Discovery of neuritogenic compound classes inspired by natural products

Article abstract of DOI:10.1002/anie.201302045

Neuroactive! An enantioselective, catalytic synthesis strategy provides rapid access to natural-product-inspired classes of neuritogenic compounds (see scheme). The goal is to find interesting chemical probes to shed light on neurodevelopmental processes and foster a better understanding of the complex biology and physiology of neuronal development and related neurodegenerative disorders. Copyright

Full text of DOI:10.1002/anie.201302045

Angewandte
Chemie
Communications
Neuritogenic Small Molecules
Neuroactive! An enantioselective,
catalytic synthesis strategy provides rapid
access to natural-product-inspired
classes of neuritogenic compounds (see
scheme). The goal is to find interesting
chemical probes to shed light on neuro-
developmental processes and foster
a better understanding of the complex
biology and physiology of neuronal
development and related neurodegener-
ative disorders.
P.-Y. Dakas, J. A. Parga, S. Hçing,
H. R. Schçler, J. Sterneckert, K. Kumar,*
H. Waldmann*
&&&& — &&&&
Discovery of Neuritogenic Compound
Classes Inspired by Natural Products
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DOI: 10.1002/anie.201302045
Neuritogenic Small Molecules
Discovery of Neuritogenic Compound Classes Inspired by Natural
Products**
Pierre-Yves Dakas, Juan A. Parga, Susanne Hçing, Hans R. Schçler, Jared Sterneckert,
Kamal Kumar,* and Herbert Waldmann*
Dedicated to the Bayer company on the occasion of its 150th anniversary
The progressive degeneration and impaired restoration of
neurons are hallmarks of neurodegenerative disorders for
which neuroprotective and neurite-growth-promoting small
molecules[1] are in high demand.[2] The characteristic struc-
tural scaffolds of classes of neuroprotective or neurotrophic
natural products (NPs)[3] may define biologically prevalidated
starting points in vast chemical structure space inspiring the
design and synthesis of compound collections endowed with
the same or similar kind of biological activity.[4] Different
iridoid glycosides[5] and sesquiterpenoids[6] possess pro-
nounced neuritogenic properties (for relevant examples see
Figure 1a), and therefore their structural scaffolds may
provide valuable targets for the synthesis of natural-prod-
uct-inspired compound libraries endowed with neurite-
growth-promoting activity.
Here we report the enantioselective synthesis[7] of an
iridoid-inspired compound collection, its investigation in
phenotypic assays monitoring modulations in neurite out-
growth from primary hippocampal neurons and motor
neurons derived from mouse embryonal stem cells, and the
Figure 1. a) Natural products with neurobiological activities. b) Plan
for the synthesis of two focused libraries based on the pentalenone (9)
[*] Dr. P.-Y. Dakas, Dr. K. Kumar, Prof. H. Waldmann
Max Planck Institut fꢀr molekulare Physiologie
Otto-Hahn Strasse 11, 44227 Dortmund (Germany)
and the cyclopenta[c]pyranone scaffold (10).
Dr. K. Kumar, Prof. H. Waldmann
discovery of two novel natural-product-inspired neuritogenic
compound classes. The screen revealed two novel classes of
natural-product-inspired neuritogenic compounds.
We envisaged that the [3+2] cycloaddition of allene-
derived zwitterions 8[8] and cyclopentenones 7 catalyzed by
a chiral phosphine[9] would provide pentalenones 9, and that
subsequent regioselective Baeyer–Villiger (BV) oxidation[10]
would yield the iridoid-inspired scaffold 10 (Figure 1b).
Cyclopentenones have not been employed previously in this
zwitterionic annulation.[11]
Technische Universitꢁt Dortmund, Fachbereich Chemie
44221 Dortmund (Germany)
E-mail: Kamal.Kumar@mpi-dortmund.mpg.de
Herbert.Waldmann@mpi-dortmund.mpg.de
Dr. J. A. Parga,[+] Dr. S. Hçing, Prof. H. R. Schçler, Dr. J. Sterneckert
Department of Cell and Developmental Biology
Max Planck Institute for Molecular Biomedicine
Mꢀnster (Germany)
Prof. H. R. Schçler
University of Mꢀnster, Medical Faculty
Mꢀnster (Germany)
[+] Present address:
While cyclopentenone 7 (R = H) did not undergo the
cycloaddition, cyclopentenone 11a reacted smoothly with the
zwitterion derived from allene ester 12a to yield the desired
pentalenone ring system 13a (Scheme 1).The additional
carbonyl group embedded in 11a enhances the reactivity of
the cyclopentenone and provides an additional opportunity to
increase the diversity of the final products (see below).
