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VOLUME ONE HUNDRED AND TWENTY ONE
ADVANCES IN
HETEROCYCLIC CHEMISTRY
Heterocyclic Chemistry in the
21st Century: A Tribute to
Alan Katritzky
EDITORIAL ADVISORY BOARD
A. T. Balaban Galveston, Texas, United States of America
A. J. Boulton Norwich, United Kingdom
M. Brimble Auckland, New Zealand
D. L. Comins Raleigh, North Carolina, United States of America
J. Cossy Paris, France
J. A. Joule Manchester, United Kingdom
V. I. Minkin Rostov-on-Don, Russia
B. U. W. Maes Antwerp, Belgium
A. Padwa Atlanta, Georgia, United States of America
V. Snieckus Kingston, Ontario, Canada
B. Stanovnik Ljubljana, Slovenia
C. V. Stevens Ghent, Belgium
J. A. Zoltewicz Gainesville, Florida, United States of America
VOLUME ONE HUNDRED AND TWENTY ONE
ADVANCES IN
HETEROCYCLIC CHEMISTRY
Heterocyclic Chemistry in the
21st Century: A Tribute to
Alan Katritzky
Editors
ERIC F. V. SCRIVEN
Department of Chemistry,
University of Florida,
Gainesville, FL, USA
CHRISTOPHER A. RAMSDEN
Lennard-Jones Laboratories,
Keele University, Staffordshire,
United Kingdom
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CONTRIBUTORS
Saadia T. Chaudhry
Department of Chemistry, Purdue University, West Lafayette, IN, USA
Johannes G. de Vries
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Rostock, Germany
Andrew J.F. Edmunds
Syngenta Crop Protection AG, Basel, Switzerland
Jian-Bo Feng
Peter Maienfisch
Syngenta Crop Protection AG, Basel, Switzerland
Charles M. Marson
Department of Chemistry, University College London, Christopher Ingold Laboratories,
London, UK
Colin H. McAteer
Vertellus Specialties Inc., Indianapolis, IN, USA
Jianguo Mei
Ramiah Murugan
Jean’ne M. Shreeve
Department of Chemistry, University of Idaho, Moscow, ID, USA
Yarlagadda V. Subba Rao
Xiao-Feng Wu
Ping Yin
Department of Chemistry, University of Idaho, Moscow, ID, USA
Tony Y. Zhang
Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and
Company, Indianapolis, IN, USA
Xikang Zhao
ix j
PREFACE
A short tribute to Alan Katritzky highlighting the aspects of his major work
in heterocyclic chemistry (structure, mechanism, theory, QSAR, synthetic
methods, applications, and the review literature) appeared in Volume 113
of Advances in Heterocyclic Chemistry. For over 50 years, Alan was at the fore-
front of advances in and applications of heterocyclic chemistry. He initiated
the publication of Advances in Heterocyclic Chemistry in 1963 and personally
commissioned and edited 112 volumes. When we considered what would
be a fitting tribute to his contribution, we posed the question, as we felt
Alan would have, “What is happening now, and what next?” In response
to this question, we have been fortunate to receive chapters from leaders
currently involved in heterocyclic chemistry and its applications. These
cover the latest advances in the areas mentioned above together with a broad
scope of new developments.
This, the third and final volume of the tribute, contains eight chapters
which focus on synthetic approaches and applications of heterocycles with
current or prospective commercial importance. The first chapter by Tony
Zhang (Eli Lilly and Co.) contains an analysis of the structures of heterocy-
clic drugs and drug candidates, which illustrates the need for robust reactions
that lead to more diverse structures. In Chapter 2, Charles Marson (Univer-
sity College London) reviews saturated heterocycles (with one heteroatom,
spiroheterocyclic, and heterobicyclo systems) with applications in medicinal
chemistry covering the period 2013–2015. Peter Maienfisch and Andrew
Edmunds (Syngenta Crop Protection AG) present an account of the contri-
bution of thiazoles and isothiazoles to crop protection in Chapter 3. Jean’ne
Shreeve and Ping Yin (University of Idaho) (Chapter 4) review nitrogen-
rich azoles as high-density energy materials. In Chapter 5, Jianguo Mei,
Xikang Zhao, and Saadia Chaudhry (Purdue University) describe the use
of five-membered ring heterocycles used as building blocks for production
of organic semiconductors.
In Chapter 6, Colin McAteer, Ramiah Murugan, and Yarlagadda Subba
Rao (Vertellus Specialties, Inc.) give a broad treatment of heterogeneously
catalyzed synthesis of three- to seven-membered heterocycles including dis-
cussion of catalyst choice, process, and economic considerations. The main
advances (2013–2015) in palladium-catalyzed carbonylative synthesis, espe-
cially of five- and six-membered heterocycles, is given by Xiao-Feng Wu
and Jian-Bo Feng (Leibnitz Institute for Catalysis, University of Rostock)
xi j
xii Preface
in Chapter 7. In the final chapter, Johannes de Vries (Leibnitz Institute for

Catalysis, University of Rostock) discusses powerful new catalytic methods
available and in development that allow the utilization of renewable
resources, particularly 5-hydroxymethylfurfural as a platform chemical.
Chris Ramsden and Eric Scriven

September, 2016.
CHAPTER ONE
The Evolving Landscape of

Heterocycles in Drugs and Drug
Candidates
Tony Y. Zhanga
Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, IN, USA
E-mail: zhang@lilly.com
Contents
1. Introduction 2
2. Method 3
3. Results and Discussion 3
4. Conclusion 9
Acknowledgments 11
References 11
Abstract
Substructure analysis of approved drugs and drug candidates in clinical trials was per-
formed to illustrate the evolving roles of heterocycles in pharmaceutical research. The
increasing representation of biaryls and heteroaromatics is noted and attributed pre-
dominantly to their better accessibility brought upon by advances in metal catalyzed
cross-coupling and hetero-coupling reactions. Possible future focus of academic
research is proposed for improving structural diversity and probability of success for
drug research, and enhancing the impact of heterocyclic chemistry to the develop-
ment of new medicines.
Keywords: Analysis; Biaryl; Cross-coupling; Drug; Drug candidates; Drug of the future;
Heterocycle; Palladium catalysis; Pharmacophore; Pyrazole; Pyridine; Structural diversity;
Substructures; Synthetic accessibility; Synthetic feasibility; Synthetic methodology
development
a
This paper is dedicated to the memory of Professor Alan R. Katritzky, from whom the author learned
the reason of being for heterocycles.
Advances in Heterocyclic Chemistry, Volume 121
© 2017 Elsevier Inc.
j
ISSN 0065-2725
http://dx.doi.org/10.1016/bs.aihch.2016.05.001 All rights reserved. 1
2 Tony Y. Zhang
1. INTRODUCTION
Heterocycles have played a prominent role among pharmaceuticals, as
they have been essential in the perpetuation, propagation, and evolution of
life in molecular forms such as nucleotides, carbohydrates, hemes, and amino
acids. While most drugs achieve the desired therapeutic outcomes through
interactions with proteins or DNA/RNA, the morphology of successful
drugs does not necessarily resemble that of their biological targets. In fact,
the shapes of drugs are heavily influenced by three artificial factors, i.e.,
(a) the structure of the initial hit or lead; (b) the synthetic feasibility for
the intended structure; and (c) the availability of starting material for the
preparation (Figure 1). The feedback loop connecting compound synthesis
and biological testing during structural activity relationship (SAR) studies is
still a relatively long and arduous process.
It is worth noting that all these three major factors are a culmination of
historic synthetic chemistry efforts and natural product explorations in the
last 200 years. As a result they tend to be biased toward certain chemical lin-
eages, such as petroleum, coal tar, naval store chemicals, and existing drugs
supply chain. For example, hits are usually obtained from screening an exist-
ing compound collection, which itself was collected through the years from
various sources. We want to note that in recent years more tailor-designed
libraries of hit structures, guided by insights into protein structures with the
aid of computational chemistry and NMR techniques (e.g., fragment-based
drug discovery/design) (2015DDT(20)1104) are matriculating into the
De novo design
insights
Hit/Lead
structures
In vitro /in vivo activity

and selectivity
ADME and toxicology
Availability of properties
Synthetic
starting
feasibility
material
Figure 1 Major influencers of drug structures during the discovery process.

The Evolving Landscape of Heterocycles in Drugs 3
public and industrial collections to compliment compounds of natural and

industrial origin. However, composition of these libraries is heavily influ-
enced by high efficiency chemistry and separation technology that enabled
their facile synthesis and purification. For SAR investigation, most chemists
prefer reactions that are reliable and highly efficient, starting from commer-
cially available starting materials. In other words, compounds that are easily
synthesized are biased to have a better chance of progressing in the drug dis-
covery journey.
2. METHOD
To have a more quantitative glimpse at the structural trend of drug
molecules, we performed a substructure analysis of approved drugs as well
as drug candidates currently in clinical and preclinical development using
the Drug Data Report (MDDR) database (2016MI1). MDDR is a commer-
cial database that retrieves chemical structures from published documents.
The database includes the respective therapeutic classes and status of devel-
opment of drug candidates. It is difficult to compile a historical overview of
snap shots of the shapes of molecules in development as the numbers are
constantly changing. Therefore, we plot the data of all launched drugs
(N ¼ 1631), those drugs that have been approved in the last decade
(2005e2014, N ¼ 221); the previous decade (1995e2004, N ¼ 331);
drug candidates currently in Phase III (N ¼ 351), Phase II (N ¼ 1457),
and Phase I (N ¼ 1161); or in preclinical development (N ¼ 17,580), as
of Sept 2015. Only compounds with defined structures were included
and as a consequence large molecules such as antibodies and large peptides
were omitted. The database also has a “Biological testing” category for
development stage, which covers a broad range of the compounds that
have not yet entered into preclinical development. They were not included
in the analysis due to the lack of commonly accepted criteria for the mile-
stone. Compounds with a development stage classified as “registered,”
“pre-registered,” “recommended approval,” and those between phases
were not included due to the small representation.
3. RESULTS AND DISCUSSION

