Cinchona-based primary amine-catalyzed enantioselective aza-Michael reactions of pyrroles with α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetasy.2014.09.002

The cinchona-based primary amine-catalyzed enantioselective aza-Michael reaction of α,β-unsaturated aldehydes with 4,5-dihalo-1H-pyrrole-2-carbonitriles as the N-centered heteroaromatic nucleophile, followed by chemoselective reduction provided the corres

Full text of DOI:10.1016/j.tetasy.2014.09.002

Tetrahedron: Asymmetry 25 (2014) 1383–1388
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Cinchona-based primary amine-catalyzed enantioselective
aza-Michael reactions of pyrroles with a,b-unsaturated aldehydes
⇑
Su-Jeong Lee, Jun-Gi Ahn, Chang-Woo Cho
Department of Chemistry, Kyungpook National University, Daegu 702-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2014
Accepted 3 September 2014
The cinchona-based primary amine-catalyzed enantioselective aza-Michael reaction of
a,b-unsaturated
aldehydes with 4,5-dihalo-1H-pyrrole-2-carbonitriles as the N-centered heteroaromatic nucleophile, fol-
lowed by chemoselective reduction provided the corresponding chiral aza-Michael products in good
yields and with excellent enantioselectivities (90–97% ee).
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Previous work of our laboratory
O
X
Pyrrole is one of the most ubiquitous heterocycles found in
natural products1 and pharmaceuticals2 that exhibit various
appealing biological properties. Due to the prevalence of pyrroles,
the synthesis of enantioenriched C-alkylated pyrroles via organo-
catalytic routes has been a subject of active research.3 Recently,
we reported on the organocatalytic asymmetric aza-Michael reac-
tion4 of pyrroles as an N-centered heteroaromatic nucleophile5
with TBDPS-protected (E)-4-hydroxybut-2-enal using chiral diaryl-
prolinol trimethylsilyl ether6 as the secondary amine catalyst7 and
benzoic acid as the acid additive (Fig. 1),5c and its application as the
key step in the enantioselective formal synthesis of bromopyrrole
alkaloid natural products. Due to the importance of enantiopure
N-alkylated pyrroles as pharmacophores in biologically active nat-
ural products,1 we sought to further develop the aza-Michael reac-
Ar
OTMS
Ar
1. cat.
H
N
H
PhCO2H
CN
toluene
Y
N
Ar = 3,5-(CF3)2C6H3
cat.
OTBDPS
CN
2. reduction
X
+
(secondary
OTBDPS
amine catalyst)
HO
Y
N
H
Herein
O
X
OCH3
1. cat.
Ph3CCO2H
toluene
H
X
H
N
CN
R
Y
N
R
+
NH2
tion of pyrroles with an expanded scope of
a,b-unsaturated
2. reduction
N
aldehydes in the presence of various chiral primary amine cata-
lysts8–10 to show the applicability of these organocatalysts in this
synthetic route. Although chiral primary amine-catalyzed asym-
cat.
CN
Y
(primary
N
H
HO
amine catalyst)
metric aza-Michael reactions of
N-centered heteroaromatic nucleophiles have been reported,5b,11
to the best of our knowledge the corresponding use of ,b-unsatu-
a,b-unsaturated ketones with
Figure 1. Organocatalytic asymmetric aza-Michael reactions of pyrroles with
,b-unsaturated aldehydes.
a
a
rated aldehydes as substrates has not been reported. For the
successful progress of this organocatalytic reaction, the pKa of the
pyrrole NH should be sufficiently low to be deprotonated by a
base to generate the resulting nucleophilic pyrrole anion.5
Herein we report a cinchona-based primary amine-catalyzed
by a chemoselective reduction that affords the corresponding chiral
aza-Michael products with excellent enantioselectivities (Fig. 1).
2. Results and discussion
enantioselective aza-Michael reaction of various
a,b-unsaturated
aldehydes with 4,5-dihalo-1H-pyrrole-2-carbonitriles, followed
In order to explore the feasibility of chiral primary amine-cata-
lyzed enantioselective aza-Michael reactions of
aldehydes with pyrroles, we investigated the aza-Michael reaction
a,b-unsaturated
⇑
Corresponding author. Tel.: +82 53 950 5334; fax: +82 53 950 6330.
E-mail address: cwcho@knu.ac.kr (C.-W. Cho).
http://dx.doi.org/10.1016/j.tetasy.2014.09.002
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1384
S.-J. Lee et al. / Tetrahedron: Asymmetry 25 (2014) 1383–1388
Table 1
III
1. catalyst (20 mol %)
X
Optimization of chiral primary amine-catalyzed enantioselective aza-Michael reac-
Ph3CCO2H (40 mol %)
toluene (0.1 M)
O
X
tions of 4,5-dibromo-1H-pyrrole-2-carbonitrile 1a with (E)-4-oxobut-2-enyl benzoate
−20 oC, 24 h
2aa
Br
CN
N
+
H
Br
Br
CN
2. NaBH4 (2.1 equiv)
EtOH (0.1 M)
N
H
R
R
−20 oC, 1 h
I V
- (20 mol %)
1. catalyst
Br
2
1a, X = Br
1b, X = Cl
(2 equiv)
CN
Br
H
HO
additive (40 mol %)
toluene (0.1 M)
temp (oC), 24 h
N
H
1a
3a
j
−
CN
Br
N
O
+
Br
Br
Br
Br
2. NaBH4 (2.1 equiv)
EtOH (0.1 M)
OBz
temp (oC), 1 h
Br
CN
CN
Br
CN
HO
N
OBz
N
N
3a
2a
(2 equiv)
OBz
OR'
N
HO
HO
HO
OR
Boc
Cbz
3a
3b, R' = TBDPS
3da
CH3
NH2
H
N
62% yield, 90% ee
72% yield, 94% ee
53% yield, 95% ee
3c
, R' = Bn
III, R = CH3
IV, R = H
65% yield, 90% ee
NH2
H2N
NH2
V
, R = CH2C(CH3)3
N
I
II
Br
Br
Cl
Entry
Cat.
