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...

Aurantioclabine (1a) and clavicipitic acid (1b) are members of ergot alkaloids (Fig. 1).2) Na,Nb-Dimethylserotonin (2a), serotonin (2b), and Nb-methylserotonin (2c) are well known biologically active amines.3) Combination of the former compounds with the latter ones results in a chimera skeleton such as 7-substituted 3,4,5,6-tetrahydro-1H-azepino- [5,4,3-cd]indole, as shown in a general formula (3). In our attempt to develop biologically active substances, we have identified 3 and its various derivatives to be possible promising compounds.In 1988, we reported the preparation of 3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd]indole derivatives (4) starting from 4-cyanoindoles.4) However, the synthetic route is not applicable for the preparation of 3, because suitably functionalized 4-cyanoindole derivatives are not readily available.5) On the other hand, we have established a simple method for serotonin congeners 6a) (2a-c) utilizing our 1-hydroxyindole chemistry.7) Making use of 2a-c as starting materials, we now wish to report our success in developing a novel synthetic method for 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino- [5,4,3-cd]indoles (5) as one of our targets (3). Synthesis of 3,4, 5,5,4,indole (5a) was easily attained by refluxing the MeOH solution of Na, in the presence of excess Et 3 N under an oxygen atmosphere. The results of this novel reaction are summarized in Table 1. The desired 5a and an unreacted 2a were obtained in 26 and 74% yields, respectively, after refluxing for 20 h (entry 1). As can be seen from entries 1-3, the longer the reaction time, the better the yield of 5a. It should be noted that the reaction was clean, and no tar formation was observed; thus, even after 68 h refluxing, only 5a and 2a were obtained in 49 and 50% yields, respectively (entry 3). Interestingly, the introduction of bubbling oxygen into the reaction medium did not improve the rate of formation or the yield of 5a. I. A Novel Reaction for Preparing 3,4,5,6-Tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indolesThe compound (5a) was found to be identical by direct comparison with the sample prepared in 91% yield, alternatively, by reacting 2a with acetaldehyde under similar reac- Serotonins were found to produce 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles by simple heating with amines under an oxygen atmosphere. Serotonins also reacted with various aldehydes to provide 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles rather than b b-carbolines under basic conditions. In these novel reactions, the presence of the 5-hydroxy group on the indole nucleus was suggested to be essential. Possible mechanisms are discussed.

-Utilizing novel Nb-substituted serotonins, 5-and/or 6-substituted 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino [5,4,3-cd]indole derivatives are produced simply by treating serotonins with aldehydes under basic conditions. Synthesis of 2,2a,3,4,5,6-hexahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole-2-one derivatives is also reported.In our synthetic project for discovering new biologically active compounds, we have thus far succeeded in the creation of efficient synthetic methods 3a-d with high originality rate, 4a,c-e intellectual property factor, 4a,b and application potential factor 4a,b culminating in the production of novel leads for an α 2 -blocker, 3d,5 an inhibitor of platelet aggregation, 3c,6 an anti-osteoporosis agent, 3d,7 and potent root growth promotor. 3a,b,8 These results are based on our hypothesis 8,9 that any metabolite of tryptophan has each own function in vivo, and the combination of each structure is a promising method for designing a new possible drug.

The Chemistry of Indoles. Part 138. A Novel Synthesis of 3,4,5,6-Tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole Derivatives from Serotonin. -Novel substituted serotonins (IV) are used for the synthesis of similarly new azepino[5,4,3-cd]indoles (VI). With the exception of bulky educts, the underlying reaction of (IV) with aldehydes under basic conditions is proved to be a general and convenient method. -(YAMADA, K.; TERANISHI, S.; MIYASHITA, A.; ISHIKURA, M.; SOMEI*, M.; Heterocycles 83 (2011) 11, 2547-2562, http://dx.doi.org/10.3987/com-11-12345 ; Fac. Pharm. Sci., Kanazawa Univ., Takara, Kanazawa 920, Japan; Eng.) -H. Haber 11-160

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