A Formal Synthesis of (+)-Hannokinol Using a Chiral Horner–Wittig Reagent

Abstract

Herein, we report a concise and efficient formal synthesis of (+)-hannokinol. Key to this new strategy is the use of a chiral Horner–Wittig reagent, readily available from 2-deoxy-D-ribose, to introduce the chiral 1,3-diol motif.

1. Introduction

(+)-Hannokinol (1) is a linear diarylheptanoid that belongs to a group of naturally occurring compounds characterized by two aromatic rings connected by a seven-carbon aliphatic chain containing a 1,3-diol moiety (Scheme 1A) [1,2]. It was first isolated from the seeds of Alpinia blepharocalyx in 1995, and it was identified with a variety of potent biological activities, including anti-inflammatory, antioxidant, anticancer, and antiviral [3,4,5,6,7,8,9]. In 2002, it was also extracted from the rhizomes of Tacca chantrieri, which are used in traditional Chinese medicine to treat gastric ulcers, enteritis, and hepatitis [3]. Furthermore, it has been hypothesized that it can act as a synthon during the biosynthesis of other natural products, such as taccachanfurans [10].

In 2015, the first total syntheses of 1 were independently reported by Yadav and Babu following similar synthetic routes (Scheme 1B). Yadav and coworkers reported the total synthesis of (+)-hannokinol [11], using compound 2 as the key intermediate in their strategy. This species can be readily accessed from known aldehyde 2a via Keck–Maruoka allylation [12,13], followed by Upjohn dihydroxylation [14] and oxidative cleavage. Next, compound 2 undergoes aldol addition followed by oxidation and TBS removal, which cyclizes to tetrahydropyran 3. Selective hydrogenation of 3 produces intermediate 4, which, upon deprotection, affords (+)-hannokinol in 16% yield after eight steps from aldehyde 2a. A few months later, Babu and coworkers reported a similar strategy for the synthesis of (+)-hannokinol from compound 2 [15]. In this case, aldehyde 2 was prepared from 2b via Brown’s asymmetric allylation [9], followed by Upjohn dihydroxylation [14] and oxidative cleavage. The key step in Babu’s route was a diethylzinc (Et₂Zn)-mediated diastereoselective alkynylation of 2 to access alkyne 5, which, after hydrogenation, affords intermediate 6. Deprotection of the latter afforded (+)-hannokinol in 50% yield after six steps from aldehyde 2b. Due to its compelling biological activities and its potential use as a natural building block, (+)-hannokinol has captured the interest of organic and medicinal chemists. Therefore, the development of alternative and scalable synthetic strategies from readily available starting materials is of high interest.

Herein, we present our strategy to access diol intermediate 4, leading to the formal total synthesis of 1 (Scheme 1C). Key to our approach is the use of our modular strategy for the construction of 1,3-diols using chiral building block 7 [16,17], which is prepared from commonly accessible and inexpensive 2-deoxy-D-ribose [18]. In recent years, we have demonstrated the application of this reagent to the synthesis of complex natural products, such as bastimolide [19], aureosurfactin [20], cryptoconcatone D [18], and harzialactone A [21]. During our retrosynthetic analysis to access intermediate 4, we envisioned the construction of the core linear diarylheptanoid skeleton via reduction of olefin 8, which could be readily built via a Heck coupling from compound 9. The latter could be synthesized through an Evans–Tishchenko anti-reduction of β-hydroxy-ketone 10 [22,23,24], which can be readily accessed from 7 and aldehyde 11 using a Horner−Wittig reaction.

2. Results and Discussion

2.1. Initial Approach towards the Total Synthesis of (+)-Hannokinol

Our initial approach towards the synthesis of (+)-hannokinol (1) started with the conversion of commercially available benzyl-protected 4-hydroxyphenyl acetic acid (12) to the corresponding methyl ester 13 using classical Fischer esterification conditions (Scheme 2) [25]. The subsequent reduction of 13 using diisobutylaluminium hydride (DIBAL-H) afforded primary alcohol 14 in 98% yield. The latter could be selectively oxidized to the corresponding aldehyde using 2-iodoxybenzoic acid (IBX) in acetonitrile at 80 °C, affording 11a in 93% yield [26]. Next, we proceeded to build the key heptanoid chain and the anti-1,3-diol motif. Using a robust Horner–Wittig reaction involving aldehyde 11a and the chiral building block 7 (readily prepared in 7 steps from 2-deoxy-D-ribose) [20], β-hydroxy-ketone 15 was obtained in 87% yield. To access the anti-1,3-diol motif, we considered two strategies: (A) direct reduction of 15 to access anti-1,3-diol 16 using Evans–Saksena conditions [27] or (B) reduction of 15 under Evans–Tishchenko conditions [21,28] followed by deprotection of the resulting acetate-protected product to access anti-1,3-diol 16. Unfortunately, the most direct reduction using Evans–Saksena conditions afforded irreproducible yields (25–56%) and diastereoselectivities (d.r. 5:1–9:1). Therefore, we proceeded with strategy B: Evans–Tishchenko reduction, followed by deprotection. Synthesis of anti-1,3-diol monoester 16a was achieved by directed anti-reduction using samarium (II) iodide (SmI₂) and acetaldehyde in THF from –50 °C to –20 °C for 18 h and used in the next step without purification. Subsequent deprotection under basic conditions [29] afforded the targeted anti-1,3-diol 16 in 66% yield over two steps and excellent diastereoselectivity (d.r. > 20:1). Next, the diol motif was converted to the corresponding dibenzyl protected species 17 in 52% yield using benzyl bromide in the presence of tetra-n-butylammonium iodide (TBAI) and sodium hydride (NaH). After the protection step, 17 was subjected to Pd-catalyzed Heck coupling [20] with benzyl-protected 4-iodophenol 18. This afforded the key intermediate 19 in 55% yield. The last step of our strategy was the simultaneous reduction of the alkene in 19 and the global benzyl deprotection of the phenol core and anti-1,3-diol motif to access (+)-hannokinol (1). Unfortunately, using 10 mol% of Pd/C under a hydrogen atmosphere (1 bar) afforded only a trace amount of 1, which was observed using mass spectrometry. We hypothesized that failure at this stage could be due to inefficient benzyl deprotection, as the benzyl moiety is susceptible to aromatic saturation, resulting in low yields of deprotected products [30,31].

