Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin

Julio C Pastre; Philip R D Murray; Duncan L Browne; Guilherme A Brancaglion; Renan S Galaverna; Ronaldo A Pilli; Steven V Ley

doi:10.1021/acsomega.0c02390

Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin

ACS Omega. 2020 Jul 17;5(29):18472-18483. doi: 10.1021/acsomega.0c02390. eCollection 2020 Jul 28.

Authors

Julio C Pastre^{1

2}, Philip R D Murray², Duncan L Browne², Guilherme A Brancaglion¹, Renan S Galaverna¹, Ronaldo A Pilli¹, Steven V Ley²

Affiliations

¹ Institute of Chemistry, University of Campinas-UNICAMP, P.O. Box 6154, 13083-970 Campinas, SP, Brazil.
² Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.

Abstract

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 (16) (20.9 g prepared over 3 h), 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 an (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 explored under several conditions in both batch and flow regimes. In a batch operation, the Grubbs second-generation was shown to be effective 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 were attenuated relative to the batch mode; however, after further optimization, the residence time could be reduced to 16 min with good selectivity and good yield of the target 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.