Enantioselective Michael Addition of Malonates to Chalcone Derivatives Catalyzed by Dipeptide-derived Multifunctional Phosphonium Salts

Article abstract of DOI:10.1021/acs.joc.6b01752

Highly enantioselective Michael addition of malonates to enones catalyzed by dipeptide-derived multifunctional phosphonium salts has been developed. The newly established catalytic system was characterized with its wide substrate scope featured with aliphatic aldehyde-derived enones and substituted malonates. The gram scale-up synthesis of adducts can also be successfully achieved under optimal conditions with both excellent yield and enantioselectivity.

Full text of DOI:10.1021/acs.joc.6b01752

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Note
Enantioselective Michael Addition of Malonates to Chalcone Derivatives
Catalyzed by Dipeptide-derived Multifunctional Phosphonium Salts
Dongdong Cao, Guosheng Fang, Jiaxing Zhang, Hongyu Wang, Changwu Zheng, and Gang Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01752 • Publication Date (Web): 23 Sep 2016
Downloaded from http://pubs.acs.org on September 25, 2016
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Enantioselective Michael Addition of Malonates to Chalcone
Derivatives Catalyzed by Dipeptideꢀderived Multifunctional
Phosphonium Salts
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Dongdong Cao, Guosheng Fang, Jiaxing Zhang, Hongyu Wang, Changwu Zheng and
Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China
Eꢀmail: zhaog@mail.sioc.ac.cn
ABSTRACT: Highly enantioselective Michael addition of malonates to enones
catalyzed by dipeptideꢀderived multifunctional phosphonium salts has been
developed. The newly established catalytic system was characterized with its
wide substrate scope featured with aliphatic aldehydeꢀderived enones and
substituted malonates. The gram scaleꢀup synthesis of adducts can also be
successfully achieved under optimal conditions with both excellent yield and
enantioselectivity.
T
he development of highly effective, mild, and catalytic transformations for the
construction of carbonꢀcarbon bonds is an appealing and demanding topic in
asymmetric synthesis. Among those wellꢀestablished reactions, asymmetric Michael
addition provides a powerful tool for the synthesis of numerous valuable
enantioenriched compounds via the combination of different electrophiles and
nucleophiles. Chalcone derivatives 1, a challenging Michael addition acceptor with
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malonates 2 has been extensively studied for the resulting synthetically useful adducts
highly functionalized with carbonyls and ester groups. A variety of highly efficient
chiral catalysts such as Lꢀproline derivatives,1 phaseꢀtransfer catalysts,2 metalꢀligand
complexes,3 ionic liquid4 and other organocatalysts5 have been developed to promote
this reaction. In spite of these great achievements, limited success has been reported
for aliphatic aldehydeꢀderived enones (e.g. R1 = alkyl, CF3, CO2Et, R2 = Ar), and
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2ꢀsubstituted malonates 2 (X = alkyl or Cl) were mostly restricted to react with cyclic
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enones,
yneꢀenones7 and 4ꢀoxoꢀ4ꢀarybutenoates.8 Specifically, the reported
asymmetric Michael addition of fluoromalonates to acyclic enones only gave the
moderate enantioselectivies.2fꢀg
Asymmetric phaseꢀtransfer catalysis has been recognized as a versatile and
powerful tool for synthesis of the valuable enantioenriched compounds.9 However, in
the past few decades, tremendous efforts have focused on chiral quaternary
ammonium salts catalysis. In contrast, the application of chiral quaternary
phosphonium salts in asymmetric synthesis are rather limited9c,9d,10. To our knowledge,
related investigation on Michael addition of malonates to chalcone derivatives
promoted by multifunctional chiral quaternary phosphonium salts has not been
reported so far. Our group has been engaged in the design and synthesis of novel
bifunctional quaternary ammonium and phosphonium salts and their application to
asymmetric synthesis11. Recently, we have reported a new family of the
dipeptideꢀderived multifunctional phosphonium salts in an asymmetric cyclization via
Michael additionꢀSN2 sequence12 and synthesis of highly functionalized cyclopentane
derivatives.13 As further evaluation of versatility of these catalysts in carbonꢀcarbon
bond formation reactions, we reported herein highly enantioselective
dipeptideꢀderived multifunctional phosphonium saltsꢀcatalyzed Michael addition of
malonates to enones featured with wide substrate scope.
Asymmetric Michael addition of methyl malonate 2a to chalcone 1a was chosen as
a model reaction to establish the optimal catalyst conditions (Table 1). Lꢀamino
acidsꢀderived bifunctional phosphonium salts 3aꢀ3d, which were previously
developed in our laboratory for asymmetric azaꢀHenry reaction,11b were firstly
introduced to catalyze this reaction. As shown in Table 1, good results were obtained
with Lꢀphenylalanineꢀderived bifunctional amideꢀphosphonium salt 3a to give the
product 4a in 97% yield and with 53% ee (Table 1, entries 1ꢀ4). Enantioselectivity can
then be further improved to 76% ee in the presence of catalyst 3e which was
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synthesized from 3,5ꢀbis(trifluoromethyl)benzyl bromide (entry 5). As only one NꢀH
bond exists in the catalyst and actually two reactants need to be activated, we assumed
that the inferior results might be attributed to the fact that the prochiral center is
relatively far away from the chiral center of catalysts (Figure 1, a). To further improve
the enantioselectivity, rational design of new chiral quaternary phosphonium salts is
desirable. Of the fact that small synthetic peptides have proved to be efficient
organocatalysts14 and metal ligands15 in asymmetric synthesis and (Thio)Urea is an
versatile activator for the carbonyl compounds16, we envision that introduction of new
stereocenter (R′) and (thio)urea moiety in the corresponding dipeptideꢀderived
multifunctional phosphonium salts 3 can enhance the facial enantiodiscrimination of
prochiral center (Figure 1, b), which would provide the high stereoselectivity.
Moreover, it is expected that stronger double hydrogen bond would be advantage for
the enantioselectivity. Based on these results, several novel dipeptideꢀderived
multifunctional phosphonium salts 3fꢀ3k were synthesized.
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Figure 1. Rational design of dipeptideꢀderived multifunctional quaternary phosphonium salts 3.
To our delight, product 4a can be obtained in 97% yield and 92% ee in a shorter
reaction time by employing LꢀPheꢀLꢀtertꢀLeuꢀderived multifunctional phosphonium
salt 3f and the thiourea moiety as hydrogenꢀbond donor proved to be better than urea
(entries 6 and 7). Decreased enantioselectivity was also observed with
LꢀPheꢀGlyꢀderived catalyst 3h which lacks the stereocenter of R′ (entry 8). Further
screening of other phosphonium salts showed the LꢀPheꢀLꢀPhgꢀderived
multifunctional phosphonium salt 3j with stronger double hydrogenꢀbond donor was
the optimal catalyst of choice (entries 9ꢀ11). Reducing the catalyst loading amount to
3 mol% or 1 mol% almost had no effect on yield and enantioselectivity of the product
(entries 12 and 13) albeit with a longer reaction time (entry 13). Other reaction
parameters such as the structure of malonate, solvent, base and temperature were also
screened (See Supporting Information for details). Therefore, the optimal reaction
conditions had been established as methyl malonate, 3 mol% of catalyst 3j,
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mesitylene as a solvent and 2 equivalents of K2CO3 as a base (Table 1, entry 12) at 0
oC.
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Table 1. Optimization of Catalystsa
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Entry
1
3
t/h
24
36
24
24
24
9
Yield/%b
97
Ee/%c
53
3a
3b
3c
3d
3e
3f
2
95
36
3
97
ꢀ47
24
4
96
5
95
76
6
97
92
7
3g
3h
3i
9
96
78
8
9
96
69
9
9
98
95
10
11
12d
13e
3j
9
99
99
3k
3j
24
9
85
88
99
99
3j
14
99
98
a Unless otherwised noted, the reaction was performed with 0.1 mmol of 1a, 0.5
mmol of 2a and 2 equiv of K2CO3 in the presence of 5 mol% of 3 in mesitylene
(1 mL) at 0 oC; b Isolated yield. c Determined by HPLC using chiral stationary
phase. d 3 mol% of 3j was used; e 1 mol% of 3j was used.
With the optimized reaction conditions for the asymmetric Michael addition of methyl
malonate to enones in hand, we set out to investigate the scope of substrate. As shown
in Table 2, when R2 is fixed to phenyl group, both electronic nature and substituent
effect on aromatic rings (when R1 = Ar) have little influence on the results. The
corresponding products were obtained with uniformly excellent yields (97ꢀ99%) and
enantioselectivities (94ꢀ99%) (Table 2, entries 2ꢀ14). It is noteworthy that satisfactory
enantioselectivity could be obtained at lower temperature for the enone bearing a
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strong electronꢀwithdrawing group on aromatic ring (entry 7). Enones involving
heteroaromatic or condensed ring also proved to be applicable (entries 15ꢀ17). To our
delight, this catalytic system can be successfully applied to previously
lessꢀinvestigated aliphatic aldehydesꢀderived enones (R1 = alkyl) in terms of the
excellent yields (97ꢀ98%) and good to excellent enantioselectivities (86ꢀ97%) (entries
18ꢀ23). Generally, enones with electronꢀwithdrawing groups on aromatic rings reacted
faster than those with electronꢀdonating groups due to the enhanced electrophilicity.
When R1 was stronger electron withdrawing group such as CF3 or CO2Et, the reaction
still finished smoothly within 3 h at ꢀ10 oC. The gram scaleꢀup synthesis of product
4a can also be successfully achieved under optimal conditions with 98% yield
and 99% ee (Table 2, entry 24).
