Conjugate addition of aryl nucleophiles to α,β-unsaturated cinnamic acid derivatives containing Evans type chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2016.07.003

Cinnamides containing oxazolidin-2-one type auxiliaries have been prepared. A novel pathway to chiral 4-aryl-6-methyl-3,4-dihydrocoumrines via the asymmetric conjugate addition of arylmagnesium bromides to these cinnamides is described.

Full text of DOI:10.1016/j.tetasy.2016.07.003

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Conjugate addition of aryl nucleophiles to
a,b-unsaturated cinnamic
acid derivatives containing Evans type chiral auxiliaries
⇑
ꢀ
Zigmars Leitis , Viesturs Lusis
¯
Latvian Institute of Organic Synthesis, Aizkraukles Street 21, Riga LV-1006, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
Cinnamides containing oxazolidin-2-one type auxiliaries have been prepared. A novel pathway to chiral
4-aryl-6-methyl-3,4-dihydrocoumrines via the asymmetric conjugate addition of arylmagnesium
bromides to these cinnamides is described.
Received 10 June 2016
Accepted 20 July 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
The conjugate addition of aryl nucleophiles to cinnamic acid
derivatives linked with a chiral auxiliary is a straightforward
4-Aryl-3,4-dihydrocoumarins (4-arylchroman-2-ones) are nat-
urally occurring compounds that are a major structural type of
neoflavonoids of which both enantiomers widely occur in plants.1
Recently compounds with high antioxidant capacity have been
obtained in this class.2,3 4-Aryl-3,4-dihydrocoumarins are also
versatile synthons for the preparation of 1,3-diarylpropylamines
possessing muscarinic receptor antagonist properties,4,5 as well
as intermediates for the preparation of 1,3-diaryl-2,3-dihydro-
1H-indene-2-carboxylic acid derivatives, known as endothelin
antagonists.6
approach to construct an alkyl chain bearing stereogenic carbon
having two different aryl groups. Oxazolidinones5 and imidazolidi-
nones7 are recommended as suitable chiral auxiliaries for this
purpose.
The pathway leading to (R)- or (S)-6-substituted 4-aryl-3,4-
dihydrocoumarin can be switched by applying an auxiliary of
opposite configuration or by altering the substituents in the cin-
namoyl and arylmagnesium moieties and using the same auxiliary.
2. Results and discussion
Herein we report an approach to both enantiomerically
enriched 4-aryldihydrocoumarin isomers based on the asymmetric
conjugate addition of aryl magnesium species to cinnamic acid
derivatives. The selection of the cinnamic substrate and the
organomagnesium reagent is focused on the preparation of 6-
methyl-4-aryl-3,4-dihydrocoumarins that would be suitable scaf-
folds for antimuscarinic drug (Tolterodine, Fesoterodine) synthesis.
With the above analysis in mind, we examined copper assisted
addition of arylmagnesium species to 3-cinnamoyl-oxazolidin-2-
ones 2a–i and their phenyl ring analogues 2j–l and 7a–c.
N-Cinnamoyl oxazolidinones 2a–i were prepared from cin-
namoyl chloride 1a and N-unsubstituted oxazolidinones XcAH 3
in the presence of n-butyl lithium as a base (Scheme 1). Cinnamoyl
oxazolidinones 2j–l were prepared in the same way starting with
the synthesis from corresponding acid.
O
Commercially unavailable (R)- and (S)-4-isobutyl-5,5-dimethyl-,
(S)-4-secbutyl-5,5-dimethyl-, (R)- and (S)-4-phenyl-5,5-dimethyl-
and (S)-4-benzyl-5,5-dimethyloxazolidinones necessary for the
preparation of cinnamides 2c–g and 7b were obtained from methyl
Xc
O
R
R
Xc
*
*
O
O
O
OH
R
ester of the corresponding D- or L-amino acid in accordance with
Xc
the general method.8 Their enantiomeric purity was confirmed
by comparison of the specific rotation of both enantiomers.
Other phenyl ring cinnamoyl derivatives, namely 3-(3-(2-ben-
zyloxy-5-methylphenyl)acryloyl)oxazolidin-2-ones 7a–c were
prepared in three steps from the corresponding heterocycles 3
(Scheme 2). Acylation of the oxazolidinones with halogenacetyl
chloride followed by the interaction of N-halogenacetyl derivatives
4 with triethylphosphite analogues9 gave phosphonates 5a–c.
OH
⇑
Corresponding author.
E-mail address: zigmars@osi.lv (Z. Leitis).
http://dx.doi.org/10.1016/j.tetasy.2016.07.003
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
Z. Leitis, V. Lusis / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
O
O
O
O
Xc-H
Xc-H
N
3a-i
Cl
3d
N
O
O
n-BuLi;
n-BuLi;
R1
-78 °C
R
R
-78 °C
R3
R2
2a-i
2j-l
j
(60-78%)
1a-d
(47-87%)
a R1 = (R)- Ph; R2 = R3 = H
R=OMe
k R=F
a R=H
b R1 = (S)- Ph; R2 = R3 = H
b
R=OMe
c
d
l R=CF3
R
R
1 = (R)- i-Bu; R2 = R3 = Me
1 = (S)- i-Bu; R2 = R3 = Me
c R=F
d
R=CF3
e R1 = (S)- sec-Bu; R2 = R3 = Me
f R1 = (R)- Ph; R2 = R3 = Me
g R1 = (S)- Ph; R2 = R3 = Me
h
R
1 = (S)- i-Pr; R2 = R3 = H
i
R
1 = (R)- i-Pr; R2 = R3 = H
Scheme 1. Preparation of cinnamides 2a–l.
OBn
OBn
O
O
P
O
O
O
O
O
O
O
X
CHO
X
N
O
N
N
P(OEt)3
6
Cl
HN
R1
O
O
O
O
O
K2CO3, D, 12h
n-BuLi,
100 °C,
12h
R1
R1
R1
R3
R3
R3
R3
R2
R2
(14-70%)
-78 °C
R2
R2
5a-c
(95-97%)
7a-c
3c,j,k
4a-c
(36-56%)
c R1 = (R)- i-Bu; R2 = R3 = Me; X = Br
j R1 = (S)- Bn; R2 = R3 = Me; X = Cl
k R1 = (R)- Bn; R2 = R3 = H; X = Cl
Scheme 2. Preparation of cinnamides 7a–c.
O
Xc
(S)-Xc
(R)-Xc
O
O
2a-i
cat.Cu(I)
cat.Cu(I)
-30 to -20 °C
-30 to -20 °C
Xc
Xc
OBn
O
OBn
OBn
(R)-Xc
(S)-Xc
Xc
8b,d,e,g,h,l
8a,c,f,i-k
(14-81%)
(23-82%)
7a-c
O
O
O
O
(S)-9
(R)-9
(73-99%, ee 16-99%)
(73-95%, ee 15-99%)
Scheme 3. Reaction of cinnamides 2 and 7 with arylmagnesium with subsequent cyclization of 3,3-diarylsubstrates 8 to coumarines 9.
Condensation with 2-benzyloxy-5-methylbenzaldehyde 6, which
was obtained reaction of arylmagnesium bromide with DMF,
resulted in the formation of cinnamoyl derivatives 9a–c.10
N-Cinnamoyl oxazolidinones 2 and 7 underwent regioselective
copper catalysed 1,4-addition of arylmagnesium in good yields
(Table 1) and with moderate to high stereoselectivity (Table 2)
depending on the structure of oxazolidinone 3 moiety. The prod-
ucts of this conjugate addition were 3,3-diarylpropionyl-oxazolidi-
nones 8. These products were treated with BBr3 to remove the
O-benzyl protection and to give phenol intermediates, which were
subjected to interaction with trimethylamine, leading to chroman
ring closure and affording dihydrocoumarins 9.
A correlation between the oxazolidinone auxiliary C-4 configu-
ration in the cinnamide and the structure of the 3-aryl-3-phenyl-
propanoic acid derivative is already known: the (R)-auxiliary
initiates the formation of the (R)-propionyl chaine.5 4-Phenyloxa-
zolidinones ensure excellent stereoselectivity whereas asymmetric
induction using 4-alkyl or 4-benzyl oxazolidinone derivatives as an
auxiliary is only moderate. This indicated the key role of
p–p
stacking in the 1,4-addition transition state. Consequently,
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Z. Leitis, V. Lusis / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
Cu-catalysed conjugate aryl-/phenylmagnesium addition to cinnamoyl oxazolidinones 2a-i and 7a–c via Scheme 4
Entry
Substrate 2
Copper source
3,3-Diarylpropanoyl-oxazolidinone 8
Compd
R
Config.
Compd
Yield
de, %
Config.
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2d
2d
2d
2e
2f
2g
2h
2i
7a
7b
7c
Ph
Ph
(R)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(R)
(R)
(S)
(R)
Me2SÁCuBr
Me2SÁCuBr
CuBr
8a
8b
8c
8d
8d
8d
8d
8e
8f
8g
8h
8i
8j
8l
61
62
83
81
84
82
76
49
55
50
14
23
51
29
46
99
99
—
—
—
—
—
—
—
—
—
—
—
86
—
(R,R)
(S,S)
(R,R)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(R,R)
(S,S)
(S,S)
(R,R)
(R,S)
(S,R)
(R,S)
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
sec-Bu
Ph
Me2SÁCuBr
CuBr
2LiClÁCuCN
Li2CuCl4
CuBr
Me2SÁCuBr
Me2SÁCuBr
Me2SÁCuBr
CuBr
CuBr
CuBr
CuBr
9
10
11
12
13
14
15
Ph
i-Pr
i-Pr
i-Bu
Bn
Bn
8k
In Table 1 only three examples are shown (entry 1, 2 and 14) where de values were measured in a 3,3-diarylpropionamides. Others (including entries 1 and 2) were converted
into coumarine 9 and then the ee values were measured.
Table 2
a few experiments which is not enough to draw this as a general
conclusion.
Chemical yields and selectivity of coumarine 9 prepared from 8a–k via Scheme 3
The electronic influence of the substituent in the cinnamoyl
moiety was evaluated studying the addition of 2-benzyloxy-5-
methylphenyl magnesium to cinnamoyloxazolidinones 2j–k
(Scheme 4).
The addition of arylmagnesium to C@C double bond proceeded
with approximately the same diastereoselectivity (de 10a 66%, 10b
60% and 10c 64%) regardless of the nature of the cinnamoyl
para-substituent. The stereoselectivity of the conjugate addition
to substrates 2 was established by HPLC, by applying a Chiralpak
IA column. The yields of the diarylpropionyloxazolidinones 10
decreased in the presence of electron withdrawing groups in the
cinnamoyl moiety: 10a 82%, 10b 62%, 10c 40%.
Entry
3,3-Diarylpropanoyl-oxazolidinone 8
Coumarine 9
Yield
ee, %
Config.
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8d
8d
8d
8e
8f
8g
8h
8i
8j
8l
90
92
93
73
90
89
96
85
99
95
94
93
91
—
99
99
65
63
71
52
65
76
99
99
15
16
49
—
(R)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(R)
(S)
(R)
(S)
9
10
11
12
13
14
15
While searching for an appropriate auxiliary, besides the cin-
namides discussed above, cinnamates 11 derived from inexpensive
natural alcohols (L-menthol, L-borneol) were prepared. However
8k
73
60
the ester function turned out to be unsuitable to prepare
3,3-diarylpropanoic derivatives (Scheme 5).
p-interactions dominate over the steric bulkiness of the oxazolidi-
none 4-substituent.
3. Conclusion
The recognition of (3R)- and (3S)-diarylpropionamides 8a,b
bearing a 4-phenyloxazolidinone moiety was achieved by HPLC
using a Chiralcel OD column (Table 1; entry 1, 2).
These cinnamates do not react with 2-benzyloxy-5-
methylphenylmagnesium in the presence of Me2SÁCuBr. More than
80% of unconverted esters were recovered in these trials. The same
interaction of menthyl ester with arylmagnesium in the presence
of Cu(I)Cl (10 mol %, THF, À10 °C) gave product of simultaneous
1,4- and 1,2-addition i.e., 1,3-bis-(2-benzyloxy-5-methyl-phenyl)-
3-phenylpropan-1-one 12 in 26% yield; a remarkable amount
(65%) of starting material was also recovered. The application of
arylmagnesium without the addition of copper catalyst proceeded
Chiral HPLC conditions suitable to distinguish the 3-diarylpro-
pionamide diastereomers 8c–k derived from 4-alkyl oxazolidi-
nones were not found. Therefore the efficiency of these
auxiliaries was evaluated by comparison of the ee values measured
for the final product of this transformation, i.e. the ee value of 6-
methyl-4-phenyl-3,4-dihydrocoumarin 9; in this case the enan-
tiomeric excess was measured by using a Chiralcel OD-H column
(Table 2).
Usually Cu(I) salts or their complexes are used to promote con-
jugate addition of arylmagnesium species. All cuprous salts tested
led to the formation of diarylpropionic acid derivative 8g in similar
yields (81–84%) (Table 1; entries 3–6). The highest diastereoselec-
tivity was achieved when using Me2SÁCuBr complex. Remarkably
the same reaction selectivity and product outcome were obtained
when Cu(II) was applied in the Li2CuCl4 form (Table 1; entry 7).
The presence of the ortho-substituent in the starting cinnamoy-
loxazolidinone compounds 7a–c decreased the yield (29–51%) of
3,3-diarylpropanoyloxazolidinones in comparison to derivatives
unsubstituted in the cinnamoyl compound benzene ring (Table 1;
entry 13–15). The substituent also diminishes the stereoselectivity
of the addition reaction (Table 1; entry 14). However these are only
MgBr
OBn
O
O
O
O
BnO
N
O
N
O
cat. CuBr,
-20 °C
R
R
2j-l
10a-c
(40-82%, de 60-66%)
j
R= OMe,
R= F,
k
l
R=CF3
Scheme 4. Preparation of cinnamides 2j–l and the reaction of arylmagnesium.
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Z. Leitis, V. Lusis / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4
O
O
BnO
O
OBn
ArMgBr
Cu(I)
R*-H
Cl
OR*
r.t. 48h
cat. CuCl
-10 °C
11a,b
1
(84-87%)
12 (26%)
R*=
L
L
-menthyl
a
b
-bornyl
Scheme 5. Preparation of cinnamoyl esters 11a,b and the reactions of arylmagnesium.
in a similar manner: compound 12 was isolated in 16% yield and
63% of ester 11a was recovered. This result is in disagreement with
addition of some aryllithium reagents to t-butyl cinnamates.11
4.2.4. 4-Trifluorocinnamoyl chloride 1d
Light yellow solid (0.48 g, yield 89%); mp 60–62 °C. 1H NMR
(200 MHz, CDCl3) d 6.73 (d, J = 15.6 Hz, 1H, CH@CHACO), 7.70
(m, 4H, aromH), 7.85 (d, J = 15.6 Hz, 1H, CH@CHACO).
4. Experimental section
4.1. General information
4.3. General procedure of chiral cinnamic acid amides 2a–l
n-Butyllithium (1.15 mL, 1.0 equiv, 2.3 M in hexanes) was added
to a cooled until À75 °C solution of the corresponding oxazolidinone
(2.6 mmol) in anhydrous THF (12 mL), then the resulting solution
was warmed to À30 °C and stirred for 20 min. At the same temper-
ature, a solution of cinnamoyl chloride (1.0 equiv) in anhydrous THF
(7 mL) was added dropwise and then allowed to rise to at room tem-
perature and left overnight with continuous stirring. After work-up
with 10% NH4Cl (15 mL), the organic layer was separated and the
aqueous layer was extracted with ethyl acetate (2 Â 25 ml). The
combined organic phase was dried over Na2SO4, filtered and evapo-
rated under reduced pressure. The crude products were purified by
chromatography or crystallized from appropriate solvents.
NMR spectra were recorded on a Varian Mercury 200, 300, 400
and 600 MHz in CDCl3 and DMSO-d6 using signal of the solvent as
internal standard. Specific rotation was measured on polarimeter
Atago AP-100, the concentration c is given as g/100 mL in CHCl3.