2.2. Change of Strategy: Synthesis of Intermediate 4, Formal Synthesis of (+)-Hannokinol

Since the simultaneous global benzyl deprotection/olefin reduction step proved to be more difficult than initially anticipated, we decided to slightly alter our strategy. We realized that changing the protecting groups at both the aromatic rings and the diol unit would enable us to use our strategy to access intermediate 4, thus intercepting Yadav’s route for the synthesis of 1 (Scheme 3).

Our new strategy began with the conversion of commercially available 4-methoxyphenylacetic acid 20 to the corresponding methyl ester 21 (94% yield). Carefully controlling the reduction of 21, following a procedure reported by Tao using DIBAL-H [32], enabled the selective reduction of the ester moiety to the corresponding aldehyde 11 in 89% yield. Next, the key Horner–Witting reaction of 11 with chiral building block 7 furnished β-hydroxy-ketone 22 in 85% yield. Subsequent anti-reduction under Evans–Tishchenko conditions and deprotection afforded anti-1,3-diol 23 in high yields (80%) and high stereoselectivity (d.r. > 20:1). Protection of the 1,3-diol motif using tert-butyldimethylsilylchloride (TBSCl) and imidazole furnished the corresponding bis-TBS-protected species 24 in 95% yield. The latter was then subjected to Pd-catalyzed Heck cross coupling with iodide 25 following a modified procedure reported by Kalesse [33]. Gratifyingly, the reaction proceeded smoothly, affording compound 26 in 84% yield. Subsequent hydrogenation of the alkene motif in 26 using 10 mol% Pd/C under 1.0 bar of hydrogen afforded the corresponding alkane 27 in nearly quantitative yields (93%). Finally, deprotection of the silyl ethers with HF·pyridine complex [34] afforded 4 in excellent yields (87%), thus intercepting the synthetic route for the preparation of (+)-hannokinol (1) reported by Yadav and coworkers [11].

3. Materials and Methods

3.1. General Remarks

The commercially available reagents and solvents were used as purchased. Thin layer chromatography (TLC) was conducted with precoated aluminum sheets (silica gel 60 F254) and visualized by exposure to UV light (254 nm) or staining with potassium permanganate (KMnO₄) or ceric ammonium molybdate (CAM) and subsequent heating. Flash column chromatography was performed on silica gel (40–60 µm); the eluent used is reported in the respective experiments. Abbreviations for solvents and chemicals are as follows: CyHex: cyclohexane, EA: ethyl acetate, THF: tetrahydrofuran, DCM: dichloromethane, MeOH: methanol, DMF: N,N-dimethylformamide, DE: diethyl ether, PE: petroleum ether, and MeCN: acetonitrile. IR spectra were measured using the ATR technique in the range of 400–4000 cm⁻¹. ¹H NMR spectra were recorded with 600 MHz or 400 MHz instruments from Bruker, (Billerica, MA, USA), ¹³C NMR spectra at 151 MHz or 101 MHz, and ¹⁹F NMR spectra at 376 MHz. Chemical shifts are reported in ppm relative to the solvent signal and coupling constants J in Hz. Multiplicities were defined by standard abbreviations. High-resolution mass spectra (HRMS) were obtained using ESI ionization (positive) on a Bruker micrOTOF. The optical rotation of unknown chiral substances were measured using a Krüss Optronic at 584 nm wavelength. The temperature during measurements was kept at 20 °C with a defined concentration (g/100 mL) in the described solvent.

3.2. Synthesis and Charaecterization of Compounds

3.2.1. Methyl 2-(4-(Benzyloxy)phenyl)acetate (13)

To a solution of 2-(4-(benzyloxy)phenyl)acetic acid 12 (5.00 g, 20.6 mmol, 1.0 equiv.) in MeOH (65 mL) was added conc. H₂SO₄ (1.33 mL, 1.2 equiv.). The reaction mixture was heated under reflux (65 °C) for 3 h. After this time, the reaction mixture was allowed to cool down to room temperature, concentrated in vacuo, and dissolved in EA. The resulting solution was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a methyl ester 13 (5.13 g, yield 97%) as a yellow oil. TLC: R_f = 0.44 (EA/CyHex = 3:7) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.43 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 15.0 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 3.69 (s, 3H), 3.57 (s, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 172.5, 158.1, 137.2, 130.4, 128.7, 128.1, 127.6, 126.5, 115.1, 70.2, 52.1, 40.5. HRMS (ESI) m/z: [M + Na⁺] calcd. for C₁₆H₁₆NaO₃: 279.0991; found: 279.0992. All the characterization data are consistent with the literature [25].

