The intramolecular tandem Michael/Mannich-type reaction of α,β-unsaturated carbonyl compounds with acyliminium ions provides access to chiral indolizidines

Article abstract of DOI:10.1016/j.tetasy.2007.06.009

The intramolecular tandem Michael/Mannich-type (Michael addition/halo-Mannich-type) reaction using TiCl₄/n-Bu₄NI system between the α,β-unsaturated carbonyl compounds possessing an Evans oxazolidinone as a chiral auxiliary and N-acyl

Full text of DOI:10.1016/j.tetasy.2007.06.009

Tetrahedron: Asymmetry 18 (2007) 1533–1539
The intramolecular tandem Michael/Mannich-type reaction
of a,b-unsaturated carbonyl compounds with acyliminium
ions provides access to chiral indolizidines
Yuji Koseki,* Koji Fujino, Ai Takeshita, Hiroto Sato and Tatsuo Nagasaka*
Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 3 April 2007; accepted 8 June 2007
Abstract—The intramolecular tandem Michael/Mannich-type (Michael addition/halo-Mannich-type) reaction using TiCl4/n-Bu4NI sys-
tem between the a,b-unsaturated carbonyl compounds possessing an Evans oxazolidinone as a chiral auxiliary and N-acyliminium ion
intermediates is described. The reaction was promoted in a mixed solvent of AcOEt–CH2Cl2 to afford indolizidine compounds with three
stereogenic centers.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The three-component tandem Michael-halo aldol type
reaction has become an active topic of research because
the resulting halo aldols can be converted into Morita–
Baylis–Hillman (MBH) adducts by treatment with tertiary
amines or other organic bases.1–4 In particular, intramole-
cular coupling reactions between a,b-unsaturated carbonyl
compounds and aldehydes via a sequential Michael addi-
tion–aldol reaction with the use of halides as nucleophiles
are useful strategies.5 Recently, the synthesis of aza Mori-
ta–Baylis–Hillman adducts using an intermolecular tandem
Michael/Mannich-type reaction of acetylenic ketones or
esters with imines in the presence of nucleophilic halides
has been reported by Li et al.6 However, few examples of
a tandem Michael/Mannich-type reaction between a,b-
unsaturated carbonyl compounds and N-acyliminium ion
intermediates have been reported,7 and such a method
has not been applied to asymmetric cyclization.8,9
Preparation of the requisite a,b-unsaturated carbonyl com-
pounds 1 possessing an Evans oxazolidinone involves a
straightforward, high-yield, four-step synthesis starting
with succinimide, as shown in Scheme 1.
N-Butenylsuccinimide 3 was prepared from the reaction of
succinimide with but-3-enol under Mitsunobu conditions,
according to a previously reported procedure.10 The partial
reduction of the imide carbonyl group of 3 followed by
ethoxylation afforded the acyliminium ion precursor 4,
which was subjected to ozone oxidation to give aldehyde
5. In this oxidation step, only the reaction in the presence
of ozonizable dye (sudan III) as an indicator11 and the
use of EtOH as a solvent afforded a satisfactory yield. A
subsequent Wittig reaction with phosphonate 6 gave the
a,b-unsaturated carbonyl compound 1 possessing the
Evans oxazolidinone.12
Herein we report the intramolecular tandem Michael/Man-
nich-type reaction of a,b-unsaturated carbonyl compounds
1 possessing an Evans oxazolidinone as the chiral auxiliary
via an N-acyliminium ion intermediate.
The resulting a,b-unsaturated carbonyl compounds 1 were
then applied to the intramolecular cyclization utilizing the
Michael/Mannich-type reaction via an N-acyliminium ion
intermediate. Reaction conditions were optimized by vary-
ing the solvents, and the results are shown in Table 1.
Compound 1a was initially applied to the TiCl4/n-Bu4NI
system (in CH2Cl2)5 as reported by Oshima et al. However,
this resulted in formation of an insoluble complex of 1a
*
Corresponding authors. Tel./fax: +81 42 676 4480 (Y.K.); tel./fax: +81 42
676 4479 (T.N.); e-mail addresses: kosekiy@ps.toyaku.ac.jp; nagasaka@
ps.toyaku.ac.jp
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.009

1534
Y. Koseki et al. / Tetrahedron: Asymmetry 18 (2007) 1533–1539
O3, sudan (III)
EtOH, -78 °C
1. NaBH4 (4.2 equiv)
MeOH, -5 °C
O
O
O
known10
N
N
NH
O
then, PPh3 (1 equiv)
-78 °C to 0 °C
2. p-TsOH (cat.)
EtOH, rt
O
OEt
87%
83%
4
3
succinimide
NaN(TMS)2
(0.90 equiv)
THF
O
O
O
N
O
O
O
P
OEt
O
-15 °C
EtO
N
O
N
N
O
O
then, THF
(1.0 eq.)
R
OEt
R
-25 °C to -15 °C
OEt
6a: R = Ph
6b: R = Bn
1a: R = Ph (87%)
1b: R = Bn (92%)
5
Scheme 1. Preparation of a,b-unsaturated carbonyl compounds 1.
