Design and Synthesis of Fsp3-Rich, Bis-Spirocyclic-Based Compound Libraries for Biological Screening

Article abstract of DOI:10.1021/acscombsci.6b00005

The exploration of innovative chemical space is a critical step in the early phases of drug discovery. Bis-spirocyclic frameworks occur in natural products and other biologically relevant metabolites and show attractive features, such as molecular compactness, structural complexity, and three-dimensional character. A concise approach to the synthesis of bis-spirocyclic-based compound libraries starting from readily available commercial reagents and robust chemical transformations has been developed. A number of novel bis-spirocyclic scaffold examples, as implemented in the European Lead Factory project, is presented.

Full text of DOI:10.1021/acscombsci.6b00005

Research Article
pubs.acs.org/acscombsci
Design and Synthesis of Fsp3‑Rich, Bis-Spirocyclic-Based Compound
Libraries for Biological Screening
Silvia Stotani, Christoph Lorenz, Matthias Winkler, Federico Medda, Edwige Picazo,
Raquel Ortega Martinez, Anna Karawajczyk, Jorge Sanchez-Quesada,† and Fabrizio Giordanetto*,‡
Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Strasse 76a, 44227 Dortmund, Germany
S
* Supporting Information
ABSTRACT: The exploration of innovative chemical space is a critical step in
the early phases of drug discovery. Bis-spirocyclic frameworks occur in natural
products and other biologically relevant metabolites and show attractive features,
such as molecular compactness, structural complexity, and three-dimensional
character. A concise approach to the synthesis of bis-spirocyclic-based compound
libraries starting from readily available commercial reagents and robust chemical
transformations has been developed. A number of novel bis-spirocyclic scaffold
examples, as implemented in the European Lead Factory project, is presented.
KEYWORDS: spirocyclic, spirocenter, compound library design, compound library synthesis, European Lead Factory
Factory (ELF) efforts to populate innovative chemical space
for high throughput screening (HTS) and drug discovery
activities,22−25 we focused our attention on bis-spirocyclic frame-
works as structural complexity multipliers for small molecule
compound libraries and our approach is herein described.
INTRODUCTION
■
Biologically relevant chemical space represents an ideal starting
point for the identification of bioactive compounds to investigate
pathophysiological processes and seed drug discovery programs.
Biology-oriented synthesis1,2 is one of the most straightforward
strategies for the design of novel, bioactive compound libraries to
be used in biological screening campaigns. Here, by focusing on
the chemical scaffolds and structural features of known natural
products, synthetic procedures are devised to afford natural
product-like compounds through the introduction of appropriate
diversification elements.3,4 A peculiar feature of many natural
products, when compared to standard small molecules, is their
enhanced structural complexity, high degree of saturation and
chirality content,5 which then results in a significant preference
for binding and selectivity to proteins,6 improved physicochem-
ical properties and is generally perceived as having a positive
impact on compound developability.7,8 Natural products’
structural complexity often originates from the presence of spiro-
cyclic elements, where rings are connected through a single atom
(i.e., the spiroatom). Here, the spiroatom is normally a quater-
nary carbon, thus offering the potential for chirality when the two
rings differ in their size, atomic composition or substitution.
Several natural products display bis-spirocyclic elements where
two or more spiroatoms are forming three or more connected
rings, showing a wide spectrum of biological activities. Because of
their inherent structural complexity and novelty contributions,
it is not surprising that spirocyclic elements are finding more
frequent applications in medicinal chemistry.9 These include
for example derivatives of plant origin from the labdane
terpenoid family (e.g., leolorin C10) or isoquinoline alkaloids
(e.g., roemeridine11), marine toxins of the cyclic imine group
(e.g., 13-desmethyl spirolide C12,13), or aza group (e.g., aza-
spiracid 114−16), soil fungi’s metabolites with sesquiterpene
RESULTS AND DISCUSSION
■
Overall Concept and Library Design. The majority of
naturally occurring bis-spirocycles are spiroketals originating
from biosynthetic sequences involving dehydration of the
corresponding diols, followed by elimination or lactonization
steps. Examples of bis-spirocycles containing hemiaminal
ethers, lactams and amines also exist but these are typically
parts of more extended fused and bridged frameworks. This
mainly results in bis-spirocyclic scaffolds displaying a central
tetrahydrofuran ring bearing a 1,3 spiroatomic pattern
(Figure 1a). We thus decided to focus on the exploration
of general bis-spirocyclic frameworks with spiroatoms in a
1,3 arrangement and opportunities for at least three diversity
vectors, as shown in Figure 1b. Here, a five-membered central
ring bearing at least one nitrogen atom was preferred to (a)
afford novel nitrogen-containing bis-spirocyclic when com-
pared to oxygen-containing natural products, (b) facilitate ring
formation via conformational and preorganization effects
mediated by the five-membered ring in contrast to less strained
six- and seven-membered ring alternatives,26−30 and (c) offer
opportunities for diversification via functionalization of the
nitrogen atom. Furthermore, the size and composition of the
two terminal rings, alongside any installed functional groups,
would provide additional avenues for introducing diversity
elements (Figure 1b). Intriguingly, a survey of the scientific
Received: January 15, 2016
Revised: May 10, 2016
(e.g., expansolide A17,18) or alkaloid (e.g., asperparaline A19−21
)
skeletons, as shown in Figure 1a. As part of the European Lead
© XXXX American Chemical Society
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Figure 1. (a) Representative natural products that feature bis-spirocyclic elements in their structures and (b) general structure of the bis-spirocyclic
frameworks addressed in the present study and associated synthetic precursors. R1, R2, and R3 indicate diversification elements, while X and Y
represent further sites of heteroatomic diversity.
