Diastereoselective copper-catalysed 1,4-addition of Grignard reagents to N-enoyl oxazolidinones

Article abstract of DOI:10.1039/c3ra42024h

Conjugate additions of organometallic reagents to α,β- unsaturated carboxylic acid derivatives give access to numerous β-substituted chiral building blocks. Chiral oxazolidinones serve as useful surrogates of carboxylic function in the asymmetric conjugate addition of Grignard reagents. N-Enoyl oxazolidinones undergo this 1,4-addition with a catalytic amount of copper salt and using either chiral or achiral phosphine ligands. In particular, chiral ferrocenyl phosphane oxazolines proved useful in achieving high diastereoselectivities. The resulting N-acyl oxazolidinones were obtained in good yields and with high diastereoselectivities (up to single diastereomer).

Full text of DOI:10.1039/c3ra42024h

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Diastereoselective copper-catalysed 1,4-addition of
Grignard reagents to N-enoyl oxazolidinones3
Cite this: RSC Advances, 2013, 3,
9881
ˇ
ˇ
´
Michal Drusan, Zuzana Galestokova and Radovan Sebesta*
Conjugate additions of organometallic reagents to a,b-unsaturated carboxylic acid derivatives give access
to numerous b-substituted chiral building blocks. Chiral oxazolidinones serve as useful surrogates of
carboxylic function in the asymmetric conjugate addition of Grignard reagents. N-Enoyl oxazolidinones
undergo this 1,4-addition with a catalytic amount of copper salt and using either chiral or achiral
phosphine ligands. In particular, chiral ferrocenyl phosphane oxazolines proved useful in achieving high
diastereoselectivities. The resulting N-acyl oxazolidinones were obtained in good yields and with high
diastereoselectivities (up to single diastereomer).
Received 24th April 2013,
Accepted 26th April 2013
DOI: 10.1039/c3ra42024h
www.rsc.org/advances
easily cleaved under mild conditions allowing transformation
to other useful derivatives once the conjugate addition is
Introduction
Asymmetric copper-catalysed additions of organometallic
reagents to a,b-unsaturated compounds belong to the most
important C–C bond forming reactions.1 A wide variety of
chiral catalysts can enantioselectively introduce alkyl groups
via organozinc, Grignard and organoaluminium reagents.
Among them are also prominent catalyst classes like phos-
phoramidites,2 N-heterocyclic carbenes3 and ferrocenyl phos-
phanes.4 Conjugate additions to a,b-unsaturated ketones,
including those with tri-substituted b-carbon, can now be
performed with high yields and enantioselectivities. However,
1,4-addition to unsaturated compounds having other electron
accepting groups are less developed. From a synthetic point of
view, particularly carboxylic acid derivatives are useful in terms
of potential derivatizations or functional group interconver-
sions. In recent years great advances have been achieved in
conjugate additions to esters and lactones,5 however, these
substrates have low reactivity at the b-carbon, posing problems
with regioselectivity. Thioesters are better Michael acceptors
than esters and conjugate additions work well on them,6 but
they are generally unpleasant to work with. Catalytic 1,4-
additions of organometallic reagents to unsaturated amides or
lactams were also less studied,7 and unreactivity of simple
amides makes them difficult to modify or cleave after the
conjugate addition. On the other hand, N-enoyl oxazolidinones
combine several features, which make them appealing as
surrogates of carboxylic group in the conjugate addition. They
are good Michael acceptors. Furthermore, CO–N bond can be
finished. In addition, oxazolidinones can be easily synthesized
from chiral amino alcohols and thus possess stereogenic
information, which can itself direct or enhance stereoselectiv-
ity of the addition. N-Enoyl oxazolidinones allow for additions
of stabilized nucleophiles8 as well as heteroatom nucleophiles,
such as amides9 and thiols.10 Organometallic, non-stabilized,
nucleophiles can add to N-enoyl oxazolidinones either as
preformed organocuprates11 or with the help of stoichiometric
amount of a copper salt as catalyst.12 Additions with a catalytic
amount of copper and a chiral ligand are rare. Hird and
Hoveyda described the only example of enantioselective
conjugate addition of dialkylzinc reagents to achiral N-enoyl
oxazolidinones.13 An addition of Grignard reagents to N-enoyl
oxazolidinones using catalytic amount of copper-complex is
unknown.
In this context, we studied addition of Grignard reagents to
achiral and chiral N-enoyl oxazolidinones using catalytic
amount of copper salts. We have also investigated the
influence of chiral ligands. Finally, we demonstrate synthetic
utility of this approach on a larger scale.
Results and discussion
Initial experiments on oxazolidinone 1a with EtMgBr,
CuBr?SMe2 and Josiphos (L1) as chiral ligand led only to
decomposition of the starting material. We hypothesized that
a highly reactive Grignard reagent, which is present in the
reaction mixture when there is only catalytic amount of copper
salt, attacks oxazolidinone ring (Scheme 1).
Therefore, we replaced oxazolidinone 1a with oxazolidinone
1b with two methyl groups to provide some steric shielding for
the oxazolidinone ring. Compound 1b was indeed more stable
Department of organic chemistry, Faculty of Natural Sciences, Comenius University,
Mlynska dolina CH-2, SK-84215 Bratislava, Slovak Republic.
