Lithium binaphtholate-catalyzed michael reaction of malonates with maleates and its application to the enantioselective synthesis of tricarboxylic acid derivatives

Article abstract of DOI:10.1248/cpb.c18-00993

The Michael reaction of malonates with maleates afforded the corresponding adducts in high yields with high enantioselectivities (up to 98% enantiomeric excess (ee)) by using dilithium 3,3′-dichlorobinaphtholate as a catalyst. The obtained Michael adducts

Full text of DOI:10.1248/cpb.c18-00993

4
52
Chem. Pharm. Bull. 67, 452–460 (2019)
Vol. 67, No. 5
Regular Article
Lithium Binaphtholate-Catalyzed Michael Reaction of Malonates
with Maleates and Its Application to the Enantioselective Synthesis of
Tricarboxylic Acid Derivatives
Midori Sakamoto, Tetsuya Kaneko, Yuya Orito, Yasushi Shimoda,* and Makoto Nakajima*
Graduate School of Pharmaceutical Sciences, Kumamoto University; 5–1 Oe-honmachi, Chuo-ku, Kumamoto 862–
0
973, Japan.
Received December 17, 2018; accepted January 11, 2019
The Michael reaction of malonates with maleates afforded the corresponding adducts in high yields with
high enantioselectivities (up to 98% enantiomeric excess (ee)) by using dilithium 3,3ꢀ-dichlorobinaphtholate
as a catalyst. The obtained Michael adducts could be converted to optically active tricarboxylic acid (TCA)
derivatives via the Krapcho reaction.
Key words Michael reaction; lithium binaphtholate; tricarboxylic acid ester; Krapcho reaction; stereoselec-
tivity
Introduction
lithium atom in the solvent (entry 2). Changing the solvent
The Michael reaction of various nucleophiles with acceptors to tert-butyl methyl ether (TBME) and lowering catalyst
is one of the most versatile tools for the carbon–carbon bond concentration (0.01mmol/mL) dramatically improved the
1–7)
formation reaction.
Enantioselective Michael reaction has enantioselectivity for 3aa to 90% enantiomeric excess (ee)
emerged as a key step in the construction of complex natu- (entry 5). Neither lowering the catalyst concentration below
ral products. Therefore, an elegant and economical Michael 0.01mmol/mL nor lowering the temperature (0°C) increased
reactions have still attracted considerable attentions. To date, the enantioselectivity of 3aa (entries 6 and 7). When cyclo-
numerous catalytic enantioselective Michael reactions have pentyl methyl ether (CPME) was used as an ether solvent, the
8
–20)
21,22)
been demonstrated. Generally, enones,
maleimides
same effect as TBME was obtained (entry 8). In the case of
and others have been used as Michael acceptors. In contrast, l,2-dimethoxyethane (DME) (entry 9), the Michael reaction
maleates have been used as acceptors to a lesser extent as did not proceed at all owing to its high chelation ability.
acceptors. The Michael reaction of malonates to maleates is
Next, we investigated the effect of the substitution on
a typical example of this conjugate addition, which has been the 3,3′-position of binaphthols in more detail. The catalyst
n
previously described even in an early volume of the famous 4b, prepared from (R)-3,3′-Br -BINOL and BuLi, afforded
2
2
3)
‘
Organic Syntheses.’ However, to the best of our knowledge, the Michael adduct in high yield with high enantioselec-
no reports are available on the enantioselective Michael reac- tivity (entry 10), whereas unsubstituted (R)-BINOL-Li (4c),
2
tions of malonates to maleates. Our group has reported enan- (R)-3,3′-Me -BINOL-Li (4d), and (R)-3,3′-Ph -BINOL-Li (4e)
2
2
2
2
2
4–33)
tioselective reactions catalyzed by metal binaphtholates.
were ineffective in this Michael reaction (entries 11–13). From
3
4–45)
Metal binaphtholates,
,2′-binaphthols (BINOLs) and metal bases, such as BuLi or increase catalytic activity.
Grignard reagents, act as Brønsted bases to promote asym- Next, the Michael reactions between various malonates and
which are easily prepared from these results, it is suggested that the electron deficiency might
n
2
metric reactions. Recently, we also reported the first example maleates were carried out under optimized reaction conditions
of the enantioselective Michael reaction of malonates to male- (Table 2). As for the Michael acceptors, reduced stereoselec-
4
6)
ates, affording tetracarboxylic acid esters as Michael ad- tivities were obtained with dimethyl maleate (2b) or dibenzyl
ducts in high yields with high enantioselectivities. Herein, we maleate (2c), or substituted dibenzyl maleates (2d and 2e)
describe the details of this reaction, including the extension of were found to be decreased (entries 2–4). These results indi-
substrates and the mechanism of lithium binaphtholate-cata- cate that the electronic and steric effects affect for the reaction
lyzed Michael reaction of maleates as acceptors. Furthermore, rate of this reaction. Di-n-propyl maleate (2f) reacted with
we demonstrate the transformation of obtained product to the malonate 1a to give the corresponding Michael adduct 3af,
tricarboxylic acid (TCA) derivatives, which are often found in albeit in low enantioselectivity, but diallyl maleate (2g) gave a
47,48)
biologically active compounds, through decarboxylation.
result similar to that of diethyl maleate (2a). Among the other
The initial experiment was started with the addition of Michael donors, no alkyl malonate performed better than
dibenzyl malonate (1a) to diethyl maleate (2a) in diethyl dibenzyl malonate (1a) (entries 9–11). As the general Michael
ether using lithium binaphtholate catalyst (4a), which was acceptors, the enantioselectivities of N-phenylmaleimide (2h)
n
prepared from (R)-3,3′-Cl -BINOL and BuLi. The reaction and chalcone (2i) were decreased (entries 12, 13). Interest-
2
49)
proceeded smoothly, resulting in the corresponding prod- ingly, fumarate 2j, the trans-isomer of maleate 2a, gave an
uct 3aa in high yield with moderate selectivity within 0.5h almost racemic product 3aa (entry 14), suggesting that the cis
(
Table 1, entry 1). Enantioselectivity decreased using toluene geometry of the C–C double bond of 2a allows both carbonyl
as a solvent, probably owing to the lack of coordination of groups to coordinate with lithium metals. A ketone with a cis
*
To whom correspondence should be addressed. e-mail: yshimoda@kumamoto-u.ac.jp; nakajima@gpo.kumamoto-u.ac.jp
2019 The Pharmaceutical Society of Japan
©

Vol. 67, No. 5 (2019)
Chem. Pharm. Bull.
453
Table 1. Optimization of Enantioselective Michael Reaction of Malonate 1a with Maleate 2a
a)
b)
c,d)
Entry
Solvent
c (mol/L) (%)
Cat.: X
Conditions
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
Et O
0.1
4a: Cl
4a: Cl
4a: Cl
4a: Cl
4a: Cl
4a: Cl
4a: Cl
4a: Cl
4a: Cl
4b: Br
4c: H
r.t., 0.5h
r.t., 0.5h
r.t., 4h
93
92
45 (R)
20 (R)
57 (R)
58 (R)
90 (R)
90 (R)
91 (R)
91 (R)
—
2
Toluene
THF
0.1
0.1
85
TBME
TBME
TBME
TBME
CPME
DME
0.1
r.t., 0.5h
r.t., 1h
94
0.01
0.003
0.1
94
r.t., 1h
92
0°C, 3h
r.t., 1h
88
0.01
0.01
0.01
0.01
0.01
0.01
87
r.t., 15h
r.t., 1h
N. R.
94
1
1
1
1
0
1
2
3
TBME
TBME
TBME
TBME
87 (R)
20 (R)
25 (R)
18 (R)
r.t., 24h
r.t., 24h
r.t., 3h
65
4d: Me
4e: Ph
99
79
a) Catalyst concentration. b) Isolated yield. c) Determined by HPLC. d) The absolute configuration was determined by the comparison to literature value and authentic
sample 3ca prepared from Michael adduct 3aa.
