Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin.
Pastre, Julio C
Murray, Philip RD
Brancaglion, Guilherme A
Galaverna, Renan S
Pilli, Ronaldo A
American Chemical Society
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Pastre, J. C., Murray, P. R., Browne, D. L., Brancaglion, G. A., Galaverna, R. S., Pilli, R. A., & Ley, S. (2020). Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin.. ACS omega, 5 (29), 18472-18483. https://doi.org/10.1021/acsomega.0c02390
An integrated batch and continuous flow process has been developed for the gram-scale synthesis of goniothalamin. The synthetic route hinges upon a telescoped continuous flow Grignard addition followed by an acylation reaction capable of delivering a racemic goniothalamin precursor (15) (20.9 g prepared over 3 hours), with a productivity of 7 g.h-1. An asymmetric Brown allylation protocol was also evaluated under continuous flow conditions. This approach employing (–)-Ipc2B(allyl) provided (S)-goniothalamin intermediate in 98% yield and 91.5% enantiomeric excess (ee) with a productivity of 1.8 g.h-1. For the final step, a ring-closing metathesis reaction was investigated under a variety of conditions in both batch and flow regimes. In a batch operation, Grubbs second-generation catalyst proved to be efficient and highly selective for the desired ring closure product over those arising from other modes of reactivity, and the reaction was complete in 1.5 h. In a flow operation, reactivity and selectivity was attenuated relative to batch mode, however after further optimisation, residence time could be reduced to 16 minutes with good selectivity and good yield of the desired product. A tube-in-tube reactor was investigated for in-situ ethylene removal to favor ring-closing over cross-metathesis, in this context. These results provide further evidence of the utility of flow chemistry for organometallic processing and reaction telescoping. Using the developed integrated batch and flow methods, a total of 7.75 g of goniothalamin (1) was synthesized.
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External DOI: https://doi.org/10.1021/acsomega.0c02390
This record's URL: https://www.repository.cam.ac.uk/handle/1810/307112
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