The Fluoro-Pauson-Khand Reaction in the Synthesis of Enantioenriched Nitrogenated Bicycles Bearing a Quaternary C-F Stereogenic Center

Article abstract of DOI:10.1021/acs.orglett.9b02557

A variety of enantioenriched fluorinated 6H-cyclopenta[c]pyridin-6-one bicycles, a scaffold present in several classes of monoterpenic alkaloids with varied biological activity, were synthesized in just five steps from simple aldehyde starting materials.

Full text of DOI:10.1021/acs.orglett.9b02557

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
The Fluoro-Pauson−Khand Reaction in the Synthesis of
Enantioenriched Nitrogenated Bicycles Bearing a Quaternary C−F
Stereogenic Center
†
†
,‡
,†,‡
†
§
Alberto Llobat, Raquel Roman, Natalia Mateu,* Daniel M. Sedgwick, Pablo Barrio,
́
,
†
Mercedes Medio-Simon,* and Santos Fustero*
́
†
‡
§
Departmento de Química Organ
Laboratorio de Moleculas Organicas, Centro de Investigacion
Departamento de Química Organica e Inorganica, Faculdad de Química, Universidad de Oviedo, Avda. Julian
Oviedo, Spain
S Supporting Information
́
ica, Universitat de Valen
̀
cia, 46100 Burjassot, Spain
́
́
́
Príncipe Felipe, 46012 Valencia, Spain
́
́
́
Clavería no. 8, 33006
*
ABSTRACT: A variety of enantioenriched fluorinated 6H-cyclopenta-
c]pyridin-6-one bicycles, a scaffold present in several classes of
[
monoterpenic alkaloids with varied biological activity, were synthesized
in just five steps from simple aldehyde starting materials. The synthesis
presented wide functional group tolerance and moderate to high yields
and diastereoselectivities and could be carried out on a gram scale. These
products were suitable for further transformations, such as hydrogenation
and deprotection of the tert-butylsulfonyl protecting group.
itrogen-containing heterocycles are highly prevalent in
pharmaceuticals and agrochemicals as well as in other
bush native to Latin America, infusions of which have long been
used in Mexico to treat symptoms of diabetes. In fact, extracts of
this plant have been shown to exert a significant hypoglycemic
response in both rabbits and dogs, attributed to the action of
N
bioactive molecules. This is immediately apparent upon
consideration of the alkaloid class of natural products;
morphine, caffeine, nicotine, and atropine all belong to this
diverse family and present a wide range of biological activities. A
somewhat understudied scaffold is the cyclopenta[c]pyridin-6-
one bicycle, present in various natural products such as
tecomanine, tecostanine, and certain compounds belonging to
3
,4
these two monoterpenic alkaloids. In view of this activity,
compounds presenting this bicyclic structure could be useful in
the search for new antidiabetic compounds, a class of
pharmaceuticals that is increasingly important in the modern
5
world.
1
,2
In terms of synthesis, racemic tecomanine has been
synthesized through a variety of synthetic methods, including
a Pauson−Khand reaction, which allows the prior introduction
of all of the necessary substituents directly into the precursor and
the kinabalurine series (Figure 1). Both tecomanine and
tecostanine are present in the leaves of Tecoma stans, a species of
creates the bicyclic molecular complexity in just one reaction
6
(
Scheme 1a). Series of enantioenriched products with similar
7
1
structures have been prepared by both Gais and Evans, again
through the use of a Pauson−Khand reaction as the key step to
form the bicyclic scaffold.
On the other hand, fluorine has become increasingly
important in several key industrial fields, including but not
limited to medicinal and pharmaceutical chemistry, agro-
chemistry, and materials science. The strategic incorporation
of fluorine into biologically active molecules can improve the
drug-like properties of a given compound, such as the metabolic
Figure 1. Structures of monoterpenic alkaloids bearing the target
bicyclic structure.
