The Ankaloid

THE ALKALOIDS: Chemistry and Pharmacology
VOLUME 50

THE ALKALOIDS
Chemistry and Biology

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THE ALKALOIDS: Chemistry and Pharmacology
VOLUME 50

THE ALKALOIDS
Chemistry and Biology
Edited by

Geoffrey A. Cordell
College of Pharmacy
University of Illinois at Chicago
Chicago, Illinois

ACADEMIC PRESS
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I


CONTENTS

CONTRIBUTORS.
...........................................................................
PREFACE
.................................................................................

xi
...

XI11

R. H. F. Manske: Fifty Years of Alkaloid Chemistry

D. B. MACLEAN
A N D V. SNIECKUS
1. Introduction .................................................................
....................................
11. Childhood and Formative Years..
111. Higher Education and Early Empl
..........
................

IV.
V.
VI.
VII.
VIII.

Scientific Career and Research ............................................
Editorship.. .........
.................................................
...............
The Scientist and SOC
Naturalist. Orchidist,
Concluding Remarks
.................................................
Publications of R. H.
...............

3
7
8
18

40
42
45
47
51

Chemistry and Biology of Steroidal Alkaloids
A N D M. IQBALCHOUDHARY
ATTA-UR-RAHMAN

I. Introduction. .........................................
.......
....
11. Isolation and Structure Elucidation ...........................................
111. Physical Properties .
....
.....................................
IV. Biogenesis.. ....................
V. Some Synthetic Studies and Chemical Transformations.. ....................
VI. Pharmacology.. ................
References ...........................................

61
63
75
90
92
98
103

Biological Activity of Unnatural Alkaloid Enantiomers
ARNOLD
BROSSIA N D XUE-FENG
PEI
Introduction ...............
.......................
Analytical Criteria. .......
...........................
Unnatural Alkaloid Enan
(+)-Morphine.. .............................................................
(+)-Physostigmine.. ..
.................................................
VI. (+)-Colchicine .............................
VII. (+)-Nicotine ................................................................
1.
11.
111.
IV.
V.

V

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110

112
118

123
128
133


vi

CONTENTS

VIII. Conclusions . . . . . .. . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . .. . . . . . .. . . . . . .. . .. . .. .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . .

135
136

The Nature and Origin of Amphibian Alkaloids
JOHNW. DALY
Introduction.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..............
.. . .. . .. .. ... .. ..
1. Introduction..
11. Sarnandarines . . . . . . . . . . . ...................................................
.. ... .. ... . .. .. . .. ... .. ... .. ... .. .
111. Batrachotoxins., .. ... ... .. .. . . . . .. . .. .. , ...................
. . . .. . .. . _. _ _. _... .. .. . .. .. . . . .. . .. ...

IV.
V.
VI.
VII.
VIII.

IX.
X.
XI.
XII.
XIII.
XIV.
XV.

The Purniliotoxin Class.
......................
Histrionicotoxins.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Histrionicotoxins..
.......................................
Gephyrotoxins . . . . . . . . . .
Gephyrotoxins
Decahydroquinolines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Decahydroquinolines..
Cyclopenta[b]quinolizidines.... .. . .. ...... .. .. ..... ... .. ...
. .. . . . .. ... . . .. ... .. .
.......................................
......................
Epibatidine.. . . . . . . . . . . . .
Epibatidine..
......................
Pseudophrynamines . . ,. .
Pseudophrynamines
Pyrrolizidine Oximes
Pyrrolizidine
Oxirnes . . . . . . . . . . . . . . . . . . . . ..................................
. . . .. . . . . . . . . . . . .

Coccinellines
Coccinellines.. . . . . . . . . . . ........................................................
..................................
....
Bicyclic “Izidine” Alkal
Monocyclic Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . .. . . . . . . . . .
.......................................
Summary and Prospects
Prospects
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Biochemistry of Ergot Alkaloids-Achievements
DETLEF
GROCERA N D HEINZG.
I.
11.
111.
IV.
V.
VI.
VII.
VIII.

141
142
142
145
149
151
1.51

152
154
1.54
155
156
157
157
158
159
164
165
16.5
167

and Challenges

FLOSS

Introduction.. . .
........................................................
Historical Background..
......................
The Natural Ergot Alka
Producing Organisms.. .
......................
......................
Biosynthesis.. . . . . . . .. . ..
Biotechnologica
Pharmacologica
......................

