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1. Single-cell analysis of chromatin accessibility in the adult mouse brain

Author

Zu, Songpeng, Li, Yang Eric, Wang, Kangli, Armand, Ethan J, Mamde, Sainath, Amaral, Maria Luisa, Wang, Yuelai, Chu, Andre, Xie, Yang, Miller, Michael, Xu, Jie, Wang, Zhaoning, Zhang, Kai, Jia, Bojing, Hou, Xiaomeng, Lin, Lin, Yang, Qian, Lee, Seoyeon, Li, Bin, Kuan, Samantha, Liu, Hanqing, Zhou, Jingtian, Pinto-Duarte, Antonio, Lucero, Jacinta, Osteen, Julia, Nunn, Michael, Smith, Kimberly A, Tasic, Bosiljka, Yao, Zizhen, Zeng, Hongkui, Wang, Zihan, Shang, Jingbo, Behrens, M Margarita, Ecker, Joseph R, Wang, Allen, Preissl, Sebastian, and Ren, Bing

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Stem Cell Research, Neurosciences, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Animals, Humans, Mice, Brain, Cerebral Cortex, Chromatin, Deep Learning, DNA Transposable Elements, Gene Regulatory Networks, Neurons, Single-Cell Analysis, General Science & Technology
Abstract

Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete1-4. Here we report a comprehensive atlas of candidate cis-regulatory DNA elements (cCREs) in the adult mouse brain, generated by analysing chromatin accessibility in 2.3 million individual brain cells from 117 anatomical dissections. The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1,482 distinct brain cell populations, adding over 446,000 cCREs to the most recent such annotation in the mouse genome. The mouse brain cCREs are moderately conserved in the human brain. The mouse-specific cCREs-specifically, those identified from a subset of cortical excitatory neurons-are strongly enriched for transposable elements, suggesting a potential role for transposable elements in the emergence of new regulatory programs and neuronal diversity. Finally, we infer the gene regulatory networks in over 260 subclasses of mouse brain cells and develop deep-learning models to predict the activities of gene regulatory elements in different brain cell types from the DNA sequence alone. Our results provide a resource for the analysis of cell-type-specific gene regulation programs in both mouse and human brains.

Published
2023

2. Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain.

Author

Liu, Hanqing, Zeng, Qiurui, Zhou, Jingtian, Bartlett, Anna, Wang, Bang-An, Tian, Wei, Kenworthy, Mia, Altshul, Jordan, Nery, Joseph, Chen, Huaming, Castanon, Rosa, Zu, Songpeng, Li, Yang, Lucero, Jacinta, Osteen, Julia, Pinto-Duarte, Antonio, Lee, Jasper, Rink, Jon, Cho, Silvia, Emerson, Nora, Nunn, Michael, OConnor, Carolyn, Wu, Zhanghao, Stoica, Ion, Yao, Zizhen, Smith, Kimberly, Tasic, Bosiljka, Luo, Chongyuan, Dixon, Jesse, Zeng, Hongkui, Ren, Bing, Behrens, M, Ecker, Joseph, and Berube, Peter

Subjects
Animals, Mice, Brain, Chromatin, Cytosine, Datasets as Topic, DNA Methylation, Epigenome, Multiomics, Single-Cell Analysis, Transcription Factors, Transcription, Genetic
Abstract

Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq)1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain.

Published
2023

3. An atlas of gene regulatory elements in adult mouse cerebrum

Author

Li, Yang Eric, Preissl, Sebastian, Hou, Xiaomeng, Zhang, Ziyang, Zhang, Kai, Qiu, Yunjiang, Poirion, Olivier B, Li, Bin, Chiou, Joshua, Liu, Hanqing, Pinto-Duarte, Antonio, Kubo, Naoki, Yang, Xiaoyu, Fang, Rongxin, Wang, Xinxin, Han, Jee Yun, Lucero, Jacinta, Yan, Yiming, Miller, Michael, Kuan, Samantha, Gorkin, David, Gaulton, Kyle J, Shen, Yin, Nunn, Michael, Mukamel, Eran A, Behrens, M Margarita, Ecker, Joseph R, and Ren, Bing

Subjects
Human Genome, Genetics, Biotechnology, Brain Disorders, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, Neurosciences, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Animals, Atlases as Topic, Cerebrum, Chromatin, Chromatin Assembly and Disassembly, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Male, Mice, Mice, Inbred C57BL, Nervous System Diseases, Neuroglia, Neurons, Regulatory Sequences, Nucleic Acid, Sequence Analysis, DNA, Single-Cell Analysis, General Science & Technology
Abstract

