D-Tryptophan methyl ester

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 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... 

Cook and co-workers (212) have developed a strategy that permits an enantiospecific synthesis of compound 126. A b-Benzyl D-(+)-tryptophan methyl ester (127) was transformed with methyl 4,4-dimethoxybutyrate (or methyl y-aldobutyrate) to the trans diester 128, which, after 60 hours reflux (NaH/MeOH/toluene) led, via epimerization and Dieckmann condensation, to the /3-ketoester 129 (enantiomeric purity s 98%). Acid-induced decarboxylation of the /3-ketoester 129 afforded the desired compound 126... 

Fig. 4.7.2. Affinity chromatography of a-chymotrypsin on inhibitor Sepharose columns. The columns (50x5 mm) were equilibrated and run with O.OS M Tris-hydrochloric acid buffer (pH 8.0). Each sample (2.5 mg) was applied in 0.5 ml of the same buffer. The columns were run at room temperature with a flow-rate about 40 ml/h and fractions containing 1 ml were collected. The arrows indicate a change of elution buffer (0.1 M acetic acid, pH 3.0). (A) Sepharose coupled with e-aminocaproyl-D-tryptophan methyl ester (B) Sepharose coupled with D-tryptophan methyl ester (C) unsubstituted Sepharose. The first peaks in A and B were devoid of enzyme activity. Reproduced with permission from Ref. 46.

However, as was observed, the described chromatography of chymotrypsin on unsubstituted Sepharose does not provide sufficient evidence of non-specific sorption. On the contrary, Hofstee [47] demonstrated for Sepharose with coupled e-aminocaproyl-D-tryptophan methyl ester that it sorbed, for example, serum albumin or y-globulin quite non-specifically. Thus, it was found that a series of substances contained hydrophobic regions on the surface of their molecules, by which they were capable of being bound to hydrophobic spacers, such as hexa-methylenediamine or e-aminocaproic acid. The utilization of this phenomenon for the separation of a number of biological macromolecules gave rise to a new technique, the hydrophobic chromatography [14,15]. 

Aminoethyl glycopyranosides (D-galactoside, D-glucoside) 6-Aminohexanoyl-D-tryptophan methyl ester... 

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... 

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... 

The asymmetric dioxygenation of N-acetyl-L(+)- and N-acetyl-D(-)-tryptophan methyl ester (53) with O has been achieved in the... 

Ultrogel , a commercially available polyacrylamide-agarose medium, has been used as support matrix for the coupling of D-tryptophan methyl ester in a comparative study of the efficacy of two condensation agents, l-cyclohexyl-3-(2-morpholinoethyl)-carbodi-imide-metho-4-toluene sulphonate and A-ethoxy-... 

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