Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones

Article abstract of DOI:10.1021/acs.orglett.9b02549

We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.

Full text of DOI:10.1021/acs.orglett.9b02549

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Densely Functionalized N‑Alkenyl 2‑Pyridones via
Benzyne-Induced Ring Opening of Thiazolino-Fused 2‑Pyridones
†
†
†
Pardeep Singh, Andrew G. Cairns, Dan E. Adolfsson, Jorgen Åden, Uwe H. Sauer,
̈
́
and Fredrik Almqvist*
Department of Chemistry, Umeå University, 90187 Umeå, Sweden
*
S Supporting Information
ABSTRACT: We report the synthesis of 6-arylthio-substi-
tuted-N-alkenyl 2-pyridones by ring opening of bicyclic
thiazolino-2-pyridones with arynes. Varied functionalization
was used to investigate scope and substituent influences on
reactivity. Selected conditions favor thioether ring opening
over [4 + 2] cycloaddition and an unusual aryne incorporating
ring expansion. Deuterium labeling was used to clarify
observed reactivity. Using the knowledge, we produced
drug-like molecules with complex substitution patterns and
show how thioether ring opening can be used on scaffolds
with competing reactivities.
he reactivity of arynes with sulfides has attracted
considerable attention due to the potential to access
T
scaffolds not easily prepared by other methods. This reactivity
1
was initially demonstrated by Mertz and others and more
2
recently further investigated in other laboratories. Specific
developments include Studer and coworkers’ report of the
stereoselective synthesis of alkenes via the [3 + 2] cyclo-
2
e
2a
addition of vinyl sulfides with arynes and Hoye and Tan
and Xu’s
2
b−d
ring opening of cyclic sulfides to obtain
functionalized thioethers. Although this pioneering work has
demonstrated the potential synthetic power of the trans-
formation, the application of these methods to complex, drug-
like scaffolds with varied and competing reactivities has not yet
been investigated.
Figure 1. Previous work and our new strategy.
N-Alkenyl and alkyl 2-pyridones are core structural
components in many natural products and pharmacologically
active compounds. They have also been used as substrates in
Furthermore, the resulting compounds would access new
functionalities and spatial arrangements while retaining the
characteristics of bicyclic 2-pyridones associated with pre-
viously observed biological activity.
Herein we report our investigation of the aryne reactivity
with thiazolino-fused 2-pyridone systems and our efforts to
develop substrates and conditions to efficiently produce
complex, densely functionalized 6-arylthio-substituted-N-al-
kenyl 2-pyridones.
3
cycloadditions and polymerization reactions. There are a
number of synthetic methods available for the synthesis of N-
4a−h
alkenyl 2-pyridones (Figure 1);
however, all of these
methods are more applicable to simple substrates, and the
outcome is very substrate-dependent. Therefore, new strategies
to access N-alkenyl 2-pyridones as a part of functionalized
scaffolds are desirable.
Our investigations started with 2-(trimethylsilyl)phenyl
In our previous research, we have made use of the
8
5
triflate 2 and a set of diversely substituted 2-pyridones, 1a−
biologically active thiazolino-fused 2-pyridone scaffold to
h, to identify the substrates that could provide ring-opened
products 3 in preference to the formation of [4 + 2] adducts 4
build fluorescent and nonfluorescent polyheterocycles of
6
biological interest. We judged this system to be ideal for
(
Scheme 1). The combination of KF/18-crown-6 at −10 °C
assessing the applicability of aryne-mediated ring opening to
complex molecules, as the cyclic thioether of the thiazolino
ring must compete with the aryne [4 + 2] cycloaddition across
was found to give good results with selected substrates.
