Enantioselective merger of aminocatalysis with π-Lewis Acid Metal Catalysis: Asymmetric Preparation of Carbo- and Heterocycles

Article abstract of DOI:10.1002/cctc.201300313

The metallo-organocatalyzed enantioselective synthesis of various five-membered carbo- and heterocyclic structures through the merger of aminocatalysis with the catalytic indium(III) or copper(I) activation of α-disubstituted formyl alkynes is described. The use of indium trichloride associated with the (R)-1,1′-bis-(2-naphthylamine) ligand led to encouraging results with up to 85:15 enantiomeric ratio. After a careful examination of several other strategies, the best synergic catalytic system, which combines a chiral copper(I) complex with cyclohexylamine, afforded the enantioselective preparations of cyclopentane, indane, and pyrrolidine scaffolds with moderate to excellent control of the all-carbon quaternary stereogenic centers created through such cyclization processes.

Full text of DOI:10.1002/cctc.201300313

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An easy merger: The enantioselective
metallo-organocatalyzed synthesis of
various five-membered carbo- and het-
erocyclic structures through the merger
of aminocatalysis with the catalytic
indium(III) or copper(I) activation of
a-disubstituted formyl alkynes is
described.
C. Praveen, B. Montaignac, M. R. Vitale,
V. Ratovelomanana-Vidal,* V. Michelet*
&& – &&
Enantioselective Merger of
Aminocatalysis with p-Lewis Acid
Metal Catalysis: Asymmetric
Preparation of Carbo- and
Heterocycles
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DOI: 10.1002/cctc.201300313
Enantioselective Merger of Aminocatalysis with p-Lewis
Acid Metal Catalysis: Asymmetric Preparation of Carbo-
and Heterocycles
Chandrasekaran Praveen, Benjamin Montaignac, Maxime R. Vitale, Virginie Ratovelomanana-
Vidal,* and Vꢁronique Michelet*[a]
The metallo-organocatalyzed enantioselective synthesis of vari-
ous five-membered carbo- and heterocyclic structures through
the merger of aminocatalysis with the catalytic indium(III) or
copper(I) activation of a-disubstituted formyl alkynes is de-
scribed. The use of indium trichloride associated with the (R)-
1,1’-bis-(2-naphthylamine) ligand led to encouraging results
with up to 85:15 enantiomeric ratio. After a careful examina-
tion of several other strategies, the best synergic catalytic
system, which combines a chiral copper(I) complex with cyclo-
hexylamine, afforded the enantioselective preparations of cy-
clopentane, indane, and pyrrolidine scaffolds with moderate to
excellent control of the all-carbon quaternary stereogenic cen-
ters created through such cyclization processes.
Introduction
In the last five years, we have witnessed a tremendous expan-
sion of new catalytic processes based on the use of two or
more catalysts that act in a synergic manner.[1] Such a strategy
has led not only to the discovery of original reactivity that
would not occur under the action of a single catalyst but also
to new ways of controlling enantioselectivity.[1,2] The specific
cooperative association of a metal catalyst with an organocata-
lyst that takes place in “metallo-organocatalysis” prevails in this
field, most probably owing to the opportunities offered by the
combination of divergent activation modes.[3] In 2008, the pio-
neering work of Kirsch’s and Dixon’s groups demonstrated that
upon treatment with catalytic quantities of both a secondary
amine and a gold(I) or copper(I) metal complex, carbonyl al-
kynes could undergo racemic carbocyclization to cyclopen-
tenes,[4] thus enlarging the scope of Conia–ene-type reactions,
the vast majority of which rely on the involvement of eno-
lates.[5] Since then, this original concept of merging amino cat-
alysis to p-Lewis metal catalysis was applied to the preparation
of various carbo- and heterocyclic skeletons, such as cyclopen-
tenes, dihydrofurans, and dihydropyrroles.[6] Unfortunately, in
all these processes,[4,6] the resulting exocyclic double bond un-
dergoes internal isomerization, which in turn results in the de-
struction of the a-formyl stereogenic center formed via the
key metallo-organocatalyzed cyclization step. Thus, we became
involved in a related metallo-organocatalysis approach to
carbo- and heterocyclic systems and focused our investigations
on the carbocyclization reactions of a-disubstituted formyl al-
kynes. The presence of the extra substituent in the a position
relative to the aldehyde residue prevents the occurrence of
any isomerization and thus enables the retention of a valuable
all-carbon quaternary stereogenic center.[7] In the last few
years, we validated this metallo-organocatalytic approach and
applied it to the racemic preparation of various cyclopentanes,
indanes, pyrrolidines, and furans while merging the use of an
amine catalyst either with a catalytic quantity of indium(III)
chloride or with an in situ generated copper(I) complex.[8]
Since then, our efforts have been devoted to the develop-
ment of an unprecedented enantioselective version of these
metallo-organocatalytic carbocyclizations as it would offer new
perspectives for the long-standing challenging control of all-
carbon quaternary stereogenic centers.[9] We reported that the
use of a catalytic chiral copper(I) complex in union with a cata-
lytic primary amine enabled the preparation of enantioen-
riched cyclopentanes in good to excellent yields and enantio-
selectivities.[10] Herein, we report in full details asymmetric met-
allo-organocatalysis with indium- and copper-based catalytic
systems, which leads to the preparation of various enantioen-
riched carbo- and heterocyclic systems (Scheme 1).
[a] Dr. C. Praveen, Dr. B. Montaignac, Dr. M. R. Vitale,
Dr. V. Ratovelomanana-Vidal, Dr. V. Michelet
Chimie ParisTech
Results and Discussion
Laboratoire Charles Friedel
UMR CNRS 7223
11, rue Pierre et Marie Curie, 75231 Paris Cedex 05 (France)
Fax: (+33)1-44071062
E-mail: virginie-vidal@chimie-paristech.fr
veronique-michelet@chimie-paristech.fr
Indium(III)-based enantioselective metallo-organocatalytic
system
At the beginning of this study, we turned our investigations to
the discovery of an indium-based enantioselective metallo-or-
ganocatalytic system. As few examples of indium(III)-catalyzed
asymmetric transformations have been described thus far, such
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300313.
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temperature from 100 to 208C resulted in a significant increase
in enantiocontrol because 2a could be isolated, after 40 h at
208C, in an encouraging 68:32 enantiomeric ratio (er; Table 1,
entries 2 and 3). Under these latter reaction conditions, some
other chiral amines were also tested, such as (S)-1-(2-naphthy-
l)ethylamine [(S)-B], (S)-1,2,3,4-tetrahydro-1-naphtalenamine
[(S)-C], and phenylalanine ester derivatives (S)-D and (S)-E;
however, none increased enantioinduction (Table 1, entries 4–
7). Consequently, selecting A as the most promising organoca-
talyst, a solvent screening was performed. Of the different sol-
vents examined, dioxane proved to be the best, in terms of
both isolated yield and er, but did not bring any significant im-
provement compared to 1,2-dichloroethane [(DCE); Table 1, en-
tries 8–12]. At this point, we decided to alternatively induce
enantioselectivity through the use of chiral indium complexes.
By studying the carbocyclization of 1a with cyclohexylamine
(20 mol%) as an organocatalyst and indium trichloride
(20 mol%) in DCE, we evaluated (R,R)-isopropyl-pyridine-2,6-bi-
s(oxazoline) (PyBOX) and (R)-1,1’-bi-2-naphthol as chiral addi-
tives (22 mol%) because both are used frequently in asymmet-
ric indium(III)-catalyzed carbonyl–ene, Mukayama aldol, and al-
lylation reactions (Scheme 2).[12]
Scheme 1. Asymmetric metallo-organocatalysis with indium- and copper-
based catalytic systems; the aim of this work. R1 =alkyl, aryl; Z=C(R2)2, NR2.
an approach was challenging.[11,12] We demonstrated previously
that indium(III) chloride with a primary amine, such as cyclo-
hexylamine, selectively promoted the carbocyclization of a-dis-
ubstituted formyl alkynes through an enamine-type mecha-
nism whereas a secondary amine partly induced an undesira-
ble enolate cyclization pathway.[8b] For this reason, we initially
envisioned that the use of chiral primary amine organocata-
lysts could induce appreciable enantioselectivity in such carbo-
cyclization processes. Thus, we selected a set of chiral primary
amines A–E, which possess various electronic and steric prop-
erties and were commercially available, in the indium-mediated
enantioselective carbocyclization of the model formyl alkyne
1a (Table 1).
In the presence of indium trichloride (20 mol%), the screen-
ing of chiral primary amines A–E (20 mol%) was realized, to-
gether with the optimization of several parameters such as re-
action temperature and solvent. The use of (S)-1-(1-naphthyl)e-
thylamine [(S)-A] as a chiral organocatalyst enabled us to
obtain cyclopentane 2a with weak, yet present, enantioselec-
tivity (Table 1, entry 1). A progressive decrease in the reaction
Table 1. Evaluation of chiral primary amines with the indium(III)-based
metallo-organocatalytic system.
Scheme 2. Evaluation of a chiral indium catalyst-based strategy.
However, none of these two chiral additives enabled us to
induce encouraging enantioselectivities (er<46:54). Converse-
ly, the use of the more Lewis basic diamino analogue of (R)-
1,1’-bi-2-naphthol, (R)-1,1’-bis-(2-naphthylamine) ((R)-BINAM),
which has demonstrated previously its usefulness in the coor-
dination of metal complexes,[13] enabled the formation of cy-
clopentane 2a in 86% yield and encouraging 64:36 er in only
5 h at room temperature (Scheme 2). After a careful examina-
tion of solvent effects, benzene proved to be more suitable for
this enantioselective transformation because, despite the inferi-
or reaction rate, carbocycle 2a was isolated in encouraging
85:15 er (Scheme 2). Notably, the primary amino groups of
BINAM proved to be essential for inducing good enantioselec-
tivity and reactivity because, under identical reaction condi-
tions, the use of the N,N’-bisphenyl analogue of BINAM[14]
Entry
Amine
Solvent
T
[8C]
t
[h]
Yield[a]
[%]
Enantiomeric ratio[b]
[S/R]
1
2
3
4
5
6
7
8
(S)-A
(S)-A
(S)-A
(S)-B
(S)-C
(S)-D
(S)-E
(S)-A
(R)-A
(R)-A
(R)-A
(R)-A
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
CH2Cl2
Et2O
THF
dioxane
100
60
20
20
20
20
20
20
20
20
20
20
3
4
92
92
87
18
12
18
18
30
27
41
68
83
59:41
63:37
68:32
55:45
53:47
41:59
37:63
55:45
38:62
41:59
35:65
32:68
40
90
15
87
82
45
40
23
28
67
9
10
11
12
[a] Isolated yield; [b] Determined by using HPLC Chiralpak IC 80:20
hexane/iPrOH.
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caused the sluggish formation of 2a as a racemate (48 h, 22%
yield).
Copper(I)-based enantioselective metallo-orga-
nocatalytic system
Next, we investigated the opportunity offered by metallo-or-
ganocatalysis to merge a chiral organocatalyst with a chiral
metal catalyst.[2] Considering the enantioselectivity generated
with (S)-1-(1-naphthyl)ethylamine [(S)-A; Table 1, entry 3], we
combined the catalytic use of this amine in either of its enan-
tiomeric forms with the indium(III) chloride–(R)-BINAM catalytic
system in DCE at 208C. Although in both cases cyclopentane
2a was obtained in good yields, this dual chiral induction strat-
egy was disappointing because lower enantioselectivities were
obtained (Scheme 3).
Taking into account that the racemic process relies on the
in situ generation of a copper(I) metal catalyst through the re-
duction of copper(II) triflate with achiral triphenylphosphi-
ne,[8c,d] we evaluated various chiral mono- and bidentate phos-
phorous ligands. This screening revealed that such a metallo-
organocatalyzed carbocyclization process requires sterically de-
manding diphosphine ligands to induce significant enantioin-
duction. The most promising result was obtained with
7.5 mol%
of
(R)-3,5-di-tert-butyl-4-methoxyphenyl-MeOBI-
PHEP[15] (L*; MeOBIPHEP=(6,6’-dimethoxybiphenyl-2,2’-diyl)-
bis(diphenylphosphine)) with which, in conjunction with
5 mol% of Cu(OTf)2 (Tf=trifluoromethanesulfonyl) and
20 mol% of cyclohexylamine in DCE at 208C, 2a was isolated
in encouraging 11.5:88.5 er and excellent 95% yield (Table 2,
entry 1). After conserving L*, we performed the optimization
of several reaction parameters such as the catalytic copper
source and the solvent medium (Table 2).
Scheme 3. Evaluation of a dual chiral induction strategy.
Table 2. Optimization of the copper-based enantioselective catalytic
system.
Consecutively, the effect of the starting formyl alkyne was
assessed with the a-butyl-substituted aldehyde 1b and the dii-
sopropylmalonate derivative 1c (Scheme 4). Under the best
Entry [Cu]
L* Solvent
t
Yield[a] Enantiomeric ratio[b]
[h] [%]
[S/R]
1
Cu(OTf)2
Cu(OTf)2
CuTC[f]
Cu(CH3CN)4BF4
CuOTf·0.5benzene (R) DCE
CuCl+AgOTf
Cu(OTf)2
Cu(OTf)2
(S) DCE[c]
(S) DCE
(S) DCE
(S) DCE
16 95
90 63
70 40
87 32
168 63
62 40
17 90
40 44
72 63
67 44
11.5:88.5
10:90
41.5:58.5
17.5:82.5
69:31
21.5:78.5
14:86
23:77
15.5:84.5
13.5:86.5
9.5:90.5
9.5:90.5
7:93
2[d]
3[e]
4[e]
5[e]
6[e]
7
(S) DCE
Scheme 4. Evaluation of the enantioselective indium-based catalytic system
for aldehydes 1b and c.
(S) CH2Cl2
(S) MeOH
(S) AcOEt
(S) Et2O
(S) benzene 48 50
(S) THF 72 77
(S) dioxane 65 52
(R) dioxane 29 84
(R) dioxane 29 88
8
9
Cu(OTf)2
10[e] Cu(OTf)2
optimized conditions, with cyclohexylamine (20 mol%),
indium(III) chloride (20 mol%), and (R)-BINAM (22 mol%) in
benzene at 208C, both substrates showed moderate reactivity
and did not yield 2b or c in enantioselectivities higher than
that of 2a, which indicates a limited substrate scope for this
enantioselective catalytic system.
11
12
13
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
14[g] Cu(OTf)2
15[g,h] Cu(OTf)2
92.5:7.5
93.5:6.5
[a] Isolated yield; [b] Determined by using HPLC Chiralpak IC 80:20
hexane/iPrOH; [c] DCE=1,2-Dichloroethane; [d] Reaction performed at
108C; [e] L* (5 mol%); [f] Copper(I)-thiophene-2-carboxylate; [g] Cu(OTf)2
(6 mol%) with L* (15 mol%); [h] Cyclohexylamine (10 mol%).
Therefore, even if we could obtain up to 70% ee through
the use of enantiopure BINAM additive, both the reactivity and
the level of chiral induction generated by such an indium-
based metallo-organocatalytic system were not fully satisfacto-
ry. With cyclohexylamine as an organocatalyst, we demonstrat-
ed that indium(III) chloride could be efficiently substituted
with a copper(I) complex, which resulted in a mild catalytic
system promoting the room temperature preparation of
a large range of carbo- and heterocyclic rings.[8d] Thus, we de-
cided to investigate the possibility of using an alternative cop-
per(I)-based metallo-organocatalytic system for this enantiose-
lective transformation.
