β-Isocupreidine-hexafluoroisopropyl acrylate method for asymmetric Baylis-Hillman reactions

Article abstract of DOI:10.1016/j.tet.2005.09.072

Key features of the β-isocupreidine (β-ICD)-catalyzed asymmetric Baylis-Hillman reaction of aldehydes with 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) are presented. In addition, an improved method using azeotropically dried β-ICD is described.

Full text of DOI:10.1016/j.tet.2005.09.072

Tetrahedron 62 (2006) 381–389
b-Isocupreidine–hexafluoroisopropyl acrylate method for
asymmetric Baylis–Hillman reactions
Ayako Nakano, Sakie Kawahara, Saori Akamatsu, Kenji Morokuma, Mari Nakatani,
*
Yoshiharu Iwabuchi, Keisuke Takahashi, Jun Ishihara and Susumi Hatakeyama
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
Received 30 August 2005; revised 16 September 2005; accepted 16 September 2005
Available online 10 October 2005
Abstract—Key features of the b-isocupreidine (b-ICD)-catalyzed asymmetric Baylis–Hillman reaction of aldehydes with 1,1,1,3,3,3-
hexafluoroisopropyl acrylate (HFIPA) are presented. In addition, an improved method using azeotropically dried b-ICD is described.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Hillman reactions using various congeners of b-ICD7 as
well as a panel of fluorine-containing acrylates (Scheme 1).
The Morita–Baylis–Hillman reaction has attracted con-
siderable interest due to the fascinating tandem Michael-
aldol sequence catalyzed by a Lewis base and the promising
utility of the multifunctional products. However, the major
problems associated with this reaction are its slow reaction
rate and difficulty in realization of a high level of
asymmetric induction. This situation has brought about
significant progress in rate acceleration as well as
asymmetric induction based on various imaginative ideas.1
Recently, we have developed a highly enantioselective
asymmetric Baylis–Hillman reaction of aldehydes2 as well
as imines3 by use of b-isocupreidine (b-ICD)4,5 as a chiral
Lewis base catalyst and 1,1,1,3,3,3-hexafluoroisopropyl
acrylate (HFIPA) as an activated alkene. In addition, we
have successfully demonstrated the synthetic utility of this
reaction via syntheses of biologically intriguing natural
products.6 This b-ICD–HFIPA method has remarkable
advantages in terms of the high enantioselectivity, the
broad applicability, and the availability of both b-ICD and
HFIPA. We speculate that hydrogen bonding between the
oxy anion and the phenolic OH should play the crucial role
during the enantio-controlling event as depicted in 1.2
Scheme 1. b-ICD–HFIPA method.
2. Results and discussion
For the purpose of attaining more mechanistic information
about the b-ICD–HFIPA method and seeking a better
reaction system, we have investigated asymmetric Baylis–
2.1. Preparation of the b-ICD-congeners
In order to investigate the structure-catalytic ability
relationship of b-ICD, its seven congeners 2–87 were
prepared from quinidine (Scheme 2). Hoffmann et al.
reported7b that treatment of quinidine with 3 equiv of KBr in
85% H3PO4 at 100 8C for 3 days produced a mixture of
tricyclic ethers 2, 3, and 6. We found that when this reaction
Keywords: b-Isocupreidine; 1,1,1,3,3,3-Hexafluoroisopropyl acrylate;
Organic catalysis.
*
Corresponding author. Tel./fax: C81 95 819 2426;
e-mail: susumi@net.nagasaki-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.072

382
A. Nakano et al. / Tetrahedron 62 (2006) 381–389
1–4), while compounds 2, 3, 6, 7, 9, and 10 were found to be
very poor catalysts (entries 9–14). Importantly, the results
listed in entries 4–8 indicate that compound 8 is also a useful
catalyst for asymmetric Baylis–Hillman reactions of
aromatic aldehydes.
Scheme 3. Chiral amine-catalyzed Baylis–Hillman reaction.
Table 1. Chiral amine-catalyzed reaction of aldehydes with HFIPAa
Entry
Alde-
hyde
Catalyst
Time
(h)
Yield (%),b
Config (% ee)c,d
14
15e
1
2
3
4
5
6
7
8
13a
13a
13a
13a
13b
13c
13g
13h
13a
13a
13a
13a
13a
13a
b-ICD
1
1
1
7
24
28
61
42
6
6
1
6
3
58, R (91)
59, R (89)
51, R (89)
41, R (93)
68, R (98)
71, R (95)f
11, R (4)
19, R (38)
18, R (26)
20, R (51)
0
4
5
8
8
8
8
8
2
3
6
7
9
10
0
25, R (100) 20, R (17)
15, R (92)
18, ndh
24, R (36)
74, R (10)
2, R (3)
0
21, S (61)
29, R (45)
32, R (32)
7, ndh
9, R (11)
26, R (4)
27, R (2)
9g
10g
11g
12
13
14
3
0
a Reactions were carried out at K55 8C in DMF (1 M) using 13 (1 equiv),
HFIPA (1.3 equiv), and catalyst (0.1 equiv), unless otherwise stated.
b Isolated yield.
c Determined by comparison of the specific rotation of the corresponding
methyl ester with that of the authentic sample obtained by kinetic
resolution under Sharpless asymmetric epoxidation conditions.
d Determined by HPLC analysis using a chiral column.
e Cis:trans; 15a: 99:1, 15g: 70:30, 15h: 90:10.
f
1
Determined by H NMR analysis of the R- and S- MTPA derivatives of
the corresponding methyl ester, unless otherwise stated.
Scheme 2. Preparation of b-ICD-congeners.
g HFIPA (3 equiv) was used.
h Not determined.
was conducted using the increased amount of KBr (5 equiv)
for longer reaction time (10 days), demethylation of the
methoxy group also occurred together with cycloisomeriza-
tion of quinidine to give 4, 5, and b-ICD in 20, 7, and 25%
yields, respectively. In addition, it was gratifyingly found
that, under the harsher conditions (KBr (10 equiv), 10 days),
b-ICD was directly obtained from quinidine in 61% yield
through the equilibration involving 11 and 12. TIPS ether 8
was prepared by demethylation8 of the known compound
77b available from quinidine. Compounds 9 and 109 were
also prepared from hydroquinidine.
These results suggest that both the rigid tricylic structure
and the phenolic OH are indispensable for obtaining a high
degree of asymmetric induction as well as the remarkable
rate acceleration. As seen in b-ICD,2 such a cage-like
structure is responsible for rate enhancement because it
2.2. Catalytic ability of the b-ICD-congeners
To evaluate the catalytic ability of the b-ICD-congeners, we
examined the reaction of p-nitrobenzaldehyde with HFIPA
using 0.1 equiv of compounds 2–10 in DMF at K55 8C
(Scheme 3, Table 1). Interestingly, compounds 4,5, and 8
exhibited similar catalytic ability to that of b-ICD (entries
Figure 1. Significant NOE observed in NOESY spectra in DMF-d7.

A. Nakano et al. / Tetrahedron 62 (2006) 381–389
383
renders the quinuclidine moiety more nucleophilic by
relieving steric congestion arising from C8–C9 bond
rotation. In addition, the tricyclic structure makes the
nucleophilic nitrogen face to the phenolic OH as indicated by
the NOESY spectra (Fig. 1), so that the oxy anion intermediate
stabilized by hydrogen bonding becomes operative resulting
in high enantioselectivity as depicted in 1.2
enantioselectivity although the yields were still unsatis-
factory (entries 7, 8). These reactions failed under the
original conditions using the undried b-ICD. In the case of
aliphatic aldehydes, the use of the dried b-ICD exerted little
effect on yield and enantioselectivity although the reaction
rate increased (entries 10–13). It is important to note that
this improved procedure using the dried b-ICD did not work
at all for pivalaldehyde (entry 14), thus defining the steric
limitation of this method.
