International Congress Series 1304 (2007) 46 – 59 www.ics-elsevier.com Variety of natural products derived from tryptophan and stereoselective synthesis of tetrahydro-β-carboline derivatives of pharmacological importance Piotr Roszkowski a , Stefan Czarnocki a , Jan K. Maurin b,c , Aleksandra Siwicka a , Anna Zawadzka a , Joanna Szawkało a , Andrzej Leniewski a , Zbigniew Czarnocki a,⁎ a Faculty of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland b National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland c Institute of Atomic Energy, 05-400 Otwock-Świerk, Poland Abstract. The use of chiral inductors belonging to different classes of compounds is elaborated. Tetrahydro-β-carboline derivatives were constructed stereoselectively by the use of (R)-1- arylethylamine and L-amino acids. Asymmetric transfer hydrogenation was proven highly effective in enantioselective synthesis of several alkaloids. © 2007 Elsevier B.V. All rights reserved. Keywords: Alkaloids; Biomimetic synthesis; Chirality transfer; Stereocontrolled synthesis; Organocatalysis; Metal complexes; Secondary metabolites; L-tryptophan 1. Introduction One of the most challenging topics in modern organic chemistry is the synthesis of natural products. Despite the considerable exploration within this field to date, there is still a need for further development of alternative, preferably biomimetic and/or catalytic ways for preparation of bioactive compounds. Among the numerous families of natural products, isoquinoline and β-carboline alkaloids seem to attract the biggest attention due to their abundant presence in plants and even in the ⁎ Corresponding author. Tel.: +48 22 822 02 11; fax: +48 22 822 59 96. E-mail address: firstname.lastname@example.org (Z. Czarnocki). 0531-5131/ © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2007.07.003 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 47 animal kingdom, along with their often important physiological activities . Their bioactivity ranges from highly toxic, for example strychnine , to antihypertensive, for example ajmalicyne  and reserpine , and the cytotoxic activity shown by vincoleucoblastine and vincristine used for cancer chemotherapy [5,6]. All these medicinal alkaloids (Scheme 1) are basically indole derivatives formed from tryptamine provided by tryptophan and a terpenoid part provided by the iridoid glucoside secologanin. Tryptamine and secologanin are condensed to form stereoselectively strictosidine, which is the common precursor of all indole alkaloids . The biodifferentiation of enantiomers together with clinical applications and regulatory pressure upon the pharmaceutical industry, constitute important reasons for the preparation of tetrahydroisoquinolines and of tetrahydro-β-carboline in their enantiomerically pure forms. 2. Stereoselective synthesis from popular chiral inductors The tetrahydro-β-carboline skeleton is a common structural feature of numerous secondary metabolites, including Vinca-, Rauwolfia- and Harman-alkaloids. Many of these bases possess a tremendous value to pharmacology and were attractive synthetic targets for both academic and industrial research groups. In the synthesis of this class of compounds, the chirality on the C-1 carbon atom was often introduced by the use of chiral adjuvant in a stochiometric amount serving as a chiral building block or diastereoinducing auxiliary. All “classical” methods for tetrahydro-β-carboline framework formation were modified by the introduction of the stereochemistry source. The Pictet–Spengler, Bischler–Napieralski and the Pomeranz–Fritsch cyclizations gained the highest popularity . Natural hydroxyacids constitute an important group of enantiopure compounds that have generated a tremendous impact on organic stereochemistry. Among them, tartaric and malic acids were most frequently used as cheap and relatively configurationally stable reagents available in both enantiomeric forms. They can be used as resolving agents, chiral building blocks, chiral auxiliaries and ligands for asymmetric transformations . Surprisingly, the stereoselective synthesis of tetrahydroisoquinoline and β-carboline systems has not taken advantage of the Scheme 1. Selected L-tryptophan secondary metabolites. 