HETEROCYCLES

Paper | Special issue | Vol. 84, No. 2, 2012, pp. 1045-1056
Received, 14th July, 2011, Accepted, 15th August, 2011, Published online, 16th August, 2011.
DOI: 10.3987/COM-11-S(P)82

■ Chiba-G-Catalyzed Intramolecular Oxo-Michael Addition: Synthetic Approaches to Vitamin E Skeleton

Sayaka Tokunou, Waka Nakanishi, Natsuko Kagawa, Takuya Kumamoto, and Tsutomu Ishikawa*

Graduate School of Pharmaceutical Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

A chroman skeleton with quaternary carbon chiral center, leadable to vitamin E after manipulation, was constructed through 6-exo-trig type intramolecular oxo-Michael addition in up to 44% yield with 81% ee when a phenol with (Z)-α,β-unsaturated ester at ortho position was reacted in the presence of a guanidine-type organocatalyst, Chiba-G [(-)-(4R,5R)-2-[(S)-1-hydroxymethyl-2-phenylethyl]imino-1,3-dimethyl-4,5-diphenylimidazolidine (or the enantiomer)].

INTRODUCTION
Development of enantioselective construction of 2,2-disubstituted chroman skeletons is an important issue in the synthesis of biologically active natural products, such as vitamin E (1)1 with lipophilic antioxidant activity and trans-δ-tocotrienoloic acid (2)2 with antibacterial activity, for the purpose of further therapeutic modification (Figure 1).

Hayashi,3 Achiwa,4 Trost,5 and Tietze6 and their co-workers have reported the palladium-catalyzed asymmetric synthesis of 2,2-disubstituted chiral chromans. However, although much attention has been paid for the use of organocatalyst instead of metal catalyst in asymmetric synthesis,7 there had been no reports on the construction of 2,2-disubstituted chiral chroman skeletons by using organocatalyst. We have uncovered potential functionality of guanidine compounds as chiral auxiliaries8 and recently reported the model asymmetric construction of 2,2-disubstituted chroman skeleton from phenols with tri-substituted α,β-unsaturated esters by 6-exo-trig type intramolecular oxo-Michael addition (IOMA) catalyzed by chiral guanidines.9 In this paper we present the synthetic application of this methodology using a backbone guanidine catalyst in the model reaction, Chiba-G [(-)-(4R,5R)-2-[(S)-1-hydroxymethyl-2-phenylethyl]imino-1,3-dimethyl-4,5-diphenylimidazolidine (or its enantiomer)] (Figure 1), to the construction of vitamin E core.

RESULTS AND DISCUSSION
Trials for IOMA of 2-hydroxy-5-methoxy-3,4,6-trimethylphenyl vinyl ketone 9: 6-endo-trig type reaction. We have developed 6-endo-trig type IOMA catalyzed by quinine for the preparation of 2,3-disubstituted chroman-4-one system and applied the method to the enantioselective synthesis of anti-HIV-1 active coumarins such as (+)-calanolide A.10 Thus, at first, we examined Chiba-G-catalyzed 6-endo-trig type IOMA of 2-hydroxy-5-methoxy-3,4,6-trimethylphenyl vinyl ketone 9, which was prepared as shown in Scheme 1. Reaction of a MOM-protected benzaldehyde 5, which was derived from a commercially available 2,3,6-trimethylhydroquinone (3) by conventional methods in 4 steps, with 6-benzyloxyhex-1-yne afforded an alkynyl alcohol 6 in 67% yield. Oxidation of 6 with MnO2 followed by treatment with

