Enantioselective phase-transfer catalytic α-alkylation of 2-methylbenzyl tert-butyl malonates

Article abstract of DOI:10.1039/c3ob40481a

A new asymmetric synthetic method to prepare α,α- dialkylmalonates for the construction of a quaternary carbon center via phase-transfer catalytic (PTC) alkylation has been developed. Enantioselective α-alkylation of 2-methylbenzyl tert-butyl α-methylmalonates under phase-transfer catalytic conditions in the presence of (S,S)-3,4,5- trifluorophenyl-NAS bromide (10) afforded the corresponding α,α- dialkylmalonates in high chemical (up to 99%) and optical yields (up to 91% ee), which were selectively hydrolyzed to malonic monoacids under alkali basic conditions for conversion to versatile chiral intermediates. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40481a

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Enantioselective phase-transfer catalytic α-alkylation of
2-methylbenzyl tert-butyl malonates†
Cite this: Org. Biomol. Chem., 2013, 11,
4030
Min Woo Ha,a Suckchang Hong,a Cheonhyoung Park,a Yohan Park,b Jihye Lee,a
Mi-hyun Kim,a Jihoon Leea and Hyeung-geun Park*a
A new asymmetric synthetic method to prepare α,α-dialkylmalonates for the construction of a quaternary
carbon center via phase-transfer catalytic (PTC) alkylation has been developed. Enantioselective α-alky-
lation of 2-methylbenzyl tert-butyl α-methylmalonates under phase-transfer catalytic conditions in the
presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (10) afforded the corresponding α,α-dialkylmalo-
nates in high chemical (up to 99%) and optical yields (up to 91% ee), which were selectively hydrolyzed
to malonic monoacids under alkali basic conditions for conversion to versatile chiral intermediates.
Received 8th March 2013,
Accepted 12th April 2013
DOI: 10.1039/c3ob40481a
www.rsc.org/obc
Introduction
C–C bond formation is the most important organic unit
process for the construction of the skeleton of organic mole-
cules. Malonates have been regarded as one of the most funda-
mental synthetic starting materials for C–C bond formation by
coupling itself with electrophilic carbon resources, such as
alkyl halides, imines, and carbonyl compounds including
α,β-unsaturated carbonyls.1 Notably, chiral α,α-dialkylmalo-
nates have been quite popularly employed for the construction
of chiral quaternary carbon centers of biologically active
natural products and pharmaceuticals.2 Chiral malonates can
mostly be obtained by enzymatic resolution of ( )-α,α-dialkyl-
malonates or ( )-α,α-dialkylmalonic acids.3 Construction of
chiral quaternary carbon centers from malonates has been
reported via asymmetric α-alkylation using a chiral auxiliary or
α-fluorination in combination with organometallic catalysis.4
However, enantioselective catalytic direct α-alkylation of malo-
nates has not been well studied to date.
Scheme 1 Enantioselective phase-transfer catalytic α-alkylation of malonamide
esters and malonates.
of this study, we expanded the substrate to the malonate
system for the construction of quaternary carbon centers using
diphenylmethyl tert-butyl α-methylmalonate (3), which is the
first enantioselective catalytic direct α-alkylation process of
malonates.6 The resulting diphenylmethyl tert-butyl α,α-dialkyl-
malonates (4) could be successfully converted into various ver-
satile chiral intermediates via selective deprotection of the
diphenylmethyl group by catalytic hydrogenation. However,
selective deprotection of the tert-butyl group was not success-
ful due to partial hydrolysis of the diphenylmethyl group
under acidic conditions (trifluoroacetic acid or 1 M HCl). In
alkali basic conditions (aq.-KOH), the diphenylmethyl ester
was not hydrolyzed due to steric hindrance. In order to extend
the usefulness of our synthetic method to versatile derivatiza-
tion, especially in the case of α-substitution with unsaturated
electrophiles, a new substrate needed to be developed. In this
article, we report new hydrolyzable malonate substrates under
alkali basic conditions for enantioselective phase-transfer cata-
lytic alkylation.7
Recently, we reported a new synthetic method for chiral
α-alkylmalonamide esters (2) through phase-transfer catalytic
(PTC) mono-α-alkylation of N,N-diarylmalonamide esters (1),
and successfully applied the compound to the synthesis of
various chiral building blocks (Scheme 1).5 As a continuation
aResearch Institute of Pharmaceutical Sciences and College of Pharmacy,
Seoul National University, Seoul 151-742, Republic of Korea. E-mail: hgpk@snu.ac.kr;
Fax: +82 2872 9129; Tel: +82 2880 8264
bCollege of Pharmacy, Inje University, 607 Obang-dong, Gimhae,
Gyeongnam 621-749, Korea
†Electronic supplementary information (ESI) available: Representative experi-
mental procedures and spectroscopic characterization of all new compounds.
See DOI: 10.1039/c3ob40481a
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Scheme 2 Preparation of tert-butyl α-methylmalonates.
Results and discussion
First, we needed to design new malonates possessing one
hydrolyzable ester group. Since the tert-butyl ester group has
historically been more essential for high enantioselectivity
than the diphenylmethyl group in previous enantioselective
PTC α-alkylations,8 the diphenylmethyl group was changed to
a series of less sterically hindered ester groups. Twelve tert-
butyl alkyl methylmalonates were prepared in two steps from
α-methylmeldrum’s acid (Scheme 2). tert-Butanolysis of
α-methylmeldrum’s acid (5) followed by esterification with
various alkyl halides or alcohols in the presence of triethyl-
amine or EDC, respectively, resulted in the corresponding
hydrolyzable tert-butyl α-methylmalonates (7) under alkali
basic conditions (Scheme 3).
The prepared malonates (13–24) were examined for their
efficiency as substrates by α-benzylation under typical PTC con-
ditions based on our previous report (Table 1).6 Enantio-
selective PTC benzylation was performed using the previously
optimized PTC catalyst (10),9 along with benzyl bromide (5.0
equiv.) and 50% KOH (5.0 equiv.) at 0 °C in toluene.
As shown in Table 1, the enantioselectivity varied depend-
ing on the alkyl ester group. Biphenyl groups (entry 2, 14, 80%
ee; entry 3, 15, 72% ee; entry 4, 16, 81% ee) gave around 10%
ee higher or comparable enantioselectivity to the benzyl group
(entry 1, 13, 70% ee). In the case of bulky groups, the
α-naphthylmethyl group (entry 6, 18, 53% ee) showed lower
enantioselectivity than that of the β-naphthylmethyl group
(entry 5, 17, 71% ee). The functional group on the phenyl ring
did not significantly affect the enantioselectivity (entry 9–11,
21–23, 65–74% ee). However, the 2,6-difluorobenzyl group
decreased the enantioselectivity (entry 12, 24, 31% ee). Among
the prepared substrates, the 2-methylbenzyl group showed the
highest enantioselectivity. The chirality of the 2-methylbenzyl
moiety did not show a significant difference in enantio-
selectivity. However, the R-isomer (entry 7, 19, 83% ee) showed
slightly higher enantioselectivity than that of the S-isomer
(entry 8, 20, 77% ee). We speculated that the slight difference
might come from the match/mismatch of the chirality between
Scheme 3 Phase-transfer catalytic α-alkylation of malonates.
Michael addition of tert-butyl malonates in the presence of
N-9-anthracenylcinchonium bromide, respectively.10 Therefore,
we employed cinchonium type catalysts (1111 and 1212) along
with a binaphthyl type catalyst (10). As shown in Table 2, both
Cinchona derived catalysts showed slightly lower enantio-
selectivity compared to catalyst 10. However, their catalytic
turnover rates were 8–20 times faster than that of catalyst 10
(entries 1, 5, 6), with higher chemical yields. A lower tempera-
ture afforded the higher enantioselectivities (entries 1, 3, 4).
The best enantioselectivity was observed in the presence of 10
at −40 °C (entry 4, 91% ee).
Further investigation into the scope and limitations of
unsaturated alkylating agents including benzyl bromides was
performed under the optimized PTC conditions (Table 2, entry
4). The high enantioselectivities (up to 91% ee) in Table 3 indi-
cate that this reaction system is an efficient enantioselective
synthetic method for the preparation of α,α-dialkylmalonates.
However, unactivated alkyl halide such as methyl iodide pro-
vided poor chemical yield (data not shown).
