HETEROCYCLES

Paper | Regular issue | Vol. 91, No. 5, 2015, pp. 959-969
Received, 14th January, 2015, Accepted, 16th March, 2015, Published online, 26th March, 2015.
DOI: 10.3987/COM-15-13172

■ Divergent Synthesis of 2,6-Disubstituted Piperidine Alkaloid, (+)-Spectaline by Palladium-Catalyzed Cyclization

Masatomo Katsuyama, Masahiro Furuta, Kazuya Kobayashi, Kenta Teruya, Hidefumi Makabe, Kenichi Akaji, and Yasunao Hattori*

Department of Medicinal Chemistry, Pharmacetuical Chemistry, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan

Abstract

Convergent synthesis of 2,6-disubstituted piperidine alkaloid, (+)-spectaline is described. Using substrate-controlled diastereo-selective Pd(II)-catalyzed cyclization, both cis-2,6- and trans-2,6-disubstituted piperidine backbones were constructed from adequately protected precursors with high selectivity. Synthesis of (+)-spectaline containing cis-2,6-disubstituents was accomplished by 10 step reactions with a 31% total yield.

INTRODUCTION
2,6-Disubstituted piperidin-3-ol is a subclass of hydroxypiperidine alkaloid which shows interesting biological activity including antibiotic and DNA-damaging activities.1,2 Comparing the biological activities of several natural products with the 2,6-disubustituted piperidine backbone (Figure 1), it has been shown that the configurations of the substituents at the 2- and 6-positions markedly influence biological activity.3-5 To address this stereostructure-activity relationship, a concise and diastereo-selective construction of the 2,6-disubstituted piperidine backbone would have practical utility. In this paper, we examined an application of Pd(II)-catalyzed cyclization for the construction of cis-2,6- and trans-2,6-disubstituted piperidine backbones, as well as its application to a total synthesis of (+)-spectaline (1). Although (+)-spectaline (1), isolated from the leaves of Cassia spectabilis, has been stereo-selectively synthesized by several groups,6-9 further refinement would be desirable regarding the overall steps and/or convergence of the synthetic route. In addition, in our previous syntheses of related piperidine derivatives, (-)-cassine and (+)-azimine,10,11 rather long reaction steps were required for the construction of cis-2,6-disubstituted piperidin-3-ol backbone (14 steps, 4.5%). Therefore, we applied Pd(II)-catalyzed cyclization10,11 to a substrate-controlled diastereoselective cyclization for the convergent synthesis of the spectalines.

RESULTS AND DISCUSSION
The retro-synthetic route for (+)-spectaline (1) is shown in Scheme 1. The aliphatic side-chain of 1 was introduced by a cross-metathesis reaction of the key intermediates 3 and 5. Pd(II)-catalyzed diastereo-selective cyclization gave the necessary key intermediate 3 or 4, depending on the structure of the cyclization precursor 6 containing a different combination of the protecting groups. Precursor 6 could be synthesized by chain elongation using conventional Horner-Wadsworth-Emmons reaction from a known alcohol 7.12

The cyclization intermediates 6a to 6c were synthesized according to the route shown in Scheme 2. The hydroxy group of a known alcohol 7 was protected with TBDMS or TBDPS group and following hydroboration with 9-BBN gave the primary alcohol 8a or 8b. Oxidation of each alcohol with AZADO13 and PhI(OAc)2 followed by Horner-Wadsworth-Emmons reaction yielded the ester 9a or 9b. Reduction with DIBAL-H of 9a gave cyclization precursor 6a, and reduction of 9b followed by esterification with 2,4,6-trimethylbenzoyl chloride or 4-phenylbenzoyl chloride gave precursor 6b and 6c, respectively.