Flush chromatography separations were carried out over Merck sil-
ica gel 60 (0.035–0.070 mm) or Silasorb 600 (0.030 mm). The elu-
ent compositions are given as v/v ratio. The reactions were
monitored on thin layer precoated silica gel plates (DC-Alufolien
Kieselgel 60 F254), the spots were visualized under UV light. Melt-
ing points were determined using OptiMelt MPA100 apparatus and
are uncorrected. Chiral HPLC analyses were detected at 254 nm
and performed on following Daicel columns: OD-H
(0.46 Â 25 cm); the eluent hexane/isopropanol 90:10, flow rate
0.5 mL/min —6-methyl-4-phenyl-3,4-dihydrocoumarine 9, OD
(0.46 Â 25 cm); eluent hexane/isopropanol 70:30, flow rate
4.3.1. (R)-4-Phenyl-3-[(E)-(3-phenylacryloyl)]-oxazolidin-2-one 2a
White crystals (0.28 g, 62% yield) after crystallization (Et2O/
EtOAc, 1:1); mp 169–170 °C. 1H NMR (200 MHz, CDCl3) d 4.32
(dd, J = 3.8, 8.8 Hz, 1H, NCHCH2), 4.74 (t, J = 8.8 Hz, 1H, NCHCH2),
5.56 (dd, J = 3.8, 8.8 Hz, 1H, NCHCH2), 7.28–7.48 (m, 8H, aromH),
7.52–7.66 (m, 2H, aromH), 7.78 (d, J = 15.7 Hz, 1H, CH@CHACO),
7.95 (d, J = 15.7 Hz, 1H, CH@CHACO). 13C NMR (75 MHz, CDCl3) d
58.0, 70.1, 117.0, 126.1, 128.7, 128.8, 129.0, 129.3, 130.8, 134.6,
139.2, 146.8, 153.9, 164.9.
1.0 mL/min
—3,3-diarylpropionamides
8a,b,l
and
IA
(0.46 Â 25 cm); eluent hexane/isopropanol 90:10, flow rate
0.5 mL/min—3,3-diarylpropionamides 10a–c.
4.2. General procedure for preparation of cinnamoyl chlorides
1a–d
4.3.2. (S)-4-Phenyl-3-[(E)-(3-phenylacryloyl)]-oxazolidin-2-one
2b
White crystals (1.2 g, 69% yield). Melting point, dH and dC spec-
tra were identical to 2a [(R)-isomer].
Cinnamic acid (10.0 g, 0.067 mol) solution in thionyl chloride
(100 ml, 20 equiv) was refluxed for 1.5 h, and then evaporated
under reduced pressure. The crude product was used in the next
step without further purification.
4.3.3. (S)-4-Isobutyl-5,5-dimethyl-3-[(E)-(3-phenylacryloyl)]-
oxazolidin-2-one 2d
4.2.1. Cinnamoyl chloride 1a
Colourless oil (9.0 g, yield 80%); mp 30–35 °C. 1H NMR
(200 MHz, CDCl3) d 6.65 (d, J = 15.3 Hz, 1H, CH@CHACO), 7.35–
7.52 (m, 3H, 3,4,5-aromH), 7.52–7.64 (m, 2H, 2,6-aromH), 7.85
(d, J = 15.3 Hz, 1H, CH@CHACO).
White crystals (7.4 g, 72% yield) after crystallization (Et2O); mp
109–110 °C; [a]
29 = +78 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) d
D
1.00 (m, 6H, (CH3)2CH), 1.47 (s, 6H, 2 Â 5-CH3), 1.51–1.68 (m, 3H,
CHCH2), 4.30 (m, 1H, NCHCH2), 7.34–7.44 (m, 3H, 3,4,5-aromH),
7.55–7.66 (m, 2H, 2,6-aromH), 7.84 (d, J = 15.7 Hz, 1H,
CH@CHACO), 7.92 (d, J = 15.7 Hz, 1H, CH@CHACO). 13C NMR
(75 MHz, CDCl3) d 21.8, 22.5, 23.1, 25.4, 28.5, 39.4, 61.1, 82.4,
117.6, 128.7, 129.0, 130.7, 134.8, 146.1, 153.2, 165.8. MS: m/z
301 (59, M+), 258 (26), 172 (16), 154 (22), 130 (100), 128 (18),
111 (14). Found: C, 71.71%; H, 7.73%; N, 4.58%. C18H23NO3 requires
C, 71.73%; H, 7.69%; N, 4.65%.
4.2.2. 4-Methoxycinnamoyl chloride 1b
Light yellow solid (0.52 g, yield 99%); mp 45–49 °C. 1H NMR
(200 MHz, CDCl3) d 6.51 (d, J = 15.4 Hz, 1H, CH@CHACO), 6.94 (d,
J = 8.8 Hz, 2H, 2,6-aromH), 7.53 (d, J = 8.8 Hz, 2H, 3,5-aromH),
7.79 (d, J = 15.4 Hz, 1H, CH@CHACO).
4.2.3. 4-Fluorocinnamoyl chloride 1c
Green-yellow solid (0.48 g, yield 87%); mp 40–44 °C. 1H NMR
(200 MHz, CDCl3) d 6.58 (d J = 15.5 Hz, 1H, CH@CHACO), 7.07–
7.21 (m, 2H, 3,5-aromH), 7.52–765 (m, 2H, 2,6-aromH), 7.80 (d
J = 15.5 Hz, 1H, CH@CHACO).
4.3.4. (R)-4-Isobutyl-5,5-dimethyl-3-[(E)-(3-phenylacryloyl)]-
oxazolidin-2-one 2c
White crystals (1.3 g, 60% yield); [
a]
29 = À77 (c 1.0, CHCl3).
D
Melting point, dH and dC spectra are identical to 2d [(S)-isomer].
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5
4.3.5. (S)-4-sec-Butyl-5,5-dimethyl-3-[(E)-(3-phenylacryloyl)]-
oxazolidin-2-one 2e
4.30 (m, 1H, NCHCH2), 7.63 (d, J = 8.6 Hz, 2H, 3,5-aromH), 7.70 (d,
J = 8.6 Hz, 2H, 2,6-aromH), 7.82 (d, J = 15.7 Hz, 1H, CH@CHACO),
7.99 (d, J = 15.7 Hz, 1H CH@CHACO).
White solid (1.8 g, 78% yield) after chromatography (PE/EtOAc,
10:1); mp 81–83 °C. 1H NMR (200 MHz, CDCl3) d 0.94 (t, J = 7.3 Hz,
3H, CH3CH2), 1.07 (d, J = 7.3 Hz, 3H, MeCH), 1.11–1.34 (m, 1H,
CH3CH2), 1.43 (s, 3H, 5-CH3), 1.45–1.67 (m, 1H, CH3CH2), 1.53 (s,
3H, 5-CH3), 1.81–2.03 (m, 1H, CH3CH), 4.29 (d, J = 3.6 Hz, 1H, NCH),
7.33–7.44 (m, 3H, aromH), 7.56–7.66 (m, 2H, aromH), 7.83 (d,
J = 15.3 Hz, 1H, CH@CHACO), 7.99 (d, J = 15.3 Hz, 1H, CH@CHACO).
13C NMR (75 MHz, CDCl3) d 12.2, 17.2, 21.9, 24.5, 29.3, 36.7, 66.8,
82.9, 117.4, 128.7, 129.0, 130.7, 134.8, 146.3, 153.7, 165.9.
4.4. General procedure for the preparation of halogen
acetyloxazolidinones 4a–c
To a cooled (À78 °C) solution of the corresponding oxazolidinone
3 (1.9 mmol) in THF (15 mL), n-butyllithium (1.07 mL, 2.5 M,
1.1 equiv) was added under stirring. The temperature was allowed
rise to À20 °C and the mixture was stirred for 1 h, then cooled down
to À78 °C, repeatedly. The halogenacetylchloride (0.23 mL,
1.5 equiv) was added dropwise at this temperature under stirring
and the reaction mixture was left overnight at room temperature,
after which it was quenched with 50 mL of 10% NH4Cl. The organic
layer was separated and aqueous phase was extracted by ethyl acet-
ate (3 Â 30 mL) and dried over Na2SO4. Concentration in vacuo gave
a crude product, which was then purified by column chromatogra-
phy or crystallized from appropriate solvents at À18 °C.
4.3.6. (R)-4-Phenyl-5,5-dimethyl-3-[(E)-(3-phenylacryloyl)]-
oxazolidin-2-one 2f
White crystals (1.6 g, 66% yield) after crystallization (PE/EtOAc,
5:1); mp 153–155 °C. 1H NMR (200 MHz, DMSO-d6) d 0.89 (s, 3H,
5-CH3), 1.62 (s, 3H, 5-CH3), 5.29 (s, 1H, NCH), 7.16–7.50 (m, 8H,
aromH), 7.56–7.72 (m, 2H, aromH and 1H, CH@CHACO), 7.89 (d,
J = 16.1 Hz, 1H, CH@CHACO). 13C NMR (75 MHz, CDCl3) d 23.9,
29.1, 67.4, 82.6, 117.3, 126.5, 128.7, 128.8, 128.9, 129.0, 130.8,
134.7, 136.4, 146.7, 153.4, 165.2.