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Next, we fixed the R1 as phenyl group and evaluated R2 group on 1 as well as
substituted malonates. The reaction also demonstrated a broad substrate scope (Table
3). Electronic nature and position of substitutes on aromatic rings (R2 = Ar) had no
influence on yield (94ꢀ99%) and enantioselectivity (96ꢀ99%) as before. Enones
bearing heteroaromatic or condensed ring also proved to be competent candidates
a
Table 2. Substrate Scope of Reaction
O
R1
3j
(3 mol%)
O
CO2Me
CO2Me
+
MeO2C
CO2Me
Ph
R1
Ph
K2CO3 (2 equiv)
mesitylene, 0 oC
1
2a
4
Entry
1
R1/1
t/h
Yield/%b
99
Ee/%c
99
96
98
96
98
99
98
96
97
96
94
97
98
96
97
96
96
97
C6H5/1a
4a
4b
4c
4d
4e
4f
9
12
15
5
2
4ꢀFC6H4/1b
4ꢀClC6H4/1c
4ꢀBrC6H4/1d
4ꢀMeC6H4/1e
97
3
99
4
99
5
21
27
10
8
99
6
4ꢀMeOC6H4/1f
4ꢀNO2C6H4/1g
3ꢀBrC6H4/1h
99
7d
8
4g
4h
4i
97
99
9
2,4ꢀCl2C6H3/1i
4ꢀCF3C6H4/1j
4ꢀCNC6H4/1k
4ꢀPhC6H4/1l
8
99
10
11
12
13
14
15
16
17
18
4j
5
98
4k
4l
5
99
7
99
2ꢀFC6H4/1m
4m
4n
4o
4p
4q
4r
4
99
3ꢀMeOC6H4/1n
2ꢀthienyl/1o
9
97
5
99
1ꢀnaphthyl/1p
2ꢀnaphthyl/1q
(E)ꢀPhCH=CH2ꢀ/1r
5
98
36
52
99
98
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19
20
Me/1s
pentyl/1t
CO2Et/1u
CF3/1v
Cy/1w
Ph
4s
4t
6
8
98
97
98
97
98
98
95
97
94
86
94
99
21d
22d
23
4u
4v
4w
4a
2
3
24
24
24e
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a Unless otherwised noted, all reactions were performed with 0.1 mmol of 1, 0.5
0.5 mmol of 2a and 2 equiv of K2CO3 in the presence of 3 mol% of 3j in mesityꢀ
lene (1 mL) at 0 oC; b Isolated yield; c Determined by HPLC using chiral stationꢀ
nary phase; d At ꢀ10 oC. e 5 mmol scaleꢀup.
(Table 3, entries 1ꢀ12). Likewise, reaction of enones with electronꢀwithdrawing
groups on aromatic rings finished within a shorter time than those with
electronꢀdonating groups. To our delight, (E)ꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone, a challenging
Michael acceptor in asymmetric phaseꢀtransfer catalysis,2d delivered the product in
85% yield and 91% ee albeit with a longer reaction time (entry 13) while
(E)ꢀ6ꢀphenylhexꢀ3ꢀenꢀ2ꢀone gave only 19% ee (entry 14). It is noteworthy that the
sterically bulky diethyl and dibenzyl malonates had no inferior effect on the yield and
enantioselectivity (entries 15 and 16). Cyclic enones such as cyclopentenone and
cyclohexeone gave poor enantioselectivities (entries 17 and 18). Challenging
2ꢀsubstituted malonates such as 2ꢀmethyl or 2ꢀfluoro methyl malonates could also be
applicable to this catalytic system in excellent yields and enantioselectivies (Table 3,
entries 19 and 20) with a prolonged time. The absolute configuration of the product 4
was assigned as S by analogy to specific rotation of known compound.3d,5cꢀf
Table 3. Substrate Scope of Reactiona
Entry
R1/R2/1
2/4
t/h
7
Yield/%b Ee/%c
1
2
3
4
5
6
7
8
9
Ph/4ꢀFC6H4/1x
2a/4x
2a/4y
2a/4z
2a/4a'
2a/4b'
2a/4c'
2a/4d'
2a/4e'
2a/4f'
98
94
99
98
99
99
99
98
99
98
99
97
99
98
98
96
99
97
Ph/4ꢀClC6H4/1y
Ph/4ꢀBrC6H4/1z
Ph/4ꢀMeC6H4/1a'
Ph/4ꢀMeOC6H4/1b'
Ph/4ꢀNO2C6H4/1c'
Ph/2ꢀBrC6H4/1d'
Ph/3ꢀClC6H4/1e'
Ph/2ꢀthienyl/1f'
7
5
20
16
8
3
10
4
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Ph/2ꢀfuryl/1g'
Ph/1ꢀnaphthyl/1h'
Ph/2ꢀnaphthyl/1i'
Ph/Me/1j'
2a/4g'
2a/4i'
4
16
4
97
95
99
85
67
99
99
98
38
95
89
96
95
99
91
19
99
99
17
16
98
98
12
13d
14d
15
16
17
18
19
20e
2a/4i'
2a/4j'
2a/4k'
2b/4l'
96
96
24
24
41
96
120
30
PhCH2CH2/Me/1k′
Ph/Ph/1a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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Ph/Ph/1a
2c/4m′
2c/4n′
2c/4o′
2a′/4p'
2a′′/4q′
cyclopentenone/1l'
cyclohexenone/1m'
Ph/Ph/1a
Ph/Ph/1a
a Unless otherwised noted, the reaction was performed with 0.1 mmol of
1, 0.5 mmol of 2 and 2 equiv of K2CO3 in the presence of 3 mol% of 3j in
mesitylene (1 mL) at 0 oC; b Isolated yield. c Determined by HPLC using
chiral stationary phase; d 10 equiv of 2a was used. e1a: 2a′′ = 5:1, and 5
equiv of K2CO3 was used.
To gain some insights into the mechanism of the reaction, some control
experiments were conducted as shown in Scheme 1. Both yields and
enantioselectivities decreased dramatically when dipeptideꢀderived phosphine
precursor 3l or Nꢀmethyl protected dipeptideꢀderived phosphonium salt 3m was
employed (Figure 2, a). The results showed that both hydrogen bonding and
phosphonium moiety of the catalyst were indispensable for the reactivity and
enantioselectivity of reaction.
Figure 2. (a) Control experiment; (b) Plausible transition state.
Based on these results, a plausible transition state TSꢀ1 was proposed to explain the
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absolute configuration of the adduct (Figure 2, b). We proposed that thiourea moiety
of chiral phosphonium salt 3j might activate the electrophilic enones 1 through double
hydrogenꢀbond interactions while the amide and phosphonium salt cation of the
catalyst 3j might direct the nucleophilic malonate carbanion 2′ via hydrogenꢀbond
interaction and electrostatic interaction, respectively to attack from the less sterically
hindered Re face to afford the target product 4 with Sꢀselectivity.
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To demonstrate the synthetic utility of the product, compound 4a was converted to
transꢀcyclopropane derivative 5 in presence of 1,8ꢀDiazabicyclo[5.4.0]undecꢀ7ꢀene
(DBU) and Iodine17 in excellent yield as a single stereoisomer. With inorganic base in
DMF18, chiral oxetane derivative 6 was also obtained in high yield (Scheme 1). As we
know, chiral cyclopropane19 and oxetane20 derivatives are versatile building blocks in
organic synthesis, and structural motif in some pharmaceuticals and biologically
active natural compounds. This protocol provided an alternative method for the
asymmetric cyclopropanation of chalcone derivatives.21
Scheme 1. Transformation of Product 4a
In conclusion, we have reported asymmetric Michael addition of malonates to
enones catalyzed by dipeptideꢀderived multifunctional phosphonium salts with wide
substrate scope under mild reaction conditions in terms of excellent yields and
enantioselectivities. It is noteworthy that this catalytic system can be applied to alkyl
enones (R1 or R2 = alkyl) in addition to aromatic ones. More challenging methyl
enone and 2ꢀsubstituted malonates were all applicable to deliver the corresponding
products in excellent yields and enantioselectivities. Gram scaleꢀup synthesis of
product was also successfully achieved with excellent yield and enantioselectivity.
Experimental Section
1
The H NMR spectra were recorded at 400 MHz in CDCl3 using tetramethylsilane
(TMS) as internal standard. All chemical shifts (δ) were given in ppm. Data were
reported as follows: chemical shift, multiplicity (s = single, d = doublet, t = triplet, q =
quartet, br = broad, m = multiplet), coupling constants (Hz) and integration. 13C NMR
spectra were recorded at 100 MHz in CDCl3 and run with broadband decoupling. 19F
NMR and 31P NMR spectra were recorded at 376 Hz and 162 Hz respectively.
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Highꢀresolution mass spectra (HRMS) of compounds was reported for molecular ion
(M+H) or (M+Na)+ under TOF conditions. Analytical high performance liquid
chromatography (HPLC) was carried out on chiral stationary columns using nꢀhexane
and isopropanol as mobile phase. Melting points were determined on a microscopic
melting point meter without correction. Specific optical rotations were measured at λ
= 589 nm. IR spectra were reported in wave number (cmꢀ1). Flash column
chromatography was performed using H silica gel (300ꢀ400 mesh). For thinꢀlayer
chromatography (TLC), silica gel plates (HSGF 254) were used and compounds were
visualized by irradiation with UV light. Phaseꢀtransfer catalysts 3aꢀ3d,[11b] and
3fꢀ3m[12] have been described, and the catalyst 3e was synthesized according to
procedures reported previously.[11b] All reactions were carried out employing
ovenꢀdried glassware. All solvents and reagent were directly used as received without
further manipulation.
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Spectra data of catalyst 3e.
