Enantioselective Synthesis of Chiral α-Thio-Quaternary Stereogenic Centers via Phase-Transfer-Catalyzed α-Alkylation of α-Acylthiomalonates

Article abstract of DOI:10.1021/acs.joc.7b02605

An efficient synthetic method for establishing chiral α-thio-α-quaternary stereogenic center was successfully developed. The enantioselective α-alkylation of α-acylthiomalonates under phase-transfer catalytic conditions [50% aq. KOH, toluene, -20 °C, and

Full text of DOI:10.1021/acs.joc.7b02605

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Note
Enantioselective Synthesis of Chiral #-Thio-Quaternary Stereogenic
Centers via Phase-Transfer-Catalyzed #-Alkylation of #-Acylthiomalonates
Min Woo Ha, Jun Young Lee, Doyoung Kim, Geumwoo Lee,
Jae Kyun Lee, Suckchang Hong, and Hyeung-Geun Park
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02605 • Publication Date (Web): 20 Dec 2017
Downloaded from http://pubs.acs.org on December 21, 2017
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Enantioselective Synthesis of Chiral α-Thio-Quaternary
Stereogenic Centers via Phase-Transfer-Catalyzed α-
Alkylation of α-Acylthiomalonates
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†
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‡
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Min Woo Ha, Jun Young Lee, Doyoung Kim, Geumwoo Lee, Jae Kyun Lee, Suckchang Hong,
†,
and Hyeungꢀgeun Park *
†
Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University,
Seoul 151-742, Korea.
‡
Neuro-Medicine Center, Korea Institute of Science and Technology, PO Box 131, Cheongyang,
Seoul 130-650, Republic of Korea.
Corresponding author
Hyeungꢀgeun Park, Tel.: +82ꢀ2ꢀ880ꢀ7821, 8264, Fax: +82ꢀ2ꢀ872ꢀ9129, Eꢀmail: hgpark@snu.ac.kr
Abstract
An efficient synthetic method for establishing chiral αꢀthioꢀαꢀquaternary stereogenic center was
successfully developed. The enantioselective αꢀalkylation of αꢀacylthiomalonates under phaseꢀ
transfer catalytic conditions [50% aq. KOH, toluene, –20 °C and (S,S)ꢀ3,4,5ꢀtrifluorophenylꢀNAS
bromide] provided the corresponding αꢀacylthioꢀαꢀalkylmalonates in high chemical yields (up to
99%) and high optical yields (up to 98% ee).
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Organosulfur compounds play important roles in biological systems. Two natural amino
acids contain sulfur residues (cysteine and methionine), and their functional groups mediate various
biological processes in the enzymes of living organisms. Additionally, many commercially available
1
organosulfur compounds are bestꢀselling drugs. As the need for variable sulfurꢀcontaining
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compounds for the development of new drugs increases, the development of asymmetric synthetic
methods for organosulfur compounds having chirality at the sulfur carbon has become increasingly
important. The asymmetric preparation of secondary chiral sulfur (II) compounds via stereospecific
2
substitution is well developed. However, few methods are available for the asymmetric synthesis of
tertiary thiols. Although chiral tertiary alcohols are generally obtained by the enantioselective
3
addition of a nucleophile to a prochiral ketone , the analogous approach to the preparation of chiral
tertiary thiols is difficult due to the instability of thioketones and the possibility of nucleophilic
4
attack occurring at the sulfur rather than at the carbon. Therefore, the synthesis of enantiomerically
pure tertiary thiols is very challenging despite the simplicity of their structures.
Scheme 1. Synthetic methods for tertiary thiol or thioether
Three general synthetic approaches are available for the preparation of a chiral tertiary thiol,
and they are classified according to the disconnection of either a C–S (A and B) or a C–C bond (C)
5
(
Scheme 1). The thiol can be obtained by stereoselective attack of either a sulfur nucleophile on an
6
7
electrophilic carbon (A) or a nucleophilic carbon on an electrophilic sulfur (B) . Additionally, the
stereoselective α-alkylation of a secondary organosulfur substrate can generate a quaternary
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stereogenic center (C). Generally, the CꢀC bond formation methods (C) use a chiral auxiliary, a
stoichiometric chiral base, a rearrangement reaction or selfꢀregeneration of a chiral secondary sulfide
to impart tertiary chirality. However, a catalytic synthesis of a chiral tertiary sulfur system via CꢀC
bond formation has not yet been reported.
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In 2011, we reported the asymmetric synthesis of quaternary chiral α,αꢀdialkylmalonates as
versatile chiral starting materials in both high chemical and optical yields via enantioselective phaseꢀ
9
10
transfer catalytic (PTC) αꢀalkylation of malonates with chiral quaternary ammonium salts. The
11
established synthetic method was applied to the preparation of chiral quaternary αꢀaminomalonates
1
2
(
Scheme 2, A) and αꢀhydroxymalonates (Scheme 2, B), which were successfully converted to
useful chiral molecules bearing quaternary stereogenic centers. To expand our enantioselective
PTC αꢀalkylation methodology, we planned to synthesize chiral quaternary αꢀthiomalonates that
have not yet been reported. As shown in the synthetic strategy illustrated in Scheme 2, a sulfur group
is incorporated into the αꢀposition of malonates, and the subsequent enantioselective PTC αꢀ
alkylations with various electrophiles afford a versatile library of quaternary chiral αꢀthiomalonates
(
Scheme 2, C). Herein, we report efficient enantioselective synthetic method for the preparation of
quaternary αꢀthioꢀαꢀalkylmalonates.
Scheme 2. Synthetic strategy for chiral quaternary αꢀthiomalonates.
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First, we designed enantiotopic unsymmetrical αꢀthiomalonates, bearing non nucleophilic
sulfur as substrate for the PTC αꢀalkylation. Since both diphenylmethyl and tertꢀbutyl ester groups
11,12
were shown to be necessary for high enantioselectivity in previous reports
diphenylmethyl tertꢀbutyl malonate (1) as a template. Two αꢀacylthiomalonates were prepared by αꢀ
bromination using CBr in the presence of 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) followed by
, we chose
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substitution with benzothiolic acid or potassium thioacetate to afford αꢀbenzoylthiomalonate (3) or
αꢀacetylthiomalonate (4), respectively (Scheme 3).
Scheme 3. Preparation of αꢀacylthiomalonates.
The phaseꢀtransfer catalytic αꢀallylation of the prepared αꢀacylthiomalonates were
performed to examine their efficiency as substrates. The enantioselective PTC allylations of 3 and 4
1
2
were carried out under typical PTC conditions [allyl bromide (5.0 equiv.), 50% KOH (aq., 5.0
13
equiv.), toluene, room temperature] in the presence of chiral quaternary ammonium salts (5 – 9)
(Figure 1). As shown in Table 1, both αꢀacylthiomalonates successfully afforded their corresponding
αꢀallylated products in the presence of the Maruoka’s catalyst, (S,S)ꢀ3,4,5ꢀtrifluorophenylꢀNAS
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bromide (5) (entries 1 – 2). The acetylthio group (4, 78% ee) gave a higher enantioselectivity than
that of the benzoylthio group (3, 72% ee). This result is opposite of that obtained for the αꢀ
12
hydroxymalonates system , which may be due to the difference in size between the two atoms
oxygen and sulfur).
