Synthesis of nitrogen-functionalized cyclohexanes using chemoselective conjugate addition of phenyllithium to linear ω-nitro-α,β, ψ,ω-unsaturated ester and subsequent stereoselective intramolecular nitro-Michael cyclization

Article abstract of DOI:10.1248/cpb.52.1109

Nitrogen-functionalized cyclohexane derivatives with three contiguous chiral centers were synthesized by nitroalkene-selective conjugate addition of phenyllithium to a ω-nitro-α,β,ψ, ω-unsaturated ester and subsequent stereocontrolled intramolecular nitro

Full text of DOI:10.1248/cpb.52.1109

September 2004
Chem. Pharm. Bull. 52(9) 1109—1113 (2004)
1109
Synthesis of Nitrogen-Functionalized Cyclohexanes Using Chemoselective
w
a b y w
Conjugate Addition of Phenyllithium to Linear -Nitro- , , , -
Unsaturated Ester and Subsequent Stereoselective Intramolecular
Nitro-Michael Cyclization
Tomohisa YASUHARA,a Katsumi NISHIMURA,b Emi OSAFUNE,a Osamu MURAOKA,a and
,b
*
Kiyoshi TOMIOKA
a School of Pharmaceutical Sciences, Kinki University; 3–4–1 Kowakae, Higashi-osaka, Osaka 577–8502, Japan: and
b Graduate School of Pharmaceutical Sciences, Kyoto University; Yoshida, Sakyo-ku, Kyoto 606–8501, Japan.
Received May 21, 2004; accepted June 14, 2004; published online June 16, 2004
Nitrogen-functionalized cyclohexane derivatives with three contiguous chiral centers were synthesized by ni-
troalkene-selective conjugate addition of phenyllithium to a w-nitro-a,b,y,w-unsaturated ester and subsequent
stereocontrolled intramolecular nitro-Michael cyclization with cesium fluoride and a quaternary ammonium
bromide. The cyclohexanes were applicable to the total synthesis of a-, b- and g-lycoranes.
Key words nitroolefin; conjugate addition; nitro-Michael cyclization; lycorane
The conjugate addition reaction of a carbonucleophile to a lithium to w-Nitro-a,b,y,w-Unsaturated Ester A w-
nitroalkene1) has been proven to be one of the powerful nitro-a,b,y,w-unsaturated ester 3 was prepared via four
methodologies for a carbon–carbon bond formation.2—14) An steps from 7 in 65% overall yield by the modified procedure
organolithium reagent rapidly undergoes the Michael addi- developed by Denmark36) (Chart 3). The Wittig reaction of 7
tion to a nitroalkene with reasonably high stereoselectiv- gave an alcohol 8, which was then oxidized by the
ity15,16) and were incorporated in the total syntheses of bio- Pfitzner–Moffat method to give a trans-aldehyde 9 after
logically active compounds as the critical step17,18) As well chromatographical separation of Z-isomer. The nitro-aldol
the nitro-Michael reaction has been attracted much attentions reaction of 9 with nitromethane was catalyzed by triethyl-
23)
due to its relevance in the strategy of synthetic chemistry.19—
amine giving 10 and was followed by dehydration with triflu-
Based on these progresses, we designed a synthesis of carbo- oroacetic anhydride and triethylamine to afford 3 in 65%
cycles with three contiguous chiral centers by the sequential overall yield from 7.
two reactions of the conjugate addition of a nucleophile to a
The reaction of 3 with phenyllithium in a 0.05 M THF solu-
nitroalkene moiety of a w-nitro-a,b,y,w-unsaturated ester tion at ꢀ78 °C for 15 min gave a nitroalkene-selective addi-
and subsequent intramolecular Michael addition of a ni- tion product 11 in 91% isolated yield (Table 1, entry 3). The
tronate to an enoate moiety.24—27) We have been involved in
the development of the conjugate addition28)-based cycliza-
tion methodology in these years.29—35) Described herein is the
full details of a new methodology for the construction of ni-
trogen-functionalized cyclohexanes with three contiguous
chiral centers 1 by the sequential nitroalkene-selective conju-
gate addition of phenyllithium to a w-nitro-a,b,y,w-unsatu-
rated ester 3 and subsequent stereoselective intramolecular
nitro-Michael cyclization of 2 (Chart 1).
