Enantioselective metallo-organocatalyzed preparation of cyclopentanes bearing an all-carbon quaternary stereocenter

Article abstract of DOI:10.1039/c2cc32823b

Enantioselective metallo-organocatalyzed carbocyclizations of formyl-alkynes have been developed. The cooperation between aminocatalysis and a chiral copper(i) complex granted access to enantio-enriched cyclopentanes through the challenging formation of all-carbon quaternary stereocenters.

Full text of DOI:10.1039/c2cc32823b

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COMMUNICATION
Enantioselective metallo-organocatalyzed preparation of cyclopentanes
bearing an all-carbon quaternary stereocenterw
Benjamin Montaignac,ab Chandrasekaran Praveen,ab Maxime R. Vitale,ab
ab
Veronique Michelet* and Virginie Ratovelomanana-Vidal*ab
´
Received 20th April 2012, Accepted 3rd May 2012
DOI: 10.1039/c2cc32823b
Enantioselective metallo-organocatalyzed carbocyclizations of
formyl-alkynes have been developed. The cooperation between
aminocatalysis and a chiral copper(I) complex granted access to
enantio-enriched cyclopentanes through the challenging formation
of all-carbon quaternary stereocenters.
The catalytic enantioselective construction of quaternary
stereocenters is an established challenge in organic chemistry.1
More specifically, the stereoselective catalytic formation of
all-carbon quaternary stereocenters is even more complex
because of the steric repulsion existing between the four
carbon substituents.2 The use of either metal catalysis or
organocatalysis has partially allowed solving that longstanding
problem through the development of a plethora of asymmetric
processes.1,2 Very recently, the catalysis landscape has widened to
cooperative catalytic strategies aimed at the synergistic associa-
tion of several co-catalysts.3 While merging metal catalysis
with organocatalysis,4 new types of reactivity and/or ways of
Scheme 1
controlling stereoselectivity have been unveiled, including very
recent examples dealing with the stereoselective formation of
reactions leading to cyclopentenes, combining the use of catalytic
quantities of secondary amines and either gold or copper(I)
all-carbon quaternary centers. List and co-workers reported
the enantioselective palladium–chiral phosphoric acid-catalyzed
catalysts.8a,b Since then, several enantioselective syntheses of
cyclopentenes, dihydrofurans, and dihydropyrroles have been
reported, all based on a similar concept of cascade iminium–
allylation of a,a-disubstituted aldehydes with allylic amines or
alcohols.5 Dixon and co-workers developed an enantioselective
enamine-metallo activation of alkynes, followed by isomerization
Conia-Ene reaction of alkynyl-b-ketoesters with a copper(I)–
of the exocyclic double bond (Scheme 1).9 Considering the
added value of quaternary stereogenic centers, we focused our
attention toward the related carbocyclization of a,a-disubstituted
aldehydes.10 We reported several cooperative catalytic systems
based on the use of indium trichloride or copper(I) catalysts that
allowed the racemic preparation of a broad range of 5-membered
rings, including cyclopentanes and pyrrolidines.11 We report
herein an enantioselective version of this metallo-organocatalytic
process, in which an all-carbon quaternary stereogenic center is
formed through addition of a transient enamine onto an alkyne
activated by a chiral copper(I) complex (Scheme 1). To the best of
our knowledge, this strategy is unprecedented.
cinchona based urea catalytic system.6 Lastly, Amat and
co-workers reported the enantioselective formal [3+2] cyclo-
addition of isocyanoacetates with a,b-unsaturated ketones
catalyzed by silver(I) and cupreine.7
We and others have been interested for some time in merging
aminocatalysis to the catalytic metallo activation of alkynes.8–11
In 2008, seminal works by Dixon and Kirsch independently
showed that formyl-alkynes may undergo carbocyclization
a E.N.S.C.P., Chimie-ParisTech, UMR 7223,
Laboratoire Charles Friedel (LCF), 75005 Paris, France.
E-mail: virginie-vidal@chimie-paristech.fr,
veronique-michelet@chimie-paristech.fr; Fax: +33-1-4407-1062
Investigating the enantioselective carbocyclization of the
model substrate 1 to cyclopentane 2, a variety of chiral
phosphorus ligands A–F were tested in the presence of
5 mol% of copper(II) trifluoromethanesulfonate and 20 mol%
of cyclohexylamine in 1,2-dichloroethane at 20 1C. To insure
in situ reduction of copper(II) to copper(I), the Cu(OTf)2–chiral
b CNRS UMR 7223, 75005 Paris, France
w Electronic supplementary information (ESI) available: General
cyclization procedures and analytical descriptions of new substrates
and new carbocyclization products. X-Ray structure data of 4-chloro-
3-nitrobenzoate ester derived from 18 (CIF). See DOI: 10.1039/
c2cc32823b
c
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Chem. Commun., 2012, 48, 6559–6561 6559