2.3. Improved b-ICD–HFIPA method
The enhanced catalytic activity of the dried b-ICD is
ascribed to the prevention of the partial hydrolysis of HFIPA
giving two acidic products, acrylic acid (pKa 4.311) and
HFIP (pKa 9.312). In fact, addition of 10 mol% of acrylic
acid completely inhibited the b-ICD-catalyzed reaction of
3-methylbutanal with HFIPA, while HFIP did not affect the
reaction significantly. In view of the pKa value of the
phenolic OH of 6-hydroxy quinoline (pKa 9.313), it is
reasonable that HFIP is less influential against b-ICD. It is
assumed that, in the case of the less reactive aromatic
aldehydes apart from p-nitrobenzaldehyde, the reaction rate
is comparable with that of hydrolysis of HFIPA and
therefore, the reaction is retarded by the generated acrylic
acid, which attenuates the catalytic activity of b-ICD by
protonation of the nucleophilic nitrogen. On the other hand,
p-nitrobenzaldehyde reacts with HFIPA so rapidly that the
reaction cannot be influenced by moisture contents of
b-ICD. It was observed that the procedure using the dried
b-ICD is markedly more effective than the previous one for
aliphatic aldehydes having moderate reactivity in terms of
rate acceleration.
1
During H NMR tracing experiments of a 1:1 mixture of
b-ICD and HFIPA in DMF-d7 at K40 8C, we incidentally
found that HFIPA was partially hydrolyzed to produce 1,1,
1,3,3,3-hexafluoro-2-propanol (HFIP) and acrylic acid. The
employed b-ICD was prepared from quinidine (Scheme 2)
and purified by silica gel chromatography using 10%
methanol–chloroform as the eluent followed by recrystal-
lization from MeOH–H2O. The combustion elemental
analysis and X-ray analysis10 of b-ICD thus obtained
suggested the molecular formula to be C19H22N2O2$
MeOH$H2O. We therefore, concluded that the water bound
to b-ICD caused the unexpected partial hydrolysis of
HFIPA. This finding allowed us to come up with azeotropic
removal of the water of b-ICD by repeating evaporation of
its THF solution prior to use.
To our surprise, the azeotropically dried b-ICD showed
remarkable catalytic activity, in particular, for aromatic
aldehydes apart from the very reactive p-nitrobenzaldehyde
(Scheme 3, Table 2). Thus, benzaldehyde was converted
into 14b in 97% ee in 75% yield, which was previously
obtained as 95% ee in 57% yield using the catalyst without
azeotropic operation2 (entries 3, 4). The drying effect was
also demonstrated by the reactions of cinnamaldehyde and
2-naphthylaldehyde, which gave the corresponding
products in 64% (94% ee) and 82% (97% ee) yields,
respectively (entries 5, 6, 9). In addition, even less reactive
p-methoxybenzaldehyde and 1-naphthylaldehyde were
converted to the corresponding adducts with excellent
2.4. HFIPA and its related fluorine-containing acrylates
as an activated alkene
Table 3 summarizes b-ICD-catalyzed reaction of p-nitro-
benzaldehyde with a panel of commercially available
Table 3. b-ICD-catalyzed reaction of p-nitrobenzaldehyde with fluorine-
containing acrylatesa
Table 2. Improved b-ICD–HFIPA methoda
Entry
Aldehyde Catalystb Time
(h)
Yield (%),c
Config (% ee)d
14
15e
1
2
3
4
13a
13a
13b
13b
13c
13c
13d
13e
13f
13g
13g
13h
13h
13i
A
B
A
B
A
B
B
B
B
A
B
A
B
B
1
58, R (91)
57, R (95)
57, R (95)
75, R (97)
24, R (92)
64, R (94)
27, R (95)
23, R (97)
82, R (97)
11, R (4)
17, R (49)
1.5
48
48
72
4
72
120
58
65
17
72
19
72
0
0
0
0
0
0
0
5f
6f
7
Entry
Acrylate
Time (h)
Yield (%),b Config (% ee)c
8
9
Ester
15ad
10
11
12
13
14
21, R (100) 29, R (53)
1e
2
3
4
16a
16b
16c
16d
36
72
72
72
1
17a: 69, S (8)
17b: 43, S (3)
17c: 50, S (2)
17d: 53, (0)
0
38, R (98)
31, R (97)
36, R (99)
0
21, Racemate
23, S (76)
22, S (65)
0
6, S (6)
8, S (4)
4, R (4)
5
HFIPA
14a: 58, R (91) 11, R (4)
a All reactions were carried out at K55 8C in DMF (1 M) using 13
(1 equiv), HFIPA (1.3 equiv), and catalyst (0.1 equiv).
b A: undried b-ICD, B: dried b-ICD.
a Reactions were carried out at K55 8C in DMF (0.5 M) using 13a
(1 equiv), acrylate (1.3 equiv), and b-ICD (0.1 equiv).
b Isolated yield.
c Isolated yield.
d Determined in the same manner as noted in Table 1.
e Cis:trans; 15a: 99:1, 15g: 70:30, 15h: 90:10.
Catalyst (0.2 equiv) was used.
c Determined in the same manner as noted in Table 1.
d Cis:trans; 15a: 99: 1.
f
e The reaction was conducted at 20 8C.

384
A. Nakano et al. / Tetrahedron 62 (2006) 381–389
fluorine-containing acrylates 16b–d and HFIPA as well as
methyl acrylate. It was observed that, compared with methyl
acrylate, all fluorine-containing acrylates brought about
remarkable rate acceleration due to the high electron-
withdrawing nature of fluorine atom. It should be stressed
that HFIPA having a branched alkoxy group exerts the
striking effect both on rate acceleration and enantio-
selectivity. Other fluorine-containing acrylates 16b–d
having a linear alkoxy group did not induce any appreciable
level of enantioselectivity.
4.2. Reaction of quinidine with KBr–H3PO4
Method A. Quinidine (2.0 g, 6.16 mmol) was added
portionwise to a solution of KBr (2.20 g, 18.5 mmol) in
85% H3PO4 (30 mL) at room temperature, and the mixture
was stirred at 100 8C for 3 days. After being cooled to room
temperature, the mixture was added dropwise to an ice-
cooled 25% KOH (200 mL). The pH was adjusted to ca. 8
with 25% NH4OH and extracted with CHCl3. The organic
layer was washed with brine, dried over K2CO3, and
chromatographed (SiO2, CHCl3/MeOHZ9:1–4:1) to give 2
(938 mg, 47%), 3 (199 mg, 10%), and 6 (100 mg, 5%).
3. Summary
Method B. A mixture of quinidine (660 mg, 2.00 mmol),
KBr (1.20 g, 10.0 mmol) in 85% H3PO4 (10 mL) was heated
at 100 8C for 5 days and worked up in the same manner as
described in Method A. Purification of the crude material by
column chromatography (SiO2, CHCl3/MeOHZ9:1–4:1)
gave 4 (124 mg, 20%), 5 (43 mg, 7%), and b-ICD (155 mg,
25%).
In the present work, we proved that both the cage-like
tricyclic structure and the phenolic OH of b-ICD as well as
the branched structure of HFIPA are necessary for obtaining
a high level of asymmetric induction as well as rate
acceleration. This fact implies that intermediate 1 stabilized
by hydrogen bonding would be responsible for the highly
enantioselective production of R enriched adducts. In
addition, we demonstrated that compound 8 is also able to
serve as a chiral catalyst for asymmetric Baylis–Hillman
reactions, suggesting that the C3 substituent on the
quinuclidine ring exerts little effect on the catalytic ability.
It should be highlighted that the azeotropically dried b-ICD
was found to display remarkable catalytic ability. By this
improved b-ICD–HFIPA method, the aromatic aldehydes
except very reactive p-nitrobenzaldehyde can be converted
into the corresponding Baylis–Hillman adducts in O94%ee
without concomitant formation of undesired dioxanones.
