Asymmetric Synthesis of Chiral Pyrrolizine-Based Triheterocycles by Organocatalytic Cascade Aza-Michael-Aldol Reactions

Article abstract of DOI:10.1002/ejoc.201301260

New, chiral pyrrolizine-based triheterocycles were obtained by the organocatalytic asymmetric cascade aza-Michael-aldol reaction of α-branched α,β-unsaturated aldehydes with 2-(trifluoroacetyl)pyrroles. High enantioselectivities (90-95 % ee) and excellent

Full text of DOI:10.1002/ejoc.201301260

FULL PAPER
DOI: 10.1002/ejoc.201301260
Asymmetric Synthesis of Chiral Pyrrolizine-Based Triheterocycles by
Organocatalytic Cascade Aza-Michael–Aldol Reactions
Hyo-Jun Lee[a] and Chang-Woo Cho*[a]
Keywords: Organocatalysis / Asymmetric catalysis / Domino reactions / Heterocycles / Polycycles
New, chiral pyrrolizine-based triheterocycles were obtained
by the organocatalytic asymmetric cascade aza-Michael–
aldol reaction of α-branched α,β-unsaturated aldehydes with
2-(trifluoroacetyl)pyrroles. High enantioselectivities (90–
95%ee) and excellent diastereoselectivities (dr up to Ͼ20:1)
were achieved by employing this synthetic strategy. The
highly functionalized, trifluoromethyl-substituted cascade
products have three consecutive stereogenic centers that in-
clude two chiral quaternary centers. The chemoselective
stepwise Suzuki cross-coupling reaction of the cascade prod-
ucts with two different arylboronic acids provided chiral pyr-
rolizine-based triheterocycles that contain two distinct aryl
substituents in good yields.
Introduction
Methods for the construction of polyheterocyclic skel-
etons have been the focus of intensive research efforts be-
cause of the structural features and interesting biological
activities of these molecules.[1] In particular, the develop-
ment of efficient routes for the asymmetric synthesis of
stereogenic complex compounds, which include chiral
polyheterocycles, from simple precursors in a single step has
become a challenging topic in modern organic chemistry.[2]
In this regard, we recently reported the organocatalytic
asymmetric cascade aza-Michael–aldol reactions of α,β-un-
saturated carbonyl compounds with pyrroles as the N-cen-
tered heteroaromatic nucleophiles to provide a variety of
chiral pyrrolizines (see Figure 1).[3] Because of the impor-
tance of pyrrolizines to the development of antitumor,[4] an-
tileukemic,[5] and anti-inflammatory agents,[6] we plan to
synthesize unprecedented pyrrolizine-based polyhetero-
cycles as potential scaffolds for pharmaceutical prepara-
tions. Herein, we report the organocatalytic asymmetric
cascade aza-Michael–aldol reaction[7,8] of the α-branched
α,β-unsaturated aldehydes such as cyclopent-1-enecarb-
aldehyde and 4,5-dihydrofuran-2-carbaldehyde with 2-(tri-
fluoroacetyl)pyrroles as the N-centered heteroaromatic nu-
cleophiles (see Figure 1). Our synthetic strategy provides
unique and highly functionalized chiral pyrrolizine-based
triheterocycles with three consecutive stereogenic centers
that include two chiral quaternary centers.
The incorporation of a trifluoromethyl group into a mo-
lecule is known to improve the biological and pharmacolog-
[a] Department of Chemistry, Kyungpook National University,
Daegu 702-701, Republic of Korea
E-mail: cwcho@knu.ac.kr
http://synthesis.knu.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301260.
Figure 1. Organocatalytic asymmetric cascade aza-Michael–aldol
reactions of pyrroles with enals and enones.
Eur. J. Org. Chem. 2014, 387–394
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
387

H.-J. Lee, C.-W. Cho
FULL PAPER
ical properties of bioactive compounds.[9] For the success of Table 1. Optimization of organocatalytic asymmetric cascade aza-
Michael–aldol reaction of 1-(4,5-dibromo-1H-pyrrol-2-yl)-2,2,2-tri-
this cascade reaction, the pKa value of the NH of the pyr-
role should be sufficiently low for deprotonation by a base
fluoroethanone (1a) with cyclopent-1-enecarbaldehyde (2).[a]
to generate the requisite anionic pyrrole nucleophile,[3,10]
which will undergo the initial aza-Michael reaction[11] with
the α-branched α,β-unsaturated aldehyde. In addition, the
carbonyl group of the trifluoroacetyl moiety of the pyrrole
should serve as the electrophile for the subsequent aldol
reaction. Concomitantly, the chemoselective stepwise Su-
zuki cross-coupling reactions of the cascade products with
two different arylboronic acids provide the chiral pyrroliz-
ine-based triheterocycles that contain two distinct aryl sub-
stituents.
Results and Discussion
To explore the feasibility of the organocatalytic asym-
metric cascade reaction of α-branched α,β-unsaturated al-
dehydes with 2-(trifluoroacetyl)pyrroles, the cascade reac-
tion of 1-(4,5-dibromo-1H-pyrrol-2-yl)-2,2,2-trifluoroeth-
anone (1a) with cyclopent-1-enecarbaldehyde (2) with
PhCO2H (40 mol-%) as the acid additive in toluene at 0 °C
were performed in the presence of chiral organocatalysts
I and II (TMS = trimethylsilyl), respectively (see Table 1,
Entries 1 and 2). Although catalyst I gave no corresponding
product, catalyst II provided the desired cascade product 3a
as a single diastereomer in 57% yield and with 33%ee. All
of the products from these cascade reactions were obtained
after the in situ reduction of the cascade aldehyde product
with NaBH4 in EtOH to give the alcohol. Upon lowering
Entry Catalyst T [°C] Time [h] % Yield[b] % ee[c]
dr[d]
1
2
3
4
I
II
II
II
II
II
II
III
0
0
48
48
48
48
72
96
96
96
n.r.[e]
57
43
26
38
50
74
38
–
–
33
80
95
95
94
93
94
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
–20
–40
–40
–40
–40
–40
5
6
7[f]
8
[a] Reagents and conditions: 2 (0.4 mmol) was added to a mixture
of 1a (0.2 mmol), catalyst (0.04 mmol), and PhCO2H (0.08 mmol)
in toluene (2 mL) in one portion. The reaction mixture was stirred
the reaction temperature to –40 °C, cascade product 3a at 0, –20, or –40 °C for 48, 72, or 96 h, at which point the aldehyde
was directly reduced to an alcohol with NaBH4 (0.22 mmol) in
EtOH (2 mL). [b] Isolated yield for two steps. [c] Determined by
showed a considerable increase of the ee value to 95%, but
the yield decreased to 26% (see Table 1, Entries 3 and 4).
