The effect of pre-existing stereocenters in the intramolecular asymmetric Stetter reaction

Article abstract of DOI:10.1016/j.tet.2005.03.121

A series of disubstituted cyclopentanones have been synthesized by the intramolecular Stetter reaction. Racemic substrates containing one chiral center were used, allowing us the opportunity to observe a parallel kinetic resolution in the synthesis of 2,3- and 2,4-disubstituted cyclopentanones. The Stetter reaction of 2,5-disubstituted cyclopentanones proved to be substrate controlled, resulting in the selective formation of the cis-diasteromers with low ee.

Full text of DOI:10.1016/j.tet.2005.03.121

Tetrahedron 61 (2005) 6368–6378
The effect of pre-existing stereocenters in the intramolecular
asymmetric Stetter reaction
*
Nathan T. Reynolds and Tomislav Rovis
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 23 November 2004; revised 27 January 2005; accepted 4 March 2005
Available online 27 April 2005
Abstract—A series of disubstituted cyclopentanones have been synthesized by the intramolecular Stetter reaction. Racemic substrates
containing one chiral center were used, allowing us the opportunity to observe a parallel kinetic resolution in the synthesis of 2,3- and 2,4-
disubstituted cyclopentanones. The Stetter reaction of 2,5-disubstituted cyclopentanones proved to be substrate controlled, resulting in the
selective formation of the cis-diasteromers with low ee.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The application of chiral catalysts to racemic substrates
offers the opportunity for kinetic resolution.6 Kinetic
resolutions by non-enzymatic systems have become
increasingly valuable. Traditional kinetic resolution occurs
when one enantiomer of substrate reacts at a faster rate than
the other allowing for the synthesis of enantiopure product
with a maximum yield of 50%. Dynamic kinetic resolution
occurs when the pre-existing stereocenter is racemized
faster than the desired enantioselective process offering the
potential to synthesize single enantiomer products in high
yields from racemic material. Parallel kinetic resolution
occurs when different products are formed from each
substrate enantiomer.7 In this context, we became interested
in assessing the impact of substitution at every position
between the aldehyde and the Michael acceptor on rate and
enantioselectivity in the intramolecular asymmetric Stetter
reaction (Eq. 1).
The asymmetric synthesis of disubstituted cyclopentanones
remains a challenge for organic chemists. The most
common route to disubstituted cyclopentanones relies on
conjugate addition to an appropriately substituted cyclo-
pentenone. This strategy has been used for the enantiopure
synthesis of 2,3- and 2,4-disubstituted cylcopentanones, the
latter via kinetic resolution.1 We have recently developed a
family of catalysts for the asymmetric intramolecular Stetter
reaction, which are capable of forming substituted cyclo-
pentanones in high ee and yield (Fig. 1).2–5 During the
course of these investigations, we became interested in the
effect of pre-existing stereocenters in the backbone.
Although we were naturally intrigued by the possibility of
inducing a kinetic resolution, we were also cognizant of the
need to understand how these catalysts would behave with
chiral substrates, since one might envision using this
reaction at a late stage in a complex molecule synthesis.
Herein, we describe our results.
(1)
2. 2,4-Disubstituted cyclopentanones
2.1. Substrate synthesis
Substrate synthesis commenced with the appropriate
3-substituted glutaric anhydride. Reduction with sodium
borohydride provides the 3-substituted lactone. Further
reduction with Dibal-H affords the lactol that may be treated
with (carboethoxymethylene) triphenyl-phosphorane.
Figure 1. Catalysts for the intramolecular asymmetric Stetter reaction.
Keywords: Stetter reaction; Cyclopentanones; Stereoselective.
*
Corresponding author. Tel.: C1 970 491 7208; fax: C1 970 491 1801;
e-mail: rovis@lamar.colostate.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.121

N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
6369
Scheme 1. Synthesis of 7 and 8.
Swern oxidation of the resultant primary alcohol completes
a four step unoptimized synthesis of 7 and 8 (Scheme 1).
treatment with N,N-dimethyl hydrazine. Alkylation of this
intermediate with iodomethane, followed by removal of the
hydrazone afforded the intermediate aldehyde.9 The alde-
hyde was treated with (carboethoxymethylene) triphenyl-
phosphorane, followed by triflouroacetic acid to afford 12
(Scheme 3).
2.2. Intramolecular Stetter results
The results for the cyclization of 7 and 8 are shown in
Scheme 2. Substrate 7 cyclizes to provide trans-9 in 98% ee
and cis-9 in 94% ee, as an equimolar mixture of inseparable
diastereomers. Substrate 8 cyclizes to provide trans-10 in
98% ee and cis-10 in 96% ee, as an equimolar mixture. The
outcome appears to be independent of steric bulk suggesting
that the pre-existing stereocenters at the 5-position have no
effect on the intramolecular Stetter reaction.
The synthesis of 14 began with the addition of allyl
magnesium chloride to isopropylacrolein. The secondary
alcohol then underwent an anionic oxy-cope rearrarange-
ment by treatment with KH in hot dioxane. Treatment of the
resulting aldehyde with (carboethoxymethylene) triphenyl-
phosphorane, followed by Lemieux oxidation affords 14
(Scheme 4).10
3. Synthesis of 2,3-disubstituted cyclopentanones
3.1. Substrate synthesis
3.2. Intramolecular Stetter results
The results for the cyclization of 12 and 14 are shown in
Scheme 5. Upon treatment with catalyst A, 12 cyclizes
smoothly to afford trans-15 in 90% ee and cis-15 in 95% ee,
again as an inseparable mixture of diastereomers. Subjec-
tion of 14 to catalyst A revealed a different picture affording
cis-16 in 96% ee, and trans-16 in 84% ee. The lower
Two different routes were used for the synthesis of
substrates 12 and 14. The synthesis of 12 began with the
differentially protected dialdehyde from the Schreiber
ozonolysis of cyclopentene.8 The hydrazone is formed by
Scheme 2. Synthesis of 2,4-disubstituted cyclopentanones.
Scheme 3. Synthesis of 12.

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N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
Scheme 4. Synthesis of 14.
enantioselectivity for the latter was reflected in a slightly
skewed diastereomeric mixture of these two, favoring trans-
16 by 53:47. These results could be improved by the use of
catalyst B.
(6)
4. Synthesis of 2,5-disubstituted cylopentanones
4.1. Substrate synthesis
4.2. Synthesis of 2,5-disubstituted cyclopentanones
The synthesis of substrate 19 began with alkylation of
hydrocinnamaldehyde N,N-dimethyl hydrazone with
4-bromobutene.11 After hydrazone cleavage, the aldehyde
was subjected to cross metathesis with methyl acrylate,12
providing 19 (Scheme 6).
The results for the cyclization of 19 and 21 are shown in
Scheme 7. Under the conditions used for the previous
substrates (20 mol% catalyst), 19 failed to give reproducible
results, a situation that was rectified upon increasing the
catalyst loading to 50 mol%. Cyclization of 19 affords a
95% yield of product, with 85:15 selectivity favoring the cis
diastereomer, formed as a racemate. Cyclization of 21
affords cis-23 in low ee but excellent selectivity over its
trans isomer, validating the fact that the alpha stereocenters
overrides catalyst preference and determines selectivity in
Substrate 21 was made by cross metathesis of 5-cyclohexyl-
hex-5-enal (20) with methyl acrylate (Eq. 6). The enal 20
was prepared in direct analogy to the precursor to 13 (see
Scheme 4).
Scheme 5. Synthesis of 2,3-disubstituted cyclopentanones.
Scheme 6. Synthesis of 19.

N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
6371
Scheme 7. Synthesis of 2,5-disubstituted cyclopentanones.
these cyclizations. In an incomplete reaction with this
substrate (Eq. 8), we noted that the unreacted starting
material was modestly enantioenriched which corresponds
to an s value of 1.4.
6. Conclusion
We have shown that the Stetter reaction is a viable option
for the synthesis of disubstituted cyclopentanones. 2,3- and
2,4-disubstituted cyclopentanones are synthesized via a
parallel kinetic resolution providing both trans and cis
diastereomers in high ee. There appears to be little effect of
steric bulk at the 4- and 5- positions of the substrates
indicating that there is very little interaction with the
catalyst. Substituents next to the aldehyde seem to override
catalyst control and dictate the course of the reaction to
selectively form the 2,5-cis disubstituted cyclopentanones
in good yield.
5. Kinetic and thermodynamic ratios
In light of the above results we set out to determine the
kinetic and thermodynamic ratios for the disubstituted
cyclopentanones 10, 16, and 22. The kinetic ratios were
determined by cyclization with 1 equiv of achiral triazolium
salt and the thermodynamic ratios were determined by
heating the substrates in toluene in the presence of excess
triethylamine (Scheme 8). It is intriguing to note that the
achiral catalyst provides low selectivity in the formation of
22. This is in sharp contrast to the ability of our chiral
triazolium salts to form the cis product in high diastereo-
selectivity, a situation that we ascribe to the large steric
differences between the achiral and chiral azolium salts.
7. Experimental
7.1. General
General procedure for the intramolecular asymmetric
Stetter reaction. To a flame dried round bottom flask was
Scheme 8. Kinetic and thermodynamic ratios of disubstituted cyclopentanones.

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N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
added 0.2 equiv of catalyst. Toluene (5 mL) was then added
followed by KHMDS (0.5 M in tetrahydrofuran). The
solution was stirred for 10 min followed by the addition of
substrate. After 24 h the reaction mixture was filtered
through a short plug of silica gel eluting with diethyl ether.
Column chromatography (9:1, hexane/ethyl acetate)
afforded analytically pure material.
The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The clear oil was purified by column
chromatography (3:1, hexane/ethyl acetate) affording 1.01 g
product as a colorless oil (5.7 mmol, 60%). RfZ0.13 (3:1,
1
hexane/ethyl acetate); H NMR (400 MHz, CDCl3) d 7.21
(m, 5H), 4.42 (m, 1H), 4.30 (ddd, 1H, JZ11.2, 10.7,
3.6 Hz), 3.15 (m, 1H), 2.82 (m, 1H), 2.54 (m, 1H), 2.08 (m,
1H), 1.94 (m, 1H); 13C NMR (400 MHz, CDCl3) d 170.5,
142.7, 128.8, 127.0, 126.3, 68.5, 37.4, 37.2, 30.1.
7.1.1. 4-Methyl-tetrahydro-pyran-2-one (1).15
7.1.3. 4-Methyl-tetrahydro-pyran-2-ol (3).
To a stirred solution of 3-methylglutaric anhydride (1.0 g,
7.8 mmol) in 30 mL tetrahydrofuran was added sodium
borohydride (0.59 g, 15.6 mmol). After stirring overnight,
10 mL of 10% v/v HCl was slowly added. The solution was
then placed in a separatory funnel and extracted with diethyl
ether (3!). The organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo. The yellow oil was
then dissolved in 5 mL methylene chloride and 0.3 mL
trifluoroacetic acid was added followed by stirring over-
night. To the mixture was then added 50 mL diethyl ether
and the solution placed in a separatory funnel, followed by
washing with sat. aq. NaHCO3 (3!), and brine (1!). The
organic layer was then dried over MgSO4 and concentrated
in vacuo. The resulting oil was then purified by column
chromatography eluting with (9:1, hexane/diethyl ether) to
afford 0.260 g product (2.28 mmol, 29%). RfZ0.18 (3:1
To a stirred solution of 1 (0.260 g, 2.28 mmol) in 10 mL
toluene at K78 8C was added Dibal-H (3.0 mL, 3.00 mmol,
1 M in hexane). The mixture was stirred for 2 h at which
time 10 mL of a saturated aq. solution of Rochelle’s Salt
was added. The solution was allowed to warm to room
temperature and stirred overnight. 10 mL of a saturated aq.
solution of sodium bicarbonate was added and the organic
layer was separated. The aq. layer was then extracted 3!
with 10 mL diethyl ether. The organic layers were dried
over MgSO4, and concentrated in vacuo. This afforded
0.203 g of pure product as a mixture of diastereomers
(1.75 mmol, 77%). RfZ0.17 (3:1, hexane/ethyl acetate); 1H
NMR (300 MHz, CDCl3) d 5.27 (s, 1H), 4.65 (d, 1H, JZ
9.2 Hz), 3.99 (m, 2H), 3.62 (m, 1H), 3.48 (ddd, 1H, JZ12.1,
11.9, 2.2 Hz), 3.41 (s, 1H), 2.83 (s, 1H), 2.00 (m, 1H), 1.89
(m, 1H), 1.46–1.77 (m, 4H), 1.15–1.34 (m, 3H), 1.04 (m,
1H), 0.97 (d, 3H, JZ6.6 Hz), 0.91 (d, 3H, JZ6.6 Hz); 13C
NMR (75 MHz, CDCl3) d 96.1, 91.5, 65.6, 59.7, 41.6, 38.7,
34.1, 33.5, 29.4, 23.6, 22.1, 21.9; IR (NaCl, neat) 3386,
1
hexane/ethyl acetate); H NMR (300 MHz, CDCl3) d 4.39
(m, 1H), 4.23 (ddd, 1H, JZ11.2, 10.6, 3.7 Hz), 2.65 (m,
1H), 2.03–2.13 (m, 2H), 1.89 (m, 1H), 1.49 (m, 1H), 1.04 (d,
3H, JZ6.23 Hz); 13C NMR (75 MHz, CDCl3) d 171.0, 68.5,
38.2, 30.7, 26.6, 21.5; IR (NaCl, neat) 1732, 1458, 1444,
1257, 1229 cmK1
.
