Enantioselective formation of quaternary stereocenters using the catalytic intramolecular Stetter reaction

Article abstract of DOI:10.1016/j.tet.2006.06.042

Asymmetric formation of quaternary stereocenters has been accomplished using the catalytic intramolecular Stetter reaction. A?variety of tethered aldehydes and Michael acceptors are cyclized in excellent yields and enantioselectivities.

Full text of DOI:10.1016/j.tet.2006.06.042

Tetrahedron 62 (2006) 11477–11482
Enantioselective formation of quaternary stereocenters
using the catalytic intramolecular Stetter reaction
*
Jennifer L. Moore, Mark S. Kerr and Tomislav Rovis
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 1 April 2006; revised 11 June 2006; accepted 13 June 2006
Available online 7 July 2006
Abstract—Asymmetric formation of quaternary stereocenters has been accomplished using the catalytic intramolecular Stetter reaction.
A variety of tethered aldehydes and Michael acceptors are cyclized in excellent yields and enantioselectivities.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Work in our laboratory has focused on the development of
chiral triazolinylidene carbenes, derived from 1 and 2.18
These catalysts are capable of inducing addition of aromatic
and aliphatic aldehydes to a,b-unsaturated esters, ketones,
and nitriles.18a,b Recent work includes the extension of intra-
molecular Stetter reaction for the formation of contiguous
stereocenters using a,b-disubstituted Michael acceptors18d
and the desymmetrization of cyclohexadienones.18f We
have previously communicated the formation of quaternary
stereocenters using b,b-disubstituted Michael acceptors.18c
Herein, we describe an expansion of the scope of this
reaction to include a variety of heteroatoms tethering the
aldehyde and Michael acceptor as well as the generation
of five- and six-membered rings in the process of forming
quaternary stereocenters in high enantioselectivity.
Catalytic carbon–carbon bond formation resulting in the
creation of a quaternary stereocenter is a useful but challeng-
ing tool in organic chemistry.1 In addition to established
approaches using chiral auxiliaries,2 significant progress
has been made in recent years aimed at catalytic methods
for the formation of quaternary stereocenters. These include
the intramolecular Heck reaction,3 rearrangement of enol
carbonates,4 transition metal-mediated p-allyl chemistry,5
copper catalyzed SN20 displacement of allylic leaving
groups6 and conjugate additions of b-keto esters to acryla-
tes,1b phase-transfer alkylation of 1-indanones,7 arylation
of ketone enolates,8 and enantioselective alkylation of tri-
butyl tin enolates catalyzed by Cr(salen)Cl,9 among others.
Most recently, Stoltz and Trost have each reported the
deracemization of quaternary stereocenters via Pd-catalyzed
decarboxylative allylation of racemic b-keto esters.10,11
Each of these approaches is useful but limited to a specific
substrate scope.
O
F
N
N
F
N
N
N
N
Bn
F
BF4
BF4
F
F
1c
2
Reactivity umpolung reverses the normal mode of aldehyde
polarity, thus rendering an aldehyde nucleophilic.12 Both
benzoin and Stetter reactions exploit this reactivity and
have been the subject of much recent research.13 Both
processes are catalyzed by azolium salts in the presence of
base.14 The benzoin reaction provides a-hydroxy ketones
and has classically been limited to the homocoupling of
two aldehydes.15 Recently, creative approaches have been
taken to expand its utility to provide cross-benzoin prod-
ucts.16 The Stetter reaction, on the other hand, involves the
addition of an aldehyde to a Michael acceptor and is an
excellent way to access 1,4-dicarbonyl systems.17
2. Results and discussion
Investigation of the formation of quaternary stereocenters
began with substrates such as 3. Substrates were prepared
via phenol alkylation of the thioacetal of salicylaldehyde,
followed by deprotection. A brief catalyst screen provided
reaction conditions that afforded excellent yields and enan-
tioselectivities of benzofuranone products (Eq. 1). Reaction
of electron rich para-methoxy phenyl substituted amino-
indanol-derived catalyst with 3 provides 5 in 45% yield
and excellent enantiomeric excess. Catalyst 1b provides an
increase in yield and retains 99% ee. Pentafluorophenyl
substituted catalyst 1c proved to be the most efficient in
terms of yield and enantioselectivity.