Varying the reaction time revealed that 96 h was ideal for
these cascade reactions, and 3a was obtained in 50% yield
with 94%ee (see Table 1, Entries 5 and 6). Finally, when
the loading of 2 was increased to 3 equiv. under otherwise
chiral HPLC analysis (Chiralpak AD-H). [d] Diastereomeric ratio
(dr) determined by 1H NMR spectroscopy. [e] n.r.: no reaction.
[f] 3 equiv. of 2 was used.
identical conditions, the highly functionalized chiral pyrrol- can be employed in carbon–carbon coupling reactions to
izine-based triheterocycle 3a was obtained as a single dia- provide a wide variety of chiral pyrrolizine-based trihetero-
stereomer in 74% yield and with 93%ee (see Table 1, En- cycles.[13] In particular, the dibromopyrrole moiety of 3a is
try 7).[12] When catalyst II was replaced by III, cascade found in an important class of natural products that exhibit
product 3a was obtained with an ee value of 94%, but the a variety of appealing biological activities.[14]
yield decreased to 38% (see Table 1, Entries 6 vs. 8).
To expand the scope of the α-branched α,β-unsaturated
Subsequently, a range of 2-(trifluoroacetyl)pyrroles 1 aldehydes employed in the organocatalytic asymmetric cas-
were explored as the nucleophiles in the enantio- and dia- cade reactions, the reactions between 4,5-dihydrofuran-2-
stereoselective organocatalytic cascade aza-Michael–aldol carbaldehyde (4) and a series of 1-(4,5-dihalo-1H-pyrrol-2-
reaction with cyclopent-1-enecarbaldehyde (2) under the yl)-2,2,2-trifluoroethanones 1 were performed at –10 °C un-
optimized conditions. A series of 2-(trifluoroacetyl)pyrroles der otherwise identical conditions (see Scheme 2). In all
that contain various substituents such as a 4,5-dihalo or a cases, the desired cascade products 5a–5d were obtained as
4-nitro group were examined (see Scheme 1). In all cases, single diastereomers and with excellent enantioselectivities,
the chiral pyrrolizine-based triheterocycles 3a–3i were ob- but the yields were somewhat lower in comparison to those
tained in good yields and with excellent enantioselectivities. obtained from the reaction with 2. This decrease of reac-
In addition, with regard to the diastereoselectivity of the tivity is a result of the electronic effects of the oxygen atom
reaction to give chiral cascade products 3a–3i, all products on the 4,5-dihydrofuranyl ring of 4.
with the exception of 3i, which was produced with a dr of
In an effort to expand the molecular diversity of the chi-
17.5:1, were obtained as single diastereomers. The halo ral pyrrolizine-based triheterocycles, chemoselective step-
groups on the pyrrole moiety of cascade products 3a–3h wise Suzuki cross-coupling reactions of the cascade prod-
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 387–394

Asymmetric Synthesis of Chiral Pyrrolizine-Based Triheterocycles
Scheme 2. Organocatalytic asymmetric cascade aza-Michael–aldol
reaction of 4,5-dihydrofuran-2-carbaldehyde (4) with various 2-(tri-
fluoroacetyl)pyrroles 1 (see Exp. Section for detailed procedures).
Reported yields are of isolated products obtained over two steps.
Enantiomeric excess values were determined by chiral HPLC analy-
sis (Chiralcel OD-H, Chiralcel OJ-H, or Chiralpak AD-H). Dia-
1
stereomeric ratios were determined by H NMR spectroscopy.
Scheme 1. Organocatalytic asymmetric cascade aza-Michael–aldol
reaction of cyclopent-1-enecarbaldehyde (2) with various 2-(tri-
fluoroacetyl)pyrroles 1 (see Exp. Section for detailed procedure).
Reported yields are of isolated products obtained over two steps.
Enantiomeric excess values were determined by chiral HPLC analy-
sis (Chiralpak AD-H). Diastereomeric ratios were determined by
1H NMR spectroscopy. [a] Reaction at –30 °C.
ucts were carried out with two different arylboronic acids
(see Scheme 3). On the basis of our previous reaction condi-
tions for chemoselective Suzuki cross-coupling reactions of
dihalopyrrolizines,[13a] the chemoselective Suzuki cross-cou-
pling reactions of 3b and 5b with phenylboronic acid
(1.5 equiv.) were performed in the presence of Pd(PPh3)4
(10 mol-%) and K2CO3 (2 equiv.) in a solution of 1,4-diox-
ane/H2O at 80 °C for 4 h. These reactions afforded the
6-bromo-5-phenyl-substituted
pyrrolizine-based
tri-
heterocycles 6a and 6b, respectively, as the desired coupling
products in good yields without the 5-iodo-6-phenyl-substi-
tuted pyrrolizine-based triheterocycle byproducts. Next, the
sequential second Suzuki cross-coupling reactions of 6a and
6b were carried out under otherwise identical conditions
with 4-methoxyphenylboronic acid at 100 °C for 6 h to ob-
tain the desired unsymmetrical 5,6-diaryl-substituted chiral
pyrrolizine-based triheterocycles 7a and 7b, respectively, in
good yields.
Scheme 3. Synthesis of chiral pyrrolizine-based triheterocycles that
contain two different aryl substituents through the chemoselective
stepwise Suzuki cross-coupling reactions of 3b and 5b.
