Solution-Phase Parallel Synthesis of Dissymmetric Disubstituted Malonamides Carrying Amino Ester Residues

Abstract

Amino esters were used as nucleophiles in the reaction with Meldrum’s acid to obtain monosubstituted malonic acids that reacted under coupling reaction conditions with a second different amino ester residue to give single >COCH₂CO< retropeptide units in high overall yields. The synthetic procedure led to the construction of a 4 × 5 combinatorial library of malonyl peptides.

Key words

amino acids - combinatorial chemistry - Meldrum’s ­acid - amides - retropeptides

References and Notes

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13

The molar ratios of Meldrum’s acid to amino ester were a crucial point in order to avoid the undesired formation of a symmetric disubstituted malonamide.

14

By refluxing in toluene only the N-acetyl amino ester was obtained as a consequence of the decarboxylation reaction.

15

The reaction was monitored by IR and MS-Q-TOF every 30 min until completion.

16

Typical Experimental Procedure
Equimolar amounts (from 250 mg up to multigram scale) of a suitable amino ester hydrochloride and Et₃N were stirred in THF (3 mL/mmol) at r.t. After 30 min, a twofold excess of Meldrum’s acid was added, and then the reaction mixture was allowed to reflux for 3 h. After filtration and solvent removal, the malonic acid monoamides were obtained as crude products and used as such. The crude malonic acid monoamides were dissolved in CH₂Cl₂ and equimolar amounts of a suitable amino ester hydrochloride and DMAP were added. After stirring for 15 min, an equimolar amount of DCC was added and the mixture was stirred for additional 12 h. After reaction completion, the crude mixture was filtered and the expected malonyl peptides were collected as pure compounds after chromatography on silica gel (eluent mixture: hexane-EtOAc = 5:95).

17

Representative Spectral Data for 3A{1-4}B1
Methyl (2 S )-2-({3-[(2-Methoxy-2-oxoethyl)amino]-3-oxopropanoyl}amino)-3-phenylpropanoate (3A1B1)
Viscous oil. IR: 3442, 3328, 1739, 1679 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.92-3.18 (m, 2 H), 3.19 (s, 2 H), 3.64 (s, 3 H), 3.68 (s, 3 H), 3.96 (d, J = 5.4 Hz, 2 H), 4.71-4.82 (m, 1 H), 7.05-7.26 (m, 5 H), 7.62-7.76 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 37.6, 41.0, 42.1, 52.1 (two), 53.5, 126.8, 128.3, 129.0, 135.8, 167.0, 167.3, 169.8, 171.5. HRMS (ES Q-TOF): m/z calcd for C₁₆H₂₁N₂O₆ [M + H]⁺: 337.1394; found: 337.1387
Methyl (2 S )-2-({3-[(2-Methoxy-2-oxoethyl)amino]-3-oxopropanoyl}amino)propanoate (3A2B1)
Viscous oil. IR: 3424, 3326, 1744, 1678 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.36 (d, J = 7.2 Hz, 3 H), 3.28 (s, 2 H), 3.68 (s, 3 H), 3.69 (s, 3 H), 3.94-4.01 (m, 2 H), 4.42-4.56 (m, 1 H), 7.73 (d, J = 6.9 Hz, 1 H), 7.77-7.83 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 17.6, 41.1, 42.1, 52.2 (two), 52.3, 166.9, 167.6, 169.9, 173.0. HRMS (ES Q-TOF): m/z calcd for C₁₀H₁₇N₂O₆ [M + H]⁺: 261.1081; found: 261.1079 Methyl 3-({3-[(2-Methoxy-2-oxoethyl)amino]-3-oxopropanoyl}amino)propanoate (3A3B1)
Viscous oil. IR: 3445, 3327, 1737, 1679 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.42-2.48 (m, 2 H), 3.17 (s, 2 H), 3.37-3.44 (m, 2 H), 3.58 (s, 3 H), 3.63 (s, 3 H), 3.92 (d, J = 5.4 Hz, 2 H), 7.60-7.65 (m, 1 H), 7.92-7.94 (m, 1 H).¹³C NMR (75 MHz, CDCl₃): δ = 33.4, 34.8, 41.0, 42.2, 51.5, 51.9, 167.2, 167.7, 169.9, 172.2. HRMS (ES Q-TOF): m/z calcd for C₁₀H₁₇N₂O₆ [M + H]⁺: 261.1081; found: 261.1090
Methyl (2 S )-2-({3-[(2-Methoxy-2-oxoethyl)amino]-3-oxopropanoyl}amino)-3-methylbutanoate (3A4B1)
Viscous oil. IR: 3425, 3326, 1742, 1679 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3 H), 2.10-2.20 (m, 1 H), 3.31 (s, 2 H), 3.70 (s, 3 H), 3.71 (s, 3 H), 4.00 (d, J = 5.4 Hz, 2 H), 4.41-4.48 (m, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 17.7, 18.9, 30.8, 41.0, 42.0, 52.0, 52.2, 57.5, 167.2, 167.7, 169.9, 172.2. HRMS (ES Q-TOF): m/z calcd for C₁₂H₂₁N₂O₆ [M + H]⁺: 289.1394; found: 289.1401.