Tryptamines, precursors

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

From a biogenetic standpoint these bases can be considered to be built up from protoemetine (90) and tryptamine precursors. ... 

A significant improvement in the yield was also achieved in Takayama s concise synthesis of we.so-chimonanthine 121), via hypervalent iodine-mediated dimerization of a tryptamine precursor, giving we.so-chimonanthine in 30% yield over three steps (Scheme 12). This approach has also been applied by Takayama to the synthesis of chimonanthidine 108). A similar three-step procedure to we.so-chimonan-thine, albeit in lower overall yield, involving thallium trifluoroacetate-mediated oxidative coupling of the same tryptamine precursor has also been reported 122). 

C2 halogenated tryptamine precursor 261, followed by intramolecular aza-Michael addition. In this example, by Stewart and Pfeifer, the order of these reaction was controlled by the type of protecting group on the nitrogen, while a range of acrylate systems were reported in good to excellent yields. Others have also reported similar Heck/Michael processes [129-131]. 

Trace Amines. Figure 1 The main routes of trace amine metabolism. The trace amines (3-phenylethylamine (PEA), p-tyramine (TYR), octopamine (OCT) and tryptamine (TRP), highlighted by white shading, are each generated from their respective precursor amino acids by decarboxylation. They are rapidly metabolized by monoamine oxidase (MAO) to the pharmacologically inactive carboxylic acids. To a limited extent trace amines are also A/-methylated to the corresponding secondary amines which are believed to be pharmacologically active. Abbreviations AADC, aromatic amino acid decarboxylase DBH, dopamine b-hydroxylase NMT, nonspecific A/-methyltransferase PNMT, phenylethanolamine A/-methyltransferase TH, tyrosine hydroxylase. 

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

Since tryptophan (and its decarboxylation product, tryptamine) serve as precursors in many synthetic and biosynthetic routes to /J-carbolincs, it is not surprising that C-1 of the /J-carbolinc ring is the most common site of substitution (as it is the only ring atom of the /J-carbolinc ring system not derived from tryptophan). Indeed, this is the only site of substitution for many /J-carboline natural products. Two examples of naturally occurring /J-carbolines substituted only at C-1 which possess antitumor activity are manzamine A and manzamine C (Fig. 2). Owing to its greater simplicity and nearly equal antitumor activity, most initial synthetic efforts were directed toward manzamine C [11,12]. 

Kreuger and Carew (141) examined the effects of a number of alkaloid precursors on alkaloid production in suspension cultures and found that at 100 mg/liter tryptamine hydrochloride enhanced alkaloid production. The alkaloids produced, however, were A-acetyltryptamine and N,N-dimethyltryptamine, rather than the monoterpenoid indole alkaloids. Added geraniol and mevalonic acid had no effect on alkaloid production. 

Dialkyltryptamines. JCS, 7175-79 (1965). First the tryptamine must be methylated as follows. Dissolve the tryptamine in ether (methanol also works and is cheaper), add 2.5 g of diazomethane (careful, this is nasty stuff see the making precursors chapter for synthesis and hazards) in ether and heat for 20 hours on oil bath. Evaporate in vacuo to get product. 

L-tryptophane is the precursor of serotonin and other biological substances like tryptamine, kynure-nine and quinolinic acid. Furthermore, it is an essential substrate in the protein synthesis. The dietary intake of L-tryptophane might increase the production of serotonin. For this reason the aminoacid is used for the therapy of light sleeping disorders. 

Some prominent 3-substituted derivatives include skatole (3-methylin-dole), which has a faecal odour, and indoIyl-3-acetic acid (sold as a plant rooting powder). Many indoles are biologically important for example, tryptamine is the precursor of two hormones serotonin, a vasoconstrictor, and melatonin, which is involved in the control of circadian rhythm. In addition, the amino acid tryptophan is an essential component of proteins (see Box 7.1). 

Tryptophan, the metabolic precursor to tryptamine, is itself a centrally active amino acid. There is a complex, and little appreciated story associated with it as to its human psychopharmacology. Although tryptamine is only active parentally, tryptophan is active orally is directly converted to tryptamine, the two compounds must be considered in concert. What is the action of tryptophan, taken orally Here are some quotations from the published literature, mostly with the voice of the giver, not the taker, with some copy taken from health-food store fliers of a decade ago. 

An efficient synthesis of ( )-quebrachamine is based on the construction of a suitable precursor via ring cleavage of an a-diketone monothioketal (810) (80JCS(P1)457). This monothioketal, available from 4-ethoxycarbonylcyclohexanone ethylene ketal, was fragmented to the dithianyl half ester (811) with sodium hydride in the presence of water. Reaction of (811) with tryptamine and DCC provided an amide which was converted to the stereoisomeric lactams (812) on hydrolysis of the dithiane function. Reduction of either the a- or /3-ethyl isomer with lithium aluminum hydride followed by conversion of the derived amino alcohol to its mesylate produced the amorphous quaternary salt (813). On reduction with sodium in liquid ammonia, the isomeric salts provided ( )-quebrachamine (814 Scheme 190). 

One of the few examples of a synthetically useful 6-exo-trig cyclization from 3-aza-6-heptenyl radicals is found in the total synthesis of ( )-melinonine-E (159, Scheme 31) by Bonjoch et al. [66]. The cyclization precursor, a,P-unsaturated nitrile 157 was prepared from 1,4-cyclohexanedione monoethylene acetal (156) and tryptamine in 5 steps with 41% overall yield. Initially, when 157 was treated with 1.1 equiv. of n-BujSnH and 0.1 equiv. of AIBN in toluene for 16 h, the expected cyclization to the 2-azabicyclo[3.3.1]nonane ring took place to give 158 only as a minor product, along with its C(14) chloro- and dichloro-substituted derivatives as major products. An additional treatment of the crude mixture with 2.2 equiv. of BujSnH brought about the reduction of the C-Cl bonds to provide nitrile 158 in 38% yield over... 

The other three classes of alkaloids arise from the complex iridoid tryptamine biogenetic pathway. The majority of the alkaloids which have been characterized from the Rubiaceae have the same early precursor. An alternative pathway, involving dopamine instead of tryptamine (16), leads to emetine-type alkaloids, which were found only in Cephaelis, a member of the tribe Psychotrieae. 

Within the natural products field, the investigation of complete biosynthetic pathways at the enzyme level has been especially successful for plant alkaloids of the monoterpenoid indole alkaloid family generated from the monoterpene gluco-side secologanin and decarboxylation product of tryptophan, tryptamine [3-5]. The most comprehensive enzymatic data are now available for the alkaloids ajmalicine (raubasine) from Catharanthus roseus, and for ajmaline from Indian Rauvolfia serpentina [6] the latter alkaloid with a six-membered ring system bearing nine chiral carbon atoms. Entymatic data exsist also for vindoline, the vincaleucoblastin (VLB) precursor for which some studies on enzymatic coupling of vindoline and catharanthine exist in order to get the so-called dimeric Catharanthus indole-alkaloids VLB or vincristine [7-9] with pronounced anti-cancer activity [10, 11]. 

Thomas (23) predicted that the non-tryptamine moiety of the indole alkaloids is derived from a cyclopentanoid monoterpene precursor. Wenkert (2k) independently reached to the same conclusion. 

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