Table 2. Michael Reaction of Malonates with Various Acceptors
a)
b)
Entry
Donor
Acceptor
Conditions
Product
Yield (%)
ee (%)
2
3
c)
c)
1
2
3
4
1a: R = Bn
2a (R = Et)
r.t., 1h
r.t., 1h
r.t., 1h
r.t., 4h
50°C, 24h
r.t., 3h
r.t., 5h
r.t., 1h
r.t., 1h
r.t., 1h
r.t., 1h
r.t., 2h
r.t., 1h
r.t., 24h
50°C, 1h
3aa
3ab
3ac
3ad
3ae
3af
94
94
75
94
80
66
90
93
92
82
99
69
78
83
79
90 (R)
85 (R)
83
2
3
1a: R = Bn
2b (R = Me)
2
3
1a: R = Bn
2c (R = Bn)
2
3
1a: R = Bn
2d (R = PBB)
78
d)
2
3
5
1a: R = Bn
2e (R = PMB)
72
2
3
6
1a: R = Bn
2f (R = nPr)
74
d)
2
3
7
1a: R = Bn
2g (R = allyl)
3ag
3bb
3ba
3ca
3da
3ah
3ai
91
2
3
e)
c)
8
9
1b: R = Me
2b (R = Me)
85 (R)
77
2
3
1b: R = Me
2a (R = Et)
2
3
10
11
12
13
14
15
1c: R = Et
2a (R = Et)
88 (R)
55
2
3
1d: R = tBu
2a (R = Et)
2
1a: R = Bn
2h
18
2
1a: R = Bn
2i
20
2
1a: R = Bn
2j
3aa
3ak
−8
4
2
1a: R = Bn
2k
a) Isolated yield. b) Determined by HPLC. c) The absolute configuration was determined by the comparison to literature value and authentic sample 3ca prepared from each
n
Michael adduct. d) (R)-3,3′-Cl -BINOL (20mol%), BuLi (40mol%). e) The absolute configuration was determined to be R by the comparison with the literature values of the
2
8)
HPLC retention time [CHIRALPAK AD-H, hexane–2-PrOH (9:1), 0.5mL/min; 23.4min (S), 24.32min (R)].
5
0)
geometry (2k) yielded very low selectivity (entry 15).
ga, ha, ic, ja, and kc with a sterically congested carbons in
Introduction of an additional substituent, such as a methyl, good yields with high enantioselectivities (entries 1–8), al-
ethyl, benzyl, isopropyl, and halogen groups on the 2-position though 2-isopropyl malonates (1h and 1i) required 20mol%
of malonates afforded adducts containing quaternary carbon catalyst and heating to 50°C to achieve a smooth reaction.
(
Table 3).
This Michael reaction is not limited to 2-alkylmalonates. In
2
-Alkyl malonate donors prepared the adducts 5ea, fa, fd, the case of malonate bearing a chlorine atom (1l), the elimina-

4
54
Chem. Pharm. Bull.
Vol. 67, No. 5 (2019)
Table 3. Michael Reaction of Substituted Malonates with Maleates
a)
b)
Entry
Donor
Acceptor
Conditions
Product
Yield (%)
ee (%)
1
2
3
1
2
3
4
1e: R = Me, R = Me
2a (R = Et)
r.t., 1h
r.t., 1h
5ea
5fa
5fd
5ga
5ha
5ic
91
93
92
88
91
79
36
44
79
91
74
94
1
2
3
c)
1f: R = Me, R = Bn
2a (R = Et)
98 (R)
1
2
3
1f: R = Me, R = Bn
2d (R = PBB)
r.t., 1h
93
1
2
3
c)
1g: R = Et, R = Bn
2a (R = Et)
r.t., 3h
92 (R)
d)
1
i
2
3
c)
5
1h: R = Pr, R = Bn
2a (R = Et)
50°C, 17h
50°C, 17h
r.t., 3h
95 (R)
1
i
2
3
6
7
8
9
1i: R = Pr, R = Et
2c (R = Bn)
90
86
79
74
1
2
3
1j: R = Bn, R = Bn
2a (R = Et)
5ja
5kc
5la
1
2
3
1k: R = Bn, R = Et
2c (R = Bn)
r.t., 87h
r.t., 17h
r.t., 15h
r.t., 2h
1
2
3
1l: R = Cl, R = Et
2a (R = Et)
1
2
3
c)
1
0
1
1m: R = F, R = Bn
2a (R = Et)
5ma
5na
91 (S)
1
2
3
1
1n: R = F, R = Et
2a (R = Et)
98
a) Isolated yield. b) Determined by HPLC. c) The absolute configuration was determined by the comparison with authentic samples prepared from the known compound 3aa.
n
d) (R)-Cl -BINOL (20mol%), BuLi (40mol%).
2
Chart 2. Determination of the Absolute Configurations of Compounds
Bearing Quaternary Carbon Center
Chart 1. Determination of the Absolute Configurations of Compounds
by Their Introduction into a Known Compound Using Transesterification
tion reaction proceeded from the adduct, resulting in a low
yield of Michael adduct with moderate enantioselectivity
(entry 9). However, 2-fluoro malonates 1m and 1n afforded the
corresponding adducts in high yields with high enantioselec-
tivities (entries 10, 11).
The absolute configuration of the Michael adduct 3bb pre-
pared from 1b and 2b (Table 2, entry 8) was found to be R,
Fig. 1. Proposed Transition State in the Asymmetric Michael Reaction
which was assigned via the comparison with the HPLC data 2a (Table 1, entry 1). As shown in Chart 2, compound 5fa
8)
to the literature value. Furthermore, methyl ester 3bb was could be prepared from the obtained adduct 3aa by reacting
51,52)
converted to ethyl ester 3ca by the transesterification reaction with methyl iodide in the presence of base.
Comparing the
using Ti(OEt) (Chart 1A). The values of HPLC retention time HPLC value of this methylated product and Michael adduct
4
from the two methods, transesterification product and Michael from 1f and 2a, the absolute configuration of 5fa was found to
adduct prepared from 1c and 2a were identical. From these be R. Therefore, these results indicate that the adduct synthe-
experiments, the absolute configuration of the obtained 3ca sized from 2-methyl benzyl malonate (1f) have the same abso-
was determined to be R. Similarly, the absolute configuration lute configuration as the adducts from unsubstituted malonate
of other adducts 3aa and 3ab were found to be R, after con- (1a). In addition, the absolute configurations of 5ga and 5ha
version to 3ca by transesterification (Chart 1B). As a result, were determined to be R by the comparison with the values
it was found that the adducts 3bb, 3aa, and 3ab, respectively, of the HPLC retention time after substitution reactions with
have the same absolute configuration. It is suggested that the appropriate alkyl halides in the presence of bases. Similarly,
other Michael adducts possess the same configuration. Next, that of 5ma was determined to be S after fluorination reaction
to determine the absolute configuration of compounds 5fa, using the Selectfluor.
5
ga, 5ha, and 5ma, we conducted the functionalization for
Considering of the absolute configuration of products, the
the known compound 3aa, which was prepared from 1a and proposed transition state of this reaction is shown in Fig. 1.

Vol. 67, No. 5 (2019)
Chem. Pharm. Bull.
455
through base-catalyzed Michael reaction.
In conclusion, we report the first example of enantioselec-
tive Michael reaction of malonates to maleates, catalyzed
by dilithium 3,3′-dichlorobinaphtholate, affording the tet-
racarboxylic acid esters with high enantioselectivities. This
Michael reaction can accommodate a wide range of donors
and acceptors, even producing adducts with quaternary car-
bon. Furthermore, the resulting adduct can successfully be
functionalized to biologically important compounds. Further
investigation including the application to other substrates is
ongoing in our laboratory.