2952, 2928, 1068, 1026, 988 cmK1
.
7.1.2. 4-Phenyl-tetrahydro-pyran-2-one (2).15
7.1.4. 4-Phenyl-tetrahydro-pyran-2-ol (4).
A flame-dried flask was charged with 3-phenylglutaric acid
(2.00 g, 9.6 mmol) and 30 mL methylene chloride. The
solution was cooled to 0 8C and triflouroacetic anhydride
(4.0 mL, 28.8 mmol) was added. The mixture was stirred for
2 h at this temperature, then concentrated in vacuo. The
solution was placed under vacuum (1 mmHg) overnight.
The white solid was then dissolved in 50 mL tetrahydro-
furan and sodium borohydride was added (0.73 g,
19.2 mmol), followed by stirring for 24 h. 20 mL 10% v/v
HCl was then slowly added, followed by 20 mL diethyl
ether; the layers were separated and the aq. layer was
extracted with 20 mL diethyl ether. The combined organic
layers were dried over MgSO4 and concentrated in vacuo
affording an oil. The oil was dissolved in 50 mL methylene
chloride and 1 mL triflouroacetic acid was added, followed
by stirring for 16 h. 50 mL saturated. aq. sodium bicarbon-
ate was slowly added and the layers separated. The organic
layer was extracted with 20 mL methylene chloride (2!).
2 (0.50 g, 2.8 mmol) was dissolved in 20 mL toluene and
chilled to K78 8C. Dibal-H (0.54 mL, 3.0 mmol) was then
added and the reaction stirred for 2 h at K78 8C. Methanol
(1 mL) was then added and the solution warmed to room
temperature. Diethyl ether 20 mL and Rochelle’s salt
(saturated. aq. 20 mL) were then added. The solution was
stirred until the layers separated. The layers were separated
and the aq. layer was extracted with diethyl ether (50 mL).
The combined organics were dried over MgSO4, and
concentrated in vacuo. Column chromatography (3:1,
hexane/diethyl ether) afforded 0.370 g product as a white
solid (mixture of diastereomers) (2.1 mmol, 75%). RfZ0.15
1
(3:1, hexane/ethyl acetate); H NMR (300 MHz, CDCl3) d
7.19–7.30 (m, 10H), 5.41 (s, 1H), 4.80 (s, 1H), 4.11–4.19
(m, 2H), 3.74 (m, 1H), 3.64 (m, 1H), 3.16–3.24 (m, 2H),
2.82 (m, 1H), 2.67 (s, 1H), 2.12 (m, 1H), 1.97 (m, 1H), 1.69–
1.84 (m, 5H), 1.56 (m, 1H); 13C NMR (300 MHz, CDCl3) d
145.5, 144.5, 128.6, 128.5, 127.4, 126.8, 126.7, 126.6,

N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
6373
126.3, 96.3, 91.7, 65.8, 59.8, 40.6, 40.3, 37.5, 34.5, 33.0,
32.8.
with brine, dried over MgSO4, and concentrated in vacuo.
The oil was subjected to column chromatography (4:1,
hexane/ethyl acetate), affording 0.400 g (2.17 mmol, 48%)
of product as a clear oil. RfZ0.13 (3:1, hexane/ethyl
7.1.5. 7-Hydroxy-5-methyl-hept-2-enoic acid ethyl ester
(5).
1
acetate); H NMR (300 MHz, CDCl3) d 9.75 (t, 1H, JZ
1.5 Hz), 6.89 (m, 1H), 5.83 (d, 1H, JZ15.6 Hz), 4.18 (q,
2H, JZ7.2 Hz), 2.43 (m, 1H), 2.13–2.33 (m, 4H), 1.28 (t,
3H, JZ7.3 Hz), 1.00 (d, 3H, JZ6.2 Hz); 13C NMR
(75 MHz, CDCl3) d 201.7, 166.3, 146.2, 123.5, 60.3, 50.2,
39.1, 27.5, 19.9, 14.2; IR (NaCl, neat) 1721, 1654, 1270,
1167 cmK1; HRMS (FABC) calcd for C10H16O3,
184.1099. Found 184.1099.
To a stirred solution of 3 (0.083 g, 0.714 mmol) in 5 mL
tetrahydrofuran was added (carboethoxymethylene) tri-
phenyl-phosphorane (0.497 g, 1.4 mmol). The solution
was heated to 40 8C and stirred overnight. The solution
was concentrated in vacuo and subjected to column
chromotagraphy (3:1, hexane/ethyl acetate) affording
0.107 g product as a clear oil (0.62 mmol, 87%). RfZ0.06
7.1.8. 7-Oxo-5-phenyl-hept-2-enoic acid ethyl ester (8).
1
(3:1, hexane/ethyl acetate); H NMR (300 MHz, CDCl3) d
6.93 (m, 1H), 5.82 (d, 1H, JZ15.7 Hz), 4.18 (q, 2H, JZ
7.1 Hz), 3.69 (m, 2H), 2.23 (m, 1H), 2.08 (m, 1H), 1.81 (m,
1H), 1.63 (m, 1H), 1.43 (m, 1H), 1.28 (t, 3H, JZ7.1 Hz),
0.94 (d, 3H, JZ6.6 Hz).
To a flamed dried flask was added 10 mL methylene
chloride and oxalyl chloride (0.29 mL, 3.34 mmol). The
solution was cooled to K78 8C and DMSO (0.47 mL,
6.60 mmol) was added. After 5 min 6 (0.75 g, 3.0 mmol)
was added. The solution was stirred for 15 min, followed by
addition of triethylamine (1.52 g, 15 mmol). After 5 min the
solution was warmed to room temperature and stirred
overnight. Water (50 mL) was added and the layers
separated, followed by extraction with methylene chloride.
The combined organics were dried over MgSO4 and
concentrated in vacuo. The oil was subjected to column
chromatography (4:1, hexane/ethyl acetate) affording 0.45 g
of product as a yellow oil (1.8 mmol, 60%). RfZ0.17 (3:1,
7.1.6. 7-Hydroxy-5-phenyl-hept-2-enoic acid ethyl ester
(6).
To a flame dried flask was added (carboethoxymethylene)
triphenyl-phosphorane (4.5 g, 12.9 mmol) and 20 mL tetra-
hydrofuran, followed by addition of 4 (1.25 g, 10.8 mmol).
