Asymmetric reductive aldol-type reaction with carbonyl compounds using dialkyl tartrate as a chiral ligand

Article abstract of DOI:10.1248/cpb.c14-00223

An asymmetric reductive aldol-type reaction of α,β-unsaturated esters with carbonyl compounds using Rh catalyst and Et2Zn was investigated. A chiral zinc complex from α,β-unsaturated ester was easily generated as the key intermediate from Et2Zn and Wilkin

Full text of DOI:10.1248/cpb.c14-00223

9
56
Regular Article
Chem. Pharm. Bull. 62(10) 956–961 (2014)
Vol. 62, No. 10
Asymmetric Reductive Aldol-Type Reaction with Carbonyl Compounds
Using Dialkyl Tartrate as a Chiral Ligand
Motoyuki Isoda, Kazuyuki Sato, Yoriko Tokura, Atsushi Tarui, Masaaki Omote, and
Akira Ando*
Faculty of Pharmaceutical Sciences, Setsunan University; 45–1 Nagaotoge-cho, Hirakata, Osaka 573–0101, Japan.
Received March 11, 2014; accepted July 5, 2014
An asymmetric reductive aldol-type reaction of α,β-unsaturated esters with carbonyl compounds using
Rh catalyst and Et Zn was investigated. A chiral zinc complex from α,β-unsaturated ester was easily gener-
2
ated as the key intermediate from Et Zn and Wilkinson’s catalyst with diisopropyl L-(ꢀ)-tartrate to give a
2
variety of enantioenriched β-hydroxy esters. The reaction was also applied to the intramolecular reductive
aldol cyclization.
Key words asymmetric reaction; reductive aldol-type reaction; aldol-type cyclization; RhCl(PPh ) ; biszinc–
3
3
tartrate complex
Enantiomerically pure β-hydroxy esters are frequently RhCl(PPh ) and Et Zn (Reformatsky–Honda reaction condi-
3
3
2
2
0,21)
found in bioactive natural products, for example, erythromy- tion)
(Chart 1). We herein report an asymmetric reductive
cin. Furthermore, β-hydroxy esters are useful key intermedi- aldol-type reaction with various aldehydes and ketones.
1)
14,22,23)
ate to synthesize versatile building blocks of natural products,
2
)
3)
for example, (+)-tedanolide and (+)-discodermolide (Fig. 1). Results and Discussion
Reductive aldol reaction is understood as a sequential reac-
First, we conducted a series of reactions to determine the
tion involving conjugate reduction of α,β-unsaturated esters most effective chiral ligand for the asymmetric reductive
and subsequent aldol reaction of the ester enolate with various aldol-type reaction using benzaldehyde (1a) and methyl acry-
4
,5)
carbonyl compounds using metals such as rhodium,
co- late (2a) (Table 1). 1a and 2a were treated with Et Zn (3.6eq.)
2
6
–10)
11,12)
balt,
and copper
catalysts. The reductive aldol reaction in the presence of RhCl(PPh ) and a ligand to give β-hydroxy
3 3
is one of the most useful tools in organic chemistry because esters (3a) (method A). Using amino alcohol ligands, the de-
it provides direct access to synthetic β-hydroxy esters. Fur- sired product 3a was obtained in moderate to good yield, but
thermore, the asymmetric variants of ligand-based, auxiliary- poor enantioselectivities were observed, as shown in entries
based, and catalyst-based reactions have proven to be reliable 1–3. Use of diamine, diamide or diol ligands did not give
13–17)
routes to homochiral aldol adducts.
On the other hand, the product at all (entries 4–8). However, use of diisopropyl
Honda and his co-workers reported a Rh catalyzed Refor- L-(+)-tartrate L9 gave the desired reductive aldol-type prod-
18)
matsky-type reaction. Based on their report, we reported uct in good yield with moderate enantioselectivity for the
19)
Reformatsky–Honda reaction using BrCF COOEt. Further- anti-diastereomer (entry 9). Furthermore, once a chiral zinc
2
more, we recetnly reported a reductive aldol-type reaction of complex was formed from Et Zn with a ligand then used it
2
α,β-unsaturated esters with aldehydes and ketones to give the for the reaction, the enantioselectivity was slightly improved
corresponding products in good to excellent yields by using (entry 10, method B). On the other hand, using 2.4 equivalents
of Et Zn did not give the product at all (entry 11). A further
2
four tartrates L10–13 were also investigated but these did not
improve the enantioselectivity and were difficult to separate
from the product (entries 12–15). The reaction conditions were
found to be optimal using L9 (Table 1, entry 10).
The scope and limitations of the reaction were examined
Chart 1. Rh-Catalyzed Reductive Aldol-Type Reaction with Various with various carbonyl compounds, and the results are summa-
Carbonyl Compounds
rized in Table 2. The reactions proceeded smoothly and gave
Fig. 1. Some Natural Products That Synthesized from β-Hydroxy Esters
The authors declare no conflict of interest.
*
To whom correspondence should be addressed. e-mail: aando@pharm.setsunan.ac.jp
© 2014 The Pharmaceutical Society of Japan

October 2014
957
Table 1. Optimization of Reaction Conditions
c)
d)
Yield (%)
e.e. (%)
a,b)
Entry
Chiral ligand
Et Zn (X eq.)