48 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 Scheme 2. Reaction sequence leading to diastereoselective synthesis of tetrahydro-β-carboline derivatives (9a,b and 10a,b). reach chemistry of these acids except in only a few examples [10–13]. Other compounds that were used as chiral auxiliaries in asymmetric synthesis of isoquinoline and β-carboline derivatives are amino acids. Many examples of the use of α-amino acids in different optical activation methods were already thoroughly summarized. In the detailed works by Coppola and Schuster  and later by Rozwadowska , the vast amount of references was reviewed. In asymmetric transformations the enantiopure 1-phenylethylamine and its congeners still remain attractive chirality sources. Their use as resolving agents, chiral ligands in catalytic processes and synthetic chiral auxiliaries in stereodifferentiating reactions of prochiral substrates has been the subject of in-depth reviews . 2.1. (R)-1-phenylethylamine and its analogs as chiral auxiliaries in diastereoselective synthesis of tetrahydro-β-carboline derivatives In the field of the stereoselective synthesis of pharmacologically relevant compounds, we presented recently the application of α-phenylethylamine (α-PEA) in the preparation of enantiomerically pure lortalamine analogs  and (R)-(−)-mianserin  — both compounds being well-known antidepressants. The Bischler–Napieralski cyclization followed by a diastereoselective reduction of the imine bond were the key steps in enantiodivergent synthesis of both enantiomers of N-acetylcalycotomine that were carried out in our laboratory . Being encouraged by positive results of using α-PEA in the stereoselective formation of isoquinoline alkaloids, we decided to extend this procedure to tetrahydro-β-carboline analogs. The synthetic sequence started with the reaction of tryptamine 1 with diethyl oxalate followed by the treatment with (R)-1-phenylethylamine to afford diamide 5 almost quantitatively (Scheme 2). After careful optimization we found that the subsequent P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 49 Table 1 Diastereoselectivity in the reduction with various borohydrides Entry Reducing reagent 9(10)a:9(10)b 1 NaBH4 62:38 (66:34) 2 NaBH(CH3COO)3 75:25 (76:24) 3 NaBH[(CH3)2CHCOO]3 66:34 (64:36) 4 NaBH[(CH3)3CCOO]3 78:22 (83:17) Bischler–Napieralski cyclization gave the best results when performed in refluxing dichloromethane with POCl3. The resulting hydrochloride salt of imine 7 was treated with sodium borohydride in EtOH and a pair of diastereomeric amines 9a and 9b was formed in 62:38 ratio respectively, based upon the 1H NMR spectrum taken on the crude reaction mixture. The ratio of 9a and 9b was affected neither by a prolonged contact with a strongly basic solution of the reducing agent nor by the solvent variations, and observations ruled out the possibility of an asymmetric transformation. Disappointingly, the diastereoselectivity was not improved significantly when the hydrides NaBH(AcO)3, NaBH(i-PrCOO)3 and NaBH(t-BuCOO)3 were applied. Fortunately, the mixture of isomers could be effectively separated by column chroma- tography affording pure and stable compounds 9a and 9b. The configuration at C-1 in both compounds was assigned indirectly based on the comparison of the 1H and 13C NMR spectroscopic data and the specific rotation values with those recorded for the isoquinoline series prepared previously by us  and for which the stereochemistry was established by X- ray studies. Seeking further improvement in stereoselectivity, we decided to apply the same synthetic sequence using (R)-(+)-1-(-1-naphthyl)ethylamine 4 as a chiral auxiliary, another well-known and effective chiral inductor . Thus, compound 8 was prepared in good yield from tryptamine 1 and was consecutively subjected to a series of reactions affording diastereomers 10a and 10b. The results were summarized in Table 1. In contrast to previous results in the isoquinoline series , the increase of steric parameters, neither in the reducing agent molecule nor in the imine-containing target derivative 8, gave a significant improvement of the stereochemical outcome. In a search for a feasible explanation of the above observation we investigated the problem using quantum chemical methods. We performed a molecular modelling to find the optimal geometry of 7. The procedure consisted of a consecutive molecular mechanic search through a conformational space and ab initio calculations used for conformers to optimize their geometries . Fig. 1. Lowest energy conformer of imine 7 by Haetree–Fock 6–31G⁎⁎. 