Tryptophan methyl ester, reaction

For the kinetically controlled formation of 1,3-disubstituted tetrahydro-P-carbolines, placing both substituents in equatorial positions to reduce 1,3-diaxial interactions resulted in the cw-selectivity usually observed in these reactions." Condensation reactions carried out at or below room temperature in the presence of an acid catalyst gave the kinetic product distribution with the cw-diastereomer being the major product observed, as illustrated by the condensation of L-tryptophan methyl ester 41 with benzaldehyde. At higher reaction temperatures, the condensation reaction was reversible and a thermodynamic product distribution was observed. Cis and trans diastereomers were often obtained in nearly equal amounts suggesting that they have similar energies."... 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

Grieco and coworkers have independently described the same type of Pictet-Spengler cyclization reactions involving tryptophan methyl ester and aldehydes, but using methanol as solvent and hydrochloric acid as a catalyst (microwave irradiation, 50 °C, 20-50 min) [416], Moderate to good product yields were obtained. 

Scheme 7.1. Reaction of tryptophane methyl ester with R...

The effect of added co-solvent on the initial state is also important in more complicated reactions. For example, in the a-chymotrypsin-catalysed hydrolysis of p-nitrophenyl acetate and of N-acetyl-L-tryptophan methyl ester, the difference in the pattern of rates of hydrolysis when the solvent composition is varied can be attributed to the variation in the properties of the initial states of the esters (Bell et al., 1974). 

The structures of the vast majority of PD-5 inhibitor compounds aimed at erectile dysfunction consist of modified purines. The structure of the recently approved drug for this indication tadalafll (113) differs markedly from the prototypes. Tryptophan methyl ester (108) provides the starting material for large scale enantioselective synthesis. Condensation of that compound with piperonal (109) in the presence of acid leads to formation of the tricyclic intermediate (110). This transform involves initial addition of the amine to the aldehyde. The carhocation from the newly formed carhinolamine then attacks the indole 2-position to form the the fused piperidine. The stereochemistry of the new chiral center is guided by that from the tryptophan carhon across the ring. The secondary amine is next acylated with chloroacetyl chloride in the presence of triethylamine to afford 111. Reaction of this intermediate with methylamine goes on to form the desired product in a single step. This reaction can he rationalized... 

The target isomeric tadalafil molecule is shown in Scheme 8.2. Thus, D-tryptophan methyl ester reacted with piperonal 3 under Pictet-Spen-gler reaction condition (TFA/CH2Cl2/MeOH) to furnish two diastereo-mers 4 and 6 in 25% and 24% yields, respectively. Condensation of 4 or 6 with chloroacetyl chloride provided acylated intermediate 5 or 7 in almost quantitative yield. Subsequent cyclization of 5 with N-methyl amine in methanol at 50 °C for 16 h provided diastereomers tadalafil (1) in 54% yield. Compound 1 is in full accordance with the literature data [a]D ° = + 71.4 (c 1.00, CHCI3) lit. [o(]d ° = + 71.2 (c 1.00, CHCI3) [17,18]. Thus, under the elongated reaction time, 48 h, compound 8 was obtained from precursor 7 with decreased yield of 21%. 

As depicted in Scheme 8.5, L-tr) tophan methyl ester hydrochloride (13) was first treated with 1.1 equiv of piperonal in nitromethane at reflux temperature. Similar to D-tryptophan methyl ester hydrochloride, the highly stereoselective Pictet-Spengler reaction of L-tryptophan methyl ester hydrochloride with piperonal produced the hydrochloride salt of (lS,3S)-l,3-disubstituted-tetrahydro-p-carboline 14-HCl [17,25]. After neutralization of 14-HCl, compound 14 was obtained in 95% yield and with 99% ee. Compound 14 was then treated with 1.2 equiv of benzyl chloroformate in ethyl acetate at around 5 °C in the presence of 3 equiv of potassium carbonate powder to afford (lS,3S)-l,2,3-trisubstituted-tetra-hydro-p-carboline (15) in 94% yield. The base-catalyzed epimerization of... 

Tseng and colleagues [58] reported a three-step synthesis of fused tetrahydro-P-carbolinequinoxalinones, solely based on the use of ionic liquids as solvents. Tetrahydro-P-carboline is a central core for many biologically important indole alkaloids, and the moiety of quinoxalinone often exhibits a wide spectrum of biological activities such as being anti-HIV, antihypertensive, and a ligand for a number of protein receptors. As a first step, tryptophan methyl ester was reacted with an aldehyde to form tetrahydro-p-carboline by Pictet-Spengler cyclization that further reacted with l-fluoro-2-nitrobenzene to form iV-aryl-tetrahydro-P-carboline. Intramolecular cyclization upon a reduction reaction in step three provided the desired tetrahydro-P-carbolinequinoxalinones. The entire process was based on the use of 1-n-butyl-... 

S)-valine, whose amino terminal was modified with phenoHc Schiff base of 2-hydroxy-l-naphthaldehyde (Nap), and (S)-tryptophan methyl ester, [7 Nap-(S)-Val-(S)-Trp-OMe see reaction (l)in Scheme 1] catalyzed the addition ofHCNto various aldehydes to yield (l )-cyanohydrins with up to 90% ee.[35,36,37]. 

R, S) Pyridindolol (64) was synthesized by Pictet-Spengler reaction of tryptophan methyl ester with 2,3-O-isopropylidene-D-glyceraldehyde (61) as shown in Scheme 20 [78H(9)175 79JOC535]. 