Fig. 2. Examples of Tricarboxylic Acid in Natural and Bioactive Com-
pounds
Experimental
General All reactions were performed under argon atmo-
sphere using dried glasswares equipped with a rubber septum
and a magnetic stirring bar. The column chromatography
purifications were performed using Kanto Chemical Silica Gel
6
0N (spherical, neutral, 63–210µm). The IR spectra were re-
1
corded using a PerkinElmer, Inc. Frontier MIR/NIR. The H-
and C-NMR spectra were recorded in CDCl using a JEOL
13
3
JNM-ECX-400 spectrometer. The chemical shifts are reported
in ppm relative to the internal tetramethylsilane (TMS) stan-
1
dard (δ 0.00ppm) for the H-NMR spectra and solvent signals
13
(
δ 77.0ppm) for the C-NMR spectra. The mass spectra were
recorded using a JEOL JMS-700MStation mass spectrometer.
The HPLC analyses were performed using JASCO P-2080 and
UV-2075.
Chart 3. Decarboxylation of Tetracarboxylic Acid Ester
It is presumed that maleate ester approaches to the catalyst-
Typical Procedure of Michael Reaction (Table 1, Entry
binding malonates while avoiding steric hindrance caused by 5) Under argon atmosphere, n-butyllithium (0.10mmol,
the substitution of a catalyst, leading an enantioselective car- 20mol%) in hexane (0.15M, 0.67mL) was added to a solu-
bon–carbon bond formation.
tion of (R)-3,3′-Cl -BINOL (17.8mg, 0.05mmol, 10mol%)
2
Next, to demonstrate the utility of this reaction, the trans- in TBME (5.0mL) at 0°C. After stirring for 1min, dibenzyl
formation of tetracarboxylic acid ester is accomplished. Opti- malonate (1a) (0.125mL, 0.5mmol, 1.0eq) and diethyl maleate
cally active tricarboxylic acids (TCA) are widely found in bio- (2a) (0.096mL, 0.6mmol, 1.2eq) was successively added to
logically and pharmaceutically active compounds. Important the mixture at room temperature (r.t.). After 1h, the reaction
5
3–63)
natural compounds such as Fumonisin Bl
or pharmaceuti- was quenched with sat. NH Cl aq. (2mL) and stirred for 0.5h.
4
6
4–67)
cal compounds such as J-104, 118
acid moiety and possess bioactivities (Fig. 2).
For instance, in the reported methods for the synthesis and dried over Na SO . After filtration and concentration, the
contain tricarboxylic The aqueous layer was extracted with EtOAc (3×10mL). The
combined organic layers were washed with brine (20mL),
2
4
of tricarboxylic acid moiety of Fumonisins or J-104, 118, crude product was purified by column chromatography (hex-
enantioselective syntheses were achieved by using chiral ane–EtOAc =9:1, SiO : 10g) to give product 3aa as a color-
2
4
7,48,58,62)
auxiliary
using stoichiometric amount of chiral amines.
improve the efficiency of the synthesis of such compounds, we boxylate (3aa)
envisioned that Michael reaction of malonates to maleates and 0.52 (hexane–EtOAc=4:1, stained white with anisaldehyde).
or optical resolution of racemic compound less oil (214mg, 94% yield, 90% ee).
6
4–66)
In order to
(R)-1,1-Dibenzyl 2,3-Diethyl Propane-1,1,2,3-tetracar-
4
6)
Colorless oil. 214mg. 94% yield. TLC: Rf
2
7
1
subsequent decarboxylation would afford the desired tricar- [α]4 +11.5 (c=1.03, CHCl ) for 90% ee. H-NMR (CDCl )
35
3
3
boxylic acid derivatives.
δ: 1.15 (3H, t, J=7.2Hz), 1.23 (3H, t, J=7.6Hz), 2.66 (1H,
Our study for decarboxylation commenced with reaction dd, J=17.0, 5.2Hz), 2.79 (1H, dd, J=17.0, 7.6Hz), 3.60–3.62
6
8)
under acidic media, but the decarboxylation product was (1H, m), 4.04–4.12 (5H, m), 5.14 (2H, s), 5.15 (2H, s), 7.28–7.37
not obtained by heating with aqueous HCl after deprotection (10H, m). The enantiomeric excess was determined to be
of benzyl group (Chart 3A). To improve this transformation, 90% ee by chiral HPLC with Daicel Chiralpak AD-H column
we performed the Krapcho reaction of 3ag in the presence [eluent: hexane–IPA=9:1; flow rate: 1.0mL/min; detection:
6
9–73)
of lithium salt,
but enantioselectivity of the product 6ag 254nm; t : 22.0min (R), 23.7min (S)].
R
decreased. Finally, we discovered that on heating with water
in a sealed tube in the absence of alkali bases caused the boxylate (3ab)
(R)-1,1-Dibenzyl 2,3-Dimethyl Propane-1,1,2,3-tetracar-
74)
46)
Colorless oil. 201mg. 94% yield. TLC: Rf
decarboxylation reaction to proceed well, without the loss of 0.41 (hexane–EtOAc=4:1, stained blue with phosphomolyb-
29
35
1
remarkable enantioselectivity (Chart 3B). As mentioned above, dic acid). [α]4 +7.5 (c=0.88, CHCl ) for 85% ee. H-NMR
3
these tricarboxylic acids and its derivatives are common and (CDCl ) δ: 2.67 (1H, dd, J=17.0, 4.8Hz), 2.80 (1H, dd,
3
versatile structures in biologically active natural products. Our J=17.0, 8.0Hz), 3.58 (3H, s), 3.60–3.64 (1H, m), 3.65 (3H, s),
method allows facile access to the optically active tricarbox- 4.03 (1H, d, J=6.8Hz), 5.15 (2H, s), 5.16 (2H, s), 7.26–7.37
ylic acid derivatives from commercially available materials (10H, m). The enantiomeric excess was determined to be

4
56
Chem. Pharm. Bull.
Vol. 67, No. 5 (2019)
+
8
[
5% ee by chiral HPLC with Daicel Chiralpak AD-3 column 485.2175). MS m/z: 485 (M+H ), 91. The enantiomeric excess
eluent: hexane–IPA=19:1; flow rate: 1.0mL/min; detection: was determined to be 74% ee by chiral HPLC with Daicel
254nm; t : 54.0min (R), 56.9min (S)].
Chiralpak AD-H column [eluent: hexane–IPA=9:1; flow rate:
1.0mL/min; detection: 254nm; t : 15.9min (major), 17.4min
R
4
6)
(
+)-Tetrabenzyl Propane-1,1,2,3-tetracarboxylate (3ac)
R
Colorless oil. 217mg. 75% yield. TLC: Rf 0.33 (hexane– (minor)].
EtOAc =4:1, stained blue with phosphomolybdic acid). [α]
+
2
3
7
3
1
(+)-2,3-Diallyl 1,1-Dibenzyl Propane-1,1,2,3-tetracar-
11.4 (c=1.15, CHCl ) for 83% ee. H-NMR (CDCl ) δ: boxylate (3ag) Colorless oil. 216mg. 90% yield. TLC: Rf
.72 (1H, dd, J=17.0, 5.2Hz), 2.88 (1H, dd, J=17.0, 7.6Hz), 0.47 (hexane–EtOAc=4:1, stained purple with anisaldehyde).