Optically enriched α-methyl-α-allylmalonate (19b) could be
successfully hydrolyzed to the corresponding acids 25 by 50%
KOH (Scheme 4). (R)-2-Methylbenzyl alcohol also could be suc-
cessfully recovered during the workup process. However, selec-
tive hydrolysis of tert-butyl ester failed. TFA acidic conditions
hydrolyzed not only tert-butyl ester but also 2-methylbenzyl
ester. Iodolactonization of 25 with iodine in the presence of
sodium bicarbonate under a mixture of CHCl3–H2O success-
fully afforded the corresponding iodolactones (26 and 27) with
3 : 1 diastereoselectivity.
Conclusion
the substrate (19 and 20) and the catalyst 10. The above cumu- As a summary, a novel enantioselective PTC alkylation of
lative results suggest that over-sized ester groups may not be 2-methylbenzyl tert-butyl malonate has been developed. Asym-
suitable for favorable binding with catalyst 10, and there is no metric PTC α-alkylation of 2-methylbenzyl tert-butyl α-methyl-
electronic effect on enantioselectivity.
malonate afforded the corresponding α,α-dialkylmalonates in
Next, optimization of PTC catalyst, base and reaction temp- high chemical (up to 99%) and optical yields (up to 91% ee). It
erature was performed in the presence of the best substrate 19 is notable that selective hydrolysis of the 2-methylbenzyl group
under toluene (Table 2). During our research on the develop- in alkali base conditions extended the usefulness of enantio-
ment of new substrates, the Itoh group and the Harned group selective PTC alkylation of the malonate system. Our new cata-
successfully reported PTC alkylation and intramolecular lytic system provides an attractive synthetic method for various
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Table 1 Enantioselective PTC alkylation of α-methylmalonatesa
Table 2 Optimization of catalyst and reaction temperaturea
Entry Substrate
1
Time (h) Yieldb (%) eec (%)
Entry Cat Base
T (°C) Time (h) Yieldb (%) dec (%)
16
13
83
60
90
90
99
99
70(+)
80(+)
72(+)
81(+)
1
2
3
4
5
6
10
10
10
10
11
12
50% KOH
Solid KOH
50% KOH
50% KOH
50% KOH
50% KOH
0
0
168
7
168
168
8
91
57
87
91
97
98
83
66
88
91
75
74
−20
−40
0
2
3
4
0
19
a Reactions were performed with 5.0 equiv. of benzyl bromide and 5.0
equiv. of 50% KOH (aq.) under the given conditions. b Isolated yields.
c de was determined by chiral HPLC analysis of the corresponding
diphenylmethyl tert-butyl ester derivative prepared from the benzylated
product 19c.
5
6
44
18
91
97
71(+)
53(+)
under reduced pressure using a Büchi rotary evaporator. As the
commercially available KOH was a pellet type, solid KOH
should be ground to a powder form. Phase-transfer catalyst
(12) was prepared according to the reported procedure.12
Phase-transfer catalysts (10, 11) were purchased from a com-
mercial source (Wako and Sigma Aldrich). Flash column
chromatography was carried out using silica gel
(230–400 mesh). Nuclear magnetic resonance spectra were
7
168
91
91
82
90
88
87
83d(S)
77d(S)
65(+)
74(+)
71(+)
8
1
measured on a 300 MHz or 400 MHz instrument. All H-NMR
9
72
spectra were reported in ppm relative to CHCl3 (δ 7.24). All
13C-NMR spectra were reported in ppm relative to the central
CDCl3 (δ 77.23) or CD3OD (δ 49.15). All HPLC analyses were
performed using a 4.6 mm × 250 mm chiral column as the
stationary phase.
10
11
96
72
Typical experimental procedure A for the preparation of PTC
substrates (13–17, 21–24)
12
72
98
31(+)
The tert-butanolysis of α-methylmeldrum’s acid (5) followed by
esterification with various alkyl halides in the presence of tri-
ethylamine resulting in the corresponding tert-butyl α-methyl-
malonates (6). Triethylamine (0.88 mL, 6.31 mmol) was added
to a stirred solution of α-methyl-malonate mono-tert-butyl
ester (6, 1 g, 5.74 mmol) in dichloromethane (19 mL). 3-Phenyl
benzyl bromide (1.6 g, 6.31 mmol) was added to the reaction
mixture. After reflux for 15 hours, the reaction mixture was
diluted with dichloromethane (100 mL), quenched with
ammonium chloride (150 mL), washed with brine (150 mL),
dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography
(silica gel, hexane–EtOAc = 40 : 1) to afford 15 (1.14 g, 58%
yield) as a pale yellow oil.
a Reactions were performed with 5.0 equiv. of benzyl bromide and 5.0
equiv. of 50% KOH (aq.) under the given conditions. b Isolated yields.
c Enantioselectivity (ee) was determined by chiral HPLC analysis of the
benzylated products. d Diastereoselectivity (de) was determined by
chiral HPLC analysis of diphenylmethyl tert-butyl ester derivative
prepared from the benzylated product.
chiral building blocks which could be readily converted to ver-
satile chiral target molecules with involvement of quaternary
carbon centers. Further applications are now under investigation.
Typical experimental procedure B for the preparation of PTC
substrates (18–20)
Experimental section
General methods
The tert-butanolysis of α-methylmeldrum’s acid (5) followed
All reagents bought from commercial sources were used by esterification with various alcohols by EDC coupling reac-
without further purification. Organic solvents were concentrated tion. α-Methyl-malonate mono-tert-butyl ester (6, 531 mg,
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Table 3 Enantioselective PTC alkylation of 19a
Entry
1
E+
Product
Time (h)
72
Yieldb (%)
80
dec (%)
75(+)
CHuCCH2Br (a)
2d
3
CH2vCCH2Br (b)
BnBr (c)
21
99
91
81(+)
168
91(1S, 2R)e
4
5
PhCHvCHCH2Br (d)
4-MeC6H4CH2Br (e)
72
72
99
82(+)
90(+)
168
6
4-FC6H4CH2Br (f)
168
95
91(+)
a Reactions were performed with 5.0 equiv. of benzyl bromide and 5.0 equiv. of 50% KOH under the given conditions. b Isolated yields. c de was
determined by chiral HPLC analysis of the alkylated products except 19c. d Solid KOH (85%) was used at −20 °C. e de and absolute
stereochemistry of C(1) of 19c was determined by chiral HPLC analysis of the corresponding diphenylmethyl tert-butyl ester derivative prepared
from 19c and comparison of the optical rotation value with the reported value.6
3.05 mmol) was dissolved with 1-naphthalenemethanol
(627 mg, 3.96 mmol) in dichloromethane (7 mL) under
an argon atmosphere. 4-Dimethylaminopyridine (522 mg,
4.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodi-
imide hydrochloride (760 mg, 3.96 mmol) were added to a
stirred solution. After stirring for 15 hours, water (15 mL) was
added to the reaction mixture. The reaction mixture was
extracted with dichloromethane (2 × 100 mL), dried over anhy-
drous MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, hexane–
EtOAc = 80 : 1) to afford 18 (425 mg, 44% yield) as a pale
yellow oil.
Typical experimental procedure for enantioselective
phase-transfer catalytic alkylation
Benzyl bromide (128 μL, 1.08 mmol) was added to a solution
of 1-tert-butyl 3-((R)-1-phenylethyl) 2-methylmalonate (19,
60 mg, 0.22 mmol) and (S,S)-3,4,5-trifluorophenyl-NAS
bromide (10, 9.9 mg, 0.011 mmol) in toluene (0.72 mL) at Scheme 4 Selective hydrolysis of 19b and iodolactonization of 25.
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room temperature. At the designated low temperature (0 °C), 3058, 3031, 2979, 2941, 1908, 1748, 1730, 1602, 0567, 1522,
aqueous 50% KOH (121 μL, 1.08 mmol) was added to the reac- 1488, 1455, 1410, 1392, 1369, 1330, 1281, 1252, 1228, 1146,
tion mixture and stirred until the starting material dis- 1093, 1079, 1030, 1009, 961, 947, 901, 848, 763, 739, 698 cm−1
;
appeared. After the completion of the reaction, the reaction LRMS (FAB): m/z 340; HRMS (FAB): calcd for [C21H24O4]+:
mixture was diluted with ethyl acetate (20 mL), washed with 340.1675, found: 340.1665.
brine (10 mL × 2), dried over anhydrous MgSO4, filtered, and
(S)-1-([1,1′-Biphenyl]-4-ylmethyl) 3-tert-butyl 2-benzyl-
2-methylmalonate (16c)
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane–EtOAc = 40 : 1) to afford
19c (72 mg, 91% yield) as a pale yellow oil. The absolute con- Following the general PTC procedure from 16, 16c was
figurations were assigned as (S) based on the absolute con- obtained as a white solid (99% yield). 1H-NMR (300 MHz,
figurations of 4 (19c was modified to 4; hydrolysis and CDCl3) δ 7.58–7.55 (d, J = 7.86 Hz, 4H), 7.46–7.32 (m, 5H),
esterification into diphenylmethyl ester).
