SUMMARY

Cyclocurcumin is a natural product that possesses several biological activities such as cytotoxicity to cancer cell lines. Interestingly, this natural product also has a pyranone frame and a structure that is very similar to the 2,3-dihydro-4-pyranone compounds that were synthesized using tandem aldol/vinylogous aldol reaction catalyzed with chiral phosphine oxide. Hence, we ascertained if this natural product could also be readily accessed using tandem aldol/vinylogous aldol reaction. By reacting an acetyl-protected aldehyde 2h with the enone substrate 1a in the presence of a base, tetrachlorosilane, and (S)-BINAPO; we afforded the pyranone adduct 3h in good yields and excellent selectivities. Unfortunately, due to the difficulty of the separation of the diastereomers, we used 3h as diastereomeric mixture for the elimination and deprotection steps, which caused the reduction of the enantiomeric excess to 80% ee. Nevertheless, we were still able to synthesize cyclocurcumin natural product in an overall 60% yield in 4 steps.

EXPERIMENTAL SECTION

TLC was performed using Merck silica gel plates. Visualization was accomplished with UV light, phosphomolybdic acid, and/or anisaldehyde. Optical rotations were recorded on a JASCO P-1010 polarimeter. ¹H- and ¹³C-NMR spectra were measured in CDCl3 with JEOL JNM-ECX400 or BRUKER AVANCE 600 spectrometers. Chemical shifts were reported in ppm relative to an internal TMS standard (δ 0.00 ppm) for ¹H-NMR spectra, and to the solvent signals (δ 77.0 ppm for CDCl3) for ¹³C-NMR spectra. IR spectra were recorded on a PerkinElmer, Inc.

Frontier. Mass spectra were measured on a JEOL JMS-700MStation or BRUKER Impact II. HPLC was performed on JASCO P-2080 and UV-2075.

All reactions were performed under an argon atmosphere using dried glassware equipped with a rubber septum and a magnetic stirring bar. Column chromatography was performed using Kanto Chemical Silica Gel 60N (spherical, neutral, 63–210 µm).

α,β-Enones 1a-1c were synthesized according to literature procedures.⁴³ Dehydrated stabilizer-free dichloromethane was purchased from Kanto Chemical Co., Inc. All other solvents and chemicals were purified based on standard procedures or used as received.

Typical Procedure A: Synthesis of 2,3-dihydro-4-pyranone derivative 3a

(Table 1, Entry 2)

To a solution of 4-methoxy-3-penten-2-one (1a) (28.5 mg, 0.25 mmol, 1.0 eq.),

aldehyde 2a (0.10 mL, 1.0 mmol, 4.0 eq.) and (S)-BINAPO (16.4 mg, 0.025 mmol, 10 mol %) in dichloromethane (5 mL) was subsequently added N,N-diisopropylethylamine (0.22 mL, 1.25 mmol, 5.0 eq.) and tetrachlorosilane (0.09 mL, 0.75 mmol, 3.0 eq.) at –60 °C. The reaction was tracked with TLC analysis and was stirred on the same temperature for 24 hours. The reaction was quenched with an aqueous solution of potassium fluoride (1.5 M) and formic acid (3.0 M) and the slurry was stirred at room temperature for 1 h. It was afterwards extracted with EtOAc (20 mL x 3). The combined organic layer was washed with:

1) 10% HCl solution, 2) sat. NaHCO3 and 3) brine; and was dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by silica gel column chromatography (hexane/EtOAc=5:1, SiO2). The enantiomeric excess was determined by HPLC with Daicel Chiralpak AY-H column [eluent:

Hexane/IPA = 6 : 1; flow rate = 1.0 mL/min; detection: 254 nm; tR: 33.4 min (minor), 61.5 min (major)] to give the product in 55% yield with 92% ee, 93:7 dr.