Additive
Temp (°C)
Yieldb (%)
eec (%)
Br
CN
Me
Br
CN
Br
CN
N
N
N
1
2
3
4
5
6
7
8
I
II
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
CH3CO2H
4-NO2–C6H4CO2H
Ph3CCO2H
Ph3CCO2H
0
0
0
0
0
À20
À30
À20
À20
À20
À30
56
56
59
54
56
50
21
23
41
62
56
0
0
III
IV
V
III
III
III
III
III
III
62
56
54
88
93
85
90
90
90
Ph
OBz
HO
HO
HO
3ea
3f b
3g
69% yield, 93% ee
53% yield, 92% ee
67% yield, 91% ee
9
Cl
Cl
Cl
10
11d
Br
CN
Br
N
CN
Br
CN
a
N
N
Procedure: 2a (0.4 mmol) was added to a mixture of 1a (0.2 mmol), catalyst
(0.04 mmol), and additive (0.08 mmol) in toluene (2 mL) in one portion. The
reaction mixture was stirred at 0, À20, or À30 °C for 24 or 48 h, at which point the
aldehyde was directly reduced to an alcohol with NaBH4 (0.42 mmol) in EtOH
(2 mL).
N
Ph
HO Boc
Cbz
HO
Me
HO
3ia
70% yield, 91% ee
3jb
3h
b
Isolated yield for two steps.
Determined by HPLC analysis (Chiralpak AD-H).
67% yield, 91% ee
72% yield, 94% ee
c
d
For 48 h.
Figure 2. Organocatalytic enantioselective aza-Michael reactions of 5-bromo-4-
halo-1H-pyrrole-2-carbonitriles 1a,b with various ,b-unsaturated aldehydes 2. The
cited yields are of isolated products obtained over two steps. The ee values were
determined by chiral HPLC analysis (Chiralcel OD-H, Chiralcel OJ-H, or Chiralpak
AD-H). a3 equiv of 2 were used at À30 °C. b3 equiv of 2 were used.
a
of 4,5-dibromo-1H-pyrrole-2-carbonitrile 1a with (E)-4-oxobut-2-
enyl benzoate 2a using PhCO2H (40 mol %) as the acid additive in
toluene at 0 °C, in the presence of catalysts I–V (Table 1). The prod-
uct was isolated as alcohol 3a following NaBH4 reduction of the
aza-Michael aldehyde product. Among the organocatalysts assayed
(Table 1, entries 1–5), catalyst III proved to be the best and
afforded the desired aza-Michael product 3a in 59% yield with
62% ee. Lowering the reaction temperature with III to À20 °C pro-
vided 3a in 50% yield with 88% ee (Table 1, entry 6). Lowering the
temperature further to À30 °C gave 3a with an increased ee of 93%,
but with a considerably decreased yield of 21% (Table 1, entry 7).
Finally, among the additives tested, Ph3CCO2H was seen to be ideal
for the reaction, and 3a was obtained in 62% yield with 90% ee
(Table 1, entries 8–10).12 However, in case of the reaction at
À30 °C for 48 h under otherwise identical conditions, 3a was
obtained in a decreased yield of 56%, while sustaining the ee at
90% (Table 1, entry 11).
in 3a–f was found to be in an important class of marine natural
products that show various interesting biological properties.13
Similarly, 1b underwent the aza-Michael reaction with various
a,b-unsaturated aldehydes bearing Bz-protected hydroxyalkyl,
doubly N-protected aminoalkyl, aliphatic, and aromatic-
substituted alkyl substituents to provide the desired products
3g–j in good yields and excellent enantioselectivities.
Further exploration of the organocatalytic enantioselective aza-
Michael reactions with 4-bromo-5-iodo-1H-pyrrole-2-carbonitrile
1c was then carried out by varying the a,b-unsaturated aldehydes
2 (Fig. 3). Following our reaction conditions for the chemoselective
reductions of the aza-Michael aldehyde products generated from
4-halo-5-iodo-1H-pyrrole-2-carbonitriles,5c the NaBH4 reduction
of the products generated from 1c led to the reduction of the iodo
group, as well as the aldehyde, to afford alcohols 3k–m.
Conversely, the reduction of the same aza-Michael aldehyde prod-
ucts using BH3ÁSMe2 in THF provided the alcohol products 3n–p
without any reduction of the iodo group. In all cases, the corre-
sponding aza-Michael products 3k–p were obtained in good yields
and with excellent enantioselectivities. In addition, the halo groups
on the pyrrole moiety in 3a–p can be used in carbonAcarbon bond
Subsequently, the scope of
ble to the organocatalytic enantioselective aza-Michael reaction
with 5-bromo-4-halo-1H-pyrrole-2-carbonitriles 1a,b was
explored under the optimized conditions (Fig. 2). The reaction of
1a with an assortment of ,b-unsaturated aldehydes bearing vari-
a,b-unsaturated aldehydes 2 amena-
a
ously protected hydroxyalkyl, doubly N-protected aminoalkyl, ali-
phatic, and aromatic-substituted alkyl substituents afforded the
desired aza-Michael products 3a–f in good yields and with excel-
lent enantioselectivities. The dibromopyrrole moiety incorporated

S.-J. Lee et al. / Tetrahedron: Asymmetry 25 (2014) 1383–1388
1385
O
was determined to be (S)-configured by comparing the specific
rotation of 3a with that reported in the literature.5c From this
obtained absolute stereochemistry, the proposed transition state
of the aza-Michael reaction is briefly outlined as shown in Figure 4.
The aza-Michael addition of the anionic pyrrole nucleophile from
the Re face of the iminium intermediate,16 generated from the
reaction of the amino group of the cinchona-based primary amine
Br
H
+
III
catalyst (20 mol %)
I
CN
N
H
1c
Ph3CCO2H (40 mol %)
R
toluene (0.1 M), −20 oC, 24 h
2
(2 equiv)
Br
catalyst III with the
Ph3CCO2H, provided the desired product.
a,b-unsaturated aldehyde in the presence of
I
CN
N
BH3.SMe2 (1.1 equiv)
NaBH4 (2.1 equiv)
EtOH (0.1 M)
−20 oC, 1 h
R
THF (0.1 M)
−20 oC to −10 oC, 1 h
3. Conclusion
O
In conclusion, the cinchona-based primary amine-catalyzed
Br
Br
enantioselective aza-Michael reaction of
a,b-unsaturated alde-
hydes with 4,5-dihalo-1H-pyrrole-2-carbonitriles using Ph3CCO2H
as the acid additive, followed by chemoselective reduction pro-
vided the corresponding chiral aza-Michael products in good yields
and with excellent enantioselectivities (90–97% ee). This is the
CN
I
CN
R
N
N
R
HO
HO
3k−m
3n−p
only example of the use of a,b-unsaturated aldehydes as substrates
in chiral primary amine-catalyzed asymmetric aza-Michael reac-
tions with N-centered heteroaromatic nucleophiles. This synthetic
strategy provides an efficient route for generating various enantio-
enriched N-alkylated pyrroles as core structures of biologically
active natural products and pharmaceutical agents. Further studies
will focus on the application of these species to the synthesis of
biologically potent compounds.