(S)ꢀ(2ꢀ(3,5ꢀBis(trifluoromethyl)benzamido)ꢀ3ꢀphenylpropyl)(3,5ꢀbis(trifluoromethyl)benzyl)diphe
o
24.0
nylphosphonium bromide (3e): 217 mg, yield = 70%, white solid, m. p. = 137ꢀ138 C, [α]D
=
1
+48.6 (c = 1.0, CH2Cl2); H NMR (CDCl3, 400 MHz) δ 9.35 (d, J = 8.4 Hz, 1H), 8.28 (s, 2H),
7.87ꢀ7.92 (m, 3H), 7.73 (s, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.24ꢀ7.45 (m, 12 H), 7.01 (dd, J = 7.8,
11.8 Hz, 2H), 5.22ꢀ5.30 (m, 1H), 5.10ꢀ5.20 (m, 1H), 4.58ꢀ 4.70 (m, 1H), 4.36ꢀ4.43 (m, 1H),
3.28ꢀ3.34 (m, 1H), 2.99 (dd, J = 11.0, 12.2 Hz, 1H), 2.68 (t, J = 13.6 Hz, 1H). 13C NMR (CDCl3,
100 MHz) δ 163.9, 136.9, 135.0 (d, JCꢀP = 5.9 Hz), 134.9 (d, JCꢀP = 6.2 Hz), 134.5, 133.8 (d, JCꢀP
= 9.8 Hz), 133.3 (d, JCꢀP = 9.3 Hz), 132.1 (q, JCꢀF = 33.7 Hz), 132.0 (q, JCꢀF = 33.7 Hz), 131.3 (q,
JCꢀF = 33.6 Hz), 130.5 (d, JCꢀP = 8.5 Hz), 130.4 (brs), 130.1 (d, JCꢀP = 12.5 Hz ),129.9 (d, JCꢀP
=
12.7 Hz), 129.5, 128.9, 128.3 (d, JCꢀP = 2.4 Hz), 127.1, 124.8 (brs), 123.0 (q, JCꢀF = 271.4 Hz),
122.4 (q, JCꢀF = 271.4 Hz), 122.1, 116.3 (d, JCꢀP = 82.1 Hz), 115.4 (d, JCꢀP = 83.2 Hz), 47.3 (d, JCꢀP
= 4.9 Hz), 42.5 (d, JCꢀP = 14.1 Hz), 30.2 (d, JCꢀP = 46.7 Hz), 22.9 (d, JCꢀP = 50.2 Hz); 19F NMR
(CDCl3, 376 MHz) δ ꢀ62.6, ꢀ63.1; 31P NMR (CDCl3, 162 MHz) δ 25.6; IR (KBr): ν 3327, 2963,
1662, 1539, 1439, 1374, 1337, 1279, 1182, 1136, 908, 846, 804, 743, 700 cmꢀ1; HRMS
(MALDIꢀFT): calcd. for [MꢀBr]+ (C39H29F12NOP)+ requires 786.1790; found 786.1795.
General procedure for asymmetric Michael addition of malonates to enones.
To a solution of 1 (0.1 mmol) and dipeptideꢀderived multifunctional phosphonium
bromide 3j (0.003 mmol, 2.8 mg) in mesitylene (1.0 mL) was added methyl malonate
o
(5 equiv, 0.5 mmol, 66 mg, 57 ꢁL). After cooling to 0 C, anhydrous K2CO3 powder
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(2 equiv, 0.2 mmol, 28 mg) was added in one portion, and then the mixture continued
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to stir vigorously at 0 C until the disappearance of the enones monitored by TLC.
H2O (5.0 mL) was added to quench the reaction, and then the aqueous solution was
extracted with ethyl acetate (5.0 mL × 3). The combined organic phase was washed
with brine, dried over anhydrous Na2SO4 and removed in vacuo. The resulting residue
was purified by flash column chromatography (ethyl acetate/petroleum ether as
eluent) to afford the desired products 4.
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Spectra data of product 4
(S)ꢀDimethyl 2ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)malonate (4a)[3d]: 34 mg, yield = 99%; white
solid; m. p. = 95ꢀ96 oC; [α]D26.9 = +21.0 (c = 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.89 (d,
J = 7.6 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.27ꢀ7.22 (m, 4H), 7.15ꢀ7.20 (m,
1H), 4.20 (dt, J = 5.2, 9.2 Hz, 1H), 3.86 (d, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.45ꢀ3.58 (m, 5H); 13
C
NMR (CDCl3, 100 MHz) δ 197.5, 168.7, 168.1, 140.4, 136.7, 133.0, 128.5, 128.4, 128.0, 127.2,
57.3, 52.6, 52.4, 42.3, 40.7 (one peak for aromatic carbon was not found probably due to
overlapping); Enantiomeric excess: 99%, determined by HPLC (Phenomenex Celluloseꢀ2,
hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 15.4 min, tminor = 23.6 min, λ = 254 nm)
.
(S)ꢀDimethyl 2ꢀ(1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4b)[3d]: 35 mg,
o
y
ield = 97%; white solid; m.p. = 82ꢀ84 C; [α]D25.8 = +18.7 (c = 0.90, CHCl
3
); 1H NMR (CDCl3,
400 MHz) δ 7.89 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.22ꢀ7.26
(m, 2H), 6.94 (t, J = 8.4 Hz, 2H), 4.15ꢀ4.21 (m, 1H), 3.82 (d, J = 9.2 Hz, 1H), 3.74 (s, 3H),
3.41ꢀ3.56 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 197.3, 168.5, 168.0, 161.7 (d, JCꢀF = 244.5 Hz),
136.6, 136.0 (d, JCꢀF = 3.2 Hz), 133.1, 129.7 (d, JCꢀF = 8.0 Hz), 128.6, 128.0, 115.3 (d, JCꢀF = 21.2
Hz), 57.2, 52.7, 52.4, 42.3, 40.0; Enantiomeric excess: 96%, determined by HPLC (Phenomenex
Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 12.6 min, tminor =17.7 min, λ =
254 nm).
(S)ꢀDimethyl 2ꢀ(1ꢀ(4ꢀchlorophenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4c)[3d]: 37 mg,
o
yield = 99%; white solid; m.p. = 84ꢀ86 C; [α]D26.5 = +23.9 (c = 0.93, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 7.89 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.19ꢀ7.24
(m, 4H), 4.17 (dt, J = 4.8, 9.2 Hz, 1H), 3.83 (d, J = 9.6 Hz, 1H), 3.73 (s, 3H), 3.42ꢀ3.56 (m, 5H);
13C NMR (CDCl3, 100 MHz) δ 197.1, 168.5, 167.9, 138.9, 136.5, 133.2, 132.9, 129.5, 128.6,
128.5, 128.0, 57.0, 52.7, 52.5, 42.1, 40.5; Enantiomeric excess: 98%, determined by HPLC
(Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 12.7 min, tminor
=
16.6 min, λ = 254 nm).
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(S)ꢀDimethyl 2ꢀ(1ꢀ(4ꢀbromophenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4d)[5e]: 41 mg,
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yield = 99%; white solid; m.p. = 89ꢀ91 C; [α]D25.5 = +19.5 (c = 1.0, CHCl3); H NMR (CDCl3,
400 MHz) δ 7.89 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.37 (d, J =
8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.13ꢀ4.19 (m, 1H), 3.83 (d, J = 9.2 Hz, 1H), 3.73 (s, 3H),
3.42ꢀ3.56 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 197.1, 168.4, 167.9, 139.5, 136.6, 133.2, 131.6
129.9, 128.6, 128.0, 121.1, 56.9, 52.7, 52.5, 42.0, 40.1 ; Εnantiomeric excess: 96%, determined by
HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 13.2 min,
tminor = 16.9 min, λ = 254 nm).
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(S)ꢀDimethyl 2ꢀ(3ꢀoxoꢀ3ꢀphenylꢀ1ꢀ(pꢀtolyl)propyl)malonate (4e)[5e]: 35 mg, yield = 99%; white
solid; m.p. = 72ꢀ73 oC; [α]D26.7 = +15.1 (c = 0.89, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.90 (d,
J = 7.2 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.05 (d,
J = 8.0 Hz, 2H), 4.13ꢀ4.18 (m, 1H), 3.84 (d, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.42ꢀ3.56 (m, 5H), 2.26
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 197.5, 168.7, 168.1, 137.3, 136.8, 136.7, 133.0, 129.1,
128.5, 128.0, 127.8, 57.3, 52.6, 52.3, 42.4, 40.4, 21.0; Enantiomeric excess: 98%, determined by
HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 16.5 min,
tminor = 23.9 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4f)[3d]: 37 mg, yield = 99%,
1
o
white solid; m.p. = 75ꢀ76 C; [α]D25.1 = +18.1 (c = 1.0, CHCl3); H NMR (CDCl3, 400 MHz)
δ 7.89 (d, J = 6.8 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.17 (d, J = 8.8 Hz,
2H), 6.78 (d, J = 8.8 Hz, 2H), 4.11ꢀ4.17 (m, 1H), 3.82 (d, J = 9.6 Hz, 1H), 3,74 (s, 3H), 3.73 (s,
3H), 3.39ꢀ3.54 (m, 5H). 13 C NMR (CDCl3, 100 MHz) δ 197.6, 168.7, 168.2, 158.5, 136.8, 133.0,
132.2, 129.1, 128.5, 128.1, 113.8, 57.4, 55.1, 52.6, 42.5, 40.1; Enantiomeric
excess:
99%,
determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min;
tmajor = 23.5 min, tminor = 32.2 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(1ꢀ(4ꢀnitrophenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4g) [3d]: 37 mg, yield = 97%;
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white solid; m. p. = 74ꢀ76 C; [α]D26.8 = +33.5 (c = 0.96, CHCl3); H NMR (CDCl3, 400 MHz)
δ 8.13 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.42ꢀ7.49 (m, 4H),
4.28ꢀ 4.34 (m, 1H), 3.89 (d, J = 9.6 Hz, 1H), 3.75 (s, 3H), 3.51ꢀ3.63 (m, 5H); 13C NMR (CDCl3,
100 MHz) δ 196.6, 168.1, 167.6, 148.2, 147.0, 136.3, 133.5, 129.2, 128.7, 128.0, 123.6, 56.5, 52.9
52.6, 41.7, 40.3; Enantiomeric excess: 98%, determined by HPLC (Chiralpak column AD,
hexane/iꢀPrOH 50/50, flow rate 0.8 mL/min; tmajor = 30.9 min, tminor = 16.0 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(1ꢀ(3ꢀbromophenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4h): 41 mg, yield = 99%;
colourless oil; [α]D26.7 = +24.9 (c = 0.84, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.90 (d, J = 7.2
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Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.41ꢀ7.45 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.0 Hz,
1H), 7.13 (t, J = 7.8 Hz, 1H), 4.14ꢀ 4.20 (m, 1H), 3.83 (d, J = 8.8 Hz, 1H), 3.72 (s, 3H), 3.44ꢀ3.58
(m, 5H), 13C NMR (CDCl3, 100 MHz) δ 197.0, 168.4, 167.9, 142.9, 136.5, 133.2, 131.0, 130.3,
130.0, 128.6, 128.0, 126.9, 122.4, 56.9, 52.7, 52.5, 41.9, 40.1; IR (Neat): ν 3073, 3012, 2953,
2924, 2862, 1736, 1687, 1596, 1568, 1448, 1434, 1257, 1157, 1075, 1021, 785, 754, 693 cmꢀ1;
HRMS (ESI): calcd. for [M+H]+ (C20H20BrO5)+ requires 419.0494; found 419.0494; Enantiomeric
excess: 96%, determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8
mL/min; tmajor = 12.6 min, tminor = 18.0 min, λ = 254 nm).
