Synthesis of derivatives of ω-isocyanato-α-methylamino, ω-ureido-α-methylamino, and Nα-methyl-α,ω-diamino acids

Article abstract of DOI:10.1007/PL00010315

Homochiral N^α-methyl-2,3-diaminopropionic and N^α-methyl-2,4-diaminobutyric acid derivatives 8a,b were obtained via a stereoconservative four-step synthesis starting from hexafluoroacetone protected L-aspartic and L-glutamic acid 2a,b, respectively. Hexafluoroacetone protected ω-isocyanato-α-methylamino acids 4a,b - the key intermediates of the synthesis - are versatile building blocks for amino acid and peptide modification and promising candidates for combinatorial chemistry. Upon reaction with alcohols, compounds 4 give activated N^ω-urethane protected ω-amino-α-methylamino acid derivatives 5-7; upon reaction with amines, ω-ureido-α-methylamino acid derivatives 10-12 and 3-methylamino-pyrrolidin-2-ones 13 are available.

Full text of DOI:10.1007/PL00010315

Monatshefte fuÈr Chemie 131, 463±473 (2000)
Synthesis of Derivatives of x-Isocyanato-
a-methylamino, x-Ureido-a-methylamino,
and Na-Methyl-a,x-diamino Acids
Klaus Burger1;Ã, Jan Spengler1, Lothar Hennig1, Rainer Herzschuh2,
and Samy A. Essawy3
1
Department of Organic Chemistry, University of Leipzig, D-04103 Leipzig, Germany
2
Department of Analytical Chemistry, University of Leipzig, D-04103 Leipzig, Germany
3
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
Summary. Homochiral Nꢀ-methyl-2,3-diaminopropionic and Nꢀ-methyl-2,4-diaminobutyric acid
derivatives 8a,b were obtained via a stereoconservative four-step synthesis starting from
hexa¯uoroacetone protected L-aspartic and L-glutamic acid 2a,b, respectively. Hexa¯uoroacetone
protected !-isocyanato-ꢀ-methylamino acids 4a,b ± the key intermediates of the synthesis ± are
versatile building blocks for amino acid and peptide modi®cation and promising candidates for
combinatorial chemistry. Upon reaction with alcohols, compounds 4 give activated N!-urethane
protected !-amino-ꢀ-methylamino acid derivatives 5±7; upon reaction with amines, !-ureido-ꢀ-
methylamino acid derivatives 10±12 and 3-methylamino-pyrrolidin-2-ones 13 are available.
Keywords. Hexa¯uoroacetone; !-Isocyanato-ꢀ-methylamino acid derivatives; Nꢀ-Methyl-2,3-dia-
minopropionic acid derivatives and homologues; !-Ureido-ꢀ-methylamino acids; 3-Methylamino-
pyrrolidin-2-ones.
Introduction
The development of new routes to homochiral non-proteinogenic and non-natural
amino acids is of current interest [1]. ꢀ-N-Methylamino acids, an interesting
subclass of ꢀ-amino acids, are constituents of various peptides and depsipeptides
isolated from plants, microorganisms, and marine species. Some of them exhibit
highly interesting biological properties [2]. Incorporation of ꢀ-N-methylamino
acids into key positions of peptides and depsipeptides should lead to enhanced
proteolytic stability and to an increase in lipophilicity. Furthermore, certain ꢀ-N-
methylamino acids themselves are biologically active compounds [3]. Conse-
quently, a number of synthetic routes to homochiral ꢀ-N-methylamino acids
already have been developed [4]. Especially multifunctional amino acids are
interesting candidates for templates to construct apeptidic bioactive compounds.
Ã
Corresponding author

464
K. Burger et al.
L-2,3-Diaminopropionic acid and its homologue L-2,4-diaminobutyric acid are
non-proteinogenic amino acids found in a variety of natural products [5].
Interestingly, the family of anti-methicillin resistant Staphylococcus aureus peptide
antibiotics TAN-1057 contains L-Nꢀ-methyl-2,3-diaminopropionic acid [6]. !-
Isocyanato- and !-ureido-ꢀ-methylamino acids and their derivatives are unknown
to the best of our knowledge.
Results and Discussion
Recently we have described a new protection/activation strategy for ꢀ-amino, ꢀ-
hydroxy, and ꢀ-mercapto acids using hexa¯uoroacetone. Hexa¯uoroacetone and ꢀ-
amino acids react to give 2,2-bis(tri¯uoromethyl)-1,3-oxazolidin-5-ones (1!2) in
high yield [7]. This heterocyclization process results in a simultaneous protection
of the ꢀ-amino group and the adjacent carboxylic group. Therefore, in the case of
!-carboxy-ꢀ-amino acids the ꢀ-carboxylic group is regioselectively activated
towards nucleophiles [8]. Since the !-carboxy group remains unaffected, the
method can be applied for regioselective ꢀ-functionalization of !-carboxy-ꢀ-
amino acids. On the other hand, the !-carboxy group can be selectively activated
by transformation into its acid chloride [9].
Furthermore, hexa¯uoroacetone protected ꢀ-amino acids are perfectly suited
for N-alkylation. They react in a three-component reaction with paraformaldehyde
and thionyl chloride exothermally ± without the need of a solvent ± to give N-
chloromethylamino acid derivatives which can be transformed into the correspond-
ing N-methylamino acid derivatives by treatment with triethylsilane/tri¯uoroacetic
acid in a one-pot procedure [10]. Recently, the N-methylation procedure was
successfully applied to !-carboxy-ꢀ-amino acids. Under the reaction conditions
used the !-carboxylic group is transformed into the acid chloride 3. Compounds
3a,b are distillable liquids and therefore easy to purify [11].
Heating of compounds 3 with trimethylsilyl azide results in the formation of
isocyanates 4. The latter are doubly activated derivatives of Nꢀ-methyl-ꢀ,!-diamino
acids. Generally, the isocyanate function is more reactive towards nucleophiles than the
lactone function. Consequently, compunds 4 can be regioselectively functionalized.
NMR investigations of 4a show the non-equivalence of the two geminal CF3
1
groups. In the H NMR spectrum, the NCH3 group furnishes a quartet (J ˆ 2 Hz)
caused by a ®ve-bond coupling with one of the CF3 groups. This coupling
manifests itself in the 19F NMR spectrum as a broad quartet at 4.28 ppm, whereas
the quartet at 0.57 ppm consists of sharp lines. The 13C NMR spectrum gives a
broad singlet for the NCH3 group at 32.85 ppm and two quartets (120.83 ppm
1
1
ꢀ JC;F ˆ 287 Hz†; 121.98 ppm ꢀ JC;F ˆ 295 Hz†† for the geminal pair of CF3
groups. All four lines of the ®rst quartet are additionally split into quartets with a
very small coupling constant. Remarkably, the signal for the quarternary carbon
atom connected to both CF3 groups at 89.92 ppm is split into a septet. It represents
an AB3C3 spin system with different coupling constants ꢀJAB ˆ 32:8 Hz;
JA;C ˆ 30:1 Hz† as could be veri®ed by spin simulation.
Heating compounds 4 with equimolar amounts of 9-¯uorenyl methanol, tert
butanol, or benzyl alcohol in chloroform gives the N!-Fmoc, N!-Boc, and N!-Z
protected carboxy group activated derivatives 5±7 of !-amino-ꢀ-methylamino

Synthesis of Derivatives of Non-Proteinogenic Amino Acids
465
Scheme 1
Scheme 2

466
K. Burger et al.
acids, respectively. Subsequent lactone ring opening by nucleophiles like amino
acid amides provides a simple preparative access to N-protected dipeptide
derivatives of type 8. The amide bond formation is connected with deprotection of
the methylamino group which can be further functionalized.
When the !-amino group of 7b is deblocked hydrogenolytically, a spontaneous
intramolecular aminolytic ring cleavage takes place to give 3(S)-3-methylamino-
pyrrolidin-2-one. The compound is obtained analytically pure as its hydrochloride 9.
Scheme 3

Synthesis of Derivatives of Non-Proteinogenic Amino Acids
467
Scheme 4
The structural relationship of 9 with 3(S)-3-hydroxypyrrolidin-2-one, a biological
active compound which seems to promote the process of human learning [12], is
obvious. Compound 9 represents an ꢀ-methylamino GABA derivative.
Isocyanates 4 and sec. amines like morpholine react regioselectively to give !-
ureido-ꢀ-methylamino acid derivatives 10a,b which are carboxyl group activated
species. Therefore, they can be further functionalized by reaction with nucleophiles
(10a!11).
Likewise, the primary amine D-ꢀ-methylbenzylamine adds to the isocyanate
4a to give the ureido substituted ꢀ-methylamino acid derivative 12 with an
unaffected lactone moiety. In contrast, the adduct ®rst formed from benzylamine
and 4b spontaneously undergoes an intramolecular aminolytical lactone ring
opening ± similar to reaction 7b!9 ± to give compound 13.
The mass spectrum of compound 13 shows a fragmentation pattern similar to
‡
pyrrolidin-2-one 9. The fragment ion [M-29] is the result of a McLafferty-type
elimination of [H2C ˆ NH] from the exocyclic methylamino group and is
inconsistent with structure 14. The fragement ions m/z ˆ 106 and 113 caused
by ꢀ-cleavage from the molecular ion can only be explained convincingly with
structure 13. Thus, the alternative structures 14 and 15 can be ruled out.
Compound 13 is a new chiral member of the family of acylureas, some of which
exhibit powerful insectizidal properties [13]. The reaction 4b!13 is an interesting
alternative approach to this class of compounds. All synthetic steps described in this
paper proceed stereoconservatively as shown by NMR experiments. Starting from
D-aspartic and D-glutamic acid, the corresponding multifunctional N-methylamino
acids of the D-series become available by the new strategy.
Experimental
Solvents were puri®ed and dried prior to use. Reagents were used as purchased. Thin layer
chromatography (TLC) was performed on alumina plates coated with Merck silica gel 60 F254
.
