Chiral pyrrolidines and piperidines from enantioselective rhodium-catalyzed cascade arylative cyclization

Article abstract of DOI:10.1021/acs.orglett.5b00493

A new rhodium-catalyzed asymmetric arylative cyclization of nitrogen-tethered alkyne-enoate with arylboronic acids is described. In this process two new carbon-carbon bonds and one stereocenter are formed, providing access to pyrrolidines and piperidines

Full text of DOI:10.1021/acs.orglett.5b00493

Letter
pubs.acs.org/OrgLett
Chiral Pyrrolidines and Piperidines from Enantioselective Rhodium-
Catalyzed Cascade Arylative Cyclization
Fabien Serpier,† Benjamin Flamme,† Jean-Louis Brayer,‡ Benoît Folleas,‡ and Sylvain Darses*,†
́
†PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 11 rue Pierre et Marie Curie, 75005,
Paris, France
‡Diverchim, ZAC du Moulin, 6 rue du Noyer, 95700 Roissy-en-France, France
S
* Supporting Information
ABSTRACT: A new rhodium-catalyzed asymmetric arylative cyclization of
nitrogen-tethered alkyne-enoate with arylboronic acids is described. In this
process two new carbon−carbon bonds and one stereocenter are formed,
providing access to pyrrolidines and piperidines with good enantioselectivities
by to the use of C1-symmetric chiral monosubstituted diene ligands.
ransition-metal catalyzed cascade reactions provide
powerful methods for the elaboration of complex
arylative cyclization of allenyl aldehydes to provide chiral
pyrrolidines.6 Xu et al. described the preparation of pyrrolidines
bearing a tertiary allylic alcohol chiral center via the rhodium-
catalyzed tandem cyclization of nitrogen-bridged 5-alkynones
with arylboronic acids.7 In most of these processes,
carbocyclization occurs through the addition of the generated
vinyl- or alkylrhodium species to an aldehyde or ketone. We
wondered if we could access N-heterocyclic compounds via the
trapping of the vinylrhodium species with an enoate
(carbocyclization of alkyne tethered enoate), an approach
that has scarcely been described in the carbocyclic series,3d,f and
recently via the desymmetrization of alkyne tethered cyclo-
hexadiones.4b
T
molecules because they involve multiple carbon−carbon or
carbon−heteroatom bond formations from relatively simple
substrates in an atom-economical way.1 Among them, rhodium-
and palladium-catalyzed tandem annulations triggered by the
addition of organoboron reagents to activated alkenes or
alkynes afford a useful strategy for the construction of cyclic
compounds.2
In this approach, a molecule bearing two unsaturated
functional groups is cyclized in the presence of Rh(I)-aryl or
Pd(II)-aryl species generated in situ from transmetalation of the
arylboron species (Scheme 1). The more reactive functional
In our continuous interest in rhodium-catalyzed reactions
with organoboron compounds,8 we report for the first time the
enantioselective rhodium-catalyzed arylative cyclization of
nitrogen-tethered alkyne-enoate to provide chiral pyrrolidines
and piperidines.
Scheme 1. Rhodium- and Palladium-Catalyzed Tandem
Annulations Triggered by the Addition of Organoboron
Reagents
As a reaction model, we first investigated the formation of
pyrrolidine 3aa via the reaction of readily available alkyne-
enoate 1a with phenylboronic acid (2a), in the presence of
rhodium complexes and chiral ligands (Table 1).
As the reaction was very sluggish in the presence of chiral
phosphane ligands (entries 1−2) we envisaged the use of chiral
diene ligands that have been really useful in rhodium-catalyzed
processes and other reactions.9 In the presence of commercially
available disubstituted C2-type symmetric chiral dienes (entries
3−5), low yields and moderate enantioselectivities were
achieved. However, using C1-type symmetric dienes developed
by Carreira and us,10 better yields were obtained and the levels
of enantioselectivity could be easily tuned by the nature and the
group (for example an alkyne) provides the entry point for the
addition of the Rh(I)-aryl via a first intermolecular
carbometalation reaction, which triggers the second intra-
molecular carbometalation of the less reactive functional group
to construct a cyclic skeleton.