(
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Figure 1. Representative chiral phaseꢀtransfer catalysts.
a
Table 1. Enantioselective PTC αꢀalkylation of αꢀacylthiomalonates.
b
c
entry substrate
cat.
yield (%)
97
ee (%)
72
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a
Reactions were performed with 5.0 equiv. of allyl bromide and 5.0 equiv. of 50% KOH(aq.) under
b
c
the given conditions. Isolated yields. Enantiopurity was determined by HPLC analysis using a
chiral column (DAICEL Chiralpak ADꢀH).
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Among the examined chiral PTC catalysts, the Maruoka’s catalyst (5) gave the highest
enantioselectivity (entries 1 and 2). The lower enantioselectivities obtained for the other catalysts (6
–
9), including Lygo’s catalysts (7, 8), were consistent with the trends observed in the previous
11,12
reports.
Table 2. Optimization of the reaction conditions for the enantioselective PTC αꢀallylation of αꢀ
a
acetylthiomalonate.
T
time yield ee
entry
base
solvent
b
c
(°C) (h)
(%) (%)
1
2
3
4
5
6
7
8
9
50% KOH toluene rt
50% CsOH toluene rt
1
99
87
96
36
75
85
95
95
78
71
72
76
65
45
84
89
90
1
sꢀKOH
toluene rt
toluene rt
1
sꢀCsOH
1
50% KOH CH
50% KOH THF
50% KOH toluene
2
Cl
2
rt
rt
0
1
1
20
50% KOH toluene –20 40
50% KOH toluene –40 144 33
a
b
Reactions were performed with 5.0 equiv. of allyl bromide and 5.0 equiv. of base under the given conditions. Isolated
c
yields. Enantiopurity was determined by HPLC analysis using a chiral column (DAICEL Chiralpak ADꢀH).
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Next, the optimization of the base and temperature conditions were performed using
substrate 4 and the best catalyst (S,S)ꢀ5 (Table 2). Chemical yield and enantioselectivity were
dependent on the base and solvent conditions at room temperature (entries 1 – 6). The highest
enantioselectivity was observed with 50% KOH base in toluene (entries 1). In case of temperature,
higher enantioselectivities were observed at lower reaction temperatures (entry 1, entries 7 – 9).
However, a longer reaction time resulted in a lower chemical yield at –40 °C (entry 9). When the
PTC reaction was kept for 1 week, the alkylated product was partially hydrolyzed and immediately
desulfurized to monoꢀalkylated malonate that was further alkylated to α,αꢀdialkylated malonate as a
side product. Consequentially, 50% KOH base in toluene at –20 °C was selected as the optimal
reaction conditions based on the chemical yield, optical yield, and reaction time (entry 8; 95% yield,
1
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89% ee).
We then turned our attention to determine the scope and limitations of electrophiles in the
optimized enantioselective PTC alkylation of 4. As shown in Table 3, most of the alkylating agents
afforded very high enantioselectivities (10c–p, 90–98% ee). However, an unactivated alkylating
reagent gave no alkylated product (data not shown), and propargyl bromide (10a) resulted in a
relatively poor enantioselectivity, which may be due to geometrical constraints. The achievement of
very high enantioselectivities (up to 98% ee) shows that this methodology is very efficient for the
enantioselective synthesis of quaternary αꢀthioꢀαꢀalkylmalonates. Note that the enantioselectivities
12
were higher than those of the αꢀacyloxymalonate system (up to 93% ee). To the best of our
knowledge, this is the first report to accomplish the enantioselective catalytic synthesis of quaternary
αꢀthioꢀαꢀalkylmalonates.
a
Table 3. Enantioselective synthesis of αꢀacetylthioꢀαꢀalkylmalonates via PTC αꢀalkylation
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(
S,S)-5 (5 mol%)
Ph
O
O
Ph
O
O
R
RX
5 equiv.)
(
*
Ph
O
Ot-Bu
Ph
O
Ot-Bu
50% KOH
AcS
SAc
(5 equiv.)
o
toluene, -20 C
4
10
time yield
(h)
ee
c
entry RX
b
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(%)
(%)
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1
CH≡CBr (a)
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81
61
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CH
CH
CH
2
2
2
=CHCH
=C(CH )CH
=C(Br)CH Br (d)
Br (e)
4ꢀMeꢀPhCH
4ꢀFꢀPhCH Br (g)
4ꢀClꢀPhCH Br (h)
4ꢀBrꢀPhCH Br (i)
2
Br (b)
40
23
23
8
95
91
86
99
96
99
99
99
98
99
99
3
2
Br (c)
2
PhCH
2
2
Br (f)
4
2
4
2
7
2
5
0
4ꢀNO ꢀPhCH Br (j)
4
2
2
11
4ꢀtꢀBuꢀPhCH
2
Br (k)
7
12
4ꢀCF ꢀPhCH Br (l)
6
3
2
d
13
4ꢀCF
3
OꢀPhCH
2
Br (m)
Br (n)
5
86 96(R)
14
4ꢀCO
3ꢀCH
2
3
MeꢀPhCH
2
6
99
96
91
96
96
90
15
OꢀPhCH
2
Br (o)
Br (p)
9
16
βꢀnaphthylꢀCH
2
30
a
b
d
Reactions were performed with 5.0 equiv. of alkyl bromide and 5.0 equiv. of 50% KOH(aq.) under the given conditions.
c
Isolated yields. Enantiopurity was determined by HPLC analysis using a chiral column (DAICEL Chiralpak ADꢀH).
14
Absolute configuration of 10m was determined as R by Xꢀray crystallography (Figure 2) and the absolute
configuration of other compounds were tentatively assigned as R based on the Xꢀray crystallography of 10m.
14
Figure 2. Xꢀray Crystallographic Structure of 10m.
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Scheme 4 Derivatizations of chiral acetylthiomalonate 10b
As a demonstration of the synthetic potential of this methodology, derivatizations of 10b
were performed, as illustrated in Scheme 4. The hydrolysis of chiral acetylthiomalonate 10b under 1%
2 3
aqꢀKOH or aqꢀK CO conditions in the presence of benzyl bromide or tertꢀbutyl acrylate directly
1
5
provided the corresponding
S
ꢀalkylated products 11 and 12, respectively. Additionally, the
hydroboration of 10b by borane and hydrogenperoxide afforded the corresponding alcohol 13. The
mesylation of 13 followed by hydrolysis using 1% aqꢀKOH in dimethylformamide (DMF)
16
successively afforded the cyclized tetrahydrothiofuran 15.
In conclusion, a new asymmetric synthetic method was successfully developed for the
preparation of
alkylations of diphenylmethylꢀtertꢀbutyl
acetylthioꢀ
Our newly established PTC reaction provides an efficient method to prepare useful versatile chiral
α
ꢀacylthioꢀ
α
ꢀalkylmalonates via PTC
αꢀalkylation. The enantioselective PTC
αꢀ
αꢀacetylthiomalonate provided the corresponding
αꢀ
αꢀalkylmalonates in high chemical yields (up to 99%) and optical yields (up to 98% ee).
molecules containing
αꢀsulfur quaternary stereogenic centers.