Compounds were visualized by spraying with ceric ammonium nitrate in 9 M H2SO4 followed by
heating to 100ꢁC. Column chromatography was carried out on silica gel (32±63 mm, ICN
Biomedicals). Melting points were determined with a Boetius heating table. Optical rotation indices
[ꢀ]D were measured with a Polartronic polarimeter (Schmidt & Haensch) in a 5 cm cell. For C, H, N

468
K. Burger et al.
analyses a CHNO-Rapid-Elemental-Analyser (Hereaus) was used. The experimental values agreed
satisfactorily with the calculated ones. Mass spectra were recorded on a VG 12-250 (Masslab)
electron ionization spectrometer (EI ˆ 70 eV) or by a VG ZAB-HSQ FAB spectrometer. IR spectra
1
were obtained using an FTIR spectrometer (Genesis ATI Mattson). H (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. Internal TMS was used as reference for 1H
and 13C NMR spectra, external tri¯uoroacetic acid for 19F NMR spectra. Starting materials (2, 3)
were prepared according to Refs. [8, 11]. Abbreviations used: DAP ˆ L-2,3-diaminopropionic acid,
DAB ˆ L-2,4-diaminobutyric acid.
3!4 (General procedure)
To a solution of acid chloride 3 (20 mmol) in toluene (25 cm3), a solution of trimethylsilyl azide
(2.9 g, 25 mmol) in toluene (25 cm3) was added dropwise and stirred at 80ꢁC for several hours until
the N2 evolution ceased. After removal of the solvent the residue was distilled.
(4S)-4-Isocyanatomethyl-3-methyl-2,2-bis(tri¯uoromethyl)-1,3-oxazolidin-5-one (4a; C8H6F6N2O3)
6.27 g (20 mmol) 3a gave 4.79 g (82%) 4a. M.p.: ꢂr.t.; b.p.: ꢂ60ꢁC (0.1 mm Hg, Kugelrohr);
[ꢀ]2D5 ˆ ‡8:7ꢁ (c ˆ 6.0, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 2.76 (q, J ˆ 2.0 Hz, 3H, CH3), 3.57 (dd, 3J
2
3
2
ˆ 2.3 Hz, J ˆ 13.9 Hz, 1H, CH2), 3.68 (m, 1H, CH), 3.79 (dd, J ˆ 3.5 Hz, J ˆ 13.9 Hz, 1H,
CH2) ppm; 13C NMR (CDCl3): ꢁ ˆ 32.85 (br, (CH3), 41.08 (CH2), 61.25 (CH), 89.92 (m, JC;F
ˆ
2
2
1
1
32.8 Hz, JC;F ˆ 30.1 Hz, C(CF3)2), 120.83 (qq, JC;F ˆ 287 Hz, CF3), 121.98 (q, JC;F ˆ 295 Hz,
CF3), 125.05 (NCO), 167.76 (CO) ppm; 19F NMR (CDCl3): ꢁ ˆ 0.57 (q, J ˆ 8.1 Hz, 3F, CF3),
4.28 (br q, J ˆ 8.1 Hz, 3F, CF3), ppm; IR (®lm): ꢂ = 2279 (NCO), 1842 (COlactone) cm 1; MS (EI):
‡
m/z (%) ˆ 292 [M] (5), 236 (57), 195 (4).
(4S)-4-(2-Isocyanatoethyl)-3-methyl-2,2-bis(tri¯uoromethyl)-1,3-oxazolidin-5-one
(4b; C9H8F6N2O3)
6.55 g (20 mmol) 3b gave 5.27 g (86%) 4b. M.p.: 22±24ꢁC; b.p.: ꢂ70ꢁC (0.1 mm Hg, Kugelrohr);
1
[ꢀ]2D5 ˆ ‡52.0ꢁ (c ˆ 1.0, CHCl3); H NMR (CDCl3): ꢁ ˆ 2.08 (m, 1H, CH2CH), 2.16 (m, 1H,
CH2CH), 2.75 (q, J ˆ 1.9 Hz, 3H, CH3), 3.53 (m, 2H, NCH2), 3.69 (m, 1H, CH) ppm; 13C NMR
(CDCl3): ꢁ ˆ 29.8 (CH2CH), 32.7 (br, CH3), 37.5 (NCH2), 57.8 (CH), 89.5 (m, C(CF3)2), 120.5 (q,
J ˆ 289 Hz, CF3), 121.6 (q, J ˆ 295 Hz, CF3), 122.3 (NCO), 169.1 (CO) ppm; 19F NMR (CDCl3): ꢁ
ˆ
0.99 (q, J ˆ 8.3 Hz, 3F, CF3), 4.40 (br q, J ˆ 8.3 Hz, 3F, CF3) ppm; IR (®lm): ꢂ ˆ 2277
‡
(NCO), 1840 (COlactone) cm 1; MS (EI): m/z (%) ˆ 306 [M] (4), 263 (8), 237 (11).
