This paper reports exclusive γ-conjugation of poly­(ethylene glycol) (PEG) to folic acid (FA) and the synthesis of its fluorescein (Fl)-labeled derivative. FA is first reacted with 1 equiv of n-BuLi that forms the metal salt exclusively at the γ-position. Model reactions between γ-lithiated FA and bromo-alcohols were used to demonstrate exclusive γ-conjugation. γ-PEGylated FA was then synthesized by reacting γ-lithiated FA with a bromine-functionalized methoxy-PEG (Br-PEGM) that is prepared by Candida antarctica Lipase B (CALB)-catalyzed transesterification of ethyl 5-bromovalerate (EBV) with methoxy-PEG (HO-PEGM). Fl-labeled γ-PEGylated FA was also synthesized by CALB-catalyzed Michael addition of FA-γ-SH to acrylate-PEG-Fl that was made by a series of CALB-catalyzed transformations. NMR spectroscopy and MALDI-ToF spectrometry verified the structure and purity of the compounds. These lithiation-based methods are superior compared to both the currently used activated ester method that gives a mixture of γ, α, and double-substituted FA and the multistep retrosynthesis methods.

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Oxygen tolerant polymerizations including Photoinduced Electron/Energy Transfer-Reversible Addition-Fragmentation Chain-Transfer (PET-RAFT) polymerization allow for high-throughput synthesis of diverse polymer architectures on the benchtop in parallel. Recent developments have further increased throughput...

This paper investigates the transesterification of methyl 3-mercaptopropionate (MP-SH) with tetraethylene glycol (TEG) and poly(ethylene glycol)s (PEG)s catalyzed by Candida antarctica Lipase B (CALB) without the use of solvent (in bulk). The progress of the reactions was monitored by 1H-NMR spectroscopy. We found that the reactions proceeded in a step-wise manner, first producing monothiols. TEG-monothiol was obtained in 15 min, while conversion to dithiol took 8 h. Monothiols from PEGs with Mn = 1000 and 2050 g/mol were obtained in 8 and 16 h, respectively. MALDI-ToF mass spectrometry verified the absence of dithiols. The synthesis of dithiols required additional fresh CALB and MP-SH. The structure of the products was confirmed by 1H-NMR and 13C-NMR spectroscopy. Enzyme catalysis was found to be a powerful tool to effectively synthesize thiol-functionalized TEGs and PEGs.