* Corresponding author. Tel.: +1 970 491 7208; fax: +1 970 491 1801;
e-mail: rovis@lamar.colostate.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.042

11478
J. L. Moore et al. / Tetrahedron 62 (2006) 11477–11482
O
O
O
reaction beginning with substrates that contained aromatic
20 mol % catalyst
20 mol % KHMDS
backbones (Table 1). Benzofuranones 5 and 6 were obtained
in high yields and enantiomeric excess. Thioethers are
also competent substrates and react efficiently to provide
benzothiophenone products in high yield and enantioselec-
tivity (Entries 4 and 5). Reaction of thioether 7 provides
benzothiophenone in 95% yield and 92% ee. A propyl group
in the b-position is tolerated, providing 54% yield and 87%
ee with triethylamine (Entry 4). Phenethyl substitution
of the thioether substrate affords 12 in lower yield and
88% ee. A direct comparison between substrates 7 and 13
leads to the conclusion that an increase in steric bulk or
electronic differences, i.e., ethyl versus phenyl, suppresses
the reactivity while having little effect on enantioselectiv-
ity. An all carbon five-membered ring is formed in 95%
yield and 99% ee (Entry 7). Overall, the intramolecular
Stetter reaction tolerates aromatic aldehydes with varied
b,b-substitution of the Michael acceptors and heteroatom
tethers.
Et
Et
(1)
CO2Me
N
CO2Me
O
°
PhMe, 25
C
5
3
O
Ar
cat.
yield (%) ee (%)
N
N
p-OMePh
Ph
1a
1b
1c
45
80
85
99
99
99
Ar
BF4
C6F5
1 a-c
Using catalyst precursor 1c, we further optimized the re-
action conditions by using the very mild base triethylamine
to generate the active catalyst. Having identified an efficient
catalyst system providing desired reactivity with excellent
enantioselectivity and yield, we examined the scope of this
Table 1. Scope of aromatic substrates
O
F
F
N
N
N
F
O
X
O
BF4
20 mol%
F
F
R
R
EWG
Base, PhMe, 25 °C, 24 h
X
EWG
Entry
Substrate
Producta
Base
Yield (%)
ee (%)b
O
Et
O
O
X
X
Et
CO2Me
CO2Me
O
1
2
X = H
3
X = H
= Br
5
NEt3
NEt3
96
92
97
89
= Br
4
6
O
O
Et
Et
CO2Me
NEt3
KOt-Bu
95
90
92
97
3c
CO2Me
CO2Me
S
S
8
7
O
O
Pr
Pr
CO2Me
NEt3
KOt-Bu
54
83
87
98
4
S
S
10
9
O
Ph
O
Ph
NEt3
KOt-Bu
33
91
88
99
5
6
CO2Me
CO2Me
CO2Et
S
CO2Me
S
12
11
O
O
Ph
Ph
CO2Me
NEt3
KOt-Bu
11
15
82
82
S
S
14
13
O
O
Me
Me
CO2Et
7
NEt3
95
99
15
16
a
Absolute configuration assigned analogy to 8.
Enantiomeric excess determined by HPLC analysis on chiral stationary phase.
Absolute configuration established by single-crystal X-ray analysis.
b
c

J. L. Moore et al. / Tetrahedron 62 (2006) 11477–11482
Table 2. Effect of substrate geometry
11479
The observation that sulfur containing compounds generally
provide cyclized products in lower yields and more moder-
ate enantioselectivities prompted an additional screen of
reaction conditions. This catalyst screen was performed
using thioether 9, which contains propyl substitution b to
the ester. As expected, we found that aminoindanol catalyst
1c and phenylalanine-derived catalyst 2 afford opposite en-
antiomers of the desired product in high selectivity (Eq. 2).