Method C. A mixture of quinidine (10.0 g, 30.8 mmol), KBr
(36.7 g, 308 mmol) in 85% H3PO4 (150 mL) was heated at
100 8C for 10 days and worked up in the same manner as
described in Method A. Purification of the crude material by
column chromatography (SiO2, CHCl3/MeOHZ9:1–4:1)
gave b-ICD (5.85 g, 61%) as a pale yellow amorphous solid,
which was spectroscopically pure. b-ICD thus obtained was
dissolved in NH3–MeOH and filtered to remove insoluble
precipitates. Concentration of the filtrate gave b-ICD as a
crystalline solid, which was recrystallized from MeOH–
H2O to afford colorless needles.
4. Experimental
4.1. General
4.2.1. (8R,9S,10R)-10,11-dihydro-9,10-epoxy-60-methoxy-
cinchonane (2). A pale yellow amorphous solid; [a]D18
C79.2 (c 1.06, MeOH); FT-IR (neat) 3369, 2937, 2562,
2206, 1621, 1510, 1232, 1103, 1027 cmK1 1H NMR
;
(500 MHz, CDCl3) d 8.72 (d, JZ4.5 Hz, 1H), 8.01 (d, JZ
9.0 Hz, 1H), 7.62 (dd, JZ4.5, 1.0 Hz, 1H), 7.36 (dd, JZ9.0,
2.5 Hz, 1H), 7.32 (d, JZ3.0 Hz, 1H), 5.95 (s, 1H), 4.26 (dq,
JZ1.5, 6.5 Hz, 1H), 4.03 (s, 3H), 3.77 (d, JZ14.0 Hz, 1H),
3.49 (d, JZ9.0 Hz, 1H), 3.23–3.19 (m, 2H), 2.86–2.82 (m,
1H), 2.45 (ddd, JZ13.0, 6.0, 2.0 Hz, 1H), 2.38 (ddd, JZ5.0,
5.0, 5.0 Hz, 1H), 1.85 (dd, JZ8.0, 5.5 Hz, 1H), 1.74–1.65
(m, 2H), 1.48 (d, JZ6.5 Hz, 3H), 1.27 (dd, JZ12.5, 8.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 158.2, 147.5, 145.3,
144.2, 131.7, 126.0, 121.6, 117.8, 101.7, 79.1, 72.4, 62.5,
56.6, 51.7, 47.3, 38.8, 25.2, 23.0, 22.3, 20.9; HRMS (EI)
calcd for C20H24N2O2 (MC): 324.1837, found 324.1840.
The spectral data were identical with those reported.7b
Where appropriate, reactions were performed in flame-dried
glassware under an argon atmosphere. All extracts were
dried over K2CO3 and concentrated by rotary evaporation
below 30 8C at ca. 25 Torr unless otherwise noted. Thin-
layer chromatography was performed using Merck F-254
TLC plates. Column chromatography was performed
employing silica gel 60 (230–400 mesh ASTM, Merk).
Commercial reagents and solvents were used as supplied
with the following exceptions. Anhydrous tetrahydrofuran
(THF) (stabilizer free) was purchased from Kanto Chemical
Co., Inc. Dichloromethane (CH2Cl2), triethylamine, and
N,N-dimethyformamide (DMF) were distilled from CaH2.
All melting points were taken on a Yanagimoto micro
melting point apparatus and are uncorrected. Optical
rotations were recorded on a JASCO DIP-370 polarimeter
at ambient temperature. Infrared spectra were measured on a
4.2.2. (8R,9S,10S)-10,11-dihydro-9,10-epoxy-60-methoxy-
cinchonane (3). A pale yellow amorphous solid; [a]D17
C60.4 (c 1.02, MeOH); FT-IR (neat) 3350, 2931, 2459,
2210, 1622, 1508, 1471, 1232, 1136, 1076, 1030 cmK1; 1H
NMR (500 MHz, CDCl3) d 8.74 (d, JZ5.0 Hz, 1H), 8.01 (d,
JZ9.0 Hz, 1H), 7.58 (dd, JZ4.5, 1.0 Hz, 1H), 7.35, (dd,
JZ9.0, 2.5 Hz, 1H), 7.24 (d, JZ2.5 Hz, 1H), 6.03 (s, 1H),
4.70 (dq, JZ1.0, 6.5 Hz, 1H), 3.96 (s, 3H), 3.79, (d, JZ
14.0 Hz, 1H), 3.42 (d, JZ9.5 Hz, 1H), 3.08 (dd, JZ13.0,
8.5 Hz, 1H), 2.87 (dd, JZ12.5, 8.5 Hz, 1H), 2.83–2.76 (m,
1H), 2.24 (ddd, JZ13.0, 5.5, 2.5 Hz, 1H), 2.11 (ddd, JZ5.5,
5.5, 5.5 Hz, 1H), 1.83–1.80 (m, 1H), 1.74–1.70 (m, 1H),
1
JASCO FT/IR-230 spectrometer. H and 13C NMR spectra
were measured on a Varian Gemini 300, JEOL JNM-AL
400, or a Varian Unity plus 500 spectrometer. Chemical
shifts are reported in parts per million (ppm) downfield from
tetramethylsilane (TMS) in d units and coupling constants
are given in hertz. TMS was defined as 0 ppm for 1H NMR
spectra and the center of the triplet of CDCl3 was also
defined as 77.10 ppm for 13C NMR spectra. HRMS (EI)
spectra were measured on a JEOL JMS-DX303 or a JEOL
JMS-700N.

A. Nakano et al. / Tetrahedron 62 (2006) 381–389
385
1.60–1.53 (m, 1H), 1.32 (d, JZ6.5 Hz, 3H), 1.23 (ddd, JZ
13.5, 9.5, 1.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 157.9,
147.5, 146.7, 144.1, 131.6, 126.1, 121.4, 118.2, 101.4, 75.7,
74.1, 60.1, 56.1, 47.3, 44.9, 39.6, 26.5, 24.9, 22.9, 22.1;
HRMS (EI) calcd for C20H24N2O2 (MC): 324.1837, found
324.1838. The spectral data were identical with those
reported.7b
4.2.6. (3R,8R,9S)-10,11-dihydro-3,9-epoxy-60-hydroxy-
cinchonane (b-ICD). Colorless needles; mp 258–259 8C;
[a]2D2 C8.6 (c 1.00, MeOH); FT-IR (neat) 3400–3200, 2962,
1
2713, 1620, 1508, 1469, 1280, 1240, 1012, 858 cmK1; H
NMR (500 MHz, CDCl3) d 8.71 (d, JZ4.5 Hz, 1H), 7.99 (br
s, 1H), 7.97 (d, JZ9.0 Hz, 1H), 7.57 (dd, JZ4.5, 1.0 Hz,
1H), 7.24 (dd, JZ9.0, 2.5 Hz, 1H), 6.00 (s, 1H), 3.68 (d, JZ
13.5 Hz, 1H), 3.46 (d, JZ6.0 Hz, 1H), 3.19 (dd, JZ13.0,
8.5 Hz, 1H), 3.09–3.03 (m, 1H), 2.77 (d, JZ14.0 Hz, 1H),
2.21–2.19 (m, 1H), 1.87 (ddd, JZ13.0, 6.5, 2.0 Hz, 1H),
1.79–1.73 (m, 1H), 1.69 (dq, JZ3.5, 7.5 Hz, 2H), 1.63–1.58
(m, 1H), 1.24 (dd, JZ13.6, 1.0 Hz, 1H), 1.04 (t, JZ7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 156.4, 146.7, 143.0,
142.2, 131.3, 127.0, 122.3, 119.1, 105.2, 77.0, 72.7, 56.0
54.0, 46.4, 32.7, 27.4, 23.5, 23.3, 7.3; HRMS (EI) calcd for
C19H22N2O2 (MC): 310.1681, found 310.1691. Anal. Calcd
for C19H22N2O2$CH3OH$H2O: C 66.64, H 7.83, N 7.77;
found C 66.51, H 7.50, N 7.58.