Chart 1. A Synthetic Way to 1 by Nitroalkene-Selective Conjugate Addi-
tion of Organolithium to 3 and Nitro-Michael Cyclization of 2
Nitroalkene-Selective Conjugate Addition of Phenyl-
lithium The key to our approach sits on the possible
chemoselectivity in the conjugate addition of a carbonucle-
ophile to a nitroalkene moiety in the presence of another
Michael acceptor, an enoate in the same molecule 3. We
found the chemoselectivity was available from a model reac-
tion. The reaction of one equiv of phenyllithium with a mix-
ture of an equal amount of trans-b-nitrostyrene (4) and tert-
butyl trans-3-phenylpropenoate (5) in an each 0.05 M THF
solution at ꢀ78 °C for 15 min afforded a nitroalkene-selec-
tive conjugate addition product, 2-nitro-1,1-diphenylethane
(6) in 88% isolated yield, and 95% of 5 was recovered un-
changed (Chart 2). This reaction clearly demonstrated that
the reactivity of a nitroalkene is superior to an enoate, and a
nitroalkene-selective reaction is possible with an organo-
lithium reagent.
Chart 2. The Nitroalkene-Selective Michael Addition Reaction of Phenyl-
lithium with a Mixture of a Nitroalkene 4 and an Enoate 5
Nitroalkene-Selective Conjugate Addition of Phenyl-
Chart 3. The Four-Step Synthesis of 3 from 7
* To whom correspondence should be addressed. e-mail: tomioka@pharm.kyoto-u.ac.jp
© 2004 Pharmaceutical Society of Japan

1110
Vol. 52, No. 9
Table 1. The Conjugate Addition of Phenyllithium to 3 in Different Con- Table 2. The Intramolecular Nitro-Michael Cyclization of 11 with Cesium
centrations and Solvents Fluoride and Ammonium Bromide in Different Solvents
Entry
Solvent
R4NBr
Yield (%)
13 : 14 a)
Concentration
(M)
Entry
Solvent
11 (%)
12 (%)
3 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
EtOH
THF
Dioxane
DME
DMF
Et2O
MeCN
Toluene
CH2Cl2
CHCl3
THF
C13H27Me3
C13H27Me3
C13H27Me3
C13H27Me3
C13H27Me3
C13H27Me3
C13H27Me3
C13H27Me3
C13H27Me3
C13H27Me3
Me4
0
67
90
73
73
70
80
87
62
77
80
90
97
2.3 : 1
1 : 1
1 : 1
1 : 1.3
1 : 1.3
1 : 1.4
1 : 1
1 : 11
0 : 1
1
2
THF
THF
THF
THF
DME
t-BuOMe
Et2O
Toluene
Hexane
1.0
0.1
0.05
0.05
0.1
0.1
0.1
0.1
0.1
16
77
91
16
76
69
58
50
0
16
3
4a)
5
16
16
62
6
7
8
9
2 : 1
1.3 : 1
1 : 1.5
THF
THF
Et4
n-Bu4
a) A THF solution of 3 was added to a 0.05 M solution of PhLi.
a) Determined by 1H-NMR.
selectivity and chemical yield were highly affected by the
concentration of 3. In the 1.0 M concentration of 3, the reac-
tion afforded a mixture of 11 (16%) and a double phenylation
product 12 in 16% yield (entry 1). A 0.1 M solution gave 11
as a sole product in 77% yield (entry 2). An excess presence
of phenyllithium to 3 suffers from the concentration influ-
ence, and thus addition of THF solution of 3 to a 0.05 M THF
solution of phenyllithium resulted in 16% yield of 11 along
with 16% of 12 (entry 4). No observation of an enoate-selec-
tive adduct in every conditions indicates the efficient reaction
chemoselectivity in THF.
Although THF and dimethoxyethane (DME) were the
good solvents for high yields (entries 3, 5), other ethereal
solvents, tert-butyl methyl ether and diethyl ether were also
relatively good solvents, affording chemoselective adduct 11
in 69% and 58% yields, respectively (entries 6, 7). Toluene
was a comparable solvent giving 11 in 50% yield (entry 8).
Hexane was the inapplicable solvent, recovering 3 in 62%
yield (entry 9).
Table 3. Ammonium Bases for the Intramolecular Nitro-Michael Cycliza-
tion of 11.
Entry
Reagent
Time
Yield (%)
13 : 14 : 15a)
1
2
3
4
Me4NF
Et4NF
n-Bu4NF
Triton B
5 min
5 min
5 min
5 min
99
99
99
70
1.4 : 1 : 1
1.5 : 1 : 1.4
1.4 : 1 : 1
1 : 1.3 : 0.9
a) Determined by 1H-NMR.
