Cinchona-based primary amine-catalyzed asymmetric cascade aza-michael-aldol reactions of enones with 2-(1 H -Pyrrol-2-yl)-2-oxoacetates: Synthesis of chiral pyrrolizines with multistereocenters

Article abstract of DOI:10.1021/jo4001614

Cinchona-based primary amine-catalyzed cascade aza-Michael-aldol reactions of α,β-unsaturated ketones with 2-(1H-pyrrol-2-yl)-2-oxoacetates provided highly functionalized chiral pyrrolizines bearing multistereocenters including a chiral quaternary carbon center in good yields (up to 92%) with excellent levels of stereocontrol (90-95% ee, >20:1 dr in all cases). The ketone group in the cascade product was asymmetrically reduced to chiral secondary hydroxyl groups in good yields.

Full text of DOI:10.1021/jo4001614

Article
pubs.acs.org/joc
Cinchona-Based Primary Amine-Catalyzed Asymmetric Cascade Aza-
Michael−Aldol Reactions of Enones with 2‑(1H‑Pyrrol-2-yl)-2-
oxoacetates: Synthesis of Chiral Pyrrolizines with Multistereocenters
Hyo-Jun Lee and Chang-Woo Cho*
Department of Chemistry, Kyungpook National University, Daegu 702-701, Republic of Korea
S
* Supporting Information
ABSTRACT: Cinchona-based primary amine-catalyzed cascade aza-Michael−aldol reactions of α,β-unsaturated ketones with 2-
(1H-pyrrol-2-yl)-2-oxoacetates provided highly functionalized chiral pyrrolizines bearing multistereocenters including a chiral
quaternary carbon center in good yields (up to 92%) with excellent levels of stereocontrol (90−95% ee, >20:1 dr in all cases).
The ketone group in the cascade product was asymmetrically reduced to chiral secondary hydroxyl groups in good yields.
with 2-(1H-pyrrol-2-yl)-2-oxoacetates that afford highly
functionalized chiral pyrrolizines having three consecutive
stereocenters (Figure 1). To the best of our knowledge, this
is the only example of the use of α,β-unsaturated ketones as
substrates in the organocatalytic asymmetric aza-Michael-
participated cascade reactions with N-centered heteroaromatic
nucleophiles. Concomitantly, the ketone group in the cascade
product is asymmetrically reduced to versatile chiral secondary
hydroxyl groups.
INTRODUCTION
■
Pyrrolizines are an important class of bicyclic heterocycles that
exhibit a variety of appealing biological activities and thus have
found application in the development of pharmaceuticals such
as antitumor,1 antileukemic,2 analgesic, and anti-inflammatory3
agents. However, despite their importance, little focus has been
placed on the synthesis of chiral pyrrolizines. The known
asymmetric synthesis of chiral pyrrolizines has utilized
intramolecular cycloaddition of chiral pyrrole-based nitrone
intermediates.4 Recently, however, we reported the chiral
diarylprolinol silyl ether-catalyzed asymmetric cascade aza-
Michael−aldol reactions of α,β-unsaturated aldehydes with 2-
trihaloacetylpyrroles as N-centered heteroaromatic nucleophiles
as a new synthetic route to chiral pyrrolizines.5 With the intent
to prepare a wide variety of chiral pyrrolizines, we strategically
utilized the organocatalytic asymmetric cascade aza-Michael−
aldol reactions6−8 of α,β-unsaturated ketones with 2-(1H-
pyrrol-2-yl)-2-oxoacetates (Figure 1). The success of this
reaction is based on the NH of the pyrroles having a low
enough pKa value to facilitate deprotonation by a base to
generate the requisite pyrrole anions as the nucleophile for the
initial aza-Michael reaction9,10 in the cascade reaction.
Furthermore, the α-keto ester group in the pyrroles, which
acts as the electrophile for the subsequent aldol reaction, should
be transformed into a versatile α-hydroxy ester group involving
construction of a quaternary stereocenter.11 Herein, we report
the cinchona-based primary amine-catalyzed12 asymmetric
cascade aza-Michael−aldol reactions of α,β-unsaturated ketones
RESULTS AND DISCUSSION
■
As the initial step in the exploration of the feasibility of the
organocatalytic asymmetric cascade reactions of α,β-unsatu-
rated ketones with 2-(1H-pyrrol-2-yl)-2-oxoacetates, the
cascade reactions of methyl 2-(4,5-dibromo-1H-pyrrol-2-yl)-2-
oxoacetate (1a) to (E)-pent-3-en-2-one (2a) using PhCO2H
(40 mol %) as the acid additive were performed in toluene at
ambient temperature in the presence of the chiral secondary
amine catalysts I−III, respectively (Table 1, entries 1−3).
Neither of these catalysts afforded the corresponding cascade
products, presumably due to steric constraints in generating the
iminium intermediates13 from the chiral secondary amines and
the α,β-unsaturated ketone.9d However, in the case of the chiral
primary amine catalyst IV, the cascade reaction furnished the
desired cascade product 3a in 32% yield and 39% ee as a single
Received: January 30, 2013
© XXXX American Chemical Society
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Figure 1. Organocatalytic asymmetric cascade aza-Michael−aldol reactions of α,β-unsaturated carbonyl compounds with pyrroles, followed by
reductions.
diastereomer under otherwise identical conditions (Table 1,
entry 4). Gratifyingly, the use of the quinine-derived primary
amine catalyst V in the cascade reaction under identical
conditions generated the cascade product 3a in 70% yield and
84% ee as a single diastereomer (Table 1, entry 5). The yield
and ee of the product 3a were both decreased with the use of
the catalyst VI having the hydroxyl group (Table 1, entry 6).
