Syntheses of all the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane

Abstract

All the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane were stereoselectively synthesized by employing (S)- and (R)-Evans’ auxiliaries to construct the stereochemistry. (+)- and (−)-Kadangustin J and their diastereomers were also prepared. The optical purity of the synthesized butanol type 1,7-seco-2,7′-cyclolignane was more than 99%ee.

Graphical Abstract

All the stereoisomers of butanol type 1,7-seco-2,7'-cyclolignane with more than 99%ee were stereoselectively synthesized. (+)- and (-)-Kadangustin J and their diastereomers were also prepared.

Key words:

• lignan
• 1,7-seco-2,7′-cyclolignane
• neolignan
• kadangustin J

Lignans, which are biosynthesized as secondary metabolites in many plant families, are constructed from two phenylpropanoid units. The biological activity of many kinds of classical lignan that are bonded at the 8 and 8′ positions of phenyl propane has been clarified.¹⁾ Neolignans with combinations other than the 8-8′ bond have also been reported.^2,3) 1,7-Seco-2,7′-cyclolignane, in which the shift of the 7-aryl group to the 7′ position has been observed, are types of neolignans.³⁾ Some 1,7-seco-2,7′-cyclolignanes bearing a lactone^4–6) or butanol^7,8) structure have been isolated and the cytotoxic activity and anti-HIV activity have been found. Stimulated by the unique lignan bearing diphenyl methyl structure and its biological activity, we turned our attention to synthesizing all the stereoisomers of butane type 1,7-seco-2,7′-cyclolignanes 1, 2 and butanol type 1,7-seco-2,7′-cyclolignanes 3–8, 34–37 (Fig. 1). Although many kinds of biological activity have been discovered in the course of lignan and neolignan research, we have been unable to find information on the effect of stereochemistry on this biological activity in many cases. Our efforts to establish the relationship between the stereochemistry and biological activity of lignans and neolignans have been continuing.^9–13) We began this synthetic research to develop a study on the effects of the stereochemistry of butane or butanol on their biological activity. The collation of stereoisomer libraries of natural products should contribute to the process for determination of the receptor. In our previous research, a synthetic route to compounds 1 and 2 was developed.¹⁴⁾ The syntheses of all the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignanes 3–8 and kadangustin J 34–37 are described in this article. The success of this project would enable us to estimate the biological activity of all the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane containing kadangustin J.

Fig. 1. All the stereoisomers of butane-type 1,7-seco-2,7′-cyclolignane 1 and 2, Butanol-type 1,7-seco-2,7′-cyclolignane 3–8, and Kadangustin J 34–37.

Results and discussion

As illustrated in Scheme 1, the diphenylmethyl structures of target compounds 3 and 5 can be, respectively, obtained by the Friedel-Crafts reaction from benzyl alcohols 9 and 10. The stereochemistry at C-3 of benzyl alcohols 9 and 10 can be constructed by methylations to 11 and 12, respectively, bearing S- and R-Evans’ auxiliaries. Requisite intermediates 11 and 12 can be transformed from alcohol 13¹⁵⁾ by reductive elimination of the primary hydroxy group and oxidative cleavage of the olefin to carboxylic acid, introduction of the auxiliary. Enantiomers 4 and 6 can be obtained from the enantiomer of 13 by the same route. Positional isomer 7 can be converted from amide 14, which can be obtained from protected lactone type 1,7-seco-2,7′-cyclolignane 15, which had previously been synthesized in our laboratory.¹⁴⁾ Compound 8 can be obtained from the enantiomer of 15.

Scheme 1. Proposed general strategy for synthesis of butanol-type 1,7-seco-2,7′-cyclolignane.

Syntheses of stereoisomers 3 and 5 were started with alcohol 13¹⁵⁾ (Scheme 2). After the reduction of the hydroxy methyl group to the methyl group via a tosylate, resulting compound 16 was converted to carboxylic acid 17 by oxidative cleavage of the alkene which was, respectively, combined with (S)- and (R)-Evans’ auxiliaries to give 18 and 19. Stereoselective methylation followed by the removal of auxiliary gave primary alcohols 22 and 23, whose hydroxy groups were, respectively, protected as benzoyl esters 24 and 25. To obtain the substrates for the Friedel-Crafts reaction, the silyl ethers were cleaved, giving benzyl alcohols 26 and 27. The Friedel-Crafts reactions of 26 and 27 with 3-benzyloxy-4-methoxyphenol in the presence of FeCl₃¹⁶⁾ gave diphenylmethyl compounds with diastereomeric ratios of 1:1. After conversion of the resulting phenolic hydroxy groups to triflates, removal of the resulting aromatic triflates was performed by using LiCl, HCO₂NH₄, and Pd(Ph₃P)₂Cl₂¹⁷⁾, respectively, giving 28 and 29. Finally, deprotection of 28 and 29, respectively, gave stereoisomers 3 and 5. (+)-Kadangustin J⁸⁾ (34) and 36 were, respectively, obtained from 3 and 5 by selective methylation of the phenolic hydroxy groups using dimethyl sulfate and K₂CO₃.

Scheme 2. Synthesis of butanol-type 1,7-seco-2,7′-cyclolignane (I).

Protected lactone type 1,7-seco-2,7′-cyclolignane 15¹⁴⁾ was selected as a starting material for the synthesis of 7 (Scheme 3). Ring opening of the lactone to amide 30 was accomplished by reaction with diethylamine in the presence of AlMe₃, whose hydroxy group was protected as a silyl ether. After a two-steps reduction of the silyloxy amide 31 to the corresponding primary alcohol, mesylation followed by treatment with Super-hydride gave 32. The reduction of the mesylate was not successful by NaBH₄ reduction in HMPA. Wolff–Kishner reduction of the aldehyde prepared from silyloxy amide 31 by DIBAL-H reduction gave 33 in a very low yield. Finally, deprotection of 33 afforded 7.

Scheme 3. Synthesis of butanol type 1,7-seco-2,7′-cyclolignane (II).

Enantiomers 4 and 6 were obtained from the enantiomer of 13 by applying the same method. Enantiomer 8 was obtained by the same synthetic method as that described for 7 from the enantiomer of 15 (Scheme 4). The enantiomeric excess of all synthesized compounds was more than 99%. (−)-Kadangustin J¹⁸⁾ (35) and 37 were also, respectively, obtained from 4 and 6.

Scheme 4. Syntheses of the enantiomers.

Experimental setup

Optical rotations were measured on a Horiba SEPA-200 instrument. IR data were measured with a Horiba FT-720 instrument. NMR data were obtained using a JNM-EX400 spectrometer. EIMS data were measured with a JMS-MS700V spectrometer. IR data were measured with a Horiba FT-720 instrument. The silica gel used was Wakogel C-300 (Wako, 200–300 mesh). The purity of each compound containing enantiomers was confirmed by ¹H NMR. HPLC analysis was performed with Shimadzu LC-6AD and SPD-6AV instruments. The chiral column used for HPLC analysis of enantiomeric excess was a 250 mm × 4.6 mm i.d., 5 μM, CHIRALCEL AD-H (DAICEL Chemical Industries, Ltd, Tokyo, Japan).