Intramolecular Nitro-Michael Cyclization of 11 An
intramolecular nitro-Michael cyclization reaction of 11 was
examined using cesium fluoride as a nitronate-generating
reagent.35) Treatment of 11 with 2.0 eq of cesium fluoride
and 0.1 eq of myristyltrimethylammonium bromide in THF
at rt for 24 h afforded a 2.3 : 1 mixture of the cyclization
products 13 and 14 in 67% combined yield (Table 2, entry
2). Cyclization in dichloromethane gave a highly selective
1 : 11 mixture of 13 and 14 in 62% combined yield (entry 9).
Diastereomerically pure all-substituents equatorial 14 was
obtained by a nitro-Michael addition in chloroform (entry
10). The reaction in ethanol did not give the product, recov-
ering 11 unchanged (entry 1). Other ammonium bromides
were also effective in THF to give a 2 : 1 to 1 : 1.5 mixture in
high yield (entries 11—13). It is noteworthy that only two of
four possible stereoisomers were observed. The highly selec-
tive and specific formation of all equatorial-14 in methylene
chloride and chloroform implies the thermodynamic control
is operative in these bromide and fluoride dissolving sol-
vents.
Fig. 1. 1H-NMR of 13—15
Tetraalkylammonium fluorides were found to be more ef-
fective to give the cyclization products within 5 min (Table
3). It is interesting to find that the third diastereomer 15 was
observed in a comparable yield. Prolonged 24 h reaction with
ammonium fluoride gave the same level of diastereoselectivi-
ties, indicating that the reactions are kinetically as well as
thermodynamically controlled.
Determination of the Stereochemistry of 13—15 The
stereochemistry of 13—15 was well determined by 1H-NMR
(Fig. 1). Vicinal coupling constants of methine protons at-
tached by phenyl and nitro groups indicate that phenyl, nitro
and acetate groups are all equatorial in 14, two are equatorial
and one is axial in 13, and two are equatorial excepting an
axial nitro group in 15.

September 2004
1111
internal tetramethylsilane. J values were shown in Hz. The IR spectroscopy
was presented in cmꢀ1 for the wave numbers of maximum absorption peaks.
2-Nitro-1,1-diphenylethane (6) To a solution of a mixture of trans-b-
nitrostyrene (4, 149 mg, 1.0 mmol) and tert-butyl 3-phenylpentenoate (5,
204 mg, 1.0 mmol) in THF (20 ml) was added phenyllithium (1.81 M cyclo-
hexane–ether, 0.55 ml, 1.0 mmol) at ꢀ78 °C. The mixture was stirred for
15 min, and was then successively treated at ꢀ78 °C with methanol (1 ml),
sat. NH4Cl (20 ml), and brine (20 ml). The mixture was extracted with ethyl
acetate (20 mlꢂ3). Chromatography (hexane : AcOEtꢃ50 : 1 to 1 : 1) gave
194 mg (95% recovery) of 5 as a colorless oil and 199 mg (88%) of the
known 646) as pale yellow crystals of mp 69—70 °C (ethanol). 1H-NMR:
4.81—4.91 (3H, m), 7.16—7.28 (10H, m). 13C-NMR: 48.9, 79.2, 127.5,
127.6, 129.0, 139.2. IR (CHCl3): 1545. MS m/z: 227 (Mꢄ), 150 (MꢄꢀPh).
2,2-Dimethylethyl 7-Hydroxyhept-2-enoate (2E : 2Zꢃ9 : 1) (8) To a
solution of
7 (0.5 g, 4.9 mol) in toluene (10 ml) was added at rt
t
Ph3P=CHCO2 Bu. The mixture was stirred at 60 °C for 10 min. Hexane
(50 ml) was added at 0 °C. The mixture was filtrated and concentrated.
Hexane (50 ml) was again added and the mixture was filtrated again. Con-
centration and chromatography (hexane : AcOEtꢃ3 : 2) gave 0.891 g (91%)
1
of a 9 : 1 mixture of E- and Z-8 as a colorless oil. H-NMR: 1.48 (9H, s),
Chart 4. Reduction of a Nitro Group and Lactam Formation.
Hatched Lines Indicate NOE.
