Unravelling the Synthesis and Chemistry of Stable, Acyclic, and Double-Deficient 1,3-Butadienes: An endo-Selective Diels–Alder Route to Hedgehog Pathway Inhibitors

Article abstract of DOI:10.1002/chem.201805823

The first synthetic access to stable and acyclic 1,3-butadienes with two electron-withdrawing carbonyl groups and their potential to deliver new molecular scaffolds through intriguing endo-selective Diels–Alder cycloadditions are presented. The bicyclic scaffolds produced through the cycloaddition chemistry of electron-deficient dienes afforded potent Hedgehog signaling pathway inhibitors.

Full text of DOI:10.1002/chem.201805823

A Journal of
Accepted Article
Title: Unravelling Synthesis and Chemistry of Stable, Acyclic and
Double-Deficient 1,3-Butadienes: An endo-selective Diels-Alder
Route to Hedgehog Pathway Inhibitors
Authors: Kamal Kumar, Xiaoyi Xin, Stefan Zimmermann, Jana Flegl,
Felix Otte, Lena Knauer, Carsten Strohmann, and Slava
Ziegler
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201805823
Link to VoR: http://dx.doi.org/10.1002/chem.201805823
Supported by

Chemistry - A European Journal
10.1002/chem.201805823
COMMUNICATION
Unravelling Synthesis and Chemistry of Stable, Acyclic and
Double-Deficient 1,3-Butadienes: An endo-Selective Diels-Alder
Route to Hedgehog Pathway Inhibitors
[
a]
[a,b]
[a,b]
Felix Otte,[b] Lena Knauer,[b] Carsten
Xiaoyi Xin, Stefan Zimmermann,
Jana Flegel,
Strohmann,[b] Slava Ziegler and Kamal Kumar*
[a]
[a]
Abstract: The first synthetic access to stable and acyclic 1,3-
butadienes with two electron-withdrawing carbonyl groups and their
potential to deliver novel molecular scaffolds via intriguing endo-
selective Diels-Alder cycloadditions is presented. The bicyclic
scaffolds emanating from cycloaddition chemistry of electron-deficient
dienes afforded potent hedgehog signaling pathway inhibitors.
A deeper understanding of their chemical reactivity and thereby
their potential in organic synthesis remains largely unexplored.
Here we report a facile synthesis of electron-deficient, acyclic and
stable 1,3-butadienes and unravel their intriguing cycloaddition
chemistry affording novel carbo- and heterocyclic small molecules
which led to the discovery of a novel class of small molecule
inhibitors of Hedgehog signaling pathway.
Conjugated 1,3-dienes represent an important class of building
blocks that had been extensively utilized to form carbo- and
heterocyclic molecules largely through their exquisite
cycloaddition reactions.[ Besides offering access to numerous
complex molecules of natural and synthetic origin, the
cycloaddition and annulation chemistry of dienes have inspired
the development of diverse ligands and catalytic systems.[2] The
emergence of concepts like frontier orbital control and the
stereoselectivity rules have a historic connection with the
cycloaddition chemistry of dienes.[3] The chemistry of carbadienes
is largely covered by electron-rich 1,3-butadienes like the
DanishefskyKitahara´s-,[4] Brassard´s-,[5] and Rawal´s-diene.[6]
These dienes bear at least two electron-donating groups (1,
Scheme 1) from where they derive their peculiar electron-rich
nature and also dictate the chemo- and regio-selectivities in
cycloaddition reactions. In contrast, their double-deficient
counterparts (2) – dienes with two electron-withdrawing groups at
relative 1,3-position are often unstable and tend to oligomerize
and therefore had only rarely been synthesized.[7]
1]
Figure 1. Representative acyclic electron-poor 1,3-carbadienes reported in
literature.
Although cyclic electron-deficient dienes[8] (3, Scheme 1) are
relatively stable and have marked their presence in organic
chemistry literature;[9] acyclic, stable and electron-poor
butadienes (2) remain largely inaccessible despite the dedicated
efforts from some groups in the last quarter of twentieth century.
