Asymmetric Synthesis of Fluorinated Monoterpenic Alkaloid Derivatives from Chiral Fluoroalkyl Aldimines via the Pauson-Khand Reaction

Article abstract of DOI:10.1002/adsc.201901504

Enantioenriched fluorinated monoterpenic alkaloid analogues were synthesised, employing a strategy based on the previously undescribed diastereoselective propargylation of fluorinated tert-butanesulfinyl imines, and subsequent Pauson-Khand reaction of res

Full text of DOI:10.1002/adsc.201901504

Title: Asymmetric synthesis of fluorinated monoterpenic alkaloid
derivatives from chiral fluoroalkyl aldimines via the Pauson-
Khand reaction
Authors: Santos Fustero, Alberto Llobat, Daniel M. Sedgwick, Albert
Cabré, Raquel Roman, Natalia Mateu, Mercedes Medio-
Simon, Vadim Soloshonok, Jianlin Han, Antoni Riera, and
Jorge Escorihuela
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901504
Link to VoR: http://dx.doi.org/10.1002/adsc.201901504

Advanced Synthesis & Catalysis
10.1002/adsc.201901504
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric synthesis of fluorinated monoterpenic alkaloid
derivatives from chiral fluoroalkyl aldimines via the Pauson-
Khand reaction
a
a
b, c
a
Alberto Llobat, Daniel M. Sedgwick, Albert Cabré, Raquel Román, * Natalia
a
a
a
d, e
Mateu, Jorge Escorihuela, Mercedes Medio-Simón, * Vadim Soloshonok, Jianlin
Han, Antoni Riera, and Santos Fustero *
f
b, c
a
a
Departamento de Química Orgánica, Universitat de València, 46100 Burjassot, València, Spain.
Email: raquel.roman@uv.es; santos.fustero@uv.es; mercedes.medio@uv.es
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac
b
1
0, 08028 Barcelona, Spain.
c
Departament de Química Inorgànica i Orgànica, Secció Orgànica, Universitat de Barcelona, Martí i Franquès 1, 08028
Barcelona, Spain.
Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country, UPV/EHU, 20018 San
Sebastian, Spain.
IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical
Engineering, Nanjing Forestry University, Nanjing 210037 Jiangsu, People’s Republic of China.
d
e
f
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Enantioenriched fluorinated monoterpenic marine alkaloid nakadomarin A,[3a] or those
alkaloid analogues were synthesised, employing a strategy belonging to the kinabalurine, incarvilline and
[
3c]
based on the previously undescribed diastereoselective skytanthine families.
In contrast, access to the
propargylation of fluorinated tert-butanesulfinyl imines, tecomanine skeleton through the Pauson-Khand
and subsequent Pauson-Khand reaction of resulting enyne cycloaddition of chiral N-tethered 1,7-enynes has
[4,5]
derivatives, carried out both stoichiometrically and
catalytically. The Pauson-Khand reaction tolerated both
substituted alkenes and alkynes, and took place in good
yields and diastereoselectivities, even when applied to a
gram-scale synthesis.
been more scarcely explored.
In terms of fluorinated derivatives, our group recently
reported the synthesis of similar bicyclic structures
via fluoro-Pauson-Khand reaction, resulting in a
[6]
stereogenic bridgehead C—F bond (Scheme 1). In
addition, Bonnet-Delpon and co-workers briefly
explored the synthesis of racemic trifluoromethylated
Keywords: N-tert-butanesulfinyl imine; propargylation;
Pauson-Khand; organofluorine chemistry; asymmetric
synthesis
derivatives of the same heterobicylic skeleton
[7]
(
Scheme 1).