Me2CuLi yielded an alkenyl ketone 8. After the repeated chromatographic separation of the E/Z-isomers of 8, removal of the MOM-deprotection was examined under various conditions. The use of NaHSO4-SiO2 complex11 successfully provided a targeted vinyl ketone 9 in high yield; however, a partial isomerization was observed during the deprotection [E : Z = 1 : 0.3 from E-7; E : Z = 0.25 : 1 from Z-7].
The results of separate IOMA on (E)- and (Z)-enriched 2-hydroxy-5-methoxy-3,4,6-trimethylphenyl vinyl ketone 9 were summarized in Table 1. No reactions occurred in the presence of a tertiary amine such as quinine or quinidine (runs 1 and 2), while Chiba-G worked as a catalyst; but both chemical yield and enantioselectivity of cyclized product 10 were low in the use of CHCl3 as solvent (runs 3 and 4) or without solvent (run 6). Reaction rate was greatly accelerated when reaction was carried out in MeOH; however, no asymmetric induction was observed (run 5). The recovered starting vinyl ketone 9 was found to be an (E)-enriched mixture, even from a (Z)-enriched 9, suggesting a possible retro-IOMA. Thus, the 6-endo-trig type IOMA of a vinyl ketone 9 resulted in unfruitful cyclization.

Trials for IOMA of methyl 5-(2-hydroxy-5-methoxy-3,4,6-trimethylphenyl)-3-methylpent-2-enoate (14): 6-exo-trig type reaction. Next, we turned our attention to 6-exo-trig type reaction and methyl 5-(2-hydroxy-5-methoxy-3,4,6-trimethylphenyl)-3-methylpent-2-enoate (14) was chosen as a substrate for the IOMA. The ester 14 was prepared from the MOM-protected benzaldehyde 5, according to the procedure adopted in our model examination9 (Scheme 2). Four-successive reactions of aldol condensation with acetone, catalytic hydrogenation, Hornor-Emmons-Wadsworth reaction with methyl p,p-bis(2,2,2-trifluoroethyl)phosphonoacetate, and the MOM-deprotection afforded (E)- methyl ester E-14 and (Z)-methyl ester Z-14.
Smooth cyclization of both (E)- and (Z)-isomers was, as expected, observed in the tetramethylguanidine (TMG)-catalyzed reactions (Table 2, runs 1 and 2). Similarly, Chiba-G worked well as a catalyst in the reaction of (E)-substrate E-14 to give a chroman product 15 in 81% yield, but selectivity was not satisfactory (30% ee) (run 3). On the other hand, acceptable enantioselectivity (81% ee) was obtained, even moderate chemical yield (44%), when (Z)-substrate Z-14 was subjected to the IOMA (run 4). This

reaction was tolerant to temperature and, interestingly, the increment of chemical yield (62%) with slight loss of enantioselectivity (81% → 74% ee) was observed (run 5). Unfortunately, both chemical yield and enantioselectivity in the IOMA of Z-14 were not improved in the screening of solvents (runs 6-9); however, no occurrence of a retro-path in these reactions was suggested by the recovery of the staring Z-14.
Thus, it was found that chloroform was the best solvent among solvents examined for the 6-exo-trig type IOMA of Z-14 (run 4 in Table 2). We had observed the rate acceleration of 6-endo-trig type IOMA in calanolide A synthesis when chlorobenzene was used as a solvent,10 Next, (-)-Chiba-G-catalyzed IOMA of Z-14 in a chlorinated solvent was examined (Table 3). In general, high enantioselectivity, especially 87% ee in the use of dichloromethane (run 4), was obtained, but chemical yields were not improved in spite of their permittivity.

Absolute configuration of the cyclization product 15 was determined by comparison with a known (S)-(+)-vinylogous chroman S-(+)-17 {[α]D +15.4 (CHCl3)}.6 DIBAH-reduction of (+)-15 {[α]D +2.8 (CHCl3)}with 77% ee, derived from the (-)-Chiba-G-catalyzed IOMA of Z-14, followed by Wittig reaction afforded (-)-vinylogous chroman R-(-)-17 {[α]D -10.8 (CHCl3)}, the ee of which was estimated to be 68% (Scheme 3). These facts indicated that asymmetric induction leading R-configuration was controlled in the (-)-Chiba-G-catalyzed IOMA of Z-14, with accordance to the results of our model IOMA.9

CONCLUSION
We examined 6-endo-trig and 6-exo-trig type IOMAs for the asymmetric construction of vitamin E core carrying a 2,2-disubstituted chroman skeleton and found that the latter 6-exo-trig type cyclization could be effectively catalyzed by Chiba-G when (Z)-unsaturated ester was used as a substrate.

