4-bromotryptamine

The medicinal importance of 2-aryltryptamines led Chu and co-workers to develop an efficient route to these compounds (130) via a Pd-catalyzed cross-coupling of protected 2-bromotryptamines 128 with arylboronic acids 129 [137]. Several Suzuki conditions were explored and only a partial listing of the arylboronic acids is shown here. In addition, boronic acids derived from naphthalene, isoquinoline, and indole were successfully coupled with 128. The C-2 bromination of the protected tryptamines was conveniently performed using pyridinium hydrobromide perbromide (70-100%). 2-Phenyl-5-(and 7-)azaindoles have been prepared via a Suzuki coupling of the corresponding 2-iodoazaindoles [19]. 

Altematamides A-C (92-94), bromotryptamine peptides from the Atlantic bryozoan Amathia alternata, show modest antibacterial activities against Staphylococcus aureus, Staphylococcus epidermidis,... 

Fig. 3.19 Flustrafoliacea, a North Sea bryozoan and a producer of many bromotryptamines and brominated indole alkaloids, such as 1343-1346 (Photo A. D. Wright)...

Peters L, Konig GM, Terlau H, Wright AD (2002) Four New Bromotryptamine Derivatives from the Marine Bryozoan Flustra foliacea. J Nat Prod 65 1633... 

Lee N-K, Fenical W, Lindquist N (1997) Altematamides A-D New Bromotryptamine Peptide Antibiotics from the Atlantic Marine Bryozoan Amathia alternata. J Nat Prod 60 697... 

Eudistomidin A (11) and eudistomins H (7), I (8) and P (9) have been made (127, 128) by the Bischler-Napieralski (BN) reaction, a method used extensively by the Hino group. Appropriately substituted tryptamine was condensed with BOC-prolinoyl chloride, then treated under BN conditions (POCl3 or polyphosphoric ester (PPE)) to produce a 5,7-disubstituted eudistomin skeleton (163). Eudistomin I thus results when starting from tryptamine (Scheme 9, R = R = H), eudistomin H from 5-bromotryptamine (Scheme 9, R = Br, R = H), eudistomidin A from 5-bromo-7-hydroxytryptamine (Scheme 9, R = Br, R = tosylate) eudistomin P is obtained from the use of 6-bromo-5-methoxytryptamine. 

Radiotracer experiments were used to elucidate the biosynthetic precursors to eudistomin H (7) and I (8) in Floridian collections of Eudistoma olivaceum. Both radiolabeled tryptophan and proline were incorporated by E. olivaceum into eudistomins H and I and tryptamine was incorporated into eudistomin I, to the exclusion of eudistomin H. Bromotryptamine and bromotryptophan are incorporated into eudistomin H (Scheme 30). These results suggest eudistomin biosynthesis proceeds from the amino acids via decarboxylation, halogenation, then condensation with proline. 

Bromotryptamine (107) has been reported [14] from a collection of a Lissoclinum sp. from the GBR, and from Didemnum candidum from the Gulf of Mexico [77], while 5-bromo-N,N-dimethyl tryptamine (108) was reported from a New Caledonian collection of Eudistoma fragum where it co-occurred with woodinine [78]. 5-Bromo-N,N-dimethyltryptamine exhibited antimicrobial activity (with 12 mm and 17 mm zones of inhibition reported at 100 pg per 6 mm disk against S. aureus and E coli resp. 17mm and 22 mm zones at 200 pg per disk against the same microorganisms). A synthesis of 5-bromo-N,N-dimethyltryptamine has been reported [79]. 

Peters, L., Konig, G.M., Terlau, H. and Wright, A.D. (2002) Four new bromotryptamine derivatives from the marine bryozoan Flustrafoliacea. Journal of Natural Products, 65, 1633-1637. 

The requisite bis-Boc-protected 4-bromotryptamine 1459 was available in four steps from 4-bromoindole (Scheme 1.374). The other component of the biaryl coupling, the boronic acid 1460, was prepared from 2-(allyloxy)-bromobenzene. Suzuki coupling of 1459 and 1460 proceeded in excellent yield to afford 1461, which was elaborated to the ot-diazo-p-ketoester 1462. It required some experimentation to prepare 1462. Dirhodium(II) acetate-catalyzed N-H insertion of 1462 with (5)-benzyloxycarbonylvalinamide, followed by cyclodehydration, gave 1463, albeit in low overall yield (13%, two steps). Nonetheless, the authors had prepared a highly functionalized 4-aryltryptamine analog that could serve as a precursor to construct the B, E, and H rings. 