50 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 Scheme 3. The construction of chiral nonracemic β-carbolines from L-amino acids. The lowest energy conformer of imine 7 is shown in Fig. 1. A strong hydrogen bond between the amide carbonyl group and the indole NH define the basic shape of the reacting part of the molecule causing the chiral auxiliary part to adopt a remote position from the imine moiety. Apparently, such a disfavoring interaction was not present in the isoquinoline analog of imine 7, allowing us to achieve much better chirality induction . 2.2. L-amino acids as chiral inductors in stereoselective synthesis of tetrahydro-β-carboline derivatives Amino acids are of fundamental importance due to their versatility and their widespread use in organic synthesis. Many methods utilize amino acids as a substantial fragment of the final molecule, as the chiral ligands, or as part of the catalyst applied in sub-molar amounts. The Pictet–Spengler reaction starting from L-tryptophan (the use of its enantiomer is known but much less common), appears to be the most direct way of forming a chiral β-carboline skeleton [21,22]. Among other amino acids, L-proline is the second most frequently used chiral adjuvant after tryptophan enantiomers. The proline molecule plays more often a chirality-inducing role than being a chiral building block. Simple amino acids like L-alanine and L-valine could also provide a high level of the chiral induction while being used as building blocks . P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 51 Fig. 2. 1H NMR of the crude reaction mixture of compounds 19a and 19b. 2.2.1. L-alanine and L-valine as chiral inductors in stereoselective synthesis of β-carboline derivatives Following the contemporary approach of applying biogenic amino acids into the synthesis of the alkaloidal system, we would like to present our recent results in constructing indole derivatives in a stereoselective way using amino acids as chiral inductors. This work is connected with the construction of psychoactive compounds found in the human body, so- called mammalian alkaloids, and is of considerable interest to neurochemistry. Recently, we proposed a general method for the construction of isoquinoline and β- carboline systems, which utilized natural amino acids as the source of chirality [23–25]. As shown in Scheme 3, the first step consisted of the preparation of amides 13, 14, from N- blocked-N-methyl-L-amino acids in the presence of BOP as a coupling mediator and subsequent deblocking of the nitrogen atom under hydrogenolytic conditions. This sequence proved to be extremely efficient, according to the enantiomeric integrity as well as to the chemical yield. Subsequent BOP-mediated coupling of amides 13 or 14 with phenylpyruvic acid gave ketoamides 15 or 16 easily isolated from the reaction mixture. Initial attempts to apply the Pictet–Spengler-type condensation with methanolic hydrogen chloride solution provided low diastereoselectivity. Thus, we decided to change the solvent into the aprotic one and to manipulate with temperature conditions. Accordingly, we found that the best diastereoselec- tivity was obtained when ethyl acetate was applied as a solvent at room temperature. The diastereomeric mixture of L-alanine derivatives 19a and 19b had a ratio of 91:9 while those derived from L-valine (20a and 20b) had a ratio of 93:7 (in both cases diastereoisomer ratio was established on the basis of 1H NMR of the crude reaction mixture (Fig. 2). Fig. 3. X-ray analysis of the major diastereoisomer 20a. 52 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 Scheme 4. The construction of chiral nonracemic β-carbolines from L-proline. The X-ray analysis of the predominant diastereomer 20a revealed the (R)-configuration at the newly created stereogenic center (Fig. 3). 