A new approach to N-methylaspartic, N-methylglutamic, and N-methyl-α- aminoadipic acid derivatives

Article abstract of DOI:10.1002/(SICI)1099-0690(200001)2000:1<199::AID-EJOC199>3.0.CO;2-8

N-Methylaspartic acid derivatives and its homologues are obtained by a stereoconservative one-pot procedure from hexafluoroacetone-protected aspartic and glutamic acid, 2a and 2b, respectively, α-Aminoadipic acid (5c) and its derivative 6c are accessible from the corresponding glutamic acid derivative 9b by a Wolff rearrangement. A variety of homochiral N-methylamino acids, 5 and 12, and their derivatives, 6 and 8-11, become readily available by the new synthetic concept.

Full text of DOI:10.1002/(SICI)1099-0690(200001)2000:1<199::AID-EJOC199>3.0.CO;2-8

FULL PAPER
A New Approach to N-Methylaspartic, N-Methylglutamic,
and N-Methyl-␣-aminoadipic Acid Derivatives
Klaus Burger,*[a] and Jan Spengler[a]
Keywords: Hexafluoroacetone / N-Methylaspartic acid / N-Methylglutamic acid / N-Methyl-α-aminoadipic acid /
N-Methylthiazol-4-yl-α-amino acids
N-Methylaspartic acid derivatives and its homologues are
obtained by a stereoconservative one-pot procedure from
hexafluoroacetone-protected aspartic and glutamic acid, 2a
and 2b, respectively. α-Aminoadipic acid (5c) and its
derivative 6c are accessible from the corresponding glutamic
acid derivative 9b by a Wolff rearrangement. A variety of
homochiral N-methylamino acids, and 12, and their
derivatives, 6 and 8Ϫ11, become readily available by the
5
new synthetic concept.
sweetener “aspartame”.[8] Selective activation of the ω-car-
boxylic group can be achieved by transformation into the
acid chloride, as demonstrated by a five-step synthesis of
HON (5-hydroxy-4-oxo-norvaline) starting from aspartic
acid.[9]
Introduction
The development of new strategies for the synthesis of
homochiral non-proteinogenic and non-natural amino ac-
ids is of current interest.[1] Some represent new building
blocks for the construction of peptide mimetics, glycopep-
tide mimetics, synthetic enzymes, new drugs, and agrochem-
icals.[2] Furthermore, they are valuable starting materials
for combinatorial chemistry.[3]
α-N-Methylamino acids, an interesting subclass of α-am-
ino acids, are constituents of various peptides and depsi-
peptides, isolated from plants, microorganisms, and marine
species. Some of them exhibit highly interesting biological
activities.[4] Incorporation of α-N-methylamino acids into
key positions of peptides and depsipeptides leads to an en-
hanced proteolytic stability, to an increase in lipophilicity,
and to a stabilization of secondary structure domains. Cer-
tain α-N-methylamino acids are themselves biologically ac-
tive compounds.[5] Consequently, a number of synthetic
routes to homochiral α-N-methylamino acids have been de-
veloped.[6]
Scheme 1. Regioselective functionalization of α-amino acids
Furthermore, hexafluoroacetone-protected α-amino ac-
ids are also perfectly suited for N-alkylation. In a three-
component reaction, hexafluoroacetone-protected α-amino
acids, paraformaldehyde, and thionyl chloride react to give
N-chloromethylamino acid derivatives, which can be trans-
formed into N-methylamino acid derivatives on treatment
with triethylsilane/trifluoroacetic acid.[10]
We now want to disclose that the new N-methylation pro-
cedure can also be applied to ω-carboxy α-amino acids.
Results and Discussion
Recently, we decribed a new protection/activation strat- Hexafluoroacetone-protected aspartic and glutamic acid[8]
egy for α-amino acids using hexafluoroacetone. Hexa- react in trifluoroacetic acid (as solvent) with paraformal-
fluoroacetone and α-amino acids react to give bis(trifluoro- dehyde and thionyl chloride, giving N-chloromethylation. In
methyl)-substituted oxazolidin-5-ones in high yields. This a parallel reaction, the ω-carboxylic group is transformed
heterocyclization process results in a simultaneous protec- into the acid chloride. The presence of trifluoroacetic acid
tion of the α-amino group and the α-carboxylic group. Fur- as a solvent avoids the formation of the pyroglutamic acid
thermore, the α-carboxylic group is activated towards nucle- derivative in the case of glutamic acid. The reaction mixture
ophiles. Functional groups present in the side chain Ϫ like was treated with triethylsilane to transform the chlorome-
the carboxyl moiety Ϫ remain unaffected.[7] Consequently, thyl group into the methyl group. After evaporation of the
the method can be applied to regioselective group manipu- volatiles in vacuo, the residue was heated under reflux with
lation of ω-carboxy α-amino acids. The efficiency of this an excess of thionyl chloride to ensure that the ω-carboxylic
concept was demonstrated by a two-step synthesis of the group is completely transformed into the acid chloride 3
which can be easily purified by distillation.
[a]
Department of Organic Chemistry, University of Leipzig,
The free acids 4 were obtained from acid chlorides 3
upon stirring in wet THF at room temperature. Complete
deblocking of the amino acids was obtained by stirring with
Johannisallee 29, D-04103 Leipzig, Germany
Fax: (internat.) ϩ 49-(0)341/973-6599
E-mail: burger@organik.chemie.uni-leipzig.de
Eur. J. Org. Chem. 2000, 199Ϫ204
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0101Ϫ199 $ 17.50ϩ.50/0
199

K. Burger, J. Spengler
FULL PAPER
knowledge, homochiral α-(methylamino)adipic acid and
their derivatives are not described so far.
Scheme 2. N-Methylation of α-amino acids
Scheme 5. Synthesis of α-(methylamino)adipic acid derivatives
concd. HCl at 80°C for 12 h (4 Ǟ 5). Since the N-methyl-
ated amino acid derivatives 4 are α-carboxylic group acti-
vated species, they readily can be transformed into dipep-
tide derivatives (4 Ǟ 6). Compounds 3 can be regioselec-
In all experiments described in the paper, no substantial
racemization could be detected. Starting from -aspartic
and -glutamic acid, the corresponding N-methylamino ac-
ids of the -series became available.
Experimental Section
General Remarks: Solvents were purified and dried prior to use.
Reagents were used as purchased. Ϫ Thin layer chromatography
(TLC) was performed on aluminia plates coated with Merck silica
gel 60F254. Compounds were visualized by spraying with ceric am-
monium nitrate in 9  H2SO4 followed by heating up to 100°C. Ϫ
Column chromatography was carried out on silica gel (32Ϫ63 µm,
ICN Biomedicals). Ϫ Melting points were determined with a Boe¨t-
ius heating table. Ϫ Optical rotation indices [α]D were measured
with a Polartronic polarimeter (Schmidt & Haensch) in a 5-cm cell.