Fig. 1. Rapid-scanning stoppcd-flow (RSSF) study of the reaction ofN-furylacryloylr-tryptophan methyl ester (FATME) with a-chymotrypsin (a-Ct) at pH 5.0 in the absence and presence of proflavin. (A) RSSF difference spectra for the reaction of 19 pM a-Ctwith 7.5 pM FATME in 0.1 M pH 5.0 sodium acetate buffer at 25°. Spectrum 0 is 7.5 pM free FATME, spectra 1 -5 are difference spectra measured during reaction wherein the spectrum of a-Ct has been subtracted from the set. Spectrum 6 is the spectrum of the hydrolysis product furylacryloyl i-tryptophan with the spectrum of a-Ct removed by subtraction. Spectra were measured at the following time intervals after flow had stopped (1) 8.54, (2) 162.3, (3) 341.6 (4) 1409.1 and (5) 3074.4 ms. Spectrum 6, t = oo.

An intramolecular DA reaction of the oxazole-olefin 116, obtained through a highly stereoselective route starting from L-tryptophan methyl ester, was the key step in the total synthesis of Rauwolfia alkaloids, as norsuaveoline 118 <04TL6471>. 

Nucleophilic tert-prenylation. When using prenylboranes instead of tert-prenylboranes, tert-prenylation of 3-chloroindolenines becomes possible. The Danishefsky tert-prenylation has also been extensively used for the synthesis of 3-tert-prenylindoles which can be obtained from 2-tert-prenylated precursors (see Sect. 4). The 1995 synthesis of the acyl-CoA-cholesterol acyltransferase inhibitor gypsetin (94) [91, 92] was the first occasion to publish that elegant reaction (Scheme 19) [88, 93]. On treatment of phthalimide-protected tryptophan methyl ester (85) with tcrt-BuOCl, the 3-chloroindolenine is formed in sim, which is nucleophilicaUy attacked by prenyl-9-BBN with regioinversion of the prenyl group. Hydrazinolysis afforded 2-tert-prenyltryptophan methyl ester (91). 

The Pictet-Spengler reaction is a form of intermolecular Friedd-Crafts alkylation reaction. An example of this is the ionic liquid catalyzed and Levns acid catalyzed one-pot Pictet-Spengler reactions of tryptophan methyl ester or tryptamine vnth aliphatic and aromatic aldehydes [59]. Short reaction times were achieved with the aid of microwave irradiation (Scheme 5.2-17). 

Electrophilic substitutions on the indole ring overwhelmingly favor the C3 position. However, when the energy outcome is favorable, C2 electrophilic substitutions do occur, especially for intramolecular substitutions. For instance, in the synthesis of tadalafil (Cialis), the Pictet-Spengler reaction is used to prepare the cw-p-carboline where the C2 electrophilic substitution takes place. In the presence of trifluoroacetic acid (TFA), Z)-tryptophan methyl ester is condensed with piperonal. The C2-carbon of the indole adds to the resulting iminium ion to give a mixture of the cA-B-carboline and the... 

In 1988, Zhang et al. ° achieved the synthesis of the optically active tetracyclic ketone 160, in a stereospecific fashion by employing the asymmetric Pictet—Spengler reaction. Many improvements have been made to prepare both the Na-H and the Na-Me tetracyclic ketones (158 and 160, respectively). The Pictet—Spengler reaction is now carried out in one pot to provide only the desired iraws-diastereomer with high diaster-eoselectivity and enantioselectivity. As illustrated in Scheme 2, after Nb-benzylation of d-(+)-tryptophan methyl ester (156) with benzaldehyde and sodium borohydride in methanol, trifluoroacetic acid (TFA) was added to the reaction vessel at 0 °C to neutralize the reaction mixture. After removal of the solvent, CH2CI2, TFA, and methyl 4,4-dimethoxybutyrate... 

Yu et al. reported the synthesis of Na-methyl-16-ep/-pericychvine (180) (Scheme 5). The pentacyclic ketone 181 (which was obtained from D-(4-)-tryptophan methyl ester (156) similarly, and is described in Schemes 2 and 3) was subjected to a Wittig reaction, followed by hydrolysis to... 

In 2002 Wearing et al. pubhshed the stereospecific total synthesis of (+)-alstonisine. Using a similar sequence as employed for the synthesis of talcarpine (245) by Yu et al. (Scheme 16), vinyl ether 251 was synthesized from D-tryptophan methyl ester (156) via tetracychc ketone 158 (Scheme 21). The regiospecific oxyselenation of the olefin 251 was carried out with N-phenylselenophthahmide in CH2Cl2/methanol at 0 °C in the presence of p-TSA, and this was followed by treatment with NaI04 in THF/MeOH/H20 solution at 0 °C for 10 h to afford acetal 252 as a mixture of Z/E isomers in a 4 1 ratio in 90% combined yield. Reaction... 

Typical procedure. 2-Adamantyl-a-methYltryptophan derivative 112 [61] To a stirred solution of 2-adamantol (912 mg, 5.9 mmol) in anhydrous didiloromethane (15 mL) were added triphosgene (653 mg, 2.20 mmol) and pyridine (474 mg, 5.99 mmol) in anhydrous dichloromethane (10 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was then removed in vatnio at 30 °C, the residue was redissolved in EtOAc (30 mL), and this solution was stirred for 10 min. The precipitate was filtered off and the solvent was removed in vatnio at 30 °C to leave an oil, which solidified upon standing (1.29 g, 100%). To a stirred solution of this solid (965 mg, 4.5 mmol) in anhydrous THF (10 mL) was added a solution of a-methyl-(f )-tryptophan methyl ester 110 (928 mg,... 

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