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Experimental Section
General Methods
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All reagents purchased from commercial sources were used without further purification.
Commercially available KOH pellet (99%) was grinded to prepare Solid KOH as powder form. 50%
w/v aqueous KOH was used as stock solution. Phaseꢀtransfer catalysts (8 and 9) were prepared
according to the reported procedure. Phaseꢀtransfer catalysts (5, 6, and 7) were purchased from the
commercial sources. TLC analyses were performed using preꢀcoated TLC plate (silica gel 60 GF254,
0.25 mm). Flash column chromatography was performed on flash silica gel 230~400 mesh size. The
values of enantiomeric excess (ee) of chiral products were determined by HPLC using 4.6 mm
× 250
1
mm Daicel Chiralpak ADꢀH. Infrared analyses (KBr pellet) were performed by FTꢀIR. HꢀNMR
spectra was recorded at 300MHz, 400MHz, or 500MHz with reference to CHCl (δ 7.24) or CH OH
3
3
1
3
(
δ 3.31). CꢀNMR spectra was obtained by 100 MHz, 125 MHz, or 150MHz spectrometer relative to
1
the central CDCl
3
(δ 77.0) or CD
3
OD (δ 49.0) resonance. Coupling constants (
J
) in HꢀNMR are in
Hz. Lowꢀresolution mass spectra (LRMS) and highꢀresolution mass spectra (HRMS) were measured
on positiveꢀion FAB, CI, or QꢀTOF (ESI) spectrometer. Melting points were measured on melting
point apparatus and were uncorrected. Optical rotations were measured on polarimeter and calibrated
with pure solvent as blank.
(A) Procedure for preparation of PTC substrates
To a stirred solution of benzhydryl tertꢀbutyl malonate (1, 1.63 g, 5.0 mmol) prepared according to
the already reported procedure in dry THF (100 mL) was added DBU (822 µL, 5.5 mmol) at ꢀ78 °C
under argon atmosphere. After stirring for 1 hour at the designated temperature, carbon tetrabromide
(2 g, 6.0 mmol) was added little by little, and the reaction mixture was stirred for 3 hours at the same
temperature. When the starting material was consumed, a saturated ammonium chloride solution was
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added. Extraction using dichloromethane (150 mL x 2), drying over anhydrous MgSO , filtration,
and concentration were performed to yield the residue which can be purified by flash column
chromatography (silica gel, Hexane : EtOAc = 30:1 ) to afford the αꢀmonoꢀbrominated malonate, 2
(1.8 g, 89%) as a pale yellow oil. Potassium thioacetate (423 mg, 3.7 mmol) was added to a stirred
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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6
0
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2
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6
7
8
9
0
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2
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4
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7
8
9
0
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2
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4
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7
8
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8
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0
1
2
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4
5
6
7
8
9
0
solution of αꢀbromomalonate, 2 (1.0 g, 2.47 mmol) in dry dimethylformamide (10 mL) at room
temperature under argon atmosphere. The reaction was stirred until the TLC analysis showed that the
reaction was complete. The reaction solvent was evaporated and diluted with EtOAc (100 ml),
4
extracted with brine (100 ml x 2), dried over anhydrous MgSO , filtered, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel, Hexane : EtOAc = 10:1) to afford 1ꢀ
benzhydryl 3ꢀ(tertꢀbutyl) 2ꢀ(acetylthio)malonate (4, 801 mg, 81% yield) as a white solid. 1ꢀ
benzhydryl 3ꢀ(tertꢀbutyl) 2ꢀ(benzoylthio)malonate (3) was synthesized in the same manner using 1.5
equivalent of benzothiolic acid and triethylamine in anhydrous methanol instead of potassium
thioacetate in DMF.
(
B) Typical experimental procedure for enantioselective phase-transfer catalytic alkylation.
To a solution of 1ꢀbenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀ(acetylthio)malonate (4, 30 mg, 0.075 mmol) and
)ꢀ3,4,5ꢀtrifluorophenylꢀNAS bromide (5, 3.4 mg, 0.0037 mmol) in toluene (250 ꢁL) was added
(S,S
allyl bromide (32.5 ꢁL, 0.38 mmol) at room temperature. At the designated low temperature,
aqueous 50% w/v aqueous KOH (32.6 ꢁL, 0.38 mmol) was added to the reaction mixture and stirred
until the starting material disappeared. After completion of the reaction, the reaction mixture was
4
diluted with ethyl acetate (20 mL), washed with brine (10 mL x 2), dried over anhydrous MgSO ,
filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on
silica gel eluting with HexaneꢀEtOAc solution (15:1) to afford 10b (32.7 mg, 99% yield) as a
colorless oil.
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(C) Analytical data
1-Benzhydryl 3-(tert-butyl) 2-(benzoylthio)malonate (3)
Following the procedure (A) from the compound 2 (1.0 g, 2.47 mmol), the title molecule 3 was
1
obtained as a colorless oil (960 mg, 84% yield). HꢀNMR (500 MHz, CDCl ) δ 7.95 (d,
J = 7.85 Hz,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
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9
0
2H), 7.59 (t,
J
= 7.35 Hz, 1H), 7.45 (t,
J
= 7.73 Hz, 2H), 7.36 ~ 7.26 (m, 10H), 6.96 (s, 1H), 5.31 (s,
) δ 188.6, 165.3, 164.3, 139.20, 139.18, 135.7,
13
1H), 1.38 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl
3
134.0, 128.7, 128.5, 128.4, 128.08, 128.06, 127.5, 127.2, 127.1, 83.9, 78.9, 51.6, 27.6 ppm; IR (KBr)
ꢀ
1
+
3033, 2980, 1738, 1675, 1449, 1288, 1144, 906, 772 cm ; HRMS (FAB) m/z: [M+Na] Calcd for
C H O SNa 485.1399; found 485.1404.
27
26
5
1-Benzhydryl 3-(tert-butyl) 2-(acetylthio)malonate (4)
Following the procedure (A) from the compound 2 (1.0 g, 2.47 mmol), the title molecule 4 was
o
; 1
obtained as a white solid (801mg, 81% yield). mp 70 C HꢀNMR (300 MHz, CDCl
3
) δ 7.32 ~ 7.24
13
(m, 10H), 6.90 (s, 1H), 5.07 (s, 1H), 2.37 (s, 3H), 1.33 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl ) δ
3
1
2
92.2, 165.2, 164.3, 139.2, 139.1, 128.48, 128.45, 128.13, 128.09, 127.2, 127.1, 83.9, 78.8, 51.6,
ꢀ1
9.9, 27.6 ppm; IR (KBr) 3033, 2981, 1738, 1545, 1446, 1220, 1139, 948, 767 cm ; HRMS (FAB)
+
m/z: [M+Na] Calcd for C22
H
24
O
5
SNa 423.1242; found 423.1247.