7
the pyridone ring system. The ring-opening reaction would
Received: July 22, 2019
result in the N- and C-6 substitution of the 2-pyridone ring.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Treatment of Various 2-Pyridones with in Situ
Generated Benzyne
products is theoretically possible; however, from the analysis
by H NMR, it is clear that a single diastereomer was formed.
e
1
The crystal structure of 4h (Figure S2) confirmed that benzyne
approaches from the least hindered side, opposite to the
methyl carboxylate. To investigate the biological activity of
ring-opened analogues of bioactive 2-pyridones, we tested the
ring opening of 2-pyridone 1i, which is a precursor to a
6b
promoter of α-synuclein amyloid formation. Unfortunately
both ring-opened product 3i and 4 + 2 cycloaddition adduct 4i
were isolated in low yield.
Given the low to moderate yields of ring-opened products,
we next introduced conjugated electron-donating and -with-
drawing substituents at position C-6 of the 2-pyridone scaffold,
investigating whether cycloaddition can be avoided to afford
N-alkenyl 2-pyridones selectively. We synthesized a number of
C-6 aryl/alkyl-substituted 2-pyridones, 7a−j, and tested their
reactivity with benzyne and 3-methoxy benzyne (Schemes 2
and 3).
Scheme 2. Treatment of 2-Pyridones 7 with in Situ
a
Generated Benzyne
a
b
c
9
2% complete. Reaction was carried out at rt (17 h). 2.0 equiv of 2
d
and 3.0 equiv of 18-crown-6 in acetonitrile at rt (16 h). 3.0 equiv of
1
8-crown-6. The concentration of 1i was 0.3 M, and the reaction
e
mixture was stirred at 0 °C. 2-Pyridone of general structure 1 was
treated with 2.5 equiv each of 2-(trimethylsilyl)phenyl-trifluorome-
thanesulfonate 2, KF, and 18-crown-6 in dry THF. The mixtures were
stirred at −10 °C until the complete consumption of 1 was indicated
by TLC (1−5 days). The concentration of 1 was 0.07 M.
Notably, lowering the reaction temperature from room
temperature to −10 °C improved the selectivity for ring-
opened product 3 in preference to [4 + 2] cycloaddition
product 4.
The substituents on the 2-pyridone ring had a pronounced
effect on the reaction outcome. The reactions of 1a and 1d
with benzyne under established conditions gave conversion to
ring-opened products 3a and 3d. The C-7- or C-8-substituted
a
2-Pyridone of general structure 7 was treated with 2-(trimethylsilyl)-
phenyl-trifluoromethanesulfonate 2 (1.4 equiv), KF (2.0 equiv), and
1
by TLC analysis (8.5 h to 2 days). The concentration of 7 was 0.3 M.
8-crown-6 (2.5 equiv) in dry THF at 0 °C until confirmed complete
2
-pyridones 1b, 1c, and 1e afforded mixtures of ring-opened
and [4 + 2] cycloaddition products. Substitution with a
strongly electron-withdrawing C-6 nitro group (1f) reduces the
nucleophilicity of the sulfur, resulting in [4 + 2] cycloaddition.
The loss of conjugation increases the sulfur nucleophilicity
toward a second equivalent of benzyne, giving 5f. Additionally,
a ring-expanded product 6f was observed. (The structure was
established by 1D and 2D NMR experiments and was further
supported by a crystal structure of the analogous compound V
Initial tests of 7a with benzyne precursor 2 carried out under
our established conditions showed a very slow reaction.