Future Challenges . . . . . . .. . .. .. . . . . . . . . . . . .
References . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

172
172
173
182
183
20 1
204
208
212

Natural Polyamine Derivatives-New Aspects of Their Isolation,
Structure Elucidation, and Synthesis
HESSE
ARMIN
GUGGISBERC A N D MANFRED

.......................................
I. Introduction.. . . . . . . . . . . .
...........
11. Alkaloids with the Sper
111. Spermine Alkaloids. . . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IV. 3-Phenylpropenoyl Derivatives of Sperrnine and Spermidine . . . . . . . . . . .. . . . .
V. Polyamines from Spiders, Wasps, and Marine Sponges
References . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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22 1
243
247
249
254


CONTENTS

vii

Molecular Genetics of Plant Alkaloid Biosynthesis

TONIM. KUTCHAN
I. Introduction.. ..........................................................
11. Monoterpenoid lndole Alkaloids.. ............................................
111. TetrahydrobcnzylisoquinolineAlkaloids ......................................
IV. Bisbenzylisoquinoline Alkaloids ...........................
V. Tropane and Nicotine Alkaloids.. .............................................
VI. Acridone Alkaloids
................................
VII. Conclusions and Fu
..................................
References ......................................................................

258
259
272
290

295
304
309
311

Pseudodistomins: Structure, Synthesis, and Pharmacology

ICHIYA NINOMIYA.
TOSHIKO
KIGUCHI.
A N D TAKEAKI
NAITO
I. Introduction. ....................................................................
.................
111. Synthesis ........................................................................
IV. Biogenesis.. .....................................................................
V. Pharmacology
References ......................................................................
11. Isolation and Structure.. . . .

317
318
322
338
340
341

Synthesis of the Aspidosperma Alkaloids

J. EDWIN

SAXTON
I.
11.
111.
IV.
V.
VI.
VII.
VIII.

Introduction.. ..................................................
The Aspidospermine Group ...................................................
Vindorosine and Vindoline ...
...................................
.....
The Vincadifformine Group .................................
The Vindolinine Group ........................................................
..................................
The Meloscine Group . . . . . . . . . .
The Aspidofractinine Group.. ..............................
The Kopsine Group ............................................................
References ......................
.................................

343
344
346
355
361
366

366
369
374

Synthetic Studies in Alkaloid Chemistry
CSABASZANTAY
1. Introduction. ....................................................................

11. Synthesis of Ipecacuanha Alkaloids ...........................................
111. Synthesis of Yohimbine Alkaloids.
........................................

IV.
V.
VI.
VII.
VIII.

Synthesis
Synthesis
Synthesis
Synthesis
Synthesis

of
of
of
of
of

Corynantheidine Alkaloids.. .....................................
Rauwolfia Alkaloids.. ............................................
Berbane
Vincamine and Structurally Related Alkaloids .................
Aspicfospenna Alkaloids .........................................

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379
380
383
384
385
386
399


...

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CONTENTS

IX. Synthesis of Alkaloids from Catharanthus roseus.. ...........................
X. Synthesis of Morphine.. ........................................................
XI. Synthesis of Epibatidine.. ......................................................
References ......................................................................

400

405
407
41 1

Monoterpenoid Indole Alkaloid Syntheses Utilizing Biomimetic Reactions
HIROMITSU
TAKAYAMA
A N D SHIN-ICHIRO SAKAl
1. Introduction.. .........................

...........................

11. Biomimetic Syntheses of Corynanthe
aloids from Secologanin.
Strictosidine. and Their Analogs. ..............................................
111. Biomimetic Syntheses of Aspidospernia and fboga Alkaloids ...............
IV. Biomimetic Skeletal Rearrangements and Fragmentations .........
V. Biomimetic Synthesis in the Sarpagine Family.. ..............................
............................
VI. Biomimetic Bisindole Alkaloid Syntheses
......
VII. Conclusions .........................................
References
................................................

415
416
419
428
436

444
447
448

Plant Biotechnology and the Production of Alkaloids: Prospects of Metabolic Engineering
I.
11.
111.
IV.
V.
VI.

V A N DER HEIJDEN.
A N D J. MEMELINK
RoeERr VERPOORTE. ROBERT
Introduction
......................
Plant Cell Cultures for the Production of Alkaloids .........................
Metabolic Engineering ............................
Transcriptional Regulati
ansduction Pathways ..............
Conclusions .....................
........
................
Future Prospects.. .................................
................
References ..............
.......................................

453

455
462
491
496
497
499

History and Future Prospects of Camptothecin and Taxol

c. W A N 1
MONROE
E. WALL A N D MANSUKH
I. Camptothecin ...................................................................
11. Taxol ............................................................................
References ......................................................................

509
521
531

Alkaloid Chemosystematics
PETERG. WATERMAN

I. Introduction.. ...................................................................
11. Alkaloids in Chemical Systematics: Laying Down the Rules ................
111. The Evolution of Alkaloids.. ..................................................
IV. Handling Alkaloid Data in Systematic Studies ...............................

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539
540
544


CONTENTS

ix

V. Systematically Significant Distributions of Alkaloids
in Higher Plant Taxa ...........................................................
VI. Concluding Comments .........................................................
References ......................................................................

548
563
564

.......................................................
CUMULATIVE
INDEX OF TITLES..
INDEX ..................................................................................

561
517

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CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors' contributions begin.

AITA-UR-RAHMAN
(61), H. E. J. Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan
ARNOLD
BROSSI
(109), School of Pharmacy, University of North Carolina,
Chapel Hill, North Carolina 27599
M. IQBALCHOUDHARY
(61), H. E. J. Research Institute of Chemistry,
University of Karachi, Karachi-75270, Pakistan
JOHNW. DALY(141), Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes
of Health, Bethesda, Maryland 20892
(171), Department of Chemistry, University of WashingHEINZG. FLOSS
ton, Seattle, Washington 98195
DETLEFGROCER(171), Institute for Plant Biochemistry, Halle (Saale),
Germany
ARMINGUCCISBERG
(219), Organisch-chemisches Institut der Universitat
Zurich, 8057 Zurich, Switzerland
MANFRED
HESSE(219), Organisch-chemisches Institut der Universitat
Zurich, 8057 Zurich, Switzerland

TOSHIKO
KIGUCHI
(317), Kobe Pharmaceutical University, Higashinada,
Kobe 658, Japan

TONIM. KUTCHAN
(257), Laboratorium fur Molekulare Biologie, Universitat Munich, 80333 Munchen, Germany

D. B. MACLEAN
(3), Department of Chemistry, McMaster University,
Hamilton, Ontario, Canada L8S 4M1
J. MEMELINK
(453), Institute of Molecular Plant Sciences, Leiden University, 2300RA Leiden, The Netherlands
TAKEAKI
NAITO(317), Kobe Pharmaceutical University, Higashinada,
Kobe 658, Japan
xi

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xii

CONTRIBUTORS

ICHIYA
NINOMIYA
(317), Kobe Pharmaceutical University, Higashinada,
Kobe 658, Japan
XUE-FENG

PEI(109), Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892
SHIN-ICHIRO
SAKAI
(415), Faculty of Pharmaceutical Sciences, Chiba University, Chiba 263, Japan
J. EDWINSAXTON
(343), Department of Chemistry, The University of
Leeds, Leeds LS2 9JT, United Kingdom
V. SNIECKUS
(3), Guelph-Waterloo Center for Graduate Work in Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
CSABA
SZANTAY
(377), Institute of Organic Chemistry, Technical University, and Central Research Institute for Chemistry, H-1525 Budapest,
Hungary
HIROMITSU
TAKAYAMA
(415), Faculty of Pharmaceutical Sciences, Chiba
University, Chiba 263, Japan
ROBERT
VAN DER HEIJDEN
(453), Division of Pharmacognosy, Leiden/
Amsterdam Center for Drug Research, Leiden University, 2300RA Leiden,
The Netherlands
ROBERT
VERPOORTE
(453), Division of Pharmacognosy, Leiden/Amsterdam Center for Drug Research, Leiden University, 2300RA Leiden, The
Netherlands
MONROE
E. WALL(509), Research Triangle Institute, Research Triangle
Park, North Carolina 27709
MANSUKH

C. WANI(509), Research Triangle Institute, Research Triangle
Park, North Carolina 27709
PETERG. WATERMAN
(537), Phytochemistry Research Laboratories, Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow
G1 lXW, Scotland, United Kingdom