3.2.2. 2-(4-(Benzyloxy)phenyl)ethan-1-ol (14)

To a solution of methyl 2-(4-(benzyloxy)phenyl)acetate 13 (3.70 g, 14.4 mmol, 1.0 equiv.) in anhydrous THF (58 mL) was added dropwise DIBAL-H (1.0 M solution in toluene, 28.9 mL, 28.9 mmol, 2.0 equiv.) at −78 °C. After the addition, the cold bath was removed, and the reaction mixture was stirred at room temperature for 7 h. Glycerol (8 mL) and K/Na-tartrate solution (20 mL) were then added at 0 °C. The mixture was stirred overnight at room temperature and then extracted three times with EA. The combined organic phase was washed with a sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA/CyHex = 3:7) to give product 14 (3.26 g, yield 98%) as a colorless solid. TLC: R_f = 0.18 (EA/CyHex = 3:7) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.43 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.06 (s, 2H), 3.83 (t, J = 6.5 Hz, 2H), 2.82 (t, J = 6.5 Hz, 2H), 1.43 (br, 1H). ¹³C NMR (151 MHz, CDCl₃) δ 157.7, 137.3, 130.9, 130.1, 128.7, 128.1, 127.6, 115.2, 70.2, 64.0, 38.5. All the characterization data are consistent with the literature [25].

3.2.3. 2-(4-(Benzyloxy)phenyl)acetaldehyde (11a)

To a solution of 2-(4-(benzyloxy)phenyl)ethan-1-ol 14 (4.00 g, 17.5 mmol, 1.0 equiv.) in dry acetonitrile (88 mL) was added IBX (13.0 g, 52.6 mmol, 3.0 equiv.), and the suspension was stirred at 80 °C for 2 h and then cooled to room temperature. The suspension formed after cooling was filtered through a pad of celite and washed with EA. The filtrate was washed with a sodium bicarbonate solution, and the aqueous phase was extracted with EA (3 × 50 mL). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (EA/CyHex = 2:8 → 3:7) to give product 11a (3.69 g, yield 93%) as a yellowish solid. TLC: R_f = 0.63 (EA/CyHex = 1:5) [KMnO₄]. ¹H NMR (400 MHz, CDCl₃) δ 9.73 (t, J = 2.4 Hz, 1H), 7.47–7.38 (m, 4H), 7.36–7.30 (m, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 3.63 (d, J = 2.4 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 199.8, 158.3, 137.0, 130.8, 128.8, 128.2, 124.1, 115.5, 70.2, 49.9. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 3032, 2868, 1719, 1610, 1583, 1509, 1454, 1238, 1176, 1014, 927, 861, 612, 593. HRMS (ESI) m/z: [M + Na⁺] calcd. for C₁₅H₁₄NaO₂: 249.0886; found: 249.0886. All the characterization data are consistent with the literature [25].

3.2.4. (S)-1-(4-(Benzyloxy)phenyl)-5-hydroxyhept-6-en-3-one (15)

To a solution of diisopropylamine (2.15 mL, 15.3 mmol, 2.1 equiv.) in dry THF (73 mL) was added n-butyllithium (2.5 M in hexane, 6.13 mL, 15.3 mmol, 2.1 equiv.) at −78 °C. After the cooling was removed for 15 min, (S)-building block (2.50 g, 7.30 mmol, 1.0 equiv.) dissolved in dry THF (24 mL) was added slowly at −78 °C. The solution was allowed to stir for 1 h at this temperature. Following the addition of 2-(4-(benzyloxy)phenyl)acetaldehyde 11a (3.50 g, 15.5 mmol, 3.0 equiv.) dissolved in dry THF (9 mL), the reaction was allowed to warm to rt within 1 h. After the addition of potassium tert-butoxide (863 mg, 7.30 mmol, 1.0 equiv.), the reaction mixture was stirred for one more hour at room temperature and was quenched with a saturated aqueous ammonium chloride solution (30 mL), and the aqueous layer was extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with hydrochloric acid (2 M, 2 × 50 mL), and the aqueous layer was again extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the crude residue was purified by silica gel column chromatography (EA/CyHex = 3:7) to give the product 15 (1.97 g, yield 87%) as a light-yellow oil. TLC: R_f = 0.21 (EA/CyHex = 3:7) [KMnO₄]. ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.34 (m, 5H), 7.35–7.28 (m, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.84 (ddd, J = 17.2, 10.5, 5.5 Hz, 1H), 5.28 (dt, J = 17.2, 1.4 Hz, 1H), 5.12 (dt, J = 10.5, 1.4 Hz, 1H), 5.04 (s, 2H), 4.56 (dtt, J = 7.0, 5.5, 1.5 Hz, 1H), 2.92–2.80 (m, 2H), 2.74 (ddd, J = 8.2, 6.8, 1.1 Hz, 2H), 2.62 (d, J = 5.5 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 210.4, 157.5, 139.2, 137.3, 133.2, 129.4, 128.7, 128.1, 127.6, 70.3, 68.8, 49.1, 45.5, 28.8. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 3351, 3281, 3091, 3059, 3037, 3008, 2929, 2902, 2872, 1705, 1644, 1610, 1580, 1510, 1465, 1454, 1418, 1410, 1378, 1340, 1322, 1297, 1239, 1174, 1148, 1117, 1096, 1045, 1010, 994, 976, 917, 860, 845, 820, 807, 782, 747. [α]²⁰_D = −9.5 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₂₀H₂₂NaO₃: 333.1465; found: 333.1461.