EXPERIMENTAL
General. Melting points were determined on a micro melting point hot-stage instrument Yanagimoto MP-SI and are uncorrected. IR spectra were recorded with ATR on a JASCO FT/IR-300E spectrometer. Specific rotation, [α]D, was recorded on a JASCO DIP-140 polarimeter. 1H and 13C NMR spectra were recorded with JEOL JNM ECP 400 spectrometer in CDCl3. HREIMS was performed on JASCO MS-GCMATE spectrometer. For column chromatography silica gel 60 or 60N (spherical, 70-230 mesh, Kanto) and for flash chromatography silica gel (230-400 mesh, Merck) were used.

Compound 6. To a solution of 6-benzyloxy-1-hexyne (3.76 g, 20.0 mmol) in THF (40 mL) was added a 1.57 M solution of nBuLi in hexane (13.5 mL, 21.2 mmol) at 0 °C over 5 min under Ar, and the mixture was stirred at the same temperature for 1 h and then cooled to -42 °C. To the cooled mixture was added a solution of 5 (4.07 g, 17.1 mmol) in THF (30 mL) over 10 min, and the whole was stirred at -42 °C for 1 h, quenched with sat. NaHCO3 (50 mL), and extracted with AcOEt (50 mL x 3). The combined organic solutions were washed with brine (50 mL), dried (MgSO4), and evaporated. Column chromatography of the residue (hexane : AcOEt = 6 : 1) afforded 6 (4.86 g, 67%) as a colorless oil; IR νmax: 3422, 2361 cm-1; 1H NMR δ: 1.58-1.64, 1.67-1.72 (each 2H, m, CH2), 2.16, 2.19, 2.44 (each 3H, s, Me), 2.25 (2H, dt, J = 7.0, 2.1 Hz, CH2), 3.47 (2H, t, J = 6.3 Hz, CH2), 3.57 (1H, d, J = 7.4 Hz, OH, exchangeable), 3.635, 3.943 (each 3H, s OMe), 4.48 (2H, s, OCH2O), 4.94, 5.01 (each 1H, d, J = 5.7 Hz, OCH2Ph), 5.85 (1H, dt, J = 7.4, 2.1 Hz, CH), 7.28-7.36 (5H, m, ArH); 13C NMR δ: 12.1, 12.6, 13.1, 18.4, 25.0, 28.5, 57.3, 58.5, 59.6, 69.4, 72.4, 80.5, 85.1, 99.8, 127.1, 127.2, 127.6, 128.0, 130.5, 131.2, 138.2, 149.2, 153.5; HREIMS: m/z 426.2409 (calcd for C26H34O5: 426.2406).

Compound 7. A mixture of 6 (0.392 g, 0.92 mmol) and MnO2 (0.804 g, 9.25 mmol) in CH2Cl2 (5 mL) was stirred at rt for 10 h and filtered through celtie pad. Evaporation of the filtrate gave 7 (0.358 g, 92%) as a yellow oil; IR νmax: 2205, 1651 cm-1; 1H NMR δ: 1.69-1.72 (4H, m, CH2 x 2), 2.18, 2.21, 2.25 (each 3H, s, Me), 2.43 (2H, dif. t, J = 6.6 Hz, CH2), 3.48 (2H, dif. t, J = 5.8 Hz, CH2), 3.54, 3.65 (each 3H, s OMe), 4.48 (2H, s, OCH2O), 4.89 (2H, s, OCH2Ph), 7.28-7.36 (5H, m, ArH); 13C NMR δ: 12.1, 12.6, 18.5, 24.1, 28.4, 57.1, 59.5, 69.0, 72.3, 82.5, 95.7, 100.1, 125.4, 127.0, 127.8, 129.0, 132.8, 133.5, 138.0, 148.2, 152.9, 181.0; HREIMS: m/z 424.2262 (calcd for C26H32O5: 424.2250).

