Total Synthesis of Conidiogenone B Open Access

Abstract

Conidiogenone B is a complex cyclopiane diterpene that exhibits potent antibacterial activity against multidrug-resistant pathogens. Conidiogenone B and its congeners possess a highly congested 6/5/5/5 (A/B/C/D) tetracyclic carbon framework containing multiple stereocenters, including four all-carbon quaternary centers. A principal challenge in the total synthesis of this family lies in the efficient construction of the tetracyclic framework, particularly the A/B hydrindane motif bearing two vicinal all-carbon quaternary centers at the ring junction. Inspired by prior elegant syntheses of conidiogenone, we developed a highly efficient and scalable synthetic strategy toward Conidiogenone B that prioritizes efficiency. Central to this approach is a metal-catalyzed hydrogen atom transfer (MHAT)-initiated reductive olefin–nitrile radical cyclization, enabling rapid construction of the six-membered A ring while simultaneously forming a challenging angular methyl-containing all-carbon quaternary center adjacent to a pre-installed stereocenter generated via a Johnson–Claisen rearrangement. To access the B ring, we evaluated two complementary strategies: (1) a stepwise sequence culminating in an intramolecular aldol condensation, and (2) a one-pot annulation leveraging a doubly activated cyclopropane phosphonium salt as a formal 1,3-dipole, enabling sequential α-alkylation and Wittig olefination. Collectively, these enabling transformations deliver Conidiogenone B in seven steps without the use of protecting groups, maximizing C–C bond-forming events while minimizing functional group manipulations. This work demonstrates how modern radical-based methodologies can streamline access to complex bioactive scaffolds and provides a platform for future analog development and antibiotic discovery efforts.

Table of Contents

ABSTRACT. iv

ACKNOWLEDGMENTS. vii

LIST OF FIGURES. ix

LIST OF SCHEMES. xi

LIST OF TABLES. xv

ABBREVIATIONS. xvi

Chapter 1: Structure, history and bioactivity of the cyclopiane diterpenes

1.1       Discovery Introduction. 2

1.2       Structural Complexity. 3

1.3      Postulated Biosynthetic pathway. 5

1.4       Isolation. 6

1.5       Biological Activity. 7

1.5.2        Anticancer Activity. 8

1.5.3        Anti-inflammatory. 9

1.6       Synthetic Significance. 9

Chapter 2: Analysis of Prior Routes toward Cyclopiane Diterpene Family

2.1       Spacial Score Analysis. 12

2.2      Reported syntheses of cyclopiane diterpene family. 15

2.2.1       Tu’s synthesis. 16

2.2.2       Snyder’s synthesis. 18

2.2.3        Zhai’s synthesis. 21

2.2.4        S. Han, H.-Y. Lee’s synthesis. 23

2.2.5        Zhou, H. Li, Hao’s synthesis. 25

2.2.6       W. Han, Z. Li, C. S. Lee’s synthesis. 27

2.3       Conclusion. 30

Chapter 3: Cargill Inspired rearrangement towards Conidiogenone B

3.1      Introduction of fused 6/4 bicyclic rearrangement 33

3.1.1       Synthetic inspiration from Dai lab’s use of the Cargill rearrangement 33

3.1.2        6/4 bicyclic system rearrangements. 36

3.2       Cargill rearrangement inspired total synthesis of conidiogenone B.. 39

3.2.1       Retrosynthetic analysis. 39

3.2.2       Model Studies of acid catalyzed rearrangement 42

3.2.3        Strategy 1: tricyclic enone construction via intramolecular [3+2] 44

3.2.4        Strategy 2: tricyclic enone construction via Pauson Khand Reaction. 48

3.2.5        Strategy 3: tricyclic enone construction via Robinson annulation. 50

3.2.6        Advancements towards building six-membered A-ring of conidiogenone B.. 51

3.3 Conclusion. 56

3.4      Experimental Data. 58

3.4.1        Experimental Procedures. 59

3.4.2        Spectral Data Characterization. 70

Chapter 4: Leveraging MHAT Cyclizations to Construct Conidiogenone B

4.1      Metal–hydride Hydrogen Atom Transfer in Total Synthesis. 94

4.1.1       MHAT–enabled cyclizations of complex natural products within Dai group. 94

4.1.2        MHAT Mechanistic Background and Reactivity 97

4.1.3        Intramolecular MHAT of Six Membered Rings in Total Synthesis. 101

4.1.4        6-exo-dig MHAT cyclizations with Cyano Acceptors 110

4.2      Retrosynthetic Analysis. 113

4.3       Model Studies of MHAT via 1,2-addition. 114

4.4      D-ring construction. 115

4.5       B-ring Construction via Strategy 1 – Aldol Condensation. 116

4.5.1        Strategy 1 – Aldol Condensation. 116

4.5.2        Strategy 2 – Intramolecular [3+2] cycloaddition. 118

4.6       A-ring Construction. 126

4.6.1        Johnson–Claisen Rearrangement 126

4.6.2        Building A ring carbon framework. 127

4.6.3        End Game. 128

4.7       Conclusion. 131

4.8       Experimental Data. 133

4.8.1        Experimental Procedures and Spectra Data. 134

4.8.2        1H and 13C NMR spectra. 149

3.8.4        NMR Comparison Tables. 178

References. 180

Publications. 188

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	quaternary carbon MHAT acid catalyzed rearrangement Johnson-Claisen rearrangement total synthesis
Committee Chair / Thesis Advisor	Mingji Dai, Emory University
Committee Members	Simon Blakey, Emory University Huw Davies, Emory University

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