DOI: 10.1002/asia.201500246
Full Paper
Total Synthesis
Bicyclic Guanidine Catalyzed Asymmetric Tandem Isomerization Intramolecular-Diels–Alder Reaction: The First Catalytic Enantioselective Total Synthesis of (+ +)-alpha-Yohimbine Wei Feng,[c] Danfeng Jiang,[a] Choon-Wee Kee,[a] Hongjun Liu,[b] and Choon-Hong Tan*[a] Abstract: Hydroisoquinoline derivatives were prepared in moderate to good enantioselectivities via a bicyclic guanidine-catalyzed tandem isomerization intramolecular-Diels–
Alder (IMDA) reaction of alkynes. With this synthetic method, the first enantioselective synthesis of (+ +)-alpha-yohimbine was completed in 9 steps from the IMDA products.
Introduction
tacyclic rings, which contain five chiral centers. Several investigations have been documented for the synthesis of yohimbine[2] and reserpine,[3] both racemic and enantioselective versions. However, less effort has been devoted to the synthesis of alpha-yohimbine.[4] To the best of our knowledge, there is no report on the enantioselective synthesis of alpha-yohimbine. The most concise construction of the pentacyclic rings was reported by Jacobsen and co-workers.[2k] An acyl-Pictet–Spengler reaction was employed to construct the ring C, which was followed by an intramolecular Diels–Alder reaction[2m] to form the rings D and E. For the synthesis of alpha-yohimbine, the most efficient method, developed by Martin and co-workers, was to form the D and E rings using an intramolecular Diels– Alder reaction, which was followed by oxidative cyclization to form the ring C.[2h, 4f] However, only racemic products were achieved. The only report on optical active alpha-yohimbine was based on its isolation from Rauwolfia leaves.[4g] Here we report our enantioselective synthesis of (+ +)-alpha-yohimbine and its full characterization.
The yohimbine family of indole alkaloids (Figure 1), of which alpha-yohimbine (1), yohimbine (2), and reserpine (3) are representative members, have attracted extensive attention from chemists due to their synthetically challenging structures and pharmacological activities.[1] The synthesis of yohimbines is challenging mainly due to difficulties in constructing the pen-
Figure 1. Monoterpenoid alkaloids. [a] D. Jiang, Dr. C.-W. Kee, Dr. C.-H. Tan Division of Chemistry and Biological Chemistry School of Physical and Mathematical Science Nanyang Technological University 21 Nanyang Link, Singapore 637371 (Singapore) E-mail: [email protected]
Results and Discussion We have been interested in the development of Brønstedbase-catalyzed enantioselective transformations.[5] We have developed the synthesis of chiral allenoates through the enantioselective isomerization of alkynoates using bicyclic guanidine 4 as catalyst [Scheme 1, Eq. (1)].[5s] N-Phthalimido-protected 5aminoalkynoates underwent isomerization with high yield and high enantioselectivity. We, thus, became interested to trap such a chiral allene generated through an intramolecular-azaMichael reaction, in a tandem fashion, to construct the axially chiral N-arylated 2-alkylidene lactam [Eq. (2)].[5t] The N-arylated 2-alkylidene lactam exists as an atropisomer due to the large ortho-substitution on the aryl protecting group, which restricts the rotation around the N¢C bond. Encouraged by these results, we became interested to explore this concept further and attempted a tandem isomeriza-
[b] Dr. H. Liu Key Laboratory of Natural Medicine and Immunoengineering of Henan Province Henan University Henan 475004 (China) [c] Dr. W. Feng Department of Chemistry National University of Singapore 3 Science Drive 3, Singapore 117543 (Singapore) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201500246. This manuscript is part of a special issue on catalysis and transformation of complex molecules. Click here to see the Table of Contents of the special issue. Chem. Asian J. 2016, 11, 390 – 394
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Full Paper Table 1. Tandem-isomerization intramolecular Diels–Alder reaction.
Entry
8 (PG, R)
Yield [%][a]
d.r.[b]
ee [%][c]
1 2 3 4 5 6 7 8 9
8 a (Piv, Et) 8 b (Piv, tBu) 8 c (Boc, tBu) 8 d (Cbz, tBu) 8 e (Ts, tBu)[d] 8 f (4-BrBz, tBu) 8 g ((1H-Indol-3-yl)-acetyl, tBu)[d] 8 h (Boc, CEt3) 8 i (Piv, CEt3)
89 75 91 89 80 83 72 80 80
3:1 4:1 3.3:1 4:1 2:1 2.5:1 4:1 4:1 3:1
60/60 83/83 79/77 77/77 76/80 65/65 68/69 87/88 87/88
Reactions were run on a 0.2 mmol scale with 10 mol % of catalyst in 10 mL of hexane at room temperature. [a] Isolated yield (9 + 10). [b] Determined by 1H NMR spectroscopy (9:10). [c] Determined by HPLC analysis, 9/10. [d] The reaction was run in THF due to low solubility.
Scheme 1. Enantioselective isomerization of alkynoates.
tion intramolecular-Diels–Alder reaction [Eq. (3)]. This reaction should lead to a bicyclic structure and with proper choice of tether, which should then lead us to hydroisoquinolines,[6] a class of biologically active compounds. The key intermediate, alkynyl amine 8 a, was prepared on a gram scale (Scheme 2). We began the synthesis by alkylating furfury amine 5 with propargyl bromide. The secondary amine
enantioselectivity (entry 9). The IMDA adducts 9 b, 9 c, and 10 b, as well as the hydrogenation product of compound 9 c, were confirmed by X-ray crystallography and 1H and 13C NMR spectroscopic analyses.[11] The absolute configurations of 9 c and 10 c were determined by DFT calculation to be (5S, 6S, 9R) and (5R, 6S, 9R).[9] To further support the result of the calculation, product 9 e was re-crystallized to 93 % ee, and determination of the absolute configuration of 9 e by X-ray crystallography[11] gave a result consistent with the calculation. The IMDA adducts are hydroisoquinolines, which resemble the lower two rings of alpha-yohimbine, with correctly placed functional groups and chiral centers (Scheme 3). Retrosynthetic
Scheme 2. Preparation of key intermediate, alkynyl amide 8 a.
6 was obtained in 80 % yield together with 10 % of dialkylated byproduct.[7] Protection of the amine with pivaloyl chloride went smoothly to give the protected-amine 7 a in high yield. Finally, amine 7 a was coupled with diazo compounds in the presence of CuI to provide alkynoate 8 a in 75 % yield.[8] Bicyclic guanidine was found to catalyze the tandem-isomerization intramolecular-Diels–Alder (IMDA) reaction of alkynyl amine 8 a (Scheme 2 and Table 1, entry 1). The IMDA adducts were bicyclic hydroisoquinolines containing an oxo-bridge on one of the rings. Several solvents were tested and hexane was found to provide best yields and good levels of enantioselectivity (see the Supporting Information). A good yield of 89 % with an 3:1 ratio of endo:exo adducts was obtained, with 8 % of starting material 8 a recovered. A series of alkynoates 8 b– i were prepared containing different protecting groups for the amine as well as ester group (Table 1, entries 2–9). In general, amine protecting groups did not significantly affect the enantioselectivities, while a bulky ester group such as a triethyltype ester led us to alkynoate 8 i that gave the best level of Chem. Asian J. 2016, 11, 390 – 394
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Scheme 3. Retrosynthetic analysis.
analysis shows that we could establish the (C3) chiral center at the last step via oxidative cyclization.[2h] The indole moiety can be installed by reductive amination using (indol-3-yl)acetaldehyde. The ring opening of the oxo-bridge of the IMDA adduct followed by hydrogenation should then lead to the precursor for the reductive amination step. The stereochemistry of the two newly formed chiral centres (C15 and C20) is expected to be controlled by the steric effect of the bulky ester group during heterogeneous hydrogenation. The IMDA adducts 9 c underwent reductive opening of the oxo-bridge using the Lautens’ condition,[10] which employ a cat391
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Full Paper alytic amount of Ni(COD)2. Byproducts produced from olefin hydroalumination and ester reduction were also detected. Increasing Ni(COD)2 to a stoichiometric amount and lowering the reaction temperature led to a better yield of dialkene 11 (Scheme 4). Direct hydrogenation of 11 gave several products with relatively low yields. However, when the hydroxyl group is acetylated, the hydrogenation proceeded smoothly with Pt/
tioselective total synthesis of (+ +)-alpha-yohimbine. The synthetic natural product was also fully characterized and confirmed by comparing the NMR data with those in the literature.[2h] The absolute configuration was confirmed to be as shown in Scheme 4 by an X-ray crystallographic analysis of the HCl salt of the synthetic natural product 1.[12]
Conclusions In conclusion, a bicyclic guanidine-catalyzed asymmetric tandem isomerization intramolecular-Diels– Alder (IMDA) reaction of alkynoates provides a high degree of enantioselective control in the synthesis of substituted hydroisoquinolines. This method has proved to be successful in the first catalytic enantioselective total synthesis of (+ +)-alpha-yohimbine.
Experimental Section General 1
H and 13C NMR spectra were recorded on a 500 MHz Bruker DRX NMR spectrometer or an AMX500 (500 MHz) spectrometer. Chemical shifts are reported in parts per million (ppm). The residual solvent peak was used as an internal reference. Low-resolution mass spectra were obtained on a Finnigan/MAT LCQ spectrometer in the ESI mode. High-resolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer. Enantiomeric excess values were determined by chiral HPLC analysis on a Dionex Ultimate 3000 HPLC unit, including an Ultimate 3000 Pump and Ultimate 3000 variable detectors. Optical rotations were recorded on a Jasco DIP-1000 polarimeter with a sodium lamp of wavelength 589 nm. Flash chromatography separations were performed on Merck 60 (0.040–0.063 mm) mesh silica gel. Hexane was purified via simple distillation. MeCN was dried by using a molecular sieve. Dichloromethane was distilled from CaH2 and stored under N2 atmosphere. Other reagents and solvents were commercial grade and were used as supplied without further purification, unless otherwise stated. Experiments involving moistureand/or air-sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet. Reactions requiring a temperature of ¢20 8C were stirred in either Thermo Neslab CB-60 with Cryotrol temperature controller or Eyela PSL-1400 with digital temperature controller cryobaths. Isopropanol was used as the bath medium. All experiments were monitored by analytical thin layer chromatography (TLC). Instrumentations 1H and 13C NMR spectra were recorded in CDCl3 unless otherwise stated; 1H (500.1331 MHz) and 13C NMR (125.7710 MHz) measurements with complete proton decoupling and 1H NOESY NMR measurements were performed on a 500 MHz Bruker DRX NMR spectrometer. All compounds synthesized were stored at ¢34 8C.
Scheme 4. Total synthesis of (+ +)-alpha-yohimbine.
C as the catalyst at 70 8C. Bicyclic amine 13 was obtained as an inseparable mixture of diastereomers with a d.r. of 8:1, as assessed by using the 1H NMR spectrum of the crude reaction product. The Boc group was easily removed using trifluoroacetic acid (TFA) in dichloromethane at 0 8C without affecting the acetyl and triethyl ester. The diastereomers of 14 were still inseparable. They were then subjected to the reductive amination directly. Unfortunately, the product 15 was inseparable from the byproduct 2-(1H-indol-3-yl)ethanol which was generated from the reduction of 2-(1H-indol-3-yl)acetaldehyde. The mixture of 15 and 2-(1H-indol-3-yl)ethanol underwent the subsequent trans-esterification by treatment with camphorsulfonic acid (CSA) in refluxing MeOH. The acetyl group was cleaved and the triethyl ester was converted into the methyl ester in a single step. A single diastereomer of indolyl amine 16 was obtained in 31 % yield over 4 steps. The enantiomeric purity was maintained when indolyl amine 16 was analyzed with chiral HPLC. Indolyl amine 16 was fully characterized, and the stereochemistry was established by NOESY analysis and also confirmed by comparing the 1H and 13C NMR spectroscopic data with the reported data.[2h] The oxidative cyclization step was followed by NaBH4 reduction to complete the first enanChem. Asian J. 2016, 11, 390 – 394
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Synthesis of compound 6 To a 200 mL round-bottomed flask was added a stirring bar, 10 mmol LiOH .H2O and 10 mL DMF (AR grade), followed by the addition of 30 mmol furfurylamine 5. The mixture was stirred vigorously, and 10 mmol propargyl bromide in 30 mL of DMF was added slowly over 1 h. After stirring for another 3 h, the mixture
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Full Paper was filtered through Celite and washed thoroughly with diethyl ether. The filtrate was washed four times with water. The combined aqueous layer was extracted again with diethyl ether and the combined organic layers were washed with brine and dried over sodium sulfate, concentrated in vacuo, and purified by flash silica gel chromatography (hexane:EtOAc = 6:1) to afford 6 as a pale yellow oil in 80 % yield.
were added. Finally, Ac2O (0.9 mmol) was added, and the reaction mixture was brought to room temperature. The reaction was monitored by TLC until completion (usually around 10 h). Following removal of the solvent in vacuo the crude mixture was purified by flash silica gel chromatography (hexane:EtOAc, 10:1) to afford 12 was obtained as colorless oil in 80 % yield.
Synthesis of 13
Synthesis of compound 7
Compound 12 (0.25 mmol, 110 mg) was dissolved in 2.5 mL of EtOH in a 10 mL Schlenk flask, which was equipped with an adapter attached with a H2 balloon, and Pt/C (50wt %, 55 mg) was added. The system was evacuated and charged with H2 (4 times). The reaction mixture was heated to 70 8C and was stirred for 4 days. The reaction was monitored by 1H NMR spectroscopy of the crude mixture until the reaction was complete. Subsequently, Pt/C was filtered off and the filtrate was concentrated and used directly in the next step without further purification. The 1H NMR spectrum of the crude product shows that 13 was obtained as a mixture of diastereomers (8:1).
Synthesis of 7 a: To a solution of 6 (8 mmol) in dry CH2Cl2 (50 mL) under nitrogen atmosphere was added Et3N (8.8 mmol, 1.1 equiv). After the mixture was cooled to 0 8C, pivaloyl chloride was added dropwise. Then the reaction mixture was warmed to room temperature and stirred until full conversion as indicated by TLC (usually around 1 h). The product 7 a was obtained as a colorless oil in 95 % yield following silica gel chromatography purification (hexane:EtOAc, 8:1) .