E-mail: Radovan.sebesta@fns.uniba.sk; Fax: +421 2 60296337;
Tel: +421 2 60296208
Electronic supplementary information (ESI) available: 1H, 13C NMR, including
3
DEPT spectra for all compounds. See DOI: 10.1039/c3ra42024h
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Table 1 Screening of chiral ligands in the conjugate addition to achiral
oxazolidinone 1ba
Ligand
Yield of 2b (%)
e.r.b
L1
L2
L3
L4
78
67
65
63
67
88
69
62
91
68
65
50 : 50
50 : 50
50 : 50
50 : 50
50 : 50
66 : 34
56 : 44
56 : 44
33 : 67
48 : 52
47 : 53
Scheme 1 Enantioselective 1,4-addition of EtMgBr to N-enoyl oxazolidinones 1.
L5
L6a
L6b
L7
L8a
L8b
L8c
towards the Grignard reagent, and the conjugate addition
proceeded well. However, the product of this reaction,
oxazolidinone 2b, was racemic. We have then screened a
selection of structurally diverse chiral ligands, which were
effective in other 1,4-additions of Grignard reagents. Solvias
ferrocenyl phosphines L1–4 were effective for additions to
cyclic14 and acyclic enones,15 esters,5d and thioesters.6b
Ferrocenyl oxazolines L5–6 were among the first chiral ligands
for additions of Grignard reagents to enones.16 BINAP (L7) in
connection with CuI was efficient catalyst for 1,4-additions to
linear esters.11 Recently, Schmalz and co-workers showed that
TADDOL-based phosphine-phosphite ligands L7 performed
excellently in conjugate additions (Fig. 1).17 Therefore, we have
tested also three of these ligands.
However, none of the tested ligands afforded product 2b
with higher enantiomeric purity than e.r. 67 : 33. The results
of ligand screening are gathered in Table 1.
After we found out that none of 11 tested chiral ligands was
able to provide high enantioselectivity in the conjugate
addition to achiral N-enoyl oxazolidinones, we decided to test
chiral oxazolidinones. Oxazolidinone 3a, derived from (S)-
a
CuBr?SMe2 (5 mol%), ligand (6 mol%), 1b 0.375 mmol, EtMgBr
b
(0.563 mmol). Determined by enantioselective HPLC.
valine, was subjected to the addition of EtMgBr catalyzed by a
copper salt and a phosphane ligand (Scheme 2).
The reaction with only copper iodide, without additional
ligand, was slow and afforded product in only 43% yield
(Table 2, entry 1). Interestingly, the 1,4-addition catalysed by a
copper complex with achiral ligands, such as tributylpho-
sphane or 1,19-bis(diphenylphosphano)ferrocene (DPPF),
afforded product 4a with only low diastereoselectivities
(Table 2, entries 2 and 3). Improvement was achieved by the
use of chiral ferrocenyl phosphane oxazoline ligands L6.
Copper sources, CuBr and CuI either gave similar results, but
(CuI)4(SMe2)3 seemed slightly superior. Ethereal solvents like
Et2O, tBuOMe or 2-methyltetrahydrofurane (2-MeTHF) can be
used. Interestingly, the best results were achieved in dichlor-
omethane, which is compatible with Grignard reagents at low
temperatures. After optimization of the reaction conditions,
the addition product 4a was isolated in 79% yield and with
diastereomeric ratio of 96 : 4 (Table 2, entry 20). The best
conditions comprised CH2Cl2 as solvent, (CuI)4(SMe2)3 as a
copper salt, BF3?OEt2 as additional Lewis acid and dilution of
commercially available Grignard reagent with 2-MeTHF to
approximately 1 M concentration. The additional Lewis acid
seems to increase electrophilicity of the b-carbon, thus
facilitating nucleophilic attack by the Grignard reagent. This
effect is manifested in higher chemical yield of the addition,
while stereochemical outcome of the reaction remained the
same.
Evaluation of other oxazolidinones, such as 3b and 3c
which have tert-butyl and phenyl group instead of iso-propyl,
resulted in a further increase of the diastereoselectivity
Fig. 1 Chiral ligands used in the enantioselective 1,4-addition to N-enoyl
Scheme 2 Conjugate addition of EtMgBr to valinol-based oxazolidinone 3a.
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oxazolidinones.
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Table 2 Optimization of reaction conditions for addition of EtMgBr on chiral oxazolidinone 3aa
Entry
Ligand
Conditions
Yield (%)
d.r.b
1
2
3
4
5
6
7
8
—
CuI, Et2O, 0 uC
43
—
—
63
—
65
32
41
41
52
—
—
—
—
—
—
—
—
—
79
61 : 39
60 : 40
63 : 37
66 : 33
57 : 43
78 : 22
58 : 42
62 : 38
55 : 45
62 : 38
78 : 22
89 : 11
76 : 24
78 : 22
88 : 12
79 : 21
52 : 48
85 : 15
90 : 10
96 : 4
DPPF
PBu3
L8a
L8b
L6a
L2
L1
L2
L1
L6a
L6a
L6a
L6a
L6a
L6a
L6a
L6a
L6c
L6c
CuBr?SMe2, tBuOMe, 260 uC
CuBr?SMe2, tBuOMe, 260 uC
CuBr?SMe2, tBuOMe, 260 uC
CuBr?SMe2, tBuOMe, 260 uC
CuBr?SMe2, tBuOMe, 260 uC
CuBr?SMe2, tBuOMe, 260 uC
CuBr?SMe2, tBuOMe, 278 uC
CuBr?SMe2, tBuOMe, 278 uC
CuBr?SMe2, tBuOMe, 260 uC
CuBr?SMe2, tBuOMe/LiCl, 260 uC
CuBr?SMe2, 2-MeTHF, 260 uC
CuBr?SMe2, tBuOMec, 260 uC
CuBr?SMe2, tBuOMec, 278 uC
CuBr?SMe2, CH2Cl2, 278 uC
CuBr?SMe2, 2-MeTHF, 278 uC
CuBr?SMe2, 2-MeTHF, 278 uC
CuBr?SMe2, CH2Cl2, 278 uC
CuBr?SMe2, CH2Cl2d, 278 uC
(CuI)4?(SMe2)3, CH2Cl2d/BF3?Et2O, 278 uC
9
10
11
12
13
14
15
16
17
18
19
20
a
b
CuX (5 mol%), ligand (6 mol%), 3a 0.375 mmol, EtMgBr (0.563 mmol). Determined by 1H NMR or GC of the crude reaction mixture.