The mammalian cerebrum performs high-level sensory perception, motor control and cognitive functions through highly specialized cortical and subcortical structures1. Recent surveys of mouse and human brains with single-cell transcriptomics2-6 and high-throughput imaging technologies7,8 have uncovered hundreds of neural cell types distributed in different brain regions, but the transcriptional regulatory programs that are responsible for the unique identity and function of each cell type remain unknown. Here we probe the accessible chromatin in more than 800,000 individual nuclei from 45 regions that span the adult mouse isocortex, olfactory bulb, hippocampus and cerebral nuclei, and use the resulting data to map the state of 491,818 candidate cis-regulatory DNA elements in 160 distinct cell types. We find high specificity of spatial distribution for not only excitatory neurons, but also most classes of inhibitory neurons and a subset of glial cell types. We characterize the gene regulatory sequences associated with the regional specificity within these cell types. We further link a considerable fraction of the cis-regulatory elements to putative target genes expressed in diverse cerebral cell types and predict transcriptional regulators that are involved in a broad spectrum of molecular and cellular pathways in different neuronal and glial cell populations. Our results provide a foundation for comprehensive analysis of gene regulatory programs of the mammalian brain and assist in the interpretation of noncoding risk variants associated with various neurological diseases and traits in humans.

Published
2021

4. DNA methylation atlas of the mouse brain at single-cell resolution

Author

Liu, Hanqing, Zhou, Jingtian, Tian, Wei, Luo, Chongyuan, Bartlett, Anna, Aldridge, Andrew, Lucero, Jacinta, Osteen, Julia K, Nery, Joseph R, Chen, Huaming, Rivkin, Angeline, Castanon, Rosa G, Clock, Ben, Li, Yang Eric, Hou, Xiaomeng, Poirion, Olivier B, Preissl, Sebastian, Pinto-Duarte, Antonio, O’Connor, Carolyn, Boggeman, Lara, Fitzpatrick, Conor, Nunn, Michael, Mukamel, Eran A, Zhang, Zhuzhu, Callaway, Edward M, Ren, Bing, Dixon, Jesse R, Behrens, M Margarita, and Ecker, Joseph R

Subjects
Neurosciences, Human Genome, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Animals, Atlases as Topic, Brain, Chromatin, Cytosine, DNA Methylation, Datasets as Topic, Dentate Gyrus, Enhancer Elements, Genetic, Epigenome, Epigenomics, Gene Expression Profiling, Hippocampus, Male, Mice, Mice, Inbred C57BL, Models, Biological, Neural Pathways, Neurons, Single-Cell Analysis, General Science & Technology
Abstract

Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing1,2 to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data3 enabled prediction of high-confidence enhancer-gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments4. By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum.

Published
2021

9. Radical additions to arenes : cyclisations, rearrangements and applications to natural product synthesis

Author

Nunn, Michael Ian Thomas

Subjects
547, Aromatic compounds
Abstract

The work described in this thesis concerns the intramolecular addition of an aryl radical to an arene tethered by differing linkages. Exposure of 2-iodoaryl benzyl ethers to tributyltin hydride and AIBN resulted in the formation of an aryl-aryl bond. Attack of the aryl radical occurred in a 5-exo-trig manner with a subsequent fragmentation and concomitant rearomatisation. A suitably placed radical acceptor or hydrogen atom donor was found to be bias the reaction pathway. 2-Iodostilbenes were subjected to tributyltin-mediated radical forming conditions with cyclisation occurring via a 6-exo/endo-trig pathway to give the corresponding phenanthrenes in good to excellent yield. 2-Iododihydrostilbenes gave poorer results with a mixture of dihydrophenathrene and direct reduction products observed. Mechanistic details of the reaction are also discussed. The methodology has been applied to the synthesis of [5]helicenes by an iterative radical cyclisation approach. Tandem radical cyclisations are described providing a three step synthesis of [5]helicenes. Application of the methodology towards the synthesis of the macrocyclic biarylheptanoid acerogenin E is detailed. The first total synthesis of toddaquinoline is also described. Preliminary work on the use of tributyltin hydride in combination with tetrabutylammonium fluoride for the reduction of aryl halides is illustrated.

