A new general and facile method for the synthesis of 4-alkyl-1,3-oxazoline- 4-carboxylic acids from N-acyl-2-alkylserines

Article abstract of DOI:10.1055/s-2007-983708

A new synthesis of 4-alkyl-1,3-oxazoline-4-carboxylic acids involves the thermal rearrangement of 4-alkyl-4-hydroxymethyl-1,3-oxazolin-5-ones prepared from N-acyl-2-alkylserines or N-protected peptides with a C-terminal 2-alkylserine residue. The rearrang

Full text of DOI:10.1055/s-2007-983708

PAPER
1807
A New General and Facile Method for the Synthesis of 4-Alkyl-1,3-oxazoline-
4-carboxylic Acids from N-Acyl-2-alkylserines
Synthesis of
4e
bacarboxylic
sA
cids tian Olczyk,a Janina E. Kamińska,*a Beata Kolesińska,b Zbigniew J. Kamińskib
a
Institute of General Food Chemistry, Technical University of Łódź, ul. B. Stefanowskiego 4/10, 90-924 Łódź, Poland
Fax +48(42)6362860; E-mail: janina.kaminska@p.lodz.pl
b
Institute of Organic Chemistry, Technical University of Łódź, ul. S. Żeromskiego 116, 90-924 Łódź, Poland
Received 12 February 2007; revised 20 March 2007
al flexibility.6 2-Alkylserines themselves are the object of
extensive studies7 as substitutes of the serine residue in
the active site of peptides, strongly influencing their activ-
ity.8 In most of the cases, esters of 1,3-oxazoline-4-car-
Abstract: A new synthesis of 4-alkyl-1,3-oxazoline-4-carboxylic
acids involves the thermal rearrangement of 4-alkyl-4-hydroxy-
methyl-1,3-oxazolin-5-ones prepared from N-acyl-2-alkylserines or
N-protected peptides with a C-terminal 2-alkylserine residue. The
rearrangement is fast and affords HPLC pure title compounds in boxylic acids and their 4-substituted analogues were
68–96% yield both from racemic and enantiomerically pure N-acyl-
propriate serine derivatives,9 application of Burgess re-
2-alkyl serines as well as from respective peptides.
Key words: 2-alkylserines, heterocycles, rearrangement
prepared by multistep procedures by modification of ap-
agent,10 or others.11 Herein we describe a general, simple,
and efficient method of preparation of 4-alkyl-1,3-oxazo-
line-4-carboxylic acids 3 based on the new rear-
rangement12 of 4-alkyl-4-hydroxymethyl-1,3-oxazolin-5-
ones 2 readily accessible by cyclodehydration of N-acyl-
2-alkylserines 1 (Scheme 1).
Derivatives of oxazole and thiazole carboxylic acids and
their dihydro analogues are substructures of numerous
natural products.1 Many of them are found in pharmaceu-
tically interesting antibiotics2 and others.3,4 The biogene-
sis of oxazole heterocycles is believed to proceed from
amino acid or peptide substrates. Cyclodehydration in-
volving serine or threonine side chains creates dihydro-
The N-acyl-2-alkylserines 1 when treated at 0–5 °C with
2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in the
presence of N-methylmorpholine (NMM) were converted
into ‘superactive esters’, which at room temperature easi-
ly underwent cyclization to 4-alkyl-4-hydroxymethyl-1,3-
oxazolin-5-ones 2 in almost quantitative yields (Table 1).
This protocol was advantageous because any side prod-
ucts were easily removed by simple extractive work-up,
affording crude 2 which was sufficiently pure (95–98% by
HPLC) for the next synthetic step.
heterocycles
–
oxazoline and methyloxazoline,
respectively – which subsequently can undergo reduction
to an oxazolidine or oxidation to an oxazole. All three ox-
idation states of these heterocycles were found in biolog-
ically active compounds. Heterocyclization alters the
peptide backbone, connectivity, and electronic distribu-
tion, and affords new elements for highly specific recog-
nition and interactions with targets such as DNA, RNA, or
proteins. From that point of view 4-alkyl-1,3-oxazoline-4-
carboxylic acids derived from 2-alkylserines deserve spe-
cial attention5 because of severely reduced conformation-
1,3-Oxazolin-5-ones 2a–e subsequently rearranged with-
in 20–90 minutes in boiling m-xylene into 4-alkyl-1,3-ox-
azoline-4-carboxylic acids 3a–e in excellent yields. We
have found that the rearrangement12 of 2a proceeded also
O
N
OH
H
N
O
N
H
N
R
NMM, CH2Cl2
0–5 °C
R
OH
N
N
+
R'
OH
N
N
R'
O
O
O
O
O
O
Cl
R'
O
1
O
N
OH
R
m-xylene, reflux
20–90 min
r.t.