Br
Br
Br
CN
CN
CN
N
N
N
OBn
N
Ph
HO
HO Boc
Cbz
HO
3k
3l
3ma
4. Experimental
4.1. General
63% yield, 97% ee
Br
63% yield, 93% ee
Br
61% yield, 95% ee
Br
The NMR spectroscopic data were recorded with a Bruker
400 MHz spectrometer using tetramethylsilane as the internal
reference. Mass spectra data were obtained from the Korea Basic
Science Institute (Daegu) on a Jeol JMS 700 high resolution mass
spectrometer. Enantiomeric excess values were determined by
HPLC analysis with a chiral stationary phase column (Chiralcel
OD-H, OJ-H, or Chiralpak AD-H).
I
CN
I
CN
I
CN
N
N
N
OBn
N
Ph
HO
HO Boc
Cbz
HO
3n
3o
3pa
60% yield, 96% ee
53% yield, 93% ee
60% yield, 94% ee
Figure 3. Organocatalytic enantioselective aza-Michael reactions followed by
chemoselective reductions of 4-bromo-5-iodo-1H-pyrrole-2-carbonitrile 1c with
4.2. Materials
various
a,b-unsaturated aldehydes 2. The cited yields are of isolated products
Pyrroles 113b,c,17 and
prepared according to reported procedures.
a
,b-unsaturated aldehydes 218 were
obtained over two steps. The ee values were determined by chiral HPLC analysis
(Chiralcel OD-H, Chiralcel OJ-H, or Chiralpak AD-H). a3 equiv of 2 were used.
4.3. General procedure for the organocatalytic enantioselective
aza-Michael reactions
*
H
N
To a mixture of pyrrole 1 (0.2 mmol), catalyst III (0.04 mmol),
H
N
and Ph3CCO2H (0.08 mmol) in toluene (2 mL) was added
a,
H
N
b-unsaturated aldehyde 2 (0.4 mmol) in one portion. The reaction
mixture was allowed to stir at À20 °C for 24 h, at which point
the aldehyde was directly reduced with either NaBH4 (0.42 mmol)
in EtOH (2 mL) or BH3ÁSMe2 (0.22 mmol) in THF (2 mL) to the
alcohol. After 1 h, the reaction was quenched by saturated aqueous
NaHCO3. The mixture was poured into ethyl acetate, and the layers
were separated. The organic layer was washed with saturated
aqueous NaHCO3 and brine, and dried over MgSO4. The organic
layer was filtered off and evaporated. The crude residue was puri-
fied by silica gel column chromatography.
NC
R
Y
Re face attack
X
Figure 4. Proposed transition state of the aza-Michael reaction.
forming reactions to synthesize a variety of potentially biologically
active pyrrole-based compounds.14 Some of the aza-Michael prod-
ucts consist of two conformers, according to analysis of 1H and 13
C
NMR spectra, which may be explained by the hindered internal
rotation due to the steric interactions among the pyrrole
substituents.15
The absolute stereochemical assignment of all aza-Michael
products was based on the absolute stereochemistry of 3a, which
4.3.1. (S)-2-(2,3-Dibromo-5-cyano-1H-pyrrol-1-yl)-4-hydroxybutyl
benzoate 3a
Colorless oil (55 mg, 62%); [
NMR (400 MHz, CDCl3) d 7.92 (d, J = 7.2 Hz, 2H), 7.59–7.54 (m, 1H),
a]
22 = +6.9 (c 1, CH3OH) 90% ee; 1H
D

1386
S.-J. Lee et al. / Tetrahedron: Asymmetry 25 (2014) 1383–1388
7.44–7.41 (m, 2H), 6.99 (s, 1H), 5.32–5.22 (m, 1H), 4.82–4.67 (m,
2H), 3.82–3.79 (m, 1H), 3.54–3.47 (m, 1H), 2.58–2.46 (m, 1H),
2.35–2.23 (m, 1H), 1.64 (s, 1H); 13C NMR (100 MHz, CDCl3) d
165.8, 133.3, 129.6, 128.9, 128.4, 124.3, 113.7, 112.7, 102.7, 99.5,
65.2, 58.0, 57.3, 32.7; FTIR (neat) 3557, 2945, 2218, 1716, 1412,
1326, 1312, 1263, 1120, 705 cmÀ1; HRMS (EI) calcd for [M]+ C16-
H14Br2N2O3 439.9371, found 439.9373; HPLC (Chiralpak AD-H,
Hexane/IPA = 90:10, 0.9 mL/min, k = 254 nm) 23.7 min (minor iso-
mer), 26.0 min (major isomer).
CDCl3) major conformer: d 123.9, 113.1, 112.9, 102.2, 98.8, 58.6,
58.5, 36.9, 36.6, 19.3, 13.5; FTIR (neat) 3431, 2959, 2931, 2873,
2219, 1411, 1379, 1309, 1047, 804 cmÀ1; HRMS (EI) calcd for
[M]+ C11H14Br2N2O 347.9473, found 347.9472; HPLC (Chiralcel
OD-H, Hexane/IPA = 95:5, 0.8 mL/min, k = 220 nm) 14.7 min
(minor isomer), 18.4 min (major isomer).
4.3.6. (R)-4,5-Dibromo-1-(4-hydroxy-1-phenylbutan-2-yl)-1H-
pyrrole-2-carbonitrile 3f
Mixture of two conformers (major/minor = 80:20), colorless oil
4.3.2. (S)-4,5-Dibromo-1-[1-(tert-butyldiphenylsilyloxy)-4-
hydroxybutan-2-yl]-1H-pyrrole-2-carbonitrile 3b
(53 mg, 67%); [a]
25 = +58.0 (c 1, CHCl3) 91% ee; 1H NMR (400 MHz,
D
CDCl3) d 7.25–7.18 (m, 3H), 7.09–7.05 (m, 2H), 6.93 and 6.60
(major: s, minor: s, 1H), 5.06–4.93 (m, 1H), 3.70–3.67 (m, 1H),
3.51–3.32 (m, 2H), 3.21–3.13 (m, 1H), 2.66–2.60 and 2.54–2.46
(minor: m, major: m, 1H), 2.24–2.16 (m, 1H), 1.44 and 1.36 (minor:
s, major: s, 1H); 13C NMR (100 MHz, CDCl3) major conformer: d
136.1, 128.7, 128.5, 127.0, 123.9, 113.3, 113.2, 102.1, 98.7, 60.1,
58.4, 40.8, 36.2, minor conformer: d 136.1, 128.6, 128.6, 127.0,
120.4, 111.6, 108.7, 107.0, 101.7, 61.6, 58.5, 39.5, 35.1; FTIR (neat)
3442, 2927, 2219, 1411, 1311, 1045, 751, 699 cmÀ1; HRMS (EI)
calcd for [M]+ C15H14Br2N2O 395.9473, found 395.9473; HPLC
(Chiralpak AD-H, Hexane/IPA = 95:5, 0.8 mL/min, k = 254 nm)
24.6 min (minor isomer), 27.3 min (major isomer).