Unexpectedly, BV oxidation of 13a yielded the undesired
regioisomer 14 (Scheme 1), indicating that in the presence of
an ester group, formation of the tertiary carbocation is still
favored. Introduction of an a,a-dimethyl group, which favors
the formation of a stabilized carbocation, and exchange of the
Center for Research in Molecular Medicine and Chronic Diseases
University of Santiago de Compostela (Spain)
[**] This work was funded by the European Union Seventh Framework
Programme under grant agreement no. HEALTH-F2-2009-241498
(“EUROSPIN” project) and the German Federal Ministry for
Education and Research through the German National Genome
Research Network-Plus (NGFNPlus) (grant no. BMBF 01GS08104).
P.-Y.D. thanks the Alexander von Humboldt Foundation for
a fellowship. We also thank Dr. Sonja Sievers, COMAS, MPI
Dortmund for helping with the data analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302045.
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Table 1: Enantioselective [3+2] annulation of cyclopentenones 11 with
allene-derived zwitterions.
Entry
Prod.
R1
R2
Yield [%]
ee [%]
PBu3/16
1
2
3
4
5
6
7
8
13b
13c
13d
13e
13 f
13g
13h
13i
Ph
Ph
H
Me
H
H
H
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
66/72
54/76
61/69
64/71
59/77
54/70
51/73
68/81
85/90
58/71
65/70
65/80
61/75
60/66
53/71
58/56
60/55
33/–
95
90
94
93
92
97
90
95
92
94
91
93
91
96
88
98
81
–
Scheme 1. Synthesis of target scaffolds.
1-naphthyl
4-PhC6H4
3,5-tBu2C6H3
3,4-BrFC6H3
3,4-BrFC6H3
3-(4-ClC6H4)C6H4
3-(4-ClC6H4)C6H4
4-(BnO)C6H4
4-(BnO)C6H4
3,5-MeOC6H3
3,5-MeOC6H3
2-benzofuryl
2-benzofuryl
4-(2-methyloxazolyl)
4-(2-methyloxazolyl)
4-pyridyl
4-pyridyl
isopropyl
isopropyl
cyclohexyl
cyclohexyl
t-butyl
t-butyl
ester for a more strongly electron-withdrawing ketone
efficiently changed the regioselectivity in the BVoxidation.[10]
Thus, treatment of 13b with magnesium bis(monoperoxyph-
thalate) hexahydrate (MMPP)[12] yielded the desired iridoid
natural-product-inspired scaffold 15 (Scheme 1).
9
13j
13k
13l
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
For the synthesis of the compound collection, cyclo-
pentenone building blocks 11 (Table 1) (for their synthesis see
the Supporting Information) were subjected to the [3+2]
cycloaddition in the presence of either tri-n-butylphosphine
or the enantiopure bidentate N-acylaminophosphine catalyst
16[9d] (Table 1). Use of g-methyl allene ester 12b (R2 = Me,
entry 2) resulted in a good yield of a cyclopentenone product
with an extra methyl group; product 13c contains three
contiguous stereogenic centers including an all-carbon qua-
ternary center. The relative stereochemistry and the absolute
configuration of the cycloadducts were ascertained by means
of NOE experiments and modified Mosher ester analysis,
respectively (for details, see the Supporting Information).
The asymmetric [3+2] annulation in the presence of
organocatalyst 16 proceeded in high yield, and with high
regio-, diastereo-, and enantioselectivity at room temperature
(Table 1). The yields were significantly better than those
obtained from the reactions with tri-n-butylphosphine
(Table 1), and generally only one regioisomer was formed
with high enantiomeric excess (for details see the Supporting
Information). Decreasing the reaction temperature to À208C
did not improve the enantioselectivity but lowered the yields.
The [3+2] annulation tolerates a variety of aryl and alkyl
substituents appended to the keto group, including bulky,
electron-deficient, and electron-rich aryl groups (Table 1,
entries 1–13). The reaction also proceeded well with cyclo-
pentenones bearing heterocyclic ketones (Table 1, entries 14–
17). Also in these cases catalyst 16 afforded higher yields than
tri-n-butylphosphine and provided high to excellent ee values.
