Asymmetric one-pot sequential organo-and gold catalysis for the enantioselective synthesis of dihydropyrrole derivatives

Article abstract of DOI:10.1002/chem.201001123

A direct asymmetric one-pot synthesis of optically active 2,3-dihydropyrroles from propargylated malononitrile and N-Boc-protected (Boc= tert-butoxycarbonyl) imines is presented. The approach is based on a bifunctional organocatalytic Mannich-type reaction and a subsequent gold-catalyzed alkyne hydroamination and isomerization. The compatibility of both catalytic systems is presented and the overall transformation results in good yields (up to 70%) with high selectivities (endo/exo>10:1) and enantioselectivities (up to 88% ee). The absolute configuration of the final products is unambiguously established by X-ray analysis. To highlight the synthetic potential of the accessed heterocyclic compounds, their transformation into 1-pyrrolines, which represent direct precursors of pyrrolidines, is presented.

Full text of DOI:10.1002/chem.201001123

DOI: 10.1002/chem.201001123
Asymmetric One-Pot Sequential Organo- and Gold Catalysis for the
Enantioselective Synthesis of Dihydropyrrole Derivatives
David Monge, Kim L. Jensen, Patrick T. Franke, Lennart Lykke, and
Karl Anker Jørgensen*[a]
Abstract: A direct asymmetric one-pot
synthesis of optically active 2,3-dihy-
dropyrroles from propargylated malo-
nonitrile and N-Boc-protected (Boc=
tert-butoxycarbonyl) imines is present-
ed. The approach is based on a bifunc-
tional organocatalytic Mannich-type re-
action and a subsequent gold-catalyzed
alkyne hydroamination and isomeriza-
tion. The compatibility of both catalytic
systems is presented and the overall
transformation results in good yields
(up to 70%) with high selectivities
(endo/exo>10:1) and enantioselectivi-
ties (up to 88% ee). The absolute con-
figuration of the final products is un-
ambiguously established by X-ray anal-
ysis. To highlight the synthetic potential
of the accessed heterocyclic com-
pounds, their transformation into 1-pyr-
rolines, which represent direct precur-
sors of pyrrolidines, is presented.
Keywords: asymmetric catalysis
·
bifunctional thioureas · gold · one-
pot processes · organocatalysis
Introduction
lar complexity from simple starting materials, or unexplored
combinations of reactants.[6] Consequently, the combination
of efficient catalytic methods in a tandem[7] or one-pot pro-
cess[8] could provide a powerful tool for preserving both
energy and resources.[9] To this end a multicatalytic asym-
metric cascade reaction to cyclopentene carbaldehydes from
a,b-unsaturated aldehydes and alkyne-tethered nucleophiles
employing a combination of iminium–enamine and Lewis
acid catalysis was recently reported.[7c–e] Furthermore, Alex-
akis and co-workers have described a one-pot process con-
sisting of an enantioselective organocatalytic Michael addi-
tion to nitroenynes and a subsequent gold-catalyzed acetali-
zation/cyclization for the synthesis of nitro-substituted tetra-
hydrofuranyl ethers.[8a]
In continuation of our research in combining organocatal-
ysis with other chemical concepts,[10] and inspired by the
work of Dixon et al.[11] who presented a cascade reaction to
access racemic 2-methylenepyrrolidines from protected
imines and propargylated malonates using base and cop-
per(I) catalysis; we now report a novel approach to highly
functionalized optically active 2,3,3,5-tetrasubstituted 2,3-di-
hydro-1H-pyrroles from imines and propargylated pronu-
cleophiles (Scheme 1).
Optically active 2,3-dihydropyrroles are important unsatu-
rated heterocyclic compounds applied as synthetic building
blocks, potential therapeutic leads, and materials in modern
chemistry. In addition, pyrrole derivatives can be trans-
formed into multisubstituted pyrrolidines, serve as templates
for the design of new organocatalysts and also be applied to
the total synthesis of natural products.[1] Despite their nu-
merous applications, the asymmetric catalytic synthesis of
optically active 2,3-dihydropyrroles remains limited to, for
example, metal-catalyzed partial hydrogenations of 2,3,5-tri-
substituted pyrroles[2] and organocatalytic formal [3+2] cy-
cloaddition reactions of isocyanoesters with nitroolefins.[3]
The need and interest for practically simple and syntheti-
cally efficient organic transformations has led to the devel-
opment of many innovative strategies, concepts, and meth-
odologies. The idea of combining transition-metal catalysis[4]
with organocatalysis[5] in
a multicatalytic fashion has
emerged as a promising strategy in asymmetric synthesis, al-
lowing access to new chemical reactivities and high molecu-
[a] Dr. D. Monge, K. L. Jensen, P. T. Franke, L. Lykke,
Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8619-6199
Results and Discussion
E-mail: kaj@chem.au.dk
We started our investigations by reducing the operational
complexity of the strategy presented in Scheme 1 by divid-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001123.