Condition
Time (h)
2
syn-3a
anti-3a
syn-3a
anti-3a
1
2
3
4
5
6
7
8
9
L1
L2
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
2.4
3.6
3.6
3.6
3.6
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method B
Method B
Method B
Method B
Method B
Method B
1
2
3
5
3
3
1
1
1
1
1
5
3
3
1
32
35
ND
53
0
0
ND
3
L3
32
62
4
6
L4
ND
ND
ND
ND
ND
38
ND
ND
ND
ND
ND
46
—
—
—
—
—
7
—
—
—
—
—
50
64
—
—
−3
30
53
L5
L6
L7
L8
L9
1
1
1
1
1
1
0
1
2
3
4
5
L9
40
55
0
L9
ND
ND
33
ND
ND
33
—
—
8
L10
L11
L12
L13
42
21
−1
−28
50
43
a) Method A: to a solution of RhCl(PPh ) (2mol%) in CH Cl was added ligand (1.2eq.), benzaldehyde (1; 1eq.) and α,β-unsaturated ester (2; 1.2eq.) at 0°C. Then Et Zn
3
3
2
2
2
(3.6eq.) was slowly added, and stirred for the time.
b) Method B: to a solution of RhCl(PPh ) (2mol%) in CH Cl was added ligand (1.2eq.), and Et Zn (1.2eq.) at 0°C and stirred for 15min. Benzaldehyde (1; 1eq.) and α,β-
3
3
2
2
2
unsaturated ester (2; 1.2eq.) was added to the mixture, and then Et Zn (2.4eq. or 1.2eq.) was slowly added and stirred for the time.
2
c) Isolated yield. d) Detected by chiral HPLC.
the desired products in good to excellent yields in all cases, dride complex 7 via the elimination of ethylene from an ethyl
although they showed low diastereoselectivity. In the reaction rhodium complex 6. 1,4-Reduction of α,β-unsaturated ester 1
with aromatic aldehydes, the anti-form products formed in by 7 to form rhodium enolate 8 is followed by transmetala-
moderate enantioselectivities (Table 2, entries 1–6). Electron- tion with a chiral zinc–tartrate complex 9 to give a chiral zinc
withdrawing groups decreased the enantioselectivity with intermediate (Int A*), which then reacts with the carbonyl
the nonasymmetric background reaction being predominant compound to give the corresponding β-hydroxy esters 3 with
(entries 2–4). It is interesting that the reaction gave the cor- enantioselectivity. Inomata and coworkers reported reactions
responding products in good yields even if ketones were used that used a combination of organozinc reagent and tartrate,
as substrates (entries 7–9). Cyclohexanone and acetophenone and they proposed the generation of a biszinc–ligand com-
2
7–29)
offered moderate enantioselectivities, while benzophenone plex.
entry 8) did not.
been generated in situ in our experiment, as shown in Fig. 3,
We also examined an intramolecular reductive aldol cycliza- and would have been involved in generation of the chiral key
A similar biszinc–tartrate complex 9 would have
(
2
4)
tion to improve diastereoselectivity. Using a model substrate intermediate (Int A*). In our method, the fact that the reaction
, the reaction proceeded smoothly to give the desired prod- needed more than three molar equivalents of Et Zn strongly
4
2
uct in moderate yield with slight enantioselectivity, although supports this mechanism.
diastereoselectivity was not improved (Chart 2). However, this
In conclusion, we investigated an asymmetric reductive
result confirmed that the approach would provide a promising aldol-type reaction with various aldehydes and ketones under
route to such a cyclic compound, because a number of studies Reformatsky–Honda reaction conditions. The reaction gave
have reported on the enantioselective reductive aldol cycliza- the corresponding products in good to excellent yields with
13,25,26)
tion.
moderate enantioselectivities. This result is significant in that
On the basis of previous results and various examinations of we were able to achieve the enantioselective intramolecular
2
0,21)
reaction conditions,
we proposed the following mechanism reductive aldol cyclization. We are currently examining ways
(
Fig. 2). RhCl(PPh ) reacted with Et Zn to give a rhodium hy- to further improve the enantioselectivity of the reductive aldol
3
3
2

9
58
Vol. 62, No. 10
Table 2. Scope and Limitations of Asymmetric Reductive Aldol-Type Reaction
a)
b)
Yield (%)
e.e. (%)
Entry
Substrate 1
Time (h)
syn-3
anti-3
syn-3
anti-3
1
2
3
4
5
6
X=H
X=CF3
X=COOMe
X=Cl
X=OMe
X=Me
3a
3b
3c
3d
3e
3f
1
3
7
3
1
1
40
36
39
31
40
39
55
48
52
42
57
54
0
4
7
5
6
6
64
34
38
45
56
51
7
8
9
3g
3h
3i
1
5
1
78
61
17
56
7
65
14
40
a) Isolated yield. b) Detected by chiral HPLC.
Chart 2. Intramolecular Reductive Aldol Cyclization
Fig. 2. Proposed Reaction Mechanism
cyclization reaction.
ppm from tetramethylsilane (TMS) as an internal standard
at 0ppm. Chemical shifts of F-NMR are reported in ppm
19
Experimental
from benzotrifluoride (BTF) as an internal standard at 0ppm.