Compound 8. A 0.83 M solution of MeLi in Et2O (24 mL, 19.9 mmol) was added to a mixture of CuI (1.87 g, 9.82 mmol) in THF (40 nL) at -40 °C over 10 min, and the whole was stirred at the same temperature for 15 min. After addition of a solution of 7 (1.81 g, 4.26 mmol) in THF (20 mL) over 20 min at -40 °C the mixture was stirred at the same temperature for 20 min, poured into ice-water (150 mL), and extracted with AcOEt (100 mL x 3). The combined organic solutions were washed with brine (50 mL), dried (MgSO4), and evaporated. Column chromatography of the residue (hexane : AcOEt = 15 : 1) afforded a 1 : 0.6 mixture of E- and Z-8 (1.87 g, 100%) as a pale yellow oil, which could be separated to be each isomer by repeated chromatographies; IR νmax: 1669 cm-1; 1H NMR δ: For (E)-isomer: 1.60-1.61 (4H, m, CH2 x 2), 2.13, 2.15, 2.19, 2.21 (each 3H, s, Me), 2.18-2.19 (2H, m, CH2), 3.46-3.48 (2H, m, CH2), 3.46, 3.65 (each 3H, s OMe), 4.49 (2H, s, OCH2O), 4.83 (2H, s, OCH2Ph), 6.26 (1H, s, CH), 7.31-7.35 (5H, m, ArH); For (Z)-isomer: 1.58-1.70 (4H, m, CH2 x 2), 1.91, 2.13, 2.18, 2.20 (each 3H, s, Me), 2.64 (2H, dif. t, J = 8.1 Hz, CH2), 3.46, 3.64 (each 3H, s OMe), 3.51 (2H, dif. t, J = 8.1 Hz, CH2), 4.52 (2H, s, OCH2O), 4.83 (2H, s, OCH2Ph), 6.26 (1H, s, CH), 7.28-7.35 (5H, m, ArH); 13C NMR δ: For (E)-isomer: 12.44, 12.89, 12.98, 19.3, 24.2, 29.2, 41.0, 57.4, 59.98, 69.8, 72.78, 100.3, 125.14, 126.0, 127.42, 127.496, 128.24, 129.05, 136.10, 138.4, 147.51, 153.323, 159.0, 196.4; For (Z)-isomer: 12.43, 12.88, 12.97, 24.8, 25.5, 29.7, 33.5, 57.5, 59.96, 70.0, 72.75, 100.4, 125.12, 126.37, 127.35, 127.504, 128.22, 129.03, 136.13, 138.6, 147.49, 153.316, 159.9, 195.8; HREIMS: m/z 440.2572 (calcd for C27H36O5: 440.2563).