Published
2002

10. Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain

Author

Liu, Hanqing, primary, Zeng, Qiurui, additional, Zhou, Jingtian, additional, Bartlett, Anna, additional, Wang, Bang-An, additional, Berube, Peter, additional, Tian, Wei, additional, Kenworthy, Mia, additional, Altshul, Jordan, additional, Nery, Joseph R., additional, Chen, Huaming, additional, Castanon, Rosa G., additional, Zu, Songpeng, additional, Li, Yang Eric, additional, Lucero, Jacinta, additional, Osteen, Julia K., additional, Pinto-Duarte, Antonio, additional, Lee, Jasper, additional, Rink, Jon, additional, Cho, Silvia, additional, Emerson, Nora, additional, Nunn, Michael, additional, O’Connor, Carolyn, additional, Yao, Zizhen, additional, Smith, Kimberly A., additional, Tasic, Bosiljka, additional, Zeng, Hongkui, additional, Luo, Chongyuan, additional, Dixon, Jesse R., additional, Ren, Bing, additional, Behrens, M. Margarita, additional, and Ecker, Joseph R, additional

Published
2023
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13. A multimodal cell census and atlas of the mammalian primary motor cortex

Author

Callaway, Edward M., Dong, Hong-Wei, Ecker, Joseph R., Hawrylycz, Michael J., Huang, Z. Josh, Lein, Ed S., Ngai, John, Osten, Pavel, Ren, Bing, Tolias, Andreas Savas, White, Owen, Zeng, Hongkui, Zhuang, Xiaowei, Ascoli, Giorgio A., Behrens, M. Margarita, Chun, Jerold, Feng, Guoping, Gee, James C., Ghosh, Satrajit S., Halchenko, Yaroslav O., Hertzano, Ronna, Lim, Byung Kook, Martone, Maryann E., Ng, Lydia, Pachter, Lior, Ropelewski, Alexander J., Tickle, Timothy L., Yang, X. William, Zhang, Kun, Bakken, Trygve E., Berens, Philipp, Daigle, Tanya L., Harris, Julie A., Jorstad, Nikolas L., Kalmbach, Brian E., Kobak, Dmitry, Li, Yang Eric, Liu, Hanqing, Matho, Katherine S., Mukamel, Eran A., Naeemi, Maitham, Scala, Federico, Tan, Pengcheng, Ting, Jonathan T., Xie, Fangming, Zhang, Meng, Zhang, Zhuzhu, Zhou, Jingtian, Zingg, Brian, Armand, Ethan, Yao, Zizhen, Bertagnolli, Darren, Casper, Tamara, Crichton, Kirsten, Dee, Nick, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Dougherty, Elizabeth L., Fong, Olivia, Goldman, Melissa, Goldy, Jeff, Hodge, Rebecca D., Hu, Lijuan, Keene, C. Dirk, Krienen, Fenna M., Kroll, Matthew, Lake, Blue B., Lathia, Kanan, Linnarsson, Sten, Liu, Christine S., Macosko, Evan Z., McCarroll, Steven A., McMillen, Delissa, Nadaf, Naeem M., Nguyen, Thuc Nghi, Palmer, Carter R., Pham, Thanh, Plongthongkum, Nongluk, Reed, Nora M., Regev, Aviv, Rimorin, Christine, Romanow, William J., Savoia, Steven, Siletti, Kimberly, Smith, Kimberly, Sulc, Josef, Tasic, Bosiljka, Tieu, Michael, Torkelson, Amy, Tung, Herman, van Velthoven, Cindy T. J., Vanderburg, Charles R., Yanny, Anna Marie, Fang, Rongxin, Hou, Xiaomeng, Lucero, Jacinta D., Osteen, Julia K., Pinto-Duarte, Antonio, Poirion, Olivier, Preissl, Sebastian, Wang, Xinxin, Aldridge, Andrew I., Bartlett, Anna, Boggeman, Lara, O’Connor, Carolyn, Castanon, Rosa G., Chen, Huaming, Fitzpatrick, Conor, Luo, Chongyuan, Nery, Joseph R., Nunn, Michael, Rivkin, Angeline C., Tian, Wei, Dominguez, Bertha, Ito-Cole, Tony, Jacobs, Matthew, Jin, Xin, Lee, Cheng-Ta, Lee, Kuo-Fen, Miyazaki, Paula Assakura, Pang, Yan, Rashid, Mohammad, Smith, Jared