Exposing 9 to catalyst 2 provides 10 in similar yield with
an increase in enantioselectivity to 90%. Catalyst 1c was
then used with triethylamine but gave 10 in only moderate
yield and selectivity. By changing the base to potassium
tert-butoxide, an increase in yield and enantioselectivity
was observed. The reaction conditions for thioether contain-
ing substrates were found to be 20 mol % catalyst loading,
with 20 mol % potassium tert-butoxide, in toluene at 25 ꢀC.
Increased yields and enantioselectivities were obtained
with potassium tert-butoxide in each sulfur containing sub-
strate with the exception of 13. A slight increase in reactivity
was observed with 13 while the enantioselectivity remains
82%. We ascribe the reluctance of this substrate to partici-
pate in this reaction to steric crowding.
O
F
N
N
F
N
O
S
O
F
BF4
R
F
R
F
CO2Me
S
CO2Me
20 mol %
°
KOtBu, PhMe, 25 C, 24 h
Entry
Substrate
Product
O
O
Et
Et
CO2Me
CO2Me
S
S
8
1
(E) 90% yield,
97% ee
(Z) 89% yield,
86% ee
E-7
Z-7
O
S
O
Pr
Pr
CO2Me
CO2Me
S
2
10
E-9
Z-9
(E) 83% yield,
98% ee
(Z) 85% yield,
89% ee
O
S
O
O
S
O
20 mol % catalyst
Base, PhMe, 25 °C
(2)
CH2CH2Ph
CO2Me
Pr
CH2CH2Ph
CO2Me
Pr
CO2Me
CO2Me
S
S
12
10
(E) 91% yield,
99% ee
(Z) 92% yield,
84% ee
3
E-11
Z-11
9
cat.
2
base
KHMDS
NEt3
yield (%) ee (%)
80
54
83
90(S)
87(R)
98(R)
1c
1c
O
O
KOt-Bu
CO2Me
CO2Me
CO2Me
S
S
To further investigate the requirements of substrates that
give high yield and enantioselectivity we synthesized both
alkene isomers of the Michael acceptors. The use of either
(E)- or (Z)-isomer results in good yields and enantioselectiv-
ities. Thioether E-7 gives cyclized benzothiophenone in 90%
yield and 97% ee. The corresponding Z-7 gives 8 in 89%
yield and 86% ee under the same reaction conditions. Highly
electrophilic bis-ester 18 was obtained in the (Z)-geometry
and provided cyclized product 19 in 85% yield and 90%
ee when using catalyst 17. Similar yields and lower enantio-
selectivities were also observed for the (E)-isomer of propyl-
and phenethyl-substituted Michael acceptors. Use of
(E)-isomers provided uniformly higher yields and enantio-
selectivities and provided the impetus for us to focus on
(E)-isomers for the majority of the study (Table 2).
CO2Me
19
(Z) 85% yield,
4
18
90% eea
a
Results with catalyst 17 and KHMDS.
20 to the same reaction conditions with chiral catalyst 1c
provides no desired product and only the starting material
was recovered. After investigating our most reactive cata-
lysts, we found that catalyst 2 provides 21 in 11% yield
and >99% ee. As we have noted a higher reactivity associ-
ated with ketones versus esters, we decided to investigate
the six-membered ring formation utilizing a ketone Michael
acceptor. In the event, exposure of methyl ketone 23 contain-
ing phenyl substitution to our reaction conditions provides
the desired product in 55% yield and 99% ee (Eq. 4).
O
N
N
N
O
O
OMe
Me
BF4
20 mol % catalyst
CO2Et
(3)
S
CO2Et
17
KHMDS
S
PhMe, 25 oC
Me
20
21
Although, the formation of five-membered rings and con-
comitant creation of quaternary stereocenters are very effi-
cient, formation of the corresponding six-membered rings
remains a challenge. Treatment of thioether 20 under the
standard reaction conditions (20 mol % azolium salt and
20 mol % KHMDS in toluene) with achiral catalyst 22 af-
fords cyclized product in 11% yield (Eq. 3). Exposure of
N
N
F
cat.
yield (%) ee (%)
N
22
1c
2
11
0
-
F
BF4
-
11
>99
F
F
F
22

11480
J. L. Moore et al. / Tetrahedron 62 (2006) 11477–11482
O
O
cyclopentanone in 85% yield and 96% ee (Eq. 5). Cycliza-
tion proceeds in lower yield and enantioselectivity for Z-25.