(4S,5R)-5-(4-Benzyloxy-3-methoxyphenyl)-4-methyl-5-(triisopropylsilyloxy)-1-pentene (16)

To an ice-cooled solution of alcohol 13 (16.5 g, 34.0 mmol) and pyridine (9.52 mL, 0.12 mol) in CH₂Cl₂ (80 mL) was added p-TsCl (12.5 g, 65.6 mmol). The reaction solution was stirred at room temperature for 5 h before additions of H₂O and CH₂Cl₂. The organic solution was separated and washed with 1 M aq. HCl solution. After further washing with sat. aq. NaHCO₃ solution, the organic solution was dried (Na₂SO₄). After concentration, the residue was applied to silica gel column chromatography (EtOAc/hexane = 1/9) to give unstable tosylate (20.3 g, 32.8 mmol, 96%) as a colorless oil; +24 (c 1.2, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.90–0.95 (21H, m), 1.59 (1H, m), 2.08 (1H, m), 2.20 (1H, m), 2.44 (3H, s), 3.85 (3H, s), 3.93 (1H, dd, J = 9.6, 8.3 Hz), 4.13 (1H, dd, J = 9.6, 4.8 Hz), 4.79 (1H, d, J = 6.1 Hz), 4.84 (1H, d, J = 17.5 Hz), 4.91 (1H, d, J = 10.0 Hz), 5.12 (2H, s), 5.55 (1H, m), 6.62 (1H, d, J = 8.2, 2.0 Hz), 6.75 (1H, d, J = 8.2 Hz), 6.86 (1H, d, J = 2.0 Hz), 7.26–7.38 (5H, m), 7.43 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 12.4, 17.95, 18.02, 21.6, 30.1, 46.3, 55.9, 69.6, 71.1, 73.6, 110.7, 113.4, 117.1, 119.4, 127.4, 127.8, 128.0, 128.5, 129.8, 133.1, 134.9, 135.6, 137.1, 144.7, 147.5, 149.4, 158.0. A solution of tosylate (20.3 g, 31.8 mmol) in THF (20 mL) was added to an ice-cooled suspension of LiAlH₄ (1.21 g, 31.9 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 1 h before additions of sat. aq. MgSO₄ solution (5 mL) and K₂CO₃. The mixture was filtered, and then the filtrate was concentrated. The residue was applied to silica gel column chromatography (EtOAc/hexane = 1/9) to give 16 (11.3 g, 24.1 mmol, 76%) as a colorless oil;  +40 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.87 (3H, d, J = 6.8 Hz, CH₃), 0.89–1.00 (21H, m), 1.57 (1H, m, 4-H), 1.83 (1H, m, 3-H), 2.32 (1H, m, 3-H), 3.87 (3H, s, CH₃), 4.59 (1H, d, J = 5.2 Hz, 5-H), 4.94 (1H d, J = 16.7 Hz, 1-H), 4.95 (1H, d, J = 16.5 Hz, 1-H), 5.12 (2H, s, OCH₂Bn), 5.72 (1H, m, 2-H), 6.69 (1H, dd, J = 8.7, 1.8 Hz, ArH), 6.79 (1H, d, J = 8.7 Hz, ArH), 6.91 (1H, d, J = 1.8 Hz, ArH), 7.25–7.37 (3H, m, ArH), 7.43–7.45 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 12.5, 15.4, 18.05, 18.12, 36.2, 41.8, 55.9, 71.2, 78.8, 111.0, 113.20, 113.23, 115.5, 119.2, 119.4, 127.4, 127.8, 128.5, 136.8, 137.4, 138.0, 147.1, 149.1; IR (CHCl₃) cm⁻¹: 2945, 2868, 1510, 1463, 1261, 1090. MS (EI) m/z: 468 (M⁺, 3), 399 (100). Anal. Calcd for C₂₉H₄₄O₃Si: C, 74.31; H, 9.48%. Found: C, 74.34; H, 9.50%. (4R,5S)-(16). 81% yield, −40 (c 1.1, CHCl₃).

(3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-3-methyl-4-(triisopropylsilyloxy)butanoic acid (17)

A reaction solution of 16 (9.94 g, 21.2 mmol), 4-methylmorpholine N-oxide (2.95 g, 25.2 mmol), and OsO₄ (2% aq. solution, 1.60 mL) in acetone (90 mL), tert-BuOH (20 mL), and H₂O (20 mL) was stirred at room temperature for 20 h before the addition of sat. aq. Na₂S₂O₃ solution. After concentration of the mixture, the residue was dissolved in EtOAc and H₂O. The organic solution was separated, washed with brine, and dried (Na₂SO₄). Concentration gave crude glycol. A reaction mixture of crude glycol and NaIO₄ (5.40 g, 25.2 mmol) in MeOH (200 mL) was stirred at room temperature for 1 h before concentration to give crude aldehyde. To an ice-cooled solution of crude aldehyde, 2-methyl-2-butene (8.90 mL, 84.0 mmol), and NaH₂PO₄·2H₂O (32.8 g, 0.21 mol) in tert-BuOH/H₂O (3/1, 100 mL) was added a solution of NaClO₂ (11.4 g, 0.13 mol) in tert-BuOH/H₂O (3/1, 50 mL). The reaction mixture was stirred at room temperature for 1 h before additions of sat. aq. NH₄Cl solution and CHCl₃. The organic solution was separated, washed with H₂O, and dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/5) gave carboxylic acid 17 (10.0 g, 20.5 mmol, 97%) as a colorless oil;  +34 (c 0.7, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.92 (3H, d, J = 6.9 Hz, CH₃), 0.95–1.01 (21H, m, TIPSi), 1.90 (1H, dd, J = 15.3, 9.1 Hz, 2-H), 2.41 (1H, m, 3-H), 2.61 (1H, dd, J = 15.3, 4.8 Hz, 2-H), 3.88 (3H, s, OCH₃), 4.68 (1H d, J = 4.8 Hz, 4-H), 5.14 (2H, s, OCH₂Bn), 6.69 (1H, d, J = 7.2 Hz, ArH), 6.80 (1H, d, J = 7.2 Hz, ArH), 6.93 (1H, s, ArH), 7.26–7.38 (3H, m, ArH), 7.43–7.45 (2H, m, ArH), 7.26–7.45 (1H, overlapped, CO₂H); ¹³C NMR (100 MHz, CDCl₃) δ: 12.4, 16.3, 18.0, 18.1, 36.3, 38.4, 55.9, 71.1, 78.0, 110.9, 113.2, 119.4, 127.4, 127.8, 128.5, 135.2, 137.2, 147.3, 149.1, 179.8; IR (CHCl₃) cm⁻¹: 3500, 2945, 1707, 1508, 1464, 1261, 1093. MS (EI) m/z: 486 (M⁺, 6), 399 (100). Anal. Calcd. for C₂₈H₄₂O₅Si: C, 69.10; H, 8.70%. Found: C, 69.22; H, 8.78%. (2R,3S)-(17). 87% yield, −34 (c 2.1, CHCl₃).

(S)-4-Benzyl-3-[(3S,4R)-4-(4-benzyloxy-3-methoxyphenyl)-3-methyl-4-(triisopropylsilyloxy)butanoyl]-2-oxazolidinone (18)

To a solution of carboxylic acid 17 (4.66 g, 9.57 mmol) in THF (100 mL) were added Et₃ N (1.34 mL, 9.61 mmol) and PivCl (1.18 mL, 9.58 mmol) added at −75 °C. After the mixture was stirred at 0 °C for 1 h, lithium salt of (S)-4-benzyl-2-oxazolidinone, which was prepared from (S)-4-benzyl-2-oxazolizinone (1.70 g, 9.59 mmol) and n-BuLi (3.70 mL, 2.70 M in hexane, 9.99 mmol) in THF (80 mL) at −75 °C, was added at −75 °C. The reaction mixture was stirred at 0 °C for 1 h before the addition of sat. aq. NH₄Cl solution. The organic solution was separated, washed with brine, and dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/5) gave alkanoly oxazolidinone 18 (6.18 g, 9.57 mmol, 100%) as a colorless oil;  +33 (c 1.9, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.95–1.01 (24H, m, TIPSi, CH₃), 2.53 (1H, m, CHCH₃), 2.61–2.72 (2H, m, C = OCH₂), 3.21–3.26 (2H, m, CH₂Bn), 3.91 (3H, s, OCH₃), 4.08 (2H, d, J = 5.1 Hz, 5-CH₂), 4.54 (1H, m, 4-H), 4.67 (1H, d, J = 5.4 Hz, TIPSOCHAr), 5.12 (2H, s, OCH₂Bn), 6.72 (1H, d, J = 8.2 Hz, ArH), 6.80 (1H, d, J = 8.2 Hz, ArH), 6.98 (1H, s, ArH), 7.16–7.18 (2H, m, ArH), 7.28–7.36 (6H, m, ArH), 7.42–7.43 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 12.5, 16.5, 18.0, 18.1, 37.77, 37.83, 38.0, 55.1, 55.8, 66.0, 71.1, 78.4, 110.8, 113.0, 119.6, 127.3, 127.4, 127.8, 128.5, 128.9, 129.4, 135.4, 136.1, 137.2, 147.2, 149.2, 153.3, 172.8; IR (CHCl₃) cm⁻¹: 2945, 1783, 1699, 1508, 1456, 1384, 1261,1090. MS (EI) m/z: 645 (M⁺, 7), 602 (100); HRMS (M⁺) m/z calcd for C₃₈H₅₁O₆NSi: 645.3485, found: 645.3480. (4R)-3-[(3R,4S)]-(18). 97% yield, −34 (c 1.6, CHCl₃).