1-Benzhydryl 3-(tert-butyl) 2-(benzoylthio)-2-allylmalonate (3’)
Following the procedure (B) from the substrate 3 (30 mg, 0.065 mmol), the title molecule 3’ (not
1
numbered in the manuscript) was obtained as a colorless oil (31.7 mg, 97% yield). HꢀNMR (500
MHz, CDCl
3
) δ 7.84 (d,
J = 7.40 Hz, 2H), 7.56 (t, J = 7.40 Hz, 1H) 7.41 (t, J = 7.78 Hz, 2H), 7.35 ~
7
3
1
.24 (m, 8H), 7.14 ~ 7.12 (m, 3H), 6.98 (s, 1H), 5.84 ~ 5.75 (m, 1H), 5.06 ~ 5.03 (m, 2H), 3.23 ~
1
3
.15 (m, 2H), 1.27 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl ) δ 190.0, 166.4, 165.5, 139.5, 139.3,
3
36.5, 133.6, 132.1, 128.6, 128.4, 128.2, 128.1, 127.8, 127.6, 127.20, 127.16, 119.7, 84.0, 78.6, 66.0,
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ꢀ
1
39.1, 27.6 ppm; IR (KBr) 3033, 2979, 1732, 1665, 1449, 1370, 1219, 911, 772 cm ; HRMS (FAB)
+
m/z: [M+Na] Calcd for C30
H
30
O
5
SNa 525.1712; found 525.1707. The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow
rate = 1.0 ml/min, 23 °C, λ = 254 nm) retention time; major isomer 15.34 min, minor isomer 19.55
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
min, 72% ee, [α] = −16.21 (c 1.0, CHCl3).
D
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(prop-2-yn-1-yl)malonate (10a)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using propargyl bromide, the
1
title molecule 10a was obtained as a yellow oil (26.6 mg, 81% yield). HꢀNMR (300 MHz, CDCl ) δ
3
7
.32 ~ 7.26 (m, 10H), 6.94 (s, 1H), 3.32 (ddd, J1 = 23.66 Hz, J2 = 17.45 Hz, J3 = 2.60 Hz, 2H), 2.23
13
(
s, 3H), 2.01 ~ 2.00 (m, 1H), 1.30 (s, 9H) ppm; CꢀNMR (100 MHz, CDCl
3
) δ 194.2, 165.2, 164.1,
1
2
39.2, 139.1, 128.39, 128.35, 128.2, 128.09, 128.08, 127.4, 127.3, 84.5, 79.0, 78.7, 71.8, 65.3, 29.9,
ꢀ1
7.4, 26.6 ppm; IR (KBr) 2979, 1738, 1705, 1370, 1258, 954, 756, 700 cm ; HRMS (FAB) m/z:
+
[M+Na] Calcd for C H O SNa 461.1399; found 461.1395. The enantioselectivity was determined
25
26
5
by chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0
mL/min, 23 °C, λ = 254 nm) retention time: major isomer 12.06 min, minor isomer 18.71 min, 61%
20
ee, [α]
D 3
= −3.47 (c 1.0, CHCl ).
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-allylmalonate (10b)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using allyl bromide, the title
1
molecule 10b was obtained as a colorless oil (31.4 mg, 95% yield). HꢀNMR (500 MHz, CDCl
3
) δ
= 5.20 Hz, 1H), 3.10
) δ 193.6, 166.2, 165.3,
7.34 ~ 7.25 (m, 10H), 6.92 (s, 1H), 5.76 ~ 5.68 (m, 1H), 5.04 (s, 1H) 5.02 (d, J
13
~
3.02 (m, 2H), 2.18 (s, 3H), 1.26 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl
3
1
39.4, 139.3, 132.0, 128.4, 128.3, 128.1, 128.0, 127.5, 127.2, 119.6, 83.9, 78.6, 65.7, 39.0, 30.0, 27.5
ꢀ1
ppm; IR (KBr) 2927, 1732, 1695, 1451, 1370, 1220, 1153, 953, 768 cm ; HRMS (FAB) m/z:
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4
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5
5
5
5
6
+
[M+Na] Calcd for C25
H
28
O
5
SNa 463.1555; found 463.1557. The enantioselectivity was determined
by chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow rate = 1.0
mL/min, 23 °C, λ = 254 nm) retention time: minor isomer 10.51 min, major isomer 15.96 min, 89%
20
ee, [α] = −14.47 (
c
1.0, CHCl3).
D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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2
3
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6
7
8
9
0
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(2-methylallyl)malonate (10c)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 3ꢀbromoꢀ2ꢀ
1
methylpropene, the title molecule 10c was obtained as a pale yellow oil (31.0 mg, 91% yield). Hꢀ
NMR (300 MHz, CDCl ) δ 7.37 ~ 7.26 (m, 10H), 6.94 (s, 1H), 4.81 (s, 1H), 4.67 (s, 1H), 3.14 (s,
3
13
2
1
2
H), 2.20 (s, 3H), 1.64 (s, 3H), 1.27 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl ) δ 193.9, 166.6, 165.7,
3
40.4, 139.32, 139.30, 128.4, 128.3, 128.1, 128.0, 127.6, 127.3, 116.1, 83.9, 78.7, 65.7, 41.4, 29.9,
ꢀ1
7.4, 23.4 ppm; IR (KBr) 2853, 1732, 1693, 1455, 1370, 1255, 1200, 950, 761 cm ; HRMS (FAB)
+
m/z: [M+Na] Calcd for C26
H
30
O
5
SNa 477.1712; found 477.1726. The enantioselectivity was
determined by chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow
rate = 1.0 mL/min, 23 °C, λ = 254 nm) retention time: minor isomer 8.44 min, major isomer 12.60
20
min, 94% ee, [α]
D 3
= −23.78 (c 1.0, CHCl ).
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(2-bromoallyl)malonate (10d)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 2,3ꢀbromopropene, the
1
title molecule 10d was obtained as a yellow oil (33.5 mg, 86% yield). HꢀNMR (300 MHz, CDCl ) δ
3
7
.37 ~ 7.27 (s, 10H), 6.94 (s, 1H), 5.53 (s, 1H), 5.50 (d,
J
= 1.83 Hz, 1H), 3.63 (dd,
1 2
J = 22.40 Hz, J
13
=
15.83 Hz, 2H), 2.22 (s, 3H), 1.28 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl
3
) δ 194.3, 165.7, 164.6,
1
39.1, 128.44, 128.36, 128.2, 128.1, 127.5, 127.3, 127.2, 121.9, 84.5, 79.1, 65.5, 44.0, 29.9, 27.4
ꢀ1
ppm; IR (KBr) 2928, 1735, 1692, 1370, 1245, 1146, 1003, 953, 761 cm ; HRMS (FAB) m/z:
+
[
M+Na] Calcd for C H O BrSNa 541.0660; found 541.0655. The enantioselectivity was
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determined by chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow
rate = 1.0 mL/min, 23 °C, λ = 254 nm) retention time: minor isomer 10.58 min, major isomer 15.07
20
min, 92% ee, [α]
D 3
= −1.29 (c 1.0, CHCl ).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
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8
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2
3
4
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8
9
0
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-benzylmalonate (10e)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using benzyl bromide, the
1
title molecule 10e was obtained as a colorless oil (36.4 mg, 99% yield). HꢀNMR (500 MHz, CDCl
3
)
δ 7.36 ~ 7.31 (m, 4H), 7.30 ~ 7.25 (m, 6H), 7.20 ~ 7.13 (m, 3H), 7.02 (d,
H), 3.67 (dd, J1 = 25.78 Hz, J2 = 14.43 Hz, 2H), 2.17 (s, 3H), 1.25 (s, 9H) ppm; CꢀNMR (125
MHz, CDCl ) δ 194.0, 166.3, 165.2, 139.24, 139.23, 135.4, 130.6, 128.5, 128.3, 128.2, 127.95,
J = 6.90 Hz, 2H), 6.94 (s,
13
1
3
1
1
27.91, 127.7, 127.2, 127.1, 84.0, 78.8, 67.3, 39.5, 30.0, 27.5 ppm; IR (KBr) 3033, 2979, 1732, 1691,
ꢀ1
+
30 5
455, 1220, 1147, 951, 773 cm ; HRMS (FAB) m/z: [M+Na] Calcd for C29H O SNa 513.1712;
found 513.1722. The enantioselectivity was determined by chiral HPLC analysis (DIACEL
Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm)
20
retention time: minor isomer 11.94 min, major isomer 16.44 min, 95% ee, [α]
= +74.53 (c 1.0,
D
3
CHCl ).