Compound 9 from E-8. A mixture of E-8 (25.3 mg, 57.4 mmol) and NaHSO4˖SiO2 (12. 0 mg) in CH2Cl2 (0.5 mL) was stirred at rt for 1 h and filtered through celite pad. After evaporation of the filtrate column chromatography of the residue (hexane : AcOEt = 15 : 1) gave a 1 : 0.3 mixture of E- and Z-9 (21.8 mg, 96%) as a yellow oil; IR νmax: 3734, 1633 cm-1; 1H NMR δ: For (E)-isomer: 1.61-1.71 (4H, m, CH2 x 2), 2.16-2.18 (6H, br, Me x 2), 2.19-2.27 (2H, m, CH2), 2.24, 2.39 (each 3H, s, Me), 3.48-3.53 (2H, m, CH2), 3.65 (3H, s OMe), 4.51 (2H, s, OCH2Ph), 6.34-6.35 (1H, m, CH), 7.25-7.34 (5H, m, ArH), 11.26 (1H, s, OH, exchangeable); For (Z)-isomer: 1.61-1.71 (4H, m, CH2 x 2), 1.96 (3H, d, J = 1.3 Hz, Me), 2.16, 2.24, 2.39 (each 3H, s, Me), 2.61 (2H, dif. t, J = 7.6 Hz, CH2), 3.48-3.53 (2H, m, CH2), 3.65 (3H, s OMe), 4.51 (2H, s, OCH2Ph), 6.32-6.33 (1H, m, CH), 7.25-7.34 (5H, m, ArH), 11.30 (1H, s, OH, exchangeable); 13C NMR δ: For (E)-isomer: 11.7, 13.3, 15.8, 19.7, 24.1, 29.4, 40.9, 60.1, 69.8, 72.9, 121.5, 123.7, 126.7, 127.49, 127.53, 127.58, 128.30, 136.8, 138.4, 149.6, 154.9, 157.9, 198.0; For (Z)-isomer: 11.7, 13.3, 15.7, 24.8, 25.3, 29.7, 33.7, 60.1, 70.0, 72.8, 121.4, 123.7, 126.7, 127.4, 127.55, 127.58, 128.27, 136.8, 138.6, 149.6, 155.0, 158.0, 197.7; HREIMS: m/z 396.2297 (calcd for C25H32O4: 396.2300).

IOMA of 9 (Table 1, run 3): 2-(4-Benzyloxybutyl)-6-methoxy-2,5,7,8-tetramethylbenzo[b]pyran-4(3H)-one (10). A solution of an (E)-majored 9 (22.8 mg, 57.5 µmol) and (-)-Chiba-G (4.6 mg, 11.5 µmol) in CHCl3 (0.5 mL) was stirred at rt and then under reflux (total 1 day). After evaporation of the solvent, flash chromatography of the residue (hexane : AcOEt = 15 : 1) afforded 10 (6.7 mg, 29%) as a yellow oil together with the recovery of the staring 9 (E : Z = 1 : 0.5) (11.6 mg, 51%); IR νmax: 1678 cm-1; 1H NMR δ: 1.35 (3H, s, Me), 1.46-1.68 (5H, m, CH2 x 2, CH2 x 1/2), 1.78 (1H, ddd, J = 13.6, 11.6, 5.3 Hz, CH2 x 1/2), 2.12, 2.24, 2.54 (each 3H, s, Me), 2.58, 2.72 (each 1H, d, J = 15.7 Hz, CH2), 3.47 (2H, t, J = 6.2 Hz, CH2), 3.62 (3H, s, OMe), 4.49 (2H, s, OCH2Ph), 7.27-7.36 (5H, m, ArH); 13C NMR δ: 12.0, 13.6, 13.9, 20.3, 23.7, 29.9, 39.2, 49.2, 60.3, 70.0, 72.9, 79.6, 117.1, 124.1, 127.5, 127.6, 128.3, 129.5, 138.2, 138.5, 150.4, 154.8, 194.7; HREIMS m/z: 396.2308 (calcd for C25H32O4: 396.2300); HPLC (CHIRALCEL OD-H, λ = 254 nm, eluent: hexane : iPrOH = 100 : 1, flow rate: 1.1 mL/min): tR for a major 10: 24.7 min (52%), tR for a minor 10: 29.6 min (48%).