(4S)-4-Benzyl-3-[(2S,3S,4R)-4-(4-benzyloxy-3-methoxyphenyl)-2,3-dimethyl-4-(triisopropylsilyloxy)butanoyl]-2-oxazolidinone (20)

To a solution of KHMDS (14.4 mL, 0.50 M in toluene, 7.20 mmol) in THF (20 mL) was added a solution of 18 (3.10 g, 4.80 mmol) in THF (10 mL) at −75 °C. After the mixture was stirred at −75 °C for 20 min, MeI (12.0 mL, 0.19 mmol) was added. The reaction solution was stirred at −70 °C for 1 h, and then warmed to −15 °C. After 1.5 h at −15 °C, sat. aq. NH₄Cl solution and EtOAc were added. The organic solution was separated, washed with brine, and dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/8) gave 20 (1.00 g, 1.52 mmol, 32%) as a colorless oil along with recovered 18 (1.92 g, 2.97 mmol, 62%);  +46 (c 1.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.91–1.05 (21H, m, TIPSi), 1.08 (3H, d, J = 6.9 Hz, CH₃), 1.09 (3H, d, J = 6.8 Hz, CH₃), 2.51 (1H, m, C = OCHCHCH₃), 2.63 (1H, dd, J = 13.3, 9.5 Hz, CH₂Bn), 3.08 (1H, dd, J = 13.3, 2.0 Hz, CH₂Bn), 3.63 (1H, m, C = OCHCH₃), 3.87 (1H, d, J = 8.7 Hz, 5-H), 3.90 (3H, s, OCH₃), 3.98 (1H, d, J = 8.7 Hz, OCH₃), 4.20 (1H, m, 4-H), 4.47 (1H, d, J = 6.7 Hz, ArCHOTIPS), 5.09 (2H, s, OCH₂Bn), 6.76 (2H, s, ArH), 6.95 (1H, s, ArH), 7.13–7.17 (2H, m, ArH), 7.26–7.31 (6H, m, ArH), 7.37–7.38 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 12.7, 13.3, 15.5, 18.0, 18.1, 37.8, 38.5, 42.4, 55.3, 55.8, 65.7, 71.1, 79.7, 111.6, 113.0, 120.3, 127.2, 127.4, 127.9, 128.5, 128.9, 129.4, 135.4, 136.5, 137.1, 147.1, 148.9, 152.6, 177.0; IR (CHCl₃) cm⁻¹: 2945, 1781, 1700, 1508, 1466, 1382, 1093. MS (EI) m/z: 659 (M⁺, 7), 617 (100); HRMS (EI) m/z calcd for C₃₉H₅₃O₆NSi: 659.3642, found: 659.3632. (4R)-3-[(2R,3R,4S)]-(20). 33% yield, −46 (c 1.1, CHCl₃).

(2S,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-2,3-dimethyl-4-(triisopropylsilyloxy)-1-butanol (22)

To an ice-cooled solution of LiBH₄ (0.32 g, 14.7 mmol) and MeOH (0.65 mL, 16.0 mmol) in THF (50 mL) was added a solution of alkanoyl oxazolidinone 20 (2.20 g, 3.33 mmol) in THF (20 mL). The reaction solution was stirred at room temperature for 1 h, and then sat. aq. NH₄Cl solution was added. After concentration, the residue was dissolved in EtOAc and H₂O. The organic solution was separated, washed with brine, and dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/3) gave alcohol 22 (1.50 g, 3.08 mmol, 92%) as a colorless oil; +41 (c 1.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.68 (3H, d, J = 6.8 Hz, CH₃), 0.93–0.99 (21H, m, TIPSi), 0.97 (3H, d, J = 6.1 Hz, CH₃), 1.47 (1H, m, 3-H), 1.57 (1H, br. s, OH), 1.96 (1H, m, 2-H), 3.40 (2H, d, J = 6.7 Hz, 1-H), 3.86 (3H, s, OCH₃), 4.53 (1H, d, J = 7.4 Hz, 4-H), 5.12 (2H, s, OCH₂Bn), 6.72 (1H, d, J = 8.1 Hz, ArH), 6.78 (1H, d, J = 8.1 Hz, ArH), 6.95 (1H, s, ArH), 7.27–7.37 (3H, m, ArH), 7.42–7.44 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 11.60, 11.63, 12.5, 18.0, 18.1, 35.3, 42.3, 56.0, 67.5, 71.1, 78.8, 110.7, 113.3, 119.6, 127.4, 127.8, 128.5, 137.2, 137.3, 147.3, 149.5; IR (CHCl₃) cm⁻¹: 3566, 2945, 1505, 1452, 1259, 1139, 1059, 1025. MS (EI) m/z: 486 (M⁺, 6), 400 (100); HRMS (EI) m/z calcd for C₂₉H₄₆O₄Si: 486.3166, found: 486.3167. (2R,3R,4S)-(22). 95% yield, −41 (c 1.2, CHCl₃).

(2S,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-2,3-dimethyl-4-(triisopropylsilyloxy)butyl benzoate (24)

To an ice-cooled solution of alcohol 22 (1.50 g, 3.08 mmol) and pyridine (0.49 mL, 6.06 mmol) in CH₂Cl₂ (5 mL) was added BzCl (0.54 mL, 4.65 mmol). The reaction mixture was stirred at room temperature for 20 h before additions of H₂O and CH₂Cl₂. The organic solution was separated and washed with 1 M aq. HCl solution. After further washing with sat. aq. NaHCO₃ solution, the organic solution was dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/8) gave benzoate 24 (1.43 g, 2.42 mmol, 79%) as a colorless oil; +69 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.80 (3H, d, J = 7.0 Hz, CH₃), 0.92–0.99 (21H, m, TIPSi), 1.05 (3H, d, J = 6.9 Hz, CH₃), 1.82 (1H, m, 3-H), 2.01 (1H, m, 2-H), 3.80 (3H, s, OCH₃), 4.08 (1H, dd, J = 10.7, 6.3 Hz, 1-H), 4.17 (1H, dd, J = 10.7, 7.5 Hz, 1-H), 4.55 (1H, d, J = 7.8 Hz, 4-H), 5.13 (2H, s, OCH₂Bn), 6.72 (1H, dd, J = 8.2, 2.0 Hz, ArH), 6.78 (1H, d, J = 8.2 Hz, ArH), 6.92 (1H, d, J = 2.0 Hz, ArH), 7.25–7.56 (7H, m, ArH), 7.54 (1H, m, ArH), 7.96–7.97 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 11.1, 11.5, 12.6, 18.0, 18.2, 32.1, 42.5, 55.8, 68.7, 71.1, 78.3, 110.4, 113.3, 119.5, 127.4, 127.8, 128.3, 128.5, 129.5, 130.4, 132.8, 137.2, 137.6, 147.4, 149.6, 166.5; IR (CHCl₃) cm⁻¹: 2945, 1711, 1504, 1460, 1279, 1137, 1116, 1063. MS (EI) m/z: 590 (M⁺, 13), 547 (100); HRMS (EI) m/z calcd for C₃₆H₅₀O₅Si: 590.3428, found: 590.3412. (2R,3R,4S)-(24). 80% yield, −69 (c 1.4, CHCl₃).