A decrease in the reaction temperature to 108C resulted in
a dramatic decrease in the cyclization rate but without any
substantial improvement in the enantioselectivity (Table 2,
entry 2). In contrast, switching from the copper(II) triflate pre-
catalyst to copper(I) sources such as copper(I)-thiophene-2-car-
boxylate, tetrakis(acetonitrile) copper(I) tetrafluoroborate, the
air-sensitive copper(I) triflate·0.5benzene complex, or copper(I)
chloride in the presence of an equimolar amount of silver tri-
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flate was detrimental to enantioselectivity and/or yield
(Table 2, entries 3–6). Thus, the in situ generation of the chiral
copper(I) catalyst starting from Cu(OTf)2 and L* appeared to be
the best option. Notably, by using a dual chiral induction strat-
egy, with each enantiomer of 1-(1-naphthyl)ethylamine (A) as
an organocatalyst, no significant improvement could be ob-
served in enantiocontrol. Of the various solvents then tested
(Table 2, entries 7–13), even though at the expense of the cycli-
zation rate, dioxane significantly improved the enantioselectivi-
ty of the catalytic system because 2a was obtained in 7:93 er
(Table 2, entry 13). The lack of reactivity associated with the
use of dioxane could be circumvented with 6 mol% of
Cu(OTf)2, 15 mol% of L*, and either 20 or 10 mol% of cyclo-
hexylamine (Table 2, entries 14 and 15). In the latter case, cy-
clopentane 2a was obtained in 88% yield and 93.5:6.5 er after
29 h at 208C (Table 1, entries 15).[16]
per(I) p-complex, led to the formation of cyclopentanes 2i and
c in higher enantiopurity, reaching excellent er values of 94:6
and 97:3, respectively (Scheme 5).
Conversely, the effect of the a-formyl group on the enantio-
selectivity was assessed by studying the enantioselective car-
bocyclization of diisopropylmalonate substrates 1j–n
(Scheme 6). As a general trend, the bulkier substituent a to the
aldehyde moiety induced longer reaction time as well as
We then evaluated this enantioselective catalytic system in
the preparation of a larger range of chiral cyclopentanes under
the optimized reaction conditions. While investigating the car-
bocyclization of different a-methyl-substituted substrates
(Scheme 5), the nature of the linkage existing between the
formyl and alkyne moieties proved to have a substantial effect
Scheme 6. Extended scope of the enantioselective cyclization of carbon-
tethered substrates. PMB=p-methoxybenzyl group, CyN-
H2 =cyclohexylamine.
a moderate decrease in enantiocontrol. Thus, the a-ethyl-sub-
stituted cyclopentane 2j was obtained after 14 days at 308C in
60% yield and 95:5 er. The gradual increase in the steric
demand of the substituent next to the aldehyde moiety pro-
gressively weakened the enantioselectivity. The switch from an
ethyl group to an n-propyl, n-butyl, benzyl, and p-methoxyben-
zyl residue resulted in the er values from 95:5 (2j) to 88.5:11.5
(2n). Hence, if the enantioselective preparation of cyclopen-
tanes is considered, high enantioselectivities could be obtained
through the use of sterically demanding formyl-alkyne tethers,
an effect that could be partially counterbalanced if larger
groups are introduced in the a position of the aldehyde
moiety.
Aromatic tethered formyl alkynes 3a,b were also submitted
to enantioselective cyclization, and in both cases, indanes
4a,b were obtained in good yields. However, disappointing
enantioselectivities were obtained for this class of compounds,
which highlighted the prominent effect of the aldehyde/alkyne
linkage on stereoinduction (Scheme 7).
Scheme 5. Scope of the enantioselective metallo-organocatalytic preparation
of a-methyl-substituted cyclopentanes.
on the enantioselectivity. Replacing the dimethylmalonate link-
age by less sterically hindered tethers such as gem-dimethoxy-
methyl, gem-dibenzyloxymethyl, or gem-diacetoxymethyl re-
sulted in inferior enantiocontrol during the carbocyclization
process. Thus, cyclopentanes 2d–f were obtained in er values
ranging from 70.5:29.5 to 79:21. Comparable enantioselectivi-
ties were obtained with gem-diphenylsulfonyl (2g) or 9-fluror-
enyl (2h) linkages, although they were more sterically hin-
dered. The reaction of gem-dibenzyl malonate (1i) or gem-dii-
sopropyl malonate (1c), the hindered ester moieties of which
probably favor an enhanced steric interaction with the cop-
We demonstrated previously that the mild reaction condi-
tions arising from the use of a copper-based metallo-organoca-
talytic system enabled the efficient preparation of racemic pyr-
rolidines.[8d] Thus, several nitrogen-tethered substrates 5a–j
were submitted to the optimized enantioselective reaction
conditions as it would enable the preparation of the corre-
sponding valuable enantioenriched nitrogen heterocycles
(Table 3).[17] By starting with the N-tosyl-protected a-methyl al-
dehyde 5a, the desired pyrrolidine product 6a was isolated in
91% yield and 78:22 er after 1 day at 208C (Table 3, entry 1).
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served during the investigation of the enantioselective prepa-
ration of cyclopentanes led us to consider the use of more
sterically demanding sulfonyl groups on the nitrogen atom.
Thus, the N-2,3,5-trimethylbenzene-sulfonyl and N-2,3,5-tri(iso-
propyl)-benzenesulfonyl substrates 5i,j were prepared and
submitted to cyclization. Such modification of the substrate
structure enabled the formation of trimethylphenylsulfonyl
pyrrolidine 6i with an improved 85.5:14.5 er (Table 2, entry 9),
which could not be improved further with the triisopropyl ana-
logue 5j (Table 2, entry 10). Therefore, nitrogen-tethered sub-
strates were also good partners in this enantioselective cop-
per(I)-based metallo-organocatalyzed carbocyclization process
even if the enantioselectivity obtained for this class of com-
pounds was lower than that obtained with the carbon-teth-
ered substrates. Hence, not only the steric hindrance but also
the geometry (sp2 versus sp3) of the aldehyde–alkyne linkage
proved to have a substantial effect on enantioinduction.
Scheme 7. Enantioselective preparation of indanes.
Table 3. Enantioselective metallo-organocatalytic preparation of pyrroli-
dines.
Proposition of a model for enantioselectivity
Entry
R
PG[a]
Product,
Enantiomeric ratio[c]
[S/R]
Previous studies on the racemic copper(I) metallo-organocata-
lyzed cyclization of formyl alkynes led us to propose a chair-
like transition state in which the CꢀC bond formation process,
the rate-determining step of the reaction, stems from the anti-
attack of an organocatalytically formed enamine onto the
alkyne moiety activated by a copper(I) complex.[19,20] After the
reasonable assumption that the use of chiral ligands on the
copper(I) catalyst does not change this effect, we suggest that
the cyclization step could then occur according to four diaste-
reoisomeric intermediates I–IV, depending on the facial ap-
proach of the enamine residue as well as the pseudo-axial or
pseudo-equatorial position occupied by the R group in the
a position of the initial aldehyde moiety (Figure 1).
yield[b] [%]
1
2
3
4
5
6
7
8
9
Me
Ts[d]
Ts
Ts
Ts
6a, 91
6b, 84
6c, 80
6d, 81
6e, 86
6 f, 87
6g, 82
6h, 91
6i, 88
78:22
nBu
Bn[e]
PMB
(CH2)2OBn Ts
Ph
Me
nBu
Me
72.5:27.5
69.5:30.5
72.5:27.5
75.5:24.5
62.5:37.5
80:20
Ts
Ns[f]
Ns
SO2-2,3,5-
(Me)3C6H2
SO2-2,3,5-
(iPr)3C6H2
73.5:26.5
85.5:14.5
10
Me
6j, 81
83:17
[a] Protecting group; [b] Isolated yield; [c] Determined by using chiral sta-
tionary phase HPLC; [d] Tosyl; [e] Benzyl; [f] Nosyl.
On the basis of the significant effect of the bulkiness of the
R group on both the racemic and enantioselective cyclization
rates, we are inclined to believe that the R group occupies
a pseudo-axial (Figure 1, I and II) rather than a pseudo-equato-
rial position (Figure 1, III and IV). The enhanced 1,3-diaxial
strains in I and II associated with a larger R substituent would
account for the slower reactivity observed experimentally. By
studying the enantioselective preparation of cyclopentanes,
we determined that with the R enantiomer of the ligand L*,
the major enantiomer of 2c possesses the S configuration.[10]
Hence, L* would favor either intermediate I or IV (Figure 1).
Therefore, we suggest that with (R)-L*, the cyclization process
should preferentially occur according to intermediate I. In con-
tinuation to this hypothesis, the effect on the enantioselectivity
of the steric hindrance generated by the Y groups, which was
observed in the cyclopentane series, led us to postulate that
enantiodiscrimination would arise from steric interactions be-
tween the chiral copper(I) complex and the Y groups of the al-
dehyde–alkyne linkage.