Compound 11. A mixture of 5 (0.657 g, 2.76 mmol) and acetone (0.67 mL, 9.12 mmol) in 10% NaOH (2.6 mL, 6.5 mmol) and H2O (4 mL) was stirred at 45 °C for 1 day under Ar, quenched with H2O (10 mL), and extracted with CHCl3 (20 mL and then 10 mL x 2). The combined organic solutions were washed with brine (10 mL), dried (MgSO4), and evaporated. Column chromatography of the residue (hexane : AcOEt = 10 : 1) afforded 11 (0.645 g, 84%) as colorless solid; IR νmax: 1682 cm-1; 1H NMR δ: 2.21, 2.23, 2.31, 2.38 (each 3H, s, Me), 3.56, 3.65 (each 3H, s OMe), 4.84 (2H, s, OCH2O), 6.67 (1H, d, J = 16.7 Hz, CH), 7.75 (1H, d, J = 16.7 Hz, C4-H); 13C NMR δ: 13.25, 13.32, 13.6, 27.6, 57.9, 60.2, 99.9, 126.4, 128.4, 129.1, 132.1, 132.7, 139.5, 150.9, 153.6, 198.8; Anal. Calcd for C16H22O4: C, 69.04; H, 7.97. Found: C, 69.00; H, 8.07.

Compound 12. A mixture of 11 (0.642 g, 2.31 mmol) and 5% Pd/C (0.057 g) in AcOEt (20 mL) was stirred at rt for 2 h under H2 atmosphere and filtered through celite pad. After evaporation of the filtrate column chromatography of the residue (hexane : AcOEt = 7 : 1) afforded 12 (0.567 g, 88%) as a colorless oil; IR νmax: 1711 cm-1; 1H NMR δ: 2.16 (6H, s Me x 2), 2.18, 2.21 (each 3H, s, Me), 2.64, 2.91 (each 2H, dif. t, J = 8.1 Hz, CH2), 3.58, 3.63 (each 3H, s OMe), 4.89 (2H, s, OCH2O); 13C NMR δ: 12.2, 12.8, 13.6, 21.8, 29.8, 43.6, 57.4, 60.1, 99.9, 127.1, 128.2, 128.6, 131.1, 150.7, 153.4, 208.6; HREIMS m/z: 280.1671 (calcd for C16H24O4: 280.1674).

Compound 13. A 60% mineral oil of NaH (0.308 g, 7.71 mmol) was washed with dry hexane (5 mL) and suspended in THF (6 mL). To the suspension was added methyl p,p-bis(2,2,2-trifluoroethyl)-phosphonoacetate (1.3 mL, 6.13 mmol) under ice-cooling over 10 min, and the mixture was stirred at rt for 1 h. To the mixture was added a solution of 12 (0.839 g, 2.99 mmol) in THF (7 mL) over 5 min, and the whole was stirred at rt for 4.5 h, quenched with H2O (50 mL), and extracted with AcOEt (10 mL x 3). The combined organic solutions were washed with brine (20 mL), dried (MgSO4), and evaporated. Column chromatography of the residue (hexane : AcOEt = 12 : 1) afforded a 1 : 0.8 mixture of E– and Z-13 (0.890 g, 89%) as colorless solid; IR νmax: 1716 cm-1; 1H NMR δ: For (E)-isomer: 2.16, 2.18, 2.23 (each 3H, s, Me), 2.26 (3H, d, J = 1.3 Hz, Me), 2.27-2.32, 2.79-2.83 (each 2H, m, CH2), 3.60, 3.64, 3.71 (each 3H, s OMe), 4.90 (2H, s, OCH2O), 5.77 (1H, m, CH); For (Z)-isomer: 1.97 (3H, d, J = 1.3 Hz, Me), 2.18 (6H, s, Me x 2), 2.32 (3H, s, Me), 2.79-2.83 (4H, m, CH2 x 2), 3.62, 3.65, 3.68 (each 3H, s OMe), 4.92 (2H, s, OCH2O), 5.69 (1H, m, CH); 13C NMR δ: For (E)-isomer: 12.1, 12.8, 13.6, 18.9, 25.3, 40.8, 50.8, 57.4, 60.0, 99.8, 114.8, 126.9, 128.1, 128.6, 131.2, 150.6, 153.3, 160.3, 167.2; For (Z)-isomer: 12.0, 12.8, 13.6, 26.0, 26.2, 33.4, 50.7, 57.5, 60.0, 99.8, 115.9, 127.6, 128.0, 128.3, 131.7, 150.4, 153.2, 159.9, 166.5; HREIMS: m/z 336.1921 (calcd for C19H28O5: 336.1937).