(2S,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-4-hydroxy-2,3-dimethylbutyl benzoate (26)

A reaction solution of silyl ether 24 (1.43 g, 2.42 mmol) and (n-Bu)₄NF (3.60 mmol, 1 M in THF, 3.60 mmol) in THF (10 mL) was stirred at room temperature for 1 h before the addition of sat. aq. NH₄Cl solution and EtOAc. The organic solution was separated and washed with sat. aq. CuSO₄ solution. After further washing with sat. aq. NaHCO₃ solution followed by brine, the organic solution was dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/2) gave alcohol 26 (0.98 g, 2.26 mmol, 93%) as a colorless oil; +60 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.92 (3H, d, J = 7.0 Hz, CH₃), 1.02 (3H, d, J = 6.8 Hz, CH₃), 1.85 (1H, m, 3-H), 1.92–2.12 (1H, br., OH), 2.04 (1H, m, 2-H), 3.79 (3H, s, OCH₃), 4.17–4.23 (2H, m, 1-H₂), 4.55 (1H, d, J = 7.4 Hz, 5-H), 5.13 (2H, s, OCH₂Bn), 6.76 (1H, d, J = 8.1 Hz, ArH), 6.81 (1H, d, J = 8.1 Hz, ArH), 6.88 (1H, s, ArH), 7.25–7.44 (7H, m, ArH), 7.55 (1H, m, ArH), 7.99–8.00 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 10.0, 12.1, 33.5, 40.9, 55.9, 68.1, 71.1, 76.7, 109.6, 113.6, 118.8, 127.3, 127.8, 128.4, 128.5, 129.5, 130.3, 132.9, 137.0, 137.2, 147.6, 149.8, 166.5; IR (CHCl₃) cm⁻¹: 3619, 1976, 1716, 1520, 1452, 1277, 1138, 1026. MS (EI) m/z: 434 (M⁺, 25), 243 (100); HRMS (EI) m/z calcd for C₂₇H₃₀O₅: 434.2093, found: 434.2094. (2R,3R,4S)-(26). 93% yield, −60 (c 1.0, CHCl₃).

(2S,3R)-4,4-Bis(4-benzyloxy-3-methoxyphenyl)-2,3-dimethylbutyl benzoate (28)

A reaction mixture of 3-benzyloxy-4-methoxyphenol (0.42 g, 1.82 mmol), benzyl alcohol 26 (0.71 g, 1.63 mmol), and FeCl₃ (13 mg, 0.080 mmol) in CH₂Cl₂ (30 mL) was stirred at room temperature for 1.5 h before the addition of sat. aq. NaHCO₃ solution. The organic solution was separated and dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/5) gave bisphenol compound (0.95 g, 1.47 mmol, 90%) as a diastereomeric mixture of 1/1; HRMS (EI) m/z calcd for C₄₁H₄₂O₇: 646.2931, found: 646.2911. To a solution of bisphenol compound (0.78 g, 1.21 mmol) and 2,6-lutidine (0.48 mL, 4.11 mmol) in CH₂Cl₂ (5 mL), Tf₂O (0.27 mL, 1.60 mmol) was added at 0 °C. After stirring at 0 °C for 40 min, H₂O and CH₂Cl₂ were added. The organic solution was separated and washed with sat. aq. CuCO₄ solution. After further washing with sat. aq. NaHCO₃ solution, the organic solution was dried (Na₂SO₄). Concentration followed by silica gel column chromatography (5% EtOH in EtOAc/hexane = 1/3) gave triflate (0.97 g, 1.25 mmol, 77%) as a diastereomeric mixture of 1/1. The diastereomeric isomers could be partially separated; Rf = 0.24, +31 (c 0.4, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.77 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.8 Hz), 1.26 (1H, m), 2.12 (1H, m), 3.80 (3H, s), 3.81 (3H, s), 4.10 (1H, d, J = 11.4 Hz), 4.13 (1H, dd, J = 10.7, 6.6 Hz), 4.24 (1H, dd, J = 10.7, 7.9 Hz), 5.04 (1H, d, J = 12.3 Hz), 5.09 (2H, s), 5.10 (1H, d, J = 12.3 Hz), 6.72 (1H, s), 6.78 (1H, d, J = 8.4 Hz), 6.80 (1H, d, J = 8.4 Hz), 6.86 (1H, s), 6.87 (1H, s), 7.20–7.46 (11H, m), 7.58 (1H, m), 7.65 (1H, m), 8.03–8.05 (2H, m); ¹³C NMR (100 MHz, CDCl₃) δ: 9.70, 11.3, 24.4, 32.8, 55.9, 56.3, 58.3, 68.7, 71.1, 71.5, 107.3, 112.4, 114.2, 119.4, 119.8 (q, J = 278.7 Hz), 122.9, 124.1, 127.3, 127.4, 127.8, 128.3, 128.4, 128.46, 128.52, 128.7, 129.5, 129.8, 130.4, 133.0, 134.9, 136.0, 137.2, 137.3, 140.0, 144.2, 147.0, 147.1, 149.6, 149.7, 166.5; MS (EI) m/z: 778 (M⁺, 18), 587 (100); HRMS (EI) m/z calcd for C₄₂H₄₁O₉F₃S: 778.2423, found: 778.2431. Rf = 0.29, +21 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.81 (3H, d, J = 6.5 Hz), 0.94 (3H, d, J = 6.8 Hz), 2.07 (1H, m), 2.59 (1H, m), 3.72 (3H, s), 3.87 (3H, s), 4.01 (1H, d, J = 11.9 Hz), 4.18 (1H, dd, J = 10.8, 6.5 Hz), 4.26 (1H, dd, J = 10.8, 6.3 Hz), 5.06 (1H, d, J = 12.2. Hz), 5.10 (1H, d, J = 12.2 Hz), 5.11 (2H, s), 6.73 (1H, s), 6.80 (1H, d, J = 8.4 Hz), 6.82 (1H, d, J = 8.4 Hz), 6.88 (1H, s), 6.98 (1H, s), 7.29–7.50 (12H, m), 7.60 (1H, m), 8.04–8.06 (2H, m); ¹³C NMR (100 MHz, CDCl₃) δ: 10.0, 11.9, 33.1, 36.7, 47.4, 55.9, 56.2, 68.5, 71.1, 71.5, 107.4, 110.6, 112.9, 114.1, 119.3, 119.7 (q, J = 74.4 Hz), 127.3, 127.4, 127.8, 128.2, 128.46, 128.50, 128.7, 129.48, 129.51, 133.1, 135.4, 136.0, 137.3, 140.4, 146.8, 149.4, 149.5, 149.6, 166.4; MS (EI) m/z: 778 (M⁺, 43), 587 (100); HRMS (EI) m/z calcd for C₄₂H₄₁O₉F₃S: 778.2424, found: 778.2410. A reaction mixture of triflate (0.26 g, 0.33 mmol), LiCl (0.29 g, 6.84 mmol), HCO₂NH₄ (1.71 g, 27.1 mmol), and Pd(Ph₃P)₂Cl₂ (0.13 g, 0.19 mmol) in DMF (2.3 mL) was stirred at 140 °C under N₂ gas for 20 h. After additions of H₂O and EtOAc, the organic solution was separated, washed with brine, and dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/5) gave bisphenyl compound 28 (0.17 g, 0.27 mmol, 82%) as a colorless oil; +38 (c 0.1, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.75 (3H, d, J = 6.6 Hz, CH₃), 0.87 (3H, d, J = 6.9 Hz, CH₃), 2.08 (1H, m, 3-H), 2.55 (1H, m, 2-H), 3.53 (1H, d, J = 11.7 Hz, 4-H), 3.79 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 4.15 (1H, dd, J = 10.7, 6.6 Hz, 1-H), 4.22 (1H, dd, J = 10.7, 8.0 Hz, 1-H), 5.07 (2H, s, OCH₂Bn), 5.08 (2H, s, OCH₂Bn), 6.75–6.81 (6H, m, ArH), 7.26–7.47 (12H, m, ArH), 7.57 (1H, m, ArH), 8.03–8.05 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 9.9, 12.1, 32.9, 37.0, 55.8, 56.0, 56.1, 68.8, 71.1, 111.8, 112.1, 114.2, 119.7, 127.3, 127.8, 128.4, 128.5, 128.6, 129.48, 129.52, 130.5, 132.9, 137.4, 137.9, 146.7, 146.8, 149.5, 149.7, 166.5; IR (CHCl₃) cm⁻¹: 3012, 2960, 1714, 1510, 1277. MS (EI) m/z: 630 (M⁺, 5), 204 (100); HRMS (EI) m/z calcd for C₄₁H₄₂O₆: 630.2981, found: 630.3001. (2R,3S)-(28). 61% yield, two steps, −37 (c 0.6, CHCl₃).