7.21–7.19 (dd, J1 = 5.04 Hz, J2 = 1.74 Hz, 3H), 7.10–7.07
(m, 2H), 5.18 (s, 2H), 3.27–3.12 (dd, J1 = 30.93 Hz, J2 = 13.74
Hz, 2H) ppm; 13C-NMR (100 MHz, CDCl3) δ 171.89, 170.76,
1-([1,1′-Biphenyl]-3-ylmethyl) 3-tert-butyl 2-methylmalonate (15)
Following the general procedure (A) from 6, 15 was obtained as 141.26, 140.60, 136.30, 134.51, 130.24, 129.00, 128.76, 128.05,
a pale yellow oil (58% yield). 1H-NMR (300 MHz, CDCl3) 127.41, 127.20, 127.04, 126.75, 81.69, 66.52, 55.36, 41.01,
δ 7.60–7.54 (m, 4H), 7.47–7.33 (m, 5H), 5.28–5.18 (dd, J1
=
27.68, 13.78 ppm; IR (KBr) 3461, 3060, 3031, 2978, 2935, 1951,
17.03 Hz, J2 = 12.26 Hz, 2H), 3.44–3.37 (dd, J1 = 14.46 Hz, J2 = 1882, 1730, 1604, 1584, 1567, 1520, 1488, 1454, 1409, 1392,
7.32 Hz, 1H), 1.42–1.39 (d, J = 7.32 Hz, 3H), 1.36 (s, 9H) ppm; 1369, 1323, 1279, 1251, 1154, 1112, 1032, 1009, 970, 948, 913,
13C-NMR (100 MHz, CDCl3) δ 170.20, 168.96, 141.52, 140.62, 849, 827, 793, 763, 738, 700 cm−1; LRMS (FAB): m/z 430; HRMS
136.08, 128.88, 128.68, 127.37, 127.06, 127.03, 127.01, 81.58, (FAB): calcd for [C28H30O4]+: 430.2144, found: 430.2148, mp
66.70, 47.08, 27.67, 13.45 ppm; IR (KBr) 3461, 3060, 3033, 110 °C. The enantioselectivity was determined by chiral HPLC
2979, 2941, 1952, 1748, 1730, 1600, 1577, 1481, 1455, 1424, analysis after modification of 16c into (S)-α-benzyl-α-methyl-
1392, 1369, 1331, 1281, 1252, 1229, 1146, 1093, 1080, 1029, malonic acid diphenylmethyl ester tert-butyl ester (4c)
958, 923, 898, 847, 799, 758, 728, 700 cm−1; LRMS (FAB): m/z (DAICEL Chiralpak AD-H, hexane–2-propanol = 98 : 2, flow
340; HRMS (FAB): calcd for [C21H24O4]+: 340.1675, found: rate = 1.0 mL min−1, 23 °C, λ = 254 nm, retention time;
340.1677.
major isomer(S) 15.1 min, minor isomer(R) 13.7 min, 81% ee).
[α]2D5 = +19.27 (c 1.0, CHCl3).
(S)-1-([1,1′-Biphenyl]-3-ylmethyl) 3-tert-butyl 2-benzyl-
2-methylmalonate (15c)
1-tert-Butyl 3-(naphthalen-2-ylmethyl) 2-methylmalonate (17)
Following the general PTC procedure from 15, 15c was Following the general procedure (A) from 6, 17 was obtained as
1
obtained as a pale yellow oil (99% yield). H-NMR (300 MHz,
CDCl3) δ 7.58–7.56 (m, 4H), 7.47–7.33 (m, 6H), 7.22–7.19 δ 7.83–7.81 (m, 4H), 7.50–7.42 (m, 3H), 5.36–5.27 (m, 2H),
(m, 2H), 7.11–7.08 (m, 2H), 5.23 (s, 2H), 3.29–3.13 (dd, J1 3.43–3.36 (dd, J1 = 14.46 Hz, J2 = 7.14 Hz, 1H), 1.40–1.35
a
white solid (78% yield). 1H-NMR (300 MHz, CDCl3)
=
32.31 Hz, J2 = 13.65 Hz, 2H), 1.34–1.32 (m, 12H) ppm; (m, 12H) ppm; 13C-NMR (100 MHz, CDCl3) δ 170.25, 168.99,
13C-NMR (100 MHz, CDCl3) δ 171.91, 170.78, 141.57, 140.66, 133.07, 133.05, 132.96, 128.24, 127.86, 127.59, 127.30, 126.20,
136.61, 136.04, 130.24, 128.94, 128.75, 128.06, 127043, 127.38, 126.18, 125.77, 81.59, 66.86, 47.12, 27.69, 13.47 ppm; IR (KBr)
127.11, 126.76, 81.71, 66.81, 55.38, 41.03, 27.66, 19.82 ppm; IR 3646, 3461, 3057, 2979, 2941, 2883, 1916, 1748, 1730, 1636,
(KBr) 3062, 3031, 2979, 2935, 1950, 1883, 1730, 1603, 1496, 1604, 1510, 1456, 1392, 1369, 1328, 1274, 1252, 1229, 1175,
1481, 1455, 1424, 1392, 1369, 1323, 1279, 1252, 1154, 1112, 1146, 1093, 1081, 1030, 964, 949, 896, 853, 818, 750 cm−1
;
1030, 971, 887, 848, 799, 757, 738, 700 cm−1; LRMS (FAB): m/z LRMS (FAB): m/z 314; HRMS (FAB): calcd for [C19H22O4]+:
430; HRMS (FAB): calcd for [C28H30O4]+: 430.2144, found: 314.1518, found: 314.1516, mp 53 °C.
430.2143. The enantioselectivity was determined by chiral
(S)-1-tert-Butyl 3-(naphthalen-2-ylmethyl) 2-benzyl-
HPLC analysis (DAICEL Chiralcel OD-H, hexane–2-propanol =
2-methylmalonate (17c)
99.5 : 0.5, flow rate = 1.0 mL min−1, 23 °C, λ = 254 nm, reten-
tion time; major isomer 23.9 min, minor isomer 20.6 min, Following the general PTC procedure from 17, 17c was
72% ee). [α]2D5 = +11.60 (c 1.0, CHCl3).
obtained as a white solid (91% yield). 1H-NMR (300 MHz,
CDCl3) δ 7.84–7.81 (m, 4H), 7.54–7.42 (m, 3H), 7.22–7.07
(m, 5H), 5.32 (s, 2H), 3.29–3.15 (dd, J1 = 30.03 Hz, J2 = 13.53
1-([1,1′-Biphenyl]-4-ylmethyl) 3-tert-butyl 2-methylmalonate (16)
Following the general procedure (A) from 6, 16 was obtained as Hz, 2H), 1.34–1.32 (d, J = 5.31 Hz, 12H) ppm; 13C-NMR
a pale yellow oil (83% yield). 1H-NMR (300 MHz, CDCl3) (100 MHz, CDCl3) δ 171.98, 170.80, 136.31, 133.11, 132.93,
δ 7.60–7.56 (m, 4H), 7.47–7.33 (m, 5H), 5.26–5.16 (dd, J1
=
130.25, 128.29, 128.05, 127.95, 127.64, 126.75, 126.26, 126.08,
17.03 Hz, J2 = 12.26 Hz, 2H), 3.44–3.37 (q, J = 7.26 Hz, 1H), 81.72, 66.97, 55.43, 41.06, 27.68, 19.83 ppm; IR (KBr) 3461,
1.42–1.39 (m, 12H) ppm; 13C-NMR (100 MHz, CDCl3) δ 170.20, 3060, 3030, 2978, 2929, 2855, 1950, 1730, 1635, 1604, 1583,
168.95, 141.19, 140.54, 134.55, 128.70, 128.68, 127.36, 127.16, 1510, 1496, 1455, 1392, 1368, 1323, 1278, 1252, 1154, 1111,
127.00, 81.58, 66.44, 47.10, 27.69, 13.43 ppm; IR (KBr) 3461, 1066, 1032, 1019, 972, 950, 890, 853, 817, 746, 702 cm−1; LRMS
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(FAB): m/z 404; HRMS (FAB): calcd for [C26H28O4]+: 404.1988, (S)-1-tert-Butyl 3-((R)-1-phenylethyl) 2-methyl-
found: 404.1988, mp 66 °C. The enantioselectivity was deter- 2-propynlmalonate (19a)
mined by chiral HPLC analysis (DAICEL Chiralcel OJ-H,
Following the general PTC procedure from 19, 19a was
obtained as a pale yellow oil (80% yield). H-NMR (300 MHz,
hexane–2-propanol = 95 : 5, flow rate = 1.0 mL min−1, 23 °C,
λ = 254 nm, retention time; major isomer 21.3 min, minor
isomer 24.7 min, 72% ee). [α]2D5 = +17.70 (c 1.0, CHCl3).