Under similar reaction conditions, 35 generates many products such as 7-bromo- (59), 2,7-dibromotryptamines (60), 57, 7-bromo- (61), 5-bromo-2-oxindoles (62), 56,2-bromotryptamine (63), and 58, depending on the bromination conditions (entries 1-3). l-Hydroxy-Wh-methoxycarbonyltryptamine (52) shows almost the same results as 35. It should be noted that the ratio of all of the 7-brominated indoles to the total products, observed in the bromination of 1-hydroxyindole derivatives (35 and 52), is much higher than that of the N(l)-H compound (55). 

When 54 is treated with hydrogen halides, rapid nucleophilic substitution reactions take place within 10 min at room temperature (Table 7). In the reaction with HCl/f-BuOH, 5-chloro- (131, 60%), 7-chlorotryptamines (132, 4%), and tryptamine (55, 3%) are produced. The reaction of 54 with HBr/f-BuOH affords 5-bromo- (36), 7-bromotryptamines (59), and tryptamine (55) (entry 1). In the same reaction, the employment of formamide as a solvent dramatically changes the reaction pathway to yield 1-hydroxytryptamine (52) as a sole product (entry 2) [24]. 

Preparation of (5)-6-bromo-8-(3-prenyl)-3a-(3-oxo-propyl)-3,3a,8,8a-tetrahydro-2//-pyrrolo[2,3-6)indole-l-carboxylic acid tert-butyl ester (222) from A -lO-BOC-l-prenyl-6-bromotryptamine (220), acrolein (213), and MacMillan catalyst 211A... 

To an amber 2-dram vial equipped with a magnetic stir bar was added (2iS,55)-5-benzyl-2-ter/-butyl-3-methyl-imidazolidin-4-one (catalyst 211 A) in 4.2 mL CH2CI2 cooled to -84°C, 258 mg acid (9.8 pL, 0.13 mmol) was added, followed by trifluoroacetic acid (0.64 mmol) and 7V-10-BOC-1-prenyl-6-bromotryptamine (220). The solution was stirred for 5 min before addition of 0.17 mL (2.56 mmol) acrolein 213 and then stirred for 72 h. The resulting suspension was stirred at constant temperature until complete consumption of the indole was observed as determined by TLC. The reaction mixture was then treated with 20 mL pH 7.0 buffer and extracted with diethyl ether (2 x 25 mL) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (solvents noted) to afford 222 as a colorless oil (231 mg, 78% yield, 90% ee) after silica gel chromatography in 10% EtOAc/hexanes as a colorless, viscous oil. [a]o = -218.9 (c = 1.0, CHCI3). 

Fekete M, Kolonits P, Hien NT, Novak L (2005) Synthesis of novel tryptamine and P-carboline derivatives via palladium-catalyzed reaction of bromotryptamine with organic boronic acids. Cen Eur J Chem 3 792-802... 

In an elegant synthesis of the marine alkaloid flustramine B, MacMillan and coworkers have used catalyst 2 to promote the first organocatalytic addition/ cyclization process that allows the preparation of the chiral pyrroloindoline motif in a single step [82]. The transformation occurs between 6-bromotryptamine derivative 90 and acrolein via the intermediary formation of indolium ion 91, which is in turn readily trapped in an intramolecular way by the Boc-amino group, giving rise to intermediate 92 (Scheme 35.24). Then, six further additional steps were necessary to accomplish the synthesis of (—)-flustramine B. 

The already known 6-bromotryptamine and the new (3-carboline derivative (+)-7-bromo-trypargine were isolated from the Australian sponge Ancorim sp. This later compound displays antimalarial activity against both Dd2 and 3D7 strains of Plasmodium falciparum (Davis et al., 2010). 

Bromotryptamine and two bis-indolic derivatives, one of which contains a piperazine, have been isolated from the species Didemnum candidum collected on the roots of mangrove trees in a mangrove swamp in the Gulf of California (Fahy, Potts, and Faulkner, 1991). 

Fahy, E., Potts, B.C.M., and Eaulkner, D.J. (1991) 6-Bromotryptamine derivatives from the Gulf of California tunicate Didemnum candidum. J. Nat. Prod., 54, 564-569. 

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