Of tetrahydro-P-carboline

This reaction is also a key method for the formation of tetrahydro-P-carbolines 5 from indole bases 4 and aldehydes, ketones, or 1,2-di carbonyl compounds 2. These reactions are similarly acid-catalyzed or thermally-induced and have been utilized in the synthesis of numerous indole alkaloids. 

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

Bonnet and Ganesan [12] developed a new route toward the solid-phase synthesis of tetrahydro-P-carboline hydantoins, which appear in a diverse array of biologically active alkaloids. Due to the presence of tetrahydro-P-carbolines and diketo-piperazine ring skeletons in several bioactive natural products, these two scaffolds became attractive targets for developing a combinatorial chemistry program. 

Figure 15.3 Retrosynthetic analysis of tetrahydro-P-carboline hydantoins.

Scheme 42 Coupling-amination-aza-annulation-Pictet-Spengler four-component synthesis of tetrahydro-P-carbolines 74...

A collection of tetrahydro-P-carbolines has been prepared [401] by first attaching various tryptamines to Novabiochem s vinylsulfonytmethyl resin (560) by Michael addition involving the tryptamine amino groups. Subsequent reaction with various aromatic aldehydes in the presence of catalytic p-TSA in toluene at 80 °C afforded the desired tetrahydro-P-carboline derivatives (563) in excellent yields (Scheme 117). 

Many of today s drugs are heterocyclic compounds. Heterocyclic compound libraries are therefore the focus of many pharmaceutical companies drug discovery processes. Benzodiazepines were the first heterocyclic compounds prepared by solid-phase chemistry [2,3,6]. Since then, solid-phase routes to many heterocyclic structures have been published using well-established solution-phase protocols e.g. Pictet-Spengler reaction in the preparation of tetrahydro-P-carbolines. 

Conducted in an intramolecular sense, Mannich reactions have been much used for the construction of tetrahydro-P-carbolines. ° Tryptamines carrying a 2-carboxylic acid group, which can be conveniently prepared (20.16.6.3), but are not easily decarboxylated as such, undergo cyclising Mannich condensation with aldehydes and ketones, with loss of the carbon dioxide in a final step. ° ... 

A palladium-catalyzed allylation of indoles with allyl carbonates furnished 3-alkylated indoles <04OL3199>. An intramolecular variation with indolyl carbonates provided a novel synthesis of tetrahydro-p-carbolines and pyrazinoll,2-a indoles. 

Differences in the mutagenic and antimutagenic properties of the stereoisomers of tetrahydro-p-carbolines (PTCCs)... 

Conducted in an intramolecular sense, both Mannich and Vilsmeier reactions have been much used for the construction of tetrahydro-p-carbolines (dihydro-P-carbolines), such as are found in many indole alkaloids (p-carboline is the widely used, trivial name for the pyrido[3,4-Z ]indole nucleus). 

This hydroformylation Fischer indole synthesis was extended and developed by Eilbracht and his research group [88-93]. A small selection of this elegant chemistry is shown in Scheme 10 (equations 1-5). This chemistry has been adapted to the synthesis of tetrahydro-p-carbolines, a process that uses 2,5-dihydropyrroles and arylhydrazines and features spiroindoleninium cation intermediates (equation 5) [92]. 

Chernov V, Shul ts EE, Shakirov MM, Tolstikov GA (2002) Synthetic transformations of higher terpenoids VII. Synthesis of tetrahydro-P-carbolines of the labdane series. Russ J Org Chem 38 665-671. Translated from Zhumal Organicheskoi Khimii 38 ... 

Pictet-Spengler cyclocondensation is a versatile method for the construction of tetrahydro-P-carboline ring systems. It comprises the acid-catalyzed reaction... 

The sequential combination of RCM and double-bond isomerization was recently employed by You s group [42] for the design of an RCM-isomerization-Pictet-Spengler cascade for a highly efficient enantioselective synthesis of tetrahydro-P-carbolines 21, where a Hoveyda-Grubbs II complex and a chiral phosphoric acid (CPA-H) cooperatively acted as a bicatalytic system (Scheme 12.13). 

Scheme 5.4. Solid-phase parallel synthesis of tetrahydro-p-carboline alkaloid library, (a) FmocTrpOH, HATU, DMAP, DIPEA, DMF (b) 25% piperidine in DMF (c) Fmoc-protected amino acid, DIC, HOBt, DIPEA, DMF (d) 25% piperidine in DMF (e) dimethoxyacetaldehyde, NaBHaCN, MeOH/DMF (1 1) (f) r nCO, DIPEA, DCE (g) neat formic acid, 50°C, 3h.

In a new development in alkaloid synthesis, Myers and Hellring have shown that the p-amino-carbanion from tetrahydro-p-carboline can be employed as a precursor for the ring systems (103), (104), and (105), which are found amongst natural indole alkaloids. Thus, the conversion of tetrahydro-P-carboline into the amidine derivative (101), followed by protection of the indole nitrogen and treatment with t-butyl-lithium, generated the (3-amino-carbanion (102). Addition of various electrophiles, followed by further manipulations of the functional groups, then led to the alkaloid ring-systems (103), (104), and (105). 

MTCC has been isolated and identified from Allium macrostemon 71). Also, MTCC has been reported to be contained in various types of foods, such as alcoholic beverages, fermented products, flour, milk, fruit products and chocolate (72,73,74). MTCdiC has been also reported from seasoning sauces, soy sauces, yeast extracts, wine, vinegar, beer and fruit syrup (75). There are several reports on the biological activity of tetrahydro-P-carbolines. It was demonstrated that these compounds have strong antioxidant activity in several... 

TABLE 2.11 Scope of the Deracemization of Tetrahydro-p-Carbolines (THBCs, Scheme 3.22 by Two Variants of the Monoamine Oxidase N (MAO-N) Originating from Aspergillus niger ... 

MAO-N Dll and MAO-N D9 were also found to be effective in the oxidation of tetrahydro-p-carbolines (THBCs) and related heterocycles. Several 1-substituted aliphatic and alicyclic THBCs were deracemized in good yields and high enantioselectiv-ity by the proper choice of the catalyst employed (Scheme 2.43 and Table 2.11) [146,147]. 

Bernhardt P, Usera AR, O Connor SE. Biocatalytic asymmetric formation of tetrahydro-p-carbolines. Tetrahedron Lett. 2010 51 4400-4402. 

Panarese, J.D. and Waters, S.P. (2010) Room-temperature aromatization of tetrahydro-P-carbolines by 2-iodobenzoic acid Utility in a total synthesis of eudistomin U. Org. Lett., 12,4086-4089. 

Figure 33 Use of enzyme-labile solid phase linker in the synthesis of tetrahydro-P-carbolines.

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