Synthesis of new 1,2,4-oxadiazoles carrying (1'S,2'S)-t-butyloxycarbonyl-1-amino-2- methyl-1-butyl and (1'S)-t-butyloxycarbonyl-1'-amino-1'-ethyl groups at C-5

SHORT REPORT

Synthesis of new 1,2,4-oxadiazoles carrying (1'S,2'S)-t-butyloxycarbonyl-1-amino-2- methyl-1-butyl and (1'S)-t-butyloxycarbonyl-1'-amino-1'-ethyl groups at C-5

Vanildo Martins L. Braga^I; Sebastião J. de Melo^{I, *}; Rajendra M. Srivastava^II,*; Emerson Peter da S. Falcão^I

^IDepartamento de Antibióticos, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego s/n, Cidade Universitária, 50670-901 Recife-PE, Brazil

^IIDepartamento de Química Fundamental, Universidade Federal de Pernambuco, Av. Prof. Luiz Freire, Cidade Universitária, 50740-540 Recife-PE, Brazil

ABSTRACT

A facile and efficient synthesis of 3-aryl-5-[(1S)-t-butyloxycarbonyl-1-amino-(2 S)-methyl-1-butyl)]-1,2,4-oxadiazoles 4a-f and 3-phenyl-5-[(1S)-t-butyloxycarbonyl-1-amino-1-ethyl]-1,2,4 -oxadiazole 6 starting from arylamidoximes, N-t-Boc-L-isoleucine and N-t- Boc-L-alanine is decribed. The structures of the intermediates and final compounds have been deduced from spectroscopic data.

Keywords: chiral drugs, 1,2,4-oxadiazoles, arylamidoximes, isoleucine, alanine, antiinflammatory, antipyretic

RESUMO

Uma síntese fácil e eficiente de 3-aril-5[(1S)-t-butiloxicarbonil-1-amino-( 2S)-metil-1-butil)]-1,2,4-oxadiazóis 4a-f e 3-fenil-5-[(1S)-t-butiloxicarbonil-1-amino-1-etil]-1,2,4-oxadiazol 6 partindo de arilamidoximas, N-t-Boc-L-isoleucina e N-t-Boc-L-alanina é descrita. As estruturasedos intermediários e compostos finais foram determinadas a partir dos dados espectroscópicos.

Introduction

It is known that stereoisomers of chiral drugs often exhibit pronounced differences in their pharmacokinetic and pharmacodynamic properties both in quantitative and qualitative terms.¹ So, it is extremely necessary to study each stereoisomer separately. With the correct therapeutic information it is possible to maximize the properties of the drug by taking the most potent enantiomer, the eutomer,² or eliminating the enantiomer that may cause side effects, the distomer. The latter can be linked to a secondary molecular target.³ The pharmaceutical market has converged strongly to this idea of single enantiomers as substitutes for their racemates. The change to chiral technologies offers many advantages to the pharmaceutical industry, including fewer toxicological tests, lower costs for liberation and less metabolites. These advantages are also beneficial for the patient's health.⁴ In the not too distant future, chiral drugs in single enantiomeric forms will probably substitute most of the existing racemates and will eventually touch every area of clinical medicine.⁷

Only in a few situations that are not common at all, it is more appropriate to use the racemate instead of the eutomer, for example with ibuprofen, a nonsteroidal antiinflammatory drug (NSAID) commercially available in the market. In this particular case, there is an enzymatic inversion of the R(-) distomer to the eutomer (S) responsible for the activity.⁵ In any event, it is a single enantiomer (S) which is important. However, in other NSAIDs such as flurbiprofen⁶ and ketoprofen,⁷ this inversion is insignificant in humans, and so the application of the chiral technology for the use of the eutomer is more appropriate.

In view of the great importance of single enantiomers, our current research is focused on synthesizing new 1,2,4-oxadiazoles containing asymmetric centers in their C-5 side chain. Our main goal was to synthesize compounds possessing an amino group in the C-5 side chain. It is well known that a tertiary amine function attached to the C-5 alkyl chain of 1,2,4-oxadiazoles possess antiinflammatory as well as other interesting pharmacological activities.^8,9 With this idea in mind, we synthesized seven Boc protected amines. In fact, two of these new compounds 4d and 4e showed antiinflammatory activity. These are very significant in the sense that they can be deprotected easily to remove the Boc group into N,N-dialkyl amino compounds. These compounds will be potential candidates for analgesic, antiinflammatory and antipyretic activity. Therefore, this communication describes some biologically active 1,2,4-oxadiazoles with one or two asymmetric centers in their side chain. Such compounds have not been cited in the literature before.

