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Observations Concerning the Synthesis of Tryptamine Homologues

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Observations Concerning the Synthesis of Tryptamine Homologues Tetrahedron 72 (2016) 2233e2238 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet Observations concerning the synthesis of tryptamine homologues and branched tryptamine derivatives via the borrowing hydrogen process: synthesis of psilocin, bufotenin, and serotonin Silvia Bartolucci, Michele Mari, Giovanni Di Gregorio, Giovanni Piersanti * Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Piazza del Rinascimento 6, 61029 Urbino PU, Italy article info abstract Article history: Observations concerning the synthesis of substituted tryptamine derivatives starting from indoles and Received 1 January 2016 1,n-amino alcohols via the borrowing hydrogen process are discussed. This catalytic, single-step, and Received in revised form 13 February 2016 modular approach to tryptamines and homotryptamines allows the synthesis of branched and non- Accepted 1 March 2016 branched tryptamines as well as tryptamine-based natural products such as psilocin, bufotenin, and Available online 8 March 2016 serotonin. Ó 2016 Elsevier Ltd. All rights reserved. Keywords: Indoles Amino alcohols Alkylation Borrowing hydrogen Natural products 1. Introduction alkyl halides or sulfonates as alkylating agents, which are both potentially genotoxic and relatively unstable.5 In light of their occurrence in a wide range of biologically active We recognized that tryptamine derivatives and tryptamine molecules, pharmaceuticals, and naturally occurring compounds, homologues could be accessed rapidly if suitable two-carbon or such as those outlined in Fig. 1, tryptamine derivatives have three-carbon nitrogen-containing electrophiles could be utilized. attracted comprehensive and continuous interest from the chem- To this end, we recently described the selective iridium-catalyzed ical community.1 In addition, tryptamine is the basis for some C3-alkylation of indoles with stable N-protected ethanolamines condensed ring alkaloids, and it is a key starting building block for involving the redox-neutral ‘borrowing hydrogen’ strategy under many intents and purposes, such as the total synthesis of polycyclic solvent-free conditions as a convenient and sustainable method for tryptamine-derived indole alkaloids.2 the direct construction of tryptamine derivatives from indoles.6 Based on that stated above, it is not surprising that an enormous Such catalytic redox-neutral oxidation-condensation-reduction amount of effort has recently been devoted to the development of processes7 offer several potential advantages over existing tech- efficient and operationally simple (i.e., atom-, step-, and redox- niques, such as the absence of unstable synthetic intermediates economical) methods for the direct synthesis of substituted trypt- (e.g., a-amino aldehydes), atom economy (water is the only amines from readily available starting materials, ideally indoles.3 byproduct of the reaction), operational simplicity, and reduced However, direct installation of an aminoalkyl group at the C3- environmental impact (solvent and waste stream reduction).8 position of the indole ring is challenging because of the lack of Herein, we present an extension of our methodology for the con- suitable (nontoxic and stable) electrophilic reagents that include venient and efficient formation of N-acetyl-protected branched a free or protected amino group. Thus, tryptamines are generally tryptamines and homotryptamine derivatives, as well as N-meth- synthesized in a multistep sequence requiring the use of a strong ylated tryptamine cores of biological importance such as psilocin, reducing agent4 or via ring-opening reactions of aziridines and bufotenin, and serotonin. 2. Results and discussion * Corresponding author. E-mail address: [email protected] (G. Initial studies were carried out using N-acetyl-protected prop- Piersanti). anolamine (2a) and butanolamine (2b) as representative suitable http://dx.doi.org/10.1016/j.tet.2016.03.007 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved. 2234 S. Bartolucci et al. / Tetrahedron 72 (2016) 2233e2238 Me Me NHAc Me Me Me NHAc NH2 N N OH MeO MeO HO HO N N H Cl N N N H H H H Melatonin TIK-301 Serotonin Bufotenin Psilocin Me Me Me N Me N N F O O MeHN H S S N MeHN O O N O H N N H H Sumatriptan Naratriptan LY- 334370 H2NOC O N H N NHMe N NC Br N N N H H H Vilazodone Desformylflustrabromine Aurantioclavine Fig. 1. Some important tryptamine-derived drugs (marketed and candidate) and natural products. three-carbon and four-carbon nitrogen-containing electrophiles. Lower conversions and increased byproduct formation were gen- Pleasingly, complete indole consumption and good yields of erally observed when solvents such as