Canvass: a crowd-sourced, natural-product screening library for exploring biological space

NCATS thanks Dingyin Tao for assistance with compound characterization. This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331). J.C. acknowledges support from the Fogarty International Center, NIH (TW009872). P.A.C. acknowledges support from the National Cancer Institute (NCI), NIH (R01 CA158275), and the NIH/National Institute of Aging (P01 AG012411). N.K.G. acknowledges support from NSF (CHE-1464898). B.C.G. thanks the support of NSF (RUI: 213569), the Camille and Henry Dreyfus Foundation, and the Arnold and Mabel Beckman Foundation. C.C.H. thanks the start-up funds from the Scripps Institution of Oceanography for support. J.N.J. acknowledges support from NIH (GM 063557, GM 084333). A.D.K. thanks the support from NCI, NIH (P01CA125066). D.G.I.K. acknowledges support from the National Center for Complementary and Integrative Health (1 R01 AT008088) and the Fogarty International Center, NIH (U01 TW00313), and gratefully acknowledges courtesies extended by the Government of Madagascar (Ministere des Eaux et Forets). O.K. thanks NIH (R01GM071779) for financial support. T.J.M. acknowledges support from NIH (GM116952). S.M. acknowledges support from NIH (DA045884-01, DA046487-01, AA026949-01), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256), and NCI, NIH, through a Cancer Center Support Grant (P30 CA008748). K.N.M. thanks the California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board for support. B.T.M. thanks Michael Mullowney for his contribution in the isolation, elucidation, and submission of the compounds in this work. P.N. acknowledges support from NIH (R01 GM111476). L.E.O. acknowledges support from NIH (R01-HL25854, R01-GM30859, R0-1-NS-12389). L.E.B., J.K.S., and J.A.P. thank the NIH (R35 GM-118173, R24 GM-111625) for research support. F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC) for financial support. I.S. thanks the University of Oklahoma Startup funds for support. J.T.S. acknowledges support from ACS PRF (53767-ND1) and NSF (CHE-1414298), and thanks Drs. Kellan N. Lamb and Michael J. Di Maso for their synthetic contribution. B.S. acknowledges support from NIH (CA78747, CA106150, GM114353, GM115575). W.S. acknowledges support from NIGMS, NIH (R15GM116032, P30 GM103450), and thanks the University of Arkansas for startup funds and the Arkansas Biosciences Institute (ABI) for seed money. C.R.J.S. acknowledges support from NIH (R01GM121656). D.S.T. thanks the support of NIH (T32 CA062948-Gudas) and PhRMA Foundation to A.L.V., NIH (P41 GM076267) to D.S.T., and CCSG NIH (P30 CA008748) to C.B. Thompson. R.E.T. acknowledges support from NIGMS, NIH (GM129465). R.J.T. thanks the American Cancer Society (RSG-12-253-01-CDD) and NSF (CHE1361173) for support. D.A.V. thanks the Camille and Henry Dreyfus Foundation, the National Science Foundation (CHE-0353662, CHE-1005253, and CHE-1725142), the Beckman Foundation, the Sherman Fairchild Foundation, the John Stauffer Charitable Trust, and the Christian Scholars Foundation for support. J.W. acknowledges support from the American Cancer Society through the Research Scholar Grant (RSG-13-011-01-CDD). W.M.W.acknowledges support from NIGMS, NIH (GM119426), and NSF (CHE1755698). A.Z. acknowledges support from NSF (CHE-1463819). (Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH); CHE-1665145 - NSF; CHE-1665331 - NSF; CHE-1464898 - NSF; RUI: 213569 - NSF; CHE-1414298 - NSF; CHE1361173 - NSF; CHE1755698 - NSF; CHE-1463819 - NSF; GM126221 - NIH; 5R01GM110131 - NIH; GM 063557 - NIH; GM 084333 - NIH; R01GM071779 - NIH; GM116952 - NIH; DA045884-01 - NIH; DA046487-01 - NIH; AA026949-01 - NIH; R01 GM111476 - NIH; R01-HL25854 - NIH; R01-GM30859 - NIH; R0-1-NS-12389 - NIH; R35 GM-118173 - NIH; R24 GM-111625 - NIH; CA78747 - NIH; CA106150 - NIH; GM114353 - NIH; GM115575 - NIH; R01GM121656 - NIH; T32 CA062948-Gudas - NIH; P41 GM076267 - NIH; R01GM114061 - NIGMS, NIH; R15GM116032 - NIGMS, NIH; P30 GM103450 - NIGMS, NIH; GM129465 - NIGMS, NIH; GM119426 - NIGMS, NIH; TW009872 - Fogarty International Center, NIH; U01 TW00313 - Fogarty International Center, NIH; R01 CA158275 - National Cancer Institute (NCI), NIH; P01 AG012411 - NIH/National Institute of Aging; Camille and Henry Dreyfus Foundation; Arnold and Mabel Beckman Foundation; Scripps Institution of Oceanography; P01CA125066 - NCI, NIH; 1 R01 AT008088 - National Center for Complementary and Integrative Health; W81XWH-17-1-0256 - Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program; P30 CA008748 - NCI, NIH, through a Cancer Center Support Grant; California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board; American Lebanese Syrian Associated Charities (ALSAC); University of Oklahoma Startup funds; 53767-ND1 - ACS PRF; PhRMA Foundation; P30 CA008748 - CCSG NIH; RSG-12-253-01-CDD - American Cancer Society; RSG-13-011-01-CDD - American Cancer Society; CHE-0353662 - National Science Foundation; CHE-1005253 - National Science Foundation; CHE-1725142 - National Science Foundation; Beckman Foundation; Sherman Fairchild Foundation; John Stauffer Charitable Trust; Christian Scholars Foundation)Published versionSupporting documentatio