Through modification of the methoxy group of the quinine-
based primary amine catalyst V in the cascade reactions, the
catalyst VII having the neopentyloxy group was identified as the
optimal (fine-tuned) catalyst, affording a yield of 78% and 87%
ee (Table 1, entry 7). Finally, when PhCO2H was replaced with
Ph3CCO2H under otherwise identical conditions, the cascade
product 3a was obtained in 86% yield and 91% ee as a single
diastereomer (Table 1, entry 8).
Subsequently, the scope of 2-(1H-pyrrol-2-yl)-2-oxoacetates
1 as nucleophiles in the enantio- and diastereoselective
organocatalytic cascade aza-Michael−aldol reactions of (E)-
pent-3-en-2-one (2a) was explored under the optimized
conditions (Scheme 1). A series of methyl 2-(1H-pyrrol-2-yl)-
2-oxoacetates bearing various dihalo substituents were selected
as nucleophiles due to the potential for carbon−carbon bond
formation utilizing the halo groups in the pyrrolizine products
to generate a wide variety of chiral pyrrolizine derivatives.14 In
all cases, the chiral pyrrolizines 3a−f were obtained as single
diastereomers in good yields and excellent enantioselectivities.
In particular, the dibromopyrrole moiety in 3a has been found
to be an important class of marine natural products that display
a variety of interesting biological activities.15
otherwise identical conditions (Scheme 2). The cascade
reactions of the dibromopyrrole 1a with various α,β-
unsaturated ketones bearing alkyl, aromatic-substituted alkyl,
heteroaromatic-substituted alkyl, variously protected hydrox-
yalkyl, benzyl-protected mercaptoalkyl, and doubly N-protected
aminoalkyl substituents afforded the desired pyrrolizines 3g−o
as single diastereomers in good yields and excellent
enantioselectivities.
In an effort to explore further manipulation of the cascade
products, the asymmetric reduction of the ketone 3a was
carried out with BH3·SMe2 (120 mol %) at −40 °C in THF to
afford the chiral secondary alcohol 4a possessing four
consecutive stereocenters, in 76% yield as a 9:1 mixture of
diastereomers (Scheme 3).16 The product may be formed by
the hydride attack on the less hindered face of the carbonyl
group through a closed transition state in which the boron
atom would be intramoleculary coordinated by the two oxygens
of the hydroxyl group and the ketone group. Contrastingly, in
order to obtain the diastereomeric secondary alcohol 5a as
major reduction product, the asymmetric reduction of 3a was
carried out with BH3·SMe2 (120 mol %) and (S)-(−)-2-methyl-
CBS-oxazaborolidine (120 mol %) at room temperature in
THF to afford the desired chiral secondary alcohol 5a in 79%
yield as a 2.9:1 mixture of diastereomers.17,18 The absolute
stereochemical assignment of all cascade products 3a−o and
the reduction products 4a−5a is based upon single-crystal X-
ray diffraction analysis of the isonicotinic ester derivative 6a,
which was generated from 5a, as described in the Supporting
Information. From the absolute stereochemistry of the
pyrrolizines, the proposed transition states of the cascade
reaction are briefly outlined in Figure 2. The aza-Michael
reaction of the iminium intermediate with the pyrrole
nucleophile provides the aza-Michael intermediate (Figure 2
Therefore, further exploration of the asymmetric organo-
catalytic cascade reactions with methyl 2-(4,5-dibromo-1H-
pyrrol-2-yl)-2-oxoacetate (1a) were executed by varying the
α,β-unsaturated ketones 2 at 0 °C for 24 or 48 h under
B
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Table 1. Optimization of Organocatalytic Asymmetric
Cascade Aza-Michael−Aldol Reactions of Methyl 2-(4,5-
Dibromo-1H-pyrrol-2-yl)-2-oxoacetates (1a) to (E)-Pent-3-
Scheme 1. Asymmetric Organocatalytic Cascade Aza-
Michael−Aldol Reactions of (E)-Pent-3-en-2-one (2a) with
a
Various Pyrroles 1
a
en-2-one (2a)
b
c
entry
catalyst
additive
yield (%)
ee (%)
a
Procedure: 2a (0.4 mmol) was added to a mixture of 1 (0.2 mmol),
d
1
2
3
4
5
6
7
8
I
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
Ph3CCO2H
nr
catalyst VII (0.04 mmol), and Ph3CCO2H (0.08 mmol) in toluene (2
mL) in one portion. The mixture was stirred at rt for 24 h.
Enantiomeric excess was determined by chiral HPLC analysis
(Chiralpak AD-H or Chiralcel OJ-H). Diastereomeric ratio was
d
II
nr
d
III
IV
V
nr
32
70
33
78
86
39
84
74
87
91
1
determined by H NMR.
VI
VII
VII
EXPERIMENTAL SECTION
■
1
General Methods. H and 13C NMR spectra were recorded on a
a
Procedure: 2a (200 mol %) was added to a mixture of 1a (100 mol
400 MHz spectrometer with tetramethylsilane as the internal
reference. HRMS data were measured on a magnetic sector-electric
sector double focusing mass analyzer with EI or FAB ionization source.
Enantiomeric excess was determined by HPLC analysis with chiral
stationary phase column. Pyrroles 119 and α,β-unsaturated ketones 220
were prepared according to the reported procedures.
%), catalyst (20 mol %), and additive (40 mol %) in toluene (0.1 M)
in one portion. The mixture was stirred at rt for 24 h. The solvent was
removed, and the residue was isolated by silica gel chromatography.
Diastereomeric ratio was determined by H NMR and >20:1 dr in all
cases. Isolated yield. Determined by chiral HPLC analysis (Chiralpak
1
b
c
d
AD-H). No reaction.