4!5, 6, 7 (General procedure)
A mixture of 4 (9 mmol) and the corresponding alcohol (for 5: 9-¯uorenyl methanol (1.67 g,
8.5 mmol), for 6: tert. butanol (0.63 g, 8.5 mmol), for 7: benzyl alcohol (0.92 g, 8.5 mmol)) in CHCl3
was stirred under re¯ux for 40 h. After removal of the solvent and the unreacted starting material in
vacuo the residue was puri®ed by ¯ash chromatography.
(4S)-4-(9-Fluorenylmethoxycarbonylamino)methyl-3-methyl-2,2-bis(tri¯uoromethyl)-
1,3-oxazolidin-5-one (5a; C22H18F6N2O4)
2.65 g (9 mmol) 4a gave 3.57 g (86%) 5a. Oil; Rf ˆ 0.3 (light petroleum/ethyl acetate ˆ 2:1); [ꢀ]D25
1
ˆ ‡21.6ꢁ (c ˆ 2.5, CHCl3); H NMR (CDCl3): ꢁ ˆ 2.82 (br, 3H, CH3), 3.62 (m, 3H, CHN,

Synthesis of Derivatives of Non-Proteinogenic Amino Acids
469
CH2N), 4.19 (m, 1H, CHCH2O), 4.40 (m, 2H, CH2O), 5.07 (br, 1H, NH), 7.26±7.81 (8H,
¯uorenyl) ppm; 13C NMR (CDCl3): ꢁ ˆ 33.4 (br, CH3), 39.5 (CH2N), 47.6 (CHCH2O), 61.5 (CHN),
67.7 (CH2O), 90.1 (m, C(CF3)2), 120.9 (q, J ˆ 287 Hz, CF3), 122.0 (q, J ˆ 295 Hz, CF3), 120.5,
125.5, 127.6, 128.2, 141.8, 144.1 (¯uorenyl), 157.0 (CONH), 169.22 (CO) ppm; 19F NMR (CDCl3):
ꢁ ˆ 0.94 (q, J ˆ 8.2 Hz, 3F, CF3), 4.14 (br q, J ˆ 8.2 Hz, 3F, CF3) ppm; IR (®lm): ꢂ ˆ 1838
‡
(COlactone), 1710 (COurethane) cm 1; MS (EI): m/z (%) ˆ 488 [M] (11), 178 (100).
(4S)-4-(2-(9-Fluorenylmethoxycarbonylamino)ethyl)-3-methyl-2,2-bis(tri¯uoromethyl)-
1,3-oxazolidin-5-one (5b; C23H20F6N2O4)
2.76 g (9 mmol) 4b gave 4.14 g (97%) 5b. M.p.: 86±88ꢁC; Rf ˆ 0.17 (ethyl acetate/light petroleum,
ˆ 1:3); [ꢀ]2D5 ˆ ‡28.0ꢁ (c ˆ 6.0, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 2.05 (br, 1H, CH2CH), 2.15 (m,
1H, CH2CH), 2.73 (m, 3H, CH3), 3.23 (m, 1H, NCH2), 3.41 (m, 1H, NCH2), 3.66 (m, 1H, CHN),
4.14 (m, 1H, CHCH2O), 4.42 (m, 2H, CHCH2O), 4.92 (br, 1H, NH), 7.27±7.80 (8H, ¯uorenyl) ppm;
13C NMR (CDCl3): ꢁ ˆ 29.0 (CH2CH), 33.3 (br, CH3), 36.5 (NCH2), 47.7 (CHCH2O), 59.0 (CHN),
67.3, (CHCH2O), 90.0 (m, C(CF3)2), 121.0 (q, J ˆ 287 Hz, CF3), 122.0 (q, J ˆ 295 Hz, CF3),
120.5, 125.5, 127.5, 128.2, 141.8, 144.3 (¯uorenyl), 156.8 (CONH), 169.9 (CO) ppm; 19F NMR
(CDCl3): ꢁ ˆ 0.83 (q, J ˆ 8.1 Hz, 3F, CF3), 4.45 (br q, J ˆ 8.1 Hz, 3F, CF3) ppm; IR (KBr): ꢂ ˆ
‡
1835 (COlactone), 1695 (COurethane) cm 1; MS (EI): m/z (%) ˆ 502 [M] (7).
(4S)-4-(tert. Butoxycarbonylamino)methyl-3-methyl-2,2-bis(tri¯uoromethyl)-1,3-oxazolidin-5-one
(6a; C12H16F6N2O4)
2.63 g (9 mmol) 4a gave 1.59 g (51%) 6a. M.p.: 97ꢁC; Rf ˆ 0.49 (light petroleum/ethyl acetate ˆ
3:1); [ꢀ]2D5 ˆ ‡8.3ꢁ (c ˆ 3.0, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 1.42 (s, 9H, C(CH3)3), 2.81 (q, J ˆ
2.0 Hz, 3H, NCH3), 3.52 (m, 2H, CH2), 3.61 (m, 1H, CH), 4.79 (br, 1H, NH) ppm; 13C NMR
(CDCl3): ꢁ ˆ 28.6 (C(CH3)3), 33.3 (br, NCH3), 38.8 (CH2), 61.8 (CH), 80.5 (C(CH3)3), 89.4 (m,
C(CF3)2), 120.9 (q, J ˆ 285 Hz, CF3), 121.9 (q, J ˆ 295 Hz, CF3), 156.3 (CONH), 169.4 (CO) ppm;
19F NMR (CDCl3): ꢁ ˆ 0.86 (q, J ˆ 8.1 Hz, 3F, CF3), 4.15 (br q, J ˆ 8.1 Hz, 3F, CF3) ppm; IR
‡
(KBr): ꢂ ˆ 1842 (COlactone), 1709 (COurethane) cm 1; MS (EI): m/z (%) ˆ 366 [M] (5), 293 (14),
237 (41), 168 (26), 57 (100).