3.2.5. (3S,5R)-7-(4-(Benzyloxy)phenyl)hept-1-ene-3,5-diol (16)

To a solution of (S)-1-(4-(benzyloxy)phenyl)-5-hydroxyhept-6-en-3-one 15 (530 mg, 1.71 mmol, 1.0 equiv.) in dry THF (12 mL) was added acetaldehyde (337 µL, 5.98 mmol, 3.5 equiv.). At −50 °C, SmI₂ (0.1 M in THF, 12.8 mL, 1.28 mmol, 0.75 equiv.) was added slowly under the exclusion of light. The reaction mixture was allowed to stir at −20 °C for 18 h. After the addition of a saturated aqueous sodium bicarbonate solution (15 mL), the layers were separated, and the aqueous layer was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the crude residue was purified by column chromatography (EA/CyHex = 2:8) to give the product 16 (563 mg, yield 93%) as a colorless oil.

To a solution of (3S,5R)-7-(4-(benzyloxy)phenyl)-5-hydroxyhept-1-en-3-yl acetate (500 mg, 1.41 mmol, 1.0 equiv.) in MeOH/H₂O (4,2 mL, 3:1) was added potassium carbonate (389 mg, 2.82 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred for 4 h at 0 °C and then allowed to warm up to room temperature. Upon completion of the reaction indicated by TLC analysis, H₂O (10 mL) and ethyl acetate (10 mL) were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the crude residue was purified by column chromatography (EA/CyHex = 3:7) to give the product 16 (313 mg, yield 71%) as a colorless oil. TLC: R_f = 0.29 (EA/CyHex = 1:1) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.43 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 5H), 7.32 (t, J = 7.3 Hz, 2H), 7.11 (d, J = 8.5 Hz, 5H), 6.90 (d, J = 8.6 Hz, 5H), 5.93 (ddd, J = 17.3, 10.5, 5.5 Hz, 3H), 5.29 (d, J = 17.2 Hz, 2H), 5.15 (s, 1H), 5.04 (s, 6H), 4.48 (dt, J = 5.4, 1.7 Hz, 2H), 3.97 (dd, J = 4.7, 3.2 Hz, 2H), 2.73 (ddd, J = 13.8, 9.8, 5.7 Hz, 3H), 2.62 (ddd, J = 13.9, 9.7, 6.4 Hz, 3H), 2.02 (s, 9H), 1.90–1.56 (m, 12H). ¹³C NMR (151 MHz, CDCl₃) δ 157.1, 140.7, 137.2, 134.2, 129.3, 128.6, 127.9, 127.5, 114.9, 114.5, 70.8, 70.1, 68.7, 42.3, 39.4, 31.2. [α]²⁰_D = 16.8 (c = 1.0, DCM). IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 3286, 3090, 3066, 3035, 3015, 2928, 2906, 2852, 1646, 1611, 1582, 1511, 1422, 1402, 1382, 1349, 1312, 1296, 1278, 1240, 1173, 1134, 1110, 1069, 1038, 1026, 1014, 1001, 991, 975, 918, 903, 863, 837, 825, 808, 781, 734, 696. HRMS (ESI) m/z: [M + Na⁺] calcd. for C₂₀H₂₄NaO₃: 335.1620; found: 335.1618.

3.2.6. ((((3S,5R)-7-(4-(Benzyloxy)phenyl)hept-1-ene-3,5-diyl)bis(oxy))bis(methylene))dibenzene (17)

To a solution of (3S,5R)-7-(4-(benzyloxy)phenyl)hept-1-ene-3,5-diol 16 (34.9 mg, 109 µmol, 1.0 equiv.) in 1.0 mL of dry DMF was added tetra-n-butylammonium iodide (8.40 mg, 22.9 µmol, 0.20 equiv.) and NaH (13.1 mg, 60% in mineral oil, 327 µmol, 3.0 equiv.). The reaction mixture was stirred for 30 min at 0 °C. Then, benzyl bromide (39.0 µL, 56.2 mg, 328 µmol, 3.0 equiv.) was added to the mixture and stirred for 5 h at room temperature under argon. After reaction completion, the crude mixture was directly purified by column chromatography (EA/CyHex = 1:9 → 2:8). A further separation was carried out using preparative HPLC (MeCN:H₂O = 9:1) to give product 17 (27.7 mg, yield 52%) as a colorless solid. TLC: R_f = 0.54 (EA/CyHex = 2:8) [KMnO₄]. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 7.1 Hz, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.37–7.26 (m, 11H), 7.08 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.79 (ddd, J = 17.5, 10.3, 7.5 Hz, 1H), 5.31–5.19 (m, 2H), 5.06 (s, 2H), 4.58 (d, J = 11.6 Hz, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.35 (d, J = 11.4 Hz, 1H), 4.24 (d, J = 11.6 Hz, 1H), 4.01 (td, J = 8.0, 4.5 Hz, 1H), 3.79–3.68 (m, 1H), 2.64 (t, J = 8.0 Hz, 2H), 1.94–1.73 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 157.0, 139.1, 138.9, 138.7, 134.8, 129.3, 128.6, 128.3, 127.9 (d, J = 1.7 Hz), 127.9, 127.5 (d, J = 4.1 Hz), 116.7, 114.8, 75.0, 71.2, 70.3, 70.1, 41.2, 36.3, 30.4. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 3087, 3063, 3030, 3007, 2860, 1610, 1583, 1509, 1496, 1453, 1420, 1380, 1355, 1310, 1298, 1237, 1175, 1089, 1067, 1026, 993, 924, 860, 820, 732, 694, 644, 613, 560, 532, 514, 458. [α]²⁰_D = 16.6 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₃₄H₃₆NaO₃: 515.2564; found: 515.2567.

