(S)-Phenylalanine-derived chiral phosphorus-olefin ligands in rhodium-catalyzed asymmetric 1,4-addition reactions

Article abstract of DOI:10.1016/j.tetasy.2012.02.007

Chiral phosphorus-olefins (S)-1, (S)-4, and (S)-5 have been designed and synthesized. These ligands were all synthesized from (S)-phenylalanine derivatives and act as phosphorus-olefin bidentate ligands to rhodium. The coordination face of the olefin can

Full text of DOI:10.1016/j.tetasy.2012.02.007

Tetrahedron: Asymmetry 23 (2012) 284–293
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Tetrahedron: Asymmetry
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(S)-Phenylalanine-derived chiral phosphorus–olefin ligands
in rhodium-catalyzed asymmetric 1,4-addition reactions
Rintaro Narui a, Sayuri Hayashi a, Haruka Otomo a, Ryo Shintani a, , Tamio Hayashi a,b,
⇑
⇑
a Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
b Chemistry Department, Faculty of Science, King Abdulaziz University, PO Box 80203, Jeddah 21589, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral phosphorus–olefins (S)-1, (S)-4, and (S)-5 have been designed and synthesized. These ligands were
all synthesized from (S)-phenylalanine derivatives and act as phosphorus–olefin bidentate ligands to rho-
dium. The coordination face of the olefin can be effectively controlled by the original chirality of (S)-phen-
ylalanine in all cases; the rhodium complexes coordinated with these ligands have been employed as
Received 29 January 2012
Accepted 10 February 2012
Available online 13 March 2012
catalysts for the asymmetric 1,4-addition of arylboronic acids to
a,b-unsaturated ketones, to give 1,4-
adducts with high enantioselectivities for cyclic enones and moderate enantioselectivities for acyclic
enones.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
R
Ph
Ph
R
Ph
Ph
P
N
P
Since the first report on the development of effective chiral
diene ligands for asymmetric catalysis,1 a structurally diverse
range of chiral dienes have been synthesized and utilized as li-
gands for various transition metal-catalyzed enantioselective pro-
cesses.2 The success of this new class of chiral ligand prompted
many researchers to design and synthesize chiral olefin ligands
bearing another coordinating group based on a phosphorus,3,4
nitrogen,5 or sulfoxide group.6 Our group also introduced chiral
phosphine–olefins A as early examples of this type of hybrid chiral
olefin ligands (Fig. 1, left).4 Ligands A have a bicyclo[2.2.1]heptene
backbone with high rigidity, and provide highly active and stereo-
selective catalysts for the rhodium-catalyzed asymmetric 1,4-addi-
tion of arylboronic acids to electron-deficient olefins.4a,c However,
these ligands require a long synthetic scheme involving a resolu-
tion of the two enantiomers using chiral HPLC. In order to solve
this synthetic problem while maintaining the good chiral
environment around the olefin, we recently developed a new class
of phosphorus–olefin ligand B based on 1-(diphenylphosphino)-
2,5-dihydro-1H-pyrrole, whose chirality is derived from natural
(S)-phenylalanine (Fig. 1, right), and have demonstrated that these
ligands are highly effective for the rhodium-catalyzed asymmetric
addition of arylboroxines to N-sulfonyl imines.7 Herein, we intro-
duce new members of this family of phosphorus–olefin ligand
and describe the use of these ligands in the rhodium-catalyzed
Ph
A
B
Figure 1. Previously developed chiral phosphine–olefin ligand A (left) and newly
prepared chiral phosphorus–olefin ligand B (right).
asymmetric 1,4-addition of arylboronic acids to
ketones.8
a,b-unsaturated
2. Results and discussion
2.1. The design and synthesis of chiral phosphorus–olefins B
and their analogues
A new class of phosphorus–olefins B, the configuration of which
can be derived from natural (S)-phenylalanine, were designed to
coordinate with a transition-metal by the phosphorus atom and
the olefin, as was the case for ligands A. The coordination face of
the olefin should be controlled by the stereogenic carbon center
with a benzyl group on the dihydropyrrole ring. Thus, in order to
avoid the unfavorable steric interaction of the benzyl group, the
bre-face of the olefin should preferentially coordinate with a metal
M and thereby the substituent on the olefin (R) effectively dictates
the chiral environment around the metal (Fig. 2). As an initial
member of this class of ligand B, we prepared compound (S)-1a
from the readily available allylamine derivative (S)-2 (Scheme 1),
which is known to be easily synthesized from (S)-phenylalanine.9
N-Alkylation of (S)-2 with 2-methyl-2-propenyl bromide, followed
⇑
Corresponding authors.
E-mail addresses: shintani@kuchem.kyoto-u.ac.jp (R. Shintani), thayashi@ku-
chem.kyoto-u.ac.jp (T. Hayashi).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.02.007

R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
285
cases. For the synthesis of (S)-4, a 3-methyl-3-butenyl group was
installed on the nitrogen atom of (S)-2 by sequential N-deprotec-
tion, alkylation, and reprotection,11 and the resulting 1,7-diene
was subjected to the ruthenium-catalyzed ring-closing metathesis
to give (S)-6 in a 46% overall yield. Removal of the tert-butoxycar-
bonyl group and subsequent N-phosphination with chlorodiphen-
ylphosphine gave (S)-4 in an 82% yield from (S)-6. The synthesis of
(S)-5 was initiated by the installation of an allyl group on the nitro-
gen atom of (S)-712 through a similar sequence of N-deprotection,
allylation, and reprotection to give (S)-8 in a 58% yield. Treatment
of (S)-8 with methylmagnesium chloride provided the methyl ke-
tone, which was then reacted with a phosphonium ylide to give
(S)-9 with 98% ee. Recrystallization of this material from hexane
gave (S)-9 with >99% ee in a 60% overall yield from (S)-8. The
ruthenium-catalyzed ring-closing metathesis of (S)-9, followed by
removal of the tert-butoxycarbonyl group and the subsequent
N-phosphination with chlorodiphenylphosphine, completed the
synthesis of (S)-5 in a 66% yield from (S)-9.
Ph
Ph
Ph
Ph
R
Ph
Ph
P
P
α
β
P
N
vs.
N
N
M
M
H
Ph
Ph
Ph
H
R
R
B
βre-face
βsi-face
disfavored
favored
Figure 2. Structure of phosphorus–olefin
B
and its coordination modes to a
transition metal.
Me
Me
Boc NH
(a), (b)
(c), (d)
Boc
N
Ph2P
N
Ph
(S)-2
Ph
(S)-3a
Ph
Ph
Ph
(S)-1a
O
Ph2P
N
Ph2P
Ph
N
Ph
(S)-1b
62% overall yield
(S)-1c
85% overall yield
2.2. Structures of rhodium complexes coordinated with
phosphorus–olefins (S)-1a, (S)-4 and (S)-5
Scheme 1. Synthesis of chiral phosphorus–olefins (S)-1. Reagents and conditions:
(a) NaH, 2-methyl-2-propenyl bromide, DMF, rt; 95%; (b) cat. Grubbs 2nd
generation, C6H6, 60 °C; 98%; (c) CF3CO2H, CH2Cl2, rt; 95%; (d) (i) NaOH (aq) then
Et2O extraction, (ii) Ph2PCl, Et3N, THF, 0 °C to rt; 83%.
A ligand exchange reaction of Rh(acac)(C2H4)2 with (S)-1a (31
P
NMR: 43.5 ppm; 1H NMR: 5.24 ppm for the olefin H in benzene-
d6) in benzene cleanly produced Rh(acac)((S)-1a) [10; 31P NMR:
127.9 ppm (J = 202 Hz); 1H NMR: 3.75 ppm for the olefin H in ben-
zene-d6] in an 85% yield (eq 1). Recrystallization of this complex
from benzene/pentane afforded single crystals suitable for X-ray
crystallographic analysis (Fig. 3 and Table 1).13 As shown in Fig-
ure 3, (S)-1a acts as a phosphorus–olefin bidentate ligand to rho-
dium while the olefin coordinates with its bre-face to keep the
benzyl group on the dihydropyrrole ring away from rhodium, suc-
cessfully satisfying the initial design of this ligand. In addition, it
shows that two phenyl groups on the phosphorus atom are sym-
metrically projected, and the chiral environment around the rho-
dium is effectively constructed by the steric difference between
the two substituents (Me and H) on the olefin. Similarly, Rh(a-
cac)((S)-4) [11; 31P NMR: 105.5 ppm (J = 202 Hz); 1H NMR:
4.14 ppm for the olefin H in benzene-d6] and Rh(acac)((S)-5) [12;
31P NMR: 128.2 ppm (J = 204 Hz); 1H NMR: 3.87 ppm for the olefin
H in benzene-d6] were also isolated in good yields as single isomers
(eq 1), indicating that the coordination face of the olefins is effec-
tively controlled in both cases by the stereogenic carbon center
having the benzyl group. Single crystals suitable for X-ray analysis
were obtained for complex 11 by recrystallization from Et2O/pen-
tane and its X-ray crystal structure is illustrated in Figure 4 (see
by ruthenium-catalyzed ring-closing metathesis,10 gave (S)-3a in a
93% yield over two steps. Removal of the tert-butoxycarbonyl
group and subsequent N-phosphination with chlorodiphenylphos-
phine completed the synthesis of (S)-1a in a 79% yield from (S)-3a.
Chiral phosphorus–olefins (S)-1b and (S)-1c with a benzyloxym-
ethyl group and a phenyl group on the olefin, respectively, were
also prepared from (S)-2 in good overall yield by following the
same synthetic scheme for (S)-1a.
In addition to these ligands (S)-1a–1c, we also synthesized anal-
ogous phosphorus–olefins (S)-4 with a tetrahydropyridine frame-
work instead of dihydropyrrole (Scheme 2) and (S)-5 with a
methyl group at the b-carbon instead of at the
a-carbon
(Scheme 3), starting from (S)-phenylalanine derivatives in both
Boc NH
(a), (b), (c)
Boc
Ph
N
Me (d), (e)
Ph2P
Ph
N
Me
Ph
(S)-6
(S)-4
(S)-2
Scheme 2. Synthesis of chiral phosphorus–olefin (S)-4. Conditions: (a) CF3CO2H,
CH2Cl2, rt; 87%; (b) (i) NaHCO3 (aq) then CH2Cl2 extraction, (ii) 3-methyl-3-butenyl
methanesulfonate, K2CO3, MeCN, rt, (iii) (Boc)2O, Et3N, THF, rt; 55%; (c) cat. Grubbs
2nd generation, C6H6, 60 °C; 96%; (d) CF3CO2H, CH2Cl2, rt; 99%; (e) (i) NaOH (aq)
then Et2O extraction, (ii) Ph2PCl, Et3N, THF, rt; 83%.
