Access to Polyfunctionalized Chiral Piperidines through Enantioselective Addition-Carbocyclization Cascade Reaction Catalyzed by a Rhodium(I)-Diene Complex

Article abstract of DOI:10.1021/acs.orglett.5b02858

A new addition-carbocyclization cascade reaction initiated by arylboronic acids and catalyzed by a rhodium/chiral diene complex is described. Starting from N-bridged oxoenoate derivatives, highly functionalized piperidines bearing three contiguous stereogenic centers were obtained with excellent enantio- and diastereoselectivities.

Full text of DOI:10.1021/acs.orglett.5b02858

Letter
pubs.acs.org/OrgLett
Access to Polyfunctionalized Chiral Piperidines through
Enantioselective Addition−Carbocyclization Cascade Reaction
Catalyzed by a Rhodium(I)−Diene Complex
Fabien Serpier,† 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 addition−carbocyclization cascade re-
action initiated by arylboronic acids and catalyzed by a
rhodium/chiral diene complex is described. Starting from N-
bridged oxoenoate derivatives, highly functionalized piper-
idines bearing three contiguous stereogenic centers were
obtained with excellent enantio- and diastereoselectivities.
N-Heterocyclic compounds are found in many natural
molecules and drugs1 and are a class of compounds that
exhibits interesting biological activities. As a consequence,
several metal-catalyzed approaches have been developed in the
past decade to access such functionalized scaffolds both in
racemic and enantioselective versions, mainly cycloaddition,2
hydroamination,3 cycloisomerization,4 ring-closing methathe-
sis,5 hydrogenation,6 and reductive cyclization.7 Formation of 5-
membered saturated cycles (pyrrolidine) are by far the most
studied compared to the 6-membered saturated analogues
(piperidines). As a part of the reductive cyclization methods,
the rhodium- or palladium-catalyzed carbocyclization reactions,
initiated by the addition of organoboron reagents, represent a
powerful approach for the formation of diversely substituted
carbo- and heterocyclic compounds.8 In most of the described
examples, alkyne-tethered electron-deficient olefins, alkynals, or
alkynones are the substrate of choice in such reactions and react
via hydroarylation of the alkyne followed by intramolecular
carbocyclization, leading to carbo- and O-heterocycles bearing
one stereogenic center (Scheme 1, eq 1).9,10 Although few
approaches have been recently published to access pyrrolidines
with high enantioselectivities,11 the majority of the examples
concern the formation of racemic nitrogen-containing five- and
six-membered rings,12 and only one method for the formation
of chiral piperidines has been recently reported by our group.11c
To extend the usefulness of carbocyclization reactions
triggered by organoboron species, we wondered if chiral
piperidines could be obtained in one step starting from the N-
bridged oxoenoate derivatives (Scheme 1, eq 2), combining an
α,β-unsaturated ester moiety as the entry point and a ketone as
a secondary electrophilic function.
This approach would allow the formation of new piperidine
derivatives with three stereogenic centers, including one
quaternary center. A similar approach has been developed by
Krische et al. for the formation of chiral carbocyclic compounds
and also for the desymmetrization of prochiral diketones using
a rhodium(I)/(R)-BINAP complex via an intramolecular
conjugate addition/aldol cyclization sequence.13 Even though
this strategy was very effective for the formation of 5- and 6-
membered carbocycles, the formation of optically active
piperidines had not been explored, and the cyclization did
not occur with α,β-unsaturated esters.
In our continuous interest in rhodium-catalyzed reactions
with organoboron compounds,14 we report for the first time the
enantio- and diastereoselective rhodium-catalyzed arylative
cyclization of nitrogen-tethered keto-enoate to provide chiral
piperidines bearing three stereogenic centers (Scheme 2).
After some short investigations, we were pleased to find the
reaction of substrate 1a with phenylboronic acid (2a) was
catalyzed by a chiral rhodium catalyst, generated in situ in the
presence of the chiral C2-symmetric diene (R,R)-Ph-Bod*,15
using NaOH as a base and conducting the reaction at 80 °C
(Table 1, entry 1). Two equivalents of sodium hydroxide was
Scheme 1. Addition−Carbocyclization Reactions Triggered
by the Addition of Boron Derivatives
Received: October 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02858
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Organic Letters
Letter
ranging from 96 to over 99% were observed in all cases. We
also evaluated the carbocyclization of substrate 1d, possessing a
phenyl ketone (Table 1, entries 14−17). In order to occur, the
reaction needed to be heated to 100 °C to observe a full
conversion of the starting material and avoid the formation of a
mixture of the desired piperidine 3 and the 1,4-addition adduct.
Under these more forcing conditions, cyclization of substrate
1d afforded diversely substituted chiral piperidines with a slight
decrease in both yields and enantioselectivities (90−96% ee).
The structure of piperidine 3ca was confirmed unambigu-
ously by single-crystal X-ray analysis (Figure 1). The absolute
Scheme 2. Chiral Piperidines from Rhodium-Catalyzed
Cascade Reactions
Table 1. Rhodium-Catalyzed Addition−Carbocylization
Reaction Triggered by ArB(OH)2 on N-Bridged Oxoenoate
a
Substrates
e
f
entry
1
2
3
yield (%)
ee (%)
1
2
3
4
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
2a
2a
2a
2b
2c
2d
