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Progress in the Chemistry of Organic Natural Products
125
Tigliane
Diterpenoids
A. Douglas Kinghorn · Heinz Falk ·
Simon Gibbons · Yoshinori Asakawa ·
Ji-Kai Liu · Verena M. Dirsch Editors
By Giovanni Appendino and
Simone Gaeta
Progress in the Chemistry of Organic Natural
Products
Series Editors
A. Douglas Kinghorn
,
College of Pharmacy, The Ohio State University,
Columbus, USA
Heinz Falk
,
Institute of Organic Chemistry, Johannes Kepler University, Linz,
Austria
Simon Gibbons
, Natural and Medical Sciences Research Center, University of
Nizwa, Nizwa, Oman
Yoshinori Asakawa
, Faculty of Pharmaceutical Sciences, Tokushima Bunri
University, Tokushima, Japan
Ji-Kai Liu
, School of Pharmaceutical Sciences, South-Central University for
Nationalities, Wuhan, China
Verena M. Dirsch
, Department of Pharmaceutical Sciences, University of
Vienna, Vienna, Austria
Advisory Editors
Giovanni Appendino
, Department of Pharmaceutical Sciences, University of
Eastern Piedmont, Novara, Italy
Jun’ichi Kobayashi, Graduate School of Pharmaceutical Sciences, Hokkaido
University, Sapporo, Japan
Agnieszka Ludwiczuk
, Department of Pharmacognosy, Medical University of
Lublin, Lublin, Poland
C. Benjamin Naman
, San Diego Botanic Garden, Encinitas, CA, USA
Rachel Mata
,
Facultad de Química, Universidad Nacional Autónoma de México,
Mexico City, Mexico
Dirk Trauner
,
Department of Chemistry, University of Pennsylvania,
Philadelphia, PA, USA
Alvaro Viljoen
, Department of Pharmaceutical Sciences, Tshwane University of
Technology, Pretoria, South Africa
The volumes of this classic series, now referred to simply as “Zechmeister” after its
founder, Laszlo Zechmeister, have appeared under the Springer Imprint ever since
the series’ inauguration in 1938. It is therefore not really surprising to find out that
the list of contributing authors, who were awarded a Nobel Prize, is quite long: Kurt
Alder, Derek H. R. Barton, George Wells Beadle, Dorothy Crowfoot-Hodgkin, Otto
Diels, Hans von Euler-Chelpin, Paul Karrer, Luis Federico Leloir, Linus Pauling,
Vladimir Prelog, with Walter Norman Haworth and Adolf F. J. Butenandt serving as
members of the editorial board.
The volumes contain contributions on various topics related to the origin, distri-
bution, chemistry, synthesis, biochemistry, function or use of various classes of
naturally-occurring substances ranging from small molecules to biopolymers.
Each contribution is written by a recognized authority in the field and provides
a comprehensive and up-to-date review of the topic in question. Addressed to biol-
ogists, technologists, and chemists alike, the series can be used by the expert as a
source of information and literature citations and by the non-expert as a means of
orientation in a rapidly developing discipline.
All contributions are listed in PubMed.
A. Douglas Kinghorn · Heinz Falk ·
Simon Gibbons · Yoshinori Asakawa · Ji-Kai Liu ·
Verena M. Dirsch
Editors
Tigliane Diterpenoids
Volume 125
By Giovanni Appendino and Simone Gaeta
Editors
A. Douglas Kinghorn
College of Pharmacy
Ohio State University
Columbus, OH, USA
Simon Gibbons
Natural and Medical Sciences Research
Center
University of Nizwa
Nizwa, Oman
Ji-Kai Liu
School of Pharmaceutical Sciences
South Central University for Nationalities
Wuhan, China
Heinz Falk
Institute of Organic Chemistry
Johannes Kepler University Linz
Linz, Austria
Yoshinori Asakawa
Faculty of Pharmaceutical Sciences
Tokushima Bunri University
Tokushima, Japan
Verena M. Dirsch
Department of Pharmaceutical Sciences
University of Vienna
Vienna, Austria
ISSN 2191-7043 ISSN 2192-4309 (electronic)
Progress in the Chemistry of Organic Natural Products
ISBN 978-3-031-67179-1 ISBN 978-3-031-67180-7 (eBook)
https://doi.org/10.1007/978-3-031-67180-7
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2024
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse
of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by similar
or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or
the editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
If disposing of this product, please recycle the paper.