Synthesis of compound 8 Synthesis of 8 a: Compound 7 a (6 mmol) was dissolved in MeCN (AR grade) under N2 atmosphere, and CuI (0.6 mmol) was added to the solution. The mixture was stirred for 10 min. Then ethyl diazoacetate (9 mmol) was added and the mixture was stirred for 10 h. Subsequently, the solvent was removed. Purification of the resulting residue by silica gel chromatography (hexane:EtOAc = 10:1) afforded 8 a as a colorless oil in 75 % yield. The IMDA products (9 a and 10 a) were obtained in 10 % yield.
Synthesis of 14 The mixture of 13 was dissolved in 3 mL CH2Cl2 and cooled to 0 8C. Then 0.75 mL TFA was added, and the reaction mixture was stirred at 0 8C for 10 min. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with saturated NaHCO3 and extracted with CH2Cl2 for 4 times. The combined organic layers were dried over Na2SO4, concentrated, and dried under vacuum. The crude product 14 (a mixture of diastereomers of 8:1 as assessed by 1H NMR spectroscopy) was used directly in the next step.
General procedure for the IMDA reaction Synthesis of 9 a and 10 a: Substrate 8 (0.2 mmol) was dissolved in 10 mL distilled hexane. Subsequently, 10 mol % of catalyst was added and the mixture was stirred at room temperature. The reaction was monitored by TLC until the starting material was completely consumed. The solvent was removed in vacuo and purification of the resulting residue by flash chromatography (hexane:EtOAc, 10:1) afforded 9 and 10 in 72–88 % yields and 60–88 % ee. The two cycloadducts can be separated using flash chromatography.
Synthesis of compound 15 Compound 14 (crude product), HOBz, and NaCNBH3 were mixed in 5 mL toluene in a 50 mL round-bottomed flask under N2 atmosphere. The reaction mixture was stirred for 30 min at room temperature. Then 2-(1H-indol-3-yl)acetaldehyde (freshly prepared from methyl 2-(1H-indol-3-yl)acetate via DIBAL-H reduction) in 5 mL toluene was added and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2 for 4 times. The combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by silica gel chromatography (hexane:EtOAc, 2:1) afforded a mixture of 15 and 2-(1H-indol3-yl)ethanol, of which the latter is produced from the reduction of the aldehyde, as evidenced by 1H NMR spectroscopy of the crude reaction mixture. The mixture could not be separated and was used directly in the next step.
Synthesis of compound 11 In a glovebox, 9 c (2 mmol) was added to a 100 mL round-bottomed flask, followed by addition of PPh3 (8 mmol ) and Ni(COD)2 (2 mmol). The mixture was then dissolved in 20 mL dry toluene. After stirring in the glovebox for 1 h at room temperature, the flask was sealed with a rubber septum and taken out of the glovebox. Under a N2 balloon, the mixture was cooled to 0 8C. Subsequently, 2.5 mmol of DIBAL-H (1 m in toluene) was diluted with 20 mL dry toluene and added to the mixture slowly over 1 h using a syringe pump. After addition, the reaction was monitored by TLC until complete conversion. The reaction was then quenched with saturated NH4Cl solution and extracted with CH2Cl2 (4 Õ 50 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by flash silica gel chromatography afforded 11 (hexane:EtOAc, 4:1) as a colorless oil in 50 % yield.
Synthesis of compound 16 The mixture of 15 and 2-(1H-indol-3-yl)ethanol was dissolved in 4 mL MeOH in a sealed tube. Next, CSA (0.25 mmol) was added and the mixture was heated to 80 8C. After 24 h, the mixture was cooled to room temperature and MeOH was removed in vacuo. The resulting mixture was dissolved in CH2Cl2 and neutralized with 1 m NaOH. Extraction was done with CH2Cl2 for 4 times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification of the resulting residue by flash silica gel chromatography (hexane:EtOAc, 1:1 followed by DCM:MeOH, 20:1) afforded compound 16 as a white foam in 31 % yield over 4 steps.
Synthesis of compound 12 In a dry round-bottomed flask, 11 (0.6 mmol) was dissolved in 12 mL of dry CH2Cl2 under a N2 atmosphere. The reaction mixture was cooled to 0 8C and Et3N (0.9 mmol) and DMAP (0.06 mmol) Chem. Asian J. 2016, 11, 390 – 394
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[4] For alpha-yohimbine synthesis: a) L. Tçke, K. Honty, L. Szabû, G. Blaskû, C. Szntay, J. Org. Chem. 1973, 38, 2496 – 2500; b) L. Tçke, Z. Gombos, G. Blaskû, K. Honty, L. Szabû, J. Tams, C. Szntay, J. Org. Chem. 1973, 38, 2501 – 2509; c) C. Szntay, K. Honty, L. Tçke, L. Szabû, Chem. Ber. 1976, 109, 1737 – 1748; d) E. Wenkert, T. D. J. Halls, G. Kunesch, K. Orito, R. L. Stephens, W. A. Temple, J. S. Yadv, J. Am. Chem. Soc. 1979, 101, 5370 – 5376; e) K. Honty, E. Baitz-Gacs, G. Blaskû, C. Szntay, J. Org. Chem. 1982, 47, 5111 – 5114; f) S. F. Martin, H. Rìeger, Tetrahedron Lett. 1985, 26, 5227 – 5230; g) A. von Stoll, A. Hofmann, R. Brunner, Helv. Chim. Acta 1955, 38, 270 – 283. [5] For selected reviews, see: a) T. Ishikawa, T. Kumamoto, Synthesis 2006, 5, 737 – 752; b) D. Leow, C.-H. Tan, Chem. Asian J. 2009, 4, 488 – 507; c) X. Fu, C.-H. Tan, Chem. Commun. 2011, 47, 8210 – 8222. For examples from other groups, see: d) E. J. Corey, M. J. Grogan, Org. Lett. 1999, 1, 157 – 160; e) T. Kita, A. Georgieva, Y. Hashimoto, T. Nakata, K. Nagasawa, Angew. Chem. Int. Ed. 2002, 41, 2832 – 2834; Angew. Chem. 2002, 114, 2956 – 2958; f) T. Ishikawa, T. Isobe, Chem. Eur. J. 2002, 8, 552 – 557; g) Y. Sohtome, Y. Hashimoto, K. Nagasawa, Adv. Synth. Catal. 