24 h
N
R
OH
O
R'
O
O
2
3
Scheme 1 Synthesis of 4-alkyl-1,3-oxazoline-4-carboxylic acids from N-acyl-2-alkylserines
SYNTHESIS 2007, No. 12, pp 1807–1810
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.06.2007
DOI: 10.1055/s-2007-983708; Art ID: P01807SS
© Georg Thieme Verlag Stuttgart · New York

1808
S. Olczyk et al.
PAPER
(S,S)-Whelk-O1 column was used with a mixture of hexane–pro-
pan-2-ol (8:2) at 2 mL/min as mobile phase. Specific rotations were
measured on Rudolph Research Autopol IV polarimeter in 1 dm
tube at the sodium D line. Concentrations are given in g/100 mL.
Melting points were determined in open capillary tubes and are un-
corrected.
Table 1 Synthesis of 4-Alkyl-1,3-oxazoline-4-carboxylic Acids 3
from N-Acyl-2-alkylserines 1a–e and Peptides 1f,g via 4-Alkyl-4-hy-
droxymethyl-1,3-oxazolin-5-ones 2a–g
1
RCO
R¢
2
3
Yield (%)a
Yield (%)a
1a
benzoyl
benzoyl
benzoyl
benzoyl
benzoyl
benzoyl
benzoyl
benzoyl
Z-Aibb
Me
Me
Et
2a 90
3a 70
4-Alkyl-4-hydroxymethyl-1,3-oxazolin-5-ones 2; General Pro-
cedure
(S)-1a
1b
(S)-2a 92
2b 90
(S)-3a 72
3b 80
To a stirred solution of CDMT (0.352 g, 2 mmol) in CH2Cl2 (10
mL), was added N-methylmorpholine (0.22 mL, 2 mmol) at 0–5 °C,
followed by addition of the N-acyl-2-alkylserine 1 (2 mmol). The
mixture was stirred for 24 h at r.t., then diluted with CH2Cl2 (30
mL), successively washed with distilled H2O (20 mL), aq 1 M
NaHSO4 (3 × 10 mL), aq 1 M NaHCO3 (3 × 10 mL), H2O (1 × 20
mL), and dried (MgSO4). The solvent was evaporated under re-
duced pressure and the residue dried in a desiccator over KOH and
P2O5. Product was of 95–98% purity according to HPLC analysis
and was directly used in the next step.
1c
i-Pr
i-Bu
Bn
2c 87
3c 91
1d
2d 98
3d 68
1e
2e 99
3e 96
(S)-1e
(R)-1e
1f
Bn
(S)-2e 90
(R)-2e 91
2f 99
(S)-3e 90
(R)-3e 88
3f 92
Bn
4-Hydroxymethyl-4-methyl-2-phenyl-1,3-oxazolin-5-one (rac-
2a)
White solid; yield: 90%; mp 125–127 °C.
1H NMR: d = 1.47 (s, 3 H), 3.88 (d, J = 11.3 Hz, 1 H), 3.95 (d,
J = 11.3 Hz, 1 H), 7.45–7.58 (m, 3 H), 7.97–8.00 (m, 2 H).
13C NMR: d = 18.9, 66.5, 77.5, 127.9, 128.4, 128.7, 133.5, 161.9,
173.9.
Me
Me
1g
Z-Achc
2g 98
3g 94
a Isolated yields.
b Z-Aib: N-benzyloxycarbonylaminoisobutyryl.
c Z-Ach: N-benzyloxycarbonylaminocyclohexanoyl.
in boiling toluene or benzene, but in those solvents pro-
longed reaction times were required. 1,3-Oxazolin-5-ones
2f,g derived from N-protected dipeptides 1f,g containing
a 2-alkylserine residue in the C-terminal position rear-
ranged noticeably less readily although appropriate 3f,g
were also isolated in high yield. Determination of an opti-
cal purity of 3a,e by HPLC on chiral stationary phase con-
firmed that rearrangement of optically active 1a,e
proceeded without loss of enantiomeric homogeneity.