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For many younger chemists and biologists, for whom this volume may
be the initial foraging into the mystical, marvelous world of alkaloid chemistry and biology, the name “Manske” has an indescribable aura attached
to it. Perhaps advised by a more senior colleague or faculty member to
“look it up in Manske,” the younger scientist’s prototypical response is the
question “What’s ‘Manske?’ Is it some acronym for a computerized database on alkaloids?” (“Many Alkaloids, New and Structurally Korrect, ‘Ere”
comes to mind, and, incidentally, reflects my Cockney upbringing.) “Oh,
it’s that book series on alkaloids. Can’t recall who’s the editor now. Used
to be Manske in the old days. Don’t really know who he was though,”
comes back the response from the learned professor.
Thousands of alkaloid chemists and biologists, as well as many natural
product scientists, know this series only as “Manske” or “Manske’s Alkaloids.’’ Only when they have to write a citation reference do these chemists
and biologists discover that the last volume edited by Manske was published
in 1977, the year of his death, and that the title of the series began as The
Alkaloids: Chemistry and Physiology and was changed, with the publication
of Volume 21 in 1983, to The Alkaloids: Chemistry and Pharmacology. This
volume marks a transition in the title of the series, which will be changed
again as of Volume 51 to The Alkaloids: Chemistry and Biology. I believe
that this reflects the transition that is being made to cover not only the
biological and pharmacological effects of alkaloids once isolated, but also
their role in their host organism or secondary site, as well as the substantial
advances in the biotechnological aspects of alkaloid formation and production.

The period following the death of Manske benefited from the expertise
of two other editors. Russell Rodrigo, a colleague of Manske, served as
editor for Volumes 17-20, and then Arnold Brossi took over as very energetic editor for Volumes 21-40. Brossi and I coedited Volumes 41 and 45.
Why then isn’t it called “Brossi’s Alkaloids?” Chapter 1 in this celebratory
volume may provide an answer, as well as a response to some of the other
issues raised above.
When I first decided to put together a special volume of the series in
celebration of the publication of Volume 50, I had the idea to ask a select
group of alkaloid chemists to prepare a chapter on their own areas of

...

Xlll

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xiv

PREFACE

interest, indicating some of the recent progress and speculating on where
their area of the field would be moving in the years ahead. I was extremely
fortunate to persuade many outstanding scientists to contribute to this
volume. Then I received a letter from Victor Snieckus indicating that he
and D. B. MacLean were preparing a biography on Manske. They were
asking if I could help them publish this article in the series or recommend
another site for publication. The synchronicity was perfect. Their outline
was exciting; it reflected a very personal view of an exceptional human
being, and thus it was an easy decision that this biography would be the

first chapter in the celebratory volume.
Embellished with Manske’s own autobiographical and laboratory notes
and some wonderful anecdotes and photographs, the completed chapter
shows Manske as an outstanding alkaloid chemist and as a person who was
committed to the role of scientist as a contributor to society (“If we leave
the decisions to politicians and theologians we will inherit a society which
scientists will not like and we will only have ourselves to blame,” p. 44).
In addition, it shows his love of cooking, of growing orchids, and of ecology.
Suddenly, this is not merely the name on the spine of some musty old
volumes-not just the name in colloquial use for a book series. This is a
real person, someone who has almost been brought back to life. There is
no longer an excuse when asked “Who was Manske?” or “Why is the series
still called Manske’s Alkaloids?”
In addition to bringing out the human qualities of the founder of this
series, this chapter reveals another astonishing fact: that the chemistry that
Manske and his colleagues accomplished was done, for the most part,
without the benefit of either chromatography or spectroscopy. Current
graduate students and postdocs should stand in awe of these achievements,
and those of the other legends of alkaloid chemistry, for that matter. We
are truly standing on the shoulders of giants, yet their presence is rarely
acknowledged as we rush to run the next gradient-enhanced HMBC spectrum. As a result, this unique perspective of alkaloid chemistry offers a
wonderful historical overview of life as an alkaloid chemist in the mid1920s to the mid-1970s.
The remaining chapters in this volume are written by a selection of the
leading scientists working in the field of alkaloid chemistry and biology
today and are arranged alphabetically by author. Atta-ur-Rahman and
Chaudhary describe some of the prominent recent chemical and biological
work, much of it conducted in their own laboratories, on the steroidal
alkaloids from terrestrial plants and animals and from marine organisms.
Since most physiologically active alkaloids are pure enantiomers, it is intriguing chemically and biologically to prepare and evaluate the unnatural
enantiomers of important alkaloids. Brossi and Pei describe some of the