The mixture was stirred overnight and subjected directly to
column chromatography (4:1, hexane/ethyl acetate), afford-
ing 0.82 g of product (3.3 mmol, 31%). RfZ0.20 (3:1,
1
hexane/ethyl acetate); H NMR (300 MHz, CDCl3) d 9.67
(d, 1H, JZ1.5 Hz), 7.28 (m, 5H), 6.79 (m, 1H), 5.79 (dd,
1H, JZ37.1, 1.1 Hz), 4.15 (q, 2H, JZ7.0 Hz), 3.39 (m, 1H),
2.78 (d, 2H, JZ7.3 Hz), 2.55 (t, 2H, JZ7.0 Hz) 1.26 (t, 3H,
JZ7.0 Hz); 13C NMR (300 MHz, CDCl3) d 200.8, 166.1,
145.5, 142.4, 128.8, 127.3, 127.0, 123.6, 60.3, 49.4, 39.0,
1
hexane/ethyl acetate); H NMR (300 MHz, CDCl3) d 7.22
14.2; IR (NaCl, neat) 1721, 1660, 1276, 1204 1045 cmK1
;
HRMS (FABC) calcd for C15H18O3, 247.1334. Found
247.1335.
(m, 5H), 6.81 (m, 1H), 6.75 (d, 1H, JZ15.6 Hz), 4.12 (q,
2H, JZ7.0 Hz), 3.48 (m, 1H), 2.90 (m, 1H), 2.51 (ddd, 2H,
JZ7.4, 7.4, 1.2 Hz), 1.97 (m, 1H), 1.81 (m, 1H), 1.23 (t, 3H,
JZ7.2 Hz), 1.13 (s, 1H, –OH); 13C NMR (300 MHz,
CDCl3) d 166.4, 146.8, 143.5, 128.7, 128.5, 147.5, 126.7,
122.9, 60.7, 60.2, 41.6, 39.6, 38.6, 14.2.
7.1.9. (4-Methyl-2-oxo-cyclopentyl)-acetic acid ethyl
ester (9).
7.1.7. 5-Methyl-7-oxo-hept-2-enoic acid ethyl ester (7).
According to the general procedure, 7 (0.035 g, 0.19 mmol),
catalyst A (0.014 g, 0.038 mmol), and KHMDS (0.076 mL,
0.038 mmol, 0.5 M in tetrahydrofuran), produced the
product as a 1:1, mixture of inseparable diastereomers.
Purification by column chromatography (95:5, hexane/
diethyl ether) afforded 9 (34.0 mg, 97%). RfZ0.44 (3:1,
Oxalyl chloride (0.628 g, 4.95 mmol) and 10 mL methylene
chloride was added to a flask and chilled to K78 8C. DMSO
(0.773 g, 9.90 mmol) was added and the solution stirred for
5 min, then 5 (0.84 g, 4.50 mmol) in 10 mL methylene
chloride was added. After 15 min triethylamine (2.29 g,
22.50 mmol) was added, the mixture was stirred for 5 min at
K78 8C, then allowed to warm to room temperature and
stirred overnight. 20 mL water was added and the organic
layer separated. The aqeous layer was extracted 2! with
10 mL methylene chloride. The organic layers were washed
1
hexane/ethyl acetate); H NMR (300 MHz, CDCl3) d 4.13
(q, 4H, JZ7.3 Hz), 2.64–2.74 (m, 3H), 2.33–2.54 (m, 7H),
2.19 (m, 1H), 1.78–2.03 (m, 4H), 1.25 (t, 6H, JZ7.2 Hz),
1.14 (d, 3H, JZ6.4 Hz), 1.09 (d, 3H, JZ6.4 Hz); 13C NMR
(75 MHz, CDCl3) d 219.7, 218.7, 172.1, 172.0, 60.6, 47.2,

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N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
46.0, 45.9, 42.7, 38.0, 36.1, 34.6, 34.0, 29.6, 27.8, 20.9,
20.2, 14.2; IR (NaCl, neat) 1721, 1654, 1270, 1167 cmK1
bicarbonate solution was added and the layers separated.
The aq. layer was washed with 50 mL (2!) methylene
chloride. The combined organic extracts were dried over
MgSO4 and concentrated in vacuo to afford 4.65 g of
product (27.0 mmol, 85%). RfZ0.10 (3:1, hexane/ethyl
;
HRMS (FABC) calcd for C10H16O3, 184.1099. Found
184.1092. GC analysis (G-TA, 100 8C, 3.0 mL/min; trans
(tr (minor)Z32.4 min, tr (major)Z28.7 min), cis (tr
(minor)Z29.7 min, tr (major)Z33.8 min)) gave the
enantiomeric composition of the trans product: 98% ee,
and the cis product: 94% ee.
1
acetate); H NMR (400 MHz, CDCl3) d 6.40 (d, 1H, JZ
6.4 Hz), 4.30 (t, 1H, JZ5.5, 5.8 Hz), 3.24 (d, 6H, JZ1 Hz),
2.64 (s, 6H), 2.31 (m, 1H), 1.40 (m, 2H), 1.56 (m, 2H), 1.00
(d, 3H, JZ6.8 Hz); 13C NMR (400 MHz, CDCl3) d 143.3,
104.4, 52.6, 52.5, 43.2, 36.8, 30.1, 30.0, 19.0.
7.1.10. (2-Oxo-4-phenyl-cyclopentyl)-acetic acid ethyl
ester (10).
N0-(5,5-Dimethoxy-2-methyl-pentylidene)-N,N-dimethyl-
hydrazine (1.50 g, 7.4 mmol) was dissolved in 100 mL
tetrahydrofuran and 100 mL 0.1 M pHZ7 phosphate buffer
(95 mL H2O, 2.85 mL 1 M Na2HPO4, 2.12 mL 1 M
NaH2PO4). Sodium periodate (8.5 g, 40.0 mmol) was
added and the mixture stirred overnight. The solution was
then diluted with 100 mL diethyl ether and the layers
separated. The aq. layer was then extracted with 100 mL
diethyl ether. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Column chromato-
graphy (4:1, hexane/diethyl Ether) afforded 0.4 g of product
as a clear oil (2.5 mmol, 34%). RfZ0.38 (3:1, hexane/ethyl
acetate); 1H NMR (400 MHz, CDCl3) d 9.56 (s, 1H), 4.29 (t,
1H, JZ5.5 Hz), 3.25 (s, 6H), 2.29 (m, 1H), 1.72 (m, 1H),
1.56 (m, 1H), 1.33 (m, 1H), 1.04 (d, 3H, JZ7.0 Hz); 13C
NMR (400 MHz, CDCl3) d 204.5, 104.1, 52.7, 45.8, 29.7,
25.2, 13.3.