3.2.7. 4,4′-((3S,5R,E)-3,5-Bis(benzyloxy)hept-1-ene-1,7-diyl)bis((benzyloxy)benzene) (19)

In a 4 mL vial was added palladium (II) acetate (1.23 mg, 5.48 µmol, 10 mol%), DPPE (4.37 mg, 11.0 µmol, 20 mol%), potassium carbonate (15.1 mg, 110 µmol, 2.0 equiv.), and 100 µL of dry DMF. A solution of alkene 17 (27.0 mg, 54.8 mmol, 1.0 equiv.) and 1-benzyloxy-4-iodobenzene 18 (25.5 mg, 82.2 µmol, 1.5 equiv.) in 700 µL of dry DMF was added dropwise. The reaction mixture was stirred for 18 h at 90 °C under argon. The solution was then cooled to room temperature and purified directly by column chromatography (EA:CyHex = 1:9). A small amount of the solid was dissolved in acetonitrile and separated via preparative HPLC (MeCN:H₂O = 9:1). It was again purified by silica gel column chromatography (EA/CyHex = 1:9) to give 19 in the form of a slightly brownish solid (20.3 mg, yield 55%). TLC: R_f = 0.49 (EA/CyHex = 2:8) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.46–7.27 (m, 20H), 7.04 (dd, J = 15.7, 8.7 Hz, 4H), 6.94 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.48 (d, J = 15.9 Hz, 1H), 5.99 (dd, J = 15.9, 8.0 Hz, 1H), 5.12 (s, 1H), 5.08 (s, 1H), 5.03 (s, 2H), 4.59 (d, J = 11.7 Hz, 1H), 4.49 (d, J = 11.4 Hz, 1H), 4.35 (d, J = 11.3 Hz, 1H), 4.27 (d, J = 11.7 Hz, 1H), 4.12 (td, J = 8.5, 4.1 Hz, 1H), 3.81–3.67 (m, 1H), 2.63 (t, J = 8.0 Hz, 2H), 1.87 (m, 4H). ¹³C NMR (151 MHz, CDCl₃) δ 158.7, 157.1, 139.0, 138.9, 137.4, 137.1, 134.9, 131.7, 129.5, 128.7 (d, J = 6.5 Hz), 128.5 (d, J = 2.6 Hz), 128.1 (d, J = 6.3 Hz), 128.0, 127.8, 127.7–127.5 (m), 115.2, 114.9, 75.1, 71.3, 70.3, 70.2 (d, J = 2.0 Hz), 41.6, 36.5, 30.5. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 3088, 3063, 3031, 2924, 2858, 1729, 1606, 1583, 1509, 1454, 1381, 1297, 1240, 1174, 1070, 1026, 969, 913, 860, 819, 735, 696, 613, 512, 458. [α]²⁰_D = −20.3 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₄₇H₄₆NaO₄: 697.3281; found: 697.3288.

3.2.8. Methyl 2-(4-Methoxyphenyl)acetate (21)

To a solution of 4-methoxyphenylacetic acid 20 (6.00 g, 36.0 mmol, 1.0 equiv.) in MeOH (112 mL) was added conc. H₂SO₄ (2.32 mL, 43.3 mmol, 1.2 equiv.). The reaction mixture was heated under reflux (65 °C) for 3 h. The resulting mixture was cooled to room temperature, and the solvent was removed under vacuum. The crude residue was redissolved in EA, dried with sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EA/CyHex = 1:1) to give the methyl ester (6.10 g, yield 94%) as a colorless oil. TLC: R_f = 0.82 (EA/CyHex = 1:1) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.20 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 3H), 3.57 (s, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 172.4, 158.9, 130.4, 126.2, 114.1, 55.4, 52.1, 40.4. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 2952, 1732, 1612, 1511, 1299, 1242, 1151, 1012, 788. HRMS (ESI) m/z: [M + Na⁺] calcd. for C₁₀H₁₂NaO₃: 203.0678; found: 203.0679. All the characterization data are consistent with the literature [32].