Results and Discussion

The strategy used to achieve our goals explored known protected amino acids as starting materials. We have already published one paper relating to the synthesis of 3-aryl-1,2,4-oxadiazoles carrying a protected L-alanine side chain, starting from arylamidoximes and protected aspartic acid,¹⁰ and it has been established that the products obtained from the condensation of arylamidoximes and an appropriately protected amino acid didn't lead to isomerization. Applying a similar strategy, but using Boc-protected L-isoleucine or L-alanine and arylamidoximes, we synthesized seven 1,2,4-oxadiazoles, six containing two asymmetric centers 4a-f and one oxadiazole having only one asymmetric center 6, as shown below (Scheme 1). Earlier, another group has observed that even in pyridine as reaction solvent, no significant racemization occurs in the case of 1,2,4-oxadiazoles having an asymmetric carbon attached to C-5.¹¹

Since the reaction conditions in the present work are mild and similar to the one reported earlier,¹⁰ it is assumed that no racemization occurred during the synthesis of these 1,2,4-oxadiazoles. This conclusion is supported by the ¹H NMR spectra, which showed the presence of only one H-3 absorption for 3a-f; had there been racemization, one would expect two diastereomers hence more than one absorption. The 300 MHz ¹H NMR spectra of compounds 3a-f showed a triplet at d 0.95 ppm and a doublet at d 1.02 ppm for the terminal and C-3 methyl groups. In compounds 4a-f, the doublet due to methyl group shifted to higher field and generally overlapped with the triplet of the other methyl group. This shift is attributed to the ring current effect causing C-3 methyl group signals to move upfield.

The mass analyses agreed with the proposed structures. However the compounds 4d, e and f, show a sequence of fragmentations which occurs during the decomposition of M^+•. These include the loss of t-butyloxide radical (73 mass units), the extrusion of carbon monoxide (28 mass units), rearrangement and finally the elimination of butene-2 molecule (56 mass units) to provide the major fragments a', at m/z 204 (4d), b' m/z 208 (4e) and c', m/z 219 for the compound 4f. These are depicted in Scheme 2.

The synthesis of compound 6 was carried out with the aim to shorten the side-chain containing the amino group and consequently reduce the lipophilicity.

Experimental

Melting points were determined with a Thomas Hoover apparatus and are uncorrected. Elemental analyses of compounds 4a-f were performed in the Central Analítica do Departamento de Química Fundamental da Universidade Federal de Pernambuco. Infrared spectra were recorded on a Bruker spectrophotometer Model IFS66. 300 MHz ¹H-NMR and 75 MHz ¹³C NMR spectra were recorded on a Varian Unity plus instrument, using CDCl₃ as solvent and TMS as internal reference. Thin-layer chromatography (tlc) was done on plates coated with silica gel having a fluorescent indicator P₂₅₄ (Merck) and the spots were detected under ultraviolet light. Arylamidoximes were obtained following the methodology reported in the literature.¹²

General Procedure for the Synthesis of O-[(2S, 3S)-2-t-Butyloxycarbonylamino-3-methylpentanoyl] arylamidoximes (3a-f). The appropriate arylamidoxime 1a-f (3.7 mmol) was allowed to react with N-t-Boc-L-isoleucine 2 (3.7 mmol) and N,N'-dicyclohexylcrbodiimide (4.1 mmol) in dry CH₂Cl₂ 10 mL under N₂ atmosphere at room temperature for periods varying from 3 to 5 hours. The completion of the reaction was monitored by TLC. Generally, the products were purified by column chromatography on silica gel using n-hexane-ethyl acetate (7.0:3.0) as eluent. The same solvent system was employed for developing the TLC plates. An ultraviolet lamp was used for the detection of the spots.