2.2.2. L-proline as chiral inductor in the stereoselective synthesis of β-carboline derivatives Due to our previous findings in the field of isoquinoline alkaloids , we expected better stereochemical outcome along with the opposite diastereomeric preference in the case of the use of L-proline as a chiral inductor. The Pictet–Spengler reaction catalyzed by hydrogen chloride in ethyl acetate afforded the mixture of diastereomers 25a and 25b in a ratio of 93:7 (Scheme 4). In a search for a compound forming suitable crystals for rentgenographic study, we prepared the chloroderivative 26a in 41% overall chemical yield and in 98% de. Subsequent X-ray analysis confirmed the previously postulated (S) configuration at C-1 atom (Fig. 4). Fig. 4. Structure and X-ray analysis of major diastereoizomer 26a. P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 53 Scheme 5. The different chirality induction in the Pictet–Spengler reaction from acyclic L-amino acids and L-proline. In summary, several tetrahydroisoquinoline and β-carboline derivatives bearing a quaternary carbon atom were prepared in a stereoselective way under the chiral influence of L-amino acids. The biomimetic type Pictet–Spengler condensation was accompanied by 1,4-chirality transfer which in several cases proceeded in surprisingly high efficiency approaching 100% de with good-to-excellent chemical yield. The stereochemistry of the final diketopiperazines strongly depended on the structure of L-amino acids used: acyclic amino acids gave predominantly the (R)-configuration at the newly created stereogenic center, whereas L-proline afforded the formation of the opposite configuration (Scheme 5). This interesting feature allows the diastereodivergent creation of chirality within these reactions. Again, the X-ray analysis proved to be an indispensable tool for the stereochemical assignments. 3. Enantioselective synthesis of β-carbolines by asymmetric transfer hydrogenation Transition-metal catalyzed asymmetric transfer hydrogenation (ATH) has emerged as an efficient and practical method for the enantioselective reduction of prochiral ketones and imines to secondary alcohols and amines. In recent years, a considerable number of chiral metal complexes have been prepared and examined as catalysts in the reduction reactions . The most successful catalysts so far are based on [RuCl2(arene)]2 combined with chiral, enantiomerically pure 1,2-amino alcohols or mono-N-sulfonated 1,2-diamines (e.g., TsDPEN) [27,28] — Scheme 6. The most common hydrogen source for the catalytic transfer hydrogenation of ketones is 2-propanol, although the use of formic acid, in particular a 5:2 formic acid/triethyl amine azeotropic mixture, is usually the preferred reductant because of the favorable irreversible process. 3.1. Enantioselective synthesis of 1-alkyl-tetrahydro-β-carbolines The tetrahydro-β-carboline skeleton is a common structural feature of numerous secondary metabolites, including Vinca-, Rauvolfia-, and Harman-type alkaloids. Many of 54 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 Scheme 6. The most effective ligands used in ATH. these bases have a tremendous value to pharmacology and were attractive synthetic targets for both academic and industrial research groups. Recently, it was shown that several tetrahydro-β-carbolines have the ability to bind with high affinity to serotonin receptors in the central nervous system. This is probably responsible for their observed neuroactivity . On the other hand, the derivatives of biologically important amines (e.g., catechola- mines) and long-chain fatty acids have gained considerable interest in recent years as a new family of lipids . Bioactive fatty acid amides have been recently suggested to play an important role in the nervous system . The possibility that neurotransmitters exist in N- acylated forms was postulated in 1998 by Pokorski and Matysiak . Pokorski and Czarnocki  have recently shown on the basis of radioactive labeling that N- acyldopamines can easily move through the brain–blood barrier and may therefore play a role as pro-drugs capable of slow-release of dopamine within the brain. During our collaboration with biochemical investigators the need arose for the synthesis of an analogous