(4S)-4-(2-(tert. Butoxycarbonylamino)ethyl)-3-methyl-2,2-bis(tri¯uoromethyl)-1,3-oxazolidin-5-one
(6b; C13H18F6N2O4)
2.76 g (9 mmol) 4b gave 2.42 g (75%) 6b. Oil; Rf ˆ 0.37 (ethyl acetate/light petroleum ˆ 1:3);
1
[ꢀ]2D5 ˆ ‡41ꢁ (c ˆ 4.0, CHCl3); H NMR (CDCl3): ꢁ ˆ 1.42 (s, 9H, C(CH3)3), 2.05 (m, 2H,
CHCH2), 2.72 (q, J ˆ 2.2 Hz, 3H, NCH3), 3.06 (m, 1H, NHCH2), 3.32 (m, 1H, NHCH2), 3.63 (m,
1H, CH), 4.67 (br, 1H, NH); 13C NMR (CDCl3): ꢁ ˆ 28.7 (C(CH3)3), 29.1 (CHCH2), 33.2 (br,
NCH3), 36.0 (NHCH2), 58.8 (CH), 80.1 (C(CH3)3), 89.5 (m, C(CF3)2), 121.0 (q, J ˆ 290 Hz, CF3),
122.2 (q, J ˆ 296 Hz, CF3), 156.4 (CONH), 170.0 (CO) ppm; 19F NMR (CDCl3): ꢁ ˆ 0.89 (q, J
ˆ 8.6 Hz, 3F, CF3), 4.38 (br q, J ˆ 8.6 Hz, 3F, CF3) ppm; IR (®lm): ꢂ ˆ 1840 (COlactone), 1696
(COurethane) cm 1; MS (EI): m/z (%) ˆ 324 (14), 307 (10), 280 (64).
(4S)-4-(Benzoxycarbonylaminomethyl)-3-methyl-2,2-bis(tri¯uoromethyl)-1,3-oxazolidin-5-one
(7a; C15H14F6N2O4)
2.63 g (9 mmol) 4a gave 2.93 g (86%) 7a. Needles; m.p.: 90±91ꢁC (n-hexane); Rf ˆ 0.4 (light
petroleum/ethyl acetate ˆ 2:1); [ꢀ]D25 ˆ ‡18.4ꢁ (c ˆ 2.5, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 2.80 (br,
3H, CH3), 3.60 (m, 3H, CH, CHCH2), 5.05 (m, 3H, NH, CH2O), 7.34 (m, 5H, arom.) ppm; 13C NMR

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K. Burger et al.
(CDCl3): ꢁ ˆ 33.3 (br, CH3), 39.3 (CHCH2), 61.6 (CH), 67.6 (CH2O), 90.0 (m, C(CF3)2), 120.9 (q,
J ˆ 287 Hz, CF3), 121.9 (q, J ˆ 295 Hz, CF3), 128.6, 128.8, 129.1, 136.6 (phenyl), 157.1 (CONH),
169.3 (CO) ppm; 19F NMR (CDCl3): ꢁ ˆ 0.98 (q, J ˆ 8.1 Hz, 3F, CF3), 4.14 (br q, J ˆ 8.1 Hz,
3F, CF3) ppm; IR (KBr): ꢂ ˆ 1838 (COlactone), 1699 (COurethane) cm 1; MS (EI): m/z (%) ˆ 400
‡
[M] (4), 309 (7), 236 (13), 91 (100).
(4S)-4-(2-(Benzoxycarbonylamino)ethyl)-3-methyl-2,2-bis(tri¯uoromethyl)-1,3-oxazolidin-5-one
(7b; C16H16F6N2O4)
2.76 g (9 mmol) 4b gave 3.24 g (92%) 7b. M.p.: 39±42ꢁC; Rf ˆ 0.27 (CHCl3); [ꢀ]D25 ˆ ‡28.0ꢁ (c
ˆ 1.0, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 2.05 (m, 1H, CHCH2), 2.15 (m, 1H, CHCH2), 2.73 (br, 3H,
CH3), 3.21 (m, 1H, CH2NH), 3.41 (m, 1H, CH2NH), 3.66 (m, 1H, CH), 4.89 (br, 1H, NH), 5.11 (m,
2H, CH2O), 7.36 (m, 5H, phenyl) ppm; 13C NMR (CDCl3): ꢁ ˆ 28.7 (CHCH2), 32.6 (br, CH3), 36.0
(CH2NH), 58.3 (CH), 66.7 (CH2O), 89.5 (m, C(CF3)2), 120.6 (q, J ˆ 287 Hz, CF3), 121.7 (q, J ˆ
295 Hz, CF3), 127.9, 128.1, 128.4, 136.6 (phenyl), 156.6 (CONH), 169.5 (CO) ppm; 19F NMR
(CDCl3): ꢁ ˆ 0.86 (q, J ˆ 8.1 Hz, 3F, CF3), 4.43 (br q, J ˆ 8.1 Hz, 3F, CF3) ppm; IR (KBr): ꢂ ˆ
‡
1837 (COlactone), 1702 (COurethane) cm 1; MS (EI): m/z (%) ˆ 414 [M] (7).