White solid (83 mg, 72%); mp 99–101 °C; [a]
24 = +20.4 (c 1, CH3-
D
OH) 94% ee; 1H NMR (400 MHz, CDCl3) d 7.59–7.57 (m, 2H), 7.52–
7.35 (m, 8H), 6.92 (s, 1H), 5.07–4.96 (m, 1H), 4.11 (t, J = 10.0 Hz,
1H), 3.92–3.88 (m, 1H), 3.70–3.63 (m, 1H), 3.47–3.38 (m, 1H),
2.34–2.27 (m, 1H), 2.08–2.02 (m, 1H), 1.38 (s, 1H), 0.96 (s, 9H);
13C NMR (100 MHz, CDCl3) d 135.4, 132.6, 132.3, 129.9, 129.8,
127.7, 123.8, 114.2, 112.8, 102.4, 99.0, 65.0, 60.3, 58.3, 32.3, 26.4,
18.9; FTIR (neat) 3368, 2928, 2858, 2223, 1416, 1310, 1112, 699
cmÀ1; HRMS (EI) calcd for [M]+ C25H28Br2N2O2Si 574.0287, found
574.0286; HPLC (Chiralpak AD-H, Hexane/IPA = 95:5, 1.0 mL/min,
k = 254 nm) 8.8 min (minor isomer), 9.9 min (major isomer).
4.3.3. (S)-1-[1-(Benzyloxy)-4-hydroxybutan-2-yl]-4,5-dibromo-
1H-pyrrole-2-carbonitrile 3c
4.3.7. (S)-2-(2-Bromo-3-chloro-5-cyano-1H-pyrrol-1-yl)-4-hy-
droxybutyl benzoate 3g
Colorless oil (56 mg, 65%); [
a
]
D
24 = +3.2 (c 1, CHCl3) 90% ee; 1H
Colorless oil (55 mg, 69%); [
a]
22 = À2.8 (c 1, CHCl3) 93% ee; 1H
D
NMR (400 MHz, CDCl3) d 7.34–7.28 (m, 3H), 7.21–7.19 (m, 2H),
6.91 (s, 1H), 5.08–4.99 (m, 1H), 4.57–4.44 (m, 2H), 4.00–3.96 (m,
1H), 3.80–3.76 (m, 1H), 3.73–3.68 (m, 1H), 3.46–3.41 (m, 1H),
2.39–2.30 (m, 1H), 2.17–2.09 (m, 1H), 1.45 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 137.2, 128.3, 127.7, 127.4, 123.8, 113.6,
112.8, 102.4, 99.1, 72.9, 70.6, 58.2, 58.2, 33.0; FTIR (neat) 3436,
2925, 2869, 2219, 1413, 1312, 1093, 738 cmÀ1; HRMS (EI) calcd
for [M]+ C16H16Br2N2O2 425.9579, found 425.9580; HPLC (Chir-
alpak AD-H, Hexane/IPA = 95:5, 0.9 mL/min, k = 254 nm) 33.4 min
(major isomer), 36.6 min (minor isomer).
NMR (400 MHz, CDCl3) d 7.92 (d, J = 7.6 Hz, 2H), 7.59–7.54 (m,
1H), 7.44–7.41 (m, 2H), 6.92 (s, 1H), 5.29–5.19 (m, 1H), 4.84–
4.66 (m, 2H), 3.82–3.79 (m, 1H), 3.53–3.48 (m, 1H), 2.58–2.47
(m, 1H), 2.34–2.24 (m, 1H), 1.57 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 165.8, 133.3, 129.5, 128.9, 128.4, 121.6, 113.9, 112.8, 111.2,
101.7, 65.1, 58.0, 56.9, 32.6; FTIR (neat) 3502, 2925, 2219, 1719,
1315, 1266, 1109, 708 cmÀ1; HRMS (EI) calcd for [M]+ C16H14-
BrClN2O3 395.9876, found 395.9872; HPLC (Chiralpak AD-H, Hex-
ane/IPA = 90:10, 0.9 mL/min, k = 254 nm) 21.9 min (minor
isomer), 23.3 min (major isomer).
4.3.4. (S)-1-[1-[(Benzyloxycarbonyl)(tert-butoxycarbonyl)amino]-
4-hydroxybutan-2-yl]-4,5-dibromo-1H-pyrrole-2-carbonitrile 3d
Mixture of two conformers (major/minor = 83:17), colorless oil
4.3.8. (S)-1-[1-[(Benzyloxycarbonyl)(tert-butoxycarbonyl)amino]-
4-hydroxybutan-2-yl]-5-bromo-4-chloro-1H-pyrrole-2-carbo-
nitrile 3h
(61 mg, 53%); [
a]
25 = +61.2 (c 1, CHCl3) 95% ee; 1H NMR (400 MHz,
Mixture of two conformers (major/minor = 82:18), colorless oil
D
CDCl3) d 7.38–7.32 (m, 5H), 6.78 and 6.69 (major: s, minor: s, 1H),
5.24–4.93 (m, 3H), 4.50 and 4.46 (minor: dd, J = 14.8, 9.6 Hz, major:
dd, J = 14.8, 10.4 Hz, 1H), 3.93 and 3.90 (minor: dd, J = 14.4, 3.6 Hz,
major: dd, J = 14.8, 3.2 Hz, 1H), 3.74–3.67 (m, 1H), 3.50–3.39 (m,
1H), 2.46–2.31 (m, 1H), 2.25–2.16 (m, 1H), 1.64 and 1.59 (minor:
t, J = 5.2 Hz, major: t, J = 5.2 Hz, 1H), 1.41 and 1.39 (minor: s, major:
s, 9H); 13C NMR (100 MHz, CDCl3) major conformer: d 153.2, 151.3,
134.8, 128.7, 128.5, 128.4, 123.6, 113.2, 112.9, 103.6, 98.9, 83.8,
68.8, 58.3, 57.7, 49.1, 33.9, 27.7, minor conformer: d 153.2, 151.4,
135.0, 128.6, 128.4, 128.4, 120.8, 111.4, 108.8, 108.5, 101.7, 84.0,
68.8, 59.2, 58.6, 48.1, 33.3, 27.7; FTIR (neat) 3510, 2978, 2930,
2221, 1736, 1694, 1339, 1308, 1217, 1142, 1107, 751 cmÀ1; HRMS
(EI) calcd for [M]+ C22H25Br2N3O5 569.0161, found 569.0164; HPLC
(Chiralcel OJ-H, Hexane/IPA = 90:10, 0.95 mL/min, k = 254 nm)
14.5 min (minor isomer), 19.1 min (major isomer).