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(S)ꢀDimethyl 2ꢀ(1ꢀ(2,4ꢀdichlorophenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4i): 40 mg, yield = 99%;
colourless oil; [α]D26.7 = +36.3 (c = 0.82, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J = 7.2
Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.24ꢀ7.26 (m,
1H), 7.14 (dd, J = 2.4, 8.4 Hz 1H), 4.58ꢀ4.64 (m, 1H), 4.06 (d, J = 8.4 Hz, 1H), 3.67ꢀ3.74 (m, 4H),
3.58ꢀ3.64 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 197.1, 168.4, 168.0, 136.5, 136.4, 134.8, 133.4,
133.3, 129.9, 128.6, 128.0, 127.1, 54.6, 52.7, 52.6, 39.9, 36.8 (one peak for aromatic carbon was
not found probably due to overlapping); IR (Neat) ν 2954, 2917, 2849, 1737, 1687, 1589, 1475,
1449, 1435, 1232, 1157, 1106, 1023, 869, 826, 754, 733, 691cmꢀ1; HRMS (ESI): calcd. for
[M+H]+ (C20H19Cl2O5)+ requires 409.0610; found 409.0600; Enantiomeric excess: 97%,
determined by HPLC (Chiralpak column AD, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor
=
13.9 min, tminor = 11.0 min, λ = 254 nm).
(S)ꢀ2ꢀ(3ꢀOxoꢀ3ꢀphenylꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)propyl)malonate (4j): 40 mg, yield = 98%;
o
white solid; m.p. = 107ꢀ109 C; [α]D26.6 = +22.3 (c = 0.82, CHCl
3
); 1H NMR (CDCl3, 400 MHz)
δ 7.89 (d, J = 7.2 Hz, 2H), 7.51ꢀ7.57 (m, 3H), 7.44 (d, J = 11.6 Hz, 2H), 7.42 (d, J = 12.0 Hz, 2H),
4.24ꢀ4.30 (m, 1H), 3.88 (d, J = 9.2 Hz, 1H), 3.74 (s, 3H), 3.48ꢀ3.60 (m, 5H); 13C NMR (CDCl3,
100 MHz) δ 196.9, 168.4, 167.9, 144.7, 136.5, 133.3, 129.4 (q, JCꢀF = 32.3 Hz), 128.6, 128.5,
128.0, 125.4 (q, JCꢀF = 3.8 Hz), 124.1 (q, JCꢀF = 270.6 Hz), 56.8, 52.8, 52.5, 41.9, 40.3;19F NMR
(CDCl3, 282 MHz) δ ꢀ62.6; IR (KBr) ν 2955, 1731, 1680, 1334, 1240, 1165, 1122, 843, 686 cmꢀ1;
HRMS (ESI): calcd. for [M+H]+ (C21H20F3O5)+ requires 409.1263; found 409.1251; Enantiomeric
excess: 96%, determined by HPLC (Chiralpak column AD, hexane/iꢀPrOH 50/50, flow rate 0.8
mL/min; tmajor = 13.7 min, tminor = 9.0 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(1ꢀ(4ꢀcyanophenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4k): 36 mg, yield = 99%,
colourless oil; [α]D25.6 = +31.3 (c = 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.89 (d, J = 7.2 Hz,
2H), 7.55ꢀ7.57 (m, 3H), 7.44 (d, J = 12.4 Hz, 2H), 7.43 (d, J = 12.8 Hz, 2H), 4.22ꢀ4.27 (m, 1H),
3.86 (d, J = 9.2 Hz, 1H), 3.74 (s, 3H), 3.48ꢀ3.60 (m, 5H); 13C NMR (CDCl3, 100 MHz)
δ 196.7, 168.2, 167.7, 146.1, 136.3, 133.4, 132.2, 129.1, 128.7, 128.0, 118.6, 111.1, 56.5, 52.8,
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52.6, 41.7, 40.5; IR (Neat) ν 2955, 2917, 1749, 1734, 1680, 1508, 1449, 1317, 1262, 1156, 1016,
977, 841, 755, 726, 687 cmꢀ1; HRMS (ESI): calcd. for [M+H]+ (C21H20NO5)+ requires 366.1341;
found 366.1333; Enantiomeric excess: 94%, determined by HPLC (Chiralpak column,
hexane/iꢀPrOH , flow rate 0.8 mL/min; tmajor = 26.2 min, tminor = 15.8 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(1ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4l): 41 mg, yield = 99%,
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white solid. m.p. = 146ꢀ147 C; [α]D26.4 = +24.6 (c = 0.99, CHCl3); H NMR (CDCl3, 400 MHz)
δ 7.97 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.4 Hz,
2H), 7.38 (t, J = 7.4 Hz, 1H), 7.23ꢀ7.30 (m, 4H), 7.16ꢀ7.20 (m, 1H), 4.19ꢀ 4.25 (m, 1H), 3.88 (d, J
= 9.6 Hz, 1H), 3.73 (s, 3H), 3.47ꢀ3.61 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 197.1, 168.7,
168.1, 145.7, 140.4, 139.8, 135.4, 128.9, 128.7, 128.5, 128.2, 128.0, 127.2, 127.1, 57.3, 52.7, 52.4,
42.3, 40.8 (one peak for aromatic carbon was not found probably due to overlapping); IR (KBr) ν
2956, 2910, 1732, 1676, 1604, 1431, 1296, 1237, 1156, 1024, 759, 701, 691 cmꢀ1; HRMS (ESI):
calcd. for [M+H]+ (C26H25O5)+ requires 417.1702; found 417.1690; Enantiomeric excess: 97%,
determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 50/50, flow rate 0.8 mL/min;
tmajor = 14.6 min, tminor = 18.0 min, λ = 254 nm).
o
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(S)ꢀDimethyl 2ꢀ(1ꢀ(2ꢀfluorophenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4m)[5e]: 35 mg, yield = 99%;
colourless oil; [α]D25.7 = +31.1 (c = 0.99, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.90 (d, J = 7.2
Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.26ꢀ7.30 (m, 1H), 7.15ꢀ7.20 (m, 1H),
6.96ꢀ7.04 (m, 2H), 4.34ꢀ4.40 (m, 1H), 4.04 (d, J = 10.0 Hz, 1H), 3.73 (s, 3H), 3..49ꢀ3.65 (m, 5H);
13C NMR (CDCl3, 100 MHz) δ 197.3, 168.5, 168.0, 161.0 (d, JCꢀF = 245.0 Hz), 136.6, 133.1,
130.9 (d, JCꢀF = 4.9 Hz), 128.9 (d, JCꢀF = 8.6 Hz), 128.5, 128.0, 126.9 (d, JCꢀF = 13.1 Hz), 124.0 (d,
JCꢀF = 3.3 Hz), 115.7 (d, JCꢀF = 22.3 Hz), 55.3 (d, JCꢀF = 2.2 Hz), 52.7, 52.4, 40.7 (d, JCꢀF = 2.1 Hz),
36.4; Enantiomeric excess: 98%, determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH
80/20, flow rate 0.8 mL/min; tmajor = 13.9 min, tminor = 18.8 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(1ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4n)[5e]: 36 mg, yield = 97%,
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colourless oil; [α]D26.4 = +21.4 (c = 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.90 (d, J = 7.6
Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.6
Hz, 1H), 6.80 (t, J = 1.8 Hz, 1H), 6.72 (dd, J = 2.2, 8.2 Hz 1H), 4.15ꢀ 4.20 (m, 1H), 3.86 (d, J =
9.2 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.44ꢀ3.56 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 197.4,
168.6, 168.1, 159.4, 142.1, 136.7, 133.0, 129.4, 128.5, 128.0, 120.2, 113.9, 112.4, 57.1, 55.1, 52.6,
52.4, 42.2, 40.6; Enantiomeric excess: 96%, determined by HPLC (Chiralpak column ASꢀH,
hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 20.3 min, tminor = 15.5 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀoxoꢀ3ꢀphenylꢀ1ꢀ(thiophenꢀ2ꢀyl)propyl)malonate (4o): 34 mg, yield = 99%;
colourless oil; [α]D24.0 = +30.5 (c = 0.87, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.93 (d, J = 7.6
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Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.12 (d, J = 5.2 Hz, 1H), 6.92 (d, J =
2.8 Hz, 1H), 6.87 (dd, J = 3.6, 5.2 Hz, 1H), 4.51ꢀ4.57 (m, 1H), 3.92 (d, J = 8.4 Hz, 1H), 3.73 (s,
3H), 3.62 (s, 3H), 3.58 (d, J = 6.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 197.1, 168.4, 168.0,
143.5, 136.6, 133.2, 128.6, 128.1, 126.6, 125.7, 124.2, 57.5, 52.7, 52.6, 42.9, 35.9; IR (Neat) ν
2960, 1748, 1721, 1682, 1449, 1296, 1264, 1173, 851, 753, 686 cmꢀ1; HRMS (ESI): calcd. for
[M+H]+ (C18H19O5S)+ requires 347.0953; found 347.0943; Enantiomeric excess: 97%, determined
by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 15.6 min,
tminor = 20.9 min, λ = 254 nm).
