A Convenient Synthesis of 4-Hydroxy[1-13C]benzoic Acid and Related Ring-Labelled Phenolic Compounds

Abstract

4-Hydroxy[1-13 C]benzoic acid ( 5 ) was synthesized starting from commercially available sodium [2-13 C]acetate (1) by a 4-step sequence in an overall yield of 55-65% . Key step in this synthesis is the formation of the benzene ring by base-catalyzed condensation of diethyl [2-13 C]malonate ( 3 ) with 4 H -pyran-4-one. Acid 5 or its ethyl ester could be converted into 3,4-dihydroxy[1-13 C]benzoic acid ( 9 ), D,L-[1 ′ -13 C]tyrosine ( 14 ) and 1,2,4-trihydroxy[4-13 C]benzene ( 19 ) with high efficiency.

SAIL – stereo-array isotope labeling

“…For the synthesis of Tyr 1a (Scheme 1), the hydroxyl group of 5 was methylated and the ester was reduced by LiAlD 4 . The following oxidation by PDC yielded 6 (Beyer et al 1998). Then, 6 was converted into the dehydrotyrosine derivative 7 by a condensation with labeled Gly derivatives (Erlenmeyer, 1893; Ojima et al 1989).…”

Synthesis and In Situ Behavior of 1,4- and 2,5-(13C) Isotopomers of p-Phenylenediamine in Reconstructed Human Epidermis Using High Resolution Magic Angle Spinning NMR

“…Following hydrolysis and subsequent cyclization of the bis-acetal under acidic conditions, the 13 C substituted pyran-4-one 4 was isolated from the aqueous phase as described by Marshall et al 42 Next, the second key step was the incorporation of the second 13 C atom using the commercially available ( 13 C)nitromethane as a precursor followed by aromatization under acidic conditions during the workup to yield nitrophenol 5 13 C substituted at positions 1 and 4 in 66% yield. This method, which combines pyranone and prenucleophiles, was originally reported by Steglich in 1998 43 for the synthesis of mono 13 C ring labeled phenolic compounds and further optimized by Marshall et al 33 The structure of compound 5 and the positions of the 13 C atoms were confirmed by proton NMR, where the spectrum shows a pair of doublet of doublet of doublet at 6.92 and 8.18 ppm corresponding to the aromatic protons each coupled with both 13 C atoms of the aromatic ring ( 2 J CH and 3 J CH ) and with the adjacent proton ( 3 J HH = 9.14 Hz). It is noteworthy that the proton of the phenolic OH is coupled through the oxygen to the 13 C atom of the ring and manifested by a doublet ( 2 J CH = 2.35 Hz) at 5.72 ppm.…”

NMR Assignment Methods for the Aromatic Ring Resonances of Phenylalanine and Tyrosine Residues in Proteins

“…For the synthesis of Tyr 1a (Scheme ), the hydroxyl group of 5 was methylated, and the ester was reduced by LiAlD 4 . The following oxidation by PDC yielded 6 . Then, 6 was converted into the dehydrotyrosine derivative 7 by a condensation with labeled Gly derivatives. , Compound 7 was subjected to hydrogenation in the presence of ( S , S )-Et-DuPhos-Rh, as a catalyst in MeOH, and then was deprotected to give Tyr 1a …”