Figure 2. Ketones (R1) and acyl chlorides (R2) used as diversification elements in the synthesis of the two libraries.
a
Scheme 1. Synthesis of the Bis-Spiro-Imidazolinone Library
a
Reagents and conditions: (a) NaCN (1.25 equiv), NH4Cl (1.3 equiv), NH4OH (aq), i-PrOH, rt, overnight (2, 99%); (b) H2SO4 (95−98%,
20.0 equiv), DCM, 0 °C to rt, overnight (3, 97%); (c) p-TSA (0.2 equiv), ketone (1.2−3.0 equiv), MeOH, reflux, 1−6 day(s) (4{1−7} 61−87%),
see Table 1; (d) R2COCl (2.5−3.0 equiv), DIPEA (4.0−6.0 equiv), DCM, 0 to 40 °C, 1−3 day(s) (5{1−10}, 36−59%), see Table 2; (e) H2 (1 atm),
Pd(OH)2/C (0.05 equiv), MeOH, rt, 2−6 h (6{1−10} 88−98%); (f) R3COCl (1.5 equiv), Et3N (5.0 equiv), THF, rt, overnight;
(f′) R3COOH (2.0 equiv), HOBt (2.0 equiv), EDC*HCl (2.5 equiv), DIPEA (5.0 equiv), DCM, 50 °C, overnight (7); (g) R3CHO (2.0 equiv),
NaBH(AcO)3 (2.5 equiv), AcOH (2.0 equiv), DCE, rt, overnight (8); (h) R3SO2Cl (1.5 equiv), Et3N (5.0 equiv), THF, rt, overnight (9);
(i) R3NCO (1.5 equiv), Et3N (5.0 equiv), DCM, rt, overnight (10).
literature for such bis-spirocyclic substructures revealed a very
limited number of examples31−34 and no reports originating
from parallel chemistry approaches, thus reaffirming the high
novelty attribute of the concept.
In keeping with a combinatorial approach to the potential
synthesis of several thousand compounds from different
scaffolds, we envisioned the two spiroatoms to originate from
a sequence of well-known, robust manipulations on two
different, commercially available cyclic ketones, as indicated
in Figure 2. Here, selection of symmetric cyclic ketones would
eliminate the issue of separating isomers during synthesis.
Additionally, the cyclic ketones could serve as common
precursors in branched pathways. For instance, their carbonyl
groups could be aptly transformed in diverse synthons for the
preparation of several heterocyclic core systems. Lastly, by
swapping the order of manipulation of the two cyclic ketones in
the planned synthetic scheme, one would further generate
regioisomeric scaffolds of clear practical utility during HTS
triaging and structure activity relationships (SAR) exploration.
To showcase this pragmatic and versatile approach, we
exemplify the syntheses of imidazolinone- and oxazolidine-
based bis-spirocyclic scaffolds.
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Once optimal conditions for the key condensation step were
established, the potential to install a second chemical diversity
vector on the imidazolinone nitrogen atoms was explored.
Here, the most reactive amine nitrogen atom is severely hindered
given that it is connecting two spiroatoms, and it was crucial
to verify its reactivity under acylating conditions. As shown in
Table 2, the least sterically encumbered imidazolinone 4{1}
tended to reacted better than imidazolinone 4{4} to the
corresponding acylated product, (cf., 56−67% (Table 2, entry
1 and 2) and 18−59% (Table 2, entry 4 and 5)) with the latter
yielding no isolatable product when steric bulk at the acyl
chloride increased, as in the case of benzoyl chloride (Table 2,
entries 3 and 6). On the basis of these results, introduction of
diversity at the central ring of the bis-spirocyclic core was
anticipated to be limited to small alkyl and heteroalkyl side
chains. The establishment of successful acylation conditions was
nevertheless very important to minimize the intrinsic chemical
instability of the aminal precursors 4{1−7}, as shown in Figure 3.