5!8, 10a!11 (General procedure)
A mixture of compound 5 or 10a (0.5 mmol) and L-phenylalanine amide (0.16 g, 1.0 mmol) was
dissolved in a mixture of 2-propanol (2 cm3) and Et2O (2 cm3) and stirred for several days. After
consumption of the oxazolidinone (TLC control), the white precipitate was ®ltered off and washed
carefully with Et2O to give a white powder.
Nꢃ-(9-Fluorenylmethoxycarbonyl)-Nꢀ-methyl-L-2,3-diaminopropionyl-L-phenylalanine amide
(8a; C28H30N4O4)
1
0.98 g (2 mmol) 5a gave 0.58 g (60%) 8a. M.p.: 157±158ꢁC; [ꢀ]D25 ˆ ‡8.0ꢁ (c ˆ 1.0, DMSO); H
NMR (CD3OD): ꢁ ˆ 2.06 (s, 3H, CH3), 2.87 (m, 1H, CH2Phe), 3.02 (m, 1H, CH2DAP), 3.20 (m, 3H,
CHDAP, CH2DAP, CH2Phe), 4.19 (t, J ˆ 6.7 Hz, 1H, CHCH2), 4.35 (d J ˆ 6.6 Hz, 2H, CHCH2), 4.70
(m, 1H, CHPhe), 7.16±7.40 (m, 9H, arom.), 7.63 (m, 2H, arom.), 7.78 (m, 2H, arom.) ppm; 13C NMR
(DMSO-d6): ꢁ ˆ 34.3 (CH3), 38.2 (CH2Phe), 43.0 (CH2DAP), 47.0 (CHCH2O), 53.3 (CHPhe), 64.4
(CHDAP), 65.7 (CHCH2O), 120.4, 125.5, 126.5, 127.3, 127.9, 128.2, 129.5, 137.9, 141.0, 144.1
‡
(arom.), 156.6 (COurethane), 171.7, 173.1 (2  CO) ppm; MS (FAB): m/z ˆ 487.3 [M‡H] , 509.2
‡
[M‡Na] .
Nꢄ-(9-Fluorenylmethoxycarbonyl)-Nꢀ-methyl-L-2,4-diaminobutyryl-L-phenylalanine amide
(8b; C29H32N4O4)
1.05 g (2 mmol) 5b gave 0.55 g (55%) 8b. M.p.: 141±143ꢁC [ꢀ]D25 ˆ ‡16.3ꢁ (c ˆ 1.0, DMSO ‡ 5%
1
TFA); H NMR (DMSO-d6 ‡ 5% TFA): ꢁ ˆ (m, 2H, CHCH2DAB), 2.02 (s, 3H, CH3), 2.76 (m, 1H,
CH2Phe), 3.11 (m, 3H, CH2N, CH2Phe), 3.54 (m, 1H, CHDAB), 4.17 (m, 1H, CHCH2), 4.35 (m, 2H,
CHCH2), 4.72 (m, 1H, CHPhe), 7.05±7.35 (m, 9H, arom.), 7.59 (m, 2H, arom.), 7.78 (m, 2H,
arom) ppm; 13C NMR (DMSO-d6 ‡ 5% TFA): ꢁ ˆ 30.2 (CHCH2DAB), 30.6 (CH2N), 35.6 (CH3) 38.3
(CH2Phe), 46.9 (CHCH2O), 53.7 (CHPhe), 58.6 (CHDAB) 65.4 (CHCH2O), 119.5, 124.6, 126.1, 126.6,
127.2, 127.7, 128.9, 137.1, 140.7, 143.6 (arom.), 158.4 (COurethane), 166.1, 172.6 (2 Â CO) ppm; MS
‡
‡
(FAB): m/z ˆ 523 [M‡Na] , 501 [M‡H] .

