Design and Scale-Up of a Practical Enantioselective Route to 5-Phenylbicyclo[2.2.2]oct-5-en-2-one

Abstract

A practical enantioselective route to chiral 5-phenylbicyclo[2.2.2]oct-5-en-2-one 1 has been designed and developed. The target compound has been obtained as colorless crystals in 22% yield from 2-cyclohexenone, with an enantiomeric ratio higher than 99.5:0.5 and notably high chemical purity (> 99%). Three intermediates out of nine chemical steps are isolated. It is noteworthy that this process is devoid of any chromatography or distillation although all but one intermediate are oils. Key to success was the optimization of an intramolecular aldol reaction of an in situ prepared ketone aldehyde leading to the solid intermediate (1R,4R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one 9a that is isolated in very high chemical and chiral purity. This is an example of an intramolecular crystallization-induced diastereomer transformation (CIDT). The dehydration of this secondary alcohol to 1 required an extensive screen of reaction conditions to secure an excellent purity, essential for crystallization of this low-melting compound. The final process is simple and concentrated as demonstrated by an expeditious synthesis of 1 kg of 1 in a 30-L reactor in 10 working days.

Dehydration reactions in polyfunctional natural products

“…32 In contrast, geometries that obstruct anti-periplanar E2 elimination may significantly hamper reaction outcomes, for instance, as demonstrated by the elimination of a bicyclic alcohol derivative (11) under the requirement of an E2 syn-elimination of the corresponding mesylate derivative (12) (see Scheme 4B). 33 Following sampling of various dehydration strategies, highly concentrated reaction conditions using refluxing 2,4,6-collidine as solvent/base, were needed to access to 5-phenylbicyclo[2.2.2]oct-5-en-2-one (13) in an efficient process from (11). Such forcing conditions, however, do not have general applicability.…”

Daring the Challenge and Thinking Big: The Value of Early Process R&D

“…Further safety investigations restricted the scale of this reaction at the low kgrange in agitated glass vessels. [9] We hence replaced acetoxyacrylonitrile (4) by other dienophiles like acrylonitrile (6) or chloroacrylonitrile (7). The Diels-Alder reaction of 6 with 5 suffered from the same limitations as the one with 4.…”

“…Especially approach h) was of importance as the Shibasaki reaction, [6] i.e. the asymmetric Michael addition of dimethylmalonate to cyclohexenone, established the first chiral center in an efficient manner and allowed for the first enantioselective approach to 1, [7] and ultimately paved the way to the final organocatalytic approach i), [8] both described as 2 nd generation routes below.…”

Daring the Challenge and Thinking Big: The Value of Early Process R&D

“…The dehydration to 1 using standard methods produced black tarry mixtures. [7] The bicyclic system is suspected to be prone to skeletal rearrangements. After extensive scouting, a fine-tuned two-step process turned out to be optimal.…”

“…Subjecting these isomers separately to the dehydration to 1 led to the following observations: (i) 28c did not react in the elimination sequence; (ii) 28a and 28b were comparable in reactivity (kinetics & purity); hydroxybicyclo[2.2.2]octan-2-one 28a via an intramolecular aldol reaction (Scheme 9). [7] The process (9 chemical steps, 22% yield) is simple and volume-efficient as demonstrated by an expeditious synthesis of a 1-kg batch of 1 in a 30-L reactor in less than 10 working days.…”