Next, Pd(II)-catalyzed cyclization of the precursors 6a, 6b, and 6c were examined (Table 1). As expected from our previous studies,10,11 PdCl2 catalyst gave the cis-2,6-disubstituted piperidine backbone as a major product when the unprotected primary alcohol was employed as the precursor (entry 2 to 4), while Pd(0) catalyst [Pd(dba)2] was ineffective (entry 1). THF was found to be a superior solvent for the cyclization reaction (entry 4). Use of TBDMS group as a hydroxyl protecting group instead of MOM group, which was used in the previous synthesis of (+)-azimine,11 improved the yield of the desired cyclized product 3 from 61% to 88%. Relative stereochemistry of the cis-products was confirmed by an NOE experiment. In contrast, it was assumed that a trans-2,6-disubstituted piperidine backbone could be obtained when the precursor containing a relatively bulky protecting group at the terminal alcohol was used.14 Cyclization of precursor 6c gave a 1:1 mixture of cis- and trans-piperidine products with a 62% yield (entry 5). Cyclization of 6b gave the trans-2,6-piperidine with high selectivity, although the yield was relatively low, probably due to the steric hindrance (entry 6).

Construction of cis-2,6-disubstitued piperidine backbone described above was assumed to proceed via the transition state A shown in Figure 2, in which the chelation effect between palladium and allylic hydroxyl group was thought to be crucial as in our previous synthesis of (-)-cassine.10 In the construction of the trans-2,6-disubstituted piperidine backbone, the transition state B exhibiting the chelation effect between the palladium and oxygen of the acyl carbonyl would be favorable to transition state C, probably due to 1,3-diaxial repulsion.

Finally, synthesis of 1 was completed according to the route shown in Scheme 3. Cross-metathesis of 3 and tetradec-13-en-2-one 5 using a second generation Grubbs catalyst15 proceeded under reflux to give 10 as a mixture of E/Z isomers (E:Z = 10:1). Deprotection of the TBDMS- and Boc-groups by treatment with conc. HCl followed by catalytic hydrogenation yielded (+)-spectaline (1) without difficulty. Thus, synthesis of 1 was accomplished by 10 step reactions with a 31% total yield. The optical rotation of synthetic 1 was consistent with those reported for natural and synthetic 1. The 1H and 13C NMR spectra of synthetic 1 were also in good agreement with the reported values.

EXPERIMENTAL
General Methods. 1H NMR spectra were recorded in CDCl3 on agilent UNITY INOVA 400 NB or Bruker AM-300 spectrometers. Chemical shifts are expressed in ppm relative to tetramethylsilane (0.00 ppm). The coupling constants are given in Hz. 13C NMR spectra were recorded on the same spectrometers at 100 or 75 MHz, using the central resonance of CDCl3 (δC 77.0 ppm) as the internal reference. High-resolution mass spectra (HRMS) were obtained on a Shimadzu GC mate II (EI and CI). Optical rotations were determined with a HORIBA SEPA-300 polarimeter.

(2S,3S)-2-[N-(tert-Butoxycarbonyl)amino]-3-(tert-butyldimethylsilyloxy)hex-5-ene: To a solution of 7 (1.42 g, 6.62 mmol) in DMF (30 mL) was added TBDMSCl (1.10 g, 7.28 mmol) and imidazole (451 mg, 9.93 mmol). The mixture was stirred for 16 h at room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 20:1) to give silyl ether as a colorless oil (2.12 g, 97%). 1H NMR (400 MHz, 10:1 mixture of two diastereomers,17 major isomer) δ: 0.07 (6H, s), 0.91 (9H, s), 1.10 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 2.14-2.21 (1H, m), 2.23-2.30 (1H, m), 3.57-3.60 (1H, m), 3.73-3.76 (1H, m), 4.47 (1H, brd, J = 8.8 Hz), 5.04-5.09 (2H, m), 5.72-5.83 (1H, m); 13C NMR (100 MHz) δ: -4.7, -4.2, 18.1, 18.8, 25.9, 28.4, 39.2, 48.3, 74.9, 78.9, 117.6, 134.3, 155.5; HRCIMS [M+H]+: Found, 330.2467. Calcd. for C17H36NO3Si: 330.2465.

(2S,3S)-2-[N-(tert-Butoxycarbonyl)amino]-3-(tert-butyldiphenylsilyloxy)hex-5-ene: 3.88 g (99%) of TBDPS ether was obtained from 1.86 g (8.64 mmol) of 7 as described above. 1H NMR (300 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 1.08 (9H, s), 1.11 (3H, d, J = 6.8 Hz), 1.46 (9H, s), 2.04-2.12 (1H, m), 2.20-2.30 (1H, m), 3.57-3.60 (1H, m), 3.74-3.79 (1H, m), 4.76-4.91 (3H, m), 5.50-5.59 (1H, m), 7.35-7.46 (6H, m), 7.67-7.71 (4H, m); 13C NMR (75 MHz) δ: 19.2, 19.5, 27.1, 28.4, 38.9, 48.0, 76.4, 78.9, 117.8, 127.5, 127.66, 129.67, 129.8, 133.1, 133.7, 134.1, 135.87, 135.93, 155.5; HRCIMS [M+H]+: Found, 454.2775. Calcd. for C27H40NO3Si: 454.2778.

(2S,3S)-2-[N-(tert-Butoxycarbonyl)amino]-3-(tert-butyldimethylsilyloxy)hexan-6-ol (8a): To a solution of above ether (2.12 g, 6.42 mmol) in THF (30 mL) was added 9-BBN (0.5 mol/L in THF, 25.7 mL, 12.8 mmol) at 0 oC under an argon gas atmosphere. The mixture was stirred for 6 h at room temperature and quenched with 3 mol/L NaOH (40 mL). Aqueous H2O2 (30%, 15 mL) was added at 0 oC and the mixture was stirred for 14 h at room temperature. The resultant mixture was diluted with H2O and the whole was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 5:1) to give 8a as a colorless oil (1.92 g, 86%). 1H NMR (400 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 0.08 (6H, s), 0.90 (9H, s), 1.12 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 1.57-1.61 (4H, m), 3.55-3.68 (4H, m), 3.75-3.79 (1H, m), 4.65 (1H, brd, J = 9.2 Hz); 13C NMR (100 MHz) δ: -4.7, -4.3, 18.0, 18.6, 25.9, 28.4, 28.7, 30.3, 48.3, 62.6, 74.9, 79.1, 155.8; HRCIMS [M+H]+: Found, 348.2574. Calcd. for C17H38NO4Si: 348.2570.

(2S,3S)-2-[N-(tert-Butoxycarbonyl)amino]-3-(tert-butyldiphenylsilyloxy)hexan-6-ol (8b): 3.11 g (77%) of 8b was obtained from 3.88 g (8.56 mmol) of above TBDPS ether. 1H NMR (400 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 1.07 (9H, s), 1.14 (3H, d, J = 6.8 Hz), 1.22-1.39 (3H, m), 1.46 (9H, s), 1.54-1.61 (2H, m), 3.31 (1H, m), 3.56-3.58 (1H, m), 3.79 (1H, m), 4.77 (1H, brd, J = 9.6 Hz), 7.27-7.46 (6H, m), 7.67-7.69 (4H, m); 13C NMR (100 MHz) δ: 19.2, 19.6, 27.1, 28.37, 28.43, 30.2, 48.2, 62.3, 76.5, 79.2, 127.5, 127.6, 127.7, 129.7, 129.9, 133.2, 134.3, 135.89, 135.94, 156.0; HRCIMS [M+H]+: Found, 472.2876. Calcd. for C27H42NO4Si: 472.2883.

(6S,7S)-Ethyl 7-[N-(tert-butoxycarbonyl)amino]-6-(tert-butyldimethylsilyloxy)oct-2-enonate (9a): A solution of 8a (1.92 g, 5.51 mmol) and AZADO (8.4 mg, 0.055 mmol) in CH2Cl2 (20 mL) was added PhI(OAc)2 (2.66 g, 8.27 mmol). The mixture was stirred for 1 h at room temperature and the reaction mixture was diluted with ether and quenched with saturated aqueous NaHCO3, followed by a saturated aqueous Na2S2O3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was roughly purified by silica gel column chromatography (hexane/EtOAc = 10:1). The product was used for the next step without further purification. Triethyl phosphonoacetate (1.3 mL, 6.1 mmol) was added to a suspension of NaH (264 mg, 6.61 mmol) in THF (20 mL) at 0 oC under an argon gas atmosphere. After stirring for 30 min, a solution of the product obtained above was dissolved in THF (10 mL). The mixture was stirred for 2 h at the same temperature, and the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 20:1) to give 9a as a colorless oil (1.26 g, 55%, 2 steps). 1H NMR (400 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 0.07 (3H, s), 0.08 (3H, s), 0.90 (9H, s), 1.11 (3H, d, J = 6.8 Hz), 1.28 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 1.50-1.59 (2H, m), 2.17-2.24 (2H, m), 3.59 (1H, m), 3.75 (1H, m), 4.18 (2H, q, J = 7.2 Hz), 4.60 (1H, brd, J = 10.0 Hz), 5.82 (1H, dt, J = 15.7, 1.6 Hz), 6.93 (1H, dt, J = 15.5, 6.9 Hz); 13C NMR (100 MHz) δ: -4.6, -4.3, 14.2, 18.0, 18.3, 25.8, 28.1, 28.4, 32.3, 48.4, 60.1, 74.1, 79.0, 121.4, 148.5, 155.5, 166.5; HRCIMS [M+H]+: Found, 416.2834. Calcd. for C21H42NO5Si: 416.2832.

(6S,7S)-Ethyl 7-[N-(tert-butoxycarbonyl)amino]-6-(tert-butyldiphenylsilyloxy)oct-2-enonate (9b): 2.17 g (61%, 2 steps) of 9b was obtained from 3.11 g (6.59 mmol) of 8b. 1H NMR (400 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 1.06 (9H, s), 1.12 (3H, d, J = 6.8 Hz), 1.27 (3H, t, J = 7.0 Hz), 1.39-1.45 (1H, m), 1.45 (9H, s), 1.61-1.64 (1H, m), 1.88-1.90 (1H, m), 2.06 (1H, m), 3.56 (1H, m), 3.75 (1H, m), 4.14 (2H, q, J = 7.1 Hz), 4.71 (1H, brd, J = 8.8 Hz), 5.55 (1H, d, J = 16.0 Hz), 6.61 (1H, td, J = 15.1, 7.4 Hz), 7.39-7.45 (6H, m), 7.66-7.68 (4H, m); 13C NMR (100 MHz) δ: 14.2, 19.0, 19.5, 27.0, 27.1, 28.3, 28.4, 32.4, 48.2, 60.1, 75.8, 79.1, 121.3, 127.57, 127.64, 127.7, 129.8, 129.9, 132.9, 134.0, 135.8, 135.9, 148.1, 155.6, 166.5; HRCIMS [M+H]+: Found, 540.3149. Calcd. for C31H46NO5Si: 540.3145.

(6S,7S)-7-[N-(tert-Butoxycarbonyl)amino]-6-(tert-butyldimethylsilyloxy)oct-2-en-1-ol (6a): To a solution of 9a (1.26 g, 3.02 mmol) in CH2Cl2 (30 mL) was added DIBAL-H (1.0 mol/L in hexane, 6.6 mL, 6.6 mmol) at -78 oC under an argon gas atmosphere. After stirring for 15 min, the reaction was quenched with MeOH. The mixture was warmed to room temperature and filtered through celite and silica gel layer, and the filtrate was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 5:1) to afford 6a (1.12 g, 99%) as a colorless oil, 1H NMR (400 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 0.07 (6H, s), 0.90 (9H, s), 1.10 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 1.50-1.66 (3H, m), 2.01-2.13 (2H, m), 3.54-3.58 (1H, m), 3.75-3.78 (1H, m), 4.02-4.10 (2H, m), 4.67 (1H, brd, J = 8.8 Hz), 5.58-5.69 (2H, m); 13C NMR (100 MHz) δ: -4.6, -4.3, 18.1, 18.6, 25.9, 28.2, 28.4, 33.3, 48.3, 63.5, 74.8, 79.1, 129.5, 132.6, 155.6; HREIMS [M]+: Found, 373.2640. Calcd. for C19H39NO4Si: 373.2648.

(6S,7S)-7-[N-(tert-Butoxycarbonyl)amino]-6-(tert-butyldiphenylsilyloxy)-1-(4-phenylbenzoyloxy)oct-2-ene (6b): 1.96 g (98%) of alcohol as above was obtained from 2.17 g (4.02 mmol) of 9b as described above. 1H NMR (300 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 1.06 (9H, s), 1.12 (3H, d, J = 6.4 Hz), 1.46 (9H, s), 1.55-1.60 (3H, m), 1.80-1.84 (2H, m), 3.52-3.55 (1H, m), 3.77 (1H, m), 3.91 (2H, d, J = 5.4 Hz), 4.80 (1H, brd, J = 9.3 Hz), 5.23-5.31 (1H, m), 5.35-5.42 (1H, m), 7.39-7.45 (6H, m), 7.66-7.69 (4H, m); 13C NMR (75 MHz) δ: 19.2, 19.6, 27.1, 27.9, 28.4, 33.2, 48.2, 63.5, 76.3, 79.2, 127.5, 127.7, 129.4, 129.7, 129.8, 132.2, 133.1, 135.9, 136.0, 155.7; HRCIMS [M+H]+: Found, 498.3032. Calcd. for C29H44NO4Si: 498.3040. To a solution of the alcohol (1.96 g, 3.95 mmol) in pyridine (15 mL) were added 4-phenylbenzoyl chloride (1.28 g, 5.93 mmol) and DMAP (965 mg, 7.90 mmol) at 0 oC. The mixture was stirred for 16 h at room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 20:1) to give 6b as a colorless oil (1.07 g, 40%). 1H NMR (300 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 1.06 (9H, s), 1.13 (3H, d, J = 7.2 Hz), 1.39-1.50 (1H, m), 1.46 (9H, s), 1.60-1.63 (1H, m), 1.84 (1H, m), 1.94 (1H, m), 3.58 (1H, m), 3.76 (1H, m), 4.61 (2H, d, J = 3.2 Hz), 4.75 (1H, brd, J = 9.6 Hz), 5.41-5.43 (2H, m), 7.35-7.49 (9H, m), 7.62-7.68 (8H, m), 8.08-8.10 (2H, m); 13C NMR (75 MHz) δ: 19.1, 19.6, 27.1, 27.9, 28.4, 33.1, 48.2, 65.5, 75.8, 79.0, 124.1, 127.0, 127.3, 127.5, 127.7, 128.1, 128.9, 129.1, 129.7, 129.9, 130.1, 133.1, 135.2, 135.9, 136.0, 140.0, 145.6, 155.7, 166.2; HRCIMS [M+H]+: Found, 678.3607. Calcd. for C42H52NO5Si: 678.3615.