Eur. J. Org. Chem. 2014, 387–394
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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389

H.-J. Lee, C.-W. Cho
FULL PAPER
The absolute stereochemical assignments of all the cas-
cade products were made on the basis of the single-crystal
X-ray diffraction analysis of pyrrolizine-based triheterocy-
cle 3b (see Figure 2).[15] From the absolute stereochemistry
of the cascade products, the proposed catalytic cycle, which
includes the course of the asymmetric induction of the cas-
cade reaction, is described in Scheme 4. The aza-Michael
reaction of the iminium intermediate,[16] which is generated
from the chiral diarylprolinol trimethylsilyl ether catalyst[17]
and the α-branched α,β-unsaturated aldehyde in the pres-
ence of PhCO2H, with the anionic pyrrole nucleophile af-
fords the aza-Michael intermediate. The subsequent intra-
molecular aldol reaction of the aza-Michael intermediate
followed by hydrolysis provides the desired cascade product.
Conclusions
Unique and chiral pyrrolizine-based triheterocycles were
obtained by the enantio- and diastereoselective cascade aza-
Michael–aldol reactions of the α-branched α,β-unsaturated
aldehydes such as cyclopent-1-enecarbaldehyde and 4,5-di-
hydrofuran-2-carbaldehyde with 2-(trifluoroacetyl)pyrroles
using chiral diarylprolinol trimethylsilyl ether II as the or-
ganocatalyst and benzoic acid as the acid additive. High
enantioselectivities (90–95%ee) and excellent diastereo-
selectivities (dr up to Ͼ20:1) were achieved by employing
this synthetic strategy. The highly functionalized and tri-
fluoromethyl-substituted cascade products have three con-
secutive stereogenic centers that include two chiral quater-
nary centers. In addition, the chemoselective stepwise Su-
zuki cross-coupling reactions of the cascade products with
two different arylboronic acids afforded chiral pyrrolizine-
based triheterocycles that contain two distinct aryl substitu-
ents in good yields. This strategy provides an efficient route
for the stereoselective synthesis of a variety of chiral pyrrol-
izine-based triheterocycles, which are potential scaffolds for
pharmaceutical agents. The application of these trihetero-
cycles to the syntheses of biologically potent compounds
will be a topic of further studies.
Experimental Section
General Methods: The NMR spectroscopic data were recorded with
a Bruker 400 MHz spectrometer using tetramethylsilane as the in-
ternal reference. Mass spectroscopic data were obtained from the
Korea Basic Science Institute (Daegu) with a JEOL JMS 700 high
resolution mass spectrometer. Enantiomeric excess values were de-
termined by HPLC analysis with a chiral stationary phase column
(Chiralcel OD-H, Chiralcel OJ-H, or Chiralpak AD-H). Pyrroles
1,[13c,18] cyclopent-1-enecarbaldehyde (2),[19] and 4,5-dihydrofuran-
2-carbaldehyde (4)[20] were prepared according to reported pro-
cedures.
Figure 2. The molecular structure of 3b as determined by single-
crystal X-ray diffraction analysis.
General Procedure for the Organocatalytic Asymmetric Cascade
Aza-Michael–Aldol Reactions of α-Branched α,β-Unsaturated Alde-
hydes with 2-(Trifluoroacetyl)pyrroles: α-Branched α,β-unsaturated
aldehyde 2 (0.6 mmol) was added in one portion to a mixture of 1
(0.2 mmol), catalyst II (0.04 mmol), and PhCO2H (0.08 mmol) in
toluene (2 mL). The reaction mixture was stirred at –30 or –40 °C
for 96 h. Then, the aldehyde was directly reduced to the alcohol by
the addition of NaBH4 (0.22 mmol) in EtOH (2 mL). The reaction
mixture was stirred for 0.5 h and then it was warmed to room temp.
and quenched by the addition of saturated NaHCO3. The resulting
mixture was extracted with ethyl acetate. The organic layer was
washed with brine and then dried with MgSO4. Filtration of the
organic layer followed by evaporation of the solvents gave the crude
residue, which was purified by silica gel column chromatography
to provide the desired cascade product 3. This general procedure
was applied to α-branched α,β-unsaturated aldehyde 4 at –10 °C
under otherwise identical conditions to provide the desired cascade
product 5.
(3aR,8R,8aS)-5,6-Dibromo-8a-(hydroxymethyl)-8-(trifluoromethyl)-
1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3a): White so-
lid (62 mg, 74%); m.p. 77–79 °C. [α]1D9 = –51.0 (c = 1, CH3OH);
Scheme 4. Proposed catalytic cycle of the organocatalytic asymmet-
ric cascade aza-Michael–aldol reaction.