4.2.3. (8R,9S,10R)-10,11-dihydro-9,10-epoxy-60-hydroxy-
cinchonane (4). A pale yellow amorphous solid; [a]D17
C114.0 (c 1.00, MeOH); FT-IR (neat) 3200–2600, 2939,
2567, 1620, 1508, 1468, 1232, 754 cmK1 1H NMR
;
(500 MHz, CDCl3) d 8.66 (d, JZ4.5 Hz, 1H), 7.94 (d, JZ
9 Hz, 1H), 7.86 (d, JZ2.5 Hz, 1H), 7.55 (dd, JZ4.5,
1.0 Hz, 1H), 7.24 (dd, JZ9.0, 2.5 Hz, 1H), 5.92 (s, 1H),
4.23 (q, JZ6.5 Hz, 1H), 3.73 (d, JZ13.5 Hz, 1H), 3.47 (d,
JZ8.0 Hz, 1H), 3.25–3.18 (m, 2H), 2.92–2.87 (m, 1H), 2.51
(ddd, JZ13.0, 6.0, 1.5 Hz, 1H), 2.42 (m, 1H), 1.88 (dd, JZ
9.0, 5.5 Hz, 1H), 1.79–1.70 (m, 2H), 1.48 (d, JZ6.5 Hz,
3H), 1.28 (dd, JZ13.0, 8.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 156.2, 146.9, 144.7, 143.3, 131.5, 125.9, 121.9,
117.3, 105.7, 79.0, 72.1, 62.6, 51.0, 47.0, 39.0, 25.2, 22.8,
22.2, 20.9; HRMS (EI) calcd for C19H22N2O2 (MC):
310.1681, found 310.1683. The spectral data were identical
with those reported.7b
4.2.7. (3R,8R,9S)-3-triisopropylsilyloxy-3,9-epoxy-60-
hydroxy-10,11-dinorcinconane (8). NaH (60% in mineral
oil; 2.00 g, 50.1 mmol) was washed with hexane, dried, and
suspended in DMF (40 mL). Ethanethiol (8.17 mL,
110.3 mmol) was added dropwise to the suspension over
20 min with cooling in an ice bath, and the mixture was
stirred at room temperature for 10 min. A solution of 77b
(2.35 g, 5.01 mmol) in DMF (35 mL) was added at room
temperature and the mixture was heated at 60 8C for 12 h.
The reaction mixture was allowed to cool to room
temperature, quenched with saturated NH4Cl, and extracted
with CH2Cl2. The extract was washed with brine, dried over
Na2SO4, and concentrated. Purification of the residue by
column chromatography (SiO2 75 g, CHCl3/MeOHZ10:1),
followed by lyophilization gave 8 (1.59 g, 70%) as a pale
yellow amorphous solid; [a]2D3 K18.6 (c 1.35, CHCl3);
FT-IR (neat) 3600–2300, 1622, 1468, 1348, 1238,
4.2.4. (8R,9S,10S)-10,11-dihydro-9,10-epoxy-60-hydroxy-
cinchonane (5). A pale yellow amorphous solid; [a]D18
C47.8 (c 1.06, MeOH); FT-IR (neat) 3100–2500, 2929,
1842, 1618, 1510, 1469, 1236, 1138, 1092, 910, 733 cmK1
;
1H NMR (500 MHz, CDCl3) d 8.68 (d, JZ4.5 Hz, 1H), 7.95
(d, JZ9.0 Hz, 1H), 7.93 (dd, JZ3.0, 1.0 Hz, 1H), 7.54, (d,
JZ4.5 Hz, 1H), 7.24 (dd, JZ9.0, 3.0 Hz, 1H), 6.02 (s, 1H),
4.69 (dq, JZ7.0, 1.5 Hz, 1H), 3.81, (d, JZ14.0 Hz, 1H),
3.36 (d, JZ8.5 Hz, 1H), 3.14 (dd, JZ12.5, 9.5 Hz, 1H),
2.93 (dd, JZ14.0, 9.0 Hz, 1H), 2.83–2.77 (m, 1H), 2.34
(ddd, JZ13.0, 6.0, 2.0 Hz, 1H), 2.18 (ddd, JZ6.0, 6.0,
6.0 Hz, 1H), 1.87 (dd, JZ9.0, 6.0 Hz, 3H), 1.79–1.73 (m,
1H), 1.66–1.61 (m, 1H), 1.30 (d, JZ7.0 Hz, 3H), 1.26 (dd,
JZ13.0, 8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 156.5,
146.8, 146.2, 143.3, 131.3, 126.6, 122.3, 117.9, 106.3, 75.5,
73.0, 60.4, 47.0, 44.5, 39.6, 26.5, 25.1, 22.5, 22.6; HRMS
(EI) calcd for C19H22N2O2 (MC): 310.1681, found
310.1691. The spectral data were identical with those
reported.7b
1
1192 cmK1; H NMR (400 MHz, CDCl3) d 8.74 (d, JZ
8.0 Hz, 1H), 8.11 (br s, 1H), 7.97 (d, JZ12.0 Hz, 1H), 7.65
(d, JZ8.0 Hz, 1H), 7.23 (dd, JZ4.0, 12.0 Hz, 1H), 6.13 (s,
1H), 3.82 (d, JZ12.0 Hz, 1H), 3.41 (d, JZ8.0 Hz, 1H),
3.31–3.21 (m, 1H), 3.10–2.98 (m, 1H), 2.94 (d, JZ8.0 Hz, 1
H), 2.36 (m, 1H), 2.14–1.97 (m, 2H), 1.69 (m, 1H), 1.32–
0.98 (m, 22H); 13C NMR (100 MHz, CDCl3) d 155.9, 146.4,
142.7, 140.8, 130.8, 126.7, 121.6, 118.5, 106.1, 99.2, 73.7,
55.9, 55.9, 46.1, 37.4, 24.4, 22.8, 17.9, 17.8, 12.8; HRMS
(EI) calcd for C26H38N2O3Si (MC): 454.2651, found
454.2644.
4.2.5. (3R,8R,9S)-10,11-dihydro-3,9-epoxy-60-methoxy-
cinchonane (6). A pale yellow amorphous solid; [a]D19
K8.2 (c 1.02, MeOH); FT-IR (neat) 3350, 2966, 2517,
1622, 1508, 1232, 1028 cmK1; 1H NMR (500 MHz, CDCl3)
d 8.80 (d, JZ4.5 Hz, 1H), 8.03 (d, JZ9.0 Hz, 1H), 7.73 (dd,
JZ4.5, 1.0 Hz, 1H), 7.35 (dd, JZ9.0, 2.5 Hz, 1H), 7.16 (d,
JZ3.0 Hz, 1H), 5.94 (s, 1H), 3.96 (s, 3H), 3.55 (d, JZ
13.5 Hz, 1H), 3.48 (d, JZ6.0 Hz, 1H), 3.02–3.00 (m, 2H),
2.68 (d, JZ14.0 Hz, 1H), 2.14 (dd, JZ5.5, 5.0 Hz, 1H),
1.77 (ddd, JZ13.0, 6.5, 2.5 Hz, 1H), 1.70–1.64 (m, 1H),
1.66 (q, JZ7.5 Hz, 2H), 1.54–1.49 (m, 1H), 1.27 (dd, JZ
13.5, 6.5 Hz, 1H), 1.04 (t, JZ7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 157.9, 147.6, 144.0, 142.3, 131.7,
126.4, 121.6, 119.3, 100.5, 77.1, 73.0, 56.2, 55.9, 54.7, 46.7,
32.9, 27.4, 24.2, 23.5, 7.3; HRMS (EI) calcd for
C20H24N2O2 (MC): 324.1838, found 324.1827. The spectral
data were identical with those reported.7b
4.2.8. (3R,8R,9S)-10,11-dihydro-3,60-dihydroxycincho-
nane (9). NaH (60% in mineral oil; 122 mg, 3.06 mmol)
was washed with hexane, dried, and suspended in DMF
(2 mL). Ethanethiol (500 mL, 6.75 mmol) was added
dropwise to the suspension, and the mixture was stirred at
room temperature for 10 min. To this mixture was added a
solution of hydroquinidine (100 mg, 0.31 mmol) in DMF
(3 mL), and stirring was continued at room temperature for
1 h and at 100 8C for 20 h. The reaction mixture was
allowed to cool to room temperature, acidified with 1 M
HCl, and extracted with CH2Cl2. The aqueous layers were
adjusted to pH 8 with 25% aqueous ammonia and extracted
with CH2Cl2. Combined extracts were washed with brine,
dried over K2CO3, and concentrated. Purification of the
residue by column chromatography (SiO2 deactivated by

386
A. Nakano et al. / Tetrahedron 62 (2006) 381–389
exposure to MeOH and Et3N, 10 g, CHCl3/MeOHZ10:1),
followed by lyophilization gave 9 (55 mg, 57%) as a
colorless amorphous solid; [a]2D0 C250.1 (c 1.03, MeOH);
FT-IR (neat) 3130–2636, 2944, 1616, 1466, 1234 cmK1; 1H
NMR (300 MHz, CD3OD) d 8.57 (d, JZ4.5 Hz, 1H), 7.88
(d, JZ9.3 Hz, 1H), 7.61, (d, JZ4.5 Hz, 1H), 7.31 (dd, JZ
9.0, 2.7 Hz, 1H), 7.22 (d, JZ2.7 Hz, 1H), 5.56 (d, JZ
2.7 Hz, 1H), 3.41–3.35 (m, 1H), 3.10–3.01 (m, 1H), 2.99–
2.85 (m, 2H), 2.85–2.75 (m, 1H), 2.18–2.11 (m, 1H), 1.72
(br s, 1H), 1.60–1.47 (m, 5H), 1.08–0.99 (m, 1H), 0.93 (t,
JZ6.9 Hz, 3H); 13C NMR (75 MHz, CD3OD) d 158.7,
149.4, 147.1, 143.7, 131.3, 128.4, 123.7, 119.6, 105.1, 72.0,
60.7, 51.8, 50.9, 38.3, 27.5, 27.4, 26.0, 20.7, 12.3; HRMS
(EI) calcd for C19H24N2O2 (MC): 312.1838, found
312.1853.
Dried b-ICD. b-ICD (0.1 mmol) was dissolved into THF
(2 mL) and the solution was evaporated by rotary
evaporation at room temperature. After repeating this
operation three times, the resulting amorphous solid was
dried under vacuum at room temperature for 10 min.
4.4. Conversion of 14 and 15 into the corresponding
methyl ester for the determination of their optical purity
A mixture of 14 or 15 (1.0 mmol) and triethylamine
(0.7 mL) in MeOH (7 mL) was stirred at room temperature
for 30 min and the reaction was quenched by the addition of
Dowex 50 (HC form). The reaction mixture was filtered,
concentrated, and chromatographed (SiO2, solvent system:
EtOAc/hexane). The optical purity of the methyl ester was
determined by HPLC analysis using a chiral column.
4.2.9. (3R,8R)-10,11-dihydro-3,60-methoxycinchonane
(10). To an ice-cooled solution of hydroquinidine (1.20 g,
3.68 mmol) in CH2Cl2 (5 mL) were added 4-DMAP (45 mg,
0.34 mmol), pyridine (0.89 mL, 11.0 mmol) and methane-
sulfonyl chloride (0.57 mL, 7.35 mmol), and the mixture
was stirred at room temperature for 3 days. The mixture was
diluted with CHCl3, washed with saturated NaHCO3 and
brine, dried, and concentrated. Purification of the residue by
column chromatography (SiO2 30 g, CHCl3/MeOHZ20:1)
gave the corresponding mesylate (1.20 g, 81%). To a
solution of the mesylate in THF (10 mL) was added
dropwise lithium triethylborohydride (1 M in THF,
5.9 mL, 5.92 mmol) at K70 8C. The mixture was allowed
to slowly warm to K55 8C, and stirred at that temperature
for 3 days. The reaction mixture was acidified with 1 M
HCl, and extracted with CHCl3. The aqueous layers were
adjusted to pH 8 with 25% NH4OH and extracted with
CHCl3. The combined extracts were washed with brine,
dried over K2CO3, and concentrated. Purification of the
residue by column chromatography (SiO2 25 g, CHCl3/
MeOHZ20:1) gave 10 (673 mg, 73%) as a pale yellow
amorphous solid; [a]1D8 C117.8 (c 1.02, MeOH); FT-IR
4.4.1. 1,1,1,3,3,3-Hexafluoropropan-2-yl (R)-3-hydroxy-
2-methylene-3-(4-nitrophenyl)propanoate (14a). A color-
less oil (95% ee); [a]2D4 K40.9 (c 0.87, CHCl3); FT-IR (neat)
3533, 1751, 1525, 1352, 1286, 1232, 1120, 1115 cmK1; 1H
NMR (300 MHz, CDCl3) d 8.23 (d, JZ8.7 Hz, 2H), 7.58 (d,
JZ8.7 Hz, 2H), 6.66 (s, 1H), 6.27 (s, 1H), 5.80–5.74 (m,
2H), 2.47 (d, JZ4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d
162.5, 147.9, 147.5, 139.2, 130.9, 127.6, 123.9, 120.3 (q,
2
1JC,FZ281 Hz), 71.8, 66.9 (hept, JC,FZ34.2 Hz); HRMS
(EI) calcd for C13H9NO5F6 (MC): 373.0385, found
373.0389.
4.4.2. (2R,6R)-2,6-di(4-nitrophenyl)-5-methylene-1,3-
dioxan-4-one (15a). A colorless oil (49% ee); [a]2D5 C3.2
(c 0.57, CHCl3); FT-IR (neat) 3082, 2862, 1741, 1523,
1
1348, 1173 cmK1; H NMR (300 MHz, CDCl3) d 8.32 (d,
JZ8.7 Hz, 2H), 8.31 (d, JZ8.7 Hz, 2H), 7.79 (d, JZ
8.7 Hz, 2H), 7.64 (d, JZ8.7 Hz, 2H), 6.74 (d, JZ2.7 Hz,
1H), 6.62 (s, 1H), 5.92 (br s, 1H), 5.42 (d, JZ2.1 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 161.3, 149.0, 148.6, 144.2,
141.1, 135.2, 130.6, 128.8, 127.5, 124.3, 123.9, 99.5, 80.4;
HRMS (EI) calcd for C17H12N2O7 (MC): 356.0644, found
356.0663.
(neat) 3371, 2937, 2868, 1622, 1510, 1466, 1234, 1032 cmK1
;
1H NMR (500 MHz, CDCl3) d 8.66 (d, JZ4.5 Hz, 1H), 8.01
(d, JZ9.5 Hz, 1H), 7.37 (dd, JZ9.0, 2.5 Hz, 1H), 7.33, (d,
JZ2.5 Hz, 1H), 7.23 (d, JZ4.5 Hz, 1H), 3.97 (s, 3H), 3.49–
3.47 (m, 1H), 3.18 (dt, JZ14, 8.5 Hz, 1H), 3.07 (dd, JZ
13.5, 9.5 Hz, 1H), 3.01 (dd, JZ14, 9.5 Hz, 1H), 2.99–2.89
(m, 1H), 2.70 (ddd, JZ13.5, 7.5, 2.5 Hz, 1H), 1.69 (br s,
1H), 1.60–1.44 (m, 4H), 1.47 (q, JZ7.5 Hz, 2H), 1.42–1.36
(m, 1H), 0.94 (t, JZ7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 157.6, 147.3, 144.3, 143.6, 132.5, 128.5, 121.7,
121.3, 101.5, 55.5, 55.5, 49.2, 49.2, 37.4, 37.2, 27.9, 26.9,
25.9, 25.6, 11.9; HRMS (EI) calcd for C20H26N2O (MC):
310.2045, found 310.2048.
