Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers through the Primary Amine-Catalyzed Michael Addition Reaction of α-Substituted Cyclic Ketones at High Pressure

Article abstract of DOI:10.1002/ejoc.201500411

The enantioselective Michael addition reaction of α-substituted cyclic ketones with acrylates was efficiently promoted by a primary amine chiral catalyst under high-pressure conditions (1.0 GPa) in tetrahydrofuran. This method was highly successful for the construction of an all-carbon-substituted quaternary-carbon stereogenic center at the α-position of cyclic ketones in high enantiomeric excess, and could be conveniently applied to the formal synthesis of (+)-aspidospermidine. The Michael addition reaction of α-substituted cyclic ketones was efficiently promoted by a primary amine-based organocatalyst under high-pressure conditions (1.0 GPa) in tetrahydrofuran.

Full text of DOI:10.1002/ejoc.201500411

FULL PAPER
DOI: 10.1002/ejoc.201500411
Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers through
the Primary Amine-Catalyzed Michael Addition Reaction of α-Substituted
Cyclic Ketones at High Pressure[‡]
Ryo Horinouchi,[a] Kouhei Kamei,[a] Riki Watanabe,[a] Nobushige Hieda,[a] Naoki Tatsumi,[a]
Keiji Nakano,[a] Yoshiyasu Ichikawa,[a] and Hiyoshizo Kotsuki*[a]
Keywords: Organocatalysis / Asymmetric catalysis / High-pressure chemistry / Michael addition / Ketones
The enantioselective Michael addition reaction of α-substi-
quaternary-carbon stereogenic center at the α-position of cy-
tuted cyclic ketones with acrylates was efficiently promoted clic ketones in high enantiomeric excess, and could be con-
by a primary amine chiral catalyst under high-pressure con- veniently applied to the formal synthesis of (+)-aspido-
ditions (1.0 GPa) in tetrahydrofuran. This method was highly
successful for the construction of an all-carbon-substituted
spermidine.
the asymmetric alkylation reaction of α-substituted cyclic
ketones through an imine-enamine activation process by
using 1-phenylethylamine as a chiral auxiliary.[5,7] On the
other hand, the palladium-catalyzed asymmetric decarb-
oxylative allylic alkylation reaction of allyl carboxylates has
also been shown to have substantial utility in this area.[6]
As an organocatalytic version, Kang and Carter reported
primary amine-thiourea-catalyzed asymmetric Michael ad-
dition reactions for the enantioselective synthesis of α,α-
disubstituted cyclic ketones.[8]
Very recently, Maruoka and co-workers presented a new
method for the asymmetric alkylation of 2-arylcyclohex-
anones under chiral phase-transfer conditions.[9] In this pa-
per, we describe our own approach based on the primary
amine-catalyzed asymmetric Michael addition reaction of
α-substituted cyclic ketones with acrylates.
Introduction
There is a strong demand for the catalytic asymmetric
synthesis of quaternary carbon stereogenic centers, particu-
larly all-carbon-substituted centers, because of their wide-
spread distribution as pivotal structural units in complex
biologically active natural products.[1] Among several ap-
proaches, considerable attention has recently been focused
on organocatalytic asymmetric transformation as an ef-
ficient and convenient methodology owing to its environ-
mentally friendly characteristics,[2] and asymmetric Michael
addition reactions are generally accepted as the most conve-
nient and reliable of these transformations.[2] In our ongo-
ing studies in this area,[3] we recently found that a primary
amine-thiourea conjugate bifunctional organocatalyst, e.g.
catalyst A, strongly supported the asymmetric Michael ad-
dition reactions of α,β-unsaturated ketones with malonates
under atmospheric or high-pressure conditions.[4] As an ex-
tension of this chemistry, we were particularly interested in
its application to α-substituted cyclic ketones as Michael
donors, because the whole process would constitute an ex-
peditious route for the construction of an all-carbon-substi-
tuted quaternary-carbon stereogenic center at the α-posi-
tion of cyclic ketones in an enantio-controlled manner.
With regard to this synthetic endeavor, various ap-
proaches that use a chiral auxiliary or palladium-catalyzed
technique have been developed.[5,6] Several years ago, Pfau,
d’Angelo and others reported an efficient strategy based on
Results and Discussion
To find the optimum reaction conditions, the Michael
addition reaction of 2-methylcyclohexanone (1a) with
methyl acrylate (2a; 3.0 equiv.) was carried out in the pres-
ence of a variety of primary amine-based chiral organocata-
lysts (Figure 1). The results are summarized in Table 1.
