, 99% ee (R), pale yellow oil, 51.5 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 40.0/60.0, 254 nm, tmajor = 13.4 min (R), tminor = 11.1 min (S); [α]25 D −47 (c 0.3, CHCl3) for 99% ee (R); 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 3.03 (d, JP−H = 22.8 Hz, 2H), 3.40 (d, J = 7.6 Hz, 2H), 3.64−3.77 (m, 6H), 4.81 (t, J = 7.4 Hz, 1H), 7.13−7.31 (m, 9H); 31P NMR (CDCl3, 121 MHz) δ 22.3; 13C NMR (125 MHz, CDCl3) δ 19.8, 41.4, 41.6, 42.4, 50.3, 52.9, 53.0, 126.1, 126.3, 126.4, 126.5, 128.1, 128.5, 130.8, 136.4, 141.2, 143.2, 199.8, 199.9; HRMS (ESI) calcd for C19H24O4P+ [M + H]+ 347.1407, found 347.1404. Dimethyl (R)-(2-Oxo-4-phenyl-4-(m-tolyl)butyl)phosphonate (3c): 98% yield, 93% ee (R), pale yellow oil, 50.9 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2propanol = 60.0/40.0, 254 nm, tmajor = 19.7 min (R), tminor = 15.4 min 1 (S); [α]25 D −2.0 (c 0.5, CHCl3) for 93% ee (R); H NMR (300 MHz, CDCl3) δ 2.22 (s, 3H), 2.93 (d, JP−H = 22.7 Hz, 2H), 3.32 (dd, J = 7.5, 1.7 Hz, 2H), 3.60 (dt, JP−H = 11.3, 2.1 Hz, 6H), 4.47 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.94−6.98 (m, 2H), 7.08 (t, J = 7.5 Hz, 2H), 7.15−7.22 (m, 4H); 31P NMR (CDCl3, 121 MHz) δ 22.2; 13C NMR (125 MHz, CDCl3) δ 21.4, 41.4, 42.4, 45.7, 50.0, 52.9, 53.0, 124.7, 126.4, 127.3, 127.8, 128.4, 128.5, 128.6, 138.1, 143.5, 143.7, 199.8, 199.9; HRMS (ESI) calcd for C19H24O4P+ [M + H]+ 347.1407, found 347.1404. Dimethyl (R)-(2-Oxo-4-phenyl-4-(p-tolyl)butyl)phosphonate (3d): 91% yield, 93% ee (R), pale yellow oil, 47.2 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 40.0/60.0, 254 nm, tmajor = 12.8 min (R), tminor = 11.5 min (S); [α]25 D −1.6 (c 0.4, CHCl3) for 93% ee (R); 1H NMR (300 MHz, CDCl3) δ 2.31 (s, 3H), 3.03 (dd, JP−H = 22.8, 1.5 Hz, 2H), 3.41 (d, J = 7.6 Hz, 2H), 3.71 (dt, JP−H = 11.3, 2.0 Hz, 6H), 4.58 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H), 7.13−7.22 (m, 3H), 7.23−7.33 (m, 4H); 31P NMR (CDCl3, 121 MHz) δ 22.3; 13C NMR (125 MHz, CDCl3) δ 20.9, 41.4, 42.4, 45.4, 50.0, 52.9, 53.0, 126.4, 127.6, 127.7, 128.5, 129.3, 136.0, 140.5, 143.8, 199.86, 199.91; HRMS (ESI) calcd for C19H24O4P+ [M + H]+ 347.1407, found 347.1404. Dimethyl (R)-(4-(4-Methoxyphenyl)-2-oxo-4-phenylbutyl)-phosphonate (3e): 94% yield, 93% ee (R), pale yellow oil, 51.1 mg at 0.15 mmol scale; HPLC analysis Chiralcel IB column, 1.0 mL/min, hexane/2-propanol = 60.0/40.0, 254 nm, tmajor = 15.3 min (R), tminor = 1 16.9 min (S); [α]25 D −2.3 (c 0.4, CHCl3) for 93% ee (R); H NMR (300 MHz, CDCl3) δ 3.00 (d, JP−H = 22.6 Hz, 2H), 3.37 (d, J = 7.6 Hz, 2H), 3.68 (dd, JP−H = 11.1, 1.7 Hz, 6H), 3.75 (s, 3H), 4.54 (t, J = 7.4 Hz, 1H), 6.76−6.85 (m, 2H), 7.11−7.30 (m, 7H); 31P NMR (CDCl3, 121 MHz) δ 22.1; 13C NMR (125 MHz, CDCl3) δ 41.4, 42.4, 45.0, 50.1, 52.9, 53.0, 55.2, 114.0, 126.4, 127.7, 128.5, 128.7, 135.7, 143.9, 158.2, 199.88, 199.93; HRMS (ESI) calcd for C19H24O5P+ [M + H]+ 363.1356, found 363.1352. Dimethyl (R)-(4-(3-Chlorophenyl)-2-oxo-4-phenylbutyl)-phosphonate (3f): 91% yield, 96% ee (R), pale yellow oil, 50.0 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 40.0/60.0, 254 nm, tmajor = 15.9 min (R), tminor = 1 12.3 min (S); [α]25 D −12 (c 0.3, CHCl3) for 96% ee (R); H NMR (300 MHz, CDCl3) δ 3.04 (d, JP−H = 22.9 Hz, 2H), 3.40 (m, 2H), 3.69 (dd, JP−H = 11.3, 4.5 Hz, 6H), 4.57 (t, J = 7.4 Hz, 1H), 7.10−7.34 (m, 9H); 31P NMR (CDCl3, 121 MHz) δ 21.9; 13C NMR (125 MHz, CDCl3) δ 41.4, 42.4, 45.3, 49.6, 53.0, 126.1, 126.7, 126.8, 127.7, 127.9, 128.7, 129.8, 134.3, 142.8, 145.7, 199.2, 199.3; HRMS (ESI) calcd for C18H21ClO4P+ [M + H]+ 367.0860, found 367.0858. Dimethyl (R)-(4-(3-Bromophenyl)-2-oxo-4-phenylbutyl)-phosphonate (3g): 97% yield, 95% ee (R), pale yellow oil, 59.9 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 60.0/40.0, 254 nm, tmajor = 22.2 min (R), tminor = 5872

