Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products

Enantioselective Synthesis of Cyclopentadienes by Gold(I)- Catalyzed Cyclization of 1,3-Dien-5-ynes

An asymmetric synthesis of elusive chiral cyclopentadienes has been developed by gold(I)-catalyzed alkoxycyclization of 1,3-dien-5-ynes. The application of these substrates in completely diastereoselective Diels–Alder cycloaddition reactions, which can be carried out in one pot from achiral 1,3-dien-5-ynes, allows the preparation of highly functionalized products bearing five stereogenic centers with high enantiomeric excessesMinisterio de Ciencia e Innovacion (MICINN) and FEDER (CTQ2010-15358 and CTQ2009-09949/BQU) and Junta de Castilla y Leon (BU021A09 and GR-172) for financial support. A. M. S. thanks Junta de Castilla y Leon (Consejeria de Educacion) and Fondo Social Europeo for a PIRTU contract. P. G.-G. and M. A. F.-R. thank MICINN for "Juan de la Cierva" and "Ramon y Cajal" contractsThis is the peer reviewed version of the following article: Sanjuán, A. M., García-García, P., Fernández-Rodríguez, M. A. and Sanz, R. (2013), Enantioselective Synthesis of Cyclopentadienes by Gold(I)- Catalyzed Cyclization of 1,3-Dien-5-ynes. Adv. Synth. Catal., 355: 1955–1962. doi: 10.1002/adsc.201300448, which has been published in final form at 10.1002/adsc.201300448. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archivin

Gold(I) as an Artificial Cyclase: Short Stereodivergent Syntheses of (−)-Epiglobulol and (−)-4β,7α- and (−)-4α,7α-Aromadendranediols

Three natural aromadendrane sesquiterpenes, (−)‐epiglobulol, (−)‐4β,7α‐aromadendranediol, and (−)‐4α,7α‐aromadendranediol, have been synthesized in only seven steps in 12, 15, and 17 % overall yields, respectively, from (E,E)‐farnesol by a stereodivergent gold(I)‐catalyzed cascade reaction which forms the tricyclic aromadendrane core in a single step. These are the shortest total syntheses of these natural compounds

Synthesis of diverse indole-containing scaffolds by gold(I)-catalyzed tandem reactions of 3-propargylindoles initiated by 1,2-indole migrations: scope and computational studies

Similar to propargylic carboxylates and sulphides, 3- propargylindoles undergo 1,2-indole migrations under cationic gold(I)- catalysis. The intermediate Aucarbenoid complex may evolve through different pathways depending on the substituents at the propargylic and terminal positions of the alkyne moiety. Thus, 3-indenylindole derivatives were easily obtained through formal iso- Nazarov or Nazarov cyclizations. DFT computations support the formation of an alkylidenecyclopropane intermediate that undergoes aura-iso-Nazarov or aura-Nazarov cyclizations upon torquoselective ring opening. In addition, 3-dienylindoles could be accessed when none of the referred pathways were accessible and so the intermediate Au-carbenoid complex evolved via a 1,2-CH insertion reaction. We have also demonstrated that the final products can be obtained in a one-pot protocol from easily available propargylic alcohols and indolesMEC/FEDER (CTQ2007-61436/BQU) and Junta de Castilla y León (BU021A09) for financial support. We are also grateful to MEC (FPU predoctoral fellowship to D.M., “Young Foreign Researchers” contract (SB2006-0215) to M.G., “Ramón y Cajal” contract to M.A.F.-R., and “Juan de la Cierva” contract to P.G.-G.) and Fundación Ramón Areces (predoctoral fellowship to A.G.P.).This is the peer reviewed version of the following article: Sanz, R., Miguel, D., Gohain, M., García-García, P., Fernández-Rodríguez, Manuel A., González-Pérez, A., Nieto-Faza, O., de Lera, Ángel R. and Rodríguez, F. (2010), Synthesis of Diverse Indole-Containing Scaffolds by Gold(I)-Catalyzed Tandem Reactions of 3-Propargylindoles Initiated by 1,2-Indole Migrations: Scope and Computational Studies. Chem. Eur. J., 16: 9818–9828. doi:10.1002/chem.201001162, which has been published in final form at doi:10.1002/chem.201001162. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archivin

Gold(I)-Catalyzed Cycloisomerizations and Alkoxycyclizations of ortho-(Alkynyl)styrenes