1
CDCl3) δ 7.35–7.23 (m, 5H), 5.95–5.88 (qd, J1 = 6.60 Hz, J2
=
2.94 Hz, 1H), 2.74–2.71 (dd, J1 = 7.23 Hz, J2 = 2.67 Hz, 2H),
1.55–1.52 (dt, J1 = 17.04 Hz, J2 = 2.66 Hz, 1H), 1.54–1.46
(m, 6H), 1.35 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3)
1-tert-Butyl 3-(naphthalen-1-ylmethyl) 2-methylmalonate (18)
Following the general procedure (B) from 6, 18 was obtained δ 170.39, 169.63, 140.97, 128.44, 127.94, 126.13, 81.95, 79.40,
as a pale yellow oil (44% yield). 1H-NMR (300 MHz, CDCl3) 73.31, 71.14, 53.51, 27.64, 25.77, 21.82, 19.60 ppm; IR (KBr)
δ 8.04–8.00 (m, 1H), 7.90–7.82 (m, 2H), 7.57–7.40 (m, 4H), 3460, 3290, 3088, 3065, 3034, 2980, 22930, 2854, 2123, 1955,
5.66–5.57 (dd, J1 = 4.91 Hz, J2 = 12.36 Hz, 2H), 3.41–3.34 (q, J = 1732, 1605, 1586, 1496, 1456, 1425, 1393, 1370, 1293, 1250,
7.26 Hz, 1H), 1.39–1.37 (d, J = 7.14 Hz, 3H), 1.27 (s, 9H) ppm; 1218, 1196, 1159, 1119, 1061, 1030, 1008, 995, 976, 955, 937,
13C-NMR (100 MHz, CDCl3) δ 170.28, 168.95, 133.61, 131.55, 847, 761, 743, 699, 645 cm−1
, HRMS (FAB): calcd for
131.01, 129.27, 128.57, 127.51, 126.50, 125.84, 125.11, 123.50, [C19H25O4]+: 317.1753, found: 317.1747. The enantioselectivity
81.54, 65.09, 47.10, 27.56, 13.47, ppm; IR (KBr) 3460, 3050, was determined by chiral HPLC analysis (DAICEL Chiralcel
2979, 2939, 2291, 1946, 1747, 1730, 1600, 1512, 1456, 1392, OJ-H, hexane–2-propanol = 99 : 1, flow rate = 1.0 mL min−1
,
1369, 1329, 1281, 1232, 1146, 1093, 1026, 957, 901, 848, 798, 23 °C, λ = 210 nm, retention time; major isomer(S) 5.8 min,
776, 737, 647 cm−1; LRMS (FAB): m/z 314; HRMS (FAB): calcd minor isomer(R) 7.0 min, 75% ee). [α]2D5 = +53.87 (c 1.0,
for [C19H22O4]+: 314.1518, found: 314.1518.
CHCl3).
(S)-1-tert-Butyl 3-(naphthalen-1-ylmethyl) 2-benzyl-
(S)-1-tert-Butyl 3-((R)-1-phenylethyl) 2-methyl-
2-methylmalonate (18c)
2-allylmalonate (19b)
Following the general PTC procedure from 18, 18c was Following the general PTC procedure from 19, 19b was
1
1
obtained as a pale yellow oil (97% yield). H-NMR (300 MHz, obtained as a pale yellow oil (99% yield). H-NMR (300 MHz,
CDCl3) δ 8.06–8.03 (m, 1H), 7.93–7.88 (m, 2H), 7.62–7.46 CDCl3) δ 7.28–7.16 (m, 5H), 5.87–5.80 (q, J = 6.6 Hz, 1H),
(m, 4H), 7.26–7.13 (m, 5H), 5.68 (s, 2H), 3.36–3.19 (dd, J1
=
5.70–5.45 (m, 1H), 5.06–4.8 (m, 2H), 2.52–2.46 (m, 2H),
35.52 Hz, J2 = 13.71 Hz, 2H), 1.39 (s, 3H), 1.28 (s, 9H) ppm; 1.47–1.44 (dd, J1 = 6.06 Hz, J2 = 2.03 Hz, 3H), 1.27–1.23 (m,
13C-NMR (100 MHz, CDCl3) δ 170.87, 170.71, 136.25, 133.60, 12H) ppm; 13C-NMR (100 MHz, CDCl3) δ 171.40, 170.79,
131.62, 131.01, 130.20, 129.25, 128.54, 127.97, 127.64, 126.67, 141.18, 132.78, 128.42, 127.93, 126.21, 118.90, 81.45, 72.94,
126.52, 125.84, 125.10, 123.51, 81.58, 64.96, 55.46, 41.00, 53.81, 40.06, 27.73, 22.00, 19.65 ppm; IR (KBr) 3460, 3078,
27.46, 19.82 ppm; IR (KBr) 3461, 3061, 3031, 2978, 2933, 1950, 3034, 2980, 2934, 2873, 1953, 1729, 1641, 1606, 1586, 1496,
1730, 1601, 1512, 1496, 1455, 1392, 1369, 1323, 1279, 1252, 1455, 1392, 1369, 1292, 1250, 1207, 1146, 1114, 1063, 1030,
1154, 1112, 1065, 1033, 968, 908, 877, 848, 798, 776, 738, 802, 1007, 995, 920, 848, 761, 742, 699, 650 cm−1, LRMS (FAB): m/z
650 cm−1; LRMS (FAB+): m/z 404; HRMS (FAB): calcd for 319; HRMS (FAB): calcd for [C19H27O4]+: 319.1909, found:
[C26H28O4]+: 404.1988, found: 404.1990. The enantioselectivity 319.1909. The enantioselectivity was determined by chiral
was determined by chiral HPLC analysis (DAICEL Chiralcel HPLC analysis (DAICEL Chiralcel OJ-H, hexane–2-propanol =
OJ-H, hexane–2-propanol = 80 : 20, flow rate = 1.0 mL min−1
,
99 : 1, flow rate = 1.0 mL min−1, 23 °C, λ = 210 nm, retention
23 °C, λ = 254 nm, retention time; major isomer 9.3 min, time; major isomer(S) 5.3 min, minor isomer(R) 6.6 min,
minor isomer 22.4 min, 53% ee). [α]2D5 = +14.71 (c 1.0, CHCl3).
81% ee). [α]2D5 = +57.40 (c 1.0, CHCl3).