Data for O-[(2S, 3S)-2-t-butyloxycarbonylamino-3-methylpentanoyl]benzamidoxime (3a). White crystals (69% yield), mp 110-111 °C. IR (KBr) n_max/cm^-1: 3483 (nNH₂, asym); 3347 (nNH₂, sym; nNH); 2966(nC-H); 1740 (nCO_2-); 1688 (nNHCO₂); 1614 and 1519 (nC=C, ar); 1586 (nC=N) ; 1519 (nC=C band); 1172 (nC-O). ¹H NMR (CDCl₃) d: 0.95 (3H, t, J 7.5 Hz); 1.02 (3H, d, J 6.9 Hz); 1.44 (9H, s); 1.14-1.68 (2H, m); 1.84-2.00 (1H, m); 4.31 (1H, dd, J 8.7 Hz, J 6.3 Hz); 5.16 (1H, d, J 8.7 Hz); 5.37 (2H, bs); 7.35-7.52 (3H, m); 7.67-7.75 (2H, m). ¹³C NMR (CDCl₃): 11.4 (C-5); 15.3 (CH₃); 25.0 (C-4); 28.3 (CH₃)₃; 37.8 (C-3); 57.3 (C-2); 80.1 (C); 130.8 (C-1'); 128.1 (C-2' and C-6'); 128.7 (C-3' and C-5'); 131.1 (C-4'); 155.9 (C1"); 157.8 (CONH); 170.1 (C-1).

Data for O-[(2S, 3S)-2-t-butyloxycarbonylamino-3-methylpentanoyl]m-tolylamidoxime (3b). White crystals (73% yield, mp 118-119 °C. IR (KBr) n_max/cm^-1: 3494 (nNH₂, asym); 3343 (nNH₂, sym; nNH); 2967 (nC-H); 1742 (nCO₂); 1691 (nNHC0₂); 1621 and 1522 (nC=C , ar); 1587 (nC=N); 1168 (nC-O). ¹H NMR (CDCl₃) d: 0.93 (3H, t, J 7.4 Hz); 1.00 (3H, d, J 6.9 Hz); 1.43 (9H, s); 1.10-1.70 (2H, m); 1.82-2.00 (1H, m); 2.36(3H, s); 4.30 (1H, dd, J 6.0 Hz, J 8.7 Hz); 5.19 (1H, d, J 8.7 Hz); 5.29 (2H, bs); 7.62 (2H, d, J 9.3 Hz); 8.00 (2H, m). ¹³C NMR (CDCl₃): 11.4 (C-5); 15.5 (CH₃); 21.4 (Ar-CH₃); 25.0 (C-4); 28.3 (CH₃)₃; 37.6 (C-3); 57.5 (C-2); 80.0 (C); 123.8(C-6'); 127.6 (C-1'); 128.6 (C-2'); 130.2 (C-5'); 132.1 (C-4'); 138.6 (C-3'); 156.0 (C1"); 158.3 (CONH);170 (C-1).

Data for O-[(2S, 3S)-2-t-butyloxycarbonylamino-3-methylpentanoyl]p-tolylamidoxime (3c). White crystals (65% yield), mp 105-106 °C. IR (KBr) n_max/cm^-1 : 3500 (nNH_2, asym) 3358 (nNH₂, sym); 3333 (nNH); 2965 (nC-H); 1746(nCO₂); 1693 (nNHCO₂); 1614 and 1521(nC=C, ar); 1587(nC=N); 1175 (nC-O). ¹H NMR (CDCl₃) d: 0.94 (3H, t, J 7.4 Hz); 1.01 (3H, d, J 6.6 Hz); 1.44 (9H, s); 1.14-1.68 (2H, m); 1.82-2.00 (1H, m); 2.38 (3H, s); 4.30 (1H, dd, J 6.3 Hz, J 8.1 Hz); 5.21 (1H, d, J 8.4 Hz); 5.44 (2H, bs); 7.35 (2H, d, J 8.7 Hz); 7.61 (2H, d, J 8.4 Hz). ¹³C NMR (CDCl₃): 11.4 (C-5); 15.5 (CH₃); 21.2 (Ar-CH₃); 25.1 (C-4); 28.3 (CH₃)₃; 37.5 (C-3); 57.4 (C-2); 80.1 (C); 123.8 (C-1'); 127.4 (C-2' and C-6'); 129.5 (C-3' and C-5'); 141.5 (C-4'); 155.9 (C-1"); 158.3 (CONH); 170.0 (C-1).

