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

  • Author / Creator
  • 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.

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  • Graduation date
    Spring 2020
  • Type of Item
  • Degree
    Doctor of Philosophy
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