Similar to the enantioselective synthesis of cyclopentanes
(Scheme 6), hindering the a position relative to the aldehyde
moiety resulted in a significant decrease in the reaction rate as
well as a notable decrease in stereoselectivity. Thus, pyrroli-
dines 6b–e, which showed n-butyl, benzyl, p-methoxybenzyl,
and benzyloxyethyl residues, respectively, required prolonged
reaction times, 9–14 days at 208C, and were isolated in good
80–86% yields and er values ranging from 69.5:30.5 to
75.5:24.5 (Table 2, entries 2–5). The poorer enantioselectivity
for this class of compounds was obtained by starting with the
a-phenyl substrate 5 f, with which the corresponding heterocy-
cle 6 f was obtained in 62.5:37.5 er (Table 2, entry 6). Next, we
tested the use of N-nosyl-substituted substrates 5g,h, as such
an N-protecting group undergoes cleavage under milder reac-
tion conditions compared to those required for the N-tosyl
parent.[18] The corresponding N-nosyl pyrrolidines 6g,h could
be isolated in good yields and enantioselectivities, which were
close to those obtained for N-tosyl pyrrolidines 6a,b (Table 2,
entries 7 and 8).
Thus, we propose the following model of enantioselectivity
in which the bulky ligand L* would impose a quadrant-like
steric environment around the triple bond, which results from
a pseudo-trigonal planar geometry around the copper atom
(Figure 2).[21,22] As a result, the cyclization precursor would in-
Thereafter, the beneficial effect of steric hindrance generated
by the aldehyde–alkyne linkage on the enantioselectivity ob-
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Finally, the little difference of
enantiopurity observed between
the cyclopentane monoester 8b
(92.5:7.5) and the malonyl cyclo-
pentane 2a (93.5:6.5; Table 1,
entry 11) was consistent with our
proposal that regardless of the
nature of the pseudo-equatorial
substituent, chiral induction
relies principally on steric repul-
sions between the chiral cop-
per(I) catalyst and the pseudo-
axial group present on the alde-
hyde–alkyne backbone.
Figure 1. Hypothetical cyclization intermediates.
Figure 2. Proposition of a model for the enantioselectivity.
Scheme 8. Enantioselective cyclization of a dissymmetrical formyl alkyne
7a,b. dr=Diastereomeric ratio.
teract with the copper(I) complex to preferentially enable the
pseudo-axial substituent Y to remain in the vacant residual
space (Figure 2). In addition, this model is empirically support-
ed by the fact that both pyrrolidine and indane precursors led
to inferior stereoselectivities as the associated sp2 geometry of
the tether probably hampers an equally efficient enantiodiscri-
mination. It also clarified the necessity of using much sterically
hindered phosphorous ligands such as L*.
Conclusions
We report a detailed study of the enantioselective metallo-or-
ganocatalyzed cyclization of formyl alkynes. Various chiral in-
duction strategies based on the use of catalytic indium(III) or
copper(I) metal complexes associated with primary amine or-
ganocatalysts were carefully examined. Although some level of
enantioinduction could be obtained with a catalytic system
based on indium(III) chloride, enantiopure (R)-1,1’-bis-(2-naph-
thylamine) ligand, and cyclohexylamine, this approach was lim-
ited in terms of enantioselectivity, reactivity, and substrate
scope. Conversely, we demonstrated the superiority of a cop-
per(I) alternative, in which the catalytic synergy between
a chiral copper(I) complex and cyclohexylamine opened access
To further confirm this model, we performed the enantiose-
lective cyclization of the dissymmetrical tethered formyl alkyne
7a,b (1:1 mixture of diastereoisomers; Scheme 8). Such a cycli-
zation precursor resulted in the formation of diastereoisomeric
cyclopentanes 8a,b with divergent enantiopurities. Although
the major cis isomer 8a was formed as an racemic mixture
(57:43 er), the minor trans isomer 8b was obtained in 92.5:7.5
er, which is close to that of dimethylmalonate analogous cyclo-
pentane 2a (93.5:6.5 er; Table 1, entry 11).[23] These
results fit the abovementioned proposed model in
many ways. First, the significant diastereoselectivity
in favor of the cis isomer was consistent with a chair-
like transition state, in which the a-methyl group
stands in the pseudo-axial position whereas the
methyl ester moiety was preferentially in the
pseudo-equatorial position (Figure 3a and b).
Second, in the case of 8a, the presence of a small
pseudo-axial hydrogen atom does not allow induc-
ing good enantioselectivity (Figure 3a). During the
formation of 8b, a better differentiation of the two
diastereoisomeric transition states was observed be-
cause the more hindered pseudo-axial methyl ester
residue preferentially occupied the region of space
free from interactions with the chiral copper(I) com-
plex (Figure 3b).
Figure 3. Enantioselectivity model rationale.
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N-(2-Formylhexyl)-4-nitro-N-(prop-2-ynyl)benzenesulfonamide (5h):
Yellow paste; 1H NMR (300 MHz, CDCl3): d=9.71–9.58 (m, 1H),
8.41–8.25 (m, 2H), 8.02 (d, J=8.5 Hz, 2H), 4.29–4.05 (m, 2H), 3.54
(dd, J=14.2, 8.7 Hz, 1H), 3.22 (dd, J=14.2, 5.7 Hz, 1H), 2.85–2.64
(m, 1H), 2.03 (t, J=2.4 Hz, 1H), 1.80–1.59 (m, 1H), 1.59–1.43 (m,
1H), 1.43–1.19 (m, 4H), 0.98–0.79 ppm (m, 3H); 13C NMR (75 MHz,
CDCl3): d=202.8, 150.3, 144.0, 129.2, 124.2, 75.6, 75.0, 50.5, 45.5,
37.5, 28.7, 26.9, 22.7, 13.8 ppm.
to the preparation of various enantioenriched five-membered
carbo- and heterocyclic systems with fair to excellent enantio-
selectivities and yields. Finally, several factors governing the
challenging control of the all-carbon quaternary stereogenic
center created during such cyclization processes were un-
veiled, on the basis of which an empirical model for enantiose-
lectivity was proposed.
2,4,6-Trimethyl-N-(2-methyl-3-oxopropyl)-N-(prop-2-ynyl)benzene-
1
sulfonamide (5i): Colorless sticky oil; H NMR (300 MHz, CDCl3): d=
Experimental Section
9.42 (d, J=2.1 Hz, 1H), 6.96 (s, 2H), 4.09 (dd, J=18.3, 2.3 Hz, 1H),
3.98 (dd, J=18.3, 2.4 Hz, 1H), 3.58 (dd, J=14.5, 8.0 Hz, 1H), 3.34
(dd, J=14.5, 6.2 Hz, 1H), 2.79–2.65 (m, 1H), 2.59 (s, 6H), 2.37–2.24
(m, 4H), 1.05 ppm (d, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
202.8, 143.3, 140.6, 132.3, 131.9, 77.3, 74.0, 46.6, 44.9, 35.9, 23.0,
21.1, 12.2 ppm; HRMS (ESI): m/z: calcd for C16H22NO3S: 308.1314
[M+H]+; found: 308.1323.
General
1H NMR and 13C NMR signals were internally referenced to residual
protio solvent signals. High-resolution mass spectra were per-
formed on a LTQ Orbitrap apparatus. All solvents used herein were
purified according to literature methods.[24] Enantiomeric ratios
were determined by using chiral stationary phase HPLC (CSP-HPLC)
with OD-H, OJ, IA, IB, IC, or ID columns and n-hexane/iPrOH mix-
tures as mobile phases.
2,4,6-Triisopropyl-N-(2-methyl-3-oxopropyl)-N-(prop-2-ynyl)benze-
nesulfonamide (5j): Colorless sticky oil; 1H NMR (300 MHz, CDCl3):
d=9.60 (d, J=2.1 Hz, 1H), 7.17 (s, 2H), 4.15–3.87 (m, 4H), 3.73 (dd,
J=14.5, 8.0 Hz, 1H), 3.43 (dd, J=14.5, 6.1 Hz, 1H), 2.99–2.76 (m,
2H), 2.30 (t, J=2.5 Hz, 1H), 1.25 (d, J=6.9 Hz, 18H), 1.13 ppm (d,
J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=202.9, 153.9, 152.0,
130.1, 124.3, 74.1, 46.1, 45.1, 36.5, 34.3, 29.6, 25.0, 23.7, 12.5 ppm;
HRMS (ESI): m/z: calcd for C22H34NO3S: 392.2254 [M+H]+; found:
392.2263.