B., Vu, Minh, Williams, Elora, Biancalani, Tommaso, Booeshaghi, A. Sina, Crow, Megan, Dudoit, Sandrine, Fischer, Stephan, Gillis, Jesse, Hu, Qiwen, Kharchenko, Peter V., Niu, Sheng-Yong, Ntranos, Vasilis, Purdom, Elizabeth, Risso, Davide, de Bézieux, Hector Roux, Somasundaram, Saroja, Street, Kelly, Svensson, Valentine, Vaishnav, Eeshit Dhaval, Van den Berge, Koen, Welch, Joshua D., An, Xu, Bateup, Helen S., Bowman, Ian, Chance, Rebecca K., Foster, Nicholas N., Galbavy, William, Gong, Hui, Gou, Lin, Hatfield, Joshua T., Hintiryan, Houri, Hirokawa, Karla E., Kim, Gukhan, Kramer, Daniel J., Li, Anan, Li, Xiangning, Luo, Qingming, Muñoz-Castañeda, Rodrigo, Stafford, David A., Feng, Zhao, Jia, Xueyan, Jiang, Shengdian, Jiang, Tao, Kuang, Xiuli, Larsen, Rachael, Lesnar, Phil, Li, Yaoyao, Li, Yuanyuan, Liu, Lijuan, Peng, Hanchuan, Qu, Lei, Ren, Miao, Ruan, Zongcai, Shen, Elise, Song, Yuanyuan, Wakeman, Wayne, Wang, Peng, Wang, Yimin, Wang, Yun, Yin, Lulu, Yuan, Jing, Zhao, Sujun, Zhao, Xuan, Narasimhan, Arun, Palaniswamy, Ramesh, Banerjee, Samik, Ding, Liya, Huilgol, Dhananjay, Huo, Bingxing, Kuo, Hsien-Chi, Laturnus, Sophie, Li, Xu, Mitra, Partha P., Mizrachi, Judith, Wang, Quanxin, Xie, Peng, Xiong, Feng, Yu, Yang, Eichhorn, Stephen W., Berg, Jim, Bernabucci, Matteo, Bernaerts, Yves, Cadwell, Cathryn René, Castro, Jesus Ramon, Dalley, Rachel, Hartmanis, Leonard, Horwitz, Gregory D., Jiang, Xiaolong, Ko, Andrew L., Miranda, Elanine, Mulherkar, Shalaka, Nicovich, Philip R., Owen, Scott F., Sandberg, Rickard, Sorensen, Staci A., Tan, Zheng Huan, Allen, Shona, Hockemeyer, Dirk, Lee, Angus Y., Veldman, Matthew B., Adkins, Ricky S., Ament, Seth A., Bravo, Héctor Corrada, Carter, Robert, Chatterjee, Apaala, Colantuoni, Carlo, Crabtree, Jonathan, Creasy, Heather, Felix, Victor, Giglio, Michelle, Herb, Brian R., Kancherla, Jayaram, Mahurkar, Anup, McCracken, Carrie, Nickel, Lance, Olley, Dustin, Orvis, Joshua, Schor, Michael, Hood, Greg, Dichter, Benjamin, Grauer, Michael, Helba, Brian, Bandrowski, Anita, Barkas, Nikolaos, Carlin, Benjamin, D’Orazi, Florence D., Degatano, Kylee, Gillespie, Thomas H., Khajouei, Farzaneh, Konwar, Kishori, Thompson, Carol, Kelly, Kathleen, Mok, Stephanie, Sunkin, Susan, BRAIN Initiative Cell Census Network (BICCN) Corresponding authors, [missing], BICCN contributing principal investigators, [missing], Principal manuscript editors, [missing], Manuscript writing and figure generation, [missing], Analysis coordination, [missing], Integrated data analysis, [missing], scRNA-seq and snRNA-seq data generation and processing, [missing], ATAC-seq data generation and processing, [missing], Methylcytosine data production and analysis, [missing], Epi-retro-seq data generation and processing, [missing], ‘Omics data analysis, [missing], Tracing and connectivity data generation, [missing], Morphology data generation and reconstruction, [missing], OLST/STPT and other data generation, [missing], Morphology, connectivity and imaging analysis, [missing], Spatially resolved single-cell transcriptomics (MERFISH), [missing], Multimodal profiling (Patch-seq), [missing], Transgenic tools, [missing], NeMO archive and analytics, [missing], Brain Image Library (BIL) archive, [missing], DANDI archive, [missing], Brain Cell Data Center (BCDC), [missing], Project management, [missing], and BRAIN Initiative Cell Census Network (BICCN), [missing]