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Asymmetric Synthesis of Chiral Pyrrolizine-Based Triheterocycles
1
1
93%ee. H NMR (400 MHz, CDCl3): δ = 6.21 (s, 1 H), 4.86 (dd,
CH3OH); 94%ee. H NMR (400 MHz, CDCl3): δ = 6.21 (s, 1 H),
J = 6.8, 3.6 Hz, 1 H), 4.05 (dd, J = 12.0, 3.6 Hz, 1 H), 3.60 (dd, J
= 12.0, 8.8 Hz, 1 H), 3.53 (s, 1 H), 2.93 (dd, J = 8.8, 4.4 Hz, 1 H),
2.30–2.21 (m, 1 H), 2.20–2.11 (m, 1 H), 2.09–2.01 (m, 1 H), 1.81–
4.78 (dd, J = 6.8, 4.0 Hz, 1 H), 4.06 (dd, J = 12.0, 4.0 Hz, 1 H),
3.63 (dd, J = 12.0, 8.4 Hz, 1 H), 3.33 (s, 1 H), 2.80 (dd, J = 8.4,
4.0 Hz, 1 H), 2.35–2.27 (m, 1 H), 2.14–2.03 (m, 2 H), 1.81–1.73 (m,
1.74 (m, 2 H), 1.62–1.54 (m, 1 H) ppm. 13C NMR (100 MHz, 2 H), 1.63–1.58 (m, 1 H) ppm. 13C NMR (100 MHz, CD3OD): δ
1
1
2
CDCl3): δ = 133.8, 124.5 (q, JC,F = 282.0 Hz), 105.4, 101.6, 98.9,
= 138.7, 126.5 (q, JC,F = 282.0 Hz), 123.2, 104.5, 81.4 (q, JC,F =
2
3
3
80.5 (q, JC,F = 30.0 Hz), 65.9, 65.4, 64.5, 31.2, 30.3 (q, JC,F
=
30.0 Hz), 69.7, 66.1, 65.1, 64.8, 33.6, 31.3 (q, JC,F = 3.0 Hz),
3.0 Hz), 25.3 ppm. FTIR (neat): ν = 3559, 3257, 2961, 1703, 1667,
26.2 ppm. FTIR (neat): ν = 3547, 3246, 2961, 2882, 2620, 2418,
˜
˜
1406, 1280, 1160, 1115, 1072, 966, 796 cm–1. HRMS: calcd. for
1376, 1286, 1173, 1148, 1031, 963, 793 cm–1. HRMS: calcd. for
C
12H12O2NBr2F3 [M]+ 416.9187; found 416.9189. HPLC (Chi-
C
12H12O2NClF3I [M]+ 420.9553; found 420.9554. HPLC (Chi-
ralpak AD-H; hexane/isopropyl alcohol (IPA), 93:7; 0.9 mL/min; λ
= 220 nm): tR = 11.0 (minor isomer) and 14.5 min (major isomer).
ralpak AD-H; hexane/IPA, 95:5; 0.9 mL/min; λ = 220 nm): tR =
16.7 (minor isomer) and 22.0 min (major isomer).
(3aR,8R,8aS)-6-Bromo-8a-(hydroxymethyl)-5-iodo-8-(trifluoro- (3aR,8R,8aS)-5-Bromo-8a-(hydroxymethyl)-6-iodo-8-(trifluoro-
methyl)-1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3b):
methyl)-1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3f):
White solid (71 mg, 76%); m.p. 143–145 °C. [α]2D2 = –52.0 (c = 1,
White solid (62 mg, 66%); m.p. 87–89 °C. [α]2D2 = –61.0 (c = 1,
1
1
CH3OH); 95%ee. H NMR (400 MHz, CDCl3): δ = 6.27 (s, 1 H),
CH3OH); 91%ee. H NMR (400 MHz, CDCl3): δ = 6.28 (s, 1 H),
4.79 (dd, J = 6.8, 4.0 Hz, 1 H), 4.05 (dd, J = 12.0, 4.0 Hz, 1 H),
3.62 (dd, J = 12.0, 8.8 Hz, 1 H), 3.41 (s, 1 H), 2.86 (dd, J = 8.8,
4.88 (dd, J = 6.8, 4.0 Hz, 1 H), 4.06 (dd, J = 12.4, 4.0 Hz, 1 H),
3.62 (dd, J = 12.0, 8.8 Hz, 1 H), 3.30 (s, 1 H), 2.82 (dd, J = 8.8,
4.4 Hz, 1 H), 2.37–2.28 (m, 1 H), 2.13–2.02 (m, 2 H), 1.81–1.73 (m, 4.4 Hz, 1 H), 2.29–2.22 (m, 1 H), 2.17–2.10 (m, 1 H), 2.09–2.02
2 H), 1.63–1.57 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = (m, 1 H), 1.81–1.74 (m, 2 H), 1.62–1.58 (m, 1 H) ppm. 13C NMR
1
2
1
137.1, 124.5 (q, JC,F = 282.0 Hz), 109.1, 106.0, 80.5 (q, JC,F
=
(100 MHz, CDCl3): δ = 135.6, 124.5 (q, JC,F = 282.0 Hz), 110.1,
3
2
31.0 Hz), 67.9, 66.9, 65.3, 64.7, 32.1, 30.5 (q, JC,F = 3.0 Hz), 103.8, 80.2 (q, JC,F = 30.0 Hz), 69.3, 65.9, 65.8, 64.6, 31.2, 30.4
3
25.4 ppm. FTIR (neat): ν = 3556, 3259, 2960, 1389, 1290, 1164,
(q, JC,F = 3.0 Hz), 25.3 ppm. FTIR (neat): ν = 3436, 3120, 2977,
˜
˜
1 1 2 0 , 1 0 3 1 , 9 5 8 , 8 9 3 , 7 9 5 c m – 1 . H R M S : c a l c d . f o r 1430, 1391, 1278, 1162, 1109, 1060, 949, 794 cm–1. HRMS: calcd.
C12H12O2NBrF3I [M]+ 464.9048; found 464.9051. HPLC (Chi- for C12H12O2NBrF3I [M]+ 464.9048; found 464.9049. HPLC (Chi-
ralpak AD-H; hexane/IPA, 90:10; 0.9 mL/min; λ = 254 nm): tR
=
ralpak AD-H; hexane/IPA, 95:5; 0.95 mL/min; λ = 220 nm): tR =
18.7 (minor isomer) and 23.2 min (major isomer).
18.2 (minor isomer) and 21.0 min (major isomer).