Table 1. Cyclization of compounds 1 to indolizidine 2 via an N-acyliminium ion intermediate by TiCl4/n-Bu4NIa
O
O
O
I
O
O
H
H
H
O
H
O
TiCl4/n-Bu4NI
Solvent
O
N
O
N
O
N
O
N
Q
Q
Q
Q
N
N
O
O
I
I
I
OEt
R
H
H
H
H
Q =
N
O
2A
2B
1
2D
2C
R
Run
Substrate
Solvent
Product 2
2
Yieldb
Diastereomer ratioc
A
B
C
D
1
2
3
4
1a: R = Ph
1a: R = Ph
1a: R = Ph
1b: R = Bn
CH2Cl2
MeCN
AcOEt/CH2Cl2
AcOEt/CH2Cl2
2a
0
10
60
58
—
—
65
90
—
—
28
10
—
—
7
—
—
—
—
2a
2a
2b
d
d
Trace
a Reactions were carried out using TiCl4 (3 equiv) and n-Bu4NI (1.5 equiv) at ꢀ20 °C to 40 °C.
b Isolated yield of a mixture of 2A, 2B, and 2C, after purification by column chromatography on silica gel.
c Determined by 1H NMR integration of a mixture of 2A, 2B, and 2C, after passage through a short column of silica gel (CHCl3) to remove the tetrabutyl
ammonium salt.
d No formation of 2aD or 2bD was observed.
possessing an oxazolidine with a titanium species (run 1).
Attempts at using reported halo aldol conditions (e.g.,
SnCl4,7c Et2AlI8a) were also ineffective. We then investi-
gated the use of other solvents in place of CH2Cl2. When
MeCN was used, the cyclization of 1a proceeded in low
yield (run 2). Further attempts to find the most suitable
solvent for this reaction continued; the mixed solvents
of AcOEt and CH2Cl2 (4:1) afforded the cyclized product
2a (R = Ph) in 60% yield, as a 65:28:7 mixture of three
diastereomers (run 3). Application of compound 1b
possessing a benzyl oxazolidinone with TiCl4/n-Bu4NI
resulted in a high diastereomer ratio of 2bA (2b: R = Bn,
A/B/C = 90:10:trace) (run 4).
O
O
O
I
O
O
I
O
I
H
7
H
H
O
N
8a
N
R
O
O
N
N
O
O
N
N
R
O
R
H
H
H
7,8a-cis-2A
7,8a-cis-2C
( a: R = Ph, b: R = Bn )
7,8a-trans-2B
Figure 1. NOESY correlations of 2A, 2B and 2C.
Unfortunately, current attempts at both the conversion of
2 to Baylis–Hillman adducts by elimination of the iodine
and the removal of oxazolidinone from N-acyloxazolidi-
nones 2 proved unsuccessful.13
The stereostructure of 2 was determined on the basis of
NOESY correlations. The presence of a NOESY correla-
tion between the C7 and C8a protons of compounds 2A
and 2C established the cis-relationship. No such correla-
tion was observed for compound 2B, thus supporting our
stereochemical assignment (Fig. 1). The absolute configura-
tions of the major isomer, 7,8a-cis-2bA (R = Bn), and the
next major isomer, 7,8a-trans-2aB (R = Ph), were deter-
mined by single-crystal X-ray diffraction analysis (Fig. 2).
The stereochemical course of these cyclized products can be
explained by considering the required transition states for
the ring closure from iodo titanium enolate to the indolizi-
dine skeleton (Fig. 3).
The process of intramolecular cyclization of the titanium
enolate with an (S)-configured iodo-substituted carbon
atom might take place via two types of the chelated

Y. Koseki et al. / Tetrahedron: Asymmetry 18 (2007) 1533–1539
1535
minor diastereomer 2C, because large steric repulsion be-
tween the iodo-substituent and the titanium enolate is pres-
ent in the chelated chair-like form, represented by Ta0.14c
Thus, it seems that the process of 1,4-addition of the iodine
anion15 might be an important factor in determining the
transition state for enhanced diastereofacial selectivity in
such a cyclization. However, we believe that enantioselec-
tivity is probably not determined during formation of the
iodo titanium enolates, because of interconversion between
(S)- and (R)-iodo titanium enolates, which are in rapid
(dynamic) equilibrium.16 Subsequently, the cyclization pro-
cess occurred throughout the reaction sequence via the
most favored transition state, Ta, to afford the major
cyclized product 2A.17
3. Conclusion
Figure 2. Crystal structures of 2bA and 2aB; the latter, shows the trans
diaxial configuration at the C7 and C8 positions.
In conclusion, the first tandem Michael addition/Mannich-
type reaction using a TiCl4/n-Bu4NI system between the
a,b-unsaturated carbonyl compounds possessing an Evans
oxazolidinone as chiral auxiliary and N-acyliminium ion
intermediates was developed. Also, the use of mixed sol-
vents, AcOEt and CH2Cl2, in substrates possessing Evans
oxazolidinones, was shown to be effective in this study.
Although the diastereofacial selectivity involved in the pro-
cess of the 1,4-addition of iodine anions in this reaction is
indefinable, the reaction predominately afforded three ste-
reogenic centers to one diastereomer among the indolizi-
dine compounds 2. The use of chiral products 2 is
currently under investigation for the synthesis of indolizi-
dine alkaloids.
chair-like form transition structures: Ta or Tb. It was
considered that the former transition structure Ta caused
a re-face attack of the titanium enolate on an iminium
ion, leading to the major product 2A. The latter transition
structure, in which Ti coordinated to the pyrrolidinone
oxygen, oxazolidine oxygen, and enolate oxygen,14a,b led
to 2B having the trans-diaxial configuration at the C7
and C8 positions (Fig. 2). Conversely, the titanium enolate
with an R-configured iodo-substituted carbon atom
resulted in si-face attack on an iminium ion via the transi-
tion state represented by Tc. This led to the formation of a
Ln
Ti
Ln
Ti
O
O
O
O
I
O
I
O
N
N
O
N
N
O
+
+
(rapid equilibrium)
R
R
(S) iodo titanium enolate
(R) iodo titanium enolate
Ln
Ti
Ln
O
I
si-face
O
Ti
O
S
attack
O
si-face
O
H
+
I
attack
H
R
N
N
H
O
I
N
R
O
+
N
O
R
S
H
R
O
Ti
H
N
I
>>
N
H
+
H
N
N
R
H
R
O
+
O
TiLn
O
Ln
re-face
O
O
O
attack
O
Ta'
Tb
Tc
Ta
O
O
O
O
H
H
H
H
8a
O
Q
O
O
Q
Q
O
N
Q
N
N
8
7
S
N
8
7
R
O
H
I
H
I
H
H
I
R
I
S
Q =
N
O
major
next major
minor
R
(7S,8R,8aR)-
(7S,8R,8aS)-
7,8a-cis-2A
(7R,8S,8aR)-
7,8-cis-isomer
7,8a-trans-2B
7,8a-cis-2C
Figure 3. Plausible transition structures involving the reaction mechanism for the formation of 2.

1536
Y. Koseki et al. / Tetrahedron: Asymmetry 18 (2007) 1533–1539
4. Experimental
graphy on silica gel (CHCl3/t-BuOMe/hexane, 3:2:1 followed
by CHCl3/t-BuOMe, 2:1) to give 1.6 g (83%) of semi-pure
aldehyde 5 as a colorless liquid; 1H NMR (300 MHz,
CDCl3) d 9.78 (t, J = 1.2 Hz, 1H), 4.97 (dd, J = 1.3,
6.0 Hz, 1H), 3.62 (uneven t, J ffi 6.6 Hz, 2H), 3.48 (uneven
dq, J ffi 6.6, J = 1.5 Hz, 2H), 2.87 (m, 1H), 2.72 (m, 1H),
2.52 (m, 1H), 2.28 (dd, J = 3.3, 9.6 Hz, 1H), 2.13 (m,
1H), 1.97 (m, 1H), 1.22 (uneven t, J ffi 7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 200.5, 175.1, 90.02, 61.72,
42.53, 34.63, 28.64, 24.84, 15.14; IR (neat) 1720,
1700 cmꢀ1; MS (EI) 156 (M+ꢀEt), 140 (M+ꢀOEt).
4.1. General
Melting points were determined on a Yanagimoto MP-S3
microscope plate and are uncorrected. Optical rotations
were measured with a JASCO P1030 digital polarimeter.
1H and 13C NMR spectra were recorded on a Varian Mer-
cury-300 spectrometer, Bruker DPX-400 spectrometer,
Bruker DRX-500 and Bruker AV-600. Chemical shifts (d)
1
are given from TMS (0 ppm) as internal standard for H
NMR, and 13CDCl3 (77.0 ppm) for 13C NMR. IR spectra
were measured on a JASCO IR Report-100 and Mass spec-
tra on a Finigan TSQ-700 or Fisons VG Auto Spec instru-
ment. Elemental analysis was recorded on an Elemental
Vavio EL. Column chromatography was performed with
Silica Gel BW-200 (Fuji Silysia Chemical, Ltd, 150–
350 mesh). Medium-pressure liquid chromatography
(MPLC) was carried out with a UV detector using pre-
packed silica gel cartridges with Yamazen Si-40 (Yamazen,
Ltd, silica gel SiOH, 40 lm).
4.4. [5(2RS),4S]-3-[(E)-5-(2-Ethoxy-5-oxopyrrolydin-1-
yl)pent-2-enoyl]-4-phenyloxazolidin-2-one 1a
To a solution of phosphonate 6a12 (1.02 g, 2.99 mmol) in
THF (20 mL) was added NaN (TMS)2 (2.67 mL,
2.67 mmol, 1.0 M in hexane) at ꢀ15 °C under Ar. After
being stirred for 1 h, a solution of 5 (550 mg, 2.97 mmol)
in THF (3.5 mL) was added dropwise over 20 min at
ꢀ25 °C. The reaction mixture was stirred at ꢀ25 °C for
1 h, and at ꢀ15 °C for 3 h. The reaction was quenched with
a 10% citric acid solution (2.6 mL) and pH 6.86 phosphate
buffer (35 mL), after which the mixture was extracted with
AcOEt. The organic layer was washed with saturated brine,
dried over MgSO4, and concentrated in vacuo. The residue
was purified by MPLC (hexane/i-PrOH, 20–40%) to give
1a (960 mg, 87%) as a colorless viscous oil and nonsepara-
4.2. 1-(But-3-enyl)-5-ethoxypyrrolidin-2-one 4
Modification of Holmes’s procedure, as follows, provided
the desired material in higher yield.10 To a solution of 3
(4.99 g, 32.6 mmol) in abs MeOH (170 mL) under Ar was
added NaBH4 (5.17 g, 136.8 mmol) in one portion at
ꢀ10 °C. The mixture was then stirred for 3.5 h at ꢀ5 °C.