O
Ph
O
20 mol % 1c
10 eq NEt3
°
PhMe, 25 C, 24 h
(4)
O
O
O
O
O
Me
Ph Me
23
20 mol % 1c
Me
Me Ph
(5)
20% KHMDS
24
55 % yield, 99% ee
Ph
O
PhMe, 25 C, 24 h
°
E - 25
Z - 25
E-isomer 85% yield, 96% ee
Z-isomer 50% yield, 56% ee
This method can be extended to substrates with aliphatic
backbones, although the aliphatic substrates pose a particular
challenge, as they may undergo aldol side reactions. Cycli-
zation of aliphatic substrates to form tertiary stereocenters
has been previously reported.18a Enantioselectivity when
using substrates with aliphatic backbones is affected by the
geometry of the alkene in the starting material, as is the
case in earlier aromatic substrates. Optimized reaction con-
ditions for aliphatic substrates were found to be 20 mol %
catalyst and 20 mol % KHMDS in toluene. Subjecting
E-25 to the reaction conditions with catalyst 1c gives
Aliphatic substrates containing thioethers have also proven
resistant to cyclization with catalyst 1 or 2 (Table 3). By
changing the tether from a sulfide to a sulfone, cyclization
was induced, providing the product in 98% yield and 80%
ee. Thorpe–Ingold effect19 may account for the success of
this reaction. In addition, the electron withdrawing capabil-
ity of the sulfone presumably contributes to the activation of
the electron deficient alkene, thus promoting cyclization.
The scope of aliphatic substrates includes nitrogen-contain-
ing substrates such as 30 that provides desired product in
65% yield and 95% ee. a,b-Unsaturated aromatic ketones
32 and 33 give the desired product in higher yields and enan-
tioselectivities. Excellent selectivity was observed for the
formation of quaternary stereocenters in 38 and 39 imple-
menting aliphatic ketone Michael acceptors. Cyclization of
a,b-unsaturated phenyl ketone 40 provided 41 in 98% ee.
Aliphatic substrates with b-methyl substitution generally
give high enantioselectivity.
Table 3. Substrate scope of aliphatic
O
O
R
20 mol % catalyst
R
X
EWG
20% KHMDS, PhMe, 25 °C, 24 h
X
Y
Y
EWG
Entry
Substrate
Producta
Catalyst Yield ee
(%)
0
(%)
O
O
We have expanded the scope of the intramolecular enantio-
selective Stetter reaction to afford quaternary stereocenters.
The reaction is mild, general, and tolerates aromatic, ali-
phatic, sulfur, oxygen, and nitrogen tethering of aldehyde
and Michael acceptor. The current substrate scope includes
compounds with varying electronics and sterics. Ongoing ef-
forts include elucidating the mechanism of this reaction and
other factors contributing to the reactivity of these carbenes.
Pr
Pr
CO2Me
27
1
2
1c, 2
—
CO2Me
S
S
26
O
O
Pr
Pr
CO2Me
CO2Me
S
2
98
65
80b
S
O2
O2
29
28
O
O
3. Experimental
3.1. General
Me
Me
COMe
COMe
COAr
3
N
1
95
N
Ac
Ac
31
30
All reactions were carried out under an atmosphere of argon
in flame-dried glassware with magnetic stirring. Data are re-
ported as follows: chemical shift in parts per million (d, ppm)
from an internal standard (tetramethylsilane [TMS] or
deuterated chloroform [CDCl3]), multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, and br
s¼broad singlet), integration, and coupling constant (Hz).
Chemical shifts are reported in parts per million from
(CDCl3) taken as 77.0 ppm.
