Synthesis of γ-hydroxy-α-(arylmethyl)carboxylic acids from lactones: pathway to a structural motif derived from lactic acid and amino acid analogs?

Objective A synthetic pathway to γ-hydroxy-α-(arylmethyl)carboxylic acids starting from α-angelica lactone and γ-butyrolactone was investigated. These γ-hydroxycarboxylic acids resemble structural motifs of lactic acid and amino acids. The possibility of cocondensation with lactic acid towards functionalized poly(lactic acid)s was analyzed. Results The functional γ-hydroxycarboxylates sodium 4-hydroxy-2-((N-methylpyrazol-4-yl)methyl)pentanoate and sodium 4-hydroxy-2-(phenylmethyl)butanoate (2-benzyl-4-hydroxybutanoate) were synthesized in good yields as a proof of concept for the proposed reaction pathway. Additionally, sodium (E)-2-((N-methylpyrazol-4-yl)methylene)-4-oxopentanoate presenting an interesting structural motif was isolated. All products have been fully characterized by mass spectrometry, IR spectroscopy and 2D nuclear magnetic resonance (NMR) techniques. In contrast to the carboxylate anions, the corresponding carboxylic acids obtained after acidification were found to be unstable. The instability was analyzed by NMR experiments. With the help of diffusion ordered NMR spectroscopy, the cocondensation with lactic acid was elucidated. The reaction products were characterized as oligomers of pure lactic acid, while intramolecular condensation of the γ-hydroxycarboxylic acids prevents cocondensation with lactide. Electronic supplementary material The online version of this article (10.1186/s13104-019-4232-1) contains supplementary material, which is available to authorized users.


Experimental Section -Materials and Methods
All operations with air sensitive compounds were carried out at a vacuum line using Schlenk techniques. If not noted differently, chemicals were bought from Sigma-Aldrich and used as received. γ-Butyrolactone (VWR International GmbH) and benzaldehyde were distilled before use. Sodium methoxide was freshly prepared from methanol and sodium and dried in vacuo before use. α-Angelica lactone (TCI Europe GmbH), 1-methylpyrazol-4-carboxaldehyde (TCI Europe GmbH), titanium(IV) n-butoxide (VWR International GmbH) and Pd on activated IR spectra: IR spectra were recorded with a Bruker Alpha-T FT-IR spectrometer (Bruker Corporation). For ATR measurements, a Platinum diamond-ATR unit was used.
NMR spectra: NMR spectra were recorded with a Bruker Avance 400 (Bruker Corporation) (400 MHz ( 1 H), 100 MHz ( 13 C)) and Avance III 600 (600 MHz ( 1 H), 150 MHz ( 13 C)) FT-NMR spectrometer. Chemical shifts are given in ppm relative to tetramethylsilane (δ = 0.0) or the residual solvent signal of the deuterated solvent. DOSY NMR Spectra: Diffusion ordered (DOSY) NMR data were recorded on the Bruker Avance III 600 spectrometer equipped with a broad band observed (BBO) probe with zgradient. The spectrometer was additionally provided with the NMR thermometer hardware (Bruker Corporation) that ensured highly stable temperature conditions. Calibration of the gradient strength G was conducted by means of a deuterium oxide sample containing H 2 Otraces and was found to be 0.548 T•m -1 for the BBO probe. The diffusion ordered spectra were performed in 3 mm NMR tubes Wilmad 335 (Wilmad-LabGlass) under calibrated (methanol thermometer) and carefully stabilized temperature conditions, i.e. T = 298±0.1 K.
The probe head nitrogen gas flow was adjusted to 800 L•h -1 . Optimized pulse repetition 4 delays (d1 = 10 s) were obtained from inversion-recovery experiments. Sample spinning was used in order to avoid convection. The applied pulse sequence was the DOSY Oneshot experiment creating a series of 16 1-D spectra with squared increase of the gradient field strength from 10 to 80 % [1]. The intergradient delay (diffusion time) ∆ (d20) was set to 0.10 s. The corresponding length of the gradient pulse (p30; δ/2) was adjusted to 0.9 ms (1) or 1.25 ms (polycondensation products), respectively. Each single spectrum was processed with a line-broadening factor (LB) of 1.0 Hz. The DOSY data were analyzed with the DOSY Toolbox in order to calculate diffusion coefficients and generate the common DOSY plot [2].
Mass spectra: Electrospray ionization (ESI) mass spectra were recorded with an HP 1100 Series (Hewlett-Packard/Agilent Technologies, Inc.) LC/MS mass spectrometer. Negative ion mode was applied.
High-resolution electrospray ionization mass spectra (HR-MS (ESI)) were recorded on an IMPACT II (Bruker Corporation) mass spectrometer with negative ion mode.
Electron impact (EI) mass spectra were recorded with a Varian 320 MS TQ (Agilent Technologies, Inc.) mass spectrometer at 20 eV. [3M-Na] -.      Table   S1) and 155 °C (black, entry 1 in Additional file 1: Table S1) rel. to PS standard.   Table S1). Several oligomers of lactic acid (red) and only low molecular weight compounds related to 3 (grey) are identified. Measured in CDCl 3 .