Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin

Autor(es)

Pastre, Julio C. ^{[1, 2]} ; Murray, Philip R. D. ^[2] ; Browne, Duncan L. ^[2] ; Brancaglion, Guilherme A. ^[1] ; Galaverna, Renan S. ^[1] ; Pilli, Ronaldo A. ^[1] ; Ley, V, Steven

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Chem, UNICAMP, BR-13083970 Campinas, SP - Brazil

^[2] V, Univ Cambridge, Dept Chem, Cambridge CB2 1EW - England

• Tipo de documento: Artigo Científico
• Fonte: ACS OMEGA; v. 5, n. 29, p. 18472-18483, JUL 28 2020.
• Citações Web of Science: 0

Resumo

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 (-)-Ipc(2)B(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. (AU)

• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 12/05909-4 - Preparação da goniotalamina sob condições de reação em fluxo
• Beneficiário: Júlio Cezar Pastre
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 14/26378-2 - Desenvolvimento de metodologias e processos de síntese empregando uma nova plataforma tecnológica: a síntese de produtos naturais e derivados com potencial atividade farmacológica assistida por micro e meso reatores contínuos
• Beneficiário: Júlio Cezar Pastre
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores