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A facile synthetic route to (+)-allosedamine via hydrolytic kinetic resolution and olefin metathesis
Tetrahedron 60 (2004) 7353–7359
A facile synthetic route to (1)-allosedamine via hydrolytic kinetic resolution and olefin metathesis Byungman Kang and Sukbok Chang* Department of Chemistry and School of Molecular Science (BK21), Center for Molecular Design and Synthesis (CMDS), Korea Advanced Institute of Science and Technology (KAIST), 373-1, Kusong-dong, Yusong-gu, Daejeon 305-701, South Korea Received 10 March 2004; revised 22 May 2004; accepted 24 May 2004 Available online 10 June 2004 This paper is dedicated to Professor Robert H. Grubbs of California Institute of Technology on the occasion of his receiving the Tetrahedron Prize
Abstract—A concise synthesis of (þ)-allosedamine has been achieved using cobalt-catalyzed hydrolytic kinetic resolution (HKR) and ruthenium-catalyzed ring closing metathesis (RCM) as two key steps, in which HKR was used to introduce both stereogenic centers in the natural compound with a high degree of diastereomeric ratio and cyclization was carried out with the well developed RCM procedure. q 2004 Elsevier Ltd. All rights reserved.
1. Introduction Lobelia inflata, also known as Indian tobacco, has been used for the treatment of some respiratory illnesses by American settlers. It was later found that a family of piperidine alkaloids including lobeline, lobelanine, lobelanidine and allosedamine are responsible for the therapeutic effects (Fig. 1).1 Extracts of the plants have been also used for the treatment of narcotic poisoning, coal gas asphyxia, pneumonia and control of anxiety, and it has been revealed that the continual doses of its extracts cause a various side effects.2
synthesis of sedamine alkaloid in racemic3 and optically active form,4 facile and direct application of the approaches on synthesis of allosedamine turned out to be difficult in most cases.5 For example, whereas an elegant recent strategy described by Cossy et al. for the synthesis of (þ)sedamine is based on the enantioselective allyltitanation of an aldehyde precursor by chiral titanium complex followed by ring-closing metathesis to provide a N-heterocyclic system,4c Lebreton’s route for the preparation of (2)allosedamine relies on Brown’s asymmetric allylation and subsequent electrophilic cyclization.5e
2. Results and discussion
Figure 1. Lobelia alkaloids.
We were particularly interested in the development of an efficient asymmetric synthetic route of allosedamine and its diastereomeric isomer (sedamine) among those alkaloids. While numerous approaches have been reported for the Keywords: Allosedamine; Total synthesis; Hydrolytic kinetic resolution; Ring-closing metathesis. * Corresponding author. Tel.: þ82-428692841; fax: þ82-428692810; e-mail address: [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.05.054
One of the most distinguishing structural features of (þ)allosedamine is the fact that it contains a secondary free benzylic hydroxy group and a piperidine moiety. At the outset of our studies, it was anticipated that both of two stereogenic centers located at b-position each other could be readily introduced by asymmetric catalysis. Our synthetic approach for (þ)-allosedamine relies on two metalcatalyzed reactions; hydrolytic kinetic resolution (HKR) and ring-closing metathesis (RCM) (Scheme 1).6 Inversion of a hydroxyl group-containing stereogenic center at homoallylic position was envisioned to be another key step for the success in this strategy. (þ)-Styrene oxide 1 was chosen as a starting material for providing a stereogenic center at benzylic position because it is readily available in multi gram scale via a hydrolytic kinetic resolution of racemic styrene oxide.7 As shown in Scheme 2, regioselective ring opening of
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Scheme 1. Retrosynthetic analysis of (þ)-allosedamine.
Scheme 2. Construction of two stereogenic centers.
(þ)-styrene oxide 18 was most efficiently achieved by using cuprate reagents derived from tetravinyltin in THF among a variety of conditions examined leading to a homoallylic alcohol 2a.9 Employment of other sources of vinyl group or use of different solvents resulted in much lower selectivities for the desired secondary alcohol. For example, when vinylmagnesium bromide was used in the presence of Cu(I) salt,10 almost equal ratio of primary versus secondary alcohol isomer was generated albeit with higher combined yields. In addition, when vinyl bromide was utilized in combination with t-BuLi and CuCN, no desired product was obtained from the reaction. It was expected at the beginning that a directed epoxidation of homoallylic alcohol 2a would be possible giving practically acceptable diastereoselectivity under certain conditions. Some precedent examples demonstrate that either peroxy acids alone or peracids in combination with Table 1. Attempts of directed epoxidation of homoallylic alcohol 2a
Entry 1 2 3 4 5 6 a b
Reaction conditionsa
Yield (%, 3a:3b)b
MPPA, NaOH (1 M), rt MPPA, CH2Cl2, 0 8C to rt MPPA, THF, 0 8C to rt m-CPBA, CH2Cl2, 0 8C to rt Mo(CO)6, TBHP, C6H6, rt VO(acac)2, TBHP, C6H6, rt
NR 80 (1:1) 63 (1:1) 94 (1.1:1) 51 (1.2:1) 42 (2.8:1)
MPPA: monoperoxyphthalic acid, m-CPBA: 3-chloroperbenzoic acid, TBHP: t-butyl hydroperoxide. Combined yields, and ratios were determined by 1H NMR integration of the crude reaction mixture.
certain transition metal species provide high degree of directing effects in the epoxidation of homoallylic alcohols.11 This directed epoxidation is presumed to be operated mainly via hydrogen bonding interactions between the hydroxyl group of substrates and peroxy acids or peracids leading to syn epoxy alcohols. As shown in Table 1, a directed epoxidation of 2a was examined under various conditions on the basis of the reported procedures. In reality, no measurable diastereoselective induction was observed when the epoxidation of 2a was carried out with peracid or peroxide in the absence of metal species (entries 1– 4). While almost no selectivity was also observed in the presence of a Mo catalyst (entry 5), slightly improved selectivity was induced with the use of a vanadium catalyst albeit in lower yield (entry 6). The unexpectedly low diastereoselectivity would be probably derived from weak hydrogen bonding interactions between peracid oxygen and homoallylic alcohol 2a. This result led us to employ a twostep pathway for the preparation of an optically active epoxy alcohol 3a from 2a: non-selective epoxidation of 2a with m-CPBA and subsequent kinetic resolution of the resulting epoxy alcohol moiety. Protection of free hydroxyl group of 3a/3b was carried out in high yield (95%) with chloromethyl methyl ether in CH2Cl2 at 0 8C giving the corresponding MOM ethers 4a/4b in the same ratio.12 In order to perform a kinetic resolution of the diastereomeric epoxide mixture 4a/4b, Jacobsen’s (R,R)-(2)-Co(salen) catalyst (5) was employed under the optimized conditions.7 Treatment of a mixture of 4a/4b (,1:1) with 5 (1 mol%), acetic acid (4 mol%), and H2O (0.55 equiv.) in THF at room temperature provided 4a in 44% yield with .98% de. In the resolution reaction, diol 6 was isolated in 47% yield as a single diastereomer
B. Kang, S. Chang / Tetrahedron 60 (2004) 7353–7359
determined by 1H NMR. It is noteworthy that synthetic utility of the ring-opened diol 6 could be readily found in other syntheses because it is highly functionalized compound with well-defined stereochemistry. Designation of the absolute stereochemistry in the resolved epoxide, (1S,3R)-4a, was ensured by comparing it with that of an authentic sample which was prepared independently by a literature procedure.4d Residual amounts of the used cobalt catalyst in the product was completely removed by the use of pyridinium p-toluene sulfonate (PPTS) during workup processes.7c It should be particularly mentioned that the present synthetic route can be also applied to the synthesis of optically active sedamine, a diastereomer of allosedamine by the choice of the Jacobsen’s Co catalyst. With the use of (S,S)-(þ)-Co(salen) catalyst instead of (R,R)-isomer, a diastereomeric epoxide 4b would be obtained with the same efficiency and selectivity eventually leading to (2)sedamine. It should be mentioned that this synthetic route uses two resolution reactions to obtain the key epoxide intermediate 4a starting from a readily available racemic styrene epoxide. Both resolutions proceed with an excellent selectivity under mild conditions making the present synthesis highly efficient and practical. Epoxide opening of an oxirane 4a with vinyl Grignard reagent underwent smoothly in the presence of copper additives in THF affording another homoallylic alcohol 7 in 70% yield (Scheme 3). Initially, the Mitsunobu’s inversion protocol was investigated to introduce the required amino group at the homoallylic position using allylamine and its derivatives as a nucleophile.13 However, a variety of attempts with several amino groups were unsuccessful presumably because of steric hindrance around the alcohol substrate. This led us to employ a two-step alternative: conversion of the homoallyl alcohol 7 into its corresponding mesylate followed by amination with methylamine to provide an amino ether adduct 8 (43% over two steps). The fact that configuration of the free hydroxyl containing carbon in 7 was completely inverted in the substituted product 8 was readily confirmed by 1H NMR. Allylation of
Scheme 3. Final stages in the synthesis of (þ)-allosedamine.