Reversed addition. EtMgBr diluted to 1 M.
c
d
(Scheme 3). Diastereomeric ratio of 98 : 2 was achieved when
in good yields and high diastereoselectivities (Scheme 4,
Table 4).
oxazolidinone 3c in combination with ligand L6c was
employed. The use of Seebach’s oxazolidinone DIOZ (3d)12b
as chiral auxiliary did not improve the reaction. Table 3
summarizes the most important results.
Interesting observation was that achiral DPPF ligand led to
varying diastereoselectivities depending on the oxazolidinone
used (cf. Table 3, entries 4 and 6).
As oxazolidinones already possess stereogenic information,
the effect of matched/mismatched chirality was tested with
ferrocenyl ligand L6a. An experiment on the oxazolidinone 3c
using ligand (S,S)-L6a afforded product 4c with d.r. 92 : 8. On
the other hand, enantiomeric ligand (R,R)-L6a displayed
mismatched chirality as it led to compound 4c with the same
configuration albeit in only medium d.r. of 63 : 37 (cf. Table 3,
entries 7 and 8).
The developed protocol can be applied also with several
other Grignard reagents. The methodology thus leads to a
range of products 7a–d, which was obtained by the addition of
hexyl, cyclopentyl, phenyl and 2-thienylmagnesium bromides
to oxazolidinone 3c (Scheme 5). Yields were acceptable for
compounds 7a and 7b, but the reaction with aromatic
Grignard reagents phenyl and 2-thienylmagnesium bromides
were slow using a catalytic amount of copper. The products 7c,
and 7d could be obtained only using stoichiometric amount of
copper salt. Diastereomeric ratios were high for all products 7.
By interchanging the substituent on the double bond and
that of the Grignard reagent, it is possible to synthesize
diastereomeric derivatives. From oxazolidinone 3c and
PhMgBr, compound (R,S)-7c was prepared. While, the reaction
starting from compound 5a and MeMgBr leads to isomer (S,S)-
7c (Scheme 6).
Using a phenylglycine-derived oxazolidinone 5a, other acyl
groups have been evaluated too. Thus, 1,4-addition of EtMgBr
to oxazolidinones 5a–c resulted in N-acyl oxazolidinones 6a–c
Synthetic usefulness of N-enoyl oxazolidinones for con-
jugate addition demonstrates also the fact that the resulting
Scheme 4 Conjugate additions of EtMgBr to oxazolidinones with various
N-enoyl groups.
Scheme 3 Conjugate additions of EtMgBr to oxazolidinones with varying
substituents.
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Table 3 Conjugate additions of EtMgBr to oxazolidinones with varying
substituentsa
Yield
(%)
Entry Oxazolidinone Ligand [Cu]
d.r.b
1
2
3
4
5
6
7
8
3b
3b
3b
3b
3b
3c
3c
3c
3c
3d
3d
3d
3d
—
CuI
CuBr?SMe2
(CuI)4?(SMe2)3 65
(CuI)4?(SMe2)3
(CuI)4?(SMe2)3
(CuI)4?(SMe2)3
CuBr?SMe2
51
58
75 : 25
95 : 5
94 : 6
L6a
L6a
DPPF
L6c
DPPF
L6a
ent-L6a CuBr?SMe2
L6c
L6b
L6a
Bu3P
L6c
—
—
—
47
—
96 : 4
98.5 : 1.5 (GC)
75 : 25
92 : 8
63 : 37
98 : 2
88 : 12
92 : 8
85 : 15
79 : 21
Scheme 5 Compounds obtained by the addition of various Grignard reagents.
9
(CuI)4?(SMe2)3 80
10
11
12
13
CuBr?Me2S
CuBr?Me2S
CuBr?Me2S
CuBr?Me2S
43
45
65
39
a
CuX (5 mol%), ligand (6 mol%), 3b–3d 0.375 mmol, EtMgBr (0.563
mmol). Determined by 1H NMR or GC of the crude reaction
b
mixture.
N-acyl oxazolidinones can be further transformed into
carboxylic acid, ester and Weinreb amide using simple
procedures.13,18 Practicality of the methodology was tested in
the larger scale experiment. Here, 3.75 mmol of the starting
oxazolidinone 3c was used, while catalyst loading was
decreased to 1 mol% of copper and 1.2 mol% of the ligand
L6c. The product 4c was isolated in 60% yield and with high
diastereomeric ratio of 97 : 3.
Scheme 6 Access to both configurations at the b-position through exchange of
side chain and Grignard reagent substituents.