McIntosh,[10] Bäckvall[11] and Spino[12] group synthesized and
explored the dienes 4 (Fig. 1) supporting only one electron-
[13]
withdrawing group in the Diels-Alder cycloaddition reactions.
However, these dienes were prone to nucleophilic additions and
undesired dimeric cycloadditions.[11a, 14] In particular, dienes with
an ester moiety had to be generated in situ for any further
transformation.[
13, 15]
In successful cases, both electron-rich and
poor olefins reacted with dienes 4 to produce Diels-Alder
adducts.[16] Diene 5 with 1,2-dicarbonyl functions also showed
similar limitations and displayed
a relatively lesser dienic
character. Padwa et al developed a multistep synthesis of 2,4-bis-
sulfonyl 1,3-butadienes (6, Fig. 1).[17] The high electrophilicity of
the terminal olefin in 6 and sulfone being a leaving group invite
further nucleophilic additions and the tendency of dienes 6 to
follow dimeric cycloaddition in the presence of unreactive
dienophiles,[11a] were the major concerns which limited their
further exploitation as viable building blocks.
Scheme 1. Different 1,3-dienes and the proposal for the synthesis and
chemistry of acyclic electron-poor 1,3-dienes.
Taking cognizance of the fact that cyclic electron-poor
dienes are stable, we assumed that introduction of substitutions
on the butadiene with two electron-withdrawing groups at 1- and
[
a]
Dr. X. Xin, S. Zimmermann, J. Flegel, Dr. S. Ziegler Dr. K. Kumar
Max-Planck-Institut für Molekulare Physiologie, Abteilung
Chemische Biologie, Otto-Hahn-Straße 11, 44227 Dortmund,
Germany.
E-mail: kamal.kumar@mpi-dortmund.mpg.de
Web: http://www.mpi-dortmund.mpg.de/research-groups/kumar
3- positions may offer stable acyclic dienes. Also, such dienes
may have enhanced synthetic potential owing to the two
modifiable electron-withdrawing functional groups. Unlike the
reported isomerization of γ-alkyl allene esters into dienes,[18] no
isomerization of α,γ-disubstituted allene ester (7, R = H or Me)
into the desired diene (9) was observed upon treatment with
triphenylphosphine (Scheme 2a).[
[
b]
S. Zimmermann, J. Flegel, F. Otte, L. Knauer, Prof. Dr. C.
19]
Strohmann; Fakultät Chemie und Chemische Biologie, Technische
Universität Dortmund, Otto-Hahn Str. 6, 44227-Dortmund, Germany.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Addition of phosphine to allenoates (7) produces zwitterions
8) which may exist as cyclic phosphorane (8´)[20] and have been
(
successfully used in various annulation reactions.[ We assumed
21]
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201805823
COMMUNICATION
Table 1. Phosphine catalyzed synthesis of electron-deficient 1,3-dienes.
that an introduction of an electron-withdrawing group at γ-position
of allene (10) may stabilize the corresponding phosphonium
enolate (11-11´) and favours the isomerization to the desired 1,3-
diene (13, Scheme 2b). Moreover, avoiding a terminal olefin by
1
introducing substitution R may lend more stability to the diene
and disfavour their oligomerization.
R1
R2
R3
Time
h)
Yield (%)[a]
(E, E)-13
Yield (%)[a]
(Z, E)-13´
No
(
1
2
3
4
5
6
7
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
18
18
18
18
18
18
18
18
60
18
18
72
72
13a, 72
13b, 58
13c, 68
13d, 72
13e, 68
13f, 67
13g, 57
13h, -[b]
13i, 54
13j, 66
13k, 76
13l, 67
13m, 47
13´a, 26
13´b, 41
13´c, 25
13´d, 27
13´e, 31
13´f, 29
13´g, 35
13´h, -[b]
13´i, 24
13´j, 26
13´k, 23
13´l, 20
13´m, 30
2-Me-C
4-Me-C
6
H
H
4
4
6
3-MeO-C
4-CF3-C
4-Br-C
6 4
H
6 4
H
6
H
4
Scheme 2. a) An attempted transformation of allene 7 into diene 9; b) proposed
isomerization of α,γ-disubstituted allene esters (10) into dienes (13).
