Approach to enantioselective conjugate addition of organocopper reagents to cycloalkenones by the aid of chiral lactam bearing phosphine group

Article abstract of DOI:10.1016/S0040-4020(00)00141-1

The chiral lactam-phosphine ligand and copper salt mediated asymmetric conjugate addition reaction of butylmagnesium chloride and diethylzinc with cycloalkenones afforded the addition products in moderate selectivity. Among phosphines examined, 5-[(diphenylphosphiao)methyl]-3,3-dimethylpyrrolidin-2- one 5 gave rise to moderate enantioselectivity and high yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00141-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2857±2863
Approach to Enantioselective Conjugate Addition of
Organocopper Reagents to Cycloalkenones by the Aid of Chiral
Lactam Bearing Phosphine Group
*
Yuichi Nakagawa, Koichiro Matsumoto and Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Received 11 October 1999; revised 6 January 2000; accepted 13 January 2000
AbstractÐThe chiral lactam-phosphine ligand and copper salt mediated asymmetric conjugate addition reaction of butylmagnesium
chloride and diethylzinc with cycloalkenones afforded the addition products in moderate selectivity. Among phosphines examined,
5-[(diphenylphosphino)methyl]-3,3-dimethylpyrrolidin-2-one 5 gave rise to moderate enantioselectivity and high yield. q 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
tri¯ate as a copper source. The ligand±copper complex cata-
lyzes not only the reaction of cycloalkenone but also that of
acyclic enone. Chiral thiazolidinone was also developed as a
chiral ligand to afford the product in good ee.7 Since the
diphosphine or monophosphine greatly accelerates the
copper catalyzed reaction,8 a survey of the known diphos-
phine was carried out to ®nd that 0.5 mol% of copper(II)
tri¯ate and 0.5 mol% of phosphine are suf®cient, though
enantioselectivity was moderate.9 Chiral phosphite ligand-
based on tartrate also showed the same ligand accelera-
tion,10 although the ee was not so satisfactory.11 Chiral
ferrocenylphosphine±oxazoline was also introduced as a
catalytic amount of chiral ligand (12 mol%) in the reaction
of Grignard reagents and 10 mol% of copper iodide with
cyclohexenone to afford the product in good ee.12 Chiral
sulfonamide was also examined by Sewald to ®nd that
both catalytic amount of sulfonamide and copper(I) are
necessarily to catalyze the reaction, while the ee was not
satisfactory.13
Organocopper reagent has been established as an excellent
reagent for conjugate addition reaction and is readily avail-
able by treatment of copper(I) salt with organometallics
such as Grignard reagent, organolithium or organozinc.1
The reagent involves two different metals as constituents
in the cluster. A chiral modi®cation of the reagent needs a
chiral bidentate ligand of which heteroatoms coordinate
selectively to copper and other metals. Since nitrogen,
sulfur, and phosphorus atoms are known to coordinate
with copper, chiral ligands bearing these atoms in a coordi-
nating site have been examined in an asymmetric conjugate
addition reaction. Kretchmer was the ®rst who applied
chiral diamine (2)-sparteine as a ligand for methylcopper.2
The breakthrough in the stoichiometric reaction was
brought by Leyendecker who used hydroxyprolinol-derived
sul®de bearing three coordinating sites.3 Alexakis intro-
duced chiral phosphorus ligand in the reaction of medium
order cuprate with cycloalkenones in the presence of lithium
bromide to afford the conjugate addition product in high ee.4
Unfortunately, the catalytic process with the reagent derived
from organolithium was unsuccessful. Asymmetric conju-
gate additions of organozincs to enones in the presence of a
chiral ligand are a rapidly developing and exciting area.
Alexakis discovered the copper-catalyzed asymmetric
conjugate addition of diethylzinc to cyclohexenone.