series of tetrahydro-β-carbolines, possibly in a stereoselective way. In this respect, the Bischler–Napieralski-based methodology appeared quite attractive since it provided the prochiral environment for enantioselective reductions of the imine moiety . Tryptamine was subjected to reactions with fatty acids to afford appropriate amides in good yield. All amides were then treated in a Bischler–Napieralski cyclization condition (POCl3, CH2Cl2 or P2O5, toluene) yielding relatively stable imines 32a–f. They were then subjected to the asymmetric transfer hydrogenation protocol (Scheme 7) according to the procedure described by Noyori et al. . The stereochemistry of the catalyst determined that of the amine formed. As such, products with (1R) configuration were obtained when (S,S)-28 was used, whereas the (1S) isomers were obtained under the influence (R,R)-28. The results of reductions were summarized in Table 2. The amines were then transformed into their derivatives with the (R)-Mosher acid chloride in order to determine the diastereomeric ratios in 1H NMR P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 55 Scheme 7. Asymmetric transfer hydrogenation of 3,4-dihydro-β-carbolines. spectra. The Mosher amide of amine (1R)-33c was also obtained in a form of monocrystal suitable for X-ray crystallography that served for an unambiguous stereochemistry assignment . 3.2. Enantioselective synthesis of (+)-harmicine and (+)-desbromoarborescidine A The basic fraction of the ethanolic extract from the leaves of the Malaysian plant Kopsia griffithii exhibits a profound anti-leishmania activity . Among several nitrogen bases found in this extract, (R)-(+)-harmicine (+)-38 is suspected to be responsible for the pharmacological profile of the plant. An elegant synthesis of the racemic harmicine has recently been published . Also, (S)-(−)-harmicine (−)-38 was made using a chiral 1- allyl-1,2,3,4-tetrahydro-β-carboline as the starting material . The second alkaloid desbromoarborescidine 39, containing indolo [2,3-a] quinolizine heterocyclic ring system, was isolated from the bark of Dragontomelum mangiferum . Table 2 Asymmetric transfer hydrogenation of imines Imine Ru (II) catalyst with Amine Yield % e ee % f Configuration d [α]23 D 32a (S,S)-27 (1R)-33a 84 N98 R +55.6 a 32a (R,R)-27 (1S)-33a 82 N98 S − 56.8 a 32a (1R,2S)-29 (1R)-33a 30 39 R +22.0 a 32a (1S,2S)-30 (1R)-33a 28 37 S − 20.6 a 32a (R,R)-31 (1S)-33a 98 71 S − 40.0 a 32b (S,S)-27 (1R)-33b 79 N98 R +72.7 b 32b (R,R)-27 (1S)-33b 88 N98 S − 73.5 b 32c (S,S)-27 (1R)-33c 85 N98 R +54.7 b 32c (R,R)-27 (1S)-33c 81 N98 S − 54.0 b 32d (S,S)-27 (1R)-33d 79 N98 R +33.7 c 32d (R,R)-27 (1S)-33d 77 N98 S − 34.0 c 32e (S,S)-27 (1R)-33e 84 N98 R +25.8 c 32e (R,R)-27 (1S)-33e 77 N98 S − 26.5 c 32f (S,S)-27 (1R)-33f 70 N98 R +10.2 c a EtOH, c = 2. b EtOH c = 1.0. c CHCl3 c = 1.0. d By comparison of [α]D sign and X-ray analysis of 33c derivative. e Isolated yield of pure compounds. f On the basis of 1H NMR of Mosher's amides. 56 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 Scheme 8. Enantioselective synthesis of (R)-(+)-harmicine and (+)-desbromoarborescidine A. The synthetic pathway of these alkaloids used by us contain as a first step the condensation of γ-butyrolactone or δ-varelolactone with tryptamine to afford hydroxyamides 34 and 35. Subsequent Bischler–Napieralski cyclization of 34 or 35 in POCl3 gave, after a short work- up, iminium salts 36 or 37. The asymmetric transfer hydrogenation of 36 and 37 under standard conditions using (S,S)-28 as the catalyst gave (+)-harmicine (+)-19 in 81% chemical yield and (+)-desbromoarborescidine A (+)-22 in 84% chemical yield (Scheme 8) . The maximum value of the enantiomeric excess (determined by the basis of 1H NMR experiments with phosphinothioic acid for amine 38 and its selenium analog for amine 39) was only 79 and 83% respectively, despite our optimization efforts. Fortunately, after single crystallization, the enantiopure alkaloids could be obtained . Final absolute stereochemistry assignment was done by X-ray crystallography. The result that indicated the (R) configuration is in accordance with the data collected for analogous heterocyclic systems (Fig. 5a and b). Fig. 5. a. The absolute stereochemistry of (R)-(+)-38. b. The absolute stereochemistry of (R)-(+)-39. P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 57 Scheme 9. Total synthesis of (+)-trypargine. 