Boc NH
O
N
Boc
Ph
N
O
N
(a), (b), (c)
(d), (e)
Ph
(S)-7
O
(S)-8
O
α
β
Ph2P
N
(f), (g), (h)
Boc
Ph
N
Me
Ph
(S)-5
Me
(S)-9
Scheme 3. Synthesis of chiral phosphorus–olefin (S)-5. Reagents and conditions:
(a) CF3CO2H, CH2Cl2, rt; 99%; (b) allyl bromide, Na2CO3, MeCN, rt; 62%; (c) (Boc)2O,
Et3N, THF, rt; 95%; (d) MeMgCl, THF, –20 °C to rt; 81%; (e) (i) MePPh3Br,
NaN(SiMe3)2, Et2O/THF, rt, (ii) recrystallization from hexane; 74%; (f) cat. Grubbs
2nd generation, C6H6, 60 °C; 99%; (g) CF3CO2H, CH2Cl2, rt; 86%; (h) (i) NaOH (aq)
then Et2O extraction, (ii) Ph2PCl, Et3N, THF, rt; 77%.
Figure 3. X-ray crystal structure of complex 10 with thermal ellipsoids drawn at
the 50% probability level (carbon atoms of the acac moiety and hydrogen atoms are
omitted for clarity).

286
R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
Table 1
from P–O1–O2 plane = 0.000 Å), presumably due to the less com-
pact tetrahydropyridine ring. With regards to the X-ray analysis
for complex 12, only single crystals of moderate quality have been
obtained to date by recrystallization from 1,2-dichloroethane/pen-
tane; the structure is shown in Figure 5 (see also Table 1).13 This
also confirms the bre-face coordination of the olefin to rhodium
as expected, and the overall structure is almost identical to the
structure of complex 10 (Fig. 3), except that the position of the
Selected bond lengths (Å) and angles (deg) for complexes 10–12
Complex 10
Complex 11
Complex 12
Bond distances
Rh–P
Rh–C
Rh–Cb
Rh–O1
Rh–O2
P–N
P–C2
P–C3
2.1683(9)
2.138(4)
2.075(4)
2.085(2)
2.046(3)
1.746(3)
1.820(4)
1.816(4)
1.409(6)
1.516(6)
2.1748(11)
2.149(5)
2.120(5)
2.109(3)
2.065(3)
1.717(4)
1.828(4)
1.818(5)
1.405(6)
1.537(6)
2.187(6)
2.11(3)
2.14(3)
2.080(15)
2.08(2)
1.79(2)
1.811(18)
1.76(2)
1.45(3)
1.48(3)
a
methyl group on the olefin is switched from C
a to Cb. This posi-
tional change of the methyl group makes complex 12 a pseudo-
enantiomer of complex 10, although the configuration of both
complexes 10 and 12 is derived from naturally occurring (S)-
phenylalanine.
C
a–Cb
C1–C
Bond angles
a
(or C1–Cb)
\O1–Rh–O2
89.66(12)
82.08(11)
82.62(11)
39.04(16)
114.3(2)
127.1(3)
89.08(15)
88.41(13)
81.91(12)
38.43(16)
110.4(3)
89.5(7)
82.4(7)
82.8(6)
39.7(8)
113.4(19)
122(2)
C6H6
+
Rh(acac)(C2H4)2
ligand
Rh(acac)(ligand)
\P–Rh–C
a
30 °C, 1 h
\P–Rh–Cb
ð1Þ
10 (ligand = (S)-1a): 85% yield
11 (ligand = (S)-4): 70% yield
12 (ligand = (S)-5): 78% yield
\C –Rh–Cb
a
\Rh–C
a
–C1 (or \Rh–Cb–C1)
\C1–C
a–Cb (or \C1–Cb–C
a
)
121.4(4)
2.3. Asymmetric 1,4-addition reactions catalyzed by rhodium
complexes coordinated with (S)-1, (S)-4, and (S)-5
Table 2 summarizes the results of asymmetric 1,4-addition of
arylboronic acids to several
a,b-unsaturated cyclic ketones in the
presence of rhodium/phosphorus–olefin catalysts. In the reaction
of 2-cyclohexenone with phenylboronic acid, ligands (S)-1a–1c
exhibited good catalytic activity to give (S)-3-phenylcyclohexa-
none with high enantioselectivity (91–94% ee; entries 1–3). In con-
trast, ligand (S)-4 with a tetrahydropyridine ring instead of a
dihydropyrrole ring displayed much lower activity, giving the
1,4-adduct in only a 28% yield (entry 4). As expected from the li-
gand design and the X-ray structures in Figures 3 and 4, the sense
of chiral induction is the same as (S)-1a (entry 1), but the enanti-
oselectivity of the product was significantly lower with ligand
(S)-4 [77% ee (S)]. On the other hand, the use of ligand (S)-5 led
to the formation of (R)-3-phenylcyclohexanone in a 98% yield with
high enantiomeric excess (entry 5), confirming the pseudo-enan-
Figure 4. X-ray crystal structure of complex 11 with thermal ellipsoids drawn at
the 50% probability level (carbon atoms of the acac moiety and hydrogen atoms are
omitted for clarity).
Table 2
Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to
cyclic ketones
a,b-unsaturated
O
[RhCl(ligand)]2
(5 mol% Rh)
O
+
ArB(OH)2
KOH (0.5–1.0 equiv)
dioxane/H2O (10/1)
30 °C, 10 h
(
)
n
*
(
)
n
1.1–1.5equiv
Ar
Entry
Substrate
Ar
Ph
Ligand
Yielda (%)
eeb (%)
Config.
1
2
3
4
5
6
7
8
n = 2
(S)-1a
(S)-1b
(S)-1c
(S)-4
(S)-5
(S)-1a
(S)-5
(S)-1a
(S)-5
(S)-1a
(S)-5
(S)-1a
(S)-5
(S)-1a
(S)-5
89
91
81
28
98
86
93
87
84
92
99
92
93
90
87
94
93
91
77
97
96
97
94
97
95
98
93
95
87
95
(S)
(S)
(S)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
4-MeOC6H4
4-CF3C6H4
2-MeC6H4
Ph
Figure 5. X-ray crystal structure of complex 12 with thermal ellipsoids drawn at
the 30% probability level (carbon atoms of the acac moiety and hydrogen atoms are
omitted for clarity).
9
10
11
12
13
14
15
n = 1
n = 3
also Table 1).13 This structure confirms the bre-face coordination of
the olefin to rhodium; the overall structure is a somewhat dis-
torted square planar around the rhodium (distance of Rh from P–
O1–O2 plane = 0.181 Å) compared to complex 10 (distance of Rh
Ph
a
Isolated yield.
Determined by chiral HPLC.
b

R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
287
(a)
In contrast to the use of cyclic enone substrates (Table 2), both li-
gands (S)-1a and (S)-5 showed significantly lower efficiency to give
1,4-adducts with 81–85% ee using (S)-1a and with 50–65% ee using
(S)-5 (entries 1–6). In these reactions, the sense of chiral induction
with ligand (S)-5 is opposite in comparison with ligand (S)-1a.
O
Me
P
Rh
Ph
O
Ph
3. Conclusion
(S)-isomer
Rh/(S)-1a
si -face
We have designed and synthesized chiral phosphorus–olefin li-
gands (S)-1, (S)-4, and (S)-5, and analyzed the structures of their
rhodium complexes. All of these ligands can be synthesized from
(S)-phenylalanine derivatives and they act as phosphorus–olefin
bidentate ligands to rhodium. The coordination face of the olefin
can be effectively controlled by the original configuration of (S)-
phenylalanine in all cases. The rhodium complexes coordinated
with these ligands were employed as catalysts for the asymmetric
(b)
re -face
O
O
P
Rh
Ph
Me
Ph
(R)-isomer
1,4-addition of arylboronic acids to a,b-unsaturated ketones. Here-
in, it has been shown that ligands (S)-1a and (S)-5 produce the
opposite enantiomers of the 1,4-adducts with high enantioselectiv-
ities for cyclic enones and moderate enantioselectivities for acyclic
enones.
Rh/(S)-5
Figure 6. Proposed stereochemical pathways for the asymmetric 1,4-addition of
phenylboronic acid to 2-cyclohexenone catalyzed by Rh/(S)-1a (a) and Rh/(S)-5 (b).
Table 3
4. Experimental
4.1. General
Rhodium-catalyzed asymmetric 1,4-addition of phenylboronic acid to
rated acyclic ketones
a
,b-unsatu-
O
O
[RhCl(ligand)]2
(5 mol% Rh)
All air- and moisture-sensitive manipulations were carried out
with standard Schlenk techniques under nitrogen or in a glove
box under argon. THF, Et2O, and dioxane were purified by passing
through neutral alumina columns under nitrogen. C6H6 and hexane
were distilled over benzophenone ketyl under nitrogen. Pentane
was distilled over benzophenone ketyl in the presence of triglyme
under nitrogen. DMF was distilled over CaH2 under vacuum.
CH2Cl2 and 1,2-dichloroethane were distilled over CaH2 under
nitrogen. Et3N was distilled over KOH under nitrogen. Rh(acac)
(C2H4)215 and [RhCl(C2H4)2]216 were synthesized following literature
procedures.
+
PhB(OH)2
1.5 equiv
Me
Me
KOH (0.5 equiv)
dioxane/H2O (10/1)
30 °C, 10 h
*
R
Ph
R
Entry
Substrate
R = Me
Ligand
Yielda (%)
eeb (%)
Config.
1
2
3
4
5
6
(S)-1a
(S)-5
(S)-1a
(S)-5
(S)-1a
(S)-5
89
79
91
73
93
79
85
50
83
58
81
65
(R)
(S)
(R)
(S)
(S)
(R)
R = n-C5H11
R = i-Pr
4.2. Preparation of chiral phosphorus–olefin ligands
a
Isolated yield.
Determined by chiral HPLC.
4.2.1. (S)-1a
b
tiomeric nature of this ligand compared to (S)-1a as discussed
above (see Figs. 3 and 5). This relationship was also observed in
the addition of other arylboronic acids to 2-cyclohexenone, giving
(S)-products in the presence of ligand (S)-1a and (R)-products in
the presence of ligand (S)-5 with high enantioselectivity (94–98%
ee; entries 6–11). Other cyclic enones effectively undergo the
1,4-addition of phenylboronic acid as well to give (S)-3-phenylcy-
cloalkanones with ligand (S)-1a and their (R)-isomers with ligand
(S)-5 (entries 12–15).