Cyclopentenone annulation products containing pyridyl
ketones were difficult to handle and decomposed during the
reaction and purification (Table 1, entries 18 and 19). Alkyl
ketones reacted well in the annulation reaction (despite acidic
a-protons) and yielded the bicyclic ring system in high yields
(Table 1, entries 20–25). The highest enantiomeric excess was
obtained for annulation adduct 13y bearing a tert-butyl
ketone (99% ee; Table 1, entry 24). The broad scope, high
13m
13n
13o
13p
13q
13r
13s
13t
13u
13v
13w
13x
13y
13z
28/–
–
70/90
76/92
70/88
79/94
74/89
75/88
96
91
96
91
99
92
Me
yields, and enantioselectivity of the asymmetric [3+2] annu-
lations of zwitterions 8 with cyclic olefins are unprecedented .
For the BVoxidation of ketones 13 to the desired lactones
15 the best results were obtained with four equivalents of
MMPP in methanol/water (1:1) at room temperature.[12]
Under these conditions the desired lactone 15 (R1 = Ph) was
obtained in 40% yield after six days at room temperature
together with the doubly oxidized product 17 (R1 = Ph)
(Table 2, entry 1). At higher reaction temperature the doubly
oxidized products 17 were formed in higher yields (Table 2,
entries 6 and 8). In general, the BV oxidation proceeded
without formation of further undesired products and yielded
the desired lactones incorporating aromatic, heteroaromatic,
and alkyl ketones in moderate to high yields (Table 2).
For the synthesis of a focused collection of analogues the
functional groups embedded in or appended to the bicyclic
scaffolds were subjected to various transformations. Dihy-
droxylation of the olefin in 13 and 15 proceeded smoothly and
with complete diastereoselectivity providing highly substi-
tuted diols 18 and 20, respectively, in excellent yields.
Selective acylation of the secondary alcohol in 18 was
successfully achieved providing ester 19. Olefin epoxidation
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Table 2: BV oxidation of bicyclic adducts 13 to gove lactones 15 and 17.
The compound collection was screened for neurite-out-
growth-promoting activity in tests employing primary neu-
rons. Although more sensitive and technically more demand-
ing to manipulate and assay, the use of primary neuronal
cultures of hippocampi from E18/E19 Sprague Dowley rats
was preferred over frequently employed model cell lines, in
particular PC12 cells that have a tumorigenic origin.[13]
During the first days in cell culture, individual neuronal
processes emanating from hippocampal neurons can be
visualized in their entirety, thus allowing a direct observation
of, for example, growing neurites, axons, and the degree of
branching. Initially the primary neurons were treated with
racemic molecules as DMSO solutions at 10 mm and 1 mm
concentration for two days; then the cells were fixed and
stained with a membrane dye, and the overall membrane
formation was quantified by spectrophotometric readout at
550 nm (see the Supporting Information for details).
Enhanced fluorescence relative to that of the DMSO control
thus provides a direct measurement of the enhanced neurite
outgrowth induced by the compounds.
Entry R1
Conv. [%] 15 Yield [%] 17 Yield [%]
1
2
3
4
5
6
7
8
Ph
60[a]
49[b]
66[b]
85[a]
53[a]
80[b]
70[a]
80[b]
40
49
52
62
53
–
70
50
78
32
37
20
–
14
23
–
80
–
30
–
1-naphthyl
3,5-tBu2C6H3
3,4-BrFC6H3
3-(4-C6H4)C6H4
3-(4-C6H4)C6H4
3,5-MeOC6H3
3,5-MeOC6H3
9
10
11
4-(2-methyloxazolyl) 78[c]
isopropyl
cyclohexyl
32[b]
37[b]
–
–
Reaction conditions: [a] 6 days, RT; [b] 6 days, 508C; [c] 3 days, RT.