The reaction was quenched with satd NaHCO3 solution
(80 mL) and water (80 mL), and the mixture extracted with
CHCl3 (4 times). The organic layer was washed with satu-
rated brine, dried over MgSO4, and concentrated in vacuo.
This crude product was used in the next step without puri-
fication. To a solution of the crude product in abs EtOH
(60 mL) was added p-TsOH Æ H2O (76 mg, 0.4 mmol) under
Ar, and the mixture stirred at rt for 3.5 h. After the reac-
tion was complete, satd NaHCO3 solution (80 mL) and
water (100 mL) were added to the reaction mixture at
0 °C and the mixture extracted with CHCl3 (3 times). The
organic layer was washed with saturated brine, dried over
MgSO4, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (hexane/ace-
tone, 12:1–8:1) to give 4 (5.22 g, 87%) as a colorless
liquid. The spectral data were in accord with those reported
by Holmes.10
1
ble mixture of epimers (1:1); H NMR (300 MHz, CDCl3;
1:1* ratio of diastereomers) d 7.40–7.21 (m, 5H+1H), 5.47
(dd, J = 8.7, 3.9 Hz, 1H), 4.93 (m, 1H), 4.70 (uneven t,
J ffi 8.9 Hz, 1H), 4.28 (uneven dd, J ffi 8.9, 4.0 Hz, 1H),
3.44 and 3.43* (q, J = 7.8 Hz, 2H), 3.27 (m, H), 2.60–2.44
(m, 4H), 2.30 (m, 1H), 2.14 (m, 1H), 1.96 (m, 1H) 1.21
13
and 1.20* (t, J = 7.8 Hz, 3H); C NMR (75 MHz, 1:1*
ratio of diastereomers) d 174.6, 163.82, 163.79*, 153.4,
147.32, 147.26*, 138.71, 138.67*, 128.9, 128.4, 125.73,
125.70*, 121.93, 121.87*, 89.36, 89.24*, 69.98, 61.48,
57.75, 57.74*, 39.34, 39.22*, 31.23, 31.17*, 29.03, 24.93,
15.44; IR (neat) 1780, 1690 cmꢀ1; MS (ESI) m/z 327
(M+ꢀOEt); HRMS (ESI): (M+ꢀOEt) calcd for
C18H19N2O4, 327.1345; found, 327.1316.
4.5. [5(2RS),4S]-4-Benzyl-3-[(E)-5-(2-ethoxy-5-oxo-pyrrol-
ydin-1-yl)pent-2-enoyl]oxazolidin-2-one 1b
The above procedure was carried out using phosphonate
4.3. 3-(2-Ethoxy-5-oxopyrrolidin-1-yl)propanal 5
6b12 (2.0 g, 5.63 mmol),
5
(938 mg, 5.06 mmol),
NaN(TMS)2 (5.06 mL, 5.06 mmol, 1.0 M in hexane) to give
To a solution of 4 (1.90 g, 10.4 mmol) in abs EtOH (50 mL)
containing a trace amount of sudan III (as an indicator)
was bubbled ozonized O2 at ꢀ78 °C for 3 h (until the solu-
tion showed a red discoloration). The reaction was purged
of excess O3 with a stream of Ar, after which a solution of
PPh3 (2.72 g, 10.4 mmol) in toluene (25 mL) was added
gradually. The reaction mixture was stirred at ꢀ78 °C for
0.5 h, warmed to 0 °C, and stirred at the same temperature
overnight. The solvent was removed in vacuo to give the
residue, which was dissolved with t-BuOMe. After cooling
the solution at ꢀ30 °C, the resulting solid (PPh3@O) was
removed by filtration and the filtrate was concentrated in
vacuo. The residue was purified by column chromato-
1b (1.81 g, 92%) as a colorless viscous oil and nonseparable
mixture of epimers (1:1); H NMR (400 MHz, CDCl3; all
1
signals belong to both diastereomers) d 7.35–7.20 (m,
5H+1H), 7.13 (m, 1H), 4.97 (d, J = 6.3 Hz, 1H), 4.72 (m,
1H), 4.20 (m, 2H), 3.66 (m, 1H), 3.47 (q, J = 7.0 Hz,
2H), 3.33 (dd, J = 3.2, 13.4 Hz, 1H), 3.32 (m, 1H), 2,80
(dd, J = 9.5, 13.4 Hz, 1H), 2.64–2.48 (m, 3H), 2.33 (dd,
J = 3.0, 9.9 Hz 1H), 2.17 (m, 1H), 1.99 (m, 1H), 1.24 (t,
13
J = 7.0 Hz, 3H); C NMR (100 MHz, 1:1* ratio of diaste-
reomers) d 175.0, 164.60, 153.4, 147.32, 147.30*, 135.2,
129.4, 128.9, 127.3, 122.22, 122.20*, 89.35, 89.30*, 66.14,
61.42, 55.22, 55.20*, 39.18, 39.12*, 37.79, 31.09, 31.06*,
28.88, 24.72, 15.24; IR (neat) 1780, 1690 cmꢀ1; MS (ESI)

Y. Koseki et al. / Tetrahedron: Asymmetry 18 (2007) 1533–1539
1537
m/z 341 (M+ꢀOEt); HRMS (ESI): (M+ꢀOEt) calcd for
129.14, 126.5, 69.59, 57.78, 54.23, 47.40, 36.64, 29.44,
28.94, 26.39 (CHI), 20.37; IR (KBr) 1780, 1705,
1680 cmꢀ1; MS (ESI) m/z 455 (MH+); HRMS (ESI):
(MH+) calcd for C18H20IN2O4, 455.0468; found,
455.0445. Anal. Calcd for C18H19IN2O4: C, 47.59; H,
4.22; N, 6.17. Found: C, 47.64; H, 4.32; N, 6.12.