According to the general procedure, 8 (25.0 mg,
0.10 mmol), catalyst A (7.5 mg, 0.02 mmol), and KHMDS
(0.040 mL, 0.02 mmol, 0.5 M in tetrahydrofuran), produced
the product as a 50:50 mixture of inseparable diastereomers.
Purification by column chromatography (95:5, hexane/
diethyl Ether) afforded 9 (24.0 mg, 96%). RfZ0.25 (3:1,
hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) d 7.19–
7.34 (m, 10H), 4.09–4.15 (m, 4H), 3.59 (m, 1H, trans), 3.35
(m, 1H, cis), 2.30–2.80 (m, 12H), 2.22 (m, 1H), 1.81 (m,
1H), 1.23 (ddd, 6H, JZ7.1, 7.1, 2.6 Hz); 13C NMR
(300 MHz, CDCl3) d 218.7, 217.2, 171.9, 171.8, 143.8,
142.8, 128.7, 126.8, 126.7, 126.6, 60.7, 46.9, 45.2, 44.7,
42.9, 40.1, 38.3, 37.2, 36.4, 34.6, 33.8, 14.2; IR (NaCl, neat)
1734, 1180 cmK1; HRMS (FABC) calcd for C15H18O3,
247.1334. Found 247.1322. GC analysis (G-TA, 140 8C,
3.0 mL/min; trans (tr (minor)Z78.9 min, tr (major)Z
76.2 min), cis (tr (minor)Z84.5 min, tr (major)Z
90.6 min)) gave the enantiomeric composition of the trans
product: 98% ee, and the cis product: 96% ee.
7.1.12. 4-Methyl-7-oxo-hept-2-enoic acid ethyl ester (12).
7.1.11. 5,5-Dimethoxy-2-methyl-pentanal (11).
(Carboethoxymethylene) triphenyl-phosphorane (0.98 g,
2.8 mmol) was dissolved in 20 mL tetrahydrofuran and 11
(0.37 g, 2.3 mmol) was added. The reaction was stirred
overnight. The reaction was concentrated and subjected
directly to column chromatography (4:1, hexane/ethyl
acetate) to afford 0.43 g of product as a clear oil
To 5,5-dimethoxy-pentanal (21.05 g, 144.0 mmol) stirred at
0 8C was added N,N-dimethyl hydrazine (13.12 mL,
172.0 mmol) with continued stirring for 30 min. 50 mL
water and 50 mL diethyl ether were added followed by
removal of the aq. layer. The organic layer was dried over
MgSO4, and concentrated in vacuo affording 23.36 g of
product that was used without purification. To a solution of
diisopropyl amine (4.78 g, 47.2 mmol) in 50 mL tetra-
hydrofuran at K78 8C was added 1.5 M n-butyllithium
(31.9 mL, 47.2 mmol). The mixture was warmed to 0 8C
over 5 min and then cooled to K78 8C. N0-(5,5-Dimethoxy-
pentylidene)-N-N-dimethyl-hydrazone (5.08 g, 27.0 mmol)
in 50 mL tetrahydrofuran was then added and the mixture
was stirred at 0 8C for 2 h, then cooled to K78 8C. Methyl
iodide (5.75 g, 40.5 mmol) was then added and the solution
stirred for 1 h at this temperature. The solution was then
warmed to room temperature and stirred for 1 h. The
solution was poured into 200 mL of a 2:1 solution of
H2O/methylene chloride. 50 mL saturated sodium
1
(1.9 mmol, 81%). RfZ0.59 (3:1, hexane/ethyl acetate); H
NMR (300 MHz, CDCl3) d 6.82 (m, 1H), 5.76 (d, 1H, JZ
15.8 Hz), 4.31 (t, 1H, JZ5.3 Hz), 4.16 (q, 2H, JZ7.1 Hz),
3.28 (s, 6H), 2.29 (m, 1H), 1.56 (m, 2H), 1.41 (m, 2H), 1.26
(t, 3H, JZ7.1 Hz), 1.04 (d, 3H, JZ6.8 Hz); 13C NMR
(300 MHz, CDCl3) d 166.7, 153.8, 120.0, 104.4, 60.1, 52.8,
52.7, 36.3, 30.7, 30.2, 19.4, 14.2.
7,7-Dimethoxy-4-methyl-hept-2-enoic acid ethyl ester

N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
6375
(0.53 g, 2.3 mmol) was dissolved in 10 mL dichloro-
methane. H2O (1 mL), triflouroacetic acid (0.5 mL) were
added and the solution stirred overnight. Aq. sodium
bicarbonate (20 mL) was added and the layers separated.
The aq. layer was extracted with 10 mL diethyl ether. The
combined organics were dried over MgSO4, concentrated in
vacuo, and subjected to column chromatography (95:5,
hexane/ethyl acetate) affording 0.31 g of product as a clear
oil (1.7 mmol, 72%). RfZ0.36 (9:1, hexane/ethyl acetate);
1H NMR (300 MHz, CDCl3) d 9.73 (s, 1H), 6.76 (dd, 1H,
JZ15.8, 8.1 Hz), 5.76 (d, 1H, JZ15.8 Hz), 4.15 (q, 2H, JZ
7.0 Hz), 2.41 (t, 2H, JZ8.1 Hz), 2.33 (m, 1H), 1.68 (m, 2H),
1.25 (t, 3H, JZ7.2 Hz), 1.05 (d, 3H, JZ6.8 Hz); 13C NMR
(300 MHz, CDCl3) d 201.6, 166.5, 152.7, 120.7, 60.2, 41.4,
35.8, 27.7, 19.3, 14.1; IR (NaCl, neat) 1719, 1270,
1179 cmK1; HRMS (FABC) calcd for C10H16O3,
185.1177. Found 185.1179.
7.0 Hz); 13C NMR (300 MHz, CDCl3) d 166.4, 151.2,
138.3, 122.3, 114.6, 60.2, 48.6, 31.7, 31.7, 30.7, 20.7, 19.2,
14.4.
7.1.14. 4-Isopropyl-7-oxo-hept-2-enoic acid ethyl ester
(14).