1.53—1.65 (4H, m), 2.21 (1.8H, ddt, Jꢃ1.5, 7.1, 7.3, E), 2.64 (0.2H, ddt,
Jꢃ 1.5, 7.3, 7.6, Z), 3.67 (2H, t, Jꢃ6.4), 5.69 (0.1H, dt, Jꢃ1.5, 11.6, Z),
5.75 (0.9H, dt, Jꢃ1.5, 15.6, E), 6.13 (0.1H, dt, Jꢃ7.6, 11.3, Z), 6.85 (0.9H,
dt, Jꢃ7.1, 15.6, E). 13C-NMR: 24.2 (E), 25.1 (Z), 28.1 (E), 28.2 (Z), 31.7,
32.0, 62.4 (Z), 62.5 (E), 80.1, 121.7 (Z), 123.2 (E), 147.5 (E), 148.5 (Z),
166.1. IR (neat): 3440, 1735. MS m/z: 201 (MꢄꢄH).
2,2-Dimethylethyl (2E)-7-Oxohept-2-enoate (9) To a solution of a 9 : 1
mixture of 8 above (400 mg, 2.0 mmol) in toluene (7.0 ml) were successively
added at rt DMSO (7 ml), pyridine (0.16 ml, 2.0 mmol), trifluoroacetic acid
(0.08 ml, 1.0 mmol), and DCC (1.2 g, 6.0 mmol). The mixture was stirred at
rt for 18 h. After addition of toluene (30 ml), the mixture was filtrated and
washed with water (30 mlꢂ3) and brine (20 ml), and then dried over sodium
sulfate. Chromatography (hexane : AcOEtꢃ10 : 1) gave 358 mg (90%) of 9
as a colorless oil. 1H-NMR: 1.48 (9H, s), 1.80 (2H, tt, Jꢃ7.1, 7.3), 2.23 (2H,
ddt, Jꢃ1.6, 7.1, 7.7), 2.49 (2H, dt, Jꢃ1.5, 7.3), 5.76 (1H, dt, Jꢃ1.6, 15.6),
6.81 (1H, dt, Jꢃ7.1, 15.6), 9.78 (1H, t, Jꢃ1.5). 13C-NMR: 20.4, 28.1, 31.1,
43.0, 80.2, 124.0, 146.2, 165.8, 201.7. IR (neat): 1710. MS m/z: 199
(MꢄꢄH).
2,2-Dimethylethyl (2E)-7-Hydroxy-8-nitrooct-2-enoate (10) A solu-
tion of 9 (198 mg, 1.0 mmol), nitromethane (0.17 ml, 1.0 mmol) and 2 drops
of triethylamine in THF (2 ml) was stirred at reflux for 12 h. Concentration
and chromatography (hexane : AcOEtꢃ8 : 1) gave 219 mg (84%) of 10 as a
colorless oil. 1H-NMR: 1.40—1.70 (4H, m), 1.44 (9H, s), 2.19 (2H, dt,
Fig. 2. a-, b-, g-Lycoranes 22—24 and a Cyclonitroalkene 25
A nitro group of a mixture of an almost equal amount of
13—15 was reduced with zinc powder37) and 10% HCl in
ethanol at rt for 24 h gave a mixture of chromatographically
easily separable amines 16, 17 and 18 in 33%, 23% and 25%
isolated yields, respectively (Chart 4). Cyclization of 16—18
was carried out by treatment with sodium methoxide in
methanol at rt for 24 h to give the corresponding lactams 19, Jꢃ6.4, 6.7), 3.02 (1H, br s), 4.29—4.41 (3H, m), 5.72 (1H, d, Jꢃ15.6), 6.78
(1H, dt, Jꢃ6.7, 15.6). 13C-NMR: 23.7, 28.1, 31.4, 33.0, 68.3, 80.3, 80.6,
20 and 21 in 99%, 59% and 99% yields, respectively.
Vicinal coupling constants and NOEs of methine protons
of 19, 20 indicate that phenyl, amino, and acetyl moieties are
123.6, 146.8, 166.1. IR (neat): 3420, 1700, 1550. MS m/z: 260 (MꢄꢄH),
203 (MꢄꢀtBuꢄH). Anal. Calcd for C12H21NO5: C, 55.58; H, 8.16; N, 5.40.
Found: C, 55.60; H, 8.21; N, 5.62.
equatorial, equatorial, and axial in 19, all equatorial in 20,
and equatorial, axial, and equatorial in 21, confirming the
stereochemical assignments of 13—15. (Fig. 1, Chart 4). The
stereochemical pathway in the cyclization is the subject of
the future studies.
In conclusion, we have developed the nitroalkene-selective
conjugate addition of an phenyllithium to a w-nitro-
a,b,y,w-unsaturated ester and following intramolecular
nitro-Michael cyclization for the synthesis of nitrogen-func-
tionalized cycloalkanes with three contiguous chiral centers.