General Information H-NMR and C-NMR spectra All data are reported as follows: chemical shifts, relative in-
were recorded on JNM-GX400 spectrometer. F-NMR spec- tegration value, multiplicity (s=singlet, d=doublet, t=triplet,
tra were recorded on Hitachi FT-NMR R-90H spectrometer. q=quartet, br=broad, m=multiplet), coupling constants (Hz).
Chemical shifts of H-NMR and C-NMR are reported in Mass spectra were obtained on JEOL JMS-700T spectrometer.
1
13
19
1
13

October 2014
959
Fig. 3. Biszinc–Tartrate Complex and the Model for Stereochemical Outcome
2
2
IR spectra were recorded on JASCO FT/IR-410 spectropho- [α] −1.01 (c=0.2, CHCl ); HPLC: Chiralcel OD-H hexane/i-
D
3
tometer. Melting points were measured on Yanagimoto micro PrOH (95:5, v/v), flow 1mL/min, UV 220nm, tminor=9.21min
melting point apparatus MP-S3 without correction. Chiral and tmajor=10.71 min.
HPLC analysis was performed on a Shimadzu analytical
HPLC system with commercial Chiralcel columns (made in
(anti-(2R,3S/2S,3R)-3a) A colorless solid; mp 50.5–51.5°C;
1
H-NMR (400MHz, CDCl ) δ: 1.01 (3H, d, J=7.2Hz), 2.82
3
Daicel Chemical Ind., Ltd.). Peak areas were calculated on (1H, dq, J=8.4, 7.2Hz), 2.93 (1H, d, J=4.2Hz), 3.73 (3H, s),
13
Hitachi D-2500 Chromato-Integrator. Optical rotations were 4.75 (1H, dd, J=8.4, 4.2Hz), 7.28–7.39 (5H, m); C-NMR
recorded on a JASCO P1020.
(100MHz, CDCl ) δ: 14.49, 47.08, 51.90, 76.40, 126.6, 128.0,
3
+
Materials Dichloromethane (CH Cl ) was distilled over 128.4, 141.4, 176.1; MS m/z: 194 (M ). HR-MS Calcd for
2
2
+
−1
phosphorus pentoxide just before use. All commercially avail- C H O : 194.094 (M ), Found: 194.094; IR (KBr) cm :
11
14
3
2
2
able liquid aldehyde or ketone were distilled just before use. 3457, 1711; [α]D −3.25 (c=0.2, CHCl ); HPLC: Chiralcel
3
Other commercially available reagents were used without OD-H hexane/i-PrOH (95:5, v/v), flow 1mL/min, UV 220nm,
further purification. All experiments were carried out under tmajor=12.6min and tminor=20.0min.
argon atmosphere in flame-dried glassware using standard
inert techniques for introducing reagents and solvents unless propanoate (3b)
Methyl 3-Hydroxy-2-methyl-3-{4′-(trifluoromethyl)phenyl}-
2
0,21)
Each diastereomers of the title product
otherwise noted.
(3b) were purified by column chromatography (AcOEt:hex-
Typical Procedure for Asymmetric Reductive Aldol-Type ane=1:4) and were obtained in 36% (47mg; syn form) and
Reaction Method A: To a solution of RhCl(PPh ) (2mol%) 48% yield (62mg; anti form), respectively.
3
3
1
in CH Cl (1.25mL) was added diisopropyl L-(+)-tartrate
0.6mmol), benzaldehyde (1; 0.5mmol) and methyl acrylate (2; CDCl ) δ: 1.10 (3H, d, J=7.6Hz), 2.79 (1H, qd, J=7.6, 3.6Hz),
.5mmol) at 0°C. Then Et Zn (1.8mmol) was slowly added, 3.21 (1H, d, J=3.2Hz), 3.71 (3H, s), 5.19 (1H, brs), 7.47 (2H,
and stirred for 1h. The mixture was quenched with sat. NH Cl d, J=7.6Hz), 7.61 (2H, d, J=7.6Hz); C-NMR (100MHz,
(syn-(2R,3R/2S,3S)-3b) A colorless oil; H-NMR (400MHz,
2
2
(
0
3
2
13
4
and extracted with AcOEt. The AcOEt layer was washed with CDCl ) δ: 10.31, 45.98, 52.05, 72.79, 124.1 (q, J=270.6Hz),
3
sat. NaCl and dried over MgSO . The solvent was removed in 125.2 (m), 126.2, 129.6 (q, J=32.3Hz), 145.2 (m), 176.0;
4
1
9
+
vacuo, and the residue was purified by column chromatogra-
phy. After then, enantiomeric ratios were determined using HR-MS Calcd for C H O F : 262.082 (M ), Found: 262.083;
F-NMR (90MHz, CDCl ) δ: 0.24 (3F, s); MS m/z: 262 (M ).
3
+
12
13
3 3
−1
22
chiral HPLC analysis.
IR (neat) cm : 3480, 1718, 1327; [α] −0.70 (c=1.0, CHCl3);
HPLC: Chiralpak AD-H hexane/i-PrOH (90:10, v/v), flow
D
Method B: To a solution of RhCl(PPh ) (2mol%) in CH Cl
3
3
2
2
(
1.25mL) was added diisopropyl L-(+)-tartrate (0.6mmol), and 1mL/min, UV 220nm, tminor=5.85min and tmajor=6.45 min.