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(S)ꢀDimethyl 2ꢀ(1ꢀ(naphthalenꢀ1ꢀyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4p)[5e]: 37 mg, yield = 95%;
colourless oil; [α]D26.7 = +63.1 (c = 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 8.30 (d, J = 8.4 Hz,
1H), 7.88 (d, J = 7.2 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.45ꢀ7.57 (m, 3H),
7.34ꢀ7.41 (m, 4H), 5.15ꢀ5.20 (m, 1H), 4.07 (d, J = 8.4 Hz, 1H), 3.74 (d, J = 6.0 Hz, 2H), 3.65 (s,
3H), 3.44 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 197.5, 168.8, 168.3, 137.1, 137.0, 136.7, 134.0,
133.0, 131.3, 128.9, 128.5, 128.0, 127.8, 126.4, 125.6, 125.1, 123.2, 56.5, 52.5, 52.4, 41.8 ; Enantꢀ
iomeric excess: 96%, determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow
rate 0.8 mL/min; tmajor = 18.4 min, tminor = 29.7 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(1ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4q): 38 mg, yield = 98%,
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white solid. m.p. = 112ꢀ114 C. [α]D25.9 = +25.2 (c = 0.98, CHCl3); H NMR (CDCl3, 400 MHz)
δ 7.89 (d, J = 7.2 Hz, 2H), 7.74ꢀ7.76 (m, 3H), 7.70 (s, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.38ꢀ7.44 (m,
5H), 4.35ꢀ 4.41 (m, 1H), 3.98 (d, J = 9.6 Hz, 1H), 3.72 (s, 3H), 3.60ꢀ3.62 (m, 2H), 3.46 (s, 3H).
13C NMR (CDCl3, 100 MHz) δ 197.4, 168.7, 168.1, 138.0, 136.7, 133.3, 133.1, 132.5, 128.5,
128.2, 128.0, 127.8, 127.5, 126.9, 126.1, 126.0, 125.7, 57.2, 52.7, 52.4, 42.3, 40.7; IR (KBr) ν
3056, 2952, 2853, 1736, 1686, 1598, 1577, 1508, 1448, 1434, 1340, 1261, 1219, 1156, 1019, 859,
820, 750, 690 cmꢀ1; HRMS (ESI) calcd. for [M+Na]+ (C24H22NaO5)+ requires 413.1365; found
413.1369. Enantiomeric excess: 96%, determined by HPLC (Phenomenex Celluloseꢀ2,
hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 20.5 min, tminor = 30.6 min, λ = 254 nm).
(R,E)ꢀDimethyl 2ꢀ(5ꢀoxoꢀ1,5ꢀdiphenylpentꢀ1ꢀenꢀ3ꢀyl)malonate (4r)：36 mg，yield = 98%, white
solid. m.p. = 109ꢀ110 oC; [α]D24.3 = +8.2 (c = 1.22, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.96 (d,
J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.17ꢀ7.30 (m, 5H), 6.47 (d, J =
16.0 Hz, 1H), 6.24 (dd, J = 9.0, 15.8 Hz, 1H), 3.81 (d, J = 7.2 Hz, 1H), 3.65ꢀ3.74 (m, 7H), 3.39
(dd, J = 5.2, 16.8 Hz, 1H), 3.26 (dd, J = 8.0, 16.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 197.9, 168.7, 168.5, 136.8, 136.7, 133.1, 132.6, 128.6, 128.4, 128.3, 128.1, 127.5, 126.3, 55.3, 5
2.5, 52.4, 41.1, 38.8; ΙR (KBr) ν 2953, 2916, 2848, 1732, 1678, 1596, 1449, 1438, 1356, 1294,
1233, 164, 1025, 980, 755, 691 cmꢀ1; HRMS (ESI): calcd. for [M+H]+ (C22H23O5)+ requires
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367.1545; found 367.1536; Enantiomeric excess: 97%, determined by HPLC (Phenomenex
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Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 11.2 min, tminor = 13.7 min, λ =
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254 nm)
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(S)ꢀDimethyl 2ꢀ(4ꢀoxoꢀ4ꢀphenylbutanꢀ2ꢀyl)malonate (4s)[22]: 27 mg, yield = 98%, colourless oil;
[α]D25.3 = +4.8 (c = 0.93, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 7.2 Hz, 2H), 7.57 (t,
J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.54 (d, J = 6.4 Hz, 1H), 3.27
(dd, J = 4.0, 16.0 Hz, 1H), 2.90ꢀ3.04 (m, 2H), 1.09 (d, J = 6.4 Hz, 3H). 13C NMR (CDCl3, 100
MHz) δ 198.6, 169.1, 169.0, 136.8, 133.1, 128.6, 128.1, 56.1, 52.4, 52.3, 42.6, 29.5, 17.7. Enantiꢀ
omeric excess: 95%, determined by HPLC (Chiralpak column ADꢀH, hexane/iꢀPrOH 90/10, flow
rate 0.7 mL/min; tmajor = 11.4 min, tminor = 12.6 min, λ = 254 nm).
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(S)ꢀDimethyl 2ꢀ(1ꢀoxoꢀ1ꢀphenyloctanꢀ3ꢀyl)malonate (4t): 32 mg, yield = 97%, colourless oil;
[α]D26.4 = +8.9 (c = 0.84, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 7.6 Hz, 2H), 7.56 (t,
J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 3.73 (s, 3H), 3.69ꢀ3.71 (m, 4H), 3.30 (dd, J = 5.4, 17.4
Hz, 1H), 3.05 (dd, J = 7.0, 17.4 Hz, 1H), 2.85ꢀ2.93 (m, 1H), 1.61ꢀ1.65 (m, 1H), 1.43ꢀ1.46 (m, 2H),
1.27ꢀ1.40 (m, 5H), 0.86 (t, J = 6.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 199.0, 169.4, 169.2,
137.0, 133.0, 128.5, 128.1, 53.8, 52.4, 52.3, 40.1, 34.0, 32.0, 31.6, 26.7, 22.4, 14.0; IR (Neat) ν
2955, 2931, 2859, 1736, 1687, 1598, 1581, 1449, 1436, 1219, 1158, 1024, 751, 738, 691cmꢀ1;
HRMS (ESI): calcd. for [M+H]+ (C19H27O5)+ requires 335.1858; found 335.1849. Enantiomeric
excess: 97%, determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 90/10, flow rate 0.8
mL/min; tmajor = 9.8 min, tminor = 12.0 min, λ = 254 nm).
(S)ꢀ2ꢀEthyl 1,1ꢀdimethyl 4ꢀoxoꢀ4ꢀphenylbutaneꢀ1,1,2ꢀtricarboxylate (4u): 33 mg, yield =
98%,colourless oil; [α]D26.6 = ꢀ1.9 (c = 0.84 , CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.97 (d, J =
7.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 4.04 (d, J
= 6.4 Hz, 1H), 3.83ꢀ3.87 (m, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.63 (dd, J = 6.8, 18.0 Hz 1H), 3.34
(dd, J = 4.8, 18.0 Hz, 1H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 197.1, 172.0,
168.4, 168.3, 136.3, 133.3, 128.6, 128.0, 61.4, 52.7, 52.6, 51.9, 39.6, 37.3, 13.9; IR (Neat) ν 3060,
2983, 2955, 2928, 2850, 1736, 1686, 1597, 1581, 1438, 1025, 860, 755cmꢀ1; HRMS (ESI): calcd.
for [M+H]+ (C17H21O7)+ requires 337.1287; found 337.1278. Enantiomeric excess: 94%,
determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 50/50, flow rate 0.8 mL/min;
tmajor = 18.3 min, tminor = 15.5 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(1,1,1ꢀtrifluoroꢀ4ꢀoxoꢀ4ꢀphenylbutanꢀ2ꢀyl)malonate (4v): 32 mg, yield = 97%,
white solid. m.p. = 84ꢀ86 oC; [α]D26.2 = ꢀ1.9 (c = 0.83, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.99
(d, J = 8.0 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 4.00ꢀ4.11 (m, 1H), 3.88 (d, J
= 8.0 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.65 (dd, J = 6.0, 18.0 Hz, 1H), 3.37 (dd, J = 6.0, 18.0 Hz,
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1H); 13C NMR (CDCl3, 100 MHz) δ 195.2, 167.5, 167.3, 136.0, 133.5, 128.7, 128.1, 126.6 (q,
5
JCꢀF = 278.6 Hz), 53.2, 52.9, 49.1 (q, JCꢀF = 2.2 Hz), 38.2 (q, JCꢀF = 27.4 Hz), 34.4 (q, JCꢀF
=
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1.7 Ηz); F NMR (CDCl3, 282 MHz) δ ꢀ70.2 (d, JCꢀF = 5.6 Hz); IR (KBr) ν 2960, 1745, 1686,
1441, 1366, 1331, 1293, 1225, 1162, 1117, 1070, 1026, 1000, 982, 957, 932, 756, 688 cmꢀ1;
HRMS (ESI): calcd. for [M+H]+ (C15H16F3O5)+ requires: 333.0950; found 333.0940.
Enantiomeric excess: 86%, determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 90/10,
flow rate 0.5 mL/min; tmajor = 12.2 min, tminor = 11.5 min, λ = 254 nm).
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(R)ꢀDimethyl 2ꢀ(1ꢀcyclohexylꢀ3ꢀoxoꢀ3ꢀphenylpropyl)malonate (4w): 35 mg, yield = 98%,
colourless oil; [α]D26.5 = +16.3 (c = 0.87, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 7.6
Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 3.72 (d, J = 6.0 Hz, 1H), 3.69 (s, 6H),
3.29 (dd, J = 5.2, 18.0 Hz, 1H), 3.15(dd, J = 5.8, 18.2 Hz, 1H), 2.92ꢀ2.98 (m, 1H), 1.58ꢀ1.75 (m,
4H), 1.38ꢀ1.45 (m, 1H), 0.94ꢀ1.26 (m, 6H); 13C NMR (CDCl3, 100 MHz)
δ 198.7, 169.9, 169.4, 136.9, 132.9, 128.5, 128.0, 52.7, 52.5, 52.3, 40.6, 38.5, 38.2, 30.9, 29.9, 26.
5, 26.4, 26.3; IR (Neat) ν 2927, 2852, 1732, 1687, 1598, 1581, 1448, 1435, 1220, 1156, 1021, 981,
751, 691cmꢀ1; HRMS (ESI): calcd. for [M+H]+ (C20H27O5)+ requires 347.1858; found 347.1848.