This, incidentally, is the only
documented example of the propargylation of
fluorinated imines, to the best of our knowledge. The
introduction of fluorine into organic molecules has
become a common strategy to fine-tune their
Monoterpenic alkaloids possessing a piperidine
heterocycle fused with a five-membered carbocyclic
ring are of utmost interest since they present
important biological activities.[1] Tecomanine and
incarvilline, exhibiting hypoglucemic and analgesic
activity respectively, are representative examples of
this group of alkaloids. The intramolecular Pauson-
Khand reaction (PKR) has been widely applied to the
synthesis of natural products, both stoichiometrically
and catalytically,[ and has also proved to be a
feasible method for the preparation of the
cyclopentane[c]piperidine core present in this class of
[8]
biological and pharmacological activities. In this
way, the potentially positive effects derived from the
introduction of fluoroalkyl groups in heterocyclic
structures, in particular nitrogen containing
[9]
heterocycles, has been extensively demonstrated.
Currently, there are several generalised methods for
the introduction of fluorine in organic molecules, one
[10]
of which is the use of fluorinated building blocks.
2]
Imines bearing fluorinated groupings represent an
interesting class of building blocks, given that they
can be used as electrophiles in many transformations,
giving rise to amines bearing proximal fluorinated
groups that have the potential to modify the basicity
of the amine as necessary.
[3]
monoterpenic alkaloids. Recent reports from several
groups illustrate the preparation, in some cases
stereocontrolled, of similar structures such as the
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201901504
Scheme 2. Rationale behind the solvent effects observed.
The dramatic effect of the solvent in this kind of
transformation is well documented, and is attributed
to differing transition states according to the nature of
[12d,13b,15]
the solvent (Scheme 2).
Nonetheless, it is
clear that in our case the substrate also plays a role.
We suspect that the fluorinated group, given its
strong electron-withdrawing character, increases the
reactivity of the imine and decreases the difference in
energy between the two transition states in non-
Scheme 1. Previous work relevant to this report.
Specifically, fluorinated tert-butane sulfinyl imines
coordinating solvents such as CH
2
Cl . In coordinating
2
can be used to produce optically pure fluorinated
solvents such as THF, the six-membered transition
state is less favoured and therefore the reaction takes
place via the open-chain transition state, resulting in
much higher diastereoselectivity.
Accordingly, the propargylation reaction was carried
out at -78 °C in THF affording the corresponding
homopropargyl sulfinamides 2a and 2e-i in moderate
to good yields (60-87%) and excellent diastereomeric
ratios (dr >20:1) (Table 1).
amines that could be valuable to medicinal and
pharmaceutical research,[
11]
although their full
potential in organic synthesis is only recently coming
to light.[12]
Therefore, continuing our interest in this class of
fluorinated molecules, in this update we describe the
asymmetric synthesis of tecomanine analogues
through Pauson-Khand cyclisation of N-tethered 1,7-
enynes 4 bearing a series of fluorinated substituents
in a different position to those disclosed previously,
originating from chiral fluorinated imines 1 (Scheme
Allylation of the homopropargyl sulfinamides 2 to
achieve the desired enynes proved problematic, and
resulted in unsatisfactory yields (<30%). Fortunately,
we found that after oxidation of the sulfinyl group
1
). Herein, we also report a wider reaction scope of
the Pauson-Khand reaction, including an efficient
catalytic version, and new substrates bearing
substitutions at both the alkyne and alkene groups.
With the starting imines 1 in hand, we envisioned a
synthetic route with diastereoselective propargylation
of imines 1 as the key step in order to introduce the
chiral information necessary for the rest of the
sequence. To our surprise, we found that the
asymmetric propargylation of this class of fluorinated
imines remained undescribed in the scientific
literature, despite similar non-fluorinated substrates
being widely employed as electrophiles in
[16]
with m-CPBA in CH
corresponding homopropargyl sulfonamides 3a and
e-i successfully underwent allylation through
2
Cl
2
at
0
°C,
the
3
reaction with the corresponding bromide in basic
conditions at room temperature to give 4a-i with
good yields in general (Table 1).
With the goal of exploring the scope and limitations
of the final Pauson-Khand reaction, we next
synthesised N-tethered 1,7-enynes bearing an internal
triple bond. To this end, we first attempted the
preparation of phenyl-substituted 2j through the
addition of phenyl propargyl magnesium bromide to
sulfinimine 1a. However, in this case an inseparable
mixture of the corresponding homopropargyl and
allenyl products, 2j and 2j’ respectively, was
observed (Table 2). This has been described in
several reports owing to the alkyne/allene equilibrium
[13]
diastereoselective addition reactions.