.67–3.70 (1H, m), 4.05 (1H, d, J=6.8Hz), 5.00–5.08 (8H, m), [α]4 +7.8 (c=0.98, CHCl ) for 91% ee. IR (ATR) cm : 3034,
4
35
1
3
3
19
35
−1
3
1
.21–7.34 (20H, m). The enantiomeric excess was determined 1731, 1649, 1153. H-NMR (CDCl ) δ: 2.72 (1H, dd, J=17.2,
3
to be 83% ee by chiral HPLC with Daicel Chiralpak AS-H 4.6Hz), 2.85 (1H, dd, J=17.2, 7.8Hz), 3.64–3.69 (1H, m),
column [eluent: hexane–IPA=4:1; flow rate: 1.0mL/min; de- 4.05 (1H, d, J=6.9Hz), 4.51 (2H, d, J=6.0Hz), 4.55 (2H,
tection: 254nm; t : 11.5min (minor), 15.0min (major)].
d, J=6.0Hz), 5.14 (2H, s), 5.15 (2H, s), 5.17–5.32 (4H, m),
R
13
(+)-1,1-Dibenzyl 2,3-Bis(4-bromobenzyl) Propane-1,1,2,3- 5.74–5.91 (2H, m), 7.26–7.32 (10H, m). C-NMR (CDCl ) δ:
3
tetracarboxylate (3ad) Pale yellow oil. 346mg. 94% yield. 33.2, 40.4, 52.2, 65.5, 66.1, 67.6, 118.4, 118.6, 128.3, 128.4,
TLC: Rf 0.47 (hexane–EtOAc=4:1, stained white with 128.4, 128.5, 131.5, 131.8, 134.9, 135.0, 167.3, 167.4, 170.7,
1
9
anisaldehyde). [α] +5.8 (c=1.2, CHCl ) for 78% ee. IR 171.1 (three carbons overlapped). FAB-MS m/z: 481.1892
4
35
3
−1
1
+
(
ATR) cm : 3035, 1729, 1153. H-NMR (CDCl ) δ: 2.71 (1H, (Calcd for C H O : 481.1862). MS m/z: 481 (M+H ). The
3 27 29 8
dd, J=16.9, 4.6Hz), 2.86 (1H, dd, J=16.9, 7.8Hz), 3.65–3.70 enantiomeric excess was determined to be 91% ee by chiral
1H, m), 4.00–4.03 (1H, m), 4.94 (2H, s), 4.98 (2H, s), 5.04 HPLC with Daicel Chiralpak AS-H column [eluent: hex-
2H, s), 5.09 (2H, s), 7.07 (2H, d, J=8.2Hz), 7.14 (2H, d, ane–IPA =9:1; flow rate: 1.0mL/min; detection: 254nm; tR:
J=8.2Hz), 7.22–7.31 (10H, m), 7.41 (2H, d, J=8.2Hz), 7.45 16.6min (minor), 21.7min (major)].
(
(
1
3
8)
(
6
1
1
(
(
7
[
2
2H, d, J=7.8Hz). C-NMR (CDCl ) δ: 33.2, 40.3, 52.1, 66.4,
(R)-Tetramethyl Propane-1,1,2,3-tetracarboxylate (3bb)
3
5.8, 67.5, 67.6, 122.3, 122.3, 128.2, 128.4, 128.4, 128.5, 129.8, Colorless oil. 127mg. 93% yield. TLC: Rf 0.26 (hexane–
29.9, 131.6, 131.6, 134.1, 134.5, 134.7, 134.8, 167.1, 167.3, EtOAc =4:1, stained blue with phosphomolybdic acid). [α]
2
9
D
8)
25
70.7, 171.1 (two carbons overlapped). FAB-MS m/z: 759.0211 +13.4 (c=0.2, CHCl ) for 85% ee (R). [(lit : [α] +5.3,
3 D
1
Calcd for C H Br O Na: 761.0188). MS m/z: 759, 761, 763 c=0.2, CHCl ) for 93% ee (R)]. H-NMR (CDCl ) δ: 2.72
35
30
2
8
3
3
+
M+Na ), 91. The enantiomeric excess was determined to be (1H, dd, J=17.2, 4.8Hz), 2.84 (1H, dd, J=17.2, 7.0Hz),
8% ee by chiral HPLC with Daicel Chiralcel AS-H column 3.58–3.63 (1H, m), 3.70 (3H, s), 3.72 (3H, s), 3.76 (3H, s), 3.78
eluent: hexane–IPA=4:1; flow rate: 1.0mL/min; detection: (3H, s), 3.94 (1H, d, J=6.8Hz). The enantiomeric excess was
54nm; t : 24.3min (minor), 32.2min (major)].
determined to be 85% ee by chiral HPLC with Daicel Chi-
+)-1,1-Dibenzyl 2,3-Bis(4-methoxybenzyl) Propane- ralpak AD-H column [eluent: hexane–IPA=9:1; flow rate:
,1,2,3-tetracarboxylate (3ae) Colorless oil. 256mg. 80% 0.5mL/min; detection: 220nm; t : 23.4min (S), 24.3min (R)].
R
(
1
R
yield. TLC: Rf 0.44 (hexane–EtOAc=4:1, stained white with
(+)-2,3-Diethyl 1,1-Dimethyl Propane-1,1,2,3-tetracar-
anisaldehyde). [α] +9.5 (c=0.92, CHCl ) for 72% ee. IR boxylate (3ba)
19
46)
Pale yellow oil. 140mg. 92% yield. TLC:
4
35
3
−1
1
(
ATR) cm : 3034, 1732, 1153. H-NMR (CDCl ) δ: 2.68 (1H, Rf 0.71 (hexane–EtOAc=1:1, stained blue with phospho-
3
2
4
8
dd, J=16.9, 5.0Hz), 2.83 (1H, dd, J=16.9, 8.2Hz), 3.63–3.68 molybdic acid). [α]
+29.6 (c=1.02, CHCl ) for 77% ee.
35
3
1
(
4
1H, m), 3.77 (3H, s), 3.80 (3H, s), 4.02 (1H, d, J=6.9Hz),
.93–4.98 (4H, m), 5.02 (2H, s), 5.07 (2H, s), 6.81(2H, d, J=7.4Hz), 2.69 (1H, dd, J=16.8, 5.2Hz), 2.81 (1H, dd,
H-NMR (CDCl ) δ: 1.24 (3H, t, J=7.4Hz), 1.32 (3H, t,
3
J=8.7Hz), 6.85 (2H, d, J=8.2Hz), 7.16 (2H, d, J=8.7Hz), J=16.8, 8.0Hz), 3.56–3.61 (1H, m), 3.75 (3H, s), 3.76 (3H, s),
13
7
.21–7.31 (12H, m). C-NMR (CDCl ) δ: 33.4, 40.5, 52.2, 55.3, 3.94 (1H, d, J=7.6Hz), 4.15 (2H, q, J=7.4Hz), 4.17 (2H, q,
3
66.5, 67.1, 67.5, 67.5, 113.8, 113.9, 127.3, 127.7, 128.2, 128.4, J=7.4Hz). The enantiomeric excess was determined to be
128.5, 130.1, 130.2, 134.9, 135.0, 159.6, 159.6, 167.3, 167.4, 77% ee by chiral HPLC with Daicel Chiralpak AD-3 column
1
71.0, 171.3 (four carbons overlapped). FAB-MS m/z: 663.2218 [eluent: hexane–IPA=29:1; flow rate: 1.0mL/min; detection:
+
(
9
Calcd for C H O Na: 663.2206). MS m/z: 663 (M+Na ), 220nm; t : 27.6min (minor), 28.6min (major)].
37
36 10
R
1. The enantiomeric excess was determined to be 72% ee
(+)-Tetraethyl Propane-1,1,2,3-tetracarboxylate (3ca)
by chiral HPLC with Daicel Chiralcel AD-3 column [eluent: Pale yellow oil. 136mg. 82% yield. TLC: Rf 0.26 (hexane–
hexane–IPA=4:1; flow rate: 1.0mL/min; detection: 254nm; EtOAc =4:1, stained blue with phosphomolybdic acid). [α]
tR: 47.6min (major), 51.4min (minor)].
2
9
4
35
−
1
+23.2 (c=1.01, CHCl ) for 88% ee. IR (film on NaCl) cm :
3
1
(
+)-1,1-Dibenzyl 2,3-Dipropyl Propane-1,1,2,3-tetracar- 2983, 1731, 1164. H-NMR (CDCl ) δ: 1.24–1.29 (12H, m),
3
boxylate (3af) Colorless oil. 160mg. 66% yield. TLC: Rf 2.69 (1H, dd, J=16.8, 5.2Hz), 2.81 (1H, dd, J=16.8, 8.0Hz),
.26 (hexane–EtOAc=4:1, stained blue with phosphomo- 3.55–3.60 (1H, m), 3.89 (1H, d, J=7.2Hz), 4.12–4.25 (8H, m).
0
2
7
13
lybdic acid). [α] +11.5 (c=1.07, CHCl ) for 74% ee. IR
C-NMR (CDCl ) δ: 14.0, 14.1, 33.5, 40.5, 52.4, 60.8, 61.4,
4
35
3
3
−1
1
(ATR) cm : 3035, 2967, 1730, 1151. H-NMR (CDCl ) δ: 0.86 61.8, 167.7, 167.8, 171.2, 171.7 (three carbons overlapped).