4.4.1. (R)-3-(2-Bromoacetyl)-4-isobutyl-5,5-dimethyl-
oxazolidin-2-one 4a
4.3.7. (S)-4-Phenyl-5,5-dimethyl-3-[(E)-(3-phenylacryloyl)]-
oxazolidin-2-one 2g
White crystals (0.47 g, 75% yield). Melting point, dH and dC spec-
tra are identical to 2f [(R)-isomer].
This compound was prepared according general procedure
using bromo acetylchloride. Yellow oil (2.7 g, yield 36%) after chro-
matography (PE/EtOAc, 50:1). 1H NMR (200 MHz, CDCl3) d 0.93–
1.01 (m, 6H, (CH3)2CH), 1.47 (s, 6H, 5-CH3), 1.48–1.64 (m, 3H,
(CH3)2CHCH2), 4.09–4.26 (m, 1H, NCH), 4.44 (d, J = 12.4 Hz, 1H,
BrCH2), 4.57 (d, J = 12.4 Hz, 1H, BrCH2).
4.3.8. (S)-4-Isopropyl-3-[(E)-(3-phenylacryloyl)]-oxazolidin-2-
one 2h
White solid (1.5 g, 74% yield) after chromatography (PE/EtOAc,
3:1); mp 64–65 °C. 1H NMR (200 MHz, DMSO-d6) d 0.82 (d,
J = 13.1 Hz, 3H, 5-CH3), 0.85 (d, J = 13.1 Hz, 3H, 5-CH3), 2.20–2.25
(m, 1H, (CH3)2CH), 4.29–4.39 (m, 2H, NCHCH2), 4.39–4.53 (m, 1H,
NCHCH2), 7.38–7.49 (m, 3H, aromH), 7.60–7.71 (m, 2H, aromH),
7.72 (d, J = 16.1 Hz, 1H, CH@CHACO), 7.84 (d, J = 16.1 Hz, 1H,
CH@CHACO). 13C NMR (100 MHz, CDCl3) d 14.9, 18.2, 28.7, 58.8,
63.5, 117.2, 128.7, 129.0, 130.7, 134.7, 146.3, 154.3, 165.3.
4.4.2. (S)-4-Benzyl-3-(2-chloroacetyl)-5,5-dimethyl-oxazolidin-
2-one 4b
White crystals (0.3 g, 56% yield) after crystallization (PE/EtOAc,
16:1); mp 68–69 °C. 1H NMR (200 MHz, CDCl3) d 1.37 (s, 3H, 5-
CH3), 1.39 (s, 3H, 5-CH3), 2.88 (dd, J = 9.7, 14.4 Hz, 1H, PhCH2),
3.20 (dd, J = 3.8, 14.4 Hz, 1H, PhCH2), 4.50 (dd, J = 3.8, 9.7 Hz, 1H,
NCH), 4.63 (d, J = 15.9 Hz, 1H, ClCH2), 4.77 (d, J = 15.9 Hz, 1H,
ClCH2), 7.15–7.36 (m, 5H, aromH).
4.3.9. (R)-4-Isopropyl-3-[(E)-(3-phenylacryloyl)]-oxazolidin-2-
one 2i
White solid (1.4 g, 70% yield). Melting point, dH and dC spectra
are identical to 2h [(S)-isomer].
4.4.3. (R)-4-Benzyl-3-(2-chloroacetyl)-oxazolidin-2-one 4c
White crystals (0.76 g, yield 53%) after crystallization (PE/Et2O;
4:1); mp 74–75 °C. 1H NMR (200 MHz, CDCl3) d 2.81 (dd, J = 9.5,
13.1 Hz, 1H, PhCH2), 3.34 (dd, J = 3.6, 13.1 Hz, 1H, PhCH2), 4.26–
4.30 (m, 2H, NCHCH2), 4.68–4.72 (m, 1H, NCH), 4.75 (s, 2H, ClCH2),
7.15–7.41 (m, 5H, aromH).
4.3.10. (S)-4-Isobutyl-3-[(E)-3-(4-methoxyphenyl)-acryloyl]-5,5-
dimethyl-oxazolidin-2-one 2j
Yellow oil (0.64 g, yield 75%) after chromatography (PE/EtOAc,
1:1). 1H NMR (200 MHz, CDCl3) d 1.00 (m, 6H, (CH3)2CH), 1.46 (s,
6H, 2 Â 5-CH3), 1.50–1.66 (m, 3H, CH2CH), 3.83 (s, 3H, CH3O),
4.30 (m, 1H, NCHCH2), 6.86–6.94 (m, 2H, 3,5-aromH), 7.52–7.62
(m, 2H, 2,6-aromH), 7.76 (d, J = 15.7 Hz, 1H, CH@CHACO), 7.84
(d, J = 15.7 Hz, 1H, CH@CHACO).
4.5. General procedure for the preparation of phosphonates 5a–c
Halogenacetyl oxazolidinone 4 (1.1 mmol) dissolved in triethyl
phosphite (0.73 mL, 4.0 equiv) was heated at 100 °C for 12 h. Then
the solution was evaporated till dryness and then toluene
(4 Â 5 mL) was added with repeated evaporation before each
toluene addition to obtain desired phosphonate which was used
in next step without further purification.
4.3.11. (S)-4-Isobutyl-5,5-dimethyl-3-[(E)-3-(4-fluorophenyl)-
acryloyl]-oxazolidin-2-one 2k
Light yellow oil (0.30 g, yield 47%) after chromatography (PE/
EtOAc, 1:1). 1H NMR (200 MHz, CDCl3) d 1.00 (m, 6H, (CH3)2CH),
1.47 (s, 6H, 2 Â 5-CH3), 1.50–1.64 (m, 3H, CHCH2), 4.29 (m, 1H,
NCHCH2), 7.00–7.14 (m, 2H, 3,5-aromH), 7.54–7.65 (m, 2H, 2,6-
aromH), 7.78 (d, J = 17.8 Hz, 1H CH@CHACO), 7.86 (d, J = 17.8 Hz,
1H, CH@CHACO).
4.5.1. [2-((R)-4-Isobutyl-5,5-dimethyl-2-oxo-oxazolidin-3-yl)-2-
oxoethyl]phosphonic acid diethyl ester 5a
Colourless oil (3.0 g, yield 97%). 1H NMR (200 MHz, CDCl3) d
0.95 (d, J = 5.8 Hz, 6H, (CH3)2CH), 1.25–1.38 (m, 6H, 2 Â CH3CH2O),
1.43 (s, 3H, 5-CH3), 1.46 (s, 3H, 5-CH3), 1.40–1.55 (m, 3H, (CH3)2-
CHCH2), 3.50 (dd, J = 13.9, 22.7 Hz, 1H, POCH2), 3.94–4.25 (m, 4H,
2 Â CH3CH2O and 2H, POCH2).
4.3.12. (S)-4-Isobutyl-5,5-dimethyl-3-[(E)-3-(4-trifluoromethyl-
phenyl)-acryloyl]-oxazolidin-2-one 2l
White solid (0.69 g, yield 87%) after chromatography (PE/EtOAc,
4:1); mp 115–116 °C. 1H NMR (200 MHz, CDCl3) d 1.00 (m, 6H,
(CH3)2CH), 1.48 (s, 6H, 2 Â 5-CH3), 1.51–1.64 (m, 3H, CHCH2),
4.5.2. [2-((S)-4-Benzyl-5,5-dimethyl-2-oxo-oxazolidin-3-yl)-2-
oxoethyl]phosphonic acid diethyl ester 5b
Yellow oil (0.39 g, yield 97%). 1H NMR (200 MHz, CDCl3) d 1.28–
1.37 (m, 6H, 2 Â CH3CH2O), 1.33 (s, 3H, 5-CH3), 1.38 (s, 3H, 5-CH3),
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Z. Leitis, V. Lusis / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
6
2.86 (dd, J = 9.9, 14.5 Hz, 1H, PhCH2), 3.18 (dd, J = 3.7, 14.5 Hz, 1H,
PhCH2), 3.53 (dd, J = 13.9, 22.5 Hz, POCH2), 4.02 (dd, J = 13.9,
22.5 Hz, POCH2), 4.07–4.25 (m, 4H, 2 Â CH3CH2O), 4.52 (dd,
J = 3.6, 9.8 Hz, 1H, NCH), 7.23–7.33 (m, 5H, aromH).
suspension of CuBr (71 mg, 0.3 equiv) in dry THF (3 mL), then the
temperature was allowed raise to À25 °C and solution of cin-
namide 2 (1.6 mmol) in dry THF (4 mL) was added keeping the
temperature below À20 °C. After the addition was completed the
temperature was allowed to rise to room temperature and stirred
overnight. The reaction mixture was quenched with 10% NH4Cl
(10 mL) and mixture was evaporated to remove all of the organic
solvent. The aqueous layer was then extracted with ethyl acetate
(3 Â 25 mL), and washed with 30 ml of 17% NH4OH and 50 ml of
brine and dried over Na2SO4. Concentration in vacuo gave a crude
product, which was purified by chromatography or crystallized.