Enantiomeric excess: 94%, determined by HPLC (Chiralpak column AD, hexane/iꢀPrOH 80/20,
flow rate 0.8 mL/min; tmajor = 8.8 min, tminor = 9.5 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀ(4ꢀfluorophenyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4x): 34 mg, yield = 98%,
colourless oil; [α]D24.9 = +21.6 (c = 0.90, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.90ꢀ7.95 (m,
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2H), 7.23ꢀ7.27 (m, 4H), 7.16ꢀ7.21 (m, 1H), 7.06ꢀ7.11 (m, 2H), 4.14ꢀ 4.20 (m, 1H), 3.85 (d, J = 9.2
Hz, 1H), 3.73 (s, 3H), 3.40ꢀ3.56 (m, 5H); 13C NMR (CDCl3, 100 MHz)
δ 196.0, 168.7, 168.1, 165.7 (d, JCꢀF = 253.5 Hz), 140.2, 133.1 (d, JCꢀF = 2.8 Hz), 130.7 (d, JCꢀF
=
9.3 Hz), 128.5, 128.0, 127.3, 115.6 (d, JCꢀF = 21.8 Hz), 57.2, 52.7, 52.4, 42.2, 40.8; 19F NMR
(CDCl3, 376 MHz) δ ꢀ105.2 (m); IR (Neat): ν 3065, 3031, 3005, 2954, 2924, 2852, 1738, 1688,
1597, 1506, 1455, 1435, 1410, 1232, 1157, 1024, 841, 767cmꢀ1; HRMS (ESI): calcd. for [M+H]+
(C20H20FO5)+ requires 359.1295; found 359.1284. Enantiomeric excess: 98%, determined by
HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 14.1 min,
tminor = 17.6 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4y)[5e]: 35 mg, yield = 94%,
white solid. m.p. = 67ꢀ68 C; [α]D26.5 = +20.9 (c = 0.94, CHCl3); H NMR (CDCl3, 400 MHz)
δ 7.83 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.21ꢀ7.27 (m, 4H), 7.16ꢀ7.20 (m, 1H),
4.13ꢀ4.19 (m, 1H), 3.84 (d, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.40ꢀ3.56 (m, 5H). 13C NMR (CDCl3,
100 MHz) δ 196.3, 168.6, 168.0, 140.1, 139.5, 135.0, 129.5, 128.8, 128.5, 127.9, 127.3, 57.1,
52.6, 52.4, 42.2, 40.8. Enantiomeric excess: 99%, determined by HPLC (Phenomenex Celluloseꢀ2,
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hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 15.1 min, tminor = 18.1 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀ(4ꢀbromophenyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4z): 41 mg, yield = 99%,
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white solid. m.p. = 87ꢀ88 C; [α]D
= +19.7 (c = 1.0, CHCl3); H NMR (CDCl3, 400 MHz)
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δ 7.76 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.17ꢀ7.27 (m, 5H), 4.13ꢀ4.19 (m, 1H), 3.84 (d,
J = 9.2 Hz, 1H), 3.73 (s, 3H), 3.50ꢀ3.55 (m, 4H), 3.42 (dd, J = 8.8, 16.8 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 196.5, 168.7, 168.0, 140.1, 135.4, 131.8, 129.6, 128.5, 128.2, 127.9, 127.3,
57.1, 52.7, 52.4, 42.2, 40.8; IR (KBr) ν 2955, 1733, 1682, 1587, 1499, 1457, 1435, 1330, 1296,
1238, 1155, 1089, 1072, 1025, 1011, 980, 823, 786, 765, 703 cmꢀ1; HRMS (ESI): calcd. for
[M+H]+ (C20H20BrO5)+ requires 419.0494; found 419.0483. Enantiomeric excess: 97%,
determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min;
tmajor = 18.4 min, tminor = 22.1 min, λ = 254 nm).
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(S)ꢀDimethyl 2ꢀ(3ꢀoxoꢀ1ꢀphenylꢀ3ꢀ(pꢀtolyl)propyl)malonate (4a'): 35 mg, yield = 98%, white solid.
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m.p. = 76ꢀ77 C; [α]D25.4 = +21.2 (c = 0.89, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.79 (d, J =
8.0 Hz, 2H), 7.14ꢀ7.27 (m, 7H), 4.16ꢀ4.22 (m, 1H), 3.85 (d, J = 9.2 Hz, 1H), 3.71 (s, 3H),
3.41ꢀ3.54 (m, 5H), 2.38 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 197.0, 168.7, 168.1, 143.8, 140.4,
134.2, 129.2, 128.4, 128.1, 128.0, 127.1, 57.3, 52.6, 52.3, 42.1, 40.7, 21.6; IR (KBr): ν 3031, 2953,
2918, 2848, 1737, 1682, 1607, 1496, 1454, 1435, 1259, 1155, 1026, 813, 771 cmꢀ1; HRMS (ESI)
calcd. for [M+H]+ (C21H23O5)+ requires 355.1545; found 355.1540. Enantiomeric excess: 99%,
determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor
= 18.9 min, tminor = 27.8 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4b'): 39 mg, yield = 99%,
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white solid. m.p. = 60ꢀ62 C; [α]D25.9 = +20.5 (c = 0.93, CHCl3); H NMR (CDCl3, 400 MHz)
δ 7.88 (d, J = 8.8 Hz, 2H), 7.22ꢀ7.26 (m, 4H), 7.14ꢀ7.20 (m, 1H), 6.89 (d, J = 8.8 Hz, 2H), 4.15ꢀ
4.21 (m, 1H), 3.86 (d, J = 9.6 Hz, 1H), 3.84 (s, 3H), 3.72 (s, 3H), 3.38ꢀ3.51 (m, 5H). 13C NMR
(CDCl3, 100 MHz) δ 195.9, 168.7, 168.1, 163.4, 140.4, 130.3, 129.8, 128.4, 128.0, 127.1, 113.6,
57.3, 55.4, 52.6, 52.3; IR (KBr): ν 3006, 2953, 2842, 1736, 1677, 1600, 1511, 1434, 1257, 1170,
1025, 838, 775 cmꢀ1. HRMS (ESI): calcd. for [M+Na]+ (C21H21NaO6)+ requires 393.1314; found
393.1316. Enantiomeric excess: 98%, determined by HPLC (Chiralpak column AD,
hexane/iꢀPrOH 50/50, flow rate 0.8 mL/min; tmajor = 22.4 min, tminor = 15.5 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀ(4ꢀnitrophenyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4c'): 38 mg, Yield = 99%,
colourless oil; [α]D24.6 = +19.5 (c = 0.96, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 8.27 (d, J = 8.8
Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.17ꢀ7.28 (m, 5H), 4.13ꢀ4.19 (m, 1H), 3.86 (d, J = 9.2 Hz, 1H),
3.74 (s, 3H), 3.64 (dd, J = 4.8, 16.8 Hz, 1H), 3.47ꢀ3.53 (m, 4H); 13C NMR (CDCl3, 100 MHz)
δ 196.3, 168.7, 168.0, 150.2, 141.1, 139.8, 129.1, 128.6, 127.9, 127.5, 123.8, 57.0, 52.7, 52.5, 42.8,
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40.7; IR (Neat) ν 2955, 1759, 1728, 1694, 1603, 1522, 1455, 1431, 1406, 1350, 1313, 1260, 1200,
1169, 1139, 1012, 855, 744, 699 cmꢀ1; HRMS (ESI): calcd. for [M+H]+ (C20H20NO7)+ requires
386.1240; found 386.1229. Enantiomeric excess: 98%, determined by HPLC (Chiralpak column
AD, hexane/iꢀPrOH 50/50, flow rate 0.8 mL/min; tmajor = 19.6 min, tminor = 17.2 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀ(2ꢀbromophenyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4d'): 41 mg, yield = 99%,
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26.6
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white solid. m.p. = 98ꢀ99 C; [α]D
= +1.8 (c = 0.84, CHCl3); H NMR (CDCl3, 400 MHz)
δ 7.53 (d, J = 7.6 Hz, 1H), 7.18ꢀ7.26 (m, 7H), 7.10 (d, J = 5.6 Hz, 1H), 4.06ꢀ4.12 (m, 1H), 3.81 (d,
J = 8.0 Hz, 1H), 3.75 (s, 3H), 3.51ꢀ3,56 (m, 4H), 3.43 (dd, J = 9.4, 17.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 201.4, 168.5, 168.0, 141.3, 139.8, 133.5, 128.5, 128.4, 128.2, 127.3, 127.2,
118.5, 57.1, 52.7, 52.4, 46.2, 40.8 (one peak for aromatic carbon was not found probably due to
overlapping). IR (KBr) ν 2951, 1749, 1725, 1695, 1586, 1468, 1456, 1435, 1401, 1368, 1303,
1260, 1166, 1049, 1018, 754, 702 cmꢀ1; HRMS (ESI): calcd. for [M+H]+ (C20H20BrO5)+ requires
419.0494; found 419.0483. Enantiomeric excess: 96%, determined by HPLC (Phenomenex
Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 16.3 min, tminor = 20.3 min, λ =
254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀ(3ꢀchlorophenyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4e'): 39 mg, yield = 98%.