(3aR,8R,8aS)-6-Bromo-5-chloro-8a-(hydroxymethyl)-8-(trifluoro- (3aR,8R,8aS)-5-Chloro-8a-(hydroxymethyl)-6-iodo-8-(trifluoro-
methyl)-1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3c):
methyl)-1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3g):
White solid (45 mg, 60%); m.p. 85–87 °C. [α]2D2 = –36.9 (c = 1,
White solid (49 mg, 58%); m.p. 71–73 °C. [α]2D2 = –53.0 (c = 1,
1
1
CH3OH); 90%ee. H NMR (400 MHz, CDCl3): δ = 6.18 (s, 1 H),
CH3OH); 90%ee. H NMR (400 MHz, CDCl3): δ = 6.23 (s, 1 H),
4.90 (dd, J = 6.4, 4.0 Hz, 1 H), 4.07 (dd, J = 12.4, 4.0 Hz, 1 H),
3.62 (dd, J = 12.4, 8.8 Hz, 1 H), 3.37 (s, 1 H), 2.86 (dd, J = 8.8,
4.91 (dd, J = 6.8, 4.0 Hz, 1 H), 4.05 (dd, J = 12.0, 3.6 Hz, 1 H),
3.62 (s, 1 H), 3.59 (dd, J = 12.4, 8.8 Hz, 1 H), 2.98 (dd, J = 8.8,
4.0 Hz, 1 H), 2.27–2.12 (m, 2 H), 2.09–2.01 (m, 1 H), 1.82–1.75 (m, 4.0 Hz, 1 H), 2.26–2.11 (m, 2 H), 2.08–2.01 (m, 1 H), 1.81–1.74 (m,
2 H), 1.60–1.53 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 2 H), 1.59–1.53 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
2
1
2
131.7, 124.5 (q, 1JC,F = 282.0 Hz), 112.5, 104.6, 97.5, 80.5 (q, JC,F
133.8, 124.5 (q, JC,F = 282.0 Hz), 116.8, 109.2, 80.2 (q, JC,F =
3
3
= 30.0 Hz), 65.5, 65.2, 64.4, 30.5, 30.3 (q, JC,F = 3.0 Hz), 30.0 Hz), 65.9, 65.2, 64.5, 64.4, 30.6, 30.4 (q, JC,F = 3.0 Hz),
25.2 ppm. FTIR (neat): ν = 3233, 2971, 1701, 1667, 1414, 1289,
25.2 ppm. FTIR (neat): ν = 3474, 3233, 2970, 1441, 1407, 1279,
˜
˜
1165, 1119, 1085, 1012, 945, 782 cm–1. HRMS: calcd. for
C12H12O2NClBrF3 [M]+ 372.9692; found 372.9691. HPLC (Chi-
1168, 1111, 944, 788 cm–1. HRMS: calcd. for C12H12O2NClF3I
[M]+ 420.9553; found 420.9555. HPLC (Chiralpak AD-H; hexane/
IPA, 95:5; 0.95 mL/min; λ = 254 nm): tR = 16.2 (minor isomer) and
19.5 min (major isomer).
ralpak AD-H; hexane/IPA, 93:7; 0.9 mL/min; λ = 220 nm): tR
=
10.1 (minor isomer) and 13.8 min (major isomer).
(3aR,8R,8aS)-5-Bromo-6-chloro-8a-(hydroxymethyl)-8-(trifluoro- (3aR,8R,8aS)-8a-(Hydroxymethyl)-5,6-diiodo-8-(trifluoromethyl)-
methyl)-1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3d):
1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3h): White so-
White solid (48 mg, 64%); m.p. 90–92 °C. [α]2D2 = –41.0 (c = 1,
lid (65 mg, 63%); m.p. 159–161 °C. [α]2D2 = –62.0 (c = 1, CH3OH);
1
1
CH3OH); 93%ee. H NMR (400 MHz, CDCl3): δ = 6.16 (s, 1 H),
95%ee. H NMR (400 MHz, CDCl3): δ = 6.32 (s, 1 H), 4.79 (dd,
4.85 (dd, J = 6.8, 4.0 Hz, 1 H), 4.06 (dd, J = 12.0, 4.0 Hz, 1 H),
3.62 (dd, J = 12.0, 8.4 Hz, 1 H), 3.43 (s, 1 H), 2.86 (dd, J = 8.4,
4.0 Hz, 1 H), 2.29–2.21 (m, 1 H), 2.19–2.11 (m, 1 H), 2.09–2.02
(m, 1 H), 1.81–1.74 (m, 2 H), 1.60–1.54 (m, 1 H) ppm. 13C NMR
J = 6.8, 4.0 Hz, 1 H), 4.03 (dd, J = 12.4, 4.0 Hz, 1 H), 3.68 (s, 1
H), 3.58 (dd, J = 12.0, 8.8 Hz, 1 H), 3.02 (dd, J = 8.4, 4.0 Hz, 1
H), 2.36–2.28 (m, 1 H), 2.11–2.01 (m, 2 H), 1.84–1.71 (m, 2 H),
1.62–1.56 (m, 1 H) ppm. 13C NMR (100 MHz, CD3OD): δ = 140.9,
1
1
2
(100 MHz, CDCl3): δ = 132.8, 124.5 (q, JC,F = 282.0 Hz), 116.0,
126.5 (q, JC,F = 282.0 Hz), 112.2, 80.6 (q, JC,F = 30.0 Hz), 79.0,
2
3
103.0, 96.5, 80.8 (q, JC,F = 30.0 Hz), 65.9, 65.3, 64.6, 31.2, 30.4
74.3, 69.7, 66.6, 65.0, 33.7, 31.3 (q, JC,F = 3.0 Hz), 26.2 ppm.
3
(q, JC,F = 3.0 Hz), 25.3 ppm. FTIR (neat): ν = 3549, 3239, 2923,
FTIR (neat): ν = 3442, 3120, 2977, 1420, 1277, 1162, 1117, 1060,
˜
˜
1727, 1458, 1392, 1284, 1164, 1122, 1032, 974, 899, 796 cm–1
.
949, 795 cm–1. HRMS: calcd. for C12H12O2NF3I2 [M]+ 512.8910;
found 512.8910. HPLC (Chiralpak AD-H; hexane/IPA, 95:5;
HRMS: calcd. for C12H12O2NClBrF3 [M]+ 372.9692; found
372.9689. HPLC (Chiralpak AD-H; hexane/IPA, 93:7; 0.9 mL/min; 0.9 mL/min; λ = 220 nm): tR = 23.7 (minor isomer) and 26.2 min
λ = 254 nm): tR = 14.1 (minor isomer) and 21.6 min (major iso-
(major isomer).
mer).