2005, 347, 1643 – 1648; h) M. Terada, H. Ube, Y. Yaguchi, J. Am. Chem. Soc. 2006, 128, 1454 – 1455; i) M. Terada, M. Nakano, H. Ube, J. Am. Chem. Soc. 2006, 128, 16044 – 6055; j) M. Terada, T. Ikehara, H. Ube, J. Am. Chem. Soc. 2007, 129, 14112 – 14113; k) C. Palomo, M. Oiarbide, R. Lûpez, Chem. Soc. Rev. 2009, 38, 632 – 653; l) Z. Yu, X. Liu, L. Zhou, L. Lin, X. Feng, Angew. Chem. Int. Ed. 2009, 48, 5195 – 5198; Angew. Chem. 2009, 121, 5297 – 5300; m) T. Misaki, G. Takimoto, T. Sugimura, J. Am. Chem. Soc. 2010, 132, 6286 – 6287; n) T. Takeda, M. Terada, J. Am. Chem. Soc. 2013, 135, 15306 – 15309. For representative publications from our group, see: o) J. Shen, T. Nguyen, Y.-P. Goh, W. Ye, X. Fu, J. Xu, C.-H. Tan, J. Am. Chem. Soc. 2006, 128, 13692 – 13693; p) D. Leow, S. Lin, S. K. Chittimalla, X. Fu, C.-H. Tan, Angew. Chem. Int. Ed. 2008, 47, 5641 – 5645; Angew. Chem. 2008, 120, 5723 – 5727; q) X. Fu, W.-T. Loh, Y. Zhang, T. Chen, T. Ma, H. Liu, J. Wang, C.-H. Tan, Angew. Chem. Int. Ed. 2009, 48, 7387 – 7390; Angew. Chem. 2009, 121, 7523 – 7526; r) Z. Jiang, Y. Pan, Y. Zhao, T. Ma, R. Lee, Y. Yang, K.-W. Huang, M. W. Wong, C.-H. Tan, Angew. Chem. Int. Ed. 2009, 48, 3627 – 3631; Angew. Chem. 2009, 121, 3681 – 3685; s) H. Liu, D. Leow, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2009, 131, 7212 – 7213; t) H. Liu, W. Feng, C.-W. Kee, D. Leow, W.-T. Loh, C.-H. Tan, Adv. Synth. Catal. 2010, 352, 3373 – 3379; u) T. Ma, X. Fu, C.-W. Kee, L. Zong, Y. Pan, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2011, 133, 2828 – 2831. [6] a) J. D. Scott, R. M. Williams, Chem. Rev. 2002, 102, 1669 – 1730; b) M. Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104, 3341 – 3370; c) D. L. Comins, R. S. Al-awar, J. Org. Chem. 1992, 57, 4098 – 4103; d) D. L. Comins, C. A. Brooks, R. S. Al-awar, R. R. Goehring, Org. Lett. 1999, 1, 229 – 231. [7] V. Sai Sudhir, R. B. Nasir Baig, S. Chandrasekaran, Eur. J. Org. Chem. 2008, 2423 – 2429. [8] A. Surez, G. C. Fu, Angew. Chem. Int. Ed. 2004, 43, 3580 – 3582; Angew. Chem. 2004, 116, 3664 – 3666. [9] M. Kwit, M. D. Rozwadowska, J. Gawron´ski, A. Grajewska, J. Org. Chem. 2009, 74, 8051 – 8063. [10] M. Lautens, S. Ma, P. Chiu, J. Am. Chem. Soc. 1997, 119, 6478 – 6487. [11] CCDC 1029362, CCDC 1029365, CCDC 1029364, CCDC 1029363, CCDC 1052979 contain the supplementary crystallographic data for compounds 9 b, 10 b, and 9 c, and the hydrogenation product of 9 c and 9 e. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [12] CCDC 1052980 contains the supplementary crystallographic data for compound 1. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif.
Compound 16 (28 mg, 0.08 mmol) was dissolved in 1.5 mL EtOH, then an aqueous solution of Hg(OAc)2 and EDTA-2Na (1:1, 2.4 mL of a 0.1 m solution in water, 0.24 mmol) was added. The resulting solution was heated to 85 8C and refluxed for 3 h. Then the mixture was cooled to 0 8C and 2.5 mL 25 % HClO4 was added. The mixture was then stirred at 0 8C for 10 min and extracted with CH2Cl2 (4 Õ 5 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was re-dissolved in MeOH/H2O (9:1, v/v, 2.5 mL). The pH was adjusted to 6 using 5 % NaHCO3 solution. The mixture was cooled to 0 8C, and NaBH4 (0.6 mmol, 25 mg) was added. The reaction was brought to room temperature and stirred for an additional hour. The solvents were removed under reduced pressure, and the residue was partitioned between cold 10 % NH4OH and CH2Cl2. The aqueous layer was extracted with CH2Cl2 for 4 times, and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (hexane/ETOAc 1:1, then CH2Cl2/MeOH 20:1) to afford 1 as a white foam in 30 % yield.
Acknowledgements We gratefully acknowledge the financial support of grants from NTU (M4080946.110 and RG 6/12M40110018.110). Keywords: alkaloids · alkyne · chiral guanidine intramolecular-Diels–Alder reaction · total synthesis
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[1] For leading references and reviews of the monoterpenoid alkaloids of the indole family, see: a) J. E. Saxton in Specialist Periodical Reports, The Alkaloids, The Royal Society of Chemistry, Burlington House, London, 1983, 13, 221 – 237; b) T. E. Gaffney, C. A. Chidsey, E. Braunwald, Circ. Res. 1963, 12, 264 – 268. [2] For general reviews of synthetic approaches toward yohimbine alkaloids, see: a) M. E. Kuehne, R. S. Muth, J. Org. Chem. 1991, 56, 2701 – 2712. For examples of yohimbine synthesis see: b) E. E. van Tamelen, M. Shamma, A. W. Burgstahler, J. Wolinsky, R. Tamm, P. E. Aldrich, J. Am. Chem. Soc. 1958, 80, 5006 – 5007; c) E. E. van Tamelen, M. Shamma, A. W. Burgstahler, J. Wolinsky, R. Tamm, P. E. Aldrich, J. Am. Chem. Soc. 1969, 91, 7315 – 7333; d) L. Tçke, K. Honty, C. Szntay, Chem. Ber. 1969, 102, 3248 – 3259; e) G. Stork, R. N. Guthikonda, J. Am. Chem. Soc. 1972, 94, 5109 – 5110; f) E. Wenkert, J. St. Pyrek, S. Uesato, Y. D. Vankar, J. Am. Chem. Soc. 1982, 104, 2244 – 2246; g) O. Miyata, Y. Hirata, T. Naito, I. Ninomiya, J. Chem. Soc. Chem. Commun. 1983, 1231 – 1232; h) S. F. Martin, H. Rìeger, S. A. Williamson, S. Grzejszczak, J. Am. Chem. Soc. 1987, 109, 6124 – 6134; i) Y. Hirai, T. Terada, Y. Okaji, T. Yamazaki, T. Momose, Tetrahedron Lett. 1990, 31, 4755 – 4756; j) J. Aub¦, S. Ghosh, M. Tanol, J. Am. Chem. Soc. 1994, 116, 9009 – 9018; k) D. J. Mergott, S. J. Zuend, E. N. Jacobsen, Org. Lett. 2008, 10, 745 – 748; l) B. Herl¦, M. J. Wanner, J. H. van Maarseveen, H. Hiemstra, J. Org. Chem. 2011, 76, 8907 – 8912. For example of IMDAs in total synthesis: m) F. Matsuura, R. Peters, M. Anada, S. S. Harried, J. Hao, Y. Kishi, J. Am. Chem. Soc. 2006, 128, 7463 – 7465. [3] For a review of reserpine synthesis: a) E.-F. Chen, J. Huang, Chem. Rev. 2005, 105, 4671 – 4706. For more recent approaches, see: b) N. S. Rajapaksa, M. A. McGowan, M. Rienzo, E. N. Jacobsen, Org. Lett. 2013, 15, 706 – 709; c) A. G. Barcan, A. Patel, K. N. Houk, O. Kwon, Org. Lett. 2012, 14, 5388 – 5391; d) J. Huang, F.-E. Chen, Helv. Chim. Acta 2007, 90, 1366 – 1372.