Ϫ For C, H, N analyses a CHNO-Rapid-Elemental-Analyser
(Heraeus) was used. Ϫ Mass spectra were recorded with a VG
12Ϫ250 (Masslab) electron-ionization spectrometer (EI ϭ 70 eV)
or a VG ZAB-HSQ FAB spectrometer. Ϫ IR spectra were obtained
Scheme 3. Regioselective functionalization of α-methylamino acids
tively functionalized in a two-step procedure (3 Ǟ 7 Ǟ 8).
Acid chlorides 3, on reaction with an excess of diazo-
methane gave the corresponding diazo ketones 9, which by
themselves are interesting synthetic intermediates. They by using an FTIR spectrometer (Genesis ATI Mattson). Ϫ 1H-
(200.041 or 300.075 MHz), 13C- (50.305 or 75.462 MHz) and 19F-
NMR (188.205 or 282.380 MHz) spectra were recorded with a
Varian Gemini 200 or a Varian Gemini 300 spectrometer. Tetra-
methylsilane was used as reference standard for 1H- and 13C-NMR
spectra (internal) and trifluoroacetic acid for 19F-NMR spectra (ex-
ternal).
represent N-methyl derivatives of DONV[11] (5-diazo-4-
oxonorvaline, 9a) and DON[12] (5-diazo-4-oxo-norleucine,
9b), respectively. Bromo ketones 10 are obtained from 9 on
stirring with concd. HBr in THF at 0°C. Compounds 10
are versatile starting materials for the Hantzsch reaction.[13]
On treatment with thioamides, compounds 10 readily react
to give a variety of α-(methylamino) ω-(thiazol-4-yl) car-
boxylic acids, e.g. 12, via compounds 11.[14]
General Procedure (2 Ǟ 3): Oxazolidinone 2[8] (50 mmol) and par-
aformaldehyde (3.0 g, 100 mmol) were dissolved in trifluoroacetic
acid (50 mL), and thionyl chloride (10 mL) was then added. The
flask was equipped with a reflux condenser which was connected
to a bubbler. The mixture was stirred overnight at room tempera-
ture. On addition of triethylsilane (11.6 g, 16 mL, 100 mmol), a
strong exothermic reaction with gas evolution started, after a short
induction period. The mixture was stirred until gas evolution ce-
ased (ca. 0.5 h). When the reaction was complete (19F-NMR analy-
sis) the volatile compounds were evaporated in vacuo and the resi-
due was treated with thionyl chloride at reflux for 3 h. The excess
thionyl chloride was distilled off. Distillation of the residue in va-
cuo gave the pure products 3.
[(4S)-3-Methyl-5-oxo-2,2-bis(trifluoromethyl)-1,3-oxazo-
lidin-4-yl]acetyl Chloride (3a): Reaction of 2a (14.1 g, 50 mmol)
gave 10.2 g (65%) of 3a. Ϫ M.p. 28Ϫ29°C. Ϫ B.p. 48Ϫ50°C
Scheme 4. Synthesis of heterocyclic α-methylamino acids
Diazo ketones are suitable starting materials for homol-
ogation reactions of the Wolff type. The Agϩ/base-catalyzed
reaction of diazo ketones is reported to be promoted sub-
stantially by sonication at room temperature.[15] It was
found that base-free Agϩ-catalyzed Wolff rearrangement of
9b to 4c proceeds smoothly at room temperature on sonic-
25
(0.3 Torr). Ϫ [α]D ϭ ϩ17.6 (c ϭ 2.5, CHCl3). Ϫ 1H NMR
(CDCl3): δ ϭ 2.76 (q, 3 H, J ϭ 2.0 Hz, CH3), 3.33 (dd, 1 H, J ϭ
18.0 Hz, 5.2 Hz, CH2), 3.49 (dd, 1 H, J ϭ 18.0 Hz, 4.2 Hz, CH2),
3.97 (m, 1 H, CH). Ϫ 13C NMR (CDCl3): δ ϭ 33.6 (br., CH3),
47.1 (CH2), 57.7 (CH), 90.0 [m, C(CF3)2], 120.7 (q, J ϭ 287 Hz,
CF3), 121.9 (q, J ϭ 295 Hz, CF3), 168.2 (CO), 170.5 (COCl). Ϫ
ation using an ultrasound cleaning bath.[16] To our best 19F NMR (CDCl3): δ ϭ Ϫ0.66 (m, 3 F, CF3), 4.42 (m, 3 F, CF3).
200 Eur. J. Org. Chem. 2000, 199Ϫ204

N-Methylaspartic, N-Methylglutamic, and N-Methyl-α-aminoadipic Acid Derivatives
Ϫ IR (KBr): ν˜ ϭ 1842 cmϪ1 (CO), 1799 (COCl). Ϫ MS (EI), m/z
FULL PAPER
1
(c ϭ 7.0, H2O); ref.[19] ϩ21.0 (c ϭ 7.0, H2O). Ϫ H NMR (D2O):
(%): 313 [M]ϩ (13), 249 (28), 236 (35). Ϫ C8H6ClF6NO3 (313.5): δ ϭ 2.28 (m, 2 H, CH2CH), 2.66 (td, 2 H, J ϭ 7.5 Hz, 1.9 Hz,
calcd. C 30.65, H 1.93, N 4.47; found C 30.65, H 1.99, N 4.49.
CH2CO2H), 2.82 (s, 3 H, CH3), 4.00 (m, 1 H, CH). Ϫ 13C NMR
(D2O): δ ϭ 26.6 (CH2CH), 32.1 (CH2CO2H), 34.5 (CH3), 63.4
(CH), 174.0, 179.1 (2 ϫ CO2H). Ϫ MS (EI), m/z (%):161 [M Ϫ
HCl]ϩ (20), 116 [M Ϫ CO2H Ϫ HCl]ϩ (60), 98 (100). Ϫ
C5H11NO4 ϫ HCl (197.6): calcd. with /8 H2O C 36.06, H 6.18, N
7.01; found C 35.96, H 5.74, N 6.74.
3-[(4S)-3-Methyl-5-oxo-2,2-bis(trifluoromethyl)-1,3-oxazoli-
din-4-yl]propionyl Chloride (3b): Reaction of 2b (14.8 g, 50 mmol)
gave 13.4 g (82%) of 3b as a yellowish oil. Ϫ B.p. 58Ϫ60°C
1
25
(0.1 Torr). Ϫ [α]D ϭ ϩ33.0 (c ϭ 2.0, CHCl3). Ϫ 1H NMR
(CDCl3): δ ϭ 2.24 (m, 2 H, CH2CH), 2.73 (q, 3 H, J ϭ 1.9 Hz,
CH3), 3.01 (m, 2 H, CH2CO), 3.71 (m, 1 H, CH). Ϫ 13C NMR
(CDCl3): δ ϭ 23.7 (CH2CH), 32.9 (br., CH3), 40.8 (CH2CO), 59.1
(CH), 89.5 [m, C(CF3)2], 120.5 (q, J ϭ 288 Hz, CF3), 121.5 (q, J ϭ
295 Hz, CF3), 168.7 (CO), 173.1 (COCl). Ϫ 19F NMR (CDCl3):
δ ϭ Ϫ0.90 (m, 3 F, CF3), 4.37 (m, 3 F, CF3). Ϫ IR (film): ν˜ ϭ 1838
cmϪ1 (CO), 1801 (COCl). Ϫ MS (EI), m/z (%): 327 [M]ϩ (2), 292
(41), 249 (43). Ϫ C9H8ClF6NO3 (327.6): calcd. C 33.00, H 2.46, N
4.28; found C 32.86, H 2.35, N 4.07.
