Natural Products

Natural Product Targets and Past Achievements Using Flow Synthesis Methods

Spirangien A and B
One of our current flow total synthesis targets are the spirangiens. On completion this synthesis will constitute a significant demonstration of the power of combined flow methods. We have made good progress in this area using specially developed flow chemistry devices and methods. Spirangiens are polyketides consisting of 14 stereocentres, a densely functionalised spiroketal core and an unstable ZEZEZ conjugated polyene fragment. Our present synthesis utilises a number of highly stereoselective reactions, including asymmetric hydrogenation, crotylation and alkyne additions. To date, a flow-based synthesis of a key intermediate has been developed which employs polymer-supported reagents, inline analytical devices and our newly developed gas-liquid reactor as part of the flow sequence.

Spirangien

O-Methyl-Siphonazole
The bisoxazole containing natural product O-methyl siphonazole was assembled using a suite of microreactors via a flow-based approach in concert with traditional batch methods. The use of a toolbox of solid-supported scavengers and reagents to aid purification afforded the natural product in a total of nine steps.

Pseudomonas Quinolone Signal
In a collaborative effort with Dr David Spring and Dr Mark Ladlow, a tandem reaction process was devised that allows a two-step synthesis of PQS (and analogues) on a multi-gram scale from readily obtainable or commercially available materials. Access to these materials will help us to understand PQS-mediated quorum sensing systems and thus may facilitate the development of methods that could modulate these signalling networks in a useful fashion, with possible therapeutic applications in the treatment of human bacterial infections. Below is a schematic of the synthesis of PQS using a Uniqsis FlowSyn™ continuous flow reactor.

Grossamide
In 2006, we reported the first enantioselective total synthesis of 2-aryl-2,3-dihydro-3-benzofurancarboxyamide neolignan, grossamide, using a fully automated and scalable flow reactor. Its preparation using flow chemistry methods involved amide coupling of tyramine and ferulic acid using an immobilized HOBt cartridge followed by an oxidative dimerisation and an intramolecular cyclisation. For the oxidation step, this precursor was diluted (3:1) with a second input solution containing hydrogen peroxide urea complex and sodium dihydrogen phosphate buffer. The combined flow stream was then passed through a pre-packed column with the enzyme horseradish peroxidase (II) supported on silica gel which ultimately gave the desired natural product in excellent overall yield.

Oxomaritidine
This was the first multi-step synthesis of a natural product using flow methods and techniques to be reported in the literature. We did not need to isolate any intermediates along the way nor did we need to perform any distillations, crystallisations or perform any column chromatography throughout the whole synthesis. The time saved by using these flow through methods compared to conventional procedures was dramatic.