Binaphthol-based phosphorus amidite was developed by
Feringa to afford the cyclohexenone ethyl adduct in an
extremely high ee.5,6 The success is laid on the use of copper
We have been involved in this exciting ®eld and have
developed proline-derived bidentate amidophosphines 1, 2
based on the concept `metal differentiating coordination'
(Fig. 1). The carbonyl oxygen and phosphorus atoms of
the ligand selectively coordinate to copper and other metal
of organocopper species 3 that discriminates the enantioface
of alkenone. The metal differentiating coordination was
supported by NMR studies.14 The reaction of lithium
dimethylcuprate with chalcone gave an adduct in 90%
ee.15 The reaction of lithium cyanocuprate with cycloalke-
none was also highly ef®cient to give the adducts in up to
95% ee.16 However, the catalytic version of lithium cyano-
cuprate was unsuccessful. On the other hand, magnesium
cyanocuprate prepared from Grignard reagent was highly
effective to afford the products in up to 98% ee. It is
Keywords: asymmetric reactions; conjugate additions; catalysis; organo-
metals.
* Corresponding author. Tel.: 181-75-753-4553; fax: 181-75-753-4604;
e-mail: tomioka@pharm.kyoto-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00141-1

2858
Y. Nakagawa et al. / Tetrahedron 56 (2000) 2857±2863
Figure 1. Conjugate addition of butylmagnesium chloride with aid of chiral phosphines 1, 2, 4, and 5.
noteworthy that the same chiral ligand gave the products
with the reversed absolute con®guration by changing
lithium to magnesium.17 Catalytic asymmetric conjugate
addition was realized by using 8 mol% of copper iodide
and 32 mol% of the chiral amidophosphine to afford the
products in 72±94% ee.18 There is a drawback, however,
that use of 2 mol% of copper iodide and 3 mol% of the
amidophosphine gave rather poor enantioselectivity of
27±40%. Dissociation of chiral phosphine from a copper±
ligand complex 3 is attributable to these disappointing
results. Use of less reactive organozinc as an organo-
metallics is one of the possible methodologies for avoiding
dissociation.19 Another possibility is use of copper amide
that contains a covalent copper±nitrogen bond.20 It may be
reasonably expected that chiral lactams 4 and 5 bearing a
phosphine appendage should form a stable amidocopper
species whose copper is intramolecularly coordinated by
the phosphorus atom as shown in 6. We describe herein
that the asymmetric conjugate addition reaction of butyl-
magnesium chloride and diethylzinc21 was catalyzed by
the lactam-phosphine ligands 4 and 5 in the presence of
copper salt to give the corresponding addition product in
up to 64% ee.
from l-glutamic acid applying the previously reported
procedure (Fig. 2).15c Dicyclohexylphosphine 12 was
prepared from the expectation that alkylphosphine coordi-
nates to copper atom more strongly than arylphosphine. As a
reference lactam, trityl-lactam 14 was prepared from 9.
Examination of Procedure for Conjugate Addition of
Butylmagnesium Chloride to Cyclohexenone
We examined three types of reaction procedure for forming
reactive copper complex. At ®rst, stoichiometric amount of
5 was lithiated with butyllithium in THF and then treated
with stoichiometric amount of butylcopper, prepared from
CuI and butyllithium, at 2308C for 0.5 h.23 The mixture was
then treated with cyclohexenone at 2208C for 0.5 h to
afford (S)-3-butylcyclohexanone in 65% ee.24 However,
the yield was not high, 29%. Next, 15 mol% of 5 was treated
at 08C for 1 h in ether or THF with butylcopper, preformed
by 1.2 equiv. of butylmagnesium chloride and 10 mol% of
CuI or CuBr at 08C for 0.5 h. Then, treatment with cyclo-
hexenone at 2788C for 1 h gave the product in 60±90%
yield, but in poor ee of 0±11%.25 Finally, 15 mol% of
lithiated 5 was treated with 10 mol% of CuI in ether at
08C for 1 h and then with butylmagnesium chloride at
2788C for 0.5 h.26 The mixture was then treated with cyclo-
hexenone at 2788C for 1 h to give (S)-3-butylcyclohexa-
none in 89% yield and 35% ee (Table 1, entry 2).
