Peptidic amidomonophosphane ligand for copper-catalyzed asymmetric conjugate addition of diorganozincs to cycloalkenones

Article abstract of DOI:10.1002/adsc.200600562

Peptidic modification of (5)-2-[(diphenylphosphino)methyl]pyrrolidine gave a dipeptide-connected amidomonophosphane ligand for the highly efficient, copper-catalyzed asymmetric conjugate addition reaction of organozinc reagents with cycloalkenones, giving

Full text of DOI:10.1002/adsc.200600562

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DOI: 10.1002/adsc.200600562
Peptidic Amidomonophosphane Ligand for Copper-Catalyzed
Asymmetric Conjugate Addition of Diorganozincs to
Cycloalkenones
Takahiro Soeta,a Khalid Selim,a Masami Kuriyama,a and Kiyoshi Tomiokaa,*
a
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax : (+81)-75-753-4604; e-mail: tomioka@pharm.kyoto-u.ac.jp
Received: October 27, 2006
This paper is dedicated to Prof Masakatsu Shibasaki on the occasion of his 60th birthday.
Abstract: Peptidic modification of (S)-2-[(diphenyl- enantioselectivity of up to 98% ee. A model that
phosphino)methyl]pyrrolidine gave a dipeptide-con- predicts the stereochemistry of the reaction is dis-
nected amidomonophosphane ligand for the highly cussed.
efficient, copper-catalyzed asymmetric conjugate ad-
dition reaction of organozinc reagents with cycloal- Keywords: asymmetric catalysis; catalyst design; con-
kenones, giving 3-alkylated cycloalkanones in high jugate addition; copper; organozinc reagents
Introduction
oped by Imamoto[15] and Hoveyda.[16] These phospho-
rus ligands were shown to be applicable in the conju-
The copper-catalyzed asymmetric conjugate addition gate addition reaction of nitroalkenes[17–21] and a,b-un-
reaction of organometallic reagents with activated saturated lactones.[22,23] Copper-catalyzed conjugate ar-
olefins has been the subject of recent energetic re- ylation,[24,25] vinylation[26] and kinetic resolution[27]
search work.[1] Key to its successful accomplishment have been the topics of the recent brilliant studies.[28]
relies on the development of sophisticatedly designed
It is natural for us to apply the amidophosphane 1
chiral ligands for the metal catalysts.[2] For the most in the copper-catalyzed asymmetric conjugate addi-
established copper-catalyzed asymmetric conjugate tion of diorganozincs, because 1 was really effective in
addition reaction of Grignard reagents with enones, a the conjugate alkylation of Grignard reagents[6] as
chiral amine[1a,b] was the first of the successful chiral well as the Rh(I)-catalyzed conjugate arylation of ar-
sources of heterocuprates and was followed by the ylboronic acids.[29] Another reason is that we have a
zinc complexes of chiral amino alcohols[3] and chiral rich stock of amidophosphanes which were applied in
thiols,[1g] and recently by a chiral selenide[4] and a the copper-catalyzed alkylation of diorganozinc re-
chiral pyrazole derivative.[5] Other successful ap- agents with imines[30] and the rhodium-catalyzed ary-
proaches for controlling high enantioselectivity rely lation of arylboronic acids with imines.[31] We have
on the coordination of a phosphorus atom with also turned our attention to the screening and new
copper, and a chiral amidophosphane 1 proved to be design of the amidophosphanes. We describe herein
a good ligand for the copper-catalyzed conjugate ad- that dipeptidic amidophosphanes behave as a satisfac-
dition of Grignard reagents to enones,[6] which was tory ligand for copper to give the conjugate alkylation
followed by a chiral ferrocenyl-based monophos- products with up to 98% ee (Figure 1 and Figure 2).
phane[7] as well as a bisphosphane.[8] Further brilliant A stereochemical model is also discussed.