Preparation of Catalysts I−VII. Catalysts I−IV are commercially
available. Catalysts V−VI were prepared according to the reported
procedures.21
(1S)-[6-(Neopentyloxy)quinolin-4-yl](8-vinylquinuclidin-2-yl)-
methanamine (Catalyst VII). To a cooled (0 °C) solution of (1R)-[6-
(neopentyloxy)quinolin-4-yl](8-vinylquinuclidin-2-yl)methanol22
(1.41 g, 3.7 mmol) and triphenylphosphine (1.16 g, 4.5 mmol) in
THF (25 mL, 0.15 M) were added diphenyl phosphoryl azide (0.96
mL, 4.5 mmol) and diisopropyl azidocarboxylate (0.87 mL, 4.5 mmol),
and then the mixture was stirred at room temperature for 12 h. The
mixture was then heated at 50 °C for 2 h, triphenylphosphine (1.16 g,
4.5 mmol) was added, and heating was maintained for 2 h. The
mixture was cooled to room temperature, and H2O (0.5 mL) was
added and then stirred for 3 h. After removal of THF, the residue was
extracted with CH2Cl2 and 1.0 N HCl. The aqueous phase was then
alkalinized with NH4OH and washed with CH2Cl2. The combined
organic layer was dried with MgSO4. Filtration, concentration, and
purification by flash chromatography (SiO2: EtOAc/MeOH/NH4OH
= 100:100:1) provided the catalyst VII in 64% yield (0.90 g, 2.37
mmol) as light yellow oil: [α]24D +90.1 (c 1, CH3OH); 1H NMR (400
MHz, CDCl3) δ 8.74 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H),
7.59 (s, 1H), 7.44 (d, J = 4.4 Hz, 1H), 7.41 (dd, J = 9.2, 2.8 Hz, 1H),
5.86−5.77 (m, 1H), 5.04−4.96 (m, 2H), 4.59 (d, J = 9.6 Hz, 1H),
3.78−3.72 (m, 2H), 3.32−3.20 (m, 2H), 3.10−3.08 (m, 1H), 2.85−
2.78 (m, 2H), 2.29−2.28 (m, 1H), 1.88 (s, 2H), 1.64−1.63 (m, 1H),
1.60−1.52 (m, 2H), 1.48−1.42 (m, 1H), 1.10 (s, 9H), 0.79−0.74 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 157.5, 147.6, 146.8, 144.6,
141.7, 131.5, 128.7, 121.6, 119.6, 114.2, 102.4, 78.0, 77.2, 61.8, 56.2,
40.9, 39.7, 31.9, 28.1, 27.5, 26.6, 26.0; FTIR (neat) 3382, 2952, 2865,
(a)), which subsequently undergoes aldol reaction followed by
hydrolysis to afford the cascade product (Figure 2 (b)).
CONCLUSION
■
In conclusion, the enantio- and diastereoselective cascade aza-
Michael−aldol reaction of α,β-unsaturated ketones with 2-(1H-
pyrrol-2-yl)-2-oxoacetates has been achieved using the fine-
tuned quinine-based primary amine VII as the organocatalyst
and triphenylacetic acid as the acid additive. The cascade
reaction affords highly functionalized chiral pyrrolizines having
three consecutive stereocenters in good yields (up to 92%) with
excellent levels of stereocontrol (90−95% ee, >20:1 dr in all
cases). This is the only example of the use of α,β-unsaturated
ketones as substrates in the organocatalytic asymmetric aza-
Michael-participated cascade reactions with N-centered hetero-
aromatic nucleophiles. In addition, depending on the reduction
conditions, the ketone group in the cascade product 3a is
asymmetrically reduced to versatile chiral secondary hydroxyl
groups with either S or R configurations. This strategy provides
a convenient synthetic route for generating various chiral
pyrrolizines. The application of these species in the synthesis of
biologically active compounds is the topic of further studies.
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1619, 1507, 1455, 1364, 1226, 1048, 1018, 911, 851 cm−1; HRMS (EI)
calcd for [M]+ C24H33N3O 379.2624, found 379.2622.
Scheme 2. Asymmetric Organocatalytic Cascade Aza-
Michael−Aldol Reactions of Methyl 2-(4,5-Dibromo-1H-
pyrrol-2-yl)-2-oxoacetates (1a) with Various α,β-
Typical Procedure for the Synthesis of Racemic Pyrrolizines
3. α,β-Unsaturated ketone 2 (0.4 mmol) was added to a mixture of
pyrrole 1 (0.2 mmol), ( )-trans-1,2-diaminocyclohexane (0.1 mmol),
and Ph3CCO2H (0.08 mmol) in toluene (2 mL) in one portion. The
reaction mixture was stirred at rt for 12 h. The solvent was removed,
and the residue was purified by silica gel column chromatography to
furnish the corresponding racemic pyrrolizines 3.
a
Unsaturated Ketones 2
Typical Procedure for the Organocatalytic Asymmetric
Cascade Aza-Michael−aldol Reactions of α,β-Unsaturated
Ketones with 2-(1H-Pyrrol-2-yl)-2-oxoacetates. α,β-Unsaturated
ketone 2 (0.4 mmol) was added to a mixture of pyrrole 1 (0.2 mmol),
catalyst VII (0.04 mmol), and Ph3CCO2H (0.08 mmol) in toluene (2
mL) in one portion. The reaction mixture was stirred at 0 °C or rt for
24 or 48 h. The solvent was removed, and the residue was purified by
silica gel column chromatography to furnish the corresponding
products 3.