1-tert-Butyl 3-((R)-1-phenylethyl) 2-methylmalonate (19)
(S)-1-tert-Butyl 3-((R)-1-phenylethyl) 2-benzyl-
2-methylmalonate (19c)
Following the general procedure (B) from 6, 19 was obtained
as a pale yellow oil (81% yield). 1H-NMR (300 MHz, CDCl3) Following the general PTC procedure from 19, 19c was
δ 7.34–7.25 (m, 5H), 5.94–5.88 (q, J = 6.59 Hz, 1H), 3.37–3.29 obtained as a pale yellow oil (91% yield). H-NMR (300 MHz,
1
(ddd, J1 = 14.47 Hz, J2 = 7.33 Hz, J3 = 4.76 Hz, 1H), 1.55–1.52 CDCl3) δ 7.41–6.94 (m, 10H), 5.98–5.91 (q, J = 6.59 Hz, 1H),
(d, J = 6.60 Hz, 3H), 1.41–1.33 (m, 12H) ppm; 13C-NMR 3.21–3.10 (dd, J1 = 21.6 Hz, J2 = 12.99 Hz, 2H), 1.58–1.26
(100 MHz, CDCl3) δ 169.67, 169.61, 169.13, 169.04, 141.16, (m, 15H) ppm; 13C-NMR (100 MHz, CDCl3) δ 171.30, 170.96,
141.13, 128.44, 128.40, 127.93, 127.84, 126.09, 126.01, 81.55, 140.87, 136.29, 130.27, 128.51, 128.08, 127.98, 126.66, 126.50,
81.54, 73.01, 72.94, 47.38, 47.27, 27.90, 27.81, 27.75, 27.68, 81.65, 73.11, 55.24, 40.92, 31.92, 29.69, 27.77, 21.68,
21.97, 21.87, 13.44, 13.37 ppm; IR (KBr) 3064, 3033, 2981, 19.73 ppm; IR (KBr) 3461, 3087, 3064, 3032, 2979, 2929, 2855,
2936, 1732, 1604, 1496, 1454, 1370, 1294, 1233, 1175, 1151, 1950, 1879, 1805, 1730, 1604, 1585, 1496, 1455, 1392, 1369,
1108, 1064, 1029, 969, 910, 849, 742, 699, 649 cm−1; LRMS 1325, 1279, 1250, 1208, 1185, 1155, 1114, 1062, 1030, 1008,
(FAB): m/z 279; HRMS (FAB): calcd for [C16H23O4]+: 279.1596, 995, 946, 913, 849, 760, 740, 700 cm−1; LRMS (FAB+): m/z 369;
found: 279.1590. [α]2D5 = +59.18 (c 1.0, CHCl3).
HRMS (FAB): calcd for [C23H29O4]+: 369.1988, found: 368.1983.
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The enantioselectivity was determined by chiral HPLC analysis (m, 2H), 5.95–5.90 (q, J = 6.6 Hz, 1H), 3.15–3.04 (dd, J1
=
after modification of 19c into (S)-α-benzyl-α-methyl-malonic 32.02 Hz, J2 = 13.9 Hz, 2H), 1.55–1.52 (m, 3H), 1.37 (s, 9H),
acid diphenylmethyl ester tert-butyl ester (4c) (DAICEL Chiral- 1.28 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3) δ 171.11, 170.86,
pak AD-H, hexane–2-propanol = 98 : 2, flow rate = 1.0 mL 163.03–130.60 (d, J = 243.3 Hz), 140.77, 131.98–131.94 (d, J =
min−1, 23 °C, λ = 254 nm, retention time; major isomer(S) 3.2 Hz), 131.74–131.66 (d, J = 8 Hz), 128.54, 128.17, 126.54,
15.1 min, minor isomer(R) 13.7 min, 90% ee). [α]2D5 = +59.18 114.90–114.70 (d, J = 20.8 Hz), 81.77, 73.19, 55.21, 40.12, 27.77,
(c 1.0, CHCl3).
21.65, 19.74 ppm; IR (KBr) 3645, 3439, 3072, 3044, 2979, 2936,
2874, 1727, 1604, 1510, 1479, 1456, 1396, 1370, 1351, 1327,
1272, 1254, 1224, 1156, 1123, 1110, 1085, 1061, 1016, 984, 905,
(S)-1-tert-Butyl 3-((R)-1-phenylethyl) 2-cinnamyl-
2-methylmalonate (19d)
Following the general PTC procedure from 19, 19d was [C23H28FO4]+: 387.1972, found: 387.1974. The enantio-
obtained as a pale yellow oil (72% yield). H-NMR (300 MHz, selectivity was determined by chiral HPLC analysis after modi-
843, 801, 759, 726, 641 cm−1
; HRMS (FAB): calcd for
1
CDCl3) δ 7.35–7.18 (m, 10H), 6.35–6.30 (m, 1H), 6.03–5.91 fication of 19f to (S)-α-(4′-fluoro-benzyl)-α-methyl-malonic acid
(m, 2H), 2.75–2.64 (m, 2H), 1.57–1.54 (d, J = 6.78 Hz, 3H), diphenylmethyl ester tert-butyl ester (4f) (DAICEL Chiralpak
1.41–1.37 (m, 12H) ppm; 13C-NMR (100 MHz, CDCl3) δ 171.35, AD-H, hexane–2-propanol = 95 : 5, flow rate = 1.0 mL min−1
,
170.86, 141.04, 137.12, 133.81, 128.47, 128.38, 127.98, 127.20, 23 °C, λ = 254 nm, retention time; major isomer(S) 10.0 min,
126.31, 126.15, 124.34, 81.57, 73.03, 54.28, 39.28, 27.78, 21.79, minor isomer(R) 9.2 min, 91% ee). [α]2D5 = +70.64 (c 1.0, CHCl3).
19.96 ppm; IR (KBr) 3451, 3083, 3060, 3030, 2979, 2933, 2872,
1951, 1877, 1728, 1599, 1496, 1475, 1452, 1392, 1369, 1291,
1274, 1249, 1209, 1159, 1121, 1110, 1062, 1030, 1008, 995, 968,
1-tert-Butyl 3-((S)-1-phenylethyl) 2-methylmalonate (20)
Following the general procedure (B) from 6, 20 was obtained
as a pale yellow oil (79% yield). 1H-NMR (300 MHz, CDCl3)
δ 7.25–7.17 (m, 5H), 5.87–5.80 (q, J = 6.54 Hz, 1H), 3.30–3.21
(m, 1H), 1.47–1.45 (d, J = 6.54 Hz, 1H), 1.38–1.26 (m, 12H)
ppm; 13C-NMR (100 MHz, CDCl3) δ 169.55, 169.49, 169.02,
168.93, 141.10, 141.07, 128.37, 128.32, 127.85, 127.77, 126.01,
125.93, 81.41, 72.92, 72.85, 47.28, 47.18, 27.73, 27.66, 21.90,
21.80, 13.36, 13.29 ppm; IR (KBr) 2981, 2939, 1748, 1730, 1496,
1456, 1369, 1336, 1253, 1149, 1064, 1029, 996, 850, 762,
699 cm−1; LRMS (FAB+): m/z 279; HRMS (FAB): calcd for
[C16H23O4]+: 279.1596, found: 279.1597. [α]2D5 = −62.22 (c 1.0,
CHCl3).
912, 849, 760, 742, 697 cm−1
; HRMS (FAB): calcd for
[C25H31O4]+: 359.2222, found: 359.2226. The enantioselectivity
was determined by chiral HPLC analysis (DAICEL Chiralcel
OJ-H, hexane–2-propanol = 99 : 1, flow rate = 1.0 mL min−1
,
23 °C, λ = 210 nm, retention time; major isomer(S) 10.4 min,
minor isomer(R) 14.8 min, 82% ee). [α]2D5 = +63.39 (c 1.0,
CHCl3).
(S)-1-tert-Butyl 3-((R)-1-phenylethyl) 2-methyl-
2-(4-methylbenzyl)malonate (19e)
Following the general PTC procedure from 19, 19e was
1
obtained as a pale yellow oil (99% yield). H-NMR (400 MHz,
CDCl3) δ 7.39–7.30 (m, 5H), 6.94–6.92 (d, J = 7.9 Hz, 2H),
6.83–6.81 (d, J = 7.9 Hz, 2H), 5.93–5.90 (q, J = 6.5 Hz, 1H),
3.15–3.04 (dd, J1 = 29.96 Hz, J2 = 13.76 Hz, 2H), 2.24 (s, 3H),
1.53–1.52 (d, J = 6.6 Hz), 1.37 (s, 9H), 1.27 (s, 3H) ppm;
13C-NMR (100 MHz, CDCl3) δ 171.37, 171.05, 140.92, 136.15,
133.13, 130.13, 128.70, 128.50, 128.07, 126.51, 81.59, 73.07,
55.27, 40.50, 27.79, 21.72, 20.98, 19.70 ppm; IR (KBr) 3652,
3439, 2978, 2934, 2873, 2934, 2873, 1727, 1515, 1478, 1455,
1395, 1369, 1350, 1324, 1271, 1253, 1222, 1153, 1121, 1088,
1060, 980, 904, 843, 818, 794, 755, 725, 638 cm−1; HRMS (FAB):
calcd for [C24H31O4]+: 383.2222, found: 383.2216. The enantio-
selectivity was determined by chiral HPLC analysis after modi-
fication of 19e into (S)-α-(4′-methyl-benzyl)-α-methyl-malonic
acid diphenylmethyl ester tert-butyl ester (4e) (DAICEL Chiral-
pak AD-H, hexane–2-propanol = 98 : 2, flow rate = 1.0 mL
min−1, 23 °C, λ = 254 nm, retention time; major isomer(S)
21.2 min, minor isomer(R) 15.5 min, 90% ee). [α]2D5 = +64.18
(c 1.0, CHCl3).
