A Straightforward and Convenient Synthesis of Cbz-Protected 2-(1-Aminoalkyl)oxazole-5-carboxylates

Abstract

Cbz-protected 2-(1-aminoalkyl)oxazole-5-carboxylates are readily obtainable by a two-step enantioselective sequence involving reaction of benzyloxycarbonyl protected amino acids with α-chloro-β-ketoesters and subsequent cyclization of the resulting acyloxyketones to required oxazoles upon treatment with neat ammonium trifluoacetate.

aminoalkyloxazolecarboxylates - peptide mimetics - combinatorial chemistry

References

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8

Typical Synthesis of Ketoesters 7 - Preparation of 7c.
Cbz-protected glycine (0.052 g, 0.25 mmol), 2-chloro-3-oxo-butyric acid ethyl ester (0.042 g, 0.25 mmol), Et₃N (0.075 g, 0.75 mmol) and EtOAc (1 mL) were shaken in a screw-top 2-mL vial at 65 °C for 48 h. The mixture was cooled to ambient temperature and passed through a short column of silica gel. All the volatiles were removed under a steam of nitrogen to give 7c (0.082 g, 97%) in form of pale yellow oil, which was used without further purification. ¹H NMR (200 MHz, CDCl₃): δ = 1.40 (t, 3 H, J = 7.2 Hz, CH ₃CH₂O), 2.37 (s, 3 H, COCH ₃), 3.87 (app. d, 2 H, NHCH ₂CO), 4.31 (q, 2 H, J = 7.2 Hz, CH₃CH ₂O), 5.09 (s, 2 H, PhCH ₂O), 5.11 (s, 1 H, COCHCO), 5.53 (br s, 1 H, NH), 7.44 (br s, 5 H, C₆ H ₅).

9

It is not advisable to carry out the reaction for shorter reaction time or at decreased temperature (<150 °C); these conditions lead to incomplete conversion of the precursor. Alternatively, prolongation of reaction or increasing the temperature result in notable decomposition of the product. Substitution of ammonium trifluoroacetate with ammonium acetate led to partial destruction of starting materials. This is in line with earlier observations of Claiborne and co-workers (ref. 7).