Based on the configurations of compounds 7c19 and
similarly to the literature,11f,12b we suggest following stereo-
chemical model for the conjugate addition of Grignard
reagents to N-enoyl oxazolidinones (Scheme 7). The attack of
the Grignard reagent takes place from the re-face, anti to the
R-group on the stereogenic centre of the oxazolidinone. Chiral
ligand improves diastereoselectivity of the reaction in the
majority of examples; however facial selectivity remains
dictated by chiral oxazolidinone.
Conclusions
Chiral N-enoyl oxazolidinones are suitable Michael acceptors
for the 1,4-addition of Grignard reagents using catalytic
amount of copper salt. The highest diastereoselectivities were
obtained with oxazolidinones having tert-butyl and phenyl
groups. The resulting products were obtained in good yield
and high diastereomeric ratios. Chiral ferrocenyl phosphane
oxazoline ligands in connection with BF3?OEt2 as additional
Lewis acid, have led to increase of the diastereoselectivity up to
perfect diastereoselection, where in some cases only one
diastereomer was isolated. Efficiencies of ferrocenyl phos-
phane oxazolines were similar, but ligand L6c, derived from
phenylglycine, usually afforded the best results.
Table 4 Conjugate additions of EtMgBr to oxazolidinones with various N-enoyl
groupsa
Oxazolidinone
Ligand
Yield (%)
d.r.b
5a
5a
5a
5b
5b
5b
5c
5c
5c
L6a
P(n-Bu)3
L6c
P(n-Bu)3
L6a
L6c
P(n-Bu)3
L6a
L6c
70
58
57
39
50
41
58
35
68
76 : 24
94 : 6
89 : 11
88 : 12
95 : 5
97.5 : 2.5
79 : 21
85 : 15
80 : 20
a
CuBr?SMe2 (5 mol%), ligand (6 mol%), 5a–5c 0.375 mmol, EtMgBr
Scheme 7 Stereochemical model for the Cu-catalyzed 1,4-addition of Grignard
(0.563 mmol). Determined by 1H NMR of the crude reaction
b
reagents.
mixture.
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4,4-Dimethyl-3-(3-methylpentanoyl)oxazolidin-2-one (2b)
Experimental
1
Colorless liquid, 72.9 mg (91%). H NMR (600 MHz, CDCl3), d
All reactions were carried out in an inert atmosphere of Ar.
Solvents were dried and purified by standard methods before
use. NMR spectra were recorded on an instrument with 300
= 3.98 (s, 2H), 2.89 (dd, J = 5.8, 16.0 Hz, 1H), 2.67 (dd, J = 8.1,
16.0 Hz, 1H), 1.89–1.98 (m, 1H), 1.564 (s, 3H), 1.560 (s, 3H),
1.35–1.43 (m, 1H), 1.19–1.27 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H),
0.89 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (150 MHz, CDCl3) d =
174.0 (Cq, CO), 154.0 (Cq, CO), 75.1 (CH2), 60.4 (Cq), 43.6
(CH2), 31.3 (CH), 29.4 (CH2), 24.84 (CH3), 24.83 (CH3), 19.2
(CH3), 11.3 (CH3) ppm. MS (EI) m/z 214.1 (MH+). HRMS calc.
for C11H19NO3 (MH+) m/z 214.1438; found 214.1424. HPLC
(OD–H, 218 nm, hexane/iPrOH 99 : 1, 1 mL min21) tR1 = 11.1
min, tR2 = 12.3 min.
1
MHz for H and 75 MHz for 13C, and an instrument with 600
MHz for 1H and 150 MHz for 13C. Chemical shifts (d) are given
in ppm relative to tetramethylsilane. Peaks for minor
diastereomers are in italics. Specific optical rotations are
given in deg cm3 g21 dm21. Flash chromatography was
performed on silica gel 40–63 mm. Thin-layer chromatography
was performed on silica gel 60, F-254. Diastereomeric ratios
were determined by 1H NMR and GC. Enantiomeric ratios
were determined by HPLC on Chiralpak, OD-H, AS-H, IB
(Daicel Chemical Industries), column using hexane/iPrOH as a
mobile phase and detection with UV-detector at 254, 218 nm.
(4S)-4-Isopropyl-3-(3-methylpentanoyl)oxazolidin-2-one (4a)
Colorless liquid, 67.2 mg (79%). 1H NMR (300 MHz, CDCl3,
mixture of two diastereomers), d = 4.42–4.50 (m, 2H), 4.16–4.32
(m, 2H), 3.04 (dd, J = 5.5, 15.8 Hz, 1H), 2.77–2.92 (m, 2 H), 2.64
(dd, J = 8.3, 15.8 Hz, 1H), 1.89–2.07 (m, 1H), 1.87–1.97 (m,
12H), 1.34–1.49 (m, 1H), 1.19–1.32 (m, 1H) ppm. 13C NMR (150
MHz, CDCl3, mixture of two diastereomers) d = 172.89 (Cq,
CO), 172.86 (Cq, CO), 154. 01 (Cq, CO), 153.99 (Cq, CO), 63.18
(CH2), 63.17 (CH2), 58.4 (CH), 58.3 (CH), 42.2 (CH2), 42.1
(CH2), 31.4 (CH), 31.3 (CH), 29.5 (CH2), 29.2 (CH2), 28.39 (CH),
28.36 (CH), 19.2 (CH3), 19.1 (CH3), 18.0 (CH3), 14.61 (CH3),
14.58 (CH3), 11.29 (CH3), 11.27 (CH3) ppm. MS (EI) m/z 250.1
(MNa+). HRMS calc. for C12H22NO3 (MH+) m/z 228.1594; found
228.1589. HPLC (IB, 218 nm, hexane/iPrOH90 : 10, 0.75 mL
min21) tR = 9.4 min.