Synthesis of Derivatives of Non-Proteinogenic Amino Acids
471
Nꢀ-Methyl-Nꢃ-(N-morpholinylcarbonyl)-L-2,3-diaminopropionyl-L-phenylalanine amide
(11, C18H27N5O4)
0.76 g (2 mmol) 10a gave 0.52 g (71%) 11. M.p.: 177±181ꢁC; [ꢀ]D25 ˆ ‡6.0ꢁ (c ˆ 1.0, DMSO); 1H
NMR (DMSO-d6): ꢁ ˆ 1.99 (s, 3H, CH3), 2.86 (m, 1H, CH2Phe), 3.04 (m, 3H, CH2DAP CH2Phe), 3.20
(t, J ˆ 5.0 Hz, 4H, CH2N), 3.34 (m, 1H, CHDAP), 3.50 (t, J ˆ 5.0 Hz, 4H, CH2O), 4.41 (m, 1H,
CHPhe), 6.44 (br, 1H, NH), 7.17 (m, 5H, phenyl), 7.99 (br, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢁ ˆ
35.2 (CH3), 38.6 (CH2Phe), 43.6 (CH2DAP), 44.6 (CH2N), 53.9 (CHPhe), 65.7 (CHDAP), 66.8 (CH2O),
127.2, 128.9, 130.2, 138.7 (phenyl), 158.7 (COurea), 172.9, 173.9 (2  CO) ppm; MS (FAB): m/z ˆ
‡
‡
400.0 [M‡Na] , 378.0 [M‡H] .
(3S)-3-Methylaminopyrrolidin-2-one hydrochloride (9; C5H10N2O x HCl)
A mixture of 0.83 g (2 mmol) 7b and 10% Pd/C (ca. 0.1 g) was stirred in 2-propanol under an
atmosphere of H2 overnight. The mixture was ®ltered to remove the catalyst, and the solvent was
evaporated. The residue was dissolved in 3 N HCl (3 cm3). After evaporation to dryness the residue
was stirred carefully with Et2O (5 cm3)/EtOH (0.5 cm3) for 12 h. Filtration and drying gave 0.21 g
(69%) 9 as a white solid.
M.p.: 259±262ꢁC (decomp.); [ꢀ]2D5
1
ˆ
34.4ꢁ (c ˆ 0.9, H2O); H NMR (D2O): ꢁ ˆ 2.05 (m,
1H, CH2CH), 2.51 (m, 1H, CH2CH), 2.65 (s, 3H, CH3), 3.31 (m, 2H, CH2N), 3.96 (m, 1H, CH) ppm;
13C NMR (D2O): ꢁ ˆ 24.2 (CH2CH), 31.3 (CH3), 39.7 (CH2N), 58.1 (CH), 172.8 (CO) ppm; IR
(KBr): ꢂ ˆ 1731 (CO) cm 1; MS (EI): m/z (%): 114 [M-HCl] (25), 85 [M-HCl-NH ˆ CH2]
‡
‡
‡
(100), 70 [C4H8N] (21).
4!10, 4a!12, 4b!13 (General procedure)
To a solution of 4 (2 mmol) in Et2O (2 cm3), a solution of the amine (morpholine: 0.17 g, 2 mmol;
benzyl amine: 0.21 g, 2 mmol; D-ꢀ-methyl benzylamine: 0.24 g, 2 mmol) in Et2O (2 cm3) was added
dropwise. After complete consumption of the starting material (TLC control) the volatiles were
evaporated in vacuo and the residue was puri®ed by ¯ash chromatography.
(4S)-3-Methyl-4-(N-morpholinylcarbonylaminomethyl)-2,2-bis(tri¯uoromethyl)-1,3-oxazolidin-
5-one (10a; C12H15F6N3O4)
1
0.58 g (2 mmol) 4a gave 0.48 g (64%) 10a. M.p.: 126ꢁC; [ꢀ]D25 ˆ ‡44.5ꢁ (c ˆ 4.0, CHCl3); H
NMR (CDCl3): ꢁ ˆ 2.81 (q, J ˆ 2.0 Hz, 3H, CH3), 3.32 (m, 4H, NCH2), 3.58 (m, 1H, CHCH2),
3.73 (m, 1H, CHCH2), 3.67 (m, 5H, OCH2, CH), 4.84 (br, 1H, NH) ppm; 13C NMR (CDCl3): ꢁ ˆ
33.4 (br, CH3), 39.1 (CHCH2), 44.2 (NCH2), 61.2 (OCH2), 66.8 (CH), 90.0 (m, C(CF3)2), 120.9 (q, J
ˆ 287 Hz CF3), 121.9 (q, J ˆ 295 Hz, CF3), 157.8 (CONH), 169.9 (CO) ppm; 19F NMR (CDCl3): ꢁ
ˆ
0.99 (q, J ˆ 8.1 Hz, 3F, CF3), 4.22 (br q, J ˆ 8.1 Hz, 3F, CF3) ppm; IR (KBr): ꢂ ˆ 1837
(COlactone), 1640s (COurea) cm 1; MS (EI): m/z (%) ˆ 379 [M]+ (18), 310 (5), 236 (7), 143 (56),
114 (100).
