An iron-catalysed C-C bond-forming spirocyclization cascade providing sustainable access to new 3D heterocyclic frameworks

Article abstract of DOI:10.1038/nchem.2670

Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp³ -carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C-C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac) 3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.

Full text of DOI:10.1038/nchem.2670

ARTICLES
PUBLISHED ONLINE: 12 DECEMBER 2016 | DOI: 10.1038/NCHEM.2670
An iron-catalysed C–C bond-forming
spirocyclization cascade providing sustainable
access to new 3D heterocyclic frameworks
1
1
1
1
2†
1
Kirsty Adams , Anthony K. Ball , James Birkett , Lee Brown , Ben Chappell , Duncan M. Gill ,
1
1
1
1
2,3
P. K. Tony Lo , Nathan J. Patmore , Craig. R. Rice , James Ryan , Piotr Raubo
and Joseph B. Sweeney1
*
Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of
3
heterocycles containing a high proportion of sp -carbon atoms, which confer precise spatial definition upon chemical probes,
drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently
reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method
allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C–C
bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily
available from plant sources. Fe(acac) mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by
3
capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The
reactions offer potential entry to key structural motifs present in bioactive natural products.
etal-catalysed C–C bond-forming reactions have revolutio-
We hypothesized that spiroheterocycles could be accessed effi-
nized contemporary synthetic chemistry in academia and ciently via an iron-catalysed C–C bond-forming cascade (Fig. 1c),
industry, and commercial products (including polymers, involving a tandem cyclization–alkylation process. We predicted
M
diagnostic materials, fine chemicals and active drug substances) are reg- that an aryl-iron species 2 (formed by insertion into a halide or
ularly prepared in bulk using these methods. Modern catalysis research- pseudohalide bond of the iron complex created by reaction of an
ers are faced with additional financial, regulatory and environmental iron(III) salt with a Grignard reagent) would undergo dearomatizing
1
5
demands to deliver lower waste-footprints, as well as more efficient cyclization onto a pendant furan scaffold, followed by reductive
and cost-effective methods for catalytic C–C bond formation; these elimination of the most stable allyl-iron isomer (3) to give alkyl-
demands have stimulated intense interest in the use of Earth-abundant or arylated product 4. In addition to allowing an innovative entry
catalysts1 and recently the application of iron catalysts in particular to the spirocyclic motif, the incorporation of an alkene in the
–3
4–7
has received much attention . In parallel, the use of biomass to product also allows for further diversification and mapping of
deliver high-value chemical commodities has been recognized as chemical space. Here we report the realization of this strategy, and
increasingly significant when traditional sources for chemical feed- the delivery of a novel and sustainable iron(III)-catalysed arylative
stocks dwindle. The application of catalysis to encompass biomass- spirocyclization reaction which delivers spiro bis-heterocycles effi-
derived substrates is, therefore, an impactful research theme.
Chemical processes delivering functional heterocycles are also
ciently and stereoselectively.
inherently impactful, due to the known utility of these small Results
molecules. Within the broad heterocyclic sub-class, the presence of A core feature of our strategy (Fig. 1c) was the use of substrates
heteroatoms constrained about quaternary carbon centres endows that could be derived in bulk from biomass, offering the prospect
well-defined spatial constraints that are often beneficial, for instance of a more sustainable method for accessing novel spiro heterocycles.
in enhancing selectivity in drug-binding. Within this sub-class, Thus we targeted the use of furfuryl alcohol as a lynchpin biomass-
8
heterocycles bearing quaternary centres are privileged molecules ; 1,7- derived component, available in bulk directly from plant sources
1
6
bis-heterospirocycles (Fig. 1a) are members of this family of constrained (such as corn cobs ) using simple benchtop procedures. Activation
small molecules, with both natural (such as genkwanol A (ref. 9) followed by reaction with 2-halophenols gave the cyclization tem-
and aspergillines (ref. 10)) and synthetic examples (such as BRD7016 plates 5-Hal (Table 1), which were reacted with phenyl magnesium
(
refs 11,12) and compound 1 (ref. 13)) of these structures reported to bromide at room temperature in the presence of Fe(acac) (5 mol
3
1
7
be bioactive. However, synthetic access to the core framework of this %). Though reaction with the chloride was not productive , the cor-
class of spirocycle is limited. The practical preparative routes that responding bromide and iodide delivered phenylated spirocycle 6a
allow access to the ring systems shown in Fig. 1 most often feature directly (Table 1, entries 2 and 3).