(R*)-6-[(R*)-2-Hydroxy-2-phenylethyl]-2-phenyl-2,3-dihydro-4H-pyran-4-one (3a) TLC: Rf 0.20 30 (Hexane/ EtOAc=5:2, stained orange with anisaldehyde); [α]D30 –25.0 (c 1.01, CHCl3) for 98% ee; ¹H-NMR (400 MHz,

CDCl3): δ 2.16 (d, 1H, J=3.6 Hz), 2.55–2.85 (m, 4H), 5.06 (dd, 1H, J=3.6, 7.4 Hz), 5.35 (dd, 1H, J=3.2, 12.4 Hz), 5.48 (s, 1H), 7.30–7.45 (m, 10H); ¹³C-NMR (100 MHz, CDCl3) δ: 42.4, 44.6, 71.5, 81.0, 106.7, 125.6, 126.1, 128.0, 128.6, 128.8, 128.9, 137.9, 142.9, 173.9, 192.6; IR attenuated total reflectance (ATR):

1599, 1644, 3307 cm⁻¹; low resolution (LR)-MS (FAB): m/z 295 (M+H)⁺; high resolution (HR)-MS (FAB): Calcd for C19H19O3 295.1334. Found 295.1342; The enantiomeric excess was determined to be 98% ee by chiral HPLC with Daicel Chiralpak AY-H column [eluent: Hexane/isopropyl alcohol (IPA)=6 : 1; flow rate:

1.0 mL/min; detection: 254 nm; tR: 33.4 min (minor), 61.5 min (major)].

Section 1. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a at –40 °C. (Table 1, Entry 1)

Following typical procedure A, silicon tetrachloride (0.11 mL, 0.90 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (19.6 mg, 0.030 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (34.2 mg, 0.30 mmol), and aldehyde 2a (0.06 mL, 0.60 mmol, 2.0 eq.) and N,N-diisopropylethylamine (0.26 mL, 1.50 mmol, 5.0 eq.) in CH2Cl2 (5 mL) at –40 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (32.0 mg, 36% yield, 86% ee, 89:11 dr).

Section 1. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a in –78 °C. (Table 1, Entry 3)

Following typical procedure A, silicon tetrachloride (0.11 mL, 0.90 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (19.6 mg, 0.03 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (34.2 mg, 0.30 mmol, 1.0 eq.), and aldehyde 2a (0.08 mL, 0.750 mmol, 2.5.0 eq.) and N,N-diisopropylethylamine (0.26 mL, 1.50 mmol, 5.0 eq.) in CH2Cl2 (5 mL) at –78 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (24.4 mg, 28% yield, 87% ee, 90:10 dr).

Section 2. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with 2.5 equivalents of aldehyde 2a. (Table 2, Entry 1)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.750 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (16.3 mg, 0.025 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (28.5 mg, 0.250 mmol, 1.0 eq.), aldehyde 2a (0.064 mL, 0.623 mmol, 2.5.0 eq.) and N,N-diisopropylethylamine (0.219 mL, 1.25 mmol, 5.0 eq.) in CH2Cl2 (5 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (40.5 mg, 55% yield, 92% ee, 93:7 dr).

Section 2. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with 2.8 equivalents of aldehyde 2a. (Table 2, Entry 2)

Following typical procedure A, silicon tetrachloride (0.14 mL, 0.91 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (19.9 mg, 0.030 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (34.7 mg, 0.30 mmol), aldehyde 2a (0.09 mL, 0.83 mmol, 2.8 eq.), and N,N-diisopropylethylamine (0.27 mL, 1.5 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (40.5 mg, 45% yield, 90% ee, 92:8 dr).

Section 2. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with 3.3 equivalents of aldehyde 2a. (Table 2, Entry 3)

Following typical procedure A, silicon tetrachloride (0.13 mL, 0.83 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (18.2 mg, 0.028 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (31.7 mg, 0.28 mmol), aldehyde 2a (0.11 mL, 1.1 mmol, 3.3.0 eq.), and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (48.4 mg, 48% yield, 91% ee, 92:8 dr).

Section 2. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with 4.0 equivalents of aldehyde 2a. (Table 2, Entry 4)

Following typical procedure A, silicon tetrachloride (0.12 mL, 1.02 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (22.2 mg, 0.034 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (38.6 mg, 0.34 mmol), aldehyde 2a (0.14 mL, 1.35 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (50.5 mg, 51% yield, 98% ee, 96:4 dr).