4.5.3. [2-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-2-oxoethyl]-phos-
phonic acid diethyl ester 5c
Colourless oil (0.40 g, yield 95%). 1H NMR (200 MHz, CDCl3) d
1.35 (t, J = 7.0 Hz, 6H, 2 Â CH3CH2O), 2.75 (dd, J = 9.9, 13.4 Hz, 1H,
PhCH2), 3.35 (dd, J = 3.4, 13.4 Hz, 1H, PhCH2), 3.75 (q, J = 14.2 Hz,
1H, POCH2), 3.85 (q, J = 14.2 Hz, 1H, POCH2), 4.09–4.31 (m, 4H,
2 Â CH3CH2O and 2H, NCHCH2), 4.61–4.79 (m, 1H, NCHCH2),
7.17–7.40 (m, 5H, aromH).
A
O
BnO
O
4.6. 2-Benzyloxy-4-methylbenzaldehyde 6
N
O
B
This compound was prepared from appropriate arylmagnesium
bromide and DMF in 39% yield.
R
R
R
R
4.7. General procedure for the preparation of chiral cinnamic
acid amides 7a–c
4.8.1. (R)-3-[(R)-3-(2-Benzyloxy-5-methylphenyl)-3-phenylpro-
pionyl]-4-phenyl-oxazolidin-2-one 8a
A suspension of phosphonate 5 (0.87 mmol), arylaldehyde 6
(1.0 equiv) and K2CO3 (5.0 equiv) in 5 mL of dry THF was refluxed
for 12 h. The mixture was dissolved in water (50 mL) and the solution
was extracted with ethylacetate (3 Â 30 mL). Theorganicextractwas
dried (Na2SO4) and then evaporated. The crude product obtained was
subjected on silica gel using a mixture of PE and dichloromethane.
This compound was obtained from 2a (0.25 g, 0.85 mmol) in
0.26 g amount (yield 61%) after chromatography (PE/EtOAc,
1.2:1) and further recrystallization of ether. White crystals; mp
116–117 °C (Et2O); [
a]
22 = À72 (c 1.0, CHCl3); de 100%; Found: C,
D
77.50; H, 5.83; N, 2.79. C32H29NO4 requires C, 78.19; H, 5.95; N,
2.85%; 1H NMR (200 MHz, CDCl3) d 2.26 (s, 3H, CH3), 3.62 (dd,
J = 6.5, 16.8 Hz, 1H, PhCHCH2), 3.89 (dd, J = 8.9, 16.8 Hz, 1H,
PhCHCH2), 4.16 (dd, J = 3.5, 8.8 Hz, 1H, PhCHCH2), 4.50 (t,
J = 8.7 Hz, 1H, NCH), 4.92 (s, 2H, PhCH2O), 5.02 (dd, J = 6.5, 8.8 Hz,
1H, NCHCH2), 5.28 (dd, J = 3.5, 8.6 Hz, 1H, NCHCH2), 6.71 (d,
J = 8.3 Hz, 1H, 3(A)-aromH), 6.93 (dd, J = 2.1, 8.3 Hz, 1H,
4(A)-aromH), 7.06 (d, J = 2.1 Hz, 1H, 6(A)-aromH), 7.08–7.34 (m,
15H, aromH). 13C NMR (75 MHz, CDCl3) d 20.9, 40.0, 40.1, 57.7,
70.0, 70.2, 112.2, 125.7, 126.2, 127.4, 127.7, 127.9, 128.3, 128.4,
128.5, 128.6, 128.7, 129.2, 130.0, 132.0, 137.4, 139.1, 143.5,
153.9, 171.1.
4.7.1. (R)-4-Isobutyl-3-[(E)-3-(2-benzyloxy-5-methylphenyl)-acr-
yloyl]-5,5-dimethyl-oxazolidin-2-one 7a
Light yellow oil (0.53 g, yield 14%) after chromatography (PE/
DCM, 1:1.5). 1H NMR (200 MHz, CDCl3) d 0.95–1.05 (m, 6H, (CH3)2-
CH), 1.46 (s, 6H, 2 Â 5-CH3), 2.29 (s, 3H, CH3Ph), 4.23–4.35 (m, 1H,
NCH), 5.14 (s, 2H, PhCH2), 6.82 (d, J = 8.0 Hz, 1H, 3-aromH), 7.10 (dd,
J = 1.4, 8.0 Hz, 1H, 4-aromH), 7.29–7.51 (m, 6H, aromH), 7.91 (d,
J = 16.1 Hz, 1H, CH@CHACO), 8.29 (d, J = 16.1 Hz, 1H, CH@CHACO).
4.7.2. (S)-4-Benzyl-3-[(E)-3-(2-benzyloxy-5-methylphenyl)-acr-
yloyl]-5,5-dimethyl-oxazolidin-2-one 7b
Colourless oil (0.11 g, yield 25%) after chromatography (PE/
DCM, 1:2). 1H NMR (200 MHz, CDCl3) d 1.38 (s, 3H, 5-CH3), 1.39
(s, 3H, 5-CH3), 2.30 (s, 3H, CH3Ph), 2.91 (dd, J = 9.8, 14.4 Hz, 1H,
NCH), 3.31 (dd, J = 3.3, 14.4 Hz, 1H, PhCH2CH), 4.62 (dd, J = 3.3,
9.8 Hz, 1H, PhCH2CH), 5.15 (s, 2H, PhCH2O), 6.84 (d, J = 8.4 Hz,
1H, 3-aromH), 7.12 (dd, J = 2.2, 8.4 Hz, 1H, 4-aromH), 7.17–7.53
(11H, m, aromH), 7.93 (d, J = 15.8 Hz, 1H, CH@CHACO), 8.30 (d,
J = 15.8 Hz, 1H, CH@CHACO).
4.8.2. (S)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-phenylpro-
pionyl]-4-phenyl-oxazolidin-2-one 8b
This compound was obtained from 2b (0.40 g, 1.36 mmol) in
0.41 g amount (yield 62%) after chromatography (PE/EtOAc,
22
1.2:1) and recrystallization from ether. White crystals; [
a
]
=
D
+75 (c 1.0, CHCl3); de 100%. Melting point, dH and dC spectra are
identical to 8a ((R)-isomer).
4.8.3. (R)-3-[(R)-3-(2-Benzyloxy-5-methylphenyl)-3-phenylpro-
pionyl]-4-isobutyl-5,5-dimethyl-oxazolidin-2-one 8c
4.7.3. (R)-4-Benzyl-3-[(E)-3-(2-benzyloxy-5-methylphenyl)-acr-
yl-oyl]-oxazolidin-2-one 7c
This compound was obtained from 2c (0.50 g, 1.65 mmol) in
0.68 g amount (yield 82%) after chromatography (PE/EtOAc,
10:1). Light yellow oil. 1H NMR (200 MHz, CDCl3) d 0.86 (m, 6H,
(CH3)2CH), 1.19 (s, 3H, 5-CH3), 1.36 (s, 3H, 5-CH3), 1.15–1.45 (m,
3H, (CH3)2CHCH2), 2.25 (s, 3H, CH3Ph), 3.55 (dd, J = 6.7, 16.4 Hz,
1H, PhCHCH2), 3.92 (dd, J = 9.1, 16.4 Hz, 1H, PhCHCH2), 4.04
(t, J = 6.7 Hz, 1H, NCH), 5.01 (s, 2H, PhCH2O), 5.10 (dd, J = 6.7,
9.1 Hz, 1H, PhCHCH2), 6.74 (d, J = 8.3 Hz, 1H, 3(A)-aromH), 6.93
(dd, J = 1.5, 8.3 Hz, 1H, 4(A)-aromH), 7.05 (d, J = 1.5 Hz, 1H, 6
(A)-aromH), 7.09–7.42 (m, 10H, aromH).