L
-α-Methylaminoadipic Acid (5c): Reaction of 4c (0.65 g, 2 mmol)
25
gave 0.22 g (63%) of 5c. Ϫ M.p. 157Ϫ159°C. Ϫ [α]D ϭ ϩ18.7
(c ϭ 1.5, H2O). Ϫ H NMR (D2O): δ ϭ 1.51 (m, 2 H, CH2), 1.75
1
(m, 2 H, CH2CH), 2.29 (t, 2 H, J ϭ 7.0 Hz, CH2CO2H), 2.55 (s, 3
H, CH3), 3.46 (t, 1 H, J ϭ 6.0 Hz, CH). Ϫ 13C NMR (D2O): δ ϭ
22.6 (CH2), 31.4 (CH2CH), 34.6 (CH3), 36.2 (CH2CO2H), 66.0
(CH), 176.2, 180.9 (2 ϫ CO2H). Ϫ MS (EI), m/z (%): 175 [M]ϩ (8),
158 (48), 113 (100). Ϫ C7H13NO4 (175.2): calcd. C 47.99, H 7.48,
N 8.00; found C 48.21, H 7.50, N 7.84.
General Procedure (3 Ǟ 4): Oxazolidinone 3 (10 mmol) was dis-
solved in wet THF and stirred until the smell of the acid chloride
vanished (ca. 1.5 h). After evaporating in vacuo, the residue was
recrystallized from n-hexane.
(2S)-N-Methyl-3-(2-phenyl-1,3-thiazol-4-yl)alanine (12a): Reaction
of 11a (0.82 g, 2 mmol) gave 0.38 g (73%) of 12a. Ϫ M.p.
218Ϫ232°C (dec.). Ϫ [α]D25 ϭ ϩ 23.3 (c ϭ 2.0, DMSOϩ 5% TFA).
Ϫ 1H NMR ([D6]DMSO ϩ 5% TFA): δ ϭ 2.66 (s, 3 H, CH3), 3.39
(m, 2 H, CH2), 4.36 (m, 1 H, CH), 7.49 (m, 4 H, arom.), 7.93 (m,
2 H, arom.). Ϫ 13C NMR ([D6]DMSO ϩ 5% TFA): δ ϭ 30.7
(CH2), 32.5 (CH3), 60.2 (CH), 118.8 (SϪCHϭC), 127.2, 130.1,
131.3, 133.9 (phenyl), 151.4 (SϪCHϭC), 168.4 [C(Ph)], 170.6
(CO2H). Ϫ MS (EI), m/z (%): 262 [M]ϩ (4), 217 [M Ϫ CO2H]ϩ
(11), 175 (100). Ϫ C13H14N2O2S (262.3): calcd. C 59.52, H 5.38, N
10.68; found C 59.26, H 5.37, N 10.51.
[(4S)-3-Methyl-5-oxo-2,2-bis(trifluoromethyl)-1,3-oxazolidin-4-yl]-
acetic Acid (4a): Reaction of 3a (3.13 g, 10 mmol) gave 2.6 g (74%)
25
1
of 4a. Ϫ M.p. 75Ϫ78°C. Ϫ [α]D ϭ ϩ9.3 (c ϭ 2.0, CHCl3). Ϫ H
NMR (CDCl3): δ ϭ 2.75 (q, 3 H, J ϭ 2.0 Hz, CH3), 2.91 (m, 2 H,
CH2), 3.92 (m, 1 H, CH). Ϫ 13C NMR (CDCl3): δ ϭ 33.5 (br.,
CH3), 35.1 (CH2), 57.8 (CH), 89.9 [m, C(CF3)2], 120.9 (q, J ϭ
287 Hz, CF3), 122.1 (q, J ϭ 296 Hz, CF3), 169.0 (CO), 175.6
(CO2H). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ0.59 (m, 3 F, CF3), 4.42 (m,
3 F, CF3). Ϫ IR (KBr): ν˜ ϭ 1839 cmϪ1 (CO), 1710 (CO2H). Ϫ MS
(EI), m/z (%): 295 [M]ϩ (41), 249 (100), 198 (50), 180 (100). Ϫ
C8H7F6NO4 (295.1): calcd. C 32.56, H 2.39, N 4.74; found C 32.79,
H 2.64, N 5.21.
(2S)-2-(Methylamino)-4-(2-phenyl-1,3-thiazol-4-yl)butyric
Acid
(12b): Reaction of 11b (0.85 g, 2 mmol) gave 12b (0.45 g, 81%). Ϫ
25
M.p. 216Ϫ219°C (dec.). Ϫ [α]D ϭ ϩ34.3 (c ϭ 2.0, DMSO ϩ 5%
TFA). Ϫ 1H NMR ([D6]DMSO ϩ 5% TFA): δ ϭ 2.31 (m, 2 H,
CH2CH), 2.67 (s, 3 H, CH3), 2.92 (m, 2 H, CH2CH2CH), 4.06 (m,
1 H, CH), 7.48 (m, 4 H, arom.), 7.93 (m, 2 H, arom.). Ϫ 13C NMR
([D6]DMSO ϩ 5% TFA): δ ϭ 26.6 (CH2CH), 28.3 (CH2CH2CH),
31.5 (CH3), 59.7 (CH), 115.3 (SϪCHϭC), 126.3, 129.4, 130.4,
133.3 (phenyl), 155.9 (SϪCHϭC), 167.1 [C(Ph)], 170.3 (CO2H). Ϫ
MS (EI), m/z (%): 276 [M]ϩ (4), 231 [M Ϫ CO2H]ϩ (21), 188 (35),
175 (100). Ϫ C14H16N2O2S (276.4): calcd. C 60.85, H 5.84, N 10.14;
found C 60.51, H 5.70, N 10.12.
3-[(4S)-3-Methyl-5-oxo-2,2-bis(trifluoromethyl)-1,3-oxazolidin-4-yl]-
propionic Acid (4b): Reaction of 3b (3.28 g, 10 mmol) gave 2.63 g
(85%) of 4b. Ϫ M.p. 86Ϫ88°C. Ϫ [α]D25 ϭ ϩ23.8 (c ϭ 1.0, CHCl3).