(71 mg, 67%); [a]
22 = +70.8 (c 1, CHCl3) 91% ee; 1H NMR (400 MHz,
D
CDCl3) d 7.38–7.32 (m, 5H), 6.73 and 6.63 (major: s, minor: s, 1H),
5.24–4.91 (m, 3H), 4.50 and 4.46 (minor: dd, J = 14.8, 9.6 Hz, major:
dd, J = 14.8, 10.4 Hz, 1H), 3.93 and 3.90 (minor: dd, J = 14.4, 3.6 Hz,
major: dd, J = 14.8, 3.2 Hz, 1H), 3.74–3.68 (m, 1H), 3.49–3.39 (m,
1H), 2.47–2.31 (m, 1H), 2.25–2.16 (m, 1H), 1.65 and 1.59 (minor:
t, J = 5.2 Hz, major: t, J = 5.2 Hz, 1H), 1.41 and 1.39 (minor: s, major:
s, 9H); 13C NMR (100 MHz, CDCl3) major conformer: d 153.2, 151.3,
134.8, 128.7, 128.5, 128.4, 121.0, 113.4, 113.0, 110.7, 102.7,
83.8, 68.8, 58.2, 57.3, 49.0, 33.8, 27.7, minor conformer:
d
153.2, 151.4, 134.9, 128.6, 128.4, 128.4, 118.0, 115.7, 111.5,
107.7, 106.1, 84.0, 68.8, 59.2, 58.6, 48.1, 33.3, 27.7; FTIR (neat)
3512, 2977, 2930, 2220, 1736, 1694, 1339, 1314, 1143, 1107,
752 cmÀ1; HRMS (EI) calcd for [M]+ C22H25BrClN3O5 525.0666,
found 525.0667; HPLC (Chiralcel OJ-H, Hexane/IPA = 90:10,
0.95 mL/min, k = 254 nm) 16.3 min (minor isomer), 22.3 min
(major isomer).
4.3.5. (R)-4,5-Dibromo-1-(1-hydroxyhexan-3-yl)-1H-pyrrole-2-
carbonitrile 3e
Mixture of two conformers (major/minor = 81:19), colorless oil
4.3.9. (R)-5-Bromo-4-chloro-1-(1-hydroxyhexan-3-yl)-1H-pyrrole-
2-carbonitrile 3i
(37 mg, 53%); [
a]
D
25 = À12.2 (c 1, CHCl3) 92% ee; 1H NMR (400 MHz,
CDCl3) d 6.95 and 6.82 (major: s, minor: s, 1H), 4.81–4.75 (m, 1H),
3.66–3.61 (m, 1H), 3.39–3.33 (m, 1H), 2.45–2.32 (m, 1H), 2.22–2.07
(m, 2H), 1.85–1.76 (m, 1H), 1.64 (s, 1H), 1.31–1.18 (m, 1H),
1.16–1.03 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
Mixture of two conformers (major/minor = 81:19), colorless oil
(43 mg, 70%); [
a
]
20 = À13.2 (c 1, CHCl3) 91% ee; 1H NMR (400 MHz,
D
CDCl3) d 6.89 and 6.76 (major: s, minor: s, 1H), 4.78–4.73 (m, 1H),
3.68–3.63 (m, 1H), 3.41–3.33 (m, 1H), 2.52–2.33 (m, 1H), 2.24–2.07

S.-J. Lee et al. / Tetrahedron: Asymmetry 25 (2014) 1383–1388
1387
(m, 2H), 1.85–1.77 (m, 1H), 1.43 (s, 1H), 1.33–1.21 (m, 1H), 1.16–
1.03 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
major conformer: d 121.2, 113.2, 113.0, 110.6, 101.2, 58.5, 58.1,
36.9, 36.5, 19.3, 13.5; FTIR (neat) 3429, 2959, 2930, 2218, 1416,
1386, 1316, 1047, 802 cmÀ1; HRMS (EI) calcd for [M]+ C11H14-
BrClN2O 303.9978, found 303.9981; HPLC (Chiralcel OD-H, Hex-
ane/IPA = 95:5, 0.9 mL/min, k = 254 nm) 12.5 min (minor isomer),
15.9 min (major isomer).
1.0 mL/min, k = 254 nm) 8.9 min (minor isomer), 11.3 min (major
isomer).
4.3.14. (S)-1-[1-(Benzyloxy)-4-hydroxybutan-2-yl]-4-bromo-5-
iodo-1H-pyrrole-2-carbonitrile 3n
Colorless oil (57 mg, 60%); [
a]
D
20 = À4.4 (c 1, CHCl3) 96% ee; 1H
NMR (400 MHz, CDCl3) d 7.35–7.27 (m, 3H), 7.22–7.20 (m, 2H),
6.98 (s, 1H), 5.02–4.92 (m, 1H), 4.57–4.44 (m, 2H), 3.98 (dd,
J = 9.6, 9.2 Hz, 1H), 3.79 (dd, J = 10.4, 5.2 Hz, 1H), 3.70–3.68 (m,
1H), 3.44–3.39 (m, 1H), 2.39–2.33 (m, 1H), 2.18–2.10 (m, 1H),
1.47 (s, 1H); 13C NMR (100 MHz, CDCl3) d 137.2, 128.3, 127.7,
127.4, 124.4, 112.7, 106.4, 104.5, 88.7, 73.0, 70.9, 61.4, 58.2, 33.3;
FTIR (neat) 3430, 2924, 2868, 2217, 1395, 1373, 1321, 1305,
1093, 1049, 735 cmÀ1; HRMS (EI) calcd for [M]+ C16H16BrN2O2I
473.9440, found 473.9438; HPLC (Chiralpak AD-H, Hexane/
IPA = 90:10, 1.0 mL/min, k = 254 nm) 17.4 min (major isomer),
22.2 min (minor isomer).