Yellow oil (0.83 g, yield 70%) after chromatography (PE/DCM,
1:1). 1H NMR (200 MHz, CDCl3) d 2.30 (s, 3H, CH3), 2.84 (dd,
J = 9.5, 13.4 Hz, 1H, PhCH2CH), 3.39 (dd, J = 3.2, 13.4 Hz, 1H, PhCH2-
CH), 4.10–4.34 (m, 2H, NCHCH2), 4.79 (ddd, J = 3.2, 6.8, 9.5 Hz, 1H,
NCH), 5.16 (s, 2H, PhCH2O), 6.85 (d, J = 8.4 Hz, 1H, 3-aromH), 7.08–
7.17 (m, 1H, 4-aromH), 7.19–7.54 (m, 11H, aromH), 7.93 (d,
J = 15.8 Hz, 1H, CH@CHACO), 8.36 (d, J = 15.8 Hz, 1H, CH@CHACO).
4.8. General procedure for conjugate 1,4-addition of
arylmagnesium bromides to cinnamic acid derivatives 2a–l in
the presence of Cu(I) catalysts
4.8.4. (S)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-phenylpro-
pionyl]-4-isobutyl-5,5-dimethyl-oxazolidin-2-one 8d
This compound was obtained from 2d (0.50 g, 1.65 mmol) in
0.67 g amount (yield 81%) after chromatography (PE/EtOAc,
10:1). Light yellow oil. dH spectra is identical to 8c ((R,R)-isomer).
Grignard reagent, prepared from 1-benzyloxy-2-bromo-4-
methylbenzene (0.68 g, 2.4 mmol) and magnesium turnings
(0.12 g) in dry THF (10 mL), was added to a cooled (À50 °C)
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Z. Leitis, V. Lusis / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
4.8.5. (S)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-phenyl-
propionyl]-4-sec-butyl-5,5-dimethyl-oxazolidin-2-one 8e
This compound was obtained from 2e (1.82 g, 6.0 mmol) in
1.48 g amount (yield 49%) after crystallization (PE/EtOAc, 1:1).
White solid; mp 112–114 °C. 1H NMR (200 MHz, CDCl3) d 0.79–
0.83 (m, 3H, CH3CH2 and 3H, CH3CH), 0.90–1.02 (m, 1H, CH3CH2),
1.14 (s, 3H, 5-CH3), 1.34–1.46 (m, 1H, CH3CH2), 1.42 (s, 3H, 5-
CH3), 1.67–1.78 (m, 1H, CH3CH), 2.23 (s, 3H, CH3Ph), 3.70 (dd,
J = 7.4, 16.6 Hz, 1H, PhCHCH2), 3.80 (dd, J = 8.4, 16.6 Hz, 1H,
PhCHCH2), 4.02 (d, J = 3.3 Hz, 1H, NCH), 4.91 (d, J = 12.0 Hz, 1H,
PhCH2O), 4.96 (d, J = 12.0 Hz, 1H, PhCH2O), 5.03–5.07 (m, 1H,
PhCHCH2), 6.68 (d, J = 8.2 Hz, 1H, 3(A)-aromH), 6.86 (dd, J = 1.7,
8.2 Hz, 1H, 4(A)-aromH), 7.02 (d, J = 1.7 Hz, 1H, 6(A)-aromH),
7.04–7.28 (m, 10H, aromH).
J = 4.4 Hz, 1H, 4-aromH diast. isomer A), 6.89 (d, J = 4.4 Hz, 1H, 4-
aromH diast. isomer B), 6.94 (d, J = 1.6 Hz, 1H, 3-aromH diast. iso-
mer A), 6.96 (d, J = 1.6 Hz, 1H, 3-aromH diast. isomer B), 7.04 (d,
J = 1.8 Hz, 1H, aromH diast. isomer A), 7.06 (d, J = 1.8 Hz, 1H,
aromH diast. isomer B), 7.11–7.39 (m, 20H, aromH). 13C NMR
(75 MHz, DMSO-d6) d 14.4, 14.5, 17.3, 20.4, 28.2 and 28.3 (diast.),
57.9, 63.4, 69.3 and 69.4 (diast.), 112.4, 127.2, 127.3, 126.0,
127.6, 127.8, 127.9, 128.1, 128.2, 128.3, 128.3, 129.1 and 129.2
(diast.), 131.7 and 131.8 (diast.), 137.3, 143.5 and 143.6 (diast.),
153.2 and 153.3 (diast.), 154.0 and 154.1 (diast.), 170.7 and 170.8
(diast.). MS: m/z 458 (8, M+), 440 (16), 405 (94), 287 (17), 260
(100), 130 (38).
4.8.10. (S)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-(4-
methoxy-phenyl)-propionyl]-4-isobutyl-5,5-dimethyl-
oxazolidin-2-one 10a
4.8.6. (R)-3-[(R)-3-(2-Benzyloxy-5-methylphenyl)-3-phenyl-
propionyl]-4-phenyl-5,5-dimethyl-oxazolidin-2-one 8f
This compound was obtained from 2j (0.73 g, 2.2 mmol) in
0.96 g amount (yield 82%) after chromatography (PE/EtOAc, 4:1).
Yellow oil; de 66%. 1H NMR (200 MHz, CDCl3) d 0.80 (d, J = 5.7 Hz,
6H, (CH3)2CH), 1.13 (s, 3H, 5-CH3), 1.30 (s, 3H, 5-CH3), 1.11–1.35
(m, 3H, (CH3)2CHCH2), 2.18 (s, 3H, CH3Ph), 3.44 (dd, J = 6.5,
16.3 Hz, 1H, ArCHCH2), 3.68 (s, 3H, CH3O), 3.84 (dd, J = 9.4,
16.3 Hz, 1H, ArCHCH2), 3.3–4.03 (m, 1H, ArCHCH2), 4.95 (s, 2H,
PhCH2), 4.96–5.04 (m, 1H, NCH), 6.63–6.74 (m, 3H, aromH), 6.85
(dd, J = 2.0, 8.2 Hz, 1H, aromH), 6.98 (dd, J = 2.3, 6.6 Hz, 1H, 4(A)-
aromH), 7.12 (d, J = 8.7 Hz, 2H, aromH), 7.07–7.30 (m, 5H, PhCH2).
This compound was obtained from 2f (1.65 g, 5.1 mmol) in
1.45 g amount (yield 55%) after flush chromatography (20%
EtOAc/PE 10 min ? 80% EtOAc/PE 5 min ? 80% EtOAc/PE 5 min;
20 mL/min; at 210 and 254 nm). White solid; mp 140–142 °C. 1H
NMR (200 MHz, CDCl3) d 0.86 (s, 3H, 5-CH3), 1.35 (s, 3H, 5-CH3),
2.20 (s, 3H, CH3Ph), 3.57 (dd, J = 6.2, 16.8 Hz, 1H, PhCHCH2), 3.91
(dd, J = 9.0, 16.8 Hz, 1H, PhCHCH2), 4.81–4.89 (m, 2H, PhCH2O
and 1H, NCH), 4.94 (dd, J = 6.2, 9.0 Hz, 1H, PhCHCH2), 6.64 (d,
J = 8.2 Hz, 1H, 3(A)-aromH), 6.85 (dd, J = 1.5, 8.2 Hz, 1H, 4(A)-
aromH), 6.89–6.95 (m, 2H, aromH), 7.03 (d, J = 1.5 Hz, 1H, 6(A)-
aromH), 7.10–7.24 (m, 8H, aromH). 13C NMR (100 MHz, CDCl3) d
21.0, 23.8, 28.3, 47.8, 67.3, 71.0, 71.9, 83.2, 113.0, 126.7, 127.4,
127.9, 128.3, 128.4, 128.6, 128.7, 128.8, 129.0, 129.3, 130.4,
130.5, 135.9, 137.3, 140.7, 152.9, 154.5, 174.0.
4.8.11. (S)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-(4-fluoro-
phenyl)-propionyl]-4-isobutyl-5,5-dimethyl-oxazolidin-2-one
10b
This compound was obtained from 2k (0.30 g, 0.94 mmol) in
0.30 g amount (yield 62%) after chromatography (PE/EtOAc, 4:1).
