Synthesis and evaluation of the performance of a small molecule library based on diverse tropane-related scaffolds

Article abstract of DOI:10.1016/j.bmc.2020.115442

A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of 53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four compounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a fragment from another natural product class. It was concluded that the unified synthetic approach had yielded diverse scaffolds suitable for the design of performance-diverse screening libraries.

Full text of DOI:10.1016/j.bmc.2020.115442

Bioorganic&MedicinalChemistry28(2020)115442
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and evaluation of the performance of a small molecule library
based on diverse tropane-related scaffolds
⁎
⁎
Robert A. Lowea,b, Dale Taylorc, Kelly Chibaled,e,f, Adam Nelsona,b, , Stephen P. Marsdenb,
b School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
a Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK
c H3D Drug Discovery and Development Center, University of Cape Town, Private Bag, Rondebosch 7700, South Africa
d Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
e Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
f South African Medical Research Council, Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa
A R T I C L E I N F O
A B S T R A C T
Keywords:
A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The
key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium
salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of
substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of
53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance
of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four com-
pounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds
may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a
fragment from another natural product class. It was concluded that the unified synthetic approach had yielded
diverse scaffolds suitable for the design of performance-diverse screening libraries.
Molecular diversity
Molecular scaffolds
Alkaloids
Hedgehog signalling
Antimalarials
1. Introduction
bradycardia. The tropane alkaloids have also provided wider inspira-
tion in medicinal chemistry, for example in the discovery of dopamine
Natural products continue to provide rich inspiration in medicinal
chemistry and chemical biology. Natural products have played a crucial
role in shaping early-stage drug discovery: 6% of the drugs approved for
clinical use between 1981 and 2014 were unaltered natural products,
and 26% were natural product derivatives.1 Furthermore, in biology-
oriented synthesis, natural product scaffolds are used to guide the de-
sign of productive screening libraries. Screening libraries can provide
useful starting points for the discovery of both drugs and chemical
probes, and diversity-oriented synthetic approaches have been devel-
oped to increase both the chemical functional diversity that may be
explored.2a–d
reuptake inhibitors,5 muscarinic acetylcholine receptor antagonists6
and monoamine uptake inhibitors7 (e.g. 1). Recently, tropanes have
inspired the design of pseudo natural product scaffolds in which the
bicyclic is fused with other natural product-inspired ring systems: for
example indotropanes8 (fused with an indole) and pyrrotropanes9
(fused with a pyrrolidine). The indotropane myokinasib, 2, is a myosin
light chain kinase 1 inhibitor,8a whilst 3 is an inhibitor of Hedgehog
signalling.8b
We have developed a unified synthesis of diverse tropane-related
scaffolds in which the bicyclic cycloadducts 4 were exploited as key
intermediates (Scheme 1).10 It was envisaged that the functionality in
the cycloadducts 4 would enable the addition of substituents to several
positions of the tropane core (e.g. to give 5). Furthermore, the synthesis
of more complex tropane-related scaffolds would be possible, either by
cyclisation of the cycloadducts 4 (e.g. to give the scaffold 6) or by fu-
sion of additional ring(s) (e.g. to give the scaffolds 7 or 8). It was noted
that some of the resulting structures may be considered to be pseudo
natural product scaffolds in which the tropane core has been fused with
The tropane alkaloids are structurally diverse, and display a broad
range of biological functions (Fig. 1).3 Within this class of alkaloids, the
[3.2.1] bicyclic tropane core may be substituted at a wide range of
positions (as in ecgonine and catuabine A), and can also be fused with
additional rings (as in alstoniaphylline B and 2,3-dihydrodarlingine).
The tropane core is also in clinically-approved drugs including mar-
aviroc,4 an HIV-1 entry inhibitor, and atropine, a drug that used to treat
⁎ Corresponding authors at: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
E-mail addresses: a.s.nelson@leeds.ac.uk (A. Nelson), s.p.marsden@leeds.ac.uk (S.P. Marsden).
https://doi.org/10.1016/j.bmc.2020.115442
Received 7 January 2020; Received in revised form 2 March 2020; Accepted 12 March 2020
Availableonline16March2020
0968-0896/©2020ElsevierLtd.Allrightsreserved.