O
O
Me
Me
COAr
34
4
5
1
1
85
90
96
84
Ar = 4-Py
=p-NO2Ph
32
Ar = 4-Py
=p-NO2Ph 35
33
O
O
Me
Me
COR
COR
3.2. Synthesis and characterization
1
1
81
63
95
99
6
7
R = Me
36
R = Me
38
= (CH2)2Ph 37
= (CH2)2Ph 39
3.2.1. General procedure for the asymmetric intramole-
cular Stetter reaction of aromatic substrates. A flame-
dried round bottom flask was charged with triazolium salt
(0.02 mmol, 0.2 equiv), evacuated for 5 min, and then cov-
ered with argon. Substrate (0.1 mmol, 1 equiv) in toluene
(1 mL) was added via syringe, followed by the addition of
KOt-Bu (0.2 mmol, 2 equiv to substrate), and the solution
was stirred at ambient temperature under argon for 24 h.
O
O
n-Bu
COPh
40
n-Bu
COPh
41
8
1
71
98
a
Absolute configuration assigned analogy to 37.
Enantioselectivity was determined by 1H NMR using chiral shift reagent
Eu(hfbc)3.
b

J. L. Moore et al. / Tetrahedron 62 (2006) 11477–11482
11481
The reaction mixture was then poured onto a column of
silica gel and eluted with a suitable solution of ethyl acetate
in hexanes to afford analytically pure product.
Rf¼0.36 (7:3 Hex/EtOAc); [a]2D5 +20.6 (CHCl3); HPLC anal-
ysis—Chiracel AD-H column, 97:3 hexanes to isopropanol
1.0 mL/min. Minor enantiomer: 20.0 min, major enantiomer:
22.7 min; 1H NMR (300 MHz, CDCl3) d 7.81 (d, 1H,
J¼7.9 Hz), 7.58 (t, 1H, J¼8.1 Hz), 7.40 (d, 1H, J¼8.1 Hz),
7.25 (m, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 3.53 (d, 1H,
J¼17.3 Hz), 3.11 (d, 1H, J¼17.3 Hz); 13C NMR (100 MHz,
CDCl3) d 196.9, 170.3, 168.5, 151.9, 136.3, 129.7, 127.7,
125.7, 124.1, 62.4, 53.9, 52.4, 39.7; IR (NaCl, neat) 2954,
3.2.2. General procedure for the asymmetric intramole-
cular Stetter reaction of aliphatic substrates. A flame-
dried round bottom flask was charged with triazolium salt
(0.02 mmol, 0.2 equiv) and toluene (1 mL) under argon.
To this solution was added KHMDS (0.5 M in toluene)
(0.02 mmol, 0.2 equiv) via syringe and the solution was
stirred at ambient temperature for 5 min. Substrate
(0.01 mmol, 1 equiv) in toluene was added (1 mL) via
syringe and allowed to stir for 24 h at ambient temperature.
The reaction mixture was then poured onto a column of
silica gel and eluted with a suitable solution of ethyl acetate
in hexanes to afford analytically pure product.
1738, 1705, 1587 cmꢁ1
; HRMS (FAB+) calcd for
C13H13O5S: 281.0484. Found: 281.0480.
3.2.2.5. (R)-(3-Methyl-4-oxo-thiochroman-3-yl)-acetic
acid methyl ester (21). Rf¼0.38 (7:3 Hex/EtOAc); [a]D25
+41.6 (CHCl3); HPLC analysis—Chiracel OD-H column,
90:10 hexanes to isopropanol 0.5 mL/min. Minor enantio-
mer: 8.8 min, major enantiomer: 7.5 min; 1H NMR
(300 MHz, CDCl3) d 8.10 (d, 1H, J¼8.6 Hz), 7.36 (t, 1H,
J¼6.5 Hz), 7.25–7.14 (m, 2H), 4.13 (d, 1H, J¼7.1 Hz),
4.11 (q, 2H, J¼7.1 Hz), 3.74 (d, 1H, J¼13.5 Hz), 3.01 (d,
1H, J¼16.1 Hz), 2.98 (d, 1H, J¼13.5 Hz), 2.56 (d, 1H,
J¼16.1 Hz), 1.40 (s, 3H), 1.23 (t, 3H, J¼7.1 Hz); 13C
NMR (100 MHz, CDCl3) d 196.9, 171.2, 141.4, 133.2,
130.6, 130.0, 127.5, 125.2, 60.8, 43.6, 41.2, 36.6, 21.2,
3.2.2.1. (R)-(3-Oxo-2-propyl-2,3-dihydro-benzo[b]thio-
phen-2-yl)-acetic acid methyl ester (10). Rf¼0.43 (7:3
Hex/EtOAc); [a]2D5 +21.2 (CHCl3); HPLC analysis—Chiracel
OD-H column, 90:10 hexanes to isopropanol 0.5 mL/min.