Section 3. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with N,N-diisopropylethylamine. (Table 3, Entry 1)

Following typical procedure A, silicon tetrachloride (0.12 mL, 1.02 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (22.2 mg, 0.034 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (38.6 mg, 0.34 mmol), aldehyde 2a (0.14 mL, 1.35 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (50.5 mg, 51% yield, 98% ee, 96:4 dr).

Section 3. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with N,N-dicyclohexylmethylamine. (Table 3, Entry 2)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.80 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (16.6 mg, 0.025 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (28.9 mg, 0.25 mmol, 1.0 eq.), aldehyde 2a (0.10 mL, 1.0 mmol, 4.0 eq.), and N,N-dicyclohexylmethylamine (0.27 mL, 1.3 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (45.0 mg, 60.0% yield, 93:7 dr, 84% ee, 93:7 dr).

Section 3. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with N,N-dicyclohexylethylamine. (Table 3, Entry 3)

Following typical procedure A, silicon tetrachloride (0.08 mL, 0.73 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (16.0 mg, 0.024 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (27.9 mg, 0.24 mmol, 1.0 eq.), aldehyde 2a (0.10 mL, 0.98 mmol, 4.0 eq.), and N,N-dicyclohexylethylamine (0.28 mL, 1.22 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (40.2 mg, 56.0% yield, 90:10 dr, 86% ee, 90:10 dr).

Section 3. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with Ph3N. (Table 3, Entry 4)

Following typical procedure A, silicon tetrachloride (0.11 mL, 0.10 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (21.0 mg, 0.032 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (36.5 mg, 0.32 mmol, 1.0 eq.), aldehyde 2a (0.13 mL, 1.28 mmol, 4.0 eq.), and Ph3N (392.7 mg, 1.60 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. There was no observable reaction.

Section 3. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with ⁿBut3N. (Table 3, Entry 5)

Following typical procedure A, silicon tetrachloride (0.08 mL, 0.70 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (15.0 mg, 0.023 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (26.2 mg, 0.23 mmol, 1.0 eq.), aldehyde 2a (0.094 mL, 0.92 mmol, 4.0 eq.), and ⁿBu3N (0.27 mL, 1.15 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (10.0 mg, 15.0% yield, 42% ee, 61:39 dr).

Section 3. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with ⁱBut3N. (Table 3, Entry 6)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.08 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (16.5 mg, 0.025 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (28.7 mg, 0.25 mmol, 1.0 eq.), aldehyde 2a (0.10 mL, 1.0 mmol, 4.0 eq.), and ⁱBut3N (0.30 mL, 1.26 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The pyranone derivative 3a was not observed and had not been isolated.

Section 3. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with 2,6-^tBu2-pyridine. (Table 3, Entry 7)

Following typical procedure A, silicon tetrachloride (0.10 mL, 0.09 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (19.2 mg, 0.029 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (33.5 mg, 0.29 mmol, 1.0 eq.), aldehyde 2a (0.12 mL, 1.18 mmol, 4.0 eq.), and 2,6-^tBu2-pyridine (0.33 mL, 1.47 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The pyranone derivative 3a was not observed and had not been isolated.

Section 4. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with (S)-BINAPO as catalyst. (Table 4, Entry 1)

Following typical procedure A, silicon tetrachloride (0.12 mL, 1.01 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (22.2 mg, 0.034 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (38.6 mg, 0.34 mmol), aldehyde 2a (0.14 mL, 1.35 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (50.5 mg, 51% yield, 98% ee, 96:4 dr).

Section 4. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with (S)-4,4’-Br2BINAPO as catalyst. (Table 4, Entry 2)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.78 mmol, 3.0 eq.)

was added to the solution of (S)-4,4’-Br2BINAPO (21.0 mg, 0.026 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (29.5 mg, 0.26 mmol), aldehyde 2a

(0.11 mL, 1.04 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.23 mL, 1.29 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (40.0 mg, 53% yield, 93% ee, 88:12 dr).