Under our previously established conditions with
10 mol-% of catalyst A in toluene as a solvent, the reaction
proceeded sluggishly even at elevated temperatures. As ex-
pected, increased pressure dramatically accelerated the reac-
tion[10] and desired adduct 3a was obtained in excellent
enantioselectivity, albeit along with a large amount of re-
gioisomer 4a (Table 1, Entries 1 and 2). The formation of
the latter isomer suggests that the imine-enamine equilib-
rium between 1a and catalyst A might be shifted to some
extent to the less-congested αЈ-side. We next turned our at-
[‡] High Pressure Organic Chemistry, Part 40. Part 39: Ref.[3b]
[a] Laboratory of Natural Products Chemistry, Faculty of Science,
Kochi University,
Akebono-cho, Kochi 780-8520, Japan
E-mail: kotsuki@kochi-u.ac.jp
http://www.cc.kochi-u.ac.jp/~kotsuki/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500411.
Eur. J. Org. Chem. 2015, 4457–4463
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H. Kotsuki et al.
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enantiomer 3a was obtained predominantly. After several
experiments, we found that the use of 30 mol-% of catalyst
C gave the best results in terms of efficiency and feasibility
(Table 1, Entry 4 versus Entries 3 and 13–15). Consistent
with previous observations by d’Angelo et al.,[5,11] phenyl-
amines C–E were more favorable than cyclohexyl congeners
B and F (Table 1, Entries 4, 13, and 14 versus Entries 3 and
15). Furthermore, we found that the yields decreased at
lower pressures and with lower catalyst loadings (Table 1,
Entry 4 versus Entries 5–9). We briefly examined the sol-
vent effect in this Michael addition reaction: toluene,
dichloromethane, and MeCN resulted in incomplete con-
version of the reaction (Table 1, Entry 4 versus Entries 10–
12). These results suggest that, in tetrahydrofuran (THF),
the initial stage of forming a chiral imine from 1a and cata-
lyst C took place smoothly. As expected, the replacement
of catalyst C with its (R)-antipode led to complete reversal
of configuration of the product (Table 1, Entry 16).
Figure 1. Catalysts screened.
Table 1. Optimization of the Michael addition reaction between 2-
methylcyclohexanone (1a) and methyl acrylate (2).
The stereochemical outcome of this highly enantioselec-
tive Michael addition process could be rationalized by an
imine-enamine activation mode, as proposed by d’Angelo
et al. (Scheme 1).[5,11,12] Compound 1a could be condensed
with catalyst C to form imine compound I as an initial
product. After spontaneous equilibrium to enamine tauto-
mer II, methyl acrylate (2a) could be attacked from the less-
hindered side opposite a rather bulky phenyl ring (transi-
tion structure III), after hydrolysis of IV, to give final prod-
uct 3a with regeneration of catalyst C.[13] Importantly, in
this synthetic sequence the interaction between the enamine
donor and methyl acrylate (2a) as the Michael acceptor and
C–C bond-forming processes are both favorable under
high-pressure conditions, and the whole process should be
efficiently accelerated under these conditions.[12] As a result
of the unavoidable side reaction that leads to the hetero-
Michael adduct from methyl acrylate (2a) and primary
amine catalysts,[14] we conclude that at least 3 equiv. of ac-
ceptor and 30 mol-% of catalyst are necessary to attain sat-
isfactory results.[15]
Entry Catalyst Conditions
[mol-%]
Yield[a] 3a/4a[b] ee[c]
[%]
[%]
1
A [10]
A [10]
B [30]
C [30]
C [20]
C [10]
C [5]
toluene, 1 atm, 75 °C,
48 h
toluene, 1.0 GPa, 25 °C, 64
48 h
THF, 1.0 GPa, 25 °C,
48 h
THF, 1.0 GPa, 25 °C,
48 h
THF, 1.0 GPa, 25 °C,
48 h
THF, 1.0 GPa, 25 °C,
48 h
THF, 1.0 GPa, 25 °C,
48 h
8
89:11
62:38
87:13
95:5
96:4
96:4
96:4
97:3
96:4
96:4
95:5
97:3
84:16
86:14
98:2
95:5
98
2
98
74
98
98
96
98
98
87
86
93
92
98
98
86
–98
3
75
96
76
69
20
74
34
4
5
6
7
8
C [30]
C [30]
C [30]
C [30]
C [30]
D [30]
E [30]
F [30]
THF, 0.8 GPa, 25 °C,
48 h
THF, 0.6 GPa, 25 °C,
48 h
toluene, 1.0 GPa, 25 °C, 41
9
10
11
12
13
14
15
16
48 h
CH2Cl2, 1.0 GPa, 25 °C, 12
48 h
MeCN, 1.0 GPa, 25 °C, 36
48 h
THF, 1.0 GPa, 25 °C.