C19H21N2O4, 341.1501; found, 341.1478.
4.6. (4S)-7-Iodo-8-(2-oxo-4-phenyloxazolidine-3-carbonyl)-
hexahydroindolizin-3-one 2a
To a solution of n-Bu4NI (893 mg, 2.41 mmol) in CH2Cl2
(3 mL) was added dropwise TiCl4 (4.83 mL, 4.83 mmol,
1 M inCH2Cl2) at ꢀ10 °C. After being stirred for 20 min
at ꢀ15 °C, a solution of 1a (600 mg, 1.61 mmol) in abs
AcOEt (12 mL) was added. The mixture was stirred for
20 min at ꢀ10 °C, then allowed to warm to rt by removal
from the ice cooling bath, and then stirred again for 2 h.
The resulting black suspension was placed in a water bath
at 40 °C and stirred for 15 h. The reaction mixture was re-
cooled to 0 °C, quenched with satd NH4Cl solution and
water, then extracted with CH2Cl2. The organic layer was
washed with 10% Na2S2O3, saturated brine, dried over
MgSO4, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (CHCl3) to
afford 436 mg (60%) of a mixture (65/28/7) of 2aA (major
component), 2aB (next major component) and 2aC (minor
component) as a yellow solid, which was recrystallized
from AcOEt to afford pure 2aA (212 mg, recrystallized
yield: 29%) as a white solid. The parent liquor was purified
by MPLC (toluene/acetone, 15%) to afford the first frac-
tion of semi-pure 2aB (90 mg, isolated yield: 12%) and
the second fraction of enriched 2aC.
4.6.3. [7R,8S,8(4S),8aR]-7-Iodo-8-(2-oxo-4-phenyloxazol-
idine-3-carbonyl)hexahydroindolizin-3-one 2aC. The sec-
ond fraction of an enriched 2aC obtained by the above
procedure was purified by MPLC (CHCl3) to afford a
semi-pure sample of 2aC (19 mg, isolated yield: 2.7%) as
1
a white paste: H NMR (600 MHz, CDCl3) d 7.41–7.33
(m, 5H), 5.53 (dd, J = 2.9, 8.6 Hz, 1H), 4.93, (t,
J = 4.7 Hz, 1H), 4.75 (t, J = 8.8 Hz, 1H), 4.41 (dd, J =
3.0, 9.0 Hz, 1H), 4.33 (m, 1H), 4.08 (m, 1H), 3.80 (m,
1H), 2.79–2.69 (m, 2H), 2.10–2.03 (m, 2H), 1.84 (m, 1H),
1.33 (m, 1H), 1.15 (m, 1H); 13C NMR (100 MHz) d
173.4, 170.0, 153.5, 138.8, 129.2, 129.1, 126.4, 69.65,
59.19, 57.72, 46.43, 41.05, 32.11, 28.22, 21.21 (CHI),
20.91; MS (ESI) m/z 455 (MH+); HRMS (ESI): (MH+)
calcd for C18H20IN2O4, 455.0468; found, 455.0481.
4.7. 8(4S)-8-(4-Benzyl-2-oxooxazolidine-3-carbonyl)-7-iodo-
hexahydroindolizin-3-one 2b
The same procedure used in the preparation of 2a was car-
ried out using 1b (535 mg, 1.38 mmol), n-Bu4NI (767 mg,
2.08 mmol), and TiCl4 (4.15 mL, 4.15 mmol, 1 M in
CH2Cl2) to give 2b (374 mg, 58%) as a mixture (90/10/
trace) of 2bA (major component), 2bB (minor component),
and 2bC (not detected) as a yellow paste, which was recrys-
tallized from AcOEt to afford pure 2bA (288 mg, recrystal-
lized yield: 45%) as colorless crystals. The parent liquor
was concentrated in vacuo to give an enriched sample of
2bB.
4.6.1. [7S,8R,8(4S),8aS]-7-Iodo-8-(2-oxo-4-phenyloxazol-
idine-3-carbonyl)hexahydroindolizin-3-one 2aA. The white
solid of 2aA obtained by the above procedure was recrys-
tallized from t-BuOMe to give an analytically pure sample
25
of 2aA as colorless crystals: mp 184–185 °C; ½aŠ ¼ þ42:3
D
1
(c 1.01 CHCl3); H NMR (500 MHz, CDCl3) d 7.42–7.35
(m, 3H), 7.32–7.30 (m, 2H), 5.51 (dd, J = 3.2, 8.6 Hz,
1H), 4.76 (t, J = 8.8 Hz, 1H), 4.54 (t, J = 10.5 Hz, 1H),
4.35 (dd, J = 3.1, 9.0 Hz, 1H), 4.26 (dt, J = 3.9, 12.5 Hz,
1H), 3.97 (ddd, J = 1.5, 5.1, 13.5 Hz, 1H), 3.49 (m, 1H),
2.68 (m, 1H), 2.47–2.41 (m, 2H), 2.30 (m, 1H), 2.13 (ddd,
J = 5.2, 13.1, 26.2 Hz, 1H), 1.81 (m, 2H); 13C NMR
(100 MHz) d 173.3, 171.3, 153.4, 138.8, 129.3, 129.0,
125.9, 69.99, 60.64, 57.94, 54.92, 41.13, 36.48, 29.54,
23.34 (CHI), 22.09; IR (KBr) 1770, 1705, 1680 cmꢀ1; MS
(ESI) m/z 455 (MH+); HRMS (ESI): (MH+) calcd for
C18H20IN2O4, 455.0468; found, 455.0444. Anal. Calcd for
C18H19IN2O4: C, 47.59; H, 4.22; N, 6.17. Found: C,
47.80; H, 4.23; N, 6.35.