(6S,7S)-7-[N-(tert-Butoxycarbonyl)amino]-6-(tert-butyldiphenylsilyloxy)-1-(2’,4’,6’-trimethylbenzo-yloxy)oct-2-ene (6c): Yield; 69 mg (62%). 1H NMR (300 MHz, 10:1 mixture of two diastereomers, major isomer) δ: 1.06 (9H, s), 1.12 (3H, d, J = 6.6 Hz), 1.45 (9H, s), 1.57 (1H, m), 1.80-1.89 (3H, m), 2.24 (6H, s), 2.27 (3H, s), 3.55 (1H, m), 3.74 (1H, m), 4.58 (2H, d, J = 4.8 Hz), 4.73 (1H, brd, J = 9.3 Hz), 5.39-5.41 (2H, m), 6.83 (2H, s), 7.35-7.46 (6H, m), 7.65-7.68 (4H, m); 13C NMR (75 MHz) δ: 19.2, 19.6, 19.7, 21.1, 27.1, 27.9, 28.37, 28.42, 29.7, 33.2, 48.1, 65.3, 70.6, 75.9, 79.0, 123.9, 127.5, 127.6, 127.7, 128.3, 129.7, 129.9, 130.9, 133.1, 134.2, 135.1, 135.9, 136.0, 139.2, 155.7, 169.8; HREIMS [M]+: Found, 643.3700. Calcd. for C39H53NO5Si: 643.3693.

(2S,3S,6S)-N-(tert-Butoxycarbonyl)-3-(tert-butyldimethylsilyloxy)-2-methyl-6-vinylpiperidine (3): A solution of 6a (129 mg, 0.345 mmol) in THF (5 mL) was treated with PdCl2 (5.4 mg, 0.030 mmol) at 0 oC under an argon gas atomosphere. After stirring for 1 day at room temperature, the reaction mixture was filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 20:1) gave 3 (108 mg, 88%) as a colorless oil. [α]25D –37 (c 0.70, CHCl3); 1H NMR (300 MHz) δ: 0.06 (6H, s), 0.88 (9H, s), 1.09 (3H, d, J = 6.8 Hz), 1.43-1.52 (1H, m), 1.46 (9H, s), 1.65-1.78 (2H, m), 1.89-1.92 (1H, m), 3.68-3.74 (1H, m), 4.27-4.32 (1H, m), 4.61 (1H, brs), 5.06 (1H, ddd, J = 10.6, 1.8, 1.2 Hz), 5.12 (1H, td, J = 17.4, 1.6 Hz), 5.90 (1H, ddd, J = 17.4, 10.6, 5.4 Hz); 13C NMR (75 MHz) δ: -4.9, -4.7, 13.7, 18.1, 24.0, 25.8, 26.2, 28.5, 50.1, 51.7, 70.3, 79.5, 114.4, 140.1, 155.2; HRCIMS [M+H]+: Found, 356.2626. Calcd. for C19H38NO3Si: 356.2621. NOE correlation was observed between methyl group at C-2 position and methine proton of vinyl group at C-6 position.

(2S,3S,6R)-N-(tert-Butoxycarbonyl)-3-(tert-butyldiphenylsilyloxy)-2-methyl-6-vinylpiperidine (4): Treatment of 6b (58 mg, 0.085 mmol) with PdCl2 (1.5 mg, 0.0085 mmol) gave 11 mg (27%) of 4 as a colorless oil. 1H NMR (300 MHz) δ: 1.06 (9H, s), 1.22 (3H, d, J = 6.9 Hz), 1.41 (9H, s), 1.57-1.62 (2H, m), 1.67-1.81 (2H, m), 3.70-3.77 (1H, m), 4.31 (1H, m), 4.51 (1H, brs), 5.03-5.06 (1H, m), 5.07-5.12 (1H, m), 5.88 (1H, ddd, J = 17.4, 10.5, 5.1 Hz), 7.34-7.46 (6H, m), 7.64-7.69 (4H, m); 13C NMR (75 MHz) δ: 14.0, 19.2, 23.6, 25.9, 26.9, 28.4, 29.7, 50.3, 51.4, 71.2, 79.4, 114.4, 127.5, 127.7, 129.6, 129.7, 133.8, 134.5, 135.70, 135.74, 140.1, 155.1; HREIMS [M]+: Found, 479.2851. Calcd. for C29H41NO3Si: 479.2856.