Et Zn (0.6mmol) at 0°C and stirred for 15min. Benzaldehyde (anti-(2R,3S/2S,3R)-3b) A colorless solid; mp 79.0–80.0°C;
2
1
(1; 0.5mmol) and methyl acrylate (2; 0.5mmol) was added to
H-NMR (400MHz, CDCl ) δ: 1.06 (3H, d, J=7.2Hz), 2.82
3
the mixture, and then Et Zn (1.6mmol) was slowly added and (1H, dq, J=8.0, 7.2Hz), 3.22 (1H, d, J=4.8Hz), 3.73 (3H,
2
stirred for 1h. The mixture was quenched with sat. NH Cl s), 4.82 (1H, dd, J=8.0, 4.8Hz), 7.47 (2H, d, J=8.4Hz), 7.62
4
1
3
and extracted with AcOEt. The AcOEt layer was washed with (2H, d, J=8.4Hz); C-NMR (100MHz, CDCl ) δ: 14.44,
sat. NaCl and dried over MgSO . The solvent was removed in 46.81, 52.03, 75.63, 124.0 (q, J=270.8Hz), 125.4 (m), 126.9,
vacuo, and the residue was purified by column chromatogra- 130.2 (q, J=32.3Hz), 145.4 (m), 175.8; F-NMR (90MHz,
phy. After then, enantiomeric ratios were determined using CDCl ) δ: −0.17 (3F, s); MS m/z: 262 (M ). HR-MS Calcd for
3
4
1
9
+
3
+
−1
chiral HPLC analysis.
C H O F : 262.082 (M ), Found: 262.083; IR (KBr) cm :
12 13 3 3
2
0,21)
22
Methyl 3-Hydroxy-2-methyl-3-phenylpropanoate (3a)
3451, 1715, 1330; [α]D −13.6 (c=1.0, CHCl ); HPLC: Chiral-
3
Each diastereomers of the title product (3a) were purified by pak AD-H hexane/i-PrOH (95:5, v/v), flow 1mL/min, UV
column chromatography (AcOEt:hexane=2:3) and were ob- 220nm, tmajor=9.91min and tminor=11.67 min.
tained in 40% (39mg; syn form) and 55% yield (53mg; anti
Methyl 4-(1-Hydroxy-3-methoxy-2-methyl-3-oxopropyl)-
21)
form), respectively.
benzoate (3c)
Each diastereomers of the title product
1
(syn-(2R,3R/2S,3S)-3a) A colorless oil; H-NMR (400MHz, (3c) were purified by column chromatography (AcOEt:hex-
CDCl ) δ: 1.13 (3H, d, J=7.2Hz), 2.80 (1H, qd, J=7.2, 3.6Hz), ane=2:3) and were obtained in 39% (50mg; syn form) and
3
2
.92 (1H, brs), 3.68 (3H, s), 5.11 (1H, d, J=3.6Hz), 7.25–7.35 52% yield (65mg; anti form), respectively.
1
3
1
(5H, m); C-NMR (100MHz, CDCl ) δ: 10.68, 46.31, 51.86,
(syn-(2R,3R/2S,3S)-3c) A colorless oil; H-NMR (400MHz,
3
+
73.54, 125.9, 127.4, 128.2, 141.3, 176.1; MS m/z: 194 (M ). CDCl ) δ: 1.10 (3H, d, J=7.2Hz), 2.80 (1H, qd, J=7.2, 3.2Hz),
3
High resolution-mass spectrum (HR-MS) Calcd for C H O : 3.20 (1H, d, J=3.2Hz), 3.70 (3H, s), 3.91 (3H, s), 5.18 (1H,
1
1
14
3
+
−1
1
94.094 (M ), Found: 194.094; IR (neat) cm : 3478, 1731; t, J=3.2Hz), 7.42 (2H, d, J=8.4Hz), 8.02 (2H, d, J=8.4Hz);

9
60
Vol. 62, No. 10
1
3
C-NMR (100MHz, CDCl ) δ: 10.52, 46.13, 52.07, 52.07, (1H, dq, J=8.8, 7.6Hz), 2.88 (1H, d, J=4.0Hz), 3.08 (3H,
3
7
(
2
3.10, 125.8, 129.2, 129.5, 146.5, 166.8, 175.8; MS m/z: 252 s), 3.73 (3H, s), 4.70 (1H, dd, J=8.8, 4.0Hz), 6.88 (2H, d,
M ). HR-MS Calcd for C H O : 252.100 (M ), Found: J=8.8Hz), 7.25 (2H, d, J=8.8Hz); C-NMR (100MHz,
52.100; IR (neat) cm : 3496, 1723; [α] −0.59 (c=0.7, CDCl ) δ: 14.45, 47.18, 51.88, 55.23, 75.99, 113.8, 127.8,
+
+
13
13
16
5
−1
24
D
3
+
CHCl ); HPLC: Chiralpak AD-H hexane/i-PrOH (85:15, 133.6, 159.3, 176.2; MS m/z: 224 (M ). HR-MS Calcd for
v/v), flow 1mL/min, UV 220nm, tminor=8.07min and C H O : 224.105 (M ), Found: 224.105; IR (KBr) cm : 3456,
3
+
−1
12
16
4
2
2
tmajor=9.06 min.
anti-(2R,3S/2S,3R)-3c) A colorless solid; mp 97.0–98.5°C. hexane/i-PrOH (90:10, v/v), flow 1.25mL/min, UV 220nm,
H-NMR (400MHz, CDCl ) δ: 1.06 (3H, d, J=7.2Hz), 2.82 tminor=13.95min and tmajor=14.91 min.
