Asymmetric synthesis of 2,6-substituted

Chemical Papers 62 (2) 187–193 (2008) DOI: 10.2478/s11696-008-0010-6

ORIGINAL PAPER

Asymmetric synthesis of 2,6-substituted dihydropyrone catalyzed by 3-monosubstituted and 3,3-bisubstituted BINOL titanium complexes a

Hong Yu, a Ji Zhang, a Yuan-Cong Zhao, a Na Wang, a Qin Wang, a Xin-Bin Yang, a,b Xiao-Qi Yu*

a Department

of Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education), Sichuan University, Chengdu, Sichuan 610064, China

b State

Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China Received 31 March 2007; Revised 15 July 2007; Accepted 19 July 2007

Asymmetric hetero-Diels–Alder (HDA) reactions of aromatic aldehydes with Danishefsky’s diene derivative were carried out smoothly in the presence of the Ti(IV)–(R)-BINOL (1:1.2) complex to give the corresponding chiral 2,6-disubstituted dihydropyrones under mild conditions. The readily accessible I–Ti(OCH(CH3 )2 )4 (1.2:1) complex was found to be an effective catalyst for this reaction. Aromatic aldehydes afforded the corresponding products in moderate yields (up to 72 %) with good enantioselectivities (up to 80 % ee). Aromatic aldehydes in presence of the TiCl4 –NaOCH3 –II (1:4.2:1.2) complex gave the products in higher yields (up to 73 %) with better enantioseletivities (up to 84 % ee). c 2008 Institute of Chemistry, Slovak Academy of Sciences Keywords: hetero-Diels–Alder reaction, BINOL, asymmetric catalysis, dihydropyrone

Introduction Chiral pyran derivatives are important intermediates in organic synthesis. The catalytic asymmetric hetero-Diels–Alder (HDA) reaction, which is one of the most important asymmetric C—C bond-forming reactions, is among the most useful and efficient methods for the synthesis of these compounds. HDA reactions of the Danishefsky’s diene with aldehydes promoted by Lewis acids are easy to perform (Corey & Guzman-Perez, 1998; Jørgensen, 2000, 2004). BINOL and its derivatives coordinated with suitable metals such as copper, aluminium, chromium, titanium, and other transition metals or nonmetals, such as boron, have been successfully applied to the enantioselective HDA reactions. In recent studies, asymmetric HDA reactions of the Danishefsky’s diene with aldehydes provided not

only 2-substituted dihydropyrones, but also multisubstituted dihydropyrone compounds (Fu et al., 2004; Gong & Pu, 2000; Johannsen & Jørgensen, 1995; Yamashita et al., 2003; Yao et al., 1998a). Some effective catalysts for HDA reactions were developed and applied to the synthesis of natural products (Aikawa et. al., 2001; Dossetter et. al., 1999; Doyle et. al., 2001; Du et. al., 2002, 2004, 2005; Du & Ding, 2003; Endeshaw et. al., 2006; Evans et. al., 2000; Fan et. al., 2004, 2005; Gordillo et. al. 2007; Huang et. al., 2003; Kezuka et. al., 2000; Leveque et. al., 2000; Liu & Jacobsen, 2001; Long et. al., 2002; Schaus et. al., 1998; Simonsen et. al., 2000; Thompson et. al., 2001; Unni et. al., 2005; Wang et. al., 2000, 2002; Yao et al., 1998b); Baker-Glenn and co-workers (2005) reported the synthesis of enantioenriched 2-(4-methoxyphenyl)6-methyl-2,3-dihydro-4H-pyran-4-one by a bioorganic route using aldolase ab84G3 or ab93F3 (97 % ee).

*Corresponding author, e-mail: [email protected]

Unauthenticated Download Date | 8/22/15 6:07 AM

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H. Yu et al./Chemical Papers 62 (2) 187–193 (2008)

Ph

Ph

Ph OH

Ph OH OH

OH

OH

OH

OH Ph

OH

MOMCl, NaH

OMOM

III

IV 1. BuLi, THF 2. Ph2C=O, room temp.

Ph

I

OMOM

OH

II Ph

Chart 1

Ph

Ph OH

Very recently, Yang et al. (2005) reported on the relationship between the catalyst structure and catalytic activity. The reaction mechanism and the application to the synthesis of natural product (R)-(+)hepialone were also studied. The results demonstrated that steric hindrance at 3,3 -positions was disadvantageous for the reactions. In this paper, HDA reaction of aldehydes with diene using 3,3 -substituted BINOL (I ) as a chiral ligand is described. Moreover, a novel ligand, 3-monosubstituted BINOL (II, Chart 1) was prepared and applied to the enantioselective reaction. The structure of II and all HDA reaction products were confirmed by NMR and HRMS.