However, the reaction time was vastly reduced by increasing
the concentration and the temperature. The excess benzyne
precursor and potassium fluoride could also be reduced
without negatively affecting the isolated yield. 7a was found to
give good conversion to ring-opened product 8a, suggesting
that these substrates are more prone to react via the desired
nucleophilic attack. Subsequent reactions with analogues 7b−h
confirmed a trend of high sensitivity to conjugated electron-
withdrawing substituents (7f and 7g), although in some cases
(notably 7h), low yields reflect a very slow reaction rather than
the competitive formation of other products. C-8 methoxy-
substituted 2-pyridone 7d reacted to give a mixture of ring-
opened 8d and cycloaddition product 9d, likely due to the
(Figure S1).) No reaction was observed upon the addition of
benzyne to trisubstituted 2-pyridone 1g at −10 °C. Repeating
at rt yielded the [4 + 2] cycloaddition product exclusively. We
therefore believed that increasing the reaction temperature
would favor [4 + 2] cycloaddition. We treated compound 1h at
rt using acetonitrile as solvent. Gratifyingly, bridged product
4h was isolated in 50% yield along with 17% of the ring-
opened product 3h. A mixture of [4 + 2] cycloaddition
B
DOI: 10.1021/acs.orglett.9b02549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
0
Scheme 3. Treatment of 2-Pyridones 7 with in Situ
Generated 3-Methoxybenzyne
enhanced electrophilicity at C-1 of 3-methoxy benzyne. As
b
3
before, the electronic properties of the R substituents had a
pronounced effect on the yields of ring-opened products. 2-
pyridones 7a−d substituted at C-6 with phenyl groups, with or
without C4′ electron-donating groups, furnished the desired
products 11a−d in excellent yield, irrespective of the
substituents in C-8. In contrast with our previous tests with
unsubstituted benzyne, 7e reacts exclusively through sulfur
attack on 3-methoxybenzyne and provides 11e in excellent
yield. As previously observed, electron-withdrawing substitu-
ents at C-6 have a negative impact on the reaction yields, and
the alkyl-substituted 2-pyridone 7i reacted cleanly to give an
excellent yield of ring-opened product 11i.
Finally, we applied our ring-opening protocol to tricyclic 2-
pyridone 12 and polycyclic 14, which are precursors to an α-
6
f
6c
synuclein fibril binder and an aggregation inhibitor,
respectively. To our delight, the corresponding ring-opened
products 13 and 15 were isolated in excellent yield (Scheme
4
A,B).
Scheme 4. (A,B) Ring Opening of Multiring Fused 2-
Pyridones with in Situ Generated 3-Methoxybenzyne and
(
C) Hydrolysis of Methyl Ester
a
b
Reaction was performed on a 1.4 mmol scale. 2-Pyridone of general
structure 7 was treated with 3-methoxy-2-(trimethylsilyl)phenyl-
trifluoromethanesulfonate 10 (1.4 equiv), KF (2.0 equiv), and 18-
crown-6 (2.5 equiv) in dry THF. The mixtures were stirred at 0 °C
until confirmed complete by TLC analysis (7−17 h). The
concentration of 7 was 0.3 M.
activation of the diene by the methoxy group. The reaction of
C-6-thienyl 2-pyridone 7e with benzyne did not go to
completion, presumably due to competition with reactions
9
between benzyne and the thiophene ring. From the mixture,
cycloaddition product 9e was isolated in 11% yield, in addition
to the 23% of desired ring-opened product 8e and 13% of
unreacted 7e. We also considered mildly donating (7i) and
withdrawing (7j) substituents directly attached to the C-6
position. The efficient reaction of 7i shows the extended C-6
conjugation previously tested to be unnecessary for good
conversion, and the cleaner conversion observed in Scheme 2
compared with that in Scheme 1 is mainly due to the electronic
effects of the C-6 substituent, which is also consistent with the
unfavorable effect of C-6-I substitution (7j). The presence of a
phenyl substituted with a C4′ electron-withdrawing group at
position C-6 reduces the reactivity of the 2-pyridone both
toward ring-opening and cycloaddition reactions. For instance,
the 2-pyridones 7f and 7g slowly reacted with benzyne,
reducing the yields of N-alkenyl 2-pyridones and cycloaddition
products.
To investigate the biological activity of the ring-opened
products, we selected 2-pyridones 3i, 13, and 15 and
hydrolyzed them to the corresponding carboxylic acids 16,
17, and 18 in low yield (22−26%) (Scheme 4C). The
carboxylic acids were evaluated for their ability to modulate the
α-synuclein amyloid formation and fibril binding by a
fluorescence assay with amyloidophilic dye Thioflavin T
(ThT) (Figure 2). Compound 16 was observed to accelerate
the α-synuclein amyloid formation, although not as efficiently
The electrophilicity and regioselectivity of 3-substituted
arynes have been investigated in computational studies by
Garg and Houk et al., and an angle distortion model has been
proposed as an explanation for the large differences in
1
0a,b
6b
electrophilicity.