We have already accomplished total syntheses of (ꢁ)-a-38,39)
and (ꢁ)-b-lycoranes (22, 23)40) using these sequential addi-
tion reactions with 3 (Fig. 2).41) Further application was
achieved in the total synthesis of (ꢁ)-g-lycorane (24)39,42—44)
by developing a stereoselective conjugate addition of an aryl-
lithium to a cyclic nitroalkene 25.45)
2,2-Dimethylethyl 8-Nitroocta-2,7-dienoate (3) Triethylamine (0.9 ml,
7.0 mmol) was added dropwise over 3 min at 0 °C to a solution of 10
(900 mg, 3.5 mmol) and trifluoroacetic anhydride (0.5 ml, 3.5 mmol) in THF
(10 ml). The mixture was stirred at rt for 1 h, and then was diluted with
20 ml of CHCl3. The whole was washed with water (20 ml), sat. NH4Cl
(20 ml), and brine (20 ml). Combined water layers were extracted with
CHCl3 (20 mlꢂ2). Chromatography (hexane : AcOEtꢃ8 : 1) gave 804 mg
1
(96%) of 3 as a colorless oil. H-NMR: 1.49 (9H, s), 1.70 (2H, tt, Jꢃ7.4,
7.7), 2.25 (2H, dt, Jꢃ6.7, 7.4), 2.31 (2H, dt, Jꢃ7.3, 7.7), 5.77 (1H, d,
Jꢃ15.6), 6.81 (1H, dt, Jꢃ6.7, 7.4), 6.99 (1H, d, Jꢃ13.4), 7.26 (1H, dt,
Jꢃ7.3, 13.4). 13C-NMR: 26.1, 27.7, 28.1, 31.1, 80.4, 124.2, 141.6, 145.7,
145.7, 165.7. IR (neat): 1710. HR-FAB-MS m/z: Calcd for C12H19NO4:
242.1392. Found: 242.1389.
2,2-Dimethylethyl 7-Phenyl-8-nitrooct-2-enoate (11) (Table 1, Entry 3)
A solution of phenyllithium (1.84 M, 0.65 ml, 1.2 mmol) was added at
ꢀ78 °C over 1 min to a solution of 3 (241 mg, 1.0 mmol) in THF (20 ml).
After stirring for 15 min, methanol (1 ml) and sat. NH4Cl (20 ml) and brine
(20 ml) were added at ꢀ78 °C to the mixture. The mixture was extracted
with AcOEt (20 mlꢂ3). Chromatography (hexane : AcOEtꢃ50 : 1 to 1 : 1)
gave 291 mg (91%) of 11 as a pale yellow. 1H-NMR: 1.40 (2H, m), 1.52
(9H, s), 1.76 (2H, dt, Jꢃ7.6, 7.9), 2.2 (2H, m), 3.50 (1H, ddt, Jꢃ7.7, 7.9,
Experimental
Combined organic layers for extraction were dried over sodium sulfate, 8.0), 4.60 (1H, dd, Jꢃ8.0, 12.2), 4.63 (1H, dd, Jꢃ7.7, 12.2), 5.73 (1H, dt,
and then concentrated unless otherwise noted. Silica gel column chromatog-
raphy was carried out for purification. All melting points are uncorrected.
NMR (500 or 270 MHz for a proton, 125 or 67.8 MHz for a carbon) was
measured in CDCl3. Chemical shift values were expressed in ppm relative to
Jꢃ1.6, 15.6), 6.79 (1H, dt, Jꢃ7.1, 15.6), 7.32 (2H, d, Jꢃ7.6), 7.33 (1H, t,
Jꢃ7.1), 7.40 (2H, dd, Jꢃ7.1, 7.6). 13C-NMR: 25.4, 28.1, 31.6, 32.4, 44.2,
80.2, 80.8, 123.5, 127.5, 127.7, 129.0, 138.9, 146.7, 165.9. IR (neat): 1710,
1650. HR-MS m/z: Calcd for C18H26NO4: 320.1862. Found: 320.1856.

1112
2,2-Dimethylethyl 3,7-Diphenyl-5-yl-8-nitrooctanoate (12) (Table 1,
Vol. 52, No. 9
21: Colorless needles of mp: 225—226 °C (CHCl3). 1H-NMR: 1.26—1.40
(1H, m), 1.74—1.89 (5H, m), 2.00 (1H, d, Jꢃ15.7), 2.44 (1H, m), 2.52 (1H,
dd, Jꢃ7.1, 15.7), 2.88 (1H, ddd, Jꢃ3.7, 4.3, 12.8), 3.92 (1H, dd, Jꢃ4.3,
4.3), 4.92 (1H, br s), 7.19—7.36 (5H, m). 13C-NMR: 23.8, 24.3, 27.6, 35.3,
40.3, 44.0, 58.7, 127.0, 128.9, 129.0, 142.4, 177.9. IR (CHCl3): 1680. MS
m/z: 215 (Mꢄ). Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51.
Found: C, 78.33; H, 8.01; N, 6.66.