3.3. Enantioselective synthesis of (+)-trypargine (−)-Trypargine is an optically active and unique 1-substituted tetrahydro-β-carboline derivative isolated from the African frog Kassina senegalensis  and Eudistoma sp. Ascidian . Trypargine has been reported to be toxic to mice (LD50 16.9 mg/kg, intravenous administration) and to block voltage gated sodium currents in squid axon membrane in a potential-dependent manner . The group of Ishikawa reported total synthesis of (−)-trypargine started from tryptophan but this method was multistep and tedious [41,42]. In our enantioselective synthesis of (+)-trypargine we applied the asymmetric hydrogen transfer process using chiral complex (S,S)-28 — Scheme 9. The enantiopure amine 42 was obtained in good yield. Its enantiomeric purity was confirmed by 1H NMR investigations with (+)-(R)-t-buthylphenylphosphinothioic acid as a chiral solvating agent. The final product was formed after deprotection with hydrazine followed by guanidylation with N,N'-bis(Boc)-S- methylisothiourea  and subsequent deprotection of the guanidine moiety. Acknowledgment Financial support from grants PBZ-KBN-126/T09/2004/13 and KBN-1315/T09/2005/ 29 is gratefully acknowledged. References  B.T. Ho, et al., Inhibitors of monoamine oxidase, J. Pharm. Sci. 57 (1968) 269–273.  J.B. Hendrickson, in: R.H.F. Manske, H.L. Holmes (Eds.), The Alkaloids, vol. 6, Academic Press, New York, 1960, p. 179.  N. Neuss, in: J.D. Philipson, M.H. Zenk (Eds.), Indole and Biogenetically Related Alkaloids, Academic Press, London, 1980, p. 293.  J.M. Müller, E. Schlittler, H.J. Bein, Reserpin, the sedative principle from Rauwolfia serpentina B, Experientia 8 (1952) 338. 58 P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59  R. van der Heijden, et al., The Catharanthus alkaloids: pharmacognosy and biotechnology, Curr. Med. Chem. 11 (2004) 607–628.  N. Neuss, et al., Vinca alkaloids. XX. The structures of the oncolytic alkaloids vinblastine (VLB) and vincristine (VCR), J. Am. Chem. Soc. 86 (1964) 1440–1442.  T.W. Southin, J. Buckingham, Dictionary of Alkaloids, vol. 3, Chapman&Hall, London, 1979.  Z. Czarnocki, A. Siwicka, J. Szawkało, Selected recent advances in the stereoselective synthesis of isoquinoline and β-carboline derivatives with the use of chiral auxiliaries of natural origin, Curr. Org. Syn. 2 (2005) 301–331.  J. Gawroński, K. Gawrońska, Tartaric and Malic Acids in Synthesis, Wiley-Interscience, New York, 1999.  Z. Czarnocki, D.B. MacLean, W.A. Szarek, Enantioselective synthesis of isoquinoline alkaloids: phenylethylisoquinoline and aporphine alkaloids, Can. J. Chem. 65 (1987) 2356–2361.  Z. Araźny, et al., Enantioselective synthesis of (1R)-1-(hydroxymethyl)-2-acetyl-1,3,4,9-tetrahydro-2H-b- carboline from L-(+)-tartaric acid, Tetrahedron: Asymmetry 11 (2000) 2793–2800.  Y.S. Lee, et al., Asymmetric synthesis of both enantiomers of pyrrolidinoisoquinoline derivatives from L-malic acid and L-tartaric acid, J. Org. Chem. 60 (1995) 7149–7152.  Z. Kałuża, D. Mostowicz, Synthesis of enantiopure 1,2-dihydroxyhexahydropyrroloisoquinolines as potential tools for asymmetric catalysis, Tetrahedron: Asymmetry 14 (2003) 225–232.  G.M. Coppola, H.F. Schuster, Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids, John Wiley & Sons, New York, 1987.  M.D. Rozwadowska, Recent progress in the enantioselective synthesis of isoquinoline alkaloids, Heterocycles 39 (1994) 903–931.  E. Juaristi, et al., Recent applications of α-phenylethylamine (α-PEA) in the preparation of enantiopure compounds. Part 3: α-PEA as chiral auxiliary. Part 4: α-PEA as chiral reagent in the stereodifferentiation of prochiral substrates, Tetrahedron: Asymmetry 10 (1995) 2441–2495.  J. Biała, Z. Czarnocki, J.K. Maurin, Diastereoselective synthesis of lortalamine analogs, Tetrahedron: Asymmetry 13 (2002) 1021–1023.  J. Pawłowska, et al., Stereoselective synthesis of (R)-(−)-mianserin, Tetrahedron: Asymmetry 14 (2003) 3335–3342.  