successes have also been continuously reported by
using dialkylzinc reagents as sources of alkyl nucleo-
philes, which are characterized by the use of a phos- Results and Discussion
phorus-based ligand for copper.[9,10] Since the develop-
ment of a phosphoroamidite by Alexakisꢀ group,[11,12] Amino Acid-Connected Amidophosphane
binaphthol-based phosphorus ligands have been dem-
onstrated to be really effective giving over 90% ee by The conjugate ethylation of cyclohexenone 2a with di-
the endeavors of the Feringa[13] and Zhang[14] groups. ethylzinc was catalyzed by 6.5 mol% of pivaloyl-ami-
Highly efficient phosphane ligands were also devel- dophosphane 1[6,29] and 5 mol% of copper(II) triflate
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d-Val connected amidophosphane 4b gives (S)-3a in
better enantioselectivity.
In fact, the conjugate ethylation of cyclohexenone
was conducted under the catalysis of the N-Boc-d-
valine-connected amidophosphane 4b and copper(II)
triflate to give expectedly (S)-3a with higher 74% ee
in 84% yield (entry 3). The dipeptide-connected ami-
dophosphanes 5 are a logical extension from 4 to be
surveyed for the better ligand.[33] The four Val-d-Val
and Phe-d-Val connected ligands 5a–d were examined
(entries 4–7) and 5d (d-Phe-d-Val) was found to be
an extremely efficient ligand giving (S)-3a with 98%
ee in 87% isolated yield (entry 7). It is also important
to note that these dipeptidic amidophosphanes were
recovered nearly quantitatively after the reaction and
were reusable.
Other diorganozinc reagents including functional-
ized ones were applied in the asymmetric alkylation
of cyclohexenone 2a giving the corresponding substi-
tuted cyclohexanones 3 with 45–94% ee (Table 2, en-
tries 2–5). The catalytic conjugate ethylation of 4,4-di-
methylcyclohexenone 2b, cycloheptenone 2c and cy-
clooctenone 2d with 5d-Cu(I) in toluene at 08C gave
the corresponding products 3b, 3c, and 3d with 75%,
86%, and 61% ees in good isolated yields (entries 6–
8).
Figure 1. Peptidic amidomonophosphane ligands.
Figure 2. Copper-catalyzed conjugate ethylation.
Plausible Stereochemical Pathway
It is really interesting to note that a dipeptidic phos-
in toluene at 08C for 1 h to afford (S)-3-ethylcyclo- phane ligand 6 developed by Hoveyda[16] and 5d have
hexanone 3a with 13% ee in 83% yield (Table 1, the same amino acid constituents, d-Phe and d-Val,
entry 1). The enantioselectivity of 3a was determined albeit incorporated in the reverse amino acid se-
by a chiral stationary phase HPLC. N-Boc-l-valine quence, as shown in Figure 3. The striking difference
connected amidophosphane 4a was selected as a next is the enantiofacial selection in that 6 gave (R)-3a and
ligand because 4a was effective in the rhodium-cata- 5d gave (S)-3a.[34] Another structural difference is the
lyzed arylation of imines with arylboronic acids.[31,32] order of amino acid sequence; in 5d the nitrogen of a
As has been expected the conjugate ethylation was chiral pyrrolidinylphosphane is acylated at the C-ter-
catalyzed by 4a-copper(II) triflate to give (R)-3a with minal of N-Boc-d-Phe-d-Val, while in 6 achiral diphe-
moderate 56% ee in 81% yield (entry 2). It is inter- nylphosphinobenzaldehyde is connected in the form
esting to know that l-Val-connected amidophosphane of an imine at the N-terminal of d-Val-d-Phe amide.
4a gave (R)-3a, while the parent pivaloyl amidophos-
The sense of enantiofacial selection by 5d-Cu(I) is
phane 1 gave (S)-3a (entry 1). This suggests that the proposed by the model 7 illustrated in Scheme 1. The
Table 1. Copper-catalyzed asymmetric conjugate ethylation of cyclohexenone 2a.