(2S,3R)-4,4-Bis(4-hydroxy-3-methoxyphenyl)-2,3-dimethyl-1-butanol (3)

A reaction solution of benzoate 28 (0.23 g, 0.36 mmol) in EtOH (15 mL) and 1 M aq. NaOH solution (15 mL) was stirred at room temperature for 12 h before additions of H₂O and CHCl₃. The organic solution was separated and dried (Na₂SO₄). Concentration gave crude alcohol. A reaction mixture of crude alcohol and 5% Pd/C (0.20 g) in EtOAc (5 mL) was stirred under H2 gas at ambient temperature for 12 h before filtration. The filtrate was concentrated, and then the residue was applied to silica gel column chromatography (EtOAc/hexane = 1/1) to give 3 (90 mg, 0.26 mmol, 72%) as a colorless oil; +10 (c 0.7, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.68 (3H, d, J = 6.8 Hz, CH₃), 0.74 (3H, d, J = 6.9 Hz, CH₃), 1.24 (1H, br. s, 1-OH), 1.75 (1H, m, 3-H), 2.58 (1H, m, 2-H), 3.45 (1H, dd, J = 10.7, 6.6 Hz, 1-H), 3.49 (1H, d, J = 11.8 Hz, 4-H), 3.49 (1H, dd, J = 10.7, 8.3 Hz, 1-H), 3.83 (3H, s, OCH₃), 3.84 (3H, s, OCH₃), 5.56 (1H, s, OH), 5.57 (1H, s, OH), 6.76 (1H, s, ArH), 6.78 (1H, d, J = 1.3 Hz, ArH), 6.80–6.82 (4H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 9.6, 11.9, 35.98, 36.04, 55.9, 56.1, 67.0, 110.5, 114.3, 114.5, 120.3, 120.4, 136.7, 137.2, 143.8, 146.5, 146.6; IR (CHCl₃) cm⁻¹ 3630, 3017, 2974, 1512, 1269, 1219, 1036. MS (EI) m/z: 346 (M⁺, 59), 260 (100), 229 (70); HRMS (EI) m/z calcd for C₂₀H₂₆O₅: 346.1780, found: 346.1780. >99%ee (AD-H, iso-PrOH/hexane = 1.7/1, 1 mL/min, 280 nm, t_R6.6 min). (2R,3S)-(4). 71% yield, −10 (c 1.0, CHCl₃),>99%ee (AD-H, iso-PrOH/hexane = 1.7/1, 1 mL/min, 280 nm, t_R9.4 min).

(4R)-4-Benzyl-3-[(3S,4R)-4-(4-benzyloxy-3-methoxyphenyl)-3-methyl-4-(triisopropylsilyloxy)butanoyl]-2-oxazolidinone (19)

The title compound was obtained from 17 by the same synthetic method as that of compound 18 by using (R)-4-benzyloxazolidinone in 72% yield as a colorless oil; −7 (c 1, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.93 (3H, d, J = 6.7 Hz, CH₃), 0.97–1.02 (21H, m, TIPSi), 2.50 (1H, m, CHCH₃), 2.61–2.74 (2H, m, C = OCH₂), 3.24 (2H, d, J = 14.0 Hz, CH₂Bn), 3.91 (3H, s, OCH₃), 4.08–4.15 (2H, m, 5-H), 4.62 (1H, m, 4-H), 4.73 (1H, d, J = 4.9 Hz, ArCHOTIPS), 5.12 (2H, s, OCH₂Bn), 6.73 (1H, d, J = 8.2 Hz, ArH), 6.80 (1H, d, J = 8.2 Hz, ArH), 7.01 (1H, s, ArH), 7.19–7.25 (2H, m, ArH), 7.27–7.36 (6H, m, ArH), 7.42–7.43 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 12.5, 16.0, 18.05, 18.12, 37.6, 37.9, 38.1, 55.2, 55.9, 66.1, 71.1, 78.2, 110.9, 113.1, 119.4, 127.3, 127.4, 127.7, 128.5, 128.9, 129.4, 135.4, 136.0, 137.3, 147.2, 149.2, 153.3, 172.8; IR (CHCl₃) cm⁻¹: 2940, 1782, 1698, 1508, 1456, 1384, 1261,1090. MS (EI) m/z: 645 (M⁺, 4), 399 (100), 290 (57); HRMS (M⁺) m/z calcd for C₃₈H₅₁O₆NSi: 645.3485, found: 645.3456. (4S)-3-[(3R,4S)]-(19). 75% yield, +7 (c 1, CHCl₃).

(4R)-4-Benzyl-3-[(2R,3S,4R)-4-(4-benzyloxy-3-methoxyphenyl)-4-(triisopropylsilyloxy)-2,3-dimethylbutanoyl]-2-oxazolidinone (21)

The title compound was obtained from 19 by the same synthetic method as that of compound 20 in 32% yield as a colorless oil along with 61% recovery of 19; −10 (c 1.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.98–1.01 (21H, m, TIPSi), 1.08 (3H, d, J = 6.9 Hz, CH₃), 1.31 (3H, d, J = 7.0 Hz, CH₃), 2.08 (1H, m, C = OCHCHCH₃), 2.67 (1H, dd, J = 13.3, 9.6 Hz, CH₂Bn), 3.14 (1H, dd, J = 13.3, 2.8 Hz, CH₂Bn), 3.82 (1H, dd, J = 8.7, 7.9 Hz, 5-H), 3.87 (3H, s, OCH₃), 3.95 (1H, dd, J = 8.7, 7.9 Hz, 5-H), 4.02 (1H, m, C = OCH), 4.32 (1H, m, 4-H), 4.86 (1H, d, J = 4.3 Hz, ArCHOTIPS), 5.10 (2H, s, OCH₂Bn), 6.71 (1H, dd, J = 8.2, 1.4 Hz, ArH), 6.77 (1H, d, J = 8.2 Hz, ArH), 6.93 (1H d, J = 1.4 Hz, ArH), 7.15–7.17 (2H, m, ArH), 7.25–7.32 (6H, m, ArH), 7.38–7.40 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 12.7, 13.2, 16.3, 18.1, 37.8, 38.8, 45.5, 55.3, 56.0, 65.8, 71.2, 75.9, 111.0, 113.4, 119.2, 127.3, 127.8, 128.5, 128.9, 129.4, 135.4, 137.3, 147.2, 149.2, 152.7, 176.5; IR (CHCl₃) cm⁻¹: 2944, 1780, 1701, 1508, 1466, 1382, 1090. MS (EI) m/z: 659 (M⁺, 4), 400 (100), 290 (57); HRMS (EI) m/z calcd for C₃₉H₅₃O₆NSi: 659.3642, found: 659.3638. (4S)-3-[(2S,3R,4S)]-(21). 43% yield, +11 (c 0.9, CHCl₃).

(2R,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-2,3-dimethyl-4-(triisopropylsilyloxy)-1-butanol (23)

The title compound was obtained from 21 by the same synthetic method as that of compound 22 in 80% yield as a colorless oil; +40 (c 1.4, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.94–0.99 (27H, m, TIPSi, CH₃ × 2), 1.29 (1H, m, 3-H), 1.61 (1H, br. s, OH), 1.71 (1H, m, 2-H), 3.29 (1H, dd, J = 10.4, 7.3 Hz, 1-H), 3.48 (1H, dd, J = 10.4, 5.9 Hz, 1-H), 3.87 (3H, s, OCH₃), 4.74 (1H, d, J = 6.2 Hz, 4-H), 5.12 (2H, s, OCH₂Bn), 6.73 (1H, dd, J = 8.1, 1.4 Hz, ArH), 6.79 (1H, d, J = 8.1 Hz, ArH), 6.94 (1H, d, J = 1.4 Hz, ArH), 7.27–7.37 (3H, m, ArH), 7.42–7.44 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 11.5, 12.7, 16.7, 18.1, 18.2, 36.1, 45.9, 56.0, 65.4, 71.2, 77.9, 110.7, 113.5, 119.3, 127.4, 127.8, 128.5, 137.3, 138.1, 147.2, 149.4; IR (CHCl₃) cm⁻¹: 3560, 2945, 1505, 1452, 1258, 1140, 1059, 1025. MS (EI) m/z: 486 (M⁺, 9), 400 (100); Anal. Calcd for C₂₉H₄₆O₄Si: C, 71.56; H, 9.53%. Found: C, 71.43; H, 9.59%. (2S,3R,4S)-(23). 74% yield, −40 (c 0.9, CHCl₃).