(S)-1-tert-Butyl 3-((S)-1-phenylethyl) 2-benzyl-
2-methylmalonate (20c)
Following the general PTC procedure from 20, 20c was
1
obtained as a pale yellow oil (82% yield). H-NMR (300 MHz,
CDCl3) δ 7.33–6.86 (m, 10H), 5.90–5.81 (p, J = 6.6 Hz, 1H),
3.13–3.02 (m, 2H), 1.50–1.45 (m, 3H), 1.32–1.28 (m, 9H),
1.22–1.20 (d, J = 6.6 Hz, 3H) ppm; 13C-NMR (100 MHz, CDCl3)
δ 171.41, 170.95, 141.16, 136.46, 130.26, 128.50, 128.05,
126.74, 126.48, 126.10, 81.64, 73.15, 55.25, 40.96, 29.68, 27.75,
22.01, 19.91 ppm; IR (KBr) 3032, 2980, 2935, 1729, 1496, 1455,
1392, 1369, 1280, 1251, 1208, 1154, 1113, 1063, 1030, 1008,
995, 849, 761, 740, 700 cm−1
; HRMS (FAB): calcd for
[C23H29O4]+: 369.2066, found: 369.2072. The enantioselectivity
was determined by chiral HPLC analysis after modification of
20c to (S)-α-benzyl-α-methyl-malonic acid diphenylmethyl
ester tert-butyl ester (4c) (DAICEL Chiralpak AD-H, hexane–
2-propanol = 98 : 2, flow rate = 1.0 mL min−1, 23 °C, λ =
254 nm, retention time; major isomer(S) 15.1 min, minor
isomer(R) 13.7 min, 90% ee). [α]2D5 = −47.36 (c 1.0, CHCl3).
(S)-1-tert-Butyl 3-((R)-1-phenylethyl) 2-methyl-
2-(4-fluorobenzyl)malonate (19f)
1-tert-Butyl 3-(2-methoxybenzyl) 2-methylmalonate (21)
Following the general PTC procedure from 19, 19f was
1
obtained as a pale yellow oil (95% yield). H-NMR (400 MHz, Following the general procedure (A) from 6, 21 was obtained as
CDCl3) δ 7.38–7.28 (m, 5H), 6.90–6.86 (m, 2H), 6.81–6.77 a pale yellow oil (88% yield). 1H-NMR (300 MHz, CDCl3)
4036 | Org. Biomol. Chem., 2013, 11, 4030–4039
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δ 7.27–7.19 (m, 2H), 6.89–6.79 (m, 2H), 5.15 (s, 2H), 3.75 249.2 Hz, J2 = 13.0 Hz)], 136.20, 130.23, 128.11, 126.84,
(s, 3H), 3.35–3.28 (q, J = 7.26 Hz, 1H), 1.33–1.31 (t, J = 3.57 Hz, 125.50–125.44 (t, J = 2.8 Hz), 125.20–125.08 (d, J = 11.3 Hz),
12H) ppm; 13C-NMR (100 MHz, CDCl3) δ 170.39, 136.13, 124.17–124.05 (dd, J1 = 6.55 Hz, J2 = 4.83 Hz), 117.61–117.44
157.40, 129.54, 129.50, 123.96, 120.32, 110.31, 81.50, 62.23, (d, J = 16.9 Hz), 81.88, 60.15–60.08 (t, J = 3.4 Hz), 55.40, 41.02,
55.30, 47.15, 27.73, 13.50 ppm; IR (KBr) 3461, 2979, 2942, 27.68, 19.83 ppm; IR (KBr) 3470, 3087, 3063, 3031, 2965, 2933,
2840, 2054, 1747, 1730, 1605, 1591, 1496, 1461, 1441, 1370, 2873, 1950, 1732, 1631, 1600, 1494, 1456, 1370, 1289, 1258,
1330, 1290, 1250, 1146, 1093, 1081, 1050, 1030, 984, 954, 929, 1155, 1111, 1074, 1030, 975, 914, 847, 823, 788, 738, 702 cm−1
;
901, 849, 755 cm−1; LRMS (FAB): m/z 294; HRMS (FAB): calcd LRMS (FAB+): m/z 391; HRMS (FAB): calcd for [C22H25F2O4]+:
for [C16H22O5]+: 294.1467, found: 294.1472.
391.1721, found: 391.1720. The enantioselectivity was deter-
mined by chiral HPLC analysis (DAICEL Chiralcel OD-H,
hexane–2-propanol = 99 : 1, flow rate = 1.0 mL min−1, 23 °C,
λ = 254 nm, retention time; major isomer 6.3 min, minor
(S)-1-tert-Butyl 3-(2-methoxybenzyl) 2-benzyl-
2-methylmalonate (21c)
Following the general PTC procedure from 21, 21c was isomer 5.9 min, 74% ee). [α]2D5 = +29.97 (c 1.0, CHCl3).
1
obtained as a pale yellow oil (90% yield). H-NMR (300 MHz,
1-tert-Butyl 3-(2,3,4-trifluorobenzyl) 2-methylmalonate (23)
CDCl3) δ 7.29–7.03 (m, 7H), 6.88–6.79 (m, 2H), 5.18–5.09 (dd,
J1 = 15.39 Hz, J2 = 12.63 Hz, 2H), 3.75 (s, 3H), 3.21–3.05 (dd, Following the general procedure (A) from 6, 23 was obtained as
J1 = 32.49 Hz, J2 = 13.65 Hz, 2H), 1.28 (s, 9H), 1.24 (s, 3H) ppm; a pale yellow oil (99% yield). 1H-NMR (300 MHz, CDCl3)
13C-NMR (100 MHz, CDCl3) δ 172.00, 170.91, 157.48, 136.45, δ 7.15–7.07 (m, 1H), 7.00–6.90 (m, 1H), 5.22–5.12 (m, 2H),
130.25, 129.83, 129.55, 128.03, 126.68, 123.89, 120.32, 110.29, 3.39–3.31 (dd, J1 = 14.46 Hz, J2 = 7.32 Hz, 1H), 1.37–1.34 (d, J =
81.56, 62.30, 55.36, 55.25, 40.99, 27.67, 19.73, 0.97 ppm; IR 8.07 Hz, 12H) ppm; 13C-NMR (100 MHz, CDCl3) δ 170.03,
(KBr) 3460, 3064, 3032, 2931, 2857, 1729, 1640, 1604, 1496, 168.78,
[152.66–152.63,
152.57–152.54,
150.17–150.14,
1454, 1392, 1368, 1330, 1285, 1250, 1209, 1188, 1153, 1082, 150.07–150.04 (ddd, J1 = 249.9 Hz, J2 = 9.9 Hz, J3 = 3.0 Hz)]
1038, 1013, 991, 917, 848, 738, 701, 645 cm−1; LRMS (FAB+): [151.27–151.24, 151.17–151.13, 148.76–148.73, 148.66–148.63
m/z 384; HRMS (FAB): calcd for [C23H28O5]+: 384.1937, found: (ddd, J1 = 250.9 Hz, J2 = 10.3 Hz, J3 = 3.6 Hz)], [141.28–140.97,
384.1939. The enantioselectivity was determined by chiral 138.77–138.47 (dt, J1 = 250.6 Hz, J2 = 15.2 Hz)], 124.39–124.23
HPLC analysis (DAICEL Chiralpak AD-H, hexane–2-propanol = (p, J = 4.2 Hz), [120.55–120.51, 120.43–120.40 (dd, J1 = 11.8 Hz,
99 : 1, flow rate = 1.0 mL min−1, 23 °C, λ = 254 nm, retention J2 = 3.6 Hz)], [112.18–112.14, 112.00–111.97 (dd, J1 = 17.5 Hz,
time; major isomer 8.9 min, minor isomer 10.1 min, 65% ee). J2 = 3.9 Hz)], 81.84, 59.88–59.82 (t, J = 2.8 Hz), 47.00, 27.71,
[α]2D5 = +29.39 (c 1.0, CHCl3).