Synthesis of Lactam-Phosphines 4, 5, and 12
Chiral lactam-phosphines 4, 5, 12 were prepared by diphenyl-
phosphination22 of tosylates 8 and 10 or ¯uoride 11 derived
Figure 2. Synthesis of chiral phosphines, 4, 5, 12, and reference lactam 14.

Y. Nakagawa et al. / Tetrahedron 56 (2000) 2857±2863
Table 1. Effect of aging temperature and time on enantioselectivity
2859
Aging conditions
Reaction results
Yield (%)
Entry
Temperature (8C)
Time (h)
Temperature (8C)
ee (%)
1
2
3
4
5
278
278 to rt
1
1
1
0.3
3
0
22
89
92
20
96
12
35
47
31
19
278
278
0
rt
rt
rt
278
Since the third procedure gave the best result, we optimized
the reaction procedure. The aging conditions affected
enantioselectivity (Table 1). Treatment of lithiated 5 with
CuI at 2788C for 1 h resulted in quite poor reactivity,
indicating that formation of cuprated lactam requires a
temperature higher than 2788C (entry 1). Thus, treatment
at room temperature for 1 h afforded the reagent of higher
reactivity to give the product in 47% ee and 92% yield
(entry 3). Longer aging time resulted in poorer enantio-
selectivity of 19% (entry 5).
Since trityl-lactam 14 and phosphine oxide 13 gave the
product in only 4 and 1% ee, the importance of phosphorus
atom is apparent (Table 3, entry 4 and 5). Simple lactam-
phosphine 4 gave the product in surprisingly poor 2% ee
(entry 1), suggesting a directing effect of dimethyl substi-
tution at the a-position of the carbonyl group of 5. It was
disappointing that dicyclohexylphosphine 12, expected to
coordinate more tightly to copper than the diphenyl-
phosphine group of 5, however, gave rise to a similar
level of enantioselectivity (entry 3).
The amount of catalysts, lithiated 5 and CuI, was able to be
reduced to 7.5 and 5 mol% to afford the product in 44% ee
and 90% yield (Table 2, entry 4). The best ratio of 5 to CuI is
1.5 as shown in Table 2.
The reaction conditions above were applicable to the
asymmetric conjugate addition reaction of butylmagnesium
chloride with cycloalkenones to afford (S)-products in
moderate enantioselectivity (Table 4).
The reaction is highly sensitive to other factors. For
example, other solvents such as THF, toluene, hexane,
methylene dichloride, and acetonitrile gave the product in
marginal ees. Although copper bromide can be alternative to
afford 23% ee, other copper salts such as copper chloride,
cyanide, and tri¯ate are not the choice to afford marginal
selectivity.
Asymmetric Reaction of Diethylzinc
The catalytic activity of lactam-phosphine±copper
complexes was examined using diethylzinc as an organo-
metallic. A mixture of 10 mol% of 5 and 5 mol% of
27
Cu(OTf)2 in toluene was stirred at room temperature for
Table 2. Effect of amount of Cul and 5 on enantioselectivity
Table 3. Asymmetric reaction using chiral lactam
Entry
Cul (mol%)
5 (mol%)
Time (h)
Yield (%)
ee (%)
Entry
Lactam
Time (h)
Yield (%)
ee (%)
R/S
1
2
3
4
5
10
10
10
5
10
15
30
7.5
30
1
1
2
1
1
95
92
40
90
96
38
47
8
44
42
1
2
3
4
5
4
5
12
13
14
1
1
1
1
1.5
74
92
96
88
84
2
47
40
1
R
S
S
R
R
20
4

2860
Y. Nakagawa et al. / Tetrahedron 56 (2000) 2857±2863
and 84% yield.19 Toluene was the best solvent examined.
Table 4. Asymmetric reaction using 5
Ether and THF gave marginal ees. Enantioselectivity was
affected signi®cantly by the reaction temperature as shown
in Table 5. The antipode (R)-product was obtained at 2788C
for 3 days (entry 4). At a temperature below 2408C, some
reactive species giving poorer and reversed selectivity may
be involved in the reaction.
