Targeting Complex Cyclic Peptides for Synthesis: The Celogentin and Theonellamide Families

Celogentin C and theonellamide F are a class of natural products that have potential antimitotic behavior. They both contain interesting bicyclic structures with unusual linkages within a central moiety. Celogentin C\u27s highly functionalized tryptophan moiety has two unusual linkages, a β-substituted Leu connection to the C6 of the indole structure that makes up the left-hand ring, and a τ-N connection of the imidazole to the C2 of the indole constructing the right-hand ring. This right-hand ring connection was solved via a novel oxidative coupling procedure developed in our group and the left-hand ring was initially constructed via a radical conjugated addition of an isopropyl group. Due to stereoselective concerns, our group explored hydrogen bond donors as potential catalyst candidates. Unfortunately, there were challenges in limiting the background reaction and obtaining reproducible results. We then designed an alternative route to solve this left-hand ring connection which would have utilized MacMillan asymmetric hydrogenation and α-chlorination procedures. Further work towards a second generation synthesis of the β-Leu-(C6)Trp connection was halted with the publication of two formal syntheses of celogentin C. Theonellamide F contains a τ-L-histidino-D-alanine (τ-HAL) bridging unit that separates the left-and right-hand rings. Previous efforts in the synthesis of this natural product were hindered due to an inefficient regioselective synthesis of τ-HAL. Our proposed synthesis of τ-HAL began with commercially available L- and D-Ser methyl esters which were then chemically transformed and coupled to one another to create a bis-amino subunit. Further preparations afforded us with an important cyclic intermediate which should readily lead to the first regioselective synthesis of a τ-HAL

Celogentin C and Thioviridamide: Synthetic and Structural Studies

Project I Celogentin C, isolated by Kobayashi from the seeds of Celosia argentea in 2001 exhibits strong inhibitory behavior towards polymerization of tubulin – globular protein, which plays crucial role during the cell division cycle. We have attempted synthesis of the left-hand ring of celogentin C via the intramolecular alkylation and the Knoevenagel condensation strategies. Utilizing synthetic methodologies in the field of nitroacetyl chemistry, developed by Kornblum and Rajappa we have successfully prepared the intermolecular Knoevenagel condensation product – the late-stage precursor to the left-hand ring of celogentin C. Synthesis of this key intermediate subsequently led to the preparation of the left-hand ring and the total synthesis of celogentin C by other members of Castle\u27s group. Project II Thioviridamide is the potent apoptosis inducer isolated by Hayakawa from the bacterial broth of Streptomyces olivoviridis. Unusual structural features of the thioviridamide macrocycle contain two novel amino acids, never before encountered in a natural product - S-(2-aminovinyl)cysteine (avCys) and β-hydroxy-N1,N3-dimethylhistidinium (hdmHis). No stereochemical information except for the Z-configuration of the β-thioenamide linkage was reported in the literature. We have performed a computational study to predict the thioviridamide stereochemistry. Initial populations of conformers for the likely candidate structures were produced using OPLS-AA force field. Prediction of the NMR properties was accomplished at the mPW1PW91/6-311+G(2d,p) level of theory with the polarizable continuum model of salvation. Utilizing Boltzmann averaging and statistical analysis we have determined that the only possible cases of stereochemical inversion occur at the sites of the two novel amino acids. Project III Model studies towards the synthesis of the β-thioenamide subunit of thioviridamide were performed. The radical addition reaction of thiyl radicals to ynamides produces Z- (kinetic products) or E- β-thioenamides (thermodynamic products) depending on the reaction conditions. Two distinct sets of reaction conditions allowing kinetic or thermodynamic control of β-thioenamide formation were developed. Synthesis of the model β-thioenamide subunit of thioviridamide was attempted

A Radical Conjugate Addition Approach to the Total Synthesis of Celogentin C

The synthesis of five chiral DBFOX (dibenzofuran-oxazoline) ligands with either aryl or benzyl substituents will be presented. The requisite amino alcohols were obtained with high enantioselectivity either commercially (DBFOX/Bn), via Sharpless asymmetric aminohydroxylation (DBFOX/Nap, DBFOX/t-BuPh, DBFOX/Pip), or via phase-transfer catalyzed asymmetric alkylation (DBFOX/MeNap). These ligands, complexed with Mg(NTf2)2, were used as Lewis acid promoters of enantioselective radical conjugate additions to α/β-unsaturated nitro-amides/esters. A summary of these results is presented and discussed. These findings led us to believe that our initial binding model between metal, ligand, and substrate was flawed. Thus, we figured that if we started with a functionality known to bind to both nitro groups and carbonyls, and then introduced a chiral element for control, we may be able to improve the beta-carbon enantioselectivity. We have tried to accomplish this via hydrogen-bonding ligands (ureas and thioureas). Initial studies on achiral versions of this concept are discussed