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Table 1 Optimization of a chiral metallo-organocatalytic system
Table 2 Enantioselective preparation of cyclopentanes
Entry
1b
Substrate R/Z
Product
Yielda (%)
er
3
Et
59
86/14
C(CO2Me)2
Cu(OTf)2/
L* ratio
Entry L*
Solvent time (h) Yield (%) era
5
n-Bu
C(CO2Me)2
1
2
3
4
5
6
7
8
(S)-(R)-A 1.5
DCEb 24
DCEb 40
DCEb 16
DCEb 29
DCEb 15
DCEb 16
AcOEt 72
Et2O 67
Benzene 48
Dioxane 65
Dioxane 29
Dioxane 29
24
92
73
62
96
95
63
44
50
52
84
88
45/55
2b
65
66
88.5/11.5
68/32
(S)-B
(R)-C
(R)-D
(S)-E
(S)-F
(S)-F
(S)-F
(S)-F
(S)-F
(R)-F
1.5
3
46.5/53.5
60/40
59/41
39.5/60.5
11.5/88.5
15.5/85.5
13.5/86.5
9.5/90.5
7/93
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
2.5
7
Ph
3b
C(CO2Me)2
9
10
11c
9
Me
92.5/7.5
93.5/6.5
4
5
47
71
70.5/29.5
71.5/28.5
12c,d (R)-F
C(CH2OMe)2
a
b
Determined by HPLC Chiralpak IC 80/20 hexane–i-PrOH. 1,2-
Dichloroethane. c 6 mol% of Cu(OTf)2 was used. d 10 mol% of CyNH2.
11
Me
C(CH2OBn)2
ligand ratio was primarily fixed at 1.5 in the case of bidentate
ligands, and at 3 in the case of phosphoramidite C. Initial
results using (S),(R)-Josiphos A or the Pfalz phosphine-oxazoline
ligand B gave very weak stereoinduction (Table 1, entries 1 and 2).
Slightly better enantioselectivities could be obtained when
(R)-phosphoramidite C or (R)-BINAP D were employed, although
only average yields of 73% and 62% were obtained, respectively
(Table 1, entries 3 and 4). With a comparable 39.5/60.5 enantio-
meric ratio, a much better 96% yield was obtained employing
(S)-MeOBIPHEP E (Table 1, entry 5). At this point, we investi-
gated the use of much more sterically encumbered phosphines
such as (S)-4-MeO-3,5-(t-Bu)2-MeO-BIPHEP F and were
pleased to witness a significant amelioration of the enantio-
meric ratio, reaching 11.5/88.5 in good yield (Table 1, entry 6).
With this last ligand, a solvent screening revealed that in
dioxane a meaningfully higher enantiomeric ratio of 7/93
could be obtained (Table 1, entry 7–10). We then investigated
different Cu(OTf)2–4-MeO-3,5-(t-Bu)2-MeOBIPHEP ratios
using 6 mol% of copper(II) precatalyst and observed that an
optimum ratio of 2.5 allowed us, with the same level of
enantioselectivity, to increase the reactivity of the metallo-
organocatalytic system (Table 1, entry 11). Finally, reducing
the quantity of amine organocatalyst to 10 mol%, under
otherwise identical conditions, allowed access to cyclopentane
2 in 88% yield and with a respectable 93.5/6.5 enantiomeric
ratio after a 29 hour reaction period (Table 1, entry 12). With
this enantioselective metallo-organocatalytic system in hand,
we then evaluated its scope toward a range of cyclopentane
precursors. At first, the influence of the substitution pattern a
to the aldehyde moiety was surveyed while conserving a gem-
dimethylmalonate linkage between the formyl and alkyne
moieties. Accordingly, the a-ethyl, a-n-butyl and a-phenyl sub-
strates 3, 5 and 7 were subjected to enantioselective cyclizations.
For these precursors, a net decrease of reactivity was observed,
13
Me
C(SO2Ph)2
6
79
88
92
60
59
43
47
73.5/26.5
94/6
15
Me
C(CO2Bn)2
7
17
Me
C(CO2i-Pr)2
8
97/3
19
Et
9b
10b
11b
95/5
C(CO2i-Pr)2
21
n-Pr
C(CO2i-Pr)2
93/7
23
n-Bu
C(CO2i-Pr)2
91/9
25
Bn
12b
91/9
C(CO2i-Pr)2
a
b
Isolated yield. Reaction performed at 30 1C.
which prompted us to perform the reaction at 30 1C. Whereas
reasonable yields of cyclopentane 4, 6 and 8 were obtained,
a diminution of enantioinduction was witnessed with ethyl and
c
6560 Chem. Commun., 2012, 48, 6559–6561
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Further studies aimed toward the preparation of enantioenriched
pyrrolidines and tetrahydrofurans, as well as mechanistic investiga-
tions, are currently underway and will be reported in due course.
This work was supported by the Centre National de
la Recherche Scientifique (CNRS) and the Ministere de
l’Enseignement Superieur et de la Recherche for financial
