Synthesis of 4-bromo-indole, aiming the total synthesis of lysergic acid and its derivatives

• Grant number: 16/18817-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2016
• End date: November 30, 2017
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Antonio Carlos Bender Burtoloso
• Grantee: Lucas Giani Furniel
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

The principal objective of this Project, is to prepare derivatives of 4-bromo-indole via three different protocols. These building blocks in future can be efficiently use in the total synthesis of lysergic acid and its derivatives. The first strategy is based on the coupling reaction between 4-bromo-1-tosyl-indole and methyl 2-((tert-butoxycarbonyl)amino)acrylate, catalyzed by Pd(OAc)2, followed by Rh catalyzed asymmetric reduction. The second strategy arises from a reductive cross-coupling reaction catalyzed by Ni complexes between 4-bromo-3-iodo-1-tosyl-indole and (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate. The last strategy is an execution of an indole coupling between dl-serine and 4-bromo-1-tosyl-indole, resulting in an acetylated racemic derivative of 4-bromo-tryptophan. This compound will be subjected to a kinetic resolution performed by Aspergillus Acilase generating the (S)- 4-bromo-tryptophan as a pure enantiomer, which can be transformed into the desired intermediate in two steps. (AU)