95
97
55
96
48 h
THF, 1.0 GPa, 25 °C,
48 h
THF, 1.0 GPa, 25 °C,
48 h
–C [30] THF, 1.0 GPa, 25 °C,
48 h
[a] Isolated yields. [b] Determined by 1H NMR spectroscopic
analysis of the crude reaction mixture. [c] After conversion to the
corresponding benzyl ester, determined by chiral HPLC analysis by
using a Chiralpak AS-H.
tention to the use of smaller primary amine-based chiral
Scheme 1. Plausible mechanism through an imine–enamine equilib-
organocatalysts such as catalysts B–F; in every case, (R)- rium process.
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Enantioselective Synthesis of Quaternary Stereogenic C Centers
Table 2. The Michael addition reaction between cyclic ketones 1
and acrylates (2) is a general one.
With the optimized reaction conditions in hand, we in-
vestigated the general scope of this chemistry by using a
variety of cyclic ketones with acrylates (Table 2).[16] Several
cyclohexanones, such as 1a–1d, efficiently reacted with
methyl acrylate (2a) or acrylonitrile (2b) to give the desired
adducts in good to excellent yields with high enantio-
selectivity (Table 2, Entries 1–5). The procedure is highly
sensitive to steric and electronic effects. The reactions that
use 2-benzylcyclohexanone (1e) and 2-methylthiopyranone
(1f) as Michael donors are very sluggish even at high pres-
sure (Table 2, Entries 6 and 7).[17] Finally, cyclopentanone
analogs, such as 1g and 1h, were used as moderately reac-
tive Michael donors, and smooth reactions with 2a and 2b
were observed (Table 2, Entries 8–10).[18]
To demonstrate the synthetic value of this efficient or-
ganocatalytic asymmetric transformation, (+)-aspidosper-
midine (8), a well-known aspidosperma alkaloid, was tar-
geted (Scheme 2).[19,20] Treatment of 3c with potassium
hexamethyldisilazide (1.2 equiv.) followed by exposure to N-
(2-pyridyl)bis(trifluoromethanesulfonamide) gave corre-
sponding enol triflate 5 in 79% yield. This compound was
subjected to palladium-catalyzed reduction under our pre-
viously established conditions (91%),[21] and resulting cy-
clohexene 6 was oxidized by reaction with manganese tri-
acetate/tert-butyl hydroperoxide[22] to give cyclohexenone 7
in 73% yield. This can be converted into (+)-aspidospermi-
dine (8) as described in the literature,[23] and hence the for-
mal synthesis of this natural product has been com-
pleted.[24]
Scheme 2. Formal total synthesis of (+)-aspidospermidine (8).
Conclusions
In conclusion, we have developed a new efficient method
for constructing complex molecules that bear a quaternary
carbon stereogenic center at the α-position of cyclic
ketones. The reaction is performed by catalysis with chiral
1-phenylethylamine at high pressure and, depending on the
substrate, high to excellent yields can be attained. Because
this organocatalyst is commercially available in both (S)-
[a] Isolated yields. [b] Determined by 1H NMR spectroscopic
analysis of the crude reaction mixture. [c] After conversion to the
corresponding benzyl ester, determined by chiral HPLC. [d] The
antipode of catalyst C was used. [e] The absolute configuration of
the products was surmised by analogy with 3a.
Eur. J. Org. Chem. 2015, 4457–4463
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H. Kotsuki et al.
FULL PAPER
120.07, 214.34 ppm. The ee value was determined by chiral HPLC
analysis as described in 3a after conversion to the corresponding
benzyl ester (80 equiv. of PhCH2OH, 100 equiv. of conc. HCl, mi-
crowave, 150 °C, 2.0 h, 60–70% yield).
and (R)-forms and the process does not require the prepara-
tion of imine precursors and this method provides a highly
useful synthetic pathway in modern organic synthesis. Fi-
nally, the utility of this method was exemplified by its appli-
cation to the formal synthesis of (+)-aspidospermidine (8).
Further studies to extend the scope of this method are now
in progress in our laboratory.