toulene, tert-amylalcohol, homotryptamine (3a) and dihomotryptamine (3b) were observed and trifluoroethanol were employed. after 48 h at 150 C when powdered Cs2CO3 was used as the base Apart from tryptamine analogues and homologues with linear and [Cp*IrCl2]2 was used as the catalyst (Table 1, entries 1 and 2). side chains, derivatives with branched side chains, both in the a- We succeeded in carrying out the alkylation reaction even with and b-positions, are becoming increasingly studied in medicinal longer carbon chain N-acetylated primary amino alcohols; for ex- chemistry due to their ability to discriminate between the seroto- ample, using 2c, 3c has isolated in modest yield (Table 1, entry 3). nin/melatonin receptor family subtypes. Recently, the first exam- ples of branched tryptamines possessing pharmacologically interesting properties have been developed.9 Thus, we then turned Table 1 our attention to more sophisticated substituted N-acetylethanol- Synthesis of N-acetyltryptamine homologuesa amines, such as the homochiral primary N-acetyl-L-alaninol (4a) and N-acetyl-L-serine (4b), knowing their sensitivity toward race- mization, once oxidised to the transient aldehyde. Interestingly, the methyl-substituted amino alcohol derivative 4a performed poorly in this reaction, possibly due to the increased steric hindrance around the nitrogen atom that precludes effective ligand dissocia- tion from the iridium center. Notably, we did not observe any products that could arise from the potentially competitive four- Entry N-Acetylamino alcohol Product Yield (%)b membered ring cycloiridation pathway. Strong electron- withdrawing groups adjacent to the amine motif also failed to produce the desired product tryptophans in acceptable yields. In 1 54 addition, the small amounts of products 5a and 5b obtained were racemic, as expected (Table 2, entries 1 and 2). A different outcome was obtained when we examined the ap- plicability of the borrowing hydrogen reaction of indoles with ra- cemic secondary N-acetyl ethanolamines, which proceeds via 2 76 generally less electrophilic ketones (Table 2, entries 3 and 4). Therefore, we elected to examine the behavior of indole in a bor- rowing hydrogen alkylation with N-acetyl-2-propanolamine (4c) and 2-acetamido-1-phenylethanol (4d). We found that iridium- catalyzed indole alkylation with branched alcohol 4c afforded a superior yield to the parent linear congeners, and we ascribe this 3 57 reactivity to the relatively lower energetic demand of secondary alcohol dehydrogenation compared to primary alcohols, as well as a Reactions were carried out in a sealed vial at 150 C for 48 h with indole the faster elimination of water from the adduct-formed alcohol- (1 equiv), N-acetylamino alcohol (3 equiv), [Cp*IrCl2]2 (2.5 mol %), and Cs2CO3 containing products of ketone addition. Unsatisfactory results were (1.1 equiv). obtained when chiral Ir complexes and/or chiral ligands were b Isolated yield. S. Bartolucci et al. / Tetrahedron 72 (2016) 2233e2238 2235 Table 2 Since most indole-based central nervous system drugs used in a b Synthesis of - and -branched tryptamines and branched homotryptamines from the treatment of migraines and cluster headaches, as well as some indole and amino alcoholsa psychoactive natural product tryptamines, are tryptamine-based dimethylated amines,13 we used the commercially available and highly interesting amino alcohol N,N-dimethylethanolamine (7a) to further demonstrate the application of this methodology. We adopted this chemistry for the total syntheses of psilocin and bufotenin in a straightforward manner (Table 3). Thus, the reaction of known 4-benzyloxyindole (6a) and 5-benzyloxyindole (6b) with N,N-dimethylethanolamine (7a) provided the desired products, which were debenzylated under hydrogenolysis conditions to af- Entry Amino alcohol Product Yield (%)b ford psilocin and bufotenin in 61% and 67% overall yields, re- spectively. The salient features of this method include the single- step preparation of the tryptamine core through displacement of 1 37 the alcohol without the need for prior activation and without resorting to a high dilution or the use of a protected amine or final reductive alkylation for the tertiary amine. Among the biologically important hydroxytryptamines, serotonin is perhaps the most im- portant and best known as a neurotransmitter that modulates 2 15 neural activity and a wide range of neuropsychological processes.14 Despite the fact that several syntheses and biosytheses of serotonin have been described,15 none seem practical or economical; thus, serotonin is still quite expensive on the market. Using our pro- cedure of treating 5-benzyloxyindole with N-benzylethanolamine 3 78 under Ir-catalyzed borrowing hydrogen conditions, followed by double debenzylation by catalytic reduction with palladium
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