(3aR,8R,8aS)-8a-(Hydroxymethyl)-6-nitro-8-(trifluoromethyl)-
(3aR,8R,8aS)-6-Chloro-8a-(hydroxymethyl)-5-iodo-8-(trifluoro- 1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3i): White solid
methyl)-1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (3e):
(47 mg, 77%); m.p. 129–131 °C. [α]2D2 = –71.0 (c = 1, CH3OH);
90%ee. 1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 1.2 Hz, 1
White solid (65 mg, 77%); m.p. 159–161 °C. [α]2D2 = –55.0 (c = 1,
Eur. J. Org. Chem. 2014, 387–394
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
391

H.-J. Lee, C.-W. Cho
H), 6.72 (s, 1 H), 5.03 (dd, J = 6.8, 2.4 Hz, 1 H), 4.18 (dd, J = 4.87 (dd, J = 6.0, 0.8 Hz, 1 H), 4.14 (ddd, J = 9.2, 8.0, 2.0 Hz, 1
FULL PAPER
12.4, 3.6 Hz, 1 H), 3.89 (s, 1 H), 3.63 (dd, J = 12.4, 8.8 Hz, 1 H),
2.88 (dd, J = 8.8, 3.6 Hz, 1 H), 2.31–2.22 (m, 1 H), 2.11–2.04 (m,
1 H), 2.01–1.92 (m, 1 H), 1.91–1.82 (m, 1 H), 1.80–1.70 (m, 1 H),
1.59–1.53 (m, 1 H) ppm. 13C NMR (100 MHz, CD3OD): δ = 141.1,
H), 4.08 (dd, J = 12.4, 7.2 Hz, 1 H), 3.89 (dd, J = 12.4, 6.8 Hz, 1
H), 3.69 (ddd, J = 13.0, 9.2, 5.2 Hz, 1 H), 3.06 (s, 1 H), 2.57–2.53
(m, 1 H), 2.37 (t, J = 7.2 Hz, 1 H), 2.32–2.22 (m, 1 H) ppm. 13C
1
NMR (100 MHz, CDCl3): δ = 136.2, 123.9 (q, JC,F = 282.0 Hz),
1
2
2
135.6, 126.5 (q, JC,F = 282.0 Hz), 117.4, 99.7, 80.7 (q, JC,F
30.0 Hz), 68.6, 66.8, 64.1, 32.2, 30.6 (q, JC,F = 3.0 Hz), 25.6 ppm.
=
123.5, 104.2, 97.0, 79.8 (q, JC,F = 30.0 Hz), 68.8, 67.9, 64.9, 63.5,
3
32.7 ppm. FTIR (neat): ν = 3446, 3247, 2958, 1733, 1401, 1284,
˜
FTIR (neat): ν = 3138, 2959, 2367, 1503, 1289, 1173, 1090, 924,
1172, 1039, 949, 868, 794 cm–1. HRMS: calcd. for C11H10O3NClF3I
[M]+ 422.9346; found 422.9348. HPLC (Chiralcel OJ-H; hexane/
EtOH, 90:10; 0.9 mL/min; λ = 220 nm): tR = 10.5 (minor isomer)
and 13.2 min (major isomer).
˜
747 cm–1. HRMS: calcd. for C12H14O4N2F3 [M + H]+ 307.0906;
found 307.0904. HPLC (Chiralpak AD-H; hexane/IPA, 90:10;
0.9 mL/min; λ = 254 nm): tR = 11.4 (minor isomer) and 17.1 min
(major isomer).
General Procedure for the Chemoselective Suzuki Cross-Coupling
Reaction: Pd(PPh3)4 (0.02 mmol) was added to a solution of 3b
(0.2 mmol) in 1,4-dioxane (2 mL) at room temp. under argon. The
mixture was stirred at room temp. for 20 min, and then K2CO3
(0.4 mmol) in H2O (1.3 mL) and phenylboronic acid (0.3 mmol)
were added. The mixture was stirred at 80 °C for 4 h. The mixture
was then cooled to room temp. and quenched by the addition of
saturated NaHCO3. The resulting solution was extracted with ethyl
(3aR,8S,8aR)-5,6-Dibromo-8a-(hydroxymethyl)-8-(trifluoromethyl)-
3,3a,8,8a-tetrahydro-2H-furo[2,3-b]pyrrolizin-8-ol (5a): White solid
(46 mg, 55%); m.p. 133–135 °C. [α]2D2 = –78.9 (c = 1, CH3OH);
1
90%ee. H NMR (400 MHz, CDCl3): δ = 6.29 (s, 1 H), 4.94 (d, J
= 5.6 Hz, 1 H), 4.16 (ddd, J = 9.2, 7.6, 1.2 Hz, 1 H), 4.08 (dd, J =
12.4, 7.6 Hz, 1 H), 3.88 (dd, J = 12.4, 6.4 Hz, 1 H), 3.69 (ddd, J =
12.8, 9.2, 5.2 Hz, 1 H), 2.95 (s, 1 H), 2.57–2.52 (m, 1 H), 2.33 (dd, J
= 7.6, 6.8 Hz, 1 H), 2.30–2.23 (m, 1 H) ppm. 13C NMR (100 MHz, acetate. The organic layer was washed brine and dried with MgSO4.
1
CDCl3): δ = 133.8, 123.8 (q, JC,F = 282.0 Hz), 106.1, 102.6, 98.9,
Filtration of the organic layer and evaporation of the solvents gave
the crude residue, which was purified by silica gel column
chromatography to provide the 6-bromo-5-phenyl-substituted pyr-
rolizine-based triheterocycle 6a as the desired coupling product.
2
97.4, 79.4 (q, JC,F = 30.0 Hz), 68.8, 66.9, 63.5, 32.2 ppm. FTIR
(neat): ν = 3441, 3222, 2964, 1436, 1284, 1162, 1050, 868, 796 cm–1.
˜
HRMS: calcd. for C11H10O3NBr2F3 [M]+ 418.8980; found
418.8982. HPLC (Chiralpak AD-H; hexane/IPA, 95:5; 0.95 mL/ This general procedure was applied to 5b to provide the desired
min; λ = 220 nm): tR = 22.1 (minor isomer) and 24.1 min (major coupling product 6b.
isomer).