Materials
The preparation of most of the aldehyde substrates used herein
has been described previously by us.[8a–d] New aldehyde substrates
1h, 1n, 5d,g–j, 7a,b were prepared by analogy to the corre-
sponding published methods.
Methyl 2-(2-methyl-3-oxopropyl)pent-4-ynoate (7a,b): 1:1 mixture
of diastereoisomers 7a,b; colorless oil; 1H NMR (300 MHz, CDCl3):
d=9.62 (s, 1H), 9.60 (s, 1H), 3.7 (s, 6H), 2.78–2.62 (m, 2H), 2.62–
2.33 (m, 6H), 2.29–2.12 (m, 1H), 2.12–1.96 (m, 3H), 1.85–1.68 (m,
1H), 1.69–1.51 (m, 1H), 1.15 (d, J=6,5 Hz, 3H), 1.12 ppm (d, J=
6,5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=203.6, 80.6, 70.5, 52.0,
44.2, 44.1, 41.9, 31.8, 31.6, 21.7, 14.0, 13.4 ppm; HRMS (ESI): m/z:
calcd for C10H15O3: 183.1016 [M+H]+; found: 183.1018.
2-Methyl-3-(9-(prop-2-yn-1-yl)-9H-fluoren-9-yl)propanal (1h): Color-
less oil; H NMR (300 MHz, CDCl3): d=9.01 (d, J=2.2 Hz, 1H), 7.82–
1
7.67 (m, 2H), 7.65–7.50 (m, 2H), 7.48–7.27 (m, 4H), 2.91 (dd, J=
14.2, 7.0 Hz, 1H), 2.65 (d, J=2.6 Hz, 2H), 2.22 (dd, J=14.2, 4.8 Hz,
1H), 2.07 (t, J=2.7 Hz, 1H), 1.62–1.43 (m, 1H), 0.68 ppm (d, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=203.4, 148.5, 147.8, 140.8,
140.6, 128.3, 128.1, 127.5, 124.0, 123.6, 120.3, 120.2, 81.1, 71.1, 51.8,
42.8, 38.0, 30.7, 15.6 ppm.
Diisopropyl 2-(2-formyl-3-(4-methoxyphenyl)propyl)-2-(prop-2-yn-1-
yl)malonate (1n): Colorless oil; 1H NMR (300 MHz, CDCl3): d=9.56
(d, J=2.7 Hz, 1H), 7.15–6.99 (m, 2H), 6.88–6.72 (m, 2H), 5.08–4.87
(m, 2H), 3.77 (s, 3H), 2.96–2.65 (m, 5H), 2.61–2.47 (m, 1H), 2.12
(dd, J=14.8, 2.2 Hz, 1H), 1.95 (t, J=2.7 Hz, 1H), 1.32–1.07 ppm (m,
12H); 13C NMR (75 MHz, CDCl3): d=203.5, 169.5, 169.4, 158.5,
130.3, 129.7, 114.1, 78.6, 72.0, 69.7, 69.6, 56.0, 55.4, 49.5, 36.6, 30.9,
27.0, 23.6, 21 ppm; HRMS (ESI): m/z: calcd for C23H30O6Na: 425.1935
[M+Na]+; found: 425.1941.
General method for the enantioselective copper(I) metallo-
organocatalyzed cyclization
In a vial under argon atmosphere, (R)-4-MeO-3,5-(tBu)2-MeOBIPHEP
(L*; 0.03 mmol, 0.15 equiv.), copper(II) trifluoromethanesulfonate
(0.012 mmol, 0.06 equiv.), and dioxane (0.15 mL) were added suc-
cessively. The resulting mixture was stirred for 15 min at RT before
freshly purified formyl alkyne (0.2 mmol, 1 equiv.) in a freshly pre-
pared solution of cyclohexylamine (0.1m, 0.1 mL) in dioxane
(0.02 mmol, 0.1 equiv.) was added. After the introduction of addi-
tional dioxane (0.25 mL), the reaction mixture was stirred at the
specified temperature until TLC analysis indicated complete con-
version (see vide infra). The reaction mixture was then treated with
an aqueous solution of acetic acid (1 mL, 1:1 v/v) and then vigo-
rously stirred for 15 min at RT before the extraction of the aqueous
layer with DCE. The combined organic layers were dried over anhy-
drous sodium sulfate, filtered, and concentrated under reduced
pressure. The resulting crude material was purified by using flash
column chromatography to afford the pure carbo- or heterocyclic
aldehyde. The enantioselective preparation of 2a–e,g,i,j–m has
been reported previously by us.[10]
N-(2-Formyl-3-(4-methoxyphenyl)propyl)-4-methyl-N-(prop-2-yn-1-
1
yl)benzenesulfonamide (5d): Sticky colorless oil; H NMR (300 MHz,
CDCl3): d=9.65 (d, J=1.7 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.17 (d,
J=8.1 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 4.01
(d, J=2.1 Hz, 2H), 3.70 (s, 3H), 3.43–3.30 (m, 1H), 3.17–3.00 (m,
2H), 2.88 (dd, J=14.3, 7.0 Hz, 1H), 2.66 (dd, J=14.3, 6.9 Hz, 1H),
2.32 (s, 3H), 1.93 ppm (t, J=2.5 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=203.0, 158.5, 143.9, 134.8, 130.0, 129.6, 129.4, 127.9, 114.2, 76.4,
74.3, 55.3, 52.4, 45.6, 38.1, 32.7, 21.6 ppm; HRMS (ESI): m/z: calcd
for C21H24NO4S: 386.1421 [M+H]+; found: 386.1427.
N-(2-Methyl-3-oxopropyl)-4-nitro-N-(prop-2-ynyl)benzenesulfona-
1
mide (5g): Yellow paste; H NMR (300 MHz, CDCl3): d=9.67 (d, J=
1.4 Hz, 1H), 8.34 (d, J=8.9 Hz, 2H), 8.03 (d, J=8.6 Hz, 2H), 4.18 (d,
J=2.4 Hz, 2H), 3.52 (dd, J=14.3, 7.5 Hz, 1H), 3.23 (dd, J=14.3,
6.7 Hz, 1H), 2.91–2.73 (m, 1H), 2.04 (t, J=2.5 Hz, 1H), 1.19 ppm (d,
J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=202.5, 150.3, 144.1,
129.2, 124.3, 75.6, 75.0, 47.0, 45.3, 37.7, 11.9 ppm.
(3-Formyl-3-methyl-4-methylenecyclopentane-1,1-diyl)bis(methy-
lene) diacetate (2 f):[8a] Prepared according to the above general
protocol starting from 1 f (54.0 mg, 0.20 mmol) at 208C for 3 days.
Colorless oil (46 mg, 69% yield); H NMR (CDCl3, 300 MHz): d=9.29
(s, 1H), 5.18 (t, J=1.9 Hz, 1H), 4.97 (dd, J=2.3, 1.7 Hz, 1H), 4.12–
1
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3.80 (m, 4H), 2.55–2.16 (m, 3H), 2.06 (d, J=1.4 Hz, 6H), 1.43 (d, J=
14.3 Hz, 1H), 1.29 ppm (s, 3H); CSP-HPLC (ID, n-hexane/iPrOH
(64.3 mg, 0.20 mmol) at 208C for 9 days. Colorless solid (54 mg,
84% yield); H NMR (300 MHz, CDCl3): d=9.22 (s, 1H), 7.72 (d, J=
1
80:20, 1 mLminꢀ1
,
215 nm): er=79:21; tR(major)=8.74 min, tR-
8.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 5.22 (s, 1H), 5.03 (t, J=1.8 Hz,
1H), 3.95–3.67 (m, 3H), 3.09 (d, J=10.0 Hz, 1H), 2.44 (s, 3H), 1.88–
1.69 (m, 1H), 1.59–1.43 (m, 1H), 1.37–1.16 (m, 2H), 1.16–0.99 (m,
2H), 0.85 ppm (t, J=7.2 Hz, 3H); CSP-HPLC (IC, n-hexane/iPrOH
50:50, 1 mLminꢀ1, 215 nm): er=72.5:27.5; tR(minor)=36.16 min, tR-
(major)=30.84 min; ½aꢁ2D0 = +39.8 (c=1 in CHCl3).