(1’EZ,2S,3S,6S)-3-Hydroxy-2-methyl-6-(13’-oxotetradec-1’-en-1’-yl)piperidine (10): To a solution of 3 (36 mg, 0.10 mmol) and tetradec-13-en-2-one (129 mg, 0.613 mmol) in CH2Cl2 (5.0 mL) was added Grubbs 2nd catalyst (17 mg, 0.020 mmol). After stirring for 1 day under reflux, an additional solution of Grubbs 2nd catalyst in CH2Cl2 (17 mg, 0.020 mmol) was added. After stirring for 1 day under reflux, the solvent was removed and the residue was roughly purified by silica gel column chromatography (hexane/EtOAc = 20:1). The product was used for next step without further purification. The product was dissolved in MeOH (5 mL) and 12 mol/L HCl (0.5 mL) was added. After stirring for 12 h, the reaction was quenched with saturated aqueous NaHCO3. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (CHCl3/MeOH = 5:1) to give 10 (33 mg, 79%, 2 steps, E:Z = 10:1) as a yellowish oil. 1H NMR (400 MHz, major isomer) δ: 1.14 (3H, d, J = 6.4 Hz), 1.26-1.39 (10H, m), 1.43-1.56 (9H, m), 1.89-1.93 (1H, m), 1.96-2.01 (2H, m), 2.14 (3H, s), 2.42 (2H, t, J = 7.6 Hz), 2.79 (1H, qd, J = 6.6, 1.6 Hz), 3.07-3.12 (1H, m), 3.53 (1H, brs), 5.39 (1H, dd, J = 15.4, 7.4 Hz), 5.54-5.61 (1H, m); 13C NMR (100 MHz) δ: 18.6, 23.8, 26.4, 29.1, 29.2, 29.3, 29.36, 29.43, 29.5, 29.9, 31.8, 32.3, 43.8, 55.6, 59.5, 67.4, 131.4, 132.7, 209.4; HREIMS [M]+: Found, 323.2828. Calcd. for C20H37NNO2: 323.2824.

(+)-Spectaline (1). Pd-C (3.3 mg) was added to a solution of 10 (33 mg, 0.10 mmol) in CH2Cl2 (0.2 mL) and then MeOH (1 mL) was added under hydrogen gas atmosphere. After being stirred for 30 min, the mixture was filtered and concentrated to afford 1 (33 mg, quant.) as a yellowish oil, [α]26D +11 (c 0.45, CHCl3), {natural (+)-spectaline,5 [α]25D +8.0 (c 0.27, CHCl3)}; 1H NMR (400 MHz) δ: 1.10 (3H, d, J = 6.4 Hz), 1.26-1.32 (20H, m), 1.45-1.58 (5H, m), 1.87-1.92 (1H, m), 2.14 (3H, s), 2.42 (2H, d, J = 7.4 Hz), 2.51-2.55 (1H, m), 2.76 (1H, qd, J = 6.4, 1.4 Hz), 3.55 (1H, brs); 13C NMR (100 MHz) δ: 18.4, 23.8, 25.8, 25.9, 29.2, 29.4, 29.4, 29.5, 29.6, 29.8, 29.8, 32.0, 36.7, 43.8, 55.8, 57.2, 67.9, 209.5; HREIMS [M]+: Found, 325.2984. Calcd. for C20H39NO2: 325.2981.

SUPPORTING INFORMATION
Synthetic procedure of 11 and 1H NMR data of 10 and 11.

ACKNOWLEDGEMENTS
We thank NISSAN CHEMICAL INDUSTRIES, LTD. for providing AZADO. We also thank Ms. C. Teruya of Kyoto Pharmaceutical University for obtaining the Mass spectra. We would like to acknowledge the technical assistance of Mr. Kouji Ohnishi of Kyoto Pharmaceutical University.

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