Data for O-[(2S, 3S)-2-t-butyloxycarbonylamino-3-methylpentanoyl]p-anisylamidoxime (3d). Yellow crystals (80% yield), mp = 112-113 °C. IR (KBr) n_max/cm^-1: 3493 (n-NH₂, asym); 3344 (n-NH₂, sym; nNH); 2970 (nC-H); 1744 (n-CO₂); 1692 (n-NHC0₂);1615 and 1520 (nC=C, ar); 1565 (nC=N); 1165 (nC-O). ¹H NMR (CDCl₃) d 0.96 (3H, t, J 7.4 Hz,); 1.04 (3H, d, J 6.9 Hz); 1.45 (9H, s); 1.16-1.70 (2H, m); 1.86-2.00 (1H, m); 3.81 (3H, s); 4.30 (1H, dd, J 6.3 Hz, J 8.1 Hz); 5.13 (1H, d, J 8.4 Hz); 5.49 (2H, bs); 7.91 (2H, d, J 9.0 Hz); 8.27 (2H, d, J 9.0 Hz). ¹³C NMR (CDCl₃): 11.4 (C-5); 15.4 (CH₃); 25.1 (C-4); 28.3 (CH₃)₃; 37.5 (C-3); 57.4 (C-2); 55.3 (O-CH₃); 80.1 (C); 113.9 (C-3' and C-5'); 122.5 (C-1'); 128.4 (C-2' and C-6'); 155.9 (C-4'); 157.8 (C-1"); 161.9 (CONH); 170.1 (C-1).

Data for O-[(2S, 3S)-2-t-butyloxycarbonylamino-3-methylpentanoyl]p-chlorobenzamidoxime (3e). White crystals (80% yield), mp 114-115 °C. IR (KBr) n_max/cm^-1: 3500 (n-NH₂,asym); 3358 (nNH₂,sym); 3315 (n-NH); 2963 (nC-H); 1751 (nCO₂), 1692 (nNHCO₂); 1615 and 1522 (nC=C, ar); 1587 (nC=N); 1172 (nC-O). ¹H NMR (CDCl₃) d: 0.95 (3H, t, J 7.5 Hz); 1.02 (3H, d, J 6.9 Hz); 1.45 (9H, s); 1.16-1.70 (2H, m); 1.80-2.00 (1H, m); 4.32 (1H, dd, J 6.0 Hz, J 8.9 Hz); 5.13 (1H, d, J 8.7 Hz); 5.19 (2H, bs); 7.25 (2H, d, J 9 Hz); 7.60 (2H, d, J 8.1 Hz). ¹³C NMR (CDCl₃): 11.4 (C-5); 15.6 (CH₃); 25.1 (C-4); 28.4 (CH₃)₃; 37.6 (C-3); 57.5 (C-2); 80.2 (C); 128.3 (C-2' and C-6'); 128.9 (C-3' and C-5'); 129.2 (C-1'); 137.2 (C-4'); 155.1 (C-1"); 157.1 (CONH); 170.3 (C-1).

Data for O-[(2S, 3S)-2-t-butyloxycarbonylamino-3-methylpentanoyl]p-nitrobenzamidoxime (3f). White crystals (75% yield), mp 110-112 °C. IR (KBr) n_max/cm^-1: 3477 (nNH₂,asym); 3341 (n-NH₂,sym; nNH); 2967 (nC-H); 1755 (nCO2); 1691 (nNHC02); 1639 and 1522 (nC=C, ar); 1585 (nC=N); 1168 (nC-O). ¹H NMR (CDCl₃) d: 0.94 (3H, t, J 7.5 Hz); 1.02 (3H, d, J 6.9 Hz); 1.44 (9H, s); 1.10-1.76 (2H, m); 1.80-2.00 (1H, m); 4.31 (1H, dd, J 6.0 Hz, J 8.7 Hz); 5.15 (1H, d, J 9.0 Hz); 5.26 (2H, bs); 7.25-7.30 (2H, m); 7.40-7.50 (2H ,m). ¹³C NMR (CDCl₃): 11.3 (C-5); 15.5 (CH₃); 25.0 (C-4); 28.2 (CH₃)₃; 37.4 (C-3); 57.4 (C-2); 80.3 (C); 123.8 (C-3' and C-5'); 127.9 (C-2' and C-6'); 136.9 (C-1'); 149.3 (C-4'); 155.9 (C-1"); 156.1 (CONH);169.9 (C-1).