Entry
n
Yield (%)
ee (%)
R/S
The chiral lactam-phosphines exhibited a similar trend of
enantioselectivity to that observed in the reaction of butyl-
magnesium chloride (Tables 3 and 6). The relatively higher
35 and 31% ees were obtained using 5 and 12 (Table 6, entry
2 and 3). The simple lactam-phosphine 4 gave 19% ee (entry
1). Enantiofacial differentiation using 5 and 12 is also the
same as those of the reaction of butylmagnesium chloride.
1
2
3
5
6
7
75
92
47
23
47
18
S
S
S
Table 5. Temperature effect on enantioselectivity
When the phosphine group is absent in the lactam ligand as
shown by 13 and 14, the reaction was slow, but gave the
product in not marginal selectivity (Table 6, entry 4 and 5).
This suggests the possibility of simple amides as a chiral
catalyst. Then, the chiral bissulfonamides 15±1728 were
examined for evaluation of their catalytic activity. The reac-
tivity is apparently enhanced when the more acidic sulfona-
mide was used (Table 7, entry 1, 3, 5). The reagent prepared
from tri¯uoromethanesulfonamide 15 was much more reac-
tive than those derived from 17 and 16. The electrophilic
zinc in the Zn-amide derived from 15 should behave as a
better Lewis acid to promote a faster reaction. On the other
hand, higher enantioselectivity was obtained using phenyl-
sulfonamide 16.
Entry
Temperature (8C)
Time (min)
Yield (%) ee (%) R/S
1
2
3
4
20
0
240
278
15
20
180
3 d
83
84
84
80
19
35
27
7
S
S
S
R
Table 6. Asymmetric reaction using chiral lactam
The reactions of diethylzinc with cycloalkenones using 5
were examined (Table 8). Ethyl group was introduced to
cyclopentenone and cycloheptenone in 24 and 32% ees,
and in high yields. It was remarkable to ®nd that the reaction
with 4,4-dimethylcyclohex-2-enone gave the product in
64% ee and 94% yield after 4 h at 08C (entry 4).
Entry
Lactam
Time (min)
Yield (%)
ee (%)
R/S
1
2
3
4
5
4
5
12
13
14
30
20
10
420
180
82
84
93
73
76
19
35
31
9
S
S
S
S
R
6
Conclusion
The conjugate addition reaction of butylmagnesium
chloride and diethylzinc with cycloalkenone was catalyzed
by a catalytic amount of copper(I) and chiral lactam-phos-
phine 5. Covalent bond formation between lactam nitrogen
and copper(I) and subsequent internal coordination by phos-
phorus group made a copper±ligand complex stable toward
1 h. Then, a solution of 3 equiv. of diethylzinc was added at
08C and the mixture was stirred for 15 min at 08C. To the
mixture was added a solution of cyclohexenone in toluene
and the whole was stirred for 20 min at 08C. Usual workup
and puri®cation gave (S)-3-ethylcyclohexanone in 35% ee
Table 7. Asymmetric reaction using bissulfonamide
Entry
Cusalt
Et2Zn/eq
Ligand
Temp (8C)
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
CuCN
CuOTf
CuCN
CuCN
CuCN
3.0
3.0
3.0
5.0
3.0
15
15
16
16
17
0
0
rt
rt
0
0.5
0.3
20
5
91
84
46
52
76
18
14
28
26
18
4

Y. Nakagawa et al. / Tetrahedron 56 (2000) 2857±2863
Table 8. Asymmetric reaction with cycloalkenones using 5
2861
water (100 mL), the mixture was extracted with AcOEt. The
extract was washed with 10% HCl, sat. NaHCO3, brine, and
then dried over Na2SO4. Concentration and recrystallization
gave 10 (22.4 g, 85%) as colorless plates (AcOEt) of mp
120±1218C and [a]2D5ˆ117.8 (c 1.35, CHCl3). PMR d: 1.15
(6H, s, CH3), 1.55 (1H, dd, Jˆ7.6, 12.5 Hz, CH2), 2.53 (1H,
dd, Jˆ6.2, 12.5 Hz, CH2), 2.46 (3H, s, PhCH3), 3.86 (2H, m,
CH, CH2O), 4.09 (1H, m, CH2O), 6.2 (1H, brs, NH), 7.37
(2H, d, Jˆ8.1 Hz, ArH), 7.79 (2H, d, Jˆ8.1 Hz, ArH). CMR
d: 21.6, 25.1, 25.2, 38.2, 39.8, 49.4, 72.5, 127.9, 130.0,
132.4, 145.3, 182.1. IR (nujol): 3200, 1650 cm21. MS m/z:
297 (M1). Anal. Calcd for C15H21NO3: C, 60.99; H, 7.17; N,
4.74. Found: C, 60.87; H, 7.24; N, 4.90.
Entry
n
R
Time (min)
Yield (%)
ee (%)
R/S
1
2
3
4
5
6
7
6
H
H
H
Me
20
20
30
240
70
84
80
94
24
35
32
64
S
S
S
R
(1)-(S)-5-[(Diphenylphosphino)methyl]-3,3-dimethyl-
pyrrolidin-2-one (5). Small pieces of sodium (9.8 g,
424 mmol) were added to dioxane (200 mL) at 08C over
0.5 h and then chlorodiphenylphosphine (18.0 mL,
101 mmol) was added to the mixture under ice bath cooling.
After being re¯uxed for 7 h, a solution of 10 (20.0 g,
67.0 mmol) in THF (75 mL) was added at 08C. After
being stirred for 1 h, the mixture was ®ltered through Celite
to afford a pale yellow oil (28 g). Silica gel column
chromatography (PhH/AcOEtˆ2/1) gave 5 (15.6 g, 75%)
as a white powder of mp 99±1008C (AcOEt) and
[a]2D5ˆ120.1 (c 1.65, CHCl3). PMR d: 1.10 and 1.18
(each 3H, s, CH3), 1.70 (1H, dd, Jˆ8.2, 12.5 Hz, CH2),
2.16 (1H, dd, Jˆ6.6, 12.5 Hz, CH2), 2.28 (2H, d,
Jˆ7.3 Hz, CH2P), 3.63 (1H, m, CH), 5.90 (1H, brs, NH),
7.43 (10H, m, ArH). CMR d: 24.6, 25.3, 36.6 (d,
Jˆ14.7 Hz), 40.6, 45.1 (d, Jˆ8.5 Hz), 48.6 (d,
Jˆ17.1 Hz), 128.6, 128.7, 128.8, 129.1, 132.5, 132.6,
132.8, 132.9, 137.2, 137.4, 182.0. IR (nujol): 3200,
dissociation. Further studies aimed at sophisticated design
of chiral copper species are in progress in our laboratories.
Experimental29
(1)-(S)-5-{[(4-Methylphenyl)sulfonyloxy]methyl}pyrro-
lidine-2-one (8). To a mixture of 730 (5.0 g, 43.1 mmol) and
TsCl (9.1 g, 47.4 mmol) in CH2Cl2 (90 mL) was added
triethylamine (6.6 mL, 47.4 mmol) and DMAP (1.1 g,
8.62 mmol) under ice bath cooling and the whole was stirred
for 10 h at room temperature. After addition of 20 mL of
cold water, the mixture was extracted with AcOEt. The
extract was washed with 10% HCl, sat. NaHCO3, brine,
and then dried over Na2SO4. Concentration and silica gel
column chromatography (AcOEt) gave 8 as colorless plates
of mp 125±1268C (AcOEt) and [a]2D5ˆ120.4 (c 1.05,
CHCl3). PMR d: 1.78 (1H, m, CH2), 2.30 (3H, m, CH2,
CH2CO), 2.46 (3H, s, CH3), 3.88 (1H, dd, Jˆ7.4, 9.5 Hz,
CH2O), 3.92 (1H, m, CH), 4.05 (1H, dd, Jˆ3.7, 9.5 Hz,
CH2O), 6.21 (1H, brs, NH), 7.37 (d, Jˆ8.2 Hz, 2H, ArH),
7.79 (d, Jˆ8.2 Hz, 2H, ArH). IR (nujol): 3200, 1680,
1160 cm21. MS m/z: 269 (M1).