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the secondary amino moiety 8 was carried out efficiently under normal conditions to afford a dienyl compound 9, a precursor for ring-closing metathesis. Efficiency of the ring-closing metathesis reaction of 9 was examined with the use of several catalyst systems under various conditions.14 The best result was obtained when diene 9 was reacted with the Grubbs’ second generation catalyst (Im)Cl2PCy3RuCHPh 10 (10 mol%) in benzene under N2 atmosphere to generate an olefinic piperidine moiety in 54% yield. Other ruthenium carbene catalysts gave a rather reduced activity and lower yields under otherwise same conditions; Cl2(PCy3)2RuCHPh (40%) and (3-bromopyridine)2Cl2(Im)RuCHPh (47%).15 No significant improvement was observed when the cyclization was carried out under ethylene atmosphere instead of N2. In addition, when ammonium salts of diolefinic amine 9 were subjected to the metathesis conditions, noticeable improvements in chemical yields were not observed compared to free amino substrate 9. For example, RCM of ammonium salts of 9 of trifluoroacetic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid afforded the cyclized product in 54, 43, and 43% isolated yields under identical conditions, respectively.16 While tandem hydrogenation of the olefinic intermediate into a saturated piperidine adduct 11 was initially tried in the absence of additional metal catalysts,17 no desired activity of the ruthenium carbene precursor was observed for the reduction step. This led us to use another one-pot procedure: addition of platinum oxide catalyst (0.1 equiv.) after the metathesis reaction for the subsequent hydrogenation.18 Hydrogenation underwent almost quantitatively in the presence of PtO2 catalyst giving a protected allosedamine 11 in 52% yield (two steps starting from 9). To remove the residual ruthenium by products from the product, various known purification procedures were examined.19 Whereas simple silica gel column chromatography left significant amounts of residual ruthenium in the desired product, treatment of the crude reaction mixture with either lead tetraacetate (1.5 equiv. to catalyst)19a or tris(hydroxymethylphosphine) (100 equiv. to catalyst)19b
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resulted in only marginal improvement in purity and brown color was still seen from the isolated product. Most effective removal of ruthenium residues from the reaction mixture was achieved according to a recently published protocol, in which the reaction mixture was treated with activated charcoal (50 equiv. to the crude product in wt)19c for 12 h followed by a silica gel column chromatography. Subsequent deprotection of MOM group by conc. HCl in acetonitrile12 provided (þ)-allosedamine 12 in high yield, spectral data of which are identical to those of the reported literature ones.5 3. Conclusion A concise synthesis of (þ)-allosedamine has been achieved using cobalt-catalyzed hydrolytic kinetic resolution (HKR) and ruthenium-catalyzed ring closing metathesis (RCM) as two key steps. HKR was used to introduce both stereogenic centers in the natural compound with a high degree of diastereomeric ratio. Cyclization was carried out with the well-developed RCM procedure and the desired piperidine moiety was isolated after tandem hydrogenation in one-pot. With the present synthetic approach, optically active sedamine, a diastereomeric isomer of allosedamine, could be also readily accessed by a simple choice of enantiomeric cobalt catalyst via HKR. 4. Experimental 4.1. General methods Oxygen or moisture sensitive reactions were conducted in oven- or flame-dried glassware under nitrogen. Unless otherwise specified, materials were purchased from commercial supplier and used without further purification. Solvents were dried and purified prior to use. Benzene, acetonitrile, and dichloromethane were distilled from calcium hydride under argon or nitrogen atmosphere. THF was distilled from sodium metal and benzophenone. Analytical thin layer chromatography (TLC) was performed on Merck precoated silica gel 60 F254 plates. Purification by column chromatography was carried out using silica gel 60 (230 – 400 mesh, ASTM, Merck). Proton nuclear magnetic resonance spectra were recorded on a Bruker AVANCE 400 (400 MHz) spectrometer. Chemical shifts are reported in delta (d) units, parts per million (ppm) downfield from internal standard (tetramethylsilane), or in ppm relative to the singlet at 7.26 ppm of chloroform-d1. Splitting patterns are designated as follows: s; singlet, d; doublet, t; triplet, q; quintet, m; multiplet, dd; doublet of doublet, ddd; doublet of doublet of doublet, bs; broad singlet. HRMS spectra were recorded on a VG AUTOSPEC ULTIMA spectrometer. 4.1.1. (1S)-1-Phenylbut-3-en-1-ol (2a). A solution of tetravinyltin (0.46 mL, 2.45 mmol) in THF (7 mL) was cooled to 0 8C and methyllithium (1.4 M in Et2O, 6.1 mL, 8.57 mmol) was added. The colorless solution was stirred for 1 h and cooled to 278 8C. To a stirred heterogeneous solution of CuCN (392 mg, 4.37 mmol) in THF (2 mL), the colorless vinyllithium solution was added dropwise via
cannula at 278 8C. The mixture was allowed to warm slowly to 230 8C with stirring and then a heterogeneous solution changed into a homogeneous yellow solution. After cooling to 278 8C, a solution of (þ)-styrene oxide (0.20 mL, 1.75 mmol) in THF (1 mL) was added dropwise to the above solution. After stirring for 2 h at 230 8C, the mixture was allowed to warm slowly to room temperature. The reaction was quenched by addition of saturated NH4Cl and filtered through celite. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude residue was purified on silica gel (EtOAc/ n-hexane, 1:5) to afford 2a as a colorless oil (137 mg, 53%): Rf¼0.52 (EtOAc/n-hexane, 1:3); [a]D¼250.2 (c 1.45, C6H6); IR (KBr) 3386, 1640, 1603, 1493, 1453 cm21; 1H NMR (400 MHz, CDCl3) d 2.09 (d, 1H, J¼3.3 Hz), 2.51 (m, 2H), 4.72 (m, 1H), 5.11 –5.17 (m, 2H), 5.80 (m, 1H), 7.24 – 7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) d 43.7, 73.2, 118.4, 125.8, 127.5, 128.4, 134.4, 143.8; HRMS (EI) calcd for C10H12O [Mþ] 148.0888, found 148.0899. 4.1.2. (1S)-2-Oxiranyl-1-phenylethanol (3a, 3b). The mixture of olefin 2a (500 mg, 3.37 mmol), m-chloroperbenzoic acid20 (983 mg, 4.38 mmol) in CH2Cl2 (12 mL) was stirred at 0 8C for 30 min. The mixture was stirred for 12 h at room temperature and was then diluted with dichloromethane. The organic phase was extracted with saturated NaHCO3 twice. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude residue was purified on silica gel (EtOAc/n-hexane, starting from 1/6 to 1/1) to afford product as a colorless oil (521 mg, 94%) with a diastereomeric ratio of 1:1 (3a:3b, determined by 1H NMR): Rf¼0.20 (EtOAc/ n-hexane, 1:3); IR (KBr) 3423, 1494, 1454, 1410 cm21. 3a: 1H NMR (400 MHz, CDCl3) d 1.90 (dd, 1H, J¼14.1, 6.5 Hz), 2.02 (dd, 1H, J¼9.5, 4.4 Hz), 2.48 (dd, 1H, J¼4.8, 2.8 Hz), 2.74 (t, 1H, J¼4.1 Hz), 2.99 (m, 1H), 4.89– 4.96 (m, 1H), 7.25– 7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.3, 46.7, 49.8, 71.8, 125.5, 127.6, 128.5, 143.8. 3b: 1H NMR (400 MHz, CDCl3) d 1.80 (ddd, 1H, J¼14.4, 6.7, 3.5 Hz), 2.13 (ddd, 1H, J¼17.0, 9.0, 4.0 Hz), 2.59 (dd, 1H, J¼5.5, 3.5 Hz), 2.81 (t, 1H, J¼4.4 Hz), 3.16 (m, 1H), 4.89 – 4.96 (m, 1H), 7.25 – 7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.8, 46.9, 50.1, 72.7, 125.7, 127.7, 128.5, 144.1; HRMS (EI) calcd for C10H12O2 [Mþ] 164.0837, found 164.0836. 4.1.3. (1S)-Methoxymethyl-(2-oxiranyl-1-phenylethyl)ether (4a, 4b). To a solution of a mixture of alcohol 3a and 3b (506 mg, 3.08 mmol) in CH2Cl2 (8 mL) at 0 8C were added diisopropylethylamine (2.15 mL, 12.3 mmol), chloromethyl methyl ether (0.70 mL, 9.24 mmol). After being stirred at room temperature for 6 h, the resulting mixture was diluted with dichloromethane and quenched with water. The aqueous phase was extracted with dichloromethane. The combined extracts were washed with brine, dried over MgSO4, and filtered. Removal of solvent left an oil which was purified by column chromatography (EtOAc/n-hexane, 1:9), affording product (604 mg, 95%) as a colorless oil: Rf¼0.55 (EtOAc/ n-hexane, 1:3); IR (KBr) 2925, 2887, 1494, 1454, 1408 cm21.
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4a: 1H NMR (400 MHz, CDCl3) d 1.91 (ddd, 1H, J¼14.0, 6.5, 5.0 Hz), 2.09 (m, 1H), 2.44 (dd, 1H, J¼5.0, 2.7 Hz), 2.70 (t, 1H, J¼4.1 Hz), 2.90 (m, 1H), 3.37 (s, 3H), 4.54 (s, 2H), 4.79 (t, 1H, J¼6.8 Hz), 7.25 –7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) d 40.9, 46.7, 49.6, 55.5, 75.7, 93.9, 126.8, 127.8, 128.5, 141.0. 4b: 1H NMR (400 MHz, CDCl3) d 1.80 (ddd, 1H, J¼14.1, 7.1, 3.9 Hz), 2.13 (m, 1H), 2.59 (dd, 1H, J¼5.0, 2.7 Hz), 2.81 (t, 1H, J¼4.0 Hz), 3.16 (m, 1H),3.38 (s, 3H), 4.56 (s, 2H), 4.84 (dd, 1H, J¼9.4, 3.8 Hz), 7.25– 7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.4, 47.5, 49.6, 55.6, 75.2, 94.0, 126.6, 127.9, 128.5, 141.4. 4.1.4. (1S,3R)-Methoxymethyl-(2-oxiranyl-1-phenylethyl)ether (4a). A 25 ml round bottom flask equipped with a stirring bar was charged with (R,R)-Co(salen) catalyst (5, 16.8 mg, 27.8 mmol). The catalyst was treated with a solution of 4a/4b mixture (,1:1, 580 mg, 2.78 mmol), acetic acid (6.4 mL, 111 mmol) in THF (0.2 mL). The solution was cooled to 0 8C, and H2O (27 mL, 1.53 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Pyridinium p-toluenesulfonate (28 mg, 4.0 equiv. based on catalyst) and 1 mL of CH3CN/CH2Cl2 (1:1, v/v) were added, and the reaction mixture was applied to a pad of silica gel. The pad was washed with EtOAc. After the mixture was concentrated under reduced pressure, the residue was purified on silica gel (EtOAc/n-hexane, 1:6) to afford 4a as a colorless oil (255 mg, 44%, 98% de based on the 1H NMR): [a]D¼2121.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.91 (ddd, 1H, J¼14.0, 6.5, 5.0 Hz), 2.09 (q, 1H, 7.0 Hz), 2.44 (dd, 1H, J¼4.9, 2.6 Hz), 2.70 (t, 1H, J¼4.1 Hz), 2.90 (m, 1H), 3.37 (s, 3H), 4.54 (s, 2H), 4.79 (t, 1H, J¼6.8 Hz), 7.25 –7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 40.9, 46.7, 49.6, 55.5, 75.7, 93.9, 126.8, 127.9, 128.5, 141.0; HRMS (EI) calcd for C12H16O3 [Mþ] 208.1099, found 208.1097. 4.1.5. (1S,3S)-1-Methoxymethoxy-1-phenylhex-5-en-3-ol (7). To a solution of CuBr/Me2S (246 mg, 1.2 mmol) in THF (4 mL) cooled to 230 8C was added vinyl magnesium bromide (3.6 mL, 3.6 mmol, 1.0 M in THF). The resulting mixture was allowed to warm slowly to 20 8C and a solution of epoxide 4a (250 mg, 1.2 mmol) in THF (2 mL) was added at 260 8C. After being stirred at 230 8C for 1 h, the mixture was allowed to warm slowly to room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with Et2O. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on silica gel (EtOAc/n-hexane, 1:6) to afford 7 as a colorless oil (198 mg, 70%): Rf¼0.42 (EtOAc/n-hexane, 1:3); [a]D¼2159.5 (c 1.0, CHCl3); IR (KBr) 3447, 2943, 1638 cm21; 1H NMR (400 MHz, CDCl3) d 1.81 (ddd, 1H, J¼14.4, 4.6, 2.4 Hz), 1.97 (m, 1H), 2.24 (m, 1H), 3.25 (d, 1H, J¼1.7 Hz), 3.39 (s, 3H), 3.83 (m, 1H), 4.45 (s, 2H), 4.84 (dd, 1H, J¼9.5, 4.7 Hz), 5.06 (d, 1H, J¼ 2.3 Hz), 5.10 (d, 1H, J¼7.0 Hz), 5.82 (m, 1H), 7.25 –7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.9, 44.1, 55.9, 70.3, 78.0, 93.7, 117.6, 126.8, 127.9, 128.5, 134.5, 140.9; HRMS (EI) calcd for C14H20O3 [Mþ] 236.1412, found 236.1462.
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4.1.6. (1S,3R)-(1-(2-(Methoxymethoxy)-2-phenylethyl)but-3-enyl)methylamine (8). To a solution of alcohol 7 (188 mg, 0.79 mmol) in CH2Cl2 (5 mL) at 0 8C were added triethylamine (0.22 mL, 1.59 mmol), methanesulfonylchloride (0.12 mL, 1.59 mmol). After 30 min, the mixture was diluted with dichloromethane, washed with brine, dried over MgSO4, and concentrated to afford the crude mesylate. The crude mesylate was taken up in a methanolic solution of methylamine (14.6 mL, 39.2 mmol, 2.0 M in MeOH). The resulting solution was heated to 70 8C for 12 h. After cooling to room temperature, the solution was concentrated. Then it was diluted with Et2O, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified on silica gel (starting from EtOAc/n-hexane, 1:3 to MeOH/CH2Cl2, 1:12) to afford 8 as a yellow oil (86 mg, two steps 43%): Rf¼0.67 (MeOH/CH2Cl2, 1:8); [a]D¼2123.0 (c 1.0, MeOH); IR (KBr) 3354, 2936, 1638, 1493, 1454 cm21; 1H NMR (400 MHz, CDCl3) d 1.76 (ddd, 1H, J¼14.0, 8.1, 4.5 Hz), 1.91 (ddd, 1H, J¼13.3, 8.9, 4.4 Hz), 2.11 (bs, 1H), 2.28 (m, 1H), 2.41 (s, 3H), 2.75 (m, 1H), 3.39 (s, 3H), 4.54 (s, 2H), 4.82 (dd, 1H, J¼8.8, 4.4 Hz), 5.11 (d, 1H, J¼11.9 Hz), 5.77 (m, 1H), 7.28– 7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 32.8, 37.6, 41.9, 55.1, 55.7, 75.4, 94.2, 117.4, 126.6, 127.5, 128.4, 134.9, 142.0; HRMS (EI) calcd for C15H23NO2 [Mþ] 249.1729, found 249.1716. 4.1.7. (1S,3R)-N-Allyl-(1-(2-(methoxymethoxy)-2phenylethyl)but-3-enyl)methylamine (9). To a solution of amine 8 (63 mg, 0.25 mmol) in acetonitrile (3 mL) was added powder K2CO3 (105 mg, 0.76 mmol). The mixture was stirred for 30 min at room temperature, and then allylbromide (32.8 mL, 0.38 mmol) was added. After stirring for 4 h at room temperature, the resulting mixture was diluted with Et2O and quenched with water. The aqueous phase was extracted with Et2O. The extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified on silica gel (EtOAc/ n-hexane, 1:5) to afford 9 as a pale yellow oil (66 mg, 90%): Rf¼0.57 (EtOAc/n-hexane, 1:3); [a]D¼2104.2 (c 1.0, CHCl3); IR (KBr) 2942, 1639, 1493, 1452 cm21; 1H NMR (400 MHz, CDCl3) d 1.64 (ddd, 1H, J¼14.4, 9.6, 3.4 Hz), 1.80 – 1.93 (m, 2H), 2.19 (s, 3H), 2.90 (m, 1H), 3.01 (dd, 1H, J¼13.7, 6.1 Hz), 3.11 (dd, 1H, J¼13.8, 6.1 Hz), 3.32 (s, 3H), 4.53 (dd, 2H, J¼14.8, 6.6 Hz), 4.85 (dd, 1H, J¼9.6, 3.3 Hz), 5.02 (d, 2H, J¼14.2 Hz), 5.04 (d, 1H, J¼17.2 Hz), 5.15 (dd, 2H, J¼12.9, 1.3 Hz), 5.79 (m, 2H), 7.28 – 7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 33.1, 36.1, 39.8, 55.5, 56.5, 59.1, 75.3, 94.5, 116.1, 126.6, 127.2, 128.3, 137.0, 137.1, 143.1; HRMS (EI) calcd for C18H27NO2 [Mþ] 289.2042, found 289.2036. 4.1.8. (2R)-2-((22)-2-(Methoxymethoxy)-2-phenylethyl)N-methylpiperidine (11). To a solution of diene 9 (178 mg, 0.61 mmol) in anhydrous benzene (28 mL) was added a solution of the Grubbs ruthenium catalyst (Im)Cl2PCy3RuCHPh (10, 52 mg, 0.06 mmol) in benzene (2 mL) at room temperature. The mixture was refluxed at 70 8C for 12 h. It was cooled to room temperature and was concentrated in vacuo. Then, to a solution of crude metathesis product in EtOAc (8 mL) was added PtO2 (14 mg, 0.06 mmol). After 1 h under H2 (1 atm), the mixture was filtered through celite and concentrated in vacuo. The crude residue in CH2Cl2 (5 mL) was added to a solution of
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activated charcoal (10.0 g, 50 equiv. wt of the crude product) in CH2Cl2 (95 mL) and stirred for 12 h. After the carbon was filtered, the filtrate was concentrated in vacuo and purified on a silica gel column chromatography (MeOH/ CH2Cl2, starting from 1:8 to 1:3) to provide 11 as a colorless oil (84 mg, two steps 52%): Rf¼0.37 (MeOH/CH2Cl2, 1:12); [a]D¼2101.1 (c 0.5, MeOH); IR (KBr) 2943, 1631, 1454, 1376 cm21; 1H NMR (400 MHz, CDCl3) d 1.36 (m, 1H), 1.73 (m, 3H), 1.93 (m, 2H), 2.09 (m, 1H), 2.26 (m, 1H), 2.56 (s, 3H), 2.62 (m, 2H), 3.13 (m, 1H), 3.31 (s, 3H), 4.47 (dd, 2H, J¼9.7, 6.6 Hz), 4.68 (t, 1H, J¼6.9 Hz), 7.23– 7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 21.6, 22.5, 29.2, 38.2, 40.3, 54.9, 55.8, 61.5, 75.7, 94.1, 126.7, 128.3, 128.7, 139.9; HRMS (EI) calcd for C16H25NO2 [Mþ] 263.1885, found 263.1848. 4.1.9. (2R)-2-((22)-2-Hydroxy-2-phenylethyl)-N-methylpiperidine (12). A solution of piperidine 11 (50 mg, 0.19 mmol) in CH3CN (2 mL) was treated with conc. HCl (0.02 mL). After being stirred at room temperature for 4 h, the solution was diluted with EtOAc/isopropanol mixture and basified with aqueous NaHCO3 until pH 9 –10. The aqueous layer was extracted with ethyl acetate. The organic extracts were dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel (MeOH/CH2Cl2, 1:6) to afford 12 (38 mg, 93%): Rf¼0.37 (MeOH/CH2Cl2, 1:6); IR (KBr) 3363, 2943, 2692, 1453 cm21; 1H NMR (400 MHz, CDCl3) d 1.47 (m, 1H), 1.73– 1.78 (m, 2H), 1.85 (m, 1H), 1.93 –2.01 (m, 3H), 2.11 (m, 1H), 2.77 (s, 3H), 2.84 (m, 1H), 3.16 (br, 1H), 3.30 (m, 1H), 5.11 (dd, 1H, J¼9.5, 3.2 Hz), 7.18 –7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 21.3, 22.4, 27.6, 38.7, 40.7, 55.7, 62.0, 68.7, 125.5, 127.3, 128.4, 144.1; HRMS (EI) calcd for C14H21NO [Mþ] 219.1623, found 219.1624.
Acknowledgements
6.
7.
8.
9.
10. 11.
12.
This work was supported by a grant of the Korea Health 21 R and D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ1-PG1-01CH12-0002). 13.
References and notes 1. Dwoskin, L. P.; Crooks, P. A. Biochem. Pharmacol. 2002, 63, 89 – 98. 2. Fodor, G. B.; Colasanti, B. Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp 41 – 63. 3. (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103, 1172– 1176. (b) Tirel, P.-J.; Vaultier, M.; Carrie´, R. Tetrahedron Lett. 1989, 30, 1947– 1950. (c) Pilli, R. A.; Dias, L. C. Synth. Commun. 1991, 21, 2213. (d) Ozawa, N.; Nakajima, S.; Zaoya, K.; Hamaguchi, F.; Nagasaka, T. Heterocycles 1991, 32, 889– 894. 4. (a) Comins, D. L.; Hong, H. J. Org. Chem. 1993, 58, 5035– 5036. (b) Yu, C.-Y.; Meth-Cohn, O. Tetrahedron Lett. 1999, 40, 6665– 6668. (c) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002, 67, 1982– 1992. (d) Felpin, F.-X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192– 9199. 5. (a) Wakabayashi, T.; Watanabe, K.; Kato, Y.; Saito, M. Chem.
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Lett. 1977, 223– 228. (b) Liguori, A.; Ottana, R.; Romeo, G.; Sindona, G.; Uccellla, N. Chem. Ber. 1989, 122, 2019 –2020. (c) Oppolzer, W.; Deerberg, J.; Tamura, O. Helv. Chim. Acta 1994, 77, 554– 560. (d) Meth-Cohn, O.; Yau, C. C.; Yu, C.-Y. J. Heterocyclic Chem. 1999, 36, 1549– 1554. (e) Felpin, F.-X.; Lebreton, J. Tetrahedron Lett. 2002, 43, 225– 227. For recent examples of metathesis-based synthesis from this laboratory, see: (a) Jo, E.; Na, Y.; Chang, S. Tetrahedron Lett. 1999, 40, 5581 – 5582. (b) Lee, W.-W.; Chang, S. Tetrahedron: Asymmetry 1999, 10, 4473– 4475. (c) Lee, W.-W.; Shin, H. J.; Chang, S. Tetrahedron: Asymmetry 2001, 12, 29 – 31. (d) Park, S.-H.; Kang, H. J.; Ko, S.; Park, S. Y.; Chang, S. Tetrahedron: Asymmetry 2001, 12, 2621 –2624. (e) Chang, S.; Na, Y.; Shin, H. J.; Choi, E.; Jeong, L. S. Tetrahedron Lett. 2002, 43, 7445– 7448. (f) Kang, B.; Kim, D.-h.; Do, Y.; Chang, S. Org. Lett. 2003, 5, 3041 –3043. (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936– 938. (b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421– 431. (c) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687– 2688. (d) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307– 1315. It was obtained in high enantiomeric purity (.98% ee) using the Jacobsen’s protocol (Ref. 7) in multi gram scales from racemic epoxide. (a) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. J. Org. Chem. 1984, 49, 3938– 3942. (b) Lipshutz, B. H.; Wilhelm, R. S. J. Am. Chem. Soc. 1981, 103, 7672– 7674. Smith, J. G. Synthesis 1984, 629– 656. (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307– 1370. (b) Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am. Chem. Soc. 1981, 103, 7690– 7692. (c) Fringuelli, F.; Germani, R.; Pizzo, F.; Santinelli, F.; Savelli, G. J. Org. Chem. 1992, 57, 1198– 1202. (a) Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275 –1276. (b) Greene, T. W.; Wuts, P. G. M.; 3rd ed. Protective Groups in Organic Synthesis; Wiley: New York, 1999. (c) Seto, H.; Mander, L. N. Synth. Commun. 1992, 22, 2823 –2828. (d) Yang, W.-Q.; Kitahara, T. Tetrahedron 2000, 56, 1451–1461, pp 27 – 33. (a) Mitsunobu, O. Synthesis 1981, 1 – 28. (b) Edwards, M. L.; Stemerick, D. M.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 3417 –3420. (c) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373– 6374. (d) Nikam, S. S.; Kornberg, B. E.; Rafferty, M. F. J. Org. Chem. 1997, 62, 3754 –3757. For recent reviews on olefin metathesis, see: (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036 –2056. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413 –4450. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012– 3043. (d) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900– 1923. (e) In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003. Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 4035– 4037. For some selected examples of RCM using ammonium salts as a substrate, see: (a) Wright, D. L.; Schutle, J. P., II; Page, M. A. Org. Lett. 2000, 2, 1847– 1850. (b) Salim, S. S.; Bellingham, R. K.; Satcharoen, V.; Brown, R. C. D. Org. Lett. 2003, 5, 3403 –3406. (c) Verhelst, S. H. L.; Martinez, B. P.; Timmer,
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M. S. M.; Lodder, G.; van der Marel, G. A.; Overkleeft, H. S.; van Boom, J. H. J. Org. Chem. 2003, 68, 9598 –9603. 17. For some examples of tandem RCM and hydrogenation with a common ruthenium carbene precursor, see: (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312– 11313. (b) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390– 13391. 18. For some examples of tandem RCM and other catalytic reactions by the addition second catalysts, see: (a) Alexakis,
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A.; Croset, K. Org. Lett. 2002, 4, 4147– 4149. (b) Cossy, J.; Bargiggia, F.; BouzBouz, S. Org. Lett. 2003, 5, 459–462. 19. (a) Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.; Mendez-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259– 1261. (b) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137– 4140. (c) Cho, J. H.; Kim, B. M. Org. Lett. 2003, 5, 531– 533. (d) Ahn, Y. M.; Yang, K. L.; Georg, G. I. Org. Lett. 2001, 3, 1411– 1413. 20. The calculated molarity of the m-chloroperbenzoic acid was based on the 77% purity of the commercial peracid.
A facile synthetic route to (1)-allosedamine via hydrolytic kinetic resolution and olefin metathesis Byungman Kang and Sukbok Chang* Department of Chemistry and School of Molecular Science (BK21), Center for Molecular Design and Synthesis (CMDS), Korea Advanced Institute of Science and Technology (KAIST), 373-1, Kusong-dong, Yusong-gu, Daejeon 305-701, South Korea Received 10 March 2004; revised 22 May 2004; accepted 24 May 2004 Available online 10 June 2004 This paper is dedicated to Professor Robert H. Grubbs of California Institute of Technology on the occasion of his receiving the Tetrahedron Prize
Abstract—A concise synthesis of (þ)-allosedamine has been achieved using cobalt-catalyzed hydrolytic kinetic resolution (HKR) and ruthenium-catalyzed ring closing metathesis (RCM) as two key steps, in which HKR was used to introduce both stereogenic centers in the natural compound with a high degree of diastereomeric ratio and cyclization was carried out with the well developed RCM procedure. q 2004 Elsevier Ltd. All rights reserved.
1. Introduction Lobelia inflata, also known as Indian tobacco, has been used for the treatment of some respiratory illnesses by American settlers. It was later found that a family of piperidine alkaloids including lobeline, lobelanine, lobelanidine and allosedamine are responsible for the therapeutic effects (Fig. 1).1 Extracts of the plants have been also used for the treatment of narcotic poisoning, coal gas asphyxia, pneumonia and control of anxiety, and it has been revealed that the continual doses of its extracts cause a various side effects.2
synthesis of sedamine alkaloid in racemic3 and optically active form,4 facile and direct application of the approaches on synthesis of allosedamine turned out to be difficult in most cases.5 For example, whereas an elegant recent strategy described by Cossy et al. for the synthesis of (þ)sedamine is based on the enantioselective allyltitanation of an aldehyde precursor by chiral titanium complex followed by ring-closing metathesis to provide a N-heterocyclic system,4c Lebreton’s route for the preparation of (2)allosedamine relies on Brown’s asymmetric allylation and subsequent electrophilic cyclization.5e
2. Results and discussion
Figure 1. Lobelia alkaloids.
We were particularly interested in the development of an efficient asymmetric synthetic route of allosedamine and its diastereomeric isomer (sedamine) among those alkaloids. While numerous approaches have been reported for the Keywords: Allosedamine; Total synthesis; Hydrolytic kinetic resolution; Ring-closing metathesis. * Corresponding author. Tel.: þ82-428692841; fax: þ82-428692810; e-mail address: [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.05.054
One of the most distinguishing structural features of (þ)allosedamine is the fact that it contains a secondary free benzylic hydroxy group and a piperidine moiety. At the outset of our studies, it was anticipated that both of two stereogenic centers located at b-position each other could be readily introduced by asymmetric catalysis. Our synthetic approach for (þ)-allosedamine relies on two metalcatalyzed reactions; hydrolytic kinetic resolution (HKR) and ring-closing metathesis (RCM) (Scheme 1).6 Inversion of a hydroxyl group-containing stereogenic center at homoallylic position was envisioned to be another key step for the success in this strategy. (þ)-Styrene oxide 1 was chosen as a starting material for providing a stereogenic center at benzylic position because it is readily available in multi gram scale via a hydrolytic kinetic resolution of racemic styrene oxide.7 As shown in Scheme 2, regioselective ring opening of
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Scheme 1. Retrosynthetic analysis of (þ)-allosedamine.
Scheme 2. Construction of two stereogenic centers.
(þ)-styrene oxide 18 was most efficiently achieved by using cuprate reagents derived from tetravinyltin in THF among a variety of conditions examined leading to a homoallylic alcohol 2a.9 Employment of other sources of vinyl group or use of different solvents resulted in much lower selectivities for the desired secondary alcohol. For example, when vinylmagnesium bromide was used in the presence of Cu(I) salt,10 almost equal ratio of primary versus secondary alcohol isomer was generated albeit with higher combined yields. In addition, when vinyl bromide was utilized in combination with t-BuLi and CuCN, no desired product was obtained from the reaction. It was expected at the beginning that a directed epoxidation of homoallylic alcohol 2a would be possible giving practically acceptable diastereoselectivity under certain conditions. Some precedent examples demonstrate that either peroxy acids alone or peracids in combination with Table 1. Attempts of directed epoxidation of homoallylic alcohol 2a
Entry 1 2 3 4 5 6 a b
Reaction conditionsa
Yield (%, 3a:3b)b
MPPA, NaOH (1 M), rt MPPA, CH2Cl2, 0 8C to rt MPPA, THF, 0 8C to rt m-CPBA, CH2Cl2, 0 8C to rt Mo(CO)6, TBHP, C6H6, rt VO(acac)2, TBHP, C6H6, rt
NR 80 (1:1) 63 (1:1) 94 (1.1:1) 51 (1.2:1) 42 (2.8:1)
MPPA: monoperoxyphthalic acid, m-CPBA: 3-chloroperbenzoic acid, TBHP: t-butyl hydroperoxide. Combined yields, and ratios were determined by 1H NMR integration of the crude reaction mixture.