[
2+3] cycloadditions (Fig. 1b). This reaction class most often features
The tricyclic product 6a was delivered from the reaction of
1
4
tandem formation of C–C and C–X bonds, often in two distinct steps . iodoether 5-I as an 85:15 ratio of diastereoisomers (deduced from
1
2
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK. AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield SK10
3
4
TG, UK. AstraZeneca Pharmaceuticals, Oncology Chemistry, Hodgkin Building, c/o Darwin Building, Unit 310, Cambridge Science Park, Milton Road,
†
Cambridge CB4 0FZ, UK. Present address: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
e-mail: j.b.sweeney@hud.ac.uk
*
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©

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2670
ARTICLES
a
HO
b
c
O
OH
X
X
N
O
O
O
–
Y
N
O
Y
O
HO
O
+
HO
O
Core framework
OH
Me2SiAr
BRD7016
OH
Biomass-
derived
Earth-abundant
catalyst
OH
Genkwanol A
PARP-1 inhibitor
X
X
X
Carcinoma growth inhibitor
FeLn
Insertion
exo-cyclization
Y
Y
Y
Hal
Fe
H
N
Ln
N
FeLn
O
Repulsive
interaction
O
Insertion site
2
Br
O
H
O
OH
Two
C–C bonds
formed
H
OH OH
O
H
HN
X
X
N
Nucleophilic
capture
X
CO2Et
O
O
Y
Y
Y
Aspergilline A
Anti-TMV activity
1
Synthetically
tractable
RMgL
LnFe
Anti-fungal activity
R
FeLn
4
3
Figure 1 | Synthesis of spirocyclic bis-heterocycles that are the cores of natural products. a, Selected examples of biologically active natural products
featuring spirocyclic bis-heterocycles. The activity and biological properties of these molecules are often heavily predicated on the 3D arrangement of the
heteroatoms at their cores. Spirocycles result in a unique spatial arrangement of these heteroatoms and play a key role in binding to biomolecules. b, The [2+3]
cycloaddition is the most frequently used method used to access spirocyclic bis-heterocycles. However, this approach places limitations on the substrates
that can be used as precursors to spirocycles, sometimes requiring tailored electronic properties for the coupling partners. c, This work demonstrates a
new strategy for preparing spirocyclic bis-heterocycles using an iron-catalysed cyclization/nucleophile-capture process. In addition to using an inexpensive
Earth-abundant catalyst, this approach broadens the scope of suitable substrates and permits the inclusion of an alkene in the ultimate product, which can
be used for further elaboration.
Table 1 | Influence of solvent, catalyst and stoichiometry on iron-catalysed cascade.
O
O
O
Fe(acac)3 (5 mol%), PhMgBr
O
Solvent, r.t., 6 h
Hal
Ph
5
-Hal
6a
Entry
Catalyst
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
5-Hal
Solvent
PhMgBr eq.
Conversion (%)
Yield 6a (%)
1
3
5-Cl
5-Br
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
5-I
THF/NMP (8:1)
THF/NMP (8:1)
THF/NMP (8:1)
NMP
THF/NMP (1:3)
THF/NMP (1:1)
THF/NMP (3:1)
THF
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
–
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
0
0
2
3
4
5
6
7
8
9
3
29
41
9
3
3
3
36
44
27
30
33
27
37
55
27
19
0
0
12
0
0
0
3
3
3
3
Et
NMP
Et
Et
Et
Et
2
O/NMP (8:1)
1
1
1
1
1
1
1
1
1
1
0
1
3
3
2
O/NMP (1:3)
O/NMP (1:1)
O/NMP (3:1)
O
2
3
4
5
6
7
8
9
3
2
3
2
3
2
3
DMF/NMP (8:1)
DMPU/NMP (8:1)
DMA/NMP (8:1)
Dioxane/NMP (8:1)
3
3
Fe(acac)
3
–
Et
Et
Et
Et
Et
Et
Et
Et
Et
2
O/NMP (1:1)
O/NMP (1:1)
O/NMP (1:1)
O/NMP (1:1)
O/NMP (1:1)
O/NMP (1:1)
O/NMP (1:1)
O/NMP (1:1)
O/NMP (1:1)
2
2
2
2
2
2
2
2
0
1
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
FeCl
3
2
0
3
2
1.2
1.8
2.4
2.4
2.4
2.4
2.4
100
100
100
100
43
63
64
73
70
7
2
3
4
5
6
7
3
2
3
2
3
2
Fe(dbm)
Fe(dpm)
3
2
3
2
100
0
39
0
2 4
Fe (SO )
3
2
dbm, dibenzoylmethide; dpm, dipivaloylmethide; NMP, N-Methyl-2-pyrrolidone.