Methyl (S)-3-(1-Ethyl-2-oxocyclohexyl)propanoate (3c):[25] Colorless
oil. [α]2D3 = +13.33 (c = 1.00, CHCl3, 99% ee) {ref.[25] for (R)-isomer:
[α]2D3 = –9.45 (c = 0.995, CHCl , 87% ee)}. FTIR (neat): ν = 1739,
˜
3
1703 cm–1. H NMR (500 MHz, CDCl3): δ = 0.77 (t, J = 7.0 Hz,
1
3 H), 1.48 (sextet, J = 7.5 Hz, 1 H), 1.65–1.87 (m, 8 H), 1.92 (ddd,
J = 14.0, 11.5, 5.0 Hz, 1 H), 2.12 (ddd, J = 16.0, 11.5, 5.0 Hz, 1
H), 2.27 (ddd, J = 16.0, 11.5, 5.0 Hz, 1 H), 2.33–2.42 (m, 2 H),
3.66 (s, 3 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 7.67, 20.68,
27.06, 28.72, 28.95, 35.77, 39.08, 50.98, 51.66 (ϫ 2), 174.23,
214.85 ppm. ee of the corresponding benzyl ester was determined
Experimental Section
General Remarks: 1H and 13C NMR spectra were recorded with
a JEOL JNM-ECA-500 spectrometer (500 MHz and 125.8 MHz,
respectively) for solutions in CDCl3. Chemical shifts are reported
relative to residual CHCl3 (7.27 for 1H and 77.20 for 13C) as an
internal reference. IR spectra were measured with a JASCO FT/
IR-460 plus Fourier Transform Infrared spectrophotometer. High-
pressure reactions were performed in a Hikari-koatsu HR-15-B3
apparatus, which is designed for pressures up to 1.0 GPa. The silica
gel used for flash chromatography was 230–400 mesh. All reagents
were of reagent grade and used as received or distilled prior to use.
All solvents were dried according to standard procedures and
freshly distilled prior to use.
by chiral HPLC analysis with
a Chiralpak AS-H column
(0.46ϫ25 cm, hexane/2-propanol = 99:1, flow rate 0.15 cm3/min, λ
= 254 nm), tR (major) = 60.11 min and tR (minor) = 64.35 min.
Methyl 3-(3-Ethyl-2-oxocyclohexyl)propanoate (4c): Colorless oil.
1
FTIR (neat): ν = 1739, 1709 cm–1. H NMR (500 MHz, CDCl ): δ
˜
3
= 0.88 (t, J = 7.5 Hz, 3 H), 1.20 (sextet, J = 7.0 Hz, 1 H), 1.25–
1.38 (m, 2 H), 1.48–1.55 (m, 1 H), 1.68–1.89 (m, 3 H), 2.06 (sextet,
J = 7.0 Hz, 1 H), 2.11–2.21 (m, 3 H), 2.28–2.44 (m, 3 H), 3.66 (s,
3 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 11.81, 22.05, 24.66,
25.51, 31.70, 34.96, 35.53, 50.11, 51.52, 52.78, 174.15, 213.43 ppm.
HRMS: calcd. for C12H20O3 212.1412; found 212.1416.
Typical Procedure for the Michael Addition Reaction of 2-Methyl-
cyclohexanone (1a) with Methyl Acrylate (2a): A mixture of 1a
(1.0 mmol), 2a (3.0 mmol), and (S)-1-phenylethylamine (catalyst C,
0.3 mmol) in THF (1.4 mL) was placed in a Teflon® reaction vessel
and allowed to react at 1.0 GPa and room temp. After 2 d, the
mixture was concentrated and purified by silica gel column
chromatography (eluted with hexane/acetone = 10:1) to give the
desired adduct. In general, the ee value was determined by chiral
HPLC analysis after conversion to the corresponding benzyl ester
(5.2 equiv. of PhCH2OH, cat. dry pTsOH, microwave, 100 °C, 0.5 h,
84% yield).
(R)-3-(1-Ethyl-2-oxocyclohexyl)propionitrile (3d): Colorless oil.
[α]2D3 = –62.88 (c = 1.02, EtOH, 91% ee). FTIR (neat): ν = 2247,
˜
1
1702 cm–1. H NMR (500 MHz, CDCl3): δ = 0.79 (t, J = 7.5 Hz,
3 H), 1.53 (sextet, J = 7.5 Hz, 1 H), 1.62–1.83 (m, 8 H), 1.98 (ddd,
J = 14.5, 9.5, 5.5 Hz, 1 H), 2.21–2.37 (m, 3 H), 2.44 (ddd, J = 14.5,
12.0, 6.0 Hz, 1 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 7.54,
12.14, 20.50, 26.91, 27.15, 29.96, 35.28, 38.90, 51.08, 120.20,
214.02 ppm. HRMS: calcd. for C11H17NO + H 180.1388; found
180.1391. The ee value was determined by chiral HPLC analysis as
described in 3c after conversion to the corresponding benzyl ester
(80 equiv. of PhCH2OH, 100 equiv. of conc. HCl, microwave,
150 °C, 2.0 h, 60–70% yield).
