Engineering, Synthesis

Green Chemistry via Continuous Flow

“Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906” Gustafsson, T.; Sörensen, H.; Pontén, F. Org. Proc. Res. Dev. 2012, ASAP. DOI: 10.1021/op200340c

“Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin.” Lévesque, F.; Seeberger, P. H. Angew. Chem. Int. Ed.. 2012, 51, 1706-1709. DOI: 10.1002/anie.201107446

“Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy” Cervera-Padrell, A. E.; Nielsen, J. P.; Pedersen, M. J.; Christensen, K. M.; Mortensen, A. R.; Skovby, Dam-Johansen, T. K.; Kiil, S.; Gernaey, K. V. Org. Proc. Res. Dev. 2012, ASAP. DOI: 10.1021/op2002563

A little while back I wrote about an aerobic oxidation which was greatly improved by switching from a traditional round bottom flask setup to a continuous flow reactor – basically, continuous flow reactors are much better at handling oxygen, especially on scale.  But most of the advantages of the flow reactor were specific to that reaction, and it wasn’t clear to me how a flow process would improve a reaction that doesn’t use oxygen, or some other gas.  Fortunately, a lot has been published since then to help me get a handle on how continuous flow reactions can contribute towards greener processes.  In particular, this review covers continuous processing within a green chemistry context, and Organic Process Research and Developement has a continuous flow themed issue in their ASAP section, including this process-oriented review (speaking of OPRD, check out this recent editorial concerning solvent selection and green chemistry).  It turns out that flow chemistry can improve processes in a bunch of different ways, and it’s hard to get a sense for how this can work by just looking at one reaction.  So I’ll cover a few different reactions that illustrate different green aspects of continuous flow reactors.

One benefit of flow reactors is improved control over reaction temperature, due to reduced reaction volume at a given time, higher surface area, and the movement of the reaction mixture.  This is particularly helpful for very exothermic reactions, which often require cryogenic cooling to prevent runaway reactions – this type of cooling is very expensive and resource-intensive on a large scale.  One such reaction is described in a recent paper from AstraZeneca, in which a phosphinate anion adds into a glycine derivative.  The product of this reaction is an intermediate in the synthesis of a gastroesophageal reflux inhibitor drug candidate called AZD6906.

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Engineering, Synthesis

Chemical Feedstock Production by Fermentation

“Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol” Yim, H.; Haselbeck, R.; Niu, W.; Pujol-Baxley, C.; Burgard, A.; Boldt, J.; Khandurina, J.; Trawick, J. D.; Osterhout, R. E.; Stephen, R.; Estadilla, J.; Teisan, S.; Schreyer, H.B.; Andrae, S.; Yang, T. H.; Lee, S. Y.; Burk, M. J.; Van Dien, S.  Nature Chem. Bio. 2011. 7, 445-452. DOI: 10.1038/nchembio.580

The production of chemicals from biologically-derived feedstocks is a major goal of green chemistry research, but despite a lot of work that’s been done, it’s going to be hard to make the switch from petroleum-derived chemicals to bio-based ones.  This is especially true for high-volume commodity chemicals – many of these chemicals have been produced from petroleum for a hundred years, the processes have been optimized to work efficiently on enormous scale, and they are really, really cheap.  So the bar is set pretty high, and most papers from academic labs on microbial or enzymatic chemical production are too low-yielding to ever be commercialized (although to be fair, the same could be said for most synthetic chemistry papers).  That’s why I was a drawn to this paper published by Genomatica, a company based in San Diego, on the production of 1,4-butanediol by an engineered strain of E. coli – first they got the bug to produce 1,4-butanediol, then they engineered it to produce lots of the stuff.  Currently one million tons of 1,4-butanediol (BDO) are produced each year, virtually all of it derived from petroleum-based feedstock chemicals.

Apparently 40% of this is used in the production of Spandex, and the rest of it is used to make other polymers and THF.  If Genomatica’s BDO production works according to their plan, all those tons of spandex could be bio-based!

The future of spandex?

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More Stahl Aerobics

“Highly Practical Copper(I)/TEMPO Catalyst System for Chemoselective Aerobic Oxidation of Primary Alcohols” Hoover, J. M.,; Stahl, S. S.  J. Am. Chem. Soc. 2011. ASAP. DOI: 10.1021/ja206230h

To quickly follow up yesterday’s post on aerobic alcohol oxidation, I thought that this new paper from the Stahl lab on the same topic was worth mentioning.  While their continuous flow process for alcohol oxidation was a pretty big improvement over many existing methods, the reagents necessary were not ideal.  Toluene and pyridine are both toxic, and palladium is not extremely abundant, especially compared to 1st row transition metals.  So there was plenty of room for improvement, which is why I was really psyched to see this new catalyst system for primary alcohol oxidation that was published a few days ago. Virtually all of the reaction components have been replaced by greener reagents:  acetonitrile instead of toluene, N-methylimidazole instead of pyridine, and catalytic TEMPO/(bpy)Cu(I) instead of palladium acetate.  Unlike most aerobic alcohol oxidations, an atmosphere of pure oxygen was not necessary – the oxygen present in ambient air was enough for the reaction to run efficiently.  And the reaction is run at room temperature to boot.  It’s hard to imagine that this reaction would be more difficult to scale up using their flow reactor than the Pd-catalyzed version, although you never know I suppose.