4.4.3. Methyl (R)-3-hydroxy-2-methylene-3-(4-nitro-
phenyl)propanoate (methyl ester obtained from 14a). A
colorless oil (95% ee); [a]2D3 K85.6 (c 0.54, MeOH); FT-IR
(neat) 3427, 2962, 1751, 1387, 1232, 1120 cmK1; 1H NMR
(300 MHz, CDCl3) d 8.21 (dd, JZ6.9, 1.8 Hz, 2H), 7.58 (d,
JZ6.9 Hz, 2H), 6.40 (s, 1H), 5.87 (s, 1H), 5.64 (d, JZ
6.3 Hz, 1H), 3.75 (s, 3H), 3.30 (d, JZ6.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 169.5, 147.8, 146.0, 127.9, 123.5, 71.5,
58.4, 53.0, 50.0; HRMS (EI) calcd for C11H11NO6 (MC):
253.0586, found 253.0578. HPLC conditions: Daicel
Chiralcel OJ, 2-propanol/hexane 1:10 (0.5 mL/min), tRZ
29.0 min (R) and 32.4 min (S).
4.3. General procedure for asymmetric Baylis–Hillman
reactions
To a solution of aldehyde 13 (1.0 mmol) and the chiral
amine catalyst (0.1 mmol) in DMF (1 mL) at K55 8C was
added HFIPA or 16 (1.3 mmol). After stirring at K55 8C for
the indicated time in Tables 1–3, the reaction was quenched
by the addition of 0.1 M HCl (3 mL). The reaction mixture
was extracted with EtOAc, washed with saturated NaHCO3
and brine, dried over MgSO4, concentrated, and chromato-
graphed (SiO2, solvent system: EtOAc/hexane).
4.4.4. 1,1,1,3,3,3-Hexafluoropropan-2-yl (R)-3-hydroxy-
2-methylene-3-phenylpropanoate (14b). A colorless oil
(97% ee); [a]1D9 K51.1 (c 1.04, CHCl3); FT-IR (neat) 3375,
1
2970, 1755, 1387, 1298, 1132 cmK1; H NMR (300 MHz,
CDCl3) d 7.37–7.30 (m, 5H), 6.60 (s, 1H), 6.24 (s, 1H), 5.75
(hept, JZ6.0 Hz, 1H), 5.63 (br s, 1H), 2.45 (br s, 1H); 13C
NMR (75 MHz, CDCl3) d 162.6, 140.5, 140.0, 129.6, 128.8,
1
128.5, 126.8, 120.4 (q, JC,FZ305.6 Hz), 72.6, 66.8 (hept,

A. Nakano et al. / Tetrahedron 62 (2006) 381–389
387
2JC,FZ35.3 Hz); HRMS (EI) calcd for C13H10NO5F6 (MC):
328.0534, found 328.0538.
(s, 1H), 2.82 (d, JZ5.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 166.9, 159.3, 142.2, 133.5, 128.0, 125.7, 113.9,
72.8, 55.3, 52.0; HRMS (EI) calcd for C12H14O4 (MC):
222.0892, found 222.0892. HPLC conditions: Daicel
Chiralcel OJ, 2-propanol/hexane 1:5 (0.5 mL/min), tRZ
53.3 min (R) and 70.3 min (S).
4.4.5. Methyl (R)-3-hydroxy-2-methylene-3-phenyl-
propanoate (methyl ester obtained from 14b). A colorless
oil (95% ee); [a]D20 K124.6 (c 1.30, MeOH); {lit.14 [a]1D8
K111.1 (c 1.11, MeOH)}; FT-IR (neat) 3363, 3032, 2952,
1
1704, 1496, 1450 cmK1; H NMR (300 MHz, CDCl3) d
4.4.10. 1,1,1,3,3,3-Hexafluoropropan-2-yl (R)-3-hydroxy-
2-methylene-3-(naphthalen-1-yl)propanoate (14e). A
colorless oil (97% ee); [a]2D3 K42.4 (c 1.65, CHCl3);
FT-IR (neat) 3433, 2969, 1718, 1441, 1286, 1151,
7.40–7.26 (m, 5H), 6.34 (s, 1H), 5.84 (s, 1H), 5.57 (d, JZ
5.4 Hz, 1H), 3.73 (s, 3H), 3.02 (d, JZ5.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 166.8, 142.1, 141.3, 128.5, 127.9,
126.6, 126.1, 73.3, 52.0; HRMS (EI) calcd for C11H12O5
(MC): 192.0786, found 192.0788. HPLC conditions: Daicel
Chiralcel OJ, 2-propanol/hexane 1:5 (0.5 mL/min), tRZ
26.4 min (R) and 32.4 min (S).
1
1038 cmK1; H NMR (300 MHz, CDCl3) d 8.02 (d, JZ
9.0 Hz, 1H), 7.89–7.81 (m, 2H), 7.55–7.42 (m, 4H), 6.61 (s,
1H), 6.39 (br d, JZ3.9 Hz, 1H), 6.03 (s, 1H), 5.79 (hept, JZ
6.0 Hz, 1H), 2.68 (br s, 1H); 13C NMR (75 MHz, CDCl3) d
163.2, 140.0, 136.1, 134.3, 131.1, 130.9, 129.6, 129.2,
1
126.9, 126.3, 120.7 (q, JC,FZ280 Hz), 69.2, 67.2 (hept,
4.4.6. 1,1,1,3,3,3-Hexafluoropropan-2-yl (E,R)-3-
hydroxy-2-methylene-5-phenyl-4-pentenoate (14c). A
colorless oil (94% ee); [a]2D6 K39.1 (c 0.95, CHCl3);
FT-IR (neat) 3390, 3032, 2970, 1754, 1664, 1633, 1387,
2JC,FZ35.3 Hz); HRMS (EI) calcd for C17H12F6O3 (MC):
378.0690, found 378.0698.
1
1290, 1126, 1022 cmK1; H NMR (300 MHz, CDCl3) d
4.4.11.
Methyl
(R)-3-hydroxy-2-methylene-3-
7.40–7.23 (m, 5H), 6.69 (d, JZ15.9 Hz, 1H), 6.55 (s, 1H),
6.26 (s, 1H), 6.24 (dd, JZ15.9, 6.6 Hz, 1H), 5.85 (hept, JZ
6.0 Hz, 1H), 5.22 (d, JZ6.6 Hz, 1H), 2.40 (br s, 1H); 13C
NMR (75 MHz, CDCl3) d 162.6, 139.3, 136.1, 132.8, 129.7,
(naphthalen-1-yl)propanoate (methyl ester obtained
from 14e). A pale yellow oil (97% ee); [a]2D3 K46.3 (c
0.83, CHCl3); FT-IR (neat) 3433, 1718, 1441, 1286, 1151,
1
1038 cmK1; H NMR (300 MHz, CDCl3) d 8.00–7.97 (m,
1
128.7, 128.3, 128.2, 126.8, 120.5 (q, JC,FZ281 Hz), 71.3,
1H), 7.87–7.79 (m, 2H), 7.62 (d, JZ6.9 Hz, 1H), 7.51–7.44
(m, 3H), 6.36 (br s, 1H), 6.34 (s, 1H), 5.57 (s, 1H), 3.76 (s,
3H), 3.16 (s, 1H); 13C NMR (75 MHz, CDCl3) d 167.1,
141.8, 136.4, 133.7, 130.7, 128.7, 128.5, 127.1, 126.1,
125.5, 125.3, 124.4, 123.7, 69.2, 52.1; HRMS (EI) calcd for
C15H14O3 (MC): 242.0943, found 242.0936. HPLC con-
ditions: Daicel Chiralcel OJ–H, 2-propanol/hexane 1:2
(0.5 mL/min), tRZ27.6 min (R) and 57.8 min (S).
2
66.8 (hept, JC,FZ34 Hz); HRMS (EI) calcd for
C15H12NO5F6 (MC): 354.0691, found 354.0675.
4.4.7. Methyl (E,R)-3-hydroxy-2-methylene-5-phenyl-4-
pentenoate (methyl ester obtained from 14c). A colorless
oil (94% ee); [a]2D2 C12.5 (c 0.56, CHCl3); FT-IR (neat)
3442, 3028, 2952, 1718, 1631, 1440, 1277, 1153 cmK1; 1H
NMR (300 MHz, CDCl3) d 7.41–7.20 (m, 5H), 6.67 (d, JZ
16.0 Hz, 1H), 6.36 (dd, JZ16.0, 6.3 Hz, 1H), 6.30 (s, 1H),
5.92 (s, 1H), 5.13 (dd, JZ6.3, 6.3 Hz, 1H), 3.79 (s, 3H),
3.02 (d, JZ6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d
166.8, 141.3, 136.5, 131.6, 129.3, 128.6, 127.9, 126.7,
126.0, 72.2, 52.1; HRMS (EI) calcd for C13H14O5 (MC):
218.0943, found 218.0951. HPLC conditions: Daicel
Chiralcel OD, 2-propanol/hexane 1:10 (0.5 mL/min), tRZ
26.4 min (R) and 29.3 min (S).
4.4.12. 1,1,1,3,3,3-Hexafluoropropan-2-yl (R)-3-hydroxy-
2-methylene-3-(naphthalen-2-yl)propanoate (14f). A
colorless oil (97% ee); [a]2D6 K72.8 (c 1.04, CHCl3);
FT-IR (neat) 3388, 1755, 1385, 1238, 1120, 910 cmK1; 1H
NMR (300 MHz, CDCl3) d 7.86–7.73 (m, 4H), 7.54–7.44
(m, 3H), 6.64 (s, 1H), 6.27 (s, H), 5.80 (d, JZ4.8 Hz, 1H),
5.75 (hept, JZ6.0 Hz, 1H), 2.58 (d, JZ4.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 162.6, 139.8, 137.7, 133.3, 130.0,
Z
1
128.7, 128.2, 127.8, 126.5, 126.1, 124.3, 120.4 (q, JC,F
2
279.7 Hz), 72.7, 66.7 (hept, JC,FZ35.3 Hz); HRMS calcd
4.4.8. 1,1,1,3,3,3-Hexafluoropropan-2-yl (R)-3-hydroxy-
3-(4-methoxyphenyl)-2-methylenepropanoate (14d). A
pale yellow oil (95% ee); [a]2D0 K60.6 (c 1.44, CHCl3);
FT-IR (neat) 3475, 2966, 1763, 1616, 1514, 1304,
for C17H12F6O3 (MC): 378.0690, found 378.0696.
4.4.13.
Methyl
(R)-3-hydroxy-2-methylene-3-
1
1134 cmK1; H NMR (300 MHz, CDCl3) d 7.28 (d, JZ
(naphthalen-2-yl)propanoate (methyl ester obtained
from 14f). A colorless solid (97% ee); [a]2D1 K31.1 (c
0.68, CHCl3); FT-IR (neat) 3448, 2950, 1716, 1441, 1277,
8.4 Hz, 2H), 6.88 (d, JZ8.1 Hz, 2H), 6.58 (t, JZ0.8 Hz,
1H), 6.26 (dd, JZ1.5, 0.6 Hz, 1H), 5.75 (hept, JZ6.1 Hz,
1H), 5.58 (d, JZ4.2 Hz, 1H), 3.80 (s, 3H), 2.41 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 162.6, 159.7, 140.1, 132.7, 129.1,
1151, 1043, 762 cmK1 1H NMR (300 MHz, CDCl3) d
;
7.86–7.81 (m, 4H), 7.49–7.45 (m, 3H), 6.38 (t, JZ0.9 Hz,
1H), 5.88 (t, JZ0.9 Hz, 1H), 5.74 (d, JZ5.1 Hz, 1H), 3.72
(s, 3H), 3.14 (d, JZ5.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 166.9, 141.9, 138.6, 133.3, 133.1, 128.3, 128.2,
127.7, 126.4, 126.2, 126.1, 125.6, 124.6, 73.4, 73.3, 52.1;
HRMS (EI) calcd for C15H14O3 (MC): 242.0943, found
242.0947. HPLC conditions: Daicel Chiralcel OJ, 2-pro-
panol/hexane 1:5 (1.0 mL/min), tRZ52.8 min (R) and
62.9 min (S).
1
128.2, 120.4, (q, JC,FZ280.1 Hz), 114.1, 72.1, 66.6 (hept,
2JC,FZ34.7 Hz), 55.3; HRMS (EI) calcd for C14H12F6O4
(MC): 358.0632, found 358.0639.
4.4.9. Methyl (R)-3-hydroxy-3-(4-methoxyphenyl)-2-
methylenepropanoate (methyl ester obtained from
14d). A pale yellow oil (95% ee); [a]2D2 K112.2 (c 0.54,
CHCl3); FT-IR (neat) 3512, 2951, 2841, 1712, 1506, 1444,
1
1242, 1144, 1026 cmK1; H NMR (300 MHz, CDCl3) d
7.29 (d, JZ9.0 Hz, 2H), 6.87 (d, JZ9.0 Hz, 2H), 6.32 (s,
1H), 5.86 (s, 1H), 5.52 (d, JZ5.1 Hz, 1H), 3.79 (s, 3H), 3.71
4.4.14. 1,1,1,3,3,3-Hexafluoropropan-2-yl (R)-3-hydroxy-
2-methylene-5-phenylpentanoate (14g). A colorless oil

388
A. Nakano et al. / Tetrahedron 62 (2006) 381–389
(98% ee); [a]2D2 C11.5 (c 1.41, CHCl3); FT-IR (neat) 3427,
oil (99% ee); [a]2D4 K8.1 (c 0.93, CHCl3); FT-IR (neat)
3448, 2929, 2852, 1718, 1628, 1440, 1157 cmK1; 1H NMR
(300 MHz, CDCl3) d 6.25 (d, JZ1.2 Hz, 1H), 5.73 (d, JZ
1.2 Hz, 1H), 4.06 (dd, JZ7.8, 7.8 Hz, 1H), 3.78 (s, 3H),
2.56 (d, JZ8.4 Hz, 1H), 1.97 (m, 1H), 1.79–1.50 (m, 5H),
1.29–0.91 (m, 5H); 13C NMR (75 MHz, CDCl3) d 167.2,
141.1, 126.2, 77.1, 51.9, 42.4, 30.0, 28.3, 26.4, 26.1, 26.0;
HRMS (EI) calcd for C11H18O5 (MC): 198.1256, found
198.1264. HPLC conditions: Daicel Chiralcel OD, 2-pro-
panol/hexane 1:50 (0.5 mL/min), tRZ21 min (R) and
26 min (S).
1
2962, 1751, 1387, 1232, 1120 cmK1; H NMR (300 MHz,
CDCl3) d 7.32–7.24 (m, 2H), 7.22–7.17 (m, 3H), 6.49 (s,
1H), 6.15 (s, 1H), 5.85 (hept, JZ6.0 Hz, 1H), 4.52 (dd, JZ
3.6, 4.2 Hz, 1H), 2.85–2.66 (m, 2H), 2.24 (br s, 1H), 2.08–
1.89 (m, 2H); 13C NMR (75 MHz, CDCl3) d 162.7, 142.2,
1
140.6, 129.2, 128.6, 128.5, 126.2, 120.5 (q, JC,F
282.3 Hz), 70.1, 66.7 (hept, JC,FZ34.7 Hz), 37.8, 32.0;
HRMS (EI) calcd for C15H14F6O3 (MC): 356.0847, found
356.0863.