1
Ϫ H NMR (CDCl3): δ ϭ 2.20 (m, 2 H, CH2CH), 2.49 (m, 2 H,
CH2CO2H), 2.73 (q, 3 H, J ϭ 1.9 Hz, CH3), 3.71 (m, 1 H, CH). Ϫ
13C NMR (CDCl3): δ ϭ 23.6 (CH2CH), 28.1 (CH2CO2H), 33.2
(br., CH3), 59.8 (CH), 89.9 [m, C(CF3)2], 121.0 (q, J ϭ 287 Hz,
CF3), 122.1 (q, J ϭ 296 Hz, CF3), 169.7 (CO), 179.2 (CO2H). Ϫ
19F NMR (CDCl3): δ ϭ Ϫ0.83 (m, 3 F, CF3), 4.42 (m, 3 F, CF3).
Ϫ IR (KBr): ν˜ ϭ 1840 cmϪ1 (CO), 1716 (CO2H). Ϫ MS (EI), m/z
(%): 309 [M]ϩ (20), 291 (34), 263 (26), 249 (100). Ϫ C9H9F6NO4
(309.2): calcd. C 34.96, H 2.93, N 4.53; found C 35.15, H 3.10,
N 4.84.
General Procedure (4 Ǟ 6, 7 Ǟ 8): Oxazolidinone 4 or 7 (2 mmol)
and -methyl phenylalaninate (0.72 g, 4 mmol) were dissolved in
dry ether (2 mL) and stirred for several days. The progress of the
reaction was monitored by TLC. The white precipitate was filtered
off, dissolved in H2O (50 mL) and lyophilized. Hexafluoroacetone
hydrate was removed from the product by repeated lyophilization.
General Procedure (4 Ǟ 5, 11 Ǟ 12): Oxazolidinone 4 or 11
(2 mmol) was dissolved in dioxane (3 mL)/concd. HCl (3 mL) and
stirred at 80°C for 12 h. The solution was evaporated to dryness
and the residue dissolved in EtOH (1 mL). Stirring with propylene
oxide (3 mL) gave the free amino acids 5 and 12 as white precipi-
tates which were dried in vacuo.
Methyl (N-Methyl-L-asparagyl)-L-phenylalaninate (6a): Using the
above procedure, 4a (0.59 g, 2 mmol) gave 0.47 g (76%) of 6a, which
25
had a sweet taste. Ϫ M.p. 141Ϫ143°C. Ϫ [α]D ϭ Ϫ30.5 (c ϭ 2.0,
1
H2O); Ϫ H NMR (D2O): δ ϭ 2.26 (s, 3 H, CH3), 2.55 (m, 2 H,
CH2CH), 2.84 (dd, 1 H, J ϭ 14.0, 10.2 Hz, CH2Ph), 3.20 (dd, 1 H,
J ϭ 13.8, 5.0 Hz, CH2Ph), 3.63 (s, 3 H, OCH3), 3.82 (m, 1 H,
CHAsp), 4.65 (m, 1 H, CHPhe), 7.18 (m, 5 H, phenyl). Ϫ 13C NMR
L
-N-Methylaspartic Acid (5a): Reaction of 4a (0.59 g, 2 mmol) gave
0.25 g (85%) of 5a. Ϫ M.p. 183Ϫ186°C; ref.[6a] 187Ϫ190°C. Ϫ
25
[α]D ϭ ϩ14.0 (c ϭ 2.0, H2O); ref.[17] ϩ14.2 (c ϭ 2.0, H2O). Ϫ
(D2O): δ ϭ 31.9 (CH3), 36.7, 36.9 (2 ϫ CH2), 53.4, 54.5 (CHPhe
,
1H-NMR-identical to literature data.[6a]
OCH3), 59.4 (CHAsp), 127.7, 129.3, 129.7, 136.9 (phenyl), 168.5,
173.3, 176.0 (3 ϫ CO). Ϫ MS (FAB), m/z (%): 331.0 [M ϩ Na]ϩ,
L-N-Methylglutamic Acid Hydrochloride (5Јb): Oxazolidinone 4b
1
309.0 [M ϩ H]ϩ. Ϫ C15H20N2O5 (308.3): calcd. with
/ H2O C
4
0.62 g (2 mmol) was dissolved in dioxane (3 mL)/concd. HCl
(3 mL) and stirred at 80°C for 12 h. The solution was concentrated
to dryness. The residue was stirred in dry ether (20 mL), filtered
54.46, H 6.86, N 8.46; found C 54.48, H 6.28, N 8.26.
Methyl (N-Methyl-L-glutamyl)-L-phenylalaninate (6b): Reaction of
and dried in vacuo to give 0.23 g (59%) of 5Јb as a hygroscopic
4b (0.62 g, 2 mmol) gave 0.46 g (71%) of 6b. Ϫ M.p. 124Ϫ127°C.
25
25
solid. Ϫ M.p. 139Ϫ142°C; ref.[18] 156Ϫ161°C. Ϫ [α]D ϭ ϩ21.7 Ϫ [α]D ϭ Ϫ9.0 (c ϭ 2.0, H2O). Ϫ 1H NMR (D2O): δ ϭ 1.86 (m,
Eur. J. Org. Chem. 2000, 199Ϫ204
201

K. Burger, J. Spengler
FULL PAPER
25
2 H, CH2CH), 2.14 (m, 5 H, CH2CO2H, CH3), 2.82 (dd, 1 H, J ϭ
13.8 Hz, 10.4 Hz, CH2Ph), 3.22 (dd, 1 H, J ϭ 14.2 Hz, 5.4 Hz,
of 3a gave 0.78 g (65%) of 7a. Ϫ M.p. 149Ϫ150°C. Ϫ [α]D ϭ ϩ
66.0 (c ϭ 1.0, CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 1.51 (d, 3 H, J ϭ
CH2Ph), 3.63 (s, 3 H, OCH3), 3.85 (m, 1 H, CHGlu), 4.73 (dd, 1 H, 8.8 Hz, CHCH3), 2.60 (q, 3 H, J ϭ 2.2 Hz, CH3), 2.47 (dd, 1 H,
J ϭ 10.6 Hz, 5.2 Hz, CHPhe), 7.13Ϫ7.22 (m, 5 H, phenyl). Ϫ 13C J ϭ 15.2 Hz, 6.4 Hz, CH2CH), 2.73 (dd, 1 H, J ϭ 15.4 Hz, 4.8 Hz,
NMR (D2O): δ ϭ 27.1 (CH2CH), 31.7 (CH2CO2H), 33.0 (CH3), CH2CH), 4.15 (t, 1 H, J ϭ 5.6 Hz, CH), 5.12 (m, 1 H, CHCH3),
36.8 (CH2Ph), 53.4 (OCH3), 54.4 (CHPhe), 61.8 (CHGlu), 127.7, 6.00 (br., 1 H, NH), 7.32 (m, 5 H, phenyl). Ϫ 13C NMR (CDCl3):
129.3, 129.6, 136.9 (phenyl), 168.7, 173.2, 180.7 (3 ϫ CO). Ϫ MS
δ ϭ 21.9 (CHCH3), 33.6 (br., CH3), 38.8 (CH2CH), 49.8 (CHCH3),
58.0 (CH), 90.1 [m, C(CF3)2], 120.9 (q, J ϭ 287 Hz, CF3), 121.9
(FAB), m/z (%): 344.9 [M ϩ Na]ϩ, 323.0 [M ϩ H]ϩ. Ϫ C16H22N2O5
(322.4): calcd. with 3/4 H2O C 57.21, H 7.13, N 8.34; found C 57.08, (q, J ϭ 295 Hz, CF3), 126.6, 128.1, 129.3 and 143.1 (phenyl), 167.4
H 6.88, N 8.23.