13 (0.50 g, 2.4 mmol), was dissolved in 8 mL t-BuOH and
2 mL H2O followed by the addition of trimethylamine
N-oxide dihydrate (0.20 g, 2.6 mmol), pyridine (0.19 g,
2.4 mmol), OsO4 (1.45 mL, 0.24 mmol, 4 wt % solution in
H2O) and stirred at 80 8C overnight. Et2O (50 mL) was
added and the layers separated. The organics were dried
over MgSO4, concentrated in vacuo and dissolved in 50 mL
toluene. Lead tetraacetate (1.37 g, 3.1 mmol) was then
added followed by stirring for two h. Silica gel (2.0 g) was
then added followed by concentrating in vacuo. Column
chromatography afforded 0.17 g of the desired product
(0.80 mmol, 34%). RfZ0.20 (3:1, hexane/ethyl acetate); 1H
NMR (400 MHz, CDCl3) d 9.71 (s, 1H), 6.67 (dd, 1H, JZ
15.7, 9.9 Hz), 6.74 (d, 1H, JZ15.7 Hz), 4.16 (q, 2H, JZ
7.0 Hz), 2.36 (m, 2H), 1.89 (m, 2H), 1.62 (m, 2H), 1.26 (t,
3H, JZ7.0 Hz), 0.89 (d, 3H, JZ6.6 Hz), 0.85 (d, 3H, JZ
7.0 Hz); 13C NMR (300 MHz, CDCl3) d 201.5, 166.0,
150.0, 123.0, 60.3, 48.6, 42.0, 31.8, 23.7, 20.5, 19.2, 14.3;
IR (NaCl, neat) 1719, 1254, 1164 cmK1; HRMS (FABC)
calcd for C12H20O3, 213.1491. Found 213.1498.
7.1.13. 4-Isopropyl-octa-2,7-dienoic acid ethyl ester (13).
Isopropylacrolein (4.00 g, 40.8 mmol) was dissolved in
100 mL tetrahydrofuran and chilled to K78 8C. Allyl
magnesium chloride (20.3 mL, 40.8 mmol, 2.0 M solution
in tetrahydrofuran) was then added and the solution stirred
for 1 h at K78 8C. 10 mL of 10% v/v HCl was then added
and the solution warmed to room temperature. The layers
were separated and the aq. layer was extracted with 20 mL
Et2O, dried with MgSO4 and concentrated in vacuo. Column
chromatography afforded 4.80 g of product as a colorless oil
(34.2 mmol, 84%). RfZ0.54 (3:1, hexane/ethyl acetate); 1H
NMR (400 MHz, CDCl3) d 5.79 (m, 1H), 5.12 (m, 2H), 5.05
(dd, 1H, JZ1.1, 1.1 Hz), 4.91 (s, 1H), 4.12 (m, 1H), 2.40
(m, 1H), 2.25 (m, 2H), 1.64 (d, 1H, JZ4.0 Hz), 1.06 (d, 3H,
JZ6.8 Hz), 1.04 (d, 3H, JZ7.0 Hz); 13C NMR (400 MHz,
CDCl3) d 158.1, 134.8, 118.1, 107.1, 72.9, 40.9, 30.4, 23.1,
22.5.
7.1.15. (2-Methyl-5-oxo-cyclopentyl)-acetic acid ethyl
ester (15).
According to the general procedure, 12 (0.020 g,
0.11 mmol), catalyst A (0.008 g, 0.022 mmol), and
KHMDS (0.044 mL, 0.022 mmol, 0.5 M in tetrahydro-
furan), produced the product as a 50:50 mixture of
inseparable diastereomers. Purification by column chroma-
tography (95:5, hexane/diethyl ether) afforded 15 (18.0 mg,
90%). RfZ0.43 (3:1, hexane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) d 4.11–4.20 (m, 4H), 2.50–2.77 (m,
4H), 2.36 (m, 1H), 1.90–2.30 (m, 8H), 1.73 (m, 1H), 1.42
(m, 2H), 1.21–1.26 (m, 6H), 1.12 (d, 3H, JZ6.0 Hz), 0.84
(d, 3H, JZ7.2 Hz); 13C NMR (300 MHz, CDCl3) d 218.9,
218.5, 172.6, 172.1, 60.6, 53.1, 50.6, 37.6, 37.0, 34.1, 32.7,
32.2, 30.3, 29.7, 27.9, 19.1, 14.8, 14.1; IR (NaCl, neat)
1736, 1186 cmK1; HRMS (FABC) calcd for C10H16O3,
185.1177. Found 185.1183. GC analysis (G-TA, 90 8C,
2.5 mL/min; trans (tr (minor)Z44.8 min, tr (major)Z
43.3 min), cis (tr (minor)Z48.9 min, tr (major)Z
49.6 min)) gave the enantiomeric composition of the trans
product: (90% ee), and the cis product: (95% ee).
Potassium hydride (1.16 g, 29 mmol) was dissolved in
50 mL dioxane and 6-methyl-5-methylene-hept-1-en-5-ol
(2.0 g, 14.0 mmol) in 50 mL dioxane was added. The
solution was heated at 100 8C overnight. 50 mL of 10% v/v
HCl and 100 mL Et2O were then added. The layers were
separated, the organics dried over MgSO4, and concentrated
to approx. 100 mL. (carboethoxymethylene) triphenyl-
phosphorane (5.0 g, 14.4 mmol) was added and the solution
stirred overnight. Silica gel (15 g) was added and the
mixture concentrated and subjected to column chromato-
graphy affording 1.20 g of the desired product (5.7 mmol,
41%). RfZ0.56 (9:1, hexane/ethyl acetate); 1H NMR
(300 MHz, CDCl3) d 6.75 (dd, 1H, JZ9.9, 15.8 Hz), 5.76
(m, 2H), 4.97 (m, 2H), 4.81 (q, 2H, JZ7.3 Hz), 1.83–2.10
(m, 3H), 1.67 (m, 1H), 1.56 (m, 1H), 1.40 (m, 1H), 1.29 (t,
3H, JZ7.0 Hz), 0.89 (d, 3H, JZ7.0 Hz), 0.85 (d, 3H, JZ

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N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
7.1.16. (2-Isopropyl-5-oxo-cyclopentyl)-acetic acid ethyl
ester (16).
128.5, 126.4, 115.5, 52.6, 35.0, 30.1, 27.6; IR (NaCl, neat)
3064, 3028, 3977, 2926, 2855, 2715, 1728, 1641, 1603,
1497, 1454.
7.1.18. 6-Benzyl-7-oxo-hept-2-enoic acid methyl ester
(19).