Me
Me
Boc NH
Boc
N
Boc
Ph
N
Ph
Ph
(S)-2
(S)-3a
(S)-13
Me
CF3CO2
H2N
Me
Ph2P
N
Based on the results of these 1,4-additions and the X-ray struc-
ture of the Rh/(S)-1a complex (Fig. 3), the stereochemical pathway
for the 1,4-addition of phenylboronic acid to 2-cyclohexenone cat-
alyzed by Rh/(S)-1a can be explained as shown in Figure 6a.8,14
Thus, the phenylrhodium species has a trans-relationship between
the phenyl group and the olefin ligand and 2-cyclohexenone binds
to rhodium with its si-face at the cis-position of the olefin ligand,
leading to the 1,4-adduct with an (S)-configuration. The formation
of the (R)-product using Rh/(S)-5 can be similarly rationalized by
the re-face coordination of 2-cyclohexenone to rhodium as illus-
trated in Figure 6b.
Ph
(S)-1a
Ph
(S)-14
2-Methyl-2-propenyl bromide (726 mg, 5.38 mmol) and NaH
(256 mg, 6.40 mmol; 60 wt% in mineral oil) were successively
added to a solution of (S)-29 (1.01 g, 4.08 mmol) in DMF (9.0 mL)
at 0 °C and the mixture was stirred for 1.5 h at room temperature.
The reaction was quenched with H2O at 0 °C and this was extracted
with EtOAc/hexane (1/10). The organic layer was dried over
MgSO4, filtered, and concentrated under vacuum. The residue
was chromatographed on silica gel with EtOAc/hexane = 1/20 to
We also applied these phosphorus–olefin ligands to the reac-
tions of several acyclic enones with phenylboronic acid (Table 3).

288
R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
afford compound (S)-13 as a colorless oil (1.17 g, 3.88 mmol; 95%
JCP = 19.6 Hz), 130.0, 128.62 (d, JCP = 3.6 Hz), 128.59, 128.57,
128.53, 128.49, 126.3, 125.2 (d, JCP = 6.7 Hz), 73.1 (d, JCP = 30.5 Hz),
57.6 (d, JCP = 9.3 Hz), 45.2 (d, JCP = 5.7 Hz), 14.0. 31P{1H} NMR
(C6D6): d 43.5 (s). HRMS (ESI-TOF) calcd for C24H25NP (M+H+)
358.1719, found 358.1717.
yield). ½a 2D5
ꢀ
¼ ꢁ55:4 (c 1.02, CHCl3). 1H NMR (CDCl3, 50 °C): d
3
7.25 (t, JHH = 7.5 Hz, 2H), 7.19–7.15 (m, 3H), 6.00 (ddd,
3
3JHH = 17.0, 10.2, and 6.8 Hz, 1H), 5.06 (d, JHH = 10.8 Hz, 1H), 5.04
3
(d, JHH = 18.4 Hz, 1H), 4.77 (s, 1H), 4.73 (s, 1H), 4.34 (br s, 1H),
2
3.75–3.56 (m, 1H), 3.46 (d, JHH = 16.3 Hz, 1H), 3.16–3.04 (m, 1H),
2
3
2.91 (dd, JHH = 13.6 Hz and JHH = 6.8 Hz, 1H), 1.60 (s, 3H), 1.42
(s, 9H). 13C NMR (CDCl3, 50 °C): d 155.4, 142.8, 139.0, 137.5,
129.5, 128.4, 126.4, 116.2, 111.6, 79.7, 61.5, 52.2, 39.2, 28.6, 20.1.
HRMS (ESI-TOF) calcd for C19H27NO2Na (M+Na+) 324.1934, found
324.1930.
4.2.2. (S)-1b
This was synthesized from (S)-2 and 2-(benzyloxymethyl)-2-
propenyl methanesulfonate, following the procedure for (S)-1a.
Brown oil. 62% overall yield. ½a D25
ꢀ
¼ þ187 (c 0.56, THF). 1H NMR
(C6D6): d 7.57 (t, 3J = 7.1 Hz, 2H), 7.46 (t, 3J = 7.6 Hz, 2H), 7.21–
Grubbs catalyst (66.3 mg, 78.1
l
mol; 2nd generation) was
7.11 (m, 13H), 7.09–7.04 (m, 3H), 5.56–5.53 (m, 1H), 4.80–4.73
2
2
added to a solution of (S)-13 (1.16 g, 3.85 mmol) in C6H6 (38 mL)
and the mixture was stirred for 6 h at 60 °C. The solvent was re-
moved under vacuum, and the residue was chromatographed on
silica gel with EtOAc/hexane = 1/20 to afford compound (S)-3a as
a colorless oil (1.03 g, 3.77 mmol; 98% yield, ꢂ6/4 mixture of rota-
(m, 1H), 4.15 (d, JHH = 12.2 Hz, 1H), 4.11 (d, JHH = 12.1 Hz, 1H),
2
3.86–3.76 (m, 2H), 3.68–3.61 (m, 2H), 3.38 (ddd, JHH = 12.7 Hz,
4
2
3JHH = 4.2 Hz, and
JHH = 2.8 Hz, 1H), 2.80 (ddd, JHH = 12.8 Hz,
4
3JHH = 9.3 Hz, and JHH = 0.6 Hz, 1H). 13C NMR (C6D6): d 139.8 (d,
JCP = 7.2 Hz), 139.3 (d, JCP = 18.1 Hz), 139.2, 139.0, 138.9, 132.7 (d,
JCP = 20.2 Hz), 132.6 (d, JCP = 19.1 Hz), 130.0, 128.7, 128.62,
128.56, 128.55, 128.5, 127.9, 127.7, 127.3 (d, JCP = 6.7 Hz), 126.4,
72.9 (d, JCP = 31.5 Hz), 72.0, 66.9, 54.6 (d, JCP = 9.3 Hz), 44.7 (d,
JCP = 5.2 Hz). 31P{1H} NMR (C6D6): d 44.8 (s). HRMS (ESI-TOF) calcd
for C31H31NOP (M+H+) 464.2138, found 464.2130.
mers). ½a 2D5
ꢀ
¼ þ177 (c 1.10, CHCl3). 1H NMR (CDCl3): d 7.28–7.22
3
(m, 2H), 7.22–7.17 (m, 1H), 7.15 (d, JHH = 7.5 Hz, 0.8H), 7.12 (d,
3JHH = 7.5 Hz, 1.2H), 5.26 (s, 0.4H), 5.23 (s, 0.6H), 4.73–4.67 (m,
2
0.4H), 4.61–4.55 (m, 0.6H), 4.02 (d, JHH = 15.0 Hz, 0.6H), 3.89 (d,
2
4
2JHH = 14.9 Hz, 0.4H), 3.70 (dd, JHH = 14.9 Hz and JHH = 4.0 Hz,
2
4
0.6H), 3.56 (dd, JHH = 15.0 Hz and JHH = 4.8 Hz, 0.4H), 3.17 (dd,
3
2
2JHH = 12.9 Hz and JHH = 3.4 Hz, 0.4H), 3.13 (dd, JHH = 13.0 Hz
4.2.3. (S)-1c
3
2
3
and JHH = 3.4 Hz, 0.6H), 2.84 (dd, JHH = 13.0 Hz and JHH = 8.2 Hz,
This was synthesized from (S)-2 and 2-phenyl-2-propenyl bro-
mide, following the procedure for (S)-1a. Pink solid. 85% overall
2
3
0.4H), 2.69 (dd, JHH = 12.9 Hz and JHH = 8.1 Hz, 0.6H), 1.66 (s,
1.8H), 1.63 (s, 1.2H), 1.55 (s, 5.4H), 1.50 (s, 3.6H). 13C NMR (CDCl3):
d 154.2, 154.0, 138.2, 135.2, 135.1, 129.9, 129.6, 128.2, 127.9,
126.2, 126.0, 123.5, 123.3, 79.5, 79.1, 65.9, 65.6, 56.9, 56.6, 41.3,
39.8, 28.70, 28.66, 14.2, 14.1. HRMS (ESI-TOF) calcd for C17H23NO2-
Na (M+Na+) 296.1621, found 296.1617.
yield. ½a 2D5
ꢀ
¼ þ224 (c 0.53, THF). 1H NMR (C6D6): d 7.65–7.61 (m,
2H), 7.54–7.50 (m, 2H), 7.25–7.21 (m, 2H), 7.17–7.05 (m, 9H),
3
4
6.99–6.95 (m, 5H), 6.00 (dt, JHH = 4.9 Hz and JHH = 2.2 Hz, 1H),
2
4.92–4.85 (m, 1H), 4.24–4.15 (m, 2H), 3.52 (ddd, JHH = 12.8 Hz,
3JHH = 4.2 Hz, and 4J = 2.8 Hz, 1H), 2.80 (dd, JHH = 12.8 Hz and
2
Trifluoroacetic acid (7.5 mL) was added to a solution of (S)-3a
(1.03 g, 3.77 mmol) in CH2Cl2 (37 mL) and the mixture was stirred
for 1.5 h at room temperature. The solvent was removed under
vacuum, and the remaining trifluoroacetic acid was further re-
moved by dissolving the residue in C6H6 and concentrated under
vacuum three times, followed by the same sequence with hexane
three times. The residue thus obtained was chromatographed on
silica gel with MeOH/CH2Cl2 = 1/10 to afford compound (S)-14 as
3JHH = 9.5 Hz, 1H). 13C NMR (C6D6): d 139.9 (d, JCP = 8.3 Hz), 139.6,
139.14 (d, JCP = 17.6 Hz), 139.09, 134.2, 132.7 (d, JCP = 20.2 Hz),
132.5 (d, JCP = 19.6 Hz), 130.0, 128.73 (d, JCP = 3.6 Hz), 128.69,
128.68, 128.64, 128.63, 128.62, 127.8, 126.4, 125.9, 125.5 (d,
JCP = 6.7 Hz), 73.6 (d, JCP = 31.0 Hz), 54.5 (d, JCP = 9.3 Hz), 45.1 (d,
JCP = 6.2 Hz). 31P{1H} NMR (C6D6): d 44.2 (s). HRMS (ESI-TOF) calcd
for C29H27NP (M+H+) 420.1876, found 420.1864.
a purple solid (1.03 g, 3.59 mmol; 95% yield). ½a D25
ꢀ
¼ þ54:5 (c
4.2.4. (S)-4
0.32, CHCl3). 1H NMR (CDCl3): d 10.30 (br s, 1H), 9.23 (br s, 1H),
3
3
7.31 (t, JHH = 7.5 Hz, 2H), 7.25 (t, JHH = 8.1 Hz, 1H), 7.20 (d,
3JHH = 6.8 Hz, 2H), 5.34 (s, 1H), 4.70–4.62 (m, 1H), 3.84 (d,
Me
2JHH = 15.0 Hz, 1H), 3.80 (d, JHH = 15.0 Hz, 1H), 3.15 (dd,
2
Boc NH
2JHH = 13.6 Hz and JHH = 6.1 Hz, 1H), 2.95 (dd, JHH = 13.6 Hz and
3JHH = 8.9 Hz, 1H), 1.78 (s, 3H). 13C NMR (CDCl3): d 162.8 (q,
2JCF = 35.9 Hz), 135.8, 135.3, 129.2, 128.8, 127.2, 122.4, 117.0 (q,
1JCF = 293 Hz), 66.9, 53.9, 39.3, 13.6. HRMS (ESI-TOF) calcd for
3
2
CF3CO2
H3N
Boc
Ph
N
Ph
Ph
2
15
(S)-
(S)-
(S)-16
C
12H16N (M–CF3CO2–) 174.1277, found 174.1278.