Z
2
4.4.15. (6R)-2,6-Diphenethyl-5-methylene-1,3-dioxan-4-
one (15g) (70:30 cis/trans-mixture). A colorless oil;
FT-IR (neat) 3028, 2931, 1730, 1446, 1379, 1234, 1161,
4.4.20. 1,1,1-Trifluoroethyl 3-hydroxy-2-methylene-3-(4-
nitrophenyl)propanoate (17b). A pale yellow oil; FT-IR
(neat) 3523, 1734, 1522, 1348, 1282, 1173, 1055 cmK1; 1H
NMR (300 MHz, CDCl3) d 8.22 (d, JZ9.0 Hz, 2H), 7.58 (d,
JZ9.0 Hz, 2H), 6.55 (d, JZ0.6 Hz, 1H), 6.10 (s, 1H), 5.96
(d, JZ5.1 Hz, 1H), 4.50 (dq, JZ1.5, 8.1 Hz, 2H), 2.94 (dd,
1
1030 cmK1; H NMR (300 MHz, CDCl3) d 7.33–7.28 (m,
4H), 7.23–7.17 (m, 10H), 6.49–6.47 (m, 1H), 5.58 (d, JZ
2.1 Hz, 0.7H), 5.54 (d, JZ2.1 Hz, 0.3H), 5.45 (t, JZ5.1 Hz,
0.3H), 5.27 (d, JZ5.1 Hz, 0.7H), 4.71–4.67 (m, 0.3H),
4.51–4.46 (m, 0.7H), 2.93–2.65 (m, 4H), 2.22–1.90 (m, 4H);
13C NMR (75 MHz, CDCl3) d 163.7, 140.9, 140.6, 140.5,
136.8, 136.0, 128.7, 128.6, 128.5, 128.4, 126.8, 126.4,
126.2, 125.7, 101.1, 96.4, 77.5, 77.1, 76.7, 76.5, 74.2, 36.6,
35.8, 35.6, 35.3, 31.4, 30.8, 29.4, 29.3; HRMS (EI) calcd for
C21H22O3 (MC): 322.1569, found 322.1567.
JZ4.5, 4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 164.0,
1
148.2, 147.5, 140.1, 129.0, 127.6, 123.7, 122.7 (q, JC,F
Z
275.5 Hz), 71.9, 60.7 (q, 2JC,FZ36.5 Hz); HRMS calcd for
C12H10NO5F3 (MC): 305.0511, found 305.0529.
4.4.21. 1,1,1,2,2-Pentafluoropropyl 3-hydroxy-2-methyl-
ene-3-(4-nitrophenyl)propanoate (17c). A pale yellow oil;
FT-IR (neat) 3523, 1734, 1603, 1523, 1348, 1271, 1207,
4.4.16. Methyl (R)-3-hydroxy-2-methylene-5-phenyl-
pentanoate (methyl ester obtained from 14g). A colorless
oil (98% ee); [a]2D2 C28.1 (c 0.83, CHCl3); FT-IR (neat)
3487, 3024, 2947, 1720, 1631, 1444, 1149, 1074 cmK1; 1H
NMR (300 MHz, CDCl3) d 7.31–7.15 (m, 5H), 6.24–6.23
(m, 1H), 5.81 (t, JZ0.9 Hz, 1H), 4.45–4.39 (m, 1H), 3.76 (s,
3H), 2.87–2.64 (m, 3H), 2.01–1.93 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 167.1, 142.2, 141.7, 128.5, 128.5,
126.0, 125.4, 71.2, 52.0, 37.7, 32.1; HRMS (EI) calcd for
C15H16O3 (MC): 220.1099, found 220.1123. HPLC con-
ditions: Daicel Chiralcel OD–H, 2-propanol/hexane 1:5
(0.5 mL/min), tRZ13.0 min (R), tRZ15.8 min (S).
1
1149, 1051 cmK1; H NMR (300 MHz, CDCl3) d 8.22 (d,
JZ9.0 Hz, 2H), 7.58 (d, JZ9.0 Hz, 2H), 6.53 (s, 1H), 6.10
(s, 1H), 5.69 (d, JZ5.4 Hz, 1H), 4.58 (dt, JZ0.9, 12.6 Hz,
2H), 2.94 (dd, JZ5.4, 2.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 164.0, 148.2, 147.6, 140.0, 129.0, 127.6, 123.7,
1
118.4 (dt, 2 JC,FZ34.0 Hz, JC,FZ283 Hz), 111.9 (dt,
2
2
1JC,FZ254.0 Hz, JC,FZ38.0 Hz), 71.9, 59.6 (t, JC,F
Z
28.5 Hz); HRMS calcd for C13H10NO5F5 (MC): 355.0479,
found 355.0490.
4.4.22. 1,1,1,2,2,3,3-Heptafluorobutyl 3-hydroxy-2-
methylene-3-(4-nitrophenyl)propanoate (17d). A pale
yellow oil; FT-IR (neat) 3529, 1736, 1604, 1525, 1404,
4.4.17. 1,1,1,3,3,3-Hexafluoropropan-2-yl (R)-3-cyclo-
hexyl-3-hydroxy-2-methylenepropanoate (14h). A color-
less oil (99% ee); [a]2D4 K2.6 (c 1.00, CHCl3); FT-IR (neat)
1
1350, 1236, 1136, 1059, 1020 cmK1; H NMR (300 MHz,
CDCl3) d 8.22 (d, JZ9.0 Hz, 2H), 7.58 (d, JZ9.0 Hz, 2H),
6.53 (s, 1H), 6.10 (d, JZ0.9 Hz, 1H), 5.69 (d, JZ5.4 Hz,
1H), 4.62 (td, JZ13.2, 1.5 Hz, 2H), 2.94 (d, JZ6.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 164.0, 148.1, 147.7, 140.1,
3419, 2935, 2857, 1749, 1647, 1387, 1365, 1294, 1124 cmK1
;
1H NMR (300 MHz, CDCl3) d 6.50 (s, 1H), 6.07 (s, 1H),
5.84 (hept, JZ6.0 Hz, 1H), 4.26 (dd, JZ6.3, 6.3 Hz, 1H),
2.04 (d, JZ6.9 Hz, 1H), 1.92–1.50 (m, 6H), 1.32–0.94 (m,
5H); 13C NMR (75 MHz, CDCl3) d 162.9, 139.6, 129.9,
2
1
129.1, 127.6, 123.8, 117.5 (dt, JC,FZ33.0 Hz, JC,F
Z
1
2
285.7 Hz), 113.8 (dd, JC,FZ254.9 Hz, JC,FZ30.7 Hz),
1
2
2
120.5 (q, JC,FZ281.2 Hz), 75.8, 66.7 (hept, JC,F
35.3 Hz), 42.7, 29.8, 27.8, 26.4, 26.2, 26.0; HRMS (EI)
Z
108.6 (m), 72.1, 59.8 (t, JC,FZ27.3 Hz); HRMS calcd for
C14H10NO5F7 (MC): 405.0447, found 405.0454.
calcd for C13H16O5F6 (MC): 334.1003, found 334.0993.
4.4.18. (2S,6S)-dicyclohexyl-5-methylene-1,3-dioxan-4-
one (15h) (90:10 cis/trans-mixture). A colorless oil;
Acknowledgements
FT-IR (neat) 2929, 2854, 1739, 1631, 1201 cmK1 1H
;
This work was partly supported by a Grant-in-Aid for
Scientific Reseach from Ministry of Education, Culture,
Sports, Science and Technology, Japan.
NMR (300 MHz, CDCl3) d 6.40 (d, JZ2.4 Hz, 1H), 5.53 (d,
JZ1.8 Hz, 1H), 4.98 (d, JZ5.1 Hz, 1H), 4.43 (m, 1H),
1.88–1.62 (m, 12H), 1.38–1.18 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 165.7, 136.7, 125.0, 103.6, 81.5, 43.6,
41.7, 29.0, 26.6, 26.4, 26.4, 26.3, 26.3, 26.2, 26.0, 25.6,
26.5; HRMS (EI) calcd for C17H26O3 (MC): 278.1882,
found 278.1880.
References and notes
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