Entry 1) 1H-NMR: 0.93—1.07 (m), 1.24—1.78 (m), 1.43 (s), 1.47 (s),
2.06—2.24 (2H, m), 2.65—2.78 (1H, m), 3.29 (br s), 3.45 (br s), 4.41—4.46
(m), 4.50 (m), 4.57 (m), 7.02—7.45 (10H, m). 13C-NMR: 23.8, 25.0, 27.5,
28.1, 32.7, 32.9, 33.2, 34.0, 44.1, 44.3, 43.9, 80.0, 130.1, 139.4, 142.5,
142.5, 172.0, 172.1. IR (neat): 1720. HR-MS m/z: Calcd for C24H35NO4:
398.2331. Found: 398.2340.
2,2-Dimethylethyl
(2-Nitro-3-phenylcyclohexyl)acetate
(13—15)
(Table 2, Entry 2) A suspension of 11 (32 mg, 0.1 mmol), CsF (30 mg,
0.2 mmol) and myristyltrimethylammonium bromide (134 mg, 0.2 mmol) in
THF (1 ml) was stirred at rt for 24 h, and was quenched with brine (20 ml).
The mixture was extracted with AcOEt (20 mlꢂ3). Chromatography
(hexane : AcOEtꢃ10 : 1) gave 20 mg (67%) of the 2.3 : 1 mixture of 13 and
14 as a pale yellow oil.
References and Notes
1) Ono N., “The Nitro Group in Organic Synthesis,” Wiley-VCH, New
York, 2001.
2) Review on asymmetric Michael additions to nitroalkenes: Berner O.
M., Tedeschi L., Enders D., Eur. J. Org. Chem., 2002, 1877—1894
(2002).
14 (from Entry 10): 1H-NMR: 1.34 (1H, m), 1.45 (9H, s), 1.52—1.66
(2H, m), 1.86 (2H, m), 1.99—2.08 (2H, m), 2.16 (1H, dd, Jꢃ8.5, 15.9), 2.31
(1H, dd, Jꢃ3.4, 15.9), 2.40—2.55 (1H, m), 3.16 (1H, ddd, Jꢃ3.7, 11.3,
11.6), 4.58 (1H, dd, 11.0, 11.3), 7.18 (2H, d, Jꢃ7.0), 7.23 (1H, t, Jꢃ7.6),
7.30 (2H, dd, Jꢃ7.0, 7.6). 13C-NMR: 24.9, 28.1, 30.1, 32.9, 38.3, 38.9, 48.7,
81.0, 95.1, 127.1, 127.6, 128.8, 140.2, 170.3. IR (neat): 1720. FAB-MS m/z:
320 (MꢄꢄH). Anal. Calcd for C18H24NO4: C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.77; H, 7.91; N, 4.59. 3.
3) Hayashi T., Senda T., Ogasawara M., J. Am. Chem. Soc., 122, 10716—
10717 (2000).
4) Alexakis A., Benhaim C., Rosset S., Human M., J. Am. Chem. Soc.,
124, 5262—5263 (2002).
5) Luchaco-cullis C. A., Hoveyda A. H., J. Am. Chem. Soc., 124, 8192—
8193 (2002).
6) Johnson T. A., Jang D. O., Slafer B. W., Curtis M. D., Beak P., J. Am.
Chem. Soc., 124, 11689—11698 (2002).
13 (Data Selected from a 1 : 1 Mixture of 13 and 14): 1H-NMR: 1.44 (9H,
s), 1.49—1.76 (3H, m), 1.82—1.94 (2H, m), 1.99—2.08 (3H, m), 2.40—
2.55 (3H, m), 3.09 (1H, br s), 3.26 (1H, ddd, Jꢃ4.0, 11.6, 11.9), 4.96 (1H,
dd, Jꢃ4.6, 11.6), 7.18—7.29 (5H, m). 13C-NMR: 19.9, 28.0, 29.3, 33.5,
33.7, 34.6, 41.9, 81.0, 91.8, 127.0, 127.3, 128.7, 141.0, 170.6. IR (neat):
1720. FAB-MS m/z: 320 (MꢄꢄH).
7) Rimkus A., Sewald N., Org. Lett., 4, 3289—3291 (2002).
8) Duursma A., Minnaard A. J., Feringa B. L., Tetrahedron, 58, 5773—
5778 (2002).
9) Enders D., Berner O. M., Vignola N., Harnying W., Synthesis, 2002,
1945—1952 (2002).
10) Duursma A., Minnaard A. J., Feringa B. L., J. Am. Chem. Soc., 125,
3700—3701 (2003).