HRMS analyses were performed with
instrument.
a LC-IT-TOF MS
Starting materials, N-enoyl oxazolidinones, were prepared
according to literature procedures. NMR data for compounds
1a and 1b,20 3a and 5c,21 3b,22 3c and 5a,19 3d18 agree with
those in the literature. Compound 5b was prepared in analogy
to procedures in the literature18 and characterization data are
bellow.
(S,E)-3-Hex-2-enoyl-4-phenyl-oxazolidin-2-one (5b)
White solid, 522 mg (73%); mp 72–74 uC (hexane). [a]D + 23.7 (c
0.515, CHCl3). IR (ATR) n = 1774 s (CO), 1682 s (CO) cm21. H
1
NMR (300 MHz, CDCl3) d = 7.44–7.27 (m, 5H, Ph), 7.25–7.22
(m, 1H, CHLCH), 7.09 (td, J = 15.3, 6.8 Hz, 1H, CHLCH), 5.49
(dd, J = 8.8, 3.9 Hz, 1H, N–CH), 4.70 (t, J = 8.8 Hz, 1H, CH2),
4.28 (dd, J = 8.8, 3.9 Hz, 1H, CH2), 2.30–2.15 (m, 2H, CH2),
1.69–1.35 (m, 2H, CH2), 0.93 (t, J = 7.3 Hz, 3H, CH3) ppm. 13C
NMR (75 MHz, CDCl3) d = 164.7 (Cq, CO), 153.7 (Cq, CO), 152.1
(CH, CHL),139.2 (Cq, Ph), 129.2 (26CH, Ph),128.6 (CH, Ph),
125.9 (2xCH, Ph),120.3 (CH, CHL) 69.9 (CH2, CH2–O), 57.8
(CH, N–CH), 34.7 (CH2), 21.3 (CH2), 13.7 (CH3) ppm. Elem.
anal. calcd. for C15H17NO3 : C, 69.48; H, 6.61; N, 5.40. Found
C, 69.20; H 6.70; N 5.43.
General procedure for the conjugate addition.
(CuI)4?(SMe2)3 (5 mol%, 4.68.1023 mmol, 4.5 mg) and ligand
(6 mol%, 0.0225 mmol, 11.6 mg) were dissolved in CH2Cl2 (1.5
mL) and solution was stirred for 15 min at room temperature.
The mixture was then cooled to 278 uC and solution of N-enoyl
oxazolidone (0.375 mmol) in CH2Cl2 (1.5 mL) was added. Then
BF3?Et2O (1.2 eq., 0.45 mmol, 0.12 ml) was added to the
mixture. After 5 min, EtMgBr (0.563 mmol, 0.18 mL, 3.2 M in
2-MeTHF), which was diluted to 1 M with 2-MeTHF (300 ml),
was added dropwise during 30 min. The reaction was then
stirred for an additional 1.5 h at 278 uC, before it was
quenched with MeOH (1 mL) at 278 uC. The resulting mixture
was then washed with 1 M solution of NH4Cl and extracted
with CH2Cl2. The combined organic extracts were dried
(Na2SO4) and concentrated. The crude product was purified
by flash chromatography (SiO2, Hex : AcOEt 4 : 1).
(4S)-4-tert-Butyl-3-(3-methylpentanoyl)oxazolidin-2-one (4b)
Colorless liquid, 58.5 mg (65%). 1H NMR (300 MHz, CDCl3,
mixture of two diastereomers) d = 4.45 (dd, 1H, J = 1.9, 7.3 Hz,
1H), 4.18–4.32 (m, 2H), 3.01 (dd, J = 5.5, 16.1 Hz, 1H), 2.77–
2.92 (m, 2H), 2.67 (dd, J = 8.1, 16.1 Hz, 1H), 1.89–2.07 (m, 1H),
1.36–1.53 (m, 1H), 1.19–1.32 (m, 1H), 0.88–0.99 (m, 15H) ppm.
13C NMR (150 MHz, CDCl3) d = 172.8 (Cq, CLO), 154.7 (Cq,
CLO), 65.2 (CH2), 60.8 (CH), 42.1 (CH2), 35.7 (Cq), 31.4 (CH),
29.4 (CH2), 25.7 (CH3), 19.1 (CH3), 11.3 (CH3) ppm. MS (EI) m/z
264.2 (MNa+). HRMS calc. for C13H24NO3 (MH+) m/z 242.1751;
found 242.1757. GC (140 uC, 196 kPa, t inj. 250 uC, Lipodex E)
tR = 38.4 min (major), 38.9 (minor).
