Total Synthesis of Conulothiazole A

Article abstract of DOI:10.1021/acs.orglett.9b01490

An efficient total synthesis of the chlorinated thiazole-containing natural product conulothiazole A is reported. Key features of this synthesis include a novel rhodium-catalyzed enantioselective hydrogenation of a 2-enamido-thiazole and a vinylic Finkels

Full text of DOI:10.1021/acs.orglett.9b01490

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Conulothiazole A
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Antoine Nitelet, Phideline Gerard, Jimmy Bouche, and Gwilherm Evano*
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Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite libre de Bruxelles (ULB), Avenue F.
D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
S
* Supporting Information
ABSTRACT: An efficient total synthesis of the chlorinated thiazole-containing
natural product conulothiazole A is reported. Key features of this synthesis include
a novel rhodium-catalyzed enantioselective hydrogenation of a 2-enamido-thiazole
and a vinylic Finkelstein reaction that could be implemented at all stages of the
synthesis to install the chlorinated alkene.
ecause of the variety of their structures, natural products
Bhave long been a source of inspiration for the develop-
ment of new drugs and have been making a comeback in the
pharmaceutical industry recently.1 The intrinsic utility of
natural products as drug leads can indeed not be questioned
anymore, especially after the failure of combinatorial chemistry
to provide small molecule drug candidates.2 Advances in
separation and structure elucidation technologies have more-
over facilitated the discovery of an array of novel natural
products that can be fully characterized at the microgram scale.
The discovery of new natural products on such a scale however
implies the design and development of short, efficient, and
robust synthetic routes for their chemical synthesis in order to
apprehend their biological activities and potentially prepare
analogues in a diversity-oriented synthesis approach.
Amid all sources of natural products, marine organisms, and
Figure 1. Structure of conulothiazole A and related natural products.
modular total synthesis of conulothiazole A 1. Results from
these studies are reported in this manuscript.
Despite its apparent simplicity, two main challenges are
associated with the synthesis of conulothiazole A 1. The first
one actually lies in the enantioselective preparation of the
aminoethylthiazole, the only route reported to date being
in particular sponges and their associated microorganisms, are
among the most productive.3 They have indeed provided over
the years a range of bioactive substances that have often served
as starting points for biomedical applications.
In the course of the study of Caribbean sponges, the
Costantino group reported in 2016 the isolation and structure
based on a diastereoselective addition onto Ellman’s chiral
sulfinimines.8 The second and main difficulty is due to the
presence of the disubstituted chlorinated alkene, a structural
elucidation of various nonribosomal peptide/polyketides
element that is quite challenging to install with complete
hybrid compounds from the holobiome of Smenospongia
control of the stereochemistry. An analysis of total syntheses of
conulosa (i.e., the sponge and its associated microbiota)
among which include conulothiazoles A (1) and B (2) (Figure
1).4 These two novel natural products, isolated and
characterized at the microgram scale, possess an interesting
polyketide-peptide structure flanked with an aminoethylth-
iazole and a chlorinated alkene. Related natural products
include smenothiazoles A (3) and B (4)5 as well as
smenamides A (5) and B (6).6
In view of the high potency of such natural productsthe
smenamides and smenothiazoles displaying antiproliferative
activities against various cancer cell lines at nanomolar
concentrationsand based on their especially limited supply
and extremely low isolation yields (0.00000006% for
conulothiazole A) combined with our interest in natural
product synthesis,7 we envisioned developing a short and
natural products featuring such a chloroalkene, notably in the
smenamide and smenothiazole series, indeed reveals the low
levels of stereoselectivity obtained9 or the need for multistep
sequences.10 In an attempt to address these limitations and to
develop a straightforward and modular synthesis of con-
ulothiazole A 1, the disconnections shown in Figure 2 were
selected. In this approach, the optically enriched amino-
ethylthiazole moiety could be obtained by an enantioselective
hydrogenation of the corresponding enamido-thiazole in which
the heterocycle could potentially serve for chelation with the
catalyst and the disubstituted chloroalkene could be installed
using a syn-carbocupration/iodolysis/vinylic Finkelstein reac-
Received: April 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01490
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
expense of the conversion which was limited to 70%. Finally,
increasing the catalyst loading enabled a smooth enantiose-
lective hydrogenation of 7a to 8a that could be isolated in 90%
yield and 95% ee.15
Due to the efficiency of this enantioselective hydrogenation,
we decided to initiate a brief survey of its scope by evaluating
the reactivity of various enamido-heteroarenes: results from
these studies are shown in Figure 4. The reaction was found to
Figure 2. Disconnections envisioned for the total synthesis of
conulothiazole A.
tion, while a simple Wittig olefination could be used to
elaborate the central trisubstituted alkene.