(1R,2R,3R)-Methyl 2-acetyl-5,6-dibromo-1-hydroxy-3-methyl-2,3-
dihydro-1H-pyrrolizine-1-carboxylate (3a): yellow oil (68 mg, 86%);
[α]22D −19.8 (c 1, CH3OH, 91% ee); 1H NMR (400 MHz, CDCl3) δ
6.07 (s, 1H), 4.99−4.92 (m, 1H), 3.94 (s, 3H), 3.92 (dd, J = 7.2, 0.8
Hz, 1H), 3.48 (d, J = 0.8 Hz, 1H), 2.19 (s, 3H), 1.67 (d, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 201.4, 172.0, 135.9, 104.3,
101.8, 98.3, 76.5, 68.8, 56.3, 54.0, 29.8, 19.9; FTIR (neat) 3465, 2954,
1742, 1720, 1438, 1366, 1305, 1240, 1182, 1106, 1043, 788 cm−1;
HRMS (EI) calcd for [M]+ C12H13Br2NO4 392.9211, found 392.9210;
HPLC (Chiralpak AD-H, hexane/IPA = 95/5, 0.95 mL/min, λ = 254
nm) 17.0 min (minor isomer), 18.8 min (major isomer).
(1R,2R,3R)-Methyl 2-acetyl-6-bromo-5-chloro-1-hydroxy-3-meth-
yl-2,3-dihydro-1H-pyrrolizine-1-carboxylate (3b): yellow oil (64 mg,
1
91%); [α]23 −19.0 (c 1, CH3OH, 90% ee); H NMR (400 MHz,
D
CDCl3) δ 6.02 (s, 1H), 5.00−4.94 (m, 1H), 3.94 (s, 3H), 3.92 (dd, J =
7.2, 0.8 Hz, 1H), 3.46 (d, J = 0.8 Hz, 1H), 2.19 (s, 3H), 1.66 (d, J = 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.3, 172.0, 133.8, 112.4,
103.5, 97.8, 76.6, 68.9, 55.8, 54.1, 29.8, 19.5; FTIR (neat) 3467, 2926,
1743, 1720, 1447, 1366, 1307, 1240, 1182, 1108, 1041, 789 cm−1;
HRMS (EI) calcd for [M]+ C12H13BrClNO4 348.9716, found
348.9714; HPLC (Chiralpak AD-H, hexane/IPA = 95/5, 0.9 mL/
min, λ = 254 nm) 16.2 min (minor isomer), 17.5 min (major isomer).
(1R,2R,3R)-Methyl 2-acetyl-6-bromo-5-iodo-1-hydroxy-3-methyl-
a
Procedure: 2 (0.4 mmol) was added to a mixture of 1a (0.2 mmol),
catalyst VII (0.04 mmol), and Ph3CCO2H (0.08 mmol) in toluene (2
mL) in one portion. The mixture was stirred at 0 °C for 24 or 48 h.
Enantiomeric excess was determined by chiral HPLC analysis
(Chiralpak AD-H). Diastereomeric ratio was determined by 1H
b
c
2,3-dihydro-1H-pyrrolizine-1-carboxylate (3c): yellow oil (66 mg,
NMR. At 0 °C for 24 h. At 0 °C for 48 h.
1
75%); [α]22 −24.4 (c 1, CH3OH, 92% ee); H NMR (400 MHz,
D
CDCl3) δ 6.13 (s, 1H), 4.92−4.86 (m, 1H), 3.93 (d, J = 6.8 Hz, 1H),
3.92 (s, 3H), 3.69 (s, 1H), 2.18 (s, 3H), 1.67 (d, J = 6.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.6, 172.0, 139.2, 109.4, 105.0, 76.3,
68.8, 66.4, 56.9, 54.0, 29.9, 20.5; FTIR (neat) 3459, 2953, 1740, 1719,
1363, 1304, 1237, 1181, 1103, 1042, 773 cm−1; HRMS (EI) calcd for
[M]+ C12H13BrNO4I 440.9073, found 440.9073; HPLC (Chiralpak
AD-H, hexane/IPA = 95/5, 0.95 mL/min, λ = 254 nm) 21.0 min
(minor isomer), 22.6 min (major isomer).
Scheme 3. Asymmetric Reductions of the Ketone 3a
(1R,2R,3R)-Methyl 2-acetyl-5-bromo-6-chloro-1-hydroxy-3-meth-
yl-2,3-dihydro-1H-pyrrolizine-1-carboxylate (3d): yellow oil (60 mg,
1
86%); [α]22 −23.9 (c 1, CH3OH, 90% ee); H NMR (400 MHz,
D
CDCl3) δ 6.02 (s, 1H), 4.98−4.92 (m, 1H), 3.94 (s, 3H), 3.91 (dd, J =
7.2, 0.8 Hz, 1H), 3.47 (d, J = 0.8 Hz, 1H), 2.19 (s, 3H), 1.67 (d, J = 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.3, 172.0, 134.9, 116.1,
101.9, 95.9, 76.6, 68.7, 56.3, 54.1, 29.8, 19.9; FTIR (neat) 3447, 2927,
1740, 1720, 1443, 1367, 1313, 1239, 1182, 1106, 1044, 787 cm−1;
HRMS (EI) calcd for [M]+ C12H13BrClNO4 348.9716, found
348.9714; HPLC (Chiralcel OJ-H, hexane/IPA = 95/5, 0.9 mL/min,
λ = 254 nm) 36.1 min (major isomer), 41.0 min (minor isomer).