(4S)-3-(3-Methylpentanoyl)-4-phenyloxazolidin-2-one (4c)
White solid, 78.7 mg (80%); mp 51 uC (heptane). 1H NMR (300
MHz, CDCl3) d = 7.42–7.27 (m, 5H) 5.44 (dd, J = 8.8, 3.7 Hz,
1H), 4.69 (t, J = 8.8 Hz, 1H), 4.31–4.24 (m, 1H), 2.99 (dd, J =
16.0, 5.5 Hz, 1H), 2.68 (dd, J = 16.0, 8.5 Hz, 1H), 2.01–1.83 (m,
1H), 1.43–1.03 (m, 3H), 0.90–0.82 (m, 6H) ppm. 13C NMR (75
MHz, CDCl3, mixture of two diastereomers), d = 172.4 (Cq, CO),
153.7 (Cq, CO), 139.2 (Cq, Ph), 129.1 (CH, Ph), 128.7 (CH, Ph),
125.93 (CH, Ph), 125.89 (CH, Ph), 69.84 (CH2), 69.82 (CH2),
57.64 (CH), 57.60 (CH), 42.21 (CH2), 42.18 (CH2), 31.3 (CH),
31.1 (CH), 29.4 (CH2), 29.2 (CH2), 19.2 (CH3), 19.1 (CH3), 11.27
(CH3), 11.25 (CH3) ppm. Elem. anal. calcd. for C15H19NO3 (Mr
284.1) C, 68.94; H, 7.33; N, 5.36; O, 18.37. Found: C, 68.52; H,
7.30; N, 5.37. MS (EI) m/z 284.1 (MNa+). HPLC (IB, 218 nm,
hexane/iPrOH 90 : 10, 0.75 mL min21) tR = 15.4 min.
Characterisation data for products of conjugate addition.
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C
17H23NO3 (Mr 289.40): C, 70.56; H, 8.01; N, 4.84. Found C,
(4S)-4-Isopropyl-3-(3-metylpentanoyl)-5,5-diphenyloxazolidin-
2-one (4d)
70.40; H, 7.93; N, 4.88. MS (EI) m/z 290.2 (MH+). HPLC (IB, 218
nm, hexane/iPrOH 90 : 10, 0.75 mL min21) tR = 9.6 min.
1
White solid, 145 mg (76%); mp 134 uC (hexane). H NMR (300
MHz, CDCl3) d = 7.52–7.45 (m, 2H), 7.44–7.27 (m, 8H), 5.38 (d,
J = 3.3 Hz, 1H), 2.78 (dd, J = 15.4, 6.1 Hz, 1H), 2.65 (dd, J = 15.3,
7.9 Hz, 1H), 1.97 (tdd, J = 13.7, 6.8, 3.4 Hz, 1H), 1.83 (dt, J =
13.7, 6.8 Hz, 1H), 1.36–1.08 (m, 2H), 0.89 (d, J = 7.0 Hz, 3H),
0.79 (m, 9H) ppm. 13C NMR (75 MHz, CDCl3) d = 172.7 (Cq,
CO), 153.1 (Cq, CO), 142.4 (Cq, Ph), 138.1 (Cq, Ph), 128.8
(2xCH, Ph), 128.5 (CH, Ph), 128.3 (2xCH, Ph), 127.9 (CH, Ph),
125.9 (2xCH, Ph), 125.6 (2xCH, Ph), 89.3 (Cq), 64.8 (CH), 41.7
(CH2), 31.59 (CH), 29.8 (CH), 29.2 (CH2), 21.8 (CH3), 18.8
(CH3), 16.4 (CH3), 11.2 (CH3) ppm. Elem. anal. calcd. for
C24H29NO3 (Mr 379.5): C, 75.96; H, 7.70; N, 3.69. Found C,
75.92; H, 7.76; N, 3.63. MS (EI) m/z 380.1 (MH+). HPLC (IB, 218
nm, hexane/iPrOH 90 : 10, 0.75 mL min21) tR = 5.6 min.
(4S)-3-(3-Methylnonanoyl)-4-phenyloxazolidin-2-one (7a)
White solid, 72.9 mg (61%); mp 45 uC (heptane). 1H NMR (300
MHz, CDCl3, mixture of two diastereomers) d = 7.42–7.27 (m,
5H, Ph), 5.44 (dd, J = 3.8, 8.7 Hz, 1H), 4.68 (t, J = 8.8, 1H), 4.271
(dd, J = 3.8, 8.9 Hz, 1H), 4.265 (dd, J = 3.8, 8.9 Hz, 1H), 2.99 (dd,
J = 5.3, 16.0 Hz, 2H), 2.90–2.77 (m, 2H), 2.67 (dd, J = 8.5, 16.0
Hz, 1H), 2.10–1.88 (m, 1H), 1.36–1.11 (m, 10H), 0.93–0.81 (m,
6H) ppm. 13C NMR: (150 MHz, CDCl3, mixture of two
diastereomers) d = 172.4 (Cq, CO), 153.7 (Cq, CO), 139.2 (Cq,
Ph), 129.1 (CH, Ph), 128.65 (CH, Ph), 128.63 (CH, Ph), 125.93
(CH, Ph), 125.88 (CH, Ph), 69.81 (CH), 69.80 (CH), 57.60 (CH),
57.58 (CH), 53.4 (CH2), 42.6 (CH2), 42.5 (CH2), 36.8 (CH2), 36.6
(CH2), 31.83 (CH2), 31.79 (CH2), 29.74 (CH2), 29.68 (CH), 29.65
(CH), 29.4 (CH2), 26.8 (CH2), 26.7 (CH2), 22.6 (CH2), 19.7 (CH3),
19.6 (CH3), 14.1 (CH3) ppm. Elem. anal. calcd for C19H27NO3
(Mr 340.2): C, 71.89; H, 8.57; N, 4.41; O, 15.12. Found: C, 72.12;
H, 8.60; N, 4.43. MS (EI) m/z 340.2 (MNa+). HPLC (IB, 218 nm,
hexane/iPrOH 90 : 10, 0.75 mL min21) tR = 12.5 min (major), tR
= 13.7 min (minor).