On the basis of this work, the reactivity
as the previously reported accelerator FN075. Compound 17
of 3-methoxy benzyne would be biased toward nucleophilic
(Figure 2B), which is the ring-opened analogue of a tricyclic
amyloid fibril binder, retained this biological activity, as
10a
6f
attack, with a [4 + 2] cycloaddition less likely.
Although 3-methoxy benzyne has also been shown to
indicated by low ThT fluorescence signals. Compound 18 was
also observed to promote the α-synuclein amyloid formation,
as indicated by the short lag phase compared with wild-type α-
synuclein. The observed activity is of great interest because
11
participate in cycloaddition reactions, it reacted cleanly with
all pyridones 7a−j, providing the desired ring-opened products
1
1a−j exclusively (Scheme 3) in moderate to excellent yield.
12
The reactions were regioselective, presumably due to the
previous ring-opened analogues have proven inactive, and as
C
DOI: 10.1021/acs.orglett.9b02549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
pyridones 12 and 14 in excellent yield. The preliminary in vitro
biological data showed that ring-opened compounds 16 and 17
have the ability to modulate α-synuclein amyloid formation
and bind to amyloid fibrils, respectively. On the basis of this
initial data, we believe that our methodology produces a
scaffold worthy of further investigation and anticipate that both
the methodology and the products described will be proven
valuable as probe molecules or in medicinal chemistry
investigations.
Figure 2. Effect on α-synuclein aggregation.
ASSOCIATED CONTENT
Supporting Information
■
*
S
such, these are the first examples demonstrating that this
structural motif can be replaced without a loss of activity.
To better understand the ring opening that follows
electrophilic attack on the sulfur, we conducted experiments
with deuterium-labeled substrate, water, and THF (Scheme
S2). On the basis of our mechanistic experiments, we propose
the following mechanism (Scheme 5). Sulfur attacks the aryne
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02549.
Experimental procedure and spectroscopic and analytical
data for all new compounds (PDF)
Accession Codes
Scheme 5. Proposed Mechanism for the Ring Opening of
Thiazolino-Fused 2-Pyridones upon Thioether Attack on
Aryne
CCDC 1945502 and 1945580 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: Fredrik.almqvist@umu.se
ORCID
Fredrik Almqvist: 0000-0003-4646-0216
Author Contributions
†
P.S., A.G.C., and D.E.A. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
F.A. is grateful to the Swedish Research Council (2017-02339,
017-00695, and 2018-04589), the Knut and Alice Wallen-
bergs Foundation (KAW 2013.0031), the Goran Gustafsson
̈
Foundation, the Kempe Foundation (SMK-1755), the Swedish
Foundation for Strategic Research (SB12-0070), the National
Institutes of Health (R01AI134847-01A1), the Erling-Perssons
Stiftelse, and the Michael J. Fox foundation for financial
support.
■
to give a zwitterionic intermediate A, which undergoes 1,4-
intramolecular proton transfer (path a) to deliver the
sulfonium ylide B. The sulfonium ylide picks up an acidic C-
2
3
proton from unreacted 2-pyridone, from intermediates, or
from traces of water present in the reaction mixture; then,
elimination furnishes the ring-opened product. The unusual
case of the ring expansion, 6, would therefore seem to result
from the competition of intramolecular nucleophilic sub-
stitution (path b) with proton transfer in intermediate A. To
confirm that acidic C-3 proton is necessary for opening of the
ring, we treated 2-pyridone 23 with 3-methoxy benzyne
precursor 10 (Mechanistic Experiment F, Scheme S2). No
ring-opened product was detected.