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2670
ARTICLES
Table 2 | Scope of Grignard partner in iron-catalysed arylative spirocyclization.
O
O
Fe(acac)3 (5 mol%), ArMgBr
O
O
Et2O, NMP
r.t. 6 h
I
Ar
5-I
cis-6a–q
O
O
O
O
O
O
O
O
O
O
6
a
6b
76%
92:8
6c
94%
>95:5
6d
74%
94:6
6e
98%
>95:5
‡
Yield* = 73%
d.r. = 92:8
†
O
O
O
O
O
O
O
O
O
O
6
5%
5:5
f
6g
49%
90:10
6h
93%
>95:5
6j
83%
>95:5
6
5%
i
9
9
Cl
F
‡
OCF3
O
5
93:7
O
O
O
O
O
O
O
O
O
O
O
O
F
6
88%
94:6
m
6n
58%
91:9
6o
62%
>95:5
6l
68%
92:8
S
6k
84%
S
90:10
O
O
O
O
Me
Ph
6
p
6
q
Me
36%
63%
93:7
95:5
†
‡
*
Isolated yield of major diastereomer; Determined by HPLC analysis of crude product; Catalyst = FeCl3.
1
H NMR experiments), in favour of the cis-spirocycle in which the and heteroaryl Grignards (Table 2), delivering previously
two new C–C bonds are formed on opposite sides of the dihydro- unknown spiroheterocycles as predominantly cis-diastereomers
furan motif. Armed with these most encouraging preliminary (confirmed by X-ray analysis of product 6c, Supplementary page
data, we proceeded to the optimization phase of the project. Being 45). Though the reaction of aryl Grignards was productive, in
mindful of Cahiez’s seminal studies18 of the interplay of solvent accord with previous observations the use of alkyl Grignard
and additives in iron-catalysed C–C bond-forming reactions, we reagents in the spirocyclization reaction was not efficient, with
looked at the effect of solvent on the reaction, with additional only EtMgBr delivering alkylated product 6p (Table 2) in
focus on the relative NMP content (Table 1). This screening reasonable quantities.
process indicated the optimum reaction medium to be Et O/NMP
One of the attractive features of iron-catalysed organometallic
reactions is the decreased tendency for termination via
2
(1:1, Table 1, entry 12).
The next phase of optimization examined a range of stable iron(III) β-hydride elimination of C–Fe σ-bonds. Since the postulated
catalysts in the arylative spirocyclization reaction (Table 1, entries intermediates in the reaction described above did not have the
3–27). It was confirmed that the catalyst was essential for the possibility for reductive elimination, we were keen to test a sub-
reaction to take place (entry 19) and that FeCl seemed generally as strate where reductive elimination was possible, such as
2
3
1
9
effective a catalyst as Fe(acac) (entry 24). When Grignard reagent 5′-methyl substrate (easily accessible from furfuryl alcohol );
3
was omitted, starting material was returned. It was notable that when this compound was used in the arylative spirocyclization
conversion and yields were consistently improved when an excess reaction, a good yield of arylated product 6q was obtained
of Grignard reagents was employed, with the use of 2.4 equivalents (Table 2), confirming the low propensity of the intermediate
leading to the highest yields. Iron complexes bearing bulkier iron species to undergo reductive elimination.
ligands were less productive in the reaction (entries 25 and 26) but
The ability to incorporate other substituents into the aromatic
only Fe (SO ) proved ineffective, resulting in no conversion (entry ring of the substrate, and the ability to deliver nitrogen-containing
2
4 3
27). Having identified an optimized reaction protocol (Table 1, heterocycles using this method were important requirements for
entry 23), we turned to an examination of the scope of the reaction. the process. Thus we were delighted to observe that the iron-cata-
It quickly transpired that this arylative spirocyclization reaction lysed arylating spirocyclization reaction does indeed allow access
is highly stereoselective, generally efficient using a range of aryl to a range of nitrogen-containing heterocycles, and also products
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2670
Discussion
Having demonstrated the power of our new method in the prep-
aration of novel, natural-product-like spiroheterocycles, we turned
our attention to the mechanistic features of the reaction.
ARTICLES
Table3 | Scope in heteroatom and substituent pattern in
iron(III)-catalysed arylative spirocyclization.