R.A. Lowe, et al.
Bioorganic&MedicinalChemistry28(2020)115442
Fig. 1. Examples of tropane alkaloids (top) and tropane-related compounds (bottom).
Table 1
Synthesis of bicyclic intermediates (see Scheme 2).
3-Hydroxy pyridinium salt formation
Bicyclic intermediate formation
R
X
Solvent Product
(Yield)
R
R’
Product
(Yield)
Bn
Br iPrOH
10a (99%) Bn
Ph
11a (70%)
11b (57%)
11c (67%)a
Bn
10b (99%) Me
Me
Me
Me
Me
I
iPrOH
NMe2 11d (54%)
Me
Ph
11e (20%)
11f (50%)
p-FC6H4CH2-
o-BrC6H4CH2-
Br THF
Br THF
10c (99%) p-
Me
FC6H4CH2-
10d (99%) o-
BrC6H4CH2-
10e (99%) o-Br-p-
FC6H3CH2-
Ph
11 g (41%)
11 h (89%)
o-Br-p-FC6H3CH2- Br THF
Me
Scheme 1. Overview of the envisaged unified synthetic approach.
a
Ag2O was used as base; 20% yield with Et3N as base.
other natural product fragments: for example indotropanes (e.g. 8),
tetrahydroquinotropanes (e.g. 6) and pyrrotropanes (e.g. 7). In this
paper, we describe the development of the unified synthesis, and the
design and synthesis of a set of diverse screening compounds based on
many of the resulting scaffolds. In addition, we demonstrated the bio-
logical relevance of some of the approach through the discovery of both
inhibitors of Hedgehog signalling and compounds with activity against
P. falciparum.
were prepared in near-quantitative yield by alkylation of 3-hydroxy
pyridine, and were used without further purification. The 3-hydroxy
pyridinium salts 10 and appropriate dipolarophiles were treated with
triethylamine, and the corresponding cycloadducts were obtained after
reaction at elevated temperature.11 The reactions proceeded with high
regio- and stereoselectivity with a vinyl sulfone or a vinyl sulfonamide
as dipolarophile; in contrast, our and other11 studies showed that the
cycloaddition reactions were poorly selective with acrylonitrile or ac-
rylate esters as the dipolarophile. The stereochemical outcome of the
cycloadditions was consistent with previous studies,11 and the relative
configurations of derivatives of 11b, 11c and 11f were determined by
X-ray crystallography (vide infra). Although the yields of the cycload-
ducts were generally good, lower yields were often obtained with the
methylated 3-hydroxy pyridinium salt 10b which was, nevertheless,
consumed during the reactions. It was hypothesised that the iodide
counterion dealkylated 10b under the reaction conditions and, indeed,
the yield of 11c was improved from 20% to 67% when Ag2O was used
as a base that could also remove iodide from solution.
2. Results and discussion
2.1. Synthesis of bicyclic intermediates
Initially, we investigated the synthesis of the key bicyclic inter-
mediates (Scheme 2 and Table 1). The 3-hydroxy-pyridinium salts 10
Functional group manipulation of the bicyclic scaffolds 11 was
undertaken to enable subsequent scaffold syntheses (Scheme 3). For
example, hydrogenation of the enones 11 proceeded in high yield to
give the corresponding bicyclic saturated ketones 12. Furthermore,
Scheme 2. Synthesis of bicyclic intermediates (see Table 1).
2