Entry
1/4/5
AA (4)
Time [h]
3a
Yield [%]
ee [%]
A
1
2
3
4
5
6
7
1
Piv
l-Val
d-Val
l-Val-d-Val
d-Val-d-Val
l-Phe-d-Val
d-Phe-d-Val
1
1
1
1
1
20
2
87
81
84
92
88
81
87
13
56
74
21
17
22
98
S
R
S
S
S
S
S
4a
4b
5a
5b
5c
5d
630
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Peptidic Amidomonophosphane Ligand
Table 2. N-Boc-d-Phe-d-Val-P (5d)-copper
3.
A
Entry
2
R1
n
R2
x [mol%]
Time [h]
3
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2b
2c
2d
H
H
H
H
H
Me
H
H
1
1
1
1
1
1
2
3
Et
Me
i-Pr
(CH)3Ph
5
10
2
5
5
5
2
5
2
48
5
36
17
41
18
36
3a
3ab
3ac
3ad
3af
3b
8
7
45
94
98
62
97
4894
8
66
788
8
(CH)5OAc
4
75
75
61
Et
Et
Et
63c
3d
3
Figure 3. Dipeptidic phosphanes 5d and 6.
phosphorus and carbonyl oxygen of the C-terminal
amino acid form a 7-membered chelate with cop-
per(I) as has been determined in a rhodium complex
of 1.[29b] Cyclohexenone 2a coordinates with copper(I)
by the C=C double bond from the face of the chelate
opposite to an angular-like phenyl group on phospho-
rus. The small hydrogen of the C-terminal amino acid
Scheme 1. Plausible stereochemical pathway.
À
À
chiral center is on the plane of C CO N due to the
allylic strain, and points toward pyrrolidine ring.
Three carbonyl oxygens of Boc, the N-terminal amino Conclusions
acid, and cyclohexenone are coordinated by zinc(II).
The alkyl group on Cu(I) is transferred on the si-face In summary, we have disclosed a highly enantioselec-
of cyclohexenone to give (S)-3-substituted cyclohexa- tive catalytic conjugate addition reaction of cycloalken-
none 3a with the observed absolute configuration. ones with dialkylzinc reagents. Key for these efficient
When the C-terminal amino acid has the (l)-configu- enantioselective catalytic conjugate additions is a di-
ration as shown in Boc-l-Val 4a, the steric bulk of the peptidic amidophosphane ligand for copper(I). More-
amino acid moiety would direct cyclohexenone to co- over, we propose a plausible working model to pre-
ordinate in the opposite way (8) giving (R)-3a.
dict the observed sense of enantiofacial differentia-
tion.
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567 (M+); anal. calcd. for C32H46N3O4P: C 67.70, H 8.17, N
7.40; found: C 67.48, H 8.02, N 7.45.
ExperimentalSection
GeneralRemarks
(À)-N-Boc-d-Val-d-Val-2(S)-(diphenylphosphinometh-
Asymmetric reactions were carried out under argon. IR
yl)pyrrolidine (5b)
spectra were expressed in cmÀ1. H, 13C and 31P NMR spec-
1
tra were taken in CDCl3 at 500, 125 and 202 MHz, respec-
tively. Chemical shift values are expressed in ppm relative
to internal TMS or external 85% H3PO4 for 31P. Abbrevia-
tions are as follows: s, singlet; d, doublet; t, triplet; q, quar-
tet; m, multiplet; br, broad.