2e
2f
3aa
3ba
3ca
3cb
3cc
3cd
3ce
3cf
16
24
60
60
59
30
67
66
66
68
38
47
35
38
55
32
52
64
95
>99
>99
99
b
5
b
Figure 1. X-ray crystal structure of (3S, 4R, 5S)-3ca.
6
96
b
7
b
98
,
c
,
d
8
9
98
configuration of the three stereogenic centers of 3ca was
determined to be (3S,4R,5S) when (R,R)-Ph-Bod* was used as
ligand. Indeed, assuming an analogous reaction pathway, the
absolute configuration of the other described piperidines is
supposed to be the same. The syn relationship between the
ester and the methyl substituent is opposite to that observed by
Krische et al. where the ketone and the methyl were anti.13a
The overall mechanism is believed to involve transmetalation
of the arylboron reagent to the in situ generated
hydroxorhodium(I) complex followed by asymmetric 1,4-
addition, providing the first stereogenic center and generating
an oxa-π-allyl rhodium intermediate A (Scheme 3). The
diastereoselective intramolecular trapping of the rhodium−
enolate by the ketone functional group generated an
alkoxorhodium(I) species B. For the regeneration of an active
rhodium species, two pathways can be envisioned: direct
transmetalation of the boronic acid to the alkoxorhodium(I) B,
generating the arylrhodium complex, or protonation of the
alkoxorhodium intermediate by water, arising from dehydration
of boronic acid to boroxine, or boronic acid itself, generating
the hydroxorhodium complex.
The excellent diastereoselectivity observed in this reaction
could be explained by considering the transition state of the
intramolecular rhodium−enolate trapping by the keto func-
tional group. This transition state could be assumed to be
represented as a Zimmermann−Traxler-type transition state
involving the formation of decalins (Scheme 3). If the rhodium
attacks on the si face of the ketone, a trans-decalin transition
state is involved (A1), whereas a cis-decalin transition state is
involved with an attack on the re face (A2). As the cis-decalin is
destabilized by 1,3-diaxial interactions, the reaction must occur
preferentially on the si face and provides the piperidines with
the observed diastereoselectivity.
b
2g
2h
2i
3cg
3ch
3ci
98
10
11
12
13
14
15
16
17
98
b
b
96
2j
3cj
98
2k
2b
2e
2g
2h
3ck
3db
3de
3dg
3dh
98
b,
b,
b,
b,
d
d
d
d
90
91
96
91
a
The reaction was conducted with 1 (0.3 mmol), 2 (0.6 mmol, 2
equiv), and NaOH (0.6 mmol, 2 equiv) in the presence of in situ
generated chiral (R,R)-Ph-Bod*−rhodium complex (3 mol % Rh) in
degassed dioxane at 80 °C. Reaction performed with (S,S)-Ph-Bod*
as ligand. 4 equiv of boronic acid was used. Reaction performed at
100 °C. Isolated yields. Determined by HPLC analysis using a chiral
stationary phase (see the Supporting Information).
b
c
d
e
f
necessary for the success of the reaction, and water had to be
avoided to prevent the protonation of the rhodium enolate
intermediate. Starting from 1a, bearing a methyl ester moiety,
the corresponding piperidine was obtained in low yield with a
moderate enantioselectivity. By increasing the steric hindrance
of the ester moiety (entries 2 and 3),16 we were pleased to find
that both yields and enantioselectivities were improved. Indeed,
the rhodium-catalyzed cyclization of keto-enoate 1c, bearing a
tert-butyl ester, in the presence of phenylboronic acid (2a)
occurred readily to afford the expected piperidine 3ca in 60%
yield as a unique diastereoisomer and an enantioselectivity
above 99% (entry 3). Under identical conditions, we decided to
examine the scope of the reaction using a variety of boronic
acids (Table 1, entries 4−13). We were pleased to observe that
the reaction of 1c with diversely substituted arylboronic acids
afforded the corresponding chiral piperidines with moderate to
good yields and with high levels of both diastereoselectivity and
enantioselectivity. Even if the reaction was more efficient using
boronic acids containing electron-withdrawing substituents
(entries 4, 7−10), these conditions proved to be quite general
with all the arylboronic acids screened: enantioselectivities
We next examined the reactivity of the piperidines, which can
further be functionalized thanks to their versatile functional
groups such as tert-butyl ester and tertiary hydroxyl groups. As
an illustration, the reactivity of the tertiary alcohol function has
been studied: the fluorination of compound 3ca using DAST17
(diethylaminosulfur trifluoride) gave the corresponding chiral
B
DOI: 10.1021/acs.orglett.5b02858
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Letter
reported example of a rhodium-catalyzed asymmetric carbocyc-
lization of N-tethered keto-enoate induced by boronic acids.
The prepared piperidines are versatile, and the hydroxy
substituent could be easily replaced by a fluorine, affording
chiral fluorinated piperidines. Moreover, the tosyl protecting
substituent could be easily removed under mild conditions,
enhancing again the versatility of this rhodium-catalyzed
cascade reaction for the formation of polyfunctionnalized chiral
piperidine derivatives.
Scheme 3. Possible Reaction Mechanism and Models for the
Observed Diastereoselectivity
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.5b02858.
X-ray diffraction data for 3ca (CIF)
Experimental procedures, descriptions of the com-
1
pounds, and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sylvain.darses@chimie-paristech.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Fabien Serpier thanks Diverchim for a grant.
■
piperidine 4ca in 58% yield and an enantiomeric excess of 99%
(Scheme 4).
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