R.A. Lowe, et al.
Bioorganic&MedicinalChemistry28(2020)115442
Scheme 3. Functional group manipulation of bicyclic intermediates.
Scheme 5. Scaffold synthesis by cyclisation of bicyclic intermediates.
reduction of 12a with iBu2AlH gave the corresponding alcohol
with > 98: < 2 diastereoselectivity. After TBS protection, the resulting
sulfone was treated with LiHMDS and then MeSSMe; subsequent
treatment with HCl resulted in hydrolysis of both the α-methylsulfanyl
sulfone and the silyl ether to give the ketone 13 in 82% yield over 4
steps.12
11a with toluenesulfonylmethyl isocyanide13 and potassium tert-but-
oxide gave the corresponding pyrrole 14 in 85% yield. Highly diaster-
eoselective fusion of an N-benzyl pyrrolidine ring14 was possible by
treatment of enones 11b, 11c, 11e and 11f with Me3SiCH2NBnCH2OMe
and lithium fluoride in acetonitrile at room temperature (→7a-d, see
legend for details).14a The relative configuration of a derivative of 7d
was determined by X-ray crystallography (vide infra). Alternatively,
reaction of the enone 11a with N-methyl glycine and paraformalde-
hyde14b in refluxing toluene resulted in fusion of an N-methyl
2.2. Synthesis of diverse tropane-related scaffolds
A wide range of scaffolds was prepared in which additional ring(s)
were fused onto the tropane core (Scheme 4). Treatment of the enone
t
Scheme 4. Scaffold synthesis by ring fusion onto bicyclic intermediates. Conditions: (a) TsCH2NC, BuOK, THF, 0 °C → rt, 85%; (b) Me3SiCH2NBnCH2OMe, LiF,
MeCN: 7a (R = Me, R’=Ph, R’’=Bn), 67% (from 11e); 7b (R = Me, R’=Me, R’’=Bn), 50% (from 11c); 7c (R = Bn, R’=Me, R’’=Bn), 57% (from 11b); 7d (R = p-
FC6H4CH2-, R’=Me, R’’=Bn), 88% (from 11f); (c) MeNHCH2CO2H, paraformaldehyde, toluene, Δ: 7e (R = Bn, R’=Ph, R’’=Me), 77% (from 11a); (d) Me3SO I, NaH,
THF, 40%; (e) ethyl diazoacetate, THF then NaOH, H2O–MeOH, 14%; (f) EtNO2, PhNCO, THF–Et2O, 28% then DDQ, toluene, Δ, 16%; (g) 2,4,6-tri(trifluoromethyl)-
1,3,5-triazine, 10 mol% TFA, EtOH, 80 °C: 18a (R = Bn), 32% (from 12b); 18b (R = Me), 54% (from 12c); (h) NCS, 30 mol% proline, CH2Cl2 then R’’CSNH2, DMF:
19a (R’=R’’=Me), 3% over 2 steps (from 12b); 19b (R’=R’’=Ph), 30% over 2 steps (from 12a); (i) R’CCCH2NH2, 2.5 mol% NaAuCl4·2H2O, EtOH, 80 °C: 20a
(R = Bn, R’=Me, R’’=H), 63% (from 12b); 20b (R = Me, R’=Me, R’’=H), 43% (from 12b); 20c (R = Me, R’=NMe2, R’’=H), 40% (from 12d); 20d (R = Me,
R’=Me, R’’=Ph), 20% (from 12c); (j) o-IC6H4NH2, 10 mol% Pd(OAc)2, DABCO, DMF: 8a (R = Bn, R’=Ph), 40% (from 12a); 8b (R = Me, R’=NMe2), 29% (from
12d); 8c (R = Bn, R’=Me), 20% (from 12b); 8d (R = Me, R’=Me), 17% (from 12c); (k) PhNHNH2, AcOH, Δ: 8a (R = Bn, R’=Ph), 40% (from 12a).
3

R.A. Lowe, et al.
Bioorganic&MedicinalChemistry28(2020)115442
correlation with predicted coupling constants for the alternative dia-
stereomers (Supporting Information).15 Treatment of the enone 11b
with ethyl diazoacetate,16 followed by hydrolysis with aqueous sodium
hydroxide, gave, presumably after aerobic oxidation, the pyrazole 16 in
low yield. Finally, reaction of the enone 11c with an in situ generated
nitrile oxide17 could be followed by DDQ oxidation to give the isoxazole
17.
The position of ring fusion to the tropane core could be varied by
exploiting the saturated ketones 12 in place of the enones 11 (Scheme
4). Accordingly, treatment of 12b and 12c with 2,4,6-tri(tri-
fluoromethyl)-1,3,5-triazine18 and 10 mol% trifluoroacetic acid in re-
fluxing ethanol gave the pyrimidines 18a and 18b in 32% and 54%
yield respectively. Alternatively, α-chlorination of the ketones 12a and
12b,19 followed by reaction with thioacetamide or thiobenzamide,20
gave the thiazoles 19. Fusion of a pyridine ring was possible by treat-
ment of the ketones 12 and an appropriate propargylamine with
2.5 mol% NaAuCl4 (→20).21 Finally, either Fischer indole synthesis22
or Pd-catalysed indole formation23 enabled conversion of the ketones
12 into the corresponding indotropanes 8.
Scheme 6. Exploration of alternative vectors by functionalisation of bicyclic
intermediates.
Two complementary cyclisation reactions enabled conversion of the
enones 11 into more complex scaffolds (Scheme 5). Treatment of 11a
with MeLi resulted in deprotonation and cyclisation, rather then methyl
addition to the ketone, to give the cyclopropane 21 in 20% yield; the
yield of the process was improved to 60% with LiHMDS as base in place
of MeLi. Finally, reductive Heck cyclisation24 between the aryl bromide
pyrrolidine ring to give 7e in 77% yield and with high diastereoselec-
tivity. The cyclopropane 15 was prepared in good yield and with >
98: < 2 diastereoselectivity by treatment of 11a with dimethylox-
osulfonium methylide; the configuration of 15 was determined by
Fig. 2. Hierarchical relationship between the tropane-related scaffolds. Scaffolds that were found as substructrues of a random 2% of the ZINC database of com-
mercially-available compounds are noted.
4