3.2.9. 2-(4-Methoxyphenyl)acetaldehyde (11)

To a solution of methyl 2-(4-methoxyphenyl)acetate 21 (5.00 g, 27.8 mmol, 1.0 equiv.) in anhydrous toluene (70 mL) at −78 °C was added dropwise diisobutylaluminium hydride (1.2 M solution in toluene, 25.4 mL, 30.5 mmol, 1.1 equiv.). The reaction was stirred for 1 h. The reaction was quenched with MeOH (15 mL) and then poured into DCM, then washed sequentially with 1 M HCl (25 mL) and brine (25 mL). The organic phase was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DE/PE = 1:10) to give product 11 (3.70 g, yield 89%) as a colorless oil. TLC: R_f = 0.81 (DE/PE = 1:10) [KMnO₄]. ¹H NMR (400 MHz, CDCl₃) δ 9.72 (t, J = 2.4 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.63 (d, J = 2.4 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 200.1, 159.4, 131.1, 124.2, 114.9, 55.7, 50.2. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 1721, 1611, 1511, 1245, 1177, 1032, 906, 825, 726, 648, 524. HRMS (ESI) m/z: [M + Na⁺] calcd. for C₉H₁₀NaO₂: 173.0681; found: 173.0568. All the characterization data are consistent with the literature [35].

3.2.10. 5-Hydroxy-1-(4-methoxyphenyl)hept-6-en-3-one (22)

To a solution of diisopropylamine (1.70 mL, 12.3 mmol, 2.1 equiv.) in dry THF (58 mL) was added n-butyllithium (2.5 M in hexane, 6.40 mL, 12.3 mmol, 2.1 equiv.) at −78 °C. After the cooling was removed for 15 min, (S)-building block 7 (2.00 g, 5.84 mmol, 1.0 equiv.) dissolved in dry THF (19 mL) was added slowly at −78 °C. The solution was allowed to stir for 1 h at this temperature. Following the addition of 2-(4-methoxyphenyl)acetaldehyde 11 (2.63 g, 17.5 mmol, 3.0 equiv.) dissolved in dry THF (9 mL), the reaction was allowed to warm to rt within 1 h. After the addition of potassium tert-butoxide (690 mg, 5.80 mmol, 1.0 equiv.), the reaction mixture was stirred for an additional hour at rt. The reaction was quenched with a saturated aqueous ammonium chloride solution (30 mL), and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were washed with hydrochloric acid (2 M, 2 × 50 mL), and the aqueous layer was again extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the crude residue was purified by silica gel column chromatography (EA/PE = 1:4) to give the product 22 (1.16 g, yield 85%) as a light-yellow oil. TLC: R_f = 0.26 (EA/PE = 1:4) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.08 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.83 (ddd, J = 16.6, 10.6, 5.6 Hz, 1H), 5.27 (d, J = 17.1 Hz, 1H), 5.14–5.08 (m, 1H), 4.61–4.52 (m, 1H), 3.77 (s, 3H), 2.88 (s, 1H), 2.84 (t, J = 7.6 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.60 (d, J = 6.4 Hz, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 210.2, 158.1, 139.2, 132.8, 129.3, 115.0, 114.0, 68.7, 55.3, 49.1, 45.5, 28.7. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 2932, 1707, 1611, 1583, 1510, 1463, 1441, 1404, 1365, 1299, 1242, 1177, 1108, 1084, 1032, 976, 927, 823. [α]²⁰_D = +11.3 (c = 1.21, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₁₄H₁₈NaO₃: 257.1148; found: 257.1148.

3.2.11. (3S,5R)-5-Hydroxy-7-(4-methoxyphenyl)hept-1-en-3-yl acetate (23a)

To a solution of 5-hydroxy-1-(4-methoxyphenyl)hept-6-en-3-one 23a (412 mg, 1.40 mmol, 1.0 equiv.) in dry THF (3 mL) was added acetaldehyde (347 µL, 6.15 mmol, 3.5 equiv.). At −50 °C, SmI₂ (0.1 M in THF, 13.2 mL, 1.32 mmol, 0.80 equiv.) was added slowly under the exclusion of light. The reaction mixture was allowed to stir at −20 °C for 18 h. After the addition of a saturated aqueous sodium bicarbonate solution (15 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the crude residue was purified by column chromatography (EA/CyHex = 1:4) to give the product 23a (426 mg, yield 87%) as a colorless oil. TLC: R_f = 0.165 (EA/CyHex = 1:4) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.11 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.84 (ddd, J = 16.9, 10.5, 6.0 Hz, 1H), 5.52 (ddt, J = 9.5, 5.6, 3.6 Hz, 1H), 5.27 (dt, J = 17.3, 1.3 Hz, 1H), 5.16 (dt, J = 10.5, 1.3 Hz, 1H), 3.78 (s, 3H), 3.56 (tt, J = 7.8, 3.5 Hz, 1H), 2.75 (ddd, J = 14.8, 9.8, 5.5 Hz, 1H), 2.62 (ddd, J = 13.8, 9.7, 6.6 Hz, 2H), 2.08 (s, 3H), 1.84–1.63 (m, 4H). ¹³C NMR (151 MHz, CDCl₃) δ 171.7, 158.1, 136.8, 129.6, 116.6, 72.4, 67.0, 55.6, 43.0, 39.4, 31.5, 21.4. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 2928, 1608, 1510, 1463, 1247, 1174, 1037, 834, 774. [α]²⁰_D = −3.1 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₁₆H₂₂NaO₄: 301.1410; found: 301.1410.