In summary, we have used bicyclic thiazolino-2-pyridones to
explore the reactivity of arynes generated in situ to synthesize
highly functionalized N-alkenyl-2-pyridones. To make use of
this transformation, it is necessary to consider alternative
reactivity, notably the [4 + 2] cycloaddition of 2-pyridones
with benzyne and the further ring opening of these adducts.
Understanding the effect of different substituents and choosing
a more electrophilic precursor allowed us to achieve good
selectivity with highly reactive intermediates. Several examples
were isolated in >90% yield. Furthermore, to extend the scope
of the methodology, we ring-opened polycyclic bioactive 2-
REFERENCES
■
(
1) (a) Franzen, V.; Joschek, H.-I.; Mertz, C. Eur. J. Org. Chem.
962, 654 (1), 82. (b) Hellmann, H.; Eberle, D. Eur. J. Org. Chem.
1963, 662 (1), 188. (c) Iwamura, H.; Iwamura, M.; Nishida, T.;
Yoshida, M.; Nakayama, J. Tetrahedron Lett. 1971, 12, 63.
(d) Nakayama, J.; Fujita, T.; Hoshino, M. Chem. Lett. 1982, 11,
777. (e) Nakayama, J.; Kumano, Y.; Hoshino, M. Tetrahedron Lett.
989, 30, 847. (f) Nakayama, J.; Hoshino, K.; Hoshino, M. Chem.
Lett. 1985, 14, 677. (g) Nakayama, J.; Takeue, S.; Hoshino, M.
Tetrahedron Lett. 1984, 25, 2679. (h) Nakayama, J.; Ozasa, H.;
Hoshino, M. Heterocycles 1984, 22, 1053. (i) Hori, M.; Kataoka, T.;
Shimizu, H.; Ueda, N. Tetrahedron Lett. 1981, 22 (32), 3071.
1
1
1
(
j) Nakayama, J. J. Sulfur Chem. 2009, 30, 393.
2) (a) Chen, J.; Palani, V.; Hoye, T. R. J. Am. Chem. Soc. 2016, 138,
4318. (b) Zheng, T.; Tan, J.; Fan, R.; Su, S.; Liu, B.; Tan, C.; Xu, K.
Chem. Commun. 2018, 54, 1303. (c) Fan, R.; Liu, B.; Zheng, T.; Xu,
(
D
DOI: 10.1021/acs.orglett.9b02549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
K.; Tan, C.; Zeng, T.; Su, S.; Tan, J. Chem. Commun. 2018, 54, 7081.
Tetrahedron 1993, 49 (40), 9105. (c) Mariano, P. S.; Huesmann, P.
L.; Beamer, R. L.; Dunaway-Mariano, D. D. Tetrahedron 1978, 34
(17), 2617. (d) Kato, H.; Fujita, R.; Hongo, H.; Tomisawa, H.
Heterocycles 1979, 12, 1. (e) Sliwa, W. Heterocycles 1980, 14, 1793 and
references therein. . (f) Kuzuya, M.; Mano, E.; Adachi, M.; Noguchi,
A.; Okuda, T. Chem. Lett. 1982, 11 (4), 475.
(
4
d) Tan, J.; Zheng, T.; Xu, K.; Liu, C. Org. Biomol. Chem. 2017, 15,
946. (e) Li, Y.; Muck-Lichtenfeld, C.; Studer, A. Angew. Chem., Int.
̈
Ed. 2016, 55, 14435. (f) Pawliczek, M.; Garve, L. K. B.; Werz, D. B.
Chem. Commun. 2015, 51, 9165. (g) Yoshida, S.; Uchida, K.; Igawa,
K.; Tomooka, K.; Hosoya, T. Chem. Commun. 2014, 50, 15059.
(
h) Garg, P.; Singh, A. Org. Lett. 2018, 20, 1320. (i) Ahire, M. M.;
(8) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
12, 1211. (b) Bronner, S. M.; Garg, N. K. J. Org. Chem. 2009, 74,
8842. (c) Atkinson, D. J.; Sperry, J.; Brimble, M. A. Synthesis 2010,
2010, 911.