Of the more than 22,000 compounds with defined structures in the
selected dataset, a great majority (95%) contain at least one ring (top line,
4 Tony Y. Zhang
Figure 2 Percentage of ring containing molecules by substructure analysis.
Figure 2). This percentage remains more or less constant if we look at newer
drugs that have been approved in the last decade or earlier. Even for drugs
that are still under various stages of clinical development, the ratio of cyclic
compounds remains stable between 95% and 98%. The percentage of het-
erocyclic compounds, however, rose steadily from 71% to 87%. Compared
to their linear counterparts of similar composition, cyclic compounds have
fewer degrees of structural freedom, are more compact, and tend to be better
binders with the protein targets. They are generally more bioavailable.
Nevertheless, medicinal chemistry merits alone would not be able to ac-
count for their dominance. The percentage of aromatic compounds has
also shown a dramatic increase from just under 80% for all marketed drugs
to over 90% for drug candidates in preclinical development. This finding can
be considered as a predictor for the structure of drugs in the near future.
Considering the composition of drug candidates currently in Phase III clin-
ical trials as a leading indicator for the types of future drugs to be approved,
along with Phase II and Phase I molecules as yet a further indicator for what
is coming down the road for the next generation of drugs, we can see the
general trend towards more aromatic compounds. Interestingly this trend
has been noted several years ago by Lovering, Bikker, and Humblet
(2009JMC(52)6752). The drug discovery community has been alarmed by
the increasing aromaticity or decreasing presence of saturation in drug
250
200
150 cyclic
heterocyclic
Aromatic
heteroaromatic
100
Phenyl only
F-hetero
50
0
all launched Launched Launched Phase III Phase II Phase I Preclincial
1995-04 2005-2014
Figure 3 Trends of ring containing compounds.
structures. The reason for concern is that the decrease in hydrogen atom
saturation in drug candidates has been linked with poor solubility and
high attrition rate during clinical development. However, the trend toward
aromatization/unsaturation continues. The roles played by the synthetic
feasibility for shaping this thread need to be delineated from the requirement
of structural rigidity and hydrogen bonding capabilities (aromatic N atoms).
The increasing proportion of therapeutic targets of drug discovery efforts to-
ward oncology (i.e., large number of kinase targets) might also play a role in
the molecular structure of drugs, leading to an increasing presence of sp2 hy-
bridized nitrogen.
Instead of showing the absolute percentage of substructure representa-
tion, Figure 3 illustrates the change across development stages. It is worth
noting that 34% of all previously approved drugs contain at least one heter-
oaromatic ring. This number has increased by 54% for the compounds
currently in preclinical testing. On the contrary, there is nearly a 50%
drop for the simple, mono-substituted phenyl group. Explanation of this
phenomenon is complex and needs to be nuanced. Contributing factors
for the decreasing popularity of the plain phenyl might include the suscep-
tibility toward metabolism, lack of binding specificity, too high a lipophilic-
ity, or poor intellectual property positions.
One of the most prominent drug structure changes is the rise of biaryls
(Ar-Ar0 ). Biaryl as a pharmacophore obviously brings a combination of
structural rigidity and flexibility around the “free” rotating single bond
adjoining the two rings. However, its popularity has to be attributed to
6 Tony Y. Zhang
Figure 4 Transition metal catalyzed crosscoupling reactions.
the advent of palladium cross-coupling reactions (Figure 4) (2012AGE(51)

5062). Also, access to the nucleophilic aryl metals has been vastly improved
through directed ortho metalation (2014MI1) and Rh- or Ir-facilitated
direct borylation of arenes (2012ACR(45)864). In recent years, the scope
of the Ir-catalyzed borylation reaction has been greatly expanded to accom-
modate unconventional “electrophiles” with leaving groups including OH,
CN, and OMe. Biaryls (Ar-Ar0 ) have also been obtained by Rh-catalyzed
direct coupling of arenes (ArH) and aromatic aldehyde (Ar0 CHO) coupling
through a CeH activation mechanism (2010JA(132)12212).
As illustrated in Figure 5, the growth in biaryls is largely driven by the
popularity of those containing a heteroaromatic ring. This is a class of com-
pounds extremely difficult to selectively prepare without the aid of transition
40
35
30
25
Aliphatic Heterocyclic
Biary (55, 5-6, 6-6)
20
biphenyl
heterobiaryl
15
10
0
all launched Launched Launched Phase III Phase II Phase I Preclincial
1995-04 2005-2014
Figure 5 The rise of biaryls (Ar-Ar0 ).

20
Biary (55, 5-6, 6-6)
biphenl only
heterobiaryl
15
10
0
all Launched Launched Phase III Phase II Phase I Preclincial
launched 1995-04 2005-2014
Figure 6 The increasing presence of AreAr0 in drugs and drug candidates.
metal catalyzed cross-coupling. Concomitant with the rise of biaryls is the

drop in the percentage of aliphatic heterocyclic compounds. Again data
are lagging for concluding whether this is really a desirable phenomenon
or not. The same data can be visualized in a columnar format to underscore
the influence of cross-coupling reactions on the shape of drugs (Figure 6)
(1982ACR(15)340, 2011AGE(50)6722).The popularity of biaryl in drugs
corresponds well chronologically with the surge of published literature for
this powerful and differentiating synthetic methodology (Figure 7)
(2016MI2). Unequivocally, no other chemical transformation discovered
in the last century has had such a profound impact on the shapes of drug
molecules.
We then examined the representation by major heterocycle classes among
the dataset across different development stages (Figure 8) and the results were
intriguing. No significant changes were observed for the traditionally com-
mon pharmacophores such as piperidine, piperazine, indole, and pyrrolidine.
However, pyridine has replaced piperidine as the most common heterocyclic
pharmacophore. This is in line with the general trend of aromatization noted
earlier. Again, how much of a bias toward aromatic compounds due to easier
8 Tony Y. Zhang
Figure 7 Number of publications concerning palladium-catalyzed cross-coupling

reactions.
25
Piperidine
20 Piperazine
Pyrazole
Pyrazole
15 Pyrimidine
Pyrrolidine
pyridine
10 Pyrazine
midazole
1,2,4-Triazole
5 1,2,3-Triazole
Tetrazole
Indole
0 Thioazole
All launched Launched Launched Phase III Phase II Phase I Preclincial
1995-2004 2005-2014
Figure 8 Percentages of the major heterocyclic pharmacophores.
synthetic access of pyridines remains to be discerned in light of the ever

strengthening repertoire of tools including aryl CeC bond cross-coupling
(1982ACR(15)340, 2011AGE(50)6722), aryl CeN and CeO bond het-
ero-couplings (2006JA(128)3584, 2004ASC(346)1599), and aryl CeH
activation (2014BMC(22)4445).
When the relative ratios (percentage) of a certain pharmacophore at a
specific development stage are plotted against that of all launched drugs
(Figure 9), we can see the emergence of small heteroaromatic system repre-
sented by pyrazole, triazoles, and tetrazole, all containing an NeN bond.
1000
900
800 Piperidine
N NH
N Piperazine
700 Pyrazole
Pyrimidine
600
Pyrrolidine
500 NH pyridine
N Pyrazine
400 N NH Imidazole
N
1,2,4-Triazole
300 1,2,3-Triazole
N Tetrazole
200
Indole
100 Thioazole
0
All launched Launched Launched Phase III Phase II Phase I Preclincial
1995-2004 2005-2014
Figure 9 Relative ratios of heterocyclic pharmacophores at stages of development.
Actually, the percentage of NeN bond containing molecules has doubled

among preclinical compounds relative to that among launched drugs.
Because of the lag time between the discovery and utilization of new syn-
thetic methodologies and the manifestation of its impact on the structures
of drug molecules, we may expect to see a rise of 1,2,3-triazoles in the future
due to the power of Huisgen cycloaddition “Click chemistry”
(2003DDT(8)1128), even though the current growth leader is clearly pyr-
azole for a variety of reasons, most notably metabolic stability.
4. CONCLUSION
In summary, we have uncovered some interesting trends in medici-
nal chemistry through a simple and very qualitative analysis of the pheno-
typical nature of drugs and drug candidates. While the phenotypic
outcome is reasonably unambiguous, the underlying reasons affecting the
design, preparation, selection, and attrition of drug molecules can be
extremely complex (2009JMC(52)6752, 2003JMC(46)1250). We wish
to highlight the unequivocal influence of synthetic accessibility, composed
of facility of synthetic transformations and availability of starting materials.
Understanding these biases and being conscientious of their merits and
drawbacks will be instrumental in improving the efficiencies of drug dis-
covery, and managing attritions of clinical candidates during development.
10 Tony Y. Zhang
Drug discovery is a long and complex endeavor where decisions are often
made with incomplete data and without the benefits of prompt feedbacks.
Medicinal chemists have to constantly make tradeoffs between affinity,
selectivity, physical and ADME properties (2003JMC(46)1250), toxicolog-
ical findings, and synthetic route simplicity. It is noteworthy that all accu-
mulated chemistry efforts in human history have barely scratched the
surface of the vast possible chemical space. A case in point is that there
are estimated fewer than 40 million compounds with known structures,
and a typical compound collection for medicinal chemistry screening pur-
pose is in the range of 104 to 106 scale. However, the enumerated number
of possible structures with only 17 heavy atoms affording the typical size of
drug like molecules would amount to 166 billion compounds (2012MI1).
The influence of synthetic accessibility has been very strong in the last few
decades of modern drug discovery with more aromatic compounds getting
into the pipeline. As a result there is a deviation from a natural product-like
platform that tend to have higher sp3/sp2 atom ratios. The unintended
consequences include structural bulkiness, low aqueous solubility, and
poor exposure. This general pattern has been stridently recognized if not
widely heeded (2009JMC(52)6752, 2003JMC(46)1250, 2009JMC(52)
2952, 2015JMC(58)4443, 2016JMC(59)4358).
Synthetic accessibility also influences the very early stage of drug discov-
ery. Many of the intentionally designed diversity libraries lean toward ease of
synthesis and purification efficiency. A common nexus for the combinatorial
chemistry/parallel synthesis efforts is the reaction efficiency (e.g., using
excess reagents to drive reactions to completion) and separation effectiveness
(e.g., applying solid-phaseebased reagents or scavengers). With the advent
of computational chemistry and expansion of our knowledge base on pro-
tein structures, more fruitful de novo design of drug molecules is inevitable.
However, this will only reduce the hit/lead bias as compared with biological
screening of the actual compound collections. After in silico screening,
selected compounds still need to be made in the laboratories to advance to-
ward in vivo testing and ultimately human trials. The synthetic accessibility
bias can only be overcome by the invention of more convenient methodol-
ogies with impact to that of the palladium-catalyzed cross-coupling reactions
(e.g., Suzuki, Negishi, and Kumada couplings) for the preparation of biaryls.
Besides fulfilling the need of medicinal chemists to incorporate a biaryl moi-
ety into a molecular backbone, Suzuki couplings also has the advantages of
being easy to perform (nonhydroscopic reaction conditions) and general
applicability, having a growing supply of aryl halides and stable arylboronic
acids as coupling partners, and using a mild reaction condition compatible

with many existing functional groups. This underscores the importance of
robustness and generality of a new reaction. Medicinal chemists need
more powerful, efficient, and convenient tools to prepare molecules that
are more “natural product” like; have more sp3 atoms; and more flexible,
diverse, unique, and intriguing structures. Transformations that enable func-
tionalization of inactivated sp3 CeH bonds, stereoselective introduction of
small alkyls onto saturated heterocyclic ring, and explorations of hitherto
unknown heterocyclic rings (2009JMC(52)2952) are but just a few examples
of current needs. Developers of synthetic methodologies will have a greater
impact to the community if they align their expertise and curiosity with the
current and strategic needs of medicinal chemists. More frequent dialogs and
closer collaboration between industry and academia will undoubtedly
benefit this goal.
ACKNOWLEDGMENTS
The author wishes to dedicate this paper to Professor Alan R. Katritzky for his friendship and
inspirations; and thank Drs. Eric Scriven, Christine Humblet, David Mitchell, Christopher
Burcham, and Professor Victor Snieckus for their comments and review during the prepara-
tion of this manuscript.
REFERENCES
1982ACR(15)340 E. Negishi, Palladium- or nickel-catalyzed cross coupling. A new selec-
tive method for carbon-carbon bond formation, Acc. Chem. Res.,
15(11), 340e348 (1982).
2003DDT(8)1128 H.C. Kolb and K.B. Sharpless, The growing impact of click chemistry
on drug discovery, Drug Discovery Today, 8(24), 1128e1137 (2003).
2003JMC(46)1250 M.C. Wenlock, R.P. Austin, P. Barton, A.M. Davis, and P.D. Leeson,
A comparison of physiochemical property profiles of development and
marketed oral drugs, J. Med. Chem., 46(7), 1250e1256 (2003).
2004ASC(346)1599 B. Schlummer and U. Scholz, Palladium-catalyzed C-N and C-O
coupling, a practical guide from an industrial vantage point, Adv. Synth.
Catal., 346(13e15), 1599e1626 (2004).
2006JA(128)3584 S. Shekhar, P. Ryberg, J.F. Hartwig, J.S. Mathew, D.G. Blackmond,
E.R. Strieter, and S.L. Buchwald, Reevaluation of the mechanism of
the amination of aryl halides catalyzed by BINAP-ligated palladium
complexes, J. Am. Chem. Soc., 128(11), 3584e3591 (2006).
2009JMC(52)2952 W.R. Pitt, D.M. Parry, B.G. Perry, and C.R. Groom, Heteroaromatic
rings of the future, J. Med. Chem., 52(9), 2952e2963 (2009).
2009JMC(52)6752 F. Lovering, J. Bikker, and C. Humblet, Escape from flatland:
increasing saturation as an approach to improving clinical success, J.
Med. Chem., 52(21), 6752e6756 (2009).
2010JA(132)12212 S. Qi, L. Yang, X. Guo, O. Baslé, and C.J. Li, Rhodium-catalyzed
oxidative CH arylation of 2-arylpyridine derivatives via
12 Tony Y. Zhang
decarbonylation of aromatic aldehydes, J. Am. Chem. Soc., 132(35),

12212e12213 (2010).
2011AGE(50)6722 A. Suzuki, Cross-coupling reactions of organoboranes: an easy way to
construct C-C bonds, Angew. Chem. Int. Ed., 50(30), 6722e
6737 (2011).
2012ACR(45)864 J.F. Hartwig, Borylation and silylation of C-H bonds: a platform for
diverse C-H bond functionalizations, Acc. Chem. Res., 45(6), 864e
873 (2012).
2012AGE(51)5062 C.C. Johansson, M.O. Kitching, T.J. Colacot, and V. Snieckus, Palla-
dium-catalyzed cross-coupling: a Historical contextual perspective to
the 2010 Nobel Prize, Angew. Chem. Int. Ed., 51(21), 5062e
5085 (2012).
2012MI1 L. Ruddigkeit, R. van Deursen, L.C. Blum, and J.L. Reymond,
Enumeration of 166 billion organic small molecules in the chemical
universe database GDB-17, J. Chem. Inf. Model., 52(11), 2864e
2875 (2012).
2014BMC(22)4445 For a recent review in this exploding fields: see (a) M.E. Farmer,
B.N. Laforteza, and J. Yu, Unlocking nature’s C-H bonds, Bioorg.
Med. Chem., 22(16), 4445e4452 (2014).
2014MI1 V. Snieckus and E.J.-G. Anctil, The directed ortho metallation (DoM)-
cross-coupling nexus. Synthetic methodology for the formation of
aryl-aryl and aryl-heteroatom-aryl bonds, In A. De Meijere, S. Brase,
and M. Oestreich, editors: Metal-Catalyzed Cross-Coupling Reactions
and More, 3, pp 1067e1133.
2015DDT(20)1104 For a recent review, see L. Oester, S. Tapani, Y. Xue, and H. Kaeck,
Successful generation of structural information for fragment-based drug
discovery, Drug Discovery Today, 20(9), 1104e1111 (2015).
2015JMC(58)4443 D.G. Brown and J. Bostrom: Analysis of past and present synthetic
methodologies on medicinal chemistry: where have all the new reac-
tions gone? A Miniperspective. http://dx.doi.org/10.1021/acs.
jmedchem.5b01409.
2016JMC(59)4358 This very relevant paper appeared after submission of this manuscript:
N. Schneider, D.M. Lowe, R.A. Sayle, M.A. Tarselli, and G.A. Land-
rum. Big data from pharmaceutical patents: a computational analysis of
medicinal chemists’ bread and butter. http://dx.doi.org/10.1021/acs.
jmedchem.6b00153.
2016MI1 For provider website, see http://accelrys.com/products/collaborative-
science/databases/bioactivity-databases/mddr.html.
2016MI2 SciFinder data, Chemical Abstract Services, (accessed February 2016).
CHAPTER TWO
Saturated Heterocycles with

Applications in Medicinal
Chemistry
Charles M. Marson
Department of Chemistry, University College London, Christopher Ingold Laboratories, London, UK
E-mail: c.m.marson@ucl.ac.uk
Contents
1. Introduction 14
2. Ring Systems Containing One Heteroatom 15
2.1 Azetidines 15
2.2 Oxetanes 16
2.3 Pyrrolidines 17
2.4 Tetrahydrofurans 19
2.5 Piperidines 20
2.6 Tetrahydropyrans 21
3. Spirocyclic Heterocyclic Ring Systems 22
3.1 Introduction 22
3.2 Spirooxetanes 22
3.3 Spiropyrrolidines 22
3.4 Spiropiperidines 23
4. Heterobicyclo Systems 24
4.1 Azabicyclo[3.1.0]hexanes 24
4.2 Azabicyclo[2.2.1]heptanes 24
4.3 Azabicyclo[3.2.1]octanes 25
4.4 Azabicyclononanes 26
4.5 Miscellaneous Heterobicyclo Systems 27
5. Conclusions 27
References 28
Abstract
In recent years, the advantages of incorporating saturated heterocyclic rings in thera-
peutic agents have become increasingly apparent, as compared to using only aromatic
and heteroaromatic ring systems. In particular, saturated heterocyclic ring systems play
a central role in medicinal chemistry; frequent advantages include improved aqueous
Advances in Heterocyclic Chemistry, Volume 121

© 2017 Elsevier Inc.
j
ISSN 0065-2725
http://dx.doi.org/10.1016/bs.aihch.2016.03.004 All rights reserved. 13
14 Charles M. Marson
solubility and lower toxicity of metabolites, as well as the potential for greater diversity
partly through stereoisomerism. This review illustrates examples of saturated heterocy-
cles with relevance to medicinal chemistry as published in the years 2013e2015. The
three main categories discussed are small and medium ring systems containing one
heteroatom, spiroheterocyclic ring systems, and heterobicyclo systems.
Keywords: Heterobicyclo systems; Medicinal chemistry; Monocyclic heterocycles;

Saturated rings; Spiroheterocycles
1. INTRODUCTION
The importance of saturated heterocyclic systems is well illustrated
by the piperidine ring, long known in a medicinal context, and the
most abundant saturated heterocyclic system in all current small-molecule
therapeutic agents listed in the FDA Orange Book (2014JMC5845). Most
pharmaceuticals contain between one and four rings (2014JMC5845), in
part because of the lower conformational entropy to be overcome upon
binding to the target. However, saturated rings tend to be inherently
more drug-like than planar aromatic ones; toxic metabolites arising from
arene oxidation are avoided, and saturation increases water solubility and
imparts desirable three-dimensional occupancy of a drug target (2011
PNAS6799), all factors that contribute to two recently formulated criteria
that favor drug-likeness: a relatively high level of saturation and an asym-
metric center. A case study of a large number of successful clinical candi-
dates gave a ratio on 0.47 for the number of sp3 carbon atoms present to
the total number of carbon atoms per drug molecule, which also typically
contained at least one chiral center (2009JMC6752, 2013MCC515). De-
parture from using rings that are exclusively aromatic or heteroaromatic,
such as benzene, imidazole, and pyridine has additional benefits, including
greater diversity (through stereoisomerism) for a small increase in molecular
weight, and structural novelty which can assist patentability. Consequently,
the structural landscape of drug-like molecules is changing (2014JMC5845,
2011CSR5514), and has an increased emphasis on saturated ring systems,
most of which are heterocyclic. To illustrate those points, this review covers
some of the major saturated heterocycles (their low mass being a desirable
drug-like feature) as well as more complex architecture present in saturated
spiro and bicyclo heterocycles, especially where the constitution is novel or
unusual.
Saturated Heterocycles in Medicinal Chemistry 15
2. RING SYSTEMS CONTAINING ONE HETEROATOM

2.1 Azetidines
In a study to optimize potent protein kinase Cq inhibitors with the
potential to treat rheumatoid arthritis and inflammatory bowel disease, an
azetidine ring was essential in order to obtain low nanomolar potency, as
for compound 1. Analogs where oxetane or cyclobutane replaced the aze-
tidine ring were considerably less potent. Hydrogen bonding of such
substituted azetidines to Asp, and in some cases also to an Asn residue,
was confirmed by crystallography (2015JMC222) (Figure 1).
The azetidine 2 is a potent, selective and bioavailable antagonist of
G-protein bile receptor 1, an important target in the treatment of diabetes
(2014JMC3263). Analogs containing a piperidine ring in place of the azeti-
dine ring were significantly less potent. However, in a study of the inhibition
of sphingosine kinase 1, a target for fibrosis, inflammation, and cancer, while
2-substituted azetidine derivatives were potent, a 2-methylene-substituted
pyrrolidine derivative afforded much greater inhibition of G-protein bile
receptor 1, and was also highly selective for isoform 1 over isoform 2
(2015JMC1879).
O CN
NH CF3
NH N
HN 6 N N HO2C N O
N
N H
F3C 7 O H
2
1
CO2H
O O H O
N N
S H
N Cl N
3 4
HN O O
N CN
HN H
N
N
Figure 1 Enzyme inhibitors and receptor antagonists that contain an azetidine ring.
Azetidines are also a key feature of a class of free fatty acid receptor 2 an-
tagonists, compound 3 showing promise for clinical development as an anti-
inflammatory agent (2014JMC10044). In this series, the (R)-enantiomers
were the more potent, and sometimes the (S)-enantiomers were inactive.
Nicotine addiction is mediated by nicotinic acetylcholine receptors which
may also be involved in alcohol addiction. 3-(Azetidin-2-ylmethoxy)pyridine
derivatives can show selective inhibition of the a4/b2 nicotinic acetylcholine
receptor, and in a rat model of alcohol intake compound 4 showed greater
selectivity for the a4/b2 receptor subtype and fewer side effects than the
structurally related sazetidine-A (2013JMC3000). Other related compounds
exhibited antidepressant properties in a mouse model (2013JMC5495).
A preclinical candidate for the treatment of Alzheimer’s disease contained
a 3-(1-isopropyl)azetidinyl subunit and inhibited gamma secretase but did
not inhibit human CYP3A4 (which could lead to drugedrug interactions)
as did other analogs in this series, presumably through binding to iron in
the heme coenzyme (2013BMCL1621). In a series of 5-substituted benz-
imidazoles, a 3-(1-hydroxyethyl)azetidinylsulfonyl subunit was found to
confer potent selective agonism of the cannabinoid receptor (CB2) associated
with irritable bowel syndrome; the agonist was effective (ED50 0.66 mg/kg)
in a rat model of IBS and with few side effects (2015BMCL236).
Janus kinases (JAKs) are involved in signaling that is relevant to inflamma-
tory diseases. The 3-cyanoazetidine 5 showed good selectivity for JAK3 while
retaining potency against IL-2 signaling, indicating that such compounds
could be useful probes of complex signaling pathways (2013JMC345).
2.2 Oxetanes
Synthetic routes to oxetanes and chemical transformations of oxetanes have
developed markedly in recent years (2010AG(E)9052). Nucleophilic addi-
tion to the carbonyl group of oxetan-3-one can furnish a wide range of
3-substituted oxetane derivatives (2010JMC3227). The nickel-catalyzed
Suzuki coupling of a (hetero)arylboronic acid with 3-iodooxetane afforded
3-(hetero)aryloxetanes (2008OL3259).
The incorporation of an oxetane ring can greatly improve the drug-like
properties of compounds (2006AG(E)7736), increasing solubility, and usu-
ally increasing metabolic stability, as well as typically lowering log P by
about one unit (2010JMC3227). 3,3-Disubstituted oxetanes can be robust
replacements either for a methylene group or a gem-dimethyl group, and in
some cases also for a keto group (2010JMC3227). When a methylene group
in an aliphatic chain is replaced by a 3-substituted oxetane a synclinal
conformation is adopted. The oxetane ring is sufficiently chemically inert to

be found in natural products, and is thought to act as a conformational lock
in paclitaxel, defining the orientation of the 2-benzoyl group and the C-13
side chain (1999BMCL3041), all key features in the binding of paclitaxel to
tubulin.
In the progression of dual leucine zipper kinase inhibitors toward a new
agent to treat neurodegeneration, the privileged 3-oxetanyl moiety was
essential in obtaining potent inhibition of c-Jun N-terminal kinase and
sub-nanomolar in vitro enzyme inhibition of dual leucine zipper kinase;
both kinases are implicated in neurodegeneration, including Alzheimer’s
and Parkinson’s diseases (2015JMC401). Appending the oxetane lowered
the basicity of the piperidine ring and reduced efflux of compound 6
(Figure 2).
A 3-oxetanyl group, while not binding within the active site of the
kinase mTOR which is a validated anticancer target, is a significant contrib-
utor to an improved PK/PD profile of a new mTOR inhibitor that also
showed more potency than a previous preclinical candidate lacking an oxe-
tane ring (2013JMC3090).
2.3 Pyrrolidines
In a series of 6-alkyl-2-amino-4-aminosubstituted pyrimidines designed as
anti-inflammatory agents that target the histamine H4 receptor, compound
7 showed the best overall PK/PD profile, both the absolute configuration of
the amino group and the pyrrolidine ring being crucial for potency and ef-
ficacy (the amino group is protonated and binds to Asp in the H4 active site).
However, clinical progression of amine 7 during phase II evaluation against
atopic dermatitis was halted following observation of drug-induced agranu-
locytosis in two patients (2014JMC2429) (Figure 3).
C2-symmetric pyrrolidine-based 3,4-bis-N-alkylsulfonamides, such as
amine 8, contain a novel and nonpeptidic scaffold. Amine 8 exhibits the
most potent inhibition of the homodimeric human T-cell leukemia virus
F
F
N
O N N CN
HN
6 N
Figure 2 A 3-substituted oxetane with neuroprotective properties.

NH2 Bn Bn
p-H2NC6H4O2SN NSO2C6H4-p-NH2 O
N N N
N
H
N N N O B
NH2 N OH
H HO
7 8 9
Figure 3 Pyrrolidine receptor antagonists and protease inhibitors.
type 1 protease (an aspartate protease) currently known, each sulfonamide

nitrogen atom binding to one of two aspartate residues in the catalytic site
(2015JMC4845).
Disruption of the p53eMDM2 interaction, thereby restoring the tumor
suppressor activity of p53, is seen as an appealing approach to cancer treat-
ment. The difficulty of targeting the hydrophobic surface of the proteine
protein interaction was met by appending suitably oriented lipophilic groups
in a pentasubstituted pyrrole (Figure 4) (2013JMC5979). The nitrile group
was found to be essential for achieving the required puckering of the pyrro-
lidine ring, and hence the appropriate dihedral angle of the two aryl substit-
uents (2013JMC5979). This compound was highly effective when
administered orally in an osteosarcoma mouse xenograft.
The post-proline serine protease fibroblast activation protein (FAP) is
considered to contribute to tumor invasion and metastasis. The inhibitor
9 is a stable transition state analog that shows excellent selectivity for FAP
Figure 4 A substituted pyrrolidine bound in MDM2: PDB 4JRG. Reprinted with permis-
sion from Q. Ding, Z. Zhang, J.-J. Liu, N. Jiang, J. Zhang, T. M. Ross, X.-J. Chu, D. Bartkovitz,
F. Podlaski, C. Janson, C. Tovar, Z. M. Filipovic, B. Higgins, K. Glenn, K. Packman, L. T.
Vassilev and B. Graves, J. Med. Chem. 2013, 56, 5979. Copyright (2013) American Chemical
Society.
over several normal human dipeptidyl peptidases (DPP) and prolyl oligo-
peptidases (2013JMC3467). In a different series of proline-based FAP inhib-
itors, a 2-cyano-4,4-difluoropyrrolidine was found preferable to a 2-boronic
acid derivative, and showed good potential for in vivo inhibition
(2014JMC3053).
5,5-Fused systems containing one or more pyrrole rings are useful scaf-
folds in medicinal chemistry. Some octahydropyrrolo[3,4-c]pyrroles are
selective antagonists of orexin-2, and a candidate for primary insomnia has
progressed through phase I clinical trials (2015JMC5620). [3.3.0]-Octahy-
drocyclopenta[c]pyrrole antagonists of retinol-binding protein 4 have poten-
tial for the treatment of atrophic age-related macular degeneration and
Stargardt disease (2015JMC5863).
2.4 Tetrahydrofurans
The tetrahydrofuran ring present in RNA and DNA is a common scaffold in
drug design targeting pathogenic nucleic acids. The tetrahydrofuran deriv-
ative 10 is a first-in-class nucleoside respiratory syncytial virus (RSV) poly-
merase inhibitor and has entered phase II clinical trials (2015JMC1862).
Human RSV is associated with significant morbidity and mortality in child-
hood, and causes symptoms of the common cold in most patients. Other
20 -deoxy-20 -b-fluoro-substituted nucleosides show promise for the treat-
ment of hepatitis B (2015JMC3693).
Nucleoside analogs comprise the largest class of DNA methyltransferase
inhibitors, and find use in the treatment of a variety of cancers, since pro-
moter methylation can lead to inactivation of tumor suppressor genes
(2015JMC2569) (Figure 5).
The (R)-enantiomer of a 2,2-diaryltetrahydrofuran is a good inhibitor of
5-lipoxygenase activating protein and has potential for the treatment of in-
flammatory diseases. Affinity (ligand lipophilic efficiency) was higher for the
(R)-enantiomer than the (S)-enantiomer, suggesting that the ring oxygen
atom forms a specific interaction within the receptor site (2015JMC897).
NH2
OCOPri NMe
N NH OMe
O N Cl N OH
N H
H
O H O O N N
O S
Cl N N N H H
PriOCO F H H O O O O
Ph
10 11 12
Figure 5 Tetrahydrofuran-containing polymerase, kinase, and protease inhibitors.
In a hybrid approach to generating new inhibitors of the tyrosine kinase

ACK1, implicated in signal transduction that sustains hormone-refractory
cancers, the tetrahydrofuran 11, containing the common 2-anilinopyrimi-
dine unit that binds to peptide backbone regions of the kinase, showed
potent in vitro inhibition of ACK1 and good antiproliferation in several can-
cer cell lines (2015JMC2746).
Several amino-bis-tetrahydrofuran derivatives such as the acetal 12 are
very potent HIV-1 protease inhibitors that possess excellent antiviral prop-
erties. Although these compounds have the same ring systems and scaffold
as darunavir, increased binding derives from the additional isopropylamino
group hydrogen bonding with the active site backbone; enhanced lipophi-
licity of other substituents is also thought to contribute to the greater
potency of derivative 12 and some analogs compared to darunavir
(2015JMC6994).
2.5 Piperidines
Arginase overexpression is implicated in myocardial reperfusion injury.
(R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)-ethyl)hexanoic acid reduced
infarct size in a rat model and is a potent inhibitor of arginase, its boronic
acid group binding to manganese; there is also hydrogen bonding of water
to the piperidine ring and two Asp residues in the active site (2013JMC2568).
The piperidine ring is often used as a linker, and a 4-aminopiperidine
core was optimized for potency and efficacy against Mycobacterium tubercu-
losis; a 3-fluoro substituent on the piperidine ring lowered the lipophilicity
and as expected also lowered hERG inhibition (2014JMC4889).
Making use of the finding by Zimmerman in the late 1970s that
N-methyl-trans-3,4-dimethyl-4-(3-hydroxyphenyl)-piperidine was a pure
antagonist of an opioid receptor, the same piperidine linker has been incor-
porated into a 3-isoquinoline carboxamide that is a very potent and highly
selective antagonist of the k-opioid receptor, considered to be a target in
the treatment of anxiety, eating disorders, depression, and schizophrenia
(2014JMC7367).
Antagonists of the G-protein-coupled receptor (GPCR) 119 stimulate
glucose-dependent release of insulin, both directly in the pancreas, and indi-
rectly by action in the gastrointestinal tract by promoting secretion of the
incretin glucagon-like peptide-1 (GLP-1). Of a new class of GPR119 antag-
onists, pyridin-2-one 13 was effective in both chronic and acute models of
rodent diabetes, and showed an increase in total GLP-1 plasma levels in
healthy humans (2014JMC7499) (Figure 6).
Cl
Cl SO2Me
N O OH
N N N O
N OH
F N N
O H H
O
Cl
13 14
Figure 6 Piperidine antagonists of two G-protein-coupled receptors.
CC chemokine receptor-1 (CCR1) is a GPCR linked with progression

of several inflammatory diseases; the CCR1 antagonist 14 (BMS-817399),
has entered phase 2 clinical trials for the treatment of rheumatoid arthritis
(2014JMC7550). The axial hydroxy group on the piperidine ring of antag-
onist 14 binds to a His residue.
Polyhydroxylated piperidines such as nojirimycin are a rich source of
glycosidase inhibitors. Several N-(4-biphenylmethyl)oxypentyl derivatives
possessing a D-gluco-substituent assembly on the piperidine ring are potent
inhibitors of intestinal glycosidases, and may have potential for development
as agents to combat type 2 diabetes (2014JMC9096).
2.6 Tetrahydropyrans
Inhibitors of dipeptidyl peptidase 4 (DPP4) can be valuable in the treatment
of diabetes. MK-3102 (omarigliptin) 15 progressed to phase 3 clinical eval-
uation in 2014 (2014JMC3205). Compared to Merck’s previous inhibitors
of DPP4 such as sitagliptin and saxagliptin, the primary amine is rigidified
as part of a tetrahydropyran ring which in part led to improved pharmaco-
kinetics and a longer half-life. The primary amine is engaged in hydrogen
bonding with two Glu residues (2014JMC3205) (Figure 7).
Sodium-dependent glucose transporter (SGLT) inhibitors promote uri-
nary excretion of glucose, thereby permitting an insulin-independent treat-
ment of type 2 diabetes mellitus. Replacement of the ethyl group in
dapagliflozin by trideuteromethyl gave derivative 16 which shows higher
metabolic stability owing to the kinetic isotope effect, and is also a selective
SGLT2 inhibitor of long duration of action (2014JMC1236).
F
OH OH N
HO OH
F H2N
N
OH S O N
N NSO2Me O N
H
O N OMe
D3CO Cl O N
F
15 16 17
Figure 7 Antidiabetic and antibacterial tetrahydropyrans.

Compound 17 and some analogs inhibit bacterial type II topoisomerases

and are potent antibacterial agents against Gram-positive pathogens. The
tetrahydropyran 17 showed no observable cross-resistance, only weakly
inhibited hERG Kþ channels, and gave no observed adverse cardiovascular
effects in guinea pigs (2015JMC927).
3. SPIROCYCLIC HETEROCYCLIC RING SYSTEMS

3.1 Introduction
Spirocyclic scaffolds, in which a single atom is common to both rings,
are a prime category of drug-like molecules (2014BMCL3673); they possess
significant occupancy in each of three dimensions, and often have structural
novelty that may also be accompanied by new synthetic methods of access.
An example is the acetylcholinesterase inhibitor and antihypertensive agent
spirapril which contains a spiro 1,3-dithiolane bonded to C-3 of a pyrrole
ring.
3.2 Spirooxetanes
The 20 -spirooxetane system was shown to be a moderately effective scaffold
for the treatment of hepatitis C virus (2014JMC1826, 2014JMC1836). A
20 -oxetane cytidine triphosphate showed good inhibition of NS5B polymer-
ase (IC50 8.5 mM), although modest replicon activity was found for the py-
rimidine bases containing this spirooxetane unit (2014JMC1826). Some
phosphoramidate prodrugs of 20 -deoxy-20 -spirooxetane ribonucleosides
were more potent, having EC50 values down to 0.2 mM in the Huh7-repli-
con cell line, and without any observed toxicity (2014JMC1836).
3.3 Spiropyrrolidines
7-(1-Pyrrolidino)-4-oxyquinoline-2-carboxylic acids and their 8-aza deriva-
tives are commonly used in the treatment of respiratory infections. In order to
reduce toxicity in types that have fused cyclopropylamine units, spirocyclic
pyrrolidines such as derivative 18 were synthesized and evaluated. The
inability of compound 18 to undergo oxidation to an iminium ion is thought
to contribute to its low toxicity. Spirocycle 18 was effective in a murine
model of multidrug-resistant streptococcal pneumonia (2013JMC1974)
(Figure 8).
Some inhibitors of the interaction of MDM2 with p53 up-regulate the
tumor suppressor and are in clinical trials (2015JMC1038). The most potent
Another random document with
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of the coal carriages, amount to solitary confinement of the worst
order.”
Children were also employed to push the small carriages
filled with coals along the passages, and as the passages were
often very low and narrow, it was necessary to use very small
children for this purpose. “In many mines which are at present
worked, the main gates are only from 24 to 30 inches high, and
in some parts of these mines the passages do not exceed 18
inches in height. In this case not only is the employment of very
young children absolutely indispensable to the working of the
mine, but even the youngest children must necessarily work in a
bent position of the body.” As a rule the carriages were pushed
along small iron railways, but sometimes they were drawn by
children and women, “harnessed like dogs in a go-cart,” and
moving, like dogs, on all fours. Another children’s task was that
of pumping water in the under-bottom of pits, a task that kept
children standing ankle-deep in water for twelve hours. In certain
districts children were used for a particularly responsible duty. In
Derbyshire and parts of Lancashire and Cheshire it was the
custom to employ them as engine men, to let down and draw up
the cages in which the population of the pit descended to its
depths and returned to the upper air. A “man of discretion”
required 30s. a week wages; these substitutes only cost 5s. or
7s. a week. Accidents were, of course, frequent,—on one
occasion three lives were lost because a child engineman of
nine turned away to look at a mouse at a critical moment,—and
the Chief Constable of Oldham said that the coroners declined to
bring in verdicts of gross neglect from pity for the children.
VIII
Do you ask “What has all this to do with literature, or what has
literature to do with these things”? I answer that, as a matter of mere
history, literature in the nineteenth century did immensely concern
itself with these things: and I add that, as literature deals with life, so
if it deserve a place in any decent state, it should deal with these
things. And to this again I add, because they dealt righteously and
unsparingly with these things, Shelley, Dickens, Carlyle, Ruskin—
yes and, later, William Morris—live on the lips of men to-day. For
they let in light upon dark places; not only revealing them to the
public conscience, but, better still and better far, conveying light and
waking eyesight in the victims themselves.
Denunciation has its uses: and if you want to hear denunciation,
listen to Carlyle—
British industrial existence seems fast becoming one huge

poison-swamp of reeking pestilence physical and moral; a
hideous living Golgotha of souls and bodies buried alive; such a
Curtius’ gulf, communicating with the Nether Deeps, as the Sun
never saw till now. These scenes, which the Morning Chronicle
is bringing home to all minds of men,—thanks to it for a service
such as Newspapers have seldom done,—ought to excite
unspeakable reflections in every mind. Thirty-thousand outcast
Needlewomen working themselves swiftly to death; three million
Paupers rotting in forced idleness, helping said Needlewomen to
die: these are but items in the sad ledger of despair.
Thirty-thousand wretched women, sunk in that putrefying
well of abominations; they have oozed-in upon London, from the
universal Stygian quagmire of British industrial life; are
accumulated in the well of the concern, to that extent. British
charity is smitten to the heart, at the laying-bare of such a scene;
passionately undertakes, by enormous subscription of money, or
by other enormous effort, to redress that individual horror; as I
and all men hope it may. But, alas, what next? This general well
and cesspool once baled clean out to-day, will begin before night
to fill itself anew.
Yes, denunciation has its uses: and public exposure is salutary,

or at least sanitary, though its first revelations sicken to such despair
as Carlyle’s. But the true operation of light is upon the sufferer’s own
eyes, the promise in its salutation is for them. Listen to this one
sentence from Porter’s Progress of the Nation, published in 1851—
In 1839, 1840 and 1841, 40 per cent. of the men and 65 per
cent. of the women married or witnessing marriages in
Lancashire and Cheshire could not sign their names
—and at this time Leonard Horner, Inspector of Factories, reported

that in an area of thirty-two square miles comprising Oldham and
Ashton, with a population of 105,000, there was not a single public
day school for poor children. Consider these millions of children who
grew up to be men and wives in purlieus not once penetrated by so
much as a glint of the romance, the poetry, that as we look back—
you a short way, Gentlemen—I a long one—we see as Heaven lying
about us in our infancy. There lay the soul’s tragedy—
The singers have sung, and the builders have builded,

The painters have fashioned their tales of delight;
For what and for whom hath the world’s book been gilded,
When all is for these but the blackness of night?
There lay the tragedy: there the seat of cure: and if, with so much left
undone, it has become possible from this desk to preach, without
serious rebuke, that humanism can be taught even in our
Elementary Schools, and, further, that to see it is so taught may well
concern even a great University, these humanitarians of the
nineteenth century were the men and women who invaded the
borders of Zabulon and Nephthalim, until for them which sat in
darkness, in the region and shadow of death, light is sprung up.
IX
But I recall myself to my purpose; which in two following lectures
shall be as literary, as merely critical, as I can keep it. To-day I have
set out the theme and tried to show you how it had perforce to
occupy men’s minds and—since artists and imaginative writers must
have feelings as well as intellect—almost to dominate our literature
and art in the last century. In that domination of interest you will find
implicit, and will easily evolve for yourselves, the reason why the
novel in particular, being a social form of art and lending itself in so
many ways to episode, discussion, even direct preaching, became
political as it never was in the days of Richardson and Fielding, Scott
and Jane Austen. The preponderance of the theme being granted, I
next propose to examine how it took possession of two persons of
genius: a man and a woman; the man assertive, personally
ambitious, full of fire and opulent phrase: the woman staid, self-
abnegating, to me wearing the quiet, with the intensity, of a noble
statue. I can conceive, if one would trace in literature the operation of
a compelling idea, no two exponents more essentially disparate than
Benjamin Disraeli and Elizabeth Gaskell.
DISRAELI
I
FOR two reasons or (shall we say) against two main obstacles, both
serious, Benjamin Disraeli found it hard to gain the ear of Parliament
and, having gained it, had yet a long fight before attaining office. To
begin with, his race and reputation were against him. He was a Jew,
and he had written novels. He was admittedly clever to excess: but
cleverness, specially when tainted by literary skill, is, of all others,
the reputation which our British Senate most profoundly (and
perhaps on the whole wisely) distrusts. That the House “hates a man
who makes it think” was the observation of a cynic, no doubt. But I
have also heard it said by one long a member of it, that a speaker
there must always count on somebody—he knows not whom—who
knows the subject more thoroughly than he. Its instinct being for
solidity, it shrinks from brilliance as a danger: and this was specially
true of the party to which Disraeli allied himself—upon which, we
may say, he thrust himself—a Jew, an adventurer, an ambitious,
esurient fellow without any stake in the country. What had a party,
which didn’t in the least object to being called stupid, to gain by the
support of such an outsider?
And it is obvious that, for Parliamentary success, Disraeli had to
overcome something more serious—a certain bumptiousness of
manner, a youthful confidence and ease in Sion, helped out by
elaborate ringlets, mannerisms and a foppish dress very much
overdone: an opulence of speech and waistcoat, both jarring on the
very men—and probably most upon these—into whose less-oiled
heads he was fighting to drive some ideas. There is a great deal of
tactlessness in the story of Disraeli, right up to the moment of Peel’s
fall. But the story witnesses not only to a growing mastery, won by
amazing courage, over the House but—better—to a discipline won
over himself.
II
Now as Disraeli, being a novelist, was naturally suspect among
the party with whom he had chosen to cast his political lot, so his
books were naturally suspected and unjustly treated by his
opponents throughout his lifetime: and for this again we may decide
that he was largely to blame. He was, as you know, the son of a man
of letters: as he puts it, “born in a library, and trained from early
childhood by learned men who did not share the passions and
prejudices of our political and social life.” In his early work, such as
The Young Duke or The Infernal Marriage, we find, with all its excess
—the excess of youth—a hard literary finish. Let me quote from the
last-named story a few sentences for specimen:
The next morning the Elysian world called to pay their

respects to Proserpine. Her Majesty, indeed, held a drawing-
room, which was fully and brilliantly attended.... From this
moment the career of Proserpine was a series of magnificent
entertainments. The principal Elysians vied with each other in
the splendour and variety of the amusements which they offered
to the notice of their Queen. Operas, plays, balls and banquets
followed in dazzling succession. Proserpine who was almost
inexperienced in society, was quite fascinated. She regretted the
years she had wasted in her Sicilian solitude: and marvelled that
she could ever have looked forward with delight to a dull annual
visit to Olympus; she almost regretted that, for the sake of an
establishment, she could have been induced to cast her lot in
the regal gloom of Tartarus. Elysium exactly suited her.
Now that, in its way, is as neat as can be. You perceive at once
that the style is literary and controlled. Nor, even in the tumultuous
close of Vivian Grey, his first work, can you fail to perceive that,
though exuberant, it was at first controlled. He says:
I have too much presumed upon an attention which I am not

able to command. I am, as yet, but standing without the gate of
the garden of romance. True it is that, as I gaze through the ivory
bars of its golden portal I would fain believe that, following my
roving fancy, I might arrive at some green retreats hitherto
unexplored, and loiter among some leafy bowers where none
have lingered before me. But these expectations may be as vain
as those dreams of youth over which we have all mourned. The
disappointment of manhood succeeds to the delusions of youth:
let us hope that the heritage of old age is not despair.
Analyse that, and you will find it youthful, orientally luxuriant, but well
bridled, on the whole, to the cadence of good prose. Press your
analysis a little further, and you will detect the voice of a born
rhetorician even in its first sentence. Let me add but two words to it:
I have too much presumed, Mr. Speaker, upon an attention

which I am not able to command.
—and you have the House of Commons before you, with Peel and
Macaulay, Palmerston and Lord John Russell, listening. Even so
early his vocation can be detected as calling, enticing Disraeli away
from the stern discipline of letters to the easier success of rhetoric,
from the sessions of silent thought to the immediate response of an
auditory, whether in Parliament or at the foot of the hustings. As
even the noblest, most impassioned sentences of Cicero, addressed
to Senate or law-court, wear a somewhat artificial, attitudinising air to
us in comparison (say) with a colloquy of Socrates meditated and
colloquially reported by Plato, so, speaking as one who has recently
had to search for true prose, as we conceive it, among the speeches
of British orators, I promise but a thin harvest to the researcher: the
simple reason being that oratory plays to the moment, literature to
thoughts and emotions carried away, reconsidered, tested, approved
on second thought and in solitude. Not forgetting many purple
patches in Chatham, his son, Fox, Sheridan, Canning, Bright,
Lincoln, Gladstone and Disraeli himself, I yet assure you that
nowhere—save with the incomparable Burke—you will find great
gleaning on that many-acred field. And Burke, our glorious
exception, was “the dinner-bell of the House” when he rose to speak.
I fancy that the most of our legislators when lately seeking re-
election would have avoided a Burke—and wisely.
I shall have more to say of this before I conclude. For the
moment I am but concerned to point out to you that Parliamentary
practice laid a double trap for Disraeli as a writer: the first inherent in
that practice, the second a peculiar temptation for him.
“It is only by frequent and varied iteration,” says Herbert Spencer
somewhere, “that unfamiliar truths can be impressed upon reluctant
minds”: and who has ever served, for example, on a County Council
and not felt the iron of that truth penetrate his soul? How true must it
have been of a young man, brilliant but suspected, kept out of office
on suspicion, preaching a new creed not so much to the benches
opposite or into the necks of a distrustful ministry, but hammering it,
rather, upon the intelligence of supporters scarcely less distrustful
while infinitely more stupid! Can any conceivable task tempt more to
that redundancy which destroys a clean literary style?
Now for the man himself.—He was an Oriental and proud of it
(let Tancred, in particular, attest), of a race but lately admitted to the
House of Commons and, if for that reason only, challenged to display
himself in debate. With a courage perhaps unexampled in
Parliamentary story he let himself go, took the risk, triumphed. But
the dyer’s hand must inevitably acknowledge, sooner or later, its
trade. Now of all practitioners in English writing, a man of Oriental
mind and upbringing has to beware of this—that no Occidental
literature, since Greece taught it, will suffer ornament as an addition
superinduced upon style: and, after some experience, I put it quite
plainly—if harshly, yet seriously for his good—to any Indian student
who may be listening to these words—that extraneous ornament in
English is not only vapid, but ridiculous as the outpouring of a young
Persian lover who, unable equally by stress of passion and defect of
education to unburden his heart, betakes himself to a professional
letter-writer; who in his turn (in Newman’s words)—
dips the pen of desire into the ink of devotion and proceeds to
spread it over the page of desolation. Then the nightingale of
affection is heard to warble to the rose of loveliness while the
breeze of anxiety plays around the brow of expectation.
“That,” says Newman, “is what the Easterns are said to consider
fine writing”: and Disraeli, yielding to that Oriental temptation, will
give you, again and again, whole passages that might have been
hired, to depict the stateliest homes of England, from any
professional penman in any Eastern bazaar.
Speaking, in the Preface to Lothair, of his early work, Disraeli
himself admits that much of it (and Vivian Grey in particular) suffers
at least from affectation. “Books written by boys, which pretend to
give a picture of manners and to deal in knowledge of human nature,
must,” he says, “be affected. They can be, at the best, but the results
of imagination acting on knowledge not acquired by experience. Of
such circumstances exaggeration is a necessary consequence, and
false taste accompanies exaggeration.” Yes, but Lothair appeared in
1870, when its author had been Prime Minister, and had certainly
acquired by experience much knowledge of the world and human
nature: and the trouble is that in this very book the youthful
exaggeration not only persists but has exaggerated itself ten-fold,
that the Eastern flamboyancy is more flamboyant than ever. Take, for
example, the following description of the ducal breakfast-table at
Brentham—
The breakfast-room at Brentham was very bright. It opened

on a garden of its own, which at this season was so glowing, and
cultured into patterns so fanciful and finished, that it had the
resemblance of a vast mosaic. The walls of the chamber were
covered with bright drawings and sketches of our modern
masters and frames of interesting miniatures, and the meal was
served at half-a-dozen or more round tables which vied with
each other in grace and merriment....
—as well, one may pause to observe, as in rotundity. These half-a-

dozen or more round tables were
brilliant as a cluster of Greek or Italian republics.... After

breakfast the ladies retired to their morning room.
We have already been told what they did there—
One knitted a purse, another adorned a slipper, a third

emblazoned a page. Beautiful forms in counsel leant over
frames glowing with embroidery, while two fair sisters more
remote occasionally burst into melody, as they tried the
passages of a new air which had been communicated to them in
the manuscript of some devoted friend.
On the other hand
the gentlemen strolled to the stables, Lord St. Aldegonde lighting

a Manilla cheroot of enormous length. As Lothair was very fond
of horses, this delighted him.
—the cheroot, apparently.
The stables at Brentham were rather too far from the house,
but they were magnificent, and the stud worthy of them. It was
numerous and choice, and, above all, it was useful. It could
supply a readier number of capital riding horses than any stable
in England. [Advt.] Brentham was a great riding family. In the
summer season the Duke delighted to head a numerous troop,
penetrate far into the country, and scamper home to a nine
o’clock dinner. All the ladies of the house were fond and fine
horsewomen. The mount of one of these riding parties was
magical. The dames and damsels vaulted on their barbs and
genets and thorough-bred hacks with such airy majesty: they
were absolutely overwhelming with their bewildering habits and
bewitching hats.
Now, whatever else we say of that, it belongs—does it not?—to the

Arabian Nights rather than to English acres and the line of English
fiction. It is Bluebeard bewitching his guests—his next bride among
them—with a delicious fête-champêtre. Nay, can you not imagine our
poor English Duke gripping the back of his ducal head in the
endeavour to recognise himself as leader of this cavalcade? It
almost defies parody. Even Thackeray could but make fun of it, in
Codlingsby, by opposition of scene rather than by caricature of style;
by transferring the style merely and maliciously to an old clothes
shop in Holywell Street, as thus—
They entered a moderate-sized apartment—indeed Holywell

Street is not above a hundred yards long, and this chamber was
not more than half that length—and fitted up with the simple
taste of its owner.
The carpet was of white velvet—(laid over several webs of
Aubassun, Ispahan, and Axminster, so that your foot gave no
more sound as it trod upon the yielding plain than the shadow
did which followed you)—of white velvet painted with flowers,
arabesques and classic figures by Sir William Ross, J. M. W.
Turner, Mrs. Mee and Paul Delaroche, etc.
“Welcome to our snuggery, my Codlingsby. We are quieter
here than in the front of the house, and I wanted to show you a
picture.... That Murillo was pawned to my uncle by Marie
Antoinette.”
III
Disraeli’s style, in short, cried aloud for attack by critics who
hated him on other scores.
“Personal influences,” wrote he, “inevitably mingle in some

degree with such productions. There are critics who,
abstractedly, do not approve of successful books, particularly if
they have failed in the same style; social acquaintances also of
lettered taste, and especially contemporaries whose public life
has not exactly realised the vain dreams of their fussy existence,
would seize the accustomed opportunity of welcoming with
affected discrimination about nothing, and elaborate controversy
about trifles, the production of a friend: and there is always, both
in politics and literature, the race of the Dennises, the
Oldmixons, and Curls, who flatter themselves that by libelling
some eminent personage of their times, they have a chance of
descending to posterity.”
This sounds well enough, indeed. But in point of fact Disraeli has
a persistent habit of wrapping up his incomparable gift of irony in
language so detestably fustian that even a fair critic has to search
his periods carefully, separating the true from the sham. A fine ear
will separate them: but it needs a fine ear, and will tax it the most of
its time. All his life, in letters as in politics, he posed somewhat as a
Man of Mystery: and your Man of Mystery must take the rough with
the smooth: and your Cagliostro or even your honest merchant who
talks at once too floridly and too cleverly cannot blame any plain
auditor for suspecting that he talks, all the while, with his tongue in
his cheek.
It is a pity: for I do not see how any fair-minded reader of
Disraeli’s novels can fail to acknowledge, at this distance of time,
that the man was eminently serious, and in earnest, and wise even. I
spoke to you, a fortnight ago—at too great a length, you may think—
of the problem of industrial England and how the misery of the poor,
caught in its machinery, forced itself through the imaginative
sympathy of certain writers upon the national conscience: and
especially (you may remember) I spoke of the children because the
children won the battle. As Francis Thompson says, “The grim old
superstition was right. When man would build to a lasting finish, he
must found his building over a child.”
Well, I see no reason to doubt—no reason either in his writings
or his public action—that Disraeli’s concern over this industrial
misery was ever less than disinterested, sincere, even chivalrous.
No one can deny the sincerity, at least, of Sybil; no one the terrible
authenticity of its descriptive pages—such as the famous picture of a
gang emerging from a coal-mine: for research has shown that
throughout and almost sentence by sentence the author has been at
silent pains to document the almost incredible evidence of his own
eyes with evidence from Blue Books and Parliamentary Reports. I
shall not harrow your feelings by reading the passage, having
harrowed them (as I say) sufficiently a fortnight ago. But you may
take it for the moment—as you may amply satisfy yourselves by
enquiry later and at leisure—that the Inferno is faithfully depicted:
that the mill-owners Shuffle and Screw (Disraeli had a foible for such
names and for running them in double harness—you will recall those
celebrated duettists, Taper and Tadpole)—that the exactions of these
men were real exactions, that the sufferings of the handweaver
Warner and his starving family are sufferings that did actually break
actual human hearts and that even the upbringing of the factory
urchin Devilsdust is not only true to fact but typical. You may be
excused for doubting as you read how Devilsdust—so he came to be
called, for he had no legitimate name—“having survived a baby-farm
by toughness of constitution, and the weekly threepence ceasing on
his mother’s death,” was thrown out into the streets to starve or be
run over: how even this expedient failed—
The youngest and feeblest of the band of victims,

Juggernaut spared him to Moloch. All his companions were
disposed of. Three months’ play in the streets got rid of this
tender company....
You shudder as you read how the cholera visited the cellar
where he and other outcasts slept, until
—one night when he returned home he found the old woman
herself dead and surrounded only by corpses. The child before
this had slept on the same bed of straw with a corpse: but then
there were also breathing things for his companions. A night
passed only with corpses seemed to him itself a kind of death.
He stole out of the cellar, quitted the quarter of pestilence, and,
after much wandering, lay down at the door of a factory.
—where he was taken in, not from charity, but because a brat of five
was useful. Do you tell yourself that Disraeli exaggerates? Then turn
to Hansard and read that before Hanway’s Act the annual death-rate
among these pauper children was estimated at something between
60 and 70 per cent.: that this Act, as Howlett grimly put it, caused “a
deficiency of 2,100 burials a year”: that the London parishes by
custom claimed a right to dispose at will of all children of a person
receiving relief, and disposed of them to the manufacturers; and that
one Lancashire mill-owner agreed with a London parish to take one
3
idiot with every twenty sound children supplied.
3
The Town Labourer, 1760–1832, by Mr. and
Mrs. Hammond, p. 145. From Horner’s Speech,
Hansard, June 6, 1815.
IV
Man, as Aristotle tells us, is a political animal: and among
imaginative writers in the ’thirties and ’forties of the last century,
Disraeli had an eminently political mind. I say, “eminently,” because
in the years that followed the great struggle over the Reform Bill all
men’s eyes—eyes of advocates as of opponents—were turned on
this wonderful Reformed Parliament, awaiting some transformation
of our society, for good or for evil. The expectancy operated on
Disraeli as on the rest. He was a House of Commons man with his
ambition centred on success in that House. He did not believe that
this reformed House was in any way capable of producing a
millennium. With his own purpose very steadily set to advance his
career; with a sense of intrigue and a courage steadily sharpened by
disappointment; he perceived the nostrums of the new Parliament to
be nostrums no more honest than the old; as he perceived the
counteracting devices of his own party to be no more than delaying
devices devoid of principle. He hated the very name of “the
Conservative Party” invented by Croker:
I observe, indeed, a party in the State whose rule is to

consent to no change until it is clamorously called for, and then
instantly to yield; but these are Concessionary, not Conservative
principles. This party treats institutions as we do our pheasants,
they preserve but to destroy.
But he felt, with the feeling of England, that this evil of the factory
system demanded an instant redress only to be achieved by sharp
legislation: and, so far he was right. Ashley and his backers could
look nowhere but to Parliament for immediate cure. There happen
from time to time in the history of a nation (as sensible men must
admit) crises to which hasty methods must be applied, as you catch
up and spoil a valuable rug to smother an outbreak of fire.
V
We know how Disraeli, in those days, saw the full problem. Here
was a country, this England, divided into Two Nations, the rich and
the poor. Here were the nobles who should, by all devoir, be the
saviours of the State, standing by while the middle-class
manufacturer held the poor in misery; standing by while the authority
of the Crown diminished under steady depression by the Whigs;
standing by while Churchmen fought for preferment, neglecting the
oppressed, for whom—by every teaching of Christ—a true disciple is
a trustee. You all know, I doubt not, the main persons and principles
of the Young England party which rallied to Disraeli’s call. The men
were all younger than he; mostly of Eton and Cambridge—foremost
George Smythe, later Viscount Strangford, most brilliant of all, Lord
John Manners, Alexander Baillie Cochrane “the fiery and generous
Buckhurst” of Coningsby. All of them figure, under other names, in
Coningsby, and, while that novel is remembered, will be identified in
its pages; that is, long after human memory has ceased to care for
the personal romance of young men once so chivalrous and
admired—
The expectancy and rose of the fair state,

The glass of fashion and the mould of form.
But the tenets of this Young England party which gathered so

eagerly about the maturer man, Disraeli, were these, as you know:
the King stood over all, with his prerogative to be vindicated. His
rightful vindicators were our ancient nobility, and their task was to
exalt, to sustain him as protector of the poor, and so to restore the
peasantry of England (including its mill-hands, famished families,
pauper children) to the supposedly happy conditions once enjoyed in
the golden age of the monasteries, but forfeit under the oppression
of middle-class “industrialists,” as we should now term them. I find,
for my part, no real evidence of this golden age of the monasteries,
and suspect the glow they reputedly shed over a consented
medieval countryside to be very vastly enlarged by the mist of
romance. But whatever they might or might not have been, their
lethargy could never have matched, for evil, the active cruelty of the
new system. The monasteries were dead, anyhow: the mills and the
mines were grinding lives into death by tens of thousands under
men’s eyes. Disraeli knew how the bringing up of a Devilsdust turns
the grown man into a Chartist, and a danger. Disraeli understood
Chartists.
VI
In September, 1841, Peel (who owed it to him) refused Disraeli
office. We need not go into that tortuous story, or the rights of it this
way or that. The point for us is that his exclusion gave him leisure to
write Coningsby.
What were his qualifications, what his disqualifications in writing
Coningsby?
To begin with the disqualifications—(1) He had the haziest notion
of constructing a plot. From first to last he never gets beyond an
idea, and a string of episodes. (2) His hero is, for all his
recommendation, an invariable nincompoop, and his heroine (Sybil
particularly) not of flesh and blood: not even an embodiment of an
idea; a dream of it rather. Coningsby does very much less than
justice to Smythe, a man of failings and infinite wit; while in Lothair
you will pass whole pages in which the hero’s contribution to the
wisdom of the world amounts to “You don’t say so,” “I am more than
a little surprised,” “I have never looked into this matter upon which
Your Grace sheds for me, I confess, an entirely new light.” You may
say that the heroes and heroines of most Victorian novels are
puppets conducted through adversity to a chime of marriage bells.
But Disraeli deliberately presenting his heroes and heroines as
grandiose creatures of ineffable charm, has never the art to make
them justify this by what they do or say. Their golden, or raven, hair
hangs down their back, and there it ends. Lastly his prose lapses, as
the rhetorician’s hand becomes subdued to what it works in, into
sentences more and more slipshod: while fatuities abound, such as
the exclamation, at the beginning of a chapter, “What wonderful
things are events!”
So far the devil’s advocate.... But set against this, first and in
front of it, the great fact that an inventor is great not only because he
does a thing well, but because he could do it at all. Disraeli in
Coningsby invented the political novel: and I know nothing to
compare with that book unless it be his own Endymion in which so
touchingly an old man, dejected from political office and power,
seeks back with all his worldly wisdom, as one walking out into a
garden in a lunar light of memory, to recapture the rose of youth. Of
the trilogy—Coningsby, Sybil, Tancred—I confess, tracing it
backward, that I have small use for Tancred, having (be it confessed)
not only a stark insensibility to Disraeli’s enthusiasm for a mongrel
religion neither of his breed nor of mine, but a constitutional aversion
to the Lion of Judah considered as a pet. Sybil, in addition to its most
vivid pictures of the factory poor, has at least a score of pages which
no student of the art of writing in English can afford to neglect—take
for example its tour de force in exhibiting the rise of the Marney
family and the successive ennoblements of John Warren, club
waiter, and his progeny, through Sir John Warren, and Lord Fitz-
Warene, to Earl de Mowbray of Mowbray Castle. The juxtaposition of
the selfish and opulent Marney household with the wretched mines,
close by, from which they drew their wealth, is admirably managed.
But, as I have said, the heroine is but a shadowy figure, and I find
the hero little more lively: the pair of them “made for a purpose,” and
that purpose propaganda. No: Coningsby is the masterpiece: and
Peel’s refusal which led to its composition—Peel’s own fatal loss, as
it turned out—is our delightful gain. You will easily find, in almost any
period of our prose literature since Defoe, a more noble novel: and if
one goes back to early romance and thinks (say) of a page of Malory
—well, it rebukes the sensual rapture. But, for all that, I defy you to
find a more vivacious, a more scintillating book—scintillating with
joyful and irresistible malice. At the turn of any page you may
happen on such a gem as this:
Lord and Lady Gaverstock were also there, who never said
an unkind thing of anybody: her ladyship was pure as snow: but,
her mother having been divorced, she ever fancied she was
paying a kind of homage to her parent by visiting those who
might some day be in the same predicament.
It dares history, and will, for a whole chapter, recount the fall of a
Government, the passing of a Bill, the formation of a Cabinet,
unravelling actual intrigue, carrying you along by sheer logic as
though you galloped with Dumas’ Three Musketeers. Disraeli could
not invent a character: but he could at once disguise and reveal one
borrowed from life. In Coningsby he had actual men made to his
hands, to prompt the apotheosis or the caricature. He
sentimentalises his young friends, and the sense beneath the
sensibility may be read in the last paragraph of Sybil. What he could
do with an enemy let the portrait of Rigby attest.
VII
In Coningsby he invented the Political Novel. That this partus
masculus came so late to birth in our literature, as that it has
begotten few successors, admits (as Sir Thomas Browne would say)
no wide solution. Genius is rare, anyhow: the combination of political
with literary genius necessarily rarer. Given the two combined, as
they were in Burke, you still require, for superadding, the inventive
faculty, the mode, and the leisure. Not one man of letters in ten
thousand can match Disraeli’s close inner acquaintance with his
subject. Statesmen, in short, have not the leisure to write. Alcibiades
leaves no record of what Alcibiades did or suffered. By a glorious
fluke, Peel gave this chance and Disraeli took it.
VIII
For a last word to-day—
Quite apart from genuine coruscation of genius, and almost as
widely separating and casting from account that tinsel and
tawdriness which all can detect, one feels a mistrust (gnawing, as it
were, within our laurel) that even the best page of Disraeli does not
belong to us. We cannot match it somehow with a racy page of
Dryden, or of good Sir Walter Scott, of Izaak Walton, John Bunyan,
grave Clarendon, Bolingbroke. Gibbon is artificial enough, heaven
knows; yet somehow—and one remembers that he had served in the
Hampshire Militia—the scent of the hawthorn is never more afar than
a field away, even when he discourses of Tertullian or of Diocletian.
From Disraeli’s prose—or rather from my sense of it—I can never
dispel the smatch of burnt sandalwood, the smell of camels and the
bazaar. He officiates, somehow—he, a Prime Minister, over an altar
not ours—we admire the oracle, but its tongue is foreign.
Still his fame grows. I observe that, as the incense clears, each
successive study of him tells something better. He stands in politics
admittedly a champion; in literature, too, a figure certainly not among
the greatest, yet as certainly one of the great.

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Advances in heterocyclic chemistry 112 1st Edition

Advances in Heterocyclic Chemistry Volume 118 1st

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First edition 2017

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in Chapter 7. In the ﬁnal chapter, Johannes de Vries (Leibnitz Institute for

Chris Ramsden and Eric Scriven

The Evolving Landscape of

In vitro /in vivo activity

Figure 1 Major inﬂuencers of drug structures during the discovery process.

public and industrial collections to compliment compounds of natural and

3. RESULTS AND DISCUSSION

Figure 2 Percentage of ring containing molecules by substructure analysis.

Figure 3 Trends of ring containing compounds.

Figure 4 Transition metal catalyzed crosscoupling reactions.

the advent of palladium cross-coupling reactions (Figure 4) (2012AGE(51)

Figure 5 The rise of biaryls (Ar-Ar0 ).

Figure 6 The increasing presence of AreAr0 in drugs and drug candidates.

metal catalyzed cross-coupling. Concomitant with the rise of biaryls is the

Figure 7 Number of publications concerning palladium-catalyzed cross-coupling

Figure 8 Percentages of the major heterocyclic pharmacophores.

synthetic access of pyridines remains to be discerned in light of the ever

Figure 9 Relative ratios of heterocyclic pharmacophores at stages of development.

Actually, the percentage of NeN bond containing molecules has doubled

acids as coupling partners, and using a mild reaction condition compatible

decarbonylation of aromatic aldehydes, J. Am. Chem. Soc., 132(35),

Saturated Heterocycles with

Advances in Heterocyclic Chemistry, Volume 121

Keywords: Heterobicyclo systems; Medicinal chemistry; Monocyclic heterocycles;

2. RING SYSTEMS CONTAINING ONE HETEROATOM

conformation is adopted. The oxetane ring is sufﬁciently chemically inert to

Figure 2 A 3-substituted oxetane with neuroprotective properties.

type 1 protease (an aspartate protease) currently known, each sulfonamide

In a hybrid approach to generating new inhibitors of the tyrosine kinase

CC chemokine receptor-1 (CCR1) is a GPCR linked with progression

Figure 7 Antidiabetic and antibacterial tetrahydropyrans.

Compound 17 and some analogs inhibit bacterial type II topoisomerases

3. SPIROCYCLIC HETEROCYCLIC RING SYSTEMS

British industrial existence seems fast becoming one huge

Yes, denunciation has its uses: and public exposure is salutary,

—and at this time Leonard Horner, Inspector of Factories, reported

The singers have sung, and the builders have builded,

The next morning the Elysian world called to pay their

I have too much presumed upon an attention which I am not

I have too much presumed, Mr. Speaker, upon an attention

The breakfast-room at Brentham was very bright. It opened

—as well, one may pause to observe, as in rotundity. These half-a-

brilliant as a cluster of Greek or Italian republics.... After

We have already been told what they did there—

One knitted a purse, another adorned a slipper, a third

On the other hand

the gentlemen strolled to the stables, Lord St. Aldegonde lighting

—the cheroot, apparently.