Methyl (R)-3-(1-Methyl-2-oxocyclohexyl)propanoate (3a):[5a,8] Col-
orless oil. [α]2D3 = +30.5 (c = 2.95, EtOH, 98% ee) {ref.[8] [α]2D0
=
+30.0 (c = 2.95, EtOH, 98% ee)}. FTIR (neat): ν = 1739,
˜
Methyl (R)-3-(2-Oxo-1,5,5-trimethylcyclohexyl)propanoate (3e):
1
1705 cm–1. H NMR (500 MHz, CDCl3): δ = 1.07 (s, 3 H), 1.57–
Colorless oil. [α]1D9 = +16.8 (c = 1.02, CHCl3, 98% ee). FTIR (neat):
1.65 (m, 1 H), 1.67–1.91 (m, 6 H), 2.04 (ddd, J = 14.0, 11.5, 5.0 Hz,
1 H), 2.16 (ddd, J = 16.0, 11.0, 5.0 Hz, 1 H), 2.32 (ddd, J = 16.0,
11.0, 5.0 Hz, 1 H), 2.37–2.44 (m, 2 H), 3.66 (s, 3 H) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 20.97, 22.37, 27.42, 28.99, 32.48, 38.70,
39.23, 47.90, 51.67, 174.04, 215.19 ppm. ee of the corresponding
benzyl ester was determined by chiral HPLC analysis with a Chi-
ralpak AS-H column (0.46ϫ25 cm, hexane/2-propanol = 99:1,
flow rate 0.15 cm3/min, λ = 254 nm), tR (S-isomer) = 76.2 min and
tR (R-isomer) = 82.1 min.
1
ν = 1739, 1705, 1437 cm–1. H NMR (500 MHz, CDCl ): δ = 1.08
˜
3
(s, 3 H), 1.10 (s, 6 H), 1.51 (d, J = 14.5 Hz, 1 H), 1.64 (t, J =
14.5 Hz, 1 H), 1.79 (t, J = 5.0 Hz, 1 H), 1.81 (ddd, J = 14.5, 11.0,
5.0 Hz, 1 H), 1.94 (ddd, J = 14.5, 11.0, 5.0 Hz, 1 H), 2.21 (ddd, J
= 16.0, 11.0, 5.0 Hz, 1 H), 2.31 (ddd, J = 16.0, 11.0, 5.0 Hz, 1 H),
2.44 (t, J = 7.0 Hz, 1 H), 3.66 (s, 3 H) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 25.08, 29.23, 29.98, 30.34, 30.47, 34.45, 35.38, 37.98,
46.63, 50.59, 51.65, 174.03, 216.30 ppm. HRMS: calcd. for
C13H22O3 226.1569; found 226.1571. ee of the corresponding
benzyl ester was determined by chiral HPLC analysis with a Chi-
ralpak AS-H column (0.46ϫ25 cm, hexane/2-propanol = 99:1,
flow rate 0.15 cm3/min, λ = 254 nm), tR (major) = 75.0 min and tR
(minor) = 78.9 min.
Methyl 3-(3-Methyl-2-oxocyclohexyl)propanoate (4a):[12c] Colorless
oil. FTIR (neat): ν = 1738, 1709 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 1.00 (d, J = 7.0 Hz, 3 H), 1.32 (dd, J = 13.5, 4.0 Hz,
1 H), 1.36 (dd, J = 13.5, 4.0 Hz, 1 H), 1.48–1.55 (m, 1 H), 1.75 (tq,
J = 13.5, 4.0 Hz, 1 H), 1.81–1.87 (m, 1 H), 2.03–2.15 (m, 3 H),
2.29–2.45 (m, 4 H), 3.66 (s, 3 H) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 14.47, 24.71, 25.50, 31.71, 35.29, 37.40, 45.68, 49.77,
51.50, 174.14, 213.60 ppm.
Methyl
(S)-3-(7-Methyl-8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)-
propanoate (3f):[26] Colorless oil. [α]2D0 = +14.11 (c = 1.07, CHCl3,
99% ee). FTIR (neat): ν = 1738, 1709 cm–1. H NMR (500 MHz,
1
˜
CDCl3): δ = 1.13 (s, 3 H), 1.81–1.89 (m, 2 H), 1.98–2.01 (m, 2 H),
2.09–2.19 (m, 3 H), 2.31 (ddd, J = 16.0, 10.5, 4.5 Hz, 1 H), 2.54
(dt, J = 15.0, 7.0 Hz, 1 H), 2.61 (ddd, J = 15.0, 8.5, 6.0 Hz, 1
H), 3.66 (s, 3 H), 3.97–4.05 (m, 4 H) ppm. 13C NMR (125.8 MHz,
(R)-3-(1-Methyl-2-oxocyclohexyl)propionitrile (3b):[8] Colorless oil.