4.3.10. (R)-5-Bromo-4-chloro-1-(4-hydroxy-1-phenylbutan-2-
yl)-1H-pyrrole-2-carbonitrile 3j
Mixture of two conformers (major/minor = 80:20), colorless oil
(51 mg, 72%); [a]
20 = +67.0 (c 1, CHCl3) 94% ee; 1H NMR (400 MHz,
D
CDCl3) d 7.25–7.18 (m, 3H), 7.09–7.05 (m, 2H), 6.86 and 6.54
(major: s, minor: s, 1H), 5.03–4.94 (m, 1H), 3.71–3.67 (m, 1H),
3.51–3.32 (m, 2H), 3.22–3.17 (m, 1H), 2.66–2.57 and 2.55–2.46
(minor: m, major: m, 1H), 2.26–2.17 (m, 1H), 1.43 and 1.34 (minor:
s, major: s, 1H); 13C NMR (100 MHz, CDCl3) major conformer: d
136.1, 128.7, 128.5, 127.0, 121.2, 113.3, 113.1, 110.9, 101.2, 59.6,
58.4, 40.7, 36.2, minor conformer: d 136.1, 128.6, 128.6, 127.0,
117.7, 115.7, 111.8, 107.7, 104.6, 61.5, 58.6, 39.5, 35.1; FTIR (neat)
3436, 2926, 2217, 1416, 1387, 1317, 1046, 753, 699 cmÀ1; HRMS
(EI) calcd for [M]+ C15H14BrClN2O 351.9978, found 351.9982; HPLC
(Chiralpak AD-H, Hexane/IPA = 95:5, 0.9 mL/min, k = 254 nm)
19.7 min (minor isomer), 21.6 min (major isomer).
4.3.15. (S)-1-[1-[(Benzyloxycarbonyl)(tert-butoxycarbonyl)am-
ino]-4-hydroxybutan-2-yl]-4-bromo-5-iodo-1H-pyrrole-2-
carbonitrile 3o
Mixture of two conformers (major/minor = 93:7), colorless oil
(66 mg, 53%);
[a]
20 = +53.2 (c 1, CHCl3) 93% ee; 1H NMR
D
(400 MHz, CDCl3) d 7.41–7.32 (m, 5H), 6.86 and 6.72 (major: s,
minor: s, 1H), 5.23–4.92 (m, 3H), 4.54 and 4.50 (minor: dd,
J = 14.8, 9.6 Hz, major: dd, J = 14.8, 10.4 Hz, 1H), 3.94 and 3.89
(minor: dd, J = 14.8, 3.6 Hz, major: dd, J = 14.8, 2.8 Hz, 1H),
3.73–3.66 (m, 1H), 3.48–3.37 (m, 1H), 2.56–2.48 and 2.39–2.31
(minor: m, major: m, 1H), 2.30–2.16 (m, 1H), 1.68 and 1.63 (minor:
t, J = 5.2 Hz, major: t, J = 5.2 Hz, 1H), 1.41 and 1.38 (minor: s, major:
s, 9H); 13C NMR (100 MHz, CDCl3) major conformer: d 153.2, 151.2,
134.8, 128.9, 128.5, 128.4, 124.2, 112.8, 106.2, 105.6, 88.2, 83.7,
68.8, 61.0, 58.2, 49.2, 34.2, 27.7, minor conformer: d 153.2, 151.5,
134.9, 128.6, 128.4, 128.4, 120.7, 111.9, 111.3, 109.4, 88.2, 84.0,
68.8, 59.6, 58.6, 48.3, 33.8, 27.7; FTIR (neat) 3509, 2962, 2928,
4.3.11. (S)-1-[1-(Benzyloxy)-4-hydroxybutan-2-yl]-4-bromo-1H-
pyrrole-2-carbonitrile 3k
Colorless oil (44 mg, 63%); [
a]
22 = À28.1 (c 1, CHCl3) 97% ee; 1
H
D
NMR (400 MHz, CDCl3) d 7.37–7.28 (m, 3H), 7.25–7.22 (m, 2H),
6.99 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 4.68–4.62 (m, 1H),
4.56–4.45 (m, 2H), 3.75–3.69 (m, 2H), 3.68–3.62 (m, 1H), 3.47–
3.41 (m, 1H), 2.17–2.02 (m, 2H), 1.59 (s, 1H); 13C NMR (100 MHz,
CDCl3) d 137.1, 128.4, 127.8, 127.6, 124.9, 120.9, 112.5, 104.6,
96.3, 73.2, 71.5, 58.2, 56.6, 34.3; FTIR (neat) 3439, 2926, 2867,
2219, 1453, 1316, 1094, 1078, 1047, 737, 697 cmÀ1; HRMS (EI)
calcd for [M]+ C16H17BrN2O2 348.0473, found 348.0475; HPLC
(Chiralpak AD-H, Hexane/IPA = 90:10, 1.0 mL/min, k = 254 nm)
11.0 min (minor isomer), 12.9 min (major isomer).
2219, 1736, 1693, 1369, 1339, 1298, 1217, 1139, 1106, 751 cmÀ1
;
HRMS (EI) calcd for [M]+ C22H25BrN3O5I 617.0022, found
617.0021; HPLC (Chiralcel OD-H, Hexane/IPA = 90:10, 1.0 mL/min,
k = 254 nm) 18.1 min (minor isomer), 26.3 min (major isomer).