1
Minor enantiomer: 6.0 min, major enantiomer: 7.5 min; H
NMR (300 MHz, CDCl3) d 7.78 (d, 1H, J¼7.7 Hz), 7.53 (t,
1H, J¼7.9 Hz), 7.37 (d, 1H, J¼7.9 Hz), 7.2 (t, 1H, J¼
7.0 Hz), 3.56 (s, 3H), 3.07 (d, 1H, J¼16.7), 2.96 (d, 1H, J¼
16.7 Hz), 1.86 (ddd, 2H, J¼5.5, 6.8, 9.6 Hz), 1.54–1.35 (m,
1H), 1.26–1.03 (m, 1H), 0.84 (t, 3H, J¼7.3 Hz); 13C NMR
(100 MHz, CDCl3) d 203.9, 170.4, 152.1, 135.7, 131.3,
126.8, 124.9, 124.1, 62.7, 52.0, 42.8, 41.3, 17.9, 14.1; IR
(NaCl, neat) 2958, 1741, 1699, 1591, 1449 cmꢁ1; HRMS
(FAB+) calcd for C14H17O3S: 265.0898. Found: 265.0885.
14.4; IR (NaCl, neat) 2978, 1732, 1676, 1589, 1435 cmꢁ1
;
HRMS (FAB+) calcd for C14H17O3S: 265.0898. Found:
265.0905.
3.2.2.6. (1,1,3,-Trioxo-2-propyl-tetrahydro-1,6-thio-
phene-yl)-acetic acid methyl ester (29). Rf¼0.15 (7:3
1
Hex/EtOAc); [a]2D5 +24.5 (CHCl3); H NMR (300 MHz,
CDCl3) d 3.67 (s, 3H), 3.65 (ddd, 1H, J¼12.5, 11.7,
8.5 Hz), 3.50 (ddd, 1H, J¼12.5, 9.2, 2.4 Hz), 3.17 (d, 1H,
J¼17.9 Hz), 3.11 (ddd, 1H, J¼17.9, 8.5, 2.2 Hz), 3.10 (d,
1H, J¼17.9 Hz), 2.88 (ddd, 1H, J¼17.9, 11.6, 9.1 Hz),
1.87 (ddd, 1H, J¼14.1, 9.3, 7.1 Hz), 1.70 (dm, 1H, J¼
14.1 Hz), 1.48 (ddq, 2H, J¼9.3, 7.1, 7.1 Hz), 0.93 (t, 3H,
J¼7.2 Hz); 13C NMR (100 MHz, CDCl3) d 206.1, 171.4,
65.8, 52.8, 50.7, 39.4, 36.7, 36.3, 17.7, 14.4; IR (NaCl,
neat) 2964, 1732, 1439, 1313 cmꢁ1; HRMS (FAB+) calcd
for C10H16O5S: 248.0718. Found: 248.0705.
3.2.2.2. (R)-(3-Oxo-2-phenethyl-2,3-dihydro-benzo-
[b]thiophen-2-yl)-acetic acid methyl ester (12). Rf¼0.46
(7:3 Hex/EtOAc); [a]D25 ꢁ27.8 (CHCl3); HPLC analysis—
Chiracel OD-H column, 90:10 hexanes to isopropanol
0.5 mL/min. Minor enantiomer: 9.3 min, major enantiomer:
1
11.8 min; H NMR (300 MHz, CDCl3) d 7.82 (d, 1H, J¼
7.8 Hz), 7.57 (t, 1H, J¼6.9 Hz), 7.43 (d, 1H, J¼7.9 Hz),
7.26–7.10 (m, 6H), 3.59 (s, 3H), 3.12 (d, 1H, J¼16.8 Hz),
3.00 (d, 1H, J¼16.8 Hz), 2.79–2.67 (m, 1H), 2.47–2.37
(m, 1H), 2.27–2.19 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 203.3, 170.3, 152.0, 140.92, 136.0, 131.3, 128.6, 126.9,
126.3, 125.1, 124.3, 62.6, 52.2, 43.1, 41.2, 31.0; IR (NaCl,
neat) 2950, 1741, 1699, 1591, 1450 cmꢁ1; HRMS (FAB+)
calcd for C19H19O3S: 327.1055. Found: 327.1048.