13.42 ppm; IR (KBr) 3471, 3084, 2982, 2942, 1753, 1733, 1638,
1618, 1517, 1490, 1458, 1370, 1330, 1309, 1253, 1235, 1146,
1094, 1066, 1030, 997, 964, 940, 903, 881, 848, 814, 773, 747,
1-tert-Butyl 3-(2,3-difluorobenzyl) 2-methylmalonate (22)
Following the general procedure (A) from 6, 22 was obtained as 679, 623 cm−1; LRMS (FAB+): m/z 319; HRMS (FAB): calcd for
a pale yellow oil (90% yield). 1H-NMR (300 MHz, CDCl3) [C15H18F3O4]+: 319.1157, found: 319.1155.
δ 7.15–7.00 (m, 3H), 5.25–5.15 (ddd, J1 = 16.65 Hz, J2 = 12.63
(S)-1-tert-Butyl 3-(2,3,4-trifluorobenzyl) 2-benzyl-
2-methylmalonate (23c)
Hz, J3 = 1.29 Hz, 2H), 3.39–3.32 (q, J = 7.26 Hz, 1H), 1.36–1.34
(m, 12H) ppm; 13C-NMR (100 MHz, CDCl3) δ 170.02, 168.79,
[151.67–151.55, 149.21–149.08 (dd, J1 = 247 Hz, J2 = 12.3 Hz)], Following the general PTC procedure from 23, 23c was
1
[150.22–150.09, 147.73–147.60 (dd, J1 = 249.1 Hz, J2 = 13.0 Hz)], obtained as a pale yellow oil (87% yield). H-NMR (300 MHz,
125.25–125.14 (m), 124.13–124.08 (d,
124.06–124.02 (d, J = 4.8 Hz), 117.50–117.33 (d, J = 17 Hz), 1H), 5.20 (s, 2H), 3.28–3.14 (dd, J1 = 28.92 Hz, J2 = 13.53 Hz,
81.76, 60.11, 60.11–60.04 (t,
3.5 Hz), 47.00, 27.67, 2H), 1.40–1.35 (d, J = 14.82 Hz, 12H) ppm; 13C-NMR (100 MHz,
J
=
4.7 Hz), CDCl3) δ 7.29–7.21 (m, 3H), 7.17–7.09 (m, 3H), 7.03–6.94 (m,
J
=
13.40 ppm; IR (KBr) 2982, 2944, 1752, 1732, 1631, 1600, 1494, CDCl3) δ 171.73, 170.56, [152.70–152.57, 151.20–150.07 (ddd,
1458, 1370, 1331, 1290, 1222, 1147, 1094, 1034, 1021, 947, 899, J1 = 250 Hz, J2 = 10 Hz, J3 = 3.2 Hz)], [151.33–151.20,
880, 848, 827, 785, 734, 690 cm−1; LRMS (FAB+): m/z 301; 148.82–148.68 9 (ddd, J1 = 250.7 Hz, J2 = 10.1 Hz, J3 = 3.6 Hz)],
HRMS (FAB): calcd for [C15H19F2O4]+: 301.1251, found: [141.30–141.00, 138.79–138.49 (dt, J1 = 250.7 Hz, J2 = 15.1 Hz)],
301.1252.
130.22, 128.11, 126.86, 124.61–124.45 (p, J = 4.1 Hz),
[120.48–120.44, 120.36–120.32 (dd, J1 = 12 Hz, J2 = 4 Hz)],
[112.20–112.16, 112.02–111.99 (dd, J1 = 17.4 Hz, J2 = 4 Hz)],
(S)-1-tert-Butyl 3-(2,3-difluorobenzyl) 2-benzyl-
2-methylmalonate (22c)
81.90, 59.87–59.81 (t,
J = 2.6 Hz), 55.42, 41.03, 27.48,
Following the general PTC procedure from 22, 22c was 19.85 ppm; IR (KBr) 3470, 3087, 3064, 3032, 2980, 2937, 1952,
1
obtained as a pale yellow oil (96% yield). H-NMR (300 MHz, 1732, 1639, 1618, 1605, 1516, 1490, 1456, 1370, 1309, 1279,
CDCl3) δ 7.29–7.22 (m, 3H), 7.21–7.06 (m, 5H), 5.25 (d, J = 1253, 1160, 1112, 1065, 998, 977, 945, 914, 848, 812, 738, 702,
1.29 Hz, 2H), 3.29–3.15 (dd, J1 = 29.28 Hz, J2 = 13.74 Hz, 2H), 679, 623 cm−1; LRMS (FAB): m/z 409; HRMS (FAB): calcd for
1.39 (s, 9H), 1.35 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3) [C22H24F3O4]+: 409.1627, found: 409.1631. The enantio-
δ 171.75, 170.62, [151.73–151.61, 149.26–149.14 (dd, J1
=
selectivity was determined by chiral HPLC analysis (DAICEL
247 Hz, J2 = 12.3 Hz)], [150.33–150.20, 147.84–147.71 (dd, J1 = Chiralcel OD-H, hexane–2-propanol = 99 : 1, flow rate = 1.0 mL
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min−1, 23 °C, λ = 254 nm, retention time; major isomer CDCl3) δ 10.81 (s, 1H), 5.74–5.64 (m, 1H), 5.12–5.07 (m, 2H),
7.9 min, minor isomer 6.5 min, 71% ee). [α]2D5 = +15.77 (c 1.0, 2.62–2.51 (n, J = 7.5 Hz, 2H), 1.43 (s, 9H), 1.36 (s, 3H) ppm;
CHCl3).
13C-NMR (100 MHz, CDCl3) δ 177.99, 170.97, 132.44, 119.20,
82.24, 54.00, 40.18, 27.78, 27.78, 19.91 ppm; IR (KBr) 3082,
2982, 2937, 1712, 1643, 1460, 1394, 1370, 1301, 1255, 1150,
1-tert-Butyl 3-(2,6-difluorobenzyl) 2-methylmalonate (24)
Following the general procedure (A) from 6, 24 was obtained as 1120, 996, 921, 885, 847, 772, 687, 649 cm−1; LRMS (FAB): m/z
a pale yellow oil (96% yield). 1H-NMR (300 MHz, CDCl3) 215; HRMS (FAB): calcd for [C11H19O4]+: 215.1283, found:
δ 7.29–7.19 (m, 1H), 6.87–6.78 (m, 2H), 5.16 (s, 2H), 3.30–3.23 215.1281. [α]2D5 = −10.96 (c 1.0, CHCl3).
(q, J = 7.26 Hz, 1H), 1.30–1.27 (d, J = 6.75 Hz, 12H) ppm;
(3S,5R)-tert-Butyl 5-(iodomethyl)-3-methyl-
2-oxotetrahydrofuran-3-carboxylate (26)
13C-NMR (100 MHz, CDCl3) δ 170.04, 168.79, [163.13–163.05,
160.62–160.55 (dd, J1 = 250.5 Hz, J2 = 7.3 Hz)], 131.01–130.81
(t, J = 10.3 Hz), [111.43–111.37, 111.24–111.18 (dd, J1 = 18.8 Hz, A mixture of 25 (97.9 g, 0.46 mmol) and NaHCO3 (115.2 mg,
J2 = 6.1 Hz)], 81.65, 54.60–54.52 (t, J = 4.1 Hz), 46.96, 27.63, 1.37 mmol) in water (2.91 mL) was stirred at room temp. for
13.36 ppm; IR (KBr) 3078, 2982, 2943, 1752, 1732, 1658, 1630, 10 min before adding chloroform (2.91 mL). The mixture was
1596, 1564, 1474, 1370, 1332, 1275, 1238, 1147, 1093, 1060, cooled to 0 °C and stirred for 15 min before adding I2 (232 mg,
1029, 962, 936, 849, 787, 730 cm−1; LRMS (FAB): m/z 301; 0.91 mmol) in the dark. The mixture was stirred at 0 °C for
HRMS (FAB): calcd for [C15H19F2O4]+: 301.1251, found: 6 h, and then it was quenched with saturated aqueous NaS2O3
301.1254.
and the mixture was agitated until the solution turned color-
less. Et2O (100 mL) was added, and the layers were separated.
