CYCLIC TAUTOMERS OF TRYPTOPHAN - ENANTIOSELECTIVE AND DIASTEREOSELECTIVE SYNTHESIS OF BETA-SUBSTITUTED AND ALPHA-BETA-DISUBSTITUTED DERIVATIVES OF TRYPTOPHAN

A method is presented for the synthesis of enantiomerically pure erythro-beta-alkylated derivatives of L-tryptophan from L-tryptophan itself via the intermediacy of cyclic tryptophan tautomers. Dehydrogenation of the cyclic tryptophan tautomer 2 to 3 is achieved via either the 2-phenylseleno derivative 6 or its 8-phenylthio counterpart 7 by oxidation to the corresponding selenoxide or sulfoxide and formal syn-elimination. Evidence is provided that this elimination proceeds, at least in part, by a stepwise rather than a concerted pericyclic mechanism. Soft nucleophiles, including thiolates, amines, and higher order cuprates, add to 3 in conjugate fashion in high yield and with excellent diastereoselectivity from the exe-face of the bicyclic system. The enolate anion resulting from conjugate addition is likewise quenched with high selectivity from the exo face either by simple protonation or by alkylation with methyl iodide. The tetrahydropyrroloindole 3 also reacts with cyclopentadiene in a Diels-Alder reaction with excellent selectivity to give 29. Sulfur ylide chemistry enables the formation of the cyclopropane adduct 27. After conjugate addition, cycloreversion to the tryptophan skeleton is achieved by dissolution in trifluoroacetic acid. The rate of ring opening is strongly dependant on the steric bulk and orientation of the substituent at C-3, with large exo-substituents strongly retarding ring opening and endo-substituents favoring ring opening. Desulfonylation is achieved by photolysis with ascorbic acid and anisole and final deprotection by heating to reflux with 6 M hydrochloric acid. Desulfonylation of the 2,3-methano derivative 37 resulted in degradation of the cyclopropane ring. Use of a (4-methoxyphenyl)sulfonyl group in place of the phenylsulfonyl group, as in 11 and 22, enables one-step desulfonylation and ring opening by treatment with methanesulfonic acid.