1. Optimization of Partial Hydrogenation Parameters Envisaged Flow Synthesis of 1 Z-Selective semi-hydrogenation of alkynes under continuous flow as part of an envisaged synthesis of combretastatin A-4 Eduard Dolušić, Laurent De Backer, Stéphane Collin and Steve Lanners Laboratoire de Chimie Organique de Synthèse, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), Université de Namur, rue de Bruxelles 61, B-5000 Namur, Belgium eduard.dolusic@unamur.be Combretastatin A-4 (1) is a natural product isolated from the South African bushwillow tree Combretum caffrum and endowed with a powerful inhibitory activity on microtubule formation as well as a related antiangiogenic activity. 1 As such, 1 has a strong potential in anticancer therapy. A lot of effort has been done on the development of new derivatives of this compound, in order to improve the properties such as solubility and stability, and to understand the structure-activity relationships around this series. 2 Introduction The synthesis of active pharmaceutical ingredients (API) using only flow chemistry has been pioneered by S.V. Ley et. al. in 2010. 3 In order to further illustrate the feasibility of this strategy, we have devised a synthetic route for 1 which only relies on flow chemistry (Scheme 1). Scheme 1. Proposed flow synthesis of Combretastatin A-4 1. a) Lin, C. M., et al, Mol. Pharmacol. 1988, 34, 200; b) Holt, H., et al, Top. Heterocycl. Chem. 2006, 11, 465; c) Kerr, D. J., et al, Bioorg. Med. Chem. 2007, 15, 3290. 2. a) Marrelli, M., et al, Curr. Med. Chem. 2011, 18, 3035; b) Shan, Y., et al, Curr. Med. Chem. 2011, 18, 523; c) Spatafora, C., et al, Anticancer Agents Med. Chem. 2012, 12, 902; d) Mikstacka, R., et al, Cell.Mol. Biol. Lett. 2013, 18, 368. 3. Hopkin, M. D., et al, Chem. Comm. 2010, 2450. 4. a) Baxendale, I. R., et al, Angew. Chem. Int. Ed. 2009, 48, 4017; b) Zhang, Y., et al, Org. Lett. 2011, 13, 280; c) Chandrasekhar, S., et al, Tetrahedron Lett. 2011, 52, 3865. This work is supported by WBGREEN – MICROECO (Convention No. 1217714). References and Acknowledgment The envisaged Bestmann-Ohira 4a and Sonogashira 4b reactions have already been accomplished in flow. However, we anticipated that the partial hydrogenation of alkyne 5 might be problematic. Lindlar-type hydrogenation of disubstituted alkynes using H-Cube® (Fig. 1.) has been described, 4c but not on bis-aryl alkynes. We used diphenylacetylene 6 as the model substrate. Various reaction parameters were investigated. The selected results are shown in Table 1. The selected conditions were used with moderate success in a preliminary assay of hydrogenation of the alkyne precursor of 1 (Scheme 2). Figure 1. ThalesNano H-Cube® Table 1. Hydrogenation of diphenylacetylene 6. Product ratios were determined by integration of relevant signals in the 1 H-NMR spectra of the crude reaction mixtures (extraction with 5% aq. HCl when quinoline added) CatCart[6] / mgmL -1 quinoline solventtemp.flow rate% 6% 7% 8% 9 5% Pd/BaCO 3 25-hexane20 °C2 ml/min000100 5% Pd/CaCO 3 /Pb25-hexane20 °C2 ml/min146251 5% Pd/CaCO 3 /Pb25-hexane20 °C3 ml/min579115 5% Pd/CaCO 3 /Pb25-hexane30 °C3 ml/min370324 5% Pd/CaCO 3 /Pb25-hexane50 °C3 ml/min<153146 5% Pd/CaCO 3 /Pb25-MeOH20 °C3 ml/min353341 5% Pd/CaCO 3 /Pb25-EtOAc20 °C3 ml/min656444 5% Pd/CaCO 3 /Pb25-EtOH20 °C3 ml/min 2922traces49 5% Pd/CaCO 3 /Pb25-toluene20 °C3 ml/min 023077 5% Pd/CaCO 3 /Pb12,5-hexane20 °C3 ml/min 360334 5% Pd/CaCO 3 /Pb50-hexane20 °C3 ml/min 351traces44 5% Pd/CaCO 3 /Pb251 eq.hexane20 °C3 ml/min 208000 5% Pd/BaCO 3 251 eq.hexane20 °C3 ml/min 475417 5% Pd/BaCO 3 252 eq.hexane20 °C3 ml/min 38935 5% Pd/BaCO 3 253 eq.hexane20 °C3 ml/min 1086traces2 Scheme 2. Synthesis of combretastatin A-4 using Lindlar hydrogenation in flow Extending the Reaction Scope and Conclusion We decided to expand the optimized reaction conditions to a wider range of structurally various alkynes (Scheme 3 and Table 2). In some cases (substrates 16 and 17), mixtures with alcohols were used as the solvents to ensure complete solubility. The above optimized conditions gave good results for the less reactive alkynes (10 – 12); in the latter case, 10 bar of H 2 had to be applied to achieve a satisfactory outcome. On the other hand, adding as much as 5 equiv. of quinoline could not completely suppress overreduction of the more reactive substrates. In conclusion, while the generality of our method is reasonable within the substrate scope explored, fine tuning of the reaction conditions is still necessary in order to improve the selectivity towards (Z)-alkenes. Scheme 3. Lindlar hydrogenation in flow of a range of alkynes Table 2. Lindlar hydrogenations in flow. Product ratios were determined by integration of relevant signals in the 1 H-NMR spectra of the crude reaction mixtures (extraction with 5% aq. HCl) 10 11 12 13 14 15 16 17