DOI: 10.1021/acs.joc.8b00952 J. Org. Chem. 2018, 83, 5869−5875

Note

The Journal of Organic Chemistry

1 16.5 min (R); [α]25 D +4.0 (c 0.3, CHCl3) for 92% ee (S); H NMR (500 MHz, CDCl3) δ 3.04 (d, JP−H = 22.8 Hz, 2H), 3.38 (d, J = 7.5 Hz, 2H), 3.74 (dd, JP−H = 11.2, 7.2 Hz, 6H), 4.55 (t, J = 7.4 Hz, 1H), 5.92 (s, 2H), 6.71−6.78 (m, 3H), 7.18−7.23 (m, 1H), 7.24−7.34 (m, 4H); 31P NMR (CDCl3, 121 MHz) δ 22.3; 13C NMR (75 MHz, CDCl3) δ 41.0, 42.7, 45.4, 50.0, 53.0, 53.1, 100.9, 108.2, 108.3, 120.6, 126.5, 127.6, 128.6, 137.5, 143.6, 146.1, 147.8, 199.76, 199.84; HRMS (ESI) calcd for C19H22O6P+ [M + H]+ 377.1149, found 377.1150. Dimethyl (S)-(2-Oxo-4-phenylpentyl)phosphonate (3s): 91% yield, 92% ee (S), pale yellow oil, 36.8 mg at 0.15 mmol scale; HPLC analysis Chiralcel IB column, 1.0 mL/min, hexane/2-propanol = 70.0/30.0, 254 nm, tmajor = 13.2 min (S), tminor = 14.9 min (R); [α]25 D +20 (c 0.1, CHCl3) for 92% ee (S); 1H NMR (300 MHz, CDCl3) δ 1.30 (d, JP−H = 7.0 Hz, 3H), 2.82−3.06 (m, 4H), 3.25−3.44 (m, 1H), 3.74 (dd, JP−H = 12.8, 11.2 Hz, 6H), 7.16−7.27 (m, 3H), 7.27−7.29 (m, 1H), 7.32 (dt, J = 6.8, 1.2 Hz, 1H); 31P NMR (CDCl3, 121 MHz) δ 22.4; 13C NMR (75 MHz, CDCl3) δ 21.9, 35.1, 40.9, 42.6, 52.2, 53.0, 126.4, 126.9, 128.5, 145.8, 200.7, 200.8; HRMS (ESI) calcd for C13H20O4P+ [M + H]+ 271.1094, found 271.1093. Dimethyl (S)-(2-Oxo-4-phenylhexyl)phosphonate (3t): 93% yield, 96% ee (S), pale yellow oil, 40.0 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 80.0/ 20.0, 254 nm, tmajor = 25.2 min (S), tminor = 28.7 min (R); [α]25 D +22 (c 0.4, CHCl3) for 96% ee (S); 1H NMR (300 MHz, CDCl3) δ 0.79 (t, J = 7.4 Hz, 3H), 1.48−1.80 (m, 2H), 2.90−3.02 (m, 4H), 3.02−3.12 (m, 1H), 3.71 (dd, JP−H = 17.5, 11.2 Hz, 6H), 7.15−7.23 (m, 3H), 7.26− 7.33 (m, 2H); 31P NMR (CDCl3, 121 MHz) δ 22.5; 13C NMR (75 MHz, CDCl3) δ 12.0, 29.2, 41.0, 42.6, 42.7, 50.80, 50.82, 52.9, 52.97, 53.00, 53.1, 126.4, 127.6, 128.4, 143.9, 200.9, 201.0; HRMS (ESI) calcd for C14H22O4P+ [M + H]+ 285.1250, found 285.1248. Dimethyl (S)-(2-Oxo-4-(p-tolyl)pentyl)phosphonate (3u): 92% yield, 92% ee (S), pale yellow oil, 39.3 mg at 0.15 mmol scale; HPLC analysis Chiralcel IB column, 1.0 mL/min, hexane/2-propanol = 70.0/30.0, 254 nm, tmajor = 11.8 min (S), tminor = 13.1 min (R); [α]25 D +20 (c 0.2, CHCl3) for 92% ee (S); 1H NMR (300 MHz, CDCl3) δ 1.18 (d, JP−H = 6.9 Hz, 3H), 2.24 (s, 3H), 2.70−2.97 (m, 4H), 3.13− 3.31 (m, 1H), 3.66 (t, JP−H = 11.3 Hz, 6H), 7.00−7.07 (m, 4H); 31P NMR (CDCl3, 121 MHz) δ 22.6; 13C NMR (125 MHz, CDCl3) δ 20.9, 22.0, 34.8, 41.3, 42.3, 52.3, 52.9, 52.9, 53.0, 126.7, 129.2, 135.8, 142.8, 200.7, 200.8; HRMS (ESI) calcd for C14H22O4P+ [M + H]+ 285.1250, found 285.1249. Dimethyl (S)-(2-Oxo-4-(thiophen-3-yl)hexyl)phosphonate (3v): 92% yield, 97% ee (S), colorless oil, 40.1 mg at 0.15 mmol scale; HPLC analysis Chiralcel IB column, 1.0 mL/min, hexane/2-propanol = 80.0/20.0, 210 nm, tmajor = 10.3 min (S), tminor = 9.5 min (R); [α]25 D +25 (c 0.3, CHCl3) for 97% ee (S); 1H NMR (500 MHz, CDCl3) δ 0.84 (t, J = 7.3 Hz, 3H), 1.54−1.74 (m, 2H), 2.86−2.95 (m, 2H), 2.95−3.05 (m, 2H), 3.20−3.28 (m, 1H), 3.74 (dd, JP−H = 22.0, 11.2 Hz, 6H), 6.97 (dd, J = 4.9, 1.4 Hz, 1H), 7.00 (dd, J = 3.0, 1.3 Hz, 1H), 7.27 (dd, J = 5.0, 3.0 Hz, 1H); 31P NMR (CDCl3, 121 MHz) δ 22.4; 13 C NMR (125 MHz, CDCl3) δ 11.7, 28.9, 37.8, 41.2, 42.2, 50.4, 52.87, 52.93, 120.4, 125.4, 126.7, 144.7, 200.7, 200.8; HRMS (ESI) calcd for C12H20O4PS+ [M + H]+ 291.0814, found 291.0812. Dimethyl (S)-(4-(Furan-2-yl)-2-oxohexyl)phosphonate (3w): 49% yield, 95% ee (S), colorless oil, 20.2 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 80.0/ 20.0, 210 nm, tmajor = 26.1 min (S), tminor = 29.5 min (R); [α]25 D +6.2 (c 0.2, CHCl3) for 95% ee (S); 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.4 Hz, 3H), 1.66 (d, J = 7.4 Hz, 1H), 1.70 (dd, J = 7.5, 1.6 Hz, 1H), 2.89 (dd, J = 17.2, 6.4 Hz, 1H), 3.01 (dd, J = 17.2, 7.5 Hz, 1H), 3.05 (d, JP−H = 22.7 Hz, 2H), 3.26 (p, J = 7.0 Hz, 1H), 3.80 (dd, JP−H = 11.3, 8.3 Hz, 6H), 6.06 (d, J = 3.1 Hz, 1H), 6.30 (dd, J = 3.2, 1.9 Hz, 1H), 7.31−7.35 (m, 1H); 31P NMR (CDCl3, 121 MHz) δ 22.5; 13C NMR (125 MHz, CDCl3) δ 11.5, 26.8, 35.7, 41.1, 42.1, 47.9, 52.96, 53.01, 105.4, 110.0, 141.0, 200.3, 200.4; HRMS (ESI) calcd for C12H20O5P+ [M + H]+ 275.1043, found 275.1045. (R,E)-5-(4-Methoxyphenyl)-1,5-diphenylpent-1-en-3-one (4a): known compound12a 97% yield, 93% ee (R), white solid, mp 123− 125 °C, 50.0 mg at 0.15 mmol scale; HPLC analysis Chiralcel IA column, 1.0 mL/min, hexane/2-propanol = 80.0/20.0, 254 nm, tmajor =