Section 4. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with (S)-4,4’-CN2BINAPO as catalyst. (Table 4, Entry 3)

Following typical procedure A, silicon tetrachloride (0.10 mL, 0.87 mmol, 3.0 eq.) was added to the solution of (S)-4,4’-CN2BINAPO (20.4 mg, 0.029 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (33.0 mg, 0.29 mmol), aldehyde 2a (0.12 mL, 1.16 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.25 mL, 1.45 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (22.1 mg, 26% yield, 32% ee, 74:26 dr).

Section 4. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with (S)-4,4’-(TMS)2BINAPO as catalyst. (Table 4, Entry 4)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.78 mmol, 3.0 eq.) was added to the solution of (S)-4,4’-(TMS)2BINAPO (20.3 mg, 0.025 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (29.0 mg, 0.254 mmol), aldehyde 2a (0.10 mL, 1.02 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.22 mL, 1.27 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (32.4 mg, 43% yield, 93% ee, 84:16 dr).

Section 4. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a with (S)-4,4’-^tBu2SEGPHOSO as catalyst. (Table 4, Entry 5)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.78 mmol, 3.0 eq.) was added to the solution of (S)-4,4’-^tBu2SEGPHOSO (19.4 mg, 0.025 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (29.0 mg, 0.254 mmol), aldehyde 2a (0.10 mL, 1.02 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.22 mL, 1.27 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (20.0 mg, 26% yield, 79% ee, 87:13 dr).

Section 5. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1a and aldehyde 2a. (Table 5, Entry 1)

Following typical procedure A, silicon tetrachloride (0.12 mL, 1.02 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (22.2 mg, 0.034 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (38.6 mg, 0.34 mmol), aldehyde 2a (0.14 mL, 1.35 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.30 mL, 1.69 mmol, 5.0 eq.) in CH2Cl2 (10 mL). The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (50.5 mg, 51% yield, 98% ee, 96:4 dr).

Section 5. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1b and aldehyde 2a. (Table 5, Entry 2)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.82 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (22.2 mg, 0.034 mmol, 10 mol %), 4-ethoxy-3-penten-2-one (1b) (35.1 mg, 0.27 mmol), aldehyde 2a (0.11 mL, 1.1 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.24 mL, 1.37 mmol, 5.0 eq.) in CH2Cl2 (10 mL). The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a (38.0 mg, 47% yield, 91% ee, 92:8 dr).

Section 5. Synthesis of 2,3-dihydro-4-pyranone derivative 3a from ketone 1c and aldehyde 2a. (Table 5, Entry 3)

Following typical procedure A, silicon tetrachloride (0.11 mL, 0.90 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (20.2 mg, 0.031 mmol, 10 mol %), 4-trimethylsiloxy-3-penten-2-one (1c) (53.0 mg, 0.31 mmol, 1 eq.), aldehyde 2a (0.14 mL, 1.2 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.26 mL, 1.50 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3a in trace amounts.

Section 5. Synthesis of 2,3-dihydro-4-pyranone derivative 3b from ketone 1a and aldehyde 2b. (Table 5, Entry 4)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.78 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (17.0 mg, 0.026 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (29.6 mg, 0.26 mmol, 1.0 eq.), anisaldehyde (2b) (0.13 mL, 1.0 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.23 mL, 1.30 mmol, 5.0 eq.) in CH2Cl2 (10 mL). The crude product was purified by silica gel column chromatography (hexane/EtOAc = 2:1, SiO2) to give product 3b (32.0 mg, 35% yield, 93% ee, 93:7 dr).