(1R,2R,3R)-Methyl 2-acetyl-5-chloro-6-iodo-1-hydroxy-3-methyl-
2,3-dihydro-1H-pyrrolizine-1-carboxylate (3e): yellow oil (58 mg,
1
73%); [α]23 −14.0 (c 1, CH3OH, 90% ee); H NMR (400 MHz,
D
CDCl3) δ 6.07 (s, 1H), 5.01−4.95 (m, 1H), 3.94 (d, J = 6.8 Hz, 1H),
3.93 (s, 3H), 3.58 (s, 1H), 2.18 (s, 3H), 1.65 (d, J = 6.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.3, 171.9, 135.7, 116.5, 108.0, 76.2,
69.1, 64.8, 55.6, 54.0, 29.7, 19.4; FTIR (neat) 3464, 2953, 1742, 1720,
1439, 1365, 1296, 1240, 1181, 1108, 1041, 791 cm−1; HRMS (EI)
calcd for [M]+ C12H13ClNO4I 396.9578, found 396.9578; HPLC
Figure 2. Proposed transition states of (a) the aza-Michael reaction
and (b) the subsequent aldol reaction.
D
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(Chiralpak AD-H, hexane/IPA = 95/5, 0.9 mL/min, λ = 254 nm) 15.8
min (minor isomer), 17.9 min (major isomer).
(ddd, J = 8.8, 5.6, 2.8 Hz, 1H), 4.50 (d, J = 6.0 Hz, 1H), 3.90 (s, 3H),
3.73 (t, J = 6.0 Hz, 2H), 3.63 (s, 1H), 2.56−2.49 (m, 1H), 2.18 (s,
3H), 2.15−2.07 (m, 1H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.9, 172.3, 136.1, 104.3, 102.1, 98.0,
76.9, 65.5, 59.3, 59.3, 54.0, 35.3, 30.1, 25.7, 18.2, −5.4, −5.4; FTIR
(neat) 3474, 2954, 2927, 1740, 1722, 1437, 1360, 1306, 1252, 1093,
834, 777 cm−1; HRMS (FAB) calcd for [M + 1]+ C19H29Br2NO5Si
537.0182, found 537.0185; HPLC (Chiralpak AD-H, hexane/IPA =
95/5, 0.95 mL/min, λ = 254 nm) 7.80 min (minor isomer), 8.85 min
(major isomer).
(1R,2R,3R)-Methyl 2-acetyl-5,6-diiodo-1-hydroxy-3-methyl-2,3-
dihydro-1H-pyrrolizine-1-carboxylate (3f): yellow oil (68 mg, 70%);
[α]22D −23.2 (c 1, CH3OH, 92% ee); 1H NMR (400 MHz, CDCl3) δ
6.19 (s, 1H), 4.94−4.88 (m, 1H), 3.96 (d, J = 6.4 Hz, 1H), 3.92 (s,
3H), 3.55 (d, J = 0.8 Hz, 1H), 2.19 (s, 3H), 1.67 (d, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 201.5, 172.1, 140.7, 110.1, 79.4, 75.8,
72.9, 69.1, 57.0, 54.1, 29.9, 20.6; FTIR (neat) 3446, 2924, 1734, 1717,
1436, 1360, 1294, 1234, 1180, 1102, 1040, 772 cm−1; HRMS (EI)
calcd for [M]+ C12H13NO4I2 488.8934, found 488.8935; HPLC
(Chiralpak AD-H, hexane/IPA = 93/7, 0.95 mL/min, λ = 254 nm)
17.3 min (minor isomer), 19.3 min (major isomer).
(1R,2R,3R)-Methyl 2-acetyl-3-[2-(allyloxy)ethyl]-5,6-dibromo-1-
hydroxy-2,3-dihydro-1H-pyrrolizine-1-carboxylate (3l): yellow oil
1
(86 mg, 92%); [α]19 −45.0 (c 1, CH3OH, 92% ee); H NMR (400
D
MHz, CDCl3) δ 6.07 (s, 1H), 5.88−5.78 (m, 1H), 5.26−5.20 (m, 1H),
5.19−5.16 (m, 1H), 5.02 (ddd, J = 9.6, 6.4, 2.8 Hz, 1H), 4.44 (d, J =
6.4 Hz, 1H), 3.92 (s, 3H), 3.86−3.84 (m, 2H), 3.59−3.54 (m, 1H),
3.52 (s, 1H), 3.51−3.46 (m, 1H), 2.76−2.69 (m, 1H), 2.15 (s, 3H),
2.13−2.04 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 201.5, 172.4,
136.2, 134.2, 117.3, 104.2, 102.2, 97.9, 76.7, 72.0, 66.6, 66.6, 59.6, 54.1,
33.2, 30.3; FTIR (neat) 3330, 2958, 1739, 1704, 1369, 1309, 1229,
1105, 1050, 955, 797 cm−1; HRMS (FAB) calcd for [M + 1]+
C16H19Br2NO5 462.9630, found 462.9633; HPLC (Chiralpak AD-H,
hexane/IPA = 95/5, 0.95 mL/min, λ = 254 nm) 23.5 min (minor
isomer), 26.0 min (major isomer).
(1R,2R,3R)-Methyl 2-acetyl-5,6-dibromo-3-butyl-1-hydroxy-2,3-
dihydro-1H-pyrrolizine-1-carboxylate (3g): yellow oil (64 mg,
1
73%); [α]22 −22.0 (c 1, CH3OH, 95% ee); H NMR (400 MHz,
D
CDCl3) δ 6.08 (s, 1H), 4.97 (ddd, J = 8.8, 6.4, 2.8 Hz, 1H), 4.10 (d, J
= 6.4 Hz, 1H), 3.93 (s, 3H), 3.47 (d, J = 0.8 Hz, 1H), 2.20 (s, 3H),
2.18−2.09 (m, 1H), 2.04−1.94 (m, 1H), 1.42−1.32 (m, 2H), 1.29−
1.19 (m, 1H), 1.14−1.03 (m, 1H), 0.91 (t, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 201.6, 172.0, 136.0, 104.3, 101.9, 98.1, 76.9,
65.5, 60.0, 54.0, 32.1, 30.1, 25.9, 22.4, 13.8; FTIR (neat) 3467, 2956,
1741, 1723, 1438, 1366, 1306, 1232, 1176, 1088, 1047, 777 cm−1;
HRMS (EI) calcd for [M]+ C15H19Br2NO4 434.9681, found 434.9679;
HPLC (Chiralpak AD-H, hexane/IPA = 95/5, 0.95 mL/min, λ = 254
nm) 10.7 min (minor isomer), 12.3 min (major isomer).