4-NO
2 6 4
-C H
8
H
To our delight, treatment of allenoate 10a (see Supp.
Information for synthesis of allenes 10) with 10 mol% of Ph
,2-dichloroethane (DCE) and at 80 °C, delivered electron-
deficient diene 13a as two isomers i.e. E,E-13a and Z,E-13´a in
2 and 26% respectively (Table 1, entry 1). Different electron-poor
3
P in
9[c]
Me
Ph
Ph
Ph
Ph
1
10
11
12
13
7
Bn
Ph
Me
and -rich aryl groups were tolerated in the diene synthesis without
much influencing the efficiency of the reaction or the ratio of two
isomeric dienes formed (entries 2-7). The attempted
isomerization of α-methyl allene ester 10h to terminal diene 13h
led to a complex mixture of oligomers (entry 8). The α-ethyl allene
ester however, nicely yielded diene 13i and 13´i with a methyl
substitution (entry 9). This result highlights the importance of
Et
tBu
[
a] Isolated yields. [b] Oligomerization products were formed. [c] 20 mol% of
Ph P was used.
3
1
substitution (R ) in affording stable dienes. Electron-poor dienes
with different alkyl and aryl ketones (13j-l, entries 10-12) were
also synthesized in high yields except for 13m where the diene
supported
a bulky tertiary butyl ester (entry 13). The
stereochemistry of diene products was corroborated by single
crystal X-ray analysis of 13l and 13´f.[22]
Both 13a and 13´a were stable at room temperature (Scheme
3
, eq. i and ix and Supp. Information) in DCE even at higher
temperature (eqs iii and x). At higher temperature in toluene
microwave (W) irradiation, 200 °C), diene E,E-13a remained
(
stable with slight conversion to 13´a (eq ii), however, the latter
isomerized to 13a and also displayed dimerization and
decomposition (see Supp. Information). Interestingly, in DMSO-
Scheme 3. Interconversion of E,E-13a and Z,E-13'a.
d
(
6
both the dienes reached a ratio of ca. 60:40 in favor of E,E-13a
eqs iv and xi). In the presence of catalytic triphenylphosphine and
at high temperature, both dienes 13a and 13´a acquired a ratio of
4:26 with Z,E-13´a as minor isomer (Scheme 3, eqs v and vii).
reaction conditions may offer the s-cis conformation to entertain
the Diels-Alder (DA) reaction. We chose to first explore N-methyl
maleimide (NMM) as electron-poor dienophile,[10, 12a, 12b, 24] in DA
reaction with dienes 13. To this end, when the E,E- or Z,E-diene
7
Intriguingly, the phosphine mediated conversion of Z,E-13´a at
room temperature delivered almost 1:1 ratio of the two dienes.
Our interest in cycloaddition chemistry of the electron-
deficient 1,3-butadienes (13) stems from developing synthetic
methods to novel and diverse molecular scaffolds that can be
used to build compound collections for biological screenings.[23]
We assumed that a single bond rotation in dienes 13 under the
13a or 13´a respectively were heated with NMM in toluene under
W irradiation (300 W, 200 °C) for 4h, a complex and
unresolvable product mixture was formed. Performing the
reaction in xylene at 150 °C or in toluene at lower temperatures
(
rt to 80 °C) provided similar results. Interestingly, when DMSO
was employed as solvent in the reaction of diene 13a with NMM
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201805823
COMMUNICATION
at 170 °C, the reaction afforded a decarboxylated cycloadduct
respectively as the major products (Scheme 5). The NMR
analysis of reaction adduct-mixture I hinted towards the presence
of major cycloaddition product 17a wherein olefin isomerization
had already occurred and along with another product with H-
bonded enol moiety (18a).[26] DDQ-mediated oxidation of the
1
4a as the major product and the diastereomer 15a as the minor
product.[ Reaction conditions were established to deliver the
cycloadduct 14a directly from the allenes esters 10 in a one-pot,
two-step process. Different allene esters supporting electron-poor
and -rich aromatic groups were used in this one-pot cascade
reaction sequence to provide novel bicyclic molecular scaffolds
22]
adduct-mixture-I afforded
a
highly substituted N-methyl-
phthalamide (19a) and further corroborated that the
decarboxylation followed the DA-cycloaddition reaction in DMSO.