[α]2D4 = –8.48 (c = 17.5, EtOH, 95% ee) {ref.[8] [α]2D0 = –3.4 (c = 26,
EtOH, 85% ee)}. FTIR (neat): ν = 2246, 1703 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 1.16 (s, 3 H), 1.69–1.99 (m, 8 H), 2.28– CDCl3): δ = 23.47, 29.09, 33.17, 34.45, 35.63, 45.14, 46.99, 51.65,
2.40 (m, 3 H), 2.45–2.51 (m, 1 H) ppm. 13C NMR (125.8 MHz, 64.33, 64.49, 107.28, 173.91, 213.77 ppm. HRMS: calcd. for
CDCl3): δ = 12.44, 20.87, 22.33, 27.24, 33.70, 38.57, 38.60, 47.73,
C13H20O5 256.1311; found 256.1319. The ee value was determined
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Enantioselective Synthesis of Quaternary Stereogenic C Centers
by chiral HPLC analysis with
a
Chiralpak AS-H column
CDCl3): δ = 1.31 (d, J = 7.0 Hz, 3 H), 1.74 (sextet, J = 8.0 Hz, 1
H), 2.08 (sextet, J = 6.5 Hz, 1 H), 2.43–2.57 (m, 3 H), 3.64 (t, J =
10.0 Hz, 1 H), 3.76 (q, J = 7.0 Hz, 1 H), 4.42 (t, J = 10.0 Hz, 1
H), 5.12 (s, 2 H), 7.33–7.39 (m, 5 H) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 15.98, 22.59, 31.81, 45.79, 66.47, 69.97, 76.89, 128.30
(ϫ 2), 128.35, 128.60 (ϫ 2), 135.68, 172.51, 217.40 ppm. HRMS:
calcd. for C15H18O4 262.1205; found 262.1215.
(0.46ϫ25 cm, hexane/2-propanol = 99:1, flow rate 0.15 cm3/min, λ
= 210 nm), tR (major) = 24.9 min and tR (minor) = 42.9 min.
Methyl (R)-3-(1-Benzyl-2-oxocyclohexyl)propanoate (3g):[27] Color-
less oil. [α]2D3 = +6.91 (c = 1.04, EtOH, 99% ee). FTIR (neat): ν =
˜
1
1738, 1703 cm–1. H NMR (500 MHz, CDCl3): δ = 1.60–1.89 (m,
7 H), 1.97 (ddd, J = 15.5, 11.5, 5.0 Hz, 1 H), 2.12 (ddd, J = 15.5,
11.5, 5.0 Hz, 1 H), 2.39–2.47 (m, 3 H), 2.88 (ABq, JAB = 13.5 Hz,
2 H), 3.66 (s, 3 H), 7.09 (d, J = 7.0 Hz, 2 H), 7.19–7.27 (m, 3
H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 20.71, 26.74, 28.90,
29.69, 35.75, 39.41, 40.47, 51.69, 51.91, 126.42, 128.08 (ϫ 2),
130.51 (ϫ 2), 137.15, 173.83, 214.15 ppm. HRMS: calcd. for
C17H22O3 + H 275.1647; found 275.1644. The ee value was deter-
mined by chiral HPLC analysis with a Chiralpak AS-H column
(0.46ϫ25 cm, hexane/2-propanol = 99:1, flow rate 0.2 cm3/min, λ
= 254 nm), tR (minor) = 43.19 min and tR (major) = 86.89 min.
Methyl (S)-3-(1-Ethyl-2-trifluoromethylsulfonyloxy-2-cyclohexen-1-
yl)propanoate (5): To a solution of 3c (1.34 g, 6.3 mmol) in dry
THF (9 mL) at –78 °C was added slowly potassium hexamethyldis-
ilazide (0.5 m in toluene, 15.2 mL, 7.6 mmol), and the mixture was
stirred at this temperature for 2 h. Then a THF (9 mL) solution of
N-(2-pyridyl)bis(trifluoromethanesulfonimide) (2.72 g, 7.6 mmol)
was added dropwise, and the mixture was warmed to room tem-
perature and stirred for 5 h. After dilution with hexane, the mixture
was quenched by addition of cold aq. HCl (5%), washed with aq.
NaOH (5%) and brine, dried (MgSO4), and concentrated. The
Methyl 3-(3-Benzyl-2-oxocyclohexyl)propanoate (4g): Colorless oil.