(2R,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-2,3-dimethyl-4-(triisopropylsilyloxy)butyl benzoate (25)

The title compound was obtained from 23 by the same synthetic method as that of compound 24 in 85% yield as a colorless oil; +3 (c 1.4, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.94–0.99 (21H, m. TIPSi), 1.04 (3H, d, J = 6.8 Hz, CH₃), 1.08 (3H, d, J = 7.0 Hz, CH₃), 1.79 (1H, m, 3-H), 1.87 (1H, m, 2-H), 3.83 (3H, s, OCH₃), 4.06 (1H, dd, J = 10.9, 7.5 Hz, 1-H), 4.22 (1H, dd, J = 10.9, 4.9 Hz, 1-H), 4.74 (1H, d, J = 6.8 Hz, 4-H), 5.11 (2H, s, OCH₂Bn), 6.75 (1H, dd, J = 8.2, 1.4 Hz, ArH), 6.80 (1H, d, J = 8.2 Hz, ArH), 6.94 (1H, d, J = 1.4 Hz, ArH), 7.25–7.36 (3H, m, ArH), 7.40–7.44 (4H, m, ArH), 7.54 (1H, m, ArH), 8.01–8.03 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 11.6, 12.7, 17.4, 18.1, 18.2, 32.8, 46.3, 55.9, 67.3, 71.2, 77.8, 110.7, 113.6, 119.3, 127.4, 127.8, 128.3, 128.5, 129.5, 130.5, 132.8, 137.3, 137.9, 147.3, 149.4, 166.6; IR (CHCl₃) cm⁻¹: 2945, 1711, 1504, 1460, 1279, 1137, 1116, 1063. MS (EI) m/z: 590 (M⁺, 16), 547 (100); Anal. Calcd for C₃₆H₅₀O₅Si: C, 73.18; H, 8.53%. Found: C, 72.95; H, 8.63%. (2S,3R,4S)-(25). 87% yield, −3 (c 0.9, CHCl₃).

(2R,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-4-hydroxy-2,3-dimethylbutyl benzoate (27)

The title compound was obtained from 25 by the same synthetic method as that of compound 26 in 94% yield as a colorless oil; −22 (c 1.1, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.99 (3H, d, J = 7.0 Hz, CH₃), 1.11 (3H, d, J = 6.8 Hz, CH₃), 1.82 (1H, m, 3-H), 1.97 (1H, m, 2-H), 3.79 (1H, br. s, OH), 3.83 (3H, s, OCH₃), 4.14 (1H, dd, J = 10.9, 7.3 Hz, 1-H), 4.40 (1H, dd, J = 10.9, 5.2 Hz, 1-H), 4.77 (1H, d, J = 4.7 Hz, 4-H), 5.12 (2H, s, OCH₂Bn), 6.79 (1H, dd, J = 8.2, 1.4 Hz, ArH), 6.83 (1H, d, J = 8.2 Hz, ArH), 6.89 (1H, d, J = 1.4 Hz, ArH), 7.26–7.36 (3H, m, ArH), 7.41–7.45 (4H, m, ArH), 7.55 (1H, m, ArH), 8.01–8.03 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ:10.3, 16.4, 34.8, 43.5, 56.0, 67.5, 71.1, 75.6, 109.92, 109.95, 109.96, 113.8, 113.89, 113.91, 118.2, 127.3, 127.8, 128.4, 128.5, 129.5, 130.4, 132.9, 137.2, 137.4, 147.4, 149.7, 166.6; IR (CHCl₃) cm⁻¹: 3619, 1976, 1716, 1520, 1452, 1277, 1138, 1026. MS (EI) m/z: 434 (M⁺, 20), 243 (100); HRMS (EI) m/z calcd for C₂₇H₃₅O₅: 434.2093, found: 434.2094. (2S,3R,4S)-(27). 96% yield, +23 (c 1.2, CHCl₃).

(2R,3R)-4,4-Bis(4-benzyloxy-3-methoxyphenyl)-2,3-dimethylbutyl benzoate (29)

The title compound was obtained from 27 by the same synthetic method as that of compound 28 in 52% yield as a colorless oil through three steps; −5 (c 0.6, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.83 (3H, d, J = 7.0 Hz, CH₃), 1.09 (3H, d, J = 6.9 Hz, CH₃), 2.07 (1H, m, 3-H), 2.33 (1H, m, 2-H), 3.71 (1H, d, J = 11.5 Hz, 4-H), 3.80 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 4.10 (1H, dd, J = 10.9, 7.9 Hz, 1-H), 4.37 (1H, dd, J = 10.9, 5.1 Hz, 1-H), 5.07 (2H, s, OCH₂Bn), 5.08 (2H, s, OCH₂Bn), 6.75 (1H, dd, J = 8.3, 1.9 Hz, ArH), 6.77–6.80 (5H, m, ArH), 7.26–7.36 (6H, m, ArH), 7.39–7.45 (6H, m, ArH), 7.55 (1H, m, ArH), 8.01–8.03 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 13.3, 17.2, 33.1, 41.2, 55.99, 56.03, 56.1, 66.4, 71.1, 112.0, 112.1, 114.1, 114.3, 119.5, 119.8, 127.25, 127.27, 127.29, 127.7, 128.4, 128.45, 128.49, 129.5, 130.5, 132.9, 137.37, 137.40, 137.5, 137.9, 146.66, 146.70, 149.5, 149.6, 166.7; IR (CHCl₃) cm⁻¹: 3012, 2960, 1714, 1510, 1277. MS (EI) m/z: 630 (M⁺, 7), 204 (100); HRMS (EI) m/z calcd for C₄₁H₄₂O₆: 630.2981, found: 630.3001. (2S,3S)-(29). 49% yield, +6 (c 0.7, CHCl₃).

(2R,3R)-4,4-Bis(4-hydroxy-3-methoxyphenyl)-2,3-dimethyl-1-butanol (5)

The title compound was obtained from 29 by the same synthetic method as that of compound 3 in 64% yield as a colorless oil through two steps; +24 (c 0.8, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.72 (3H, d, J = 6.9 Hz, CH₃), 0.92 (3H, d, J = 6.9 Hz, CH₃), 1.20 (1H, br. s, 1-OH), 1.80 (1H, m, 3-H), 2.28 (1H, m, 2-H), 3.34 (1H, dd, J = 10.4, 7.8 Hz, 1-H), 3.66 (1H, dd, J = 10.4, 5.4 Hz, 1-H), 3.70 (1H, d, J = 11.7 Hz, 4-H), 3.826 (3H, s, OCH₃), 3.834 (3H, s, OCH₃), 5.56 (1H, s, ArOH), 5.58 (1H, s, ArOH), 6.72 (1H, d, J = 1.8 Hz, ArH), 6.75 (1H, d, J = 1.4 Hz, ArH), 6.78 (1H, dd, J = 8.2, 1.8 Hz, ArH), 6.80 (1H, d, J = 8.2 Hz, ArH), 6.80–6.84 (2H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 13.3, 16.6, 36.5, 40.9, 55.9, 56.1, 64.6, 110.6, 110.7, 114.4, 114.5, 120.1, 120.2, 136.9, 137.2, 143.8, 143.9, 146.4, 146.6; IR (CHCl₃) cm⁻¹: 3560, 3019, 2980, 1511, 1269, 1219, 1036. MS (EI) m/z: 346 (M⁺, 53), 260 (100), 229 (60); HRMS (EI) m/z calcd for C₂₀H₂₆O₅: 346.1780, found: 346.1770. >99%ee (AD-H, iso-PrOH/hexane = 1.7/1, 1 mL/min, 280 nm, t_R4.2 min). (2S,3S)-(6). 62% yield, two steps, −24 (c 0.6, CHCl₃), >99%ee (AD-H, iso-PrOH/hexane = 1.7/1, 1 mL/min, 280 nm, t_R4.7 min).