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-methylbenzyl)malonate (10f)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 4ꢀmethylbenzyl
1
bromide, the title molecule 10f was obtained as a pale yellow oil (36.4 mg, 96% yield). HꢀNMR
(500 MHz, CDCl3) δ 7.37 ~ 7.31 (m, 4H), 7.30 ~ 7.28 (m, 6H), 6.96 ~ 6.94 (m, 3H), 6.89 (d, J =
13
7.80 Hz, 2H), 3.62 (d,
J
= 3.70 Hz, 2H), 2.26 (s, 3H), 2.21 (s, 3H), 1.26 (s, 9H) ppm; CꢀNMR (125
3
MHz, CDCl ) δ 194.0, 166.4, 165.3, 139.3, 136.7, 132.2, 130.4, 128.6, 128.4, 128.3, 128.1, 127.9,
1
1
27.7, 127.2, 83.9, 78.7, 67.5, 39.1, 30.0, 27.5, 21.1 ppm; IR (KBr) 2927, 1733, 1692, 1455, 1370,
ꢀ1
+
257, 1182, 952, 746 cm ; HRMS (FAB) m/z: [M+Na] Calcd for C H O SNa 527.1868; found
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5
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2
2
2
2
2
2
2
3
3
3
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4
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4
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5
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6
527.1861. The enantioselectivity was determined by chiral HPLC analysis (DIACEL Chiralpak ADꢀ
H, hexane : 2ꢀpropanol = 80: 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm) retention time: minor
20
isomer 13.99 min, major isomer 16.66 min, 96% ee, [α]
D 3
= +93.26 (c 1.0, CHCl ).
0
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9
0
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-fluorobenzyl)malonate (10g)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 4ꢀfluorobenzyl bromide,
1
the title molecule 10g was obtained as a pale yellow oil (37.8 mg, 99% yield). HꢀNMR (300 MHz,
3 1 2
CDCl ) δ 7.38 ~ 7.26 (m, 10H), 7.00 ~ 6.95 (m, 3H), 6.86 ~ 6.80 (m, 2H), 3.64 (dd, J =16.11 Hz, J
13
=
14.67 Hz, 2H), 2.23 (s, 3H), 1.26 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl ) δ 193.9, 166.18,
3
1
1
65.17, 162.1 (d,
J
= 244.0 Hz), 139.14, 139.1, 132.1 (d,
J
= 7.80 Hz), 131.0 (d,
J
= 3.20 Hz), 128.5,
28.3, 128.2, 128.0, 127.6, 127.2, 114.7 (d,
J = 21.10 Hz), 84.1, 78.8, 67.2, 38.8, 30.0, 27.5 ppm; IR
ꢀ
1
+
(
KBr) 2930, 1732, 1692, 1509, 1257, 1221, 1148, 772, 700 cm ; HRMS (FAB) m/z: [M+Na] Calcd
FSNa 531.1617; found 531.1599. The enantioselectivity was determined by chiral
HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow rate = 1.0 mL/min,
29 5
for C29H O
20
D
23 °C, λ = 254 nm) retention time: minor isomer 12.45 min, major isomer 14.55 min, 97% ee, [α]
=
3
+56.50 (c 1.0, CHCl ).
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-chlorobenzyl)malonate (10h)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol), using 4ꢀchlorobenzyl
1
bromide, the title molecule 10h was obtained as a pale yellow oil (39.0 mg, 99% yield). HꢀNMR
(
300 MHz, CDCl3) δ 7.30 (
J
= 8.22 Hz, 2H), 6.94 ~ 6.92 (m, 3H), 3.63 (s, 2H), 2.23 (s, 3H), 1.27 (s,
) δ 193.9, 166.1, 165.1, 139.1, 139.0, 133.8, 133.1, 131.9,
13
9
1
1
5
H) ppm; CꢀNMR (125 MHz, CDCl
3
28.5, 128.3, 128.2, 128.1, 127.6, 127.2, 84.2, 78.9, 67.0, 38.9, 30.0, 27.5 ppm; IR (KBr) 2926, 1733,
ꢀ1
+
692, 1493, 1256, 1181, 951, 772 cm ; HRMS (FAB) m/z: [M+Na] Calcd for C H O ClSNa
29
29
5
47.1322; found 547.1331. The enantioselectivity was determined by chiral HPLC analysis
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(DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow rate = 1.0 mL/min, 23 °C, λ = 254
20
nm) retention time: minor isomer 15.51 min, major isomer 18.61 min, 98% ee, [α]
CHCl ).
D
= +96.64 (c 1.0,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-bromobenzyl)malonate (10i)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 4ꢀbromobenzyl
1
bromide, the title molecule 10i was obtained as a pale yellow oil (42.3 mg, 99% yield). HꢀNMR
3
(300 MHz, CDCl ) δ 7.36 ~ 7.25 (m, 12H), 6.94 (s, 1H), 6.87 (d, J = 8.43 Hz, 2H), 3.62 (s, 2H), 2.23
13
(
s, 3H), 1.27 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl ) δ 193.9, 166.1, 165.1, 139.1, 139.0, 134.4,
3
132.3, 131.0, 128.5, 128.4, 128.3, 128.1, 127.6, 127.2, 121.3, 84.2, 78.9, 67.0, 38.9, 30.0, 27.5 ppm;
ꢀ1
+
IR (KBr) 2979, 1733, 1693, 1489, 1256, 1148, 951, 759, 699 cm ; HRMS (FAB) m/z: [M+Na]
Calcd for C29 BrSNa 591.0817; found 591.0828. The enantioselectivity was determined by
29 5
H O
chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow rate = 1.0
mL/min, 23 °C, λ = 254 nm) retention time: minor isomer 18.44 min, major isomer 21.40 min, 97%
20
ee, [α] = +111.17 (c 1.0, CHCl3).