(minor)=11.11 min; ½aꢁ2D0 =ꢀ44.7 (c=0.42 in CHCl3).
3-Methyl-4-methylenespiro[cyclopentane-1,9’-fluorene]-3-carbalde-
hyde (2h): Prepared according to the above general protocol start-
ing from 1h (55.0 mg, 0.20 mmol) at 208C for 14 days. Yellow oil
(38 mg, 69% yield); 1H NMR (300 MHz, CDCl3): d=9.56 (s, 1H),
7.77–7.66 (m, 2H), 7.66–7.58 (m, 1H), 7.52–7.44 (m, 1H), 7.41–7.27
(m, 4H), 5.30 (dd, J=2.3, 1.1 Hz, 1H), 5.20 (dd, J=2.3, 1.0 Hz, 1H),
3.17 (d, J=14.4 Hz, 1H), 2.93 (dt, J=15.3, 2.3 Hz, 1H), 2.67–2.54 (m,
1H), 1.98 (d, J=14.4 Hz, 1H), 1.56 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=199.9, 153.7, 152.7, 151.6, 139.8, 139.4, 127.9, 127.6,
127.4, 127.3, 123.5, 123.0, 119.9, 119.7, 110.2, 58.1, 54.2, 46.4, 44.8,
3-Benzyl-4-methylene-1-tosylpyrrolidine-3-carbaldehyde
(6c):[8d]
Prepared according to the above general protocol starting from 5c
(71.0 mg, 0.20 mmol) at 208C for 13 days. Colorless solid (50 mg,
1
80% yield); H NMR (300 MHz, CDCl3): d=9.30 (s, 1H), 7.57 (d, J=
8.3 Hz, 2H), 7.34–7.04 (m, 5H), 7.01–6.87 (m, 2H), 5.21 (s, 1H), 5.04
(s, 1H), 3.79–3.57 (m, 2H), 3.46 (d, J=10.2 Hz, 1H), 3.17 (d, J=
10.2 Hz, 1H), 3.15 (d, J=14.0 Hz, 1H), 2.76 (d, J=14.0 Hz, 1H),
21.2 ppm; CSP-HPLC (OD-H, n-hexane/iPrOH 90:10, 1 mLminꢀ1
,
2.36 ppm (s, 3H); CSP-HPLC (IA, n-hexane/iPrOH 70:30, 1 mLminꢀ1
,
215 nm): er=72.5:27.5; tR(minor)=9.30 min, tR(major)=11.93 min;
½aꢁ2D0 = +122.28 (c=1.0 in CHCl3).
215 nm): er=69.5:30.5; tR(minor)=7.76 i, tR(major)=8.57 min;
½aꢁ2D0 = +17.7 (c=1 in CHCl3).
Diisopropyl-3-formyl-3-(4-methoxybenzyl)-4-methylenecyclopen-
tane-1,1-dicarboxylate (2n): Prepared according to the above gen-
eral protocol starting from 1n (80.4 mg, 0.20 mmol) at 408C for
12 days. Yellow oil (49 mg, 61% yield); 1H NMR (300 MHz, CDCl3):
d=9.45 (s, 1H), 7.06 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 5.29
(s, 1H), 5.13–4.90 (m, 3H), 3.77 (s, 3H), 3.12 (d, J=14.0 Hz, 1H),
3.00–2.89 (m, 1H), 2.83 (d, J=14.0 Hz, 1H), 2.74–2.63 (m, 2H), 2.42
(d, J=14.3 Hz, 1H), 1.25–1.14 ppm (m, 12H); 13C NMR (75 MHz,
CDCl3): d=199.9, 171.0, 170.7, 158.5, 148.7, 131.2, 128.8, 113.9,
111.1, 69.4, 69.3, 61.8, 58.3, 55.3, 41.6, 41.0, 36.5, 21.6 ppm; HRMS
(ESI): m/z: calcd for C23H30O6Na: 425.1935 [M+Na]+; found:
3-(4-Methoxybenzyl)-4-methylene-1-tosylpyrrolidine-3-carbaldehyde
(6d): Prepared according to the above general protocol starting
from 5d (77.0 mg, 0.20 mmol) at 208C for 13 days. Colorless oil
(63.0 mg, 81% yield); 1H NMR (300 MHz, CDCl3): d=9.37 (s, 1H),
7.65 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 6.94 (d, J=8.6 Hz,
2H), 6.75 (d, J=8.6 Hz, 2H), 5.27 (d, J=1.0 Hz, 1H), 5.10 (d, J=
1.0 Hz, 1H), 3.85–3.73 (m, 5H), 3.52 (d, J=10.2 Hz, 1H), 3.25 (d, J=
10.2 Hz, 1H), 3.16 (d, J=14.1 Hz, 1H), 2.79 (d, J=14.1 Hz, 1H),
2.44 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=197.7, 158.8, 144.4,
144.2, 132.2, 131.0, 129.8, 128.1, 127.7, 114.1, 111.5, 61.7, 55.3, 52.5,
51.5, 38.8, 21.7 ppm; HRMS (ESI): m/z: calcd for C21H24NO4S:
386.1421 [M+H]+; found: 386.1426; CSP-HPLC (IA, n-hexane/iPrOH
70:30, 1 mLminꢀ1, 215 nm): er=72.5:27.5; tR(minor)=8.58 min, tR-
(major)=10.38 min; ½aꢁ2D0 = +19.2 (c=1 in CHCl3).
425.1941; CSP-HPLC (IC, n-hexane/iPrOH 90:10, 1 mLminꢀ1
,
215 nm): er=88.5:11.5; tR(minor)=10.54 min, tR(major)=13.77 min;
½aꢁ2D0 = +63.0 (c=1 in CHCl3).
2-Methyl-1-methylene-2,3-dihydro-1H-indene-2-carbaldehyde
(4a):[8d] Prepared according to the above general protocol starting
from 3a (34.0 mg, 0.20 mmol) at 208C for 64 h. Colorless oil
(27.2 mg, 80% yield); 1H NMR (300 MHz, C6D6): d=8.94 (s, 1H),
7.05–6.92 (m, 2H), 6.88–6.70 (m, 2H), 5.23 (s, 1H), 4.58 (s, 1H), 3.01
(d, J=16.8 Hz, 1H), 2.13 (d, J=16.8 Hz, 1H), 0.92 ppm (s, 3H); CSP-
HPLC (after NaBH4 mediated reduction in MeOH, OJ, n-hexane/
iPrOH 90:10, 1 mLminꢀ1, 215 nm): er=65:35; tR(minor)=7.24 min,
tR(major)=9.16 min.
3-(2-(Benzyloxy)ethyl)-4-methylene-1-tosylpyrrolidine-3-carbalde-
hyde (6e):[8d] Prepared according to the above general protocol
starting from 5e (79.8 mg, 0.20 mmol) at 208C for 14 days. Color-
1
less solid (68.6 mg, 86% yield); H NMR (300 MHz, CDCl3): d=9.14
(s, 2H), 7.55 (d, J=8.3 Hz, 4H), 7.33–6.93 (m, 17H), 5.05 (s, 2H),
4.90 (s, 2H), 4.22 (s, 4H), 3.78–3.49 (m, 6H), 3.41–3.27 (m, 2H),
3.27–3.13 (m, 2H), 3.05 (d, J=10.1 Hz, 2H), 2.28 (s, 6H), 2.23–2.05
(m, 2H), 1.74–1.54 ppm (m, 2H); CSP-HPLC (IA, n-hexane/iPrOH
90:10, 1 mLminꢀ1, 215 nm): er=75.5:24.5; tR(minor)=19.55 min, tR-
(major)=26.14 min; ½aꢁ2D0 = +20.7 (c=1 in CHCl3).