Experimental The 1 H NMR spectra were recorded in deuteriochloroform (CDCl3 ) with tetramethylsilane (TMS) as the internal standard at ambient temperature on an INOVA-400 (Varian America) spectrometer. Melting points were measured on an Axiolab ZETSS microscope and are uncorrected. ESI-MS spectra were recorded on a Bruker Daltonics Bio TOF mass spectrometer. Enantiomeric excesses (ee) were determined by HPLC using the corresponding commercial chiral column. The experimental procedures were carried out at 25 ◦C with a UV detector at 254 nm on an LC2010AHT liquid chromatograph Shimadzu Corporation. (R)-3,3 -Bis(diphenylhydroxymethyl)-2,2-dihydroxy-1,1-binaphthalenyl (I ) was synthesized according to the reported methods (Barhate & Chen, 2002; Li et al., 2003; Wang et al., 2007). Preparation of dimethoxymethyl derivative of II (V ), was carried out under argon atmosphere according to Scheme 1. Dimethoxymethyl derivative of 2,2 -dihydroxy-1,1-binaphthalenyl (IV, 10.0 mmol, 3.74 g) was dissolved in THF (150 mL, dried with sodium/benzophenone) in a three-necked flask. BuLi (12.0 mmol, 2.5 M in hexane, 5.46 mL) was added dropwise to the solution. The reaction mixture was stirred for 3 h at room temperature, and benzophenone (12.0 mmol, 2.18 g) was added as a solid. The reaction mixture was further stirred at room temper-

Ph OH

OH

3 M HCl, THF

OMOM

OH

reflux

OMOM

V

II Scheme 1

ature overnight and quenched with saturated aqueous NH4 Cl solution. THF was removed in vacuo, and the aqueous solution was extracted with CH2 Cl2 . The organic phase was dried with MgSO4 and evaporated to dryness. The residue was recrystallized from benzene and methanol to obtain V as a white solid in a 22 % yield (1.22 g). Preparation of II was also performed under argon atmosphere. V (2.2 mmol, 1.22 g) was dissolved in THF (50 mL), and 3 M HCl (5 mL) was added. After the mixture was heated at reflux (80 ◦C) for 1 h, 10 % NaHCO3 (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine and dried with MgSO4 . After evaporation, the residue was dissolved in diethyl ether and precipitated with petroleum ether. The precipitate was recrystallized from ethyl acetate/hexane solution to obtain II as a white solid in a 95 % yield (0.98 g). 1 H NMR (400 MHz, CDCl3 ): δ: 7.92 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.67 (dd, J = 2.0, 2.4 Hz, 1H), 7.38– 7.28 (m, 15H), 7.21 (s, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.37 (s, 1H), 5.12 (s, 1H), 4.76 (s, 1H). HRMS: calculated relative molecular mass for C33 H23 O3 (negative, M – 1): 467.1714; found: 467.2413. Synthesis of substituted 4H-pyran-4-ones To obtain 6-methyl-2-(4-nitrophenyl)-2,3-dihydro4H-pyran-4-one (VIIIa) (Scheme 2), a mixture of I (39.4 mg, 0.06 mmol), Ti(OCH(CH3 )2 )4 (1 M in toluene, 50 µL, 0.050 mmol), and 4 ˚ A molecular sieves (120 mg) in toluene (1.5 mL) was heated at 35 ◦C for 1 h. The red mixture was cooled to room tem-



OMe TMSO

VII, VIII O

+ H

VI

Ar

VII 1. Catalyst, 20 mole % 2. TFA

O O

Ar

a b c d e f g h i j k l m n

Ar 4-nitrophenyl phenyl 4-methoxyphenyl 2-nitrophenyl 3-nitrophenyl 4-chlorophenyl 2-chlorophenyl 3-chlorophenyl 4-methylphenyl 2-methylphenyl 3-methylphenyl 4-bromophenyl 1-naphthyl 2-naphthyl