Silica gel column chromatography (hexane/ethyl acetate=3/
1) gave a pale yellow amorphous solid; yield: 1.27 g (83%);
1
[a]2D5: À96.7 (c 0.95, benzene). H NMR: d=0.82–0.95 (11H,
m), 1.01+1.03 (total 1H, d, J=6.8Hz), 1.40 (9H, s), 1.77–
2.09 (7H, m), 2.96 (1H, m), 3.51 (1H, m), 3.77 (1H, m),
3.93 (1H, m), 4.17 (1H, m), 4.50 (1H, m), 4.99 (1H, m),
6.50 (1H, d, J=8.6 Hz), 7.19–7.64 (10H, m); 13C NMR: d=
17.6, 17.8, 18.1, 19.2, 19.4, 21.7, 28.2, 29.5, 29.9, 30.2, 30.3,
30.7, 30.9 (d, J=13 Hz), 31.4, 32.3 (d, J=13.3 Hz), 45.3,
47.1, 55.3 (d, J=19.6 Hz), 55.6 (d, J=18.5 Hz), 79.7, 128.3,
128.4, 128.4, 128.5, 128.7, 131.2 (d, J=12.3 Hz), 132.5 (d, J=
19.5 Hz), 132.9 (d, J=19.5 Hz), 134.1, 134.2, 135.1 (d, J=
8.2 Hz), 136.7 (d, J=12.3 Hz), 139.1 (d, J=10.3 Hz), 155.6,
169.9, 170.2, 171.0, 171.6; 31P NMR: d=À24.2 (1/5P, s),
À24.3 (4/5P, s); IR (nujol): n=3340, 1710, 1630 cmÀ1; EI-
MS: m/z=567 (M+); anal. calcd. for C32H46N3O4P: C 67.70,
H 8.17, N 7.40; found: C 67.93, H 8.13, N, 7.20.
Preparation of Dialkylzinc[35]
In a Schlenk tube, hydroboration was performed by mixing
alkene (10 mmol) and diethylborane, freshly prepared by
mixing triethylborane (1.4 mL, 10 mmol) and borane-di-
methyl sulfide complex (0.47 mL, 5 mmol) in a Schlenk tube
at 08C for 5 min. After completion by stirring at room tem-
perature, the solvent was carefully distilled off (0.5 mm Hg,
08C) for 0.5 h to afford a crude product, which was treated
with a hexane solution of diethylzinc (2.0 mL, 20 mmol) at
08C. After 0.5 h, the excess diethylzinc and triethylborane
were distilled off (0.8mm Hg, 0 8C) for 3 h and the residue
was diluted with toluene (10 mL) which was directly used in
the asymmetric conjugate addition.
(À)-N-Boc-l-Phe-d-Val-2(S)-(diphenylphosphinometh-
yl)pyrrolidine (5c)
Syntheses of 4a and 4b were reported previously.[31]
Silica gel column chromatography (hexane/ethyl acetate=2/
1) gave a pale yellow amorphous solid; yield: 1.39 g (84%);
[a]2D5: À70.0 (c 1.08, benzene). 1H NMR: d=0.55+0.71+
0.76+0.80+0.85+0.91 (total 6H, d, J=6.5 Hz), 1.39+1.42
(total 9H, s), 1.67–2.00 (6H, m), 2.98–3.11 (3H, m), 3.49
(1H, m), 3.66 (1H, m), 4.12 (1H, m), 4.33–4.47 (2H, m),
4.97 (1H, m), 6.60 (1H, d, J=8.9 Hz), 7.14–7.76 (15H, m);
13C NMR: d=17.5, 17.7, 18.5, 19.1, 21.5, 23.5, 24.0, 27.9, 29.5
(d, J=10.3 Hz), 29.9 (d, J=8.3 Hz), 30.3 (d, J=11.3 Hz),
31.2, 31.9 (d, J=7.1 Hz), 32.0, 45.2, 46.6, 47.0, 55.0 (d, J=
18.5 Hz), 55.3 (d, J=20.6 Hz), 55.7, 79.3, 126.3, 128.0, 128.1,
128.2, 128.3, 128.4, 128.5, 129.0, 129.2, 132.0, 132.2 (d, J=
18.5 Hz), 132.7 (d, J=18.5 Hz), 134.0 (d, J=20.5 Hz), 135.6
(d, J=12.3 Hz), 136.5, 139.0 (d, J=12.3 Hz), 154.9, 169.3,
169.3, 170.1, 170.9; 31P NMR: d=À24.0 (3/10P, s), À24.6 (7/
10P, s); IR (nujol): n=3290, 1720, 1610 cmÀ1; MS (FAB): m/
z=616 (M+H+); HR-MS (FAB): m/z=616.3320, calcd. for
C36H46N3O4P [M+H+]: 616.3304.