There’s loads more in the paper on their catalyst development studies, and on the chemoselectivity of this process for primary alcohols versus secondary ones – definitely worth reading!

Engineering, Synthesis

The Problem with Oxygen

“Development of safe and scalable continuous-flow methods for palladium-catalyzed aerobic oxidation reactions” Ye, X.; Johnson, M. D.; Diao, T.; Yates, M. S.; Stahl, S. SGreen Chemistry, 2010, 12, 1180-1186.  DOI: 10.1039/c0gc00106f

We’ve had a pair of posts recently about using oxygen as an terminal oxidant in cross-coupling and biomass degradation, and as a green oxidant, it’s pretty hard to beat.  So I was a little surprised to learn that of the many cool aerobic synthetic methods that have been developed in the last decade, very few are used in industry.  The big drawback, especially on large scale, is safety – oxygen is usually the limiting reagent in the combustion reaction, and things can get pretty crazy when you have an oxygen-enriched atmosphere (and much crazier with liquid oxygen – check out this awesome video, and this one that Marty had in his last post).  So while stirring 100 mL of toluene under a balloon of pure oxygen might be fine, doing the same thing with 100 L is problematic.

This setup doesn't scale up very well

Safety aside, these reactions suffer because proper gas-liquid mixing is more difficult to achieve as you scale up.  All of this prompted a collaboration between Eli Lilly and Shannon Stahl‘s lab to develop a scalable continuous-flow method for aerobic alcohol oxidation, which avoids these problems. Continue reading


Direct, aerobic arene olefination

“Ligand-Enabled Reactivity and Selectivity in a Synthetically Versatile Aryl C–H Olefination”  Wang, D.-H.; Engle, K. M.; Shi, B.-F. and Yu, J.-QScience 2010327, 315-319. DOI: 10.1126/science.1182512

“Highly Convergent Total Synthesis of (+)-Lithospermic Acid via a Late-Stage Intermolecular C–H Olefination” Wang, D.-H. and Yu, J.-QJ. Am. Chem. Soc. 2011, 133, 5767-5769.  DOI: 10.1021/ja2010225

The Mizoroki-Heck reaction is a widely-used method for cross-coupling of the C-X bond of aryl halides/pseudo-halides with the C-H bond of an olefin – the reaction is so popular that Richard Heck won a share of the 2010 Chemistry Nobel for palladium cross-coupling.   An equivalent of H-X is produced as a byproduct, which is typically neutralized by the addition of stoichiometric base.

A direct coupling of two C-H bonds is an interesting and potentially green alternative to this reaction, since it could simplify the synthesis of the halide coupling partner (shorter synthesis = less waste) and improve the reaction’s atom economy.  In this sort of reaction a directing group is typically needed so the functionalization occurs at only one of the many aryl C-H positions.  Additionally, an oxidant is needed in the catalytic cycle because the metal catalyst, typically Pd(II), is reduced when it mediates the C-C coupling (this sort of mechanism has been proposed).  Typically silver or copper salts are used in superstoichiometric amounts for this purpose.  From a Green Chemistry perspective this is only a marginal improvement over the original Heck reaction – using several equivalents of a transition metal oxidant isn’t a real improvement over generating an equivalent of neutralized acid (like triethylammonium chloride).

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Presidential Green Chemistry Awards: Codexis/Merck part 2

Savile, Janey, Mundorff, Moore, Tam, Jarvis, Colbeck, Krebber, Fleitz, Brands, Devine, Huisman, and Hughes.  Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture.  Science, 2010, 329, 305-309. DOI: 10.1126/science.1188934.

Here’s a short follow-up on this previous post, which covered a biocatalytic reaction developed by Codexis to make the key intermediate in the synthesis of Merck’s drug montelukast (aka Singulair).  The 2010 Presidential Green Chemistry Awards were just announced, and the award for “Greener Reaction Conditions” went to Merck and Codexis for developing an enantioselective biocatalyst for the synthesis of sitagliptin, Merck’s blockbuster anti-diabetes drug (aka Januvia).  This work is also the subject of a recently-published Science paper from Merck and Codexis.

The paper describes the development of an enzyme-catalyzed replacement for the final reaction in the synthesis of sitagliptin, in which a ketone functionality is converted into an amine. Continue reading


Scalable biocatalytic process for asymmetric reduction in the production of montelukast

Liang, Lalonde, Borup, Mitchell, Mundorff, Trinh, Kochrekar, Cherat, Pai.  Development of a Biocatalytic Process as an Alternative to the (−)-DIP-Cl-Mediated Asymmetric Reduction of a Key Intermediate of Montelukast. Org. Process Res. Dev. 2010, 14, 193-198. DOI: 10.1021/op900272d

This article from researchers at Codexis describes the development of a biocatalytic (i.e. enzyme-catalyzed) method for creating the lone stereocenter in the synthesis of montelukast sodium, aka Merck’s asthma drug Singulair. The original Merck process route includes an enantioselective ketone reduction using a boron reagent derived from alpha-pinene called (-)-DIP-Cl. The reaction works well: high yield, high enantioselectivity (although still requiring a recrystallization step to upgrade from ~95% to 99% ee), and (-)-DIP-Cl is made in one step from cheap starting materials. The downside is that at least 1.5 equivalents of (-)-DIP-Cl must be used, and the reagent is moisture sensitive and corrosive. Codexis, being in the enzyme business, decided to find an enzyme that would catalyze this same reaction. Continue reading