(3aR,8R,8aS)-6-Bromo-8a-(hydroxymethyl)-5-phenyl-8-(trifluoro-
(3aR,8S,8aR)-6-Bromo-8a-(hydroxymethyl)-5-iodo-8-(trifluoro- methyl)-1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-8-ol (6a):
methyl)-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]pyrrolizin-8-ol (5b):
White solid (62 mg, 74%); m.p. 146–148 °C. [α]2D2 = –38.8 (c = 1,
CH3OH). 1H NMR (400 MHz, CDCl3): δ = 7.53–7.50 (m, 2 H),
7.46–7.42 (m, 2 H), 7.38–7.34 (m, 1 H), 6.26 (s, 1 H), 5.25 (dd, J
White solid (33 mg, 35%); m.p. 148–150 °C. [α]2D4 = –74.1 (c = 1,
1
CH3OH); 91%ee. H NMR (400 MHz, CDCl3): δ = 6.34 (s, 1 H),
4.87 (dd, J = 6.0, 0.8 Hz, 1 H), 4.14 (ddd, J = 9.6, 8.0, 2.0 Hz, 1 = 6.8, 3.6 Hz, 1 H), 4.12 (dd, J = 12.4, 3.6 Hz, 1 H), 3.56 (dd, J =
H), 4.08 (dd, J = 12.4, 7.0 Hz, 1 H), 3.89 (dd, J = 12.4, 6.8 Hz, 1 12.4, 9.6 Hz, 1 H), 3.46 (s, 1 H), 3.20 (dd, J = 9.6, 4.0 Hz, 1 H),
H), 3.69 (ddd, J = 12.6, 9.2, 5.2 Hz, 1 H), 2.99 (s, 1 H), 2.58–2.53 1.99–1.92 (m, 1 H), 1.81–1.73 (m, 1 H), 1.66–1.54 (m, 2 H), 1.53–
(m, 1 H), 2.34 (t, J = 7.2 Hz, 1 H), 2.32–2.22 (m, 1 H) ppm. 13C
1.47 (m, 1 H), 1.44–1.36 (m, 1 H) ppm. 13C NMR (100 MHz,
1
NMR (100 MHz, CDCl3): δ = 137.1, 123.9 (q, JC,F = 282.0 Hz),
CDCl3): δ = 132.4, 130.0, 128.8, 128.4, 127.8, 127.4, 124.8 (q, 1JC,F
2
110.0, 106.8, 97.2, 79.6 (q, JC,F = 30.0 Hz), 68.8, 68.2, 68.0, 63.5,
= 282.0 Hz), 105.0, 98.0, 80.1 (q, 2JC,F = 30.0 Hz), 65.4, 64.9, 64.3,
3
32.8 ppm. FTIR (neat): ν = 3340, 2958, 1424, 1285, 1158, 1063,
31.0, 30.3 (q, JC,F = 3.0 Hz), 25.0 ppm. FTIR (neat): ν = 3453,
˜
˜
944, 790 cm–1. HRMS: calcd. for C11H10O3NBrF3I [M]+ 466.8841;
found 466.8844. HPLC (Chiralcel OD-H; hexane/IPA, 90:10;
0.95 mL/min; λ = 220 nm): tR = 9.3 (minor isomer) and 10.8 min
(major isomer).
3131, 2971, 1419, 1290, 1174, 1152, 1054, 1001, 945, 767 cm–1
.
HRMS: calcd. for C18H17O2NBrF3 [M]+ 415.0395; found 415.0396.
(3aR,8S,8aR)-6-Bromo-8a-(hydroxymethyl)-5-phenyl-8-(trifluoro-
methyl)-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]pyrrolizin-8-ol (6b):
(3aR,8S,8aR)-5-Bromo-6-chloro-8a-(hydroxymethyl)-8-(trifluoro- White solid (67 mg, 80%); m.p. 143–145 °C. [α]2D3 = –52.9 (c = 1,
methyl)-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]pyrrolizin-8-ol (5c):
CH3OH). 1H NMR (400 MHz, CDCl3): δ = 7.53–7.45 (m, 4 H),
7.41–7.37 (m, 1 H), 6.34 (s, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 4.17
White solid (40 mg, 53%); m.p. 136–138 °C. [α]2D2 = –75.0 (c = 1,
1
CH3OH); 92%ee. H NMR (400 MHz, CDCl3): δ = 6.24 (s, 1 H), (dd, J = 12.4, 7.6 Hz, 1 H), 4.00–3.96 (m, 1 H), 3.88 (dd, J = 12.4,
4.94 (d, J = 5.6 Hz, 1 H), 4.18–4.14 (m, 1 H), 4.08 (dd, J = 12.4,
7.2 Hz, 1 H), 3.88 (dd, J = 12.4, 6.8 Hz, 1 H), 3.69 (ddd, J = 12.8,
6.4 Hz, 1 H), 3.47 (ddd, J = 13.0, 8.8, 5.2 Hz, 1 H), 2.87 (s, 1 H),
2.36 (dd, J = 7.6, 6.4 Hz, 1 H), 1.98–1.88 (m, 1 H), 1.68–1.63 (m,
9.2, 5.2 Hz, 1 H), 3.00 (s, 1 H), 2.56–2.52 (m, 1 H), 2.35 (t, J = 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 132.5, 129.6, 128.8,
7.2 Hz, 1 H), 2.31–2.22 (m, 1 H) ppm. 13C NMR (100 MHz,
128.7, 128.2, 127.4, 124.1 (q, JC,F = 282.0 Hz), 105.7, 99.2, 97.3,
1
1
2
CDCl3): δ = 132.8, 123.8 (q, JC,F = 282.0 Hz), 117.0, 103.8, 97.2,
78.6 (q, JC,F = 30.0 Hz), 68.6, 66.1, 63.5, 32.2 ppm. FTIR (neat):
2
96.4, 79.6 (q, JC,F = 30.0 Hz), 68.8, 66.8, 63.5, 32.2 ppm. FTIR
ν = 3389, 2965, 1708, 1375, 1281, 1157, 1045, 946, 768 cm–1
.
