Let’s take back our asymmetry with flow technology

For all of the work done utilizing stereoselective chemistry, we have certainly struggled with this concept in med chem from the standpoint of building chiral centers in an advanced drug candidate. With all of the synthetic knowledge, we knew that if something wasn’t naturally built in, we were going to be adding steps on the cost end of the development. I was lucky enough to be part of a number of these types of targets, and it made you think….but with continuous flow developments, this process has been streamlined. Part of the effort here is to bring it back on the table in your thought process. A reasonably recent review from Peter Seeberger et al. (Beilstein JOC 2009) provides a nice review of many of the current methods used in flow chemistry — and this particular review is on applications of homogeneous and heterogeneous asymmetric catalysis, as a sustainable cost effective way generating chiral materials from achiral starting materials.

The number of homogeneous enantioselective reactions reported using a continuous flow technique is low – with hydrogenations and silyl-cyanations reported. From the Seeberger group (Angew Chem Int Ed 2009), aldol condensations catalyzed with 5-(pyrrolidine-2-yl)tetrazole was compared with batch and microwave procedures to provide shorter reaction times and lower catalyst loadings as shown below. Clearly the benefit of these microreactor processes is the ability to screen catalysts, flow and temperature quickly.

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Moving over to the use of heterogeneous chiral catalysts, we have to way the expense of using expensive catalysts and leaching the material through the transformation….however, since we discussed the use of supported reagents, the use of a supported catalysts provides an opportunity to recover catalysts and the format is easy to develop. The downside is that these catalysts need to be put on a supported media, so screening has the potential to take longer. Below are several examples of some of the work done using this concept:

The first example (Adv Synth Catal 2008) is using a Meerifield amino-alcohol resin with the addition of Et2Zn to an aromatic aldehyde to provide good conversions with high ee%s with a flow rate of 0.24 ml/min and a residence time of 9.8 min to provide mutligram quantities of the desired compound in 98% conversion with 93%ee within 3 hr. The catalyst activity remained provided identical recoveries with different aldehydes over a 6 hr time period.

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A similar process for an ene reaction of ethyl glyoxylate and alpha-methylstyrene and a stainless steel column packed with a PyBox-Cu complex (and good for over 80 hours – 5 runs) following the load with Cu(OTf)2 to the PyBox resin (Tetrahedron: Asymmetry 2004).

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Cinchona alkaloid derivatives has been utilized in solution and solid supported reactions for a number of years. The scheme below shows a reaction of ketene (generated from an acid chloride) and imino esters for the formation of beta-lactams (JACS 2001)…so we see the ketene generation on passing through a BEMP support (so no isolation) which was then reacted with a flow of the imino ester in the presence of the supported cinchona resin, and a clean up of excess reagent and by-product and a benzyl amine scavenger. While this was elegant, the process was driven through glass columns and gravity driven, so improvements would increase the utility of the concept.

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Macroporous monolithic materials are becoming popular as strategies for a number of transformations, owing their increased surface area, improves mass-transfer between the supported reagent and liquid phase – and the advantage of not clogging or pressure fluctuation often found in gel-type resins. The ability to adjust the porosity, composition and shape provides a broader range of experimentation (we owe a shout out to our inorganic brethren for giving us insights into this strategy).

A nice example of this process can be found in (Angew Chem Int Ed 2001) from Kirschning et al. with a functionalized chiral Co(salen) complex monolith reactor used in the dynamic kinetic resolution of epibromohydrin (continuous circulated over 20 hr). This example shown could be operated continuously over a 6 day period without the loss of activity of the catalyst, and thus the corresponding ee%s.

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Several additional examples are present in the review, and this topic is receiving attention throughout the field – I imagine you have seen several examples of your own. It is pretty wide open – the wild west. Happy Reading!



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