Next, 1 M NaOH (aq) (15 mL) was added to a solution of (S)-14
CF3CO2
Boc
Ph
N
Me
Ph2P
Ph
N
Me
H2N
Me
(1.03 g, 3.59 mmol) in Et2O (5.0 mL) and the mixture was extracted
with Et2O. The organic layer was dried over MgSO4, filtered, and
concentrated under vacuum. The residue was dissolved in THF
(9.0 mL), and Et3N (2.20 mL, 15.8 mmol) and chlorodiphenylphos-
Ph
(S)-17
(S)-6
(S)-4
phine (710 lL, 3.95 mmol) were successively added to it with addi-
tional THF (2.0 mL). The mixture was stirred for 9 h at room
temperature, and the volatiles were removed under vacuum. This
was chromatographed on silica gel with degassed Et3N/hex-
ane = 1/2 to afford compound (S)-1a as a yellow oil (1.06 g,
Trifluoroacetic acid (20 mL) was added to a solution of (S)-2
(1.09 g, 4.40 mmol) in CH2Cl2 (20 mL) and the mixture was stirred
for 1 h at room temperature. After removal of the solvent under
vacuum, the residue was washed with hexane and dried under vac-
uum to afford compound (S)-15 as a pink solid (1.00 g, 3.84 mmol;
2.97 mmol; 83% yield).
½
a 2D5
ꢀ
¼ þ235 (c 1.03, THF). 1H NMR
(C6D6): d 7.58 (t, 3J = 7.2 Hz, 2H), 7.48 (t, 3J = 7.4 Hz, 2H), 7.23–
87% yield). ½a 3D0
ꢀ
¼ þ5:2 (c 0.64, CHCl3). 1H NMR (CDCl3): d 8.13 (br
7.19 (m, 2H), 7.18–7.05 (m, 9H), 5.27–5.21 (m, 1H), 4.77–4.68
s, 3H), 7.30 (t, 3JHH = 7.2 Hz, 2H), 7.24 (t, 3JHH = 7.3 Hz, 1H), 7.16 (d,
3JHH = 7.0 Hz, 2H), 5.79 (ddd, 3JHH = 17.6, 10.5, and 7.7 Hz, 1H), 5.27
2
3
(m, 1H), 3.60 (br s, 2H), 3.44 (ddd, JHH = 12.8 Hz, JHH = 3.9 Hz,
4
2
3
and JHH = 2.8 Hz, 1H), 2.75 (dd, JHH = 12.8 Hz and JHH = 9.5 Hz,
1H), 1.28 (s, 3H). 13C NMR (C6D6): d 140.2 (d, JCP = 7.7 Hz), 139.5
(d, JCP = 18.1 Hz), 139.4, 137.1, 132.7 (d, JCP = 19.6 Hz), 132.6 (d,
3
3
(d, JHH = 10.5 Hz, 1H), 5.23 (d, JHH = 17.2 Hz, 1H), 3.90–3.81 (m,
2
3
1H), 3.11 (dd, JHH = 13.5 Hz and JHH = 5.8 Hz, 1H), 2.90 (dd,

R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
289
3
2JHH = 13.5 Hz and JHH = 8.9 Hz, 1H). 13C NMR (CDCl3): d 162.7 (q,
and concentrated under vacuum. The residue was dissolved in THF
(5.0 mL), and Et3N (1.20 mL, 8.68 mmol) and chlorodiphenylphos-
phine (410 lL, 2.28 mmol) were successively added to it with addi-
tional THF (1.0 mL). The mixture was stirred for 24 h at room
temperature, and the volatiles were removed under vacuum. This
was chromatographed on silica gel with degassed Et3N/hex-
ane = 1/2 to afford compound (S)-4 as a brown oil (598 mg,
2JCF = 35.1 Hz), 135.3, 132.8, 129.5, 128.9, 127.4, 121.1, 116.7 (q,
1JCF = 286 Hz), 55.9, 39.6. HRMS (ESI-TOF) calcd for C10H14N (M–
CF3CO2–) 148.1121, found 148.1120.
Saturated NaHCO3 (aq) (10 mL) was added to a solution of (S)-
15 in CH2Cl2 (10 mL) and the mixture was extracted with CH2Cl2.
The organic layer was dried over K2CO3, filtered, and concentrated
under vacuum. The residue was dissolved in MeCN (28 mL) and
K2CO3 (514 mg, 3.71 mmol) was added to it. The mixture was stir-
red for 1 h at room temperature, and 3-methyl-3-butenyl meth-
anesulfonate was added to it. This mixture was stirred for 24 h at
90 °C and the precipitate was filtered off with CH2Cl2 at room tem-
perature. After removal of the solvent under vacuum, the residue
was extracted with CH2Cl2 and saturated NaHCO3 (aq). The organic
layer was dried over K2CO3, filtered, and concentrated under vac-
uum. This was then dissolved in THF (12 mL) and a solution of
(Boc)2O (996 mg, 4.56 mmol) in THF (7.0 mL) was added to it at
0 °C. The mixture was stirred for 21 h at room temperature, and
the solvent was removed under vacuum. The residue was extracted
with Et2O and 1 M HCl (aq), and the organic layer was dried over
MgSO4, filtered, and concentrated under vacuum. This was chro-
matographed on silica gel with EtOAc/hexane = 1/10 to afford com-
pound (S)-16 as a colorless oil (658 mg, 2.08 mmol; 55% yield).
1.60 mmol; 83% yield).
½
a 3D0
ꢀ
¼ ꢁ41:3 (c 1.00, THF). 1H NMR
(C6D6): d 7.61–7.55 (m, 2H), 7.46 (t, 3J = 7.6 Hz, 2H), 7.26–7.06
3
(m, 10H), 7.04 (t, JHH = 7.3 Hz, 1H), 5.38 (br s, 1H), 4.22 (br s,
1H), 3.25–3.17 (m, 1H), 3.17–3.07 (m, 1H), 2.90 (dd, 2JHH = 12.6 Hz
3
2
3
and JHH = 5.2 Hz, 1H), 2.74 (dd, JHH = 12.7 Hz and JHH = 9.4 Hz,
2
1H), 1.68–1.55 (m, 1H), 1.43 (s, 3H), 1.34 (d, JHH = 17.1 Hz, 1H).
13C NMR (C6D6): d 141.1 (d, JCP = 15.5 Hz), 140.9 (d, JCP = 15.5 Hz),
139.6, 133.3 (d, JCP = 21.2 Hz), 133.1, 131.7 (d, JCP = 19.6 Hz),
129.8, 129.0, 128.6, 128.5 (d, JCP = 2.6 Hz), 128.4 (d, JCP = .1 Hz),
128.2, 126.3, 124.4 (d, JCP = 5.2 Hz), 60.5 (d, JCP = 25.8 Hz), 42.9 (d,
JCP = 4.7 Hz), 42.5 (d, JCP = 4.7 Hz), 30.8 (d, JCP = 1.0 Hz), 23.6.
31P{1H} NMR (C6D6):
C
d
62.2 (s). HRMS (ESI-TOF) calcd for
25H27NP (M+H+) 372.1876, found 372.1873.
4.2.5. (S)-5
½
a 3D0
ꢀ
¼ ꢁ67:9 (c 1.11, CHCl3). 1H NMR (CDCl3, 50 °C): d 7.28–7.23
(m, 2H), 7.20–7.15 (m, 3H), 6.01–5.93 (m, 1H), 5.15–5.08 (m,
2H), 4.72–4.70 (m, 1H), 4.65–4.62 (m, 1H), 4.51 (br s, 1H), 3.17–
Boc NH
Ph
O
N
H3N
O
N
CF3CO2
2
3
HN
O
N
2.96 (m, 3H), 2.91 (dd, JHH = 13.7 Hz and JHH = 6.7 Hz, 1H), 2.22–
2.00 (m, 2H), 1.70 (s, 3H), 1.40 (s, 9H). 13C NMR (CDCl3, 50 °C): d
155.0, 143.3, 138.7, 137.7, 129.2, 128.2, 126.2, 115.9, 111.2, 79.3,
60.8, 44.9, 38.6, 37.7, 28.4, 22.5. HRMS (ESI-TOF) calcd for
Ph
Ph
O
O
O
(S)-7
19
(S)-
(S)-18
C
20H29NO2Na (M+Na+) 338.2091, found 338.2082.
Grubbs catalyst (36.4 mg, 42.8
lmol; 2nd generation) was
added to solution of (S)-16 (647 mg, 2.05 mmol) in C6H6
a
Boc
Ph
N
O
(20 mL) and the mixture was stirred for 5 h at 60 °C. The solvent
was removed under vacuum, and the residue was chromato-
graphed on silica gel with EtOAc/hexane = 1/5 to afford compound
Boc
Ph
N
O
Boc
Ph
N
N
Me
Me
(S)-20
(S)-9
O
(S)-8
(S)-6 as
a colorless oil (568 mg, 1.97 mmol; 96% yield).
