Brønsted acid-catalyzed conjugate addition of quinone methides by azlactones and indoles

Abstract

Over the past decades, quinone methides (QMs) have been widely employed as a kind of useful building blocks in the synthesis of natural products and biologically active molecules. Their typical reactivity is reviewed in Chapter 1. Because of their extremely high reactivity, early studies on QMs mainly focused on the pre-synthesized isolable ones. To address this limitation, many strategies to in situ generate QMs have been developed. Recently, a series protocols employing ortho- or para-hydroxybenzyl alcohols to in situ generate QMs in the presence of a catalytic amount of Brønsted acids have been reported. In this thesis, two new methods using this strategy to generate QMs for the synthesis useful molecules have been developed. In Chapter 2, a process of synthesizing chiral β,β-diaryl-α-amino acid derivatives via asymmetric addition of azlactones to p-QMs is described. The process is realized by using a suitable chiral phosphoric acid to not only help generating p-QMs in situ, but also catalyze the conjugate addition step in a stereocontrolled fashion. Although excellent enantioselectivity can be obtained in this process, diastereoselectivity is low throughout the condition screening. After substantial efforts, the problem is solved by one-pot protection of the free hydroxyl group in the product. Chapter 3 describes a novel C6-alkylation of indoles by employing different QMs as alkylating reagents. N-Alkylated indoles, which are considered to be kinetic products, are observed in some cases and then are converted to C6-alkylated products, which are the thermodynamic ones. Mechanistic study shows that the C–N bond foramtion is a reversible process while C–C bond formation is irreversible. This metal-free protocol enriches the toolbox of indole functionalization.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology