Unifying principles for the design and evaluation of natural product-inspired compound collections

Abstract

Natural products play a major role in the discovery of novel bioactive compounds. In this regard, the synthesis of natural product-inspired and -derived analogues is an active field that is further developing. Several strategies and principles for the design of such compounds have been developed to streamline their access and synthesis. This perspective describes how individual strategies or their elements can be combined depending on the project goal. Illustrative examples are shown that demonstrate the blurred lines between approaches and how they can work in concert to discover new biologically active molecules. Lastly, a general set of guidelines for choosing an appropriate strategy combination for the specific purpose is presented.

Full text

Unifying principles for the design and evaluation of
natural product-inspired compound collections†
Frederik Simonsen Bro and Luca Laraia *
Natural products play a major role in the discovery of novel bioactive compounds. In this regard, the
synthesis of natural product-inspired and -derived analogues is an active field that is further developing.
Several strategies and principles for the design of such compounds have been developed to streamline
their access and synthesis. This perspective describes how individual strategies or their elements can be
combined depending on the project goal. Illustrative examples are shown that demonstrate the blurred
lines between approaches and how they can work in concert to discover new biologically active
molecules. Lastly, a general set of guidelines for choosing an appropriate strategy combination for the
specific purpose is presented.
Introduction
Natural products (NPs) are an important source of bioactive
small molecules. They have co-evolved with their biosynthetic
proteins, thus exploring biologically relevant chemical space
and encoding inherent biological relevance, as a result of their
ability to bind biomolecules and cross cell membranes. In
many, though not all, cases they have also evolved to be stable,
at least for the duration of their intended bioactivity. Conse-
quently, NPs were the rst examples of therapeutics. NPs, their
derivatives, and compounds inspired by them are and have
been the foundation of organic and medicinal chemistry and
play a major role in drug discovery.
1–8
Importantly, one third of
approved drugs since 1981 fall into one of these categories,
highlighting the historical and continuing impact of NPs in this
area.
9
Despite the obvious benets of NPs, there are limitations in
terms of drug discovery. Accessing natural products by isolation
or total synthesis (TS) can sometimes be laborious and involve
inefficient processes, while oen not delivering enough mate-
rial for biological evaluation and structure–activity relationship
Frederik Simonsen Bro
Frederik Simonsen Bro achieved
his BSc in chemistry at the
Technical University of Denmark
(DTU) in 2019 which included
a bachelor's project with Prof.
Robert Madsen working on iron-
catalysed dehydrogenation of
alcohols. In 2021 he completed
his MSc in chemistry at DTU
carrying out his master's project
with Assoc. Prof. Luca Laraia in
the synthesis of an alkaloid-
inspired library. Subsequently,
he carried out his PhD studies in
the same lab focussing on the development of inhibitors of sterol
transport proteins through synthesis of sterol-inspired libraries,
which he completed in 2024, and continued as a postdoctoral
researcher in the same group.
Luca Laraia
Luca Laraia received his MSci at
Imperial College London (2009)
before completing a PhD in
chemical biology at the Univer-
sity of Cambridge (2014). He
subsequently moved to the Max
Planck Institute of Molecular
Physiology as an Alexander von
Humboldt fellow and subse-
quently project leader, before
embarking on his independent
career at the Technical Univer-
sity of Denmark as an assistant
professor. Since 2021 he has
been an associate professor for chemical biology and medicinal
chemistry. His group's work lies at the interface of chemistry and
biology, including the synthesis of natural product-inspired
compounds and the study and modulation of sterol-mediated
processes.
Department of Chemistry, Technical University of Denmark, 2800, Kongens Lyngby,
Denmark. E-mail: luclar@kemi.dtu.dk
†Electronic supplementary information (ESI) available. See DOI:
https://doi.org/10.1039/d4sc08017c
Cite this: Chem. Sci.,2025,16, 2961
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Received 26th November 2024
Accepted 24th January 2025
DOI: 10.1039/d4sc08017c
rsc.li/chemical-science
© 2025 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2025,16, 2961–2979 | 2961
Chemical
Science
PERSPECTIVE

(SAR) analysis. The reasons for this are low concentration and
extraction from complex mixtures when isolating NPs from
natural sources, and (oen) multi-step and low yielding total
syntheses of NPs. Lastly, the selection criteria for nature are
different from the selection criteria in drug discovery. As such,
NPs have evolved for their producing organisms, not human
therapeutic applications.
5,7
Though NPs cover biologically rele-
vant chemical space, their restricted natural selection means
that they only cover a limited fraction of NP-like chemical
space.
10
Thus, the vast majority of biologically relevant, NP-like
chemical space remains to be explored. In fact, investigation of
the surrounding chemical space of an NP can be more bene-
cial than investigating the NP alone in terms of drug discovery.
2
Consequently, strategies to synthesise NP-derived and -inspired
compounds in a practical and efficient way are in demand to
navigate new NP-like chemical space and obtain highly bioac-
tive compounds that can serve as drug candidates or tool
compounds.
To meet the demand, several strategies to synthesise
compounds derived from or inspired by NPs have emerged.
Diversity-oriented synthesis (DOS)
11,12
focusses on characteris-
tics typical of NPs, including a high fraction of sp
3
-hybridised
carbons (Fsp
3
) and several stereogenic centres, but is not
necessarily based on an NP or NP scaffold. The similar
privileged-substructure-based DOS (pDOS)
13,14
is based on
a privileged scaffold with proven biological relevance that is not
necessarily derived from an NP. For DOS and pDOS, molecular
scaffold diversity is a key point, which is also the case for
activity-directed synthesis (ADS).
15,16
The compounds resulting
from the strategies including pseudo-natural product (PNP)
synthesis,
17,18
biology-oriented synthesis (BIOS),
19,20
function-
oriented synthesis (FOS),
21
and pharmacophore-directed retro-
synthesis (PDR)
22
are all based on NP fragments, scaffolds, or
pharmacophores. The total synthesis (TS) of NPs is guided by
target molecules (TMs). However, the focus on a single TM
limits the exploration of chemical space. This has been a driving
force for the establishment of synthetic approaches that inves-
tigate the chemical space surrounding a guiding NP, which
include complexity-to-diversity (CtD),
23
dynamic retrosynthetic
analysis (DRA),
2,24
diverted total synthesis (DTS),
25,26
two-phase
synthesis (TPS),
27
and analogue-oriented synthesis (AOS).
28
The recently described diverse PNP (dPNP) strategy
29
combines
PNP and DOS/CtD, and thus originates from NP fragments (see
Fig. S1–S13†for graphical illustrations, explanations and
examples of the individual strategies).
To navigate the plethora of approaches outlined above, we
have found it helpful to separate them based on the qualitative
similarity of the core frameworks generated to those found in
NPs,
30
as highlighted by some representative examples
(Fig. 1).
22,31–46
It is important to note that several quantitative
computational approaches for assessing NP-likeness have been
developed. For example, the NP-score uses the prevalence of
specic atom-centred fragments to compare NPs to fully
synthetic compounds.
47
The NP character of compound
Fig. 1 Continuum of qualitative similarity to NP frameworks of compounds designed via the different strategies with representative examples:
conventional synthesis (CS): paracetamol (1); focussed library synthesis (FLS): K00135 (2);
31
combinatorial library synthesis (CLS): 3;
32
diversity-
oriented synthesis (DOS): (R)-dosabulin (4);
33
privileged-substructure-based diversity-oriented synthesis (pDOS): 5;
34
diverse pseudo-natural
product (dPNP): (−)-asteroxin-1 (6);
35
pseudo-natural product (PNP): (+)-glupin (7);
36
biology-oriented synthesis (BIOS): 8;
37,38
function-oriented
synthesis (FOS): 9;
39
pharmacophore-directed retrosynthesis (PDR): 10;
22
complexity-to-diversity (CtD): ferroptocide (11);
40
dynamic retro-
synthetic analysis (DRA): (−)-O6C-20-nor-salA ((−)-12);
45,46
diverted total synthesis (DTS): cycloproparadicicol (13);
41,42
total synthesis (TS):
strychnine (14).
43,44
TOS =target-oriented synthesis.
2962 |Chem. Sci.,2025,16, 2961–2979 © 2025 The Author(s). Published by the Royal Society of Chemistry
Chemical Science Perspective

collections is a continuum between fully synthetic compounds
(no guiding NP) and unmodied NPs. Guided by retrosynthetic
analysis, fully synthetic drugs and libraries of drug candidates
can be synthesised by conventional synthesis (CS) and focussed
or targeted library synthesis (FLS), respectively, and NPs are
synthesised by TS.
48,49
These are examples of target-oriented
synthesis (TOS) which by denition lacks diversity due to the
single target approach. Nonetheless, diversity might arise for
FLS and TS when several targets are synthesised in the same
study. This is particularly evident for divergent approaches in
TS where a common intermediate is used in the synthesis of
several members of an NP compound class.
50
When a single
compound of interest is not known, combinatorial library
synthesis (CLS) provides quick access to many compounds.
However, although combinatorial libraries can afford
complexity giving the compounds slightly higher NP-character,
structural diversity is oen still limited.
51
Here it should be
noted that complexity alone does not guarantee bioactivity,
52
nor is it always a clear predictor of properties that would be of
interest to medicinal chemists, including solubility and oral
bioavailability.
53
Increased complexity has been correlated with
increased selectivity;
54
however, increased molecular weight
and lipophilicity both correlate with increased promiscuity.
55,56
As such, a careful balance of parameters should be targeted
when employing such metrics in library design strategies.
Overall, many ways to calculate complexity have been reported
and we refer the reader to recent publications for a more
detailed discussion and their application.
52,53,57,58
The increased focus on diversity and privileged scaffolds in
the DOS and pDOS strategies brings the resulting compounds
closer to NPs than combinatorial approaches. However, there is
no strict requirement for the compounds to be NP-like, and
design considerations are oen governed by the synthetic
accessibility of the resulting products. The privileged scaffolds
incorporated can also be fully synthetic in origin, providing key
differences to strategies delivering compounds with a higher
qualitative similarity to NPs. The PNP strategy is based on the
recombination of NP fragments, and as such the resulting
scaffolds are not typically found in NPs, even though their
constituent fragments are. This gives them a lower NP score,
according to the denition of Ertl et al.
47
BIOS is for the most
part based on actual NP scaffolds, thus bringing the resulting
analogues closer to NPs compared to DOS and PNP. Since
dPNPs are the result of different combinations of PNP and
diversication strategies, they are not necessarily NP scaffolds
and may thus be less likely to have frameworks found in NPs
than both PNP and BIOS-derived compounds. The FOS, PDR,
CtD, DRA, DTS, TPS, and AOS strategies can give compounds
that are very close to, or some distance from, actual NPs. For
example, a key difference of CtD to other strategies is the
frequent use of ring distortion reactions, which can sometimes
steer compounds far away from NPs in chemical space. While
being benecial in terms of targeting unexplored chemical
space, it carries an inherently greater degree of uncertainty as to
the utility of the resulting compounds in biological screens. It is
difficult to say which strategy provides compounds with greater
NP character, as the resemblance to the parent/guiding NP
varies from case to case, thus placing them somewhere in
between BIOS and TS.
It should be noted that the denitions of most strategies are
open to a degree of interpretation and oen overlap, making the
distinction between standalone strategies and umbrella terms
difficult. For example, CtD could be considered a subset of DOS
or its own strategy. Additionally, while TPS is rooted in TS, in
principle it can be applied to diversify natural product
skeletons/scaffolds. Lastly, DOS and FOS can be grouped
together with TOS as general umbrella terms.
59
In principle, any
strategy aiming for structural diversity in an efficient manner
could be described as DOS,
11,12
while any strategy that delivers
compounds which recapitulate or even enhance the activity of
a natural product through a simplied scaffold can be
described as FOS.
21,60,61
Despite this, principles for the design of
DOS and FOS libraries applied as standalone strategies have
been described, and representative examples are included in
Fig. 1. We view this exibility as an advantage in enabling
chemists to make bolder choices in their library syntheses.
Several excellent reviews and perspectives have been pub-
lished on the design of NP-inspired compound collections
using specic strategies and approaches.
2,4,5,7,18,24,62–67
These
showcase recent ndings, examples, and thoughts in the eld
relating to individual approaches. In this perspective, our goal
is to identify unifying principles across a range of library
synthesis approaches. We will highlight such principles with
appropriate case studies and make the argument that the
existing strategies for NP-inspired compound collections are
not necessarily mutually exclusive, but rather complementary,
with signicant benets existing from a more open approach by
combining strategies or elements from them according to the
project goal compared to the use of individual strategies in
isolation. The choice of strategies for prospective projects will
vary based on whether one seeks to develop new chemistry to
increase the chemical and biological diversity of a screening
collection, identify entirely new chemical matter for a target/
phenotype, or improve potency or other properties for
a ligand of a known target or phenotype. Therefore, we will also
develop guidelines for assessing which combination of design
strategies is most benecial based on the project goal.
Current approaches: different or
complementary?
The different approaches and strategies outlined so far have
developed as a consequence of different project goals and
information available at the project outset. Key considerations
include the availability of target or phenotype information, as
well as the availability of known ligands, and particularly NPs,
as starting points for design. However, the common denomi-
nator for all the approaches and strategies is the use of NPs
themselves or their characteristics to develop and identify
bioactive molecules, whether this is in a targeted or completely
unbiased approach. The need for well-dened strategies and
the differentiation between them provides theoretical frame-
works that simplify and structure a project, ideally allowing fast
© 2025 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2025,16, 2961–2979 | 2963
Perspective Chemical Science

access to desired compounds. Differentiation between strate-
gies should thus make it easier to nd the right approach for
a specic project goal. However, we have found that in many
cases the approach ultimately used by research groups implic-
itly combines components from several different strategies
under a larger “umbrella”approach, even though the initial
strategy was presented as a single dened approach. More
recently, research groups including our own have explicitly
targeted the combination of strategies for specic applications.
To highlight how various approaches work well together and
have more similarities than differences, we have chosen illus-
trative examples based on different combinations of strategies
and the outcomes they present. We have chosen to structure the
initial discussion based on chemical strategies, rather than
biological outcome, with the latter being addressed in a subse-
quent section (vide infra). In this regard, the synthesis of six
alkaloid-inspired libraries (Scheme 1)
68
highlights the use of
multiple strategies. These include the synthesis of nicotine (19)
analogues (16 and 17) and spirocyclic analogues (24) containing
a benzylic-substituted pyrrolidine as found in anisomycin (20)
using a complexity-generating Pd-catalysed aminoarylation
reaction starting from 15 or 23. Following tert-butyloxycarbonyl
(Boc) deprotection of 16, compounds 17 could undergo
different diversication reactions to access additional
analogues including sulfonamide 18. In a similar fashion, 24
could also be diversied into additional analogues such as
sulfonamide 25. In terms of synthetic design, this can be clas-
sied as substrate-based DOS. However, the simplied nicotine
analogues could be considered as BIOS analogues and the
pyrrolidine analogues as PNP (anisomycin fragment) or pDOS
(pyrrolidine as a privileged scaffold).
69
The analogues could be
further diversied using traditional diversication methodolo-
gies. Similarly, the authors also diversied the horsline (21)
scaffold 26 using Ullmann–Goldberg cross-coupling to give 27.
Scheme 1 Synthesis of alkaloid-inspired compounds.
68
DIPEA =N,N-diisopropylethylamine, DMEDA =N,N0-dimethylethylenediamine, DPE-
Phos =bis[(2-diphenylphosphino)phenyl]ether, PMP =p-methoxyphenyl, TBTU =N,N,N0,N0-tetramethyl-O-(benzotriazol-1-yl)uronium
tetrafluoroborate.
2964 |Chem. Sci.,2025,16,2961–2979 © 2025 The Author(s). Published by the Royal Society of Chemistry
Chemical Science Perspective

Following benzyl deprotection, 28 could then undergo either
reductive amination affording 29 or urea formation to give
carbamide (30). This shares ideas from PNP and BIOS by using
the horsline scaffold as a starting point for analogue synthesis.
Furthermore, applying different reagents from 28 to generate
different analogues could be classed as reagent-based DOS. The
last example using the daphnezomine M (22)-like scaffold 31
also used the reagent-based DOS line of thought. Reductive
amination afforded 32, amide coupling afforded 33, and the
reaction with isocyanate afforded carbamide 34. In total, six
different libraries with different scaffolds were synthesised.
Overall, this elegantly demonstrates substrate- and reagent-
based DOS with the incorporation of ideas from BIOS and
PNP using alkaloid scaffolds to enhance biological relevance.
Similar published work also shares the idea of a complexity-
generating reaction followed by diversity focused reactions in
a reagent-based DOS fashion.
54,55
Focus on diversity is also a key
point in activity-directed synthesis, where chemical space is
explored by using reactions with multiple and diverse possible
outcomes.
15,16
The overall idea of generating diversity from
a single substrate is embedded in CtD as well, where NPs with
(preferably many) diversication vectors are used to create NP-
derived analogues using ring distortion, ring formation, and
diversication reactions. CtD limits itself to NPs that are not the
end point, but rather are complex starting points that can be
diversied.
23
Thus, CtD could be seen as an example of reagent-
based DOS on NPs, where simply by modifying the reagents one
can access signicant scaffold diversity. The idea of creating
diversity from a complex starting material is thus found in both
CtD and in work not related to an actual NP that could conse-
quently be viewed as “CtD on non-NPs”. For example, pDOS has
been combined with CtD by using ring distortion and ring
formation to form diverse medium/macro- and bridged
heterocyclic compounds containing the privileged scaffold
pyrimidine.
70
Employing an NP as a starting point for complexity works
well conceptually with other strategies. For example, fragment-
sized NPs like the cinchona alkaloids quinine and quinidine
can work well in DOS, BIOS, or PNP campaigns.
71
Signicant
effort has been made to make quinine-derived analogues
Scheme 2 Synthesis of quinine- and quinidine-inspired compounds
73,80
and identification of the autophagy inducer, tantalosin-1 (39),
77,78
and
autophagy inhibitor, azaquindole-1 (41a).
79
DABCO =1,4-diazabicyclo[2.2.2]octane. DCC =N,N0-dicyclohexylcarbodiimide, DMAP =4-dime-
thylaminopyridine, Mes =mesityl.
© 2025 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2025,16, 2961–2979 | 2965
Perspective Chemical Science

(“quinalogs”
72
) using different strategies (Scheme 2). Diverse
and complex macrocycles can be accessed directly from quinine
using a combination of CtD and DOS strategies,
73
which are
both useful strategies in the synthesis of diverse macrocycles.
74
Initially, quinine (35) is functionalised with terminal alkene-
containing linkers via Steglich esterication to give esters 36
which were then cyclised to form the quinine macrocycles 37
using ring-closing metathesis (RCM). Four other macrocycles
were also accessed from other quinine-derived building blocks.
This approach has a strong resemblance to the build/couple/
pair (B/C/P) strategy: “building”quinine building blocks,
intermolecular “coupling”with other functionalised building
blocks, and intramolecular “pairing”of the functional groups to
form the macrocycles. Macrocycles remain a desired moiety
since they have proven to be a privileged class of molecules for
modulating challenging targets such as protein–protein inter-
actions in drug discovery.
75,76
In this context, a complex quini-
dine (38)-inspired 20-membered macrocycle, tantalosin-I (39),
that induced autophagy by induction of microtubule-associated
protein 1A/1B light chain 3 (LC3) lipidation through disruption
of a particular part of the endosomal sorting complexes
required for transport (ESCRT) called the IST1-CHMP1B
complex was recently reported.
77,78
Additional work showed
how you could use the relatively small NPs quinine and quini-
dine in a PNP setting.
79,80
The NPs were initially transformed to
the corresponding ketones 40 in two steps by Rh-catalysed
isomerisation of the terminal alkene to the internal alkene
followed by a Malaprade–Lemieux–Johnson oxidation. Ketones
are a strategic functional group in the synthesis of NP-inspired
compounds since they serve as a suitable coupling partner for
fusion with other scaffolds.
81
They reported the synthesis of
edge-fused indoles and azaindoles 41 from quinine and quini-
dine via a one-pot imine condensation and a Hegedus–Mori–
Heck reaction. This led to the identication of an autophagy
and lipid kinase VPS34 inhibitor, azaquindole-1 (41a). More-
over, the spiro-fused chromanones 42 were accessed through
a Kabbe reaction. Thus, different PNPs could be accessed
simply by changing the reagents, the principle of reagent-based
DOS. In this work there was no specic biological target in mind
and the compounds were screened phenotypically. Importantly,
tantalosin-I (39) and azaquindole-1 (41a) show different bioac-
tivity to each other and to the parent NP, highlighting the value
of diversifying a relatively large building block, the cinchona
alkaloid framework. All the analogues in Scheme 2 come from
a synthetically easily accessible quinine- or quinidine-scaffold,
thus having a resemblance to BIOS-derived compounds. This
shows how the different strategies can overlap in a benecial
way. Another great example of this is the work on indo-
tropanes.
82
It can be seen as a BIOS library
20,83
but also shares
ideas from the PNP strategy.
84
Whether you dene it as one or
the other, the nal outcome was the identication of a novel
class of hedgehog-signalling inhibitors and the myosin light
chain kinase 1 (MLCK1) inhibitor, myokinasib.
Similarly, in addition to the abovementioned cinchona
alkaloids, stemona-inspired compounds have also been tar-
geted using diverse strategies (Scheme 3).
85–87
This work is
Scheme 3 Synthesis of stemona-inspired compounds and identification of 2-HT
1A
ligand 48a and s
1
R and s
2
R ligand 51a.
85–87
L-selectride® =
lithium tri-sec-butylborohydride, PS-PPh
3
=polystyrene bound triphenyl phosphine.
2966 |Chem. Sci.,2025,16, 2961–2979 © 2025 The Author(s). Published by the Royal Society of Chemistry
Chemical Science Perspective

particularly interesting as it can be considered an early example
of the PNP strategy before it was formally dened, with
elements from BIOS and (p)DOS. Here, the core scaffolds con-
taining a strategic ketone are synthesised from scratch and not
derived from an NP as above. Firstly, a Lewis acid-catalysed
Diels–Alder reaction between diene 43 and dienophile 44
afforded the bicyclic azido diketones 45 which could undergo
a Schmidt reaction by further treatment with a Lewis acid.
Careful choice of Lewis acid and its equivalents allowed for the
tandem Diels–Alder/Schmidt reaction to go all the way to the
tricycle. Epimerisation with base of the alkyl group of the dia-
stereoisomeric mixture of a-alkylated tricyclic ketones afforded
the thermodynamically favoured b-alkyl stemona scaffold 46.
This could then be subjected to a reductive Friedl¨
ander quin-
oline synthesis to afford edge-fused quinoline-analogues 47 in
a PNP-fashion. By denition the PNP approach only allows the
fusion of NP fragments. However, fusion with privileged scaf-
folds not found in NPs, as implied in the pDOS approach, to
access a large number of scaffold combinations, can enable the
identication of compounds that modulate diverse targets and
processes in a selective way. Even though this work predates the
PNP concept, this line of thought can be seen in the access of
the spiro-fused 3,4-dihydroquinoxalines 48, a privileged scaf-
fold, via a multicomponent reaction (MCR) with o-phenyl-
enediamines, the ketone 46, and isocyanides.
88
The 3,4-
dihydroquinoxaline 48a was found to have a binding affinity
(inhibitory constant (K
i
)) of 431 nM to the 5-hydroxytryptamine
(serotonin) 1A receptor (5-HT
1A
). Furthermore, subjecting PNPs
to general synthetic diversication strategies as in DOS can give
access to even more diverse and biologically relevant
compounds. This idea is visible in the synthesis of the carba-
mates 49, which is an important structural motif in medicinal
chemistry.
89
The ketone 46 was diastereoselectively reduced
with L-selectride® to give an alcohol which was then reacted
with isocyanates to give the carbamates 49. Other analogues
were accessed from another tricyclic ketone 50, synthesised
from 46 via an aza-Wittig reaction. The tricyclic ketone scaffold
50 is not found in NPs, but it is NP-like in terms of complexity.
From this ketone, reductive amination yielded the tertiary
amines 51 where analogue 51a showed a K
i
of 2 nM to the
sigma-1 receptor (s
1
R) and 175 nM to the sigma-2 receptor
(s
2
R). Several other analogues with different functionalities
were also accessed and in total the library consisted of 104
stemona analogues. Using the tricyclic core of stemona alka-
loids in the synthesis shares a lot of ideas from BIOS. In addi-
tion, some similarity to reagent-based DOS is obvious since the
analogues are derived from two core ketone scaffolds by
changing reagents and conditions. One may even classify this
example as an exhaustive DTS identifying 46 as the advanced
intermediate. In fact, 46 has been used in a TS en route to the
stemona alkaloid neostenine (52).
90
Our own work on a tropane- and quinuclidine alkaloid-
inspired compound collection
91
is conceptually similar to the
above. Using the commercially available quinuclidine scaffold
Scheme 4 Synthesis of tropane- and quinuclidine alkaloid-inspired compounds and identification of dual 2-HT
2B/C
antagonist (S)-SCQ1 (54a).
91
TMS =trimethylsilyl.
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53 and tropane scaffold 57 several scaffold fusions could be
carried out, again taking advantage of a reactive ketone (Scheme
4). Using the Kabbe reaction, the spirochromanones 54 and 58
could be accessed. The spirochromanone-quinuclidine
analogue 54a was identied as a selective dual serotonin 2B
(5-HT
2B
) and 2C receptor (5-HT
2C
) antagonist which was termed
(S)-SCQ1. Chromanone-tropane 58 could be further diversied
condensing with 2-aminobenzamide to give spirocyclic 2,3-
dihydroquinazolinone 60. From the quinuclidine ketone 53, the
Pictet–Spengler reaction afforded the spiro-fused tetrahydro-b-
carboline (tryptoline) 55. Additionally, the spirophthalides 56
were accessed from 2-bromobenzoic acid in a three-step
sequence going through a lithium–halogen exchange, nucleo-
philic attack, and intramolecular Fischer esterication. Lastly,
the tropane 57 could be converted to the N-tosylhydrazone
which could participate in a 1,3-dipolar (3 + 2) cycloaddition
with chalcone to give the spiropyrazoline 61, a privileged scaf-
fold. The total number of analogues was 58 including six
additional other scaffolds not presented here. The overall
strategy was presented as a mixture of PNP and DOS (reagent-
based); however, the use of privileged scaffolds and core alka-
loid skeletons makes the resemblance to pDOS and BIOS
striking. Together with the aforementioned stemona alkaloid
library, this is a representative example of the construction of
compound libraries with specic target(s) in mind. This
contrasts with the phenotypic screening approach as described
in the synthesis of, for example, the “quinalogs”.
As illustrated above, the incorporation of privileged scaffolds
and diversity-generating strategies ((p)DOS) into a PNP
approach can be very benecial. Our recent work
92
is an example
of the PNP strategy where privileged scaffolds are introduced to
access additional scaffolds. By the fusion of a trans-decalin
sterol scaffold with several NP scaffolds and “unnatural”privi-
leged scaffolds, a range of sterol-inspired analogues was syn-
thesised (Scheme 5). The ketone 62 was synthesised as a key
precursor containing the trans-sterol scaffold. The Fischer
indole synthesis afforded the indoles 64. Furthermore, the
quinoline-fused analogues 65 could be synthesised following
a microwave irradiation (MWI) assisted Friedl¨
ander quinoline
synthesis. Via the a-bromoketone 66, the imidazothiadiazoles
67 were isolated. The Pinner pyrimidone synthesis yielded the
analogues 69 from the b-ketoester 68. Lastly, the b-ketoaldehyde
70 was used in a Knorr pyrazole synthesis affording 71.In
addition, nine other scaffolds were accessed affording 65 sterol-
inspired compounds in total. The pyrazole-fused analogues led
to the identication of the potent and selective Aster-C inhib-
itor, (–)-astercin-1 (71a). Interestingly, the active enantiomer has
the “unnatural”AB-ring stereochemistry. This indicated the
importance of synthesising the library as racemic mixtures from
the beginning. This is important for libraries where the goal is
Scheme 5 Synthesis of sterol-inspired compounds and identification of Aster-C inhibitor (–)-astercin-1 (71a).
92
DIPEA =N,N-diisopropyle-
thylamine, MEM =2-methoxyethoxymethyl.
2968 |Chem. Sci.,2025,16, 2961–2979 © 2025 The Author(s). Published by the Royal Society of Chemistry
Chemical Science Perspective

biological, as well as chemical, diversity, as this is more likely to
be obtained by doubling the total number of compounds and
probing enantiomeric differences. This is relevant for libraries
where analogues are derived from scaffolds that are synthesised
de novo in contrast to analogues derived from an NP source
directly, since the majority of NPs are naturally produced as
single enantiomers.
Following the trans-decalin sterol-inspired library, we
decided to target a cis-decalin sterol-inspired compound
collection,
35
the reasoning being that compound libraries with
diverse diastereochemical attributes can result in diverse bio-
logical proles and different biological activity.
93,94
In addition
to similar edge-fused analogues targeted in the trans-decalin
library, additional analogues were targeted using the CtD
strategy. In this context, there is no reason why the CtD strategy
should be limited to NPs.
95–97
NP fragments or NP-inspired
compounds that are accessible in sufficient quantities are also
excellent substrates for the ring distortion reactions used in the
CtD approach. Indoles have proven to be useful scaffolds for the
CtD strategy.
98–102
Thus, we employed a ring distortion strategy
on the PNPs to access dPNPs (Scheme 6). The cis-fused decalone
72 was synthesised and used as the primary sterol scaffold. The
indoles 73 were accessed by the Fischer indole synthesis in
a similar manner to the trans-fused library. The indoles could be
ring-expanded to afford the ketolactams 74 in a Witkop oxida-
tion. The resulting ketolactams could be ring-contracted upon
treating with base yielding 75 though the Camps quinolone
synthesis. Oxidative ring dearomatisation of the indoles gave
the 3-hydroxyindolenines 76. The ring contraction through an
oxidative rearrangement of the indoles afforded spiro-
pseudoindoxyl 77. The spirooxepinoindoles 78 were obtained by
adifferent oxidative ring contraction in tandem with an intra-
molecular ring-forming condensation. The cis-fused sterol-
inspired library consisted of 69 compounds in total. The
morpholine-substituted spirooxepinoindole (–)-asteroxin-1 (6)
was identied as a potent and selective Aster-A inhibitor. Again,
the active enantiomer featured the unnatural stereochemistry at
the AB-fusion, though one can argue that the resulting scaffold
scarcely resembles a steroid in structure, while retaining its
bioactivity features. In this case, modifying the oxidants affor-
ded a range of diverse scaffolds from a PNP, where one could
argue that the CtD component of the library is an example of
reagent-based DOS. Importantly, the work on trans- and cis-
fused sterol-inspired compounds is another example of a target-
based screening campaign, where biological diversity was
sought within a specic class of proteins, rather than across the
whole proteome.
In addition to our own work, several other research groups
have also combined PNPs with diversity strategies (DOS) and
ring distortion (CtD) in an explicit manner.
29,103,104
In this
context dPNPs were rst dened as the combination of PNP and
DOS/CtD giving compound collections that incorporate both
biological relevance and scaffold diversity.
29
In this work
(Scheme 7), the indoles 79 underwent photocatalysed ring
rearrangement to give pseudoindoxyls 80. These products could
be fused to give 81 through an intramolecular Buchwald–
Hartwig cross-coupling. The starting indoles 79 could also be
subjected to a Pd-catalysed carbonylation/intramolecular indole
dearomatisation cascade to give the ring-spiro-fused indoly-
lindanones 82. The analogue 82a was identied as an inhibitor
of Hedgehog (Hh) signalling. The analogues 82 could be further
diversied by ring-edge-fusion to give indoline-indanone-
isoquinolines 83 via a combined Pd-catalysed arylation and
amidation. Additionally, reduction of the indolenine function-
ality in 82 afforded the spiro-indoline-indanones 84 with high
diastereoselectivity. Further diversication of this class was
achieved by substitution at the nitrogen using different halides
to give 85. A number of other compound classes were produced
to afford a compound collection of 154 analogues in total. This
work is a good example of using diversity strategies from DOS
(here B/C/P in particular) to make diverse scaffolds which by
design fall under the category of PNPs. Thus, the diversity is
Scheme 6 Synthesis of sterol-inspired compounds and identification of Aster-A inhibitor (–)-asteroxin-1 (6).
35
Oxone® =KHSO
5
$0.5KHSO
4
-
$0.5K
2
SO
4
, NBS =N-bromosuccinimide, NCS =N-chlorosuccinimide.
© 2025 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2025,16, 2961–2979 | 2969
Perspective Chemical Science

introduced in the design of the PNPs. This is slightly different
from the work on (–)-asteroxin-1 where the diversity is intro-
duced to the resulting PNPs via ring distortions aerwards and
not directly into the design of the initial PNPs.
As shown above, taking certain elements from NPs to
generate NP-inspired compounds can certainly result in bio-
logically relevant compounds. Nevertheless, the actual TS of
NPs and their simplied derivatives has long been used to
access bioactive compounds and generate SAR information
about a certain pharmacologically active NP. However, while
benecial, important areas of chemical space may be missed
due to synthetic limitations.
64
Alongside the strategies focused
on generating a wide range of structurally different analogues,
modern pragmatic takes on TS such as DTS, FOS, DRA, and PDR
have also developed in order to streamline the process of
investigating the chemical space surrounding an NP. These
share important similarities with other strategies, especially
BIOS. Recent work presents the synthesis of salvinorin A (salA)
analogues using DRA to explore the chemical space around this
NP (Scheme 8).
45,46,105
SalA is a potent k-opioid receptor agonist.
However, its TS has been troublesome due to its complexity and
instability which in turn have also made exploration of the
chemical space around it and SAR studies difficult. The NP was
treated as a dynamic TM to reduce synthetic complexity while
retaining molecular complexity. This led to the realisation that
a rational removal of the C20 methyl would ease the synthesis
and stabilise the resulting compounds. The goal of easing the
synthesis of the NP is also a key point in FOS and PDR. Addi-
tionally, the authors used molecular docking (another key
attribute in FOS) to evaluate 20-nor-salvinorin A, which sug-
gested that it would have similar binding to salA. Thus, they
synthesised the common intermediate 87 in eight steps from
Hagemann's ester (86) which could be diversied in a DTS-
fashion through a Heck reaction followed by lactonisation to
afford the rst generation of salA analogues 88 which were more
stable than salA. More importantly, the analogue (±)-20-nor-
salA (88a) showed similar potency and selectivity. They then
synthesised (±)-O6C-20-nor-salA ((±)-12)inve steps from 87
and identied that replacement of the O6 with a carbon further
stabilised the compound while retaining the potency and
selectivity. They then developed an asymmetric synthesis of 12
starting from (+)-89 which could be synthesised with a 99%
enantiomeric excess (ee). From (+)-89 the common intermediate
90 was accessed in ve steps. This intermediate was diversied
by a Hayashi conjugate addition to give the second generation
of salA analogues 91 including the enantioenriched (–)-12.
Further diversication of the second vector, the ketone, allowed
for synthesis of oximes and alcohols (92) through condensation
and nucleophilic addition/reduction, respectively. Conse-
quently, a salA analogue with improved potency (92a) was
identied. Lastly, ring expansion of 91 in a CtD-manner through
the Beckmann rearrangement and Baeyer–Villiger oxidation
afforded the corresponding lactam or lactone (93), respectively.
This second generation of salA analogues allowed for further
SAR study and exploration of the salA chemical space through
a common and diversiable intermediate similar to DTS and
AOS. In addition, some of the added functionalities are NP
fragments or privileged scaffolds showing some resemblance to
PNP and BIOS in this diversication step. In total, ve rst
generation and 29 second generation salA analogues were
synthesised.
Scheme 7 Synthesis of dPNPs and identification of Hh signalling inhibitor 82a.
29
CFL =compact fluorescent lamp, Eosin Y=2-(2,4,5,7-tet-
rabromo-6-oxido-3-oxo-3H-xanthen-9-yl)benzoate, Hantzsch ester =diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, PPTS =
pyridinium p-toluenesulfonate, Xantphos =(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane).
2970 |Chem. Sci.,2025,16,2961–2979 © 2025 The Author(s). Published by the Royal Society of Chemistry
Chemical Science Perspective

In recent work methyl deletion is also used in a FOS of 26-
nor-germanicol (94) and 26-nor-lupeol (95) (Scheme 9).
106
Here
the methyl is removed to remove the synthetically difficult
vicinal quaternary stereogenic centre from the synthesis. The
authors speculated that the biological function of lupeol and
germanicol would be retained in the nor-derivatives. They
desired to reduce synthetic complexity while retaining function
which is very similar to ideas of DRA and PDR. Initially, the
common intermediate 96 was synthesised which allowed access
to the germanicol analogue, 26-nor-germanicol (94), in six steps
and the lupeol analogue, 26-nor-lupeol (95), in 12 steps overall.
The synthesis of 95 went through 97 (six steps from 96) and 98
(four steps from 97) which was converted into 95 in two steps.
Unfortunately, biological screening of the 26-nor analogues 94
and 95 was not feasible due to dimethyl sulfoxide (DMSO)
solubility issues. Interestingly, screening the intermediates en
route to the TMs, similar to the PDR, led to the identication of
two substituted unnatural ent-estranes as androgen receptor
(AR) antagonists with similar (98) and enhanced (97) potency
compared to lupeol. Thus, these less structurally complex
intermediates retain or improve function. The late intermediate
96 allows for the synthesis of other 26-nor analogues similar to
a DTS approach to further gain SAR information.
The work on latrunculin analogues
107
should also be
mentioned. In this work, the authors simplify and streamline
the synthesis including yet another methyl deletion. They
identify a simplied analogue that shares similar actin-biding
properties to the most active member of the latrunculin
family. The work is presented as a DTS but ideas from FOS,
DRA, PDA, and even BIOS are easy to identify. The research on
analogues of sinularia NPs
108
led to the identication of new
compounds with interesting cytotoxicities and selectivities
against cancer cell lines. The compounds contain the tricyclic
cores as found in sinularia NPs but in general less complex, and
one of the compounds could serve as a useful intermediate
towards additional analogues. The work is published as an
example of PDR, but again it shares a lot of similarities to DTS,
AOS, FOS, PDA, and BIOS.
The majority of examples outlined so far focus on terpenes
and alkaloids as guiding NP targets for library synthesis.
However, polyketides and more specically polyether iono-
phores (PEIs) have received considerably less attention. This is
most likely in large part due to the absence of a bioactivity-
dening scaffold, requiring larger synthetic efforts to
approach NP complexity. Recent work has addressed this
challenge by deconstructing natural PEIs to smaller fragments
and reconstructing them in new ways to create structural
Scheme 8 Synthesis of salvinorin A analogues and identification of multiple KOR agonists.
45,46,105
BenzP*=1,2-bis(tert-butylmethylphosphino)
benzene, BINAP =2,20-bis(diphenylphosphino)-1,10-binaphthyl, COD =1,5- cyclooctadiene, QuinoxP*=2,3-bis(tert-butylmethylphosphino)
quinoxaline, (S)-Trifer =1,10-bis{1-[(R)-ferrocenyl-2-(S)-ethyl-1-(diethylamino)phenyl]-(R)-phosphino}ferrocene, XPhos =dicyclohexyl[20,40,60-
tris(propan-2-yl)[1,10- biphenyl]-2-yl]phosphane.
© 2025 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2025,16, 2961–2979 | 2971
Perspective Chemical Science

diversity and access so-called “hybrid polyethers”.
109
With this
structural optimisation they retain the antibacterial activity
found in the natural PEIs but achieve improved antibacterial
selectivity (Scheme 10). The lasalocid acid fragment 99 was
obtained from commercially available lasalocid. Using slightly
different conditions, the Z-triethylsilyl (TES) enol ether 100 and
a mixture of E-(1000) and Z-TES enol ether (2.3 : 1 E/Z) were ob-
tained. Then Mukaiyama aldol addition to the synthesised
nonthmicin and ecteinamycin fragment 101 yielded the anti
(102)orsyn (1020) product depending on the starting material.
Then silyl deprotection and ester hydrolysis afforded 103.
Through DCC-activation of the carboxylic acid, it was coupled to
fragment 104 which is proposed to be the group responsible for
cation binding in certain polyether ionophores. This yielded the
nal hybrid polyethers 105 and the new potent and selective
antibiotic 105a. This is an excellent example of streamlining the
synthesis for efficient diversication and investigation of the
chemical space and biology related to the NPs, key arguments in
FOS, DRA, and PDR. The use of coupling of NP fragments and
fragments with a known biological function have strong
resemblance to PNP and BIOS.
The described examples show the benet of rational changes
to the retrosynthetic analysis and/or synthesis to reduce
synthetic complexity while maintaining structural complexity
and biological function (FOS/DRA/PDR) coupled with diversity
methodologies to make analogues of the NP (DTS/AOS/DOS) in
Scheme 9 Synthesis of 26-nor-germanicol (94) and 26-nor-lupeol (95) and identification of AR antagonists 97 and 98.
106
Scheme 10 Synthesis of “hybrid polyethers”and identification of the potent and selective antibiotic 105a.
109
FCC =flash column chromatog-
raphy, DCC =N,N0-dicyclohexylcarbodiimide, DMAP =4-dimethylaminopyridine, MIC =minimum inhibitory concentration.
2972 |Chem. Sci.,2025,16,2961–2979 © 2025 The Author(s). Published by the Royal Society of Chemistry
Chemical Science Perspective

the pursuit of “supernatural products”.
110,111
The examples also
illustrate how the boundaries between the different synthetic
strategies can be blurred or even broken down, and that this is
more likely to be a benet than a problem. In terms of biological
screening, the majority are target-based and inuenced by the
known bioactivity of the guiding/parent NP since they are
screened against the targets known for the guiding NP.
However, compound collections may also be made to target
a biological phenotype with multiple associated targets or used
across various target classes and phenotypes altogether.
Therefore, the choice of chemical starting point(s) and synthetic
strategies must be carefully considered.
Targeted combination of approaches
for a specific project goal?
To conclude the perspective, we have chosen to provide
a prospective view to aid researchers seeking to design a strategy
for their specic goal, whether this be a target- or phenotype-
based screen, or a synthetic chemistry campaign aimed at
broad coverage of chemical and biological space. In this context
we concur with Shenvi's assertion that the “purpose dictates
strategy”.
7
We have outlined a generalised approach based on
aow chart to ask researchers to consider the project goal and
the information available to them at the start, when choosing
individual strategies or a combination thereof (Fig. 2).
For example, if the desired outcome is a ligand for a specic
target, one must determine whether the target has any known
ligands. If that is the case, then the ligand(s) can be broken
down into one or two primary scaffolds or fragments with
functionalisable handles. Then, the chemical diversity localised
around the primary scaffold/fragment should be targeted. This
can be achieved by general diversity-generating approaches like
(p)DOS and/or fusion with relevant scaffolds as in PNP, as
illustrated by the previous work on stemona alkaloids
85,86
and
our own work on alkaloid- and sterol-inspired compounds.
35,91,92
This strategy applies to all types of ligands. Additionally, if the
ligand is an NP, the NP-driven approaches such as DTS, AOS,
DRA, CtD, PDR, and FOS are also very good options. If very
specic SAR questions need to be answered by densely popu-
lating an area of chemical space, then DTS and AOS are useful.
If the NP is in high abundance, CtD is an option to quickly
access diverse analogues of the NP. Furthermore, when the
pharmacophore is known for the NP, it can be used as a primary
fragment in a (p)DOS/BIOS/PNP approach but is also applicable
in a FOS/PDR campaign. If the NP is in low abundance,
unstable, or hard to access synthetically, breaking it down
to useful fragment(s) as above or following a DRA approach
may be benecial as showcased in the work on salA
analogues.
45,46,105
On the other hand, if no ligands are known or an entirely
new chemotype is sought, one can employ an X-ray crystal
structure or AlphaFold
112,113
to model a binding site and predict
a pharmacophore model which can be targeted by synthesis.
The predicted pharmacophore can then be used as a starting
point in a (p)DOS/PNP campaign. Alternatively, a fragment-
based screen can be a cost-efficient approach to generate new
scaffolds and starting points while covering a larger proportion
of chemical space, around which a (p)DOS/PNP approach can be
centred. Notably, even the fragments themselves can be
designed by DOS to increase chemical diversity and Fsp
3
content in the fragment collection.
114
This has already been
used in some cases
115
including the reported synthesis of uo-
rinated Fsp
3
-rich fragments.
116
In addition to a target-based approach, a phenotype of interest
can also be selected and screened against. If there are known
modulators of the phenotype, then diverse fragments thereof
could be picked. The fragments are fused with diverse secondary
fragments similar to the case with known ligands. Similarly, the
NP-based approaches are also applicable if the modulators are
NPs. If no modulators of the phenotype of interest are known,
Fig. 2 Flow chart for choosing the optimal strategies based on the project goals.
© 2025 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2025,16, 2961–2979 | 2973
Perspective Chemical Science

a chemical diversity-driven approach could be applied, similarly
to (p)DOS. Compounds with suitable physicochemical properties
to reach the target site should be prioritised. In this regard, using
NP-inspired starting points as in BIOS/(d)PNP can be benecial to
reach biologically relevant space. This approach is also useful if
no specic phenotype is targeted, but an unbiased phenotypic
evaluation such as cell painting is used, as shown with the work
on quinalogs.
79,80
Cell painting is a particularly powerful method
to assess the bioactivity of a compound collection with no specic
target or phenotype in mind, in an unbiased way. Here, cells are
stained with multiple dyes covering different organelles, and
changes to staining patterns aer compound treatment can be
measured. Importantly, with a large and diverse reference set of
compounds at hand, it is possible to identify modes of action and
even target(s) of new compounds, by comparison. Recent bioac-
tivity clusters that can rapidly be discerned are lysosomotrop-
ism
117
and cholesterol homeostasis,
118
modulation of tubulin
polymerisation,
119
mitochondrial stress,
120
modulation of potas-
sium channels,
121
and pyrimidine biosynthesis,
122
amongst
others. It should be noted that in approaches with no known
ligands or modulators, high-throughput screening (HTS) is
always an option to identify starting points if time and budget
allows.
In all library synthesis strategies where bioactive scaffolds or
fragments are designed from scratch, the goal is typically to
synthesise 10–20 fragment combinations or scaffolds, with
approximately 5–20 analogues each for a total of 50–400
compounds. Fragments, or the resulting analogues, should
ideally contain diverse substituents including electron-
withdrawing groups (EWGs), electron-donating groups (EDGs),
hydrophobic and hydrophilic groups, and ideally hydrogen
bond donors (HBDs) and hydrogen bond acceptors (HBAs), at
different positions. Additionally, substituents with different
steric bulk can be explored. This includes exible or locked and
linear or branched groups. Lastly, the compounds should be
synthesised as racemic mixtures to reduce bias and obtain twice
the number of compounds for biological screening in
approaches where compounds are synthesised de novo.In
strategies where compounds are directly derived from available
NPs, this criterion is, in most cases, not possible to full. In our
experience the above criteria are both necessary and sufficient
to nd bioactive compounds for a given target or phenotype of
interest, even from a relatively modestly sized library of <100
compounds.
Outlook and conclusions
In addition to the considerations outlined thus far, we see great
benets in adopting recent developments in the eld, including
C–H and late-stage functionalisation, as well as single-atom and
skeletal editing strategies, to streamline analogue synthesis and
further expand the diversity of a given collection, but also for
the medicinal chemistry optimisation of the hit compounds
into leads. Efficiently combining library synthesis with C–H/
late-stage functionalisation has proven effective as shown
from the work on oxazatwistane-derived analogues.
123
It can
provide access to new analogues from a vector/diversication
point that is not obvious. Several strategies for C–H function-
alisation are known including free-radical, metal-catalysed,
photochemical, electrochemical, and chemoenzymatic reac-
tions.
124
Chemoenzymatic synthesis has proven to be a very
useful strategy for C–H functionalisation. Very recent work
combined chemoenzymatic synthesis with DOS and CtD, which
was termed chemoenzymatic DOS (CeDOS).
125
Chemoenzymatic
C–H functionalisation of the NP parthenolide enabled the
synthesis of a diverse parthenolide-based library using diver-
gent chemical routes. With chemoenzymatic synthesis applied
successfully to TS of NPs,
126–133
this is a powerful example of the
combination of chemoenzymatic synthesis with a diversifying
strategy such as DOS. Two main strategies can be considered
when utilising chemoenzymatic synthesis in library synthesis
and medicinal chemistry.
134
The rst is the early-stage synthesis
of novel building blocks combined with a general diversifying
strategy to access new analogues. The second is the late-stage
diversication of NP-inspired advanced key intermediates or
analogues. Late-stage single-atom and skeletal editing is an
attractive approach in medicinal chemistry to quickly elucidate
SAR of hit and lead compounds.
135
Removal, addition, or
exchange of a single atom in a molecule is oen achieved by
modifying the synthesis of the compound from an early point in
the route or by a totally different route. However, recent
advantages in direct atom deletion, insertion, and
exchange
136–153
can in some cases remove the need for new ret-
rosynthetic analysis and provide new diverse compounds more
efficiently. Additionally, subtle changes to the overall molecular
shape and not just single atoms can have a large impact on the
function and properties of compounds. Efficient methods to
access isomeric chemical space by “shapeshiing”have also
been reported.
154
This example bears some resemblance to CtD
strategies, which may also be considered skeletal editing, in
a broad sense. Even combining chemoenzymatic methods with
skeletal editing can be a powerful tool as showcased by the
recent example which allowed for ring expansion at aliphatic C–
H sites.
155
With the current and continuously growing number
of methods in the area of late-stage C–H functionalisation and
skeletal editing, we see these becoming more integrated into the
synthesis of NP-inspired compounds and lead optimisation and
in accessing new chemically and biologically relevant space.
In summary, we have outlined how a large variety of strate-
gies are available to access diverse NP-derived and -inspired
compound collections. We emphasise how combining several
strategies or elements thereof, depending on the specic need
and purpose, can be benecial in the pursuit of new bioactive
molecules in an efficient manner. We hope that the ideas out-
lined here will serve to help chemists push the boundaries in
the synthesis of natural-product inspired, biologically relevant
compound collections.
Abbreviations
5-HT
1A
5-Hydroxytryptamine 1A
5-HT
2B
5-Hydroxytryptamine 2B receptor
5-HT
2C
5-Hydroxytryptamine 2C receptor
2974 |Chem. Sci.,2025,16,2961–2979 © 2025 The Author(s). Published by the Royal Society of Chemistry
Chemical Science Perspective