colourless oil.[α]D28.6 = +24.1 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.71
1
(d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16ꢀ7.21 (m, 4H), 7.09ꢀ7.15
(m. 1H), 4.07ꢀ4.13 (m, 1H), 3.78 (d, J = 9.6 Hz, 1H), 3.66 (s, 3H), 3.43ꢀ3.49 (m, 4H), 3.38 (dd, J
= 8.8, 17.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 196.2, 168.6, 168.0, 140.2, 138.2, 134.9,
133.0, 129.9, 128.5, 128.1, 128.0, 127.3, 126.2, 57.1, 52.7, 52.4, 42.4, 40.6; IR (Neat): ν 3065,
3031, 2953, 2920, 2849, 1737, 1691, 1571, 1496, 1454, 1434, 1323, 1286, 1257, 1221, 1157, 1077,
1026, 780, 701, 682 cmꢀ1. HRMS (ESI): calcd. for [M+Na]+ (C20H19ClNaO5)+ requires 397.0819;
found 397.0820. Enantiomeric excess: 99%, determined by HPLC (Phenomenex Celluloseꢀ2,
hexane/iꢀPrOH 90/10, flow rate 0.8 mL/min; tmajor = 22.8 min, tminor = 30.0 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀoxoꢀ1ꢀphenylꢀ3ꢀ(thiophenꢀ2ꢀyl)propyl)malonate (4f'): 34 mg, yield = 99%,
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white solid. m.p. = 82ꢀ83 C; [α]D26.5 = +15.5 (c = 1.0, CHCl3); H NMR (CDCl3, 400 MHz)
δ 7.72 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.23ꢀ7.26 (m, 4H), 7.15ꢀ7.21 (m, 1H), 7.09 (t,
J = 4.2 Hz, 1H), 4.14ꢀ4.20 (m, 1H), 3.87 (d, J = 9.6 Hz, 1H), 3.73 (s, 3H), 3.50 (s, 3H), 3.47 (dd, J
= 5.2, 16.4 Hz, 1H), 3.39 (dd, J = 8.8, 16.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 190.3, 168.6, 168.0, 144.0, 140.0, 133.7, 132.0, 128.5, 128.0, 127.9, 127.3, 57.1, 52.6, 52.4, 43.0
, 41.1; IR (KBr) ν2955, 1732, 1659, 1516, 1434, 1418, 1358, 1239, 1163, 1070, 1013, 957, 854,
730 cmꢀ1; HRMS (ESI): calcd. for [M+H]+ (C18H19O5S)+ requires 347.0953; found 347.0944.
Enantiomeric excess: 97%, determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20,
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flow rate 0.8 mL/min; tmajor = 21.9 min, tminor = 28.9 min, λ = 254 nm).
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(S)ꢀDimethyl 2ꢀ(3ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4g'): 32 mg, yield = 97%, white
solid. m.p. = 106ꢀ108 oC; [α]D25.6 = +29.0 (c = 0.83, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.53
(s, 1H), 7.14ꢀ7.25 (m, 6H), 6.48 (s, 1H), 4.13ꢀ4.19 (m, 1H), 3.86 (d, J = 9.6 Hz, 1H), 3.73 (s, 3H),
3.50 (s, 3H), 3.29ꢀ3.41 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 186.5, 168.6, 168.0, 152.5, 146.3
, 140.1, 128.4, 128.0, 127.2, 117.2, 112.2, 57.2, 52.6, 52.4, 42.1, 40.6; IR (KBr) ν 3126, 3098,
2958, 1727, 1666, 1474, 1404, 1296, 1239, 1160, 1095, 1072, 1018, 980, 951, 919, 771, 700 cmꢀ1;
HRMS (ESI): calcd. for [M+H]+ (C18H19O6)+ requires 331.1182; found 331.1172. Enantiomeric
excess: 96%, determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8
mL/min; tmajor = 28.7 min, tminor = 39.9 min, λ = 254 nm).
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(S)ꢀDimethyl 2ꢀ(3ꢀ(naphthalenꢀ1ꢀyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4h'): 37mg, yield = 95%,
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white solid. m.p. = 98ꢀ99 C; [α]D25.8 = ꢀ16.8 (c = 0.88, CHCl3); H NMR (CDCl3, 400 MHz)
δ 8.11 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.2 Hz,
1H), 7.40ꢀ7.48 (m, 3H), 7.14ꢀ7.22 (m, 5H), 4.18ꢀ4.24 (m, 1H), 3.87 (d, J = 9.6 Hz, 1H), 3.74 (s,
3H), 3.67 (dd, J = 4.6, 16.6 Hz, 1H), 3.45ꢀ3.52 (m, 4H); 13C NMR (CDCl3, 100 MHz)
δ 201.8, 168.7, 168.1, 140.0, 135.9, 133.8, 132.4, 129.9, 128.5, 128.2, 127.6, 127.3, 127.2, 126.3,
125.6, 124.3, 57.3, 52.7, 52.4, 45.8, 41.3; IR (KBr) ν 2951, 1728, 1676, 1507, 1433, 1305, 1238,
1163, 1083, 774, 707 cmꢀ1; HRMS (ESI): calcd. for [M+H]+ (C24H23O5)+ requires 391.1545;
found 391.1533. Enantiomeric excess: 95%, determined by HPLC (Chiralpak column ADꢀH,
hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 15.8 min, tminor = 14.4 min, λ = 254 nm).
(S)ꢀDimethyl 2ꢀ(3ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl)malonate (4i'): 39 mg, yield = 99%,
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white solid. m.p. = 98ꢀ99
o
C; [α]D26.5 = +46.6 (c = 0.98, CHCl3); H NMR (CDCl3, 400 MHz)
δ 8.44 (s, 1H), 7.93ꢀ7.96 (m, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.52ꢀ7.60 (m, 2H), 7.23ꢀ7.30 (m, 4H),
7.14ꢀ7.20 (m, 1H), 4.24ꢀ4.29 (m, 1H), 3.91 (d, J = 9.6 Hz, 1H), 3.74 (s, 3H), 3.68 (dd, J = 5.0,
17.2 Hz, 1H), 3.61 (dd, J = 8.8, 16.8 Hz, 1H), 3.52 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 197.4,
168.7, 168.1, 140.4, 135.5, 134.0, 132.4, 129.8, 129.5, 128.5, 128.4, 128.3, 128.0, 127.7, 127.2,
126.7, 123.8, 57.3, 52.7, 52.4, 42.3, 40.9. IR (KBr) ν 3065, 3034, 2952, 2849, 1735, 1681, 1627,
1498, 1454, 1434, 1357, 1261, 1155, 1124, 1025, 862, 823, 750, 701 cmꢀ1; HRMS (ESI) calcd. for
[M+Na]+ (C24H22NaO5)+ requires 413.1365; found 413.1367. Enantiomeric excess: 99%,
determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 50/50, flow rate 0.8 mL/min;
tmajor = 14.1 min, tminor = 18.6 min, λ = 254 nm).
28.4
(S)ꢀDimethyl 2ꢀ(3ꢀoxoꢀ1ꢀphenylbutyl)malonate (4j')[23]: 24 mg, yield = 85%. colourless oil. [α]D
1
= +11.0 (c =1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 7.11ꢀ7.23 (m, 5H), 3.88ꢀ3.94 (m, 1H),
3.66 (d, J = 9.6 Hz, 1H), 3.65 (s, 3H), 3.43 (s, 3H), 2.91 (dd, J = 5.4, 17.0 Hz 1H), 2.84 (dd, J =
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8.6, 17.0 Hz, 1H), 1.96 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 206.0, 168.6, 168.0, 140.4, 128.5,
128.0, 127.3, 57.1, 52.6, 52.4, 47.1, 40.4, 30.3. Enantiomeric excess: 91%, determined by HPLC
(Chiralpak ADꢀH column, hexane/iꢀPrOH 80/20, flow rate 0.8 mL/min; tmajor = 8.8 min, tminor = 8.0
min, λ = 214 nm).
(S)ꢀDimethyl 2ꢀ(5ꢀoxoꢀ1ꢀphenylhexanꢀ3ꢀyl)malonate (4k′)[24]: 21 mg, Yield = 67%. Colourless oil.
[α]D23.8 = + 2.0 (c =1.02, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.25ꢀ7.29 (m, 2H), 7.14ꢀ7.19 (m,
3H), 3.72 (s, 3H), 3.71 (s, 3H), 3.63 (d, J = 5.6 Hz, 1H), 2.72ꢀ2.83 (m, 2H), 2.53ꢀ2.67 (m, 3H),
2.12 (s, 3H), 1.63ꢀ1.78 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ 207.2, 169.2, 169.0, 141.4, 128.4,
128.3, 125.9, 53.6, 52.4, 52.3, 45.1, 34.1, 33.4, 30.2. Enantiomeric excess: 19%, determined by
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HPLC (Phenomenex Celluloseꢀ2 column, hexane/iꢀPrOH 85/15, flow rate 0.8 mL/min; tmajor
=
10.0 min, tminor = 11.4 min, λ = 220 nm).
(S)ꢀDiethyl 2ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)malonate(4l′)[2d]
: 49 mg, Yield = 99 %. White
solid. m. p. = 65ꢀ68 oC; [α]D28.0 = +18.5 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J
= 7.2 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.21ꢀ7.27 (m, 4H), 7.14ꢀ7.18 (m,
1H), 4.14ꢀ4.26 (m, 3H), 3.95 (q, J = 7.2 Hz, 2H), 3.82 (d, J = 10.0 Hz, 1H), 3.54 (dd, J = 4.6, 16.6
Hz, 1H), 3.46 (dd, J = 9.2, 16.8 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). 13C
NMR (CDCl3, 100 MHz) δ 197.5, 168.3, 167.7, 140.4, 136.7, 133.0, 128.5, 128.3, 128.2, 128.0,
127.1, 61.6, 61.3, 57.5, 42.6, 40.7, 14.0, 13.7. Enantiomeric excess: 99%, determined by HPLC
(Phenomenex Celluloseꢀ2 column, hexane/iꢀPrOH 80/20, flow rate 1.0 mL/min; tmajor = 10.3 min,
t
minor = 16.4 min, λ = 254 nm).
(S)ꢀDibenzyl 2ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)malonate(4m′)[5b]
: 36 mg, Yield = 99 %. White
solid. m. p. = 90ꢀ91 oC; [α]D27.9 = +12.5 (c = 0.97, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.80 (d,
J = 7.6 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.13ꢀ7.27 (m, 13 H), 7.05ꢀ7.06
(m, 2H), 5.16 (d, J = 12.0 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 4.90 (s, 2H), 4.20ꢀ4.25 (m, 1H), 3.95
(d, J = 9.6 Hz, 1H), 3.44 (d, J = 6.8 Hz, 2H). 13C NMR (CDCl3, 100 MHz)
δ 197.3, 167.9, 167.4, 140.2, 136.6, 135.1, 135.0, 132.9, 128.5, 128.4 (×2), 128.3 ( ×2), 128.2,
128.1 (×3), 128.0, 127.1, 67.3, 67.1, 57.5, 42.2, 40.7. Enantiomeric excess: 99%, determined by
HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 70/30, flow rate 1.0 mL/min; tmajor = 13.4 min,
tminor = 28.1 min, λ = 254 nm).