certain transition metal species provide high degree of directing effects in the epoxidation of homoallylic alcohols.11 This directed epoxidation is presumed to be operated mainly via hydrogen bonding interactions between the hydroxyl group of substrates and peroxy acids or peracids leading to syn epoxy alcohols. As shown in Table 1, a directed epoxidation of 2a was examined under various conditions on the basis of the reported procedures. In reality, no measurable diastereoselective induction was observed when the epoxidation of 2a was carried out with peracid or peroxide in the absence of metal species (entries 1– 4). While almost no selectivity was also observed in the presence of a Mo catalyst (entry 5), slightly improved selectivity was induced with the use of a vanadium catalyst albeit in lower yield (entry 6). The unexpectedly low diastereoselectivity would be probably derived from weak hydrogen bonding interactions between peracid oxygen and homoallylic alcohol 2a. This result led us to employ a twostep pathway for the preparation of an optically active epoxy alcohol 3a from 2a: non-selective epoxidation of 2a with m-CPBA and subsequent kinetic resolution of the resulting epoxy alcohol moiety. Protection of free hydroxyl group of 3a/3b was carried out in high yield (95%) with chloromethyl methyl ether in CH2Cl2 at 0 8C giving the corresponding MOM ethers 4a/4b in the same ratio.12 In order to perform a kinetic resolution of the diastereomeric epoxide mixture 4a/4b, Jacobsen’s (R,R)-(2)-Co(salen) catalyst (5) was employed under the optimized conditions.7 Treatment of a mixture of 4a/4b (,1:1) with 5 (1 mol%), acetic acid (4 mol%), and H2O (0.55 equiv.) in THF at room temperature provided 4a in 44% yield with .98% de. In the resolution reaction, diol 6 was isolated in 47% yield as a single diastereomer
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determined by 1H NMR. It is noteworthy that synthetic utility of the ring-opened diol 6 could be readily found in other syntheses because it is highly functionalized compound with well-defined stereochemistry. Designation of the absolute stereochemistry in the resolved epoxide, (1S,3R)-4a, was ensured by comparing it with that of an authentic sample which was prepared independently by a literature procedure.4d Residual amounts of the used cobalt catalyst in the product was completely removed by the use of pyridinium p-toluene sulfonate (PPTS) during workup processes.7c It should be particularly mentioned that the present synthetic route can be also applied to the synthesis of optically active sedamine, a diastereomer of allosedamine by the choice of the Jacobsen’s Co catalyst. With the use of (S,S)-(þ)-Co(salen) catalyst instead of (R,R)-isomer, a diastereomeric epoxide 4b would be obtained with the same efficiency and selectivity eventually leading to (2)sedamine. It should be mentioned that this synthetic route uses two resolution reactions to obtain the key epoxide intermediate 4a starting from a readily available racemic styrene epoxide. Both resolutions proceed with an excellent selectivity under mild conditions making the present synthesis highly efficient and practical. Epoxide opening of an oxirane 4a with vinyl Grignard reagent underwent smoothly in the presence of copper additives in THF affording another homoallylic alcohol 7 in 70% yield (Scheme 3). Initially, the Mitsunobu’s inversion protocol was investigated to introduce the required amino group at the homoallylic position using allylamine and its derivatives as a nucleophile.13 However, a variety of attempts with several amino groups were unsuccessful presumably because of steric hindrance around the alcohol substrate. This led us to employ a two-step alternative: conversion of the homoallyl alcohol 7 into its corresponding mesylate followed by amination with methylamine to provide an amino ether adduct 8 (43% over two steps). The fact that configuration of the free hydroxyl containing carbon in 7 was completely inverted in the substituted product 8 was readily confirmed by 1H NMR. Allylation of
Scheme 3. Final stages in the synthesis of (þ)-allosedamine.
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the secondary amino moiety 8 was carried out efficiently under normal conditions to afford a dienyl compound 9, a precursor for ring-closing metathesis. Efficiency of the ring-closing metathesis reaction of 9 was examined with the use of several catalyst systems under various conditions.14 The best result was obtained when diene 9 was reacted with the Grubbs’ second generation catalyst (Im)Cl2PCy3RuCHPh 10 (10 mol%) in benzene under N2 atmosphere to generate an olefinic piperidine moiety in 54% yield. Other ruthenium carbene catalysts gave a rather reduced activity and lower yields under otherwise same conditions; Cl2(PCy3)2RuCHPh (40%) and (3-bromopyridine)2Cl2(Im)RuCHPh (47%).15 No significant improvement was observed when the cyclization was carried out under ethylene atmosphere instead of N2. In addition, when ammonium salts of diolefinic amine 9 were subjected to the metathesis conditions, noticeable improvements in chemical yields were not observed compared to free amino substrate 9. For example, RCM of ammonium salts of 9 of trifluoroacetic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid afforded the cyclized product in 54, 43, and 43% isolated yields under identical conditions, respectively.16 While tandem hydrogenation of the olefinic intermediate into a saturated piperidine adduct 11 was initially tried in the absence of additional metal catalysts,17 no desired activity of the ruthenium carbene precursor was observed for the reduction step. This led us to use another one-pot procedure: addition of platinum oxide catalyst (0.1 equiv.) after the metathesis reaction for the subsequent hydrogenation.18 Hydrogenation underwent almost quantitatively in the presence of PtO2 catalyst giving a protected allosedamine 11 in 52% yield (two steps starting from 9). To remove the residual ruthenium by products from the product, various known purification procedures were examined.19 Whereas simple silica gel column chromatography left significant amounts of residual ruthenium in the desired product, treatment of the crude reaction mixture with either lead tetraacetate (1.5 equiv. to catalyst)19a or tris(hydroxymethylphosphine) (100 equiv. to catalyst)19b
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resulted in only marginal improvement in purity and brown color was still seen from the isolated product. Most effective removal of ruthenium residues from the reaction mixture was achieved according to a recently published protocol, in which the reaction mixture was treated with activated charcoal (50 equiv. to the crude product in wt)19c for 12 h followed by a silica gel column chromatography. Subsequent deprotection of MOM group by conc. HCl in acetonitrile12 provided (þ)-allosedamine 12 in high yield, spectral data of which are identical to those of the reported literature ones.5 3. Conclusion A concise synthesis of (þ)-allosedamine has been achieved using cobalt-catalyzed hydrolytic kinetic resolution (HKR) and ruthenium-catalyzed ring closing metathesis (RCM) as two key steps. HKR was used to introduce both stereogenic centers in the natural compound with a high degree of diastereomeric ratio. Cyclization was carried out with the well-developed RCM procedure and the desired piperidine moiety was isolated after tandem hydrogenation in one-pot. With the present synthetic approach, optically active sedamine, a diastereomeric isomer of allosedamine, could be also readily accessed by a simple choice of enantiomeric cobalt catalyst via HKR. 4. Experimental 4.1. General methods Oxygen or moisture sensitive reactions were conducted in oven- or flame-dried glassware under nitrogen. Unless otherwise specified, materials were purchased from commercial supplier and used without further purification. Solvents were dried and purified prior to use. Benzene, acetonitrile, and dichloromethane were distilled from calcium hydride under argon or nitrogen atmosphere. THF was distilled from sodium metal and benzophenone. Analytical thin layer chromatography (TLC) was performed on Merck precoated silica gel 60 F254 plates. Purification by column chromatography was carried out using silica gel 60 (230 – 400 mesh, ASTM, Merck). Proton nuclear magnetic resonance spectra were recorded on a Bruker AVANCE 400 (400 MHz) spectrometer. Chemical shifts are reported in delta (d) units, parts per million (ppm) downfield from internal standard (tetramethylsilane), or in ppm relative to the singlet at 7.26 ppm of chloroform-d1. Splitting patterns are designated as follows: s; singlet, d; doublet, t; triplet, q; quintet, m; multiplet, dd; doublet of doublet, ddd; doublet of doublet of doublet, bs; broad singlet. HRMS spectra were recorded on a VG AUTOSPEC ULTIMA spectrometer. 