Khan, R.; Mhaske, S. B. Org. Lett. 2017, 19, 2134. (j) Xu, H.-D.; Cai,
M.-Q.; He, W.-J.; Hu, W.-H.; Shen, M.-H. RSC Adv. 2014, 4, 7623.
(3) Cycloadditions: (a) Afarinkia, K.; Vinader, V.; Nelson, T. D.;
Posner, G. H. Tetrahedron 1992, 48, 9111. Polymerization: (b) Ueda,
N.; Konda, K.; Kono, M.; Takemoto, K.; Imoto, M. Makromol. Chem.
(9) Del Mazza, D.; Reinecke, M. G. J. Org. Chem. 1988, 53, 5799.
(10) (a) Medina, J. M.; Mackey, J. L.; Garg, N. K.; Houk, K. N. J.
Am. Chem. Soc. 2014, 136, 15798. (b) Fine Nathel, N. F.; Morrill, L.
A.; Mayr, H.; Garg, N. K. J. Am. Chem. Soc. 2016, 138, 10402.
(c) Picazo, E.; Houk, K. N.; Garg, N. K. Tetrahedron Lett. 2015, 56,
3511.
1
968, 120, 13. (c) Pitha, J.; Ts’o, P. O. P. J. Org. Chem. 1968, 33,
1341. (d) Kaye, H. J. Polym. Sci., Part B: Polym. Lett. 1969, 7, 1.
Natural products: (e) Gray, D.; Gallagher, T. Angew. Chem., Int. Ed.
006, 45, 2419. (f) Huffman, J. W.; Lu, J.; Hynd, G.; Wiley, J. L.;
2
Martin, B. R. Bioorg. Med. Chem. 2001, 9, 2863. (g) Katoh, T.;
Mizuguchi, A.; Hirotaka, T. 2-Pyridone Derivatives, A Process for
Their Preparation and Their Use As Fungicides. European Patent
Appl. EP 0535980 A1, 1993. (h) Kelly, M. G.; Kincaid, J.; Fang, Y.;
Cao, Y.; Kaub, C.; Gowlugari, S.; Wang, Z. Bicycloheteroaryl
Compounds as p2 × 7 Modulators and Uses Thereof. PCT Int.
(11) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
(
12) Åberg, V.; Das, P.; Chorell, E.; Hedenstrom, M.; Pinkner, J. S.;
̈
Hultgren, S. J.; Almqvist, F. Bioorg. Med. Chem. Lett. 2008, 18, 3536.
Appl. WO2007109192 A2, 2007. (i) Sosn
Synthesis 2019, 51, A−AB.
4) (a) Yadla, R.; Rehman, H.; Rao, J. M.; Mahesh, V. K.
Tetrahedron 1989, 45, 7093. (b) Meunier, S.; Siaugue, J.-M.; Sawicki,
M.; Calbour, F.; Dezard, S.; Taran, F.; Mioskowski, C. J. Comb. Chem.
003, 5, 201. (c) Mohtat, B.; Jabbar, S.; Ghasemi, A.; Yavari, I. J.
́
icki, J. G.; Idzik, T. J.
(
́
2
Chem. Res. 2008, 2008 (10), 601. (d) Mariano, P. S.; Krochmal, E.;
Beamer, R.; Huesmann, P. L.; Dunaway-Mariano, D. Tetrahedron
1
978, 34, 2609. (e) Tasker, S. Z.; Brandsen, B. M.; Ryu, K. A.;
Snapper, G. S.; Staples, R. J.; DeKock, R. L.; Anderson, C. E. Org. Lett.
011, 13, 6224. (f) Romero, E. O.; Reidy, C. P.; Bootsma, A. N.;
2
PreFontaine, N. M.; Vryhof, N. W.; Wierenga, D. C.; Anderson, C. E.