128.3, 128.6, 132.3, 133.5, 140.9, 143.4, 199.7, 199.8; HRMS (ESI) calcd for C22H24O4P+ [M + H]+ 383.1407, found 383.1402. Dimethyl (R)-(2-Oxo-4-phenyl-4-(thiophen-3-yl)butyl)-phosphonate (3m): 88% yield, 98% ee (R), colorless oil, 44.7 mg at 0.15 mmol scale; HPLC analysis Chiralcel IB column, 1.0 mL/min, hexane/ 2-propanol = 80.0/20.0, 210 nm, tmajor = 29.6 min (R), tminor = 17.6 1 min (S); [α]25 D −29 (c 0.3, CHCl3) for 98% ee (R); H NMR (500 MHz, CDCl3) δ 3.04 (dd, JP−H = 22.9, 1.2 Hz, 2H), 3.36 (dd, J = 17.5, 7.3 Hz, 1H), 3.46 (dd, J = 17.4, 7.4 Hz, 1H), 3.73 (dd, JP−H = 11.2, 10.4 Hz, 6H), 4.69 (t, J = 7.3 Hz, 1H), 6.93 (dd, J = 5.0, 1.3 Hz, 1H), 7.03−7.08 (m, 1H), 7.19−7.30 (m, 4H), 7.30−7.34 (m, 2H); 31P NMR (CDCl3, 121 MHz) δ 22.1; 13C NMR (125 MHz, CDCl3) δ 41.3, 41.5, 42.3, 50.4, 52.9, 53.0, 120.6, 125.7, 126.6, 127.6, 127.8, 128.6, 143.3, 144.3, 199.66, 199.70; HRMS (ESI) calcd for C16H20O4PS+ [M + H]+ 339.0814, found 339.0811. Dimethyl (S)-(4-(2-Chlorophenyl)-2-oxo-4-phenylbutyl)-phosphonate (3n): 90% yield, 95% ee (S), colorless oil, 49.3 mg at 0.15 mmol scale; HPLC analysis Chiralcel IB column, 1.0 mL/min, hexane/ 2-propanol = 70.0/30.0, 254 nm, tmajor = 18.7 min (S), tminor = 39.8 1 min (R); [α]25 D +2.1 (c 0.4, CHCl3) for 95% ee (S); H NMR (300 MHz, CDCl3) δ 3.07 (d, JP−H = 22.9 Hz, 2H), 3.31−3.54 (m, 2H), 3.72 (dd, JP−H = 11.2, 5.6 Hz, 6H), 5.11 (t, J = 7.5 Hz, 1H), 7.15 (td, J = 7.9, 2.1 Hz, 1H), 7.19−7.22 (m, 1H), 7.24 (dd, J = 7.1, 1.4 Hz, 1H), 7.26−7.33 (m, 5H), 7.36 (dd, J = 7.8, 1.5 Hz, 1H); 31P NMR (CDCl3, 121 MHz) δ 22.1; 13C NMR (125 MHz, CDCl3) δ 41.0, 41.9, 42.0, 49.2, 52.3, 126.6, 126.9, 127.7, 128.1, 128.4, 128.5, 129.9, 134.0, 140.7, 141.9, 199.0, 199.1; HRMS (ESI) calcd for C18H21ClO4P+ [M + H]+ 367.0860, found 367.0858. Dimethyl (S)-(4-(3-Fluorophenyl)-2-oxo-4-phenylbutyl)-phosphonate (3o): 82% yield, 94% ee (S), pale yellow oil, 42.8 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 70.0/30.0, 254 nm, tmajor = 21.0 min (S), tminor = 1 24.2 min (R); [α]25 D +11 (c 0.3, CHCl3) for 94% ee (S); H NMR (300 MHz, CDCl3) δ 3.04 (d, JP−H = 22.9 Hz, 2H), 3.33−3.50 (m, 2H), 3.71 (dd, JP−H = 11.3, 3.1 Hz, 6H), 4.62 (t, J = 7.4 Hz, 1H), 6.88 (tdd, J = 8.4, 2.6, 1.0 Hz, 1H), 6.96 (dt, J = 10.2, 2.1 Hz, 1H), 7.01−7.08 (m, 1H), 7.16−7.22 (m, 1H), 7.22−7.26 (m, 3H), 7.26−7.33 (m, 2H); 31P NMR (CDCl3, 121 MHz) δ 22.2; 13C NMR (125 MHz, CDCl3) δ 41.8, 42.4, 45.3, 49.7, 53.0, 113.3 (d, JC−F = 21.1 Hz), 114.7 (d, JC−F = 21.8 Hz), 123.5, 123.5, 126.7, 127.7, 128.7, 129.9, 130.0, 142.9, 146.2, 146.2, 162.9 (d, JC−F = 245.8 Hz), 199.30, 199.34; HRMS (ESI) calcd for C18H21FO4P+ [M + H]+ 351.1156, found 351.1157. Dimethyl (S)-(4-(4-Chlorophenyl)-2-oxo-4-phenylbutyl)-phosphonate (3p): 85% yield, 95% ee (S), pale yellow oil, 46.7 mg at 0.15 mmol scale; HPLC analysis Chiralcel IC column, 1.0 mL/min, hexane/2-propanol = 60.0/40.0, 254 nm, tmajor = 17.1 min (S), tminor = 1 22.1 min (R); [α]25 D +8.0 (c 0.5, CHCl3) for 95% ee (S); H NMR (300 MHz, CDCl3) δ 3.04 (d, JP−H = 22.9 Hz, 2H), 3.41 (dd, J = 7.4, 1.9 Hz, 2H), 3.70 (dd, JP−H = 11.3, 0.4 Hz, 6H), 4.59 (t, J = 7.4 Hz, 1H), 7.16−7.21 (m, 3H), 7.21−7.28 (m, 5H), 7.30 (dt, J = 6.9, 1.2 Hz, 1H); 31P NMR (CDCl3, 121 MHz) δ 22.0; 13C NMR (125 MHz, CDCl3) δ 41.3, 42.3, 44.9, 49.7, 52.9, 52.3, 126.6, 127.6, 128.58, 128.61, 129.1, 132.2, 142.1, 143.0, 199.31, 199.35; HRMS (ESI) calcd for C18H21ClO4P+ [M + H]+ 367.0860, found 367.0858. Dimethyl (S)-(4-(3,4-Dichlorophenyl)-2-oxo-4-phenylbutyl)-phosphonate (3q): 94% yield, 92% ee (S), colorless oil, 56.6 mg at 0.15 mmol scale; HPLC analysis Chiralcel IB column, 1.0 mL/min, hexane/ 2-propanol = 85.0/15.0, 210 nm, tmajor = 44.6 min (S), tminor = 65.9 1 min (R); [α]25 D +16 (c 0.5, CHCl3) for 92% ee (S); H NMR (500 MHz, CDCl3) δ 3.01−3.13 (m, 2H), 3.42 (qd, J = 18.0, 7.4 Hz, 2H), 3.73 (dd, J P−H = 11.3, 6.0 Hz, 6H), 4.59 (t, J = 7.3 Hz, 1H), 7.12 (dd, J = 8.4, 2.1 Hz, 1H), 7.20−7.27 (m, 3H), 7.28−7.41 (m, 4H); 31P NMR (CDCl3, 121 MHz) δ 21.9; 13C NMR (75 MHz, CDCl3) δ 41.0, 42.7, 44.6, 49.5, 53.1, 53.2, 126.9, 127.4, 127.7, 128.8, 129.7, 130.4, 132.4, 142.4, 143.9, 199.1, 199.2; HRMS (ESI) calcd for C18H20Cl2O4P+ [M + H]+ 401.0471, found 401.0470. Dimethyl (S)-(4-(Benzo[d][1,3]dioxol-5-yl)-2-oxo-4-phenylbutyl)phosphonate (3r): 90% yield, 92% ee (S), colorless oil, 50.8 mg at 0.15 mmol scale; HPLC analysis Chiralcel IA column, 1.0 mL/min, hexane/2-propanol = 85.0/15.0, 254 nm, tmajor = 18.0 min (S), tminor = 5873