(2S,3S)-4,4-Bis(4-benzyloxy-3-methoxyphenyl)-3-hydroxymethyl-2-methyl-N,N-diethylbutanamide (30)

To an ice-cooled solution of AlMe₃ (1.40 mL, 0.98 M in hexane, 1.37 mmol) in CH₂Cl₂ (2 mL) were added Et₂NH (0.15 mL, 1.45 mmol) and lactone 15 (0.36 g, 0.67 mmol) in CH₂Cl₂ (1mL) under N₂ gas. The resulting reaction solution was stirred at room temperature for 72 h before pouring into an ice-cooled H₂O. The mixture was dissolved in EtOAc and H₂O. The organic solution was separated and washed with sat. aq. NaHSO₄ solution. After further washing with brine, the organic solution was dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/1) gave hydroxyamide 30 (0.29 g, 0.47 mmol, 70%) as a colorless oil; −30 (c 1.4, CHCl₃); ¹H NMR (400 MHz, C₅D₅ N) δ: 0.64 (3H, t, J = 6.9 Hz, CH₂CH₃), 1.11 (3H, t, J = 6.9 Hz, CH₂CH₃), 1.33 (3H, d, J = 7.3 Hz, CH₃), 2.49 (1H, m, CHHCH₃), 2.57 (1H, m, CHHCH₃), 2.74 (1H, m, 3-H), 3.14 (1H, m, CHHCH₃), 3.36 (1H, m, 2-H), 3.51 (1H, m, CHHCH₃), 3.75 (3H, s, OCH₃), 3.75–3.84 (1H, overlapped, CHHOH), 3.84 (3H, s), 4.15 (1H, dd, J = 11.6, 1.4 Hz, CHHOH), 4.61 (1H, d, J = 12.4 Hz, 4-H), 5.00 (1H, br. s, OH), 5.11 (2H, s, OCH₂Bn), 5.22 (2H, s, OCH₂Bn), 7.08 (1H, d, J = 8.3 Hz, ArH), 7.14 (1H, d, J = 8.3 Hz, ArH), 7.18 (1H, dd, J = 8.2, 1.9 Hz, ArH), 7.25 (1H, dd, J = 8.3, 1.9 Hz, ArH), 7.28–7.40 (5H, m, ArH), 7.44 (1H, d, J = 1.9 Hz, ArH), 7.55–7.61 (6H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 12.8, 13.7, 18.2, 36.8, 41.0, 42.2, 47.5, 50.2, 56.0, 56.2, 57.7, 70.9, 71.0, 112.2, 112.8, 114.0, 114.5, 119.5, 119.9, 127.09, 127.14, 127.6, 127.8, 128.4, 128.5, 136.5, 137.2, 137.4, 146.56, 146.62, 149.3, 149.9, 175.8; IR (CHCl₃) cm⁻¹: 3629, 3021, 1625. MS (EI) m/z: 611 (M⁺, 9), 129 (100); HRMS (EI) m/z calcd for C₃₈H₄₅O₆ N: 611.3247, found: 611.3252. (2R,3R)-(30). 76% yield, +30 (c 0.5, CHCl₃).

(2S,3S)-4,4-Bis(4-benzyloxy-3-methoxyphenyl)-2-methyl-3-(triisopropylsilyloxy)methyl-N,N,-diethylbutanamide (31)

To an ice-cooled solution of amide 30 (94 mg, 0.12 mmol) and 2,6-lutidine (0.045 mL, 0.39 mmol) in CH₂Cl₂ (5 mL) was added TIPSOTf (0.050 mL, 0.19 mmol). After the resulting reaction solution was stirred at room temperature for 6 h, sat. aq. NaHCO₃ solution was added. The organic solution was separated and washed with sat. aq CuCO₄ solution. After further washing with sat. aq. NaHCO₃ solution, the organic solution was dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/3) gave silyl ether 31 (0.12 g, 0.16 mmol, 75%) as a colorless oil; −1 (c 2, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.78 (3H, t, J = 7.1 Hz, CH₂CH₃), 0.90–0.93 (21H, m, TIPSi), 1.03 (3H, t, J = 6.9 Hz, CH₂CH₃), 1.19 (3H, d, J = 7.1 Hz, CH₃), 2.54 (1H, m, 3-H), 2.73 (2H, m, CH₂CH₃), 2.89 (1H, m, 2-H), 3.08 (1H, m, CHHCH₃), 3.35 (1H, m, CHHCH₃), 3.59 (1H, dd, J = 10.5, 2.8 Hz, TIPSOCHH), 3.83 (6H, s, OCH₃ × 2), 3.85 (1H, d, J = 13.6 Hz, 4-H), 4.27 (1H, dd, J = 10.5, 5.6 Hz, TIPSOCHH), 5.06 (2H, s, OCH₂Bn), 5.08 (2H, s, OCH₂Bn), 6.72–6.77 (4H, m, ArH), 6.83–6.84 (2H, m, ArH), 7.24–7.27 (2H, m, ArH), 7.30–7.34 (4H, m, ArH), 7.38–7.40 (4H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 12.0, 13.1, 14.2, 17.1, 18.2, 35.6, 40.0, 41.6, 49.6, 52.4, 56.0, 56.2, 63.4, 71.1, 71.3, 112.5, 112.7, 114.2, 114.3, 120.0, 120.1, 127.2, 127.3, 127.75, 127.82, 128.6, 137.4, 137.6, 137.7, 137.9, 146.6, 146.7, 149.4, 149.7, 175.3; IR (CHCl₃) cm⁻¹: 2940, 1626, 1512, 1464, 1261, 1141. MS (EI) m/z: 768 (M⁺, 0.6), 131 (100). Anal. Calcd for C₄₆H₆₃O₆NSi: C, 73.27; H, 8.42%. Found: C, 73.33; H, 8.48%. (2R,3R)-(31). 73% yield, +1 (c 0.8, CHCl₃).

(2R)-1,1-Bis(4-benzyloxy-3-methoxyphenyl)-3-methyl-2-(triisopropylsilyloxy)methylbutane (32)

To a solution of silyl ether 31 (0.12 g, 0.16 mmol) in toluene (5 mL) was added DIBAL-H (0.91 mL, 1 M in toluene, 0.91 mmol) at 0 °C. After the reaction solution was stirred at 0 °C for 13 h, sat. aq. NH₄Cl solution was added. The organic solution was separated, washed with brine, and dried (Na₂SO₄). The concentration gave crude aldehyde. To an ice-cooled solution of aldehyde in EtOH (8 mL) was added NaBH₄ (20 mg, 0.53 mmol), and then the reaction mixture was stirred at room temperature for 0.5 h before additions of sat. aq. NH₄Cl solution and EtOAc. The organic solution was separated, washed with brine, and dried (Na₂SO₄). Concentration gave crude alcohol. To an ice-cooled solution of alcohol and Et₃ N (36 μL, 0.26 mmol) in CH₂Cl₂ (5 mL) was added MsCl (20 μL, 0.26 mmol). After the reaction mixture was stirred at room temperature for 0.5 h, H₂O and CH₂Cl₂ were added. The organic solution was separated and dried (Na₂SO₄). Concentration gave crude mesylate. To an ice-cooled solution of mesylate in THF (10 mL) was added Super-Hydride (5.00 mL, 1.00 M in THF, 5.00 mmol), and then the reaction solution was stirred at room temperature for 1.5 h before the addition of sat. aq, NH₄Cl solution. After concentration, the residue was dissolved in CHCl₃ and H₂O. The organic solution was separated and dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/6) gave 32 (57 mg, 0.083 mmol, 52%, four steps) as a colorless oil; −3 (c 0.8, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.88 (3H, d, J = 7.3 Hz, CH₃), 0.90–0.94 (21H, m, TIPSi), 1.02 (3H, d, J = 6.9 Hz, CH₃), 1.75 (1H, m, 3-H), 2.22 (1H, m, 2-H), 3.61 (1H, dd, J = 10.3, 6.4 Hz, TIPSOCHH), 3.65 (1H, dd, J = 10.3, 3.2 Hz, TIPSOCHH), 3.77 (1H, d, J = 11.5 Hz, 1-H), 3.84 (3H, s, OCH₃), 3.86 (3H, s, OCH₃), 5.08 (4H, s, OCH₂Bn), 6.74 (1H, d, J = 8.2 Hz, ArH), 6.78–6.82 (5H, m, ArH), 7.26–7.30 (2H, m, ArH), 7.33–7.36 (4H, m, ArH), 7.39–7.42 (4H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 11.9, 17.2, 18.0, 18.1, 22.7, 27.7, 49.0, 51.6, 56.0, 56.1, 61.9, 71.1, 71.2, 112.1, 114.0, 114.3, 119.7, 120.0, 121.9, 127.2, 127.3, 127.7, 128.5, 137.5, 138.1, 146.6, 149.4; IR (CHCl₃) cm⁻¹: 2941, 2851, 1508, 1465, 1263, 1148. MS (EI) m/z: 682 (M⁺, 16), 439 (100); HRMS (EI) m/z calcd for C₄₃H₅₈O₅Si: 682.4054, found: 682.4042. (2S)-(32). 63% yield, four steps, +3 (c 1, CHCl₃).