s
1
R Sigma-1 receptor
s
2
R Sigma-2 receptor
Ac Acetyl
ADS Activity-directed synthesis
AOS Analogue-oriented synthesis
AR Androgen receptor
Ar Aryl
B/C/P Build/couple/pair
BenzP*1,2-Bis(tert-butylmethylphosphino)benzene
BINAP 2,20-Bis(diphenylphosphino)-1,10-binaphthyl
BIOS Biology-oriented synthesis
Bn Benzyl
Boc tert-Butyloxycarbonyl
CeDOS Chemoenzymatic diversity-oriented synthesis
CFL Compact uorescent lamp
CLS Combinatorial library synthesis
COD 1,5-Cyclooctadiene
conc. Concentrated
CS Conventional synthesis
CtD Complexity-to-diversity
Cy Cyclohexyl
DABCO 1,4-Diazabicyclo[2.2.2]octane
DCC N,N0-Dicyclohexylcarbodiimide
DCE Dichloroethane
DCM Dichloromethane
DIPEA N,N-Diisopropylethylamine
DMA Dimethylacetamide
DMAP 4-Dimethylaminopyridine
DMEDA N,N0-Dimethylethylenediamine
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
DOS Diversity-oriented synthesis
DPEPhos bis[(2-Diphenylphosphino)phenyl]ether
dPNP Diverse pseudo-natural product
dr Diastereoisomeric ratio
DRA Dynamic retrosynthetic analysis
DTS Diverted total synthesis
DTU Technical University of Denmark
EC
50
Half maximal effective concentration
EDG Electron-donating group
ee Enantiomeric excess
ESCRT Endosomal sorting complexes required for transport
Et Ethyl
EWG Electron-withdrawing group
FBDD Fragment-based drug-discovery
FCC Flash column chromatography
FLS Focussed library synthesis
FOS Function-oriented synthesis
Fsp
3
Fraction of sp
3
-hybridised carbons
HBA Hydrogen bond acceptor
HBD Hydrogen bond donor
HFIP Hexauoroisopropanol
Hh Hedgehog
HTS High-throughput screening
IC
50
Half maximal inhibitory concentration
K
i
Inhibitory constant
LC3 Microtubule-associated protein 1A/1B light chain 3
MCR Multicomponent reaction
Me Methyl
MEM 2-Methoxyethoxymethyl
Mes Mesityl
MIC Minimum inhibitory concentration
MLCK1 Myosin light chain kinase 1
mol.
sieves
Molecular sieves
MWI Microwave irradiation
NBS N-Bromosuccinimide
n-Bu n-Butyl
NCS N-Chlorosuccinimide
NP Natural product
o/n Overnight
pDOS Privileged-substructure-based diversity-oriented
synthesis
PDR Pharmacophore-directed retrosynthesis
PEI Polyether ionophore
Ph Phenyl
PMP para-Methoxyphenyl
PNP Pseudo-natural product
PPTS Pyridinium para-toluenesulfonate
PS Polystyrene
p-Ts para-Tosyl
QuinoxP*2,3-bis(tert-Butylmethylphosphino)quinoxaline
RCM Ring-closing metathesis
rt Room temperature
salA Salvinorin A
SAR Structure–activity relationship
(S)-Trifer 1,10-bis{1-[(R)-Ferrocenyl-2- (S)-ethyl-1-
(diethylamino)phenyl]–(R)-phosphino}ferrocene
TBTU N,N,N0,N0-Tetramethyl-O-(benzotriazol-1-yl)uronium
tetrauoroborate
t-Bu tert-Butyl
TES Triethylsilyl
Tf Trifyl
TFA Triuoroacetic acid
THF Tetrahydrofuran
TM Target molecule
TMS Trimethylsilyl
TOS Target-oriented synthesis
TPS Two-phase synthesis
TS Total synthesis
Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)
bis(diphenylphosphane)
XPhos Dicyclohexyl[20,40,60-tris(propan-2-yl)[1,10–
biphenyl]-2-yl]phosphane
Data availability
The supplementary gures with graphical illustrations, expla-
nations, and examples of the individual strategies are available
in the ESI.†
Author contributions
F. S. B. and L. L. conceived the perspective. F. S. B. produced all
gures. F. S. B. and L. L. conducted the literature search and
wrote the manuscript.
© 2025 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2025,16, 2961–2979 | 2975
Perspective Chemical Science

Conflicts of interest
There are no conicts of interest to declare.
Acknowledgements
We thank the Novo Nordisk Foundation (NNF21OC0067188),
the European Research Council (ERC, ChemBioChol,
101041783) and DTU for funding. We thank Prof. Herbert
Waldmann and Dr Daniel Foley for critical reading of the
manuscript and helpful comments.
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