Y
X
Z
X
I
Fe(acac)3 (5 mol%), ArMgBr
The mechanisms in play during iron-catalysed cross-coupling
Y
2
0,21
Et2O, NMP
r.t., 6 h
reactions
are complex and often not well-understood, and the
cis-7a–k
Z
Ar
dearomatizing arylative spirocyclization described here could
involve one of several possible pathways. We believe that it is likely
that the reaction proceeds via a catalytically competent Fe(II)
O
O
O
Boc
Boc
N
Boc
22–25
species
leading to σ-aryl iron intermediate 8 which cyclizes
N
N
1
26
3
to give η -allyl iron species 9 (Fig. 2), able to equilibrate to η -
isomer 10. If 10 is able undergo isomerization (by dissociation–
recomplexation or homolysis–recombination) to avoid a repulsive
peri interaction, it will be converted to less-hindered isomer 11,
which can be captured by Grignard reagent to deliver the observed
product after reductive elimination (and concomitant catalyst
regeneration). Alternatively, 9 may undergo direct anti-attack by
7a
7b
77%
>95:5 Me
7c
85%
>95:5
92% yield
d.r. >95:5
Ph
Boc
N
Boc
O
N
Boc
N
2
2
7
Grignard to give η -complex 12, which will again deliver the ary-
O
O
7d
lated spiroheterocyclic product, this time by decomplexation.
7
f
7e
28
77%
Finally, it is possible that the process involves a radical mechanism :
9
95:5
4%
>
95:5
63%
OMe
if the initially formed σ-Fe–C bond undergoes homolysis to give aryl
radical 13, which cyclizes to give 14, radical recombination will give
Me
O
90:10
1
Boc
Boc
O
the same η -intermediate 11 as postulated for the Fe(I)/(II) pathway.
Cl
N
N
Since reactions carried out in the presence of radical inhibitors and
scavengers had little discernable impact upon the yield of the reac-
O
tion (reaction of 5-I with Fe(acac) and PhMgBr in the presence of
O
3
5
mol% of either TEMPO or BHT gave a 76% yield of 6a in both
7
g
7h
74%
>95:5
7i
50%
86:14
8
6%
cases), a radical chain pathway seems unlikely but the involvement
of homolytic processes cannot be categorically excluded at
this point.
>
95:5
Ph
OMe
MeO
O
O
In an attempt to gain insight into the nature of the iron catalyst
involved in the reaction, we exposed Fe(acac) to one equivalent of
3
MeO2C
O
O
Grignard in the absence of iodide substrate; after careful manipu-
lation of the product of this reaction we isolated and characterized
bimetallic iron(II) complex 15. When 15 was used in place of Fe
7j
7k
77%
>95:5
58%
90:10
(
acac) in the arylative spirocyclization reaction, a similar yield of
3
product was obtained (Fig. 3), suggesting that this dearomatizing
bearing substituents in the parent carboaromatic ring (Table 3). Of spirocyclization process proceeds through the intermediacy of an
particular note are products 7i and 7k, containing potentially fragile iron(II) species. Confirming the precise mechanistic details of the
halogen and ester moieties, respectively.
transformation is the subject of our research focus at this time.
(
i)
LnFe
X
LnFe
H
Homolytic path
Y
LnFe
X
Y
Y
X
8
13
14
Ln
Fe
H
Repulsive
interaction
Iron-allyl
path
LnFe
H
LnFe
Y
H
FeLn
(ii)
Y
H
H
Y
Y
X
X
X
X
9
10
11
Direct attack
path
RMgX
(iii)
RMgX
H
X
Ln
Fe
R
H
Y
Y
R
X
12
6
Figure 2 | Polar and free-radical mechanistic possibilities in iron-catalysed arylative spirocyclization. The mechanism by which the spirocyclization reaction
proceeds could follow one of several routes: (i) Homolysis of the initial aryl-iron species 8 would lead, via ultimate radical recombination, to key π-allyl iron
2
2
intermediate 11; (ii) polar cyclization, followed by isomerization of η π-allyl iron species 9 to intermediate 11 via 10; or (iii) direct capture of η π-allyl iron
species 9 by a Grignard reagent.
4
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©

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2670
ARTICLES
a
Ph
O5
MgBr
Br1
(
1 eq.)
Fe(acac)3
+
FeBr2[Mg(acac)2]THF2
O3
THF, r.t.