R.A. Lowe, et al.
Bioorganic&MedicinalChemistry28(2020)115442
2% of the ZINC database of commercially-available compounds.29 Only
two of the 16 final scaffolds were found as substructures of these
compounds: the pyrimidine-containing scaffold and the parent tropane
core.
2.3. Design, synthesis and evaluation of a small molecule library based on
diverse tropane-related scaffolds
A range of building blocks was prepared in which the protecting
groups were chosen to enable decoration of the scaffolds at com-
plementary positions (Scheme 7). Hydrogenation of the enone 11b
under forcing conditions in methanol–acetone resulted in debenzyla-
tion, alkene and ketone reduction and isopropylation (by reaction with
acetone) to give the hydroxyl-substituted tropane 24. Reductive ami-
nation of the ketone 12c, by treatment with methylamine, Ti(OiPr)4 and
then sodium borohydride gave the secondary amine 25 in 41% and
with high diastereoselectivity; the relative configuration of similar re-
ductive amination products was determined by NOESY analysis
(Supplementary Information). In a similar vein, reaction of the ketones
22c, 22d and 7d with iBu2AlH was moderately diastereoselective
(crude dr observed with these substrates: 22c, 75:25; 22d, 90:10; 7d,
75:25) and, after purification, yielded the corresponding alcohols 27a,
27b and 28 as single diastereomers. Finally, hydrogenolysis of 22a, 27b
and 28 yielded the corresponding debenzylated building blocks 26, 27c
and 29. The relative configurations of 27a, 27b and the 2-methyl-
propionamide of 29 were determined by X-ray crystallography
(Supporting Information).30
A set of 53 screening compounds based on many of the tropane-
related scaffolds was designed and prepared. In addition to compounds
that had already been prepared (6a, 6b, 8b, 8c, 8d, 12c, 13, 14, 16, 17,
18a, 18b, 19a, 19b, 20a, 20b, 20c, 20d, 22e, 24, 25, 27a, 27c and
29), additional compounds were also synthesised by derivatisation of
building blocks (see Scheme 7) with a single capping group. Final
compounds were generally purified by mass-directed HPLC or auto-
mated reverse-phase flash column chromatography; purification was
often challenging, and low yield of purified products were often ob-
tained using these methods. The synthesis of ten exemplar screening
compounds (see Fig. 3, Panel A) is summarised in Table 2 (see also
Supplementary Information). The molecular properties (Panel B) and
shape diversity (Panel C) of the screening compounds is summarised in
Fig. 3. The screening compounds generally have drug-like molecular
properties, and are more three-dimensional than many screening sets.31
The 53 final compounds were screened in two phenotypic assays
that were selected as representative applications of the library. It was
intended that these assays would enable a preliminary assessment of the
biological relevance of the scaffolds accessible using the unified syn-
thetic approach. An osteoblast differentiation assay32 was used to
screen the compounds, initially at 10 μM, for inhibition of Hedgehog
signalling. The dose-dependent activity of hits, identified on the basis of
at least 50% inhibition of signallig and < 20% impact on cell viability,
was determined. In addition, a screen against a NF54 (chloroquine-
susceptible) P. falciparum strain was performed in dose-response mode
in which lactate dehydrogenase activity served as a marker for parasite
viability.33 The dose-dependent activity of the active compounds from
both assays is shown in Figure 4. Two inhibitors of Hedgehog signalling
were discovered (38 and 39; Panel A), both of which were based on a
tetracyclic indotropane scaffold that is a substructure of some known8b
inhibitors of this pathway (such as 3, Fig. 1). Four compounds with
weak antiplasmodium activity were also identified (16, 20, 40 and 41;
Panel B); these compounds were based on four distinct tropane-related
scaffolds that had been prepared. We note that three of the active
compounds may be considered to be pseudo natural products in which a
tropane is fused with a fragment from another natural product class: 38
and 39 are indotropanes and 41 is a pyrrolotropane.9
Scheme 7. Synthesis of building blocks for library synthesis.
and the enone of 11 g and 11 h gave the tetrahydroquinotropanes 6a
and 6b.
Substitution of the enones 11 was possible at alternative positions
(Scheme 6). Rh-catalysed conjugate addition25 of aryl-boronic acids to
the enones 11b and 11c yielded the corresponding aryl-substituted
tropanes 22a-e with high diastereoselectivity. The relative configura-
tion of derivatives of 22c and 22d was determined by X-ray crystal-
lography (vide infra). In addition, a Bayliss-Hillman reaction of the
enone 11a yielded the hydroxymethyl-substituted enone 23.
The unified approach had enabled the synthesis of sixteen distinct
deprotected graph-node-bond level26 scaffolds in which alpha atoms
had been removed. The diversity of these scaffolds may be captured in
terms of an hierarchical tree27 that formalises the relationship between
molecular scaffolds (Fig. 2). We used the open access-computional tool
LLAMA28 to assess the novelty of the scaffolds with respect to a random
5