recent work in this area. Amphibians are also recognized as being a source

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PREFACE

xv

of chemically and biologically significant alkaloids, and Daly updates the
recent studies that have led to the isolation of epibatidine and several other
interesting metabolites. The critical issue of the future sourcing of these
alkaloids is also discussed.
Groger and Floss are recognized as leaders in the field of ergot alkaloid
chemistry and biosynthesis, and for the first time in many years they bring
this area up-to-date and clearly indicate the opportunities for future research development. The natural polyamine derivatives derived from
spermine and spermidine are under rapid development currently from both
an isolation and a synthetic perspective, and Guggisberg and Hesse describe
these recent results based substantially on their own studies. The tremendous impact that .enzyme isolation and molecular genetics are having, and
will continue to have, in the future strategies for understanding the formation and availability of important alkaloids is reviewed in detail by Kutchan.
Tunicates of the genus Pseudostoma have yielded a number of novel metabolites whose structure elucidation and synthesis have been engaging several
Japanese research groups. Ninomiya, Kiguchi, and Naito clarify the confusion that has surrounded the structures of these particular alkaloids.
The past 18 years have seen some remarkable developments in the efficient formation of various members of the Aspidosperma group of alkaloids,
and Saxton provides an authoritative review of this area. Paralleling the
history of The Alkaloids series have been the tremendous synthetic efforts
in alkaloid chemistry conducted at the Central Research Institute for Chemistry in Budapest in the past 40 years, principally under the leadership of
Szantay, who here reviews some of the highly directed work on various
indole and other alkaloid groups that has led to the enhanced commercial
availability of several alkaloids. The structural diversity of the monoterpenoid indole alkaloids has led to numerous biogenetic ideas as to the formation
of these structure types, very few of which have been tested in vivo. However, many of them have been evaluated, successfully, through chemical

incitement, and these efforts are reviewed by Takayama and Sakai. Substantial drama in the past 20 years has surrounded the impact of biotechnology
on plant secondary metabolism. The chapter by Verpoorte, van der Heiden,
and Memelink nicely complements that of Kutchan in focusing on the
experimental issues that have come to light with the use of cell cultures
for the production of alkaloids and on how metabolic engineering still faces
numerous challenges. Together these chapters define well the need for
more concerted studies on how and where alkaloids are actually produced
in plant cells and indicate the mountainous pathway ahead which must be
traversed for the commercial production of medicinally important alkaloids
in vitro.
Two plant alkaloids, taxol and camptothecin, have recently been approved for marketing for the treatment of various cancerous states after

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xvi

PREFACE

many years of dedicated effort by researchers following their isolation by
Wall and Wani. This saga is described by these discoverers, and the future
developments in these important fields of alkaloid research are outlined.
Finally, the chemosystematics of alkaloids, such as it is known at present,
is discussed by Waterman, and some pertinent questions are asked. Have
we progressed since the early work by Hegnauer? What is the significance
for chemosystematics (and for alkaloid chemistry and biology) that “dormant” genes for alkaloid production can be turned on?
It is a stimulating thought indeed that many plants may already have the
genes for the production of diverse alkaloids and that in our isolation
studies we are merely looking at those genes in operation today. Is the
common genetic pool for alkaloid production more widely distributed than

we have imagined? What are the signal transducers and transcription factors
for these genes to be turned on and off? With the revolution underway in
plant biotechnology these questions will surely be answered in the next
few years, and the challenges of generating medicinally valuable agents
within new, fast-growing host systems in large bioreactors will be surmounted. The holy grail of a continuous-flow operation for the production
of an alkaloid through stabilized enzymatic synthesis will undoubtedly be
achieved, and the field identification of the individual components of complex alkaloid mixtures will become a reality through global communications
technology. Alkaloid synthesis will continue to improve as higher yield,
more steroselective, more compact, and more economical procedures become available. And, as our understanding of human biology and the
diseases with which we are afflicted improves, so more and more significant
alkaloids will be detected from the terrestrial and marine environments.
I have no doubt that the vibrancy of this field of alkaloid chemistry and
biology will contribute even more substantially in the next 50 years to the
health and welfare of humankind than it has in the past. Thus, while we
celebrate this volume of The Alkaloids: Chemistry and Pharmacology as a
milestone of continued scientific achievement, I conclude that with dedication, intuition, and an appropriate level of investment, it will be shown that
our present state of knowledge is merely a beginning to an even greater
level of understanding and awareness of our world and its potential for
sustainable development.
Geoffrey A. Cordell
University of Illinois at Chicago

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THE ALKALOIDS
Chemistry and Biology

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-CHAPTER 1-

R. H. F. MANSKE:
FIFTY YEARS OF ALKALOID CHEMISTRY
D. B. MACLEAN
Department of Chemistry
McMaster University
Hamilton, Ontario,
Canada L8S 4M1

V. SNIECKUS
Guelph- Waterloo Center for Graduate Work in Chemistry
University of Waterloo
Waterloo, Ontario
Canada N2L 3G1

I. Introduction ............................................
11. Childhood and Formative Years ..................
111. Higher Education and Early Employment ...............................................
A. Queen's University (1919-1924) .................................................
B. Manchester University (1924-1926) ...................................................
C. General Motors Corporation (1926-1927) and Yale University
(1927-1929) .................................................................
IV. Scientific Career and Research ..................
A. Calycanthine ...

