Organic Chemistry Portal
Organic Chemistry Highlights

Monday, November 27, 2017
Douglass F. Taber
University of Delaware

Flow Methods: The Collins Synthesis of Neomarchantin A

With the increasing industrial importance of synthesis in flow, much attention has been paid to details of optimal mixing and monitoring. Alessandra Puglisi and Maurizio Benaglia of the Università degli Studi di Milano described (Angew. Chem. Int. Ed. 2017, 56, 4290. DOI: 10.1002/anie.201612192) the use of 3D-printed mesoreactors for a catalytic Henry reaction. Sven R. L. Gobert and Leen C. J. Thomassen of KU Leuven wrote (Org. Process Res. Dev. 2016, 21, 531. DOI: 10.1021/acs.oprd.6b00359) about mixing efficiency and residence time distribution in milli- and microflow reactors. Andrew Livingston of Imperial College London addressed (Angew. Chem. Int. Ed. 2016, 55, 13576. DOI: 10.1002/anie.201607795) inter-reaction solvent exchange by membrane separation. Martin D. Johnson of Eli Lilly compared (Org. Process Res. Dev. 2016, 20, 1305. DOI: 10.1021/acs.oprd.6b00137) tubular and pipe-in-series reactors, both horizontal and vertical.

Kevin P. Cole and his colleagues at Eli Lilly reported (Science 2017, 356, 1144. DOI: 10.1126/science.aan0745) their experience with the flow-based synthesis of prexasertib monolactate monohydrate (4), the last steps of which were the conversion of 1 to imidazole 2 and the subsequent coupling with 3. In particular, they focused on current good manfacturing practices (CGMP), as their object was to produce active pharmaceutical ingredient on a kilogram scale. This process could be operated under interrupted flow, with the DMSO solution of 2 being held for as much as 60 days.

Seiji Suga of Okayama University used (Synlett 2017, 28, 805. DOI: 10.1055/s-0036-1589953) a magnetically immobilized lipase with isopropenyl acetate (6) to convert racemic 5 into 7 and 8 in high ee. Rudolf K. Allemann and Thomas Wirth of Cardiff University showed (Eur. J. Org. Chem. 2017, 414. DOI: 10.1002/ejoc.201601388) that immobilized amorphadiene synthase could be used to efficiently convert 9 to 10. Such terpene synthases often suffer from severe product inhibition, a problem that is alleviated in segmented flow systems.

An advantage of flow systems is that short-lived species can be used effectively. Heejin Kim and Jun-ichi Yoshida of Kyoto University observed (Science 2016, 352, 691. DOI: 10.1126/science.aaf1389) that the iodide of 11 could be converted to the aryl lithium and reacted with 12 to give 13, without acetyl transfer. Leonardo Degennaro and Renzo Luisi of the University of Bari demonstrated (Chem. Commun. 2016, 52, 9554. DOI: 10.1039/C6CC04588J) that the ester 15 could be prepared from 14 with very little accompanying byproduct tertiary alcohol. Weike Su of the Zhejiang University of Techology established (Org. Process Res. Dev. 2016, 20, 2116. DOI: 10.1021/acs.oprd.6b00238) that methyl anthranilate 16 could be diazotized and coupled to make the sulfonyl chloride 17 without hydrolyzing the methyl ester. C. Oliver Kappe of the University of Graz effected (Org. Process Res. Dev. 2016, 21, 878. DOI: 10.1021/acs.oprd.7b00160) Sonogashira coupling of 18 with gaseous propyne 19 to give 20.

Guy Bormans, also of KU Leuven, prepared (Chem. Sci. 2017, 8, 1251. DOI: 10.1039/C6SC02933G) the inverse electron demand dienophile 22 by irradiating 21 in flow. Luke D. Elliott and Kevin I. Booker-Milburn of the University of Bristol designed (Org. Process Res. Dev. 2016, 20, 1806. DOI: 10.1021/acs.oprd.6b00277) a scaled up continuous flow photoreactor that combined 23 and 24 to produce 166 grams/hour of 25.

The marchantins, illustrated by neomarchantin A (28), have shown activity against both influenza A and influenza B. Shawn K. Collins of the Université de Montréal found (Org. Lett. 2017, 19, 2889. DOI: 10.1021/acs.orglett.7b01127) that the macrocyclization of 26 to 27 proceeded efficiently with just ten minutes contact time, and that it was not necessary to remove the byproduct ethylene.

D. F. Taber, Org. Chem. Highlights 2017, November 27.