2,2-Dimethylethyl (2-Amino-3-phenylcyclohexyl)acetate (16—18)
A
mixture of 13, 14 and 15 (1 : 1 : 1) (1.6 g, 5.0 mmol), and Zn powder (1.0 g,
15.4 mmol) in EtOH (60.0 ml) and 10% HCl aq. (10 ml) was stirred at rt for
1 d. The mixture was filtrated and concentrated. The residue was diluted
with 40 ml of AcOEt, and was washed with sat. NaHCO3 (20 ml) and brine
(20 ml). The combined organic layers were dried over sodium sulfate. Con-
centration and chromatography (hexane : AcOEtꢃ10 : 1 to 1 : 1) gave 478 mg
(33%) of 16, 333 mg (23%) of 17 and 362 mg (25%) of 18.
11) Andrey O., Alexakis, A., Bernardinelli G., Org. Lett., 5, 2559—2561
(2003).
12) Alam M. M., Barala R., Adapa S. R., Tetrahedron Lett., 2003, 5115—
5119 (2003).
13) Ohe T., Uemura S., Bull. Chem. Soc. Jpn., 76, 1423—1431 (2003).
14) Denmark S. E., Amishiro N., J. Org. Chem., 68, 6997—7003 (2003).
15) Yamashita M., Yamada K., Tomioka K., J. Am. Chem. Soc., 126,
1954—1955 (2003).
16) Yamashita M., Yamada K., Tomioka K., Tetrahedron, 45, 4237—4242
(2004).
16: A colorless oil. 1H-NMR: 1.26—1.63 (6H, m,), 1.46 (9H, s), 1.80
(2H, br s), 2.27 (1H, dd, Jꢃ9.5, 15.0), 2.40 (1H, ddd, Jꢃ3.6, 10.7, 11.6),
2.45 (1H, br s), 2.70 (1H, dd, Jꢃ4.6, 15.0), 3.14 (1H, dd, Jꢃ4.6, 10.7),
7.21—7.32 (5H, m). 13C-NMR: 20.6, 28.1, 29.5, 32.6, 36.6, 46.8, 56.3, 80.1,
126.5, 127.7, 128.6, 144.3, 173.6. IR (neat): 1720. MS m/z: 289 (Mꢄ). HR-
MS m/z: Calcd for C18H27NO2: 289.2042. Found: 289.2033.
17) Hughes C. C., Trauner D., Angew. Chem. Int. Ed., 41, 2556—4559
(2002).
18) Yamada K., Kurokawa T., Tokuyama H., Fukuyama T., J. Am. Chem.
Soc., 125, 6630—6631 (2003).
1
17: A colorless oil. H-NMR: 1.22—1.29 (5H, m), 1.26 (9H, s), 1.75—
1.84 (4H, m), 2.12 (1H, dd, Jꢃ8.0, 15.0), 2.32 (1H, ddd, Jꢃ2.5, 10.1, 12.0),
2.56 (1H, dd, Jꢃ10.1, 10.1), 2.66 (1H, dd, Jꢃ5.2, 15.0), 7.19—7.34. 13C-
NMR: 26.0, 28.0, 28.1, 32.0, 40.2, 42.3, 54.0, 58.9, 80.1, 126.5, 127.8,
128.6, 144.5, 172.9. IR (neat): 1720. MS m/z: 289 (Mꢄ). HR-MS m/z: Calcd
for C18H27NO2: 289.2042. Found: 289.2051.
19) Corey E. J., Zhang F.-Y., Org. Lett., 2, 4257—4259 (2000).
20) Kisanga P. B., Ilankumaran P., Fetterly B. M., Verkade J. G., J. Org.
Chem., 67, 3555—3560 (2002).
21) Li J.-T., Cui Y., Chen G.-F., Cheng Z.-L., Li T.-S., Syn. Commun., 33,
353—359 (2003).
22) Michaud D., Hamelin J., Texier-Boullet F., Tetrahedron, 59, 3323—
3331 (2003).
23) Bakó T., Bakó P., Keglevich G., Báthori N., Czugler M., Tatai J.,
Novák T., Parlagh G., Töke L., Tetrahedron: Asymmetry, 14, 1917—
1923 (2003).
24) Takasu K., Ueno M., Ihara M., J. Org. Chem., 66, 4667—4672 (2001).
25) Richards E. L., Murphy P. J., Dinon F., Fratucello S., Brown P. M.,
Gelbrich T., Hursthouse M. B., Tetrahedron, 57, 7771—7784 (2001).
26) Schneider C., Reese O., Chem. Eur. J., 8, 2584—2594 (2002).
27) Yagi K., Turitani T., Shinokubo H., Oshima K., Org. Lett., 4, 3111—
3114 (2002).
28) Doi H., Sakai T., Iguchi M., Yamada K., Tomioka K., J. Am. Chem.