(R*)-6-[(R*)-2-Hydroxy-2-(4-methoxyphenyl)ethyl]-2-(4-methoxyphenyl)-2,3-dihydro-4H-pyran-4-one (3b) TLC: Rf 0.20 (Hexane/EtOAc=1:2, stained orange with anisaldehyde); [α]D27 −46.1 (c 0.94, CHCl3) for 93% ee; ¹H-NMR (400 MHz, CDCl3): δ 2.18 (brs, 1H), 2.51–2.85 (m, 4H), 3.81, (s, 3H), 3.84 (s, 3H), 4.98 (dd, 1H, J=3.7, 7.4 Hz), 5.28 (dd, 1H, J=2.3, 13.4 Hz), 5.45 (s, 1H), 6.87 (d, 2H, J=8.7 Hz), 6.94 (d, 2H, J=8.7 Hz), 7.26 (d, 2H, J=8.7 Hz), 7.30 (d, 2H, J=8.7 Hz);

13C-NMR (100 MHz, CDCl3): δ 42.3, 44.7, 55.4, 55.5, 71.4, 81.0, 106.4, 114.0, 114.2, 127.1, 128.0 130.1, 135.2, 159.4, 160.2, 174.2, 192.9; IR (ATR): 1243, 1599, 1648, 3388 cm⁻¹; LR-MS (FAB): m/z 355 (M+H)⁺; HR-MS (FAB): Calcd for C21H22O5 355.1545. Found 355.1539. The enantiomeric excess was determined to be 93% ee by chiral HPLC with Daicel Chiralpak IF-3 column [eluent:

Hexane/IPA=4:1; flow rate: 1.0mL/min; detection: 254 nm; tR: 27.6 min (major), 40.0 min (minor)].

Section 5. Synthesis of 2,3-dihydro-4-pyranone derivative 3c from ketone 1a and aldehyde 2c. (Table 5, Entry 5)

Following typical procedure A, silicon tetrachloride (0.10 mL, 0.80 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (17.5 mg, 0.027 mmol, 10 mol %),

4-methoxy-3-penten-2-one (1a) (30.4 mg, 0.27 mmol, 1.0 eq.), 4-bromobenzalaldehyde (2c) (0.19 mL, 1.07 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.22 mL, 1.27 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at

–60 °C, and the reaction was stirred for 24 hours. The crude product was purified

by column chromatography (Hexane/EtOAc = 2:1, SiO2: 10 g) to give product 3c (84.1 mg, 70% yield, 95% ee, 94:6 dr).

(R*)-6-[(R*)-2-Hydroxy-2-(4-bromophenyl)ethyl]-2-(4-bromophenyl)-2,3-dihydro-4H-pyran-4-one (3c) TLC: Rf 0.57 (Hexane/EtOAc=1:1, stained orange with anisaldehyde); [α]D27–21.5 (c 0.40, CHCl3) for 95% ee; ¹H-NMR (400 MHz, CDCl3): δ 2.55–2.83 (m, 4H), 5.01 (dd, 1H, J=0.5, 8.2 Hz), 5.28 (dd, 1H, J=0.3, 14.2 Hz), 5.49 (s, 1H), 7.20 (d, 2H, J=8.2 Hz), 7.24 (d, 2H, J=8.2 Hz), 7.48 (d, 2H J=8.7 Hz), 7.57 (d, 2H, J=8.7 Hz); ¹³C-NMR (100 MHz, CDCl3): δ 42.3, 44.4, 71.1, 80.2, 106.7, 122.0, 123.0, 127.4, 127.8, 131.8, 132.1, 136.8, 141.7, 172.9, 191.8; IR (ATR): 1595, 1632, 3319 cm⁻¹; LR-MS electrospray ionization (ESI):

m/z 473, 475, 477 (M+Na)⁺; HR-MS (ESI): Calcd for C19H16Br2NaO3 472.9364.

Found 472.9358. The enantiomeric excess was determined to be 95% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: Hexane/IPA=9:1; flow rate:

1.0mL/min; detection: 254 nm; tR: 53.7 min (minor), 89.4 min (major)].

Section 5. Synthesis of 2,3-dihydro-4-pyranone derivative 3d from ketone 1a and aldehyde 2d. (Table 5, Entry 6)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.90 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (16.8 mg, 0.026 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (29.2 mg, 0.26 mmol), cinnamaldehyde 2d (0.13 mL, 1.03 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.22 mL, 1.3 mmol, 5.0

eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 2:1, SiO2: 10 g) to give product 3d (42.5 mg, 48% yield, 91% ee, 94:6 dr).