General Procedure for the Synthesis of 5-[(1'S, 2'S)-1-t-Butyloxycarbonylamino-2-methylbutyl)]-3-aryl-1,2,4 -oxadiazoles 4a-f and 5-[(2S)-1-t-Butyloxycarbonyl-1-aminoeth-1-yl ]-3-phenyl-1,2,4-oxadiazole (6)

The intermediates 3 were heated at temperatures that varied from 100 to 120 °C. The reactions were acompanied by TLC and discontinued when the TLC plate showed the disappearance of the starting compound, in three to five hours. In the case of the compound starting from N-t-Boc-L-alanine 5, it was not possible to isolate the intermediate. The compounds obtained 4a-f initially had a pasty appearance, but after some days in a dry atmosphere under vacum the compounds started to crystallize. Conversion of intermediates 3 a-f to 4 a-f were quantitative; however, the yields of the pure and crystalline products are given below.

Data for 5-[(1'S, 2'S)-1'-t-Butyloxycarbonylamino-2'-methylbutyl)]-3-phenyl-1,2,4-oxadiazole (4a). Colorless crystals (69% yield), mp 73.3-74.4 °C (ethanol-water). [a]_D²² -44° ± 6 (c = 0.005, CHCl₃). IR (KBr) n_max/cm^-1: 3356 (nNH); 2976 (nC-H); 1716 (nC=O); 1569 (nC=N); 1523 (nC=C, ar); 1160 (nC-O). ¹H NMR (CDCl₃) d: 0.95 (3H, t, J 7.2 Hz); 0.94 (3H, d, J 6.3 Hz); 1.46 (9H, s); 1.16-1.70 (2H, m); 1.94-2.12 (1H, m); 5.06 (1H, dd, J 5.7 Hz, J 8.7 Hz); 5.26 (1H, d, J 9.3 Hz); 7.40-7.56 (3H, m); 8.04-8.14 (2H, m). ¹³C NMR (CDCl₃): 11.4 (C-4'); 15.1 (CH₃); 25.0 (C-3'); 28.3 (CH₃)₃; 39.2 (C-2'); 52.6 (C-1'); 80.36 (C); 126.6 (C-1"); 127.5 (C-2" and C-6"); 128.8 (C-3" and C-5"); 131.2 (C-4"); 155.1 (C-3); 168.1 (C-5); 178.9 (CO). MS, m/z (%): 332 [MH⁺, 12%], 174 (69%), 146 (81%), 119 (100%), 104 (48%). Anal. Calc. for C₁₈H₂₅N₃O₃ : C, 65.17; H, 7.54; N, 12.67. Found: C, 65.52; H, 7.53; N, 12.98.

Data for 5-[(1'S, 2'S)-1'-t-Butyloxycarbonylamino-2'-methylbutyl)]-3-m-tolyl-1,2,4-oxadiazole (4b). Colorless crystals (80% yield), mp 59.6-60.2 °C (ethanol-water). IR (KBr) n_max/cm^-1: 3360 (nNH); 2982 (nC-H); 1685 (nC=O); 1564 (nC=N); 1527 (nC=C,ar);1176 (nC-O). ¹H NMR (CDCl₃) d: 0.94 (3H, t, J 7.4 Hz); 0.93 (3H, d, J 6.3 Hz); 1.45 (9H, s); 1.14-1.82 (2H, m); 1.94-2.12 (1H, m); 2.40 (3H, s) 5.04 (1H, dd, J 6.0 Hz, J 8.9 Hz); 5.28 (1H, d, J 8.7 Hz); 7.27 (2H, d, J 8.1 Hz); 7.96 (2H, d, J 8.4 Hz). ¹³C NMR (CDCl₃):11.4 (C-4'); 15.1 (CH₃); 21.3 (Ar-CH₃); 25.1 (C-3'); 28.3 (CH₃)₃; 39.3 (C-2'); 52.7 (C-1'); 80.3 (C); 123.8 (C-6"); 127.6 (C-1"); 128.6 (C-2"); 130.2 (C-5"); 132.0 (C-4"); 138.6 (C-3"); 155.2 (C-3); 168.2 (C-5); 178.9 (CO). MS, m/z (%): 345 [M⁺, 8%], 289 (53%), 233 (71%), 188 (100%), 160 (52%), 133 (86%), 118 (37%). Anal. Calc. for C₁₉H₂₇N₃O₃ : C, 66.00; H, 7.82; N, 12.16. Found: C, 66.52; H, 7.63; N, 12.28.