We first assayed the addition of propargyl
magnesium bromide to sulfinimine 1a in CH Cl
2
2
using the conditions described by Zhang et al. for
several non-fluorinated imines,[
13a]
however, the
resulting homopropargyl amine 2a was obtained with
only slight diastereoselectivity (44:56). We therefore
changed the solvent to THF and found that not only
the diastereoselectivity was vastly improved (96:4),
but the major diastereoisomer was actually the
[17]
of the organometallic reagent in solution.
We
found that this setback could be overcome to a certain
degree modifying the reaction temperature; at higher
temperatures, the desired propargylation reaction
product 2j was favoured by up to 11:1 (Table 2).
[14]
opposite of that observed in CH
2
Cl .
2
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201901504
Table 1. Asymmetric synthesis of enynes 4a-g.a), b)
Table 3. Synthesis of enynes 4j-l.a), b)
Entry
Ar
3 (%)
4 (%)
1
2
3
Ph
3j (87)
3k (40)
3l (65)
4j (81)
4k (99)
4l (97)
2
(%)
R
F
3 (%)
a (82)
R1
R2
4 (%)
a (92)
6 4
p-MeOC H
p-ClC H
6 4
c)
(
dr)
CF
3
a (87)
H
H
Reaction conditions: i. Ar-I (1.2 equiv), Pd(Ph
mol%), CuI (8 mol%), (i-Pr) NH [0.06 M], 50 °C, 2-3 h. ii.
Allyl bromide (2 equiv), K CO (3 equiv), DMF [0.1 M],
°C – r.t., 5-12 h. Yields refer to isolated yields in all
3 2 2
) Cl (4
(
96:4)
d)
2
CF
CF
CF
3
3
3
a
a
a
a
a
a
H
H
Me
H
Me
Ph
Me
H
b (93)
c (84)
d (93)
e (53)
2
3
a)
0
b)
cases. Bus = tert-butanesulfonyl.
CHF
2
e (60)
95:5)
f (65)
e (63)
(
oxidation/allylation sequence mentioned previously
C
C
C
2
3
4
F
5
F
7
F
9
f (81)
g (82)
h (83)
i (84)
H
H
H
H
H
H
H
H
f (70)
g (55)
h (82)
i (77)
to prepare the target 4-aza-8-aryl-1,7-enynes 4j-l
(
98:2)
(
4
Table 3). Similarly, we attempted the synthesis of
g (60)
m bearing a methyl substituent at the triple bond,
(
97:3)
h (60)
99:1)
i (74)
96:4)
firstly via propargylation analogous to that previously
discussed. However, this resulted in poor yield and
diastereoselectivity. We therefore opted to directly
methylate the triple bond in 4a using HMDSLi and
methyl iodide, following a previously described
(
2
CF Cl
(
[
18]
Reaction conditions: i. Magnesium propargyl bromide (1.5
equiv), THF [0.1 M], -78 °C, 2-3 h. ii. m-CPBA (1.2
procedure (Scheme 3).
With a variety of chiral 1,7-enynes 4 in hand, we then
explored their Pauson-Khand cyclisation to obtain
adducts bearing stereodefined substitutions in various
positions. Treatment of 4a-m with 1.2 equivalents of
Co (CO) resulted in their full conversion to the
equiv), CH
2
Cl
2
[0.1 M], 0 °C – r.t., 1-2 h. iii.
CO (3 equiv),
DMF [0.1 M], 0 °C – r.t., 5-12 h. Yields refer to isolated
Corresponding allyl bromide (2 equiv), K
2
3
a)
b)
c)
yields in all cases.
Diastereomeric ratios were determined by H and F NMR
see Supporting Information). d) A 4:1 mixture of E/Z-
Bus = tert-butanesulfonyl.