Based on above results we propose that in DMSO, the
phosphine transforms allene ester 10a into dienes 13a and 13´a
in ~ 60:40 ratio. Due to an internal destabilizing interaction
between aryl group and the proton in the s-cis conformation of
E,E-13a (Scheme 5, right), the corresponding highly congested
endo-transition state is not favored. The endo-transition state
derived from s-cis-Z,E-13´a has no such destabilizing interaction
and reacts faster with NMM in a DA reaction to yield 14a. The
faster consumption of 13´a further shifts the equilibrium of the
diene interconversion towards Z,E-diene-13´a and consequently,
14 and 15 in acceptable yields (Scheme 4).
14a is formed as the major product (Scheme 5, right). As no exo-
cycloaddition derived product was observed in the reaction, we
assume that secondary orbital interactions might have contributed
to stabilize the endo-transition state.[27] Unlike a number of
reactive,
substituted
acyclic
dienes
which
deliver
thermodynamically favored exo-DA adducts, the electron-poor
1
,3-dienes 13 afforded endo-DA-derivatives.[6a, 28]
Notably, the diene interconversion is not well supported in
toluene and therefore isolated diene 13a could be used in DA
reaction with NMM to form the adduct mixture-I which upon
heating in DMSO afforded 15a – the other diastereomer as the
major adduct (Scheme 5).
Scheme 4.
A cascade reaction sequence of Diels-Alder-isomerization-
decarboxylation of electron-poor 1,3-dienes with NMM.
Extending the scope of cycloadditions of electron-deficient
dienes, 4-phenyl and 4-methyl 1,2,4-triazoline-3,5-diones (20)
Further experiments were performed to get more insights into this
unique chemistry of electron-poor dienes. In two separate control
were used as electron-poor hetero-dienophiles.
reaction condition was established for the reaction of allene esters
0 with aza-dienophiles 20 to form bicyclic triazolindiones (21a-
A one-pot
reactions of 13a and 13´a with NMM (2.0 eqv) in DMSO-d
6
at
170 °C, 14a was formed as major cycloadduct and diene Z,E-13´a
1
was consumed faster than diene E,E-13a (Supp. Fig. 1).The
reactions of 13a and 13´a with NMM were also performed in
toluene under W irradiation (200°C, 300 W) for 4 h. After a short
flash column chromatography to remove the unreacted dienes
and excess of NMM, an inseparable mixture was obtained (see
Supp. Information). Interestingly, the two adduct-mixtures I & II
obtained from the reactions of 13a and 13´a when separately
dissolved in DMSO and further heated at 170 °C for 6 h, followed
a Krapcho type decarboxylation[25] to form adducts 15a and 14a
m) with four-point variations in very high yields (Scheme 6).
When combined with dienes under prolonged heating,
acyclic and cyclic ketene acetals furnished corresponding
addition products 22 and 23a-c (Scheme 6). Interestingly, 22 is
stable under normal conditions whereas the surrogate intermedi-
ate oxidizes relatively quickly towards the biphenyl in the case of
23a-c (see Supp. Information).
Scheme 5. Control experiments to unravel the cycloaddition chemistry of electron-poor 1,3-dienes and a mechanistic proposal for stereoselective synthesis of two
diastereomeric adducts 14a and 15a.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201805823
COMMUNICATION
and therefore this compound class might inhibit the Hh pathway
thorough a different, currently unknown mode of action.[36]
a)
Scheme 6. Cycloaddition reaction of dienes 13/13´ with 1,2,4-triazoline-3,5-
diones 20, ketene acetals and enamines.
