Tryptophan methyl ester

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."... 

Conversely, when A-alkyl tryptophan methyl esters were condensed with aldehydes, the trans diastereomers were observed as the major products." X-ray-crystal structures of 1,2,3-trisubstituted tetrahydro-P-carbolines revealed that the Cl substituent preferentially adopted a pseudo-axial position, forcing the C3 substituent into a pseudo-equatorial orientation to give the kinetically and thermodynamically preferred trans isomer." As the steric size of the Cl and N2 substituents increased, the selectivity for the trans isomer became greater. A-alkyl-L-tryptophan methyl ester 42 was condensed with various aliphatic aldehydes in the presence of trifluoroacetic acid to give predominantly the trans isomers. ... 

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). 

In a closely related approach, Yen and Chu have reported the preparation of tetra-hydro-/3-carbolinediketopiperazines employing a three-step Pictet-Spengler, Schot-ten-Baumann, and intramolecular ester amidation sequence (Scheme 6.233) [415]. Throughout the synthesis, the ionic liquid l-butyl-2,3-dimethylimidazolium hexa-fluorophosphate (bdmimPF6) was employed. In a typical experiment, (S)-tryptophan methyl ester was dissolved in a 1 1 mixture of the ionic liquid and tetrahydrofuran... 

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. 

Tadalafil (3, IC-351) was discovered at ICOS and is being developed and marketed as a joint venture with Eli Lilly, D-tryptophan methyl ester (21) was condensed with piperonal by means of trifluoroacetic acid and the C2 carbon of the indole adds to the resulting iminium ion to give a mixture of cis (3-carboline 22 and trans isomer 23 (Scheme 5). The desired cis isomer 22 can be isolated by chromatography or crystallization in 42% yield. Compound 22 was acylated with chloroacetyl chloride to... 

Purification of a-chy-motrypsin by affinity chromatography on immobilized D-tryptophan methyl ester. From Affinity Chromatography Principles and Methods, Pharmacia, Uppsala, Sweden. 

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 treatment of /Vb-methoxycarbonyl-L-tryptophan methyl ester (9) with trifluoroacetic anhydride in trifluoroacetic acid gave directly the A -trifl uoroacetyl cyclic tautomer with excellent diastereoselectivity [90% yield, endo/exo 97 3 ( ll NMR)]60. Furthermore, pure A a-sulfonyl-entfo-derivatives (X-ray) were prepared from lo206,61 and were employed to prepare homochiral a-, / -, and a, -substituted tryptophan derivatives and pyrrolo[2,3-b]indole alkaloids206 59 62. Similarly, the /Va-acetyl-enc/o-pyrrolo-indole 10 was used for the synthesis of 5-substituted L-tryptophan derivatives63,64. 

The cyclization of bis(Boc)tryptophan methyl ester mediated by an electrophilic selenium reagent is described in Section 7.2.6.2.3. 

Bis(Boc)tryptophan methyl ester, on treatment with A -phenylselcnophthalimide (/V-PSP) underwent cyclization leading in good yield to the polycyclic derivative 9 as an inseparable 90 10 diastereomeric mixture (exo/endo), following the equilibration of an initial 50 50 mixture232. 

Scheme 8.1 describes a process for the synthesis of tadalafil (1) and its intermediate of formula 5 which involves reacting D-tryptophan methyl ester 2 with a piperonal 3 in the presence of methanol and cone. HCl to give compoimd 4. The later compound is then reacted with chloroacetyl chloride in the presence of NaHCOs to afford the intermediate 5, which is reacted with methylamine in chloroform to give tadalafil in 88% yield. 

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... 

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