Tryptophans 1-alkylation

C.G. Fields, G.B. Fields, Minimization of tryptophan alkylation following 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis, Tetrahedron Letters 34(1993)6661-6664. 

A kinetic study of the photosensitized oxidation of tryptophan-alkyl esters in Triton X-100 micellar solutions has been carried out by Criado et al. [24], The results obtained are presented in Table 6. These data show an important decrease in the relevance of the photo-oxidative pathway in the esterified compounds in the presence of the micelles. The magnitude of the effect seems to be extremely sensitive to the location of the probe, increasing as the length of the ester hydrocarbon chain increases. These results are interpreted in terms of the competition between the local oxygen concentration and the solvent micropolarity effect that... 

DMF. The silyl acid support (SAC) 51 [217] has been used for peptide synthesis with cleavage being effected with either TEA or fluoride ion. It was shown that when using support 51 diketopiperazine formation and tryptophan alkylation are suppressed compared with construction of the same sequence of PAC resin. 

Blumenthal, K.M. Structure and Action of Heteronemertine Polypeptide Toxins Inactivation of Cerebratulus lacteus Toxin B-IV Concomitant with Tryptophan Alkylation. Arch. Biochem. Biophys. 203, 822 (1980). 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

The appearance of the 2-(indol-3yl)ethylamine (tryptamine) unit in both tryptophan-derived natural products and in synthetic materials having potential pharmacological activity has generated a great deal of interest in the synthesis of such compounds. Several procedures which involve either direct 3-alkylation or tandem 3-functionalization/modification have been developed. Similarly, methodology applicable to preparation of tryptophan analogues has been widely explored. 

One effective method for synthesis of tryptophan derivatives involves alkylation of formamido- or acetamido- malonate diesters by gramine[l,2]. Conversion to tryptophans is completed by hydrolysis and decarboxylation. These reactions were discussed in Chapter 12. An enolate of an a-nitro ester is an alternative nucleophile. The products can be converted to tryptophans by rcduction[3,4],... 

A versatile tryptophan synthesis which proceeds directly from indoles as starting materials was developed by Gilchrist[5], The alkylation reagent is the... 

If the oximino intermediates are O-alkylated and then reduced with BHj-N(CH3)3, N-alkoxy tryptophans can be obtained[6]. 

Enantioselective synthesis of tryptophans has been accomplished via alkylation of 2,5-diethoxy-3,6-dihydropiperazines by the method developed by Schbllkopf[18]. For example, I> - -)-6-methoxytryptophan ethyl ester was prepared using l-(phcnylsulfonyl)-3-(bromomethyl)-6-methoxyindolefor alkyl-ationfl 9],... 

Diethyl acetamidomalonate is useful in the synthesis of ce-amino acids by alkylation, as, for example, histidine and tryptophan. 

The nonpolar amino acids (Figure 4.3a) include all those with alkyl chain R groups (alanine, valine, leucine, and isoleucine), as well as proline (with its unusual cyclic structure), methionine (one of the two sulfur-containing amino acids), and two aromatic amino acids, phenylalanine and tryptophan. Tryptophan is sometimes considered a borderline member of this group because it can interact favorably with water via the N-H moiety of the indole ring. Proline, strictly speaking, is not an amino acid but rather an a-imino acid. 

The Hoc group was developed for tryptophan protection to minimize alkylation during BOC-mediated peptide synthesis. It is introduced with the chloroformate (NaOH, CH2CI2, Bu4N HS04 ) and can be cleaved with HF without the need to include thiols in the cleavage mixture. 

Several factors influence the diastereoselectivity of the Pictet-Spengler condensation to form 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-P-carbolines (39 and 40, respectively). The presence or absence of an alkyl substituent on the nitrogen of tryptophan has a large influence on the relative stereochemistry of the tetrahydro-P-carboline products formed from a condensation reaction with an aldehyde under various reaction conditions. 

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. ... 

Kawahara, M., Nishida, A., Nakagawa, M. (2000) An Efficient Synthesis of Optically Active Physostigmine from Tryptophan Via Alkylative CycUzation. Organic Letters, 2, 675-678. 

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>. 

Since the order of increasing CL intensity for alkyl amines reacted with Ru(bpy)32+ is tertiary amines > secondary amines > primary amines, pharmaceutical compounds bearing a tertiary amine function (e.g., antihistamine drugs [99], anticholinergic drugs [100], erythromycin [101], and its derivatives [102]) have been sensitively determined after HPLC separation (Table 3). The method was applied to the detection of d- and L-tryptophan (Trp) after separation by a ligand-exchange HPLC [103], The detection limits for d- and L-Trp were both 0.2 pmol per injection. Oxalate in urine and blood plasma samples has also been determined by a reversed-phase ion-pair HPLC (Fig. 18) [104], Direct addition of... 

Nakagawa devised a concise synthetic route to physostigimine (169) where the key step involves the alkylative cyclization of 1,3-dimethylindole (167) with (Z)-aziridine catalyzed by Sc(OTf)3 and TMSC1 to give 168, which, in turn, can be converted into 169 . A similar asymmetric approach to this natural product was also developed by these authors via treatment of tryptophan carbamates with the Corey-Kim reagent so as to induce intramolecular cyclization to the pyrrolo-indole skeleton . 

Trifluoroacetic acid removes tert-butyl-based protectors by the S vl mechanism, with the cation being trapped by the trifluoroacetate anion however, the tert-butyl trifluoroacetate produced is an alkylating agent, and the acid is not strong enough to protonate the side chains of methionine, tryptophan, and cysteine, so these are acceptors of tert-butyl. A scavenger is required to prevent their alkylation. Anisole... 

R2 = amine, alkyl, nitrile Scheme 7.13 Halogenation of indoles by tryptophan 7-halogenase. 

Racemic jS-fluoroalkyl tyrosines and phenylalanines have been prepared by classical methods starting from the corresponding fluoroacetophenones. Synthesis of the nonracemic compounds is much more difficult, as exemplified by the preparation of jS-difluoromethyl meta-tyrosines (Figure 5.14). jS-Trifluoromethyl tryptophan is prepared by alkylation of ethyl acetamido malonate with indolyl-2,2-trifluoroethanol. Surprisingly, the decarboxylation reaction leads stereoselectively to the syn isomer (Figure 5.15). ... 

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