Furthermore, the electron-poor dienes displayed reactivity
towards electron-rich enamines, however the reactions tend to
deliver aromatic and structurally flat trisubstituted tetrahydro-
b)
naphtalenes (X = CH
Scheme 6). The reactions of electron-rich dienophiles with dienes
3/13´ supposedly proceed via inverse electron-demand Diels-
2
, 24a-c) and isochromane 24d (X = O,
1
Alder reaction, elimination and aromatization.
Cell-based phenotypic screenings[29] targeting modulation of
cell signaling pathways, like hedgehog (Hh) pathway are
important tools to identify leads for biological research.[30] Hh
pathway is important for embryonic development, tissue
regeneration and stem cell homeostasis. Aberrant activation of
Hh signaling is involved in various types of cancer.[
Consequently, novel Hh pathway inhibitors are in high demand.[32]
The bicyclic cycloadducts were exposed to osteoblast
differentiation assay in C3H10T1/2 cells as a primary screen to
identify Hh inhibitors. The Smoothened (SMO) agonist
Purmorphamine was employed to activate the Hh pathway, which
induces osteoblast differentiation and leads to the expression of
the osteoblast specific marker alkaline phosphatase.[33] The
measurable activity of the latter correlates indirectly with the Hh
31]
[
34]
pathway activity.
inhibited Hh depended cell differen-tiation with a half-maximal
inhibitory concentration (IC50 of 0.2 µM. Further, the N-
Remarkably, the bicyclic triazolindione 21f
)
methylmaleimide adduct 14e also bearing p-bromophenyl group
caused Hh inhibition with an IC50 of 4.17 ± 0.78 µM, representing
another bioactive bicyclic scaffold.
The inhibition of Hh signaling by adducts was further confirmed
by an orthogonal, GLI-dependent reporter gene assay using Shh-
LIGHT2 cells (Fig. 2a). In this assay, 21f inhibited the GLI-
dependent luciferase expression with an IC50 of 7.15 ± 1.91 µM.
Figure 2. a.) Influence of the bicyclic triazolindione and N-methyl-maleimide
compounds on GLI de-pendent reporter gene assay. Shh-LIGHT2 cells were
treated with 2 µM Purmorphamine and different concentrations of compound
or DMSO as a control for 48 h. The signal of the GLI-responsive Firefly-
luciferase was divided by the control signal of the Renilla-luciferase and the
DMSO control was set to 100%. The data are representative of three biological
replicates (n=3), given as mean values ± standard deviation. b) Influence of
active compounds on SMO-BODIPY-cyclopamine binding. HEK293T cells
ectopically expressing SMO were fixed and treated with 5 nM BODIPY-
cyclopamine (green) and compounds (20 µM) or vismodegib (5 µM), and
DMSO as controls. Cells were stained with DAPI to visualize the nuclei (blue).
Scale bar: 50 µm.
14e, 15b and 15c displayed an IC50 in the range of 9.5 - 11.2 µM
(
see Supp. Table 1). The ability of these molecules to bind to the
seven-pass transmembrane protein SMO was explored using a
competition experiment with BODIPY-cyclopamine in HEK293T
cells ectopically expressing SMO. Interestingly, the BODIPY-
fluorescence was considerably reduced after treatment with
2
0 µM 21f (Fig. 2b), indicating that this compound might bind to
the heptahelical bundle of SMO.[35] In case of carbocyclic adducts
14e, 15b, and 15c a clear displacement could not be observed
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201805823
COMMUNICATION
In summary, a facile synthesis of acyclic and stable
electron-deficient 1,3-butadienes supporting two orthogonal
carbonyl groups was developed and their prodigious potential in
organic synthesis was presented with unique endo-selective
Diels-Alder and cascade reactions. The intriguing chemistry of the
electron-poor dienes delivered two novel bicyclic scaffold classes
as promising inhibitors of the Hedgehog signaling pathway. We
believe that the stable electron-poor dienes will open many doors
to different chemical transformations as well as opportunities to
unravel new insights into novel aspects of cycloaddition and
annulation reactions and thereby will inspire new synthetic
adventures and advances.