Received: July 22, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. (a, b) Previous Related Work on the Racemic
Synthesis of Tecomanine Precursor and Other
Trifluoromethylated Derivatives via the Pauson−Khand
Reaction; (c) Synthesis of Enantioenriched Fluorinated
Tecomanine Analogues Reported in This Work
skeleton as seen in the aforementioned natural products, bearing
an all-important C−F bond at the bridged stereogenic center
(Scheme 1c).
We first carried out a retrosynthetic analysis of our target
structures (Scheme 2). The bicyclic core could be constructed
Scheme 2. Retrosynthetic Analysis of Target Bicyclic
Structures
via a fluoro-Pauson−Khand reaction of the N-tethered
fluoroenyne precursor. The vinyl fluoride could be introduced
using a suitable building block for the alkylation of the amine
group, which could in turn be synthesized through stereo-
selective propargylation of the corresponding imine.
We then decided that Ellman’s tert-butanesulfinyl imines
would be suitable starting materials for our goal of synthesizing
tecomanine analogues since they can be used as electrophiles in
many diastereoselective addition reactions with a variety of
stability or lipophilicity. −10 However, because of the scarcity of
natural products containing fluorine atoms, any advance in this
field relies on the development of new methods to synthesize
new fluorine-bearing structures. A recent trend in medicinal
organic chemistry, denominated the escape from flatland, refers
8
16,17
nucleophiles such as organometallic reagents.
Specifically,
the diastereoselective addition of propargylmagnesium bromide
to this class of imines is well-documented. Therefore, we
followed the procedure reported by Zhang et al. to obtain a
variety of sulfinylamide intermediates 2 in good yields with high
2
to a shift from the more common aromatic and similar C
tethers toward Csp centers in an attempt to provide greater 3D
molecular diversity. In particular, after approximately a decade
of exhaustive research on the formation of C −F and C −R
bonds, the asymmetric introduction of fluorine or fluorinated
groups at sp carbon centers has gained more attention in recent
sp
18
3
diastereoselectivities. Aromatic, heteroaromatic, and aliphatic
aldimines participated in the propargylation step uneventfully.
From there, the final step to form the precursors for the
Pauson−Khand reaction was the introduction of the fluoroallyl
group via alkylation of the nitrogen atom. Unfortunately, the
direct alkylation of the sulfinylamides resulted in unsatisfactory
yields (<20%). However, we found that after oxidation to the
corresponding sulfonamides, the reaction took place much more
11
2
sp
2
sp
F
1
2
3
1
3
years. With regard to this objective, perhaps the most
challenging step is the selective construction of a quaternary
stereogenic carbon center containing a C−F bond. In fact,
pharmaceutical drugs containing a stereogenic C−F bond
constitute just 1% of the drugs currently on the market as a direct
result of this problem.
We recently reported the first Pauson−Khand reactions using
enyne substrates containing a vinyl fluoride moiety as the olefin
coupling partner, which proved to be an effective way to
construct molecular complexity and the coveted quaternary C−
F group in one step, albeit in a racemic manner. Because of the
complete diastereoselectivity observed in this process, we
foresaw that enantiopure products bearing a stereodefined
quaternary C−F unit within a similar monoterpenic skeleton
could be obtained by using a suitable enantioenriched substrate.
We were surprised to find that fluorinated examples of this
class of structure had not yet been studied, the only example in
the literature being a single racemic analogue based on the same
19
successfully. In this way, a series of N-tethered fluorinated
enynes 4 were synthesized in good to high yields (Scheme 3).
We then applied our fluoro-Pauson−Khand procedure to the
14
desired precursors 4 (Scheme 4). However, our previously
reported conditions using dichloromethane at 40 °C for the
second reaction step were unsuccessful for these substrates.
Instead, we found that we had to switch the solvent to
dichloroethane and increase the temperature slightly to 65 °C.
The final bicyclic products were obtained in moderate to good
yields with excellent diastereoselectivities (dr >20:1). The
reaction was tolerant of a variety of electron-neutral and
electron-rich aromatic rings with several substitution patterns
(6a−e). The presence of a halogen atom on the aromatic ring
was also tolerated (6f). Heteroaromatic substituents at the
stereogenic center resulted in interesting scaffolds combining
two potential pharmacophores (6g−j). However, pyridine-
based 6j resulted in a low yield (see the Supporting Information
14
6
H-cyclopenta[c]pyridin-6-one scaffold bearing a trifluoro-
methyl substituent, which was also synthesized using the
Pauson−Khand reaction (Scheme 1b).