3.2.2.7. 1-Acetyl-2-methyl-(2-oxo-propyl)-pyrrolidin-
3-one (31). Rf¼0.21 (9:1 EtOAc/i-PrOH); [a]2D5 ꢁ57.1
(CHCl3); GC analysis—chiraldex BPH column, 120 ꢀC
1.5 mL/min. Minor enantiomer: 46.0 min, major enantio-
1
mer: 46.2 min; H NMR (400 MHz, CDCl3) d 4.14 (dd,
3.2.2.3. (R)-(3-Oxo-2-phenyl-2,3-dihydro-benzo[b]-
thiophen-2-yl)-acetic acid methyl ester (14). Rf¼0.46
(7:3 Hex/EtOAc); [a]D25 ꢁ10.3 (CHCl3); HPLC analysis—
Chiracel OD-H column, 90:10 hexanes to isopropanol
0.5 mL/min. Minor enantiomer: 8.4 min, major enantiomer:
1H, J¼18.6, 0 Hz), 3.82 (ddd, 1H, J¼18.1, 8.9, 8.9 Hz),
3.75 (ddd, 1H, J¼10.2, 10.2, 3.8 Hz), 2.96 (dd, 1H, J¼
18.8, 0 Hz), 2.90 (ddd, 1H, J¼17.9, 9.0, 3.6 Hz), 2.66 (ddd,
1H, J¼18.5, 9.4, 9.4 Hz), 2.03 (s, 3H), 2.01 (s, 3H), 1.36
(s, 3H); 13C NMR (100 MHz, CDCl3) d 214.6, 207.3,
170.6, 64.1, 50.9, 43.9, 29.4, 23.2, 22.2; IR (NaCl, neat)
2915, 1745, 1706, 1634, 1414 cmꢁ1; HRMS (FAB+) calcd
for C10H16NO3, 198.1130. Found 198.1135.
1
6.7 min; H NMR (300 MHz, CDCl3) d 7.70 (d, 1H, J¼
7.9 Hz), 7.44 (t, 2H, J¼8.1 Hz), 7.23–7.11 (m, 6H), 3.73
(s, 3H), 3.63 (d, 1H, J¼14.0 Hz), 3.56 (d, 1H, J¼14.0 Hz);
13C NMR (100 MHz, CDCl3) d 198.1, 169.6, 151.6, 136.1,
134.2, 130.9, 130.1, 128.0, 127.4, 127.2, 125.3, 123.9,
64.6, 53.7, 39.9; IR (NaCl, neat) 2952, 1738, 1699, 1589,
Acknowledgements
1450 cmꢁ1
;
299.0742. Found: 299.0739.
HRMS (FAB+) calcd for C17H15O3S:
We thank the National Institute of General Medical Sciences
(GM72586) for partial support of this research. J.L.M.
thanks GEM, McNair, and the NIH (GM534692—Supple-
ment) for fellowship support. M.S.K. thanks Boehringer
3.2.2.4. 2-Methoxycarbonylmethyl-3-oxo-2,3-dihydro-
benzo[b]thiophene-2-carboxylic acid methyl ester (19).

11482
J. L. Moore et al. / Tetrahedron 62 (2006) 11477–11482
9. Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127,
62–63.
10. Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2005, 44, 6924–6927.
11. Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846–2847.
12. Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239–258.