(4S)-4-Phenyl-3-(3-phenylpentanoyl)oxazolidin-2-one (6a)
1
White solid, 58.4 mg (70%); mp 81 uC (hexane). H NMR (300
MHz, CDCl3) d = 7.40–7.16 (m, 10H), 5.33 (dd, J = 9.2, 6.9 Hz,
1H), 4.50 (t, J = 8.8 Hz, 1H), 4.20 (dd, J = 8.8, 3.4 Hz, 1H), 3.45
(dd, J = 16.5, 9.2 Hz, 1H), 3.14 (dd, J = 16.5, 5.3 Hz, 1H), 3.09–
2.99 (m, 1H), 1.71–1.57 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H) ppm.13C
NMR (75 MHz, CDCl3) d = 174.0 (Cq, CO), 153.1 (Cq, CO), 140.1
(Cq, Ph), 138.3 (Cq, Ph), 129.2 (26CH, Ph), 128.8 (CH, Ph),
128.7 (26CH, Ph), 128.3 (26CH, Ph), 126.9 (CH, Ph), 125.6
(26CH, Ph), 74.1 (CH), 70.6 (CH2), 57.8 (CH), 52.8 (CH), 23.0
(CH2), 11.9 (CH3) ppm. Elem. anal. calcd. for C20H21NO3 (Mr
323.4): C, 74.28; H, 6.55; N, 4.33. Found C, 74.17; H 6.55; N,
4.32. MS (EI) m/z 324.1 (MH+). HPLC (IB, 218 nm, hexane/
iPrOH 90 : 10, 0.75 mL min21) tR = 12.6 (major); tR = 15.2
(minor) min.
(4S)-3-(3-Cyclopentylbutanoyl)-4-phenyloxazolidin-2-one (7b)
White solid, 72.8 mg (65%); mp 89 uC (heptane). 1H NMR (300
MHz, CDCl3, mixture of two diastereomers) d = 7.43–7.27 (m,
5H, Ph), 5.44 (dd, J = 3.8, 8.8 Hz, 1H), 5.43 (dd, J = 3.7, 8.7 Hz,
1H), 4.69 (t, J = 8.8 Hz, 1H), 4.68 (t, J = 8.8 Hz, 1H), 4.31–4.23
(m, 1H), 3.09 (dd, J = 4.0, 15.8 Hz, 1H), 2.98 (dd, J = 4.6, 16.0
Hz, 1H), 2.82 (dd, J = 9.0, 16.0 Hz, 1H), 2.68 (dd, J = 9.8, 15.8
Hz, 1H), 1.96–1.80 (m, 1H), 1.78–1.40 (m, 7H), 1.21–1.03 (m,
2H), 0.87–0.78 (m, 3H) ppm. 13C NMR (150 MHz, CDCl3,
mixture of two diastereomers) d = 172.60 (Cq, CO), 172.55 (Cq,
CO), 153.7 (Cq, CO), 153.6 (Cq, CO), 139.204 (Cq, Ph), 139.196
(Cq, Ph), 129.1 (CH, Ph), 128.7 (CH, Ph), 128.6 (CH, Ph), 126.0
(CH, Ph), 125.9 (CH, Ph), 69.78 (CH2), 69.76 (CH2), 57.7 (CH),
57.6 (CH), 46.2 (CH), 45.9 (CH), 41.6 (CH2), 41.4 (CH2), 34.8
(CH), 34.7 (CH), 30.6 (CH2), 30.4 (CH2), 30.1 (CH2), 29.9 (CH2),
25.37 (CH2), 25.36 (CH2), 25.34 (CH2), 25.33 (CH2), 18.13 (CH3),
18.11 (CH3) ppm. Elem. anal. calcd for C18H23NO3 (Mr 324.2):
C, 71.73; H, 7.69; N, 4.65; O, 15.93. Found: C, 72.01; H, 7.69; N,
4.63. MS (EI) m/z 324.1 (MNa+). HPLC (AS–H, 218 nm, hexane/
iPrOH 90 : 10, 0.75 mL min21) tR = 12.0 (major), tR = 13.6
(minor) min.
(4S)-3-(3-Ethylhexanoyl)-4-phenyloxazolidin-2-one (6b)
White solid, 55 mg (50%); mp 60 uC (hexane). 1H NMR (300
MHz, CDCl3) d = 7.42–7.27 (m, 5H), 5.44 (dd, J = 8.7, 3.8 Hz,
1H), 4.68 (t, J = 8.8 Hz, 1H), 4.27 (dd, J = 8.8, 3.8 Hz, 1H), 2.95
(dd, J = 16.2, 6.3 Hz, 1H), 2.77 (dd, J = 16.2, 7.3 Hz, 1H), 1.87
(td, J = 12.5, 6.3 Hz, 1H), 1.41–1.12 (m, 6H), 0.86–0.77 (m, 6H)
ppm. 13C NMR (75 MHz, CDCl3) d = 172.6 (Cq, CO), 153.5 (Cq,
CO), 139.2 (Cq, Ph), 129.1 (2x CH, Ph), 128.6 (CH, Ph), 125.9
(2xCH, Ph), 69.8 (CH2), 57.6 (CH), 39.7 (CH2), 35.4 (CH2), 35.3
(CH), 26.1 (CH2), 19.7 (CH2), 14.2 (CH3), 10.6 (CH3) ppm. Elem.
anal. calcd. for C17H23NO3 (Mr 289.40): C, 70.56; H, 8.01;
N,4.84; found: C, 70.36; H, 8.08; N,4.73. MS (EI) m/z 290.2
(MH+). HPLC (IB, 218 nm, hexane/iPrOH 90 : 10, 0.75 mL
min21) tR = 12.9 min.
