Functionalization of terpenes by selective deprotonation for the synthesis of (+)-artemisinin and related compounds
AssigneeBoard of Regents, The University of Texas System
InventorsDoug E. FRANTZ, Shawn BLUMBERG, Eliezer ORTIZ, Nicholas CLANTON, Nick WILSON
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Abstract
The present invention provides methods for the preparation of (+)-Artemisinin and intermediates thereof, including via the regioselective deprotonation of amorphadiene (AD). In other aspects, there are provided methods for the functionalization terpenes by selective deprotonation, including the utilization of 4,11-amorphadiene as an industrially viable feedstock for the synthesis of artemisinin. In some embodiments, these methods are broadly applicable to the derivatization of a variety of cyclic and linear terpenes.
Claims43
A method for the preparation of a compound of Formula II comprising deprotonating and oxidizing a compound of Formula I:
- with one or more reagents under suitable conditions to make a compound of Formula II:
- wherein:
- R1 and R2 are each independently H, alkenyl(C≤12), substituted alkenyl(C≤12), cycloalkenyl(C≤12), or substituted cycloalkenyl, with the proviso that at least one of R1 and R2 is not hydrogen;
- or
- R1 and R2 are taken together to form an alkenediyl(C≤12) or a substituted alkenediyl(C≤12).
The method of claim 9, wherein the oxidizing agent is hydrogen peroxide.
A method for the preparation of artemisinic alcohol comprising deprotonating and oxidizing
- with one or more reagents under suitable conditions to make artemisinic alcohol.
The method of claim 11, wherein the one or more reagents comprise n-BuLi, KOtBu, and 2,2,6,6-tetramethylpiperidine (TMP).
A method for the preparation of artemisinic acid comprising:
- (a) deprotonating and oxidizing
- with one or more reagents under suitable conditions to make
- (b) oxidizing
- with one or more reagents under suitable conditions to make
- (c) oxidizing
- with one or more reagents under suitable conditions to make artesimic acid.
A method of regioselectively deprotonating and oxidizing an exocyclic carbon-carbon double bond over an endocyclic carbon-carbon double, comprising contacting a substrate having both an exocyclic carbon-carbon double bond and an endocyclic carbon-carbon double bond with one or more reagents under suitable conditions to convert the substrate's exocyclic carbon-carbon double bond into a carbon-carbon single bond with a hydroxy substituent.
Dependencies are inferred from the claim text.