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Chem. Eur. J. 2010, 16, 9478 – 9484

FULL PAPER
Scheme 1. Novel approach towards optically active 2,3,3,5-tetrasubstitut-
ed 2,3-dihydro-1H-pyrroles.
ing it into two separate assignments: the initial studies focus
on the introduction of enantioselectivity, whereas the second
concentrate on the cyclization protocol.
Enantioselective organocatalytic Mannich reaction: Initially,
we examined the organocatalytic Mannich reaction of N-
Boc-protected imine 1a (Boc=tert-butoxycarbonyl) with
propargylated malononitrile 2a providing the enantioen-
riched key intermediate 4a (Table 1). Previous studies have
Table 1. Screening of catalysts for the enantioselective addition of 2a to
1a.
Scheme 2. Selection of screened catalysts for the Mannich reaction.
low enantiomeric excess (10% ee). Bifunctional urea, thiour-
ea, and squaramide organocatalysts afforded good conver-
sions at À258C (Table 1, entries 4–7 and 9–15).
Entry
Cat.
Solvent
T [8C]
Conv.[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
–
CDCl3
RT
RT
RT
5
>95
>95
>95
>95
>95
>95
80
–
–
10
16
5
48
28
10
–
À34
À32
–
Et3N
3a
3a
3b
3c
3d
3e
3e
3 f
3g
3h
3h[e]
3i
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
These preliminary results revealed catalyst 3c, derived
from quinidine,[13] as the most promising scaffold providing
4a with full conversion and 48% ee (Table 1, entry 6). Simi-
lar reactivities were observed for catalysts 3 f, 3g, and 3j, al-
though lower enantioselectivities of ent-4a were obtained
(Table 1, entries 10, 11, and 15). In contrast, urea-derived 3b
and squaramide (3i), provided poor enantioselectivities in
the model reaction (Table 1, entries 5 and 14), which sug-
gested that a thiourea functionality is essential for stereo-
control. Interestingly, different alkyne-tethered nucleophiles
2 derived from malonates or 1,3-diketones showed no reac-
tivity and the differently protected N-p-toluenesulfonyl and
N-p-methoxyphenyl imines afforded the Mannich products 4
in low yields and enantioselectivities. Substituting the N-Boc
with analogous N-benzoyl imines provided the correspond-
ing products 4 in good yields, albeit in slightly lower enan-
tioselectivities.
À25
À25
À25
À25
RT
À25
À25
À25
À25
À25
À25
À25
9
nr[d]
>95
>95
nr
>95
>95
>95
10
11
12
13
14
15
rac
10
À30
3j
[a] All the reactions were performed using 1a (0.15 mmol), 2a
(0.10 mmol), and cat. (5 mol%). [b] Determined by 1H NMR spectrosco-
py (after 20 h). [c] Determined by chiral stationary-phase HPLC. [d] nr=
no reaction. [e] Employing NaOAc (0.5 equiv) as additive.
shown that bifunctional thiourea–amine organocatalysts are
effective promoters for activation of pronucleophiles and N-
Boc-protected imines through acid–base interactions.[12]
Therefore, we performed an extensive investigation of sever-
al bifunctional catalysts (Scheme 2) and the results of the
screening are presented in Table 1. The first control experi-
ment was performed without any catalyst to examine the
background reaction, which gave only 5% conversion as de-
Having confirmed 3c as the most promising catalyst, a
survey of the reaction parameters (solvent, temperature,
and concentration) was performed as outlined in Table 2.
