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

DIFFERENT STRATEGIES FOR CONCISE TOTAL SYNTHESIS OF ALKALOIDS AND BIOLOGICAL UNDERSTANDING: ERGOT AND DAPHNIPHILLUM ALKALOIDS

This thesis comprises different projects generally divided into three main chapters. The first main project was the enantioselective total synthesis of clavine-type alkaloids through a divergent synthesis based on the key intermediate (R)-4-amino-Uhne’s ketone, chapter 3. In this chapter, is presented our strategy to synthesize this enantiopure key intermediate through an Rh(I) catalyzed 6-exo-trig intramolecular cyclization of an appropriate 4-pinacol boronic ester D-tryptophan aldehyde, followed by the oxidation of the secondary alcohol produced by this reaction, using a mixture of catalytic Cu(I)-ABNO and stochiometric O2. The next goal of the project was the implementation of this precocious substrate for the enantioselective synthesis of all four rugulovasine stereoisomers, important rearranged clavine alkaloids, through a Dreiding-Smith lactonization mediated by zinc, alkene isomerization using catalytic amount of Ru3(CO)12, and Fukuyama alkylation protocol to install the desired methyl group to the primary amine. These molecules were submitted to a preliminary biological evaluation, with an initial screening of binding properties toward an array of CNS receptors and a subsequential selection of the more active ((+)-rugulovasine B) for IC50 evaluation on different serotonin receptors. Subsequential development of this divergent approach to the class of tetracyclic clavine or ergoline has been achieved using a telescoping 3-4 steps lactamization protocol starting by the exo-cyclic conjugated olefin spiro-lactone for the formation of the fourth fused ring (D-ring). This protocol maximizes the yield and reduces the purification process, forming an advanced intermediate for synthesizing lysergine, isolysergine, and lysergol. Oxa-Michael with methoxide anion afforded the oxygen needed to place the primary alcohol of the lysergol scaffold. Finally, these tetracyclic alkaloids were synthesized by Tf2O/NaBH4 lactam reduction and reductive amination of the cyclic secondary amines to place the methyl group. In the case of lisergol, a further deprotecting step was needed to obtain the free alcohol. The second main chapter is related to the biological understanding of the biosynthetic step of forming the C–ring of the ergoline core. We envisioned the application of the newly developed photoredox catalysis protocols to generate an open-shell species starting from carboxylic acid or Redox Active Esters (RAE) of γ, γ-dimethylallyl tryptophan (DMAT) derivatives containing inactivated alkene moieties, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This protocol offers additional information for a better comprehension of ergot biosynthesis, and it is an efficient tool to activate reductively and oxidatively natural carboxylic acid using the same Ir-based photocatalyst. The last chapter is focused on the research I performed during my period abroad at the University of California, Berkeley. The project aimed to synthesize daphenylline, an alkaloid of the family of Daphniphyllum alkaloids, focusing on excess complexity approach. This tactic is based on generating excess complexity during the synthesis, followed by strategic C–C cleavage protocol to design a highly effective retrosynthetic pathway. We accessed a bicyclo[4.1.0]heptane core through a dearomative Büchner cycloaddition, which afforded the desired seven-membered ring after C–C bond cleavage. Furthermore, we developed a new protocol to install a challenging quaternary stereocenter methyl group based on a [2+2] Paternò–Büchi photocycloaddition followed by thietane reduction. Subsequential transformations afforded daphenylline in 11-step synthesis (the shortest preparation of daphenylline to date).This thesis comprises different projects generally divided into three main chapters. The first main project was the enantioselective total synthesis of clavine-type alkaloids through a divergent synthesis based on the key intermediate (R)-4-amino-Uhne’s ketone, chapter 3. In this chapter, is presented our strategy to synthesize this enantiopure key intermediate through an Rh(I) catalyzed 6-exo-trig intramolecular cyclization of an appropriate 4-pinacol boronic ester D-tryptophan aldehyde, followed by the oxidation of the secondary alcohol produced by this reaction, using a mixture of catalytic Cu(I)-ABNO and stochiometric O2. The next goal of the project was the implementation of this precocious substrate for the enantioselective synthesis of all four rugulovasine stereoisomers, important rearranged clavine alkaloids, through a Dreiding-Smith lactonization mediated by zinc, alkene isomerization using catalytic amount of Ru3(CO)12, and Fukuyama alkylation protocol to install the desired methyl group to the primary amine. These molecules were submitted to a preliminary biological evaluation, with an initial screening of binding properties toward an array of CNS receptors and a subsequential selection of the more active ((+)-rugulovasine B) for IC50 evaluation on different serotonin receptors. Subsequential development of this divergent approach to the class of tetracyclic clavine or ergoline has been achieved using a telescoping 3-4 steps lactamization protocol starting by the exo-cyclic conjugated olefin spiro-lactone for the formation of the fourth fused ring (D-ring). This protocol maximizes the yield and reduces the purification process, forming an advanced intermediate for synthesizing lysergine, isolysergine, and lysergol. Oxa-Michael with methoxide anion afforded the oxygen needed to place the primary alcohol of the lysergol scaffold. Finally, these tetracyclic alkaloids were synthesized by Tf2O/NaBH4 lactam reduction and reductive amination of the cyclic secondary amines to place the methyl group. In the case of lisergol, a further deprotecting step was needed to obtain the free alcohol. The second main chapter is related to the biological understanding of the biosynthetic step of forming the C–ring of the ergoline core. We envisioned the application of the newly developed photoredox catalysis protocols to generate an open-shell species starting from carboxylic acid or Redox Active Esters (RAE) of γ, γ-dimethylallyl tryptophan (DMAT) derivatives containing inactivated alkene moieties, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This protocol offers additional information for a better comprehension of ergot biosynthesis, and it is an efficient tool to activate reductively and oxidatively natural carboxylic acid using the same Ir-based photocatalyst. The last chapter is focused on the research I performed during my period abroad at the University of California, Berkeley. The project aimed to synthesize daphenylline, an alkaloid of the family of Daphniphyllum alkaloids, focusing on excess complexity approach. This tactic is based on generating excess complexity during the synthesis, followed by strategic C–C cleavage protocol to design a highly effective retrosynthetic pathway. We accessed a bicyclo[4.1.0]heptane core through a dearomative Büchner cycloaddition, which afforded the desired seven-membered ring after C–C bond cleavage. Furthermore, we developed a new protocol to install a challenging quaternary stereocenter methyl group based on a [2+2] Paternò–Büchi photocycloaddition followed by thietane reduction. Subsequential transformations afforded daphenylline in 11-step synthesis (the shortest preparation of daphenylline to date)