(S)-4-Hydroxymethyl-4-methyl-2-phenyl-1,3-oxazolin-5-one
[(S)-2a]
White solid; yield: 92%; mp 116–118 °C; [a]D –1.8 (c 2.5,
CHCl3).
24
1H NMR and 13C NMR spectra were identical to those of rac-2a.
4-Ethyl-4-hydroxymethyl-2-phenyl-1,3-oxazolin-5-one (rac-2b)
Oil; yield: 90%.
1H NMR: d = 0.88 (t, J = 7.4 Hz, 3 H), 1.9 (dq, J = 7.4 Hz, 2 H),
3.99 (d, J = 11.3 Hz, 1 H), 4.05 (d, J = 11.3 Hz, 1 H), 7.44–7.59 (m,
3 H), 7.98–8.02 (m, 2 H).
13C NMR: d = 7.8, 26.2, 66.1, 77.5, 125.4, 128.0, 128.8, 132.9,
162.1, 178.8.
In conclusion, the availability of 4-substituted 1,3-oxazo-
line-4-carboxylic acids provides convenient access for
their application as sterically hindered building blocks
with reduced conformational flexibility for a construction
of new peptidomimetics, polyazole antibiotics, or DNA 4-Hydroxymethyl-4-isopropyl-2-phenyl-1,3-oxazolin-5-one
(rac-2c)
Oil; yield: 87%.
bonding oligopeptides. Moreover, one can expect that the
conformation adopted by a peptide that incorporates an
oxazoline ring will offer a new structural motif, resem-
bling, but not identical to, proline or oxoproline ana-
logues.13 Experiments on the synthesis of peptides from 4-
alkyl-1,3-oxazoline-4-carboxylic acids are in progress.
1H NMR: d = 0.92 (d, J = 6.8 Hz, 3 H), 1.04 (d, J = 6.8 Hz, 3 H),
2.23 (sept, J = 6.8 Hz, 1 H), 3.98 (d, J = 12.3 Hz, 1 H), 4.01 (d,
J = 12.3 Hz, 1 H), 7.44–7.57 (m, 3 H), 7.97–8.01 (m, 2 H).
13C NMR: d = 15.4, 15.5, 29.9, 63.1, 77.2, 123.6, 126.2, 127.4,
131.0, 160.3, 177.0.
N-Methylmorpholine (reagent grade) was stored over KOH,
CH2Cl2 was dried over CaCl2. Racemic N-benzoyl-2-alkylserines14
and 2-chloro-4,6-dimethoxy-1,3,5-triazine15 (CDMT) were pre-
pared according to procedure described previously. Enantiomeri-
cally pure N-benzoyl-2-methyl- and N-benzoyl-2-benzylserines
were obtained by enzymatic resolution of racemates.16 All other re-
agents from commercial sources were used as received. IR spectra
were recorded on a Specord-IR 71 spectrometer; solids were record-
ed as KBr discs, unless otherwise stated. 1H NMR (250 MHz) and
13C NMR (62.5 MHz) spectra were taken on a Bruker DPX 250
spectrometer in CDCl3 with tetramethylsilane as an internal stan-
dard. Analytical high-performance liquid chromatography was
done on Dionex ASI 100 chromatograph consisting of oven, au-
tosampler and UV-diode-array detector. Chiral stationary phase
4-Hydroxymethyl-4-isobutyl-2-phenyl-1,3-oxazolin-5-one (rac-
2d)
Oil; yield: 98%.
1H NMR: d = 0.84 (d, J = 6.5 Hz, 3 H), 0.89 (d, J = 6.5 Hz, 3 H),
1.65–1.88 (m, 3 H), 3.85 (d, J = 11.3 Hz, 1 H), 3.90 (d, J = 11.3 Hz,
1 H), 7.43–7.57 (m, 3 H), 7.95–7.99 (m, 2 H).
13C NMR: d = 22.9, 23.9, 25.5, 42.4, 67.1, 76.0, 125.4, 128.0, 128.8,
132.9, 161.7, 179.4.