Excellent reactivity and moderate enantioselectivity were
obtained in toluene (Table 2, entry 1); however, increased
enantioselectivity was observed by employing halogenated
solvents such as CH2Cl2 or CHCl3, giving the product 4a in
66 and 70% ee, respectively (Table 2, entries 7 and 8). Con-
ducting the reaction in dioxane, THF, or hexane[14] had a
detrimental effect on the reactivity and enantioselectivity of
the reaction giving 4a with up to 50% conversion (after
22 h) and poor enantioselectivities (Table 2, entries 2, 3, and
5). Interestingly, other polar aprotic solvents like CH3CN
1
tected by H NMR spectroscopy (Table 1, entry 1). Using 5
mol% of Et3N, the adduct 4a was obtained with full conver-
sion, providing easy access to rac-4a. Preliminary results
showed that imine 1a might be effectively activated by hy-
drogen bonding at RT (Table 1, entries 3 and 8), albeit with
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9479

K. A. Jørgensen et al.
Table 2. Optimization for the enantioselective addition of 2a to 1a cata-
lyzed by 3c.
Entry 3c [mol%]
ACHTUNGTRENNUNG
[2a] [m] Solvent T [8C] Conv.[b] [%] ee[c] [%]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
2
1
1
1
0.25
toluene À25
>95
40
50
>95
50
>95
>95
>95
>95
>95
>95
50
48
10
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.05
0.05
0.05
0.05
0.05
dioxane RT
THF
À25
rac
À16
À13
À16
66
70
78
82
82
CH3CN À25
hexane À25
acetone À25
CH2Cl2 À25
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
À25
À25
À60
À60
À60
À60
Scheme 3. Gold-catalyzed intramolecular alkyne hydroamination of 4a.
9
10
11
12[d]
13[e]
Rh, Fe, Pt, Zn, or In salts) described for this type of trans-
formation were inactive in the present system (see the Sup-
porting Information). However, we were pleased to find
82
–
nr
[a] All the reactions were performed using 1a (0.15 mmol), 2a
(0.10 mmol), and 3c and were stirred for 22 h. [b] Determined by
1H NMR spectroscopy. [c] Determined by chiral stationary-phase HPLC.
[d] 1 mol% of TFA as additive. [e] 2 mol% of TFA as additive.
[18]
that activation of the triple bond by AuCl or AuCl3 salts
afforded 5a in 80% conversion (after 22 h) with high selec-
tivity (endo/exo 9:1) referring to the positional isomerism of
the double bond.
and acetone afforded full conversions to ent-4a, albeit with
lower enantioselectivity (Table 2, entries 4 and 6). This ste-
reochemical reversal may be indicative of a change in opera-
tion pathway of the catalyst. Self-association of the cincho-
na-alkaloid derived thiourea catalysts as noncovalent dimers
in solution has been observed.[15] Equilibria between mono-
and dimeric species, in different solvents, can give different
stereochemical outcomes.
Dilution of the reaction mixture ([2a]=0.05m) increased
the enantioselectivity, providing 4a in 78% ee (Table 2,
entry 9). Under these conditions, lowering the catalyst load-
ing to 1mol% and decreasing the reaction temperature to
À608C provided an increased selectivity of 82% ee (Table 2,
entry 11). Similar observations have been made in other
studies using this class of catalysts.[16] Finally, the influence
of cocatalysts in the reaction was investigated by employing
trifluoroacetic acid (TFA) as an additive. The addition of
1 mol% of TFA led to a slower reaction and no influence
on the enantioselectivity was found (Table 2, entry 12). In-
creasing the amount of TFA to 2 mol% deactivated catalyst
3c (Table 2, entry 13), indicating the importance of the basic
functional group(s) in the catalyst.
Gold catalysts are well known for activating alkynes by
forming p-complexes. The triple bond of 4a is activated to-
wards the attack by the nitrogen atom in a 5-exo-dig fashion
as outlined in Scheme 3, and subsequent protodemetallation
affords the 2-methylenepyrrolidine kinetic product 5a-exo,
followed by alkene isomerization to 5a-endo (see below).
One-pot bifunctional organocatalytic Mannich, gold-cata-
lyzed alkyne hydroamination cascade: Having optimized the
enantioselective organocatalytic Mannich addition of 2a to
1a and identified AuI- or AuIII-salts as suitable Lewis acids
for intramolecular alkyne hydroamination of adduct 4a, we
then examined the combination of both catalytic reactions
providing the 2,3-dihydropyrrole derivative 5a in a multica-
talytic cascade process (Scheme 4). Preliminary experiments
combining thiourea and gold catalysis were unsuccessful,
since organocatalyst 3c and Au-salts exhibit strong affinities
for each other, as observed by 31P NMR spectroscopy.