V.
VI.
VII.
VIII.

C. The Isoquinoline Alkaloids ............................................................
D. The Lycopodiurn Alkaloids ...
E. Miscellany ..................................................................................
F. Heterocyclic Chemistry .........
Editorship ...............................................
The Scientist and Society ...........
Naturalist, Orchidist, Musician, and Cuisinier ..........................................
Concluding Remarks .....................................................................
Publications of R. H. F. Manske ...........................................................

8
9

20
36

45
51

I. Introduction
My mother discovered that tincture of laudanum relieved my insomnia. . . . I slept
long and peacefully and became a model child.
-R. H. F. Manske commented on his first acquaintance with alkaloids at the age
of 18 months. [2]
THE ALKALOIDS, VOL. 50

3

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MACLEAN AND SNIECKUS

Richard H. F. Manske was an outstanding Canadian chemist who will
be remembered for his many contributions to the isolation and structural
elucidation of alkaloids, particularly those of the isoquinoline family. As a
leading authority on alkaloids, he was chosen to become the founding editor
of The Alkaloids in 1950 and continued as editor until his untimely death
in 1977. We were fortunate to have known him as a boss and collaborator
(D. B. M. from 1946) and as a colleague (V. S. from 1966) and we, and
many others, benefited from his broad knowledge and his enthusiasm for
research. Outside his office and laboratory, he found time to be an avid
gardener and orchid grower; also, he enjoyed music, played the violin,
watched birds and stars, made an excellent martini, was keen to discuss
science, religion, and philosophy, and even wrote a book on cooking. A
truly remarkable man!
The celebration of the fiftieth volume of The Alkaloids is an opportune
occasion to honor his eminent contributions to alkaloid chemistry.

All of these studies were accomplished by what may now be known as the classical
methods-reactions carried out in glass with the usual inorganic reagents . . . , with
reagents for the detection of functional groups, but without electronic gadgetry. There
were no crooked lines to interpret because there were no machines to make them. [ 1 )

When Manske began his research, alkaloids were separated by fractional
crystallization [3] of the bases or their salts and purified to constant melting
point by repeated crystallization. Thus by trial and error, infinite patience,
and superb experimental skill, separation of complicated mixtures was
achieved. Compositions were established by elemental analysis and molecular weight determinations of the alkaloids and their derivatives and functional group analyses were used extensively to gain initial structural insight.
Complex structures were elucidated by degradation to smaller fragments
and these, after identification (usually by synthesis), were intuitively reassembled to arrive at a tentative structure in accord with the molecular
composition. The ultimate proof of structure was the synthesis, by unambiguous methods, of the proposed structure and the establishment of its identity
with the natural product [4]. The chemists of the day were limited to the
determination of the skeletal arrangement of the atoms in the molecule
since, without NMR spectroscopic and X-ray techniques, degradation and
synthesis often provided little stereochemical information. Although enantiomeric relationships were readily resolved, the establishment of absolute
stereochemistry was not possible. Diastereomeric relationships were recognizable, e.g., in the phthalideisoquinoline alkaloids, but the determination
of relative stereochemistry was seldom realized.
Morphine, the Proteus of organic compounds, succumbed to the assaults upon it
and strychnine was just beginning to give up some of its mysteries. [l]

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R. H. F. MANSKE: FIFTY YEARS OF ALKALOID CHEMISTRY

5

These are some of the classical problems to whose solution I was a spectator. Perhaps
the most spectacular was that of strychnine because more skilled chemists had been
concerned with it than with any other substance . . . [ l ]
It is taken for granted that almost any compound can be synthesized if enough manpower is available for it. Even so, organic chemistry has not yet reached the stage
when a synthesis can be achieved by merely pushing buttons. 111