½
a 3D0
ꢀ
¼ þ172 (c 1.07, CHCl3). 1H NMR (CDCl3, 60 °C): d 7.25 (t,
3JHH = 7.3 Hz, 2H), 7.21–7.14 (m, 3H), 5.29–5.24 (m, 1H), 4.51 (br
Ph2P
N
CF3CO2
H2N
Boc
N
2
3
s, 1H), 4.11 (br s, 1H), 2.85 (dd, JHH = 12.9 Hz and JHH = 6.3 Hz,
1H), 2.77 (ddd, JHH = 13.1 Hz and JHH = 11.8 and 3.9 Hz, 1H),
2.73 (dd, JHH = 12.8 Hz and JHH = 7.7 Hz, 1H), 2.19–2.08 (m, 1H),
Me
Me
Me
2
3
Ph
Ph
(S)-22
Ph
(S)-21
2
3
(S)-5
2
3
4
1.75 (dd, JHH = 16.6 Hz and JHH = 2.5 Hz, 1H), 1.68 (d,
JHH = 1.1 Hz, 3H), 1.38 (s, 9H). 13C NMR (CDCl3, 60 °C): d 154.6,
138.8, 133.3, 129.6, 128.3, 126.2, 122.0, 79.4, 53.7, 40.7, 36.9,
29.9, 28.5, 23.3. HRMS (ESI-TOF) calcd for C18H25NO2Na (M+Na+)
310.1778, found 310.1775.
Trifluroacetic acid (46 mL) was added to a solution of (S)-712
(4.08 g, 12.1 mmol) in CH2Cl2 (46 mL) and the mixture was stirred
for 1 h at room temperature. The solvent was removed under vac-
uum, and the remaining trifluoroacetic acid was further removed
by dissolving the residue in CH2Cl2 and concentrated under vac-
uum twice, followed by the same sequence with hexane twice, to
afford compound (S)-18 as a white solid (4.21 g, 12.0 mmol; 99%
Trifluoroacetic acid (3.9 mL) was added to a solution of (S)-6
(563 mg, 1.96 mmol) in CH2Cl2 (3.9 mL) and the mixture was stir-
red for 1 h at room temperature. The solvent was removed under
vacuum, and the remaining trifluoroacetic acid was further re-
moved by dissolving the residue in CH2Cl2 and concentrated under
vacuum twice, followed by the same sequence with hexane twice,
to afford compound (S)-17 as a colorless oil (590 mg, 1.95 mmol;
yield). ½a 3D0
ꢀ
¼ þ51:2 (c 0.55, THF). 1H NMR (CD3OD): d 7.37 (t,
3JHH = 7.2 Hz, 2H), 7.33 (t, JHH = 7.3 Hz, 1H), 7.27 (d, JHH = 7.5 Hz,
3
3
3
99% yield). ½a 3D0
ꢀ
¼ þ29:8 (c 1.05, CHCl3). 1H NMR (CDCl3): d 9.84
2H), 4.84 (br s, 3H), 4.66 (dd, JHH = 9.4 and 5.8 Hz, 1H), 3.60–
3.54 (m, 1H), 3.54–3.44 (m, 2H), 3.44–3.34 (m, 2H), 3.29–3.22
3
(br s, 1H), 9.06 (br s, 1H), 7.30 (t, JHH = 7.3 Hz, 2H), 7.27–7.19
2
3
(m, 1H), 3.19 (dd, JHH = 13.2 Hz and JHH = 5.7 Hz, 1H), 3.05 (dd,
(m, 3H), 5.27 (s, 1H), 3.98 (br s, 1H), 3.42–3.30 (m, 1H), 3.14 (dd,
2JHH = 13.2 Hz and JHH = 9.5 Hz, 1H), 2.88–2.77 (m, 2H). 13C NMR
3
3
2JHH = 13.3 Hz and JHH = 5.9 Hz, 1H), 3.10–3.00 (m, 1H), 2.81 (dd,
2
(CD3OD): d 168.4, 163.1 (q, JCF = 32.6 Hz), 135.4, 130.8, 130.1,
3
2JHH = 13.3 Hz and JHH = 9.4 Hz, 1H), 2.51–2.40 (m, 1H), 2.09 (d,
1
129.0, 118.4 (q, JCF = 284 Hz), 67.1, 66.9, 51.6, 47.1, 43.6, 38.7.
2JHH = 18.2 Hz, 1H), 1.74 (s, 3H). 13C NMR (CDCl3): d 162.4 (q,
2JCF = 35.1 Hz), 135.3, 134.3, 129.5, 128.9, 127.4, 117.9, 116.8 (q,
2JHH = 293 Hz), 54.5, 40.6, 39.4, 26.5, 23.1. HRMS (ESI-TOF) calcd
for C13H18N (M–CF3CO2–) 188.1434, found 188.1433.
HRMS (ESI-TOF) calcd for C13H19N2O2 (M–CF3CO2–) 235.1441,
found 235.1443.
Na2CO3 (4.08 g, 81.0 mmol) and allyl bromide (1.52 g,
12.6 mmol) were successively added to a solution of (S)-18
(4.03 g, 11.5 mmol) in MeCN (39 mL) at 0 °C, and the mixture
was stirred for 24 h at room temperature. The reaction was
NaOH (aq, 1 M) (10 mL) was added to a solution of (S)-17
(586 mg, 1.94 mmol) in Et2O (10 mL) and the mixture was ex-
tracted with Et2O. The organic layer was dried over MgSO4, filtered,

290
R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
quenched with H2O at 0 °C and this was extracted with EtOAc. The
organic layer was dried over MgSO4, filtered, and concentrated un-
der vacuum. The residue was chromatographed on silica gel with
MeOH/CH2Cl2 = 1/10 to afford compound (S)-19 as a yellow oil
The reaction was quenched with 1 M HCl (aq) (150 mL) at 0 °C
and this was extracted with EtOAc. The organic layer was dried
over MgSO4, filtered, and concentrated under vacuum. The residue
was chromatographed on silica gel with EtOAc/hexane = 1/10, fol-
lowed by recrystallization from hexane, to afford compound (S)-9
(1.98 g, 7.24 mmol; 62% yield). ½a D25
ꢀ
¼ þ50:4 (c 1.01, CHCl3). 1H
NMR (CDCl3): d 7.28 (t, JHH = 7.2 Hz, 2H), 7.23 (tt, JHH = 7.3 Hz
as a white solid (1.20 g, 3.97 mmol; 74% yield). ½a D30
¼ ꢁ187 (c
ꢀ
3
3
4
3
3
and JHH = 1.3 Hz, 1H), 7.21–7.17 (m, 2H), 5.87 (ddt, JHH = 17.0,
10.3, and 5.9 Hz, 1H), 5.16 (dd, JHH = 17.2 Hz and JHH = 1.6 Hz,
1.03, CHCl3). 1H NMR (CDCl3, 50 °C): d 7.24 (t, JHH = 7.3 Hz, 2H),
3
4
3
7.21–7.14 (m, 3H), 5.72 (br s, 1H), 5.04 (d, JHH = 17.1 Hz, 1H),
3
3
1H), 5.10 (d, JHH = 10.3 Hz, 1H), 3.77 (dd, JHH = 10.0 and 5.1 Hz,
5.02–4.95 (m, 3H), 4.74 (br s, 1H), 3.72–3.59 (m, 1H), 3.54 (dd,
2
3
3
2
1H), 3.65 (ddd, JHH = 13.3 Hz and JHH = 5.8 and 2.4 Hz, 1H), 3.58
2JHH = 15.5 Hz and JHH = 6.5 Hz, 1H), 3.01 (dd, JHH = 14.0 Hz and
2
3
2
3
(ddd, JHH = 10.7 Hz and JHH = 5.5 and 2.4 Hz, 1H), 3.47–3.30 (m,
3JHH = 5.6 Hz, 1H), 2.94 (dd, JHH = 14.0 Hz and JHH = 9.4 Hz, 1H),
1.73 (s, 3H), 1.32 (s, 9H). 13C NMR (CDCl3): d 155.5, 144.3, 138.9,
135.7, 129.2, 128.1, 126.1, 116.0, 112.7, 79.4, 61.4, 59.9, 46.2,
36.6, 28.2, 21.8. HRMS (ESI-TOF) calcd for C19H27NO2Na (M+Na+)
324.1934, found 324.1931.
2
3
3H), 3.27 (dd, JHH = 13.7 Hz and JHH = 5.5 Hz, 1H), 3.13 (ddd,
2JHH = 13.3 Hz and 3JHH = 7.6 and 3.2 Hz, 1H), 3.07 (dd,
2JHH = 13.8 Hz and JHH = 6.6 Hz, 1H), 3.05 (dd, JHH = 13.2 Hz and
3
2
3JHH = 5.2 Hz, 1H), 2.82 (dd, JHH = 12.8 Hz and JHH = 10.0 Hz, 1H),
2
3
2
3
2.77 (ddd, JHH = 13.3 Hz and JHH = 5.5 and 3.0 Hz, 1H), 2.69
Grubbs catalyst (61.2 mg, 72.0 lmol; 2nd generation) was
2
3
(ddd, JHH = 11.6 Hz and JHH = 7.5 and 2.9 Hz, 1H), 1.96 (br s, 1H).
13C NMR (CDCl3): d 173.0, 137.5, 136.8, 129.4, 128.5, 126.8,
116.4, 66.6, 66.0, 57.7, 50.5, 45.5, 42.1, 40.8. HRMS (ESI-TOF) calcd
for C16H23N2O2 (M+H+) 275.1754, found 275.1752.
added to a solution of (S)-9 (1.08 g, 3.60 mmol) in C6H6 (36 mL)
and the mixture was stirred for 5 h at 60 °C. The solvent was re-
moved under vacuum, and the residue was chromatographed on
silica gel with EtOAc/hexane = 1/5 to afford compound (S)-21 as a
colorless oil (981 mg, 3.58 mmol; 99% yield, ꢂ5/5 mixture of rota-
Et3N (3.50 mL, 25.1 mmol) and (Boc)2O (2.05 g, 9.40 mmol)
were added to a solution of (S)-19 (1.96 g, 7.17 mmol) in THF
(53 mL) at 0 °C, and the mixture was stirred for 24 h at room tem-
perature. The reaction was quenched with saturated NH4Cl (aq) at
0 °C and this was extracted with EtOAc. The organic layer was
dried over MgSO4, filtered, and concentrated under vacuum. The
residue was chromatographed on silica gel with EtOAc/hex-
ane = 1/3?1/2 to afford compound (S)-8 as a colorless oil (2.55 g,
mers). ½a 2D0
ꢀ
¼ þ145 (c 0.56, CHCl3). 1H NMR (CDCl3): d 7.25–7.15
3
(m, 3H), 7.10 (d, JHH = 7.4 Hz, 2H), 5.26 (s, 0.5H), 5.20 (s, 0.5H),
2
4.62 (br s, 0.5H), 4.55 (br s, 0.5H), 3.97 (d, JHH = 14.7 Hz, 0.5H),
2
3.83 (d, JHH = 15.2 Hz, 0.5H), 3.46–3.31 (m, 1H), 3.30–3.15 (m,
1H), 2.88–2.80 (m, 1H), 1.76 (s, 1.5H), 1.72 (s, 1.5H), 1.54 (s,
4.5H), 1.50 (s, 4.5H). 13C NMR (CDCl3): d 154.0, 153.9, 137.5,
137.4, 137.2, 137.0, 129.9, 129.7, 128.0, 127.7, 126.3, 126.1,
120.9, 120.8, 79.6, 79.0, 67.1, 66.9, 53.2, 52.8, 37.4, 35.7, 28.74,
6.81 mmol; 95% yield). ½a D30
ꢀ
¼ ꢁ106 (c 1.07, CHCl3). 1H NMR
(CDCl3, 60 °C): d 7.28–7.14 (m, 5H), 5.79 (br s, 1H), 5.28 (br s,
28.66, 14.4, 14.3. HRMS (ESI-TOF) calcd for
C17H23NO2Na
3
3
1H), 5.13 (d, JHH = 17.2 Hz, 1H), 5.07 (d, JHH = 10.1 Hz, 1H),
(M+Na+) 296.1621, found 296.1624.