2-Benzyl-1-methylene-2,3-dihydro-1H-indene-2-carbaldehyde
(4b):[8d] Prepared according to the above general protocol starting
from 3b (50.0 mg, 0.20 mmol) at 208C for 80 h. Colorless oil
3-Phenyl-4-methylene-1-tosylpyrrolidine-3-carbaldehyde
(6 f):[8d]
1
Prepared according to the above general protocol starting from 5 f
(68.2 mg, 0.20 mmol) at 208C for 14 days. Colorless solid (59.0 mg,
(41 mg, 82% yield); H NMR (300 MHz, C6D6): d=9.28 (s, 1H), 7.26–
7.17 (m, 1H), 7.11–6.81 (m, 8H), 5.53 (s, 1H), 4.87 (s, 1H), 3.21 (d,
J=14.0 Hz, 1H), 3.11 (d, J=17.0 Hz, 1H), 2.73 (d, J=14.0 Hz, 1H),
2.70 ppm (d, J=17.0 Hz, 1H); CSP-HPLC (IC, n-hexane/iPrOH 95:5,
1 mLminꢀ1, 215 nm): er=61.5:38.5; tR(minor)=5.66 min, tR(major)=
7.33 min.
1
87% yield); H NMR (300 MHz, CDCl3): d=9.37 (s, 1H), 7.62 (d, J=
8.3 Hz, 2H), 7.34–7.17 (m, 5H), 7.11–7.02 (m, 2H), 5.46 (s, 1H), 5.18–
4.91 (m, 1H), 4.15 (d, J=9.9 Hz, 1H), 4.03–3.73 (m, 2H), 3.21 (d, J=
9.9 Hz, 1H), 2.37 ppm (s, 3H); CSP-HPLC (IA, n-hexane/iPrOH 50:50,
1 mLminꢀ1, 215 nm): er=62.5:37.5; tR(minor)=6.46 min, tR(major)=
12.16 min; ½aꢁ2D0 =ꢀ6.1 (c=1 in CHCl3).
3-Methyl-4-methylene-1-tosylpyrrolidine-3-carbaldehyde
(6a):[8a]
Prepared according to the above general protocol starting from
5a (55.8 mg, 0.20 mmol) at 208C for 1 day. Colorless solid (51 mg,
91% yield); 1H NMR (CDCl3, 300 MHz): d=9.29 (s, 1H), 7,31–7.22
(m, 2H), 7.38–7.34 (m, 2H), 5.21 (t, J=1.8 Hz, 1H), 5.01 (t, J=
2.3 Hz, 1H), 3.88–3.84 (m, 2H), 3.80 (d, J=9.9 Hz, 1H), 3.03 (d, J=
10.0 Hz, 1H), 2.04 (s, 3H), 1.24 ppm (s, 3H); CSP-HPLC (IA, n-
hexane/iPrOH 70:30, 1 mLminꢀ1, 215 nm): er=78:22; tR(minor)=
8.66 min, tR(major)=12.66 min; ½aꢁ2D0 = +30.1 (c=1 in CHCl3).
3-Methyl-4-methylene-1-(4-nitrophenylsulfonyl)pyrrolidine-3-carbal-
dehyde (6g): Prepared according to the above general protocol
starting from 5g (70.4 mg, 0.23 mmol) at 208C for 10 days. Color-
1
less sticky oil (58.0 mg, 82% yield); H NMR (300 MHz, CDCl3): d=
9.19 (s, 1H), 8.48–8.32 (m, 2H), 8.09–7.97 (m, 2H), 5.27 (s, 1H),
5.15–5.06 (m, 1H), 4.02–3.91 (m, 2H), 3.86 (dt, J=13.9, 2.3 Hz, 1H),
3.09 (d, J=10.0 Hz, 1H), 1.26 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=196.8, 150.5, 144.2, 142.1, 129.0, 124.5, 111.6, 57.1, 53.5,
51.9, 18.1 ppm; HRMS (ESI): m/z: calcd for C13H15N2O5S: 311.0696
[M+H]+; found: 311.0701; CSP-HPLC (IA, n-hexane/iPrOH 30:70,
3-Butyl-4-methylene-1-tosylpyrrolidine-3-carbaldehyde (6b):[8d] Pre-
pared according to the above general protocol starting from 5b
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1 mLminꢀ1, 215 nm): er=80:20; tR(minor)=10.73 min, tR(major)=
15.13 min; ½aꢁ2D0 = +31.9 (c=1 in CHCl3).
Acknowledgements
This work was supported by the Centre National de la Recherche
Scientifique and the Ministꢀre de l’Enseignement Supꢁrieur et de
la Recherche (MESR) for financial support. B.M. is grateful to
MESR 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-
(tBu)2-MeOBIPHEP ligand.
3-Butyl-4-methylene-1-(4-nitrophenylsulfonyl)pyrrolidine-3-carbal-
dehyde (6h): Prepared according to the above general protocol
starting from 5h (70.4 mg, 0.20 mmol) at 208C for 14 days. Color-
1
less solid (64.0 mg, 91% yield); H NMR (300 MHz, CDCl3): d=9.12
(s, 1H), 8.40 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.8 Hz, 2H), 5.29 (s, 1H),
5.12 (s, 1H), 4.04–3.89 (m, 2H), 3.78 (dt, J=13.9, 2.2 Hz, 1H), 3.19
(d, J=10.0 Hz, 1H), 1.85 (ddd, J=14.0, 10.3, 6.7 Hz, 1H), 1.55 (ddd,
J=14.0, 10.9, 6.3 Hz, 1H), 1.38–1.19 (m, 2H), 1.18–0.99 (m, 2H),
0.86 ppm (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=196.9,
150.4, 143.2, 142.3, 129.0, 124.5, 111.6, 61.1, 51.9, 51.1, 32.7, 26.7,
23.1, 13.8 ppm; HRMS (ESI): m/z: calcd for C16H21N2O5S: 353.1166
[M+H]+; found: 353.1171; CSP-HPLC (IC, n-hexane/iPrOH 20:80,
Keywords: aldehydes · alkynes · asymmetric catalysis · metal
catalysis · organocatalysis
1 mLminꢀ1
,
215 nm): er=73.5:26.5; tR(minor)=17.89 min, tR-
(major)=20.94 min; ½aꢁ2D0 = +47.5 (c=1 in CHCl3).
[1] For reviews, see: a) J. M. Lee, Y. Na, H. Han, S. Chang, Chem. Soc. Rev.
2004, 33, 302–312; b) M. Shibasaki, M. Kanai, S. Matsunaga, N. Kuma-
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1378; b) A. E. Allen, D. W. C. MacMillan, Chem. Sci. 2012, 3, 633–658;
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224; d) C. Zhong, X. Shi, Eur. J. Org. Chem. 2010, 2999–3025; e) Z. Shao,
H. Zhang, Chem. Soc. Rev. 2009, 38, 2745–2755.
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10, 1025–1028; b) T. Yang, A. Ferrali, L. Campbell, D. J. Dixon, Chem.
Commun. 2008, 2923–2925.
1-(Mesitylsulfonyl)-3-methyl-4-methylenepyrrolidine-3-carbaldehyde
(6i): Prepared according to the above general protocol starting
from 5i (61.4 mg, 0.20 mmol) at 208C for 3 days. Colorless solid
(54.0 mg, 88% yield); 1H NMR (300 MHz, CDCl3): d=9.31 (s, 1H),
6.96 (s, 2H), 5.25 (s, 1H), 5.07 (s, 1H), 4.05–3.95 (m, 1H), 3.92–3.82
(m, 1H), 3.76 (d, J=9.8 Hz, 1H), 3.14 (d, J=9.8 Hz, 1H), 2.62 (s, 6H),
2.30 (s, 3H), 1.26 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=197.7,
145.7, 143.2, 140.7, 132.1, 131.5, 110.8, 57.1, 52.6, 50.9, 22.9, 21.1,
18.6 ppm; HRMS (ESI): m/z: calcd for C16H22NO3S: 308.1315 [M+H]+
;
found: 308.1320; CSP-HPLC (IC, n-hexane/iPrOH 70:30,
1 mLminꢀ1
,
215 nm): er=85.5:14.5; tR(minor)=24.44 min, tR-
(major)=27.25 min; ½aꢁ2D0 = +41.5 (c=1 in CHCl3).
[5] For a review, see: a) F. Dꢁnꢂs, A. Pꢁrez-Luna, F. Chemla, Chem. Rev.