4-Benzyl-4-hydroxymethyl-2-phenyl-1,3-oxazolin-5-one (rac-
2e)
White solid; yield: 99%; mp 121–122 °C.
Synthesis 2007, No. 12, 1807–1810 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Alkyl-1,3-oxazoline-4-carboxylic Acids
1809
1H NMR: d = 3.08 (d, J = 13.5 Hz, 1 H), 3.15 (d, J = 13.5 Hz, 1 H),
3.95 (d, J = 11.4 Hz, 1 H), 4.06 (d, J = 11.4 Hz, 1 H), 7.18 (br s, 5
H), 7.25–7.48 (m, 3 H), 7.73–7.77 (m, 2 H).
13C NMR: d = 39.1, 66.0, 126.8, 127.2, 127.7, 128.1, 128.5, 129.6,
129.9, 132.7, 162.1, 177.6.
(S)-4-Methyl-2-phenyl-1,3-oxazoline-4-carboxylic Acid [(S)-3a]
White solid; yield: 72%; mp 111 °C; [a]D24 +3.9 (c 5.0, MeOH).
HPLC: tR (S) = 21.2 min (100%).
1H NMR and 13C NMR spectra were identical with those of rac-3a.
4-Ethyl-2-phenyl-1,3-oxazoline-4-carboxylic Acid (rac-3b)
White solid; yield: 80%; mp 110–111 °C.
(S)-4-Benzyl-4-hydroxymethyl-2-phenyl-1,3-oxazolin-5-one
[(S)-2e]
White solid; yield: 90%; mp 103–104 °C; [a]D –135.5 (c 2.5,
CHCl3).
24
HPLC: tR1 = 22.8 min (50%), tR2 = 26.7 min (50%).
IR (KBr): 3424, 3208, 2976, 2928, 1728, 1632, 1496, 1472, 1448,
1256 cm–1.
1H NMR and 13C NMR spectra were identical to those of rac-2e.
1H NMR: d = 1.00 (t, J = 7.4, 3 H), 2.00 (dq, J = 7.1, 7.4, 2 H), 4.36
(d, J = 9 Hz, 1 H), 4.76 (d, J = 9 Hz, 1 H), 7.41–7.58 (m, 3 H), 7.96–
7.99 (m, 2 H).
13C NMR: d = 7.8, 31.0, 73.9, 77.9, 126.0, 128.4, 128.7, 132.3,
165.9, 175.2.
(R)-4-Benzyl-4-hydroxymethyl-2-phenyl-1,3-oxazolin-5-one
[(R)-2e]
White solid; yield: 91%; mp 104–105 °C; [a]D +142.0 (c 2.5,
CHCl3).
24
1H NMR and 13C NMR spectra were identical to those of rac-2e.
Anal. Calcd for C12H13NO3·0.5H2O: C, 63.15; H, 6.18; N, 6.14.
Found: C, 63.30; H, 6.02; N, 6.24.
2-(1-Benzyloxycarbonylamino-1-methylethyl)-4-hydroxymeth-
yl-4-methyl-1,3-oxazolin-5-one (rac-2f)
White solid; yield: 99%; mp 130–131 °C.
4-Isopropyl-2-phenyl-1,3-oxazoline-4-carboxylic Acid (rac-3c)
White solid; yield: 91%; mp 155–157 °C.
IR (KBr): 2968, 1728, 1640, 1480, 1448, 1360, 1292 cm–1.
1H NMR: d = 0.81 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H),
2.25 (sept, J = 6.8 Hz, 1 H),), 4.26 (d, J = 9.1 Hz, 1 H), 4.65 (d,
J = 9.1 Hz, 1 H), 7.32–7.47 (m, 3 H), 7.84–7.87 (m, 2 H).
13C NMR (DMSO-d6): d = 16.7, 16.9, 33.1, 70.7, 82.3, 127.6,
127.8, 128.5, 131.2, 160.9, 174.2.
IR (CCl4): 3472, 3320, 1820, 1684, 1536, 1288, 1096, 1032, 796
cm–1.
