Asymmetric Total Synthesis of All Rugulovasine Stereoisomers and Preliminary Evaluation of Their Biological Properties

A unified enantioselective synthesis and the biological evaluation of all rugulovasine stereoisomers are reported. The syntheses are centered on the divergent and stereochemical modular combination of each enantiomer of 4-amino Uhle's ketone and a methacrylate derivative to build the unsaturated oxaspirolactone moiety by the Dreiding-Schmidt reaction, followed by Fukuyama alkylation to afford the required N-methyl secondary amine in excellent yield. The modularity of this divergent approach, the diastereoselectivities of the reactions, and the late-stage site-selective methylation permit the rapid asymmetric syntheses of all rugulovasine stereoisomers, including the first total syntheses of optically pure (+)- and (−)-rugulovasine B and their trideuteromethylated derivatives. All enantiopure stereoisomers of rugulovasine were tested for their binding affinities to dopamine, serotonin, and adrenergic neuroreceptors, revealing their preferred selectivity for the serotonin 1 A receptor

C3-Alkylation of indoles and oxindoles by alcohols by means of borrowing hydrogen methodology

Transition metal‐catalyzed C3‐alkylation of indoles and oxindoles with nonderivatized alcohols, by means of borrowing hydrogen (BH) activation of the alcohol substrates, avoids the use of environmentally unfriendly alkylating agents. Only water is formed as the byproduct, thus making the BH process atom‐economical and environmentally benign. Diverse homogeneous and heterogeneous transition‐metal catalysts, indoles and oxindoles, and nonderivatized alcohols can be used for this transformation, hence rendering the BH process promising for replacing those procedures that use traditional alkylating agents. Although some earlier literature is discussed, this review mainly covers the literature published since 2015

Large-Scale Preparation of N-Butanoyl-l-glutathione (C4-GSH)

A novel two-step synthesis of N-butanoyl-l-glutathione (C4-GSH) was developed involving the chemical modification of the commercially available starting material l-glutathione (GSH). This process not only has the advantage of selective acylation of the GSH amino group without the use of previous solid-phase organic synthesis and/or protecting group chemistry but also highlights the use of inexpensive reagents such as butyric anhydride and sodium methoxide as well as environmentally acceptable solvents such as water and methanol. This chromatography- and salt-free synthesis of C4-GSH is cost-effective, safe, efficient, and easy to scale up

Total Synthesis of (-)-Clavicipitic Acid via γ,γ-Dimethylallyltryptophan (DMAT) and Chemoselective C-H Hydroxylation

The first total synthesis of natural (-)-clavicipitic acid from γ,γ-dimethylallyltryptophan (DMAT), its biosynthetic precursor, is described. This is done by regio- and chemoselective, remote, nondirected C(sp3)-H hydroxylation followed by aminocyclization. This study also features regio- and chemoselective Pd(0)-catalyzed linear prenylation at C4 of l-tryptophan boronic pinacol ester derivate, the latter obtained by a Lewis acid-promoted aziridine amino acid ring opening with 4-boronated indole. In addition, these results support the hypothesis that oxidative cyclization between amino acid nitrogen and the prenyl chain during clavicipitic acid biosynthesis can occur through the transient hydroxylated intermediate

Organocatalytic Aza-Friedel-Crafts/Lactonization Domino Reaction of Naphthols and Phenols with 2-Acetamidoacrylate to Naphtho- and Benzofuranones Bearing a Quaternary Center at the C3 Position

N-Acetyl ketimine generated from methyl 2-acetamidoacrylate was explored to develop an unprecedented domino aza-Friedel-Crafts/lactonization reaction with naphthols and phenols (including 5-hydroxyindoles). This novel method requires a catalyst loading of only 5 mol % of a phosphoric acid catalyst and provides a new series of 3-NHAc-naphtho- and benzofuranone derivatives bearing tetra-substituted stereogenic centers in moderate-to-good yields. The enantioselective variant using BINOL-derived phosphoric acids was also explored with 1-naphthol, providing the desired product with moderate enantioselectivities (up to 99:1 following recrystallization)

Asymmetric Alkylation of Cyclic Ketones with Dehydroalanine via H-Bond-Directing Enamine Catalysis: Straightforward Access to Enantiopure Unnatural α-Amino Acids

The growing importance of structurally diverse and functionalized enantiomerically pure unnatural amino acids in the design of drugs, including peptides, has stimulated the development of new synthetic methods. This study reports the challenging direct asymmetric alkylation of cyclic ketones with dehydroalanine derivatives via a conjugate addition reaction for the synthesis of enantiopure ketone-based α-unnatural amino acids. The key to success was the design of a bifunctional primary amine-thiourea catalyst that combines H-bond-directing activation and enamine catalysis. The simultaneous dual activation of the two relatively unreactive partners, confirmed by mass spectrometry studies, results in high reactivity while securing high levels of stereocontrol. A broad substrate scope is accompanied by versatile downstream chemical modifications. The mild reaction conditions and consistently excellent enantioselectivities (>95 % ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical enantiopure α-amino-acid building blocks

Concise and Convergent Enantioselective Total Syntheses of (+)- and (-)-Fumimycin

The concise and convergent total syntheses of (+)- and (-)-Fumimycin have been achieved by taking advantage of strategies for the asymmetric aza-Friedel-Crafts reaction of a highly substituted hydroquinone and N-fumaryl ketimine generated from the corresponding dehydroalanine. The enantiomerically pure natural product and its enantiomer were prepared in seven steps and 22% overall yield by employing both enantiomers of a BINOL-derived chiral phosphoric acid (CPA) catalyst

Concise catalytic asymmetric synthesis of (R)-4-amino Uhle's ketone

A practical and asymmetric synthesis of (R)-4-amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole, an enantiopure framework shared by most ergot alkaloids, was accomplished. Our method involves a Rh(i)-catalyzed 6-exo-trig intramolecular cyclization of an appropriate 4-pinacolboronic ester d-tryptophan aldehyde followed by the oxidation of the resulting secondary benzylic alcohol with a Cu(i)-ABNO catalyst and final deprotection under acidic conditions. This new procedure offers significant advantages over previous synthetic approaches, including brevity, mild reaction conditions, preservation of chiral integrity, and high overall yield and avoids the use of stoichiometric amounts of strongly basic and pyrophoric organometallic reagents

Synthesis and Fluorescence Properties of 4-Cyano and 4-Formyl Melatonin as Putative Melatoninergic Ligands

Fluorescent ligands are imperative to many facets of chemical biology and medicinal chemistry. Herein, we report the syntheses of two fluorescent melatonin-based derivatives as potential ligands of melatonin receptors. The two compounds, namely, 4-cyano and 4-formyl melatonin (4CN-MLT and 4CHO-MLT, respectively), which differ from melatonin by only two/three atoms that are very compact in size, were prepared using the selective C3-alkylation of indoles with N-acetyl ethanolamines involving the "borrowing hydrogen" strategy. These compounds exhibit absorption/emission spectra that are red-shifted from those of melatonin. Binding studies on two melatonin receptor subtypes showed that these derivatives have a modest affinity and selectivity ratio

General synthesis of unnatural 4-, 5-, 6-, and 7-bromo-d-tryptophans by means of a regioselective indole alkylation

A general two-step approach to enantiopure bromotryptophans from unprotected bromoindoles has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted with cyclic sulfamidates derived from enantiopure D-serine to form 4-, 5-, 6-, or 7-bromo-D-tryptophan and some other halogenated tryptophans in moderate yields but with complete regioselectivity. The bromotryptophan derivatives were deprotected using mild conditions