(À)-N-Boc-l-Val-d-Val-2(S)-(diphenylphosphinometh-
yl)pyrrolidine (5a)
Under an argon atmosphere, to a solution of (S)-N-tert-bu-
toxycarbonyl-2-[(diphenylphosphino)methyl]pyrrolidine
(1.11 g, 3.0 mmol) in dioxane (4.4 mL) was added 5.4 N
HCl-dioxane (11 mL, 60 mmol) at 08C over 5 min, and then
the whole was stirred at room temperature for 1 h. The mix-
ture was concentrated to give a yellow amorphous solid, to
which in anhydrous DMF (30 mL) and CH2Cl2 (30 mL)
were added N-Boc-l-Val-d-Val (3.03 mmol), HOOBt
(523 mg, 3.21 mmol), EDC·HCl (691 mg, 3.6 mmol), and N-
methylmorphorine (1.32 mL, 12.0 mmol) at À208C. After
this temperature had been maintained for 30 min, the reac-
tion mixture was stirred at 08C for 18h and at room temper-
ature for 1 h. AcOEt (100 mL), brine (20 mL), and 10%
aqueous citric acid (20 mL) were added. The organic layer
was washed with 10% aqueous citric acid (20 mL), saturated
aqueous sodium bicarbonate (30 mL ” 2), water (30 mL),
and brine (30 mL), and then dried over Na2SO4. Concentra-
tion and silica gel column chromatography (hexane/ethyl
acetate=3/1) gave a pale yellow amorphous solid; yield:
(À)-N-Boc-d-Phe-d-Val-2(S)-(diphenylphosphinometh-
yl)pyrrolidine (5d)
Silica gel column chromatography (hexane/ethyl acetate=
1
1.41 g (92%); [a]2D5: À8.26 (c 1.09, benzene). H NMR: d=
2/1) gave a pale yellow amorphous solid; yield: 1.23 g
1
0.85–1.15 (12H, m), 1.42+1.43 (total 9H, s), 1.89–2.16 (7H,
m), 2.95 (1H, m), 3.50 (1H, m), 3.75 (1H, m), 4.10 (1H, m),
4.14 (1H, m), 4.50 (1H, m), 5.06 (1H, m), 6.55 (1H, d, J=
8.9 Hz), 7.23–7.64 (10H, m); 13C NMR: d=17.9, 17.1, 17.7,
17.9, 19.1, 19.9, 20.8, 21.3, 23.5, 24.1, 28.0, 29.5 (d, J=
8.3 Hz), 30.3, 30.9, 31.3 (d, J=14.3 Hz), 35.6 (d, J=16.3 Hz),
45.2, 46.6, 55.5 (d, J=21.6 Hz), 55.8, 59.4, 60.4, 79.3, 128.0,
128.1, 128.3, 128.4, 129.3, 129.4, 130.0 (d, J=9.3 Hz), 131.0
(d, J=10.3 Hz), 132.3 (d, J=19.5 Hz), 132.6 (d, J=19.5 Hz),
136.7 (d, J=12.3 Hz), 138.8 (d, J=12.3 Hz), 155.4, 169.4,
169.9, 170.2, 171.3; 31P NMR: d=À24.2 (1/13P, s), À24.3 (12/
13P, s); IR (nujol): n=3350, 1720, 1630 cmÀ1; EI-MS: m/z=
(74%); [a]2D5: +2.15 (c 1.16, benzene). H NMR: d=0.53+
0.64+0.75+0.80+0.86+0.90 (total 6H, d, J=6.8Hz),
1.37+1.39 (total 9H, s), 1.71–2.11 (6H, m), 2.95–3.11 (3H,
m), 3.47–3.64 (2H, m), 4.12 (1H, m), 4.15–4.49 (1H, m),
4.97 (1H, m), 6.59 (1H, d, J=9.2 Hz), 7.03–7.67 (15H, m);
13C NMR: 17.6, 17.8, 19.1, 19.2, 19.8, 23.4, 23.9, 27.9, 29.4 (d,
J=9.3 Hz), 30.8, 31.3 (d, J=15.5 Hz), 37.7, 38.5, 55.3 (d, J=
21.5 Hz), 55.7, 79.3, 126.3, 127.9, 128.0, 128.1, 128.2, 128.2,
128.3, 128.4, 128.9, 132.2 (d, J=19.5 Hz), 132.6 (d, J=
19.5 Hz), 136.3 (d, J=10.3 Hz), 138.9 (d, J=12.3 Hz), 154.9,
169.2, 169.7, 169.9, 170.9; 31P NMR: À23.8(12/13P, s), À24.2
(1/13P, s); IR (nujol): n=3300, 1720, 1610 cmÀ1; MS (FAB):
632
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Peptidic Amidomonophosphane Ligand
m/z=616 (M+H+); HR-MS (FAB): m/z=616.3294, calcd.
for C36H46N3O4P [M+H+]: 616.3304.
12.1, 14.8Hz), 2.23–2.49 (3H, m); 13C NMR: d=12.1, 19.4,
23.2, 28.6, 32.8, 38.2, 40.4, 42.3, 48.7, 212.2; IR (neat): n=
1720 cmÀ1; EI-MS: m/z=154 (M+).
Asymmetric Conjugate Ethylation of Cyclohexenone
2a with Diethylzinc by the Catalysis of 5d-Copper(I)
giving (À)-(S)-3-Ethylcyclohexanone (3a; Table 1,
entry 7)
(+)-3-Cyclooctane-1-one (3d)[37]
Silica gel column chromatography (hexane then hexane/di-
ethyl ether=20/1) gave (+)-3d as a colorless oil; yield:
217 mg (83%); [a]2D5: +8.21 (c 1.23, CHCl3). The ee was de-
termined to be 61% by GC (g-Dex 225, 30 m”0.25 mm,
A solution of 5d (68.2 mg, 0.111 mmol) in 7.8 mL of toluene
was added to a suspension of Cu(MeCN)4BF4 (26.7 mg,
A
1
1008C, major 28.0 min and minor 26.1 min). H NMR: d=
0.085 mmol) in 24.5 mL of toluene. The resulting solution
was stirred for 1 h at room temperature. A solution of cyclo-
hexenone 2a (1.7 mmol) in 22 mL of toluene was added at
room temperature. After stirring at room temperature for
10 min, the mixture was cooled to 08C. A hexane solution
of diethylzinc (3.4 mL, 3.4 mmol) was added at 08C and the
whole was stirred at 08C for 2 h. The reaction was quenched
with 10% HCl and stirred at room temperature for 0.5 h.
The organic layer was separated and the water layer was ex-
tracted with diethyl ether. The combined organic layers
were washed with saturated NaHCO3 and brine, and then
dried over Na2SO4. Concentration and silica gel column
chromatography (hexane then hexane/diethyl ether=20/1)
0.92 (3H, t, J=7.3 Hz), 0.99 (3H, s), 1.14–1.96 (11H, m),
2.30–2.47 (4H, m); 13C NMR: d=11.6, 23.7, 14.6, 27.7, 30.0,
33.0, 39.7, 42.9, 46.9, 217.2. IR (neat): n=1710 cmÀ1; EI-MS:
m/z=149 (M+).
