Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin

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 (−)-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.

Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades**

“… [9] Further to this, the utilization of continuous flow systems facilitates the integration of several reaction steps resulting in telescoped synthetic sequences. [10] …”

“…Another advantage is that continuous flow systems can be composed of different modules (different reactor types), which can enable the combination of a broad range of chemistries that are incompatible under batch conditions (Figure 1). [9] Further to this, the utilization of continuous flow systems facilitates the integration of several reaction steps resulting in telescoped synthetic sequences [10] …”

Improved Synthesis of Bioactive Molecules Through Flow Chemistry

“…They started the synthesis with cinnamaldehyde and allylmagnesium chloride (Fig. 12) [21]. In batch this is usually carried out at À78 C and the reaction takes 30 min to complete.…”

Production of High Value Amine Intermediates via Biocatalytic Cascades in Continuous Flow

“…9 Further to this, the utilization of continuous flow systems facilitates the integration of several reaction steps resulting in telescoped synthetic sequences. 10 Issues that arise with analytical biotransformations not being translatable to scale or different biocatalytic reaction types being incompatible, has led to the emergence of continuous flow biocatalysis as a favorable option to alleviate these issues. 11 Operating under a continuous regime allows for greater control of reaction conditions as well as providing opportunities for inline analysis and purification, as well as automation.…”

“…Pleasingly 95% conversion to 12 was achieved and maintained for four hours with a system residence time of 24 mins (STY: 2.24 g L -1 h -1 ). Again, the implementation of several switching valves allowed rapid change of flow path and enabled the generation of three RedAm products (10,11,12) without isolation or purification of any intermediates.…”