1716; [α]D −24.4 (c=1.0, CHCl ); HPLC: Chiralpak AD-H
3
(
1
3
21)
(1H, dq, J=8.0, 7.2Hz), 3.16 (1H, d, J=4.8Hz), 3.72 (3H,
Methyl 3-Hydroxy-2-methyl-3-p-tolylpropanoate (3f)
s), 3.92 (3H, s), 4.82 (1H, dd, J=8.0, 4.8Hz), 7.42 (2H, d, Each diastereomers of the title product (3f) were purified by
13
J=8.0Hz), 8.03 (2H, d, J=8.0Hz); C-NMR (100MHz, column chromatography (AcOEt:hexane:toluene=1:2:2) and
CDCl ) δ: 14.46, 46.93, 51.99, 52.11, 75.86, 126.5, 129.7, were obtained in 39% (41mg; syn form) and 54% yield (56mg;
3
+
1
29.8, 146.6, 166.7, 175.7; MS m/z: 252 (M ). HR-MS Calcd anti form), respectively.
+
−1
1
for C H O : 252.100 (M ), Found: 252.100; IR (KBr) cm :
(syn-(2R,3R/2S,3S)-3f) A colorless oil; H-NMR (400MHz,
13
16
5
2
4
3
457, 1717, 1699; [α]D −15.7 (c=1.0, CHCl ); HPLC: Chiral- CDCl ) δ: 1.12 (3H, d, J=7.2Hz), 2.33 (3H, s), 2.77 (1H,
3
3
pak AD-H hexane/i-PrOH (85:15, v/v), flow 1mL/min, UV qd, J=7.2, 4.0Hz), 2.91 (1H, brs), 3.66 (3H, s), 5.05 (1H, d,
2
20nm, tminor=11.54min and tmajor=13.83 min.
J=4.0Hz), 7.14 (2H, d, J=7.6Hz), 7.22 (2H, d, J=7.6Hz);
13
Methyl 3-(4′-Chlorophenyl)-3-hydroxy-2-methylpropano-
C-NMR (100MHz, CDCl ) δ: 10.88, 21.10, 46.44, 51.83,
3
2
0,21)
+
ate (3d)
Each diastereomers of the title product (3d) 73.58, 125.8, 128.9, 137.0, 138.4, 176.1; MS m/z: 208 (M ).
+
were purified by column chromatography (AcOEt:hex- HR-MS Calcd for C H O : 208.109 (M ), Found: 208.110; IR
12
16
3
−1
23
D
ane=1:4) and were obtained in 31% (36mg; syn form) and (neat) cm : 3475, 1720; [α] −1.09 (c=1.0, CHCl ); HPLC:
3
42% yield (48mg; anti form), respectively.
Chiralcel OJ-H hexane/i-PrOH (90:10, v/v), flow 1mL/min,
1
(
syn-(2R,3R/2S,3S)-3d) A colorless oil; H-NMR (400MHz, UV 220nm, tminor=14.00min and tmajor=15.25 min.
CDCl ) δ: 1.10 (3H, d, J=7.2Hz), 2.74 (1H, qd, J=7.2, 3.8Hz),
(anti-(2R,3S/2S,3R)-3f) A colorless solid; mp 50.0–51.0°C;
3
1
3
.13 (1H, brs), 3.68 (3H, s), 5.07 (1H, d, J=3.8Hz), 7.26–7.32
H-NMR (400MHz, CDCl ) δ: 1.00 (3H, d, J=7.2Hz), 2.34
3
13
(
5
4H, m); C-NMR (100MHz, CDCl ) δ: 10.64, 46.20, (3H, s), 2.81 (1H, dq, J=8.4, 7.2Hz), 2.82 (1H, d, J=4.0Hz),
3
1.95, 72.90, 127.3, 128.3, 133.1, 139.8, 176.0; MS m/z: 228 3.73 (3H, s), 4.17 (1H, dd, J=8.4, 4.0Hz), 7.16 (2H, d,
+
+
13
(
(
1
M ). HR-MS Calcd for C H O Cl: 228.055 (M ), 229.059 J=8.8Hz), 7.23 (2H, J=8.8Hz); C-NMR (100MHz, CDCl3)
11 13 3
+
−1
M +1), Found: 228.055, 229.061; IR (neat) cm : 3478, 1730, δ: 14.45, 21.10, 47.09, 51.79, 76.21, 126.4, 129.0, 137.6, 138.4,
2
2
+
091; [α] −0.20 (c=1.0, CHCl ); HPLC: Chiralpak AD-H 176.0; MS m/z: 208 (M ). HR-MS Calcd for C H O : 208.109
D
3
12 16
3
+
−1
23
D
hexane/i-PrOH (90:10, v/v), flow 1mL/min, UV 220nm, (M ), Found: 208.111; IR (KBr) cm : 3481, 1724; [α]
tminor=7.21min and tmajor=8.01 min.
anti-(2R,3S/2S,3R)-3d) A colorless solid; mp 67.0–68.0°C; (90:10, v/v), flow 1mL/min, UV 220nm, tminor=12.07min and
H-NMR (400MHz, CDCl ) δ: 1.03 (3H, d, J=6.8Hz), 2.77 tmajor=14.25 min.