(4S)-3-Methyl-4-[2-(N-morpholinylcarbonylamino)ethyl]-2,2-bis(tri¯uoromethyl)-1,3-oxaxolidin-
5-one (10b; C13H17F6N3O4)
0.61 g (2 mmol) 4b gave 0.76 g (97%) 10b. Viscous oil; Rf ˆ 0.27 (ethyl acetate); [ꢀ]2D5 ˆ ‡38.0ꢁ
(c ˆ 4.0, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 2.06 (m, 1H, CHCH2), 2.19 (m, 1H, CHCH2), 2.73 (q, J
ˆ 2.0 Hz, 3H, CH3), 3.27 (m, 1H, NHCH2), 3.41 (m, 1H, NHCH2), 3.30 (m, 4H, NCH2), 3.66 (m,
5H, CH, OCH2), 4.60 (br, 1H, NH) ppm; 13C NMR (CDCl3): ꢁ ˆ 28.6 (CHCH2), 33.3 (br, CH3),

472
K. Burger et al.
36.3 (NHCH2), 44.3 (NCH2), 59.2 (CH), 66.9 (OCH2), 90.6 (m, C(CF3)2), 121.1 (q, J ˆ 287 Hz,
CF3), 122.1 (q, J ˆ 298 Hz, CF3), 158.0 (CONH), 170.5 (CO) ppm; 19F NMR (CDCl3): ꢁ ˆ 0.69
(q, J ˆ 8.1 Hz, 3F, CF3), 4.46 (br q, J ˆ 8.1 Hz, 3F, CF3) ppm; IR (®lm): ꢂ ˆ 1838 (COlactone),
‡
1632 (COurea) cm 1; MS (EI): m/z (%) ˆ 393 [M] (48).
(4S)-3-Methyl-4-(N-(D-ꢀ-methylbenzylamino)carbonylamino)methyl-2,2-bis(tri¯uoromethyl)-
1,3-oxazolidin-5-one (12; C16H17F6N3O3)
0.58 g (2 mmol) 4a gave 0.65 g (79%) 12. Oil; Rf ˆ 0.43 (ethyl acetate/light petroleum ˆ 1:1);
1
[ꢀ]2D5 ˆ ‡49.2ꢁ (c ˆ 5.0, CHCl3); H NMR (CDCl3): ꢁ ˆ 1.41 (br, J ˆ 6.8 Hz, 3H, CH3), 2.71
(br, 3H, NCH3), 3.52 (m, 3H, CH, CH2) 4.76 (br, 1H, NH), 5.13 (m, 1H, CHCH3), 5.25 (br, 1H, NH),
7.28 (m, 5H, phenyl) ppm; 13C NMR (CDCl3): ꢁ ˆ 23.0 (CH3), 32.8 (br, NCH3), 38.3 (CH2), 50.2
(CHCH3), 61.0 (CH), 89.5 (m, C(CF3)2), 120.5 (q, J ˆ 287 Hz, CF3), 121.5 (q, J ˆ 295 Hz, CF3),
125.8, 127.3, 128.7, 144.0 (phenyl), 157.5 (CONH), 169.5 (CO) ppm; 19F NMR (CDCl3): ꢁ ˆ
0.97 (q, J ˆ 8.1 Hz, 3F, CF3), 4.22 (br q, J ˆ 8.1 Hz, 3F, CF3) ppm; IR (®lm): ꢂ ˆ 1838
‡
(COlactone), 1638 (COurea) cm 1; MS (EI): m/z (%) ˆ 413 [M] (4).
(3S)-1-Benzylaminocarbonyl-3-methylaminopyrrolidin-2-one (13; C13H17N3O2)
0.61 g (2 mmol) 4b gave 0.42 g (85%) 13. Oil; Rf ˆ 0.67 (ethyl acetate); [ꢀ]D25
ˆ
16.3ꢁ (c ˆ 2.4,
1
CHCl3); H NMR (CDCl3): ꢁ ˆ 1.78 (m, 1H, CHCH2), 2.11 (br, 1H, NH), 2.27 (m, 1H, CHCH2),
2.44 (s, 3H, CH3), 3.49 (m, 2H, CH2N), 3.95 (m, 1H, CH), 4.47 (d ˆ 5.8 Hz, 2H, CH2Ph), 7.28 (m,
5H, phenyl), 8.66 (br, 1H, NH) ppm; 13C NMR (CDCl3): ꢁ ˆ 25.6 (CHCH2), 34.4 (CH3), 42.6
(CH2N), 44.2 (CH2Ph), 62.3 (CH), 127.9, 128.1, 129.1, 138.7 (phenyl), 153.2 (CONH), 176.9
‡
(CO) ppm; IR (®lm): ꢂ ˆ 1720 (COlactam), 1542 (COurea) cm 1; MS (EI): m/z (%) ˆ 247 [M] (18),
‡
‡
‡
218 [M-NH ˆ CH2] (25), 216 (28), 204 [M-CONH] (3), 133 [PhCH2NCO] (5), 113 [M-
‡
‡
‡
‡
CONHCH2Ph] (22), 106 [C6H5CHNH2] (16), 91 [C7H7] (69), 85 [C4H7NO] (25), 70
‡
[C4H8N] (85), 65 [C5H5] (18), 56 [C3H6N]6 (100).
‡
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft, the Hermann Schlosser Stiftung,
and the Fonds der Chemischen Industrie.
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Synthesis of Derivatives of Non-Proteinogenic Amino Acids
473
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È È
Lunkenheimer W (1977) In: BuÈchel KH (ed) P¯anzenschutz and Schadlingsbekampfung.
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Received November 17, 1999. Accepted November 26, 1999