Methyl -α-Methylaminoadipyl)-
pound 4c (0.63 g, 2 mmol) gave 0.45 g (68%) of 6c. Ϫ M.p.
(CO), 170.2 (CONH). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ1.13 (m, 3 F,
CF3), 4.39 (m, 3 F, CF3). Ϫ IR (KBr): ν˜ ϭ 1848 cmϪ1 (COlactone),
1649 (COamide). Ϫ MS (EI), m/z (%): 398 [M]ϩ (5), 294 (11), 250
(13), 105 (100). Ϫ C16H16F6N2O3 (398.3): calcd. C 48.25, H 4.05,
N 7.03; found C 47.96, H 4.04, N 6.82.
(L
L-phenylalaninate (6c): Com-
25
1
150Ϫ152°C. Ϫ [α]D ϭ Ϫ7.5 (c ϭ 2.0, H2O). Ϫ H NMR (D2O):
δ ϭ 1.52 (m, 2 H, CH2), 1.75 (m, 2 H, CH2CH), 2.04 (t, 2 H, J ϭ
6.6 Hz, CH2CO2H), 2.21 (s, 3 H, CH3), 2.95 (dd, 1 H, J ϭ 14.0,
11.0 Hz, CH2Ph), 3.30 (dd, 1H, J ϭ 13.6, 5.0 Hz, CH2Ph), 3.67 (m,
1 H, CH), 3.73 (s, 3 H, OCH3), 4.85 (m, 1 H, CHPhe), 7.21Ϫ7.40
(m, 5 H, phenyl). Ϫ 13C NMR (D2O): δ ϭ 23.7 (CH2), 32.9
(CH2CH), 34.1 (CH3), 39.2 (CH2CO2H), 39.4 (CH2Ph), 56.0
(OCH3), 56.9 (CHPhe), 64.3 (CH), 130.1, 131.7, 132.1, 139.4 (phe-
nyl), 171.0, 175.6, 184.7 (3 ϫ CO). Ϫ MS (FAB), m/z (%): 359.0
[M ϩ Na]ϩ, 337.0 [M ϩ H]ϩ. Ϫ C17H24N2O5 (336.4): calcd. with
1/3 H2O C 59.63, H 7.26, N 8.18; found C 59.57, H 7.09, N 8.05.
N-(D-α-Methylbenzyl)-3-[(4S)-3-methyl-5-oxo-2,2-bis(trifluoro-
methyl)-1,3-oxazolidin-4-yl]propionyl Amide (7b): Reaction of 3b
(0.98 g, 3 mmol) gave 0.8 g (65%) of 7b. Ϫ M.p. 52Ϫ54°C (n-hex-
25
1
ane). Ϫ [α]D ϭ ϩ 80.0 (c ϭ 1.0, CHCl3). Ϫ H NMR (CDCl3):
δ ϭ 1.49 (d, 3 H, J ϭ 7.0 Hz, CHCH3), 2.08Ϫ2.06 (m, 4 H,
CH2CH, CH2CO), 2.68 (q, 3 H, J ϭ 2.2 Hz, CH3), 3.68 (m, 1 H,
CH), 5.09 (m, 1 H, CHCH3), 5.68 (br., 1 H, NH), 7.21Ϫ7.30 (m,
5 H, phenyl). Ϫ 13C NMR (CDCl3): δ ϭ 22.1 (CHCH3), 24.5
(CH2CH), 29.8 (CH2CO), 32.1 (br., CH3), 49.4 (CHCH3), 59.8
(CH), 89.3 [m, C(CF3)2], 121.0 (q, J ϭ 287 Hz, CF3), 122.1 (q,
J ϭ 295 Hz, CF3), 126.6, 127.8, 129.1, 143.8 (phenyl), 170.3, 171.0
(2 ϫ CO). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ0.83 (m, 3 F, CF3),
4.40 (m, 3 F, CF3). Ϫ IR (KBr): ν˜ ϭ 1838 cmϪ1 (COlactone), 1641
Methyl
[L-N-Methyl-β-(D-α-methylbenzylamido)asparagyl]-L-phe-
nylalaninate (8a): The reaction of 7a (0.8 g, 2 mmol) gave 0.63 g
(76%) of 8a. Purification was performed by column chromatogra-
phy; Rf ϭ 0.35 (CHCl3/light petroleum ether/MeOH, 6:3:1). Ϫ M.p.
80Ϫ82°C. Ϫ 1H NMR (CDCl3): δ ϭ 1.40 (d, 3 H, J ϭ 6.9 Hz,
CHCH3), 2.21 (br., 1 H, NH), 2.25 (s, 3 H, CH3), 2.23 (m, 1 H,
CH2CH), 2.41 (m, 1 H, CH2CH), 2.94 (dd, 1 H, J ϭ 13.9, 7.2 Hz,
CH2Ph), 3.01 (dd, 1 H, J ϭ 13.8, 5.7 Hz, CH2Ph), 3.22 (m, 1 H,
CHAsp), 3.66 (s, 3 H, OCH3), 4.74 (m, 1 H, CHPhe), 5.00 (m, 1 H,
CHCH3), 6.69 (br., 1 H, NH), 7.03Ϫ7.65 (m, 10 H, 2 ϫ phenyl),
7.65 (br., 1 H, NH). Ϫ 13C NMR (CDCl3): δ ϭ 22.6 (CHCH3),
35.1 (CH3), 38.4 (CH2Asp and CH2Phe), 49.3 (CHCH3), 52.7
(OCH3), 53.4 (CHPhe), 62.3 (CHAsp), 126.6, 127.5, 127.7, 129.0,
129.1, 129.7, 135.5, 144.0 (2 ϫ phenyl), 170.6, 172.2, 173.7
(COamide).
Ϫ
MS (EI), m/z (%): 412 [M]ϩ (19), 342 (2),
306 (24). Ϫ C17H18F6N2O3 (412.3): calcd. C 49.53, H 4.40, N 6.80;
found C 49.13, H 4.47, N 6.56.