M. Ziółkowski, et al., (S)-(−)-α-methylbenzylamine as an efficient chiral auxiliary in enantiodivergent synthesis of both enantiomers of N-acetylcalycotomine, Tetrahedron: Asymmetry 10 (1999) 3371–3380.  We used a Spartan'04 for Windows software (Spartan'04, Wavefunction Inc., Irvine, California, USA, 2005) for both tasks. A conformational search using MMFF94 force field and a Monte Carlo algorithm was performed. Two different low energy conformers were selected for further ab initio optimization. A restricted Hartree–Fock method with the standard 6–31G⁎⁎ basis set was then applied. These calculations showed that the conformational energy ΔE between 7a and 7b was 2.383 kcal/mol.  D.B. Bailey, et al., A concise, efficient route to fumitremorgins, Tetrahedron Lett. 42 (2001) 113–115.  A. Ardeo, et al., A practical approach to the fused β-carboline system. Asymmetric synthesis of indolo[2,3-a] indolizidinones via a diastereoselective intramolecular á-amidoalkylation reaction, Tetrahedron Lett. 44 (2003) 8445–8448.  A. Zawadzka, et al., Diastereoslective synthesis of 1-benzyltetrahydroisoquinoline derivatives from amino acids via 1,4 chirality transfer Part 1, Org. Lett. 3 (2001) 997–999.  A. Zawadzka, et al., Diastereoselective synthesis of 1-benzyltetrahydroisoquinoline derivatives from amino acids by 1,4 chirality transfer, Eur. J. Org. Chem. (2003) 2443–2453.  A. Siwicka, et al., Diastereodivergent synthesis of 2,5-diketopiperazine derivatives of b-carboline and isoquinoline from L-amino acids, Tetrahedron: Asymmetry 16 (2005) 975–993.  T. Ohkuma, R. Noyori, in: E.N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis I, Springer, Heidelberg, 1999, pp. 199–246.  R. Noyori, S. Hashiguchi, Asymmetric transfer hydrogenation catalyzed by chiral ruthenium complexes, Acc. Chem. Res. 30 (1997) 97–102.  M.J. Palmer, M. Wills, Asymmetric transfer hydrogenation of C_O and C_N bonds, Tetrahedron: Asymmetry 10 (1999) 2045–2061.  A. Agarwal, et al., Three-dimensional quantitative structure–activity relationships of 5-HT receptor binding data for tetrahydropyridinylindole derivatives: a comparison of the Hansch and CoMFA methods, J. Med. Chem. 36 (1993) 4006–4014.  D.L. Boger, S.J. Henriksen, B.F. Cravat, Oleamide: an endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules, Curr. Pharm. Des. 4 (1998) 303–314. P. Roszkowski et al. / International Congress Series 1304 (2007) 46–59 59  T. Bisogno, et al., Biosynthesis and degradation of bioactive fatty acid amides in human breast cancer and rat pheochromocytoma cells. Implications for cell proliferation and differentiation, Eur. J. Biochem. 254 (1998) 634–642.  M. Pokorski, Z. Matysiak, Fatty acid acylation of dopamine in the carotid body, Med. Hypotheses 50 (1998) 131–133.  M. Pokorski, et al., Brain uptake of radiolabeled N-oleyl-dopamine in the rat, Drug Dev. Res. 60 (2003) 217–224.  P. Roszkowski, et al., Enantioselective synthesis of 1-substituted tetrahydro-β-carboline derivatives via the asymmetric transfer hydrogenation, J. Mol. Catal., A Chem. 232 (2005) 143–149.  N. Uematsu, et al., Asymmetric transfer hydrogenation of imines, J. Am. Chem. Soc. 118 (1996) 4916–4917.  H.J. Knolker, S. Agarwal, Novel three-step synthesis of (±)-harmicine, Synlett 10 (2004) 1767–1768.  T. Itoh, et al., Synthesis of 1,2,3,4,6,7,12b-octahydroindolo[2,3-a]quinolizine and (S)-harmicine were carried out using chiral 1-allyl-1,2,3,4-tetrahydro-β-carboline as the starting material, Heterocycles 63 (2004) 655–661.  J. Szawkało, et al., Enantioselective synthesis of some tetrahydroisoquinoline and tetrahydro-β-carboline alkaloids, Tetrahedron: Asymmetry 18 (2007) 406–413.  T. Akizawa, et al., Trypargine, a new tetahydro-β-carboline of animal origin: isolation and chemical characterization from the skin of African rhacophorid frog, Kassina senegalensis, Biomed. Res. 3 (1982) 232–234.  R.M. van Wagoner, et al., Trypargine alkaloids from a previously undescribed Eudistoma sp. Ascidian, J. Nat. Prod. 62 (1999) 794–797.  M. Shimizu, et al., Asymmetric synthesis and absolute configuration of (−)-trypargine, Chem. Pharm. Bull. 32 (1984) 1313–1325.  M. Shimizu, et al., Total synthesis of (−)-trypargine, Chem. Pharm. Bull. 30 (1982) 909–914.  T. Gers, et al., Reagents for efficient conversion of amines to protected guanidines, Synthesis 1 (2004) 37–42.