According to the general procedure, 14 (0.020 g,
0.094 mmol), catalyst A (0.007 g, 0.019 mmol), and
KHMDS (0.036 mL, 0.018 mmol, 0.5 M in tetrahydro-
furan), produced the product as a 53:47 mixture of
inseparable diastereomers. Purification by column chroma-
tography (95:5, hexane/diethyl ether) afforded 16 (19.0 mg,
95%). RfZ0.49 (3:1, hexane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) d 4.06–4.15 (m, 4H), 2.78 (q, 1H, JZ
7.2 Hz), 2.59 (m, 2H), 2.53 (m, 1H), 2.35 (m, 2H), 2.15–
2.24 (m, 5H), 1.99 (m, 2H), 1.86 (m, 1H), 1.76 (m, 2H), 1.64
(m, 1H), 1.49 (m, 1H), 1.22 (q, 6H, JZ7.0 Hz), 0.96 (d, 3H,
JZ6.8 Hz), 0.92 (d, 3H, JZ6.6 Hz), 0.87 (d, 3H, JZ
6.8 Hz), 0.73 (d, 3H, JZ6.6 Hz); 13C NMR (400 MHz,
CDCl3) d 219.4, 219.3, 172.3, 172.0, 60.7, 60.6, 48.8, 48.4,
47.5, 44.9, 37.2, 36.6, 33.4, 30.5, 29.5, 27.8, 22.4, 22.3,
21.9, 21.2, 18.9, 17.5, 14.1; IR (NaCl, neat) 1736, 1372,
1252, 1183 cmK1; HRMS (FABC) calcd for C12H20O3,
213.1494. Found 213.1491. GC analysis (G-TA, 90 8C,
2.0 mL/min; trans (tr (minor)Z123.1 min, tr (major)Z
116.0 min), cis (tr (minor)Z151.8 min, tr (major)Z
141.8 min)) gave the enantiomeric composition of the
trans product: (84% ee), and the cis product: (96% ee).
To [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)
dichloro(phenylmethylene)-(tricyclohexyl phosphine)
ruthenium] (0.045 g, 0.053 mmol) in 10 mL methylene
chloride was added methyl acrylate (0.915 g, 10.6 mmol)
and 17 (0.200 g, 1.06 mmol). The solution was heated to
40 8C and stirred overnight. Silica gel (1 g) was then added
and the solvent removed in vacuo. Column chromatography
(9:1, hexane/ethyl acetate) yielded 0.176 g product
(0.72 mmol, 67%). RfZ0.40 (3:1, hexane/ethyl acetate);
1H NMR (300 MHz, CDCl3) d 9.69 (d, 1H, JZ1.8 Hz), 7.23
(m, 5H), 6.88 (m, 1H), 5.79 (d, 1H, JZ15.4 Hz), 3.72 (s,
3H), 3.03 (m, 1H), 2.70 (m, 2H), 2.22 (m, 2H), 1.83 (m, 1H),
1.61 (m, 1H); 13C NMR (300 MHz, CDCl3) d 203.7, 166.8,
147.8, 138.1, 128.9, 128.7, 126.6, 121.7, 52.5, 51.5, 35.1,
29.5, 26.6; IR (NaCl, neat) 1724, 1657, 1436, 1274,
1208 cmK1; HRMS (FABC) calcd for C15H18O3,
247.1334. Found 247.1327.
7.1.19. 2-Cyclohexyl-hex-5-enal (20).
7.1.17. 2-Benzyl-hex-5-enal (17).
2-Cyclohexyl-ethanal (5.50 g, 43.6 mmol), formaldehyde
(4.40 mL, 47.9 mmol, 30% in H2O), piperidine (0.22 mL,
2.2 mmol), and concentrated HCl (0.087 mL, 1.1 mmol)
were added to a flask equipped with a reflux condenser. The
solution was heated overnight at 80 8C. Steam distillation
followed by extraction with diethyl ether and standard aq.
workup afforded 4.0 g of product (29.0 mmol, 66%).13 1H
NMR (300 MHz, CDCl3) d 9.47 (s, 1H), 6.17 (s, 1H), 5.90
(s, 1H), 2.42 (m, 1H), 1.65–1.74 (m, 5H), 1.25–1.39 (m,
2H), 1.03–1.19 (m, 3H); 13C NMR (300 MHz, CDCl3) d
194.3, 155.3, 132.5, 35.8, 32.0, 26.4, 26.2.
To hydrocinnamaldehyde (8.80 g, 65.6 mmol) stirred at
0 8C was added N,N-dimethyl hydrazine (4.73 mL,
78.7 mmol) with continued stirring for 30 min. 50 mL
water and 50 mL diethyl ether were added followed by
removal of the aq. layer. The organic layer was dried over
MgSO4, and concentrated in vacuo affording 10.00 g of
product that was used without purification. To a solution of
LDA (12.5 mmol) in 30 mL of tetrahydrofuran at 0 8C was
added hydrocinnamaldehyde N,N-dimethylhydrazone
(2.00 g, 11.3 mmol) in 10 mL of tetrahydrofuran. The
resulting suspension was allowed to stir for 2 h at 0 8C, at
which time 4-bromo-1-butene (1.69 g, 12.5 mmol) was
added. After warming to room temperature the reaction
mixture was stirred for an additional 12 h. Aq. workup
afforded the crude alkylated hydrazone. The hydrazone was
dissolved in 50 mL acetone and 10 mL water, and 12 g of
amberlyst-15 was added. The mixture was stirred overnight.
Solution was then filtered and subject to column chroma-
tography (95:5, hexane/ethyl acetate) To afford 0.41 g of
pure product (2.2 mmol, 19%). RfZ0.42 (9:1, hexane/ethyl
A flame dried flask was charged with cyclohexylacrolein
(0.77 g, 5.6 mmol) and 10 mL by tetrahydrofuran followed
by cooling to K78 8C. Allyl magnesium chloride (3.1 mL,
6.1 mmol, 2 M in tetrahydrofuran) was added and the
reaction stirred for 1 h. The reaction was quenched 10%
HCl and extracted with ether. The organics were dried over
MgSO4, and concentrated in vacuo. The crude alcohol in
5 mL dioxane was then added to potassium hydride (0.45 g,
11.1 mmol) in 50 mL dioxane and heated overnight at
1
acetate); H NMR (300 MHz, CDCl3) d 9.68 (d, 1H, JZ
2.2 Hz), 7.24 (m, 5H), 5.73 (m, 1H), 5.01 (m, 2H), 2.97 (m,
1H), 2.71 (m, 2H), 2.09 (m, 2H), 1.78 (m, 1H), 1.57 (m, 1H);
13C NMR (300 MHz, CDCl3) d 204.4, 138.6, 137.5, 128.9,

N. T. Reynolds, T. Rovis / Tetrahedron 61 (2005) 6368–6378
6377
110 8C. Standard aq. workup and column chromatography
(95:5, hexane/diethyl ether) afforded the 0.55 g product as a
clear oil (3.1 mmol, 55%). RfZ0.63 (3:1, hexane/ethyl
7.1.22. (3-cyclohexyl-2-oxo-cyclopentyl)-acetic acid
methyl ester (23).14
1
acetate); H NMR (300 MHz, CDCl3) d 9.59 (d, 1H, JZ
3.3 Hz), 5.72 (m, 1H), 4.97 (m, 2H), 1.86–2.13 (m, 3H),
1.53–1.76 (m, 8H), 1.00–1.28 (m, 5H); 13C NMR
(300 MHz, CDCl3) d 205.4, 137.7, 115.1, 57.0, 38.3, 31.7,
30.8, 30.1, 26.5, 26.3, 25.1.