D
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-nitrobenzyl)malonate (10j)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 4ꢀnitrobenzyl bromide,
1
the title molecule 10j was obtained as a pale yellow oil (39.4 mg, 98% yield). HꢀNMR (300 MHz,
CDCl ) δ 7.96 (d,
J
= 8.43 Hz, 2H), 7.34 ~ 7.25 (m, 10H), 7.15 (d,
= 16.65 Hz, = 14.28 Hz, 2H), 2.25 (s, 3H), 1.29 (s, 9H) ppm; CꢀNMR (125 MHz,
3
) δ 193.8, 165.8, 164.9, 147.1, 143.1, 138.9, 138.8, 131.4, 128.5, 128.4, 128.2, 127.5, 127.2,
J = 8.43 Hz, 2H), 6.94 (s, 1H),
3
1
3
3.76 (dd,
J
1
J
2
CDCl
1
7
23.0, 84.5, 79.1, 66.5, 39.3, 30.1, 27.5 ppm; IR (KBr) 2926, 1732, 1694, 1522, 1348, 1147, 951,
ꢀ
1
+
64, 699 cm ; HRMS (FAB) m/z: [M+Na] Calcd for C H O NSNa 558.1562; found 558.1591.
2
9
29
7
The enantioselectivity was determined by chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane :
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2
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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5
5
5
5
5
5
5
5
5
6
2ꢀpropanol = 80: 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm) retention time: minor isomer 24.01
20
min, major isomer 26.66 min, 95% ee, [α]
D 3
= +79.89 (c 1.0, CHCl ).
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-(tert-butyl)benzyl)malonate (10k)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 4ꢀ(tertꢀbutyl)benzyl
1
bromide, the title molecule 10k was obtained as a pale yellow oil (40.6 mg, 99% yield). HꢀNMR
(500 MHz, CDCl
3
) δ 7.36 ~ 7.25 (m, 10H), 7.15 (d,
J = 8.20 Hz, 2H), 6.97 (d, J = 8.15 Hz, 2H), 6.94
(s, 1H), 3.63 (dd,
J
1
= 31.40 Hz, = 14.45 Hz, 2H), 2.21 (s, 3H), 1.25 (s, 9H), 1.23 (s, 9H) ppm;
J
2
1
3
CꢀNMR (125 MHz, CDCl ) δ 194.0, 166.4, 165.3, 149.9, 139.3, 132.2, 130.3, 128.4, 128.3, 128.1,
3
1
1
5
27.9, 127.6, 127.3, 124.8, 83.9, 78.7, 67.3, 39.1, 34.4, 31.3, 30.0, 27.5 ppm; IR (KBr) 2963, 1733,
ꢀ1
+
692, 1456, 1257, 1182, 952, 759, 699 cm ; HRMS (FAB) m/z: [M+Na] Calcd for C33
38 5
H O SNa
69.2338; found 569.2325. The enantioselectivity was determined by chiral HPLC analysis
(DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 90: 10, flow rate = 1.0 mL/min, 23 °C, λ = 254
20
nm) retention time: minor isomer 14.78 min, major isomer 16.53 min, 96% ee, [α] = +53.64 (
c
1.0,
D
CHCl3).
(R
)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-(trifluoromethyl)benzyl)malonate (10l)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 4ꢀ
(trifluoromethyl)benzyl bromide, the title molecule 10l was obtained as a pale yellow oil (41.5 mg,
1
99% yield). HꢀNMR (300 MHz, CDCl ) δ 7.40 ~ 7.25 (m, 12H), 7.11 (d,
J
= 7.86 Hz, 2H), 6.95 (s,
) δ 193.9, 166.0, 165.0,
= 32.10 Hz), 128.5, 128.3, 128.2, 128.1, 127.6, 127.2, 124.8
J = 270.50 Hz), 84.3, 78.9, 66.8, 39.3, 30.0, 27.5 ppm; IR (KBr) 2926,
3
1
3
1
H), 3.72 (s, 2H), 2.24 (s, 3H), 1.27 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl
39.5, 139.04, 138.99, 130.9, 129.4 (d,
= 3.00 Hz), 124.1 (d,
733, 1694, 1371, 1148, 1067, 761, 699 cm ; HRMS (FAB) m/z: [M+Na] Calcd for
3
1
J
(d,
J
ꢀ1
+
1
C H O F SNa 581.1586; found 581.1575. The enantioselectivity was determined by chiral HPLC
30 29
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analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 99: 1, flow rate = 1.0 mL/min, 23 °C, λ =
20
254 nm) retention time: minor isomer 78.77 min, major isomer 87.07 min, 96% ee, [α]
D
= +36.16
(c
3
1.0, CHCl ).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(R
)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-(trifluoromethoxy)benzyl)malonate (10m)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 4ꢀ
(trifluoromethoxy)benzyl bromide, the title molecule 10m was obtained as a white solid (37.0 mg, 86%
o
1
yield). mp 68 C; HꢀNMR (300 MHz, CDCl
3
) δ 7.37 ~ 7.26 (m, 9H), 7.06 ~ 6.95 (m, 6H), 3.67 (dd,
1
3
J1 = 20.16 Hz, J2 = 14.46 Hz, 2H), 2.23 (s, 3H), 1.25 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl ) δ
3
1
1
7
93.9, 166.1, 165.1, 148.4, 139.10, 139.06, 134.1, 132.0, 128.5, 128.3, 128.2, 128.1, 127.6, 127.2,
20.3, 84.3, 78.9, 66.9, 38.9, 30.0, 27.4 ppm; IR (KBr) 2981, 1733, 1693, 1508, 1371, 1149, 951,
ꢀ
1
+
29 6 3
43, 699 cm ; HRMS (FAB) m/z: [M+Na] Calcd for C30H O F SNa 597.1535; found 597.1545.
The enantioselectivity was determined by chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane :
2ꢀpropanol = 99: 1, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm) retention time: minor isomer 54.51
20
min, major isomer 56.66 min, 96% ee, [α] = +52.02 (c 1.0, CHCl3).