Indenes and related polycyclic structures have been efficiently synthesized by gold(I)-catalyzed cycloisomerizations of appropriate ortho-(alkynyl)styrenes. Disubstitution at the terminal position of the olefin was demonstrated to be essential to obtain products originating from a formal 5-endo-dig cyclization. Interestingly, a complete switch in the selectivity of the cyclization of o-(alkynyl)-α-methylstyrenes from 6-endo to 5-endo was observed by adding an alcohol to the reaction media. This allowed the synthesis of interesting indenes bearing an all-carbon quaternary center at C1. Moreover, dihydrobenzo[a]fluorenes can be obtained from substrates bearing a secondary alkyl group at the β-position of the styrene moiety by a tandem cycloisomerization/1,2-hydride migration process. In addition, diverse polycyclic compounds were obtained by an intramolecular gold-catalyzed alkoxycyclization of o-(alkynyl)styrenes bearing a nucleophile in their structure. Finally, the use of a chiral gold complex allowed access to elusive chiral 1H-indenes in good enantioselectivitiesMinisterio de Economia y Competitividad (MINECO) and FEDER (CTQ2010-15358 and CTQ2013-48937-C2-1-P) and Junta de Castilla y Leon (BU237U13) for financial support. A.M.S. thanks the Junta de Castilla y Leon (Consejeria de Educacion) and the Fondo Social Europeo for a PIRTU contract. M.A.R. and P.G.-G. thank MEC for a "Young Foreign Researchers" (SB2009-0186) contract and MINECO for "Juan de la Cierva" contract, respectivelyThis is the peer reviewed version of the following article: Sanjuán, A. M., Rashid, M. A., García-García, P., Martínez-Cuezva, A., Fernández-Rodríguez, M. A., Rodríguez, F. and Sanz, R. (2015), Gold(I)-Catalyzed Cycloisomerizations and Alkoxycyclizations of ortho-(Alkynyl)styrenes. Chem. Eur. J., 21: 3042–3052. doi: 10.1002/chem.201405789, which has been published in final form at 10.1002/chem.201405789. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archivin

The Development and Application of Gold(I)-Catalyzed Cyclization Cascades

The formation of saturated carbon-carbon bonds in a precise andcontrolled manner is arguably the principal objective of organic synthesis.Carbocyclic ring systems comprise the underlying structure for thepreponderance of natural products and pharmaceutical agents. Therefore,synthetic methods capable of selectively initiating polycyclization processes inthe presence of spectating functionality are of significant value, particularly sowhen multiple stereocenters are formed enantioselectively. The emergence of phosphine gold(I) catalysis over the past decade hasopened up new avenues to carbocycle formation via π activation of alkynesoccurring under exceedingly mild conditions and with excellent chemoselectivity.The research described herein describes the use of homogenous gold(I)complexes to initiate electrophilic cyclization cascades. Through rationalsubstrate design, carbocationic centers may be generated in a predictablemanner and employed in subsequent intramolecular cyclization processes.Chapter 1 introduces the unique reactivity observed in complexes of goldimparted by its relativistically accelerated valence electrons. One consequence ofthis perturbation is the linear geometry maintained by gold(I) complexes,minimizing the influence of ligand-based chirality on reactions occurring atcoordinated alkynes. In spite of this challenge, moderate levels ofenantioselectivity were achieved in the desymmetrization of dienynes bycycloisomerization using chiral bisphosphite gold(I) catalysts. Ultimately, we were able to achieve selectivities up to 98% ee usinghindered chiral bisphosphine gold(I) catalysts during the evaluation of anotherenyne cycloisomerization reaction, described in chapter 2. In this process, aninitial regioselective cyclization was used to generate a carbocationic speciespoised to undergo intramolecular trapping. Consistently high enantioselectivitywas maintained using various pendant oxygen, carbon and nitrogen nucleophiles.The diastereomerically pure bi- and tricyclization products obtained providedsupport for a concerted polyene cyclization mechanism as predicted by the Stork-Eschenmoser postulate. Chapter 3 describes another tandem process exploiting the transientcationic species arising from gold(I)-promoted enyne cycloisomerization. In thiscase, a gold(I)-initiated tandem cyclopentannulation reaction was employed inthe total synthesis of the novel triquinane ventricosene. A cyclopropanol unitembedded in the enyne substrate underwent a semipinacol rearrangement inresponse to the carbocation, leading cleanly to bicyclo[3.2.0]heptan-6-oneproducts. For cyclopentenyl substrates, the hindered all-carbon quaternary centerand all of the ring fusions of the angular triquinane ring system were formed atonce. The choice of a hydrocarbon target highlighted the utility of gold(I) catalystsas selective activators of carbon unsaturation; throughout the synthesis only asingle heteroatom was present. This work concludes by extending the scope gold(I)-catalyzedcarbocyclization reactions which generate useful cationic intermediates. Thegold(I)-catalyzed Rautenstrauch rearrangement forms a cyclopentene-basedcationic species which was shown to undergo efficient trapping by pendantarenes to give a saturated 5,6-ring fusion comprising a chiral benzylic quaternarycenter. The chirality transfer observed in the parent process was found to beconserved in the tandem process. Interestingly, cyclization of racemic substratesby chiral bisphosphine digold catalysts was found to proceed with moderateenantioselectivity, suggesting a competing mechanism is in effect whichproceeds through an achiral intermediate