−25.7 (c=1.0, CHCl ); HPLC: Chiralcel OJ-H hexane/i-PrOH
3
(
1
3
(1H, qd, J=8.4, 6.8Hz), 3.08 (1H, d, J=4.8Hz), 3.73 (3H,
Methyl 3-Cyclohexyl-3-hydroxy-2-methylpropanoate
21)
s), 4.73 (1H, dd, J=8.4, 4.8Hz), 7.28 (2H, m), 7.33 (2H, m); (3g)
Title product (3g) was purified by column chroma-
13
C-NMR (100MHz, CDCl ) δ: 14.41, 46.93, 51.99, 75.61, tography (AcOEt:hexane=1:4) and obtained in 78% (73mg).
3
+
1
127.9, 128.6, 133.7, 140.0, 175.9; MS m/z: 228 (M ). HR-MS A colorless oil; H-NMR (400MHz, CDCl ) δ: 1.20 (3H, d,
3
+
+
Calcd for C H O Cl: 228.055 (M ), 229.059 (M +1), Found: J=7.2Hz), 1.20–1.30 (2H, m), 1.35–1.73 (8H, m), 2.52 (1H, q,
11
13
3
−1
22
D
13
228.055, 229.059; IR (KBr) cm : 3474, 1714, 827; [α]
J=7.2Hz), 2.94 (1H, brs), 3.71 (3H, s); C-NMR (100MHz,
−
17.7 (c=1.0, CHCl ); HPLC: Chiralcel OJ-H hexane/i-PrOH CDCl ) δ: 11.60, 21.67, 21.96, 25.74, 33.87, 37.01, 48.04, 51.55,
3
3
+
(
90:10, v/v), flow 1mL/min, UV 220nm, tminor=13.69 and 71.31, 177.1; MS m/z: 186 (M ). HR-MS Calcd for C H O :
tmajor=15.35 min.
10
18
3
22
D
+
−1
186.126 (M ), Found: 186.126; IR (neat) cm : 3475, 1720; [α]
Methyl 3-Hydroxy-3-(4′-methoxyphenyl)-2-methyl- −33.0 (c=1.1, CHCl ); HPLC: Chiralcel OJ-H hexane/i-PrOH
3
2
0,21)
propanoate (3e)
3e) were purified by column chromatography (AcOEt:hex- tminor=15.25 min.
ane=1:4) and were obtained in 40% (45mg; syn form) and Methyl 4,4-Diphenyl-3-hydroxy-2-methylbutanoate
7% yield (64mg; anti form), respectively. The crude solid of title product (3h) was washed
Each diastereomers of the title product (90:10, v/v), flow 1mL/min, UV 220nm, tmajor=14.00min and
(
2
0,21)
5
(3h)
syn-(2R,3R/2S,3S)-3e) A colorless oil; H-NMR (400MHz, with hexane and was obtained in 61% yield (82mg). A color-
1
(
1
CDCl ) δ: 1.14 (3H, d, J=7.2Hz), 2.76 (1H, qd, J=7.2, less solid; mp 127.0–128.5°C; H-NMR (400MHz, CDCl ) δ:
.6Hz), 2.87 (1H, brs), 3.65 (3H, s), 3.80 (3H, s), 5.01 (1H, 1.16 (3H, d, J=6.4Hz), 3.60 (3H, s), 3.66 (1H, q, J=6.4Hz),
3
3
4
d, J=4.6Hz), 6.87 (2H, d, J=8.8Hz), 7.25 (2H, d, J=8.8Hz); 4.67 (1H, s), 7.14–7.20 (2H, m), 7.25–7.30 (4H, m), 7.44–7.47
1
3
13
C-NMR (100MHz, CDCl ) δ: 11.10, 46.56, 51.79, 55.21, (2H, m), 7.53–7.55 (2H, m); C-NMR (100MHz, CDCl ) δ:
3
3
+
7
3.45, 113.6, 127.1, 133.5, 158.9, 176.0; MS m/z: 224 (M ). 12.94, 46.68, 51.97, 78.02, 125.2, 125.3, 126.5, 126.8, 128.0,
+
+
HR-MS Calcd for C H O : 224.105 (M ), Found: 224.105; 128.2, 143.9, 147.4, 177.8; MS m/z: 270 (M ). HR-MS Calcd
IR (neat) cm : 3491, 1731; [α] 0.94 (c=1.1, CHCl ); HPLC: for C H O : 270.126 (M ), Found: 270.125; IR (KBr) cm :
Chiralpak AD-H hexane/i-PrOH (90:10, v/v), flow 1mL/min, 3454, 1706; [α]D −1.88 (c=1.0, CHCl ); HPLC: Chiralcel OJ-H
12
16
4
−1
22
D
+
−1
3
17 18
3
2
4
3
UV 220nm, tminor=10.21min and tmajor=11.37 min.
anti-(2R,3S/2S,3R)-3e) A colorless solid; mp 55.0–56.0°C; tminor=15.00min and tmajor=17.77 min.