D
(R
)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(4-(methoxycarbonyl)benzyl)malonate (10n)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using methyl 4ꢀ
(bromomethyl)benzoate, the title molecule 10n was obtained as a pale yellow oil (40.7 mg, 99%
1
yield). HꢀNMR (300 MHz, CDCl ) δ 7.82 (d,
J
= 8.22 Hz, 2H), 7.36 ~ 7.26 (m, 10H), 7.09 (d,
= 16.02 Hz, = 14.37 Hz, 2H), 2.23 (s, 3H),
) δ 193.9, 166.8, 166.0, 165.0, 140.8, 139.1, 139.0,
30.6, 129.2, 129.0, 128.5, 128.3, 128.2, 128.0, 127.6, 127.2, 84.3, 78.9, 66.9, 52.0, 39.4, 30.0, 27.5
J =
3
8
1
1
.25 Hz, 2H), 6.95 (s, 1H), 3.88 (s, 3H), 3.71 (d,
J
1
J
2
13
.27 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl
3
ꢀ1
ppm; IR (KBr) 2925, 1725, 1693, 1370, 1147, 1021, 952, 760, 700 cm ; HRMS (FAB) m/z:
+
[
M+Na] Calcd for C H O SNa 571.1766; found 571.1755. The enantioselectivity was determined
31 32
7
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
by chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow rate = 1.0
mL/min, 23 °C, λ = 254 nm) retention time: minor isomer 16.98 min, major isomer 21.67 min, 96%
20
ee, [α]
D 3
= +110.02 (c 1.0, CHCl ).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
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0
1
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3
4
5
6
7
8
9
0
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(3-methoxybenzyl)malonate (10o)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 3ꢀmethoxybenzyl
1
bromide, the title molecule 10o was obtained as a pale yellow oil (37.5 mg, 96% yield). HꢀNMR
(300 MHz, CDCl
3
) δ 7.39 ~ 7.23 (m, 10H), 7.11 ~ 7.05 (m, 1H), 6.96 (s, 1H), 6.76 ~ 6.72 (m, 1H),
6
9
1
.64 ~ 6.61 (m, 2H), 3.66 (dd, J1 = 18.03 Hz, J2 = 14.58 Hz. 2H), 3.66 (s, 3H), 2.22 (s, 3H), 1.25 (s,
13
H) ppm; CꢀNMR (125 MHz, CDCl ) δ 194.0, 166.3, 165.2, 159.1, 139.2, 136.9, 128.8, 128.5,
3
28.3, 128.1, 128.0, 127.5, 127.3, 122.9, 116.3, 112.6, 84.0, 78.7, 67.2, 55.0, 39.5, 30.0, 27.4 ppm;
ꢀ1
+
IR (KBr) 2931, 1733, 1692, 1455, 1370, 1148, 1052, 953, 771 cm ; HRMS (FAB) m/z: [M+Na]
Calcd for C30 SNa 543.1817; found 543.1808. The enantioselectivity was determined by chiral
HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80: 20, flow rate = 1.0 mL/min,
32 6
H O
20
D
23 °C, λ = 254 nm) retention time: minor isomer 11.29 min, major isomer 14.08 min, 96% ee, [α]
=
3
+35.86 (c 1.0, CHCl ).
(R)-1-Benzhydryl 3-(tert-butyl)-2-(acetylthio)-2-(naphthalen-2-ylmethyl)malonate (10p)
Following the procedure (B) from the substrate 4 (30 mg, 0.075 mmol) using 2ꢀ(bromomethyl)
1
naphthalene, the title molecule 10p was obtained as a pale yellow oil (37.0 mg, 91% yield). HꢀNMR
3
(300 MHz, CDCl ) δ 7.78 ~ 7.75 (m, 1H), 7.66 ~ 7.59 (m, 2H), 7.49 (s, 1H), 7.44 ~ 7.26 (m, 12H),
7
3
1
1
.18 (d,
J
1 2
= 8.40 Hz, 1H), 6.97 (s, 1H), 3.90 ~ 3.80 (dd, J = 17.10 Hz, J = 14.37 Hz, 2H), 2.24 (s,
13
H), 1.26 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl
3
) δ 194.1, 166.3, 165.3, 139.22, 139.18, 133.04,
33.00, 132.5, 129.4, 128.6, 128.5, 128.3, 128.2, 128.0, 127.7, 127.6, 127.5, 127.4, 127.2, 125.8,
25.7, 84.1, 78.8, 67.5, 39.6, 30.0, 27.5 ppm; IR (KBr) 2928, 1732, 1691, 1370, 1216, 1147, 771,
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ꢀ
1
+
700 cm ; HRMS (FAB) m/z: [M+Na] Calcd for C33
H
32
O
5
SNa 563.1868; found 563.1887. The
enantioselectivity was determined by chiral HPLC analysis (DIACEL Chiralpak ADꢀH, hexane : 2ꢀ
propanol = 80: 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm) retention time: minor isomer 13.96
20
min, major isomer 19.34 min, 90% ee, [α] = +188.19 (
c
1.0, CHCl3).
D
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(R)-1-Benzhydryl 3-tert-butyl 2-allyl-2-(benzylthio)malonate (11)
To a solution of acetylthioꢀallylmalonate, 10b (27 mg, 62 ꢁmol) and benzyl bromide (11 ꢁL, 93 ꢁmol)
in dimethylformamide (1.5 mL) were added 1% aq. KOH (0.52 mL, 93 ꢁmol) at room temperature.
After completion of the reaction, the mixture was diluted with ethyl aceatate (10 mL) and the organic
layer was separated and collected. Drying over anhydrous MgSO , filtration, and concentration were
4
performed, and the residue was purified by flash column chromatography on silica gel eluting with
HexaneꢀEtOAc solution (24:1) to afford the desired product, 11 (22.6 mg, 75% yield) as a colorless
1
oil. HꢀNMR (300 MHz, CDCl
3
) δ 7.44 ~ 7.15 (m, 15H), 6.97 (s, 1H), 3.69 (s, 2H), 5.87 ~ 5.73 (m,
13
1H), 5.10 ~ 5.04 (m, 2H), 2.88 (d, J = 7.2 Hz, 2H), 1.35 (s, 9H) ppm; CꢀNMR (125 MHz, CDCl ) δ
3
1
1
1
67.9, 167.0, 139.7, 139.6, 136.3, 131.7, 129.6, 128.72, 128.69, 128.66, 128.4, 128.3, 127.8, 127.5,
27.4, 119.6, 83.5, 78.6, 62.4, 38.5, 34.6, 27.9 ppm; IR (KBr) 2979, 1726, 1496, 1369, 1232, 1130,
ꢀ1
+
32 4
027, 841, 772 cm ; HRMS (ESI) m/z: [M+Na] Calcd for C30H O SNa 511.1914; found 511.1917.
2
0
[
D 3
α] = −1.27 (c 1.0, CHCl ).
(
R)-1-Benzhydryl 3-tert-butyl 2-allyl-2-((3-(tert-butoxy)-3-oxopropyl)thio)malonate (12)
To a solution of acetylthioꢀallylmalonate, 10b (44 mg, 0.10 mmol) in methanol (2.0 mL) were added
CO (21 mg, 0.15 mmol) and tertꢀbutyl acrylate (22 ꢁL, 0.15 mmol) at room temperature. After
K
2
3
completion of the reaction, the methanol was removed in vacuo and the residure was diluted with
ethyl acetate (10 mL) and the organic layer was washed with brine and separated. Drying over
anhydrous MgSO , filtration, and concentration were performed, and the residue was purified by
4
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
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6
flash column chromatography on silica gel eluting with HexaneꢀEtOAc solution (20:1) to afford the
1
desired product, 12 (43 mg, 82% yield) as a colorless oil. HꢀNMR (300 MHz, CDCl
3
) δ 7.40 ~ 7.25
(m, 10H), 6.92 (s, 1H), 5.83 ~ 5.69 (m, 1H), 5.08 ~ 5.03 (m, 2H), 2.83 (d,
J
= 6.9 Hz, 2H), 2.75 ~
13
2
1
7
.60 (m, 2H), 2.35 (t,
J
= 7.5 Hz, 2H) 1.42 (s, 9H), 1.32 (s, 9H) ppm; CꢀNMR (200 MHz, CDCl ) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
70.7, 167.7, 166.9, 139.40, 139.36, 131.4, 128.4, 128.1, 128.0, 127.5, 127.1, 119.3, 83.2, 80.8, 78.4,
7.2, 77.0, 76.8, 61.8, 38.2, 34.9, 28.0, 27.6, 24.5 ppm; IR (KBr) 2932, 1729, 1641, 1496, 1369,
ꢀ1
+
38 6
1253, 1080, 843, 772 cm ; HRMS (ESI) m/z: [M+Na] Calcd for C30H O SNa 549.2281; found
2
0
549.2285. [α]
D 3
= −1.63 (c 1.0, CHCl ).