˜
(neat): ν = 3450, 3246, 2951, 1407, 1285, 1173, 1045, 868, 794 cm–1.
HRMS: calcd. for C17H15O3NBrF3 [M]+ 417.0187; found 417.0185.
˜
HRMS: calcd. for C11H10O3NClBrF3 [M]+ 374.9485; found
374.9486. HPLC (Chiralpak AD-H; hexane/IPA, 95:5; 0.9 mL/min;
λ = 220 nm): tR = 18.9 (minor isomer) and 20.8 min (major iso-
mer).
General Procedure for the Sequential 2nd Suzuki Cross-Coupling Re-
action: Pd(PPh3)4 (0.02 mmol) was added to a solution of 6a
(0.2 mmol) in 1,4-dioxane (2 mL) at room temp. under argon. The
mixture was stirred at room temp. for 20 min, and then K2CO3
(3aR,8S,8aR)-6-Chloro-8a-(hydroxymethyl)-5-iodo-8-(trifluoro- (0.4 mmol) in H2O (1.3 mL) and 4-methoxyphenylboronic acid
methyl)-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]pyrrolizin-8-ol (5d):
(0.3 mmol) were added. The mixture was stirred at 100 °C for 6 h.
The mixture was then cooled to room temp. and quenched by the
addition of saturated NaHCO3. The resulting solution was ex-
White solid (37 mg, 44%); m.p. 147–149 °C. [α]2D2 = –63.1 (c = 1,
1
CH3OH); 90%ee. H NMR (400 MHz, CDCl3): δ = 6.28 (s, 1 H),
392
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 387–394

Asymmetric Synthesis of Chiral Pyrrolizine-Based Triheterocycles
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Under the optimized reaction conditions, the cascade reaction
did not proceed with cyclohex-1-enecarbaldehyde.
tracted with ethyl acetate. The organic layer was washed brine and
dried with MgSO4. Filtration of organic layer and evaporation of
the solvents gave the crude residue, which was purified by silica gel
column chromatography to provide the unsymmetrical 5,6-diaryl-
substituted pyrrolizine-based triheterocycle 7a as the desired cou-
pling product. The general procedure was applied to 6b to provide
the desired coupling product 7b.
[3]
[4]
[5]
[6]
(3aR,8R,8aS)-8a-(Hydroxymethyl)-6-(4-methoxyphenyl)-5-phenyl-
8-(trifluoromethyl)-1,2,3,3a,8,8a-hexahydrocyclopenta[b]pyrrolizin-
8-ol (7a): White solid (80 mg, 90%); m.p. 76–78 °C. [α]2D2 = +8.9 (c
1
= 1, CH3OH). H NMR (400 MHz, CDCl3): δ = 7.35–7.27 (m, 5
H), 7.14–7.10 (m, 2 H), 6.77–6.74 (m, 2 H), 6.26 (s, 1 H), 5.23 (dd,
J = 6.8, 3.6 Hz, 1 H), 4.12 (dd, J = 12.4, 4.0 Hz, 1 H), 3.76 (s, 3
H), 3.59 (dd, J = 12.4, 9.6 Hz, 1 H), 3.20 (dd, J = 9.6, 3.6 Hz, 1
H), 3.09 (s, 1 H), 2.06–1.99 (m, 1 H), 1.78–1.70 (m, 1 H), 1.64–1.58
(m, 2 H), 1.53–1.50 (m, 1 H), 1.42–1.33 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.6, 132.6, 132.0, 129.5, 129.0, 128.6,
128.5, 127.2, 126.8, 126.1, 125.0 (q, 1JC,F = 282.0 Hz), 113.6, 101.9,
2
3
80.1 (q, JC,F = 30.0 Hz), 65.9, 64.6, 63.7, 55.1, 31.5, 30.5 (q, JC,F
= 3.0 Hz), 25.2 ppm. FTIR (neat): ν = 3306, 2952, 1734, 1512,
˜
[7]
1447, 1289, 1245, 1159, 1033, 946, 833, 797 cm–1. HRMS: calcd.
for C25H24O3NF3 [M]+ 443.1708; found 443.1710.
(3aR,8S,8aR)-8a-(Hydroxymethyl)-6-(4-methoxyphenyl)-5-phenyl-8-
(trifluoromethyl)-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]pyrrolizin-8-ol
(7b): White solid (83 mg, 93%); m.p. 50–52 °C. [α]2D2 = –14.1 (c =
1, CH3OH). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.29 (m, 5 H),
7.15–7.12 (m, 2 H), 6.78–6.75 (m, 2 H), 6.35 (s, 1 H), 5.27 (d, J =
5.6 Hz, 1 H), 4.19 (dd, J = 12.4, 8.0 Hz, 1 H), 4.00–3.95 (m, 1 H),
3.89 (dd, J = 12.4, 6.4 Hz, 1 H), 3.77 (s, 3 H), 3.56 (ddd, J = 12.6,
8.8, 4.8 Hz, 1 H), 2.84 (s, 1 H), 2.44 (dd, J = 7.6, 6.8 Hz, 1 H),
1.95–1.85 (m, 1 H), 1.65–1.60 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.8, 132.7, 131.6, 129.4, 129.1, 128.8, 128.2, 127.8,
[8]
[9]
1
127.5, 125.9, 124.3 (q, JC,F = 282.0 Hz), 113.7, 102.5, 97.8, 78.4
2
(q, JC,F = 30.0 Hz), 68.6, 65.1, 63.7, 55.1, 32.5 ppm. FTIR (neat):
ν = 3306, 2930, 1610, 1511, 1447, 1291, 1245, 1158, 1028, 835,
˜
799 cm–1. HRMS: calcd. for C24H22O4NF3 [M]+ 445.1501; found
445.1504.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all new compounds
as well as chiral HPLC analysis data of 3a–3i and 5a–5d.
[10]
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Received: August 21, 2013
Published Online: October 15, 2013
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