(À)-(S)-3-Methylcyclohexane-1-one (3ab)
Silica gel column chromatography (hexane then hexane/di-
ethyl ether=20/1) gave (À)-(S)-3ab as a colorless oil; yield:
117 mg (62%); [a]2D5: À6.67 (c 1.14, CHCl3). The ee was de-
termined to be 45% from the specific rotation.[6h] 1H NMR:
d=0.88 (3H, t, J=7.3 Hz), 1.01 (3H, d, J=6.0 Hz), 1.34
(1H, m), 1.70 (1H, m), 1.82–2.08 (4H, m), 2.16–2.40 (3H,
m); IR (neat): n=1720 cmÀ1; MS: m/z=112 (M+).
gave (À)-(S)-3-ethylcyclohexanone 3a[36] as a colorless oil;
22
365
yield: 186 mg (87%); [a] : À173.4 (c 0.68, CHCl3). The ee
was determined to be 98% by 13C NMR of its diastereo-
(À)-3-Isopropylcyclohexan-1-one (3ac)
1
meric aminal. H NMR: d=0.95 (3H, t, J=7.0 Hz), 1.3–2.5-
(9H, m); IR (neat): n=1740 cmÀ1; MS: m/z=126 (M+).
Silica gel column chromatography (hexane then hexane/di-
ethyl ether=20/1) gave (À)-3ac as a colorless oil; yield:
221 mg (97% yield); [a]D20: À96.3 (c 1.36, CHCl3). The ee
was determined to be 94% via the diastereomeric ketal.
1H NMR: d=0.91 (6H, t, J=6.3 Hz), 1.22–2.43 (10H, m);
IR (neat): n=2910, 1720 cmÀ1; EI-MS: m/z=140 (M+).
Determination of the ee of (À)-(S)-3a[6f-h]
A mixture of (À)-(S)-3a formed above (50 mg, 0.39 mmol),
(À)-(1S,2S)-1,2-diphenylethane-1,2-diamine
(100 mg,
0.47 mmol) and MS 4Š (20 mg) in CDCl3 (2 mL) was stirred
1
at room temperature for 12 h. H NMR: d=0.88 (3H, t, J=
Determination of the ee of (À)-3ac.[6h]
7.2 Hz), 1.23–2.10(15H, m), 3.55 (1H, m), 2.98(1H, m), 3.41
G
(1H, m), 3.82 (1H, m), 4.11 (1H, m), 5.15 (1H, m), 6.47
(1H, d, J=7.6 Hz), 7.00–7.66 (15H, m); 13C NMR: d=11.3,
20.0, 29.7, 31.6, 36.4 (major), 37.2 (minor), 39.7 (minor), 40.2
(major), 45.8(major), 46.0 (minor). From these three sets of
integration ratios (major/minor=1/0.01, 1/0.01, 1/0.01), the
ee was determined to be 98% ee.
A mixture of (À)-3ac above (0.5 mmol), (R,R)-2,3-butane-
diol (0.71 mmol), MS 4Š (40 mg), and p-toluenesulfonic
acid monohydrate (10 mg) in benzene (15 mL) was refluxed
for 12 h. After addition of 10% Na2CO3 (10 mL), the mix-
ture was extracted with benzene (20 mL”3). The organic
layer was washed with brine and dried over Na2SO4. Con-
centration gave a colorless oil; yield: 89%. 1H NMR: d=
0.82 (6H, t, J=6.3 Hz), 1.22–1.68(16H, m), 3.60 (2H, m);
(À)-R-3-Ethyl-4,4-dimethylcyclohexane-1-one (3b)
IR (neat): n=2910, 1450 cmÀ1 13C NMR: d=16.9, 17.0, 19.4,
;
Silica gel column chromatography (hexane then hexane/di-
ethyl ether=20/1) gave (À)-(R)-3b as a colorless oil; yield:
173 mg (66%); [a]2D0: À17.2 (c 1.38, CHCl3). The (R) abso-
lute configuration and 75% ee were determined from the
specific rotation.[6j] 1H NMR: d=0.88 (3H, t, J=7.3 Hz),
0.99 (3H, s), 1.03 (3H, s), 1.40 (1H, m), 1.54–1.75 (3H, m),
2.01 (1H, ddd, J=0.99, 12.1, 14.8Hz), 2.23–2.49 (3H, m);
13C NMR: d=12.1, 19.4, 23.2, 28.6, 32.8, 38.2, 40.4, 42.3,
48.7, 212.2; IR (neat): n=1720 cmÀ1; MS: m/z=154 (M+).