3
(
2
3
3H, t, J=7.4Hz), 0.91 (3H, t, J=7.3Hz), 1.50–1.66 (4H, m), FAB-MS m/z: 333.1559 (Calcd for C H O : 333.1549). MS
15 25 8
+
.67 (1H, dd, J=17.0, 4.6Hz), 2.81 (1H, dd, J=17.0, 7.8Hz), m/z: 333 (M+H ), 259. The enantiomeric excess was de-
.60–3.62 (1H, m), 4.04–4.12 (5H, m), 5.14 (2H, s), 5.15 (2H, termined to be 88% ee by chiral HPLC with Daicel Chiral-
13
s), 7.28–7.37 (10H, m) C-NMR (CDCl ) δ: 10.2, 10.3, 21.7, pak AS-H column [eluent: hexane–IPA=49:1; flow rate:
2
3
1.8, 33.4, 40.5, 52.3, 66.4, 67.0, 67.5, 128.2, 128.4, 128.4, 1.0mL/min; detection: 220nm; t : 17.1min (minor), 18.7min
R
128.5, 135.0, 135.0, 167.3, 167.5, 171.1, 171.5 (three carbons (major)].
overlapped). FAB-MS m/z: 485.2173 (Calcd for C H O :
(+)-1,1-Di-tert-butyl 2,3-Diethyl Propane-1,1,2,3-tetra-
2
7
33
8

Vol. 67, No. 5 (2019)
Chem. Pharm. Bull.
457
4
6)
carboxylate (3da)
Colorless oil. 192mg. 99% yield. J=16.4, 10.4Hz), 3.69–3.72 (1H, m), 3.75 (6H, s), 4.14 (2H, q,
TLC: Rf 0.29 (hexane–EtOAc=4:1, stained blue with phos- J=6.8Hz), 4.15 (2H, q, J=7.2Hz). The enantiomeric excess
2
9
phomolybdic acid). [α]
+11.5 (c=1.13, CHCl ) for 55% was determined to be 94% ee by chiral HPLC with Daicel
4
35
3
1
ee. H-NMR (CDCl ) δ: 1.23–1.28 (6H, m), 1.46 (18H, s, Chiralpak AD-H column [eluent: hexane–IPA=19:1; flow
8H), 2.69 (1H, dd, J=16.8, 4.4Hz), 2.78 (1H, dd, J=16.8, rate: 1.0mL/min; detection: 220nm; t : 13.6min (major),
.4Hz), 3.45–3.50 (1H, m), 3.71 (1H, d, J=7.2Hz), 4.14 (2H, 15.0min (minor)].
q, J=7.6Hz), 4.18 (2H, q, J=7.2Hz). The enantiomeric
excess was determined to be 55% ee by chiral HPLC with ylate (5fa)
3
1
8
R
(R)-3,3-Dibenzyl 1,2-Diethyl Butane-1,2,3,3-tetracarbox-
4
6)
Pale yellow oil. 219mg. 93% yield. TLC: Rf
Daicel Chiralpak AD-H column [eluent: hexane–IPA=29:1; 0.34 (hexane–EtOAc=4:1, stained white with anisaldehyde).
2
9
1
flow rate: 1.0mL/min; detection: 220nm; t : 9.7min (minor), [α] −11.4 (c=1.0, CHCl ) for 98% ee. H-NMR (CDCl ) δ:
R
D
3
3
11.4min (major)].
1.16 (3H, t, J=7.2Hz), 1.24 (3H, t, J=7.6Hz), 1.50 (3H, s),
−)-Dibenzyl 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)malo- 2.56 (1H, dd, J=16.6, 3.2Hz), 2.77 (1H, dd, J=16.6, 10.4Hz),
(
4
6)
nate (3ah)
Colorless prisms. mp: 90.0–92.0°C. 158mg. 3.76 (1H, dd, J=10.4, 3.2Hz), 4.03 (2H, q, J=7.2Hz), 4.10
6
9% yield. TLC: Rf 0.66 (hexane–EtOAc=1:1, stained blue (2H, q, J=7.6Hz), 5.08 (1H, d, J=12.4Hz), 5.12 (2H, s),
3
0
with phosphomolybdic acid). [α] −5.8 (c=0.94, CHCl ) for 5.14 (1H, d, J=12.4Hz), 7.22–7.25 (4H, m), 7.30–7.32 (6H,
4
35
3
1
1
8% ee. H-NMR (CDCl ) δ: 2.88–3.00 (2H, m), 3.45–3.51 m). The enantiomeric excess was determined to be 98% ee
3
(
7
1H, m), 4.31 (1H, d, J=4.0Hz), 5.18 (2H, s), 5.21 (2H, s), by chiral HPLC with Daicel Chiralpak AD-3 column [eluent:
.19 (2H, d, J=7.6Hz), 7.26–7.45 (13H, m). The enantiomeric hexane–IPA=19:1; flow rate: 1.0mL/min; detection: 254nm;
excess was determined to be 18% ee by chiral HPLC with tR: 29.6min (S), 30.8min (R)].
Daicel Chiralcel OZ-H column [eluent: hexane–IPA=1:1;
(−)-3,3-Dibenzyl 1,2-Bis(4-bromobenzyl)butane-1,2,3,3-
46)
flow rate: 1.0mL/min; detection: 254nm; t : 19.5min (minor), tetracarboxylate (5fd)
Pale yellow oil. 345mg. 92%
R
4
0.0min (major)].
S)-Dibenzyl 2-(3-Oxo-1,3-diphenylpropyl)malonate (3ai)
yield. TLC: Rf 0.41 (hexane–EtOAc=4:1, stained white
10)
27
(
with anisaldehyde). [α]D −12.8 (c=0.69, CHCl ) for 93%
3
1
Colorless oil. 192mg. 78% yield. TLC: Rf 0.51 (hexane– ee. H-NMR (CDCl ) δ: 1.49 (3H, s), 2.62 (1H, dd, J=16.6,
EtOAc =4:1, stained blue with anisaldehyde). [α] +1.6 3.2Hz), 2.86 (1H, dd, J=16.6, 11.0Hz), 3.81 (1H, dd, J=11.0,
3
2
5
D
10)
25
(
c=1.0, CHCl ) for 20% ee. [(lit : [α] +18.4 (c=1.0, CHCl3) 3.2Hz), 4.83–5.02 (8H, m), 7.08 (2H, d, J=8.0Hz), 7.14–7.20
3 D
1
for 91% ee (S)]. H-NMR (CDCl ) δ: 3.44 (2H, d, J=6.8Hz), (6H, m), 7.26–7.30 (6H, m), 7.41 (2H, d, J=8.4Hz), 7.45 (2H,
3
3
(
.94 (1H, d, J=9.8Hz), 4.19–4.25 (1H, m), 4.90 (2H, s), 5.12 d, J=8.0Hz). The enantiomeric excess was determined to be
1H, d, J=12.4Hz), 5.17 (1H, d, J=12.4Hz), 7.05–7.07 (2H, 93% ee by chiral HPLC with Daicel Chiralpak AD-3 column
m), 7.15–7.34 (13H, m), 7.36–7.43 (2H, m), 7.46–7.55 (1H, m), [eluent: hexane–IPA=4:1; flow rate: 1.0mL/min; detection:
7
.80 (2H, d, J=8.2Hz). The ee was determined to be 20% ee 254nm; t : 31.9min (minor), 40.0min (major)].
R
by chiral HPLC with Daicel Chiralpak AS-H column [eluent:
(R)-3,3-Dibenzyl-1,2-diethylpentane-1,2,3,3-tetracarbox-
4
6)
hexane–IPA=9:1; flow rate: 1.0mL/min; detection: 254nm; ylate (5ga)
tR: 19.9min (R), 23.0min (S)].
Colorless oil. 212mg. 88% yield. TLC: Rf
0.31 (hexane–EtOAc=4:1, stained white with anisaldehyde).