Indeed, depending on the ratio of 3c/[Au] employed simul-
We propose that the imine is activated by the thiourea
moiety through hydrogen bonding and the nucleophile is
concurrently activated through base-catalysis by one of the
basic sites in the catalyst.
Intramolecular metal-catalyzed alkyne hydroamination: In
the next stage of our studies, the intramolecular metal-cata-
lyzed alkyne hydroamination[17] of intermediate 4a into the
corresponding tert-butyl 3,3-dicyano-5-methyl-2-phenyl-2,3-
dihydro-1H-pyrrole-1-carboxylate (5a) (Scheme 3) in the
presence of various metal sources and additives was investi-
gated. Surprisingly, a series of metal salts (Cu, Ag, Pd, Ni,
Scheme 4. Preliminary experiments combining 3c and Au salts in a cas-
cade process. Conditions: A) 3c (1 mol%)/[Au] (5 mol%); B) 3c
(3 mol%)/[Au] (5 mol%); C) 3c (5 mol%)/[Au] (5 mol%); D) 3c
(10 mol%)/[Au] (5 mol%).
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Chem. Eur. J. 2010, 16, 9478 – 9484

Asymmetric One-Pot Sequential Organo- and Gold Catalysis
FULL PAPER
taneously, different results were obtained. Employing excess
or equimolar amounts of gold to 3c led to inhibition of the
Mannich reaction (Scheme 4, conditions A–C). When an
excess of thiourea was employed (3c/[Au], 2:1), intermedi-
ate 4a was formed in >95% conversion (Scheme 4, condi-
tion D). Unfortunately, employing this reaction condition
resulted in deactivation of the Au complex for the subse-
quent alkyne hydroamination.
Therefore, taking into consideration the proved inactiva-
tion of thiourea 3c in the presence of Au salts for the initial
Mannich reaction, we decided to investigate the possibility
of accomplishing both catalytic reactions in a sequential
one-pot procedure (Table 3). Then, the organocatalytic
Mannich reaction was performed employing the optimized
ment employing p-TsOH (10 mol%) in the absence of a
gold salt was performed to rule out the possibility of acid-
catalyzed hydroamination[19] of 4a (Table 3, entry 8).
We also observed a dramatic effect when using bases as
additives in terms of reactivity, from no reaction in the pres-
ence of a proton sponge (DMAN) (Table 3, entry 9) to de-
composition by a retro-Mannich reaction when applying
stronger bases, such as KOtBu. These investigations demon-
strate that additives have a tremendous effect on the out-
come of the reaction. Acidic cocatalysts increase the reactiv-
ity and selectivity (endo/exo) of the process.
To shed light over the isomerization step, control experi-
ments were conducted in CDCl3. As outlined in Scheme 5,
1H NMR spectroscopic monitoring of a mixture of 5a (endo/
exo 4:1) in the presence of p-TsOH (10 mol%) ruled out a
rapid Brønsted acid catalyzed alkene isomerization (5a
endo/exo 6:1 after 20 h). However, PPh3AuNTf2 promoted
the isomerization[20] in the standard reaction time scale (5a
endo/exo 7:1 after 30 min, 10:1 after 2 h). Therefore, it is be-
lieved that excess p-TsOH prevents deactivation of the AuI-
catalyst by protonating the basic quinuclidine and quinoline
moieties of 3c.[21]
Table 3. Optimization of the one-pot synthesis of 2,3,3,5-tetrasubstituted
2,3-dihydropyrrole 5a.
Entry AuLn
Additive (%)
t[b] Conv.[c]
endo/exo[c]
[h] [%]
1
2
3
4
5
6
7
8
9
AuCl
AuCl3
–
22
22
9
9
9
6
4
22
70
70
>95
2:1
2:1
3:1
3:1
8:1
9:1
AgOTf (15)
AgOTf (5)
–
PPh3AuCl
PPh3AuNTf2
PPh3AuNTf2 EtOH (500)
PPh3AuNTf2 PhCO2H (20)
PPh3AuNTf2 p-TsOH (10)
>95 (76)[d]
>95 (30)[d]
>95 (60)[d]
>95 (70)[d] >10:1
–
p-TsOH (10)
nr
nr
–
–
PPh3AuNTf2 proton sponge (20) 22
[a] All the reactions were carried out on a 0.1 mmol scale (0.05m) using
1a (0.15 mmol), 2a (0.10 mmol), and 3c (0.001 mmol). [b] Reaction time
for the second step. [c] Determined by 1H NMR spectroscopy. [d] Yield
of the isolated product.