(1R,2R,3R)-Methyl 2-acetyl-3-[2-(benzyloxy)ethyl]-5,6-dibromo-1-
hydroxy-2,3-dihydro-1H-pyrrolizine-1-carboxylate (3m): yellow oil
1
(92 mg, 89%); [α]22 −45.1 (c 1, CH3OH, 94% ee); H NMR (400
(1R,2R,3R)-Methyl 2-acetyl-5,6-dibromo-1-hydroxy-3-isobutyl-
D
MHz, CDCl3) δ 7.35−7.25 (m, 5H), 6.06 (s, 1H), 5.04 (ddd, J = 9.6,
6.0, 2.8 Hz, 1H), 4.43 (d, J = 6.0 Hz, 1H), 4.38 (s, 2H), 3.86 (s, 3H),
3.64−3.52 (m, 2H), 3.48 (d, J = 0.8 Hz, 1H), 2.73−2.66 (m, 1H),
2.19−2.10 (m, 1H), 1.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
201.6, 172.3, 137.6, 136.2, 128.3, 127.7, 127.7, 104.3, 102.2, 97.9, 76.8,
73.1, 66.8, 66.5, 59.6, 54.0, 33.1, 30.1; FTIR (neat) 3446, 2926, 2861,
1740, 1721, 1437, 1362, 1306, 1234, 1096, 739, 698 cm−1; HRMS (EI)
calcd for [M]+ C20H21Br2NO5 512.9786, found 512.9788; HPLC
(Chiralpak AD-H, hexane/IPA = 90/10, 0.9 mL/min, λ = 254 nm)
16.4 min (minor isomer), 29.8 min (major isomer).
2,3-dihydro-1H-pyrrolizine-1-carboxylate (3h): yellow oil (55 mg,
1
63%); [α]22 −79.6 (c 1, CH3OH, 95% ee); H NMR (400 MHz,
D
CDCl3) δ 6.08 (s, 1H), 4.94 (ddd, J = 10.8, 4.8, 3.2 Hz, 1H), 4.05 (d, J
= 4.8 Hz, 1H), 3.91 (s, 3H), 3.67 (s, 1H), 2.24 (ddd, J = 13.6, 10.4, 3.2
Hz, 1H), 2.20 (s, 3H), 1.59 (ddd, J = 14.0, 10.8, 3.6 Hz, 1H), 1.54−
1.44 (m, 1H), 1.00 (d, J = 6.4 Hz, 3H), 0.95 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.8, 172.1, 135.5, 104.4, 102.1, 97.9,
77.3, 66.7, 59.0, 54.1, 43.3, 30.3, 25.4, 23.8, 21.4; FTIR (neat) 3465,
2957, 1741, 1724, 1438, 1365, 1307, 1236, 1173, 1088, 796 cm−1;
HRMS (EI) calcd for [M]+ C15H19Br2NO4 434.9681, found 434.9680;
HPLC (Chiralpak AD-H, hexane/IPA = 95/5, 0.95 mL/min, λ = 254
nm) 10.7 min (minor isomer), 12.1 min (major isomer).
(1R,2R,3R)-Methyl 2-acetyl-3-[2-(benzylthio)ethyl]-5,6-dibromo-
1-hydroxy-2,3-dihydro-1H-pyrrolizine-1-carboxylate (3n): yellow oil
1
(82 mg, 77%); [α]22 −51.0 (c 1, CH3OH, 91% ee); H NMR (400
(1R,2R,3R)-Methyl 2-acetyl-5,6-dibromo-1-hydroxy-3-phenethyl-
D
MHz, CDCl3) δ 7.34−7.23 (m, 5H), 6.06 (s, 1H), 4.98 (ddd, J = 8.4,
6.0, 2.4 Hz, 1H), 4.05 (d, J = 6.0 Hz, 1H), 3.90 (s, 3H), 3.73 (s, 2H),
3.49 (d, J = 1.2 Hz, 1H), 2.47−2.32 (m, 2H), 2.26−2.15 (m, 2H), 2.14
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.3, 171.9, 137.6, 136.0,
128.8, 128.5, 127.1, 104.5, 102.3, 98.0, 76.8, 65.5, 59.3, 54.1, 36.0, 32.1,
30.1, 25.6; FTIR (neat) 3466, 2953, 1740, 1721, 1437, 1359, 1306,
1237, 1180, 1091, 770, 702 cm−1; HRMS (EI) calcd for [M]+
C20H21Br2NO4S 528.9558, found 528.9553; HPLC (Chiralpak AD-
H, hexane/IPA = 90/10, 0.95 mL/min, λ = 254 nm) 13.8 min (minor
isomer), 18.8 min (major isomer).