Colourless oil, de 60%. 1H NMR (400 MHz, CDCl3) d 0.80–0.91 (m,
6H, (CH3)2CH), 1.21 (s, 3H, 5-CH3), 1.38 (s, 3H, 5-CH3), 1.17–1.44
(m, 3H, (CH3)2CHCH2), 2.26 (s, 3H, CH3Ph), 3.53 (dd, J = 6.6,
16.4 Hz, 1H, ArCHCH2), 3.89 (dd, J = 9.2, 16.4 Hz, 1H, ArCHCH2),
4.01–4.10 (m, 1H, ArCHCH2), 4.99 (d, J = 3.1 Hz, 2H, PhCH2), 4.94–
5.11 (m, 1H, NCH), 6.74 (d, J = 8.3 Hz, 1H, 3(A)-aromH), 6.83–6.98
(m, 3H, 4(A) and 3,5(B)-aromH), 7.03 (d, J = 1.7 Hz, 1H, 6(A)-
aromH), 7.15–7.40 (m, 7H, 2,6(B) and PhCH2). 13C NMR
(100 MHz, CDCl3) d 20.9, 21.7, 22.7, 22.9, 25.1, 27.9, 39.2, 39.7,
39.9, 60.8, 70.3, 82.3, 112.1, 115.0 (J = 21.1 Hz), 127.4, 127.8,
128.1, 128.5, 129.9 (J = 7.8 Hz), 130.0, 131.8, 137.4, 139.1
(J = 3.2 Hz), 153.2, 153.9, 161.5 (J = 243.9 Hz), 171.9.
4.8.7. (S)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-phenyl-
propionyl]-4-phenyl-5,5-dimethyl-oxazolidin-2-one 8g
This compound was obtained from 2g (0.47 g, 1.4 mmol) in
0.38 g amount (yield 50%) after flush chromatography (20%
EtOAc/PE 10 min ? 80% EtOAc/PE 5 min ? 80% EtOAc/PE 5 min;
20 mL/min; at 210 and 254 nm). White solid. Melting point, dH
and dC spectra are identical to 8f [(R,R)-isomer].
4.8.8. (S)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-phenylpro-
pionyl]-4-isopropyl-oxazolidin-2-one 8h
This compound was obtained from 2h (1.49 g, 5.7 mmol) in
0.36 g amount (yield 14%) after flush chromatography (20%
EtOAc/PE 10 min ? 80% EtOAc/PE 5 min ? 80% EtOAc/PE 5 min;
20 mL/min; at 210 and 254 nm). Yellow oil. dH and dC spectra are
identical to 8i [(R,R)-isomer].
4.8.12. (S)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-(4-
trifluoro-methylphenyl)-propionyl]-4-isobutyl-5,5-dimethyl-
oxazolidin-2-one 10c
4.8.9. (R)-3-[(R)-3-(2-Benzyloxy-5-methylphenyl)-3-phenylpro-
pionyl]-4-isopropyl-oxazolidin-2-one 8i
This compound was obtained from 2l (0.47 g, 1.2 mmol) in
0.29 g amount (yield 40%) after chromatography (PE/EtOAc, 8:1).
White solid; mp 115–116 °C; de 64%. 1H NMR (200 MHz, CDCl3) d
0.87 (m, 6H, (CH3)2CH), 1.17 (s, 3H, 5-CH3), 1.23–1.47 (m, 3H,
(CH3)2CHCH2), 1.37 (s, 3H, 5-CH3), 2.27 (s, 3H, CH3Ph), 3.54 (dd,
J = 6.5, 16.5 Hz, 1H, ArCHCH2), 3.94 (dd, J = 9.3, 16.5 Hz, 1H,
ArCHCH2), 4.04 (m, 1H, ArCHCH2), 4.97 (s, 2H, PhCH2), 5.08 (dd,
J = 6.6, 9.4 Hz, 1H, NCH), 6.75 (d, J = 8.1 Hz, 1H, 3(A)-aromH), 6.96
(dd, J = 2.0, 8.1 Hz, 1H, 4(A)-aromH), 7.06 (d, J = 2.0 Hz, 1H, 6(A)-
aromH), 7.17–7.39 (m, 7H, PhCH2 and 2,6(B)-aromH), 7.40–7.49
(m, 2H, 3,5(B)-aromH). 13C NMR (100 MHz, CDCl3) d 20.9, 21.7,
22.6, 22.9, 25.1, 27.9, 39.2, 39.3, 40.6, 60.8, 70.2, 82.3, 112.1,
124.3 (J = 271.7 Hz), 125.0 (J = 3.9 Hz), 127.5, 127.9, 128.3
(J = 32.2 Hz), 128.5, 128.8, 130.1, 131.0, 137.2, 147.7, 153.1,
153.9, 171.7. MS: m/z 568 (12, M+), 550 (17), 506 (14), 370 (39),
172 (100), 59 (15).
This compound was obtained from 2i (1.42 g, 5.4 mmol) in
0.58 g amount (yield 23%) after flush chromatography (20%
EtOAc/PE 10 min ? 80% EtOAc/PE 5 min ? 80% EtOAc/PE 5 min;
20 mL/min; at 210 and 254 nm). Yellow vitreous material. 1H
NMR (400 MHz, DMSO-d6) d 0.59 (d, J = 6.9 Hz, 3H, (CH3)2CH) diast.
isomer A), 0.72 (d, J = 7.0 Hz, 3H, (CH3)2CH) diast. isomer A), 0.67
(d, J = 6.9 Hz, 3H, (CH3)2CH) diast. isomer B), 0.76 (d, J = 7.0 Hz,
3H, (CH3)2CH diast. isomer B), 1.85–2.03 (m, 2H, (CH3)2CH), 2.20
(s, 3H, CH3Ph diast. isomer A), 2.21 (s, 3H, CH3Ph diast. isomer B),
3.32 (dd, J = 7.4, 16.3 Hz, 1H, ArCHCH2 diast. isomer A), 3.80 (dd,
J = 8.1, 16.9 Hz, 1H, ArCHCH2 diast. isomer A), 3.41 (dd, J = 7.6,
16.9 Hz, 1H, ArCHCH2 diast. isomer B), 3.90 (dd, J = 8.5, 16.6 Hz,
1H, ArCHCH2 diast. isomer B), 4.17–4.32 (m, 6H, ArCHCH2 and
2H, NCHCH2), 4.90–5.07 (m, 4H, PhCH2O and 2H, NCH), 6.87 (d,
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8
4.9. General procedure for conjugate 1,4-addition of
phenylmagnesium bromide to cinnamic acid derivatives 7a–c
in the presence of CuBr
7.09–7.13 (m, 2H, aromH), 7.16 (dd, J = 1.4, 8.0 Hz, 1H, 7(Ar)-
aromH), 7.23–7.43 (m, 3H, aromH). 13C NMR (75 MHz, CDCl3) d
20.9, 37.3, 40.9, 117.0, 125.5, 127.6, 127.7, 128.8, 129.2, 129.4,
134.4, 140.6, 149.8, 168.0.
To a cooled (À50 °C) CuBrÁSMe2 complex (16 mg, 0.08 mmol)
solution in a mixture of THF (1 mL) and dimethyl sulphide
(0.5 mL), phenyl magnesium bromide (0.29 ml, 0.28 mmol, 1.0 M)
was added under stirring, then the mixture was warmed to
À30 °C, after which cinnamide 7 (0.26 mmol) in 10 mL of THF
was added at this temperature. The reaction mixture was stirred
overnight at room temperature, then quenched with 10% NH4Cl
(10 mL). The aqueous/organic emulsion was evaporated until all
of dimethyl sulfide was gone then extracted by ethyl acetate
(2 Â 20 mL), washed with 10 mL of 17% NH4OH and 10 mL of brine
and dried over Na2SO4. Concentration in vacuo gave a crude pro-
duct, which was purified by chromatography with mixture of PE/
EtOAc.
4.11. General procedure for preparation of chiral cinnamic acid
esters 11a,b
The corresponding alcohol (0.024 mol) was added to cinnamoyl
chloride 1a (4.0 g, 0.024 mol) solution of dry benzene (10 mL) and
the mixture was stirred at room temperature for 48 h, then evapo-
rated under reduced pressure. The residue was distilled in vacuum
to give title ester.
