Tryptophan methyl ester, reaction with aldehydes

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). 

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... 

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]. 

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). 

AB ABCE ABCDE - ABCDEF W-G aldehyde (-)-Strychnine] (27) After his racemic synthesis of strychnine (26), Kuehne also achieved an enantioselective synthesis of (—)-strychnine (Scheme 9). To avoid the low yield conversion of isostrychnine to strychnine, the second approach was directed to the W-G aldehyde. Starting from L-tryptophan methyl ester (86), the cyclization precursor 87 was prepared in seven steps in a similar way as in the previous racemic synthesis. The domino condensation-electrocyclization reaction of 87 with dienal 88 proceeded with quite high diastereoselectivity (>95% de) [AB ABCE, C7 quaternary center] (85). After conversion of the tetracyclic compound 89 to tosylate 92, removal of the benzyl group resulted in the clean formation of the D ring [ABCE ABCDE ]. Unlike in the first synthesis, introduction of the hydroxyethylidene side chain by a Horner-Wadsworth-Emmons reaction of ketone 93 proceeded with high stereoselectivity (E Z = 17 1). Einally, the E isomer 94E was converted to (-)-strychnine via the W-G aldehyde (50). 

Reaction of the aldehyde, Na-methylvellosimine (168), with 37% aqueous formaldehyde (25 equiv.) and 2 N KOH (10 equiv.) in methanol at room temperature for 10 h afforded optimum yields of the desired diol 211. The two prochiral hydroxymethyl functions in 211 were differentiated by the DDQ-mediated oxidative cyclization of the hydroxyl group at the 3-axial position of C-17 with the benzylic position at C-6. This gave the desired cyclic ether 212. Oxidation of the hydroxymethyl functionality was achieved with (PhSe0)20 to provide the aldehyde, which was further oxidized with KOH/R/MeOH to the methyl ester 210. Consequently, the total synthesis of (-l-)-dehydrovoachalotine (210) was achieved in 28% overall yield from D-(- -)-tryptophan. 

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