The Chemistry of Indoles. CIII. Simple Syntheses of Serotonin, N-Methylserotonin, Bufotenine, 5-Methoxy-N-methyltryptamine, Bufobutanoic Acid, N-(Indol-3-yl)methyl-5-methoxy-N-methyltryptamine, and Lespedamine Based on 1-Hydroxyindole Chemistry.

Abstract

Tryptamine alkaloids such as serotonin 2) (1a, Chart 1), Nmethylserotonin 3) (1b), bufotenine 4a,b) (1c), 5-methoxy-Nmethyltryptamine 5) (2a), and melatonin 6) (2b) have marked physiological effects in spite of their simple chemical structures. Members of the alkaloid family are still increasing, thus bufobutanoic acid 7) (3a) and N- (indol-3-yl)methyl-5-methoxy-N-methyltryptamine 8) (4, Chart 2) have recently been isolated from Ch'an Su and the roots of Antirhea lucida (Sw.) HOOK (Rubiaceae), respectively. Lespedamine 9) (5, Chart 4) is an alkaloid isolated from Lespedeza bicolor var. japonica NAKAI.From the viewpoint of developing novel biologically active substances, the tryptamine alkaloids seem to be attractive target compounds. Although synthetic methods for 1a-c [2][3][4] and 2a,b 6) have already been established, they require many steps starting from expensive indoles having an oxygen functional group at the 5-position. In the case of 5, the unique 1-methoxyindole structure required chemists to devise an ingenious synthesis.10) Generally speaking, the above syntheses are complex compared to the simple structures of the target compounds. How to prepare a simple target in a simple way is the most challenging ongoing subject in our group.We have proposed 1-hydroxyindole hypotheses, 11) which could unify the biogenesis of many indole alkaloids by assuming 1-hydroxytryptamines (or 1-hydroxytryptophans) as common intermediates. In order to verify these hypotheses, we have created synthetic methods for the previously unknown 1-hydroxytryptamines.12) We have also realized unprecedented nucleophilic substitution reactions in indole chemistry, 13) which had been predicted in the hypotheses. 11)These findings were successfully applied to two simple synthetic routes to melatonin 1) (2b), starting from 6b and 6d through 8b and 8d, respectively. The present paper is a full report of the previous communications 14) and describes further applications of the above findings to novel and simple syntheses of 1a-c, 2a, 3a, 4, and 5 from tryptamine (6c). An alternative synthesis of 5 through 1-methoxy-2-oxindole derivatives is also reported.Syntheses of 1a, 1b, and 1c Syntheses of 1a-c were achieved as follows. First, N-methoxycarbonyltryptamine (6d), readily and quantitatively available from 6c by a conventional method, was converted to 7d by reduction with triethylsilane 15) (Et 3 SiH) in CF 3 COOH (TFA) in 97% yield. 1)Next, our 1-hydroxyindole synthetic method, 12) employing 30% hydrogen peroxide (H 2 O 2 ) in the presence of sodium tungstate dihydrate (Na 2 WO 4 · 2H 2 O) as a catalyst, was applied to 7d to produce a 67% yield of 1-hydroxy-N-methoxycarbonyltryptamine 1) (8d), a potent inhibitor of blood platelet aggregation.16) However, an attempt to obtain 8a from 7a by the 1-hydroxyindole synthetic method was unsuccessful because of the unstable nature of 8a.The desired regioselective nucleophilic hydroxylation at the 5-position was realized by reacting 8d with 85% formic acid (HCOOH) at room temperature for 14 h to a...

Isolation ofN,N-Dimethyl andN-Methylserotonin 5-O-β-Glucosides from ImmatureZanthoxylum piperitumSeeds

“…Their spectral data were identical to those of synthetic 3a or 3b prepared from serotonin by methylation, although they were not identical to those reported in the literature. 10,11) The discrepancy between our data and the literature data was due to the strong basicity of these compounds, the compounds reported in the literature being considered to be the carbonates of y To whom correspondence should be addressed. Tel/Fax: +81-58-293-2919; E-mail: nakatsu@gifu-u.ac.jp amines rather than the free amine.…”

Notoamides A–D: Prenylated Indole Alkaloids Isolated from a Marine‐Derived Fungus, Aspergillus sp.

“…The CD spectrum of 1 reveals that the absolute stereochemistry is the same as that of 2 (see http://www.wiley-vch.de/contents/jc_2002/2007/z604381_s.pdf). This is the first report of a naturally occurring 1‐hydroxy‐2‐oxindole alkaloid, although the synthesis of simple 1‐hydroxy‐2‐oxindoles has been reported 9…”

A Novel Synthesis of 3,4,5,6-Tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole Derivatives from Serotonin

“…Since various types of Nb-substituted serotonins are known as biologically active alkaloids, 17 it would be safe to expect that the compounds, 7 and 8, have biological activities as well. …”