(S)ꢀDibenzyl 2ꢀ(3ꢀoxocyclopentyl)malonate(4n′)[25]: 36 mg, Yield = 98 %. Colourless oil;
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[α]D28.0 = ꢀ6.9 (c = 0.97, CHCl3). H NMR (400 MHz, CDCl3) δ 7.28ꢀ7.32 (m, 10 Η), 5.13ꢀ5.16
(m, 4H), 3.45 (d, J = 9.2 Hz, 1H), 2.81ꢀ2.92 (m, 1H), 2.42ꢀ2.48 (m, 1H), 2.25ꢀ2.33 (m, 1H),
2.10ꢀ2.22 (m, 2H), 1.95ꢀ202 (m, 1H), 1.55ꢀ1.67 (m, 1H). 13C NMR (CDCl3, 100 MHz)
δ 216.9, 167.7, 167.6, 135.0, 134.9, 128.5 (×2), 128.4 (×2), 128.2 (×2), 67.3, 67.2, 56.4, 42.7, 38.1
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, 36.3, 27.3. Enantiomeric excess: 17%, determined by HPLC (Phenomenex Celluloseꢀ2,
hexane/iꢀPrOH 88/12, flow rate 0.8 mL/min; tmajor = 49.3 min, tminor = 44.2 min, λ = 220 nm).
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(S)ꢀDibenzyl 2ꢀ(3ꢀoxocyclohexyl)malonate(4o′)[25]
: 14 mg, Yield = 38 %. White solid. m. p.
= 55ꢀ57 oC. [α]D26.5 = +1.4 (c = 0.73, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.27ꢀ7.34 (m, 10H),
5.15 (s, 2H), 5.14 (s, 2H), 5.41 (d, J = 7.6 Hz, 1H), 2.51ꢀ2.60 (m, 1H), 2.35ꢀ2.46 (m, 2H),
2.15ꢀ2.27 (m, 2H), 1.98ꢀ2.05 (m, 1H), 1.88ꢀ1.91 (m, 1H), 1.57ꢀ1.69 (m, 1H), 1.41ꢀ1.51 (m, 1H).
13C NMR (CDCl3, 100 MHz) δ 209.4, 167.5, 167.4, 135.0 (×2), 128.5, 128.4 (×2), 128.2, 67.2
(×2), 56.7, 45.0, 40.9, 38.1, 28.6, 24.4 (two peaks for aromatic carbon were not found probably
due to overlapping). Enantiomeric excess: 16%, determined by HPLC (Chiralpak ASꢀH column,
hexane/iꢀPrOH 90/10, flow rate 0.5 mL/min; tmajor = 75.9 min, tminor = 62.9 min, λ = 220 nm).
(R)ꢀDimethyl 2ꢀmethylꢀ2ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)malonate (4p'): 35 mg, Yield = 98%.
White solid. m. p. = 135ꢀ136 oC. [α]D25.8 = +53.1 (c = 0.50, CHCl3). 1H NMR (400 MHz, CDCl3)
δ 7.84 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.07ꢀ7.18 (m, 5H),
4.12 (dd, J = 2.8, 10.8 Hz, 1H), 3.65ꢀ3.72 (m, 4H), 3.57 (s, 3H), 3.49 (dd, J = 2.8, 17.2 Hz, 1H),
1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.7, 171.9, 171.7, 138.8, 136.9, 132.9, 129.2,
128.4, 128.1, 128.0, 127.3, 57.9, 52.5, 52.4, 45.5, 41.0, 19.4 ; IR (KBr): ν 3008, 2994, 2952, 1739,
1716, 1672, 1447, 1374, 1301, 1254, 1231, 1124, 1107, 750, 703, 689 cmꢀ1; HRMS (ESI): calcd.
for [M+Na]+ (C21H22NaO5)+ requires 377.1365; found 377.1364. Enantiomeric excess: 98%,
determined by HPLC (Chiralpak ADꢀH column, hexane/iꢀPrOH 90/10, flow rate 0.7 mL/min; tmajor
=24.2 min, tminor = 15.9 min, λ = 254 nm).
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(R)ꢀDimethyl 2ꢀfluoroꢀ2ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)malonate (4q'): 32 mg, yield = 89%.
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White solid. m. p. = 122ꢀ123 C. [α]D25.5 = +60.2 (c = 0.5, CHCl3). H NMR (400 MHz, CDCl3)
δ 7.81ꢀ7.83 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H),
7.12ꢀ7.21 (m, 3H), 4.46 (ddd, J = 3.8, 9.4 Hz, JHꢀF = 32.6 Hz, 1H), 3.78 (s, 3H), 3.59 (dd, J = 9.4,
17.4 Hz, 1H), 3.48 (s, 3H), 3.33 (dd, J = 4.0, 17.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 196.2,
165.9 (d, JCꢀF = 25.8 Hz), 165.2 (d, JCꢀF = 26.4 Hz), 137.0, 136.4, 133.3, 129.2 (d, JCꢀF = 1.9 Hz),
128.6, 128.4, 128.0, 127.8, 97.4 (d, JCꢀF = 204.6 Hz), 53.7, 53.1, 44.9 (d, JCꢀF = 18.6 Hz), 39.3 (d,
JCꢀF = 3.4 Hz). 19F NMR (376 MHz, CDCl
) δ ꢀ173.4 (d, JCꢀF = 32.7 Hz). IR (KBr): ν 3064, 3032,
3
2960, 2921, 2890, 1758, 1736, 1682, 1448, 1431, 1300, 1267, 1240, 1145, 1092, 1049, 1039, 959,
940, 788, 755, 702, 687 cmꢀ1; HRMS (ESI): calcd. for [M+Na]+ (C20H19FNaO5)+ requires
381.1114; found 381.1103. Enantiomeric excess: 98%, determined by HPLC (Chiralpak ASꢀH
column, hexane/iꢀPrOH 80/20, flow rate 0.7 mL/min; tmajor = 13.0 min, tminor = 15.5 min, λ = 254
nm).
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The procedure for synthesis of compound 5[17]
.
To a solution of product 4a (0.1 mmol, 34 mg) and iodine (1.2 equiv, 0.12 mmol,
31 mg) in toluene (1 mL) under argon was added 1,8ꢀDiazabicyclo[5.4.0]undecꢀ7ꢀ
ene (DBU) (3 equiv, 0.3 mmol, 46 mg, 44 ꢁL), and then the solution was stirred at
ambient temperature for 0.5 h before being quenched by 10% Na2S2O3 aqueous
solution (5.0 mL). The aqueous phase was extracted with ethyl acetate for three times
(5 mL × 3). The combined organic phase was washed with saturated brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue
was purified by flash column chromatography (petroleum ether/ethyl acetate = 6 : 1)
to deliver the desired single diastereomer transꢀcyclopropane derivative 5.
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(2S,3R)ꢀDimethyl 2ꢀbenzoylꢀ3ꢀphenylcyclopropaneꢀ1,1ꢀdicarboxylate (5)[21]: 30 mg, yield = 90%.
colourless oil. [α]D28.4 = +28.1 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.2 Hz,
2H), 7.62 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.27ꢀ7.34 (m, 5H), 4.14 (d, J = 7.6 Hz, 1H),
3.88 (d, J = 7.6 Hz, 1H), 3.71 (s, 3H), 3.54 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 193.8, 166.5, 166.1, 136.7, 133.7, 133.3, 128.8, 128.5, 128.4, 127.7, 53.0, 52.9, 46.0, 36.6, 35.0.
(one peak for aromatic carbon was not found probably due to overlapping). Enantiomeric excess:
94%, determined by HPLC (Phenomenex Celluloseꢀ2, hexane/iꢀPrOH 80/20, flow rate 0.8
mL/min; tmajor = 9.5 min, tminor = 11.6 min, λ = 254 nm).
The procedure for synthesis of compound 6[18]
.
To a solution of product 4a (0.1 mmol, 34 mg) and iodine (1.5 equiv, 0.15 mmol, 38
mg) in DMF (1 mL) was added Na2CO3 (3 equiv, 0.3 mmol, 32 mg). Then the mixture
was stirred under air at 35 oC for 16 h. After cooling to room temperature, the mixure
was diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O
(5 mL) and brine respectively, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The resulting residue was purified by flash column chromatography
(petroleum ether/ethyl acetate = 10 : 1) to give the product 6.
Dimethyl (3S,4R)ꢀ4ꢀbenzoylꢀ3ꢀphenyloxetaneꢀ2,2ꢀdicarboxylate (6)[18b]
: 29 mg, yield = 81%;
colourless oil. [α]D27.0 = ꢀ15.4 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.2 Hz,
2H), 7.50 (t, J = 7.6 Hz, 1H), 7.38ꢀ7.26 (m, 7H), 6.07 (d, J = 7.6 Hz, 1H), 4.92 (d, J = 7.2 Hz, 1H),
3.78 (s, 3H), 3.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.8, 167.6, 166.9, 134.1, 133.7, 133.1
, 128.8, 128.7, 128.5, 128.0, 87.3, 82.3, 53.4, 52.5, 49.0 (one peak for aromatic carbon was not
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found probably due to overlapping); Enantiomeric excess: 99%, determined by HPLC (Chiralpak
ADꢀH column, hexane/iꢀPrOH 90/10, flow rate 1 mL/min; tmajor = 18.7 min, tminor = 24.5 min, λ =
254 nm).
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at DOI:
1H and 13C NMR spectra and HPLC traces (PDF)
AUTHOR INFERMATION
Corresponding Authors
*Eꢀmail: zhaog@mail.sioc.ac.cn, Fax: 0086ꢀ21ꢀ64166128. Tel: 0086ꢀ21ꢀ54925182.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from Chinese Academy of Sciences (XDB 20020100) and the
National Natural Science Foundation of China (Nos. 21272247, 21572247, 21290184)
is gratefully acknowledged.
Notes and references
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