UC Santa Barbara

I. Savie is a new biodegradable surfactant derived from vitamin E and polysarcosine (PSar) that spontaneously self-aggregates to form nanomicelles intended for use in organic synthesis. It obviates the need for environmentally egregious organic solvents, and is applicable to a multitude of reaction types. These range from Pd-catalyzed cross-couplings using ppm quantities of metal, to biocatalytic transformations, as well as multistep, 1-pot chemoenzymatic sequences, among others. Use of Savie frequently leads to higher yields in several of the most commonly used reactions compared to those obtained from previous generations of non-biodegradable PEGylated surfactants. Moreover, it reduces dependence on the presence of organic co-solvents to achieve adequate emulsions.

II. Two sustainable routes to the antimalarial drug pyronaridine have been developed: (1) a linear route involving a 2-step, 1-pot sequence leading to the targeted drug in 87% overall yield; and (2) a convergent route involving a 3-step tandem sequence, affording pyronaridine in 95% overall yield. Comparisons to an existing process reveal a 5-fold decrease in environmental impact, as measured by Sheldon’s E Factors, along with major potential cost-savings which may enable the low-cost manufacture and distribution of this drug to the developing world.

III. An environmentally responsible 7-step, 3-pot synthesis of nirmatrelvir, the key ingredient in Paxlovid, is described, arriving at the targeted drug in 70% overall yield. The route features several newly developed green methodologies, including the Pd-catalyzed dehydration, in water, of a primary amide to furnish a nitrile, thereby avoiding use of the Burgess reagent and chlorinated solvents. Also featured are several amide bond-forming reactions that no longer rely on traditional (environmentally egregious) coupling reagents.