Despite the above limitations, complex structural problems were being
tackled with great promise. Morphine, strychnine, thyroxine, Vitamin A,
cholesterol, and the bile acids were among the significant molecules which
revealed their structures using classical methods; UV spectroscopy was
available but its use for structural work began only in the late 1920s. In
the arena of complex synthesis, strychnine, sucrose, and, in the later years
of Manske’s life, chlorophyll and Vitamin BI2were conquered and retrosynthetic analysis became common practice [5].
Richard Manske’s introduction to research was oriented toward physical
organic chemistry, first under the direction of J. A. McRae at Queen’s
University, Kingston, Ontario, and subsequently with A. Lapworth at ManChester, England. His first experience with alkaloids was gained also in
Manchester where, as part of his Ph.D. thesis under the supervision of
Robert Robinson, he accomplished the total synthesis of harmaline. As Eli
Lilly Research Fellow and Sterling Fellow at Yale University, he continued
work on alkaloids and, in 1931, shortly after joining the National Research
Council (NRC) of Canada as Associate Research Chemist, he published
his first paper on the degradation of calycanthine, an alkaloid that he had
isolated at Yale. This paper was followed by the first of several papers on
the Senecio alkaloids and, in 1932, the first of a flood of publications, initially
from NRC and later from the Dominion Rubber Co., on alkaloids of the
Fumariaceous plants. This work greatly expanded the number of isoquinoline alkaloids and resulted in the discovery of several new ring systems.
Through his outstanding research on the Fumariaceous plants, he gained
early recognition and became an internationally renowned alkaloid chemist.
Beginning in 1942, Manske, in collaboration with Leo Marion, examined

the Lycopodiaceae for alkaloid content, an investigation which led to the
isolation of some 30 alkaloids, and opened up a completely new field of
alkaloid research [6].
As Head of the Organic Chemistry Section at NRC, Manske championed
the pursuit of fundamental research and, by example, did much to improve
the quality of research in Canada. Leo Marion, who succeeded him at NRC,
followed similar objectives with equal vigor [6]. Manske regarded Marion
as an excellent chemist, and from Marion’s account [7], the admiration was
reciprocated. It was in Ottawa that his two daughters, Barbara and Cory,
were born. At the time of Cory’s birth he was reaping a great harvest of

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MACLEAN AND SNIECKUS

alkaloids from Corydulis species, hence the name [8]. Also during this
period he was made a Fellow of the Royal Society of Canada (1935) and
was awarded the D.Sc. degree from Manchester University (1937).
Staff and equipment were difficultly accessible in 1943 but we lit our first Bunsen
burner on June first of that year. It has burned ever since. [l]

In 1943, given carte blanche by the then President, Paul C. Jones, Manske
assumed the challenging position of Director of Research, Dominion Rubber Co., in Guelph, Ontario, and saw the research laboratories develop into
a leading industrial research center in Canada. Although understandably
relegated to a secondary position, alkaloids, were not neglected. Thus, it
was here that he resolved the structure of the cularine alkaloids by exploiting
a key reductive cleavage reaction of diary1 ethers. Furthermore, he continued work initiated at NRC on the synthesis of quinolines and the isomeric

pyridocarbazoles in collaboration with M. Kulka and A. E. Ledingham
whose contributions he warmly acknowledged. On Marshall Kulka, he
remarked, “I regard him as one of the more skillful experimentalists that
I know,” and on Archie Ledingham, he commented, “. . .a superb operator
in the organic laboratory. We performed many experiments which required
the use of four hands. His pair were as efficient as mine and I often marveled
at the synchronism that we achieved.” Whenever time was available from
his diverse duties, the Director was found at the bench. He encouraged his
younger colleagues to collaborate in alkaloid work on a part-time basis
thereby stimulating some into academic careers. It was also here that,
without Xerox or Chemdraw, the maiden volume of The Alkaloids was
compiled and saw publication in 1950.
It . . . is my opinion that a group of scientists whose sole objective is practical
application will soon degenerate into mere technicians. Consequently, I laid special
emphasis on pursuing basic research problems, not so much to find whole products or
processes, but to maintain an active esprit de corps and to develop ever more competent
scientists. I am proud to record that the results bear out my contention although I do
not entirely overlook the smile of lady luck. I do maintain however that fortune would
not have been our reward without a staff of highly competent scientists. I further
maintain that the solution of major problems seldom lies in a pointed attack. It is the
by-products, those observations that had not and in general could not have been
anticipated, that generate new attacks and new solutions. Models on a much grander
scale are the research laboratories of the General Electric Co. and of the Bell Telephone
co. [l]

True to these principles, Manske hired the best chemists available, some
of whom established their careers under his guidance and others, such as
A. N. Bourns, R. Y.Moir, and J. M. Pepper, left the company and became
excellent teachers, researchers, and administrators at Canadian universities.
In the ensuing years, his contributions to science were recognized by several

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1. R.