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Manuscript received: March 15, 2015 Accepted Article published: April 30, 2015 Final Article published: June 12, 2015
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Full Paper
Total Synthesis
Bicyclic Guanidine Catalyzed Asymmetric Tandem Isomerization Intramolecular-Diels–Alder Reaction: The First Catalytic Enantioselective Total Synthesis of (+ +)-alpha-Yohimbine Wei Feng,[c] Danfeng Jiang,[a] Choon-Wee Kee,[a] Hongjun Liu,[b] and Choon-Hong Tan*[a] Abstract: Hydroisoquinoline derivatives were prepared in moderate to good enantioselectivities via a bicyclic guanidine-catalyzed tandem isomerization intramolecular-Diels–
Alder (IMDA) reaction of alkynes. With this synthetic method, the first enantioselective synthesis of (+ +)-alpha-yohimbine was completed in 9 steps from the IMDA products.
Introduction
tacyclic rings, which contain five chiral centers. Several investigations have been documented for the synthesis of yohimbine[2] and reserpine,[3] both racemic and enantioselective versions. However, less effort has been devoted to the synthesis of alpha-yohimbine.[4] To the best of our knowledge, there is no report on the enantioselective synthesis of alpha-yohimbine. The most concise construction of the pentacyclic rings was reported by Jacobsen and co-workers.[2k] An acyl-Pictet–Spengler reaction was employed to construct the ring C, which was followed by an intramolecular Diels–Alder reaction[2m] to form the rings D and E. For the synthesis of alpha-yohimbine, the most efficient method, developed by Martin and co-workers, was to form the D and E rings using an intramolecular Diels– Alder reaction, which was followed by oxidative cyclization to form the ring C.[2h, 4f] However, only racemic products were achieved. The only report on optical active alpha-yohimbine was based on its isolation from Rauwolfia leaves.[4g] Here we report our enantioselective synthesis of (+ +)-alpha-yohimbine and its full characterization.
The yohimbine family of indole alkaloids (Figure 1), of which alpha-yohimbine (1), yohimbine (2), and reserpine (3) are representative members, have attracted extensive attention from chemists due to their synthetically challenging structures and pharmacological activities.[1] The synthesis of yohimbines is challenging mainly due to difficulties in constructing the pen-
Figure 1. Monoterpenoid alkaloids. [a] D. Jiang, Dr. C.-W. Kee, Dr. C.-H. Tan Division of Chemistry and Biological Chemistry School of Physical and Mathematical Science Nanyang Technological University 21 Nanyang Link, Singapore 637371 (Singapore) E-mail: [email protected]
Results and Discussion We have been interested in the development of Brønstedbase-catalyzed enantioselective transformations.[5] We have developed the synthesis of chiral allenoates through the enantioselective isomerization of alkynoates using bicyclic guanidine 4 as catalyst [Scheme 1, Eq. (1)].[5s] N-Phthalimido-protected 5aminoalkynoates underwent isomerization with high yield and high enantioselectivity. We, thus, became interested to trap such a chiral allene generated through an intramolecular-azaMichael reaction, in a tandem fashion, to construct the axially chiral N-arylated 2-alkylidene lactam [Eq. (2)].[5t] The N-arylated 2-alkylidene lactam exists as an atropisomer due to the large ortho-substitution on the aryl protecting group, which restricts the rotation around the N¢C bond. Encouraged by these results, we became interested to explore this concept further and attempted a tandem isomeriza-
[b] Dr. H. Liu Key Laboratory of Natural Medicine and Immunoengineering of Henan Province Henan University Henan 475004 (China) [c] Dr. W. Feng Department of Chemistry National University of Singapore 3 Science Drive 3, Singapore 117543 (Singapore) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201500246. This manuscript is part of a special issue on catalysis and transformation of complex molecules. Click here to see the Table of Contents of the special issue. Chem. Asian J. 2016, 11, 390 – 394
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Full Paper Table 1. Tandem-isomerization intramolecular Diels–Alder reaction.
Entry
8 (PG, R)
Yield [%][a]
d.r.[b]
ee [%][c]
1 2 3 4 5 6 7 8 9
8 a (Piv, Et) 8 b (Piv, tBu) 8 c (Boc, tBu) 8 d (Cbz, tBu) 8 e (Ts, tBu)[d] 8 f (4-BrBz, tBu) 8 g ((1H-Indol-3-yl)-acetyl, tBu)[d] 8 h (Boc, CEt3) 8 i (Piv, CEt3)
89 75 91 89 80 83 72 80 80
3:1 4:1 3.3:1 4:1 2:1 2.5:1 4:1 4:1 3:1
60/60 83/83 79/77 77/77 76/80 65/65 68/69 87/88 87/88
Reactions were run on a 0.2 mmol scale with 10 mol % of catalyst in 10 mL of hexane at room temperature. [a] Isolated yield (9 + 10). [b] Determined by 1H NMR spectroscopy (9:10). [c] Determined by HPLC analysis, 9/10. [d] The reaction was run in THF due to low solubility.
Scheme 1. Enantioselective isomerization of alkynoates.
tion intramolecular-Diels–Alder reaction [Eq. (3)]. This reaction should lead to a bicyclic structure and with proper choice of tether, which should then lead us to hydroisoquinolines,[6] a class of biologically active compounds. The key intermediate, alkynyl amine 8 a, was prepared on a gram scale (Scheme 2). We began the synthesis by alkylating furfury amine 5 with propargyl bromide. The secondary amine
enantioselectivity (entry 9). The IMDA adducts 9 b, 9 c, and 10 b, as well as the hydrogenation product of compound 9 c, were confirmed by X-ray crystallography and 1H and 13C NMR spectroscopic analyses.[11] The absolute configurations of 9 c and 10 c were determined by DFT calculation to be (5S, 6S, 9R) and (5R, 6S, 9R).[9] To further support the result of the calculation, product 9 e was re-crystallized to 93 % ee, and determination of the absolute configuration of 9 e by X-ray crystallography[11] gave a result consistent with the calculation. The IMDA adducts are hydroisoquinolines, which resemble the lower two rings of alpha-yohimbine, with correctly placed functional groups and chiral centers (Scheme 3). Retrosynthetic
Scheme 2. Preparation of key intermediate, alkynyl amide 8 a.
6 was obtained in 80 % yield together with 10 % of dialkylated byproduct.[7] Protection of the amine with pivaloyl chloride went smoothly to give the protected-amine 7 a in high yield. Finally, amine 7 a was coupled with diazo compounds in the presence of CuI to provide alkynoate 8 a in 75 % yield.[8] Bicyclic guanidine was found to catalyze the tandem-isomerization intramolecular-Diels–Alder (IMDA) reaction of alkynyl amine 8 a (Scheme 2 and Table 1, entry 1). The IMDA adducts were bicyclic hydroisoquinolines containing an oxo-bridge on one of the rings. Several solvents were tested and hexane was found to provide best yields and good levels of enantioselectivity (see the Supporting Information). A good yield of 89 % with an 3:1 ratio of endo:exo adducts was obtained, with 8 % of starting material 8 a recovered. A series of alkynoates 8 b– i were prepared containing different protecting groups for the amine as well as ester group (Table 1, entries 2–9). In general, amine protecting groups did not significantly affect the enantioselectivities, while a bulky ester group such as a triethyltype ester led us to alkynoate 8 i that gave the best level of Chem. Asian J. 2016, 11, 390 – 394
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Scheme 3. Retrosynthetic analysis.