4.1.1. (1S)-1-Phenylbut-3-en-1-ol (2a). A solution of tetravinyltin (0.46 mL, 2.45 mmol) in THF (7 mL) was cooled to 0 8C and methyllithium (1.4 M in Et2O, 6.1 mL, 8.57 mmol) was added. The colorless solution was stirred for 1 h and cooled to 278 8C. To a stirred heterogeneous solution of CuCN (392 mg, 4.37 mmol) in THF (2 mL), the colorless vinyllithium solution was added dropwise via
cannula at 278 8C. The mixture was allowed to warm slowly to 230 8C with stirring and then a heterogeneous solution changed into a homogeneous yellow solution. After cooling to 278 8C, a solution of (þ)-styrene oxide (0.20 mL, 1.75 mmol) in THF (1 mL) was added dropwise to the above solution. After stirring for 2 h at 230 8C, the mixture was allowed to warm slowly to room temperature. The reaction was quenched by addition of saturated NH4Cl and filtered through celite. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude residue was purified on silica gel (EtOAc/ n-hexane, 1:5) to afford 2a as a colorless oil (137 mg, 53%): Rf¼0.52 (EtOAc/n-hexane, 1:3); [a]D¼250.2 (c 1.45, C6H6); IR (KBr) 3386, 1640, 1603, 1493, 1453 cm21; 1H NMR (400 MHz, CDCl3) d 2.09 (d, 1H, J¼3.3 Hz), 2.51 (m, 2H), 4.72 (m, 1H), 5.11 –5.17 (m, 2H), 5.80 (m, 1H), 7.24 – 7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) d 43.7, 73.2, 118.4, 125.8, 127.5, 128.4, 134.4, 143.8; HRMS (EI) calcd for C10H12O [Mþ] 148.0888, found 148.0899. 4.1.2. (1S)-2-Oxiranyl-1-phenylethanol (3a, 3b). The mixture of olefin 2a (500 mg, 3.37 mmol), m-chloroperbenzoic acid20 (983 mg, 4.38 mmol) in CH2Cl2 (12 mL) was stirred at 0 8C for 30 min. The mixture was stirred for 12 h at room temperature and was then diluted with dichloromethane. The organic phase was extracted with saturated NaHCO3 twice. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude residue was purified on silica gel (EtOAc/n-hexane, starting from 1/6 to 1/1) to afford product as a colorless oil (521 mg, 94%) with a diastereomeric ratio of 1:1 (3a:3b, determined by 1H NMR): Rf¼0.20 (EtOAc/ n-hexane, 1:3); IR (KBr) 3423, 1494, 1454, 1410 cm21. 3a: 1H NMR (400 MHz, CDCl3) d 1.90 (dd, 1H, J¼14.1, 6.5 Hz), 2.02 (dd, 1H, J¼9.5, 4.4 Hz), 2.48 (dd, 1H, J¼4.8, 2.8 Hz), 2.74 (t, 1H, J¼4.1 Hz), 2.99 (m, 1H), 4.89– 4.96 (m, 1H), 7.25– 7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.3, 46.7, 49.8, 71.8, 125.5, 127.6, 128.5, 143.8. 3b: 1H NMR (400 MHz, CDCl3) d 1.80 (ddd, 1H, J¼14.4, 6.7, 3.5 Hz), 2.13 (ddd, 1H, J¼17.0, 9.0, 4.0 Hz), 2.59 (dd, 1H, J¼5.5, 3.5 Hz), 2.81 (t, 1H, J¼4.4 Hz), 3.16 (m, 1H), 4.89 – 4.96 (m, 1H), 7.25 – 7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.8, 46.9, 50.1, 72.7, 125.7, 127.7, 128.5, 144.1; HRMS (EI) calcd for C10H12O2 [Mþ] 164.0837, found 164.0836. 4.1.3. (1S)-Methoxymethyl-(2-oxiranyl-1-phenylethyl)ether (4a, 4b). To a solution of a mixture of alcohol 3a and 3b (506 mg, 3.08 mmol) in CH2Cl2 (8 mL) at 0 8C were added diisopropylethylamine (2.15 mL, 12.3 mmol), chloromethyl methyl ether (0.70 mL, 9.24 mmol). After being stirred at room temperature for 6 h, the resulting mixture was diluted with dichloromethane and quenched with water. The aqueous phase was extracted with dichloromethane. The combined extracts were washed with brine, dried over MgSO4, and filtered. Removal of solvent left an oil which was purified by column chromatography (EtOAc/n-hexane, 1:9), affording product (604 mg, 95%) as a colorless oil: Rf¼0.55 (EtOAc/ n-hexane, 1:3); IR (KBr) 2925, 2887, 1494, 1454, 1408 cm21.
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4a: 1H NMR (400 MHz, CDCl3) d 1.91 (ddd, 1H, J¼14.0, 6.5, 5.0 Hz), 2.09 (m, 1H), 2.44 (dd, 1H, J¼5.0, 2.7 Hz), 2.70 (t, 1H, J¼4.1 Hz), 2.90 (m, 1H), 3.37 (s, 3H), 4.54 (s, 2H), 4.79 (t, 1H, J¼6.8 Hz), 7.25 –7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) d 40.9, 46.7, 49.6, 55.5, 75.7, 93.9, 126.8, 127.8, 128.5, 141.0. 4b: 1H NMR (400 MHz, CDCl3) d 1.80 (ddd, 1H, J¼14.1, 7.1, 3.9 Hz), 2.13 (m, 1H), 2.59 (dd, 1H, J¼5.0, 2.7 Hz), 2.81 (t, 1H, J¼4.0 Hz), 3.16 (m, 1H),3.38 (s, 3H), 4.56 (s, 2H), 4.84 (dd, 1H, J¼9.4, 3.8 Hz), 7.25– 7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.4, 47.5, 49.6, 55.6, 75.2, 94.0, 126.6, 127.9, 128.5, 141.4. 4.1.4. (1S,3R)-Methoxymethyl-(2-oxiranyl-1-phenylethyl)ether (4a). A 25 ml round bottom flask equipped with a stirring bar was charged with (R,R)-Co(salen) catalyst (5, 16.8 mg, 27.8 mmol). The catalyst was treated with a solution of 4a/4b mixture (,1:1, 580 mg, 2.78 mmol), acetic acid (6.4 mL, 111 mmol) in THF (0.2 mL). The solution was cooled to 0 8C, and H2O (27 mL, 1.53 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Pyridinium p-toluenesulfonate (28 mg, 4.0 equiv. based on catalyst) and 1 mL of CH3CN/CH2Cl2 (1:1, v/v) were added, and the reaction mixture was applied to a pad of silica gel. The pad was washed with EtOAc. After the mixture was concentrated under reduced pressure, the residue was purified on silica gel (EtOAc/n-hexane, 1:6) to afford 4a as a colorless oil (255 mg, 44%, 98% de based on the 1H NMR): [a]D¼2121.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.91 (ddd, 1H, J¼14.0, 6.5, 5.0 Hz), 2.09 (q, 1H, 7.0 Hz), 2.44 (dd, 1H, J¼4.9, 2.6 Hz), 2.70 (t, 1H, J¼4.1 Hz), 2.90 (m, 1H), 3.37 (s, 3H), 4.54 (s, 2H), 4.79 (t, 1H, J¼6.8 Hz), 7.25 –7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 40.9, 46.7, 49.6, 55.5, 75.7, 93.9, 126.8, 127.9, 128.5, 141.0; HRMS (EI) calcd for C12H16O3 [Mþ] 208.1099, found 208.1097. 4.1.5. (1S,3S)-1-Methoxymethoxy-1-phenylhex-5-en-3-ol (7). To a solution of CuBr/Me2S (246 mg, 1.2 mmol) in THF (4 mL) cooled to 230 8C was added vinyl magnesium bromide (3.6 mL, 3.6 mmol, 1.0 M in THF). The resulting mixture was allowed to warm slowly to 20 8C and a solution of epoxide 4a (250 mg, 1.2 mmol) in THF (2 mL) was added at 260 8C. After being stirred at 230 8C for 1 h, the mixture was allowed to warm slowly to room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with Et2O. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on silica gel (EtOAc/n-hexane, 1:6) to afford 7 as a colorless oil (198 mg, 70%): Rf¼0.42 (EtOAc/n-hexane, 1:3); [a]D¼2159.5 (c 1.0, CHCl3); IR (KBr) 3447, 2943, 1638 cm21; 1H NMR (400 MHz, CDCl3) d 1.81 (ddd, 1H, J¼14.4, 4.6, 2.4 Hz), 1.97 (m, 1H), 2.24 (m, 1H), 3.25 (d, 1H, J¼1.7 Hz), 3.39 (s, 3H), 3.83 (m, 1H), 4.45 (s, 2H), 4.84 (dd, 1H, J¼9.5, 4.7 Hz), 5.06 (d, 1H, J¼ 2.3 Hz), 5.10 (d, 1H, J¼7.0 Hz), 5.82 (m, 1H), 7.25 –7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.9, 44.1, 55.9, 70.3, 78.0, 93.7, 117.6, 126.8, 127.9, 128.5, 134.5, 140.9; HRMS (EI) calcd for C14H20O3 [Mþ] 236.1412, found 236.1462.