.
1670 cm21 MS m/z: 311 (M1). Anal. Calcd for
C19H22NOP: C, 73.29; H, 7.12; N, 4.50. Found: C, 72.96;
H, 7.20; N, 4.41.
(1)-(S)-5-Fluoromethyl-3,3-dimethylpyrrolidin-2-one
(11).31 A mixture of 10 (1.06 g, 3.4 mmol) and KF (395 mg,
6.8 mmol) in diethylene glycol (10 mL) was stirred for 7 h
at 1508C. After addition of water (10 mL), the mixture was
extracted with AcOEt. The extract was washed with water
and brine, and then dried over Na2SO4. Concentration and
silica gel column chromatography (AcOEt) gave 11
(370 mg, 75%) as colorless needles (AcOEt) of mp 105±
1078C and [a]2D5ˆ127.2 (c 1.27, CHCl3). PMR d: 1.20 (3H,
s, CH3), 1.21 (3H, s, CH3), 1.62 (1H, dd, Jˆ7.9, 12.8 Hz,
CH2), 2.04 (1H, dd, Jˆ7.3, 12.8 Hz, CH2), 3.91 (1H, dddd,
Jˆ3.4, 7.3, 7.3, 7.9 Hz, CH), 4,25 (1H, ddd, JHHˆ7.3,
9.5 Hz, JHFˆ48 Hz, CH2F), 4.44 (1H, ddd, JHHˆ3.4,
9.5 Hz, JHFˆ48 Hz, CH2F), 7.28 (1H, brs, NH). CMR d:
25.25, 25.30, 37.1 (Jˆ6 Hz), 39.9, 50.4 (Jˆ20 Hz), 85.7
(Jˆ172 Hz), 182.6. IR (nujol): 3200, 1660 cm21. MS m/z:
145 (M1). Anal. Calcd for C7H12NOF: C, 57.91; H, 8.33; N,
9.65. Found: C, 57.85; H, 8.21; N, 9.82.
(1)-(S)-5-[(4-Diphenylphosphino)methyl]pyrrolidine-2-
one (4). To a suspension of sodium (1.6 g, 69.9 mmol) in
dioxane (30 mL) was added chlorodiphenylphosphine
(3.0 mL, 16.7 mmol) at 08C over 10 min. After being
re¯uxed for 7 h, a solution of 8 (3.0 g, 11.1 mmol) in THF
(20 mL) was added at 08C. After being stirred for 5 min, the
mixture was ®ltered through Celite to afford a red oil (4.1 g).
Silica gel column chromatography (AcOEt) gave 4 (2.6 g,
83%) as colorless needles of mp 111±1128C (ether) and
[a]2D5ˆ127.2 (c 1.27, CHCl3). PMR d: 1.87 (1H, m,
CH2), 2.28 (5H, m, CH2P, CH2O, one of CH2), 3.67 (1H,
m, CH), 6.07 (1H, brs, NH), 7.41 (10H, m, ArH). CMR d:
29.0, 30.1, 36.5, 36.6, 52.1, 52.2, 128.6, 128.7, 129.1, 132.6,
132.7, 132.9, 137.3, 137.4, 177.5. IR (nujol): 3200,
.
1670 cm21 MS m/z: 283 (M1). Anal. Calcd for
C17H18NOP: C, 72.07; H, 6.40; N, 4.94. Found: C, 72.12;
H, 6.35; N, 4.84.
