Development of a Novel Cascade Cyclization Reaction and its Application Towards the Total Synthesis of Malagashanine: A Chloroquine Efflux Inhibitor Open Access

Delgado, Ricardo (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/9306sz91j?locale=en
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Abstract

A cascade cyclization reaction was developed to access the core of the
malagashanine alkaloids with the necessary stereochemistry at C(2), C(3), C(7). The
transformation employed stable N-tosyl-O-TMS-aminols to generate highly reactive
β,γ-unsaturated iminium ion intermediates, and the method was amenable to both
electron rich and electron poor tryptamine substituents, as well as furans and tryptophol
nucleophiles. Additionally, the sequence was successfully employed with intermolecular
indole nucleophiles. For the synthesis of malagashanine, the use of a tri-substituted
β,γ-unsaturated acid permitted the installation of the fourth requisite stereocenter at
C(16). Additionally, the E ring was constructed via a formal olefin hydroacylation
reaction, and C(19)-C(20)-dehydro-malagashanine was subsequently synthesized.

Table of Contents

1. Chapter One: Introduction to the Monoterpene Indole Alkaloids.......................1


1.1. Total Synthesis of Strychnos Alkaloids and Related Natural Products..............1


1.2. The Malagashanine Alkaloids: Isolation, Structure and Stereochemistry............2


1.3. Biological Activity ............................................................................................4


1.4. Biosynthesis and Related Natural Products ........................................................6


1.5. Van Tamelen, Harley-Mason, and Waterfield: An Ingenious Approach to the


Strychnos and Aspidosperma Alkaloids.......................................................................8


1.6. Application of Büchi's Approach to Vindorisone, Vindoline and Other Targets.


…………………………………………………………………………………..11


1.7. The Corey Approach to Aspidophytine............................................................ 15


1.8. Our Strategy to Access the Core of the Malagashanine Alkaloids .................... 19


2. Chapter Two: Development of a Cascade Cyclization Reaction to Access the


Core of the Malagashanine Alkaloids......................................................................... 24


2.1. Early Attempts: Synthesis of β,γ-Unsaturated Imine 80 via Condensation of


Aldehyde 86 and Tryptamine 36................................................................................ 24


2.1.1. Synthesis of β,γ-Unsaturated Aldehyde 86 ................................................ 24


2.1.2. Attempted Condensation of β,γ-Unsaturated Aldehyde 86 with Tryptamine


36…….. ................................................................................................................ 26


2.2. Accessing the Key Iminium Ion Intermediate by Reduction of a Stable Amide


Precursor................................................................................................................... 27


2.2.1. N-Cbz-O-TMS-Aminols are Iminium Ion Precursors ................................ 27


2.2.2. Synthesis of N-Cbz-O-TMS-Aminol 110 .................................................. 30


2.2.3. Cyclization of N-Cbz-O-TMS-Aminol 110: Preliminary Results ............... 32


2.3. Effect of Na and Nb Susbtituents on the Key Cyclization Reaction ................... 36


2.3.1. The Substituents on the Nitrogen Atoms Can Have Significant Effects on


Product Distribution .............................................................................................. 36


2.3.2. Exploring the Effect of Na Substitution: Synthesis and Cyclization of


Na-Benzyl-Nb-Cbz-O-TMS-Aminol 148 ................................................................ 39


2.3.3. Exploring the Effect of Na Substitution: Synthesis and Cyclization of


Na-H-Nb-Cbz-O-TMS-Aminol 156 ........................................................................ 42


2.3.4. Exploring the Effect of Na Substitution: Synthesis and Cyclization of


Na-Tosyl-Nb-Cbz-O-TMS-Aminol 168 .................................................................. 45


2.3.5. Exploring the Effect of Nb Substitution: Synthesis and Cyclization of


Na-Benzyl-Nb-Carbomethoxy- and Na-Benzyl-Nb-Boc-O-TMS-Aminols 180 and 181


……………………………………………………………………………...48


2.3.6. Exploring the Effect of Nb Substitution: Synthesis and Cyclization of


Na-Benzyl-Nb-Piv-O-TMS-Aminol 186 ................................................................. 49