2
3
4.02–3.86 (m, 1H), 3.78 (dd, JHH = 15.7 Hz and JHH = 6.5 Hz, 1H),
Trifluoroacetic acid (7.0 mL) was added to a solution of (S)-21
(950 mg, 3.47 mmol) in CH2Cl2 (34 mL) and the mixture was stir-
red for 1 h at room temperature. The solvent was removed under
vacuum, and the remaining trifluoroacetic acid was further re-
moved by dissolving the residue in CH2Cl2 and concentrated under
vacuum twice, followed by the same sequence with hexane twice.
The residue was chromatographed on silica gel with MeOH/
2
3.70–3.28 (m, 8H), 3.25–3.08 (m, 1H), 2.96 (dd, JHH = 13.2 Hz
3
and JHH = 6.9 Hz, 1H), 1.34 (br s, 9H). 13C NMR (CDCl3, 60 °C): d
168.8, 154.9, 137.6, 135.0, 129.5, 128.2, 126.3, 116.4, 80.2, 66.5,
54.7, 45.8, 42.3, 36.3, 28.1. HRMS (ESI-TOF) calcd for C21H30N2O4Na
(M+Na+) 397.2098, found 397.2090.
Methylmagnesium chloride (11.0 mL, 10.2 mmol; 0.93 M solu-
tion in THF) was added dropwise over 1 h to a solution of (S)-8
in THF (26 mL) at –20 °C, and the mixture was stirred for 2 h at –
20 °C and for 20 min at room temperature. The reaction was
quenched with 1 M HCl (aq) (14 mL) at 0 °C and this was extracted
with EtOAc. The organic layer was dried over MgSO4, filtered, and
concentrated under vacuum. The residue was chromatographed on
silica gel with EtOAc/hexane = 1/5 to afford compound (S)-20 as a
colorless oil (1.66 g, 5.46 mmol; 81% yield, ꢂ6/4 mixture of rota-
CH2Cl2 = 1/10 to afford compound (S)-22 as
a purple solid
(857 mg, 2.98 mmol; 86% yield). ½a D20
ꢀ
¼ ꢁ10:6 (c 0.54, CHCl3). 1H
NMR (CDCl3): d 10.42 (br s, 1H), 9.05 (br s, 1H), 7.31–7.19 (m,
5H), 5.41 (s, 1H), 4.52 (br s, 1H), 3.61 (br s, 2H), 3.15 (dd,
3
2
2JHH = 14.8 Hz and JHH = 5.1 Hz, 1H), 2.95 (dd, JHH = 14.8 Hz and
3JHH = 8.5 Hz, 1H), 1.72 (s, 3H). 13C NMR (CDCl3): d 162.0 (q,
2JCF = 34.8 Hz), 138.0, 135.4, 129.1, 128.8, 127.2, 119.3, 116.7 (q,
1JCF = 293 Hz), 67.5, 50.2, 37.0, 13.6. HRMS (ESI-TOF) calcd for
mers). ½a 2D5
ꢀ
¼ ꢁ245 (c 1.11, CHCl3). 1H NMR (CDCl3): d 7.31–7.25
C
12H16N (M–CF3CO2–) 174.1277, found 174.1276.
3
3
(m, 2H), 7.22 (d, JHH = 7.1 Hz, 1H), 7.17 (d, JHH = 7.4 Hz, 0.8H),
NaOH (aq, 1 M) (10 mL) was added to a solution of (S)-22
3
7.13 (d, JHH = 7.4 Hz, 1.2H), 5.72–5.57 (m, 1H), 5.09 (d,
(258 mg, 0.898 mmol) in Et2O (8 mL) and the mixture was ex-
tracted with Et2O. The organic layer was dried over MgSO4, filtered,
and concentrated under vacuum. The residue was dissolved in THF
3JHH = 10.1 Hz, 0.6H), 5.04 (d, JHH = 10.2 Hz, 0.4H), 4.98 (d,
3
3JHH = 17.1 Hz, 1H), 4.14 (dd, JHH = 8.9 and 5.2 Hz, 0.4H), 4.07
3
2
3
(dd, JHH = 14.6 Hz and JHH = 4.9 Hz, 0.6H), 3.85–3.68 (m, 1H),
(1.5 mL), and Et3N (570
lL, 4.08 mmol) and chlorodiphenylphos-
2
3
3.39–3.23 (m, 1 H), 3.08 (dd, JHH = 15.2 Hz and JHH = 7.2 Hz,
phine (190 L, 1.05 mmol) were successively added to it with addi-
l
2
3
0.4H), 3.03 (dd, JHH = 13.9 Hz and JHH = 9.5 Hz, 0.4H), 2.93 (dd,
tional THF (1.0 mL) at 0 °C. The mixture was stirred for 20 h at
room temperature, and the volatiles were removed under vacuum.
This was chromatographed on silica gel with degassed Et3N/hex-
ane = 1/2, followed by passing through a pad of alumina with
Et3N/hexane = 1/10 under N2, to afford (S)-5 as an orange solid
2JHH = 14.0 Hz and JHH = 10.0 Hz, 0.6H), 2.82 (dd, JHH = 15.0 Hz
and 3JHH = 8.3 Hz, 0.6H), 2.14 (s, 3H), 1.46 (s, 9H). 13C NMR (CDCl3):
d 205.8, 205.3, 155.0, 154.3, 138.7, 138.6, 134.0, 133.6, 129.4,
128.6, 128.4, 126.5, 126.4, 119.1, 117.8, 81.5, 80.6, 67.8, 67.1,
51.3, 50.8, 34.9, 34.0, 28.3, 27.2, 26.7. HRMS (ESI-TOF) calcd for
3
2
(247 mg, 0.691 mmol; 77% yield). ½a D20
ꢀ
¼ þ209 (c 0.52, THF). 1H
C
18H25NO3Na (M+Na+) 326.1727, found 326.1722.
NMR (C6D6): d 7.53–7.48 (m, 2H), 7.43–7.37 (m, 2H), 7.20–7.03
(m, 11H), 5.02 (d, JHH = 1.4 Hz, 1H), 4.62–4.54 (m, 1H), 3.65–3.58
(m, 1H), 3.45–3.38 (m, 1H), 3.07 (ddd, 2JHH = 13.7 Hz, 3JHH = 6.3 Hz,
Sodium hexamethyldisilazide (5.60 mL, 10.6 mmol; 1.9 M solu-
tion in THF) was added to a solution of methyltriphenylphospho-
nium bromide (4.06 g, 11.4 mmol) in Et2O (300 mL) at 0 °C, and
the mixture was stirred for 1 h at 0 °C. A solution of (S)-20
(1.64 g, 5.39 mmol) in Et2O (37 mL) was added to it dropwise over
1 h, and this mixture was stirred for 1.5 h at room temperature.
4
2
3
and JHP = 0.5 Hz, 1H), 2.99 (ddd, JHH = 13.8 Hz, JHH = 3.8 Hz, and
4JHP = 1.5 Hz, 1H), 1.45 (br s, 3H). 13C NMR (C6D6): d 140.1 (d,
JCP = 19.6 Hz), 139.9 (d, JCP = 7.2 Hz), 139.4 (d, JCP = 5.7 Hz), 138.9,
133.1 (d, JCP = 21.1 Hz), 132.2 (d, JCP = 19.1 Hz), 130.4, 128.7,

R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
291
128.6 (d, JCP = 5.2 Hz), 128.42 (d, JCP = 6.7 Hz), 128.39, 128.1, 126.2,
123.2, 74.3 (d, JCP = 30.0 Hz), 53.8 (d, JCP = 8.8 Hz), 41.7 (d,
JCP = 4.1 Hz), 14.6. 31P{1H} NMR (C6D6): d 46.7 (s). HRMS (ESI-
TOF) calcd for C24H25NP (M+H+) 358.1719, found 358.1715.
4.3.4. General procedure for [RhCl(ligand)]2
A solution of ligand (1.0 equiv) in C6H6 (5.0–15 mL for 1.0 mmol
of ligand) was added slowly over 20 min to solution of
[RhCl(C2H4)2]2 (1.1–1.4 equiv Rh) in C6H6 (2.5 mL for 1.0 mmol of
ligand) at 30 °C, and the mixture was stirred for 1 h at 30 °C. The
reaction mixture was filtered through PTFE membrane with C6H6
and the solvent was removed under vacuum. The solid thus ob-
tained was washed with hexane and dried under vacuum to afford
complex [RhCl(ligand)]2, which was directly used as a catalyst for
the 1,4-addition reaction.
a
4.3. Preparation of rhodium/chiral phosphorus–olefin
complexes
4.3.1. Rh(acac)((S)-1a) 10
A solution of (S)-1a (318 mg, 0.890 mmol) in C6H6 (4.0 mL)
was added slowly over 25 min to a solution of Rh(acac)(C2H4)2
(214 mg, 0.829 mmol) in C6H6 (1.0 mL) at 30 °C, and the mixture
was stirred for 1 h at 30 °C. The reaction mixture was filtered
through a PTFE membrane with C6H6 and the solvent was re-
moved under vacuum. The solid thus obtained was washed with
hexane and dried under vacuum to afford complex 10 as a yellow
4.4. Rhodium-catalyzed asymmetric 1,4-addition reactions
4.4.1. General procedure for the rhodium-catalyzed asymmetric
1,4-addition (Tables 2 and 3)
At first, KOH (50
lL, 0.10–0.20 mmol; 2.0–4.0 M aqueous) was
solid (396 mg, 0.708 mmol; 85% yield). ½a D25
ꢀ
¼ ꢁ20:5 (c 0.52, THF).
added to a solution of [RhCl(ligand)]2 (10
l
mol Rh), ,b-unsatu-
a
Recrystallization of this complex from C6H6/pentane afforded sin-
gle crystals suitable for X-ray crystallographic analysis. 1H NMR
(C6D6): d 8.25–8.18 (m, 2H), 7.98–7.92 (m, 2H), 7.17–7.07 (m,
3H), 7.06–6.94 (m, 8H), 5.36 (s, 1H), 3.75 (s, 1H), 3.52–3.45 (m,
rated ketone (0.20 mmol), and arylboronic acid (0.22–0.30 mmol)
in dioxane (0.50 mL), and the resulting mixture was stirred for
10 h at 30 °C. This was directly passed through a pad of silica gel
with EtOAc and the solvent was removed under vacuum. The res-
idue was purified by silica gel preparative TLC with EtOAc/hexane
to afford the 1,4-adduct.
