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Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis

Welin, Eric R. and Ngamnithiporn, Aurapat and Klatte, Max and Lapointe, Guillaume and Pototschnig, Gerit M. and McDermott, Martina S. J. and Conklin, Dylan and Gilmore, Christopher D. and Tadross, Pamela M. and Haley, Christopher K. and Negoro, Kenji and Glibstrup, Emil and Grünanger, Christian U. and Allan, Kevin M. and Virgil, Scott C. and Slamon, Dennis J. and Stoltz, Brian M. (2019) Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis. Science, 363 (6424). pp. 270-275. ISSN 0036-8075. http://resolver.caltech.edu/CaltechAUTHORS:20181221-091725806

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Abstract

The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong gram-positive and -negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of non-natural analogs.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/science.aav3421DOIArticle
http://www.sciencemag.org/cgi/content/full/science.aav3421/DC1PublisherSupporting Information
ORCID:
AuthorORCID
Welin, Eric R.0000-0002-1760-4121
Ngamnithiporn, Aurapat0000-0002-5389-8171
Conklin, Dylan0000-0003-4708-0071
Negoro, Kenji0000-0002-8341-5089
Glibstrup, Emil0000-0002-9060-6270
Allan, Kevin M.0000-0002-7750-3621
Virgil, Scott C.0000-0001-8586-5641
Slamon, Dennis J.0000-0002-6330-498X
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2018 American Association for the Advancement of Science. 6 September 2018; accepted 26 November 2018; Published online 20 December 2018. The authors thank Stig H. Christensen for experimental assistance and M. Takase and L. Henling for assistance with x-ray structure determination. Research reported in this publication was supported by the NIH National Institute of General Medical Sciences (R01 127972), the Margaret E. Early Medical Research Trust, the NSF under the CCI Center for Selective C−H Functionalization (CHE-1205646), the Teva Pharmaceuticals Marc A. Goshko Memorial Grant Program, and the California Institute of Technology RI2 Program. E.R.W. was supported by a Postdoctoral Fellowship, PF-16-011-01-CDD, from the American Cancer Society. A.N. was supported by the Royal Thai Government Scholarship program. M.K. was supported by a postdoctoral fellowship from the German Academic Exchange Service. G.L. was supported by the Swiss National Science Foundation. G.M.P. was supported by an Erwin Schroedinger Fellowship, J 3893–N34, from the Austrian Science Fund (FWF). P.M.T. was supported by a graduate fellowship from the California HIV/AIDS Research Program. E.G. was supported by Knud Højgaards Fond and Oticon Fonden. C.U.G. was supported by a Feodor Lynen Research Fellowship from the Alexander von Humboldt Foundation. Author contributions: B.M.S. conceived and directed the project. E.R.W., C.D.G, P.M.T., K.M.A., and B.M.S. conceptualized and designed the synthetic strategy. E.R.W., A.N., M.K., G.L., G.M.P., C.D.G., P.M.T., C.K.H., K.N., E.G., and C.U.G. designed, performed, and analyzed the synthetic chemistry experiments. E.R.W., A.N., and G.M.P. designed and synthesized bis-THIQ analogs 31–34. D.J.S., M.S.J.M. and D.C. designed, performed, and analyzed biological activity experiments. S.C.V. assisted with experimental design and purification and obtained x-ray quality crystals of bis-THIQ 27. E.R.W., A.N., G.M.P., and B.M.S. prepared the manuscript. D.J.S. and B.M.S. acquired funding for the project. Data and materials availability: Crystallographic parameters for compound 27 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 1875455. Data are available in the supplementary materials. The molecular characterization of the cell lines used in this Report has been deposited in the GEO public database (GEO:GSE18496). Competing interests: B.M.S. has received financial support unrelated to the current science from 1200 Pharma, LLC, Novartis, Holoclara, and Amgen. B.M.S. is a co-founder of 1200 Pharma, LLC. D.J.S. has received financial support unrelated to the current science from Pfizer, Novartis, Eli Lilly and Company, and BioMarin Pharmaceutical. D.J.S. is a paid consultant to Novartis and Eli Lilly and Company. The California Institute of Technology holds a patent application on methods for preparing bis-tetrahydroisoquinoline-containing compounds (US patent application 16/038,968; international patent application PCT/US18/42710), on which E.R.W., A.N., M.K., G.L., G.M.P., C.D.G., P.M.T., C.K.H., K.N., C.U.G., K.M.A., S.C.V., and B.M.S. are named as inventors.
Funders:
Funding AgencyGrant Number
NIHR01 127972
Margaret E. Early Medical Research TrustUNSPECIFIED
NSFCHE-1205646
Teva PharmaceuticalsUNSPECIFIED
Caltech Rothenberg Innovation InitiativeUNSPECIFIED
American Cancer SocietyPF-16-011-01-CDD
Royal Thai GovernmentUNSPECIFIED
Deutscher Akademischer Austauschdienst (DAAD)UNSPECIFIED
Swiss National Science Foundation (SNSF)UNSPECIFIED
FWF Der WissenschaftsfondsJ 3893–N34
California HIV/AIDS Research ProgramUNSPECIFIED
Knud Højgaards FondUNSPECIFIED
Oticon FondenUNSPECIFIED
Alexander von Humboldt FoundationUNSPECIFIED
Record Number:CaltechAUTHORS:20181221-091725806
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181221-091725806
Official Citation:Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis BY ERIC R. WELIN, AURAPAT NGAMNITHIPORN, MAX KLATTE, GUILLAUME LAPOINTE, GERIT M. POTOTSCHNIG, MARTINA S. J. MCDERMOTT, DYLAN CONKLIN, CHRISTOPHER D. GILMORE, PAMELA M. TADROSS, CHRISTOPHER K. HALEY, KENJI NEGORO, EMIL GLIBSTRUP, CHRISTIAN U. GRÜNANGER, KEVIN M. ALLAN, SCOTT C. VIRGIL, DENNIS J. SLAMON, BRIAN M. STOLTZ. SCIENCE 18 JAN 2019 : 270-275. DOI: 10.1126/science.aav3421
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:91948
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:21 Dec 2018 17:37
Last Modified:18 Jan 2019 15:49

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