(4S)-4-Phenyl-3-(3-phenylbutanoyl)oxazolidin-2-one (7c)
White solid, 55.1 mg (36%); mp 113 uC (heptane). 1H NMR
(300 MHz, CDCl3) d = 7.34–7.15 (m, 8H), 7.12–7.03 (m, 2H),
5.40 (dd, J = 4.0, 8.8 Hz, 1H), 4.66 (t, J = 8.8 Hz, 1H), 4.21 (dd, J
= 4.0, 8.9 Hz, 1H), 3.48, (dd, J = 6.6, 15.7 Hz, 1H), 3.40–3.26 (m,
1H), 3.05, (dd, J = 7.8, 15.7 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3) d = 171.5 (Cq, CO), 153.6 (Cq,
CO), 145.5 (Cq, Ph), 138.8 (Cq, Ph), 129.1 (CH, Ph), 128.5 (CH,
Ph), 126.9 (CH, Ph) 126.3 (CH, Ph), 125.6 (CH, Ph), 69.9 (CH2),
57.6 (CH), 43.2 (CH2), 36.0 (CH), 21.8 (CH3) ppm. Elem. anal.
calcd for C19H19NO3 (Mr 332.1): C, 73.77; H, 6.19; N, 4.53.
Found: C, 73.45; H, 6.36; N, 4.49. MS (EI) m/z 332.2 (MNa+).
(4S)-4-Isopropyl-3-(3-phenylpentanoyl)oxazolidin-2-one (6c)
White amorphous solid, 49.5 mg (68%). 1H NMR (300 MHz,
CDCl3) d = 7.33–7.18 (m, 5H), 4.28–4.21 (m, 1H), 4.15–4.01 (m,
2H), 3.37 (dd, J = 16.1, 9.2 Hz, 1H), 3.20 (dd, J = 16.1, 5.5 Hz,
1H), 3.10 (tt, J = 9.2, 5.5 Hz, 1H), 2.26 (dtd, J = 13.9, 7.0, 3.9 Hz,
1H), 1.81–1.59 (m, 2H), 0.82 (m, 9H) ppm. 13C NMR (75 MHz,
CDCl3) d = 172.0 (Cq, CO), 154.0 (Cq, CO), 143.8 (Cq, Ph), 128.3
(26CH, Ph), 127.8 (26CH, Ph), 126.4 (CH, Ph), 63.3 (CH2),
59.9 (CH), 43.7 (CH), 41.7 (CH2), 29.5 (CH2), 28.5 (CH), 17.9
(CH3), 14.7 (CH3), 12.0 (CH3) ppm. Elem. anal. calcd. for
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HPLC (IB, 218 nm, hexane/iPrOH 90 : 10, 0.75 mL min21) tR =
26.1 min.
J. Degrado and A. H. Hoveyda, Angew. Chem., Int. Ed., 2005,
44, 5306–5310; (g) J. Schuppan, A. J. Minnaard and B.
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M. Yan, Y.-M. Li and A. S. C. Chan, Tetrahedron: Asymmetry,
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2007, 9, 5123–5126; (b) R. DesMazery, M. Pullez, F. Lopez,
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(4S)-4-Phenyl-3-(3-(thiophen-2-yl)butanoyl)oxazolidin-2-one
(7d)
White solid, 28.6 mg (9%); mp 112 uC (heptane). 1H NMR (300
MHz, CDCl3) d = 7.42–7.25 (m, 5H), 7.11 (dd, J = 1.1, 5.1 Hz,
1H), 6.88 (dd, J = 3.5, 5.1 Hz, 1H), 6.83–6.77 (m, 1H), 5.38 (dd, J
= 3.5, 8.7 Hz, 1H), 4.64 (t, J = 8.8 Hz, 1H), 4.26 (dd, J = 3.6, 8.9
Hz, 1H), 3.41 (dd, J = 7.8, 16.8 Hz, 1H), 3.65 (m, 1H), 3.16 (dd, J
= 6.3, 16.8 Hz, 1H), 1.34 (d, J = 7.0 Hz, 3H) ppm. 13C NMR (150
MHz, CDCl3) d = 170.9 (Cq, CO), 153.7 (Cq, CO), 149.6 (Cq, Ar),
139.0 (Cq, Ar), 129.2 (Ar–CH), 128.7 (Ar–CH), 126.6 (Ar–CH),
125.9 (Ar–CH), 123.2 (Ar–CH), 122.9 (Ar–CH), 70.0 (CH2), 57.6
(CH), 44.4 (CH2), 31.2 (CH), 23.0 (CH3) ppm. Elem. anal. calcd
for C17H17NO3S (Mr 338.2): C, 64.74; H, 5.43; N, 4.44; O, 15.22;
S, 10.17. Found: C, 64.54; H, 5.41; N, 4.41; S, 9.99. MS (EI) m/z
338.1 (MNa+). HPLC (IB, 218 nm, hexane/iPrOH 90 : 10, 0.75
mL min21) tR = 23.3 min.
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Acknowledgements
Financial support from Slovak Grant Agency VEGA, grant no.
VEGA 1/0623/12 is gratefully acknowledged. This publication is
the result of the project implementation: 26240120025
supported by the Research
& Development Operational
Programme funded by the ERDF. NMR measurements were
provided by Slovak State Programme project no.
2003SP200280203.
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