[18] a) B. M. Trost, U. Kazmaier, J. Am. Chem. Soc. 1992, 114, 7933-7935;
b) B. M. Trost, C. J. Li, J. Am. Chem. Soc. 1994, 116, 10819-10820.
[
19] a) C. K. W. Kwong, M. Y. Fu, C. S. L. Lam, P. H. Toy, Synthesis 2008,
2307-2317; b) C. Guo, X. Y. Lu, J. Chem. Soc. Perk Trans. 1 1993, 1921-
1923.
[
20] a) X. F. Zhu, C. E. Henry, O. Kwon, J. Am. Chem. Soc. 2007, 129, 6722-
723; b) K. C. K. Swamy, N. S. Kumar, Acc. Chem. Res. 2006, 39, 324-
333.
[21] a) H. Guo, Y. C. Fan, Z. Sun, Y. Wu, O. Kwon, Chem. Rev. 2018, 118,
10049 10293; b) M. G. Sankar, M. Garcia-Castro, C. Golz, C.
6
-
Strohmann, K. Kumar, Angew. Chem. Int. Ed. 2016, 55, 9709-9713; c) Z.
M. Wang, X. Z. Xu, O. Kwon, Chem. Soc. Rev. 2014, 43, 2927-2940; d)
B. Baskar, P. Y. Dakas, K. Kumar, Org. Lett. 2011, 13, 1988-1991.
[
[
22] CCDC 1590532 (13´f), 1590070 (13l), 1820732 (14d), 1590523 (21f),
1590526 (21h)
and 1812134 (25) contain the supplementary
Keywords: 1,3-butadienes • electron-poor dienes • Diels-Alder
reaction • allene esters • phosphine catalysis
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
23] M. Garcia-Castro, S. Zimmermann, M. G. Sankar, K. Kumar, Angew.
Chem. Int. Ed. 2016, 55, 7586-7605.
[
1]
a) Z. M. Png, H. N. Zeng, Q. Ye, J. W. Xu, Chem-As. J. 2017, 12, 2142-
159; b) V. Eschenbrenner-Lux, K. Kumar, H. Waldmann, Angew. Chem.
2
[
[
24] L. R. Domingo, Eur. J. Org. Chem. 2004, 4788-4793.
Int. Ed. 2014, 53, 11146-11157; c) M. De Paolis, I. Chataigner, J.
Maddaluno, Top. Curr. Chem. 2012, 327, 87-146; d) P. Buonora, J. C.
Olsen, T. Oh, Tetrahedron 2001, 57, 6099-6138.
25] a) A. P. Krapcho, Synthesis 1982, 805-823; b) A. P. Krapcho, E. G. E.
Jahngen, A. J. Lovey, Tetrahedron Lett. 1974, 1091-1094.
[
[
26] In one of the attempted reaction catalyzed by a Lewis acid, a partially
oxidized product 25 that apparantly is derived from 18a was isolated.
27] a) J. I. Garcia, J. A. Mayoral, L. Salvatella, Acc. Chem. Res. 2000, 33,
[
2]
a) P. Gupta, U. Sharma, T. C. Schulz, E. S. Sherrer, A. B. McLean, A. J.
Robins, L. M. West, Org. Lett. 2011, 13, 3920-3923; b) J. C. M. Monbaliu,
K. G. R. Masschelein, C. V. Stevens, Chem. Soc. Rev. 2011, 40, 4708-
658-664; b) Y. Apeloig, E. Matzner, J. Am. Chem. Soc. 1995, 117, 5375-
5376; c) R. Hoffmann, R. B. Woodward, J. Am. Chem. Soc. 1965, 87,
4388-4389.
4739; c) M. R. Tremblay, T. J. Dickerson, K. D. Janda, Adv. Synth. Catal.
2001, 343, 577-585.
[
[
3]
4]
a) R. D. Bach, J. J. W. Mcdouall, H. B. Schlegel, G. J. Wolber, J. Org.
