Catalysis, Synthesis

Iron-catalyzed C-H Borylation

“Iron-Catalyzed C-H Borylation of Arenes” Dombray, T.; Werncke, C. G.; Jiang, S.; Grellier, M.; Vendier, L.; Bontemps, S.; Sortais, J-B.; Sabo-Etienne, S.; Darcel, C. J. Am. Chem. Soc. 2015, ASAP. DOI: 10.1021/jacs.5b00895

C-H borylation, itself a green reaction for generating useful borylated compounds, is traditionally catalyzed by Ir and Rh. Much of the work has been conducted by John Hartwig’s group at Berkeley and Mitch Smith’s group at Michigan St. French scientists have now reported an iron-catalyzed version, which complements recent reports with Co complexes and dinuclear transition metal complexes. I especially like that the reported reaction is free of H2 acceptors and utilizes light to activate the catalyst.

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Update: Improving atom economy of dehydrogenative decarbonylation

“Selective Metal-Catalyzed Transfer of H2 and CO from Polyols to Alkenes” Verendel, J. J.; Nordlund, M.; Andersson, P. G. ChemSusChem, 2013, 6, 426-429. DOI: 10.1002/cssc.201200843

In a recent post I commented on the byproducts of dehydrogenative decarbonylation, namely H2 and CO.

1st reaction scheme

I wondered whether this gas mixture, syngas, could be used in a subsequent reaction. This would improve the atom efficiency of the reaction and potentially also improve the safety (of both the syngas-producing and syngas-using reactions). Both are goals of green chemistry and I especially appreciate avoiding rolling cylinders of toxic and/or flammable gases around the lab.

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Rh-catalyzed Alcohol Deoxygenation

“Acceptorless Photocatalytic Dehydrogenation for Alcohol Decarbonylation and Imine Synthesis.” Ho, H-A.; Manna, K.; Sadow, A. D. Angew. Chem. Int. Ed. 2012, 51, 8607-8610. DOI: 10.1002/anie.201203556

The use of biorenewables as feedstock chemicals for commodity chemicals as well as fuels requires mild, selective removal of oxygen-containing functional groups. This is in direct contrast to the production of these chemicals from petroleum products, which, at least for highly functionalized target molecules, necessarily involves oxygenation of hydrocarbons.

There are a large amount of methods development currently underway and I highlight the recent report from the Sadow group on the decarbonylation of alcohols under Rh catalysis. I think the described reaction is a good example of green chemistry, as the reaction is high-yielding, selective, and performed at room temperature under photocatalytic conditions. One serious drawback is the use of benzene as the solvent, although toluene works as a solvent in at least some cases.

Reasoning that photolysis would prevent catalyst inhibition by CO binding, the researchers first screened Rh(I) catalysts under photocatalytic conditions with the test substrate cyclohexanemethanol. Unfortunately, no cyclohexane was observed under these reaction conditions. The group then tested Rh and Ir compounds known for C-H activation, such as Cp*Ir(CO)2 and Tp*Rh(CO)2, and did observe cyclohexane for one of the tested catalysts, albeit in low yield (36 % NMR yield with Tp*Rh(CO)2). CO and H2 were also observed, consistent with the targeted alcohol decarbonylation reaction. Interestingly, using their previously reported rhodium tris(oxazolinyl)borate complex ToMRh(CO)2 (1) improved the yield to > 95%. Furthermore, the related dihydride, ToMRh(H)2CO (2) was roughly three times slower and the Ir complex ToMIr(CO)2 was inactive for this reaction.