analysis shows that we could establish the (C3) chiral center at the last step via oxidative cyclization.[2h] The indole moiety can be installed by reductive amination using (indol-3-yl)acetaldehyde. The ring opening of the oxo-bridge of the IMDA adduct followed by hydrogenation should then lead to the precursor for the reductive amination step. The stereochemistry of the two newly formed chiral centres (C15 and C20) is expected to be controlled by the steric effect of the bulky ester group during heterogeneous hydrogenation. The IMDA adducts 9 c underwent reductive opening of the oxo-bridge using the Lautens’ condition,[10] which employ a cat391
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Full Paper alytic amount of Ni(COD)2. Byproducts produced from olefin hydroalumination and ester reduction were also detected. Increasing Ni(COD)2 to a stoichiometric amount and lowering the reaction temperature led to a better yield of dialkene 11 (Scheme 4). Direct hydrogenation of 11 gave several products with relatively low yields. However, when the hydroxyl group is acetylated, the hydrogenation proceeded smoothly with Pt/
tioselective total synthesis of (+ +)-alpha-yohimbine. The synthetic natural product was also fully characterized and confirmed by comparing the NMR data with those in the literature.[2h] The absolute configuration was confirmed to be as shown in Scheme 4 by an X-ray crystallographic analysis of the HCl salt of the synthetic natural product 1.[12]
Conclusions In conclusion, a bicyclic guanidine-catalyzed asymmetric tandem isomerization intramolecular-Diels– Alder (IMDA) reaction of alkynoates provides a high degree of enantioselective control in the synthesis of substituted hydroisoquinolines. This method has proved to be successful in the first catalytic enantioselective total synthesis of (+ +)-alpha-yohimbine.
Experimental Section General 1
H and 13C NMR spectra were recorded on a 500 MHz Bruker DRX NMR spectrometer or an AMX500 (500 MHz) spectrometer. Chemical shifts are reported in parts per million (ppm). The residual solvent peak was used as an internal reference. Low-resolution mass spectra were obtained on a Finnigan/MAT LCQ spectrometer in the ESI mode. High-resolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer. Enantiomeric excess values were determined by chiral HPLC analysis on a Dionex Ultimate 3000 HPLC unit, including an Ultimate 3000 Pump and Ultimate 3000 variable detectors. Optical rotations were recorded on a Jasco DIP-1000 polarimeter with a sodium lamp of wavelength 589 nm. Flash chromatography separations were performed on Merck 60 (0.040–0.063 mm) mesh silica gel. Hexane was purified via simple distillation. MeCN was dried by using a molecular sieve. Dichloromethane was distilled from CaH2 and stored under N2 atmosphere. Other reagents and solvents were commercial grade and were used as supplied without further purification, unless otherwise stated. Experiments involving moistureand/or air-sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet. Reactions requiring a temperature of ¢20 8C were stirred in either Thermo Neslab CB-60 with Cryotrol temperature controller or Eyela PSL-1400 with digital temperature controller cryobaths. Isopropanol was used as the bath medium. All experiments were monitored by analytical thin layer chromatography (TLC). Instrumentations 1H and 13C NMR spectra were recorded in CDCl3 unless otherwise stated; 1H (500.1331 MHz) and 13C NMR (125.7710 MHz) measurements with complete proton decoupling and 1H NOESY NMR measurements were performed on a 500 MHz Bruker DRX NMR spectrometer. All compounds synthesized were stored at ¢34 8C.
Scheme 4. Total synthesis of (+ +)-alpha-yohimbine.
C as the catalyst at 70 8C. Bicyclic amine 13 was obtained as an inseparable mixture of diastereomers with a d.r. of 8:1, as assessed by using the 1H NMR spectrum of the crude reaction product. The Boc group was easily removed using trifluoroacetic acid (TFA) in dichloromethane at 0 8C without affecting the acetyl and triethyl ester. The diastereomers of 14 were still inseparable. They were then subjected to the reductive amination directly. Unfortunately, the product 15 was inseparable from the byproduct 2-(1H-indol-3-yl)ethanol which was generated from the reduction of 2-(1H-indol-3-yl)acetaldehyde. The mixture of 15 and 2-(1H-indol-3-yl)ethanol underwent the subsequent trans-esterification by treatment with camphorsulfonic acid (CSA) in refluxing MeOH. The acetyl group was cleaved and the triethyl ester was converted into the methyl ester in a single step. A single diastereomer of indolyl amine 16 was obtained in 31 % yield over 4 steps. The enantiomeric purity was maintained when indolyl amine 16 was analyzed with chiral HPLC. Indolyl amine 16 was fully characterized, and the stereochemistry was established by NOESY analysis and also confirmed by comparing the 1H and 13C NMR spectroscopic data with the reported data.[2h] The oxidative cyclization step was followed by NaBH4 reduction to complete the first enanChem. Asian J. 2016, 11, 390 – 394
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Synthesis of compound 6 To a 200 mL round-bottomed flask was added a stirring bar, 10 mmol LiOH .H2O and 10 mL DMF (AR grade), followed by the addition of 30 mmol furfurylamine 5. The mixture was stirred vigorously, and 10 mmol propargyl bromide in 30 mL of DMF was added slowly over 1 h. After stirring for another 3 h, the mixture
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Full Paper was filtered through Celite and washed thoroughly with diethyl ether. The filtrate was washed four times with water. The combined aqueous layer was extracted again with diethyl ether and the combined organic layers were washed with brine and dried over sodium sulfate, concentrated in vacuo, and purified by flash silica gel chromatography (hexane:EtOAc = 6:1) to afford 6 as a pale yellow oil in 80 % yield.
were added. Finally, Ac2O (0.9 mmol) was added, and the reaction mixture was brought to room temperature. The reaction was monitored by TLC until completion (usually around 10 h). Following removal of the solvent in vacuo the crude mixture was purified by flash silica gel chromatography (hexane:EtOAc, 10:1) to afford 12 was obtained as colorless oil in 80 % yield.
Synthesis of 13
Synthesis of compound 7
Compound 12 (0.25 mmol, 110 mg) was dissolved in 2.5 mL of EtOH in a 10 mL Schlenk flask, which was equipped with an adapter attached with a H2 balloon, and Pt/C (50wt %, 55 mg) was added. The system was evacuated and charged with H2 (4 times). The reaction mixture was heated to 70 8C and was stirred for 4 days. The reaction was monitored by 1H NMR spectroscopy of the crude mixture until the reaction was complete. Subsequently, Pt/C was filtered off and the filtrate was concentrated and used directly in the next step without further purification. The 1H NMR spectrum of the crude product shows that 13 was obtained as a mixture of diastereomers (8:1).
Synthesis of 7 a: To a solution of 6 (8 mmol) in dry CH2Cl2 (50 mL) under nitrogen atmosphere was added Et3N (8.8 mmol, 1.1 equiv). After the mixture was cooled to 0 8C, pivaloyl chloride was added dropwise. Then the reaction mixture was warmed to room temperature and stirred until full conversion as indicated by TLC (usually around 1 h). The product 7 a was obtained as a colorless oil in 95 % yield following silica gel chromatography purification (hexane:EtOAc, 8:1) .
