Scalable total synthesis

The scalable total synthesis of the cytotoxic natural product (+)-FR182877 was accomplished in the laboratory of E.J. Sorensen.The key steps of the synthetis were an intramolecular Tsuji-Trost allylation to prepare the 19-membered macrocyclic pentaene followed by a double transannular DIels-Alder cycloadditlon to obtain the desired pentacyclic structure. The allylic carbonate was exposed to 10 mol% of the Pd-catalyst under high dilution conditions in THF. The new bond between Cl and Cl 9 was formed with complete diastereoselectivity and in good yield, although the configuration at Cl 9 was not determined. 

Davies SG, Roberts PM, Stephenson PT, Storr HR, Thomson JE (2009) A practical and scalable total synthesis of the jaborandi alkaloid (-l-)-pilocarpine. Tetrahedron 65 8283-8296. doi 10.1016/j.tetlet.2009.03.021... 

Fanands, R, Mendoza, A., Arto, T., Temelli, B., Rodriguez, R (2012). Scalable total synthesis of (—)-berkelic acid by using a protecting-group-free strategy. Angewandte Chemie International Edition, 51, 4930-4933. 

Berkelic Acid Lessons Learned From Our Investigations on a Scalable Total Synthesis... 

Smith et al. successfully applied this discovery to the total synthesis of numerous natural products. Among them, the spongistatins highlighted the method in a scalable total synthesis.The spongistatins, isolated by Pettit in 1993, belong to a family of marine natural products that... 

In 2006, Ley reported the application of a continuous flow-through platform for the preparation of the neolignan natural product Grossamide (Scheme 8.48) [63], This was the first report of the enantioselective total synthesis of Grossamide utilizing a fully automated and scalable flow reactor with supported-reagents and scavengers. This principle has a wider impact on multiple step assembly of libraries and natural products. 

P.S. (2012) Scalable enantioselective total synthesis of taxanes. Nat. Chem., 4, 21-25. 

The first enantioselective total synthesis of the 2-aryl-2,3-dihydro-3-benzofuran-carboxyamide neolignan grossamide was also developed using a fully automated and scalable fiow reactor [39]. 

Even though significant effort has been invested in developing methods for the total synthesis of oxygenated cardenolides, a scalable and modular... 

The most recently released microwave synthesis equipment is the Anton Paar Synthos 3000 (Fig. 8) [41]. This microwave reactor is dedicated for scale-up synthesis in quantities of up to approximately 250 g per run and designed for chemistry under high-pressure and high-temperature conditions. The instrument enables direct scalability up to 1 L total volume of already elaborated and optimized reaction protocols from single-mode cavities without changing the reaction parameters. 

While the three reported total syntheses of ( )-berkelic acid allowed access to synthetic samples of the natural product, achieving a scalable and modular synthesis of this target remained, for various reasons, an unmet challenge. It should also be noted that Pettus and Brimble s groups have also reported formal total syntheses of (—)-berkelic acid. 

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