The Development and Application of Gold(I)-Catalyzed Cyclization Cascades

The formation of saturated carbon-carbon bonds in a precise andcontrolled manner is arguably the principal objective of organic synthesis.Carbocyclic ring systems comprise the underlying structure for thepreponderance of natural products and pharmaceutical agents. Therefore,synthetic methods capable of selectively initiating polycyclization processes inthe presence of spectating functionality are of significant value, particularly sowhen multiple stereocenters are formed enantioselectively. The emergence of phosphine gold(I) catalysis over the past decade hasopened up new avenues to carbocycle formation via π activation of alkynesoccurring under exceedingly mild conditions and with excellent chemoselectivity.The research described herein describes the use of homogenous gold(I)complexes to initiate electrophilic cyclization cascades. Through rationalsubstrate design, carbocationic centers may be generated in a predictablemanner and employed in subsequent intramolecular cyclization processes.Chapter 1 introduces the unique reactivity observed in complexes of goldimparted by its relativistically accelerated valence electrons. One consequence ofthis perturbation is the linear geometry maintained by gold(I) complexes,minimizing the influence of ligand-based chirality on reactions occurring atcoordinated alkynes. In spite of this challenge, moderate levels ofenantioselectivity were achieved in the desymmetrization of dienynes bycycloisomerization using chiral bisphosphite gold(I) catalysts. Ultimately, we were able to achieve selectivities up to 98% ee usinghindered chiral bisphosphine gold(I) catalysts during the evaluation of anotherenyne cycloisomerization reaction, described in chapter 2. In this process, aninitial regioselective cyclization was used to generate a carbocationic speciespoised to undergo intramolecular trapping. Consistently high enantioselectivitywas maintained using various pendant oxygen, carbon and nitrogen nucleophiles.The diastereomerically pure bi- and tricyclization products obtained providedsupport for a concerted polyene cyclization mechanism as predicted by the Stork-Eschenmoser postulate. Chapter 3 describes another tandem process exploiting the transientcationic species arising from gold(I)-promoted enyne cycloisomerization. In thiscase, a gold(I)-initiated tandem cyclopentannulation reaction was employed inthe total synthesis of the novel triquinane ventricosene. A cyclopropanol unitembedded in the enyne substrate underwent a semipinacol rearrangement inresponse to the carbocation, leading cleanly to bicyclo[3.2.0]heptan-6-oneproducts. For cyclopentenyl substrates, the hindered all-carbon quaternary centerand all of the ring fusions of the angular triquinane ring system were formed atonce. The choice of a hydrocarbon target highlighted the utility of gold(I) catalystsas selective activators of carbon unsaturation; throughout the synthesis only asingle heteroatom was present. This work concludes by extending the scope gold(I)-catalyzedcarbocyclization reactions which generate useful cationic intermediates. Thegold(I)-catalyzed Rautenstrauch rearrangement forms a cyclopentene-basedcationic species which was shown to undergo efficient trapping by pendantarenes to give a saturated 5,6-ring fusion comprising a chiral benzylic quaternarycenter. The chirality transfer observed in the parent process was found to beconserved in the tandem process. Interestingly, cyclization of racemic substratesby chiral bisphosphine digold catalysts was found to proceed with moderateenantioselectivity, suggesting a competing mechanism is in effect whichproceeds through an achiral intermediate