Abstract
Rhodium-catalyzed hydroacylation using alkynes substituted with pendant nucleophiles, delivers linear α,β-unsaturated enone intermediates with excellent regioselectivity. These adducts are used to construct a broad range of diversely substituted, saturated O-, N- and S-heterocycles in a one-pot process. Judicious choice of cyclisation conditions enabled isolation of O-heterocycles with high levels of diastereoselectivity. A variety of derivatisation reactions are also performed, generating functionalised hydroacylation products. This sequence serves as a general approach for the synthesis of fully saturated heterocycles.
Highlights
Since Lovering's seminal ‘ atland’ epiphany,[1] more emphasis lies on increasing saturation within therapeutics.[1,2] This increased three-dimensionality results in the improved aqueous solubility,1,2g,3 and target selectivity of drug candidates.[4]
A variety of derivatisation reactions are performed, generating functionalised hydroacylation products. This sequence serves as a general approach for the synthesis of fully saturated heterocycles
We targeted the synthesis of sulfur containing heterocycles,[27] and for our initial investigation aldehyde 1a was paired with alkanethiol 6a under our previously optimized hydroacylation conditions (Scheme 4)
Summary
Since Lovering's seminal ‘ atland’ epiphany,[1] more emphasis lies on increasing saturation within therapeutics.[1,2] This increased three-dimensionality results in the improved aqueous solubility,1,2g,3 and target selectivity of drug candidates.[4]. In this article we describe a one-pot hydroacylation/ diastereoselective conjugate-addition sequence, that delivers an exceptional scope of saturated N-, O- and S-heterocycles from simple unactivated substrates. Alkyl sul de 5i and 2aminobenzaldehyde-derived product 5j, were obtained with good to moderate dr, but required alternative Rh-catalysts.8b,23 Di- and Mono-substituted b-ketoamides 5k and 5l, both displayed excellent ring-closing diastereoselectivity, with yields of 92% and 64%, respectively.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