Synthesis of compound 8 Synthesis of 8 a: Compound 7 a (6 mmol) was dissolved in MeCN (AR grade) under N2 atmosphere, and CuI (0.6 mmol) was added to the solution. The mixture was stirred for 10 min. Then ethyl diazoacetate (9 mmol) was added and the mixture was stirred for 10 h. Subsequently, the solvent was removed. Purification of the resulting residue by silica gel chromatography (hexane:EtOAc = 10:1) afforded 8 a as a colorless oil in 75 % yield. The IMDA products (9 a and 10 a) were obtained in 10 % yield.
Synthesis of 14 The mixture of 13 was dissolved in 3 mL CH2Cl2 and cooled to 0 8C. Then 0.75 mL TFA was added, and the reaction mixture was stirred at 0 8C for 10 min. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with saturated NaHCO3 and extracted with CH2Cl2 for 4 times. The combined organic layers were dried over Na2SO4, concentrated, and dried under vacuum. The crude product 14 (a mixture of diastereomers of 8:1 as assessed by 1H NMR spectroscopy) was used directly in the next step.
General procedure for the IMDA reaction Synthesis of 9 a and 10 a: Substrate 8 (0.2 mmol) was dissolved in 10 mL distilled hexane. Subsequently, 10 mol % of catalyst was added and the mixture was stirred at room temperature. The reaction was monitored by TLC until the starting material was completely consumed. The solvent was removed in vacuo and purification of the resulting residue by flash chromatography (hexane:EtOAc, 10:1) afforded 9 and 10 in 72–88 % yields and 60–88 % ee. The two cycloadducts can be separated using flash chromatography.
Synthesis of compound 15 Compound 14 (crude product), HOBz, and NaCNBH3 were mixed in 5 mL toluene in a 50 mL round-bottomed flask under N2 atmosphere. The reaction mixture was stirred for 30 min at room temperature. Then 2-(1H-indol-3-yl)acetaldehyde (freshly prepared from methyl 2-(1H-indol-3-yl)acetate via DIBAL-H reduction) in 5 mL toluene was added and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2 for 4 times. The combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by silica gel chromatography (hexane:EtOAc, 2:1) afforded a mixture of 15 and 2-(1H-indol3-yl)ethanol, of which the latter is produced from the reduction of the aldehyde, as evidenced by 1H NMR spectroscopy of the crude reaction mixture. The mixture could not be separated and was used directly in the next step.
Synthesis of compound 11 In a glovebox, 9 c (2 mmol) was added to a 100 mL round-bottomed flask, followed by addition of PPh3 (8 mmol ) and Ni(COD)2 (2 mmol). The mixture was then dissolved in 20 mL dry toluene. After stirring in the glovebox for 1 h at room temperature, the flask was sealed with a rubber septum and taken out of the glovebox. Under a N2 balloon, the mixture was cooled to 0 8C. Subsequently, 2.5 mmol of DIBAL-H (1 m in toluene) was diluted with 20 mL dry toluene and added to the mixture slowly over 1 h using a syringe pump. After addition, the reaction was monitored by TLC until complete conversion. The reaction was then quenched with saturated NH4Cl solution and extracted with CH2Cl2 (4 Õ 50 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by flash silica gel chromatography afforded 11 (hexane:EtOAc, 4:1) as a colorless oil in 50 % yield.
Synthesis of compound 16 The mixture of 15 and 2-(1H-indol-3-yl)ethanol was dissolved in 4 mL MeOH in a sealed tube. Next, CSA (0.25 mmol) was added and the mixture was heated to 80 8C. After 24 h, the mixture was cooled to room temperature and MeOH was removed in vacuo. The resulting mixture was dissolved in CH2Cl2 and neutralized with 1 m NaOH. Extraction was done with CH2Cl2 for 4 times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification of the resulting residue by flash silica gel chromatography (hexane:EtOAc, 1:1 followed by DCM:MeOH, 20:1) afforded compound 16 as a white foam in 31 % yield over 4 steps.
Synthesis of compound 12 In a dry round-bottomed flask, 11 (0.6 mmol) was dissolved in 12 mL of dry CH2Cl2 under a N2 atmosphere. The reaction mixture was cooled to 0 8C and Et3N (0.9 mmol) and DMAP (0.06 mmol) Chem. Asian J. 2016, 11, 390 – 394
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Full Paper Synthesis of compound 1
[4] For alpha-yohimbine synthesis: a) L. Tçke, K. Honty, L. Szabû, G. Blaskû, C. Szntay, J. Org. Chem. 1973, 38, 2496 – 2500; b) L. Tçke, Z. Gombos, G. Blaskû, K. Honty, L. Szabû, J. Tams, C. Szntay, J. Org. Chem. 1973, 38, 2501 – 2509; c) C. Szntay, K. Honty, L. Tçke, L. Szabû, Chem. Ber. 1976, 109, 1737 – 1748; d) E. Wenkert, T. D. J. Halls, G. Kunesch, K. Orito, R. L. Stephens, W. A. Temple, J. S. Yadv, J. Am. Chem. Soc. 1979, 101, 5370 – 5376; e) K. Honty, E. Baitz-Gacs, G. Blaskû, C. Szntay, J. Org. Chem. 1982, 47, 5111 – 5114; f) S. F. Martin, H. Rìeger, Tetrahedron Lett. 1985, 26, 5227 – 5230; g) A. von Stoll, A. Hofmann, R. Brunner, Helv. Chim. Acta 1955, 38, 270 – 283. [5] For selected reviews, see: a) T. Ishikawa, T. Kumamoto, Synthesis 2006, 5, 737 – 752; b) D. Leow, C.-H. Tan, Chem. Asian J. 2009, 4, 488 – 507; c) X. Fu, C.-H. Tan, Chem. Commun. 2011, 47, 8210 – 8222. For examples from other groups, see: d) E. J. Corey, M. J. Grogan, Org. Lett. 1999, 1, 157 – 160; e) T. Kita, A. Georgieva, Y. Hashimoto, T. Nakata, K. Nagasawa, Angew. Chem. Int. Ed. 2002, 41, 2832 – 2834; Angew. Chem. 2002, 114, 2956 – 2958; f) T. Ishikawa, T. Isobe, Chem. Eur. J. 2002, 8, 552 – 557; g) Y. Sohtome, Y. Hashimoto, K. Nagasawa, Adv. Synth. Catal. 2005, 347, 1643 – 1648; h) M. Terada, H. Ube, Y. Yaguchi, J. Am. Chem. Soc. 2006, 128, 1454 – 1455; i) M. Terada, M. Nakano, H. Ube, J. Am. Chem. Soc. 2006, 128, 16044 – 6055; j) M. Terada, T. Ikehara, H. Ube, J. Am. Chem. Soc. 2007, 129, 14112 – 14113; k) C. Palomo, M. Oiarbide, R. Lûpez, Chem. Soc. Rev. 2009, 38, 632 – 653; l) Z. Yu, X. Liu, L. Zhou, L. Lin, X. Feng, Angew. Chem. Int. Ed. 2009, 48, 5195 – 5198; Angew. Chem. 2009, 121, 5297 – 5300; m) T. Misaki, G. Takimoto, T. Sugimura, J. Am. Chem. Soc. 2010, 132, 6286 – 6287; n) T. Takeda, M. Terada, J. Am. Chem. Soc. 2013, 135, 15306 – 15309. For representative publications from our group, see: o) J. Shen, T. Nguyen, Y.