H-NMR (400MHz, CDCl ) δ: 0.98 (3H, d, J=7.6Hz), 2.79 Methyl 3-Hydroxy-2-methyl-3-phenylbutanoate (3i)
hexane/i-PrOH (50:50, v/v), flow 1mL/min, UV 220nm,
(
1
15)
3

October 2014
961
Each diastereomers of the title product (3i) were purified by 23.69, 24.09, 45.90, 83.38, 87.77, 125.8, 127.8, 128.4, 138.6,
+
column chromatography (AcOEt:hexane=1:9) and were ob- 176.4; MS m/z: 220 (M ). HR-MS Calcd for C H O : 220.110
13
16
3
+
−1
25
tained in 17% (18mg; syn form) and 65% yield (67mg; anti (M ), Found: 220.110; IR (KBr) cm : 3424, 1738; [α] −5.48
D
form), respectively.
syn-(2S,3R/2R,3S)-3i) A colorless solid; mp 52.5–54.0°C; v/v), flow 0.5mL/min, UV 220nm, tminor=20.0min and
H-NMR (400MHz, CDCl ) δ: 0.96 (3H, d, J=7.2Hz), 1.56 tmajor=20.9min.
(c=1.0, CHCl ); HPLC: Chiralcel OJ-H hexane/i-PrOH (90:10,
3
(
1
3
(
3H, s), 2.86 (1H, q, J=7.2Hz), 3.76 (3H, s), 3.81 (1H, brs),
7
.29–7.26 (1H, m), 7.33–7.36 (2H, m), 7.42–7.44 (2H, m); References
13
C-NMR (100MHz, CDCl ) δ: 12.85, 30.00, 49.33, 51.92,
1) McGuire J. M., Bunch R. L., Anderson R. C., Boaz H. E., Flynn
E. H., Powell H. M., Smith J. W., Antibiot. Chemother., 2, 281–283
(1952).
2) Dunetz J. R., Julian L. D., Newcom J. S., Roush W. R., J. Am.
Chem. Soc., 130, 16407–16416 (2008).
3
+
7
4.30, 124.8, 126.6, 128.0, 144.9, 177.5; MS m/z: 208 (M ).
+
HR-MS Calcd for C H O : 208.110 (M ), Found: 208.110;
IR (KBr) cm : 3494, 1707; [α] 2.52 (c=0.7, CHCl ); HPLC:
Chiralcel OJ-H hexane/i-PrOH (80:20, v/v), flow 1mL/min,
12
16
3
−1
22
D
3
3)
Smith A. B. III, Beauchamp T. J., LaMarche M. J., Kaufman M. D.,
UV 220nm, tminor=10.25min and tmajor=16.32 min.
Qiu Y., Arimoto H., Jones D. R., Kobayashi K., J. Am. Chem. Soc.,
1
(anti-(2S,3S/2R,3R)-3i)
A
colorless
oil;
H-NMR
1
22, 8654–8664 (2000).
(
3
400MHz, CDCl ) δ: 1.32 (3H, d, J=6.8Hz), 1.46 (3H, s),
3
4) Revis A., Hilty T. K., Tetrahedron Lett., 28, 4809–4812 (1987).
5) Willis M. C., Woodward R. L., J. Am. Chem. Soc., 127, 18012–
18013 (2005).
.02 (1H, q, J=6.8Hz), 3.46 (3H, s), 4.00 (3H, brs), 7.22 (1H,
13
m), 7.31 (2H, m), 7.42 (2H, m); C-NMR (100MHz, CDCl3)
δ: 12.56, 26.69, 48.60, 51.66, 74.65, 124.6, 126.7, 128.0, 147.4,
6) Isayama S., Mukaiyama T., Chem. Lett., 18, 2005–2008 (1989).
+
7
)
Baik T. G., Luis A. L., Wang L. C., Krische M. J., J. Am. Chem.
Soc., 123, 5112–5113 (2001).
1
77.0; MS m/z: 208 (M ). HR-MS Calcd for C H O : 208.110
12
16
3
+
−1
22
(
M ), Found: 208.110; IR (neat) cm : 3498, 1713; [α] −15.0
D
8
)
Wang L. C., Jang H.-Y., Roh Y., Lynch V., Schultz A. J., Wang X.,
Krische M. J., J. Am. Chem. Soc., 124, 9448–9453 (2002).
Lam H. W., Joensuu P. M., Murray G. J., Fordyce E. A. F., Prieto
O., Luebbers T., Org. Lett., 8, 3729–3732 (2006).
(c=1.1, CHCl ); HPLC: Chiralpak AD-H hexane/i-PrOH
3
(
97:3, v/v), flow 0.75mL/min, UV 220nm, tminor=11.34min
9)
and tmajor=12.11 min.
2
-Methyl-1-oxo-1-phenylpropan-2-yl Acrylate (4) To
a solution of 2-hydroxy-2-methylpropiophenone (5mmol) in
CH Cl (50mL) was added triethylamine (8mmol) and stirred
1
0) Lumby R. J. R., Joensuu P. M., Lam H. W., Org. Lett., 9, 4367–4370
(2007).
2
2
11) Ooi T., Doda K., Sakai D., Maruoka K., Tetrahedron Lett., 40,
for 30min. Then, acryloyl chloride (6mmol) was added to the
2133–2136 (1999).
mixture and stirred for 19h. The mixture was quenched with 12) Welle A., Díez-González S., Tinant B., Nolan S. P., Riant O., Org.
0% HCl and extracted with CH Cl . The CH Cl layer was
Lett., 8, 6059–6062 (2006).
3) Lam H. W., Joensuu P. M. A., Org. Lett., 7, 4225–4228 (2005).