(1)-(S)-5-[(Dicyclohexylphosphino)methyl]-3,3-dimethyl-
pyrrolidin-2-one (12) and oxide (13). To a solution of
dicyclohexylphosphine (13.6 g, 68.8 mmol) in ether
(100 mL) was added a hexane solution of BuLi (50 mL,
68.8 mmol) at room temperature and the mixture was stirred
for 0.5 h at room temperature. After addition of a solution of
11 (5.0 g, 34.4 mmol) in dioxane (50 mL) under ice bath
(1)-(S)-3,3-Dimethyl-5-{[(4-methylphenyl)sulfonyloxy]-
methyl}pyrrolidin-2-one (10). To a mixture of 915c (13.0 g,
89 mmol) and TsCl (17.0 g, 89 mmol) in AcOEt (600 mL)
was added triethylamine (12.0 mL, 89 mmol) and DMAP
(11.0 g, 89 mmol) under ice bath cooling. The whole was
stirred for 8 h at room temperature. After addition of cold

2862
Y. Nakagawa et al. / Tetrahedron 56 (2000) 2857±2863
cooling, the whole was stirred for 10 h at room temperature.
Usual workup and puri®cation by alumina column chroma-
tography (AcOEt) gave 12 (445 mg, 4%) as a colorless oil
and 13 (9.0 g, 77%) as a white solid.
08C. The above solution was added to a suspension of CuI
(30 mg, 0.16 mmol, 10 mol%) in ether (10 mL) at room
temperature. After being stirred for 1 h, BuMgCl
(0.96 mL, 1.87 mmol, 1.2 equiv.) in ether was added at
2788C. After stirring for 30 min, a solution of cyclohex-
2-enone (150 mg, 1.56 mmol) in ether (4 mL) was added
dropwise over 15 min at 2788C and the whole was stirred
for 1 h at the same temperature. Usual workup and puri®-
cation by silica gel column chromatography (hexane±
12: [a]2D5ˆ134.5 (c 0.95, CHCl3). PMR d: 1.16 (3H, s,
CH3), 1.19 (3H, s, CH3), 1.23±1.46 (12H, m, cyclohexyl-
H), 1.59 (1H, dd, Jˆ8.5, 12.5 Hz, CH2), 1.69±1.97 (12H, m,
cyclohexyl-H, P-CH and CH2P), 2.21 (1H, dd, Jˆ5.2,
12.5 Hz, CH2), 3.51±3.66 (1H, m, CH), 7.04 (1H, s, NH).
CMR d: 24.0, 24.2, 24.6, 25.1, 25.2, 25.3, 25.50, 25.54,
25.2, 26.0, 26.2, 26.31, 26.33, 26.4, 26.5, 30.1 (d,
Jˆ12.0 Hz), 35.3, 36.5, 36.0, 36.3, 39.9, 45.0 (d, Jˆ7 Hz),
47.1 (d, Jˆ14.2 Hz), 180.9. IR (®lm): 3250, 1690 cm21. MS
m/z: 323 (M1). Anal. Calcd for C19H34NOP: C, 70.55; H,
10.6; N, 4.33. Found: C, 70.42; H, 9.80; N, 4.24.
etherˆ9:1) gave (S)-3-butylcyclohexanone32 (221 mg,
25
92 %) as a colorless oil of [a] ˆ238.4 (c 1.05, CHCl3)
405
in 47% ee. The ee was determined to be 47% by CMR
analysis of the corresponding diastereomeric ketals
prepared with (R,R)-2,3-butanediol (p-TsOH in benzene at
re¯ux, 95% yield).33
Asymmetric conjugate addition of diethylzinc to 4,4-
dimethyl-2-cyclohexenone controlled by 5 (Table 8,
entry 4). A mixture of 5 (37 mg, 0.12 mmol, 10 mol%)
and Cu(OTf)2 (22 mg, 0.06 mmol, 5 mol%) in toluene
(9 mL) was stirred at room temperature for 1 h. Et2Zn
(3.6 mL, 3.63 mmol, 3.0 equiv.) in hexane was added at
08C and the whole was stirred for 15 min at 08C. To the
mixture was added a solution of 4,4-dimethylcyclohex-2-
enone (150 mg, 1.21 mmol) in toluene (2 mL) and the
whole was stirred for 4 h at 08C. Usual workup and puri®-
cation by silica gel column chromatography (hexane±
13: [a]2D5ˆ174.3 (c 1.20, CHCl3). PMR d: 1.15 (3H, s,
CH3), 1.20 (3H, s, CH3), 1.24±1.45 (12H, m, cyclohexyl-
H), 1.59 (1H, dd, 1H, Jˆ8.5, 12.5 Hz, CH2), 1.69±1.97
(12H, m, cyclohexyl-H, P-CH and CH2P), 2.21 (1H, dd,
Jˆ6,4, 12.5 Hz, CH2), 3.93 (1H, m, CH), 6.79 (1H, s,
NH). CMR d: 24.5, 24.55, 24.59, 25.11, 25.13, 25.29,
25.50, 25.52, 25.8, 26.1, 26.2, 26.26, 26.3, 26.36, 26.40,
30.1 (d, Jˆ58 Hz), 35.8, 36.3, 36.5, 37.0, 39.8, 45.7 (d,
Jˆ11 Hz), 47.1 (d, Jˆ5.1 Hz), 181.2. IR (nujol): 3250,
1690, 1150 cm21. MS m/z: 339 (M1). Anal. Calcd for
C19H34NO2P: C, 67.23; H, 10.10; N, 4.13. Found: C,
67.12; H, 10.33; N, 4.08.
