Acid-Catalyzed Highly Diastereoselective And Effective Synthesis Of 1,3-Disubstituted Tetrahydropyrano[3,4-b]Indoles

Isochromans are of considerable importance in medicinal chemistry,especially1,3,4,9-tetrahydropyrano[3,4-b]indole scaffold.The general procedure to prepare THPIs is the time-honored oxa-Pictet-Spengler reaction.However,in previous studies,1,3-disubstituted tetrahydropyrano[3,4-b]indoles hardly seen to date.Similarly,secondary tryptophols,the straightforward starting materials of 1,3-disubstituted tetrahydropyrano[3,4-b]indoles using in the oxa-Pictet-Spengler reaction,and their synthesis have rarely been reported,either.We successfully explored for the first time that trifluoroacetic acid(TFA)can effectively catalyze the oxa-Pictet-Spengler reaction of secondary tryptophols and acetals to synthesize 1,3-disubstituted 1,3,4,9-tetrahydropyrano[3,4-b]indoles in high yield(up to >99%)and diastereoselectivity(>20:1).The secondary tryptophols were synthesized from indole-3-acetic acid.The one-pot synthesis of tetrahydropyrano[3,4-b]indoles was successfully developed from secondary tryptophols and in situ prepared acetals from aldehydes and trimethylorthoformate and thus the cost-efficiency of the protocol was effectively enhanced.Finally,the catalytic asymmetric synthesis of the 1,3-disubstituted tetrahydropyrano[3,4-b]indole was also demonstrated after enantioselective achievement of highly enantiopure secondary tryptophols.