DOI: 10.1021/acs.joc.8b00952 J. Org. Chem. 2018, 83, 5869−5875

Note

The Journal of Organic Chemistry 9.4 min (R), tminor = 10.3 min (S); [α]25 D −7.1 (c 0.4, CHCl3) for 93% ee (R); 1H NMR (300 MHz, CDCl3) δ 3.37 (d, J = 7.5 Hz, 2H), 3.73 (s, 3H), 4.67 (t, J = 7.5 Hz, 1H), 6.68 (d, J = 16.2 Hz, 1H), 6.76−6.84 (m, 2H), 7.12−7.19 (m, 3H), 7.21−7.28 (m, 4H), 7.33−7.39 (m, 3H), 7.45−7.53 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 45.5, 47.3, 55.2, 114.0, 126.3, 126.3, 127.8, 128.3, 128.5, 128.8, 128.9, 130.4, 134.5, 136.2, 142.7, 144.5, 158.2, 198.1. (R,E)-1-(4-Methoxyphenyl)-1-phenyloct-4-en-3-one (4b): 91% yield, 93% ee (R), yellowish oil, 42.2 mg at 0.15 mmol scale; HPLC analysis Chiralcel IA column, 1.0 mL/min, hexane/2-propanol = 98.0/ 2.0, 254 nm, tmajor = 15.8 min (R), tminor = 16.9 min (S); [α]25 D −3.0 (c 0.2, CHCl3) for 93% ee (R); 1H NMR (300 MHz, CDCl3) δ 0.82 (t, J = 7.4 Hz, 3H), 1.30−1.44 (m, 2H), 2.06 (qd, J = 7.3, 1.5 Hz, 2H), 3.16 (d, J = 7.5 Hz, 2H), 3.67 (s, 3H), 4.53 (t, J = 7.5 Hz, 1H), 5.97 (dt, J = 15.8, 1.5 Hz, 1H), 6.64−6.76 (m, 3H), 7.01−7.21 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 13.6, 21.3, 34.4, 45.4, 46.4, 55.2, 113.9, 126.2, 127.7, 128.5, 128.8, 130.6, 136.3, 147.5, 158.1, 198.4; HRMS (ESI) calcd for C21H24NaO2+ [M + Na]+ 331.1669, found 331.1668. (S)-2-Methyl-6-(p-tolyl)hept-2-en-4-one (5): known compound13 89% yield, 91% ee (S), yellowish oil, 28.8 mg at 0.15 mmol scale; HPLC analysis Chiralcel IA column, 1.0 mL/min, hexane/2-propanol = 99.6/0.4, 254 nm, tmajor = 5.8 min (S), tminor = 6.4 min (R); [α]25 D +46 (c 0.4, CHCl3) for 91% ee (S); 1H NMR (300 MHz, CDCl3) δ 1.17 (d, J = 7.0 Hz, 3H), 1.78 (d, J = 1.2 Hz, 3H), 2.03 (d, J = 1.3 Hz, 3H), 2.23 (s, 3H), 2.58 (qd, J = 15.7, 7.2 Hz, 2H), 3.12−3.28 (m, 1H), 5.91−5.99 (m, 1H), 6.96−7.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 20.7, 20.9, 22.0, 27.5, 35.3, 52.7, 124.1, 126.6, 129.1, 143.7, 154.8, 199.8.