Therefore, we decided to apply our method to the synthesis of
enantioenriched compounds presenting the same bicyclic
15
21
for details). Substrates derived from aliphatic aldehydes, both
linear and cyclic, were also successfully used (6k−n). The
absolute stereochemistry of product 6a was determined to be
B
DOI: 10.1021/acs.orglett.9b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
f
Scheme 3. Synthesis of Fluoro-Pauson−Khand Precursors 4
Scheme 4. Scope and Limitations of the Fluoro-Pauson−
Khand Reaction
a
18
The reaction was carried out as described by Zhang et al. Standard
conditions for the propargylation step: aldimine 1 (1 equiv), freshly
prepared propargylmagnesium bromide (1.5 equiv), dichloromethane
b
(
(
0.1 M), −48 °C, 16 h. Standard conditions for the oxidation step: 2
1 equiv), m-CPBA (1.2 equiv), dichloromethane (0.1 M), 0 °C to
c
r.t., 2 h. Standard conditions for the fluoroallylation step: 3 (1 equiv),
NaH (3 equiv), 5 (2 equiv), DMF (0.2 M), 0 °C to r.t., 16 h.
d
Mesylate 5 was prepared following the procedure described by
20 e
Mykhailiuk et al.
An extra reduction step was necessary for the
synthesis of 4j (see the Supporting Information for details). Isolated
yields of the final fluoroallylation step are shown.
f
(
S,R) by X-ray crystallography (see the Supporting Information
for details) (Scheme 4).
Scheme 5. (a) Examples of Further Modifications to the Final
Pauson−Khand Adducts; (b) Gram-Scale Synthesis of 6a
The double bond in the resulting bicyclic products 6 could be
efficiently and diastereoselectively (dr >20:1) hydrogenated
using palladium over activated charcoal under an atmosphere of
hydrogen. However, it is worth noting that the resulting
saturated product 7 was unstable under acidic conditions and
rapidly lost HF during column chromatography using both
standard silica gel and aluminum oxide (Scheme 5a).
2
2
Nonetheless, using FluoroFlash silica gel we were able to
purify the desired saturated cyclopentanones 7 successfully with
no loss of HF. Furthermore, the tert-butylsulfonyl group could
be removed through treatment of the resulting Pauson−Khand
adduct with trifluoromethylsulfonic acid in the presence of
23
anisole to form 8 (Scheme 5a). The resulting amine was
isolated as the hydrochloride salt, as the intermediate free amine
was found to be unstable. A gram-scale synthesis of 6a was
carried out successfully in good yield with no detectable
decrease diastereoselectivity (Scheme 5b).
In summary, the power of the intramolecular Pauson−Khand
reaction for the stereoselective construction of enantioenriched
bicyclic cyclopentenones has been showcased by the concise
asymmetric synthesis of fluorinated tecomanine analogues.
Noteworthy is the use of vinyl fluorides as olefin counterparts in
the Pauson−Khand reaction, allowing the stereoselective
introduction of a fluorine atom in an otherwise synthetically
challenging bridgehead quaternary stereocenter. Several syn-
thetic transformations have been carried out on the obtained
products, including hydrogenation of the unsaturated bicyclic
system to generate the corresponding saturated derivative and
the removal of the Bus protecting group. A gram-scale synthesis
has also been successfully achieved in five steps starting from the
corresponding aldehyde.
C
DOI: 10.1021/acs.orglett.9b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Intramolecular Pauson−Khand Reaction of 1-Sulfonimidoyl-Substi-
tuted 5-Azaoct-1-en-7-ynes. J. Org. Chem. 2003, 68, 8037−8041.
ASSOCIATED CONTENT
Supporting Information
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*
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ACS Publications website at DOI: 10.1021/acs.orglett.9b02557.