VIII

Scheme 2

perature, and 4-nitrobenzaldehyde (VIIa) (0.5 M in CH2 Cl2 , 0.5 mL, 0.25 mmol) was added. The mixture was cooled to 0 ◦C, and the Danishefsky’s diene (VI ) (91.2 µL, 0.375 mmol) was added. The contents were stirred at 0 ◦C for 72 h, and then trifluoroacetic acid (TFA, 0.1 mL) was added to this solution. The mixture was stirred overnight. Saturated NaHCO3 solution (2 mL) was added, and the solution was stirred for additional 5 min. It was diluted with 5 mL of CH2 Cl2 and filtered through a plug of Celite. The resulting layers were separated. The aqueous layer was extracted with CH2 Cl2 (3 × 5 mL), and the combined organic layers were washed with brine, dried over Na2 SO4 , and concentrated in vacuo. The crude final product was purified by flash chromatography (petroleum ether/ethyl acetate, 3:1) to obtain a pale yellow solid (42 mg, 72 % yield, 80 % ee); enantiomeric excess was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 80:20, 25 ◦C, 0.5 mL min−1 , retention time 41.6–58.1 min). 1 H NMR (400 MHz, CDCl3 ): δ: 8.29 (dd, J = 2.2, 2.2 Hz, 2H), 7.60 (dd, J = 4.8, 2.2 Hz, 2H), 5.52 (dd, J = 4, 6.4 Hz, 1H), 5.48 (s, 1H), 2.73 (dd, J = 15.4, 2.6 Hz, 1H), 2.63 (d, J = 1.2, 0.8 Hz, 1H), 2.13 (s, 3H). HRMS: calculated relative molecular mass for C12 H11 NO4 Na: 256.0580; found: 256.0583. 6-Methyl-2-phenyl-2,3-dihydro-4H-pyran-4-one (VIIIb) was obtained from diene VI and benzaldehyde (VIIb) as a pale yellow solid (19.7 mg, 42 % yield, 31 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90 : 10, 25 ◦C, 0.5 mL min−1 , retention time 22.3–26.2 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.41–7.26 (m, 5H), 5.44 (s, 1H), 5.39 (dd, J = 3.6 Hz, 1H), 2.82 (dd, J = 14.4, 14 Hz, 1H), 2.60 (dd, J = 2.2, 13 Hz, 1H), 2.09 (s, 3H). HRMS: calculated relative molecular mass for C12 H12 O2 Na: 211.0730; found: 211.0737. 6-Methyl-2-(4-mexthoxyphenyl)-2,3-dihydro-4Hpyran-4-one (VIIIc) was obtained by the reaction

189

of diene VI and 4-methoxybenzaldehyde (VIIc) as a white solid (20.5 mg, 38 % yield, 0 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90:10, 25 ◦C, 0.5 mL min−1 , retention time 29.5–32.4 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.35 (dd, J = 2.8, 2.0 Hz, 2H), 6.95 (dd, J = 2.4 Hz, 2H), 5.43 (s, 1H), 5.33 (dd, J = 3.6, 3.2 Hz, 1H), 3.83 (s, 3H), 2.83 (dd, J = 14.4 Hz, 1H), 2.56 (dd, J = 2.2 Hz, 1H), 2.06 (s, 3H). HRMS: calculated relative molecular mass for C13 H14 O3 Na: 241.0841; found: 241.0841. 6-Methyl-2-(2-nitrophenyl)-2,3-dihydro-4H-pyran4-one (VIId ) was obtained from diene VI and 4nitrobenzaldehyde (VIId ) in the form of a pale yellow solid (33.5 mg, 58 % yield, 84 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 80:20, 25 ◦C, 0.5 mL min−1 , retention time 24.2–27.0 min). 1 H NMR (400 MHz, CDCl3 ): δ: 8.06 (d, J = 9.2, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.78–7.74 (m, 12H), 7.60–7.55 (m, 1H), 6.04 (dd, J = 3.6 Hz, 1H), 5.01 (s, 1H), 2.94 (dd, J = 4.0 Hz, 1H), 2.70 (dd, J = 13.6, 14.0 Hz, 1H), 2.10 (s, 3H). HRMS: calculated relative molecular mass for C12 H11 NO2 Na: 256.0580; found: 256.0583. 6-Methyl-2-(3-nitrophenyl)-2,3-dihydro-4H-pyran4-one (VIIIe) was obtained by the reaction of diene VI with 3-nitrobenzaldehyde (VIIe) as a pale yellow solid (35.4 mg, 61 % yield, 38 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 80 : 20, 25 ◦C, 0.5 mL min−1 , retention time 37.1–44.3 min). 1 H NMR (400 MHz, CDCl3 ): δ: 8.36–8.35 (m, 1H), 8.28–8.26 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66–7.62 (m, 1H), 5.54 (d, J = 2.8 Hz, 1H), 5.51 (s, 1H), 2.80 (dd, J = 14.0, 13.6 Hz, 1H), 2.68 (dd, J = 3.6 Hz, 1H), 2.15 (s, 3H). HRMS: calculated relative molecular mass for C12 H11 NO2 Na: 256.0580; found: 256.0583. 6-Methyl-2-(4-chlorophenyl)-2,3-dihydro-4H-pyran4-one (VIIIf ) was produced from diene VI and 4chlorobenzaldehyde (VIIf) in the form of a pale yellow solid (35.3 mg, 63 % yield, 47 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90:10, 25 ◦C, 0.5 mL min−1 , retention time 25.9–30.1 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.41–7.34 (m, 4H), 5.44 (s, 1H), 5.37 (dd, J = 3.6 Hz, 1H), 2.76 (dd, J = 14.0 Hz, 1H), 2.58 (dd, J = 4.4, 4.8 Hz, 1H), 2.08 (s, 3H). HRMS: calculated relative molecular mass for C12 H12 ClO2 : 223.0526; found: 223.0527. 6-Methyl-2-(2-chlorophenyl)-2,3-dihydro-4H-pyran4-one (VIIIg) was produced by the reaction of diene VI and 2-chlorobenzaldehyde (VIIg) as a pale yellow liquid (40.5 mg, 73 % yield, 29 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90 : 10, 25 ◦C, 0.5 mL min−1 , retention time 18.5–20.0 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.63 (dd, J = 1.6 Hz, 1H), 7.43–7.31 (m, 3H), 5.81 (dd, J = 4.0, 3.6 Hz, 1H), 5.49 (s, 1H), 2.75