Scheme 5. Gold-catalyzed alkene isomerization.
conditions (3c (1 mol%), CHCl3 [0.05m], À608C) and upon
completion of the reaction (22 h), an excess amount of
AuCln (5 mol%) was added at room temperature affording
5a in 70% conversion after 22 h (Table 3, entries 1 and 2).
Surprisingly, we observed a decrease of the selectivity, with
respect to the constitutional isomers, in the one-pot proce-
dure (endo/exo 2:1, Table 3, entries 1 and 2), compared with
the two-step reaction (endo/exo 9:1, see the Supporting In-
formation). Further optimization of the cyclization step was
performed by using different gold catalysts and additives.
Cationic AuI complexes showed higher reactivities, leading
to full conversions in shorter reaction times (Table 3, en-
tries 3 and 4). Performing the reaction in the presence of
EtOH (5 equiv), provided 5a with good selectivity (endo/
exo 8:1), albeit in lower yield (Table 3, entry 5). The best re-
sults were obtained using PPh3AuNTf2 in combination with
acidic additives (Table 3, entries 6 and 7). A catalyst 3c/
PPh3AuNTf2/p-TsOH ratio of 1:5:10 proved to be the opti-
mum conditions forming 5a in good yield (70%) and selec-
tivity (endo/exo >10:1, Table 3, entry 7). A control experi-
Scope of the one-pot synthesis of optically active 2,3-dihy-
dro-1H-pyrroles: Having developed an efficient one-pot
protocol for the synthesis of 2,3,3,5-tetrasubstituted 2,3-dihy-
dropyrroles 5, the generality of the reaction was studied for
a series of N-Boc-protected imines (Table 4).
Employing alkyl-substituted aromatic imines 1b–1d
showed that the outcome of the reactions was reasonably in-
dependent of aromatic substitution pattern (Table 4, en-
tries 2–4) and the optically active 2,3-dihydropyrroles 5b–5d
were formed in good yields (60–65%) and enantioselectivi-
ties (82–88% ee). The naphthyl-based imine 1e gave rise to
the heterocycle 5e (Table 4, entry 5) in 65% yield and
72% ee. Importantly, electron-poor aromatic imines 1 f and
1g can also be employed (Table 4, entries 6 and 7) affording
the corresponding 2,3-dihydropyrroles 5 f and 5g in good
yields (74–80%) and enantioselectivities (68–72% ee). How-
ever, the more electron-rich p-methoxy phenylimine 1h and
heteroaromatic thiophene-based imine 1i gave the desired
products 5h and 5i (Table 4, entries 8 and 9) in good yields
(45–70%), albeit in moderate enantioselectivities (58% ee).
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9481

K. A. Jørgensen et al.
Table 4. Scope of the one-pot synthesis of optically active 2,3-dihydro-
1H-pyrroles.
Entry
R
2
Product
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
Ph 1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
5a
5b
5c
5d
5e
5 f
5g
5h
5i
70
65
60
60
65
80
74
45
70
93
82
84
82
88
72
72
68
58
58
78
o-Me-Ph 1b
m-Me-Ph 1c
p-Me-Ph 1d
1-napthyl 1e
p-Cl-Ph 1 f
p-Br-Ph 1g
p-MeO-Ph 1h
2-thienyl 1i
Ph 1a
9
Scheme 6. Transformation of dihydropyrroles
5 into optically active
10[d]
4b
2,3,3,5-tetrasubstituted 1-pyrrolines 6.
[a] All the reactions performed on a 0.1 mmol scale (see the Supporting
Information). [b] Isolated by flash chromatography. [c] Determined by
chiral stationary-phase HPLC. [d] Employing 3c (5 mol%), 4b: Mannich
adduct.
optically active dihydropyrroles 5 with TFA in CH2Cl2 af-
forded 1-pyrrolines 6 in good yields (88–95%) without the
need for elaborate purifications, such as flash chromatogra-
phy.
It should be noted that excellent selectivities (endo/exo>
10:1) were obtained in all cases.
