Towards Ideal Synthesis: Concise Total Syntheses of Sesquiterpene and Diterpene Natural Products Restricted; Files Only
Liu, Chang (Spring 2024)
Abstract
Bioactive natural products have played a significant role in the history of medicinal chemistry. Total syntheses of sesquiterpene and diterpene natural products, especially those with high oxidation states and/or unique polycyclic skeletons, have become a major focus of synthetic organic chemists over the past decades. These studies have not only inspired the innovation of synthetic methodologies and strategies, but also facilitated the process of drug discoveries.
The first chapter briefly introduces three total synthesis projects the author has worked on. Chapter 1.1 describes the first synthetic route towards anticancer diterpenes Curcusone A-D, especially the author’s efforts to optimize and scale up the synthesis. Chapter 1.2 focuses on the transition-metal catalysis-enabled concise and enantioselective total synthesis of Peyssonnosol A, a diterpene glycoside exhibiting antifungal and antibacterial bioactivities. Chapter 1.3 shows several unsuccessful attempts to synthesize anticancer furanosteroid Isolinderalactone, including a cascade carbonylative cyclization-based approach.
The second chapter concentrates on the total synthesis of Phaeocaulisin A, a sesquiterpene that has shown promising anti-inflammatory bioactivity. To construct its tetracyclic acetal-lactone core, three different synthetic approaches have been designed and examined. The first-generation strategy based on our carbonylative acetal-lactonization chemistry was unfruitful due to the unproductive intramolecular Kulinkovich reaction. The second-generation strategy utilized bis-methoxycarbonylation and Dieckmann condensation to build the tetracyclic core efficiently but failed to establish the desired functionality. Following these unsuccessful trials, a 10-step total synthesis of Phaeocaulisin A has been developed which is highlighted with: (1) a novel palladium-catalyzed cyclopropanol ring-opening carbonylation enabling the facile preparation of an advanced γ-ketoester intermediate; (2) a regioselective Aldol cyclization which builds the 7-membered carbocycle; and (3) an acid-catalyzed acetal-lactonization for the closure of the target tetracyclic skeleton. This synthetic route is more concise and robust compared to the previous route reported by Procter and coworkers. Besides, the newly developed carbonylation reaction has been tested for various cyclopropanol substrates and carried out on micromoles-scale to demonstrate its versatility and scalability.
Table of Contents
Chapter 1. A Brief Introduction to Three Synthesis Projects .............................................1
1.1 Total synthesis of Curcusone diterpenes...................................................................................1
1.1.1 Introduction and our synthetic route .................................................................................1
1.1.2 Optimization of the synthesis of tricyclic intermediate 1-5..............................................4
1.2 Total synthesis of (-)-Peyssonnoside A ......................................................................................7
1.2.1 Introduction and our retrosynthetic analysis....................................................................7
1.2.2 Our synthesis of (-)-Peyssonnosol .....................................................................................11
1.2.3 Synthetic route towards (-)-Peyssonnosides A and B......................................................15
1.3 Synthetic studies towards Isolinderalactone...........................................................................18
1.3.1 Introduction and our design..............................................................................................18
1.3.2 Results and discussions......................................................................................................21
Chapter 2. 10-step Concise Total Synthesis of Phaeocaulisin A........................................25
2.1 Introduction...............................................................................................................................25
2.1.1 Phaeocaulisin A and related natural products................................................................25
2.1.2 Cyclopropanol ring-opening carbonylation and its application in total synthesis.......31
2.2 Inspiration and aim...................................................................................................................37
2.3 First-generation synthetic route towards phaeocaulisin A....................................................39
2.3.1 Retrosynthetic analysis......................................................................................................39
2.3.2 Results and discussions......................................................................................................41
2.4 Second-generation synthetic route towards Phaeocaulisin A ...............................................46
2.4.1 Retrosynthetic analysis......................................................................................................46
2.4.2 Results and discussions......................................................................................................47
2.5 Third-generation synthetic route towards Phaeocaulisin A..................................................54
2.5.1 Retrosynthetic analysis......................................................................................................54
2.5.2 Synthesis of γ-ketoesters via catalytic cyclopropanol ring-opening carbonylation......56
2.5.3 Closure of the seven-membered ring via Aldol cyclization ............................................64
2.5.4 Completion of the total synthesis......................................................................................69
2.6 Summary and Plan ...................................................................................................................73
Chapter 3. Experimental Procedures...................................................................................75
3.1. Experimental procedures and spectra data for Chapter 1...................................................75
3.1.1 Total synthesis of Curcusone diterpenes..........................................................................76
3.1.2 Total synthesis of (–)-Peyssonnoside A.............................................................................80
3.1.3 Synthetic study towards Isolinderalactone ....................................................................102
3.2. Experimental procedures and spectra data for Chapter 2.................................................115
3.2.1 Total Synthesis of (±)-Phaeocaulisin A...........................................................................116
3.2.2 Synthesis of γ-ketoesters via cyclopropanol ring-opening carbonylation ...................140
3.2.3. Unsuccessful synthetic studies........................................................................................148
3.3. X-ray structure and analysis data ........................................................................................162
Chapter 4. 1H, 13C and 19F NMR spectra...........................................................................166 References.............................................................................................................................267
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