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Stereoselective Synthesis of β-Aminoalkylboronic Acid Derivatives Using 1,1-Diboron Compounds

  • Author / Creator
    Li,Xiangyu
  • As an important class of chiral alkylboron compounds, α-aminoalkylboronic acids display distinct utility in medicinal chemistry as a bioisostere of α-amino acids and α-amino aldehydes, which is highlighted by the commercialization of two anticancer drugs (bortezomib and ixazomib) and one antibiotic drug (vaborbactam). By analogy with α-aminoalkylboronic acids, β-aminoalkylboronic acids are a bioisostere of β-amino acids, thus have obvious potential in pharmaceutical drug development. Besides, β-aminoalkylboronates can act as catalysts in organic reactions and are valuable synthetic building blocks, which can be exploited to access many useful compounds, such as β-amino alcohols and 1,2-diamines. However, despite these attractive applications, the development of synthetic approaches to these valuable compounds has not received much attention until recently. Among all of the reported methods, only a small number of stereoselective methods can provide primary β-aminoalkylboronic esters, and even fewer methods are applicable to α,β-disubstituted β-aminoalkylboronic esters. This thesis describes successful efforts to develop novel and efficient approaches using 1,1-diboron compounds towards optically pure β-aminoalkylboronates, including the syn and anti diastereomers of α,β-disubstituted β-aminoalkylboronates. Chapter 2 presents a 1,2-addition/monoprotodeboronation sequence developed to access enantioenriched α,β-disubstituted β-aminoalkylboronates. The 1,2-addition of lithiated 1,1-diborylalkanes to chiral sulfinimine derivatives delivered enantiomerically pure β-sufinimido gem-bis(boronates) in good yields with high levels of diastereoselectivity. A subsequent mono-protodeboronation of the resulting β-sufinimido gem-bis(boronates) afforded syn-α,β-disubstituted β-aminoalkylboronates. In addition, studies were made to investigate the stereochemical outcome (syn-selectivity) in the monoprotodeboronation. The details of the reaction scope and synthetic applications also will be discussed. To access the elusive anti-α,β-disubstituted β-aminoalkylboronates, a complementary variant of the abovementioned monoprotodeboronation was developed. To favor the formation of the anti diastereomer, the steps of protodeboronation and deprotection of the N-sulfinyl amine were inverted. Chapter 3 describes the details of the optimization of this anti-selective monoprotodeboronation using N-desulfinylated β-amino gem-bis(boronates). The substrate scope, mechanistic studies, and synthetic applications also are discussed. Inspired by the previous work on a Cu-catalyzed asymmetric 1,2-addition of 1,1-diborylalkanes to aldehydes for the synthesis of 1,2-hydroxyboronates, it was envisioned that this 1,2-addition strategy could be applied to imines, thus providing a straightforward and catalytic approach to enantioenriched β-aminoalkylboronates. In Chapter 4, the extensive optimization of such an asymmetric 1,2-addition is presented. To enhance the enantioselectivity, a ligand high-throughput screening (HTS) approach was employed through a collaboration with a team of scientists at Pfizer and will be discussed in detail.

  • Subjects / Keywords
  • Graduation date
    Spring 2020
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/r3-dbyf-ya41
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.