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Synlett 2010(4): 587-590  
DOI: 10.1055/s-0029-1219375
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Potential of (2E,7E)-Nonadienedioates in Asymmetric Synthesis: Construction of Homopipecolic Acid and an Aminoester Building Block for Peptide Nucleic Acids

Narciso M. Garrido*, Alfonso G. Rubia, Carlos Nieto, David Díez
Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
Fax: +34(923)294574; e-Mail: nmg@usal.es;
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Publication History

Received 19 December 2009
Publication Date:
08 February 2010 (online)

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Abstract

A convenient, asymmetric synthesis of (R)-homopipecolic acid methyl ester and an homochiral peptide nucleic acid (PNA) monomer building block are described, starting from the orthogonally disubstituted (2E,7E)-nonadienedioate. The approach involves stereoselective Michael monoaddition of (R)-N-benzyl-N-α-methylbenzylamide to the unsaturated ester as the key step, and subsequent transformation of the remaining double bond of the unsaturated acid.

Key words

β-amino acids - asymmetric synthesis - Michael additions - PNA - homopipecolic acid - orthogonally substituted diene­dioate

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7

Analysis of the crude product by ¹H NMR (400 MHz) confirmed it to be diastereomerically pure as no trace was found of any other stereoisomer. An ee >95% is consistent with the high optical purity of the lithium amide used.

10

Analysis of the crude product by ¹H NMR (400 MHz) confirmed it to be diastereomerically pure as no trace was found of any other stereoisomer. The (2S,αR) diastereisomer has been prepared by non-stereoselective monoaddition of α-methylbenzylamine to (2E,8E)-decadienedioate followed by treatment with benzyl chloride. See ref. 5d

13

Typical procedure: A suspension of thymine (108.6 mg, 0.861 mmol), TBAI (34.4 mg, 0.086 mmol) and K2CO3 (59.6 mg; 0.431 mmol) in DMF (5 mL) was stirred for 30 min, then heated to 70 ˚C for 30 min. Bromide 18 (17 mg, 0.04 mmol) was added and the resulting mixture was stirred for 6 h at 70 ˚C. Then the mixture was cooled to 0 ˚C, filtered through Celite® and the filter pad was washed with EtOAc. The filtrate was washed with H2O, dried over anhydrous Na2SO4, filtered and the solvent was removed. Purification of the crude product by flash chromatography (hexane-Et2O, 1:4) provided 2 (8 mg, 38%) as an oil. ¹H NMR (400 MHz, CDCl3): δ = 1.20-1.57 (m, 10 H, H-4, H-5, H-6, H-7, H-8), 1.42 [s, 9-H, C(CH3)3], 1.92 (s, 3 H, Me-C5′), 2.50 (m, 2 H, H-2), 3.65-3.70 (m, 2 H, H-9), 3.67 (s, 3 H, OCH3), 3.89 (m, 1 H, H-3), 4.93 (d, J = 8.7 Hz, 1 H, NH), 6.97 (s, 1 H, H6′), 8.22 (s, 1 H, H-3′). IR (neat): 3365, 2931, 2857, 1736, 1712, 1483, 1366, 1166, 1094 cm-¹. ¹³C NMR (200 MHz, CDCl3): δ = 12.59, 26.12, 26.48, 28.60, 29.10, 32.14, 34.71, 39.44, 47.62, 48.70, 51.87, 77-79, 110.78, 140.67, 150.93, 164.33, 172.38. HRMS: m/z calcd for C20H33N3O6: 434.2261; found: 434.2260.