Data for 5-[(1'S, 2'S)-1'-t-Butyloxycarbonylamino-2'-methylbutyl)]-3-p-tolyl-1,2,4-oxadiazole (4c). Colorless crystals (75% yield), mp 65.4-66.8 °C (ethanol-water). [a]_D²² -58° ± 3 (c = 0.01, CHCl₃). IR (KBr) n_max/cm^-1: 3357 (n-NH); 2970 (nC-H); 1687 (nC=O); 1569 (nC=N); 1510 (nC=C, ar), 1159 (nC-O). . ¹H NMR (CDCl₃) d: 0.93 (3H, d, J 6.3 Hz), 0.94 (3H, t, J 7.2 Hz,), 1.45 (9H, s); 1.15-1.90 (2H, m); 1.94-2.12 (1H, m); 2.41 (3H, s); 5.05 (1H, dd, J 5.4 Hz, J 8.9 Hz); 5.29 (1H, d, J 9.3 Hz); 7.27-7.40 (2H, m); 7.84-7.92 (2H, m). ¹³C NMR (CDCl₃): 11.4 (C-4'); 15.1 (CH₃); 21.5 (Ar-CH₃); 25.0 (C-3'); 28.3(CH₃)₃; 39.2 (C-2'); 52.7 (C-1'); 80.3 (C); 123.8 (C-1"); 127.4 (C-2" and C-6"); 129.5 (C-3" and C-5"); 141.5 (C-4"); 155.1 (C-3); 168.1 (C-5); 178.7 (CO). MS, m/z (%): 345 [M⁺, 6%], 289 (71%), 188 (98%), 160 (48%), 133 (100%), 118 (44%). Anal. Calc. for C₁₉H₂₇N₃O₃ : C, 66.00; H, 7.82; N, 12.16. Found: C, 65.93; H, 8.11; N, 12.73.

Data for 5-[(1'S, 2'S)-1'-t-Butyloxycarbonylamino-2'-methylbutyl)]-3-p-anisyl-1,2,4-oxadiazole (4d). Colorless crystals (73% yield), mp 70.3-71.2 °C (ethanol-water). IR (KBr) n_max/cm^-1: 3349 (n-NH); 2968 (nC-H); 1689 (nC=O); 1568 (nC=N); 1529 (nC=C, ar); 1173 (nC-O). ¹H NMR (CDCl₃) d: 0.93 (3H, d, J 6.3 Hz); 0.94 (3H, t, J 6.6 Hz); 1.16-1.70 (2H, m); 1.45 (9H, s); 1.90-2.10 (1H, m); 3.85 (3H, s); 5.03 (1H, dd, J 5.7 Hz, J 9.0 Hz); 5.28 (1H, d, J 9.3 Hz); 6.97 (2H, d, J 9.0 Hz); 8.01 (2H, d, J 9.0 Hz). ¹³C NMR (CDCl₃): 11.4 (C-4'); 15.1 (CH₃); 25.1 (C-3'); 28.3 (CH₃)₃; 34.9 (O-CH₃); 39.3 (C-2'); 52.7 (C-1'); 80.4 (C); 114.2 (C-3" and C-5");119.1 (C-1"); 129.1 (C-2" and C-6"); 155.1 (C-3);161.9 (C-4"); 167.8 (C-5); 178.7 (CO). MS, m/z (%): 204 (100%), 176 (47%), 149 (70%), 133 (11%). Anal. Calc. for C₁₉H₂₇N₃O₄ : C, 63.15; H, 7.47; N, 11.63. Found: C, 63.35; H, 7.27; N, 12.22.

Data for 5-[(1'S, 2'S)-1'-t-Butyloxycarbonylamino-2'-methylbutyl)]-3-p-chlorophenyl-1,2,4-oxadiazole (4e). Colorless crystals (65% yield), mp 68.2-68.8 °C (ethanol-water). [a]_D²² = -60⁰ ± 4 (c = 0.01, CHCl₃). IR (KBr) n_max/cm^-1: 3364 (n-NH); 2968 (nC-H); 1685 (nC=O); 1562 (nC=N); 1518 (nC=C, ar); 1174 (nC-O). ¹H NMR (CDCl₃) d: 0.93 (3H, d, J 6.0 Hz); 0.95 (3H, t, J 7.5 Hz); 1.14-1.80 (2H, m); 1.45 (9H, s); 1.92-2.12 (1H, m); 5.05 (1H, dd, J 5.7 Hz, J 8.7 Hz) 5.25 (1H, d, J 8.7 Hz); 7.45 (2H, d, J 9.0 Hz); 8.02 (2H, d, J 9.0 Hz). ). ¹³C NMR (CDCl₃): 11.4 (C-4'); 15.1 (CH₃); 25.0 (C-3'); 28.2 (CH₃)₃; 39.1 (C-2'); 52.6 (C-1'); 80.4 (C); 125.1 (C-1"); 126.8 (C-2" and C-6"); 129.1 (C-3" and C-5"); 137.4 (C-4"); 155.1 (C-3); 167.3 (C-5); 179.0 (CO). MS, m/z (%): 208 (100%), 180 (47%), 153 (89%), 138, 20%). Anal. Calc. for C₁₈H₂₄N₃O₃ Cl: C, 59.10; H, 6.57; N, 11.49. Found: C, 59.39; H, 6.77; N, 11.14.