2
8
1
19
corresponding cobalt complexes after 2 hours in
CH Cl that, upon treatment with 10 equivalents of
(
2
2
crotyl bromide was used. We were unable to separate the
resulting two isomers of 4b by column chromatography,
and as such continued with the isomeric mixture.
N-methylmorpholine-N-oxide (NMO) overnight at
room temperature, underwent an efficient
intramolecular PKR to afford the corresponding
bicyclic derivatives 5a-m as single diastereomers
(Table 4).
Despite this partial solution, in the end we decided to
follow a different strategy and introduce an aryl
group at the triple bond via Sonogashira reaction with
The yields were moderate to good, and high
diastereoselectivity was observed in almost all cases.
In general, substrates with substituted olefin
components (4b-c) or longer fluoroalkyl chains (4f-h)
3
2
a, thereby eliminating completely allenyl derivative
j’ from the resulting product. In this way, the
corresponding homopropargyl sulfinamides were
obtained in moderate to good yields. These
derivatives were then subjected to the same
resulted
in
lower
yields
and
higher
diastereoselectivities (5b-c and 5f-h, Table 4).
Fortunately, when we carried out the PKR with the
isomeric mixture of E/Z-4b we obtained only two
diastereoisomers, indicating that the reaction took
place stereospecifically. Furthermore, 5b and 5b’
were separable by column chromatography, and their
stereochemistry was determined according to
NOESY experiments as well as previous literature
Table 2. Effect of temperature on alkyne vs allene
a)
selectivity.
[4]
reports involving similar substrates. Enyne 4h
bearing the CF Cl substituent resulted in a higher
2
yield but a low diastereoselectivity (5i, Table 4),
Entry
T (°C)
2j
:
2j’
1
2
3
4
-78
0
50
75
29
80
90
92
:
:
:
:
71
20
10
8
a)
19
Selectivity was measured by F NMR (see Supporting
Information).
Scheme 3. Synthesis of 1,7-enyne 4m.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201901504
Table 4. Pauson-Khand cyclisation of enynes 4a-m. a), b), c)
Table 5. Catalytic Pauson-Khand cyclisation of selected
enynes 4.
a), b)
a)
Yields refer to isolated yields in all cases. b) Bus = tert-
butanesulfonyl.
diastereoselectivity (global yield 36%, see Supporting
Information for details).
We also explored the use of 1,7-enynes 4 in a
catalytic version of the PKR, for which we selected a
new synthetic protocol recently reported by Riera and
[21]
co-workers. This procedure is based on a biphasic
system of ethylene glycol/toluene, and usually results
in an enhancement of yield and selectivity for the PK
adducts, as well as simplifying purification of the
products. By applying these reaction conditions (7
mol% catalyst, low CO pressure, and 15% v/v of
ethylene glycol in toluene) to enynes 4a, 4g, and 4j,
the corresponding bicyclic derivatives 5 were
obtained (Table 5).
For adducts 5a and 5j, the yields and
diastereoselectivities were clearly improved with
respect to the stoichiometric version. However, 5g
was obtained with a higher yield but reduced
diastereoselectivity. We suspect the higher yields
were due to the simpler purification arising from the
reaction mixture containing only small amounts of
cobalt compared with the stoichiometric version.
Furthermore, we tested the influence of the
introduction a vinyl fluoride moiety on the Pauson-
Khand cyclisation. To this end, the allylation reaction
of the homopropargyl sulfonamine 3a was carried out
with 2-fluoroallyl mesylate 6 to afford enyne 4n
a)
b)
Yields refer to isolated yields in all cases.
1
19
Diastereomeric ratios were determined by H and F NMR
c)
(
see Supporting Information). Bus = tert-butanesulfonyl.
d)
Compounds 5b and 5b’ were isolated from the same
reaction mixture using the isomeric E/Z mixture of 4b
mentioned earlier, thus the global yield for this reaction
was 55%. After addition of NMO, the cobalt complex
reverted back to starting enyne 4d (see text for details).
e)
whereas enynes containing an internal alkyne group
gave both higher yields and diastereoselectivities (5j-
m, Table 4). An exception to this was enyne 4d,
bearing a trisubstituted olefin. As could be expected,
due to the poor coordination ability of the
trisubstituted alkene, treatment with NMO lead to the
decomposition of the cobalt complex affording the
initial alkyne 4d. In fact, several precedents can be
found in the literature showing that trisubstituted
alkenes are very unreactive substrates in the Pauson-
Khand reaction.[
[22]
(
Scheme 4).