13. For reviews, see: (a) Enders, D.; Balensiefer, T. Acc. Chem.
Res. 2004, 37, 534–541; (b) Johnson, J. S. Angew. Chem.,
Int. Ed. 2004, 43, 1326–1328; (c) Pohl, M.; Lingen, B.;
Ingelheim for a graduate fellowship. T.R. thanks Johnson
and Johnson, Merck Research Laboratories, GlaxoSmith-
Kline, Eli Lilly, Amgen, and Boehringer Ingelheim for
unrestricted support, and the Monfort Family Foundation
for a Monfort Professorship. T.R. is a fellow of the Alfred
P. Sloan Foundation. We thank Jerry Murry and Michael
C. Hillier (Merck Research Laboratories) for a generous
gift of aminoindanol. We thank Susan M. Miller (CSU) for
X-ray analysis.
€
Muller, M. Chem.—Eur. J. 2002, 8, 5288–5295.
14. Breslow, R. J. J. Am. Chem. Soc. 1958, 80, 3719–3726.
15. (a) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41,
1743–1745; (b) Enders, D.; Breuer, K. Helv. Chim. Acta
1996, 79, 1217–1221; (c) Aitken, R. A.; Thomas, A. W. Hetero-
cyclic Acyl and Formyl Anion Equivalents. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic:
San Diego, CA, 2001; Vol. 79, pp 89–115; (d) Knight, R. L.;
Leeper, F. J. Tetrahedron Lett. 1997, 38, 3611–3614; (e)
Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1
1998, 1891–1893; (f) Dudding, T.; Houk, K. N. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5770–5775; (g) Sheehan, J. C.;
Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666–3667.
16. (a) Linghu, X.; Bausch, C. C.; Johnson, J. S. J. Am. Chem.
Soc. 2005, 127, 1833–1840; (b) Enders, D.; Niemeier, O.;
Balensiefer, T. Angew. Chem., Int. Ed. 2006, 45, 1–6; (c)
Hachisu, Y.; Bode, J. W.; Suzuki, K. Adv. Synth. Catal. 2004,
346, 1097–1100; (d) D€unnwald, T.; Demir, A. S.; Siegert, P.;
Pohl, M.; M€uller, M. Eur. J. Org. Chem. 2000, 2161–2170.
17. (a) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639–648;
(b) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407–496.
18. (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298–10299; (b) Kerr, M. S.; Rovis, T. Synlett
2003, 1934–1936; (c) Kerr, M. S.; Rovis, T. J. Am. Chem.
Soc. 2004, 126, 8876–8877; (d) Read de Alaniz, J.; Rovis, T.
J. Am. Chem. Soc. 2005, 127, 6284–6289; (e) Kerr, M. S.;
Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725–
5728; (f) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128,
2552–2553; (g) Pesch, J.; Harms, K.; Bach, T. Eur. J. Org.
Chem. 2004, 2025–2035; (h) Mennen, S. M.; Blank, J. T.;
Supplementary data
Synthesis and characterization for starting materials are
provided in Supplementary data. Supplementary data asso-
ciated with this article can be found in the online version,
at doi:10.1016/j.tet.2006.06.042.
References and notes
1. (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
1998, 37, 389–401; (b) Douglas, C. J.; Overman, L. E. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367; (c) Challenges
and Solutions for Organic Synthesis; Christoffers, J., Ed.;
Wiley-VCH: Weinheim, 2005.
2. (a) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56,
9843–9873; (b) Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503–9569.
3. Shibasaki, M.; Vogl, E. M. Comprehensive Asymmetric Cataly-
sis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
New York, NY, 1999; pp 475–487.
4. (a) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42,
3921–3924; (b) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am.
Chem. Soc. 2003, 125, 13368–13369.
5. Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121,
6759–6760.
6. Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2001, 40, 1456–1460.
7. Battacharya, A.; Dolling, U. H.; Grabowski, E. J. J.; Karady, S.;
Ryan, K. M.; Weinstock, L. M. Angew. Chem., Int. Ed. Engl.
1986, 25, 476–477.
ꢀ
Tran-Dube, M. B.; Imbriglio, J. E.; Miller, S. J. Chem.
Commun. 2003, 195–197.
19. (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc.
1915, 107, 1080–1106; (b) Ingold, C. K. J. Chem. Soc. 1921,
119, 305–329.
˚
8. Ahman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918–1919.