2,3-dihydro-1H-pyrrolizine-1-carboxylate (3i): yellow oil (81 mg,
1
83%); [α]20 −50.9 (c 1, CH3OH, 94% ee); H NMR (400 MHz,
D
CDCl3) δ 7.31−7.28 (m, 2H), 7.23−7.17 (m, 3H), 6.10 (s, 1H), 5.04
(ddd, J = 8.8, 6.0, 2.8 Hz, 1H), 4.14 (d, J = 6.0 Hz, 1H), 3.94 (s, 3H),
3.47 (d, J = 0.4 Hz, 1H), 2.66−2.58 (m, 1H), 2.53−2.38 (m, 3H), 2.14
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.4, 172.0, 140.2, 136.0,
128.5, 128.2, 126.3, 104.5, 102.2, 98.2, 76.9, 65.3, 59.8, 54.1, 33.6, 30.1,
30.1; FTIR (neat) 3470, 2924, 1738, 1718, 1437, 1362, 1304, 1230,
1180, 1091, 731 cm−1; HRMS (FAB) calcd for [M + 1]+
C19H19Br2NO4 482.9681, found 482.9683; HPLC (Chiralpak AD-H,
hexane/IPA = 95/5, 0.95 mL/min, λ = 254 nm) 20.2 min (minor
isomer), 21.3 min (major isomer).
(1R,2R,3S)-Methyl 2-acetyl-3-[[(benzyloxycarbonyl)(tert-
butoxycarbonyl)amino]methyl]-5,6-dibromo-1-hydroxy-2,3-dihy-
dro-1H-pyrrolizine-1-carboxylate (3o): yellow oil (119 mg, 92%);
[α]22D +26.0 (c 1, CH3OH, 95% ee); 1H NMR (400 MHz, CDCl3) δ
7.41−7.33 (m, 5H), 6.07 (s, 1H), 5.23 (d, J = 2.8 Hz, 2H), 5.20−5.15
(m, 1H), 4.65 (dd, J = 14.0, 4.4 Hz, 1H), 4.38 (d, J = 5.6 Hz, 1H), 3.98
(dd, J = 14.0, 9.2 Hz, 1H), 3.88 (s, 3H), 3.56 (d, J = 0.4 Hz, 1H), 2.02
(s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 200.9, 172.1,
153.9, 151.8, 136.5, 135.1, 128.5, 128.5, 104.8, 102.7, 98.5, 83.8, 76.7,
68.9, 64.7, 58.5, 54.1, 47.9, 29.7, 27.8; FTIR (neat) 3446, 2980, 1734,
1370, 1303, 1258, 1150, 1116, 777 cm−1; HRMS (EI) calcd for [M]+
C25H28Br2N2O8 642.0212, found 642.0214; HPLC (Chiralpak AD-H,
hexane/IPA = 80/20, 0.85 mL/min, λ = 254 nm) 11.0 min (major
isomer), 13.6 min (minor isomer).
Asymmetric Reduction of the Ketone 3a Using BH3·SMe2. To
a cooled (−40 °C) solution of the ketone 3a (79 mg, 0.2 mmol) in
THF (2 mL, 0.1 M) was added BH3·SMe2 (2.0 M solution in THF,
0.12 mL, 0.24 mmol), and then the mixture was stirred at −40 °C for
12 h. The mixture was quenched with MeOH and then stirred at room
temperature for 30 min. After the addition of H2O, the mixture was
(1R,2R,3R)-Methyl 2-acetyl-5,6-dibromo-3-[2-(furan-2-yl)ethyl]-1-
hydroxy-2,3-dihydro-1H-pyrrolizine-1-carboxylate (3j): yellow oil
1
(76 mg, 80%); [α]22 −28.0 (c 1, CH3OH, 93% ee); H NMR (400
D
MHz, CDCl3) δ 7.31 (dd, J = 1.6, 0.8 Hz, 1H), 6.29 (dd, J = 3.2, 2.0
Hz, 1H), 6.09 (s, 1H), 6.01 (dd, J = 3.2, 0.8 Hz, 1H), 5.02 (ddd, J =
8.8, 6.0, 2.8 Hz, 1H), 4.05 (d, J = 6.0 Hz, 1H), 3.92 (s, 3H), 3.61 (s,
1H), 2.70−2.61 (m, 1H), 2.58−2.44 (m, 2H), 2.42−2.34 (m, 1H),
2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.4, 172.0, 153.7,
141.2, 136.0, 110.3, 105.6, 104.5, 102.3, 98.2, 76.8, 65.3, 59.5, 54.1,
30.4, 30.1, 22.8; FTIR (neat) 3467, 2925, 1740, 1720, 1437, 1363,
1305, 1234, 1154, 1092, 1008, 734 cm−1; HRMS (FAB) calcd for [M +
1]+ C17H18O5NBr2 473.9552, found 473.9554; HPLC (Chiralpak AD-
H, hexane/IPA = 90/10, 0.9 mL/min, λ = 254 nm) 12.5 min (minor
isomer), 15.3 min (major isomer).
(1R,2R,3R)-Methyl 2-acetyl-5,6-dibromo-3-[2-(tert-
butyldimethylsilyloxy)ethyl]-1-hydroxy-2,3-dihydro-1H-pyrrolizine-
1-carboxylate (3k): yellow oil (88 mg, 82%); [α]22 −31.1 (c 1,
D
CH3OH, 93% ee); 1H NMR (400 MHz, CDCl3) δ 6.08 (s, 1H), 5.02
E
dx.doi.org/10.1021/jo4001614 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
extracted with ethyl acetate. The organic layer was washed with 1.0 N
HCl and brine and then dried over MgSO4. Filtration, concentration,
and purification by flash chromatography (SiO2: 30% EtOAc in
hexanes) provided 4a as the major diastereomer in 68% yield (54 mg)
and 5a as the minor diastereomer in 8% yield (6 mg), respectively
(total yield: 76%).