1H NMR: d = 1.35 (s, 3 H), 1.59 (s, 3 H), 1.65 (s, 3 H), 3.73 (m, 2
H), 5.02 (d, J = 12.5 Hz, 1 H), 5.09 (d, J = 12.5 Hz, 1 H), 5.20 (br s,
1 H), 7.35 (br s, 5 H).
13C NMR: d = 17.9, 25.0, 25.1, 52.4, 67.0, 67.8, 72.1, 128.1, 128.2,
128.5, 135.8, 155.2, 167.0, 179.2.
Anal. Calcd for C11H11NO3·0.25H2O: C, 63.00; H, 5.53; N, 6.68.
Found: C, 62.69; H, 5.34; N, 6.96.
2-(1-Benzyloxycarbonylamino-1-cyclohexyl)-4-hydroxymethyl-
4-methyl-1,3-oxazolin-5-one (rac-2g)
Oil; yield: 98%.
4-Isobutyl-2-phenyl-1,3-oxazoline-4-carboxylic Acid (rac-3d)
White solid; yield: 68%; mp 81–82 °C.
IR (film): 3336, 3032, 2936, 2864 1820, 1788, 1716, 1528, 1464,
1448, 1368, 1256, 1008, 916, 732 cm–1.
1H NMR: d = 1.33 (s, 3 H), 1.18–1.99 (m, 10 H), 3.99 (d, J = 8.8 Hz,
1 H), 4.05 (d, J = 8.8 Hz, 1 H), 5.02 (d, J = 12 Hz, 1 H), 5.08 (d,
J = 12 Hz, 1 H), 5.43 (br s, 1 H), 7.32 (br s, 5 H).
13C NMR: d = 17.9, 20.9, 24.8, 32.1, 32.4, 54.8, 66.9, 67.7, 71.9,
127.9, 128.1, 128.4, 135.8, 155.2, 166.6, 179.3.
IR (KBr): 3424, 3184, 2960, 1720, 1628, 1496, 1488, 1448, 1228
cm–1.
1H NMR: d = 0.95 (d, J = 6.3 Hz, 3 H), 1.00 (d, J = 6.3 Hz, 3 H),
1.80–1.92 (m, 3 H), 4.35 (d, J = 9.2 Hz, 1 H), 4.83 (d, J = 9.2 Hz, 1
H), 7.40–7.54 (m, 3 H), 7.95–7.99 (m, 2 H).
13C NMR: d = 23.3, 23.9, 24.8, 47.0, 75.2, 76.5, 126.2, 128.4, 128.7,
132.3, 165.6, 175.5.
4-Alkyl-1,3-oxazoline-4-carboxylic Acids 3; General Procedure
The appropriate 4-alkyl-4-hydroxymethyl-2-phenyl-1,3-oxazolin-
5-one 2 (2 mmol) was dissolved in m-xylene (15 mL) and refluxed.
HPLC analysis after 20–90 min showed complete conversion of
starting material. The solvent was evaporated and the oily residue
was treated with hexane under sonication. The precipitated solid
was filtered, washed with hexane, and dried in a desiccator. Purity
according to HPLC analysis was >99%.
Anal. Calcd for C11H11NO3·0.25H2O: C, 63.00; H, 5.53; N, 6.68.
Found: C, 62.69; H, 5.34; N, 6.96.
4-Benzyl-2-phenyl-1,3-oxazoline-4-carboxylic Acid (rac-3e)
White solid; yield: 96%; mp 126–127 °C.
HPLC: tR (S) = 16.1 min (50%), tR (R) = 26.2 min (50%).
IR (KBr): 3472, 3160, 1724, 1628, 1576, 1496, 1448, 1272 cm–1.
1H NMR: d = 3.18 (d, J = 13.6 Hz, 1 H), 3.35 (d, J = 13.6 Hz, 1 H),
4.46 (d, J = 9.3 Hz, 1 H), 4.76 (d, J = 9.3 Hz, 1 H), 7.22–7.27 (m, 5
H), 7.38–7.53 (m, 3 H), 7.90–7.94 (m, 2 H).
13C NMR (acetone-d6): d = 43.2, 73.5, 79.0, 127.5, 128.1, 128.8,
129.1, 129.2, 131.4, 132.5, 136.6, 165.3, 173.9.
4-Methyl-2-phenyl-1,3-oxazoline-4-carboxylic Acid (rac-3a)
White solid; yield: 70%; mp 115 °C (Lit.9c mp 130–132 °C).
HPLC: tR (S) = 21.2 min (50%), tR (R) = 22.4 min (50%).
