Title : Against all odds the development of a unique asymmetric sulfide oxidation
Abstract:
Syntheses for achieving stereoselective oxidations of pro-chiral sulfides to the corresponding enantiomerically defined sulfoxides have been known since the early 1960s (Andersen, 1962). The practical value of this methodology and other (Davis, 1980s and 90s) was limited, due to a lacking performance and preparative usefulness. A major game changer occurred (1984) when Henri Kagan and his group presented a titanium-based procedure building on the concomitantly developed stereoselective hydroxylation protocol by Sharpless using Ti, a homo-chiral tartaric acid ester, and a suitable oxidant. A major downside, however, was that a good to excellent enantiomeric outcome was only delivered when starting with simple sulfides such as methyl-benzylsulfide. In this lecture the need for an efficient, robust, and high-yielding sulfoxidation process for industrial application related to a novel proton-pump inhibitor (prevention of ulcers and other gastric problems) by the Swedish pharmaceutical company Astra will be described and discussed. In this project, the sulfide precursor was of substantial complexity, which rendered the Kagan method unsatisfactory offering just 5 % ee at most. Instead, the enantiomers of the racemic sulfoxide omeprazole (with identical atomic arrangement as the desired compound) were separated via preparative chromatography (on kg scale) – a very tedious and low-yielding operation which could immediately be discarded as non-feasible for further scale up. Instead, all efforts were invested in finding an asymmetric synthesis that would successfully generate the desired (S)-enantiomer, esomeprazole, constituting the target molecule, which later (around the year 2000) was launched as Nexium®. The successful outcome emanated in an unprecedented process that enabled the manufacture of the product in excellent yield (>90%) and with outstanding stereochemical purity (>93%) on a large tonnage scale.
Audience Take Away:
- This lecture provides an insight into an authentic case and shows the methodology used to arrive at a successful outcome.
- The contents will hopefully give the audience inspiration to not shy away from even the toughest problems.
- No doubt, if the molecular motifs under investigation are analogues to those presented in the talk.
- Inasmuch as the result of the work described was a commercial scale process delivering an important active pharmaceutical ingredient.
- It will point out a robust and highly efficient way of performing the chemical transformation in question.