2
1H), 2.84 (t, JHH = 14.0 Hz, 1H), 2.63 (dd, JHH = 12.8 Hz and
3JHP = 8.8 Hz, 1H), 2.44–2.29 (m, 2H), 1.97 (s, 3H), 1.93 (s, 3H),
1.89 (s, 3H). 31P{1H} NMR (C6D6): d 127.9 (d, JPRh = 202 Hz). Anal.
1
Calcd for C29H31NO2PRh: C, 62.26; H, 5.59. Found: C, 62.27; H,
5.52.
4.4.2. (S)-3-Phenylcyclohexanone (Table 2, entry 1)
(CAS 57344–86–2) The reaction was conducted with 1.1 equiv
of phenylboronic acid and 0.5 equiv. of KOH. Yellow oil. 89% yield.
The ee was determined on a Daicel Chiralpak AD-H column with
hexane/2-propanol = 100/1, flow = 0.5 mL/min. Retention times:
25.3 min [major enantiomer], 31.2 min [minor enantiomer]. 94%
4.3.2. Rh(acac)((S)-4) 11
A solution of (S)-4 (93.2 mg, 0.250 mmol) in C6H6 (6.0 mL) was
added slowly over 2 h to a solution of Rh(acac)(C2H4)2 (76.7 mg,
0.297 mmol) in C6H6 (2.5 mL) at 30 °C, and the mixture was stir-
red for 1 h at 30 °C. The reaction mixture was filtered through a
PTFE membrane with C6H6 and the solvent was removed under
vacuum. The solid thus obtained was washed with hexane,
recrystallized from Et2O, and dried under vacuum to afford com-
plex 11 as an orange solid (101 mg, 0.176 mmol; 70% yield).
ee. ½a 3D0
ꢀ
¼ ꢁ20:2 (c 1.02, CHCl3). 1H NMR (CDCl3): d 7.33 (t,
3
3JHH = 7.5 Hz, 2H), 7.27–7.20 (m, 3H), 3.01 (tt, JHH = 11.8 and
2
3
4
4
3.9 Hz, 1H), 2.60 (ddt, JHH = 14.0 Hz, JHH = 4.4 Hz, and
JHH = 1.9 Hz, 1H), 2.53 (ddd, JHH = 14.0 Hz, JHH = 12.3 Hz, and
2
3
2
JHH = 1.0 Hz, 1H), 2.50–2.43 (m, 1H), 2.38 (dddd, JHH = 14.3 Hz,
3JHH = 12.4 and 6.1 Hz, and JHH = 0.9 Hz, 1H), 2.19–2.12 (m, 1H),
4
½
a 2D0
ꢀ
¼ þ69:6 (c 0.58, THF). Recrystallization of this complex from
2.12–2.06 (m, 1H), 1.91–1.73 (m, 2H).
Et2O/pentane afforded single crystals suitable for X-ray crystallo-
graphic analysis. 1H NMR (C6D6): d 8.14 (t, 3J = 8.4 Hz, 2H), 8.00 (t,
3J = 8.7 Hz, 2H), 7.22–7.08 (m, 5H), 7.08–7.01 (m, 3H), 7.01–6.92
(m, 3H), 5.33 (s, 1H), 4.14 (s, 1H), 3.79–3.67 (m, 1H), 3.16–2.99
4.4.3. (R)-3-Phenylcyclohexanone (Table 2, entry 5)
(CAS 34993–51–6) The reaction was conducted with 1.1 equiv
of phenylboronic acid and 0.5 equiv of KOH. Colorless oil. 98%
yield. The ee was determined on a Daicel Chiralpak AD-H column
with hexane/2-propanol = 100/1, flow = 0.5 mL/min. Retention
times: 28.9 min [minor enantiomer], 33.7 min [major enantiomer].
2
3
(m, 1H), 2.90 (dd, JHH = 13.8 Hz and JHH = 9.1 Hz, 1H), 2.69 (dd,
2JHH = 14.1 Hz and JHH = 5.6 Hz, 1H), 2.65–2.45 (m, 2H), 1.91 (s,
3
3H), 1.86 (s, 6H), 1.48–1.39 (m, 1H). 31P{1H} NMR (C6D6): d
105.5 (d, JPRh = 202 Hz). Anal. Calcd for C30H33NO2PRh: C,
97% ee. ½a 3D0
¼ þ20:0 (c 1.03, CHCl3).
ꢀ
1
62.83; H, 5.80. Found: C, 62.98; H, 5.85.
4.4.4. (S)-3-(4-Methoxyphenyl)cyclohexanone (Table 2, entry 6)
(CAS 250782–40–2) The reaction was conducted with 1.1 equiv
of 4-methoxyphenylboronic acid and 0.5 equiv of KOH. Colorless
oil. 86% yield. The ee was determined on a Daicel Chiralpak AD-H
column with hexane/ethanol = 70/30, flow = 1.0 mL/min. Retention
times: 10.8 min [minor enantiomer], 13.4 min [major enantiomer].
4.3.3. Rh(acac)((S)-5) 12
A solution of (S)-5 (75.8 mg, 0.212 mmol) in C6H6 (4.5 mL) was
added slowly over 1 h to
a solution of of Rh(acac)(C2H4)2
(60.4 mg, 0.233 mmol) in C6H6 (2.5 mL) at 30 °C, and the mixture
was stirred for 1 h at 30 °C. The reaction mixture was filtered
through PTFE membrane with C6H6 and the solvent was removed
under vacuum. The solid thus obtained was washed with hexane
and dried under vacuum to afford complex 12 as a yellow solid
96% ee. ½a 2D0
ꢀ
¼ ꢁ17:3 (c 1.01, CHCl3). 1H NMR (CDCl3): d 7.14 (d,
3
3JHH = 8.5 Hz, 2H), 6.87 (d, JHH = 8.7 Hz, 2H), 3.80 (s, 3H), 2.97 (tt,
3JHH = 11.8 and 4.0 Hz, 1H), 2.57 (ddt, JHH = 13.9 Hz, JHH = 4.3 Hz,
and JHH = 2.2 Hz, 1H), 2.49 (ddd, JHH = 13.9 Hz, JHH = 12.4 Hz,
2
3
(92.2 mg, 0.164 mmol; 78% yield). ½a D25
¼ þ91:6 (c 0.58, THF).
ꢀ
4
2
3
Recrystallization of this complex from 1,2-dichloroethane/pen-
tane afforded single crystals suitable for X-ray crystallographic
analysis. 1H NMR (C6D6): d 8.15–8.06 (m, 2H), 7.88–7.80 (m,
2H), 7.25–7.11 (m, 3H), 7.06–6.89 (m, 8H), 5.38 (s, 1H), 3.87 (s,
1H), 3.44–3.34 (m, 1H), 2.85 t, JHH = 13.6 Hz, 1H), 2.66 (dd,
4
and
JHH = 1.1 Hz, 1H), 2.48–2.41 (m, 1H), 2.36 (dddd,
2JHH = 14.3 Hz, JHH = 12.4 and 6.1 Hz, and
JHH = 0.9 Hz, 1H),
3
4
2.17–2.10 (m, 1H), 2.10–2.02 (m, 2H), 1.86–1.71 (m, 2H).
3
3
2JHH = 13.5 Hz and JHH = 3.3 Hz, 1H), 2.43 (dd, JHP = 46.8 Hz and
4.4.5. (R)-3-(4-Methoxyphenyl)cyclohexanone (Table 2, entry 7)
(CAS 479586–33–9) The reaction was conducted with 1.1 equiv
of 4-methoxyphenylboronic acid and 0.5 equiv of KOH. Colorless
oil. 93% yield. The ee was determined on a Daicel Chiralpak AD-H
column with hexane/ethanol = 70/30, flow = 1.0 mL/min. Retention
2JHH = 13.6 Hz, 1H), 2.24 (t, J = 12.1 Hz, 1H), 1.96 (s, 3H), 1.94 (s,
3H), 1.92 (s, 3H). 31P{1H} NMR (C6D6): d 128.2 (d, JPRh = 204 Hz).
1
Anal. Calcd for C29H31NO2PRh: C, 62.26; H, 5.59. Found: C, 62.03;
H, 5.64.

292
R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
times: 9.6 min [major enantiomer], 11.9 min [minor enantiomer].
4.4.12. (S)-3-Phenylcycloheptanone (Table 2, entry 14)
97% ee. ½a 2D0
ꢀ
¼ þ18:7 (c 1.02, CHCl3).
(CAS 435269–65–1) The reaction was conducted with 1.5 equiv
of phenylboronic acid and 1.0 equiv of KOH. Colorless oil. 90%
yield. The ee was determined on two Daicel Chiralcel OD-H col-
umns with hexane/2-propanol = 98/2, flow = 0.5 mL/min. Reten-
tion times: 54.3 min [major enantiomer], 60.8 min [minor
4.4.6. (S)-3-(4-Trifluoromethylphenyl)cyclohexanone (Table 2,
entry 8)
(CAS 658711–11–6) The reaction was conducted with 1.1 equiv
of 4-trifluoromethylphenylboronic acid and 0.5 equiv of KOH.
White solid. 87% yield. The ee was determined on a Daicel Chir-
enantiomer]. 87% ee. ½a D20
ꢀ
¼ ꢁ54:0 (c 0.88, CHCl3). 1H NMR (CDCl3):
3
d 7.30 (t, JHH = 7.5 Hz, 2H), 7.22–7.16 (m, 3H), 2.97–2.86 (m, 2H),
2.70–2.54 (m, 3H), 2.13–1.95 (m, 3H), 1.80–1.67 (m, 2H), 1.55–
1.45 (m, 1H).
alpak
AS-H
column
with
hexane/2-propanol = 90/10,
flow = 0.5 mL/min. Retention times: 22.7 min [minor enantiomer],
24.7 min [major enantiomer]. 94% ee. ½a D15
¼ ꢁ11:8 (c 1.02, CHCl3).