General Procedure (3 Ǟ 9): To a solution of diazomethane (8Ϫ10
equiv.) in ether (150 mL), oxazolidinone 3 (30 mmol in 50 mL of
Et2O) was added dropwise at 0°C with stirring. Stirring was con-
tinued until gas evolution ceased (ca. 1.5 h). The reaction mixture
was allowed to warm to room temperature and the volatiles were
removed in vacuo (caution must be taken for the diazomethane).
The residue was purified by kugelrohr distillation.
1
(3 ϫ CO). Ϫ C23H29N3O4 (411.5): calcd. with /2 H2O C 65.69, H
(4S)-4-(3-Diazo-2-oxopropyl)-3-methyl-2,2-bis(trifluoromethyl)-1,3-
oxazolidin-5-one (9a): Using the above procedure, 9.4 g (30 mmol)
of 3a gave 7.18 g (75%) of 9a. Ϫ M.p. 45Ϫ47°C. Ϫ B.p. 94Ϫ97°C
7.19, N 9.99; found C 65.59, H 7.21, N 9.60.
Methyl
[L-N-Methyl-γ-(D-α-methylbenzylamido)glutamyl]-L-phen-
25
(0.7 Torr). Ϫ [α]D ϭ ϩ1.7 (c ϭ 3.0, CHCl3). Ϫ 1H NMR
ylalaninate (8b): Similarly, 0.82 g (2 mmol) of 7b gave 0.41 g (48%)
25
of 8b. Ϫ M.p. 160Ϫ163°C. Ϫ [α]D ϭ ϩ 68.7 (c ϭ 1.0, CHCl3).
(CDCl3): δ ϭ 2.70 (q, 3 H, J ϭ 1.6 Hz, CH3), 2.78 (m, 2 H,
CH2CH), 4.16 (m, 1 H, CH), 5.35 (s, 1 H, CHϭN2). Ϫ 13C NMR
(CDCl3): δ ϭ 33.8 (br., CH3), 42.0 (CH2CH), 56.2 (CHϭN2), 57.3
(CH3), 90.1 [m, C(CF3)2], 120.9 (q, J ϭ 288 Hz, CF3), 121.9 (q,
J ϭ 295 Hz, CF3), 170.0 (CO), 189.3 (COCH2). Ϫ 19F NMR
(CDCl3): δ ϭ Ϫ1.07 (m, 3 F, CF3), 4.30 (m, 3 F, CF3). Ϫ IR (KBr):
ν˜ ϭ 2112 cmϪ1 (CN2), 1842 (COlactone), 1648 (COketone). Ϫ MS
Ϫ
1H NMR (CDCl3): δ ϭ 1.45 (d, 3 H, J ϭ 6.8 Hz, CHCH3),
1.65Ϫ1.92 (m, 4 H, CH2CH, CH2CO), 2.28 (s, 3 H, CH3), 2.95 (m,
2 H, CHGlu, CH2Ph), 3.23 (m, 1 H, CH2Ph), 3.75 (s, 3 H, OCH3),
4.90 (m, 1 H, CHPhe), 5.51 (m, 1 H, CHCH3), 6.30 (br., 1 H, NH),
7.10Ϫ7.35 (m, 10 H, 2 ϫ phenyl), 7.61 (br., 1 H, NH). Ϫ 13C NMR
(CDCl3): δ ϭ 22.2 (CHCH3), 30.0 (CH2CH), 33.0 (CH2CO), 35.6
(CH3), 38.5 (CH2Ph), 49.1 (CHCH3), 52.7 (OCH3), 52.9 (CHPhe),
64.4 (CHGlu), 126.7, 127.5, 127.8, 129.0, 129.1, 129.6, 136.8, 143.8
(2 ϫ phenyl), 172.0, 172.6, 174.0 (3 ϫ CO). Ϫ MS (FAB), m/z
(EI), m/z (%):249 [M
Ϫ
COCHN2]ϩ (64), 236 [M
Ϫ
CH2COCHN2]ϩ (16), 180 (53). Ϫ C9H7F6N3O3 (319.2): calcd. C
33.87, H 2.21; found C 33.79, H 2.27.
(%):448.3 [M ϩ Na]ϩ, 426.3 [M ϩ H]ϩ. Ϫ C24H31N3O4 (425.5):
1
(4S)-4-(4-Diazo-3-oxobutyl)-3-methyl-2,2-bis(trifluoromethyl)-1,3-
oxazolidin-5-one (9b): Similarly, 3b (9.83 g, 30 mmol) gave 9.0 g
(85%) of 9b. Ϫ B.p. 75Ϫ80°C (0.1 Torr); Rf ϭ 0.3 (light petroleum/
ethyl acetate, 3:1). Ϫ [α]D25 ϭ ϩ22.7 (c ϭ 1.5, CHCl3). Ϫ 1H NMR
(CDCl3): δ ϭ 2.18 (m, 2 H, CH2CH), 2.40 (m, 2 H, COCH2), 2.70
(q, 3 H, J ϭ 2.0 Hz, CH3), 3.67 (m, 1 H, CH), 5.25 (br., 1 H, CHϭ
N2). Ϫ 13C NMR (CDCl3): δ ϭ 23.7 (CH2CH), 33.2 (br., CH3),
34.5 (COCH2), 55.2 (CHϭN2), 59.8 (CH), 90.0 [m, C(CF3)2], 121.0
(q, J ϭ 288 Hz, CF3), 122.0 (q, J ϭ 295 Hz, CF3), 169.9 (CO), 193
(COCH2). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ0.95 (m, 3 F, CF3), 4.30
(m, 3 F, CF3). Ϫ IR (film): ν˜ ϭ 2109 cmϪ1 (CN2), 1837 (COlactone),
calcd. with
/ H2O C 67.03, H 7.38, N 9.77; found C 67.22, H
4
7.21, N 9.72.
General Procedure (3 Ǟ 7): To a solution of 3 (3 mmol) in dichloro-
methane (25 mL) -α-methylbenzylamine (0.36 g, 3 mmol) was ad-
ded slowly at 0°C with stirring. The mixture was allowed to warm
up to room temperature. The organic phase was washed with water
(3 ϫ 5 mL), dried (MgSO4), filtered, and concentrated. Recrystalli-
zation or flash chromatography gave pure compounds 7.
[(4S)-3-Methyl-5-oxo-2,2-bis(trifluoromethyl)-1,3-oxazolidin-4-yl]-
N-(
D-α-methylbenzyl)acetamide (7a): Reaction of 0.94 g (3 mmol)
202
Eur. J. Org. Chem. 2000, 199Ϫ204

N-Methylaspartic, N-Methylglutamic, and N-Methyl-α-aminoadipic Acid Derivatives
1645 (COketone). (100). Ϫ C16H12F6N2O2S (410.3): calcd. C 46.83, H 2.94, N 6.83;
MS (EI), m/z (%): 333 [M]ϩ (5).