190


(dd, J = 2.4, 4.4 Hz, 1H), 2.64 (dd, J = 14.0, 14.4 Hz, 1H), 2.12 (s, 3H). HRMS: calculated relative molecular mass for C12 H12 ClO2 : 223.0526; found: 223.0527. 6-Methyl-2-(3-chlorophenyl)-2,3-dihydro-4H-pyran4-one (VIIIh) was obtained from diene VI and 3chlorobenzaldehyde (VIIh) as a white solid (28 mg, 50 % yield, 6 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90 : 10, 25 ◦C, 0.5 mL min−1 , retention time 24.8–32.5 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.45–7.27 (m, 4H), 5.46 (s, 1H), 5.38 (dd, J = 3.2, 3.6 Hz 1H), 2.78 (dd, J = 14.4, 14.0 Hz, 1H), 2.61 (dd, J = 4.8, 4.4 Hz, 1H), 2.11 (s, 3H). HRMS: calculated relative molecular mass for C12 H12 ClO2 : 223.0526; found: 223.0527. 6-Methyl-2-(4-methylphenyl)-2,3-dihydro-4Hpyran-4-one (VIIIi) was obtained from diene VI and 4-methylbenzaldehyde (VIIi) in the form of a white solid (21.6 mg, 43 % yield, 23 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90 : 10, 25 ◦C, 0.5 mL min−1 , retention time 19.8–22.8 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.32 (s, 1H), 7.30 (s, 1H), 7.24 (s, 1H) 7.22 (s, 1H), 5.43 (s, 1H), 5.35 (dd, J = 3.6 Hz, 1H), 2.82 (dd, J = 14.1, 14.0 Hz, 1H), 2.57 (dd, J = 4.4 Hz, 1H), 2.38 (s, 3H), 2.07 (s, 3H). HRMS: calculated relative molecular mass for C13 H14 O2 Na: 225.0886; found: 225.0876. 6-Methyl-2-(2-methylphenyl)-2,3-dihydro-4Hpyran-4-one (VIIIj), was produced from diene VI and 2-methylbenzaldehyde (VIIj) as a pale yellow liquid (25 mg, 50 % yield, 9 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90 : 10, 25 C, 0.5 mL min−1 , retention time 18.8–27.2 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.51–7.22 (m, 4H), 5.61 (dd, J = 3.2 Hz, 1H), 5.47 (s, 1H), 2.81 (dd, J = 14.8, 14.4 Hz, 1H), 2.56 (dd, J = 4.0, 3.2 Hz, 1H), 2.38 (s, 3H), 2.10 (s, 3H). HRMS: calculated relative molecular mass for C13 H14 O2 Na: 225.0886; found: 225.0885. 6-Methyl-2-(3-methylphenyl)-2,3-dihydro-4Hpyran-4-one (VIIIk) was obtained from diene VI and 3-methylbenzaldehyde (VIIk) as a pale yellow liquid (19.1 mg, 38 % yield, 35 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90 : 10, 25 ◦C, 0.5 mL min−1 , retention time 18.9–23.8 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.33–7.19 (m, 4H), 5.43 (s, 1H), 5.35 (dd, J = 3.6 Hz, 1H), 2.81 (dd, J = 14.4 Hz, 1H), 2.57 (dd, J = 4.4 Hz, 1H), 2.39 (s, 3H), 2.08 (s, 3H). HRMS: calculated relative molecular mass for C13 H14 O2 Na: 225.0886; found: 225.0880. 6-Methyl-2-(4-bromophenyl)-2,3-dihydro-4Hpyran-4-one (VIIIl ) was obtained from diene VI and 4-bromobenzaldehyde (VIIl) in the form of a pale yellow solid (36.8 mg, 55 % yield, 21 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90:10, 25 ◦C, 0.5 mL min−1 , retention time 27.9–34.2 min). 1 H NMR (400 MHz,