Exploitation of the third and last diversity handle, required
deprotection of the N-benzylated-piperidine element under
catalytic hydrogenation conditions using palladium hydroxide,
which afforded the desired products 6{1−10} with high
to excellent yields (88−98%). These intermediates were then
further derivatized through their piperidine nitrogen atoms using
combinatorial chemistry protocols for four typical diversity reac-
tions (i.e., amide coupling (f or f′), reductive amination
(g), sulfonylation (h) and urea formation (i)) to yield final prod-
ucts 7−10. These were performed in a parallel fashion using a
24 position Mettler Toledo block equipped with 15 mL reaction
tubes (Scheme 1).25,35 As shown in Figure 4 and 5, diversity
reagents were selected in order to ensure all final compounds
have “lead-like” properties (i.e., calculated LogP (cLogP) ≤ 4 and
Molecular Weight (MW) ≤ 400).36−38
EXPERIMENTAL PROCEDURES
■
Bis-Spiro-Imidazolinone Library. Synthesis of the bis-
spiro-imidazolinone scaffold 6 started with the cyanation of
commercially available 4-N-benzyl piperidone using sodium
cyanide under basic conditions (Scheme 1). Performing the
reaction at room temperature overnight afforded the desired
product (2) in quantitative yield. Acidic hydrolysis of the cyano
group using concentrated sulfuric acid to yield 3 (97%) was
followed by the key condensation step on an array of ketones,
to install the first diversity element. Seven different aliphatic
(i.e., linear, cyclic and heterocyclic) ketones in a 1.2−3.0 range
of equivalents, in the presence of catalytic amount (0.2 equiv)
of p-TSA, were refluxed in MeOH for 1−6 days to yield the
cyclization products 4{1−7} with moderate to good yields
(61−87%, Scheme 1 and Table 1).
Table 1. Reaction Conditions for the Cyclization Step c
Bis-Spiro-Oxazolidine Library. Synthesis of the bis-spiro-
oxazolidine scaffold 18 started with the cyanation of five different
aliphatic ketones (e.g., cyclic and heterocyclic, 11{2−3,5−7}),
under the same conditions detailed earlier, and the desired
products 12{2−3,5−7} were obtained with high to excellent
yields (81−97%).
The cyanation step was then followed by the quantitative
acidic hydrolysis of the cyano group in concentrated (37%) HCl.
The carboxylic acid functions of the resulting α-amino acids
13{2−3,5−7} were converted to their methyl ester (14{2−7},
45−82%) and then reduced under reflux in toluene with Red-Al
(70% in toluene) to afford compounds 15{2−7} in moderate to
Table 2. Acylation Conditions for Compounds 4{1} and 4{4}
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Figure 3. Sample stability profiles in acidic media (pH 2) for aminal
4{3} and hemiaminal ether 16{4} intermediates, and their acetylated
counterparts, 5{3} and 17{4}, respectively.
Figure 5. Physicochemical properties (calculated LogP (cLogP) and
molecular weight (MW), JChem, ChemAxon 6.3.0) for the theoretical
bis-spiro-imidazolinone (gray squares) and bis-spiro-oxazolidine
(white circles) libraries. Selected compounds 7{4,1}, 7{5,1}, 8{3,1},
8{3,2}, 8{3,3}, 10{4,1}, 10{5,1}, 19{3,1}, 19{4,1}, 20{3,1}, 20{5,1},
21{3,1}, 21{4,1}, 22{3,1}, and 22{3,2}, synthesized to validate the
synthetic approach, are marked as black triangles.
in slight excess (1.1 equiv) and refluxing in MeOH for 4 h. The
reactivity of the nitrogen atom of the oxazolidine central ring
under acylating conditions was limited, in line with observations
derived from the bis-spiro-imidazolinone scaffold 6 (d). Here,
acetylation of all the cyclized intermediates 16{1−7} proceeded
in almost quantitative yields (96% in average) while acylation
with bulkier acyl chlorides (i.e., benzoyl chloride) proved to be
successful only with the less sterically hindered oxazolidine
intermediates (cf., Table 3, entries 2, 4, and 6). Analogously to the
aminal intermediates previously described, hemiaminal ethers
16{1−7} also showed marked chemical instability, while their
acylated counterparts did not suffer from such limitation, as
described in Figure 3.