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Ber. 1959, 92, 2499−2505. (c) Wadsworth, W. S., Jr.; Emmons, W. D. The Utility of Phosphonate Carbanions in Olefin Synthesis. J. Am. Chem. Soc. 1961, 83, 1733−1738. (d) Boutagy, J.; Thomas, R. Olefin Synthesis with Organic Phosphonate Carbanions. Chem. Rev. 1974, 74, 87−89. (e) Maryanoff, B. E.; Reitz, A. B. The Wittig Olefination Reaction and Modifications Involving Phosphoryl Stabilized Carbanions. Stereochemistry, Mechanism, and Selected Synthetic Aspects. Chem. Rev. 1989, 89, 863−927. (2) For selected examples, see: (a) Nicolaou, K. C.; Rhoades, D.; Wang, Y.; Bai, R.; Hamel, E.; Aujay, M.; Sandoval, J.; Gavrilyuk, J. 12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents. J. Am. Chem. Soc. 2017, 139, 7318−7334. (b) Reddy, G. M.; Rao, B. U. M.; Sridhar, P. R. Stereoselective Synthesis of 2-(β-C-Glycosyl)glycals: Access to Unusual β-C-Glycosides from 3-Deoxyglycals. J. Org. Chem. 2016, 81, 2782−2793. (c) Pan, S.; Gao, B.; Hu, J.; Xuan, J.; Xie, H.; Ding, H. Enantioselective Total Synthesis of (+)-Steenkrotin A and Determination of Its Absolute Configuration. Chem. - Eur. J. 2016, 22, 959−970. (d) Dakarapu, U. S.; Bokka, A.; Asgari, P.; Trog, G.; Hua, Y.; Nguyen, H. H.; Rahman, N.; Jeon, J. Lewis Base Activation of Silyl Acetals: Iridium-Catalyzed Reductive Horner−Wadsworth−Emmons Olefination. Org. Lett. 2015, 17, 5792−5795. (e) Umezawa, T.; Seino, T.; Matsuda, F. Novel One-pot Three-component Coupling Reaction with Trimethylsilylmethylphosphonate, Acyl Fluoride, and Aldehyde through the Horner−Wadsworth−Emmons Reaction. Org. Lett. 2012, 14, 4206−4209. (f) Markiewicz, J. T.; Schauer, D. J.; Löfstedt, J.; Corden, S. J.; Wiest, O.; Helquist, P. Synthesis of 4-Methyldienoates Using a Vinylogous Horner−Wadsworth−Emmons Reagent. Application to the Synthesis of Trichostatic Acid. J. Org. Chem. 2010, 75, 2061−2064. (3) (a) Lee, S.; Kim, S. Enantioselective Radical Conjugate Addition to α′-Phosphoric Enones. Org. Lett. 2008, 10, 4255−4258. (b) Yang, H.; Hong, Y.-T.; Kim, S. Catalytic Enantioselective Friedel-Crafts Alkylations of Indoles with α′-Phosphoric Enones. Org. Lett. 2007, 9, 2281−2284. (c) Kang, Y. K.; Kwon, B. K.; Mang, J. Y.; Kim, D. Y. Chiral Pd-Catalyzed Enantioselective Friedel−Crafts Reaction of Indoles with γ,δ-Unsaturated β-Keto Phosphonates. Tetrahedron Lett. 2011, 52, 3247−3249. (4) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Rhodium-Catalyzed Conjugate Addition of Aryl- or 1-Alkenylboronic Acids to Enones. Organometallics 1997, 16, 4229−4231. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. Rhodium-Catalyzed Asymmetric 1,4-Addition of Aryl- and Alkenylboronic Acids to Enones. J. Am. Chem. Soc. 1998, 120, 5579−5580. (5) For reviews, see: (a) Jia, T.; Cao, P.; Liao, J. Enantioselective Synthesis of gem-Diarylalkanes by Transition Metal-Catalyzed Asymmetric Arylations (TMCAAr). Chem. Sci. 2018, 9, 546−559. (b) Heravi, M. M.; Dehghani, M.; Zadsirjan, V. Rh-Catalyzed Asymmetric 1,4-Addition Reactions to α,β-Unsaturated Carbonyl and Related Compounds: an Update. Tetrahedron: Asymmetry 2016, 27, 513−588. (c) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents to Construct C−C bonds. Chem. Rev. 2015, 115, 9587−9652. (d) Tian, P.; Dong, H.-Q.; Lin, G.-Q. Rhodium-Catalyzed Asymmetric Arylation. ACS Catal. 2012, 2, 95−119. (6) For selected examples, see: (a) Sakuma, S.; Miyaura, N. Rhodium(I)-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acids to α,β-Unsaturated Amides. J. Org. Chem. 2001, 66, 8944− 8946. (b) Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. Asymmetric Synthesis of 3,3-Diarylpropanals with Chiral DieneRhodium Catalysts. J. Am. Chem. Soc. 2005, 127, 10850−10851. (c) Shintani, R.; Duan, W.-L.; Hayashi, T. Rhodium-Catalyzed Asymmetric Construction of Quaternary Carbon Stereocenters: Ligand-Dependent Regiocontrol in the 1,4-Addition to Substituted Maleimides. J. Am. Chem. Soc. 2006, 128, 5628−5629. (d) Shao, C.; Yu, H.-J.; Wu, N.-Y.; Tian, P.; Wang, R.; Feng, C.-G.; Lin, G.-Q.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00952. Copies of 1H, 13C, and 31P NMR spectra and HPLC charts (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiaowei Dou: 0000-0002-0748-1279 Author Contributions §