H. F. MANSKE: FIFTY YEARS OF ALKALOID CHEMISTRY

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institutions. He was named Centenary Lecturer, The Chemical Society,
London (1954), received the Chemical Institute of Canada Medal (1959),
was awarded an honourary D.Sc. from McMaster University (1960), was
named a Canadian representative to the NATO Conference on Taxonomy
and Natural Products in Paris (1962), and became President of the Chemical
Institute of Canada (1964). Some years before his retirement from the
Dominion Rubber Co., his wife Jean, succumbed to a chronic illness. Later,
he married Doris Williams who survived him.
In 1966, Manske retired and joined the Department of Chemistry at the
University of Waterloo as Adjunct Professor. Having regained full freedom
for alkaloid research, he lost little time and no enthusiasm; an alkaloid
isolated 25 years ago revealed its structure; another, the most complicated,
fell to X-ray analysis some 40 years after isolation. And, of course, The
Alkaloids continued. Furthermore, his Waterloo colleagues were enriched
by his extraordinary grasp of practical organic chemistry. To recall an
incident, one of us (V. S.) directly learned how to prepare a rare oxygenated
benzoic acid-it was easy, Perkin had done it before the turn of the century!
He regularly gave guest lectures on his beloved benzylisoquinoline alkaloids to the enjoyment of undergraduate and graduate students. These
special treats were rich in chemistry, spiced with anecdotes about Robinson
and other famous organic chemists, and sprinkled with lessons in scientific

writing and the work ethic. One of us (V. S.) observed on numerous
occasions the amazement of students accustomed to spectroscopic methods,
when they realized that structures had once been elucidated using elemental
analysis, degradation, and, in large part, chemical intuition. Judging from
one of his last lectures [9], the rapidly advancing field of molecular biology
did not escape his attention.

11. Childhood and Formative Years

. . . I should make a correction. My first contact with alkaloids was just before age
zero. In order to expedite the count down prior to my birth the attending doctor
resorted to the use of tincture of ergot. [2]

Richard Helmuth Fred Manske was born in Berlin, Germany, on September 14,1901, and emigrated to Canada in November 1906. His father, John,
a factory worker, and his uncle Gustav preceded the family in order to
select a homestead. Bertha Manske, Richard, and his brother Hans, 3 years
his senior, sailed (third-class) to Quebec City and traveled by train to
Battleford, Saskatchewan, at that time, “the frontier town at the end of

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MACLEAN A N D SNIECKUS

the steel.” Reunion of the family was not immediate since “nature has
ways of interfering with the plans of men, particularly if the affected men
are not wise in the ways of nature,” and occurred only on Christmas Eve
in blizzard conditions. In the Spring, after a survey of arable land by ox

cart (“. . . necessarily slow. . . . The process o f . . . remastication . . .
for contented oxen must be done deliberately”), the Manske family built
a sod-house (“. . . with materials abundantly available, . . . essentially
fire proof, and above all. . .very warm”) near the Alberta border, nurtured
the homestead with meager resources, and eventually flourished by hard
and honest work, available in large part owing to the expansion of the
Canadian Pacific and other railroads in Western Canada.
It was this environment of extreme bleakness (“There are few scenes as
awe-inspiring as endless miles of snow at 40 degrees below zero Fahrenheit”) and immense beauty (“. . . the entire prairie assumed a blue hue
from the profusion of the . . . crocus”) which profoundly influenced his
early years. With no books, save a German bible, as reading material, the
young immigrant turned to the myriad of mysteries of his surroundings,
discovering the infinity of birds and plants and the vastness of nature which,
by his later admission, “urged me to study her even if not to explain.”
From this prairie homestead 110 miles from the nearest post office (Battleford), which was to be the home of his parents for half a century, and his
brother much longer, Manske took an enormous step: “. . . from an agrarian existence . . . to one of the seats of learning at the forefront of science
and the humanities.” Observing the development of a bright mind (he was
awarded a Governor General’s bronze medal in an Alberta school), his
parents offered strong encouragement and Manske found himself on the
road to Queen’s University.

111. Higher Education and Early Employment
(1919-1924)
A. QUEEN’SUNIVERSITY
It was a cold and clammy evening early in September of 1919 when 1 said goodbye to my mother. . . . I rode our pony down the lane that led to the road and the
railway station. . . . When I dismounted and sent my obedient pony homeward I still
had a peculiar sensation in the visceral region. . . . Not until I was firmly ensconced
on a dusty leather seat and speeding eastward did I believe that I was really going to
Kingston in Ontario. [l]

At Queen’s University, Kingston, Ontario, Manske “abruptly learned
that facts alone d o not constitute an education,” adapted, and obtained

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