Catalytic hydrogenation of the acylated bis-spiro-oxazolidine
intermediates afforded, in quantitative yields, the N-debenzylated
piperidine products 18{1−8} which were further derivatized in
a combinatorial approach by using appropriate diversity
reagents35,39 (see Scheme 2 and Figure 4).
CONCLUSIONS
■
The exploration of chemical space remains one of the most
critical step toward the identification of novel chemical matters
for chemical biology and drug discovery applications. In this
context, populating areas of chemical space that have biological
relevance is of special importance. As natural products represent
privileged, biologically relevant starting points for such
explorations, we sought to approximate their structural complex-
ity by focusing on their bis-spirocyclic frameworks. The bis-
spirocyclic scaffolds described here demonstrate a high level of
saturation and intrinsic three-dimensionality, well in line with
recent hypotheses on compound desirability from a molecular
properties perspective.37,40 As they are underrepresented in the
scientific literature and commercial sources, they serve an
important purpose when evaluation of novel chemical space
and generation of intellectual property are concerned.41
Importantly, as they are derived from highly parallel and robust
synthetic schemes using readily available starting materials and
reagents, they address typical limitations of natural products such
as limited synthetic tractability and cost of final products.42−44
Furthermore, the concise synthetic schemes validated in the
present study allow the introduction of diversity and variation
Figure 4. Representative examples of bis-spiro-imidazolinone and bis-
spiro-oxazolidine compounds.
high yields (59−81%). Condensation of the six different amino
alcohols 15{2−7} insofar synthesized proceeded smoothly and in
moderate yields (16{1−7}, 38−67%) using N-benzylpiperidone
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Table 3. Acylation Conditions for Compounds 16{1}, 16{3}, and 16{4}
a
Scheme 2. Synthesis of the Bis-Spiro-Oxazolidine Library
a
Reagents and conditions: (a) NaCN (1.25 equiv), NH4Cl (1.3 equiv), NH4OH (aq), i-PrOH, rt, overnight (12{2−3,5−7}, 81−97%); (j) HCl
(37%, 20.0 equiv), 1,4-dioxane, reflux, 8 h (quantitative); (k) SOCl2 (6.0 equiv), MeOH, rt, overnight (14{2−7}, 45−82%); (l) Red-Al (70% in
toluene, 3.0 equiv), toluene, 0 to 110 °C, 2 h (15{2−7}, 59−81%); (m) p-TSA (0.2 equiv), N-benzylpiperidone (1.1 equiv), MeOH (dry), reflux, 4 h
(16{1−7}, 38−67%); (d) R2COCl (2.5−3.0 equiv), DIPEA (4.0−6.0 equiv), DCM, 0 to 40 °C, 1−3 days (average 96%), see Table 3; (e) H2 (1 atm),
Pd(OH)2/C (0.05 equiv), MeOH, rt, 2−6 h (quantitative), (f) R3COCl (1.5 equiv), Et3N (5.0 equiv), THF, rt, overnight; (f′) R3COOH (2.0 equiv),
HOBt (2.0 equiv), EDC*HCl (2.5 equiv), DIPEA (5.0 equiv), DCM, 50 °C, overnight (19); (g) R3CHO (2.0 equiv), NaBH(AcO)3 (2.5 equiv), AcOH
(2.0 equiv), DCE, rt, overnight (20); (h) R3SO2Cl (1.5 equiv), Et3N (5.0 equiv), THF, rt, overnight (21); (i) R3NCO (1.5 equiv), Et3N (5.0 equiv),
DCM, rt, overnight (22).
elements at virtually every step, thus offering versatile oppor-
tunities to afford analogues and matched molecular pairs of clear
value during hit evaluation and SAR exploration campaigns.
The inclusion of bis-spirocyclic-based libraries in the Public
Compound Collection39 of the ELF and their exposure to >100
HTSs during the ELF project life cycle will provide an important
test to evaluate their biological relevance, target class propensity
and overall suitability in a drug discovery setting.
‡D.E. Shaw Research LLC, 120W 45th St., New York, NY
10036, USA.
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
ASSOCIATED CONTENT
■
■
We thank Xenia Iwanowa and Martyna Bielska for high-
throughput HPLC purification. The research leading to these
results has received support from the Innovative Medicines
Initiative Joint Undertaking under grant agreement no. 115489,
resources of which are composed of financial contribution
from the European Union’s Seventh Framework Programme
(FP7/2007-2013) and EFPIA companies’ in-kind contribution.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombsci.6b00005.
General procedures and characterization data of repre-
sentative compounds (PDF)
AUTHOR INFORMATION
■
REFERENCES
■
Corresponding Author
*Tel: +1 (212) 478 0822. E-mail: fabrizio.giordanetto@
deshawresearch.com.
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́
2 12580 Benicarlo, Spain.
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