(R)-2-Bis(4-benzyloxy-3-methoxyphenyl)methyl-3-methy-1-butanol (33)

To a solution of silyl ether 32 (57 mg, 0.083 mmol) in THF (5 mL) was added (n-Bu)₄NF (0.17 mL, 1 M in THF, 0.17 mmol). After stirring at room temperature for 2 h, sat. aq. NH₄Cl solution and EtOAc were added. The organic solution was separated, washed with brine, and dried (Na₂SO₄). Concentration followed by silica gel column chromatography (EtOAc/hexane = 1/3) gave alcohol 33 (40 mg, 0.078 mmol, 94%) as a colorless oil, −43 (c 0.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.83 (3H, d, J = 6.9 Hz, CH₃), 1.01 (3H, d, J = 6.9 Hz, CH₃), 1.76 (1H, m, 3-H), 2.21 (1H, m, 2-H), 3.57–3.66 (2H, m, 1-H₂), 3.79 (1H, d, J = 11.4 Hz, Ar₂CH), 3.85 (3H, s, OCH₃), 3.86 (3H, s, OCH₃), 5.08 (2H, s, OCH₂Bn), 5.09 (2H, s, OCH₂Bn), 6.77–6.86 (6H, m, ArH), 7.25–7.26 (2H, m, ArH), 7.28–7.36 (4H, m, ArH), 7.39–7.42 (4H, m, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 16.5, 22.1, 27.6, 49.8, 52.8, 55.9, 56.0, 61.7, 71.0, 111.7, 111.8, 113.9, 114.2, 119.6, 127.2, 127.67, 127.70, 128.4, 137.1, 137.2, 137.3, 146.6, 147.8, 149.5, 149.6; IR (CHCl₃) cm⁻¹: 3735, 3025, 3000, 1508, 1261, 1141, 1036. MS (EI) m/z: 526 (M⁺, 18), 439 (100); HRMS (EI) m/z calcd for C₃₄H₃₈O₅: 526.2720, found: 526.2735. (2S)-(33). 97% yield, +43 (c 0.8, CHCl₃).

(R)-2-Bis(4-hydroxy-3-methoxyphenyl)methyl-3-methyl-1-butanol (7)

A reaction mixture of benzyl ether 33 (40 mg, 0.078 mmol) and 5% Pd/C (0.10 g) in EtOAc (10 mL) was stirred under H₂ gas at ambient temperature for 2 h before filtration. After the filtrate was concentrated, the residue was applied to a silica gel column chromatography (EtOAc/hexane = 1/1) to give secocyclolignane 7 (23 mg, 0.066 mmol, 85%) as a colorless oil, −55 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 0.82 (3H, d, J = 6.9 Hz, CH₃), 1.02 (3H, d, J = 6.9 Hz, CH₃), 1.78 (1H, m, 3-H), 2.22 (1H, m, 2-H), 3.64 (2H, s, 1-H₂), 3.78 (1H, d, J = 11.5 Hz, Ar₂CH), 3.85 (3H, s, OCH₃), 3.86 (3H, s, OCH₃), 5.49 (1H, s, ArOH), 5.52 (1H, s, ArOH), 6.77 (1H, s, ArH), 6.81 (1H, d, J = 1.9 Hz, ArH), 6.82 (1H, d, J = 8.2 Hz, ArH), 6.84 (2H, s, ArH), 6.87 (1H, dd, J = 8.2, 1.9 Hz, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 16.6, 22.2, 27.7, 49.9, 53.0, 55.8, 55.9, 61.8, 110.46, 110.54, 114.5, 114.7, 120.1, 120.3, 136.2, 136.3, 143.9, 144.2, 146.5, 146.7; IR (CHCl₃) cm⁻¹: 3571, 3000, 1511, 1269, 1036. MS (EI) m/z: 346 (M⁺, 7), 259 (100); HRMS (EI) m/z calcd for C₂₀H₂₆O₅: 346.1780, found: 346.1774. > 99%ee (AD-H, iso-PrOH/hexane = 1.7/1, 1 mL/min, 280 nm, t_R6.5 min). (S)-8. 79% yield, +55 (c 0.5, CHCl₃),>99%ee (AD-H, iso-PrOH/hexane = 1.7/1, 1 mL/min, 280 nm, t_R4.7 min).

(2S,3R)-4,4-Bis(3,4-dimethoxyphenyl)-2,3-dimethyl-1-butanol (34), (+)-kadangustin J

A reaction mixture of butanol type secocyclolignane 3 (14 mg, 40 μmol), dimethyl sulfate (50 μL, 0.53 mmol), K₂CO₃ (0.11 g, 0.80 mmol), and dibenzo-18-crown-6 (2 mg) in CH₃CN (8 mL) was stirred at 80 °C for 24 h before additions of CHCl₃ and H₂O. The organic solution was separated, washed with brine, and dried (Na₂SO₄). Concentration followed by silica gel TLC (2% MeOH in CHCl₃) gave 34, (+)-kadangustin J (9 mg, 24 μmol, 60%) as colorless powders. The NMR data agreed with those in the literature.⁸⁾ +21 (c 0.1, MeOH), +4.9 (c 0.171, MeOH) in the literature.⁸⁾ (2R,3S)-35, (−)-kadangustin J. 65% yield, −21 (c 0.2, MeOH), −20.7 (c 1.19, MeOH) in the literature.¹⁸⁾

(2R,3R)-4,4-Bis(3,4-dimethoxyphenyl)-2,3-dimethyl-1-butanol (36)

The title compound was obtained from 5 by the same synthetic method as that of compound 34 in 68% yield as colorless powders, +18 (c 0.1, MeOH); ¹H NMR (400 MHz, CDCl₃) δ: 0.78 (3H, d, J = 6.9 Hz, CH₃), 0.99 (3H, d, J = 6.9 Hz, CH₃), 1.57 (1H, br. s, OH), 1.82 (1H, m, 3-H), 2.31 (1H, m, 2-H), 3.37 (1H, dd, J = 10.5, 7.3 Hz, 1-H), 3.67 (1H, dd, J = 10.5, 6.0 Hz, 1-H), 3.75 (1H, d, J = 11.5 Hz, 4-H), 3.82 (6H, s, OCH₃ × 2), 3.83 (6H, s, OCH₃ × 2), 6.76 (1H, d, J = 8.3 Hz, ArH), 6.77–6.78 (1H, overlapped, ArH), 6.79 (1H, d, J = 8.3 Hz, ArH), 6.80 (1H, d, J = 2.3 Hz, ArH), 6.83 (1H, dd, J = 8.3, 1.9 Hz, ArH), 6.86 (1H, dd, J = 8.3, 2.3 Hz, ArH); ¹³C NMR (100 MHz, CDCl₃) δ: 13.3, 16.6, 36.6, 40.9, 55.8, 55.87, 55.90, 56.0, 64.7, 111.2, 111.4, 119.6, 137.4, 137.8, 147.3, 147.4, 148.8, 149.0. MS (EI) m/z: 374 (M⁺, 11), 287 (100); HRMS (EI) m/z calcd for C₂₂H₃₀O₅: 374.2094, found: 374.2088. (2S,3S)-37. 67% yield, −18 (c 0.1, MeOH).

Enantiomeric excess of butane-type secocyclolignane 1 and 2

1: >99%ee, AD-H, iso-PrOH/hexane = 1/2, 1 mL/min, 271 nm, t_R10 min. 2: >99%ee, AD-H, iso-PrOH/hexane = 1/2, 1 mL/min, 271 nm, t_R8 min.

Acknowledgments

Part of this study was performed at INCS (Johoku station) of Ehime University. We are grateful to Marutomo Co. for financial support.