-P. Goh, W. Ye, X. Fu, J. Xu, C.-H. Tan, J. Am. Chem. Soc. 2006, 128, 13692 – 13693; p) D. Leow, S. Lin, S. K. Chittimalla, X. Fu, C.-H. Tan, Angew. Chem. Int. Ed. 2008, 47, 5641 – 5645; Angew. Chem. 2008, 120, 5723 – 5727; q) X. Fu, W.-T. Loh, Y. Zhang, T. Chen, T. Ma, H. Liu, J. Wang, C.-H. Tan, Angew. Chem. Int. Ed. 2009, 48, 7387 – 7390; Angew. Chem. 2009, 121, 7523 – 7526; r) Z. Jiang, Y. Pan, Y. Zhao, T. Ma, R. Lee, Y. Yang, K.-W. Huang, M. W. Wong, C.-H. Tan, Angew. Chem. Int. Ed. 2009, 48, 3627 – 3631; Angew. Chem. 2009, 121, 3681 – 3685; s) H. Liu, D. Leow, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2009, 131, 7212 – 7213; t) H. Liu, W. Feng, C.-W. Kee, D. Leow, W.-T. Loh, C.-H. Tan, Adv. Synth. Catal. 2010, 352, 3373 – 3379; u) T. Ma, X. Fu, C.-W. Kee, L. Zong, Y. Pan, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2011, 133, 2828 – 2831. [6] a) J. D. Scott, R. M. Williams, Chem. Rev. 2002, 102, 1669 – 1730; b) M. Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104, 3341 – 3370; c) D. L. Comins, R. S. Al-awar, J. Org. Chem. 1992, 57, 4098 – 4103; d) D. L. Comins, C. A. Brooks, R. S. Al-awar, R. R. Goehring, Org. Lett. 1999, 1, 229 – 231. [7] V. Sai Sudhir, R. B. Nasir Baig, S. Chandrasekaran, Eur. J. Org. Chem. 2008, 2423 – 2429. [8] A. Surez, G. C. Fu, Angew. Chem. Int. Ed. 2004, 43, 3580 – 3582; Angew. Chem. 2004, 116, 3664 – 3666. [9] M. Kwit, M. D. Rozwadowska, J. Gawron´ski, A. Grajewska, J. Org. Chem. 2009, 74, 8051 – 8063. [10] M. Lautens, S. Ma, P. Chiu, J. Am. Chem. Soc. 1997, 119, 6478 – 6487. [11] CCDC 1029362, CCDC 1029365, CCDC 1029364, CCDC 1029363, CCDC 1052979 contain the supplementary crystallographic data for compounds 9 b, 10 b, and 9 c, and the hydrogenation product of 9 c and 9 e. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [12] CCDC 1052980 contains the supplementary crystallographic data for compound 1. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif.
Compound 16 (28 mg, 0.08 mmol) was dissolved in 1.5 mL EtOH, then an aqueous solution of Hg(OAc)2 and EDTA-2Na (1:1, 2.4 mL of a 0.1 m solution in water, 0.24 mmol) was added. The resulting solution was heated to 85 8C and refluxed for 3 h. Then the mixture was cooled to 0 8C and 2.5 mL 25 % HClO4 was added. The mixture was then stirred at 0 8C for 10 min and extracted with CH2Cl2 (4 Õ 5 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was re-dissolved in MeOH/H2O (9:1, v/v, 2.5 mL). The pH was adjusted to 6 using 5 % NaHCO3 solution. The mixture was cooled to 0 8C, and NaBH4 (0.6 mmol, 25 mg) was added. The reaction was brought to room temperature and stirred for an additional hour. The solvents were removed under reduced pressure, and the residue was partitioned between cold 10 % NH4OH and CH2Cl2. The aqueous layer was extracted with CH2Cl2 for 4 times, and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (hexane/ETOAc 1:1, then CH2Cl2/MeOH 20:1) to afford 1 as a white foam in 30 % yield.
Acknowledgements We gratefully acknowledge the financial support of grants from NTU (M4080946.110 and RG 6/12M40110018.110). Keywords: alkaloids · alkyne · chiral guanidine intramolecular-Diels–Alder reaction · total synthesis
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[1] For leading references and reviews of the monoterpenoid alkaloids of the indole family, see: a) J. E. Saxton in Specialist Periodical Reports, The Alkaloids, The Royal Society of Chemistry, Burlington House, London, 1983, 13, 221 – 237; b) T. E. Gaffney, C. A. Chidsey, E. Braunwald, Circ. Res. 1963, 12, 264 – 268. [2] For general reviews of synthetic approaches toward yohimbine alkaloids, see: a) M. E. Kuehne, R. S. Muth, J. Org. Chem. 1991, 56, 2701 – 2712. For examples of yohimbine synthesis see: b) E. E. van Tamelen, M. Shamma, A. W. Burgstahler, J. Wolinsky, R. Tamm, P. E. Aldrich, J. Am. Chem. Soc. 1958, 80, 5006 – 5007; c) E. E. van Tamelen, M. Shamma, A. W. Burgstahler, J. Wolinsky, R. Tamm, P. E. Aldrich, J. Am. Chem. Soc. 1969, 91, 7315 – 7333; d) L. Tçke, K. Honty, C. Szntay, Chem. Ber. 1969, 102, 3248 – 3259; e) G. Stork, R. N. Guthikonda, J. Am. Chem. Soc. 1972, 94, 5109 – 5110; f) E. Wenkert, J. St. Pyrek, S. Uesato, Y. D. Vankar, J. Am. Chem. Soc. 1982, 104, 2244 – 2246; g) O. Miyata, Y. Hirata, T. Naito, I. Ninomiya, J. Chem. Soc. Chem. Commun. 1983, 1231 – 1232; h) S. F. Martin, H. Rìeger, S. A. Williamson, S. Grzejszczak, J. Am. Chem. Soc. 1987, 109, 6124 – 6134; i) Y. Hirai, T. Terada, Y. Okaji, T. Yamazaki, T. Momose, Tetrahedron Lett. 1990, 31, 4755 – 4756; j) J. Aub¦, S. Ghosh, M. Tanol, J. Am. Chem. Soc. 1994, 116, 9009 – 9018; k) D. J. Mergott, S. J. Zuend, E. N. Jacobsen, Org. Lett. 2008, 10, 745 – 748; l) B. Herl¦, M. J. Wanner, J. H. van Maarseveen, H. Hiemstra, J. Org. Chem. 2011, 76, 8907 – 8912. For example of IMDAs in total synthesis: m) F. Matsuura, R. Peters, M. Anada, S. S. Harried, J. Hao, Y. Kishi, J. Am. Chem. Soc. 2006, 128, 7463 – 7465. [3] For a review of reserpine synthesis: a) E.-F. Chen, J. Huang, Chem. Rev. 2005, 105, 4671 – 4706. For more recent approaches, see: b) N. S. Rajapaksa, M. A. McGowan, M. Rienzo, E. N. Jacobsen, Org. Lett. 2013, 15, 706 – 709; c) A. G. Barcan, A. Patel, K. N. Houk, O. Kwon, Org. Lett. 2012, 14, 5388 – 5391; d) J. Huang, F.-E. Chen, Helv. Chim. Acta 2007, 90, 1366 – 1372.
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Manuscript received: March 15, 2015 Accepted Article published: April 30, 2015 Final Article published: June 12, 2015
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