Trnsfer of a Functionalized Carbon-fragment via a (Substituted) N5,N10-Methylenetetrahydrofolic Acid Model. An Approach to D,L-Pyridindolol

Abstract

Reaction of dl-tryptophan hydrochloride with l-acetyl-3,4,4-trimethyl-2-[l,2-dihydroxyethyl]imidaz01id1ne acetonide(2) leads to the formation of the 6-carboline precursor of d,l- pyridindolol.The alkaloid p~ridindolol, from Streptomyces alboverticillatus, was first isolated by Umezawa and coworkers2a-c, in 1975.These authors have also established its structure and showed that it was a specific inhibitor of bovine liver B-galactosidase.In connection with a programme on the application of folic acid models in carbon-fragment transfer reactions, we have undertaken the synthesis of a varle-3 ty of indole and isoquinoline alkaloids , including that of pyridindolol.The recently reported total synthesis of pyridindolol by Cook et al.4 prompts us to describe the synthesis of the 6-carboline derivative ( 2 1 , which contains the complete structural framework of pyridindolol.has been converted into the alkaloid in 4 three conventional steps .The emphasis of the present communication lies in the demonstration that a functionalired carbon fragment can be readily transferred via the "folic acid model" approach.The strategy for the synthesis of the desired 6-carboline precursor 2 required the C(2)-functionalized imidazolidine derivative 2 as the appropriately substituted 5 10 N ,N -methylenetetrahydrofolic acid model.The importance of the gem-dimethyl substitution pattern of the nitrogen ring has been shown previously in the synthe-10 5 sis and carbon-transfer reactions of N5,N -methenyl and N ,NIO-methylenetetrahydrofolic acid models3r5.Commercially available d.1-glyceric acid (3) was esterified (Scheme I) and subsequently converted into the corresponding acetonide (4 4 5 ) by reaction with di- methoxypropane (toluene/p-TsOH, bath temp.130'; 96%).The protected ester (21 was allowed to react with 1.1-dimethyl-1.2-diaminoethane,first, under reflux condi-