Compound 14. A mixture of 13 (0.825 g, 2.45 mmol) in MeOH (35 mL) containing 10% HCl (7.8 mL, 21.4 mmol) was heated at 70 °C for 1 h, quenched with H2O (60 mL), and extracted with AcOEt (30 mL x 3). The combined organic solutions were washed with brine (20 mL), dried (MgSO4), and evaporated. Column chromatography of the residue (hexane : AcOEt = 15 : 1 to 7 : 1) afforded E-14 (0.412 g, 58%) and Z-14 (0.291 g, 41%). (i) E-14: colorless solids, mp 88 °C; IR νmax: 3375, 1712 cm-1; 1H NMR δ: 2.14, 2.20, 2.22 (each 3H, s, Me), 2.25 (3H, d, J = 1.3 Hz, Me), 2.27-2.31, 2.76-2.80 (each 2H, m, CH2), 3.62, 3.70 (each 3H, s OMe), 4.55 (1H, s, OH, exchangeable), 5.75 (1H, q, J = 1.3 Hz, CH); 13C NMR δ: 11.8, 12.1, 12.7, 18.9, 25.5, 40.2, 50.8, 60.2, 115.0, 120.1, 124.5, 126.9, 127.7, 147.9, 150.4, 160.4, 167.3; Anal. Calcd for C15H22O3: C, 69.84; H, 8.27. Found: C, 70.00; H, 8.51. (ii) Z-14: pale yellow solids, mp 97 °C; IR νmax: 3462, 1687 cm-1; 1H NMR δ: 2.04 (3H, d, J = 1.3 Hz, Me), 2.21, 2.22, 2.26 (each 3H, s, Me), 2.56-2.60 (2H, m, CH2), 2.71-2.76 (2H, m, CH2), 3.63, 3.77 (each 3H, s OMe), 5.78 (1H, q, J = 1.3 Hz, CH), 7.38 (1H, s, OH, exchangeable); 13C NMR δ: 11.8, 12.3, 12.6, 26.0, 26.5, 34.0, 51.6, 60.3, 115.3, 122.2, 125.4, 128.4, 149.3, 149.8, 161.7, 167.8; Anal. Calcd for C15H22O3: C, 69.84; H, 8.27. Found: C, 69.77; H, 8.45.

IOMA of E-14 (Table 2, run 1): 6-Methoxy-2-(methoxycarbonylmethyl)-2,5,7,8-tetramethylbenzo[b]pyran (15). To a solution of E-14 (50.4 mg, 0.172 mmol) in CHCl3 (0.1 mL) was added a solution of TMG in CHCl3 (25 µL/mL, 0.17 mL, 33.9 mmol), and the whole was stirred at rt for 7 h. After evaporation of the solvent, column chromatography of the residue (hexane : AcOEt = 7 : 1) afforded 15 (38.8 mg, 77%) as a colorless oil; IR νmax: 1736 cm-1; 1H NMR δ: 1.42 (3H, s, Me), 1.86-1.93, 1.99-2.04 (each 1H, m, CH2), 2.06, 2.14, 2.18 (each 3H, s, Me), 2.58-2.65 (4H, m, CH2 x 2), 3.36, 3.69 (each 3H, s, OMe); 13C NMR δ: 11.6, 12.5, 20.4, 24.7, 31.1, 43.7, 51.5, 60.3, 73.4, 117.1, 123.1, 125.8, 128.0, 146.9, 149.7, 171.1; HREIMS m/z: 292.1673 (calcd for C17H24O4: 292.1674).