(R*)-6-[(R*,E)-2-Hydroxy-4-phenyl-3-buten-1-yl]-2-[2-(E)-styryl]-2,3-dihydro-4H-pyran-4-one (3d) TLC: Rf 0.34 (Hexane/EtOAc=1:1, stained orange with anisaldehyde); [α]D28 −31.7 (c 1.02, CHCl3) for 91% ee; ¹H-NMR (400 MHz, CDCl3): δ 2.55–2.70 (m, 4H), 4.62–4.70 (m, 1H), 5.01–5.09 (m, 1H), 5.49 (s, 1H), 6.20–6.35 (m, 2H), 6.61–6.68 (m, 2H), 7.21–7.42 (m, 10H); ¹³C-NMR (100 MHz, CDCl3): δ 41.0, 42.9, 70.4, 79.9, 106.4, 125.0, 126.5, 126.8, 128.0, 128.5, 128.6, 128.7, 130.4, 131.1, 134.0, 135.4, 136.1, 173.5, 192.3; IR (ATR): 1598, 1648, 3374 cm⁻¹; LR-MS (ESI): m/z 369 (M+Na)⁺; HR–MS (ESI): Calcd for C23H22NaO3 369.1467. Found 369.1459. The enantiomeric excess was determined to be 91% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent:

Hexane/IPA=9 : 1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 40.1min (minor), 65.5min (major)].

Section 5. Synthesis of 2,3-dihydro-4-pyranone derivative 3e from ketone 1a and aldehyde 2e. (Table 5, Entry 7)

Following typical procedure A, silicon tetrachloride (0.094 mL, 0.82 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (17.9 mg, 0.027 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (31.2 mg, 0.26 mmol, 1.0 eq.), 1-naphthaldehyde

(2d) (0.15mL, 1.1 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.24 mL, 1.37 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 2:1, SiO2: 10 g) to give product 3e (30.3 mg, 28% yield, and 85% ee, 73:27 dr).

(R*)-6-[(R*)-2-Hydroxy-2-(1-naphthyl)ethyl]-2-(1-naphthyl)-2,3-dihydro-4H-pyran-4-one (4e) TLC: Rf 0.30 (Hexane/EtOAc=1:1, stained orange with anisaldehyde); [α]D28 +9.8 (c 1.01, CHCl3) for 85% ee; ¹H-NMR (400 MHz, CDCl3): δ 2.78–3.10 (m, 4H), 5.62 (s, 1H), 5.85 (dd, 1H, J=3.6, 9.2 Hz), 6.23 (dd, 1H, J=3.2, 14.2 Hz), 7.38–8.10 (m, 14H); ¹³C-NMR (100 MHz, CDCl3): δ 41.6, 44.1, 68.4, 78.4, 106.6, 122.6, 122.7, 123.8, 125.3, 125.4, 125.7, 126.1, 126.3, 126.8, 128.5, 129.0, 129.1, 129.6, 129.8, 130.3, 133.3, 133.7, 133.8, 138.6, 174.4, 192.8; IR (ATR): 1595, 1638, 3355 cm⁻¹; LR-MS (FAB): m/z 395 (M+H)⁺; HR-MS (FAB): Calcd for C27H23O3 395.1647. Found 395.1694. The enantiomeric excess was determined to be 85% ee by chiral HPLC with Daicel Chiralpak IF-3 column [eluent: Hexane/IPA=3:1; flow rate: 1.0 mL/min; detection: 254 nm;

tR: 36.1 min (major), 38.2 min (minor)].

Section 6. Synthesis of 2,3-dihydro-4-pyranone derivative 3f from ketone 1a and aldehyde 2f. (Table 6, Entry 1)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.75 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (16.4 mg, 0.025 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (28.5 mg, 0.25 mmol, 1.0 eq.), aldehyde 2f (337.3 mg, 1.0 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.22 mL, 1.25 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) but the desired pyranone derivative 3f has not been observed.