O2
Yellow-orange crystals
Fe1
O4
Mg1
O6
O1
15
Ph
Br2
b
O
O
FeBr2[Mg(acac)2]THF2 (5 mol%),
O
100% conversion
ArMgBr (2.4 eq.)
O
I
9
7% isolated yield
Et2O/NMP (1:1), r.t., 6 h
d.r. >95:5
(Ar = 4-Ph-C6H4)
5-I
6a
Ph
Figure 3 | Verification of the role of Fe(II) in the spirocyclization reaction. a, A bimetallic Mg–Fe(II) complex 15 is formed by the reaction of a Grignard
reagent with the Fe(III) catalyst. This complex was isolated and characterized crystallographically. b, The Fe(II) product can catalyse the arylative
spirocyclization reaction with comparable results to the reaction with Fe(acac) . While the precise mechanistic details of the reaction are still unknown, this
3
suggests that an initial in situ reduction of the Fe(III) pre-catalyst is likely the first stage of the reaction, which may have implications in future developments
of this reaction.
In summary, we have designed and implemented a novel cycliza- 11. Franz, A. K., Dreyfuss, P. D. & Schreiber, S. L. Synthesis and cellular profiling
of diverse organosilicon small molecules. J. Am. Chem. Soc. 129,
tion/anion capture process, mediated by Earth-abundant catalysts,
1020–1021 (2007).
which efficiently delivers spiro-bisheterocycles. The process is effi-
cient and rapidly delivers these complex frameworks in short
order, using biomass-derived components.
1
2. Hartwell, K. A. et al. Niche-based screening identifies small-molecule inhibitors
of leukemia stem cells. Nat. Chem. Biol. 9, 840–848 (2013).
3. Wu, J.-S., Zhang, X., Zhang, Y.-L. & Xie, J.-W. Synthesis and antifungal activities
of novel polyheterocyclic spirooxindole derivatives. Org. Biomol. Chem. 13,
4967–4975 (2015).
4. Badillo, J. J., Hanhan, N. V. & Franz, A. K. Enantioselective synthesis of
substituted oxindoles and spirooxindoles with applications in drug discovery.
Curr. Opin. Drug Discov. Devel. 13, 758–776 (2010).
5. Zhuo, C.-X., Zheng, C. & You, S.-L. Transition-metal-catalyzed asymmetric
allylic dearomatization reactions. Acc. Chem. Res. 47, 2558–2573 (2014).
6. Adams, R. & Voorhees, V. Furfural. Org. Synth. 1, 49–51 (1921).
7. Fürstner, A. et al. Preparation, structure, and reactivity of non-stabilized
organoiron compounds. Implications for iron-catalyzed cross coupling
reactions. J. Am. Chem. Soc. 130, 8773–8787 (2008).
1
Data availability
The crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre (CCDC) as CCDC 1508541 (6c at
1
150 K) and 1508540 (15 at 150 K) and can be obtained free of
1
charge from the CCDC via www.ccdc.cam.ac.uk/getstructures.
1
1
Received 1 April 2015; accepted 7 October 2016;
published online 12 December 2016
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2670
ARTICLES
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Author contributions
K.A., A.K.B., J.B., B.C., P.K.T.L. and J.R. carried out all cyclization experiments, under the
supervision of J.B.S., aided by D.M.G. and P.R. Isolation of complex 15 was carried out by
L.B. and J.B. under the supervision of N.J.P. and J.B.S. X-ray crystallography was carried out
by C.R.R. The ideas were conceived by B.C. and J.B.S. Reactions were conceived and
designed by J.B.S. The manuscript was written by J.B.S.
2
7. Sekine, M., Ilies, L. & Nakamura, E. Iron-catalyzed allylic arylation of olefins via
C(sp3)-H activation under mild conditions. Org. Lett. 15, 714–717 (2013).
8. Ekomi, A. et al. Iron-catalyzed reductive radical cyclization of organic halides in
2
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the presence of NaBH : evidence of an active hydrido iron(I) catalyst.
Angew. Chem., Int. Ed. 51, 6942–6946 (2012).
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to J.B.S.
Acknowledgements
The authors acknowledge financial support from the Engineering and Physical Sciences
Research Council (Organic Synthesis Studentship grant EP/G040247/1), AstraZeneca
Pharmaceuticals and the University of Huddersfield. J.B.S. is grateful to the Royal Society,
for the award of an Industry Fellowship. Dedicated to the memory of Sarah Hicks, a young Competing financial interests
chemist who died at Hillsborough.
The authors declare no competing financial interests.
6
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2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.