4.7.1.
[7S,8R,8(4S),8aS]-8-(4-Benzyl-2-oxooxazolidine-3-
carbonyl)-7-iodohexahydroindorizin-3-one 2bA. Mp 190–
26:4
192 °C; ½aŠ ¼ þ52:2 (c 1.01 CHCl3); 1H NMR
D
(600 MHz, CDCl3) d 7.36–7.28 (m, 3H), 7.24–7.23 (m,
2H), 4.76 (m, 1H), 4.46 (uneven t, J ffi 10.5 Hz, 1H), 4.33
(m, 1H), 4.28 (uneven t, J ffi 8.3 Hz, 1H), 4.22 (dd,
J = 2.4, 9.1 Hz, 1H), 4.02 (ddd, J = 1.6, 5.1, 6.6 Hz, 1H),
3.74 (ddd, J = 4.2, 7.7, 7.8 Hz, 1H), 3.30 (dd, J = 3.4,
13.3 Hz, 1H), 2.80 (dd, J = 9.9, 13.3 Hz, 1H), 2.76 (dd,
J = 2.2 Hz, J ffi 7.6 Hz, 1H), 2.52–2.44 (m, 2H), 2.39 (m,
1H), 2.18–2.09 (m, 2H), 1.92 (m, 1H); 13C NMR
(75 MHz) d 173.7, 172.2, 153.5, 135.0, 129.6, 129.3, 127.8,
66.75, 60.84, 56.07, 55.01, 41.45, 38.46, 36.84, 29.78,
24.04 (CHI), 22.40; IR (KBr) 1780, 1690 cmꢀ1; MS (ESI)
m/z 469 (MH+); HRMS (ESI): (MH+) calcd for
C19H22IN2O4, 469.0624; found, 469.0662. Anal. Calcd for
C19H21IN2O4: C, 48.73; H, 4.52; N, 5.98. Found: C,
48.67; H, 4.69; N, 5.83.
4.6.2. [7S,8R,8(4S),8aR]-7-Iodo-8-(2-oxo-4-phenyloxazol-
idine-3-carbonyl)hexahydroindolizin-3-one 2aB. The semi-
pure sample of 2aB derived from the first fraction obtained
by the above procedure was recrystallized from AcOEt to
give an analytically pure sample of 2aB as colorless crys-
26:8
1
tals: mp 168–170 °C; ½aŠ ¼ þ209:4 (c 1.01 CHCl3); H
NMR (400 MHz, CDClD3) d 7.4–7.31 (m, 5H), 5.40 (dd,
J = 4.1, 8.8 Hz, 1H), 4.83 (br d, J = 2.3 Hz, 1H), 4.72 (t,
J = 9.0 Hz, 1H), 4.38 (dd, J = 4.2, 9.1 Hz, 1H), 4.25 (m,
1H), 4.21 (m, 1H), 4.12 (dd, J = 4.7, 13.5 Hz, 1H), 3.01
(dt, J = 2.9, 12.5 Hz, 1H), 2.12–1.90 (m, 2H), 1.82 (m,
1H), 1.51 (ddd, J = 6.4, 11.0, 17.0 Hz, 1H), 1.12 (m, 1H);
13C NMR (100 MHz) d 173.6, 168.6, 153.3, 138.2, 129.18,
4.7.2. [7S,8R,8(4S),8aR]-8-(4-Benzyl-2-oxooxazolidine-3-
carbonyl)-7-iodohexahydroindolizin-3-one 2bB. The enriched
sample of 2bB was purified by MPLC (toluene/acetone, 15%)
to afford semipure 2bB (28 mg, isolated yield: 4%) as a white
paste accompanied by a nonseparable mixture of by-prod-
ucts. 1H NMR (400 MHz, CDCl3) d 7.37–7.20 (m, 5H),

1538
Y. Koseki et al. / Tetrahedron: Asymmetry 18 (2007) 1533–1539
Jaganmohan Rao, A. J. Org. Chem. 2003, 68, 5983; (m)
Ref. 5.
3. (a) For examples of utilizing Et2AlI mediated reactions, see
Ref. 2a; (b) Itoh, A.; Ozawa, S.; Oshima, K.; Nozaki, H.
Bull. Chem. Soc. Jpn. 1981, 54, 274; (c) Wei, H.-X.; Gao, J. J.;
4.66 (ddd, J = 3.6, 6.6, 10.0 Hz, 1H), 4.56 (br q, J = 2.7 Hz,
1H), 4.40–4.33 (m, 2H), 4.23–4.15 (m, 3H), 3.34 (dd, J = 3.5,
10.1 Hz, 1H), 3.20 (dt, J = 3.3, 13.0 Hz, 1H), 2.69 (dd,
J = 10.1, 13.0 Hz, 1H), 2.47–2.26 (m, 3H), 1.87 (m, 1H),
1.67 (m, 1H), 1.26 (m, 1H).