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Experimental procedures, characterization of all new
compounds, and their corresponding NMR spectra
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CCDC 1937096 contains 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 e-mailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.; fax: +44 1223 336033.
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(
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AUTHOR INFORMATION
Corresponding Authors
■
(
*
*
*
E-mail: santos.fustero@uv.es.
E-mail: natalia.mateu@uv.es.
E-mail. mercedes.medio@uv.es.
M.; Paquin, J.-F. Monofluorination of Organic Compounds: 10 Years of
Innovation. Chem. Rev. 2015, 115, 9073−9174. (b) Zhu, Y.; Han, J.;
Wang, J.; Shibata, N.; Sodeoka, M.; Soloshonok, V. A.; Coelho, J. A. S.;
Toste, F. D. Modern Approaches for Asymmetric Construction of
Carbon−Fluorine Quaternary Stereogenic Centers: Synthetic Chal-
lenges and Pharmaceutical Needs. Chem. Rev. 2018, 118, 3887−3964.
ORCID
Pablo Barrio: 0000-0001-7101-4037
Santos Fustero: 0000-0002-7575-9439
Author Contributions
(14) Roman, R.; Mateu, N.; Lopez, I.; Medio-Simon, M.; Fustero, S.;
́ ́
Barrio, P. Vinyl Fluorides: Competent Olefinic Counterparts in the
Intramolecular Pauson−Khand Reaction. Org. Lett. 2019, 21, 2569−
2573.
́
(15) Magueur, G.; Legros, J.; Meyer, F.; Ourevitch, M.; Crousse, B.;
Bonnet-Delpon, D. A One-Pot Synthesis of Doubly Unsaturated
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
Trifluoromethyl Amines: Easy Access to CF -Substituted Piperidines.
3
Notes
Eur. J. Org. Chem. 2005, 2005, 1258−1265.
The authors declare no competing financial interest.
(16) Cogan, D. A.; Liu, G.; Ellman, J. Asymmetric synthesis of chiral
amines by highly diastereoselective 1,2-additions of organometallic
reagents to N-tert-butanesulfinyl imines. Tetrahedron 1999, 55, 8883−
ACKNOWLEDGMENTS
■
8
(
904.
The authors are grateful to the Spanish MICINN and the AEI
17) Sedgwick, D. M.; Barrio, P.; Simon, T.; Roman, R.; Fustero, S.
́
́
(CTQ2017-84249-P) for financial support, the SCSIE (Uni-
Asymmetric Allylation/RCM-Mediated Synthesis of Fluorinated
Benzo-Fused Bicyclic Homoallylic Amines as Dihydronaphthalene
Derivatives. J. Org. Chem. 2016, 81, 8876−8887.
versitat de Valen
R. Pedrosa (Universidad de Burgos) for providing us with
MoO Cl . The technical and human support provided by
SGIker (UPV/EHU, MINECO, GV/DJ, ERDF, and ESF) is
also gratefully acknowledged. P.B. thanks the Spanish Ministry
of Economy for a Ramon
The authors are also grateful to Jose Cabeza for assistance in the
synthesis of certain starting materials.
̀
cia) for access to instrumental facilities, and M.
2
2
(18) Cui, L.; Li, C.; Zhang, L. A Modular, Efficient, and
Stereoselective Synthesis of Substituted Piperidin-4-ols. Angew.
Chem., Int. Ed. 2010, 49, 9178−9181.
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y Cajal contract (RyC-2016-20951).
(19) Hao, J.; Milcent, T.; Retailleau, P.; Soloshonok, V. A.; Ongeri, S.;
Crousse, B. Asymmetric Synthesis of Cyclic Fluorinated Amino Acids.
Eur. J. Org. Chem. 2018, 2018, 3688−3692.
(20) Tkachenko, A. N.; Radchenko, D. S.; Mykhailiuk, P. K.;
Grygorenko, O. O.; Komarov, I. V. 4-Fluoro-2,4-methanoproline. Org.
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DOI: 10.1021/acs.orglett.9b02557
Org. Lett. XXXX, XXX, XXX−XXX