An asymmetric, organocatalytic, one-pot Mannich cyclization between a hydroxylactam and acetal is described to provide fused, bicyclic alkaloids bearing a bridgehead N atom. Both aliphatic and aromatic substrates were used in this transformation to furnish chiral pyrrolizidinone, indolizidinone, and quinolizidinone derivatives in up to 89% yield and 97% ee. The total syntheses of (-)-epilupinine, (-)-tashiromine, and (-)-trachelanthamidine also achieved to demonstrate the generality of the process.
Described here is the design, synthesis, and conformational analysis of cyclic tetrapeptides (CTPs) with α3γ architecture containing a furan-based locked Z-vinylogous amino acid (Vaa). This unnatural amino acid locks into a γ-turn that induces type IαRS-turn in the CTPs. Stabilized by a 13-membered intramolecular H-bond, these CTPs show robust conformation in water and aprotic solvent irrespective of the sequence of tripeptide consisting of α-amino acids used.
Acid-catalyzed intramolecular vinylogous Mannich reactions and intramolecular Michael reactions affording pyrrolizinone-fused N-heterocycles from hydroxylactam derivatives bearing enals have been developed. Depending on the substituent on the hydroxylactam, the enal moiety acted either as a nucleophile (i.e., as an enol/enolate) or as an electrophile to react with the N-acyliminium ion or enamide generated from the hydroxylactam moiety, respectively. The reactions were demonstrated in the construction of fused N-heterocycles with 5-to 8-membered rings.B icyclic N-heterocycles bearing pyrrolidine rings or pyrrolidin-2-one moieties, such as pyrrolizines, 1 indolizines, 2 indolizinones, 2 pyrroloazepines, 3 and pyrroloazocine, 3 are present in bioactive natural products 1−3 (Figure 1).
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c00283.Experimental procedures and characterization data of the compounds (PDF) NMR spectra with assignments and related information (PDF)Accession CodesCCDC 2053902 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk
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