The aqueous layer was extracted with Et2O (100 mL), and the
combined organic layers were washed successively with water
1-tert-Butyl 3-(2,6-difluorobenzyl) 2-benzyl-
2-methylmalonate (24c)
Following the general PTC procedure from 24, 24c was (100 mL) and then brine (100 mL). The organic layer was dried
1
obtained as a pale yellow oil (98% yield). H-NMR (300 MHz, with anhydrous MgSO4, filtered, and concentrated in vacuo.
CDCl3) δ 7.41–7.20 (m, 4H), 7.15–7.12 (m, 2H), 6.97–6.91 (m, The diastereomeric mixture was separated by silica gel column
2H), 5.25 (s, 2H), 3.29–3.12 (dd, J1 = 31.31 Hz, J2 = 13.8 Hz, chromatography (12% EtOAc in hexane; Rf = 0.55) to afford 26
2H), 1.39 (s, 9H), 1.32 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3) (101.36 mg, 65% yield) as a pale yellow oil. 1H-NMR (400 MHz,
δ 171.66, 170.69, [163.19–163.12, 160.69–160.61 (dd, J1 = 250.2 CDCl3) δ 4.53–4.46 (m, 1H), 3.42–3.39 (dd, J1 = 10.44 Hz, J2 =
Hz, J2 = 7.3 Hz)], 136.25, 131.10–130.90 (t, J = 10.3 Hz), 130.20, 4.32 Hz, 1H), 3.31–3.27 (dd, J1 = 10.44 Hz, J2 = 7.16 Hz, 1H),
128.10, 126.78 [111.49–111.43, 111.30–111.24 (dd, J1 = 19 Hz, 2.85–2.80 (dd, J1 = 13.38 Hz, J2 = 6.20 Hz, 1H), 1.83–1.77 (dd,
J2 = 6.1 Hz)], 81.77, 55.26, 54.57–54.49 (t, J = 4.1 Hz), 40.91, J1 = 13.38 Hz, J2 = 9.50 Hz, 1H), 1.47–1.45 (m, 12H) ppm;
27.61, 19.72 ppm; IR (KBr) 3470, 3087, 3065, 3031, 2979, 2937, 13C-NMR (100 MHz, CDCl3) δ 174.67, 169.00, 83.31, 52.95,
2876, 1950, 1732, 1656, 1630, 1596, 1562, 1496, 1393, 1370, 41.95, 27.78, 20.53, 6.95 ppm; IR (KBr) 2979, 2937, 2872, 1781,
1321, 1279.1251, 1238, 1211, 1156, 1113, 1058, 977, 936, 915, 1737, 1456, 1416, 1394, 1370, 1338, 1272, 1229, 1191, 1150,
871, 848, 787, 735, 702 cm−1; LRMS (FAB): m/z 391; HRMS 1098, 1008, 952, 918, 871, 844, 744, 675, 620 cm−1; LRMS
(FAB): calcd for [C22H25F2O4]+: 391.1721, found: 391.1719. The (FAB): m/z 341; HRMS (FAB): calcd for [C11H18IO4]+: 341.0250,
enantioselectivity was determined by chiral HPLC analysis found: 340.0247. [α]2D5 = +2.78 (c 1.0, CHCl3).
(DAICEL Chiralpak AD-H, hexane–2-propanol = 99 : 1, flow
(3S,5S)-tert-Butyl 5-(iodomethyl)-3-methyl-2-
oxotetrahydrofuran-3-carboxylate (27)
rate = 1.0 mL min−1, 23 °C, λ = 254 nm, retention time; major
isomer 7.2 min, minor isomer 7.6 min, 31% ee). [α]2D5 = +16.67
(c 1.0, CHCl3).
A mixture of 25 (97.9 g, 0.46 mmol) and NaHCO3 (115.2 mg,
1.37 mmol) in water (2.91 mL) was stirred at room temp. for
10 min before adding chloroform (2.91 mL). The mixture was
(S)-2-(tert-Butoxycarbonyl)-2-methylpentenoic acid (25)
50% w/v aq. KOH (0.12 mL, 1.07 mmol) was added to a stirred cooled to 0 °C and stirred for 15 min before adding I2 (232 mg,
solution of (S)-1-tert-butyl 3-((R)-1-phenylethyl) 2-methyl-2-allyl- 0.91 mmol) in the dark. The mixture was stirred at 0 °C for
malonate (19b, 34 mg, 0.107 mmol) in MeOH (0.12 mL). After 6 h, and then it was quenched with saturated aqueous NaS2O3
stirring for 24 hours, the reaction mixture was evaporated, and the mixture was agitated until the solution turned color-
diluted with EtOAc (10 mL), and extracted with 5% NaHCO3 less. Et2O (100 mL) was added, and the layers were separated.
(10 mL). The EtOAc was concentrated in vacuo and the residue The aqueous layer was extracted with Et2O (100 mL), and the
was purified by column chromatography (silica gel, hexane– combined organic layers were washed successively with water
EtOAc = 10 : 1) to recover (R)-2-methylbenzyl alcohol (12 mg, (100 mL) and then brine (100 mL). The organic layer was dried
92%). The above extracted 5% NaHCO3 (10 mL) was acidified with anhydrous MgSO4, filtered, and concentrated in vacuo.
by 1 M HCl (up to pH 5–6). The residue was extracted with The diastereomeric mixture was separated by silica gel column
EtOAc (20 mL), dried over anhydrous MgSO4, filtered, and con- chromatography (12% EtOAc in hexane; Rf = 0.48) to afford 27
centrated in vacuo. The residue was purified by column chrom- (34.8 mg, 22%) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3)
atography (silica gel, hexane–EtOAc = 1 : 1) to afford 25 δ 4.58–4.54 (m, 1H), 3.46–3.42 (dd, J1 = 10.10 Hz, J2 = 4.84 Hz,
1
(22.4 mg, 98% yield) as a pale yellow oil. H-NMR (400 MHz, 1H), 3.21–3.28 (dd, J1 = 10.10 Hz, J2 = 8.46 Hz, 1H), 2.61–2.56
4038 | Org. Biomol. Chem., 2013, 11, 4030–4039
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(dd, J1 = 13.41 Hz, J2 = 7.21 Hz, 1H), 2.35–2.29 (dd, J1 = 13.41
Hz, J2 = 7.21 Hz, 1H), 1.48–1.45 (m, 12H) ppm; 13C-NMR
(100 MHz, CDCl3) δ 175.13, 169.28, 83.10, 52.09, 40.25, 27.79,
20.63, 5.87 ppm; IR (KBr) 2979, 2936, 2876, 1781, 1737, 1457,
1394, 1370, 1338, 1281, 1229, 1193, 1151, 1097, 1008, 917, 844,
745 cm−1; LRMS (FAB) m/z 341; HRMS (FAB): calcd for
[C11H18IO4]+: 341.0250, found: 340.0253. [α]2D5 = −39.51 (c 1.0,
CHCl3).
Enzymes in Synthetic Organic Chemistry, ed. J. E. Baldwin
and P. D. Magnus, Tetrahedron Organic Chemistry Series,
Pergamon Press, Oxford, 1994, vol. 12; (c) K. Faber, Bio-
transformations in Organic Chemistry, Springer-Verlag,
Berlin, 3rd edn, 1997.
4 The asymmetric α-alkylation of malonates using chiral
auxiliary was reported: (a) M. Ihara, M. Takahashi,
H. Niitsuma, N. Taniguchi, K. Yasui and K. Fukumoto,
J. Org. Chem., 1989, 54, 5413; The asymmetric catalytic
α-fluorination of malonates was reported: (b) D. S. Reddy,
N. Shibata, J. N. S. Nakamura, T. Toru and S. Kanemasa,
Angew. Chem., Int. Ed., 2008, 47, 164.
5 M.-h. Kim, S.-H. Choi, Y.-J. Lee, J. Lee, K. Nahm,
B.-S. Jeong, H.-g. Park and S.-s. Jew, Chem. Commun., 2009,
782.
6 S. Hong, J. Lee, M. Kim, Y. Park, C. Park, M.-h. Kim,
S.-s. Jew and H.-g. Park, J. Am. Chem. Soc., 2011, 133,
4924.
Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korean government
(MEST) (2012-002956) and a grant from the Korea Healthcare
Technology R&D Project, the Ministry for Health, Welfare &
Family Affairs, Republic of Korea (A092006).
7 For recent reviews on the phase-transfer catalysis, see:
(a) K. Maruoka and T. Ooi, Chem. Rev., 2003, 103, 3013;
(b) M. J. O’Donnell, Acc. Chem. Res., 2004, 37, 506;
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