´
Li, G.; Pare, P. W. Tetrahedron Lett. 2002, 43, 5677;
(d) Pei, W.; Wei, H.-X.; Li, G. Chem. Commun. 2002, 1856;
(e) Pei, W.; Wei, H.-X.; Li, G. Chem. Commun. 2002, 2412; (f)
Ref. 8.
4.8. X-ray crystallographic study
4.8.1. Crystal structure data for 2bA. C19H21IN2O4, Mr =
4. For examples of utilizing TMSI or MgI2 mediated reactions,
see (a) Wei, H.-X.; Kim, S. H.; Li, G. Org. Lett. 2002, 4,
˚
˚
468.28, monoclinic, P21, a = 11.105(5) A, b = 8.329(4) A,
3
˚
˚
´
3691; (b) Deng, G.-H.; Hu, H.; Wei, H.-X.; Pare, P. W. Helv.
c = 11.777(7) A, V = 979.35(9) A , T = 297(2) K, Z = 2,
Dx = 1.588 Mg mꢀ3, l(Mo Ka) = 1.660 mmꢀ1, 4286 mea-
sured reflections, 4286 unique reflections, 3281 observed
reflections, [I > 2r(I)] R(all) = 0.0447, R(gt) = 0.0358,
wR(ref) = 0.1038, wR(gt) = 0.0995, S(ref) = 0.848.
Chim. Acta 2003, 86, 3510; (c) Wei, H.-X.; Hu, J.; Purkiss, D.
´
W.; Pare, P. W. Tetrahedron Lett. 2003, 44, 949; (d) Wei,
´
H.-X.; Timmons, C.; Ali Farag, M.; Pare, P. W.; Li, G.
Org. Biomol. Chem. 2004, 2, 2893; (e) Wei, H.-X.; Hu, J.;
´
Jasoni, R. L.; Li, G.; Pare, P. W. Helv. Chim. Acta 2004, 87,
2359.
4.8.2. Crystal structure data for 2aB. C18H19IN2O4, Mr =
5. Yagi, K.; Turitani, T.; Shinokubo, H.; Oshima, K. Org. Lett.
2002, 4, 3111.
6. (a) Timmons, C.; Kattuboina, A.; Banerjee, S.; Li, G.
Tetrahedron 2006, 62, 7151; (b) Li, Q.; Shi, M.; Lyte, J.-M.;
Li, G. Tetrahedron Lett. 2006, 47, 7699.
˚
˚
454.25, monoclinic, P21, a = 10.198(13) A, b = 9.728(6) A,
3
˚
˚
c = 18.814(3) A, V = 1819.3(9) A , T = 297 (2)K, Z = 4,
Dx = 1.658 Mg mꢀ3, l(Mo Ka) = 1.785 mmꢀ1, 7122 mea-
sured reflections, 7122 unique reflections, 3872 observed
reflections [I > 2r(I)], R(all) = 0.0653, R(gt) = 0.0369,
wR(ref) = 0.0897, wR(gt) = 0.0858, S(ref) = 0.770.
7. (a) Wijnberg, B. P.; Speckamp, W. N. Tetrahedron Lett. 1981,
22, 5079; (b) Melching, K. H.; Hiemstra, H.; Klaver, W. J.;
Speckamp, W. N. Tetrahedron Lett. 1986, 27, 4799; (c) Taber,
D. F.; Hoerrner, R. S.; Hagen, M. D. J. Org. Chem. 1991, 56,
1287.
8. For intermolecular asymmetric halo aldol reaction, see (a) Li,
G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.;
Headley, A. D. Org. Lett. 2003, 5, 329; (b) Xu, X.; Chen, D.;
Wei, H.-X.; Li, G.; Xiao, T. L.; Armstrong, D. W. Chirality
2003, 15, 139; (c) Chen, D.; Timmons, C.; Liu, J.; Headley,
A.; Li, G. Eur. J. Org. Chem. 2004, 3330; (d) Chen, D.; Guo,
L.; Saibabu Kotti, S. R. S.; Li, G. Tetrahedron: Asymmetry
2005, 16, 1757.
All diagrams and calculations were performed using
MAXUS crystallographic software package,18 and the refine-
ment was performed using SHELXL97.19 CCDC 641914 (for
2bA) and CCDC 641915 (for 2aB) contain the supplemen-
tary crystallographic data for compounds 2bA and 2aB,
respectively, studied in this article. These data can be
obtained free of charge via http://www.ccdc.cam.au.a-
c.uk/deta_request/cif, by e-mailing data_request@ccdc.ca-
m.ac.uk, or from The Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK;
deposit@ccdc.cam.au.uk.
9. Very recently, an example of the aza-Baylis Hillman reaction
via N-acyliminium ion has been reported, see Myers, E. L.;
De Vries, J. G.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2007,
46, 1893.
10. Tarling, C. A.; Holmes, A. B.; Markwell, R. E.; Pearson, N.
D. J. Chem. Soc., Perkin Trans. 1 1999, 1695.
References
11. Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980,
807.
12. Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan,
J. M.; Sun, L.; Akhiezer, A.; Liu, J. O. J. Am. Chem. Soc
1998, 120, 12237.
1. For reviews regarding the MBH reaction, see (a) Basavaiah,
D.; Jaganmohan Rao, A.; Satyanarayana, T. Chem. Rev.
