Practical Methodologies for Amino Alcohol Based Natural Products Synthesis

Andrejs Pelšs

    Research output: ThesisDoctoral ThesisMonograph

    Abstract

    The thesis deals with the methodology development for the purpose of practical synthesis of cyclic amino alcohol based natural products – amaminol and lepadin families by complying with the principles of ideal synthesis and especially step economy. In the first chapter a historical background of the conjugate reduction reaction is laid out and the development of currently one of the most selective conjugate reduction methods is described in detail. The method is based on the copper hydride chemistry employing triisopropyl phosphite as a ligand which is the key to the reduced reaction power and hence the high selectivity of the process. In the second chapter a comprehensive review of the decahydroquinoline based natural products synthesis – pumiliotoxin C and lepadin family is provided. More than forty total syntheses are categorized according to the strategy employed and analyzed in detail placing special emphasis on the construction steps. A proposal for cyclic amino alcohol natural products biosynthesis was also put forth. In the third chapter the design of two complementary approaches to lepadin alkaloids is provided dealing with both non-biogenetic and bio-inspired approaches. The studies performed resulted in the development of two new methodologies. First, the orthogonally protected amino epoxide was identified and its successful catalytic coupling with cyclic alkenyl copper reagent was discovered and developed into a scalable method. This chemistry provides the solution to two problems: the problematic reactivity of Boc-amino epoxides with organometallic reagents and the inability to orthogonally release the reactive benzylamino functionality of the products of dibenzyl-amino epoxide reaction with organometallic reagents. The second methodology – the unprecedented silica gel mediated spontaneous stereocontrolled allylic aminocyclization to form octahydroquinolines was discovered. This reaction is an example of the remote (1,4- from hydroxyl stereocenter, 1,5- from amino stereocenter) stereo induction. Such a reaction previously would only be possible to achieve using transition metal catalysis (Pd, Ir) and externally introduced chirality of the leaving group stereocenter (either by using chiral ligands or stoichiometric chiral reagents). The spontaneous nature and ease with which this reaction proceeds might also provide an implication on how lepadins are biosynthesized in the Nature.
    Translated title of the contributionPractical Methodologies for Amino Alcohol Based Natural Products Synthesis
    Original languageEnglish
    QualificationDoctor's degree
    Awarding Institution
    • Aalto University
    Supervisors/Advisors
    • Koskinen, Ari, Supervising Professor
    • Koskinen, Ari, Thesis Advisor
    Publisher
    Print ISBNs978-952-60-5734-7
    Electronic ISBNs978-952-60-5735-4
    Publication statusPublished - 2014
    MoE publication typeG4 Doctoral dissertation (monograph)

    Keywords

    • amino alcohols
    • lepadins
    • total synthesis
    • copper hydride
    • organocopper
    • amino epoxide
    • allylic aminocyclization
    • stereocontrol

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