L.Y. and D.Z. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS X.D. thanks the financial support from the National Natural Science Foundation of China (21602253), the Natural Science Foundation of Jiangsu Province (BK20160749), and the Six Talent Peaks Plan of Jiangsu Province. C.W. is supported by the College Students Innovation Project for the R&D of Novel Drugs (J1310032). T.H. thanks the Ministry of Education (MOE) of Singapore (MOE2017-T2-1-064) for generous financial support.

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REFERENCES

(1) (a) Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Phosphororganische Verbindungen, XII. Phosphinoxyde als Olefinierungsreagenzien. Chem. Ber. 1958, 91, 61−63. (b) Horner, L.; Hoffmann, H. M. R.; Wippel, H. G.; Klahre, G. Phosphororganische Verbindungen, XX. Phosphinoxyde als Olefinierungsreagenzien. Chem. 5874

DOI: 10.1021/acs.joc.8b00952 J. Org. Chem. 2018, 83, 5869−5875

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Yakeishi, S.; Shibata, T. Effect of Multinuclear Copper/Aluminum Complexes in Highly Asymmetric Conjugate Addition of Trimethylaluminium to Acyclic Enones. Angew. Chem., Int. Ed. 2013, 52, 606− 610. (d) Afewerki, S.; Breistein, P.; Pirttilä, K.; Deiana, L.; Dziedzic, P.; Ibrahem, I.; Córdova, A. Catalytic Enantioselective β-Alkylation of α,βUnsaturated Aldehydes by Combination of Transition-Metal- and Aminocatalysis: Total Synthesis of Bisabolane Sesquiterpenes. Chem. Eur. J. 2011, 17, 8784−8788. (e) Nave, S.; Sonawane, R. P.; Elford, T. G.; Aggarwal, V. K. Protodeboronation of Tertiary Boronic Esters: Asymmetric Synthesis of Tertiary Alkyl Stereogenic Centers. J. Am. Chem. Soc. 2010, 132, 17096−17098. (f) Kamal, A.; Malik, M. S.; Azeeza, S.; Bajee, S.; Shaik, A. A. Total Synthesis of (R)- and (S)Turmerone and (7S,9R)-Bisacumol by an Efficient Chemoenzymatic Approach. Tetrahedron: Asymmetry 2009, 20, 1267−1271. (g) Rowe, B. J.; Spilling, C. D. Stereospecific Pd(0)-Catalyzed Arylation of an Allylic Hydroxy Phosphonate Derivative: Formal Synthesis of (S)(+)-ar-Turmerone. J. Org. Chem. 2003, 68, 9502−9505. (14) Compound 4a: [α]25 D − 7.1 (c 0.4, CHCl3) for 93% ee; (ref 12a) 20 [α]25 D − 7.0 (c 1.0, CHCl3) for 97% ee (R). Compound 5: [α]D +46 (c 20 0.4, CHCl3) for 91% ee; (ref 13a) [α]D +50 (c 1.0, CHCl3) for 92% ee (S).

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DOI: 10.1021/acs.joc.8b00952 J. Org. Chem. 2018, 83, 5869−5875