With this retrosynthetic analysis of conulothiazole A in
mind, we first focused our efforts on the asymmetric synthesis
of the aminoethylthiazole subunit 8a by an enantioselective
hydrogenation of the corresponding enamide 7a. A literature
survey surprisingly revealed that while the related enantiose-
lective hydrogenation in the pyridine series is well-
documented,11 the extension to other azoles still had to be
developed, despite an important synthetic potential. A
screening of catalytic systems and conditions was therefore
performed: selected and representative results are shown in
Figure 3. While a combination of Rh(cod)2BF4 and (S)-
Figure 4. Scope of the enantioselective hydrogenation of 2-enamido-
heteroarenes.
be rather general since it could be extended to benzothiazole
(8c),16 thiophene (8d),16 furan (8e), benzothiophene (8f),
and benzofuran (8g) derivatives, all of them giving excellent
yields and enantioselectivities. The acetyl group in 8a could
moreover be replaced by a trifluoroacetyl without significant
modifications of the yield and enantioselectivity, 8hwhose
methanolysis provided aminoethylthiazole 9 required for the
synthesis of conulothiazole Abeing obtained in 84% yield
and 98% ee.
Having in hand an efficient route to the aminoethylthiazole
subunit of conulothiazole A, we next initiated the synthesis of
the polyketide subunit. The synthesis began with the
carbocupration of 3-phenylprop-1-yne 10 followed by iodolysis
of the resulting vinylcopper which resulted in a clean and fully
stereoselective formation of iodoalkene 11I (Scheme 1). As a
note, trapping the intermediate vinylcopper with electrophilic
chlorination agents is not operative in such cases due to
competing dimerization. Simple functional group trans-
formation involving a selective oxidative cleavage of the
terminal alkene in 11I followed by a Wittig reaction afforded
intermediate 12I which was then subjected to the key vinylic
retro-Finkelstein reaction.17 Upon reaction under our
previously reported conditions involving tetramethyl-
ammonium chloride and catalytic amounts of copper(I) iodide
and trans-N,N′-dimethylcyclohexane-1,2-diamine,18a a smooth,
thermodynamically favored and irreversible iodine to chlorine
exchange proceeded, enabling the isolation of 12Cl in 89% yield
and full retention of the double bond geometry. Saponification
of the ester in 12Cl followed by peptide coupling with
aminoethylthiazole 9 finally led to conulothiazole A (1) whose
spectral data were in complete agreement with those of the
natural sample.4
Figure 3. Optimization of the enantioselective hydrogenation of 2-
enamido-thiazoles.
Monophos12 was found to be totally inefficient, switching to
rhodium−DuPHOS complexes13 promoted an enantioselec-
tive hydrogenation of 7a to 8a with moderate levels of
enantioselectivity but low conversions. A combination of
Rh(nbd)2BF4 and (S,S)-QuinoxP14 was gratifyingly found to
be much more efficient in terms of conversion, yield, and
enantioselectivity, the latter being however still not high
enough (84%). Replacing the rhodium precatalyst by Rh-
(cod)2BF4 allowed 92% ee to be reached, although at the
B
DOI: 10.1021/acs.orglett.9b01490
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Total Synthesis of Conulothiazole A
In a final effort to further demonstrate the synthetic
usefulness of our copper-catalyzed vinylic halogen exchange
reaction, we envisioned challenging its efficiency by performing
the iodine to chlorine exchange on all synthetic intermediates.
As demonstrated by results summarized in Scheme 2, the
In conclusion, we have developed a short, modular, and
efficient total synthesis of conulothiazole A in 7 steps (longest
linear sequence) and 30% overall yield. This synthesis enables
an easy preparation of hundreds of milligrams of this natural
product, therefore providing an efficient supply for this
nonribosomal peptide/polyketides hybrid compound that can
hardly be obtained on a milligram scale from natural sources.
Key features of our synthesis include a vinylic retro-Finkelstein
reaction that can be performed at all stages of the synthesis as
well as an efficient enantioselective rhodium-catalyzed hydro-
genation of a 2-enamido-thiazole. Importantly, this asymmetric
hydrogenation could be extended to other 2-enamido-
heteroarenes, therefore providing an efficient entry to 2-
aminoethyl-arenes, useful building blocks in synthesis and
medicinal chemistry.
Scheme 2. Early- and Late-Stage Copper-Catalyzed Vinylic
Retro-Finkelstein Reactions en Route to Conulothiazole A
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01490.
Detailed experimental procedures and characterization
data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Gwilherm.Evano@ulb.be.
ORCID
Gwilherm Evano: 0000-0002-2939-4766
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
Our work was supported by the Universite libre de Bruxelles
(ULB) and the FNRS (PDR T.0160.18). A.N. and P.G.
̀
acknowledge the Fonds pour la formation a la Recherche dans
l’Industrie et dans l’Agriculture (F.R.I.A.) for graduate
fellowships.
chlorination of all alkenyl iodides proceeded smoothly in all
cases, a lower yield being however obtained in the presence of
a carboxylic acid (13I → 13Cl, 60%). Remarkably, a late-stage
halogen exchange performed on the iodinated analogue of
conulothiazole A 1I allowed the formation of conulothiazole A
1 in quantitative yield.
REFERENCES
■
(1) Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2016, 79, 629.
C
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Letter
(2) (a) Feher, M.; Schmidt, J. M. J. Chem. Inf. Comput. Sci. 2003, 43,
218. (b) Rouhi, A. M. Chem. Eng. News 2003, 81, 77.
(3) Blunt, J. W.; Carroll, A. R.; Copp, B. R.; Davis, R. A.; Keyzers, R.
A.; Prinsep, M. R. Nat. Prod. Rep. 2018, 35, 8.
(4) Esposito, G.; Della Sala, G.; Teta, R.; Caso, A.; Bourguet-
Kondracki, M.-L.; Pawlik, J. R.; Mangoni, A.; Costantino, V. Eur. J.
Org. Chem. 2016, 2016, 2871.
(5) Esposito, G.; Teta, R.; Miceli, R.; Ceccarelli, L. S.; Della Sala, G.;
Camerlingo, R.; Irollo, E.; Mangoni, A.; Pirozzi, G.; Costantino, V.
Mar. Drugs 2015, 13, 444.
(6) Teta, R.; Irollo, E.; Della Sala, G.; Pirozzi, G.; Mangoni, A.;
Costantino, V. Mar. Drugs 2013, 11, 4451.
(7) For representative examples, see: (a) Toumi, M.; Couty, F.;
Evano, G. Angew. Chem., Int. Ed. 2007, 46, 572. (b) Toumi, M.;
Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 5027. (c) Pradal,
A.; Evano, G. Chem. Commun. 2014, 50, 11907. (d) Coste, A.; Bayle,
A.; Marrot, J.; Evano, G. Org. Lett. 2014, 16, 1306. (e) Wang, J.;
Evano, G. Org. Lett. 2016, 18, 3542. (f) Baguia, H.; Deldaele, C.;
Romero, E.; Michelet, B.; Evano, G. Synthesis 2018, 50, 3022.
(8) Ilardi, E. A.; Zakarian, A. Chem. - Asian J. 2011, 6, 2260.
(9) Caso, A.; Mangoni, A.; Piccialli, G.; Costantino, V.; Piccialli, V.
ACS Omega 2017, 2, 1477.
(10) Ma, X.; Chen, Y.; Chen, S.; Xu, Z.; Ye, T. Org. Biomol. Chem.
2017, 15, 7196.
(11) For representative examples, see: (a) Int. Pat. Appl.
WO2006123113 A2, November 23, 2006. (b) O’Shea, P. D.;
Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.; Roy, A.;
Shultz, C. S. J. Org. Chem. 2009, 74, 4547.
(12) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-
L. Angew. Chem., Int. Ed. 2002, 41, 2348.
(13) Int. Pat. Appl. WO2006082392 A1, October 8, 2006. Also see
ref 11a.
(14) Imamoto, T.; Tamura, K.; Zhang, Z.; Horiuchi, Y.; Sugiya, M.;
Yoshida, K.; Yanagisawa, A.; Gridnev, I. D. J. Am. Chem. Soc. 2012,
134, 1754.
(15) The absolute configuration of 8a was demonstrated by
chemical correlation with (S)-2-(1-aminoethyl)thiazole reported in
ref 8.
(16) The absolute configuration of 8c and 8d was demonstrated by
comparison of their optical rotations with previously reported ones.
See Supporting Information for details.
(17) For reviews on aromatic and vinylic Finkelstein reactions, see:
(a) Sheppard, T. D. Org. Biomol. Chem. 2009, 7, 1043. (b) Evano, G.;
Nitelet, A.; Thilmany, P.; Dewez, D. F. Front. Chem. 2018, 6, 114.
(18) (a) Nitelet, A.; Evano, G. Org. Lett. 2016, 18, 1904. (b) Nitelet,
A.; Jouvin, K.; Evano, G. Tetrahedron 2016, 72, 5972. (c) Nitelet, A.;
Kairouz, V.; Lebel, H.; Charette, A. B.; Evano, G. Synthesis 2019, 51,
251. For a related transformation with aryl halides, see: (d) Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844.
D
DOI: 10.1021/acs.orglett.9b01490
Org. Lett. XXXX, XXX, XXX−XXX