Furthermore, in the presence of an appropriate chiral ligand,
an asymmetric version can be envisioned to access chiral cyclic
compounds.
Although this strategy has been used for the formation of
chiral carbocyclic compounds,3 only a few examples have been
described for the formation of chiral heterocyclic compounds,4
and particularly N-heterocyclic molecules.5 The Tsukamoto
group has described the enantioselective palladium-catalyzed
Received: February 16, 2015
Published: March 12, 2015
© 2015 American Chemical Society
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Table 1. Evaluation of Chiral for the Rh-Catalyzed Arylative
Cyclization of 1a
Table 2. Chiral Pyrrolidines from Rh/Chiral Diene-
Catalyzed Arylative Cyclization of 1a
a
a
b
c
entry
Ln
yield (%)
ee (%)
d
1
L1
<10
<10
16
16
21
48
49
72
52
53
14
61
63
nd
d
2
L2
nd
3
L3
72
63
68
59
40
59
89
90
16
90
88
4
L4
5
L5
a
6
L6
The reaction was conducted with 1a (0.31 mmol), 2 (0.62 mmol, 2
equiv) in the presence of an in situ generated chiral diene−rhodium
complex (3 mol % Rh) in degassed methanol/water 10:1 at 60 °C.
7
L7
8
L8
b
c
Isolated yields of 3. Enantiomeric excess determined by chiral
9
L9
d
HPLC. Using enyne 1b bearing an isopropyl ester instead of the
methyl ester. Not determined.
10
11
12
13
L10
L11
L12
L13
e
isopropyl ester alkyne-eneoate 1b (entry 2) did not bring any
improvement to the stereochemical outcome of the reaction,
accompanied by a lower yield in carbocyclized adduct 3ba. The
optimized conditions proved to be quite general, and a variety
of arylboronic acids participated in the reaction, affording a
variety of chiral pyrrolidines bearing an all-carbon tetrasub-
stituted olefin (entries 3−11). Importantly the yields and
enantiomeric excesses of pyrrolidines 3 were not influenced by
the electronic properties (electron-withdrawing or -releasing
substituents) of the arylboron reagent (entries 3−6).
Interestingly, a bromo-substituted arylboronic acid also under-
went addition to 1a, affording highly functionalized substrate
3ae, which can be further functionalized by palladium-catalyzed
cross-coupling, providing further opportunities to access, in a
straightforward way, more complex structures. The presence of
an ortho-substituent on the arylboronic acid (entry 10) was
detrimental, and the conversion was very low.
We next envisaged to access chiral piperidines using an
analogous method, but starting from nitrogen-tethered 1,7-
enynes instead of the previously used 1,6-enynes. To that end,
two new nitrogen-tethered alkyne enoates were prepared and
evaluated: 1c bearing a supplementary carbon atom on the
enoate moiety compared to 1a and 1d where a carbon atom has
been added on the alkyne side (Scheme 2). We were pleased to
find that, under identical conditions and using the same C1-
symmetric chiral diene ligand L12, the rhodium-catalyzed
arylative cyclization occurred readily on these substrates. With
substrate 1c the levels of enantioselectivity were similar to those
observed for the formation of pyrrolidine derivatives. However,
a
The reaction was conducted with 1a (0.31 mmol), 2a (0.62 mmol, 2
equiv) in the presence of an in situ generated chiral ligand−rhodium
complex (3 mol % Rh) in degassed dioxane/water 10:1 at 60 °C.
b
c
Isolated yields of 3aa. Enantiomeric excess determined by chiral
d
HPLC. Not determined.
position of the substituent of the aromatic ring of the diene.