Deacylative Reactions: Synthetic Applications

Herein we introduce the recent developments of a new strategy based on deacylative alkylation (DaA) reactions for the generation of quaternary stereocenters based on the in situ preparation and functionalization of enolates under very mild reaction conditions. Palladium‐catalyzed deacylative allylation and benzylation reactions of carbon nucleophiles are performed with the corresponding alcohols. This methodology has been applied to the synthesis of the calcium ion channel blocker verapamil, the antiviral (+)‐hamigeran B, several oxindole precursors of esermethole, horsfiline, physostigmine, phenserine, meso‐folicanthine, meso‐chinonanthine and the dimer cyclotriptamine alkaloids. Base‐promoted deacylative reactions enable the functionalization of 2‐oxindole enolates at the 3‐position with alkyl halides and electrophilic alkenes. In the presence of oxygen or air, 3‐hydroxy‐2‐oxindoles are prepared by deacylative oxidation. Detrifluoroacylative reactions are promoted by a base generating fluoroenolates, which can participate in aldol, Mannich and Michael reactions for the preparation of important fluorinated intermediates. Finally, palladium‐catalyzed deacylative cross‐coupling of acetyl diazoacetates and phosphonates with aryl iodides let to the formation of aryl diazoacetates and phosphonates, respectively. The same process, with 2‐iodoazoarenes and 2‐iodoaryltriazenes, gives 2H‐indazoles, which are important pharmacophores.We gratefully acknowledge financial support from the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat Valenciana (PROMETEOII/2014/017), and the University of Alicante. A. O.-M. thanks MINECO for a predoctoral fellowship