2
8
1
(
S)-1,1-Dibenzyl 2,3-Diethyl Propane-1,1,2,3-tetracar- [α] +19.5 (c=0.99, CHCl ) for 92% ee. H-NMR (CDCl )
D 3 3
46)
boxylate (3aa)
Colorless oil. 189mg. 83% yield. TLC: Rf δ: 0.92 (3H, t, J=7.6Hz), 1.15 (3H, t, J=7.6Hz), 1.24 (3H, t,
0
[α]
.52 (hexane–EtOAc=4:1, stained white with anisaldehyde). J=7.2Hz), 1.93–2.03 (2H, m), 2.64 (1H, dd, J=16.6, 2.8Hz),
2
9
−1.1 (c=1.1, CHCl ) for −8% ee. The enantiomeric 2.82 (1H, dd, J=16.6, 10.8Hz), 3.62 (1H, dd, J=10.8, 2.8Hz),
4
35
3
excess was determined to be −8% ee by chiral HPLC with 4.01 (2H, q, J=7.6Hz), 4.11 (2H, q, J=7.2Hz), 5.07 (2H,
Daicel Chiralpak AD-H column [eluent: hexane–IPA=9:1; d, J=12.0Hz), 5.17 (2H, d, J=12.0Hz), 7.24–7.27 (2H, m),
flow rate: 1.0mL/min; detection: 254nm; t : 20.8min (R), 7.29–7.32 (8H, m). The ee was determined to be 92% ee by
R
22.2min (S)].
chiral HPLC with Daicel Chiralpak AS-H column [eluent:
(
S)-Dibenzyl 2-(1,4-Dioxo-1,4-diphenylbutan-2-yl)malo- hexane–IPA=19/1; flow rate: 1.0mL/min; detection: 254nm;
5
0)
nate (3ak)
White prisms. mp: 66.0–68.0°C. 205mg. 79% tR: 7.7min (S), 9.6min (R)].
(R)-3,3-Dibenzyl 1,2-Diethyl 4-Methylpentane-1,2,3,3-
yield. TLC: Rf 0.50 (hexane–EtOAc=4:1, stained blue with
2
4
50)
46)
anisaldehyde). [α] +1.1 (c=1.1, CHCl ) for 4% ee. [(lit : tetracarboxylate (5ha)
Pale yellow oil. 226mg. 91%
D
3
2
D
3
1
[
(
α] −23.4 (c=0.25, CHCl ) for 88% ee (R)]; H-NMR yield. TLC: Rf 0.37 (hexane–EtOAc=4:1, stained blue with
3
2
6
CDCl ) δ: 3.38 (1H, dd, J=18.3, 6.3Hz), 3.54 (1H, dd, phosphomolybdic acid). [α] +23.7 (c=0.7, CHCl ) for 95%
3 D 3
1
J=18.3, 5.9Hz), 4.04 (1H, d, J=8.4Hz), 4.9–5.13 (5H, m), ee. H-NMR (CDCl ) δ: 1.01 (3H, d, J=6.4Hz), 1.02 (3H, d,
3
7
(
.14–7.28 (10H, m), 7.35–7.44 (4H, m), 7.52–7.58 (2H, m), 7.13 J=6.4Hz), 1.09 (3H, t, J=6.8Hz), 1.24 (3H, t, J=6.8Hz),
2H, d, J=7.6Hz), 7.32 (2H, d, J=6.8Hz). The enantiomeric 2.43–2.51 (2H, m), 2.67 (1H, dd, J=16.4, 11.6Hz), 3.75 (1H,
excess was determined to be 4% ee by chiral HPLC with Dai- dd, J=11.6, 2.0Hz), 3.91 (2H, q, J=6.8Hz), 4.12 (2H, q,
cel Chiralpak AD-3 column [eluent: hexane–IPA=4:1; flow J=6.8Hz), 5.07 (1H, d, J=12.4Hz), 5.13 (1H, d, J=12.4Hz),
rate: 1.0mL/min; detection: 254nm; t : 51.6min (R), 54.3min 5.19 (2H, d, J=12.4Hz), 7.29–7.32 (10H, m). The ee was
R
(S)].
determined to be 95% ee by chiral HPLC with Daicel Chi-
(
−)-1,2-Diethyl 3,3-Dimethyl Butane-1,2,3,3-tetracar- ralpak AD-3 column [eluent: hexane–IPA=19:1; flow rate:
4
6)
boxylate (5ea)
Colorless oil. 144mg. 91% yield. TLC: Rf 1.0mL/min; detection: 254nm; t : 20.1min (R), 22.8min (S)].
R
0
.20 (hexane–EtOAc=4:1, stained blue with phosphomolyb-
(+)-1,2-Dibenzyl 3,3-Diethyl 4-Methylpentane-1,2,3,3-
2
4
1
46)
dic acid). [α] −22.3 (c=1.01, CHCl ) for 94% ee. H-NMR tetracarboxylate (5ic)
Pale yellow oil. 196mg. 79%
D
3
(
1
CDCl ) δ: 1.24 (3H, t, J=6.8Hz), 1.26 (3H, t, J=7.2Hz), yield. TLC: Rf 0.37 (hexane–EtOAc=4:1, stained blue with
.47 (3H, s), 2.57 (1H, dd, J=16.4, 3.2Hz), 2.82 (1H, dd, phosphomolybdic acid). [α]4 +11.5 (c=0.7, CHCl ) for 90%
3
2
4
35 3

4
58
Chem. Pharm. Bull.
Vol. 67, No. 5 (2019)
1
29
ee. H-NMR (CDCl ) δ: 1.01 (3H, d, J=7.6Hz), 1.03 (3H, d, phomolybdic acid). [α] −9.1 (c=1.0, CHCl ) for 91% ee.
3
D
3
−1
1
J=7.6Hz), 1.16 (3H, t, J=7.6Hz), 1.22 (3H, t, J=7.2Hz), IR (ATR) cm : 3067, 1734, 1215, 1024. H-NMR (CDCl ) δ:
3
2
2
.38 (1H, sept, J=7.6Hz), 2.58 (1H, dd, J=17.0, 2.0Hz), 1.14 (3H, t, J=7.3Hz), 1.24 (3H, t, J=6.9Hz), 2.47 (1H, dd,
.80 (1H, dd, J=17.0, 11.2Hz), 3.82 (1H, dd, J=11.2, 2.0Hz), J=16.9, 3.7Hz), 2.83 (1H, dd, J=16.9, 10.1Hz), 4.02–4.17
13
3.95–4.17 (4H, m), 5.01–5.13 (4H, m), 7.26–7.32 (10H, m). (5H, m), 5.21 (4H, s), 7.28–7.37 (10H, m). C-NMR (CDCl ) δ:
3
The ee was determined to be 90% ee by chiral HPLC with 13.7, 14.0, 31.1, 31.1, 45.8 (d), 61.5 (d), 68.4 (d), 68.6 (d), 94.3
Daicel Chiralcel OD-H column [eluent: hexane–IPA=19:1; (d), 128.3, 128.4, 128.6, 128.6, 128.7, 134.1, 134.3, 134.4, 164.2
flow rate: 1.0mL/min; detection: 254nm; t : 10.7min (minor), (d), 164.6 (d), 168.7 (d), 170.6. FAB-MS m/z: 475.1738 (Calcd
R
+
13.4min (major)].
for C H O F: 475.1768). MS m/z: 475 (M+H ), 91. The ee
2
5
28
8
(+)-3,3-Dibenzyl 1,2-Diethyl 4-Phenylbutane-1,2,3,3- was determined to be 91% ee by chiral HPLC with Daicel
tetracarboxylate (5ja) Pale yellow oil. 98mg. 36% yield. Chiralpak AD-3 column [eluent: hexane–IPA=9:1; flow rate:
TLC: Rf 0.39 (hexane–EtOAc=4:1, stained blue with phos- 1.0mL/min; detection: 254nm; t : 22.9min (S), 27.8min (R)].