4.11.1. (E)-3-Phenylacrylic acid L-menthyl ester 11a
Colourless oil (6.0 g, yield 87%) after distillation; bp 215–218 °C
at 9 mbar. 1H NMR (200 MHz, CDCl3) d 0.79 (d, J = 7.0 Hz, 3H, CH3),
0.92 (d, J = 7.0 Hz, 6H, 2 Â CH3), 0.97–2.16 (m, 9H, menthyl-H), 4.83
(dt, J = 4.4, 10.8 Hz, 1H, CO2CH), 6.43 (d, J = 15.8 Hz, 1H, CHCO),
7.31–7.47 (m, 3H, 3,4,5-aromH), 7.47–7.60 (m, 2H, 2,6-aromH),
7.68 (d, J = 15.8 Hz, 1H, CHPh). 13C NMR (75 MHz, CDCl3) d 16.6,
20.9, 22.2, 23.7, 26.5, 31.6, 34.5, 41.2, 47.4, 74.4, 118.9, 128.2,
129.0, 130.3, 134.7, 144.5, 166.7.
4.9.1. (R)-3-[(S)-3-(2-Benzyloxy-5-methylphenyl)-3-phenylpro-
pionyl]-4-isobutyl-5,5-dimethyl-oxazolidin-2-one 8j
This compound was obtained from 7a (0.53 g, 1.2 mmol) in
0.31 g amount (yield 51%) after chromatography (PE/EtOAc, 5:1).
Light yellow oil. dH spectra is identical to 8c [(R,R)-isomer].
4.9.2. (R)-4-Benzyl-3-[(S)-3-(2-benzyloxy-5-methylphenyl)-3-
phenylpropionyl]-oxazolidin-2-one 8k
4.11.2. (E)-3-Phenylacrylic acid [(1S)-endo]-bornyl ester 11b
Colourless oil (5.7 g, yield 84%) after distillation; bp 214–218 °C
at 13 mbar. 1H NMR (200 MHz, CDCl3) d 0.82–1.00 (m, 9H,
3 Â CH3), 1.00–2.54 (m, 7H, bornyl-H), 5.02 (ddd, J = 2.0, 3.2,
9.9 Hz, 1H, CO2CH), 6.47 (d, J = 16.0 Hz, 1H, CHCO), 7.30–7.48 (m,
3H, 3,4,5-aromH), 7.48–7.61 (m, 2H, 2,6-aromH), 7,68 (d,
J = 16.0 Hz, 1H, CHPh). 13C NMR (75 MHz, CDCl3) d 13.7, 19.0,
19.9, 27.4, 28.2, 37.0, 45.1, 48.0, 49.1, 80.1, 118.9, 128.2, 129.0,
130.3, 134.7, 144.3, 167.4.
This compound was obtained from 7c (0.83 g, 1.9 mmol) in
0.46 g amount (yield 46%) after chromatography (PE/EtOAc, 5:1).
Light yellow oil. 1H NMR (300 MHz, CDCl3) d 2.27 (s, 3H, CH3Ph),
2.62 (dd, J = 9.6, 13.4 Hz, 1H, PhCH2CH), 3.13 (dd, J = 3.3, 13.4 Hz,
1H, PhCH2CH), 3.63 (dd, J = 6.5, 16.9 Hz, 1H, ArCHCH2), 3.89 (dd,
J = 8.9, 16.9 Hz, 1H, ArCHCH2), 3.95–4.11 (m, 1H, ArCHCH2 and
1H, NCHCH2), 4.46–4.58 (m, 1H, NCHCH2), 5.02 (dd, J = 12.0,
13.9 Hz, 2H, PhCH2O), 5.13 (dd, J = 6.5, 8.8 Hz, 1H, NCH), 6.78 (d,
J = 8.2 Hz, 1H, 3-aromH), 6.96 (dd, J = 2.3, 8.2 Hz, 1H, 4-aromH),
7.00–7.38 (m, 16H, aromH).
4.12. 1,3-Bis-(2-benzyloxy-5-methylphenyl)-3-phenylpropan-1-
one 12
4.9.3. (S)-4-Benzyl-5,5-dimethyl-3-[(R)-3-(2-benzyloxy-5-meth-
ylphenyl)-3-phenylpropionyl]-oxazolidin-2-one 8l
To a cooled (À10 °C) suspension of CuCl (10 mol %) in 10 mL of
dried THF 2-benzyloxy-5-methylphenylmagnesium bromide
(1.0 equiv), freshly prepared from the corresponding bromide and
magnesium (activated with iodine) was added. At the same tem-
perature, a solution of 1.0 g (3.5 mmol) of ester 11a in THF
(15 mL) was then added and allowed to return to room tempera-
ture with continuous stirring overnight. The reaction mixture
was quenched with 50 mL of 10% NH4Cl; the organic phase was
separated and the aqueous phase was extracted with ether
(2 Â 30 mL) and dried (Na2SO4). The extract was then evaporated
and the residue subjected on silica gel (PE/CHCl3, 5:2). From first
fraction was isolated starting ester 11a (0.60 g, yield 60%), the sec-
ond gives compound of formula 12 (0.49 g, yield 26%). 1H NMR
(200 MHz, CDCl3) d 2.20 (s, 3H, CH3), 2.23 (s, 3H, CH3), 3.76 (d,
J = 7.7 Hz, 2H, CHCH2), 4.91 (s, 2H, PhCH2O), 5.05 (s, 2H, PhCH2O),
5.13 (t, J = 7.7 Hz, 1H, CHCH2), 6.68–6.72 (m, 1H, aromH), 6.83–
6.94 (m, 3H, aromH), 7.08–7.40 (m, 17H, aromH).
This compound was obtained from 7b (0.11 g, 0.25 mmol) in
40 mg amount (yield 30%) after chromatography (PE/EtOAc, 5:1).
Light yellow oil; de 86%. 1H NMR (200 MHz, CDCl3) d 1.27 (brs, 6H,
5-CH3), 2.25 (s, 3H, CH3Ph), 2.61 (dd, J = 9.9, 14.5 Hz, 1H, ArCHCH2),
2.93 (dd, J = 3.4, 14.5 Hz, 1H, ArCHCH2), 3.74 (d, J = 7.9 Hz, 2H,
PhCH2CH), 4.39 (dd, J = 3.4, 9.9 Hz, 1H, ArCHCH2), 5.01 (s, 2H,
PhCH2O), 5.11 (t, J = 7.9 Hz, 1H, NCH), 6.75 (d, J = 8.2 Hz, 1H, 3(A)-
aromH), 6.93 (dd, J = 1.9, 8.2 Hz, 1H, 4(A)-aromH), 7.07 (d,
J = 1.9 Hz, 1H, 6(A)-aromH), 7.10–7.42 (m, 15H, aromH).
4.10. (S)-6-Methyl-4-phenyl-chroman-2-one 9
To a cooled (À75 °C) solution of (S)-3-[(S)-3-(2-benzyloxy-
5-methylphenyl)-3-phenylpropionyl]-4-isobutyl-5,5-dimethyloxa-
zolidin-2-one 8g (0.58 g, 1.16 mmol) in dried DCM (25 mL), BBr3
(0.11 mL, 1.0 equiv) was added and kept overnight at À3 °C. The
solution was quenched with 0.1 M NaOH (10 mL), the organic phase
was separated and the aqueous solution extracted with DCM
(10 mL). The combined organic solution was dried (Na2SO4) and
evaporated. The residue oil was taken in 10 mL of 10% TEA solution
in toluene and refluxed for 1 h. The crude product obtained after
evaporating was subjected to chromatography on silica gel
(EtOAc/PE, 3:7) to obtain compound 9 as white crystals (0.26 g, yield
95%); mp 79–81 °C; [Found: C, 80.54; H, 5.90. C16H14O2 requires C,
80.65; H, 5.92]; 1H NMR (200 MHz, CDCl3) d 2.27 (s, 3H, CH3),
3.01–3.04 (m, 2H, CHCH2), 4.30 (t, J = 6.6 Hz, 1H, CHCH2), 6.79 (d,
J = 1.4 Hz, 1H, 5(Ar)-aromH), 7.03 (d, J = 8.0 Hz, 1H, 8(Ar)-aromH),
Acknowledgement
This work was partially supported by ERDF project «Develop-
ment of process for producing active pharmaceuticals» (No.
VPD1/ERAF/CFLA/05/APK/2.5.1./000030).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.07.
003.
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Z. Leitis, V. Lusis / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
9
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