CDCl3 ): δ: 7.55 (dd, J = 4.4, 4.0 Hz, 2H), 7.29 (dd, J = 4.4, 4.0 Hz, 2H), 5.44 (s, 1H), 5.35 (dd, J = 3.6 Hz, 1H), 2.75 (dd, J = 14.0 Hz, 1H), 2.57 (dd, J = 4.4 Hz, 1H), 2.08 (s, 3H). HRMS: calculated relative molecular mass for C12 H12 BrO2 : 267.0021; found: 267.0023. 6-Methyl-2-(naphthalene-1-yl)-2,3-dihydro-4Hpyran-4-one (VIIIm) was produced by the reaction of diene VI with 1-naphthtylaldehyde (VIIm) as a pale yellow solid (6.6 mg, 11 % yield, 21 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90 : 10, 25 ◦C, 0.5 mL min−1 , retention time 44.6–65.6 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.99–7.51 (m, 7H), 6.15 (dd, J = 3.6 Hz, 1H), 5.53 (s, 1H), 2.99 (dd, J = 14.4, 14.0 Hz, 1H), 2.80 (dd, J = 3.2 Hz, 1H), 2.13 (s, 3H). HRMS: calculated relative molecular mass for C16 H15 O2 H: 2239.1073; found: 239.1075. 6-Methyl-2-(naphthalene-2-yl)-2,3-dihydro-4Hpyran-4-one (VIIIn) was obtained from diene VI and 2-naphthtylaldehyde (VIIn) as a pale yellow solid (18.1 mg, 30 % yield, 26 % ee); ee was determined by HPLC analysis using a chiral OD column (hexane/propan-2-ol, 90 : 10, 25 C, 0.5 mL min−1 , retention time 43.7–68.2 min). 1 H NMR (400 MHz, CDCl3 ): δ: 7.92–7.85 (m, 4H), 7.55–7.51 (m, 3H), 5.56 (dd, J = 3.2, 3.6 Hz, 1H), 5.48 (s, 1H), 2.92 (dd, J = 14.4 Hz, 1H), 2.68 (dd, J = 4.4 Hz, 1H), 2.12 (s, 3H). HRMS: calculated relative molecular mass for C16 H15 O2 H: 239.1073; found: 239.1075.

Results and discussion The reaction conditions were optimized, and the results are summarized in Table 1. Dichloromethane was found to be the best solvent for the reaction; an 80 % ee was obtained when the reaction was carried out in CH2 Cl2 with I as the chiral ligand (entries 1– 6). Considering the reactions using ligand II, both the yields and the ee values decreased, and the solvents were found to have little effect on the enantioselectivity (entries 16–18). Lower temperature did not benefit the selectivity of VIII production, a lower ee (63 %) was found when the reaction temperature decreased to −20 ◦C (entry 7). In addition, the yield and enantioselectivity dropped dramatically with the rise of the reaction temperature (entry 8). The amount of catalyst was also an important factor, 20 mole % presented the optimum amount of the Ti–BINOL catalyst. Increase or decrease of the catalyst amount led to obvious decrease in both the yields and the ee values (entries 9–11). The reason might be that higher concentration causes aggregation of the catalyst. The effect of the mole ratio of I to Ti(OCH(CH3 )2 )4 on the reaction was also examined. The best mole ratio of ligand to Ti(IV) was 1.2:1, the reaction considering both the deficiency and the excess of the ligand gave unsatisfactory results (entries 12 and 13). Finally, the reaction required a relatively long time


191


Table 1. Effect of the reaction conditions on the HDA reaction of 4-nitrobenzaldehyde (VIIa) with diene VI Temperature Entry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Ligand

I I I I I I I I I I I I I I I I I I

Solvent

Catalyst content

◦C

Toluene CH2 Cl2 THF Et2 O CHCN Benzene CH2 Cl2 CH2 Cl2 CH2 Cl2 CH2 Cl2 CH2 Cl2 CH2 Cl2 CH2 Cl2 CH2 Cl2 CH2 Cl2 CH2 Cl2 THF Benzene

Time

Yielda

ee

h

%

%

72 72 72 72 72 72 72 72 72 72 72 72 72 24 48 72 72 72

56 72 72 57 15 30 53 18 16 35 56 46 33 24 37 59 65 52

35 80 59 8 23 14 63 12 22 34 22 15 18 15 66 45 40 54

n(I ): n(Ti) mole %

0 0 0 0 0 0 −20 10 0 0 0 0 0 0 0 0 0 0

20 20 20 20 20 20 20 20 10 30 40 20 20 20 20 20 20 20

1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.1 : 1 1.4 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1 1.2 : 1

a) Isolated yield of VIIIa.

Table 2. Asymmetric HDA reactions of aldehydes (VII) with diene VI Reactants

Yielda

ee

VII

VIII

%

%



72 37b 38 32 20 32 24 23 30 24 21 19 11 30

80 19b 0 10 12 23 28 13 3 24 9 19 21 26

a) Isolated yield of the product VIII. b) As a catalyst, ligand derivative II was used.

to be completed, shortening the reaction time led to a decrease in yields and ee values (entries 14 and 15). A variety of aldehydes (VII ) were investigated under the optimized reaction conditions, i.e. in the presence of 120 mg of 4˚ A MS on a 0.25 mmol scale in 1.5 mL of CH2 Cl2 with a 20 mole % catalyst loading, n(I )/n(Ti(OCH(CH3 )2 )4 ) = 1.2:1, at 0 ◦C for 72 h, and the results are listed in Table 2. The enantioselective HDA reactions of diene VI with other aldehydes did not give satisfactory results. For some aromatic aldehydes with an electron-donating group, very low ee values were obtained.