According to the general procedure, 21 (0.020 g,
0.084 mmol), catalyst A (0.005 g, 0.017 mmol), and
KHMDS (0.034 mL, 0.017 mmol, 0.5 M in tetrahydro-
furan), produced the product as a 3.5:96.5 mixture of
inseparable diastereomers. GC analysis (BDM, 3.0 mL/min;
trans (tr (minor)Z53.8 min, tr (major)Z51.5 min), cis (tr
(minor)Z49.7 min, tr (major)Z47.8 min)) gave the
enantiomeric composition of the trans product: 20% ee,
and the cis product: 6% ee.
7.1.20. 6-Cyclohexyl-7-oxo-hept-2-enoic acid methyl
ester (21).
A flame dried flask was charged with [1,3-bis-(2,4,6-
trimethylphenyl)-2-imidazolidinylidene) dichloro(phenyl-
methylene)-(tricyclohexyl phosphine) ruthenium] (0.049 g,
0.055 mmol) and 5 mL dichloromethane. 20 (0.20 g,
1.1 mmol) and methyl acrylate (1.0 mL, 11.1 mmol) were
added and the solution was heated to 40 8C for 72 h. Silica
gel (1 g) was then added and the solvent removed in vacuo.
Column chromatography (9:1, hexane/ethyl acetate) yielded
0.225 g product (0.95 mmol, 85%). RfZ0.36 (3:1, hexane/
References and notes
1. (a) Yun, J.; Buchwald, S. L. Org. Lett. 2001, 3, 1129–1131. (b)
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
2892–2893.
2. The Stetter reaction: (a) Stetter, H.; Kuhlmann, H. In Paquette,
L. A., Ed.; Organic Reactions; Wiley: New York, 1991; Vol.
40, pp 407–496. (b) Stetter, H.; Kuhlmann, H. Chem. Ber.
1976, 109, 2890–2896.
1
ethyl acetate); H NMR (300 MHz, CDCl3) d 9.61 (d, 1H,
JZ3.3 Hz), 6.89 (m, 1H), 5.80 (d, 1H, JZ15.4 Hz), 3.70 (s,
1H), 2.03–2.60 (m, 3H), 1.54–1.84 (m, 8H), 1.02–1.30 (m,
5H); 13C NMR (300 MHz, CDCl3) d 204.7, 166.7, 148.1,
121.4, 56.9, 51.4, 38.3, 30.8, 30.2, 30.1, 26.4, 26.3, 24.1; IR
(NaCl, neat) 1724, 1658, 1448; HRMS (FABC) calcd for
C14H23O3, 239.1647. Found 239.1646.
3. Intramolecular Stetter: Ciganek, E. Synthesis 1995,
1311–1314.
4. Enantioselective Intramolecular Stetter: (a) Enders, D.;
Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta 1996,
79, 1899–1920. (b) Enders, D.; Balensiefer, T. Acc. Chem. Res
2004, 37, 534–541.
7.1.21. (3-Benzyl-2-oxo-cyclopentyl)-acetic acid methyl
ester (22).
5. (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.
6. Kinetic Resolution Reviews: (a) Kagan, H. B.; Fiaud, J. C. In
Eliel, E. L., Fiaud, J. C., Eds.; Top. Stereochem.; Wiley: New
York, 1988; Vol. 18, pp 249–330. (b) Keith, J. M.; Larrow,
J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5–26. (c)
Robinson, D. E. J. E.; Bull, S. D. Tetrahedron: Asymmetry
2003, 14, 1407–1446.
According to the general procedure, 19 (0.010 g,
0.043 mmol), catalyst A (0.008 g, 0.022 mmol), and
KHMDS (0.043 mL, 0.022 mmol, 0.5 M in tetrahydro-
furan), produced the product as a 95:5 mixture of
inseparable diastereomers. Purification by column chroma-
tography (95:5, hexane/diethyl ether) afforded 22 (9.5 mg,
95%). RfZ0.40 (3:1, hexane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) d 7.13–7.28 (m, 10H), 3.66 (s, 3H),
3.65 (s, 3H), 3.15 (dd, 1H, JZ13.8, 4.0 Hz, trans), 3.04 (q,
1H, JZ9.2 Hz, cis), 2.42–2.76 (m, 8H), 2.27–2.35 (m, 2H),
2.03–2.18 (m, 3H), 1.93 (m, 1H), 1.74 (m, 1H), 1.40–1.55
(m, 3H); 13C NMR (300 MHz, CDCl3) d 219.5, 219.2,
172.5, 172.5, 139.7, 129.0, 128.9, 128.4, 126.3, 126.2, 51.8,
51.8, 50.7, 49.0, 46.0, 45.0, 36.0, 35.9, 34.1, 34.0, 27.2,
26.5, 25.6; IR (NaCl, neat) 1735, 1437, 1261, 1196,
1175 cmK1; HRMS (FABC) calcd for C15H18O3,
247.1334. Found 247.1332. HPLC analysis (AS, 99:1,
Hex/iPrOH, 0.2 mL/min; trans (tr (minor)Z130.8 min, tr
(major)Z82.2 min.), cis (tr (minor)Z104.4 min, tr
(major)Z111.7 min.)) gave the enantiomeric composition
of the trans product: !5% ee, and the cis product: !5% ee.
7. Vedejs has coined and defined the term parallel kinetic
resolution. Included in this definition is the following
statement: ‘Another PKR application is inherent in reactions
where two enantiomers of a racemic substrate are selectively
converted into separable, chiral products (regioisomers,
diastereoisomers, etc.) by a single chiral reagent or catalyst.’
See: Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119,
2584–2585. Also see: (a) Eames, J. Angew. Chem., Int. Ed.
2000, 39, 885–888. (b) Dehli, J. R.; Gotor, V. Chem. Soc. Rev.
2002, 31, 265–370.
8. Claus, R. E.; Schreiber, S. L.; Organic Syntheses Collective
Volume VII; 1990, 168.
9. Schreiber, S. L.; Meyers, H. V.; Wiberg, K. B. J. Am. Chem.
Soc. 1986, 108, 8274–8277.
10. Brown, H. C.; Weissman, S. A.; Perumal, P. T.; Dhokte, U. P.
J. Org. Chem. 1990, 55, 1217–1223.
11. Molander, G. A.; McKie, J. A. J. Org. Chem. 1995, 60,
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