support. B.M. is grateful to the Ministere de l’Enseignement
Superieur et de la Recherche for a grant (2009–2012) and C.P.
is grateful to Ville de Paris for a postdoctoral fellowship. The
authors thank Dr M. Scalone (Hoffmann-La Roche) for
generous gift of 4-MeO-3,5-(t-Bu)2-MeOBIPHEP ligand.
Fig. 1 Model for enantioselectivity.
n-butyl alkyl residues (Table 2, entries 1 and 2), which was
even more pronounced in the case of a phenyl substituent
(Table 2, entry 3). Thereafter, the impact of the aldehyde–alkyne
tether was investigated. On one hand, substituting the gem-
dimethyl malonate link by less bulky gem-dimethoxymethyl or
gem-dibenzyloxymethyl groups resulted in a significant loss
in enantiocontrol, because the corresponding carbocycles 10
and 12 were isolated in enantiomeric ratios of 70.5/29.5 and
71.5/28.5, respectively (Table 2, entries 4 and 5). With a
comparable level of enantioselectivity, the gem-diphenyl-
sulfonyl cyclopentane was obtained in 79% yield (Table 2,
entry 6). On the other hand, incorporating the somewhat more
sterically demanding gem-dibenzyl malonate afforded cyclo-
pentane 16 in 88% yield with good enantioselectivity (Table 2,
entry 7). Increasing further the steric bulk of the gem-diester
link while employing the gem-diisopropyl malonate substrate 17
resulted in a net improvement of enantioinduction, allowing
access to 18 in an excellent 97/3 enantiomeric ratio and 92%
yield. Interestingly, cyclization precursors 19, 21, 23 and 25,
displaying a diisopropyl malonate linkage but substituted a to
the aldehyde moiety with groups that gradually increased in
steric hindrance (ethyl, n-propyl, n-butyl and benzyl), led to the
corresponding cyclopentanes with respectable enantiomeric
ratios ranging from 95/5 to 91/9, and good to average yields.
Therefore, the steric environment generated by the aldehyde–
alkyne tether showed a significant influence on enantioselectivity,
which is partially unbalanced by bulkier substituents a to the
aldehyde moiety.
Notes and references
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On the basis of these experimental observations and the
determination of absolute configuration of the enantio-
enriched cyclopentanes,12 we propose the following model
for enantioselectivity in which the chiral copper(I) complex
activates the alkynyl residue, thus triggering attack of the
in situ formed (E)-enamine according to a chair-like transition
structure. Although the exact nature of this copper catalytic
species is not clearly determined yet, we propose that the very
bulky (R)-4-MeO-3,5-(t-Bu)2-MeO-BIPHEP ligand imposes a
quadrant-like steric environment around the triple bond such
that the substrate preferentially interacts with the copper
complex in such a manner that the b-pseudo-axial tether
substituent remains in the vacant residual space (Fig. 1).
We have demonstrated herein the efficiency of an original
metallo-organocatalytic approach for the challenging construction
of all carbon quaternary stereogenic centers. The cooperative
enamine catalysis and copper(I)–4-MeO-3,5-(t-Bu)2-MeO-BIPHEP
activation of alkynes granted access to enantioenriched cyclopen-
tane carbaldehydes with moderate to excellent enantioselectivities.
10 Seminal carbocyclizations of a,a-disubstituted formyl-alkynes
were decribed by Kirsch et al. (ref. 9b).
11 (a) B. Montaignac, V. Ostlund, M. R. Vitale, V. Ratovelomanana-
Vidal and V. Michelet, Org. Biomol. Chem., 2012, 10, 2300;
(b) B. Montaignac, M. R. Vitale, V. Ratovelomanana-Vidal and
V. Michelet, Eur. J. Org. Chem., 2011, 3723; (c) B. Montaignac,
M. R. Vitale, V. Ratovelomanana-Vidal and V. Michelet, J. Org.
Chem., 2010, 75, 8322; (d) B. Montaignac, M. R. Vitale,
V. Michelet and V. Ratovelomanana-Vidal, Org. Lett., 2010,
12, 2582.
12 Absolute configuration was determined by X-ray crystallography
of a 4-chloro-3-nitrobenzoate ester derived from 18. See ESIw for
more information.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6559–6561 6561