Table 3. Asymmetric HDA reactions with the use of additives Entry

Ligand

Additive

Yield/%a

ee/%

1 2 3 4

I II I II

NaOCH3 NaOCH3 NaOCH(CH3 )C2 H5 NaOCH(CH3 )C2 H5

40 49 28 41

19 75 0 47

a) Isolated yield of the product VIIIa.

To improve the 4H-pyran-4-one yield and ee, the effects of additives on the reaction of VI with VIIa (Table 3) were studied using 120 mg of 4˚ A MS on a 0.25 mmol scale in 1.5 mL of CH2 Cl2 with a 20 mole % catalyst loading, n(ligand)/n(TiCl4 ) = 1.2:1, n(TiCl4 )/n(additive) = 1:4.2, at 0 ◦C for 72 h. NaOCH3 and sodium 2-butoxide (NaOCH(CH3 )C2 H5 ) were used as additives. The best results were obtained when using NaOCH3 as an additive and II as the ligand (entry 2). Using II and NaOCH3 as an additive, HDA reaction of several aldehydes (VII) was studied in the presence of 120 mg of 4 ˚ A MS on a 0.25 mmol scale in 1.5 mL of CH2 Cl2 with a 20 mole % catalyst loading, n(II )/n(TiCl4 ) = 1.2:1, n(TiCl4 )/n(NaOCH3 ) = 1 : 4.2, at 0 ◦C for 72 h (Table 4). Yields of all respective pyranones VIII improved compared to those obtained in the reactions without any additives and in the presence of I (Table 2). The ee values were also improved for most aldehydes. Moreover, these results also revealed that the electron-withdrawing group of the substrates could benefit the reaction, on the other hand, the electron-donating group of the substrates led to unsatisfactory results. For 2-


192


Table 4. Asymmetric HDA reactions of aldehydes VII with diene VI in presence of NaOCH3 Reactants

Yielda

ee

Entry

1 2 3 4 5 6 7 8 9 10 11

VII

VIII

%

%

a b d e f g h i j k l

a b d e f g h i j k l

49 41 58 61 63 73 50 43 50 38 55

75 31 84 38 47 29 6 23 9 35 21

a) Isolated yield of the product VIII.

nitrobenzaldehyde (VIId ), an 84 % ee was achieved (entry 3).

Conclusions In summary, an efficient catalytic enantioselective HDA reaction of the Danishefsky’s diene derivative and aromatic aldehydes using the TiCl4 –NaOCH3 – (R)-BINOL complex has been documented. A wide range of aromatic aldehydes were employed, under mild conditions and provided the yield and ee within the range of 11–73 % and 0–84 %, respectively. Acknowledgements. This work was financially supported by the National Science Foundation of China (Nos. 20471038 and 20572075), Program for New Century Excellent Talents in University and Specialized Research Fund for the Doctoral Program of Higher Education.

References Aikawa, K., Irie, R., & Katsuki, T. (2001). Asymmetric hetero Diels–Alder reaction using chiral cationic metallosalen complexes as catalysts. Tetrahedron, 57, 845–851. DOI: 10.1016/S0040-4020(00)01048-6. Baker-Glenn, C., Hodnett, N., Reiter, M., Ropp, S., Ancliff, R., & Gouverneur, V. (2005). A catalytic asymmetric bioorganic route to enantioenriched tetrahydro- and dihydropyranones. Journal of the American Chemical Society, 127, 1481–1486. DOI: 10.1021/ja043925d. Barhate, N. B., & Chen, C. T. (2002). Catalytic asymmetric oxidative couplings of 2-naphthols by tridentate Nketopinidene-based vanadyl dicarboxylates. Organic Letters, 4, 2529–2532. DOI: 10.1021/ol026156g. Corey, E. J., & Guzman-Perez, A. (1998). The catalytic enantioselective construction of molecules with quaternary carbon stereocenters. Angewandte Chemie International Edition, 37, 388–401. DOI: 10.1002/(SICI)1521-3773(19980302)37:4< 388::AID-ANIE388>3.0.CO;2-V. Dossetter, A. G., Jamison, T. F., & Jacobsen, E. N. (1999). Highly enantio- and diastereoselective hetero-Diels–Alder reactions catalyzed by new chiral tridentate chromium(III) catalysts. Angewandte Chemie International Edition, 38, 2398–