We then investigated the possibility of incorporating a
phenyl group attached to the terminal alkyne as this newly
designed 2-(3-phenylprop-2-ynyl)malononitrile (2b) would
provide arylbenzyldihydropyrroles. Under standard organo-
catalytic conditions, the Mannich adduct 4b was obtained in
93% yield and 78% ee (Table 4, entry 10). Unfortunately,
no cyclization was observed by employing various condi-
tions.[22]
Conclusion
We have reported a novel synthetic approach towards opti-
cally active 2,3,3,5-tetrasubstituted 2,3-dihydro-1H-pyrroles
5. The protocol involves a combination of bifunctional thio-
urea organocatalysis and gold catalysis in a one-pot sequen-
tial fashion. In the alkyne hydroamination, thiourea-based
hydrogen bonding organocatalyst 3c and gold-based Lewis
acid PPh3AuNTf2 proved to be compatible upon protonation
by p-TsOH. The obtained highly functionalized heterocycles
5 may serve as templates for the design of new organocata-
lysts or natural product synthesis. The synthetic potential of
optically active 2,3-dihydro-1H-pyrroles 5 has been illustrat-
ed by a simple transformation into 1-pyrrolines 6, direct pre-
cursors of pyrrolidines.
Absolute configuration and synthesis of optically active
2,3,3,5-tetrasubstituted 1-pyrrolines: The absolute configura-
tion of 5i was assigned to be (R) by X-ray analysis as shown
in Figure 1.[23] The absolute configurations of the products
Experimental Section
General: NMR spectra were acquired on a Varian AS 400 spectrometer,
running at 400 and 100 MHz for 1H and 13C acquisition, respectively.
Chemical shifts (d) are reported in ppm relative to residual solvent sig-
nals (CDCl3, 7.26 ppm for 1H NMR; CDCl3, 77.0 ppm for 13C NMR).
13C NMR spectra were acquired on a broad band decoupled mode. Mass
spectra were recorded on a micromass LCT spectrometer using electro-
spray (ES+) ionization techniques. Analytical TLC was performed using
precoated aluminium-backed plates (Merck Kieselgel 60 F254) and vi-
sualized by ultraviolet irradiation, KMnO4, or vanillin stains. Optical ro-
tations were measured on a Perkin–Elmer 241 polarimeter. The enantio-
meric excess (ee) of the products was determined by chiral stationary-
phase HPLC (Daicel Chiralpak AS/AD and Daicel Chiralcel OD/OJ col-
umns). Analytical grade solvents and commercially available reagents
were used without further purification. For flash chromatography (FC)
silica gel (silica gel 60, 230–400 mesh, Fluka) was used.
Figure 1. X-ray crystal structure of compound 5i (C gray, H white, O red,
N blue, S yellow).
4–6 were assigned by assuming a uniform reaction pathway
by which the nucleophile 2 adds to the Re face of the imine
1.
To highlight the synthetic potential of the products 5,
their simple transformation into 1-pyrrolines 6, direct pre-
cursors of pyrrolidines,[24] is presented in Scheme 6. Treating
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Asymmetric One-Pot Sequential Organo- and Gold Catalysis
FULL PAPER
General procedure for synthesis of chiral 2,3,3,5-tetrasubstituted 2,3-dihy-
dro-1H-pyrroles: A solution of catalyst 3c (1 mol%, 60 mL, 9 mgmLÀ1 in
CHCl3) was added to a solution of 2 (0.1 mmol) and imine 1 (0.15 mmol)
in CHCl3 (2 mL) at À608C. The reaction was stirred at À608C for 22 h.
The mixture was allowed to warm to RT and p-toluensulfonic acid mono-
hydrate (10 mol%) and PPh3AuNTf2–1/2toluene (5 mol%) were added
sequentially. The reaction was stirred at RT until full conversion (3–5 h)
to product 5 (TLC, CH2Cl2/pentane, 2:1). Filtration through a short pad
of silica (CH2Cl2) followed by FC on silica gel afforded the enantioen-
riched product 5.
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General procedure for synthesis of optically active 2,3,3,5-tetrasubstituted
1-pyrrolines: Compound 5 was dissolved in a CH2Cl2/TFA (5:1) (0.03m)
mixture and stirred for 1 h at room temperature. The solvent was evapo-
rated, and TFA removed as an azeotrope with toluene (2ꢁ1 mL). The
residue was dissolved in EtOAc (0.5 mL), extracted with a sat. Na2CO3
solution, water, dried over Na2SO4, and evaporated to yield the pure
product 6.
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This work was made possible by grants from Carlsberg Foundation and
OChemSchool. D.M. thanks the Ministerio de Ciencia e Innovaciꢂn of
Spain for a postdoctoral fellowship. We are grateful to Dr. Jacob Over-
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Received: April 28, 2010
Published online: July 2, 2010
9484
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9478 – 9484