1
2
2
2
2
1
1
washed with sat. NaCl and dried over MgSO4. The solvent
was removed in vacuo to give a yellow solid. The solid was
4) Nishiyama H., Shiomi T., Tsuchiya Y., Matsuda I., J. Am. Chem.
Soc., 127, 6972–6973 (2005).
15) Deschamp J., Chuzel O., Hannedouche J., Riant O., Angew. Chem.
Int. Ed., 45, 1292–1297 (2006).
purified by recrystallization by hexane and was obtained in
1
83% (901mg): A colorless solid; mp 91.0–92.0°C; H-NMR
(
1
1
400MHz, CDCl ) δ: 1.76 (6H, s), 5.80 (1H, dd, J=10.8,
3
1
6) Hashimoto T., Ito J., Nishiyama H., Tetrahedron, 64, 9408–9412
2008).
7) Shiomi T., Adachi T., Ito J., Nishiyama H., Org. Lett., 11, 1011–1014
(2009).
32.2, 134.2, 164.8, 198.5; MS m/z: 218 (M ). HR-MS Calcd 18) Kanai K., Wakabayashi H., Honda T., Org. Lett., 2, 2549–2551
.2Hz), 6.05 (1H, dd, J=17.4, 10.8Hz), 6.31 (1H, dd, J=17.4,
(
13
.2Hz), 7.38 (2H, m), 7.48 (1H, m), 8.02 (2H, m); C-NMR
1
(
1
100MHz, CDCl ) δ: 25.30, 84.31, 128.0, 128.2, 128.3, 131.4,
3
+
+
−1
for C H O : 218.094 (M ), Found: 218.094; IR (KBr) cm :
(2000).
13
14
3
1
9) Sato K., Tarui A., Kita T., Ishida Y., Tamura H., Omote M., Ando
A., Kumadaki I., Tetrahedron Lett., 45, 5735–5737 (2004).
0) Sato K., Isoda M., Ohata S., Morita S., Tarui A., Omote M., Kuma-
daki I., Ando A., Adv. Synth. Catal., 354, 510–514 (2012).
1) Sato K., Isoda M., Tokura Y., Omura K., Tarui A., Omote M., Ku-
madaki I., Ando A., Tetrahedron Lett., 54, 5913–5915 (2013).
2) Russell A. E., Fuller O. N., Taylor J. S., Aurriset P., Morken P. J.,
Org. Lett., 6, 2309–2312 (2004).
1709, 1679.
4
-Hydroxy-3,5,5-trimethyl-4-phenyldihydrofuran-2(3H)-
2
one (5) Each diastereomers of the title product (5) were pu-
rified by column chromatography (AcOEt:toluene=4:1) and
were obtained in 49% (54mg; (3R,4R/3S,4S) form) and 26%
yield (29mg; (3R,4S/3S,4R) form), respectively.
2
2
(
(3R,4R/3S,4S)-5)
A
colorless solid; mp 142–146°C;
1
H-NMR (400MHz, CDCl ) δ: 1.03 (3H, s), 1.23 (3H, d,
3
23) Zhao D., Oisaki K., Kanai M., Shibasaki M., J. Am. Chem. Soc.,
128, 14440–14441 (2006).
.36–7.48 (5H, m); C-NMR (100MHz, CDCl ) δ: 7.48, 24) Freiría M., Whitehead A. J., Tocher D. A., Motherwell W. B., Tetra-
J=7.2Hz), 1.56 (3H, s), 2.04 (1H, s), 3.60 (1H, q, J=7.2Hz),
13
7
3
2
0.08, 25.28, 42.18, 83.15, 88.20, 126.1, 128.6, 128.8, 138.2,
hedron, 60, 2673–2692 (2004).
5) Lipshutz B. H., Amorelli B., Unger J. B., J. Am. Chem. Soc., 130,
14378–14379 (2008).
6) Burns A. R., Solana González J., Lam H. W., Angew. Chem. Int.
Ed., 51, 10827–10831 (2012).
7) Ukaji Y., Shimizu Y., Kenmoku Y., Ahmed A., Inomata K., Chem.
Lett., 26, 59–60 (1997).
+
2
2
2
2
176.2; MS m/z: 220 (M ). HR-MS Calcd for C H O : 220.110
13
16
3
+
−1
24
D
(
M ), Found: 220.110; IR (KBr) cm : 3439, 1749; [α] −51.1
(
(
c=1.0, CHCl ); HPLC: Chiralpak AD-H hexane/i-PrOH
3
80:20, v/v), flow 1mL/min, UV 220nm, tminor=5.57min and
tmajor=6.23min.
((3R,4S/3S,4R)-5) A colorless solid; mp 178.0–182.0°C;
8) Wei W., Kobayashi M., Ukaji Y., Inomata K., Chem. Lett., 35,
1
H-NMR (400MHz, CDCl ) δ: 0.99 (3H, d, J=6.8Hz), 1.01
3
176–177 (2006).
(
3H, s), 1.60 (3H, s), 2.19 (1H, brs), 3.28 (1H, q, J=6.8Hz), 29) Konishi A., Wei W., Kobayashi M., Fujinami S., Ukaji Y., Inomata
13
7.29–7.40 (5H, m); C-NMR (100MHz, CDCl ) δ: 8.82,
K., Chem. Lett., 36, 44–45 (2007).
3