19.6, 22.9, 23.0, 23.3, 28.1, 21.4, 36.1 (major), 37.1 (minor),
39.7 (major), 40.7 (minor), 40.9 (major), 41.5 (minor). 108.9.
From these three sets of integration ratios, the ee was deter-
mined to be 94% ee.
(À)-(S)-3-(1-Phenylpropyl)cyclohexan-1-one (3ad)[13b]
Silica gel column chromatography (hexane then hexane/di-
ethyl ether=20/1) gave (À)-3ad as a colorless oil; yield:
176 mg (48%); [a]2D5: À7.04 (c 0.98, CHCl3). The ee was de-
termined to be 94% via the diastereomeric aminal.
1H NMR: d=0.91 (6H, t, J=6.3 Hz), 1.22–2.43 (10H, m);
IR (neat): n=2910, 1720 cmÀ1; EI-MS: m/z=140 (M+).
(À)-(S)-3-Ethylcycloheptan-1-one (3c)
Silica gel column chromatography (hexane then hexane/di-
ethyl ether=20/1) gave (À)-(S)-3c as a colorless oil; yield:
203 mg (85%); [a]2D0: À52.7 (c 1.09, CHCl3). The ee was de-
termined to be 86% from the specific rotation.[6i] 1H NMR:
d=0.88 (3H, t, J=7.3 Hz), 0.99 (3H, s), 1.03 (3H, s), 1.40
(1H, m), 1.54–1.75 (3H, m), 2.01 (1H, ddd, J=0.99 Hz,
Adv. Synth. Catal. 2007, 349, 629 – 635
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
633

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Determination of the ee of (À)-3ad by the Same
Procedure as for 3a
IR (neat): n=2910, 1450 cmÀ1 13C NMR: d=11.3, 23.1, 29.7,
;
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(À)-5-(3-Oxocyclohexyl)pentyl Acetate (3af)[38]
Silica gel column chromatography (hexane then hexane/di-
ethyl ether=20/1) gave (À)-3af as a colorless oil; yield:
323 mg (84%); [a]2D5: À7.04 (c 0.98, CHCl3). The ee was de-
termined to be 75% via the diastereomeric aminal.
1H NMR: d=1.22–1.54 (6H, m), 1.56–1.73 (2H, m), 1.75–
1.87 (2H, m), 2.08 (3H, s), 2.14–2.30 (3H, m), 2.35–2.50
(2H, m), 4.11 (2H, t, J=6.7 Hz); 13C NMR: d=20.9, 25.8,
27.4, 28.3, 29.6, 35.5, 37.1, 38.5, 45.2, 64.6, 171.2, 219.0; IR
(neat): n=3560, 1740 cmÀ1; MS: m/z=213 (M+).
Determination of the ee of (À)-3af by the Same
Procedure as for 3a
IR (neat): n=2910, 1450 cmÀ1 13C NMR: d=11.3, 22.6
;
(minor), 22.9 (major), 28.2 (minor), 29.7 (major), 31.6, 37.3,
40.2, 11.3, 23.1, 29.7, 31.7, 36.5 (minor), 37.3 (minor), 40.3,
45.8, 69.3, 70.6, 126.8, 126.9, 127.2, 128.1. From the two sets
of integration ratio, the ee was determined to be 75%.
Acknowledgements
This research was partially supported by the 21 st Century
COE (Center of excellence) Program “Knowledge Informa-
tion Infrastructure for Genome Science” and a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecu-
lar Transformations of Carbon Resources” from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
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