J. Org. Chem. 2016, 81, 9895. (g) Lam, P. Y. S.; Vincent, G.; Bonne,
D.; Clark, C. G. Tetrahedron Lett. 2003, 44, 4927. (h) Ogata, M.;
Matsumoto, H.; Kida, S.; Shimizu, S.; Tawara, K.; Kawamura, Y. J.
Med. Chem. 1987, 30, 1497.
(
5) (a) Åberg, V.; Almqvist, F. Org. Biomol. Chem. 2007, 5, 1827.
b) Pinkner, J. S.; Remaut, H.; Buelens, F.; Miller, E.; Åberg, V.;
Pemberton, N.; Hedenstrom, M.; Larsson, A.; Seed, P.; Waksman, G.;
Hultgren, S. J.; Almqvist, F. Proc. Natl. Acad. Sci. U. S. A. 2006, 103
47), 17897. (c) Engstrom, P.; Krishnan, K. S.; Ngyuen, B. D.;
(
̈
(
̈
Chorell, E.; Normark, J.; Silver, J.; Bastidas, R. J.; Welch, M. D.;
Hultgren, S. J.; Wolf-Watz, H.; Valdivia, R. H.; Almqvist, F.;
Bergstro
Silver, J.; Nun
Engstrom, P.; Svensson, R.; Artursson, P.; Gylfe, Å.; Bergstro
Almqvist, F. J. Med. Chem. 2016, 59 (5), 2094. (e) Kulen
Lindgren, M.; Hansen, S.; Cairns, A. G.; Grundstrom, C.; Begum, A.;
van der Lingen, I.; Brannstrom, K.; Hall, M.; Sauer, U. H.; Johansson,
J.; Sauer-Eriksson, A. E.; Almqvist, F. J. Med. Chem. 2018, 61, 4165.
6) (a) Cegelski, L.; Pinkner, J. S.; Hammer, N. D.; Cusumano, C.
̈
m, S. mBio 2015, 6 (1), No. e02304. (d) Good, A. D. J.;
ez-Otero, C.; Bahnan, W.; Krishnan, K. S.; Salin, O.;
m, S.;
, M.;
̃
̈
̈
́
̈
̈
̈
(
K.; Hung, C. S.; Chorell, E.; Åberg, V.; Walker, J. N.; Seed, P. C.;
Almqvist, F.; Chapman, M. R.; Hultgren, S. Nat. Chem. Biol. 2009, 5,
913. (b) Horvath, I.; Weise, C. F.; Andersson, E. K.; Chorell, E.;
Sellstedt, M.; Bengtsson, C.; Olofsson, A.; Hultgren, S. J.; Chapman,
M. R.; Wolf-Watz, M.; Almqvist, F.; Wittung-Stafshede, P. J. Am.
Chem. Soc. 2012, 134 (7), 3439. (c) Singh, P.; Chorell, E.; Krishnan,
K. S.; Kindahl, T.; Åden, J.; Wittung-Stafshede, P.; Almqvist, F. Org.
Lett. 2015, 17 (24), 6194 and references therein. . (d) Pemberton, N.;
Jakobsson, L.; Almqvist, F. Org. Lett. 2006, 8 (5), 935. (e) Sellstedt,
M.; Nyberg, A.; Rosenbaum, E.; Engstro
Gullbo, J.; Bergstrom, S.; Johansson, L. B.-Å.; Almqvist, F. Eur. J. Org.
Chem. 2010, 2010, 6171. (f) Singh, P.; Adolfsson, D. E.; Åden, J.;
Cairns, A. G.; Bartens, C.; Brannstrom, K.; Olofsson, A.; Almqvist, F.
J. Org. Chem. 2019, 84 (7), 3887.
7) (a) Kuzuya, M.; Noguchi, A.; Kamiya, S.; Okuda, T. Chem.
Pharm. Bull. 1985, 33 (6), 2313. (b) Belkacemi, D.; Malpass, J. R.
m, P.; Wickstrom, M.;
̈ ̈
̈
́
̈
̈
(
E
DOI: 10.1021/acs.orglett.9b02549
Org. Lett. XXXX, XXX, XXX−XXX