2.3.7. Exploring the Effect of Nb Substitution: Synthesis and Cyclization of


Na-Benzyl-Nb-Tosyl- and Na-Benzyl-Nb-Nosyl-O-TMS-Aminols 192 and 193....... 50


2.4. Optimization of the Synthesis of N-Tosyl-O-TMS-Aminol 192........................ 55


2.5. Removal of Benzyl and Tosyl Protecting Groups From Tetracyclic Core 195 .. 59


2.6. Extending the Substrate Scope of the Cascade Annulation Reaction ................ 60


2.6.1. Synthesis and Cyclization of Substrates with Substituted Indoles .............. 60


2.6.2. Application of Our Cascade Annulation Strategy to Tryptophol-Based


System 262............................................................................................................ 67


2.6.3. Application of Our Cascade Annulation Strategy to Furan-Based System


268…….. .............................................................................................................. 70


2.6.4. Development of an Intermolecular Cascade Annulation Reaction.............. 74


2.7. Conclusions ..................................................................................................... 77


2.8. Experimental Procedures ................................................................................. 79


2.9. NMR Spectra………………………………………………………………… 190


2.10. X-Ray Structures…………………………………………………………….. 211


3. Chapter Three: Efforts Towards the Total Synthesis of Malagashanine Using


Our Cascade Cyclization Reaction Sequence........................................................... 263


3.1. First Generation Approach: Accessing Malagashanine via a Knoevenagel


Condensation and a Tandem Hydrogenation Reaction ............................................. 263


3.1.1. Retrosynthetic Analysis .......................................................................... 263


3.1.2. Initial Approach to Incorporate a Suitable C(16)-Substituent................... 265


3.1.3. Revised Approach to Incorporate a Suitable C(16)-Substituent: Synthesis of


E-Olefin Isomer N-Tosyl-O-TMS-Aminol 304 .................................................... 267


3.1.4. Cyclization of N-Tosyl-O-TMS-Aminol 304........................................... 268


3.1.5. Synthesis of N-Tosyl-O-TMS-Aminols 316 and 317 Containing the Benzyl


and TBDPS Protecting Groups Respectively ....................................................... 270


3.1.6. Synthesis of Malagashanine Cores 340 and 341 via Cyclization of N-Tosyl-


O-TMS-Aminols 316 and 317 Respectively......................................................... 275


3.1.7. Synthesis of Ketone 342 for Knoevenagel Condensation......................... 276


3.1.8. Knoevonagel Condensation of Ketone 342 and Ketoester 296................. 277


3.2. Second Generation Approach: Accessing Malagashanine via a Key Negishi


Cross-Coupling and a Tandem Hydrogenation Reaction.......................................... 280


3.2.1. Retrosynthetic Analysis .......................................................................... 280


3.2.2. Synthesis of Kinetic Enol Triflate 355 for Key Negishi Cross-Coupling with


356…….............................................................................................................. 281


3.2.3. Synthesis of the More Hindered β-tert-Butyldiphenylsiloxy Ketone 368. 285


3.2.4. Synthesis of Kinetic Enol Triflate 372 and Key Negishi Cross-Coupling


with 356 .............................................................................................................. 286


3.3. Third Generation Approach: Accessing Malagashanine via a Formal Olefin


Hydroacylation Reaction and a Late-Stage Hydrogenation ...................................... 288


3.3.1. Retrosynthetic Analysis .......................................................................... 288


3.3.2. Synthesis of Pyran 377............................................................................ 289


3.3.3. Synthesis of Ester 376 for Key Hydrogenation Reaction ......................... 292


3.3.4. Attempts to Synthesize Malagashanine by Hydrogenation of the C(19)-


C(20) Olefin and Removal of the Nb Tosyl Auxilliary. ........................................ 296


3.4. Conclusions ................................................................................................... 300


3.5. Experimental Procedures ............................................................................... 302


3.6. NMR Spectra………………………………………………………………… 350


4. References........................................................................................................... 359

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