2400. DOI: 10.1002/(SICI)1521-3773(19990816)38:163.0.CO;2-E. Doyle, M. P., Phillips, I. M., & Hu, W. (2001). A new class of chiral Lewis acid catalysts for highly enantioselective hetero-Diels–Alder reactions: Exceptionally high turnover numbers from dirhodium(II) carboxamidates. Journal of the American Chemical Society, 123, 5366–5367. DOI: 10.1021/ja015692l. Du, H., Long, J., Hu, J., Li, X., & Ding, K. (2002). 3,3 -Br2 BINOL-Zn complex: A highly efficient catalyst for the enantioselective hetero-Diels–Alder reaction. Organic Letters, 4, 4349–4352. DOI: 10.1021/ol027034r. Du, H., & Ding, K. (2003). Enantioselective catalysis of hetero Diels–Alder reaction and diethylzinc addition using a single catalyst. Organic Letters, 5, 1091–1093. DOI: 10.1021/ol034143c. Du, H., Zhao, D., & Ding, K. (2004). Enantioselective catalysis of the hetero-Diels–Alder reaction between Brassard’s diene and aldehydes by hydrogen-bonding activation: A one-step synthesis of (S)-(+)-dihydrokawain. Chemistry - A European Journal, 10, 5964–5970. DOI: 10.1002/chem.200400515. Du, H., Zhang, X., Wang, Z., & Ding, K. (2005). One catalyst for two distinct reactions: sequential asymmetric hetero Diels–Alder reaction and diethylzinc addition. Tetrahedron, 61, 9465–9477. DOI: 10.1016/j.tet.2005.08.007. Endeshaw, M. M., Bayer, A., Hansen, L. K., & Gautun, O. R. (2006). Catalytic asymmetric hetero Diels–Alder reactions of N-sulfinyl dienophiles with chiral bis(oxazoline)copper(II) and -zinc(II) triflates. European Journal of Organic Chemistry, 2006, 5249–5259. DOI: 10.1002/ejoc.200600083. Evans, D. A., Johnson, J. S., & Olhava, E. J. (2000). Enantioselective synthesis of dihydropyrans. Catalysis of hetero Diels– Alder reactions by bis(oxazoline) copper(II) complexes. Journal of the American Chemical Society, 122, 1635–1649. DOI: 10.1021/ja992175i. Fan, Q., Lin, L., Liu, J., Huang, Y., Feng, X., & Zhang, G. (2004). Highly enantioselective hetero-Diels–Alder reaction of Brassard diene with aromatic aldehydes. Organic Letters, 6, 2185–2188. DOI: 10.1021/ol049364c. Fan, Q., Lin, L., Liu, J., Huang, Y., & Feng, X. (2005). A mild and efficient asymmetric hetero-Diels–Alder reaction of the Brassard diene with aldehydes. European Journal of Organic Chemistry, 2005, 3542–3552. DOI: 10.1002/ejoc.200500126. Fu, Z., Gao, B., Yu, Z., Yu, L., Huang, Y., Feng, X., & Zhang, G. (2004). An efficient and enantioselective approach to 2,5disubstituted dihydropyrones. Synlett, 36, 1772–1775. DOI: 10.1055/s-2004-830869. Gong, L. Z., & Pu, L. (2000). The asymmetric hetero-Diels– Alder reaction of enamide aldehydes with Danishefsky’s diene and an efficient synthesis of chiral binaphthyl ligands. Tetrahedron Letters, 41, 2327–2331. DOI: 10.1016/S00404039(00)00193-3. Gordillo, R., Dudding, T., Anderson, C. D., & Houk, K. N. (2007). Hydrogen bonding catalysis operates by charge stabilization in highly polar Diels–Alder reactions. Organic Letters, 9, 501–503. DOI: 10.1021/ol0629925. Huang, Y., Unni, A. K., Thadani, A. N., & Rawal, V. H. (2003). Hydrogen bonding: Single enantiomers from a chiral-alcohol catalyst. Nature, 424, 146. DOI: 10.1038/424146a. Johannsen, M., & Jørgensen, K. A. (1995). Asymmetric hetero Diels–Alder reactions and ene reactions catalyzed by chiral copper(II) complexes. Journal of Organic Chemistry, 60, 5757–5762. DOI: 10.1021/jo00123a007. Jørgensen, K. A. (2000). Catalytic asymmetric hetero-Diels– Alder reactions of carbonyl compounds and imines. Angewandte Chemie International Edition, 39, 3558–3588. DOI: 10.1002/1521-3773(20001016)39:20 3.0.CO;2-I.



Jørgensen, K. A. (2004). Hetero-Diels–Alder reactions of ketones – A challenge for chemists. European Journal of Organic Chemistry, 2004, 2093–2102. DOI: 10.1002/ejoc. 200300766. Kezuka, S., Mita, T., Ohtsuki, N., Ikeno, T., & Yamada, T. (2000). Optically active cationic cobalt(III) complexes: Highly efficient catalysts for enantioselective hetero Diels– Alder reaction. Chemistry Letters, 29, 824–825. DOI: 10.1246 /cl.2000.824. Leveque, L., Le Blanc, M., & Pastor, R. (2000). Asymmetric heterocyclocondensation of polyfluorinated aldehydes catalysed by a chiral titanium(IV) complex. Tetrahedron Letters, 41, 5043–5046. DOI: 10.1016/S0040-4039(00)00762-0. Li, X., Hewgley, J. B., Mulrooney, C. A., Yang, J., & Kozlowski, M. C. (2003). Enantioselective oxidative biaryl coupling reactions catalyzed by 1,5-diazadecalin metal complexes: Efficient formation of chiral functionalized BINOL derivatives. Journal of Organic Chemistry, 68, 5500–5511. DOI: 10.1021/jo0340206. Liu, P., & Jacobsen, E. N. (2001). Total synthesis of (+)Ambruticin. Journal of the American Chemical Society, 123, 10772–10773. DOI: 10.1021/ja016893s. Long, J., Hu, J., Shen, X., Ji, B., & Ding, K. (2002). Discovery of exceptionally efficient catalysts for solvent-free enantioselective hetero-Diels–Alder reaction. Journal of the American Chemical Society, 124, 10–11. DOI: 10.1021/ja0172518. Schaus, S. E., Br˚ analt, J., & Jacobsen, E. N. (1998). Asymmetric hetero-Diels–Alder reactions catalyzed by chiral (Salen) chromium(III) complexes. Journal of Organic Chemistry, 63, 403–405. DOI: 10.1021/jo971758c. Simonsen, K. B., Svenstrup, N., Roberson, M., & Jørgensen, K. A. (2000). Development of an unusually highly enantioselective hetero-Diels–Alder reaction of benzaldehyde with activated dienes catalyzed by hypercoordinating chiral aluminum complexes. Chemistry - A European Journal, 6, 123–128. DOI: 10.1002/(SICI)1521-3765(20000103)6:13.0.CO;2-L. Thompson, C. F., Jamison, T. F., & Jacobsen, E. N. (2001). FR901464: Total synthesis, proof of structure, and evaluation of synthetic analogues. Journal of the American Chemical Society, 123, 9974–9983. DOI: 10.1021/ja016615t.

193

Unni, A. K., Takenaka, N., Yamamoto, H., & Rawal, V. H. (2005). Axially chiral biaryl diols catalyze highly enantioselective hetero-Diels–Alder reactions through hydrogen bonding. Journal of the American Chemical Society, 127, 1336– 1337. DOI: 10.1021/ja044076x. Wang, B., Feng, X., Cui, X., Liu, H., & Jiang, Y. (2000). Highly efficient enantioselective synthesis of optically active dihydropyrones by chiral titanium(IV) (5,5 ,6,6 ,7,7 ,8,8 octahydro-1,1 -bi-2-naphthol) complexes. Chemical Communications, 2000, 1605–1606. DOI: 10.1039/b004813p. Wang, B., Feng, X., Huang, Y., Liu, H., Cui, X., & Jiang, Y. (2002). A highly enantioselective hetero-Diels–Alder reaction of aldehydes with Danishefsky’s diene catalyzed by chiral titanium(IV) 5,5 ,6,6 ,7,7 ,8,8 -octahydro-1,1 -bi-2-naphthol complexes. Journal of Organic Chemistry, 67, 2175–2178. DOI: 10.1021/jo016240u. Wang, Q., Chen, X., Tao, L., Wang, L., Xiao, D., Yu, X. Q., & Pu, L. (2007). Enantioselective fluorescent recognition of amino alcohols by a chiral tetrahydroxyl 1,1 -binaphthyl compound. Journal of Organic Chemistry, 72, 97–101. DOI: 10.1021/jo061769i. Yamashita, Y., Saito, S., Ishitani, H., & Kobayashi, S. (2003). Chiral hetero Diels–Alder products by enantioselective and diastereoselective zirconium catalysis. Scope, limitation, mechanism, and application to the concise synthesis of (+)-prelactone C and (+)-9-deoxygoniopyrone. Journal of the American Chemical Society, 125, 3793–3798. DOI: 10.1021/ja028186k. Yang, W., Shang, D., Liu, Y., Du, Y., & Feng, X. (2005). Highly enantioselective synthesis of 2,6-disubstituted and 2,2,6-trisubstituted dihydropyrones: A one-step synthesis of (R)-(+)-hepialone and its analogues. Journal of Organic Chemistry, 70, 8533–8537. DOI: 10.1021/jo051458s. Yao, S., Johannsen, M., Audrain, H., Hazell, R. G., & Jørgensen, K. A. (1998a). Catalytic asymmetric hetero-Diels–Alder reactions of ketones: Chemzymatic reactions. Journal of the American Chemical Society, 120, 8599–8605. DOI: 10.1021/ja981710w. Yao, S., Johannsen, M., Hazell, R. G., & Jørgensen, K. A. (1998b). Total synthesis of (R)-dihydroactinidiolide and (R)actinidiolide using asymmetric catalytic hetero-Diels–Alder methodology. Journal of Organic Chemistry, 63, 118–121. DOI: 10.1021/jo971528y.
