Application of a One‐Pot Friedel–Crafts Alkylation/Michael Addition Methodology to the Asymmetric Synthesis of Ergoline Derivatives

Abstract

Herein, we report a short and facile stereoselective route to ergoline derivatives. The key steps are a one‐pot Friedel–Crafts alkylation/Michael addition sequence which, in the absence of chiral ligands, affords the trans‐trans‐stereoisomer in 44 % yield as a racemate. Screening of a range of chiral bisoxazoline ligands allowed this sequence to proceed in 42–55 % yields (six examples), with up to 99 % ee. This approach allows for the first time, substitution at the C4‐position and the introduction of 3 chiral centres in one pot. An interesting, base‐mediated conversion of the trans‐trans‐stereoisomer to the cis‐cis‐stereoisomer was discovered and both stereoisomers were characterized by X‐ray crystallography.

Further Developments and Applications of Oxazoline-Containing Ligands in Asymmetric Catalysis

“…The reaction was very sensitive to changes on the aryl group of the trans -β-nitrostyrene derivative 1134 . 403 …”

“…Subjecting the indole 1138 to the Zn­(OTf) 2 / 1125 -catalyzed reaction with a range of trans -β-nitrostyrene derivatives 1134 , followed by the addition of DBU, the tricyclic products 1139 were isolated as the anti – anti diastereomers in up to 55% yield and with up to 99% ee (Scheme ). The reaction was very sensitive to changes on the aryl group of the trans -β-nitrostyrene derivative 1134 …”

“…The reaction was very sensitive to changes on the aryl group of the trans-β-nitrostyrene derivative 1134. 403 Wang and Xu have applied ligand 1125 in the Cu-catalyzed conjugate addition of 2-substituted benzofuran-3−2H-ones 1140 to α,β-unsaturated ketones 1141 to give the corresponding enantioenriched β-substituted-β-keto esters 1142 in up to 95% yield and with high enantioselectivities up to >99% ee (Scheme 342). 404 In the same report, the substrate scope was extended to include linear β-substituted and cyclic enones, giving the linear products 1143 and 1144 with excellent enantio-and diastereoselectivities, while the cyclic products 1145 and 1146 were isolated in excellent enantioselectivities but low diastereoselectivities (Figure 53).…”

A Tandem Asymmetric Friedel–Crafts Alkylation/Michael Addition: Synthesis of Novel Ergoline Derivatives

“…In 2017, our research group were working on a related Zn II ‐bis(oxazoline)‐catalyzed one‐pot/two‐step FC alkylation/Michael addition reaction for 4‐substituted indole esters 7 and trans ‐β‐nitrostyrene derivatives 8 (Scheme b) . We were able to install three contiguous chiral centres from C 4 to C 6 in a complimentary method in up to 99 % ee .…”