3.2.12. (3S,5R)-7-(4-Methoxyphenyl)hept-1-ene-3,5-diol (23)

To a solution of (3S,5R)-5-hydroxy-7-(4-methoxyphenyl)hept-1-en-3-yl acetate 23a (300 mg, 1.08 mmol, 1.0 equiv.) in MeOH/H₂O (4 mL, 3:1) was added potassium carbonate (297 mg, 2.15 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred for 4 h at 0 °C and then allowed to warm up to room temperature. Upon completion of the reaction indicated by TLC analysis, H₂O (10 mL) and ethyl acetate (10 mL) were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the crude residue was purified by column chromatography (EA/CyHex = 3:7) to give the product 23 (234 mg, yield 92%) as a colorless oil. TLC: R_f = 0.195 (EA/CyHex = 3:7) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.11 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.92 (ddd, J = 17.1, 10.5, 5.5 Hz, 1H), 5.28 (d, J = 17.3 Hz, 1H), 5.14 (d, J = 10.5 Hz, 1H), 4.51–4.44 (m, 1H), 4.00–3.93 (m, 1H), 3.78 (s, 3H), 2.73 (ddd, J = 13.8, 9.9, 5.7 Hz, 1H), 2.62 (ddd, J = 13.9, 9.7, 6.4 Hz, 1H), 2.25 (s, 2H), 1.87–1.61 (m, 4H). ¹³C NMR (151 MHz, CDCl₃) δ 158.0, 140.8, 134.1, 129.4, 114.6, 114.0, 70.9, 68.9, 55.4, 42.5, 39.5, 31.3. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 3354, 2935, 1611, 1510, 1242, 1177, 1034, 922, 822, 526. [α]²⁰_D = +15.4 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₁₄H₂₀NaO₃: 259.1304; found: 259.1305.

3.2.13. (5R,7S)-5-(4-Methoxyphenethyl)-2,2,3,3,9,9,10,10-octamethyl-7-vinyl-4,8-dioxa-3,9-disilaundecane (24)

To a dry round-bottom flask was added diol 23 (200 mg, 846 µmol, 1.0 equiv.) in DMF (5 mL), and the solution was cooled to 0 °C for 20 min. Imidazole (460 mg, 6.77 mmol, 8.0 equiv.) and tert-butyldimethylsilyl chloride (511 mg, 3.39 mmol, 4.0 equiv.) were added, and the solution was allowed to stir at rt for 18 h. Following the addition of distilled water (15 mL) and diethyl ether (15 mL), the layers were separated, and the aqueous layer was extracted with diethyl ether (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and flash chromatography (EA/CyHex = 1:99) on silica gel afforded product 24 in 95% yield (374 mg, dr > 99:1) as a colorless oil. TLC: R_f = 0.195 (EA/CyHex = 3:7) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.10 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.81 (ddd, J = 17.2, 10.3, 7.0 Hz, 1H), 5.12 (d, J = 17.2 Hz, 1H), 5.03 (d, J = 10.3 Hz, 1H), 4.19 (d, J = 6.7 Hz, 1H), 3.87–3.80 (m, 1H), 3.79 (s, 3H), 2.60 (dddd, J = 38.9, 13.7, 10.6, 5.7 Hz, 1H), 1.82–1.69 (m, 3H), 1.65 (dt, J = 13.5, 6.0 Hz, 1H), 0.92 (s, 9H), 0.89 (s, 9H), 0.19–−0.17 (m, 12H). ¹³C NMR (151 MHz, CDCl₃) δ 157.9, 142.2, 134.9, 129.4, 114.2, 72.1, 69.4, 55.4, 46.4, 40.0, 30.6, 26.1 (d, J = 5.0 Hz), 18.3, −3.7, −3.8, −4.0, −4.4. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 2928, 1511, 1463, 1246, 1073, 833, 773. [α]²⁰_D = +1.0 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₂₆H₄₈O₃NaSi₂: 487.3034; found: 487.3034.

3.2.14. (5R,7S)-5-(4-Methoxyphenethyl)-7-((E)-4-methoxystyryl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane (26)

An oven-dried round-bottom flask was charged with (3S,5R)-7-(4-methoxyphenyl)hept-1-ene-3,5-diol 24 (320 mg, 688 µmol, 1.0 equiv.), palladium (II) acetate (46.4 mg, 210 µmol, 30 mol%), potassium carbonate (951 mg, 6.88 mmol, 10 equiv.), and tetra-n-butylammonium chloride (957 mg, 3.44 mmol, 5.0 equiv.). The flask was evacuated and backfilled with argon three times. 4-iodoanisole 25 (242 mg, 1.03 mmol, 1.5 equiv.) dissolved in DMF (5 mL; degassed by freeze–pump–thaw method) was added to the mixture. The mixture was allowed to stir at 90 °C for 19 h. After this time, the reaction mixture was allowed to cool down to room temperature and diluted with ethyl acetate (10 mL) and water (10 mL). The combined aqueous layers were extracted with ethyl acetate (3 × 10 mL), and the combined organic layers were washed with brine (8 mL), dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and flash chromatography (DE/PE = 1:50) on silica gel afforded the product 26 (300 mg, yield 84%, dr > 20:1) as a colorless oil. TLC: R_f = 0.195 (DE/PE = 1:50) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.29 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.37 (d, J = 15.9 Hz, 1H), 6.00 (dd, J = 15.8, 7.5 Hz, 1H), 4.34 (q, J = 6.9 Hz, 1H), 3.87 (p, J = 5.8 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.60 (tq, J = 19.6, 6.8 Hz, 2H), 1.89–1.68 (m, 4H), 0.92 (s, 9H), 0.90 (s, 9H), 0.09–0.02 (m, 12H). ¹³C NMR (151 MHz, CDCl₃) δ 159.3, 157.8, 134.8, 131.5, 130.0, 129.4, 129.1, 127.7, 114.2, 113.9, 71.8, 69.3, 55.4 (d, J = 7.6 Hz), 46.7, 40.1, 30.6, 18.3, −3.5, −3.9, −4.0, −4.3.z IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 2929, 1607, 1502, 1275, 1250, 1182, 1040, 906, 823, 809, 731. [α]²⁰_D −23.0 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₃₃H₅₄O₄NaSi₂: 593.3561; found: 593.3452.