For the cyclisation of this enyne
derivative, we followed the reaction conditions
previously applied by our group in analogous fluoro-
19]
The stereochemistry of the newly formed stereogenic
centre in the bridgehead position was confirmed by
X-ray crystallography of PK adduct 5a.[20] In addition,
5a was prepared starting from 1.2 grams of imine 1a
Scheme 4. Use of fluorinated mesylate 6 in the synthesis
of PKR adducts bearing a stereodefined C—F bond at the
bridgehead position. Bus = tert-butanesulfonyl.
with no significant loss of yield or
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201901504
Pauson-Khand reactions, in which DMSO is used as
molecule of CO from the cobalt centre, leaving a
vacant site for alkene coordination.
[6, 23]
the promoter instead of NMO.
that this transformation involves the asymmetric
construction of carbon-fluorine quaternary
It is worth noting
The alkene group then coordinates to the
electronically unsaturated cobalt centre, yielding
complex II and releasing another molecule of CO.
From here, the alkene is inserted into the Co—C
bond, generating a new C—C bond in the six-
membered cobaltacycle intermediate III. This
cyclisation step occurs with high diastereoselectivity
a
stereogenic centre, a goal that constitutes remarkable
interest in organic synthesis.[24] Unfortunately, after
several attempts, the catalytic version of the
Pauson-Khand could not be applied to the
synthesis of this class of previously reported
quaternary C—F containing bicycles, such as 5n due to the energy difference between the two possible
[
6, 23
]
(
Scheme 4).
The mechanism of the Pauson-Khand reaction
catalyzed by Co (CO) was initially proposed by
Magnus in 1985,[ and the same mechanism has
transition states shown by density functional theory
(DFT) calculations (see Supporting Information for
details), reinforcing the experimental results
observed. The coordination of a CO molecule to the
cobalt centre then generates complex IV, and
subsequent CO insertion into the Co—C bond yields
complex V. A second molecule of CO then
coordinates to the unsaturated cobalt centre in V to
form complex VI, and a final reductive elimination
releases the corresponding cyclopentenone product 5.
In conclusion, the Pauson-Khand cycloaddition of
fluoroalkyl substituted chiral 4-aza-1,7-enynes allows
the synthesis of fluorinated derivatives of the 6H-
cyclopenta[c]pyridine-6-one skeleton that is present
in several classes of monoterpene alkaloids. The key
step to access the enyne precursors is the
diastereoselective propargylation of fluorinated tert-
butanesulfinyl imines, which was explored here for
the first time and took place in good yields and high
diastereoselectivities, despite performing differently
to their non-fluorinated counterparts. Substitution of
both the reacting alkene and alkyne groups has been
shown to be compatible with the Pauson-Khand
reaction, allowing further functionalisation of the
heterobicyclic core. This synthetic route was also
carried out at gram scale maintaining high yields and
diastereoselectivities throughout. A catalytic version
of the Pauson-Khand reaction could also be used to
produce the desired adducts, generally offering
improved yields and diastereoselectivities. The
process was also applied to the synthesis of a
derivative bearing a fluorine atom at a fully
substituted bridgehead carbon stereogenic center, an
interesting feature given the difficulty in obtaining
similar structures by alternative methods.
2
8
25]
[26]
since been supported by theoretical studies. In our
case, 1,7-enyne 4 reacts with Co (CO) through a
ligand exchange reaction to form the alkyne-
coordinated Co (CO) complex I upon release of two
molecules of CO (Scheme 5). In the next step, the
addition of NMO facilitates the liberation of a
2
8
2
6
Experimental Section
General procedure for the stoichiometric Pauson-
Khand reaction
Sulfonamides 4 (1 equiv) were dissolved in DCM [0.1 M]
at room temperature in
a
round-bottomed flask.