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About This Book
This volume deals with the distribution, chemistry, and molecular bioactivity of
tiglianes, which are reviewed from the very beginning of the studies on these diter-
penoids, summarizing their clinical and toxicological literature mostly in its more
recent and controversial aspects, and critically analyzing various proposals for their
biosynthesis.
v
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Contents
Tigliane Diterpenoids ................................................ 1
Giovanni Appendino and Simone Gaeta
vii
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Contributors
Giovanni Appendino Department of Pharmaceutical Sciences, Università del
Piemonte Orientale, Novara, Italy
Simone Gaeta Research & Development—Chemistry Research, QBiotics Group
Limited, Taringa, QLD, Australia
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Tigliane Diterpenoids
Giovanni Appendino and Simone Gaeta
Contents
1 Introduction ................................................................ 2
2 Historical Outline ............................................................ 4
3 Phytochemistry ............................................................. 11
3.1 Isolation ............................................................... 11
3.2 Spectroscopic Properties and Structure Elucidation ........................... 20
3.3 Distribution and Structural Diversity ....................................... 26
3.4 Biogenetic Considerations ................................................ 72
4 Reactivity .................................................................. 86
4.1 The Ring A α,β-Unsaturated Tertiary Ketol System ........................... 87
4.2 The Ring B Allyl Alcohol Hotspot of Reactivity ............................. 94
4.3 The Glycol Group on the C/D-Ring System ................................. 105
4.4 Additional Sites of Functionalization ....................................... 113
4.5 Summary of the Reactivity Aspects ........................................ 115
5 Total Synthesis .............................................................. 116
5.1 The Wender Syntheses of Phorbol (1989–1997) .............................. 118
5.2 The Baran Synthesis of (+)-Phorbol (2016) ................................. 123
5.3 The Li Synthesis of (±)-Prostratin (2018) ................................... 128
5.4 The Inoue Synthesis of (+)-Prostratin (2021) ................................ 129
5.5 Summary of the Synthesis Aspects ........................................ 131
6 Biological Activity ........................................................... 132
6.1 Molecular Studies ....................................................... 133
6.2 Cellular Studies ........................................................ 145
6.3 Animal Studies ......................................................... 149
G. Appendino (
B
)
Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani, 2,
28100 Novara, Italy
e-mail: giovanni.appendino@uniupo.it
S. Gaeta
Research & Development—Chemistry Research, QBiotics Group Limited, 165, Moggill Road,
Taringa, QLD 4068, Australia
e-mail: simone.gaeta@qbiotics.com
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A. D. Kinghorn, H. Falk, S. Gibbons, Y. Asakawa, J.-K. Liu, V. M. Dirsch (eds.),
Tigliane Diterpenoids, Progress in the Chemistry of Organic Natural Products 125,
https://doi.org/10.1007/978-3-031-67180-7_1
1
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2 G. Appendino and S. Gaeta
6.4 Clinical Studies ......................................................... 157
6.5 Dietary Exposure to Tigliane Esters ........................................ 161
6.6 Accidental Exposure to Tigliane Esters ..................................... 163
6.7 Exposure to Tigliane Esters Related to Folk Medicine ......................... 164
6.8 Summary of Biological Studies ........................................... 164
7 Conclusions ................................................................ 164
References .................................................................... 166
1 Introduction
Phorbol! Woodward started his 1963 article on the total synthesis of strychnine with
the veritable equivalent of the four-note (short-short-short-long) motif of Beethoven’s
Fifth Symphony (“Strychnine!”) [
1]. Since the skin irritancy and blistering properties
of phorbol esters are in no way less legendary than the toxicity of strychnine, a similar
emphatic entry seems suitable for a review on tiglianes, the class of diterpenoids to
which phorbol (1) belongs. This polyol is one of the most well-documented natural
products in the whole biomedical literature, with a search on PubMed totaling 53,188
entries as of March 1, 2024. For comparison, Taxol (paclitaxel) had 48,391 entries,
artemisinin 11,822, strychnine 6,756, and cannabidiol 6,525, to name just a few
popular plant natural products. Despite all this attention, phorbol (1) is not at all a
literature “commodity”, and the way it is produced by plants and acts in cells and
living organisms is still far from clear, while a bird’s eye view on the phorbol/humans
interface reveals a puzzling overlapping of poisonous, medicinal, and cosmetic uses
for phorbol myristate acetate (PMA) (2), its archetypal ester. This compound has also
been referred to in the literature as TPA (tetradecanoyl phorbol acetate), a confusing
abbreviation, since tPA is also the abbreviation of the serine protease Tissue Plas-
minogen Activator. The abbreviation PMA will therefore be used throughout this
volume.
OH
OH
HO
O
OH
HO
1 (phorbol)
1
3
4
12
13
20
6
7
9
O
OAc
HO
O
OH
HO
2 (phorbol myristate acetate)
12
13
O
C
13
H
27
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