3.2.15. (5R,7R)-5,7-bis(4-Methoxyphenethyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane (27)

In an oven-dried round-bottom flask, (5R,7S)-5-(4-methoxyphenethyl)-7-((E)-4-methoxystyryl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane 26 (200 mg, 350 µmol, 1.0 equiv.) was dissolved in methanol (8 mL), and Pd/C (10% on activated charcoal, 112 mg, 105 µmol, 30 mol%) was added. The reaction mixture was stirred for 8 h at room temperature under a hydrogen atmosphere (1 atm). The suspension was then filtered through a pad of celite and washed (3 × 10 mL) with ethyl acetate. The filtrate was concentrated in vacuo, and flash chromatography (EA/CyHex = 1:9) on silica gel afforded product 27 (193 mg, yield 93%) as a colorless oil. TLC: R_f = 0.21 (EA/CyHex = 1:17) [KMnO₄]. ¹H NMR (600 MHz, CDCl₃) δ 7.09 (d, J = 8.1 Hz, 4), 6.83 (d, J = 8.6 Hz, 4H), 3.80 (d, J = 6.2 Hz, 8H), 2.67–2.53 (m, 4H), 1.72 (dt, J = 12.1, 5.8 Hz, 6H), 0.91 (s, 18H), 0.07 (d, J = 6.8 Hz, 12H). ¹³C NMR (151 MHz, CDCl₃) δ 157.9, 134.8, 129.4, 114.0, 69.9, 55.4, 45.4, 40.1, 30.6, 26.1, 18.3, −3.9. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 2928, 1511, 1462, 1244, 1176, 1037, 832, 771. [α]²⁰_D = +2.1 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₃₃H₅₆O₄NaSi₂: 595.3717; found: 595.3608.

3.2.16. (3R,5R)-1,7-bis(4-Methoxyphenyl)heptane-3,5-diol (4)

First, HF-pyridine (70% HF, 250 µL, 1.75 mmol, 20 equiv.) was dissolved in a pyridine/MeOH mixture (890 µL, 6:1) at 0 °C in a Teflon vial. In another Teflon vial, (5R,7R)-5,7-bis(4-methoxyphenethyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane 27 (50.0 mg, 871 μmol, 1.0 equiv.) was dissolved in THF (0.8 mL), and the solution was cooled to 0 °C. The prepared HF-pyridine solution was then transferred to the THF solution, and the reaction mixture was stirred at rt for 18 h. Following the addition of an excess of methoxytrimethylsilane (7 mL) at 0 °C and dilution with toluene (10 mL), the volatile compounds were removed in vacuo. The residue was diluted with toluene (5 mL) again, and the procedure was repeated three times to remove all of the pyridine. The crude residue was purified by silica gel column chromatography (EA/CyHex = 2:5) to give 1,3 diol 4 (26.2 mg, yield 87%) as a white solid. ¹H NMR (600 MHz, CDCl₃) δ 7.11 (d, J = 8.4 Hz, 4H), 6.83 (d, J = 8.6 Hz, 4H), 3.97 (dd, J = 8.4, 5.1 Hz, 2H), 3.78 (s, 6H), 2.71 (ddd, J = 15.0, 9.7, 5.7 Hz, 2H), 2.61 (ddd, J = 13.8, 9.5, 6.5 Hz, 2H), 2.12 (s, 2H), 1.83 (ddd, J = 14.3, 8.7, 5.6 Hz, 2H), 1.80 (d, J = 5.7 Hz, 2H), 1.73 (dddd, J = 13.9, 10.4, 6.5, 4.6 Hz, 2H), 1.66 (t, J = 5.6 Hz, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 158.0, 134.0, 129.4, 114.1, 69.1, 55.4, 42.7, 39.4, 31.4. IR (ATR): $\stackrel{\sim }{\nu }$ [cm⁻¹] = 3374, 2939, 1612, 1511, 1300, 1244, 1176, 1033, 814, 514. [α]²⁰_D = +6.5 (c = 1.0, DCM). HRMS (ESI) m/z: [M + Na⁺] calcd. for C₂₁H₂₈NaO₄: 367.1988; found: 367.1879. All the characterization data are consistent with the literature [11].

4. Conclusions

In summary, we successfully completed the formal synthesis of (+)-hannokinol 1 by employing a Horner–Wittig reaction and Pd-catalyzed Heck cross coupling as key steps. The key stereochemical information for the 1,3-diol unit was introduced by the use of chiral building block 7 (prepared from readily available and inexpensive 2-deoxy-D-ribose) and a directed anti-reduction under Evans–Tishchenko conditions. Our approach enables the synthesis of precursor 4 in high stereoselectivity and yields (eight steps, 37%, excluding the synthesis of 7).