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Raging Hormones – Gram-Scale Synthesis of Prostaglandin PGF2α

“Stereocontrolled organocatalytic synthesis of prostaglandin PGF in seven steps” Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature 2012, online view. DOI: 10.1038/nature11411

In my very un-scientific survey of the green chemistry-branded journals, I see way more new methodologies than I see total syntheses. I hope to single-handedly change this, and show how green a total synthesis can be by writing about the awesome recent synthesis of prostaglandin PGF by Aggarwal and coworkers. First, a few words on the target molecule. Being hormones, prostaglandins such as PGF are involved in tons of biological processes. Interestingly, instead of being synthesized by some important gland and acting in far-off regions of the body as are endocrine hormones, they are autocrine or paracrine hormones and are synthesized “on-site.” The first structural characterizations of prostaglandins came in the 1960s, some 30 years after their initial discovery. Soon after, they became the subject of numerous syntheses, the first of which was achieved by E. J. Corey in 1969. A series of syntheses followed, but even 40 years later, the structurally-related glaucoma drug latanoprost is synthesized in 20 steps using Corey’s 1969 prostaglandin strategy.

That’s right, the prostglandin structural motif is medicinally relevant. So, not only would an improved synthesis be cool from a fundamental science perspective, it might actually be moved into industrial production and have an immediate impact! Continue reading

Materials, Synthesis

A “Designer” Surfactant for Cross Couplings of Hydrophobic Reagents in Room Temperature Water

“TPGS-750-M: A Second-Generation Amphiphile for Metal-Catalyzed Cross-Couplings in Water at Room Temperature” Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood, R. J. Org. Chem. 201176, 4379-4391. DOI: 10.1021/jo101974u

I occasionally run reactions in water, and it is awesome. I LOVE not worrying as much about cancer. Unfortunately many interesting chemicals are simply too hydrophobic to allow reactions to be run in aqueous solution. As anyone who has ever scrubbed a greasy pan will know, one way to get around the solubility problem is with soap. Also called emulsifiers, surfactants, amphiphiles, a soap by any name is pretty much the same thing in my mind (though others will disagree I’m sure). Molecules with hydrophilic and hydrophobic ends can form micelles in water, creating variously-shaped and sized particles with hydrophobic cores. Using those hydrophobic cores as reaction media is a concept known as micellar catalysis. The Lipshutz group was not the first player in this arena, but they have been at it for some time. They recently teamed up with the medicinal chemistry company Kalexsyn and came out with a new amphiphile that caught my eye, dubbed TPGS-750-M. 

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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

High-Yielding Semi-Synthesis of an Artemisinin Precursor

“Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin” Westfall, P.J.; Pitera, D.J.; Lenihan, J.R.; Eng, D.; Woolard, F.X.; Regentin, R.; Horning, T.; Tsuruta, H.; Melis, D.J.; Owens, A.; Fickes, S.; Diola, D.; Benjamin, K.R.; Keasling, J.D.; Leavell, M.D.; McPhee, D.J.; Renninger, N.S.; Newman, J.D.; Paddon, C.J. Proc. Natl. Acad. Sci. U.S.A. 2012109, E111-E118. DOI: 10.1073/pnas.1110740109.

Malaria, caused mainly by the parasite Plasmodium falciparum, leads to nearly a million deaths and 250 million new infections each year. The sesquiterpene lactone endoperoxide artemisinin, derived from Artemisia annua, is very effective as an antimalarial drug, and widespread resistance hasn’t yet developed. Artemisinin is the only high-volume drug that is still isolated by extraction from its native plant producer in a low-yielding (around 10 μg per g plant material), resource-intensive process that uses volatile solvents (most commonly hexane).

Artemisia annua. Photo credit: Jorge Ferreira via Wikimedia Commons.

As a result, supplies of the drug are short, and those who need it often can’t afford it. The development of new processes for artemisinin production would therefore advance both public health and green chemistry interests. Total synthesis of the drug hasn’t been considered as a viable alternative because of low yields, but a lot of effort has been directed toward developing semi-synthetic sources of artemisinin using a combination of microbial fermentation and chemical synthesis. Toward this end, the Keasling lab reported a few years ago that they had constructed a biosynthetic pathway for the artemisinin precursor amorpha-4,11-diene in yeast with yields of ~200 mg/L—already impressive given the complexity of the molecule. Amorphadiene synthase (ADS) comes from Artemisia annua; the rest of the genes are from yeast. Here is the existing pathway:

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