FTIR (neat): ν = 1736, 1707 cm–1. H NMR (500 MHz, CDCl ): δ crude product was purified by silica gel column chromatography
1
˜
3
= 1.30 (dt, J = 13.5, 3.5 Hz, 1 H), 1.38 (dt, J = 13.5, 3.5 Hz, 1 H), (eluted with hexane/EtOAc = 4:1) to give 5 (1.71 g, 79%). Colorless
1.51–1.60 (m, 1 H), 1.64 (tq, J = 13.5, 3.5 Hz, 1 H), 1.80–1.83 (m, oil. [α]2D1 = +14.05 (c = 1.13, CHCl ). FTIR (neat): ν = 1742,
˜
3
1
1 H), 2.04–2.15 (m, 3 H), 2.27–2.46 (m, 4 H), 2.52–2.58 (m, 1 H),
3.20 (dd, J = 13.5, 4.5 Hz, 1 H), 3.66 (s, 3 H), 7.13–7.19 (m, 3 H),
7.25–7.28 (m, 2 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ =
24.67, 25.35, 31.65, 34.78, 35.36, 35.44, 50.06, 51.53, 52.83, 125.88,
128.24 (ϫ 2), 129.09 (ϫ 2), 140.47, 174.07, 212.77 ppm. HRMS:
calcd. for C17H22O3 + H 275.1647; found 275.1634.
1674 cm–1. H NMR (500 MHz, CDCl3): δ = 0.89 (t, J = 7.5 Hz,
3 H), 1.45–1.73 (m, 6 H), 1.76–1.87 (m, 2 H), 2.15–2.19 (m, 2 H),
2.32 (t, J = 8.0 Hz, 2 H), 3.68 (s, 3 H), 5.84 (t, J = 4.0 Hz, 1
H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 8.22, 18.37, 24.57,
29.25, 29.61, 30.92, 31.63, 40.86, 51.74, 118.25, 153.56, 173.96 ppm.
HRMS: calcd. for C13H19F3O5S + H 345.0984; found 345.0972.
Methyl (R)-3-(1-Methyl-2-oxocyclopentyl)propanoate (3i):[8] Color-
Methyl (S)-3-(1-Ethyl-2-cyclohexen-1-yl)propanoate (6): To a mix-
ture of enol triflate 5 (1.58 g, 4.6 mmol), Pd(OAc)2 (20 mg,
0.09 mmol), and PPh3 (47 mg, 0.18 mmol) in dry dimethylform-
amide (23 mL) at 60 °C was added Et3SiH (1.84 mL, 11.5 mmol).
At this time the solution color changed sharply from light yellow
to deep brown. The mixture was stirred for 2 d, and additional
Et3SiH (1.0 mL, 6.3 mmol) was introduced and stirred until com-
pletion of the reaction (8 h). After dilution with Et2O, the mixture
was washed with H2O, satd. NaHCO3, and brine, dried (Na2SO4),
and concentrated. The crude product was purified by silica gel col-
less oil. [α]2D3 = +40.43 (c = 1.04, CHCl3, 93% ee) {ref.[8] [α]2D0
=
1
+33.0 (c = 1.68, EtOH, 99% ee)}; FTIR (neat): ν = 1737 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 1.01 (s, 3 H), 1.69–1.98 (m, 6 H),
2.19–2.40 (m, 4 H), 3.66 (s, 3 H) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 18.56, 21.31, 29.25, 31.33, 35.99, 37.46, 47.50, 51.67,
173.87, 222.47 ppm. ee of the corresponding benzyl ester was deter-
mined by chiral HPLC analysis with a Chiralpak AS-H column
(0.46ϫ25 cm, hexane/2-propanol = 99:1, flow rate 0.15 cm3/min, λ
= 254 nm), tR (major) = 99.2 min and tR (minor) = 108.8 min.
(R)-3-(1-Methyl-2-oxocyclopentyl)propionitrile (3j):[8] Colorless oil. umn chromatography (eluted with hexane/EtOAc = 6:1) to give 6
[α]2D4 = +36.16 (c = 1.01, EtOH, 88% ee) {ref.[8] [α]2D0 = +26.5 (c =
(820 mg, 91%). Colorless oil. [α]2D1 = +30.75 (c = 1.17, CHCl3).
FTIR (neat): ν = 1741 cm–1. 1H NMR (500 MHz, CDCl ): δ = 0.82
1
1.0, EtOH, 72% ee)}. FTIR (neat): ν = 2247, 1734 cm–1. H NMR
˜
˜
3
(500 MHz, CDCl3): δ = 1.05 (s, 3 H), 1.76–2.00 (m, 6 H), 2.20– (t, J = 7.5 Hz, 3 H), 1.26–1.47 (m, 4 H), 1.57–1.66 (m, 4 H), 1.90–
2.46 (m, 4 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 12.54, 1.95 (m, 2 H), 2.24–2.27 (m, 2 H), 3.66 (s, 3 H), 5.35 (d, J =
18.50, 20.96, 32.07, 35.88, 37.25, 47.32, 119.70, 221.48 ppm. The ee
value was determined by chiral HPLC analysis as described in 3i
after conversion to the corresponding benzyl ester (80 equiv. of
PhCH2OH, 100 equiv. of conc. HCl, microwave, 150 °C, 2.0 h, 60–
70% yield).