R.A. Lowe, et al.
Bioorganic&MedicinalChemistry28(2020)115442
Fig. 3. Construction of a set of 53 screening compounds. Panel A: Exemplar screening compounds (see Table 2 for synthesis and Supplementary Information). Panels
B and C: Molecular properties (B) and shape diversity (C) of the library (see Supplementary Information). Shape diversity is represented on a principal moments of
inertia (PMI) plot in which the vertices correspond to linear (top left), flat (bottom) and spherical (top right) shapes.
11 were exploited as key intermediates which were converted into di-
verse scaffolds by the addition of substituents, cyclisation reactions, and
the fusion of additional ring(s). In total, the approach enabled the
synthesis of sixteen distinct scaffolds, only two of which were found in a
substructure search of commercially-available compounds. The biolo-
gical relevance of the scaffolds that were accessible using the approach
was determined by design, synthesis and evaluation of 53 screening
compounds. The set of screening compounds was screened, enabling
discovery of two inhibitors of Hedgehog signalling and four compounds
with activity against P. falciparum. Three of these compounds may be
considered to be indotropane or pyrrotropane pseudo natural products
in which a tropane is fused with a fragment from another natural
product class. We conclude that unified approaches for the synthesis of
diverse natural product-inspired scaffolds can underpin the design of
performance-diverse screening libraries.
Table 2
Synthesis of exemplar screening compounds.
Substrate
Method
Product (Yield)
27c
27c
27c
4-bromomethyl-benzonitrile, NaH, DMF
cPrCOCl, pyridine, CH2Cl2
30 (12a)
31 (16a)
32 (4a)
1-methylimidazole-2-sulfonyl chloride, pyridine,
DMF
29
24
24
25
isonicotinaldehyde, DMF then NaBH4
4-methoxyphenylisocyanate, NaH, DMF
2-chlorobenzoxazole, NaH, DMF
1-methylimidazole-2-sulfonyl chloride, pyridine,
DMF
33 (41b)
34 (10b)
35 (7b)
36 (21b)
25
8c
8c
3-isocyanatobenzonitrile, NaHCO3, DMF
MsCl, NaH, DMF
37 (35b)
38 (11b)
39 (19b)
BrCH2CN, NaH, DMF
a
b
Purification by mass-directed HPLC.
Purification by automated reverse-phase flash column chromatography.
Declaration of Competing Interest
3. Conclusion
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
A unified synthetic approach was developed that enabled the
synthesis of diverse tropane-related scaffolds. The bicyclic cycloadducts
6

R.A. Lowe, et al.
Bioorganic&MedicinalChemistry28(2020)115442
Fig. 4. Structures of bioactive ligands discovered. Panel A: Inhibitors of Hedgehog signalling. Panel B: Inhibitors of P. falciparum survival. Compound 41 was tested as
a 85:15 mixture of diastereomers.
Acknowledgments
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We thank EPSRC (EP/N025652/1) for funding, and Peter and Susan
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and Professor Herbert Waldmann, Max Planck Institute for Molecular
Physiology). We thank Dr Sonja Sievers and the Compound
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