4.3.12. (S)-1-[1-[(Benzyloxycarbonyl)(tert-butoxycarbonyl)amino]-
4-hydroxybutan-2-yl]-4-bromo-1H-pyrrole-2-carbonitrile 3l
4.3.16. (R)-4-Bromo-1-(4-hydroxy-1-phenylbutan-2-yl)-5-iodo-
1H-pyrrole-2-carbonitrile 3p
Colorless oil (62 mg, 63%); [a]
22 = +44.7 (c 1, CHCl3) 93% ee; 1H
D
Mixture of two conformers (major/minor = 90:10), light yel-
NMR (400 MHz, CDCl3) d 7.39–7.31 (m, 5H), 6.81 (d, J = 1.6 Hz, 1H),
6.66 (d, J = 1.6 Hz, 1H), 5.21–5.10 (m, 2H), 4.80–4.72 (m, 1H), 4.19
(dd, J = 14.4, 9.6 Hz, 1H), 3.90 (dd, J = 14.4, 4.0 Hz, 1H), 3.68–3.63
(m, 1H), 3.47–3.41 (m, 1H), 2.11–1.98 (m, 2H), 1.58 (s, 1H), 1.40
(s, 9H); 13C NMR (100 MHz, CDCl3) d 153.3, 151.4, 134.9, 128.5,
128.4, 128.4, 124.6, 121.1, 112.1, 105.1, 96.6, 83.9, 68.9, 58.2,
56.5, 49.9, 34.9, 27.7; FTIR (neat) 3541, 2926, 2224, 1740, 1726,
1332, 1116, 757 cmÀ1; HRMS (EI) calcd for [M]+ C22H26BrN3O5
491.1056, found 491.1057; HPLC (Chiralpak AD-H, Hexane/
IPA = 90:10, 1.0 mL/min, k = 254 nm) 13.2 min (minor isomer),
17.8 min (major isomer).
low oil (53 mg, 60%); [a]
22 = +45.1 (c 1, CHCl3) 94% ee; 1H NMR
D
(400 MHz, CDCl3) d 7.25–7.18 (m, 3H), 7.09–7.04 (m, 2H), 7.00
and 6.63 (major: s, minor: s, 1H), 5.06–4.98 and 4.95–4.87
(minor: m, major: m, 1H), 3.69–3.56 (m, 1H), 3.43–3.32 (m,
2H), 3.20–3.12 (m, 1H), 2.80–2.71 and 2.57–2.48 (minor: m,
major: m, 1H), 2.23–2.15 (m, 1H), 1.36 (s, 1H); 13C NMR
(100 MHz, CDCl3) major conformer: d 136.1, 128.9, 128.5, 127.0,
124.4, 113.1, 106.0, 104.2, 88.5, 63.2, 58.3, 41.0, 36.3, minor con-
former: d 136.2, 128.6, 128.6, 127.0, 120.5, 112.0, 111.5, 109.4,
88.5, 61.8, 58.6, 39.6, 35.2; FTIR (neat) 3437, 2927, 2216, 1393,
1371, 1303, 1044, 751, 699 cmÀ1; HRMS (EI) calcd for [M]+ C15-
H14BrN2OI 443.9334, found 443.9336; HPLC (Chiralpak AD-H,
Hexane/IPA = 90:10, 1.0 mL/min, k = 254 nm) 12.8 min (major
isomer), 15.5 min (minor isomer).
4.3.13. (R)-4-Bromo-1-(4-hydroxy-1-phenylbutan-2-yl)-1H-pyr-
role-2-carbonitrile 3m
Colorless oil (39 mg, 61%); [a]
22 = +74.3 (c 1, CHCl3) 95% ee; 1H
D
NMR (400 MHz, CDCl3) d 7.27–7.19 (m, 3H), 7.02–6.99 (m, 2H),
6.79 (d, J = 1.6 Hz, 1H), 6.66 (d, J = 1.6 Hz, 1H), 4.68–4.61 (m, 1H),
3.67–3.62 (m, 1H), 3.43–3.36 (m, 1H), 3.15–3.04 (m, 2H), 2.21–
2.04 (m, 2H), 1.47 (s, 1H); 13C NMR (100 MHz, CDCl3) d 136.1,
128.7, 128.6, 127.0, 123.9, 120.9, 112.4, 104.3, 96.2, 59.0, 58.3,
42.4, 37.1; FTIR (neat) 3437, 2924, 2218, 1455, 1380, 1315, 1044,
752, 699 cmÀ1; HRMS (EI) calcd for [M]+ C15H15BrN2O 318.0368,
found 318.0370; HPLC (Chiralpak AD-H, Hexane/IPA = 90:10,
Acknowledgments
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2011-0024892), and also supported by Kyungpook National Uni-
versity Research Fund, 2012.

1388
S.-J. Lee et al. / Tetrahedron: Asymmetry 25 (2014) 1383–1388
8. For recent reviews of asymmetric organocatalysis using chiral primary amines,
References
see: (a) Zhang, L.; Luo, S. Synlett 2012, 1575–1589; (b) Xu, L.-W.; Luo, J.; Lu, Y.
Chem. Commun. 2009, 1807–1821; (c) Peng, F.; Shao, Z. J. Mol. Catal. A: Chem.
2008, 285, 1–13.
1. (a) Mal, D.; Shome, B.; Dinda, B. K. In Heterocycles in Natural Products Synthesis;
Majumdar, K. C., Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, 2011; pp
187–220; (b) Dong, G. Pure Appl. Chem. 2010, 82, 2231–2246; (c) Weinreb, S. M.
Nat. Prod. Rep. 2007, 24, 931–948; (d) Fürstner, A. Angew. Chem. Int. Ed. 2003,
42, 3582–3603; (e) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753–1783; (f)
O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446.
9. For recent reviews of asymmetric organocatalysis using cinchona-based
primary amines, see: (a) Duan, J.; Li, P. Catal. Sci. Technol. 2014, 4, 311–320;
(b) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 9748–9770; (c) Jiang, L.; Chen,
Y.-C. Catal. Sci. Technol. 2011, 1, 354–365.
10. For selected examples of cinchona-based primary amine-catalyzed asymmetric
2. (a) Thompson, R. B. FASEB 2001, 15, 1671–1676; (b) Huffman, J. W. Curr. Med.
Chem. 1999, 6, 705–720.
aza-Michael reactions of a,b-unsaturated ketones, see: (a) Gogoi, S.; Zhao, C.-
G.; Ding, D. Org. Lett. 2009, 11, 2249–2252; (b) Lu, X.; Deng, L. Angew. Chem. Int.
Ed. 2008, 47, 7710–7713.
3. For examples of synthesis of chiral C-alkylated pyrroles via enantioselective
organocatalyses, see: (a) Hack, D.; Enders, D. Synthesis 2013, 45, 2904–2912; (b)
He, Y.; Lin, M.; Li, Z.; Liang, X.; Li, G.; Antilla, J. C. Org. Lett. 2011, 13, 4490–4493;
(c) Bates, R. W.; Sridhar, S. J. Org. Chem. 2011, 76, 5026–5035; (d) Sheng, Y.-F.;
Gu, Q.; Zhang, A.-J.; You, S.-L. J. Org. Chem. 2009, 74, 6899–6901; (e) Akagawa,
K.; Yamashita, T.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2009, 50, 5602–5604;
(f) Nakamura, S.; Sakurai, Y.; Nakashima, H.; Shibata, N.; Toru, T. Synlett 2009,
1639–1642; (g) Kim, S.-G. Bull. Korean Chem. Soc. 2009, 30, 2519–2920; (h)
Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C.