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

: An unusual photoredox-catalyzed radical decarboxylative cyclization cascade reaction of γ,γ-dimethylallyltryptophan (DMAT) derivatives containing unactivated alkene moieties has been developed, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This type of cyclization, which was hitherto very difficult to comprehend in ergot biosynthesis and to accomplish by more conventional procedures, enables the synthesis of ergot alkaloid precursors. In addition, this work describes a mild, environmentally friendly method to activate, reductively and oxidatively, natural carboxylic acids for decarboxylative C-C bond formation by exploiting the same photocatalyst

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

Navigating Excess Complexity: Total Synthesis of Daphenylline

Retrosynthetic analysis is a framework for designing synthetic routes to complex molecules that generally prioritizes disconnections which reduce molecular complexity. However, strict adherence to this principle can overlook pathways involving highly complex intermediates that can be easily prepared through powerful bond-forming transformations. Herein, we demonstrate this tactic of generating excess complexity, followed by strategic bond-cleavage, as a highly effective approach for the 11-step total synthesis of the Daphniphyllum alkaloid daphenylline. To implement this strategy, we accessed a bicyclo[4.1.0]heptane core through a dearomative Buchner cycloaddition, which enabled construction of the seven-membered ring after C–C bond cleavage. Installation of the synthetically challenging quaternary stereocenter methyl group was achieved through a thia-Paternò–Büchi [2 + 2] photocycloaddition followed by stereospecific thietane reduction, further illustrating how building excess complexity can enable desired synthetic outcomes after strategic bond-breaking events. This strategy leveraging bond cleavage transformations should serve as a complement to traditional bond-forming, complexity-generating synthetic strategies