ꢀ
1H NMR (CDCl3): d 7.59 (d, 3JHH = 8.0 Hz, 2H), 7.34 (d, 3JHH = 8.1 Hz,
4.4.13. (R)-3-Phenylcycloheptanone (Table 2, entry 15)
3
2
2H), 3.08 (tt, JHH = 11.9 and 3.9 Hz, 1H), 2.60 (ddt, JHH = 13.9 Hz,
(CAS 501919–44–4) The reaction was conducted with 1.5 equiv
of phenylboronic acid and 0.5 equiv of KOH. Colorless oil. 87%
yield. The ee was determined on a Daicel Chiralcel OD-H column
with hexane/2-propanol = 98/2, flow = 0.5 mL/min. Retention
times: 21.8 min [minor enantiomer], 24.2 min [major enantiomer].
3JHH = 4.4 Hz, and
JHH = 2.1 Hz, 1H), 2.52 (ddd, JHH = 14.0 Hz,
4
2
3JHH = 12.4 Hz, and
JHH = 0.9 Hz, 1H), 2.52–2.45 (m, 1H), 2.39
4
2
3
4
(dddd, JHH = 14.4 Hz, JHH = 12.6 and 6.2 Hz, and
JHH = 1.0 Hz,
1H), 2.22–2.14 (m, 1H), 2.14–2.06 (m, 1H), 1.93–1.75 (m, 2H).
95% ee. ½a 2D5
¼ þ54:2 (c 0.85, CHCl3).
ꢀ
4.4.7. (R)-3-(4-Trifluoromethylphenyl)cyclohexanone (Table 2,
entry 9)
4.4.14. (R)-4-Phenyl-2-pentanone (Table 3, entry 1)
(CAS 610273–87–5) The reaction was conducted with 1.5 equiv
of 4-trifluoromethylphenylboronic acid and 0.5 equiv of KOH.
White solid. 84% yield. The ee was determined on two Daicel Chir-
(CAS 67110–72–9) Colorless oil. 89% yield. The ee was deter-
mined on two Daicel Chiralcel OJ-H columns with hexane/2-propa-
nol = 98/2, flow = 0.7 mL/min. Retention times: 35.1 min [minor
alpak
AS-H
columns
with
hexane/2-propanol = 90/10,
enantiomer], 36.8 min [major enantiomer]. 85% ee. ½a D30
¼ ꢁ39:9
ꢀ
flow = 0.5 mL/min. Retention times: 41.9 min [major enantiomer],
(c 0.50, CHCl3). 1H NMR (CDCl3): d 7.31–7.27 (m, 2H), 7.23–7.17
46.0 min [minor enantiomer]. 97% ee. ½a D20
ꢀ
¼ þ12:0 (c 1.01, CHCl3).
(m, 3H), 3.30 (sext, JHH = 7.1 Hz, 1H), 2.75 (dd, JHH = 16.2 Hz and
3
2
3JHH = 6.5 Hz, 1H), 2.65 (dd, JHH = 16.3 Hz and JHH = 7.8 Hz, 1H),
2.06 (s, 3H), 1.27 (d, JHH = 6.9 Hz, 3H).
2
3
3
4.4.8. (S)-3-(2-Methylphenyl)cyclohexanone (Table 2, entry 10)
(CAS 475599–60–1) The reaction was conducted with 1.1 equiv
of 2-methylphenylboronic acid and 0.5 equiv of KOH. Colorless oil.
92% yield. The ee was determined on a Daicel Chiralpak AD-H col-
umn with hexane/2-propanol = 100/1, flow = 0.5 mL/min. Reten-
tion times: 22.4 min [major enantiomer], 28.9 min [minor
4.4.15. (S)-4-Phenyl-2-pentanone (Table 3, entry 2)
(CAS 32587–80–7) Colorless oil. 79% yield. The ee was deter-
mined on two Daicel Chiralcel OJ-H columns with hexane/2-propa-
nol = 98/2, flow = 0.7 mL/min. Retention times: 34.9 min [major
enantiomer]. 95% ee. ½a D25
ꢀ
¼ ꢁ44:5 (c 1.01, CHCl3). 1H NMR (CDCl3):
enantiomer], 37.0 min [minor enantiomer]. 50% ee. ½a D25
¼ þ23:5
ꢀ
d 7.25–7.19 (m, 2H), 7.18–7.11 (m, 2H), 3.27–3.16 (m, 1H), 2.55–
2.46 (m, 3H), 245–2.37 (m, 1H), 2.33 (s, 3H), 2.21–2.12 (m, 1H),
2.04–1.97 (m, 1H), 1.90–1.74 (m, 2H).
(c 1.02, CHCl3).
4.4.16. (R)-4-Phenyl-2-nonanone (Table 3, entry 3)
(CAS 435269–67–3) Colorless oil. 91% yield. The ee was deter-
mined on two Daicel Chiralcel OJ-H columns with hexane/2-propa-
nol = 98/2, flow = 0.5 mL/min. Retention times: 23.7 min [minor
4.4.9. (R)-3-(2-Methylphenyl)cyclohexanone (Table 2, entry 11)
(CAS 91663–37–5) The reaction was conducted with 1.5 equiv
of 2-methylphenylboronic acid and 0.5 equiv of KOH. Colorless
oil. 99% yield. The ee was determined on a Daicel Chiralpak AD-H
column with hexane/2-propanol = 100/1, flow = 0.5 mL/min.
Retention times: 22.7 min [minor enantiomer], 29.0 min [major
enantiomer], 25.1 min [major enantiomer]. 83% ee. ½a D25
¼ ꢁ17:0
ꢀ
3
(c 1.03, CHCl3). 1H NMR (CDCl3): d 7.28 (t, JHH = 7.4 Hz, 2H),
2
7.20–7.15 (m, 3H), 3.14–3.06 (m, 1H), 2.72 (dd, JHH = 16.0 Hz
3
2
3
and JHH = 7.3 Hz, 1H), 2.68 (dd, JHH = 16.0 Hz and JHH = 7.1 Hz,
1H), 2.00 (s, 3H), 1.65–1.50 (m, 2H), 1.28–1.05 (m, 6H), 0.82 (t,
3JHH = 6.9 Hz, 3H).
enantiomer]. 98% ee. ½a D20
¼ þ44:4 (c 1.00, CHCl3).
ꢀ
4.4.10. (S)-3-Phenylcyclopentanone (Table 2, entry 12)
(CAS 86505–50–2) The reaction was conducted with 1.5 equiv
of phenylboronic acid and 0.5 equiv of KOH. Colorless oil. 92%
yield. The ee was determined on three Daicel Chiralpak AD-H col-
umns with hexane/ethanol = 98/2, flow = 0.5 mL/min. Retention
times: 88.0 min [minor enantiomer], 92.4 min [major enantiomer].
4.4.17. (S)-4-Phenyl-2-nonanone (Table 3, entry 4)
(CAS 501919–45–5) Colorless oil. 73% yield. The ee was deter-
mined on two Daicel Chiralcel OJ-H columns with hexane/2-propa-
nol = 100/1, flow = 0.5 mL/min. Retention times: 33.8 min [major
enantiomer], 37.3 min [minor enantiomer]. 58% ee. ½a D25
¼ þ12:6
ꢀ
93% ee. ½a 2D0
ꢀ
¼ ꢁ91:1 (c 1.14, CHCl3). 1H NMR (CDCl3): d 7.37–7.32
(c 1.01, CHCl3).
(m, 2H), 7.28–7.23 (m, 3H), 3.47–3.38 (m, 1H), 2.67 (dd,
3
2JHH = 18.2 Hz and JHH = 7.3 Hz, 1H), 2.52–2.40 (m, 2H), 2.35
4.4.18. (S)-5-Methyl-4-phenyl-2-hexanone (Table 3, entry 5)
(CAS 435269–66–2) Yellow oil. 93% yield. The ee was deter-
mined on three Daicel Chiralcel OD-H columns with hexane/2-pro-
panol = 98/2, flow = 0.5 mL/min. Retention times: 38.7 min [minor
2
3
4
(ddd, JHH = 18.0 Hz, JHH = 11.2 Hz, and JHH = 1.3 Hz, 1H), 2.34–
2.26 (m, 1H), 2.05–1.94 (m, 1H).
4.4.11. (R)-3-Phenylcyclopentanone (Table 2, entry 13)
enantiomer], 43.0 min [major enantiomer]. 81% ee. ½a D25
¼ ꢁ31:1 (c
ꢀ
(CAS 86505–44–4) The reaction was conducted with 1.5 equiv
of phenylboronic acid and 0.5 equiv of KOH. Colorless oil. 93%
yield. The ee was determined on two Daicel Chiralcel OB-H col-
umns with hexane/2-propanol = 98/2, flow = 0.3 mL/min. Reten-
tion times: 141.7 min [minor enantiomer], 147.2 min [major
0.99, CHCl3). 1H NMR (CDCl3): d 7.27 (t, 3JHH = 7.4 Hz, 2H), 7.18 (tt,
4
3JHH = 7.3 Hz and JHH = 1.2 Hz, 1H), 7.15–7.14 (m, 2H), 2.91 (ddd,
2
3JHH = 8.8, 7.6, and 5.8 Hz, 1H), 2.81 (dd, JHH = 15.8 Hz and
2
3
3JHH = 5.6 Hz, 1H), 2.77 (dd, JHH = 15.9 Hz and JHH = 9.0 Hz, 1H),
3
3
1.97 (s, 3H), 1.83 (sext, JHH = 6.9 Hz, 1H), 0.93 (d, JHH = 6.7 Hz,
3H), 0.74 (d, JHH = 6.7 Hz, 3H).
enantiomer]. 95% ee. ½a D25
ꢀ
¼ þ92:9 (c 1.07, CHCl3).
3

R. Narui et al. / Tetrahedron: Asymmetry 23 (2012) 284–293
293
Tetrahedron: Asymmetry 2005, 16, 3400; (c) Duan, W.-L.; Iwamura, H.; Shintani,
R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 2130.
4.4.19. (R)-5-Methyl-4-phenyl-2-hexanone (Table 3, entry 6)
(CAS 162239–77–2) Yellow oil. 79% yield. The ee was deter-
mined on three Daicel Chiralcel OD-H columns with hexane/2-pro-
panol = 98/2, flow = 0.5 mL/min. Retention times: 38.4 min [major
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¼ þ11:6
ꢀ
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Acknowledgments
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Support has been provided in part by a Grant-in-Aid for Scien-
tific Research (S) (19105002), the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
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