Soc., 125, 2886—2887 (2003).
29) Nagaoka Y., Tomioka K., Org. Lett., 1, 1467—1469 (1999).
30) Nagaoka Y., Inoue H., El-Koussi N., Tomioka K., Chem. Commun.,
2002, 122—123 (2002).
1
18: A colorless oil. H-NMR: 1.13 (2H, br s), 1.39—1.56 (3H, m), 1.49
(9H, s), 2.20 (1H, m), 2.26 (1H, dd, Jꢃ7.3, 14.3), 2.36 (1H, dd, Jꢃ7.0,
14.3), 2.88 (1H, ddd, Jꢃ2.0, 3.0, 13.1), 3.16 (1H, dd, Jꢃ1.7, 1.9), 7.24—
7.27 (5H, m). 13C-NMR: 22.9, 25.5, 25.9, 28.1, 39.9, 40.1, 48.2, 54.6, 80.2,
126.2, 127.6, 128.4, 144.3, 172.6. IR (neat): 1720. MS m/z: 289 (Mꢄ). HR-
MS m/z: Calcd for C18H27NO2: 289.2042. Found: 289.2054.
7-Phenyloctahydroindol-2-one (19—21) (Chart 4) A solution of 16
(289 mg, 1.0 mmol) in MeOH (1 ml) was added at rt to a solution of sodium
(115 mg, 5.0 mmol) in MeOH (2 ml). After stirring for 24 h at rt, brine
(10 ml) was added. The mixture was extracted with AcOEt (20 mlꢂ3). Re-
crystallization from CHCl3/hexane gave 213 mg (99%) of 19 as colorless
needles of mp 188—190 °C. 1H-NMR: 1.47—1.58 (2H, m), 1.69—1.89 (4H,
m), 2.21 (1H, dd, Jꢃ8.5, 16.5), 2.39 (1H, dd, Jꢃ12.3, 16.5), 2.44 (1H, ddd,
Jꢃ3.4, 9.8, 12.5), 2.76 (1H, br s), 3.46 (1H, dd, Jꢃ6.7, 9.8), 5.57 (1H, br s),
7.18 (2H, d, Jꢃ7.0), 7.24 (1H, t, Jꢃ7.3), 7.32 (2H, dd, Jꢃ7.0, 7.3). 13C-
NMR: 21.1, 26.1, 30.3, 33.4, 34.9, 48.6, 59.9, 126.9, 127.6, 128.8, 143.2,
177.6. IR (CHCl3): 1680. MS m/z: 215 (Mꢄ). Anal. Calcd for C14H17NO: C,
78.10; H, 7.96; N, 6.51. Found: C, 77.97; H, 7.92; N, 6.50.
31) Inoue H., Nagaoka Y., Tomioka K., J. Org. Chem., 67, 5864—5867
(2002).
20: Colorless needles of mp 231—232 °C (CHCl3). 1H-NMR: 1.37—1.47
(1H, m), 1.49—1.67 (2H, m), 1.91—2.07 (4H, m), 2.12 (1H, dd, Jꢃ12.8,
15.3), 2.37 (1H, dd, Jꢃ6.4, 15.3), 2.63 (1H, ddd, Jꢃ3.4, 10.4, 11.3), 3.24
(1H, dd, Jꢃ10.1, 10.4), 5.28 (1H, br s), 7.18 (2H, d, Jꢃ7.4), 7.24 (1H, t,
Jꢃ7.1), 7.32 (2H, dd, Jꢃ7.1, 7.4). 13C-NMR: 26.1, 28.2, 32.8, 38.0, 44.8,
48.7, 65.1, 126.9, 127.1, 128.9, 142.3, 177.7. IR (CHCl3): 1680. MS m/z:
215 (Mꢄ). Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C,
78.23; H, 7.97; N, 6.46.
32) Nagaoka Y., El-Koussi N., Uesato S., Tomioka K., Tetrahedron Lett.,
43, 4355—4359 (2002).
33) Ono M., Nishimura K., Nagaoka Y., Tomioka K., Tetrahedron Lett.,
40, 6979—6982 (1999).
34) Ono M., Nishimura K., Tsubouchi H., Nagaoka Y., Tomioka K., J.
Org. Chem., 66, 8199—8203 (2001).
35) Nishimura K., Tsubouchi H., Ono M., Hayama T., Nagaoka Y.,
Tomioka K., Tetrahedron Lett., 44, 2323—2326 (2003).

September 2004
1113
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1135—1138 (2002).
39) Tamura O., Matsukida H., Toyao A., Takeda Y., Ishibashi H., J. Org.
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