Introduction of the tryptophan side-chain

Freund, S. Mahboobi, K. Noack. P. Schonholzer and K. Bernauer, Hetv. Chim.. 4cta 73. 439 (1990). 

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 

B By palladium-catalysed reaction with amidoacrylate esters 

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

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The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

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). 

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.)... 

Chapter 13, Introduction of the Tryptamine and Tryptophan Side-Chains. 125... 

The steps of prenylation and dehydrogenation which follow (94) in the biosynthesis of these neoechinulins is unknown but from knowledge of echinulin biosynthesis (Scheme 6) introduction of the side chain at C-2 may be the next step. Prenylation of the benzene unit seems, by inspection of structures (97) through (101), to depend on C-8—C-9 unsaturation rather than the structure of the dioxo-piperazine ring. The stereochemistry of the desaturation reaction has been explored with L-tryptophan (85) samples stereospecifically labelled with tritium at... 

N-Acetyl-tryptophan and indole-3-propionic acid have been labelled with deuterium and tritium by Spande and Fontana 371), who employed the corresponding 2-sulfenyl derivatives. The spirolactones (176) obtained from (175) by treatment with N-bromosuccinimide were reduced with NaBD4 or NaBTa in good yields back to the corresponding indole compounds specifically labelled with deuterium or tritium at the 2-position. The method seems to offer a new general procedure which permits introduction of label specifically at the 2-position of indoles bearing a propionic acid side chain at the 3-position. 

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