Subjects
Epigenomics, Male, INTERNEURONS, ORGANIZATION, MOUSE, Molecular neuroscience, Neural circuits, CLASSIFICATION, Article, Mice, Atlases as Topic, Glutamates, Species Specificity, Animals, Humans, TRANSCRIPTOMICS, SPECIFICATION, NEURONS, In Situ Hybridization, Fluorescence, Phylogeny, Neurons, Multidisciplinary, Gene Expression Profiling, Biology and Life Sciences, PATHWAYS, Brain, Callithrix, Censuses, Cellular neuroscience, Mathematics and Statistics, SINGLE, Organ Specificity, MORPHOLOGY, Motor cortex, Female, Single-Cell Analysis, Transcriptome
Abstract

Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties., The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Published
2021

17. An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum

Author

Li, Yang Eric, primary, Preissl, Sebastian, additional, Hou, Xiaomeng, additional, Zhang, Ziyang, additional, Zhang, Kai, additional, Fang, Rongxin, additional, Qiu, Yunjiang, additional, Poirion, Olivier, additional, Li, Bin, additional, Liu, Hanqing, additional, Wang, Xinxin, additional, Han, Jee Yun, additional, Lucero, Jacinta, additional, Yan, Yiming, additional, Kuan, Samantha, additional, Gorkin, David, additional, Nunn, Michael, additional, Mukamel, Eran A., additional, Behrens, M. Margarita, additional, Ecker, Joseph, additional, and Ren, Bing, additional

Published
2020
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18. DNA Methylation Atlas of the Mouse Brain at Single-Cell Resolution

Author

Liu, Hanqing, primary, Zhou, Jingtian, additional, Tian, Wei, additional, Luo, Chongyuan, additional, Bartlett, Anna, additional, Aldridge, Andrew, additional, Lucero, Jacinta, additional, Osteen, Julia K., additional, Nery, Joseph R., additional, Chen, Huaming, additional, Rivkin, Angeline, additional, Castanon, Rosa G, additional, Clock, Ben, additional, Li, Yang Eric, additional, Hou, Xiaomeng, additional, Poirion, Olivier B., additional, Preissl, Sebastian, additional, O’Connor, Carolyn, additional, Boggeman, Lara, additional, Fitzpatrick, Conor, additional, Nunn, Michael, additional, Mukamel, Eran A., additional, Zhang, Zhuzhu, additional, Callaway, Edward M., additional, Ren, Bing, additional, Dixon, Jesse R., additional, Behrens, M. Margarita, additional, and Ecker, Joseph R., additional

Published
2020
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29. Radical additions to Arenes: Cyclisations, rearrangements and applications to natural product synthesis

Author

Nunn, Michael Ian Thomas. and Nunn, Michael Ian Thomas.

Abstract

The work described in this thesis concerns the intramolecular addition of an aryl radical to an arene tethered by differing linkages. Exposure of 2-iodoaryl benzyl ethers to tributyltin hydride and AIBN resulted in the formation of an aryl-aryl bond. Attack of the aryl radical occurred in a 5-exo-trig manner with a subsequent fragmentation and concomitant rearomatisation. A suitably placed radical acceptor or hydrogen atom donor was found to be bias the reaction pathway. 2-Iodostilbenes were subjected to tributyltin-mediated radical forming conditions with cyclisation occurring via a 6-exo/endo-trig pathway to give the corresponding phenanthrenes in good to excellent yield. 2-Iododihydrostilbenes gave poorer results with a mixture of dihydrophenathrene and direct reduction products observed. Mechanistic details of the reaction are also discussed. The methodology has been applied to the synthesis of [5]helicenes by an iterative radical cyclisation approach. Tandem radical cyclisations are described providing a three step synthesis of [5]helicenes. Application of the methodology towards the synthesis of the macrocyclic biarylheptanoid acerogenin E is detailed. The first total synthesis of toddaquinoline is also described. Preliminary work on the use of tributyltin hydride in combination with tetrabutylammonium fluoride for the reduction of aryl halides is illustrated.

Published
2002

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