Indeed, with 4-substituted chiral dienes, the levels of
enantioselectivity were moderate (entries 6−8) whereas the
presence of an ortho-substituent resulted in an increase of the
ee up to 90% (entries 9−10). Increasing the steric hindrance in
the ortho position (entry 11) was detrimental on both yield and
enantioselectivity. Combining the positive effect of a 4-methoxy
substituent on the yield (entry 8) with the necessity to have an
ortho-substituent for high enantioselectivity, chiral dienes L12
and L13 were prepared and evaluated (entries 12−13). Good
enantioselectivities were achieved and yields could be slightly
increased; chiral diene L12 was selected for the rest of the study
because of its ease of preparation. After some further
optimization (solvent, amount of base) we were pleased to
find that reaction of 1a with 2a occurred smoothly at 60 °C, in
a mixture of methanol and water as solvent, in the presence of a
rhodium catalyst complexed with C1-symmetric chiral diene
ligand L12, affording chiral pyrrolidine 3aa in 63% yield and an
enantiomeric excess of 92% (Table 2, entry 1).
We wondered if an increase of steric hindrance at the ester
moiety would result in increased enantioselectivity as observed
in other rhodium-catalyzed reactions.8a,11 However, the use of
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deprotected pyrrolidine 6aa in 97% yield and unchanged
enantioselectivity (Scheme 3).13
Scheme 2. Chiral Piperidines from Rh/Chiral Diene-
Catalyzed Arylative Cyclization of 1b and 1c
a
Scheme 3. Deprotection of the Ts group
The overall mechanism is believed to involve transmetalation
of the arylboron reagent to the in situ generated
hydroxyrhodium(I) complex followed by the regioselective
insertion of the alkyne into the arylrhodium(I) bond giving a
vinylrhodium intermediate (Scheme 4). This vinylrhodium
Scheme 4. Possible Reaction Mechanism and Models for
Enantioselectivity
a
The reaction was conducted with 1c or 1d (0.31 mmol), 2 (0.62
mmol, 2 equiv) in the presence of an in situ generated chiral diene−
rhodium complex (3 mol % Rh) in degassed methanol/water 10:1 at
b
60 °C. Isolated yields of 4 or 5 and enantiomeric excess determined
by chiral HPLC.
when enyne 1d was engaged in the rhodium-catalyzed arylative
cyclization, a slight decrease in the enantioselectivity was
observed (ee = 82% and 84%). Overall, it appeared that chiral
piperidines could also be obtained using the same reaction
conditions used for the formation of pyrrolidines.
The structure of piperidine 4ce was confirmed unambigu-
ously by single-crystal X-ray analysis, and the formed chiral
center was determined to have the R configuration (Figure 1).
Indeed, assuming an analogous reaction pathway, the absolute
configuration of the other described pyrrolidines and
piperidines is supposed to be the same.
intermediate undergoes intramolecular 1,4-addition, forming
the pyrrolidine or piperidine ring and generating a rhodium-
enolate intermediate. On protonation with water, the latter
liberates product 3, regenerating the active hydroxyrhodium
species. The stereoselectivity observed during the carbocycliza-
tion can be rationalized by the dissymmetry created by the
monosubstituted chiral diene at the rhodium center. Formation
of the (R)-isomer is the result of preferred complexation of the
enoate moiety on the re-face to the rhodium center to avoid
steric interaction with the chiral diene substituent (Scheme 4).
In conclusion, we have developed a new, enantioselective
rhodium-catalyzed cascade reaction of nitrogen-tethered
alkyne-enoate with arylboronic acids, allowing access to chiral
pyrrolidine and piperidines. Good yields and high enantiose-
lectivities were generally achieved thanks to the use of an easily
accessible C1-symmetric chiral diene ligand.
Figure 1. X-ray crystal structure of (R)-4ce.
In all the prepared N-heterocyclic compounds, the
tosylamide link was used because of the ease of preparation
of the starting material compared to other protecting nitrogen
groups, but it could easily be removed using mild conditions.
Indeed, treatment of 3aa of 99% ee (obtained by recrystalliza-
tion of a 92% ee sample in methanol) with magnesium in
anhydrous methanol under ultrasonic conditions12 afforded
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, description of the compounds, and
X-ray diffraction of 4ce. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sylvain.darses@chimie-paristech.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
F. Serpier thanks Diverchim for a grant.
■
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