2003, 103, 811; (b) Langer, P. Angew. Chem., Int. Ed. 2000,
39, 3049; (c) Ciganek, E. Org. React. 1997, 51, 201; (d)
Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R. Tetrahe-
dron 1996, 52, 8001; (e) Drewes, S. E.; Roos, G. H. P.
Tetrahedron 1988, 44, 4653.
13. The reactions of 2 with organic amines (e.g., DBU, DABCO,
Et3N) for the elimination of iodine did not proceed (see Ref.
7a,c), while conduction at such a high temperature merely
caused cleavage of the oxazolidinone-ring. Attempts to
remove the oxazolidin-2-one utilizing methods reported in
the literatures (e.g., base, peroxide, NaBaH4, Lewis acid/
MeOH) gave the same result.
14. (a) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.;
Mathre, D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53,
1109; (b) Nerz-Stormes, M.; Thornton, E. R. J. Org.
Chem. 1991, 56, 2489; (c) Yan, T.-H.; Tan, C.-W.; Lee,
H.-C.; Lo, H.-C.; Huang, T.-Y. J. Am. Chem. Soc. 1993, 115,
2613.
15. For examples of the conjugated addition of chloride to a,b-
unsaturated chiral imides using Evans-type oxazolidinones,
see (a) Cadillo, G.; De Simone, A.; Gentilucci, L.; Tomasini,
C. J. Chem. Soc., Chem. Commun. 1994, 735; (b) Cardillo, G.;
Di Martino, E.; Gentilucci, L.; Tomasini, C.; Tomasoni, L.
Tetrahedron: Asymmetry 1995, 6, 1957.
2. For the three-component reactions between a,b-unsaturated
carbonyl compounds, aldehydes or ketones, and halides,
examples of utilizing TiCl4 or ZrCl4 mediated, see (a)
Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986,
27, 4767; (b) Zhang, C.; Lu, X. Synthesis 1996, 586; (c)
Uehira, S.; Han, Z.; Shinokubo, H.; Oshima, K. Org. Lett.
1999, 1, 1383; (d) Li, G.; Wei, H.-X.; Gao, J. J.; Caputo,
T. D. Tetrahedron Lett. 2000, 41, 1; (e) Wei, H.-X.; Kim,
S. H.; Caputo, T. D.; Purkiss, D. W.; Li, G. Tetrahedron
2000, 56, 2397; (f) Li, G.; Gao, J.; Wei, H.-X.; Enright, M.
Org. Lett. 2000, 2, 617; (g) Kataoka, T.; Kinoshita, H.;
Kinoshita, S.; Iwamura, T.; Watanabe, S. Angew. Chem.,
Int. Ed. 2000, 39, 2358; (h) Shi, M.; Jiang, J.-K.; Feng,
Y.-S. Org. Lett. 2000, 2, 2397; (i) Shi, M.; Jiang, J.-K.;
Cui, S.-C.; Feng, Y.-S. J. Chem. Soc., Perkin Trans. 1 2001,
390; (j) Shi, M.; Feng, Y.-S. J. Org. Chem. 2001, 66, 406;
(k) Han, Z.; Uehira, S.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2001, 66, 7854; (l) Basavaiah, D.; Sreenivasulu, B.;
16. The conjugated addition of halide to optically active a,b-
unsaturated N-acyloxazolidinone 7 under the same condi-

Y. Koseki et al. / Tetrahedron: Asymmetry 18 (2007) 1533–1539
1539
tions afforded chloride adduct 8 as a diastereomer mixture
(1:1) in 75% yield, while iodide adducts were not detected (see
the scheme below). This result suggests that the (R)- and (S)-
iodo Ti-enolate were formed reversibly and were in rapid
(dynamic) equilibrium with the starting material. Thus,
enantioselectivity was not observed, and a more stable
17. Recently, an example of the tandem Michael-aldol reaction
of chalcogenide-enones possessing a chiral oxazolidinethione
for synthesis of 3-sulfanylpropanols containing three stereo-
genic centers has been reported, see Kinoshita, H.; Takah-
ashi, N.; Iwamura, T.; Watanabe, S.; Kataoka, T.; Muraoka,
O.; Tanabe, G. Tetrahedron Lett. 2005, 46, 7155.
18. Mackay, S.; Gilmore, C. J.; Edwards, C.; Stewart, N.;
Shankland, K. MAXUS Computer Program for the Solution
and Refinement of Crystal Structures; The University of
Glasgow: Bruker Nonius, The Netherlands, MacScience,
Japan, 1999.
chloride adduct
8 was formed. However, exposure of
substrates possessing N-acyloxazolozolidinones to such reac-
tion conditions did not result in the formation of the iodide
adducts. The reason for this is not understood at present (see
Ref. 5). Compound 8: Colorless paste as a nonseparable
mixture of diastereomer (1:1); MS (ESI) m/z 393 (MH+,
Cl35), 395 (MH+, Cl37); HRMS (ESI): (MH+) calcd for
C19H22ClN2O5, 393.1217; found, 393.1096.
19. Sheldrick, G. M. SHELXL97: Program for the Refinement
of Crystal Structures; University of Go¨ttingen: Germany,
1997.
O
O
O
O
O
Cl
O
TiCl4/n-Bu4NI
N
N
O
N
N
O
AcOEt/CH2Cl2
-20 °C to rt
O
Bn
O
Bn
8 (1:1)
7