(R)-1-Benzhydryl 3-tert-butyl 2-(acetylthio)-2-(3-hydroxypropyl)malonate (13)
To a solution of the olefin, 10b (45.5 mg, 0.103 mmol) in anhydrous THF (2 mL) was added borane
dimethyl sulfide complex solution (1.0 M in DCM, 230 ꢁL, 0.227 mmol) dropwise under argon at 0
o
C, and stirred for 3 hours. After adding THF:MeOH (1:1) (1 ml) for quenching reaction, Aqueous
phosphate buffer solution (1 mL) and aqueous H O (30 % w/w, 25 ꢁL) were added dropwise and the
2
2
mixture was stirred for overnight at room temperature. After evaporating the mixture, the organic
phase was extracted for two times (5 mL x 2), combined, dried over MgSO , filtered, and then
4
concentrated. The residue was purified by column chromatography (silica gel, Hexane : EtOAc = 2:1)
1
to afford the desired primary alcohol, 13 (26.0 mg, 55% yield) as a colorless oil. HꢀNMR (300 MHz,
CDCl ) δ 7.37 ~ 7.26 (m, 10H), 6.94 (s, 1H), 3.57 (t,
J
= 6.45 Hz, 2H), 2.41 ~ 2.35 (m, 2H), 2.20 (s,
3
13
3H), 1.60 ~ 1.49 (m, 2H), 1.29 (s, 9H) ppm; CꢀNMR (200 MHz, CDCl ) δ 193.6, 166.6, 165.7,
3
139.4, 139.3, 128.4, 128.3, 128.1, 128.0, 127.5, 127.2, 83.9, 78.6, 66.1, 62.4, 31.0, 30.0, 28.3, 27.5
ꢀ1
+
ppm; IR (KBr) 3566, 2934, 1729, 1497, 1370, 1150, 951, 839, 772 cm ; HRMS (ESI) m/z: [M+Na]
20
Calcd for C25
H
30
O
6
SNa 481.1655; found 481.1651. [α]
D
= −5.83 (
c
1.0, CHCl
3
).
(R)-1-Benzhydryl 3-tert-butyl 2-(acetylthio)-2-(3-((methylsulfonyl)oxy)propyl)malonate (14)
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The primary alcohol, 13 (13.5 mg, 29.4 ꢁmol) in dichloromethane (2 mL) was treated with
methanesulfonyl chloride (3 ꢁL, 44.2 ꢁmol) in the presence of trimethylamine (8 ꢁL, 58.9 ꢁmol) at
room temperature under Ar atmosphere and stirred for 1 hour. After completion of the reaction, the
reaction mixture was added with saturated sodium bicarbonate solution (5 mL), diluted with
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
0
dichlromethane (10 mL), washed with brine (5 mL), dried over anhydrous MgSO , filtered, and
4
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
eluting with HexaneꢀEtOAc solution (3:1) to afford the desired mesylate, 14 (15.3 mg, 97% yield) as
1
a colorless oil. HꢀNMR (300 MHz, CDCl
3
) δ 7.35 ~ 7.25 (m, 10H), 6.93 (s, 1H), 4.16 (td,
J
1
= 6.3
Hz, J2 = 1.8 Hz, 2H), 2.96 (s, 3H), 2.46 ~ 2.39 (m, 2H), 2.21 (s, 3H), 1.80 ~ 1.70 (m, 2H), 1.29 (s, 9H)
13
ppm; CꢀNMR (125 MHz, CDCl ) δ 193.9, 166.4, 165.6, 139.5, 139.3, 128.7, 128.6, 128.4, 128.3,
3
1
1
5
27.7, 127.4, 84.5, 79.0, 69.4, 65.9, 37.6, 31.0, 30.2, 27.7, 25.2 ppm; IR (KBr) 2978, 1730, 1696,
ꢀ1
+
32 8 2
496, 1356, 1217, 1112, 949, 771 cm ; HRMS (ESI) m/z: [M+Na] Calcd for C26H O S Na
2
0
59.1431; found 559.1440. [α]
D 3
= −11.51 (c 1.0, CHCl ).
(R)-2-Benzhydryl 2-tert-butyl dihydrothiophene-2,2(3H)-dicarboxylate (15)
To a solution of the mesylate, 14 (16 mg, 0.03 mmol) in dimethylformamide (0.1 mL) was added 1%
aq. KOH (2 ꢁL, 35.3 ꢁmol) at room temperature. After complete conversion of the starting material
to the thiocycle compound, the mixture was diluted with Ethyl acetate (5 mL x 2) and the organic
layer was separated and collected. Drying over anhydrous MgSO , filtration, and concentration were
4
performed, and the residue was purified by flash column chromatography on silica gel eluting with
HexaneꢀEtOAc solution (24:1) to afford the desired ring product, 15 (8.5 mg, 72% yield) as a
1
colorless oil. HꢀNMR (300 MHz, CDCl
3
) δ 7.40 ~ 7.26 (m, 10H), 6.92 (s, 1H), 3.04 ~ 2.92 (m, 2H),
13
2
1
.43 ~ 2.32 (m, 2H), 2.22 ~ 2.08 (m, 2H), 1.26 (s, 9H) ppm; CꢀNMR (150 MHz, CDCl
3
) δ 169.4,
68.8, 139.6, 139.5, 128.5, 128.4, 128.1, 127.9, 127.4, 127.1, 82.7, 78.1, 67.2, 38.4, 34.0, 30.8, 27.5
ꢀ1
ppm; IR (KBr) 2977, 1734, 1496, 1369, 1256, 1133, 1047, 993, 745 cm ; HRMS (ESI) m/z:
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1
1
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
20
26 4 D 3
[M+Na] Calcd for C23H O SNa 421.1444; found 421.1439. [α] = −3.33 (c 1.0, CHCl ).
Acknowledgements
This work was supported by grants from the National Research Foundation of Korea (No.
2016R1A2B2008109) and BK21 Plus Program in 2016.
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Supporting Information
Spectral data of all new compounds as well as an Xꢀray crystallographic analysis of (
material is available free of charge via the Internet at http://pubs.acs.org.
R)ꢀ10m. This
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(
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(13) a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139; b) Kitamura, M.;
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14) Bijvoet method of anomalous Xꢀray scattering was used for the enantiomer assignment of 10m
J.
Am
. Chem. Soc. 1997, 119,
1
4
, 4245.
0
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0
(
and the molecular structure show the atomic numbering and 50% probability displacement ellipsoid.
CCDC 1533604 contains the supplementary crystallographic data for compound 10m. The data can
be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
(
15) The corresponding free thiol from the hydrolysis of 10b in alkali basic condition was unstable
and desulfurized to the corresponding monoꢀallylꢀmalonate.
16) Hakimelahi, G. H.; Just, G. Tetrahedron Lett, 1980, 21, 2119.
(
TOC
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