IOMA of Z-14 (Table 2, run 4). A solution of Z-14 (50.8 mg, 0.174 mmol) and (-)-Chiba-G (14.6 mg, 0.037 mmol) in CHCl3 (0.2 mL) was stirred at rt for 4 days. After evaporation of the solvent, column chromatography of the residue (hexane : AcOEt = 7 : 1) afforded an inseparable 1 : 0.8 mixture of Z-14 and 15 (49.8 mg, 98%) as an yellow oil; HPLC (CHIRALCEL OD-H, λ = 285 nm, eluent: hexane : iPrOH = 100 : 1, flow rate: 1.1 mL/min): tR for a major 15: 6.79 min (91%), tR for a minor 15: 8.48 min (9%); [α]D21 +2.8 (c 1.0, CHCl3).

2-(Formylmethyl)-6-methoxy-2,5,7,8-tetramethylbenzo[b]pyran (16). A 1.04 M solution of DIBAH in hexane (1.0 mL, 1.04 mmol) was added to a solution of the inseparable mixture of Z-14 and 15 [0.282 g; calculated to be 0.108 g as 15 (77% ee)] in hexane (16 mL) at -7 °C over 5 min under Ar, and the whole was stirred at the same temperature for 1 h. After successive addition of MeOH (1 mL) and H2O (20 mL) the mixture was extracted with Et2O (20 mL x 3). The combined organic solutions were washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4), and evaporated. Flash chromatography of the residue (hexane : AcOEt = 20 : 1) afforded 16 (0.044 g, 44% from a calculated 15) as a colorless oil together with Z-14 (0.049 g, 28%); IR νmax: 1721 cm-1; 1H NMR δ: 1.40 (3Η, s, Me), 1.84, 1.94 (each 1H, ddd, J = 13.6, 6.8, 6.8 Hz, CΗ2), 2.08, 2.15, 2.19 (each 3H, s, Me), 2.55 (1H, dd, J = 15.0, 3.5 Hz, CH2 x 1/2), 2.61-2.66 (2H, m, CH2), 2.72 (1H, dd, J = 15.0, 2.4 Hz, CH2 x 1/2), 3.64 (3H, s, OMe), 9.93 (1H, dd, J = 3.5, 2.4 Hz, CHO); 13C NMR δ: 11.7, 11.8, 12.5, 20.3, 24.8, 31.9, 52.3, 60.4, 73.5, 117.0, 123.1, 126.0, 128.3, 146.7, 150.0, 202.0; HREIMS m/z: 262.1568 (calcd for C16H22O3: 262.1569).

(E)-Methyl (6-Methoxy-2,5,7,8-tetramethylchroman-2-yl)but-2-enoate (17). A mixture of 16 (0.041 g, 0.158 mmol) and methyl triphenylphosphonoacetate (0.071 g, 0.214 mmol) in THF (1.75 mL) was stirred at 45 °C for 2 h. After evaporation of the solvent flash chromatography of the residue (hexane : AcOEt = 20 : 1) afforded 17 (0.032 g, 63%) as a colorless oil; IR νmax: 1723 cm-1; 1H NMR δ: 1.27 (3Η, s, Me), 1.78, 1.85 (each 1H, ddd, J = 19.1, 6.8, 6.8 Hz, CH2), 2.09, 2.14, 2.19 (each 3H, s, Me), 2.46 (1H, ddd, J = 14.1, 8.1, 1.2 Hz, CH2 x 1/2), 2.53 (1H, ddd, J = 14.1, 7.4, 1.2 Hz, CH2 x 1/2), 3.63, 3.74 (each 3H, s, OMe), 5.88 (1H, dt, J = 15.7, 1.2 Hz, CH), 7.05 (1H, dif. t, J = 15.7, 7.7 Hz, CH); HREIMS m/z: 318.1817 (calcd for C19H26O4: 318.1831); HPLC (CHIRALCEL OD-H, λ = 254 nm, eluent: hexane : iPrOH = 150 : 1, flow rate: 1.1 mL/min): tR for a major 17: 12.5 min (84%), tR for a minor 17: 13.6 min (16%); [α]D18 -10.8 (c 1.0, CHCl3).

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