10.5 Hz, 1 H), 5.68 (dt, J = 10.5, 4.0 Hz, 1 H) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 8.04, 18.98, 25.08, 29.22, 31.52, 32.13,
33.94, 36.39, 51.46, 127.17, 134.26, 174.78 ppm. HRMS: calcd. for
C12H20O2 + H 197.1542; found 197.1558.
Methyl (S)-3-(1-Ethyl-4-oxo-2-cyclohexen-1-yl)propanoate (7): To a
solution of cyclohexene 6 (20 mg, 0.1 mmol) in dry EtOAc (0.7 mL)
were added tBuOOH (2.38 m in toluene, 0.5 mL, 1.0 mmol) and
powdered MS 4A (20 mg), and the mixture was stirred at 18 °C for
30 min. Then Mn(OAc)3·2H2O (3.6 mg, 0.005 mmol) was added in
one portion, and the mixture was stirred at this temperature for
16 h. The insoluble substance was removed by filtration through
Celite, and the mixture was concentrated. The crude product was
purified by silica gel column chromatography (eluted with hexane/
EtOAc = 2:1) to give 7 (15.4 mg, 73%). Colorless oil. [α]2D0 = +45.57
(c = 1.10, EtOH, Ͼ 99% ee) {ref.[23b] for (R)-isomer: [α]2D1 = –40.4
Benzyl
(R)-3-(2-Methyl-3-oxotetrahydrofuran-2-yl)propanoate
(3k):[28] Colorless oil. [α]1D9 = +36.86 (c = 1.03, CHCl3, 95% ee).
FTIR (neat): ν = 1752, 1736 cm–1. H NMR (500 MHz, CDCl ): δ
1
˜
3
= 1.18 (s, 3 H), 1.92 (ddd, J = 14.5, 9.0, 6.5 Hz, 1 H), 1.99 (ddd, J
= 14.5, 9.0, 6.5 Hz, 1 H), 2.34 (ddd, J = 16.0, 9.0, 6.5 Hz, 1 H),
2.45 (ddd, J = 16.0, 9.0, 6.5 Hz, 1 H), 2.52 (dt, J = 8.0, 3.0 Hz, 2
H), 4.09 (sextet, J = 8.0 Hz, 2 H), 5.11 (ABq, JAB = 12.5 Hz, 2 H),
7.32–7.38 (m, 5 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ =
20.30, 28.76, 30.67, 36.24, 61.64, 66.37, 80.53, 128.24, 128.27 (ϫ
2), 128.54 (ϫ 2), 135.84, 172.88, 217.07 ppm. HRMS: calcd. for
C15H18O4 + H 263.1283; found 263.1289. The ee value was deter-
mined by chiral HPLC analysis with a Chiralpak AS-H column
(0.46ϫ25 cm, hexane/2-propanol = 99:1, flow rate 0.5 cm3/min, λ
= 254 nm), tR (major) = 37.8 min and tR (minor) = 46.8 min.
(c = 1.73, EtOH)}. FTIR (neat): ν = 1738, 1682 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 0.91 (t, J = 7.5 Hz, 3 H), 1.46–1.57 (m, 2
H), 1.78–1.90 (m, 4 H), 2.30 (ddd, J = 9.5, 7.0, 3.5 Hz, 2 H), 2.44
(t, J = 7.0 Hz, 2 H), 3.67 (s, 3 H), 5.93 (d, J = 10.0 Hz, 1 H), 6.64
(d, J = 10.0 Hz, 1 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ =
8.27, 29.03, 30.17, 30.25, 32.02, 33.74, 37.88, 51.72, 128.71, 157.06,
Benzyl 3-(2-Methyl-3-oxotetrahydrofuran-5-yl)propanoate (4k): Col-
1
orless oil. FTIR (neat): ν = 1754, 1735 cm–1. H NMR (500 MHz,
˜
Eur. J. Org. Chem. 2015, 4457–4463
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4461

H. Kotsuki et al.
FULL PAPER
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propanol = 99:1, flow rate 0.5 cm3/min, λ = 210 nm), tR (major) =
30.22 min.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra and HPLC chromatogram for all adducts.
Acknowledgments
The authors are grateful to Prof. Y. Fukuyama of Tokushima Bunri
University for MS/HRMS measurements. This work was supported
in part by a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organocatalysts”
from the Japanese Ministry of Education, Culture, Sports, Science
and Technology (MEXT)) (grant numbers 24105523 and
26105743).
[12]
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One of the reviewers pointed out some possibility that transim-
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tions. Although we did not examine the mechanism in detail,
this possibility cannot be precluded. We wish to thank the re-
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: March 29, 2015
Published Online: June 5, 2015
Eur. J. Org. Chem. 2015, 4457–4463
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4463