R
2
6
phomolybdic acid). [α] +5.6 (c=1.3, EtOH) for 86% ee. IR
(−)-Tetraethyl 1-Fluoropropane-1,1,2,3-tetracarboxylate
ATR) cm : 3065, 3033, 2981, 1727, 1173. H-NMR (CDCl ) (5na) Pale yellow oil. 129mg. 74% yield. TLC: Rf 0.26
4
35
−1
1
(
3
δ: 1.20 (3H, t, J=7.6Hz), 1.21 (3H, t, J=7.2Hz), 2.75 (1H, (hexane–EtOAc=4:1, stained white with anisaldehyde).
2
9
−1
dd, J=16.8, 2.8Hz), 2.88 (1H, dd, J=16.8, 10.8Hz), 3.33 [α] −10.3 (c=0.88, CHCl ) for 98% ee. IR (ATR) cm :
D
3
1
(
2H, s), 3.65 (1H, dd, J=10.8, 2.8Hz), 4.06–4.12 (4H, m), 2985, 1735, 1231. H-NMR (CDCl ) δ: 1.24 (3H, t, J=7.3Hz),
.96 (2H, s), 5.09 (2H, s), 7.12–7.14 (2H, m), 7.21–7.31 (13H, 1.27 (3H, t, J=7.3Hz), 1.33 (3H, t, J=7.3Hz), 1.33 (3H,
m). C-NMR (CDCl ) δ: 13.7, 14.1, 33.8, 39.6, 45.4, 60.6, t, J=7.3Hz), 2.57 (1H, dd, J=16.5, 3.7Hz), 2.88 (1H, dd,
3
4
13
3
6
1
0.8, 61.3, 67.4, 67.5, 127.2, 128.2, 128.3, 128.3, 128.4, 128.4, J=16.5, 10.1Hz), 4.04 (1H, ddd, J=26.8, 10.1, 3.7Hz),
13
28.4, 128.4, 130.5, 134.6, 134.9, 135.4, 168.7, 169.0, 171.8 4.14–4.20 (4H, m), 4.29–4.35 (4H, m). C-NMR (CDCl ) δ:
3
(
one carbon overlapped). FAB-MS m/z: 547.2333 (Calcd for 13.7, 14.0, 29.5, 31.1, 45.6 (d), 61.4 (d), 63.0 (d), 93.0 (d), 164.4
+
C H O : 547.2332). MS m/z: 547 (M+H ), 455, 91. The ee (d), 164.7 (d), 168.7, 170.7 (three carbons overlapped). FAB-
was determined to be 86% ee by chiral HPLC with Daicel MS m/z: 351.1463 (Calcd for C H O F: 351.1455). MS m/z:
Chiralpak AD-3 column [eluent: hexane–IPA=19:1; flow 351 (M+H ). The ee was determined to be 98% ee by chiral
rate: 1.0mL/min; detection: 254nm; t : 33.7min (major), HPLC with Daicel Chiralpak AD-H column [eluent: hex-
32
35
8
15
24
8
+
R
3
8.7min (minor)].
ane–IPA =19:1; flow rate: 1.0mL/min; detection: 220nm; tR:
(−)-1,2-Dibenzyl 3,3-Diethyl 4-Phenylbutane-1,2,3,3- 14.5min (major), 15.5min (minor)].
tetracarboxylate (5kc) Colorless oil. 120mg. 44% yield.
Typical Procedure of Transesterification (Chart 1)
TLC: Rf 0.42 (hexane–EtOAc=4:1, stained blue with phos- Under argon atmosphere, Ti(OEt) (0.21mL, 1.0mmol, 4.0eq)
4
2
4
phomolybdic acid). [α] −5.9 (c=1.3, MeOH) for 79% ee. IR in EtOH (2mL) was added Michael adduct 3bb (69.0mg,
ATR) cm : 3033, 1728, 1155. H-NMR (CDCl ) δ: 1.09 (3H, 0.25mmol) in EtOH (1mL). After refluxing for 14h, the re-
4
35
−1
1
(
3
t, J=6.8Hz), 1.14 (3H, t, J=7.2Hz), 2.84 (1H, dd, J=16.8, action was quenched with sat. NH Cl aq. (2mL) and stirred
4
3.2Hz), 2.97 (1H, dd, J=16.8, 11.2Hz), 3.28 (2H, s) 3.71 (1H, for 0.5h. The aqueous layer was extracted with EtOAc
dd, J=11.2, 3.2Hz), 3.95–4.08 (4H, m), 4.99–5.15 (4H, m), (3 ×10mL). The combined organic layers were washed with
13
7
.18–7.22 (5H, m), 7.27–7.37 (10H, m). C-NMR (CDCl ) δ: brine (20mL), and dried over Na SO . After filtration and con-
3
2
4
13.7, 13.8, 25.3, 33.9, 39.5, 45.3, 60.6, 61.6, 66.5, 67.3, 127.0, centration, the crude product was purified by column chroma-
1
28.0, 128.2, 128.3, 128.4, 128.5, 128.6, 130.5, 135.2, 135.6, tography (hexane–EtOAc=9:1, SiO : 5g) to give product 3ca
2
135.7, 169.0, 169.1, 171.6 (two carbons overlapped). FAB- as a pale yellow oil (76mg, 91% yield, 81% ee).
MS m/z: 547.2335 (Calcd for C H O : 547.2332). MS m/z: Typical Procedure of Alkylation of Michael Adduct
3
2
35
8
+
5
47(M +H ), 455, 91. The ee was determined to be 79% ee 3aa (Chart 2) Under argon atmosphere, methyl iodide
by chiral HPLC with Daicel Chiralpak AD-H column [eluent: (0.024mL, 0.4mmol, 4.0eq) was added to a solution of
hexane–IPA=9:1; flow rate: 1.0mL/min; detection: 254nm; Cs CO (45.6mg, 0.14mmol, 1.4eq) and Michael adduct 3aa
2
3
tR: 17.2min (minor), 18.9min (major)].
−)-Tetraethyl 1-Chloropropane-1,1,2,3-tetracarboxylate reaction was quenched with water (2mL) and stirred for 0.5h.
5la) Pale yellow oil. 144mg. 79% yield. TLC: Rf 0.53 The aqueous layer was extracted with EtOAc (3×10mL). The
hexane–EtOAc=4:1, stained yellow with phosphomolyb- combined organic layers were washed with brine (20mL),
(45.6mg, 0.1mmol, 1.0eq) in DMF (1mL) at r.t. After 14h, the
(
(
(
2
7
dic acid). [α] −8.1 (c=1.07, CHCl ) for 74% ee. IR (ATR) and dried over Na SO . After filtration and concentration,
cm : 2984, 1732, 1239, 1199, 1175, 1023. H-NMR (CDCl ) δ: the crude product was purified by column chromatography
4
35
3
2
4
−1
1
3
1
.21–1.33 (12H, m), 2.83 (1H, dd, J=16.9, 3.2Hz), 2.94 (1H, (hexane–EtOAc=9:1, SiO : 5g) to give product 5fa as a pale
2
dd, J=16.9, 9.6Hz), 4.09–4.11 (1H, m), 4.14–4.21 (4H, m), yellow oil (24mg, 50% yield, 89% ee).
1
3
4
3
.28–4.32 (4H, m). C-NMR (CDCl ) δ: 13.7, 13.8, 14.1, 29.7,
Procedure of Fluorination of Michael Adduct 3aa (Chart
3.0, 47.9, 61.0, 61.8, 63.4, 63.5, 71.1, 165.1, 165.6, 169.3, 171.3. 2) Under argon atmosphere, solution of Michael adduct
FAB-MS m/z: 367.1181 (Calcd for C H O Cl: 367.1160). MS 3aa (68.4mg, 0.15mmol, 1.0eq) in DMF (3mL) was added
3
15
24
8
+
m/z: 367 (M+H ). The ee was determined to be 74% ee by NaH (7.2mg, 0.18mmol, 1.2eq content; 60% by weight in
chiral HPLC with Daicel Chiralpak AD-3 column [eluent: oil) at 0°C and stirred for 0.5h. Then Selectfluor (69.1mg,
®
hexane–IPA=9:1; flow rate: 1.0mL/min; detection: 220nm; 0.20mmol, 1.3eq) was added to the reaction mixture and
tR: 12.0min (major), 13.9min (minor)].
stirred 14h at r.t. The reaction solution was poured into ice
(
S)-1,1-Dibenzyl 2,3-Diethyl 1-Fluoropropane-1,1,2,3- water (5mL). The aqueous layer was extracted with Et O
2
tetracarboxylate (5ma) Pale yellow oil. 215mg. 91% yield. (3 ×10mL). The combined organic layers were washed with
TLC: Rf 0.53 (hexane–EtOAc=4:1, stained blue with phos- brine (20mL), and dried over Na SO . After filtration and
2
4

Vol. 67, No. 5 (2019)
Chem. Pharm. Bull.