Science 2007, 316, 582–585; (i) Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C.
Org. Lett. 2007, 9, 4065–4068; (j) Zhang, Y.; Zhao, L.; Lee, S. S.; Ying, J. Y. Adv.
Synth. Catal. 2006, 348, 2027–2032; (k) Bonini, B. F.; Capitò, E.; Comes-
Franchini, M.; Fochi, M.; Ricci, A.; Zwanenburg, B. Tetrahedron: Asymmetry
2006, 17, 3135–3143; (l) Breistein, P.; Karlsson, S.; Hedenström, E. Tetrahedron:
Asymmetry 2006, 17, 107–111; (m) Shirakawa, S.; Berger, R.; Leighton, J. L. J.
Am. Chem. Soc. 2005, 127, 2858–2859; (n) Paras, N. A.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2001, 123, 4370–4371.
4. For selected reviews of organocatalytic asymmetric aza-Michael reactions, see:
(a) Wang, J.; Li, P.; Choy, P. Y.; Chan, A. S. C.; Kwong, F. Y. ChemCatChem 2012, 4,
917–925; (b) Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15, 11058–
11076.
5. For examples of synthesis of chiral N-alkylated pyrroles via enantioselective
organocatalyses, see: (a) Lee, H.-J.; Cho, C.-W. Eur. J. Org. Chem. 2014, 387–394;
(b) Lee, H.-J.; Cho, C.-W. J. Org. Chem. 2013, 78, 3306–3312; (c) Lee, S.-J.; Youn,
S.-H.; Cho, C.-W. Org. Biomol. Chem. 2011, 9, 7734–7741; (d) Bae, J.-Y.; Lee, H.-J.;
Youn, S.-H.; Kwon, S.-H.; Cho, C.-W. Org. Lett. 2010, 12, 4352–4355.
6. For the first development of diarylprolinol silyl ethers as organocatalysts, see:
(a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem. Int.
Ed. 2005, 44, 794–797; (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem. Int. Ed. 2005, 44, 4212–4215.
11. For examples of chiral primary amine-catalyzed asymmetric aza-Michael
reactions of
a,b-unsaturated ketones with N-centered heteroaromatic
nucleophiles, see: (a) Li, P.; Fang, F.; Chen, J.; Wang, J. Tetrahedron:
Asymmetry 2014, 25, 98–101; (b) Fu, N.; Zhang, L.; Luo, S.; Cheng, J.-P. Org.
Chem. Front. 2014, 1, 68–72; (c) Lv, J.; Wu, H.; Wang, Y. Eur. J. Org. Chem. 2010,
2073–2083; (d) Zhou, Y.; Li, X.; Li, W.; Wu, C.; Liang, X.; Ye, J. Synlett 2010,
2357–2360; (e) Luo, G.; Zhang, S.; Duan, W.; Wang, W. Synthesis 2009, 1564–
1572.
12. Under the optimized reaction conditions, 2-cyanopyrrole, 2-acetylpyrrole, 2-
(trifluoroacetyl)pyrrole, and methyl 4,5-dibromo-1H-pyrrole-2-carboxylate
did not undergo the aza-Michael reaction because the NH of the pyrroles
was not acidic enough to be deprotonated by a base to generate the resulting
nucleophilic pyrrole anions.
13. (a) Berlinck, R. G. S.; Kosuga, M. H. Nat. Prod. Rep. 2005, 22, 516–550; (b)
Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–49; (c) Hao, E.; Fromont, J.; Jardine, D.;
Karuso, P. Molecules 2001, 6, 130–141; (d) Gribble, G. W. J. Nat. Prod. 1992, 55,
1353–1395.
14. (a) Dang, T. T.; Ahmad, R.; Dang, T. T.; Reinke, H.; Langer, P. Tetrahedron Lett.
2008, 49, 1698–1700; (b) Smith, J. A.; Ng, S.; White, J. Org. Biomol. Chem. 2006,
4, 2477–2482; (c) Handy, S. T.; Sabatini, J. J. Org. Lett. 2006, 8, 1537–1539; (d)
Schröter, S.; Bach, T. Synlett 2005, 1957–1959; (e) Handy, S. T.; Bregman, H.;
Lewis, J.; Zhang, X.; Zhang, Y. Tetrahedron Lett. 2003, 44, 427–430.
15. For hindered internal rotation of pyrrole conformers, see: Catak, S.; Celik, H.;
Demir, A. S.; Aviyente, V. J. Phys. Chem. A 2007, 111, 5855–5863.
16. For iminium activation in organocatalysis, see: (a) Erkkilä, A.; Majander, I.;
Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470; (b) Lelais, G.; MacMillan, D. W.
C. Aldrichim. Acta 2006, 39, 79–87.
17. Loader, C. E.; Anderson, H. J. Can. J. Chem. 1981, 59, 2673–2676.
18. (a) Albrecht, Ł.; Dickmeiss, G.; Acosta, F. C.; Rodríguez-Escrich, C.; Davis, R. L.;
Jørgensen, K. A. J. Am. Soc. Chem. 2012, 134, 2543–2546; (b) Avi, M.; Gaisberger,
R.; Feichtenhofer, S.; Griengl, H. Tetrahedron 2009, 65, 5418–5426; (c) Fustero,
S.; Jiménez, D.; Moscardó, J.; Catalán, S.; Del Pozo, C. Org. Lett. 2007, 9, 5283–
5286; (d) Belardi, J. K.; Curtis, L. A.; Clareen, S. S.; Shimp, H. L.; Leimkuhler, C.
E.; Simonowicz, N. L.; Casillas, E. Synth. Commun. 2005, 35, 1633–1640.
7. For recent reviews of asymmetric organocatalysis using chiral secondary
amines, see: (a) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K.
A. Acc. Chem. Res. 2012, 45, 248–264; (b) Marqués-López, E.; Herrera, R. P. Curr.
Org. Chem. 2011, 15, 2311–2327; (c) Yu, X.; Wang, W. Org. Biomol. Chem. 2008,
6, 2037–2046.