etherˆ4:1) gave the (R)-ethyl adduct34 (175 mg, 94%) as
25
a colorless oil of [a] ˆ213.7 (c 1.20, CHCl3) in 64%
405
ee. PMR d: 0.88 (3H, t, Jˆ7.3 Hz), 0.99 (3H, s), 1.0 (1H,
m), 1.03 (3H, s), 1.40 (1H, m), 1.53±1.75 (3H, m), 2.02 (1H,
ddd, Jˆ0.99, 12.1, 14.8 Hz), 2.22±2.49 (3H, m). CMR d:
12.1, 19.4, 23.2, 28.6, 32.8, 38.2, 40.4, 42.2, 48.7, 212.2. IR
(neat): 1710 cm21. MS m/z: 238 (M1).
Synthesis of 12 by reduction of 13. To a stirred suspension
of 13 (4.0 g, 11.8 mmol) in CH3CN (120 mL) was added
triethylamine (8.2 mL, 59.0 mmol) at 08C. After addition
of trichlorosilane (8.8 mL, 64.9 mmol), the whole was
re¯uxed for 16 h. After addition of degassed toluene
(30 mL) and 30% NaOH (20 mL), the mixture was extracted
with degassed toluene. The extract was washed with
degassed water, degassed satd NaHCO3 and degassed
brine, and then dried over Na2SO4. Concentration and
alumina column chromatography (hexane±etherˆ1:4)
gave 12 (2.1 g, 52%).
Acknowledgements
We gratefully acknowledge ®nancial support from Japan
Society for Promotion of Science (RFTF-96P00302) and
the Ministry of Education, Science, Sports and Culture,
Japan.
(1)-(S)-3,3-Dimethyl-5-[(triphenylmethoxy)methyl]pyrro-
lidin-2-one (14). A mixture of 9 (1.3 g, 8.8 mmol), trityl
chloride (3.43 g, 12.3 mmol), triethylamine (2.5 mL) and
DMAP (215 mg, 1.76 mmol) in DMF (24 mL) was stirred
for 4 h at room temperature. After addition of cold water
(5 mL), the mixture was extracted with AcOEt. The extract
was washed with 10% HCl, sat. NaHCO3 and brine, and
then dried over Na2SO4. Concentration and silica gel
column chromatography (PhH±AcOEtˆ1:1) gave 14
(2.6 g, 78%) as a white solid. PMR d: 1.11 and 1.17 (each
3H, s, CH3), 1.44 (1H, dd, Jˆ8.1, 12.3 Hz), 1.93 (1H, dd,
Jˆ7.0, 12.3 Hz), 2.87 (1H, t, Jˆ9.0 Hz), 3.21 (1H, dd,
Jˆ3.4, 9.0 Hz), 3.81 (1H, dddd, Jˆ3.4, 7.0, 8.1, 9.0 Hz),
5.83 (1H, brs), 7.20±7.50 (15H, m). IR (nujol): 3200,
1690 cm21. MS m/z: 385 (M1).
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