Data for 5-[(1'S, 2'S)-1'-t-Butyloxycarbonylamino-2'-methylbutyl)]-3-p-nitrophenyl-1,2,4-oxadiazole (4f). Yellow crystals (80% yield), mp 76.1-77.2 °C (ethanol-water). IR (KBr) n_max/cm^-1: 3337 (nNH); 2969 (nC-H); 1690 (nC=O); 1575 (nC=N); 1528 (nC=C, ar);1172 (nC-O). ¹H NMR (CDCl₃) d: 0.97 (3H, t, J 7.4 Hz); 0.97 (3H, d, J 6.6 Hz); 1.47 (9H, s); 1.16-1.80 (2H, m); 1.96-2.12 (1H, m); 5.08 (1H, dd, J 6.0 Hz, J 9.0 Hz); 5.25 (1H, d, J 9.0 Hz), 8.29 (2H, d, J 9.0 Hz); 8.35 (2H, d, J 9.3 Hz). ). ¹³C NMR (CDCl₃): 11.22 (C-4'); 15.18 (CH₃); 25.08 (C-3' ); 28.25 (CH₃)₃; 39.07 (C-2'); 52.81 (C-1'); 80.63 (C); 124.0 (C-3" and C-5"); 126.5 (C-2" and C-6"); 132.5 (C-1"); 149.6 (C-4"); 155.1 (C-3); 166.6 (C-5); 179.9 (CO). MS, m/z (%): 219 (100%), 191 (35%), 164 (52%). Anal. Calc. for C₁₈H₂₄N₄O₅ : C, 57.44; H, 6.43. Found: C, 57.51; H, 6.72.

Data for 5-[(1'S)-t-Butyloxycarbonylaminoeth-1'-yl]-3-phenyl-1,2,4-oxadiazole (6) White crystals (70% yield), mp 89.3-90.3 °C (ethanol-water). [a]_D²² -70⁰ ± 2 (c = 0.02, CHCl₃). IR (KBr) n_max/cm^-1: 3370 (nNH); 2983 (nC-H); 1687 (nC=O); 1571 (nC=N); 1518 (nC=C, ar); 1164 (nC-O). ¹H NMR (CDCl₃) d: 1.43 (9H, s); 1.60 (3H, d, J 6.9 Hz); 5.06-5.24 (1H, m); 5.44 (1H, d, J 7.8 Hz); 7.38-7.52 (3H, m); 8.00-8.10 (2H, m). ). ¹³C NMR (CDCl₃): 20.1 (C-2'); 28.3 (CH₃)₃; 44.8 (C-1'); 80.0 (C); 126.5 (C-1"); 127.5 (C-2" and C-6"); 128.8 (C-3" and C-5"); 131.2 (C-4"); 168.3 (C-3); 173.7 (C-5); 180.1 (CO). MS, m/z (%): 289 [M⁺, 8%], 234 (51%), 174 (72%), 160 (100%), 119 (98%), 104 (80%). Anal. Calc. for C₁₅H₁₈N₃O₃ : C, 62.49; H, 6.30; N, 14.57. Found: C, 62.58; H, 6.27; N, 14.87.

Conclusion

In conclusion, we have been able to synthesize and prove the structures of seven new 1,2,4-oxadiazoles as well as six of their intermediates 3a-f derived from L-(+)-isoleucine.

Acknowledgments

We are grateful to Conselho Nacional Científico e Tecnológico (CNPq) for financial support and to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for a fellowship to V.M.L.B.

Received: March 24, 2003

Published on the web: May 17, 2004

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Publication Dates

• Publication in this collection
  15 Sept 2004
• Date of issue
  Aug 2004

History

• Received
  24 Mar 2003