3-(1-Aminoalkyl)pyrazole- and 4,5-Dihydropyrazole-5-carboxylic Acids as Peptide Bond Replacements

Abstract

Orthogonally protected 3-(1-aminoalkyl)pyrazole- and 4,5-dihydropyrazole-5-carboxylic acids are prepared by 1,3-dipolar cycloaddition of α-aminonitrile imines with electron-deficient al­kenes; the pyrazole is incorporated into pseudotri- and tetrapeptides.

cycloaddition - dipole - heterocycles - amino acids - peptide mimics

References and Notes

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<A NAME="RG25510ST-4A">4a</A> Jones RCF. Dickson J. J. Peptide Sci.  2001,  7:  220 

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<A NAME="RG25510ST-6">6</A> Pillainayagam T. PhD Thesis   Loughborough University; UK: 2005. 

<A NAME="RG25510ST-7">7</A> See, for example: Elguero J. Goya P. Jagerovic N. Silva AMS. Targets in Heterocyclic Systems   Vol. 6:  Attanasi OA. Spinelli D. Italian Society of Chemistry; Rome: 2002.  p.52 

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<A NAME="RG25510ST-8A">8a</A> Jones RCF. Choudhury AK. Iley JN. Loizou G. Lumley C. McKee V. Synlett  2010,  654 

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<A NAME="RG25510ST-9">9</A> For our exploration with azomethine imines, see: Jones RCF. Hollis SJ. Iley JN. ARKIVOC  2007,  (v):  152 

<A NAME="RG25510ST-10">10</A> For a similar approach to 4,5-dihydroisoxazole peptide mimetics, see: Chung YJ. Ryu EJ. Keum G. Kim BH. Bioorg. Med. Chem.  1996,  4:  209 

<A NAME="RG25510ST-11">11</A> Cf. for α-amino-oximes: ref. 10. For α-amino semicarbazides: Ito A. Takahashi R. Baba Y. Chem. Pharm. Bull.  1975,  23:  3081 

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<A NAME="RG25510ST-14">14</A>

Typical Procedure for NCS Chlorination and Method 1
( S )-3-(1- tert -Butoxycarbonylaminoethyl)-2-phenyl-4,5-dihydro-1 H -pyrazole-5-carboxylic Acid Ethyl Ester (7) To (S)-[1-methyl-2-(phenylhydrazono)ethyl]carbamic acid tert-butyl ester (5, 1.24 g, 4.72 mmol) in EtOAc (15 mL) at 60 ˚C was added NCS (0.71 g, 5.35 mmol, 1.1 equiv) and the mixture stirred for 1 h. Ethyl propenoate (0.918 g, 1.0 mL, 9.16 mmol, 1.9 equiv), KHCO₃ (2.41 g, 23.97 mmol, 5.1 equiv) and a few drops of H₂O were added and the mixture stirred at 70 ˚C for 20 h. The mixture was then filtered and the filtrate concentrated under reduced pressure to give a dark orange oil, purified by column chromatography on silica gel eluting with light PE-EtOAc (7:1, v/v) to yield the title compound 7 (0.72 g, 41%) in an inseparable 1:1 mixture of diastereomers, as an orange solid; mp 93-95 ˚C. IR (CHCl₃): ν_max = 3354 (NH), 1599 (C=N), 1708 (C=O), 1168 (CO), 750 (PhCH) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.16 (3 H, t, J = 7.2 Hz, CH₂CH ₃), 1.35 (3 H, d, J = 7.0 Hz, CH ₃CH), 1.38 [9 H, s, C(CH ₃)₃], 2.99 (1 H, dd, J = 7.2, 17.6 Hz, 4-CHH), 3.24 (1 H, dd, J = 12.4, 17.6 Hz, 4-CHH), 4.14 (2 H, q, J = 7.2 Hz, CH ₂CH₃), 4.43 (1 H, m, CH₃CH), 4.54, 4,57 (each 0.5 H, dd, J = 7.2, 12.4 Hz, CHCO₂Et, diastereomers 1 and 2), 5.00 (1 H, br s, NH), 6.78 (1 H, m, ArH), 6.93 (2 H, m, ArH), 7.18 (2 H, m, ArH). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.2, 21.1 (CH₃) 28.2 [(CH₃)₃C], 40.15 (4-CH₂), 46.1 (5-CH), 61.7 (OCH₂), 113.0 (PhCH), 113.0, 119.7, 119.8, 129.0 (4 × CH), 129.1 (2 × C), 145.3 (CN), 171.2, 171.5 (2 × CO). MS (EI): m/z = 362 [MH⁺], 171 (12), 154 (24), 147 (19), 123 (21), 111 (28), 109 (35), 95 (54), 81 (54), 69 (85), 57 (100), 55 (99). HRMS (EI): m/z calcd for C₁₉H₂₇N₃O₄: 362.2074 [MH⁺]; found 362.2073 [MH⁺]. Anal. Calcd (%) for C₁₉H₂₇N₃O₄: C, 63.1; H, 7.5; N, 11.6. Found: C, 62.6; H, 7.2; N, 11.8.

<A NAME="RG25510ST-15">15</A> Sharp JT. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products   Padwa A. Pearson WH. John Wiley and Sons; Hoboken: 2003.  p.473 

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Cf. ref. 16a for a discussion on the reduced rate of nitrile imine cycloadditions with electron-rich dipolarophiles and/or electron-poor dipoles.

<A NAME="RG25510ST-21">21</A>

Crystal Data for 7
C₁₉H₂₇N₃O₄, M = 361.44, monoclinic, a = 5.14990 (10), b = 11.4316 (4), c = 16.8254 (6) Å, β = 96.320 (2), U = 984.52 (5) Å^³, T = 120 (2) K, space group P2₁, graphite monochromated Mo Kα radiation, λ = 0.71073 Å, Z = 2, D _c  = 1.219 g cm^-³, F(000) = 388, colourless, dimensions 0.36 × 0.09 × 0.04 mm^³, µ = 0.086 mm^-¹, 3.02 < θ < 28.19˚, 11290 reflections measured, 2363 unique reflections, R _int = 0.0376. The structure was solved by direct methods and refined on F ^². Friedel pairs were merged due to the lack of any significant anomalous scattering. wR2 = 0.0833 (all data, 244 parameters); R1 = 0.0351 [2223 data with F ^² > 2σ(F ^² )]. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. 787832. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]).

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<A NAME="RG25510ST-22B">22b</A> Fisk JD. Powell DR. Gellman SH. J. Am. Chem. Soc.  2000,  122:  5443