IR (KBr): 3424, 3208, 2992, 1724, 1636, 1576, 1496, 1452, 1276
cm–1.
1H NMR: d = 1.66 (s, 3 H), 4.28 (d, J = 9 Hz, 1 H), 4.85 (d, J = 9
Hz, 1 H), 7.40–7.56 (m, 3 H), 7.95–7.98 (m, 2 H).
Anal. Calcd for C17H15NO3·0.33H2O: C, 71.07; H, 5.50; N, 4.87.
Found: C, 70.86; H, 5.16; N, 5.36.
13C NMR: d = 24.9, 73.6, 76.5, 126.0, 128.4, 128.7, 132.3, 165.8,
(S)-4-Benzyl-2-phenyl-1,3-oxazoline-4-carboxylic Acid [(S)-3e]
White solid; yield: 90%; mp 120–121 °C; [a]D +59.5 (c 2.5,
MeOH).
25
175.7.
Anal. Calcd for C11H11NO3·0.25H2O: C, 63.00; H, 5.53; N, 6.68.
Found: C, 62.69; H, 5.34; N, 6.96.
HPLC: tR (S) = 16.1 min (100%).
1H NMR and 13C NMR spectra were identical to those of rac-3e.
Synthesis 2007, No. 12, 1807–1810 © Thieme Stuttgart · New York

1810
S. Olczyk et al.
PAPER
Chem., Int. Ed. Engl. 1988, 27, 858. (c) Avenoza, A.;
Peregrina, J. M.; San Martin, E. Tetrahedron Lett. 2003, 44,
6413. (d) Horikawa, M.; Nakajima, T.; Ohfune, Y. Synlett
1998, 609.
(R)-4-Benzyl-2-phenyl-1,3-oxazoline-4-carboxylic Acid [(R)-3e]
White solid; yield: 88%; mp 123–124 °C; [a]D –67.0 (c 2.5,
MeOH).
25
HPLC: tR (R) = 26.2 min (100%).
1H NMR and 13C NMR spectra were identical to those of rac-3e.
(7) (a) Smith, N. D.; Wohlrab, A. M.; Goodman, M. Org. Lett.
2005, 7, 255. (b) Avenoza, A.; Busto, J. H.; Cativiela, C.;
Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Tetrahedron:
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A.; Zhang, Z. Tetrahedron 2001, 57, 6345. (d) Horikawa,
M.; Nakajima, T.; Ohfune, Y. Synlett 1997, 253.
2-(1-Benzyloxycarbonylamino-1-methylethyl)-4-methyl-1,3-ox-
azoline-4-carboxylic Acid (rac-3f)
White solid; yield: 92%; mp 102–103 °C.
(e) Shiraiwa, T.; Suzuki, M.; Sakai, Y.; Nagasawa, H.;
Takatani, K.; Noshi, D.; Yamanashi, K. Chem. Pharm. Bull.
2002, 50, 1362. (f) Moon, S.-H.; Ohfune, Y. J. Am. Chem.
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Chem. Bull. Int. Ed. 2001, 50, 1037. (i) Lee, J.; Lee, Y.-I.;
Kang, M. J.; Jee, Y.-J.; Jeong, B.-S.; Lee, J.-H.; Kim, M.-J.;
Choi, J.; Ku, J.-M.; Park, H.; Jew, S. J. Org. Chem. 2005, 70,
4158. (j) Jew, S.; Lee, Y.; Lee, J.; Kang, M. J.; Jeong, B. S.;
Lee, J. H.; Yoo, M. S.; Kim, M. J.; Choi, S.; Ku, J. M.; Park,
H. G. Angew. Chem. Int. Ed. 2004, 43, 2382. (k) Colson,
P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918.
(8) (a) Mickos, H.; Sundberg, K.; Lüning, B. Acta Chem. Scand.
1992, 46, 989. (b) Yakamura, T.; Yoshimoto, Y.; Ishida, C.;
Mabuchi, S. Synlett 2006, 930. (c) Chattopadhyay, S. K.;
Biswas, S.; Pal, B. K. Synthesis 2006, 1289.
(9) (a) Obrecht, D.; Abrecht, C.; Altorfer, M.; Bohdal, U.;
Grieder, A.; Kleber, M.; Pfyffer, P.; Müller, K. Helv. Chim.