Section 6. Synthesis of 2,3-dihydro-4-pyranone derivative 3g from ketone 1a and aldehyde 2g. (Table 6, Entry 2)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.75 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (16.4 mg, 0.025 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (28.5 mg, 0.25 mmol, 1.0 eq.), aldehyde 2g (236.3 mg, 1.0 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.22 mL, 1.25 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3g (72.1 mg, 52% yield, 95% ee).

4-((R*)-1-hydroxy-2-((R*)-2-(3-methoxy-4-(pivaloyloxy)phenyl)-4-oxo-3,4-dihydro-2H-pyran-6-yl)ethyl)-2-methoxyphenyl pivalate (3g)

TLC: Rf 0.12 (Hexane/EtOAc = 1:2, stained orange with anisaldehyde). ¹H NMR (400 MHz, CDCl3): δ 1.36 (s, 9H), 1.38 (2, 9H), 2.21 (s, broad, 1H), 2.58-2.85 (m, 4H), 3.80 (s, 3H), 3.84 (s, 3H), 5.06 (dd, 1H, J = 3.7, 7.4 Hz), 5.29 (dd, 1H, J = 3.2, 14.6 Hz), 5.53 (s, 1H), 6.90-7.10 (m, 6H). The enantiomeric excess was determined to be 95% ee by chiral HPLC with Daicel Chiralpak IB-3 column [eluent: Hexane/IPA = 9/1; flow rate = 1.0 mL/min; detection: 254 nm; tR : 67.4 min (minor), 41.7 min (major)].

Section 6. Synthesis of 2,3-dihydro-4-pyranone derivative 3h from ketone 1a and aldehyde 2h. (Table 6, Entry 3)

Following typical procedure A, silicon tetrachloride (0.09 mL, 0.75 mmol, 3.0 eq.) was added to the solution of (S)-BINAPO (16.4 mg, 0.025 mmol, 10 mol %), 4-methoxy-3-penten-2-one (1a) (28.5 mg, 0.25 mmol, 1.0 eq.), aldehyde 2h (194.2 mg, 1.0 mmol, 4.0 eq.), and N,N-diisopropylethylamine (0.22 mL, 1.25 mmol, 5.0 eq.) in CH2Cl2 (10 mL) at –60 °C. The crude product was purified by column chromatography (Hexane/EtOAc = 5:1, SiO2: 10 g) to give product 3h (77.6 mg, 66% yield, 98% ee, 88:12 dr).

4-((R*)-6-((R*)-2-(4-acetoxy-3-methoxyphenyl)-2-hydroxyethyl)-4-oxo-3,4-dihydro-2H-pyran-2-yl)-2-methoxyphenyl acetate (3h)

TLC: Rf 0.15 (Hexane/EtOAc = 1:2, stained orange with anisaldehyde).

[α]D27 –1139.34 (c 0.05, CH3OH) for 98% ee (589 nm). ¹H-NMR (400 MHz, CDCl3): δ 2.16 (s, 3H); 2.18 (s, 3H), 2.21 (s, broad, 1H), 2.58-2.85 (m, 4H), 3.94 (s, 3H), 3.96 (s, 3H) 5.02 (dd, 1H, J = 3.7, 7.4 Hz), 5.29 (dd, 1H, J = 3.2, 14.6 Hz), 5.53 (s, 1H), 6.90-7.10 (m, 6H). IR attenuated total reflectance (ATR): 3397, 3075, 2939, 1801, 1760, 1652, 1602 cm^–1. LR-MS (FAB): m/z 471.2 (M+H)⁺; HR-MS (FAB): Calcd C25H25O9Na 493.1477. Found 493.1616. The enantiomeric excess was determined to be 97~98% ee by chiral HPLC with Daicel Chiralpak ID-3/AD-3 dual column [eluent: Hexane/IPA = 3/1; flow rate = 0.25 mL/min;

detection: 254 nm; tR : 76.9 min (minor), 80.9 min (major)].