Mayotlide: synthetic approaches and structural elucidation

[eng] Mayotlide is a marine peptide isolated by PharmaMar S.A. from Spongia sp.. The sequence of the aminoacids were achieved by MS-MS spectrometry, where two of them were tryptophans. The NMR spectroscopy revealed the presence of N1-C3a bond between the tryptophans, which means that one of them was cyclized. On the first structure proposal, the aminoacids were forming two macrocyclic rings: on the ring B, all the aminoacids of molecule were tied by amide bond, remarking the presence of the cyclized tryptophan as a hexahydropyrroloindole unit (HPI). The ring A was established by three aminoacids of the ring B: one tryptophan, one isoleucine and the HPI, which became closed by the N1-C3a bond between the two tryptophans. The aminoacid analysis demonstrated the L configuration of all of them, just remaining the HPI with unknown stereochemistry. Due to the configuration of the HPI system, there can be four diasteromers. To the best of our knowledge, there were not empirical evidences about which one could be more favorable. Hence, a computational study of the ring A through the MOE program was performed, evidencing that the rings A with the exo HPI adducts (L and D) were more stable than the endo ones. Among the exo ones, another computational study with the whole molecule revealed that the mayotlide with the exo-L adduct of the HPI was more stable. Once that there was established a starting point with the HPI, it was necessary to find out a synthetic strategy that could fulfill the necessary requirements. A methodology developed by Baran and coworkers for the synthesis of the Trp-HPI fragment on molecules related to mayotlide was adapted to our proposal. On the first step of this strategy, under reaction conditions, the starting tryptophan cyclizes, providing exclusively the HPI with the exo configuration, at the same time that the N1-C3a bond between the HPI and 2-iodoaniline is formed. The 2-iodoaniline, along with a disubstituted alkyne, condense together yielding the upper tryptophan without loss of the former stereochemistry, reaching the Trp-HPI framework in two steps with high yields. Taking advantage of this methodology and an appropriate use of the protecting groups in order to perform the corresponding cyclizations of the two macrocyclic rings, the mayotlide with the exo-L HPI was accomplished. Nevertheless, nor the NMR neither the MS-MS fragmentation pattern of the final compound coincided with the natural product ones. Thus, the next alternative would consist on repeating the synthesis but with the exo-D adduct of the HPI instead. During the last synthesis, the bibliography and the analytical data of the natural product were extensively revised. There were no documented precedents of natural peptides with the Trp- HPI motif, and the initial structure did not justify the most important data extracted from the MS-MS spectrometry. the main fragmentation concerned to the isoleucine, and on the first proposal such aminoacid was not forming part of a conflictive scaffold. Likewise, among the eight proposed linear sequences for the ring B, the isoleucine just appear in one as C-terminus of the b-ions, when it is one of the aminoacids that forms part of both macrocycles. The most related family of peptides to mayotlide are the kapakahines. Kapakahines, instead of having a Trp-HPI moiety as the central part of the molecule, exhibit a Trp-α carboline, with an aminoacid establishing the bridge for a very tensioned tetracyclic system. Such structure may justify the isoleucine fragmentation pattern, but on the other hand the sequence of the aminoacids did not fix. It was necessary to invert the central sequence of the aminoacids to reach out a final structure proposal which justifies all the requirements, relabeled as “kapakahine H”.[spa] La mayotlida es un producto natural de origen marino aislado por PharmaMar. SA.. En la primera propuesta que se hizo, se elucidó como un péptido con dos anillos macrocíclicos: en el anillo B estaban contenidos todos los aminoácidos de la molécula, destacando la presencia de una unidad de HPI, que procede de la ciclación intramolecular del extremo amino de un triptófano con el C2 del anillo de indol. El anillo A está formado por tres aminoácidos del anillo B: un triptófano, una isoleucina y el HPI, quedando cerrado por la formación de un enlace entre el N1 del triptófano y el C3a del HPI. El análisis de aminoácidos demostró la configuración L de todos ellos, quedando desconocida la estereoquímica del HPI. El HPI posee tres estereocentros: los C3a y C8a, que siempre están en cis por la propia configuración del anillo y se pueden considerar como un conjunto, y el estereocentro del Cα. Por tanto, son cuatro el número total de diasterómeros posibles. El anillo A con las cuatro posibilidades de HPI fue estudiado energéticamente con el programa MOE, llegando a la conclusión que los aductos exo son más estables que los endo, y que el aducto exo-L es más estable que el exo-D. Para abordar la síntesis de la mayotlida exo-L se adaptó una metodología desarrollada por Phil Baran y colaboradores para moléculas con una estructura relacionada a la mayotlida. Tras conseguir la síntesis de la mayotlida con el aducto exo-L del HPI, se comprueba que los espectros de RMN y de MS-MS presentan grandes divergencias. Ante la incapacidad de interpretar las diferencias existentes entre el producto natural y la mayotlida exo-L, se tomó la decisión de abordar la síntesis de la mayotlida con el aducto exo-D del HPI. En el transcurso de la síntesis exo-D se revisó extensivamente la bibliografía y los datos analíticos relacionados con la mayotlida: no existían antecedentes de productos naturales peptídicos con estructura Trp-HPI, y la estructura no encajaba con los datos más transcendentales del MS-MS. La estructura fue revisada, llegando a la conclusión de que podía pertenecer a la familia de las kapakahines, con una estructura central Trp-α carbolina y con la secuencia central de los aminoácidos invertida, rebautizada como kapakahina H

Development of New Catalysts and Concepts for Enantioselective Synthesis of Amines and Alcohols:

Thesis advisor: Amir H. HOveydaChapter 1: Ag-Catalyzed Enantioselective Vinylogous Mannich Reactions of Ketoimines Few catalytic methods have been reported for the enantioselective synthesis of N-substituted quaternary carbon stereogenic centers, typically the low reactivity of the electrophilic partner cannot be overcome. Herein, a silver-based catalyst is described which promotes highly site-, diastereo-, and enantioselective additions of siloxyfurans to ansidine-derived ketoimino esters. Mechanistic investigations, undertaken to elucidate the nature of the active silver-phosphine complex, supported the proposed origin for the anti-selective Mannich-type additions. Chapter 2: New Catalysts for the Enantioselective Cu-Catalyzed Additions of Allyl Groups to Phosphinoylaldimines The deficiencies in modern organic synthesis regarding the preparation of chiral molecules bearing amines, despite their incredible significance, are addressed. The development of a new method and catalyst for the preparation of enantiomerically enriched allyl-substituted alpha-chiral amines is described. Copper based catalysts bearing chiral C1-symmetric N-heterocyclic carbenes promote reactions between diphenylphosphinoyl aldimines and allyl boronic acid pinacol ester affording the homoallylic amines with high levels of efficiency and selectivity. Furthermore, the mechanistic rationale describing the selectivity patterns of the designed catalysts is analyzed. Chapter 3: NHC-Cu-Catalyzed Enantioselective Propargyl Group Additions to Phosphinoylaldimines The copper complex of a chiral N-heterocyclic carbene is found to be uniquely effective at promoting highly selective reactions of a commercially available allenylboron reagent and diphenylphosphinoyl aldimines. The enantiomerically enriched homopropargylic amines are exclusively afforded within an hour in the presence of as low as 0.25 mol % catalyst. The utility of the method is further demonstrated through the elaboration of the appended alkyne to difficult-to-access functionalities, highlighted by the synthesis of a key fragment for the preparation of the aza-epothilones, macrocyclic lactams which exhibit acute cytotoxicity. Chapter 4: Metal-Free Catalysts for Enantioselective Synthesis of Allenic Carbinols A metal-free catalyst, unique in structure and mechanism, is developed to address the remaining deficiencies in allyl addition chemistry, an area dominated by metal catalysis. The key organizational and enabling feature of the catalyst is a proton, a simple point charge which affects the facility of the C-C bond formation through electrostatic interactions. The unique alpha-selectivity delivered by the boron-based catalyst, a product of a catalytic cycle characterized by two gamma-selective allyl transfer processes, allows for the unprecedented synthesis of enantiopure allenyl-substituted tertiary alcohols. Moreover, the described transfomations can be performed in a matter of minutes with ˂0.5 mol % catalyst

Bioactive Marine Heterocyclic Compounds

This Special Issue of Marine Drugs, entitled “Bioactive Marine Heterocyclic Compounds”, aimed to collect excellent original research articles and reviews focused on the isolation of new heterocyclic marine natural products, total synthesis, synthetic modification, or on finding important bioactivities of known heterocyclic marine natural products. As a result, five original papers on isolation and one synthetic study of metabolites from marine-derived bioorganisms or a marine sponge, along with one review paper on thiazole-based peptides, were published. I am proud to show these most recent works of outstanding scientists in this field and hope this Special issue will affect new drug developments or innovation in the future

Palladium-catalysed directed C(sp3)–H functionalisation of saturated N-heterocycles at unactivated C4 positions

Saturated N-heterocycles are prevalent motifs in bioactive compounds and represent important structures for pharmaceutical screening. As such, synthetic methods that can readily access these derivatives with high regio- and stereocontrol would be of significant value for the discovery of new therapeutics. Catalytic C–H functionalisation offers high potential for the iterative and divergent synthesis of substituted N-heterocycles from simple cyclic precursors. The research in this thesis describes the selective synthesis of cis-3,4-disubstituted pyrrolidines and piperidines by Pd-catalysed C(sp3)–H functionalisation with aryl iodides. As described in chapter 3, high regio- and stereoselectivity is achieved using an aminoquinoline amide directing group at C(3), with C(4)-functionalisation always preferred over competing C(2). Divergent directing group removal delivers various biologically relevant building blocks, containing amide, carboxylic acid and alcohol functionalities. The synthetic utility of this protocol for drug discovery applications is described in chapter 4. C(4)–H arylation followed by directing group removal enables the stereocontrolled formal synthesis of antidepressant (–)-paroxetine and the total synthesis of enantiopure Br- and I-paroxetine analogues. Furthermore, the synthesis of a library of arylated pyrrolidine and piperidine fragments for pharmaceutical screening is demonstrated. Mechanistic investigations into the observed regio- and stereoselectivity are discussed in chapter 5. Deuteration studies, kinetic analysis and DFT calculations suggest reversible C–H activation to occur at different positions on the ring. Subsequent stereodetermining oxidative addition of PdII to PdIV and turnover-limiting reductive elimination deliver the C(4)-arylated products as cis-diastereomers. During this study, evidence for a fast catalyst deactivation process is observed. Attempts to overcome this limitation are finally discussed in chapter 6. This ultimately results in the development of an improved 4-dimethylamino-8-quinolinyl amide directing group. This novel removable auxiliary provides a faster reaction rate, higher yields and a broader substrate scope, and enables the late-stage functionalisation of complex biorelevant compounds.Open Acces