Acta 1996, 79, 1315. (b) Obrecht, D.; Altorfer, M.;
Lehmann, C.; Schonhölzer, P.; Müller, K. J. Org. Chem.
1996, 61, 4080. (c) Teplan, I.; Mezö, I.; Vegh, G. Khimia
Prirod. Soed. 1971, 7, 484; Chem. Abstr. 1971, 75, 141138.
(d) Park, H.; Lee, J.; Kang, M. J.; Lee, Y. J.; Jeong, B. S.;
Lee, J. H.; Yoo, M. S.; Kim, M. J.; Choi, S.; Jew, S.
Tetrahedron 2004, 60, 4243.
IR (KBr): 3472, 3320, 1820, 1684, 1536, 1288, 1196, 1032, 796
cm–1.
1H NMR (DMSO-d6): d = 1.24 (s, 3 H), 1.33 (s, 3 H), 1.39 (s, 3 H),
4.09 (d, J = 11.3 Hz, 1 H), 4.27 (d, J = 11.3 Hz, 1 H), 4.99 (m, 2 H),
7.34 (br s, 5 H), 7.72 (br s, 2 H).
13C NMR (DMSO-d6): d = 19.6, 24.9, 25.1, 55.9, 59.0, 65.5, 67.7,
127.7, 127.9, 128.3, 136.8, 155.5, 169.7, 173.8.
FAB-MS: m/z = 321 [(M + H)+], 339 [(M + H + H2O)+].
2-(1-Benzyloxycarbonylamino-1-cyclohexyl)-4-methyl-1,3-ox-
azoline-4-carboxylic Acid rac-(3g)
White solid; yield: 94%; mp 134–136 °C.
IR (CCl4): 3344, 2936, 2856, 1716, 1600, 1528, 1448, 1264, 784
cm–1.
1H NMR (DMSO-d6): d = 1.18 (s, 3 H), 1.10–1.93 (m, 10 H), 4.07
(d, J = 11.5 Hz, 1 H), 4.24 (d, J = 11.5 Hz, 1 H), 5.00 (m, 2 H), 7.36
(m, 5 H), 7.45 (br s, 2 H).
13C NMR (DMSO-d6): d = 19.7, 20.8, 24.7, 31.8, 55.1, 58.9, 65.5,
67.6, 127.7, 127.9, 128.6, 136.8, 155.8, 169.6, 173.9.
FAB-MS: m/z = 361 [(M + H)+], 379 [(M + H + H2O)+].
Acknowledgment
(10) Khapli, S.; Dey, S.; Mal, D. J. Indian Inst. Sci. 2001, 81, 461;
The study was supported by the Polish State Committee for Scien-
tific Research under the project 4-T09A 189 25.
Chem. Abstr. 2003, 139, 84773.
(11) (a) Miyaoka, H.; Yamanishi, M.; Hoshino, A.; Kinbara, A.
Tetrahedron 2006, 62, 4103. (b) Yeh, V. S. C. Tetrahedron
2004, 60, 11995. (c) Stankova, I. G.; Videnkov, G. I.;
Golovinsky, E. V.; Jung, G. J. Peptide Sci. 1999, 5, 392.
(12) (a) Intramolecular attack of oxygen atom of 4-hydroxy-
methyl group at C-2 carbon of 2-phenyl-1,3-oxazolin-5-ones
2a–g is postulated. (b) Intermolecular nucleophilic attack
on C-2 of 1,3-oxazolin-5-one bearing two substituents at C-
4 was documented for the first time by: Leplawy, M. T.;
Jones, D. S.; Kenner, G. W.; Sheppard, R. C. Tetrahedron
1960, 11, 39 . and by (c) Weygand, F.; Steglich, W.;
Tanner, H. Liebigs Ann. Chem. 1962, 658, 128. (d) 4-
Alkyl-1,3-oxazoline-4-carboxylic acids were identified as
side-products accompanying synthesis of peptides bearing a
2-substituted serine residue: Kamiński, Z. J.; Woszczyna,
W.; Kolesińska, B.; Redliński, A. Acta Biochim. Pol. 2001,
48, 1175; Chem. Abstr. 2002, 137, 352936.
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Synthesis 2007, No. 12, 1807–1810 © Thieme Stuttgart · New York