Conditions for the metathesis of alkenes in the convergent synthesis of HDAC inhibitors have been improved by continuous catalyst flow injection in the reaction media. Intermediate and target compounds obtained were tested for their ability to induce HDAC inhibition and tubulin acetylation, revealing the key role of the tert-butyloxycarbonyl (BOC) group for more HDAC6 selectivity. Molecular modelling added rationale for this BOC effect. Epigenetic mechanisms are able to provide regulatory information to the genome without altering its primary nucleotide sequence. Such mechanisms are implicated in various processes, including gene silencing and expression, apoptosis, maintenance of stem cell pluripotency, and X-chromosome inactivation. 1 At the molecular level, epigenetic regulators include covalent modification to DNA (e.g., DNA methylation) and to histone proteins (e.g., histone acetylation, methylation and ubiquitination). 1,2 More than 350 epigenetic regulators are known to date, and classified as writers (enzymes adding groups to DNA/histones), erasers (enzymes removing groups from DNA/histones) and readers (recognition of modified protein domains). 3–5 The post-translational modifications (PTM) observed in histone proteins and DNA are known as epigenetic marks. 1 Epigenetic mechanisms are nowadays correlated to several human diseases, including cancer, neurodegenerative and metabolic disorders, as well as memory impairment and parasitic infections. In the field of cancer, mutations, abnormal expression and domain translocation in epigenetic enzymes lead to abnormal PTM levels and participate to diseases progression. The renormal-ization of aberrant PTM is thus one of the goals in epigenetic cancer therapy. Amongst the several possible marks, histone acetylation was identified as a major player. Histone acetylation is controlled by the activity of histone acetyl transferases (HAT) 6 in balance with histone deacetylases (HDAC), 7 and recognized by bromodomain-containing proteins. 8 HDAC are over expressed in several cancer cell lines where they silence some tumor suppressor genes, 9 while therapeutically active HDAC inhibitors facilitate apoptosis of tumor cells. 10 Those observations led to the development of HDAC inhibi-tors for cancer therapy. 11 HDAC enzymes are grouped in three zinc-dependent classes, classes I (HDAC1–3, 8), II (HDAC 4–7, 9, 10) and IV (HDAC11), and the NAD +-dependent class III (SIRT1– 7). There is currently four compounds targeting HDAC approved for clinical uses: 12 romidepsin 13 and vorinostat 14 (SAHA 1, suberoyl anilide hydroxy amide) for cutaneous T-cell lymphoma,