459
(
2011).
8) Espinosa M., Blay G., Cardona L., Pedro J. R., Chem. Eur. J., 19,
4861–14866 (2013).
9) Tsubo T., Yamada T., Synlett, 26, 1111–1115 (2015).
concentration, the crude product was purified by column chro-
1
matography (hexane–EtOAc=9:1, SiO : 5g) to give product
2
1
5
ma as a yellow oil (64mg, 90% yield, 88% ee).
1
Procedure of Krapcho Reaction (Chart 3) Michael ad-
2
0) Lippur K., Kaabel S., Järving I., Rissanen K., Kanger T., J. Org.
Chem., 80, 6336–6341 (2015).
duct 3ag (160mg, 0.3mmol) and H O (0.16mL, 9.0mmol,
2
3
0eq were stirred at 150°C. After 40h, the crude product was
loaded directly onto column chromatography and purified
hexane–EtOAc=12:1, SiO : 10g) to give product 6ag as a 22) Gómez-Torres E., Alonso D. A., Gómez-Bengoa E., Nájera C., Org.
2
1) Ye W., Jiang Z., Zhao Y., Goh S. L. M., Leow D., Soh Y.-T., Tan
C.-H., Adv. Synth. Catal., 349, 2454–2458 (2007).
(
2
colorless oil (78.9mg, 76% yield, 90% ee).
−)-1,2-Diallyl
6ag) Colorless oil. 78.9mg. 76% yield. TLC: Rf 0.47
Lett., 13, 6106–6109 (2011).
(
3-Benzyl-propane-1,2,3-tricarboxylate 23) Clarke H. T., Murray T. F. Org. Synth., Coll., I, 272–273 (1941).
2
4) Tanaka K., Kukita K., Ichibakase T., Kotani S., Nakajima M.,
Chem. Commun., 47, 5614–5616 (2011).
25) Ichibakase T., Nakatsu M., Nakajima M., Molecules, 16, 5008–5019
(
(
hexane–EtOAc=4:1, stained blue with phosphomolybdic
20
acid). [α]
−5.2 (c=1.05, CHCl ) for 90% ee. IR (ATR)
3
1
435
−1
(2011).
cm : 3034, 1729, 1649, 1152. H-NMR (CDCl ) δ: 2.62–2.71
3
2
2
2
6) Ichibakase T., Nakajima M., Org. Lett., 13, 1579–1581 (2011).
7) Ichibakase T., Nakajima M., Synthesis, 44, 3145–3151 (2012).
8) Ichibakase T., Kaneko T., Orito Y., Kotani S., Nakajima M., Tetra-
hedron, 68, 4210–4224 (2012).
(2H, m), 2.79–2.88 (2H, m), 3.30–3.35 (1H, m), 4.57 (4H, t,
J=5.5Hz), 5.13 (2H, s), 5.20–5.33 (4H, m), 5.80–5.93 (2H, m),
13
7
.33–7.39 (5H, m). C-NMR (CDCl ) δ: 35.2, 35.2, 37.4, 65.5,
3
65.7, 66.6, 118.4, 118.5, 128.3, 128.3, 128.5, 131.8, 131.8, 135.6,
29) Kotani S., Kukita K., Tanaka K., Ichibakase T., Nakajima M., J.
1
70.9, 171.1, 172.7. FAB-MS m/z: 347.1533 (Calcd for C H O :
Org. Chem., 79, 4817–4825 (2014).
19
23
6
+
3
47.1495). MS m/z: 347 (M+H ). The ee was determined to 30) Kotani S., Moritani M., Nakajima M. Asian, J. Org. Chem., 4,
be 90% ee by chiral HPLC with Daicel Chiralpak AD-3 col-
616–618 (2015).
1) Osakama K., Nakajima M., Org. Lett., 18, 236–239 (2016).
2) Kotani S., Asano T., Moritani M., Nakajima M., Tetrahedron Lett.,
7, 4217–4219 (2016).
3) Nakajima M., Watanabe R., Osakama K., Sakamoto M., Takemoto
3
3
umn [eluent: hexane–IPA=19:1; flow rate: 1.0mL/min; detec-
tion: 254nm; t : 18.5min (major), 19.7min (minor)].
R
5
3
Acknowledgments This work was partially supported by
Naito Foundation and the Ministry of Education, Science and
Culture of Japan.
D., Kukita K., Heterocycles, in press.10.3987/COM-18-S(T)63
4) Selected reports for the catalytic asymmetric Michael reactions
using alkali metal salts of binaphthol derivatives: Tamai Y., Kami-
fuku A., Koshiishi E., Miyano S., Chem. Lett., 24, 957–958 (1995).
3
Conflict of Interest The authors declare no conflict of 35) Kim Y. S., Matsunaga S., Das J., Sekine A., Ohshima T., Shibasaki
interest.
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3
6) Belokon Y. N., Gugkaeva Z. T., Maleev V. I., Moskalenko M. A.,
Tsaloev A. T., Khrustalev V. N., Hakobyan K. V., Tetrahedron
Asymmetry, 22, 167–172 (2011).
References and Notes
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9) Lithium salt prepared from the (R)-3,3′-Cl -BINOL (10mol%) and
2
14) Chen D., Chen Z., Xiao X., Yang Z., Lin L., Liu X., Feng X., Chem.
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5) Mase N., Fukasawa M., Kitagawa N., Shibagaki F., Noshiro N.,
Mono-lithium salt prepared from (R)-3,3′-Cl
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2
-BINOL (10mol%) and
n
1
Takabe K., Synlett, 2010, 2340–2344 (2010).
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(
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5
5
5
(31.9mg, 0.03mmol, 10% of the weight of the substrate) in EtOH
(1.0mL) was added Michael product 3aa (160mg, 0.3mmol) in
EtOH (3.0mL). After stirring for 0.5h, the reaction mixture was fil-
tered using a celite cake and the filtrate was concentrated in vacuo.
The crude product 2-(1,4-diethoxy-1,4-dioxobutan-2-yl)malonic acid
was used without further purification. A solution of obtained dicar-
boxylic acid in HCl (5.0mL, 35% in weight) was refluxed for 5h.
69) The procedure of standard Krapcho reaction: Michael adduct
5
(
5
9
7) Boyle C. D., Kishi Y., Tetrahedron Lett., 36, 4579–4582 (1995).
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3ag (160mg, 0.3mmol), H O (0.05mL. 3.0mmol, 10eq and LiCl
2
(0.6mmol, 2.0eq were stirred at 150°C in DMSO. After 11h, the
crude product was loaded directly onto column chromatography and
6
0) Sadler T. W., Merrill A. H., Stevens V. L., Sullards M. C., Wang E.,
Wang P., Teratology, 66, 169–176 (2002).
purified (hexane–EtOAc=12:1, SiO : 10g) to give product 6ag as a
colorless oil (27.0mg, 26% yield, 87% ee).
2
61) Hendricks K., Epidemiology, 10, 198–200 (1999).
70) Krapcho A. P., Synthesis, 1982, 805–822 (1982).
6
6
6
2) Pereira C. L., Chen Y.-H., McDonald F. E., J. Am. Chem. Soc., 131, 71) Krapcho A. P., Synthesis, 1982, 893–914 (1982).
6
066–6067 (2009).
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4
73) Krapcho A. P., ARKIVOC, 1–53 (2007).
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