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Abstract:
The acid-catalyzed cyclization of neral to trans-isopiperitenol has remained an unsolved challenge. Even under mildly acidic conditions, the desired cyclic allylic alcohol is labile and, therefore, prone to several side reactions. Although isopiperitenol has been previously utilized as a monoterpenoid building block in the synthesis of cannabinoids and menthol, its asymmetric access is restricted to tedious multi-step or enzymatic approaches. Given the global trend of increased legalization of cannabis for medical and recreational use, the demand for synthetic cannabinoids is rising. Thus, more efficient and industrially applicable routes are highly desired, ideally circumventing environmental-dependent extraction processes.
This work describes the development of the highly diastereo- and enantioselective Brønsted acid-catalyzed cyclization of neral using a highly fluorinated, non-C2-symmetric confined iIDP catalyst. The cyclization to trans-isopiperitenol can easily be performed on a larger scale without loss of selectivity and nearly quantitative catalyst recovery. Furthermore, obtained trans-isopiperitenol was successfully used in the asymmetric synthesis of (−)-menthol, piperitol, and several cannabinoids, such as cannabidiols and tetrahydrocannabinols, displaying each the shortest and most atom-economic routes so far. The developed method was further applied in the cyclization of various other α,β-unsaturated aldehydes to give novel cyclic allylic alcohols in high yields and selectivities. Mechanistic studies reveal that the catalyst achieves this peculiar and outstanding selectivity by binding the product in an unreactive conformation, thus suppressing the side product formation.
Along these lines, the described work solved the long-standing challenge of the Brønsted acid-catalyzed cyclization of neral to trans-isopiperitenol, a potent chiral monoterpenoid building block. While most catalytic systems – Lewis and Brønsted acids – are unable to control the high reactivity of the product in the required acidic media, our iIDP catalyst allows the highly diastereo- and enantioselective formation of trans-isopiperitenol. Furthermore, the expansion of this method to other α,β-unsaturated aldehydes and the easy scalability may aid the synthesis of menthol and cannabinoid derivatives previously inaccessible.
