Organic Chemistry Portal
Organic Chemistry Highlights

Monday, March 30, 2020
Douglass F. Taber
University of Delaware

Preparative Enzymatic Synthesis of Carbocycles: Cembranolide (Taber), Quassin (Shing), Wickerol A (Gui), Cattyleyene (Dickschat), Englerin A (Liu/Christmann), Artemisinic Acid (Paddon/Newman), Etoposide Aglycone (Satteley)

The Pd-catalyzed carbon-carbon bond formation pioneered by Heck in 1969 has dominated medicinal chemistry development for the ensuing fifty years. For the upcoming fifty years, as attention turns to more complex three-dimensional active pharmaceutical ingredients, it will be preparative enzyme-mediated assembly that will make the requisite enantiomerically-pure polyalicyclic precursors affordable.

Naturally-derived (enzymatically assembled) starting materials have long been used in target-directed synthesis. We cyclized 1, derived from farnesol, into the tetrahydrofuran 2, and carried that on to cembranolide (3) (J. Org. Chem. 1997, 62, 6603. DOI: 10.1021/jo971065w).

Carbocyclic, enantiomerically-pure carvone has been used as the starting material for many syntheses. En route to quassin (6), Tony K. M. Shing of the Chinese University of Hong Kong cyclized 4 to 5 (J. Org. Chem. 2000, 65, 7059. DOI: 10.1021/jo000877g).

Steroids as a group are probably the most widely used polyalicyclic pharmaceuticals. Most of those are derived by microbial degradation of plant sterols. Sitolactone (7), a byproduct of that degradation and so available in metric ton quantities, is also a useful starting point for synthesis, as demonstrated by the assembly of wickerol A (9) via 8 reported by Jinghan Gui of the Shanghai Institute of Organic Chemistry (J. Am. Chem. Soc. 2020, 142, 4690. DOI: 10.1021/jacs.9b11838).

There has been increasing interest in the production of complex terpenes by fermentation using designed microbes. Jeroen S. Dickshat of the University of Bonn reported using E. coli containing an enzyme from S. cattleya to convert geranylgeranyl diphosphate to the diterpene cattleyene (10) (Angew. Chem. Int. Ed. 2019, 58, 9230, DOI: 10.1002/anie.201902950; for a review, see 58, 15964, DOI: 10.1002/anie.201905312). Tiangang Liu of Wuhan University and Mathias Christmann of the Freie Universität Berlin modified S. cerevisiae to product 11 (0.8 g/L) and carried it on to englerin A (12) (J. Am. Chem. Soc. 2020, 142, 2760. DOI: 10.1021/jacs.9b12940).

C. J. Paddon and J. D. Newman of Amyris raised the production of artemisinic acid (13) in S. cerevisiae to 25 g/L, continuously extracting the product from the fermentation (Nature 2013, 496, 528. DOI: 10.1038/nature12051). This approach is not limited to microorganisms - Elizabeth S. Sattely of Stanford University engineered tobacco plants to produce etoposide aglycone 14, 0.71 mg/g dry weight (J. Am. Chem. Soc. 2019, 141, 19231. DOI: 10.1021/jacs.9b10717). Complex alicyclic starting materials are not only produced enzymatically. J. Henrique Teles of BASF isolated 15 and several other saturated polycycles as byproducts from the commercial production of cyclododecanone (J. Org. Chem. 2019, 84, 13211. DOI: 10.1021/acs.joc.9b01633).

The exploration of multi-dimensional medicinal chemistry space has only just begun. These and many other complex polyalicyclic building blocks could provide useful entry points for in silico investigation.

We note with sorrow the passing of Professor Kilian Muņiz of ICIQ, whose work has often graced these pages.

D. F. Taber, Org. Chem. Highlights 2020, March 30.