Octacarbonyl dicobalt complex (1.2 equiv) was then added
and the mixture was stirred until the starting sulfonamide
had been consumed (TLC analysis, typically 2 hours). At
this time, N-methylmorpholine N-oxide (10 equiv) was
added and the reaction was stirred overnight at room
temperature. Once the reaction had finished, the solvent
was removed under reduced pressure and products 5 were
purified by flash column chromatography (n-hexane:ethyl
acetate).
Scheme 5. a) Plausible mechanism of our Pauson-Khand
reaction. b) Most favourable transition state between
complexes II and III, determining the configuration of the
newly formed stereogenic centre (see Supporting
Information).
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201901504
General procedure for the catalytic Pauson-Khand
reaction
Compound Classes: Pharmaceuticals, Wiley-VCH,
Weinheim, 2012.
10]a) H. Mei, T. Hiramatsu, R. Takeda, H. Moriwaka, H.
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Sedgwick, R. Román, P. Barrio, Chem. Commun.
[
Sulfonamides 4 (1 equiv) were dissolved in anhydrous
toluene [0.3 M] at room temperature in a flame-dried
pressure tube containing a magnetic stirrer. Octacarbonyl
dicobalt complex (7 mol%) was then added, followed by
ethylene glycol (15% v/v). The vessel was sealed and
2
018, 54, 9706–9725; c) M.-C. Belhomme, T. Besset,
T. Poisson, X. Pannecouke, Chem. Eur. J. 2015, 21,
2836–12865; d) V. G. Nenajdenko, V. M.
2
purged with N , and then three times with CO, before
1
finally being charged with CO (1 bar) and heated to 80 °C
for 2 days (TLC analysis, typically 2 hours). The vessel
was then degassed, filtered through a plug of Celite and the
crude reaction mixture was concentrated under reduced
pressure. Products 5 were purified by flash column
chromatography (n-hexane:ethyl acetate).
Muzalevskiy, A. V. Shastin, Chem. Rev. 2015, 115,
973–1050. e) P. Bravo, A. Farina, M. Frigerio, S. V.
Meille, F. Viani, V. A. Soloshonok, Tetrahedron:
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[
[
11] C. Xie, L. Zhang, H. Mei, J. Han, V. A. Soloshonok,
Y. Pan, ChemistrySelect, 2016, 1, 4435–4439.
12]a) S. Fustero, M. Rodenes, R. Román, D. M.
Sedgwick, J. E. Aguado, V. A. Soloshonok, J. Han, H.
Mei, M. Medio-Simón, P. Barrio, Adv. Synth. Catal.
2019, 361, 3860–3867; b) H. Mei, J. Han, S. Fustero,
R. Román, R. Ruzziconi, V. A. Soloshonok, J.
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Acknowledgements
The authors are grateful to the Spanish MICINN and
the AEI (CTQ2017-84249-P and CTQ2017-87840-P)
for financial support, the SCSIE (Universitat de
Valꢀncia) for access to instrumental facilities. The
technical and human support provided by SGIker
(
UPV/EHU, MINECO, GV/DJ, ERDF, and ESF) is
also gratefully acknowledged.
8
4
742–8750; e) S. Fioravanti, Tetrahedron, 2016, 72,
449–4489. f) N. Shibata, T. Nishimine, E. Tokunaga,
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Advanced Synthesis & Catalysis
10.1002/adsc.201901504
UPDATE
Asymmetric synthesis of fluorinated
monoterpenic alkaloid derivatives from chiral
fluoroalkyl aldimines via the Pauson-Khand
reaction
Adv. Synth. Catal. Year, Volume, Page – Page
Alberto Llobat, Daniel M. Sedgwick, Albert Cabré,
Raquel Román,* Natalia Mateu, Jorge Escorihuela,
Mercedes Medio-Simón,* Vadim Soloshonok,
Jianlin Han, Antoni Riera, and Santos Fustero*
8
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