Chem. 1989, 54, 2931-2935; b) K. Fukui, Acc. Chem. Res. 1981, 14,
[
28] a) S. Jayakumar, K. Louven, C. Strohmann, K. Kumar, Angew. Chem.
Int. Ed. 2017, 56, 15945-15949; b) J. H. Zhou, B. Jiang, F. F. Meng, Y.
H. Xu, T. P. Loh, Org. Lett. 2015, 17, 4432-4435; c) M. Hatano, T. Mizuno,
A. Izumiseki, R. Usami, T. Asai, M. Akakura, K. Ishihara, Angew. Chem.
Int. Ed. 2011, 50, 12189-12192; d) Y. H. Lam, P. H. Y. Cheong, J. M. B.
Mata, S. J. Stanway, V. Gouverneur, K. N. Houk, J. Am. Chem. Soc.
363-368; c) K. Fukui, Acc. Chem. Res. 1971, 4, 57-64.
a) S. Danishefsky, Acc. Chem. Res. 1981, 14, 400-406; b) S.
Danishefsky, T. Kitahara, C. F. Yan, J. Morris, J. Am. Chem. Soc. 1979,
101, 6996-7000.
[
[
5]
6]
J. Savard, P. Brassard, Tetrahedron Lett. 1979, 4911-4914.
2009, 131, 1947-1957; e) S. Calvo-Losada, D. Suarez, J. Am. Chem.
a) S. A. Kozmin, V. H. Rawal, J. Am. Chem. Soc. 1999, 121, 9562-9573;
b) S. A. Kozmin, M. T. Green, V. H. Rawal, J. Org. Chem. 1999, 64, 8045-
Soc. 2000, 122, 390-391; f) M. Node, K. Nishide, H. Imazato, R. Kurosaki,
T. Inoue, T. Ikariya, Chem. Comm. 1996, 2559-2560; g) T. Yoon, S. J.
Danishefsky, S. Degala, Angew. Chem. Int. Ed. 1994, 33, 853-855; h) J.
Sauer, R. Sustmann, Angew. Chem. Int. Ed. 1980, 19, 779-807; i) D. W.
Jones, R. L. Wife, J. Chem. Soc. Chem. Comm. 1973, 421-422.
29] J. G. Moffat, F. Vincent, J. A. Lee, J. Eder, M. Prunotto, Nat. Rev. Drug
Discov. 2017, 16, 531-543.
8047; c) S. A. Kozmin, V. H. Rawal, J. Org. Chem. 1997, 62, 5252-5253.
[
[
7]
8]
K. D. Ahn, H. K. Hall, J. Polym. Sci. Pol. Chem. 1981, 19, 629-644.
a) G. H. Posner, H. Y. Dai, D. S. Bull, J. K. Lee, F. Eydoux, Y. Ishihara,
W. Welsh, N. Pryor, S. Petr, J. Org. Chem. 1996, 61, 671-676; b) G. H.
Posner, F. Eydoux, J. K. Lee, D. S. Bull, Tetrahedron Lett. 1994, 35,
[
[
7541-7544.
30] a) M. Sheremet, S. Kapoor, P. Schroder, K. Kumar, S. Ziegler, H.
Waldmann, Chembiochem 2017, 18, 1797-1806; b) Y. C. Lee, S. Patil,
C. Golz, C. Strohmann, S. Ziegler, K. Kumar, H. Waldmann, Nat.
Commun. 2017, 8 doi: 10.1038/ncomms14043; c) M. Garcia-Castro, L.
Kremer, C. D. Reinkemeier, C. Unkelbach, C. Strohmann, S. Ziegler, C.
Ostermann, K. Kumar, Nat. Commun. 2015, 6, doi: 10.1038/
ncomms7516.
[
9]
a) A. T. Dang, D. O. Miller, L. N. Dawe, G. J. Bodwell, Org. Lett. 2008,
10, 233-236; b) G. J. Bodwell, K. M. Hawco, R. P. da Silva, Synlett 2003,
179-182; c) G. J. Bodwell, K. M. Hawco, T. Satou, Synlett 2003, 879-881;
d) G. J. Bodwell, Z. Pi, I. R. Pottie, Synlett 1999, 477-479; e) J. Bodwell,
Z. L. Pi, Tetrahedron Lett. 1997, 38, 309-312.
[
[
10] J. M. Mcintosh, R. A. Sieler, J. Org. Chem. 1978, 43, 4431-4433.
11] a) J. E. Backvall, S. K. Juntunen, J. Am. Chem. Soc. 1987, 109, 6396-
[
[
31] J. Briscoe, P. P. Therond, Nat. Rev. Mol. Cell Bio. 2013, 14, 416-429.
32] a) T. K. Rimkus, R. L. Carpenter, S. Qasem, M. Chan, H. W. Lo, Cancers
6403; b) O. S. Andell, J. E. Backvall, Tetrahedron Lett. 1985, 26, 4555-
4558.
2016, 8, 22; doi:10.3390; b) N. Mahindroo, C. Punchihewa, N. Fujii, J.
[
12] a) C. Spino, H. Rezaei, K. Dupont-Gaudet, F. Belanger, J. Am. Chem.
Soc. 2004, 126, 9926-9927; b) C. Spino, J. Crawford, Y. P. Cui, M.
Gugelchuk, J. Chem. Soc. Perkin Trans. 2 1998, 1499-1506; c) C. Spino,
M. Pesant, Y. Dory, Angew. Chem. Int. Ed. 1998, 37, 3262-3265; d) C.
Spino, J. Crawford, Can. J. Chem. 1993, 71, 1094-1097.
Med. Chem. 2009, 52, 3829-3845.
[
[
33] X. Wu, S. Ding, Q. Ding, N. S. Gray, P. G. Schultz, J. Am. Chem. Soc.
2002, 124, 14520-14521.
34] a) M. H. Xin, X. Y. Ji, L. K. De La Cruz, S. Thareja, B. H. Wang, Med.
Res. Rev. 2018, 38, 870-913; b) S. Peukert, K. Miller-Moslin,
Chemmedchem 2010, 5, 500-512.
[
[
[
13] T. S. Chou, S. C. Hung, J. Org. Chem. 1988, 53, 3020-3027.
14] T. Cuvigny, C. H. Dupenhoat, M. Julia, Tetrahedron 1986, 42, 5329-5336.
15] P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini, G. P. Pollini, D. Simoni,
V. Zanirato, Tetrahedron 1988, 44, 6451-6454.
[
[
35] S. Sinha, J. K. Chen, Nat. Chem. Biol. 2006, 2, 29-30.
36] a) K. K. Chahal, M. Parle, R. Abagyan, Anti-Cancer Drug 2018, 29, 387-
401; b) B. Z. Chen, V. Trang, A. Lee, N. S. Williams, A. N. Wilson, E. H.
[
[
16] J. E. Backvall, F. Rise, Tetrahedron Lett. 1989, 30, 5347-5348.
17] a) A. Padwa, Y. Gareau, B. Harrison, A. Rodriguez, J. Org. Chem. 1992,
Epstein, J. Y. Tang, J. Kim, Mol. Cancer. Ther. 2016, 15, 866-876.
57, 3540-3545; b) B. H. Norman, Y. Gareau, A. Padwa, J. Org. Chem.
1991, 56, 2154-2161; c) A. Padwa, B. H. Norman, Tetrahedron Lett. 1988,
29, 2417-2420.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201805823
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
X. Xin, S. Zimmermann, J. Flegel, F.
Otte, L. Knauer, C. Strohmann, S.
Ziegler and K. Kumar*
Page No. – Page No.
Unravelling Synthesis and Chemistry
of Stable, Acyclic and Double-
Deficient 1,3-Butadienes: An endo-
Selective Diels-Alder Route to
Hedgehog Pathway Inhibitors
Uniquely deficient! A facile synthetic access to stable, electron-deficient and
acyclic 1,3-butadienes bearing two orthogonal electron-withdrawing groups is
presented that opens up door to many molecular frameworks including novel
hedgehog pathway inhibitors.
This article is protected by copyright. All rights reserved.