AUTHOR INFORMATION
Corresponding Author
*E-mail: cwcho@knu.ac.kr.
Notes
■
The authors declare no competing financial interest.
Asymmetric Reduction of the Ketone 3a Using BH3·SMe2
and (S)-Me-CBS. To (S)-(−)-2-methyl-CBS-oxazaborolidine (1.0 M
solution in toluene, 0.24 mL, 0.24 mmol) was added BH3·SMe2 (2.0 M
solution in THF, 0.12 mL, 0.24 mmol) at room temperature. After 15
min, a solution of the ketone 3a (79 mg, 0.2 mmol) in THF (2 mL, 0.1
M) was added dropwise, and the mixture was stirred at room
temperature for 3 h. The mixture was quenched with MeOH and then
stirred for 30 min. After the addition of H2O, the mixture was
extracted with ethyl acetate. The organic layer was washed with 1.0 N
HCl and brine and then dried over MgSO4. Filtration, concentration,
and purification by flash chromatography (SiO2: 30% EtOAc in
hexanes) provided 5a as the major diastereomer in 59% yield (47 mg)
and 4a as the minor diastereomer in 20% yield (16 mg), respectively
(total yield: 79%).
(1R,2S,3R)-Methyl 5,6-dibromo-1-hydroxy-2-[(S)-1-hydroxyethyl]-
3-methyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate (4a): ivory oil;
[α]23D −52.1 (c 1, CH3OH); 1H NMR (400 MHz, CDCl3) δ 6.03 (s,
1H), 4.51−4.45 (m, 1H), 4.13−4.05 (m, 1H), 4.02 (s, 1H), 3.85 (s,
3H), 3.09 (d, J = 7.6 Hz, 1H), 2.90 (dd, J = 6.8, 6.8 Hz, 1H), 1.70 (d, J
= 6.0 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 173.4, 137.1, 103.7, 101.7, 97.5, 77.8, 66.0, 62.8, 57.5, 53.7, 21.5,
20.0; FTIR (neat) 3446, 2975, 1733, 1437, 1381, 1256, 1163, 1128,
1031, 969, 783 cm−1; HRMS (EI) calcd for [M]+ C12H15Br2NO4
394.9368, found 394.9364.
ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2011-0024892).
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(1R,2S,3R)-Methyl 5,6-dibromo-1-hydroxy-2-[(R)-1-hydroxyeth-
yl]-3-methyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate (5a): ivory
1
oil; [α]25 −62.0 (c 1, CH3OH); H NMR (400 MHz, CDCl3) δ
D
(5) Bae, J.-Y.; Lee, H.-J.; Youn, S.-H.; Kwon, S.-H.; Cho, C.-W. Org.
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6.03 (s, 1H), 4.79−4.73 (m, 1H), 4.33−4.28 (m, 1H), 4.17 (s, 1H),
3.84 (s, 3H), 2.83 (d, J = 2.8 Hz, 1H), 2.79 (dd, J = 4.8, 2.4 Hz, 1H),
1.68 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 173.5, 136.5, 103.7, 101.7, 97.3, 77.9, 65.1, 62.4, 55.4,
53.9, 22.1, 20.6; FTIR (neat) 3467, 2976, 1739, 1437, 1380, 1337,
1256, 1163, 1127, 1030, 774 cm−1; HRMS (EI) calcd for [M]+
C12H15Br2NO4 394.9368, found 394.9370.
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nandez, M.; Vicario, J. L.; Reyes, E.; Carrillo, L.; Badía, D. Chem.
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(1R,2S,3R)-Methyl 5,6-dibromo-1-hydroxy-2-[(R)-1-
(isonicotinoyloxy)ethyl]-3-methyl-2,3-dihydro-1H-pyrrolizine-1-car-
boxylate (6a). To a cooled (0 °C) solution of 5a (116 mg, 0.3 mmol)
in CH2Cl2 (1 mL, 0.3 M) were added triethylamine (0.19 mL, 1.05
mmol) and isonicotinoyl chloride hydrochloride (330 mg, 0.75 mmol),
and then the mixture was stirred at 0 °C for 1 h. The mixture was then
stirred at room temperature for 12 h. The mixture was quenched by
saturated NaHCO3 and extracted with CH2Cl2. The organic layer was
washed with saturated NH4Cl and brine and then dried over MgSO4.
Filtration, concentration, and purification by flash chromatography
(SiO2: 60% Et2O in hexanes) provided the ester 6a in 55% yield (83
mg, 0.165 mmol) as yellow solid: mp 142−143 °C; [α]23D −46.3 (c 1,
́
́
1
CHCl3); H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 6.0 Hz, 2H),
7.45−7.43 (m, 2H), 6.03 (s, 1H), 5.69−5.63 (m, 1H), 4.71−4.65 (m,
1H), 4.17 (s, 1H), 3.85 (s, 3H), 3.06 (dd, J = 4.8, 4.4 Hz, 1H), 1.74 (d,
J = 6.4 Hz, 3H), 1.46 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 173.2, 163.9, 150.4, 137.3, 136.9, 122.7, 104.1, 101.6, 97.0,
77.2, 70.4, 60.7, 57.7, 53.9, 21.3, 18.6; FTIR (neat) 3446, 2925, 1733,
1437, 1410, 1380, 1285, 1243, 1162, 1121, 756 cm−1; HRMS (EI)
calcd for [M]+ C18H18Br2N2O5 499.9582, found 499.9585.
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̈
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra of all new
compounds. Chiral HPLC analysis data of 3a−o. X-ray
crystallographic data for 6a (CIF) (CCDC 909688). This
material is available free of charge via the Internet at http://
pubs.acs.org.
F
dx.doi.org/10.1021/jo4001614 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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