Enantioselective Total Syntheses of Akuammiline Alkaloids and Arynes as Building Blocks for Enantioenriched Products

This dissertation features two projects concerning natural product synthesis and reaction development. The importance of natural product synthesis in chemistry and medicine cannot be overstated. In addition to providing a complex setting to test and apply new synthetic methodologies, natural products play a vital role in public health. Their influence in the pharmaceutical industry is profound, as approximately half of all chemical entities to treat disease come from natural product mimics, derivatives, or natural products themselves. With new natural products being discovered daily, there exists an ongoing need to develop efficient syntheses of these compounds and their derivatives.Chapters One, Two, Three, and Four focus on an unusual variant of the Fischer indolization reaction and its application in the total synthesis of a particularly interesting class of indole alkaloids named the akuammilines. Specifically, Chapter One provides an overview of the so-called ‘interrupted Fischer indolization reaction’. This reaction is described from a methodological standpoint and is then evaluated in the context of akuammiline alkaloid total synthesis.Chapters Two, Three, and Four describe enantioselective syntheses of various akuammiline alkaloids, in addition to several akuammiline alkaloid derivatives. Central to our approach was the development of modern variants of the classic Fischer indolization reaction to generate high levels of complexity. These efforts culminated in the first enantioselective total syntheses of (–)-aspidophylline A, (+)-strictamine, (–)-2(S)-cathafoline, (–)-pseudoakuammigine, (+)-akuammiline, (–)-10-demethoxyvincorine, and derivatives therein.Chapters Five describes an application of the distortion/interaction model to a variety of mono and disubstituted benzynes and substituted indolynes. Chapter Six is focused on the development of a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates with b-ketoester-derived substrates. Our approach provides a general solution to the challenging problem of stereoselective b-ketoester arylation/alkenylation, with formation of a quaternary center with enantiomeric excess up to 96%

Enantioselective Total Syntheses of Akuammiline Alkaloids and Arynes as Building Blocks for Enantioenriched Products

This dissertation features two projects concerning natural product synthesis and reaction development. The importance of natural product synthesis in chemistry and medicine cannot be overstated. In addition to providing a complex setting to test and apply new synthetic methodologies, natural products play a vital role in public health. Their influence in the pharmaceutical industry is profound, as approximately half of all chemical entities to treat disease come from natural product mimics, derivatives, or natural products themselves. With new natural products being discovered daily, there exists an ongoing need to develop efficient syntheses of these compounds and their derivatives.Chapters One, Two, Three, and Four focus on an unusual variant of the Fischer indolization reaction and its application in the total synthesis of a particularly interesting class of indole alkaloids named the akuammilines. Specifically, Chapter One provides an overview of the so-called ‘interrupted Fischer indolization reaction’. This reaction is described from a methodological standpoint and is then evaluated in the context of akuammiline alkaloid total synthesis.Chapters Two, Three, and Four describe enantioselective syntheses of various akuammiline alkaloids, in addition to several akuammiline alkaloid derivatives. Central to our approach was the development of modern variants of the classic Fischer indolization reaction to generate high levels of complexity. These efforts culminated in the first enantioselective total syntheses of (–)-aspidophylline A, (+)-strictamine, (–)-2(S)-cathafoline, (–)-pseudoakuammigine, (+)-akuammiline, (–)-10-demethoxyvincorine, and derivatives therein.Chapters Five describes an application of the distortion/interaction model to a variety of mono and disubstituted benzynes and substituted indolynes. Chapter Six is focused on the development of a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates with b-ketoester-derived substrates. Our approach provides a general solution to the challenging problem of stereoselective b-ketoester arylation/alkenylation, with formation of a quaternary center with enantiomeric excess up to 96%

Computational predictions of substituted benzyne and indolyne regioselectivities

A computational study using DFT methods was performed for an array of mono and disubstituted benzynes and indolynes. The inherent distortion present in the geometry-optimized structures predicts the regioselectivity of aryne trapping by nucleophiles or cycloaddition partners. These studies will serve to enable the further use of unsymmetrical arynes in organic synthesis

Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2(S)‑Cathafoline, and (−)-Aspidophylline A

The akuammiline alkaloids are a family of natural products that have been widely studied for decades. Although notable synthetic achievements have been made recently, akuammilines that possess a methanoquinolizidine core have evaded synthetic efforts. We report an asymmetric approach to these alkaloids, which has culminated in the first total syntheses of (-)-2(S)-cathafoline and the long-standing target (+)-strictamine. Moreover, the first enantioselective total synthesis of aspidophylline A is described

Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2(<i>S</i>)‑Cathafoline, and (−)-Aspidophylline A

The akuammiline alkaloids are a family of natural products that have been widely studied for decades. Although notable synthetic achievements have been made recently, akuammilines that possess a methano­quinoliz­idine core have evaded synthetic efforts. We report an asymmetric approach to these alkaloids, which has culminated in the first total syntheses of (−)-2­(<i>S</i>)-cathafoline and the long-standing target (+)-strictamine. Moreover, the first enantioselective total synthesis of aspidophylline A is described