FULL PAPER
Ϫ
Ϫ
C10H9F6N3O3 (333.2): calcd. C 36.05, H 2.72; found C 35.77, H found C 46.83, H 2.65, N 6.77.
2.69.
(4S)-3-Methyl-4-[2-(2-phenyl-1,3-thiazol-4-yl)ethyl]-2,2-bis-
General Procedure (9 Ǟ 10): To a solution of diazo ketone 9
(15 mmol) in THF (40 mL) concd. HBr (10 mL) was added at 0°C,
stirring was continued until gas evolution ceased. The mixture was
concentrated and the residue dissolved in dichloromethane
(50 mL), washed with ice-cold NaHCO3 solution (3 ϫ 5 mL) and
water (3 ϫ 5 mL), dried (MgSO4), filtered, and concentrated.
Recrystallization or flash chromatography gave pure compounds
10.
(trifluoromethyl)-1,3-oxazolidine-5-one (11b): Reaction of 10b
(1.16 g, 3 mmol) gave 0.94 g (74%) of 11b. Ϫ M.p. 90°C; Rf ϭ 0.45
25
(light petroleum/ethyl acetate, 4:1). Ϫ [α]D ϭ ϩ41.0 (c ϭ 3.0,
1
CHCl3). Ϫ H NMR (CDCl3): δ ϭ 2.32 (m, 2 H, CH2CH), 2.74
(q, 3 H, J ϭ 2.2 Hz, CH3), 2.78 (m, 1 H, CH2CH2CH), 3.02 (m, 1
H, CH2CH2CH), 3.73 (m, 1 H, CH), 6.94 (s, 1 H, SϪCHϭC), 7.44
(m, 3 H, phenyl), 7.93 (m, 2 H, phenyl). Ϫ 13C NMR (CDCl3): δ ϭ
25.9 (CH2CH), 29.0 (CH2CH2CH), 33.3 (br., CH3), 60.1 (CH), 90.0
[m, C(CF3)2], 114.3 (SϪCHϭC), 121.1 (q, J ϭ 285 Hz, CF3), 122.2
(q, J ϭ 294 Hz, CF3), 126.9, 129.4, 130.4, 134.2 (phenyl), 156.7
(SϪCHϭC), 168.5, 170.0 [C(Ph), CO]. Ϫ 19F NMR (CDCl3): δ ϭ
Ϫ0.73 (m, 3 F, CF3), 4.40 (m, 3 F, CF3). Ϫ IR (KBr): ν˜ ϭ 1837
cmϪ1 (CO). Ϫ MS (EI), m/z (%): 424 [M]ϩ (12), 175 (100). Ϫ
C17H14F6N2O2S (424.4): calcd. C 48.12, H 3.33, N 6.60; found C
48.01, H 3.33, N 6.27.
(4S)-4-(3-Bromo-2-oxopropyl)-3-methyl-2,2-bis(trifluoromethyl)-1,3-
oxazolidin-5-one (10a): Reaction of 9a (4.79 g, 15 mmol) gave 4.24 g
(76%) of 10a. Ϫ M.p. 62Ϫ63°C (n-hexane/chloroform). Ϫ [α]D25 ϭ
1
ϩ25.7 (c ϭ 3.0, CHCl3). Ϫ H NMR (CDCl3): δ ϭ 2.69 (q, 3 H,
J ϭ 2.0 Hz, CH3), 3.06 (dd, 1 H, J ϭ 18.4 Hz, 5.4 Hz, CH2CH),
3.31 (dd, 1 H, J ϭ 18.4 Hz, 4.4 Hz, CH2CH), 3.91 (s, 2 H, CH2Br),
4.07 (t, 1 H, J ϭ 4.6 Hz, CH). Ϫ 13C NMR (CDCl3): δ ϭ 33.8 (br.,
CH3), 34.1 (CH2Br), 40.8 (CH2CH), 56.9 (CH), 89.9 [m, C(CF3)2],
120.8 (q, J ϭ 288 Hz, CF3), 121.8 (q, J ϭ 296 Hz, CF3), 169.8
(CO), 197.8 (COCH2). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ0.85 (m, 3 F,
CF3), 4.38 (m, 3 F, CF3). Ϫ IR (KBr): ν˜ ϭ 1834 cmϪ1 (COlactone),
1747 (COketone). Ϫ MS (EI), m/z (%):373 and 371 [M]ϩ (3), 292
(100), 236 (10). Ϫ C9H8BrF6NO3 (372.1): calcd. C 29.05, H 2.17,
N 3.76; found C 29.40, H 2.22, N 3.69.
4-[(4S)-3-Methyl-5-oxo-2,2-bis(trifluoromethyl)-1,3-oxazolidin-4-yl]-
butyric Acid (4c): Diazo ketone 9b (3.33 g, 10 mmol) was dissolved
in THF/H2O (15 mL/5 mL). On addition of silver benzoate (0.23 g,
1 mmol) the mixture became muddy brown. On sonication using
an ultrasound cleaning bath, gas evolution increased. The progress
of the reaction was monitored by TLC. In case the reaction ceased
before complete consumption of the starting material, further silver
benzoate was added. After complete consumption of the starting
material, the mixture was concentrated, dissolved in dichlorometh-
ane (50 mL), filtered, washed (3 ϫ 10 mL of H2O), dried (MgSO4),
and purified by flash chromatography. Compound 4c (1.78 g, 55%)
was obtained as a colourless oil. Ϫ Rf ϭ 0.1Ϫ0.4 (ethyl acetate/
(4S)-4-(4-Bromo-3-oxobutyl)-3-methyl-2,2-bis(trifluoromethyl)-1,3-
oxazolidin-5-one (10b): Reaction of 9b (5.0 g, 15 mmol) gave 4.69 g
(81%) of 10b as an oil. Ϫ Rf ϭ 0.4 (light petroleum/ethyl acetate,
25
4:1). Ϫ [α]D ϭ ϩ17.6 (c ϭ 4.5, CHCl3). Ϫ 1H NMR (CDCl3):
δ
ϭ 2.19 (m, 2 H, CH2CH), 2.67Ϫ2.82 (m, 5 H, CH3,
25
light petroleum ether/1% HOAc, 2:3). Ϫ [α]D ϭ ϩ29.3 (c ϭ 2.5,
CH2CH2CO), 3.68 (m, 1 H, CH), 3.90 (s, 2 H, CH2Br). Ϫ 13C
NMR (CDCl3): δ ϭ 22.9 (CH2CH), 33.3 (br., CH3), 33.8 (CH2Br),
34.3 (CH2CH2CO), 59.7 (CH), 89.9 [m, C(CF3)2], 120.9 (q, J ϭ
286 Hz, CF3), 122.0 (q, J ϭ 295 Hz, CF3), 169.7 (CO), 200.9
(CH2CO). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ0.84 (m, 3 F, CF3),
4.43 (m, 3 F, CF3). Ϫ IR (film): ν˜ ϭ 1837 cmϪ1 (COlactone), 1722
(COketone). Ϫ MS (EI), m/z (%): 387 and 385 [M]ϩ (7), 306 (86),
128 (100). Ϫ C10H10BrF6NO3 (386.1): calcd. C 31.11, H 2.61,
N 3.63; found C 31.30, H 2.52, N 3.88.
CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 1.49 (m, 1 H, CH2CH2CH),
1.80Ϫ1.94 (m, 3 H, CH2CH2CH, CH2CH), 2.39 (m, 2 H,
CH2CO2H), 2.71 (q, J ϭ 2.0 Hz, CH3), 3.64 (m, 1 H, CH). Ϫ 13C
NMR (CDCl3): δ ϭ 18.6 (CH2CH2CH), 28.1 (CH2CH), 33.1 (br.,
CH3), 33.6 (CH2CO2H), 60.4 (CH), 89.9 [m, C(CF3)2], 121.1 (q,
J ϭ 287 Hz, CF3), 122.2 (q, J ϭ 295 Hz, CF3), 169.9 (CO), 179.8
(CO2H). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ0.73 (m, 3 F, CF3), 4.36 (m,
3 F, CF3). Ϫ IR (KBr): ν˜ ϭ 1839 cmϪ1 (COlactone), 1714 (CO2H).
Ϫ MS (EI), m/z (%): 323 [M]ϩ (7), 305 (29), 249 (100). Ϫ
C10H11F6NO4 (323.2): calcd. C 37.16, H 3.43, N 4.33; found C
37.17, H 3.71, N 4.47.
General Procedure (10 Ǟ 11): A solution of bromo ketone 10
(3 mmol) and thiobenzamide (0.49 g, 3.6 mmol) in acetone (10 mL)
was heated under reflux for 3 h. The clear solution was stirred for
12 h at room temperature. After concentration, the residue was sus-
pended in an ice-cold concd. aqueous solution of NaHCO3 (3 mL)
and extracted with ether (20 mL). The organic layer was washed
(2 ϫ 5 mL of NaHCO3 half-concd., 2 ϫ 5 mL of H2O), dried
(MgSO4), and concentrated. Recrystallization or flash chromatog-
raphy gave pure compounds 11.
Acknowledgments
This work was supported by the Hermann-Schlosser-Stiftung, the
Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
Industrie.
(4S)-3-Methyl-4-[(2-phenyl-1,3-thiazol-4-yl)methyl]-2,2-bis-
(trifluoromethyl)-1,3-oxazolidin-5-one (11a): Reaction of 10a
(1.12 g, 3 mmol) gave 0.88 g (71%) of 11a as a yellowish oil. Ϫ Rf ϭ
[1] [1a]
[1b]
M. J. OЈDonnell, Tetrahedron 1988, 44, 5253Ϫ5614. Ϫ
[1c]
R. O. Duthaler, Tetrahedron 1994, 50, 1539Ϫ1550. Ϫ
R. M.
Williams in J. Baldwin, P. Magnus (Eds.), Organic Chemistry
Series, vol.7, Pergamon Press, Oxford, 1989.
25
0.42 (light petroleum/ethyl acetate, 4:1). Ϫ [α]D ϭ ϩ2.8 (c ϭ 2.5,
CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 2.81 (q, 3 H, J ϭ 2.0 Hz, CH3),
3.23 (dd, 1 H, J ϭ 14.8 Hz, 4.6 Hz, CH2CH), 3.35 (dd, 1 H, J ϭ
14.8 Hz, 5.2 Hz, CH2CH), 4.09 (t, 1 H, J ϭ 5.0 Hz, CH), 7.01 (s,
1 H, SϪCHϭC), 7.43 (m, 3 H, phenyl), 7.89 (m, 2 H, phenyl). Ϫ
13C NMR (CDCl3): δ ϭ 32.8 (CH2CH), 33.5 (br., CH3), 60.6 (CH),
89.9 [m, C(CF3)2], 116.6 (SϪCHϭC), 120.8 (q, J ϭ 286 Hz, CF3),
122.2 (q, J ϭ 296 Hz, CF3), 127.0, 129.5, 130.6, 134.0 (phenyl),
151.6 (SϪCHϭC), 168.7, 169.9 [C(Ph), CO]. Ϫ 19F NMR (CDCl3):
δ ϭ Ϫ1.13 (m, 3 F, CF3), 4.22 (m, 3 F, CF3). Ϫ IR (KBr): ν˜ ϭ
1840 cmϪ1 (CO). Ϫ MS (EI), m/z (%): 410 [M]ϩ (57), 395 (11), 174
[2]
[2a] J. Gante, Angew. Chem. Int. Ed. Engl. 1994, 33, 1699Ϫ1720;
[2b]
Angew. Chem. 1994, 106, 1780Ϫ1802. Ϫ
A. Giannis, T.
Kolter, Angew. Chem. Int. Ed. Engl. 1993, 32, 1244Ϫ1267; An-
gew. Chem. 1993, 105, 1303Ϫ1326. Ϫ [2c] C. Toniolo, Int. Peptide
[2d]
Protein Res. 1990, 35, 287Ϫ300. Ϫ
R. M. J. Liskamp, Recl.
Trav. Chim. Pays Bas 1994, 113, 1Ϫ19.
[3] [3a]
F. Balkenhohl, C. von dem Busche-Hünnefeld, A. Lansky,
C. Zechel, Angew. Chem. Int. Ed. Engl. 1996, 35, 2288Ϫ2337;
[3b]
Angew. Chem. 1996, 108, 2436Ϫ2488. Ϫ
see: Chem. Rev. 1997, 349Ϫ509.
For recent reviews
[4]
[4a] J. J. Chruma, D. Sames, R. Polt, Tetrahedron Lett. 1997, 38,
[4b]
5085Ϫ5086. Ϫ
R. M. Wenger, Helv. Chim. Acta 1984, 67,
Eur. J. Org. Chem. 2000, 199Ϫ204
203

K. Burger, J. Spengler
FULL PAPER
502Ϫ511. Ϫ [4c] G. R. Pettit, Y. Kamano, C. L. Herald, Y. Fujii,
H. Kizu, M. R. Boyd, F. E. Boettner, D. L. Doubek, J. M.
Schmidt, J. C. Chapuis, C. Michel, Tetrahedron 1993, 49,
9151Ϫ9170.
A. Golubev, N. Sewald, K. Burger, Tetrahedron Lett. 1993, 37,
5879Ϫ5880.
[9]
[10]
[11]
J. Spengler, K. Burger, Synthesis 1998, 67Ϫ70.
F. Weygand, H. J. Bestmann, E. Klieger, Chem. Ber. 1958, 91,
1037Ϫ1040.
[5] [5a]
A. W. Sangster, S. E. Thomas, N. L. Tingling, Tetrahedron
[5b]
[12]
[13]
[14]
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