Gratifyingly, the screen identified compounds 18b and
17b as interesting hits that substantially enhanced the overall
formation of neuronal membranes. Neurons with an
enhanced overall membrane signal can have very different
morphology which cannot be discriminated without a specific
analysis which dissects dendritic branching. In order to
visualize the complexity of the neuronal network developed
as a consequence of compound treatment, the mean total
length of the neurites should be judged against the mean total
number of neurites (Figure S1 in the Supporting Informa-
tion). Thus, the enantiomers 17b and racemic (Æ)-18b were
subjected to further indepth analysis. Quantitative analysis of
confocal images acquired after exposure for five days
revealed that (Æ)-18b (1 mm) significantly induced the
formation of more complex neuronal networks (Figure 2).
Racemic (Æ)-18b enhanced the mean total neurite length per
cell primarily because it generates a higher number of
neurites per cell than BDNF does (Figure 2a,b). The enan-
tiomers of 17b displayed remarkable differences in neuro-
trophic activity. While (R,R)-17b enhanced the mean single
neurite length by twofold relative to the DMSO control
(Figure 2c,d), enantiomeric (S,S)-17b was cytotoxic as indi-
cated by membrane blebbing (see Figure S2 in the Supporting
Information).
in 13, 15/17 smoothly provided 21 and 22, respectively in
excellent yields (see the Supporting Information for details).
Compounds 13 apparently favored a completely stereoselec-
tive epoxidation (21, Scheme 2). Epoxide ring-opening in 21
was performed with methanol as the nucleophile under mildly
acidic conditions leading to 23. DibalH reduction of the keto
group in 15 provided the iridoid scaffold 24 incorporating
a secondary alcohol. Interestingly, upon attempted formation
of an acetal, scaffold 15 underwent decarboxylation to yield
the product 25 in excellent yield (Scheme 2).
In light of the encouraging neurite-growth-enhancing
effects on primary hippocampal neurons we investigated
whether the compound collection also contains members that
modulate the differentiation and development of motor
neurons derived from mouse embryonal stem cells (ESCs).
Compounds endowed with such properties are potentially
relevant for applications in regenerative medicine and their
discovery is challenging. Glial cell line derived neurotrophic
factor (GDNF), which is important for neuronal develop-
ment, neurogenesis, and neuronal survival[14] and in neuro-
degenerative disorders,[15] was used as a positive control. The
neuronal complexity resulting after the treatment with the
compounds (10 mm) was quantitatively analyzed by measuring
parameters for neuronal cells that characterize mean and
total neurite length, neurite branching, mean and total neurite
Scheme 2. Functionalization of the bicyclic scaffolds. Reaction condi-
tons: a) OsO4, NMO, THF/H2O, RT; b) R3COCl or R3CO2H, RT;
c) mCPBA, RT; d) pTSA, MeOH, 458C, 3 days; e) DibalH, À788C;
f) pTSA, (CH2OH)2, RT. NMO=N-methylmorpholine N-oxide,
mCPBA=meta-chloroperbenzoic acid, pTSA=para-toluenesulfonic
acid, DibalH=diisobutylaluminum hydride.
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Figure 2. Neurite-outgrowth-promoting activity on primary cultured rat hippocampal neurons and quantification of morphological changes.
a) Morphology of neurons treated with DMSO (negative control; 1:10000 dilution), BDNF (positive control), and racemic 18b (1 mm);
b) comparative effect of 18b on the number and length of neurites; c) morphology of neurons treated with DMSO (negative control; 1:1000
dilution), BDNF (positive control), and enantiopure (R,R)-17b (10 mm); d) comparative effect of (R,R)-17b on the number and length of neurites.;
scale bar: 100 mm. BDNF=brain-derived neurotrophic factor, DMSO=dimethylsulfoxide, CTRL=control, untreated cells.
Figure 3. Neurite-outgrowth-promoting activity and quantification of morphological changes for ESC-derived motor neurons. a) Morphology of
neurons treated with 10 mm of compounds (2 days), DMSO, and GDNF (negative and positive controls, respectively); b) chemical structures of
active molecules; c) eight different parameters analyzed for differentiation, scale bar: 40 mm. Error bars show standard deviation (n=4). P values
were determined following two-tailed Student’s t-test. For all the individual morphological changes analyzed, P<0.05 was observed (except in the
case of branch point total count for 18m and 18d) using DMSO versus compound and GDNF control (data not shown). A P value of <0.05 was
considered significant.
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Received: March 11, 2013
Published online: && &&, &&&&
Keywords: asymmetric catalysis · iridoids · natural products ·
.
neuritogenic molecules
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These are not the final page numbers!