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Typical Conditions for Heterocyclization - Synthesis of 8c.
A mixture of 7c (0.084 g, 0.25 mmol) and ammonium trifluorocetate (0.327 g, 2.50 mmol) was stirred magnetically in a screw-top 2-mL Wheaton V-vial placed in an air bath heated to 150 °C. After the contents had completely liquefied (1.5-2 min), the mixture was stirred for another 5 min at the same temperature. The heat was removed, after which H₂O (0.050 mL) and EtOAc (1 mL) were added at r.t. to the solidified material. The mixture was stirred for 20 min and filtered through a short column of silica gel. Removal of solvent under a steam of nitrogen afforded 0.078 g of the crude product. Column chromatography (CH₂Cl₂) on silica gave the title compound 8c (0.037 g, 46%) as a pale yellow oil. HRMS: m/z calcd for C₁₆H₁₈N₂O₅: 318.1216; found: [M⁺] 318.1254. ¹H NMR (200 MHz, CDCl₃): δ = 1.35 (t, 3 H, J = 7.2 Hz, CH ₃CH₂O), 2.41 (s, 3 H, CH ₃), 4.34 (q, 2 H, J = 7.2 Hz, CH₃CH ₂O), 4.48 (br d, 2 H, J = 5.8, CH ₂NH), 5.11 (s, 2 H, PhCH ₂O), 5.51 (br t, 1 H, J = 5.8 Hz, NH), 7.31 (br s, 5 H, C₆ H ₅). Here and below the unambiguous assignment of signals in ¹³C NMR spectra was deduced from INADEQUATE, short-range (HMQC) and long-range (HMBC COLOC) 2D NMR experiments. ¹³C NMR (400 MHz, CDCl₃): δ = 12.97 (q, CH₃C=C), 14.08 (q, CH₃CH₂O), 38.44 (t, CH₂NH), 60.97 (t, CH₃ CH₂O), 67.05 (t, PhCH₂), 127.91 (d, phenyl), 127.98 (d, phenyl), 128.30 (d, phenyl), 135.99 (s, phenyl), 137.84 (s, OC=C), 145.59 (s, CH₃ C=C), 156.03 (s, OCONH), 158.30 (s, COOEt), 161.92 (s, OC=N).
Oxazoles 8d-g have been prepared analogously.
Compound 8d: white powder; mp 102-103 (from hexane- CH₂Cl₂, 5:1). [α]_D ²⁵ +13.4 (c 3.33, CHCl₃). HRMS: m/z calcd for C₂₃H₂₄N₂O₅: 408.1686; found: [M⁺] 408.1709. ¹H NMR (200 MHz, CDCl₃): δ = 1.37 (t, 3 H, J = 7.2 Hz, CH ₃CH₂O), 2.40 (s, 3 H, CH ₃C=C), 3.22 (br m, 2 H, PhCH ₂CH), 4.35 (q, 2 H, J = 7.2 Hz, CH₃CH ₂O), 5.07 (s, 2 H, PhCH ₂O), 5.25 (br m, 1 H, PhCH₂CH), 5.45 (br d, 1 H, J = 8.0 Hz, NH), 7.02-7.22 (m, 5 H, C₆ H ₅CH₂CH), 7.30 (br s, 5 H, C₆ H ₅CH₂O). ¹³C NMR (400 MHz, CDCl₃): δ = 13.17 (q, CH₃C=C), 14.25 (q, CH₃CH₂O), 39.76 (t, PhCH₂CH), 50.65 (d, PhCH₂ CH), 61.07 (t, CH₃ CH₂O), 67.01 (t, PhCH₂O), 127.09 (d, phenyl), 127.96 (d, phenyl), 128.07 (d, phenyl), 128.40 (d, phenyl), 128.55 (d, phenyl), 129.20 (d, phenyl), 135.27 (s, phenyl), 136.30 (s, phenyl), 137.89 (s, OC=C), 145.62 (s, CH₃ C=C), 156.00 (s, OCONH), 158.47 (s, COOEt), 164.19 (s, OC=N).
Compound 8e: white powder; mp 81-82 °C (from hexane-CH₂Cl₂, 5:1). [α]_D ²⁵ +24.1 (c 3.33, CHCl₃). HRMS: m/z calcd for C₂₈H₂₆N₂O₅: 470.1842; found: [M⁺] 470.1856. ¹H NMR (200 MHz, CDCl₃): δ = 1.34 (t, 3 H, J = 7.2 Hz, CH ₃CH₂O), 3.23 (br m, 2 H, PhCH ₂CH), 4.34 (q, 2 H, J = 7.2 Hz, CH₃CH ₂O), 5.09 (s, 2 H, PhCH ₂O), 5.27 (br m, 1 H, PhCH₂CH), 5.44 (br d, 1 H, J = 8.0 Hz, NH), 7.07-7.21 (m, 5 H, C₆ H ₅CH₂CH), 7.31 (br s, 5 H, C₆ H ₅CH₂O), 7.40-7.96 (m, 5 H, C₆ H ₅C=C). ¹³C NMR (400 MHz, CDCl₃): δ = 14.03 (q, CH₃CH₂O), 39.76 (t, PhCH₂CH), 50.56 (d, PhCH₂ CH), 61.38 (t, CH₃ CH₂O), 66.96 (t, PhCH₂O), 127.06 (d, phenyl), 127.93 (d, phenyl), 128.05 (d, phenyl), 128.37 (d, phenyl), 128.43 (d, phenyl), 129.21 (d, phenyl), 129.56 (d, phenyl), 129.76 (s, phenyl), 135.12 (s, phenyl), 136.00 (s, phenyl), 136.55 (s, OC=C), 146.39 (s, PhC=C), 155.38 (s, OCONH), 158.18 (s, COOEt), 163.98 (s, OC=N).
Compound 8f: pale yellow oil. [α]_D ²⁵ +16.6 (c 6.99, CHCl₃). HRMS: m/z calcd for C₁₉H₂₄N₂O₅: 360.1685; found: [M⁺] 360.1690. ¹H NMR (200 MHz, CDCl₃): δ = 0.90 [d, 6 H, J = 6.8 Hz, (CH ₃)₂CH], 1.32 (t, 3 H, J = 7.2 Hz, CH ₃CH₂O), 2.29 [m, 1 H, (CH₃)₂CH], 2.39 (s, 3 H, CH ₃C=C), 4.31 (q, 2 H, J = 7.2 Hz, CH₃CH ₂O), 4.75 (br m, 1 H, CHNH), 5.07 (s, 2 H, PhCH ₂), 5.59 (br d, 1 H, J = 8.0 Hz, NH), 7.28 (br s, 5 H, C₆ H ₅). ¹³C NMR (400 MHz, CDCl₃): δ = 12.64 (q, CH₃C=C), 13.72 (q, CH₃CH₂O), 17.44 (q, CH₃CH), 18.41 (q, CH₃CH), 32.04 [d, (CH₃)₂ CH], 54.64 [d, (CH₃)₂CHCH], 60.45 (t, CH₃ CH₂O), 66.39 (t, PhCH₂O), 127.87 (d, phenyl), 127.90 (d, phenyl), 128.36 (d, phenyl), 135.90 (s, phenyl), 137.11 (s, OC=C), 144.99 (s, CH₃ C=C), 155.70 (s, OCONH), 157.94 (s, COOEt), 164.49 (s, OC=N).
Compound 8g: white powder; mp 88-90 °C (from hexane-CH₂Cl₂, 5:1). [α]_D ²⁵ +48.0 (c 4.45, CHCl₃). HRMS: m/z calcd for C₂₄H₂₆N₂O₅: 422.1842; found: [M⁺] 422.1844. ¹H NMR (200 MHz, CDCl₃): δ = 0.98 [d, 6 H, J = 6.8 Hz, (CH ₃)₂CH], 1.35 (t, 3 H, J = 7.2 Hz, CH ₃ CH₂O), 2.30 [m, 1 H, (CH₃)₂CH], 4.36 (q, 2 H, J = 7.2 Hz, CH₃CH ₂ O), 4.93 (br m, 1 H, CHNH), 5.13 (s, 2 H, PhCH ₂ ), 5.48 (br d, 1 H, J = 8.0 Hz, NH), 7.33 (br s, 5 H, C₆ H ₅CH₂), 7.40-8.02 (m, 5 H, C₆ H ₅ C=C). ¹³C NMR (400 MHz, CDCl₃): δ = 13.99 (q, CH₃CH₂O), 17.66 (q, CH₃CH), 18.61 (q, CH₃CH), 32.62 [d, (CH₃)₂ CH], 54.86 [d, (CH₃)₂CHCH], 61.26 (t, CH₃ CH₂O), 67.01 (t, PhCH₂O), 127.88 (d, phenyl), 127.94 (d, phenyl), 128.01 (d, phenyl), 128.35 (d, phenyl), 129.24 (d, phenyl), 129.47 (d, phenyl), 129.93 (s, phenyl), 136.06 (s, phenyl), 136.50 (s, OC=C), 146.31 (s, PhC=C), 155.89 (s, OCONH), 158.22 (s, COOEt), 164.45 (s, OC=N).