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4.1.6. (1S,3R)-(1-(2-(Methoxymethoxy)-2-phenylethyl)but-3-enyl)methylamine (8). To a solution of alcohol 7 (188 mg, 0.79 mmol) in CH2Cl2 (5 mL) at 0 8C were added triethylamine (0.22 mL, 1.59 mmol), methanesulfonylchloride (0.12 mL, 1.59 mmol). After 30 min, the mixture was diluted with dichloromethane, washed with brine, dried over MgSO4, and concentrated to afford the crude mesylate. The crude mesylate was taken up in a methanolic solution of methylamine (14.6 mL, 39.2 mmol, 2.0 M in MeOH). The resulting solution was heated to 70 8C for 12 h. After cooling to room temperature, the solution was concentrated. Then it was diluted with Et2O, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified on silica gel (starting from EtOAc/n-hexane, 1:3 to MeOH/CH2Cl2, 1:12) to afford 8 as a yellow oil (86 mg, two steps 43%): Rf¼0.67 (MeOH/CH2Cl2, 1:8); [a]D¼2123.0 (c 1.0, MeOH); IR (KBr) 3354, 2936, 1638, 1493, 1454 cm21; 1H NMR (400 MHz, CDCl3) d 1.76 (ddd, 1H, J¼14.0, 8.1, 4.5 Hz), 1.91 (ddd, 1H, J¼13.3, 8.9, 4.4 Hz), 2.11 (bs, 1H), 2.28 (m, 1H), 2.41 (s, 3H), 2.75 (m, 1H), 3.39 (s, 3H), 4.54 (s, 2H), 4.82 (dd, 1H, J¼8.8, 4.4 Hz), 5.11 (d, 1H, J¼11.9 Hz), 5.77 (m, 1H), 7.28– 7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 32.8, 37.6, 41.9, 55.1, 55.7, 75.4, 94.2, 117.4, 126.6, 127.5, 128.4, 134.9, 142.0; HRMS (EI) calcd for C15H23NO2 [Mþ] 249.1729, found 249.1716. 4.1.7. (1S,3R)-N-Allyl-(1-(2-(methoxymethoxy)-2phenylethyl)but-3-enyl)methylamine (9). To a solution of amine 8 (63 mg, 0.25 mmol) in acetonitrile (3 mL) was added powder K2CO3 (105 mg, 0.76 mmol). The mixture was stirred for 30 min at room temperature, and then allylbromide (32.8 mL, 0.38 mmol) was added. After stirring for 4 h at room temperature, the resulting mixture was diluted with Et2O and quenched with water. The aqueous phase was extracted with Et2O. The extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified on silica gel (EtOAc/ n-hexane, 1:5) to afford 9 as a pale yellow oil (66 mg, 90%): Rf¼0.57 (EtOAc/n-hexane, 1:3); [a]D¼2104.2 (c 1.0, CHCl3); IR (KBr) 2942, 1639, 1493, 1452 cm21; 1H NMR (400 MHz, CDCl3) d 1.64 (ddd, 1H, J¼14.4, 9.6, 3.4 Hz), 1.80 – 1.93 (m, 2H), 2.19 (s, 3H), 2.90 (m, 1H), 3.01 (dd, 1H, J¼13.7, 6.1 Hz), 3.11 (dd, 1H, J¼13.8, 6.1 Hz), 3.32 (s, 3H), 4.53 (dd, 2H, J¼14.8, 6.6 Hz), 4.85 (dd, 1H, J¼9.6, 3.3 Hz), 5.02 (d, 2H, J¼14.2 Hz), 5.04 (d, 1H, J¼17.2 Hz), 5.15 (dd, 2H, J¼12.9, 1.3 Hz), 5.79 (m, 2H), 7.28 – 7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 33.1, 36.1, 39.8, 55.5, 56.5, 59.1, 75.3, 94.5, 116.1, 126.6, 127.2, 128.3, 137.0, 137.1, 143.1; HRMS (EI) calcd for C18H27NO2 [Mþ] 289.2042, found 289.2036. 4.1.8. (2R)-2-((22)-2-(Methoxymethoxy)-2-phenylethyl)N-methylpiperidine (11). To a solution of diene 9 (178 mg, 0.61 mmol) in anhydrous benzene (28 mL) was added a solution of the Grubbs ruthenium catalyst (Im)Cl2PCy3RuCHPh (10, 52 mg, 0.06 mmol) in benzene (2 mL) at room temperature. The mixture was refluxed at 70 8C for 12 h. It was cooled to room temperature and was concentrated in vacuo. Then, to a solution of crude metathesis product in EtOAc (8 mL) was added PtO2 (14 mg, 0.06 mmol). After 1 h under H2 (1 atm), the mixture was filtered through celite and concentrated in vacuo. The crude residue in CH2Cl2 (5 mL) was added to a solution of
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activated charcoal (10.0 g, 50 equiv. wt of the crude product) in CH2Cl2 (95 mL) and stirred for 12 h. After the carbon was filtered, the filtrate was concentrated in vacuo and purified on a silica gel column chromatography (MeOH/ CH2Cl2, starting from 1:8 to 1:3) to provide 11 as a colorless oil (84 mg, two steps 52%): Rf¼0.37 (MeOH/CH2Cl2, 1:12); [a]D¼2101.1 (c 0.5, MeOH); IR (KBr) 2943, 1631, 1454, 1376 cm21; 1H NMR (400 MHz, CDCl3) d 1.36 (m, 1H), 1.73 (m, 3H), 1.93 (m, 2H), 2.09 (m, 1H), 2.26 (m, 1H), 2.56 (s, 3H), 2.62 (m, 2H), 3.13 (m, 1H), 3.31 (s, 3H), 4.47 (dd, 2H, J¼9.7, 6.6 Hz), 4.68 (t, 1H, J¼6.9 Hz), 7.23– 7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 21.6, 22.5, 29.2, 38.2, 40.3, 54.9, 55.8, 61.5, 75.7, 94.1, 126.7, 128.3, 128.7, 139.9; HRMS (EI) calcd for C16H25NO2 [Mþ] 263.1885, found 263.1848. 4.1.9. (2R)-2-((22)-2-Hydroxy-2-phenylethyl)-N-methylpiperidine (12). A solution of piperidine 11 (50 mg, 0.19 mmol) in CH3CN (2 mL) was treated with conc. HCl (0.02 mL). After being stirred at room temperature for 4 h, the solution was diluted with EtOAc/isopropanol mixture and basified with aqueous NaHCO3 until pH 9 –10. The aqueous layer was extracted with ethyl acetate. The organic extracts were dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel (MeOH/CH2Cl2, 1:6) to afford 12 (38 mg, 93%): Rf¼0.37 (MeOH/CH2Cl2, 1:6); IR (KBr) 3363, 2943, 2692, 1453 cm21; 1H NMR (400 MHz, CDCl3) d 1.47 (m, 1H), 1.73– 1.78 (m, 2H), 1.85 (m, 1H), 1.93 –2.01 (m, 3H), 2.11 (m, 1H), 2.77 (s, 3H), 2.84 (m, 1H), 3.16 (br, 1H), 3.30 (m, 1H), 5.11 (dd, 1H, J¼9.5, 3.2 Hz), 7.18 –7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 21.3, 22.4, 27.6, 38.7, 40.7, 55.7, 62.0, 68.7, 125.5, 127.3, 128.4, 144.1; HRMS (EI) calcd for C14H21NO [Mþ] 219.1623, found 219.1624.
Acknowledgements
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7.
8.
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10. 11.
12.
This work was supported by a grant of the Korea Health 21 R and D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ1-PG1-01CH12-0002). 13.
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