2010, 110, 2366–2447; for selected examples involving indium catalysis,
see: b) M. Nakamura, K. Endo, E. Nakamura, J. Am. Chem. Soc. 2003,
125, 13002–13003; c) P. Angell, P. G. Blazecka, M. Lovdahl, J. Zhang, J.
Org. Chem. 2007, 72, 6606–6609; for selected examples involving
copper catalysis, see: d) N. Monteiro, G. Balme, G. Gore, Synlett 1992,
227–228; e) D. Bouyssi, N. Monteiro, G. Balme, Tetrahedron Lett. 1999,
40, 1297–1300; f) S. Montel, D. Bouyssi, G. Balme, Adv. Synth. Catal.
2010, 352, 2315–2320; for selected examples involving stoichiometric
zinc enolate, see: g) E. Lorthiois, I. Marek, J.-F. Normant, Tetrahedron
Lett. 1997, 38, 89–92; h) E. Lorthiois, I. Marek, J.-F. Normant, J. Org.
Chem. 1998, 63, 566–574; i) F. Dꢁnꢂs, F. Chemla, J.-F. Normant, Synlett
2002, 919–922.
[6] a) W. Sun, G. Zhu, C. Wu, L. Hong, R. Wang, Chem. Asian J. 2012, 18,
13959–13963; b) W. Sun, G. Zhu, L. Hong, R. Wang, Chem. Eur. J. 2011,
17, 13958–13962; c) S. Lin, G.-L. Zhao, L. Deiana, J. Sun, Q. Zhang, H.
Leijonmarck, A. Cꢃrdova, Chem. Eur. J. 2010, 16, 13930–13934; d) G.-L.
Zhao, F. Ullah, L. Deiana, S. Lin, Q. Zhang, J. Sun, I. Ibrahem, P. Dziedzic,
A. Cꢃrdova, Chem. Eur. J. 2010, 16, 1585–1591; e) K. L. Jensen, P. T.
Franke, C. Arrꢃniz, S. Kobbelgaard, K. A. Jørgensen, Chem. Eur. J. 2010,
16, 1750–1753.
3-Methyl-4-methylene-1-(2,4,6-triisopropylphenylsulfonyl)pyrroli-
dine-3-carbaldehyde (6j): Prepared according to the above general
protocol starting from 5j (75.2 mg, 0.20 mmol) at 208C for 4 days.
1
Colorless solid (61.0 mg, 81% yield); H NMR (300 MHz, CDCl3): d=
9.37 (s, 1H), 7.17 (s, 2H), 5.25 (s, 1H), 5.06 (t, J=2.0 Hz, 1H), 4.18
(hept, J=6.7 Hz, 2H), 4.00 (dt, J=13.7, 2.0 Hz, 1H), 3.94–3.80 (m,
2H), 3.20 (d, J=9.8 Hz, 1H), 3.02–2.80 (m, 1H), 1.33–1.20 ppm (m,
21H); 13C NMR (75 MHz, CDCl3): d=197.8, 153.7, 151.8, 145.9,
130.1, 124.1, 110.8, 56.9, 52.7, 51.3, 34.3, 29.6, 25.1, 25.0, 23.7,
19.0 ppm; HRMS (ESI): m/z: calcd for C22H34NO3S: 392.2254 [M+H]+
;
found: 392.2262; CSP-HPLC (IC, n-hexane/iPrOH 80:20,
1 mLminꢀ1, 215 nm): er=73:17; tR(minor)=8.27 min, tR(major)=
9.06 min; ½aꢁ2D0 = +49.2 (c=1 in CHCl3).
cis- and trans-Methyl 3-formyl-3-methyl-4-methylenecyclopentane-
1-carboxylate (8a,b): Prepared according to the above general pro-
tocol starting from 7 (37.0 mg, 0.20 mmol) at 208C for 1 day. Color-
1
less oil (32.0 mg, 81% yield) as a 86:14 mixture of 8a/8b; H NMR
(300 MHz, CDCl3) 8a: d=9.36 (s, 1H), 5.17 (t, J=1.9 Hz, 1H), 4.85
(dd, J=2.7, 2.0 Hz, 1H), 3.71 (s, 3H), 2.99 (tt, J=10.1, 7.4 Hz, 1H),
2.82–2.60 (m, 2H), 2.47 (dd, J=13.1, 10.1 Hz, 1H), 1.86 (dd, J=13.0,
6.3 Hz, 1H), 1.23 ppm (s, 3H); 8b: d=9.26 (d, J=1.1 Hz, 1H), 5.22
(t, J=1.9 Hz, 1H), 4.96 (t, J=2.3 Hz, 1H), 3.70 (s, 3H), 2.93–2.81 (m,
1H), 2.76–2.64 (m, 2H), 2.59 (dd, J=12.9, 7.0 Hz, 1H), 1.85–1.70 (m,
1H), 1.29 ppm (s, 3H); 13C NMR (75 MHz, CDCl3) 8a: d=200.0,
174.7, 151.4, 110.1, 57.1, 51.8, 41.5, 37.8, 37.0, 21.4 ppm; 8b: d=
199.6, 175.0, 150.4, 110.1, 57.3, 51.7, 40.8, 37.0, 36.4, 20.7 ppm;
HRMS (ESI): m/z: calcd for C10H14O3Na: 205.0835 [M+Na]+; found:
[7] Seminal racemic carbocyclizations of a,a-disubstituted formyl alkynes
were described by Kirsch et al.[4a]
.
[8] a) B. Montaignac, M. R. Vitale, V. Michelet, V. Ratovelomanana-Vidal, Org.
Lett. 2010, 12, 2582–2585; b) B. Montaignac, M. R. Vitale, V. Ratovelo-
manana-Vidal, V. Michelet, J. Org. Chem. 2010, 75, 8322–8325; c) B.
Montaignac, M. R. Vitale, V. Ratovelomanana-Vidal, V. Michelet, Eur. J.
Org. Chem. 2011, 3723–3727; d) B. Montaignac, V. Ostlund, M. R. Vitale,
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2300–2306.
[9] For reviews, see: a) J. Christoffers, A. Baro, Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis Wiley-VCH, Weinheim,
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205.0837; CSP-HPLC 8a: (IC, n-hexane/iPrOH 90:10, 1 mLminꢀ1
,
215 nm): er=57:43; tR(minor)=11.43 min, tR(major)=13.52 min,
8b: (ID, n-hexane/iPrOH 90:10, 1 mLminꢀ1, 215 nm): er=92.5:7.5;
tR(minor)=7.02 min, tR(major)=7.41 min.
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Org. Chem. 2007, 5969–5994; f) M. Bella, T. Gasperi, Synthesis 2009,
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[19] Former deuterium labeling experiments on the racemic cyclization tend
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alkyne moiety would be activated through the copper(I) p coordination
of the corresponding alkynyl-copper acetylide.[8]
[20] The intervention of an enol-type mechanism has been ruled out be-
cause the use of a chiral primary amine instead of cyclohexylamine sig-
nificantly affected the enantioselectivity outcome of the reaction (see
the Supporting Information).
[21] For selected examples of pseudo-trigonal planar h2 coordination of the
terminal alkyne to copper(I) complexes, see: a) N. D. Shapiro, F. D. Toste,
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ˇ
ˇ
ˇ
ˇ
´
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9292.
[15] R. Schmid, E. A. Broger, M. Cereghetti, Y. Crameri, J. Foricher, M. Lalonde,
R. K. Mꢄller, M. Scalone, G. Schoettel, U. Zutter, Pure Appl. Chem. 1996,
68, 131–138.
[16] An identical Cu(OTf)2 to L* ratio was used by Nishibayashi et al. for the
copper-catalyzed enantioselective ring-opening reaction of ethynyl ep-
oxides: G. Hattori, A. Yoshida, Y. Miyake, Y. Nishibayashi, J. Org. Chem.
2009, 74, 7603–7607.
[23] The cis stereochemistry of 8a was determined on the basis of NOESY
experiments (see the Supporting Information for more details).
[24] W. L. F. Armarego, C. L. L. Chai, Purification of Laboratory Chemicals,
6
th ed., Butterworth-Heinemann, 2009.
Received: April 25, 2013
Revised: June 4, 2013
[17] The absolute stereochemistry of the major enantiomer of pyrrolidines
6a–6j was attributed by analogy to cyclopentanes.
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