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Typically 2-(1-aminoalkyl)oxazole-5-carboxylates crystallize as aggregates of ultra-fine plates unsuitable for X-ray analysis. Oxazole 8d was the only product for which we obtained suitable crystals using mixed solvent (hexane-CH₂Cl₂, 1:1) and very slow evaporation of solvent inside a desiccator in the presence of a solvent absorber (p-xylene placed in a separate vial).
X-ray data were measured on a BRUKER P4 diffractometer with graphite monochromated MoK_α radiation using θ/2θ scans (θ<25.99°). A correction for absorption was made according to the crystal faces (transmission 0.95-0.99). The structure was solved by direct methods and refined by a full matrix least-squares anisotropic procedure using SHELXL97 program. The parameters of the hydrogen atoms were given geometrically. The final indexes are wR ₂ = 0.1340, S = 0.996 for all 2442 F ² and R ₁ = 0.0535 for 1366 Fo>4σ (300 parameters, 6 restraints). Atomic coordinates, thermal parameters, bond lengths and bond angles have been deposited with the Cambridge Crystallographic Data Centre. Data can be retrieved in CIF format by quoting the deposition no. 274488 in an e-mail request to [e-mail].
Crystallographic data for 8d: C₂₃H₂₄N₂O₅, MW = 408.44, crystal class orthorhombic, space group P2₁2₁2₁, a = 8.0298 (8), b = 9.853 (1), c = 27.308 (3) Å, V = 2160.5 (4) ų, Z = 4, d _c = 1.256 mg m^-3, µ(MoK_α) = 0.089 mm^-1, crystal size 0.6 × 0.4 × 0.08 mm.

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In preliminary experiments, it was found that both methyl and phenyl resonances in the spectra of racemic forms of oxazoles 8d-g are shifted downfield, and are each resolved into signals of individual enantiomers (ratio 1:1) upon addition of Eu(tfc)₃.