Transition Metal Catalyzed Linchpin-Based Strategies in Natural Product Synthesis: Synthesis of Asteriscunolide D, Aspergillide B and the Core of Labillarides E-H

<p>The construction of complex molecular architectures in a facile and efficient manner remains an overarching goal for the chemical sciences. The development of synthetic linchpins, simple compounds that are used to join complex molecular fragments together, represents a powerful method for improving synthetic efficiency. A major challenge associated with linchpin-based synthetic strategies is the development of chemoselective and atom economic reactions that enable late-stage introduction of the linchpin compound. Chiral propargylic alcohols are versatile synthetic intermediates and their preparation enables entry into a variety of alkyne-based linchpin strategies. Continued optimization of Zn-ProPhenol-catalyzed alkyne addition has led to the development of practical and general conditions for the asymmetric alkynylation of aldehydes. This methodology operates with relatively low catalyst loading and can avoid the use of excess alkyne and dialkylzinc reagents. The total synthesis of asteriscunolide D was completed in just nine steps using a Zn- ProPhenol-catalyzed asymmetric alkynylation and Ru-catalyzed alkene-alkyne coupling. Other highlights of this protecting-group-free synthesis include the use of a thionium-induced cyclization to form the challenging 11-membered humulene ring. At the core of this succinct and selective synthetic strategy is the use of methyl propiolate as a strategic linchpin. In just two steps, three new bonds were formed to atoms derived from methyl propiolate and this ultimately enabled the construction of this structurally challenging natural product. An enantioselective formal total synthesis of aspergillide B has been accomplished using sequential Zn-catalyzed alkyne additions to a masked butane dialdehyde linchpin. This synthesis has led to the development of new conditions for Zn-ProPhenol-catalyzed alkynylation that provide excellent yield and enantioselectivity using just a single equivalent of alkyne. Ru-catalyzed trans-hydrosilylation provides the desired E alkene geometry and also allows chemoselective differentiation of the two double bonds in a subsequent hydrogenation step. This synthetic route provides access to aspergillide B in just 15 steps, using six highly efficient transition metal-catalyzed reactions. Labillarides E-H are a group of diastereomeric oxylipin natural products with very interesting structural features and spectroscopic properties. The development of a Pdcatalyzed allylic alkylation cascade has enabled the rapid construction of the furanopyrone core and alkenyl side chain of these compounds. The use of density functional calculations, in conjunction with spectroscopic data obtained from the truncated labillaride E-H structure, has provided good evidence that labillarides E and G have a 3,6-syn configuration, whereas labillarides F and H have a 3,6-anti configuration. Subsequent development of the Pd-AA cascade methodology has led to the discovery of a highly regioselective Pd-AA cascade with non-symmetric dihydropyran substrates. The combination of allylic carbonate and anomeric siloxy leaving groups in the dihydropyran substrate enables control of the many regiochemical possibilities in this reaction. Ultimately, annulation proceeds stereoconvergently to give a cisfused furopyran from either cis- or trans-substituted starting material. During the course of this research, the assignment of the remote relative stereochemistry of a number of 3,6-dihydro-2Hpyran starting materials and side products was achieved through a novel NMR-based analysis of axial shielding magnitudes.</p>

Transition Metal Catalyzed Linchpin-Based Strategies in Natural Product Synthesis: Synthesis of Asteriscunolide D, Aspergillide B and the Core of Labillarides E-H

<p>The construction of complex molecular architectures in a facile and efficient manner remains an overarching goal for the chemical sciences. The development of synthetic linchpins, simple compounds that are used to join complex molecular fragments together, represents a powerful method for improving synthetic efficiency. A major challenge associated with linchpin-based synthetic strategies is the development of chemoselective and atom economic reactions that enable late-stage introduction of the linchpin compound. Chiral propargylic alcohols are versatile synthetic intermediates and their preparation enables entry into a variety of alkyne-based linchpin strategies. Continued optimization of Zn-ProPhenol-catalyzed alkyne addition has led to the development of practical and general conditions for the asymmetric alkynylation of aldehydes. This methodology operates with relatively low catalyst loading and can avoid the use of excess alkyne and dialkylzinc reagents. The total synthesis of asteriscunolide D was completed in just nine steps using a Zn- ProPhenol-catalyzed asymmetric alkynylation and Ru-catalyzed alkene-alkyne coupling. Other highlights of this protecting-group-free synthesis include the use of a thionium-induced cyclization to form the challenging 11-membered humulene ring. At the core of this succinct and selective synthetic strategy is the use of methyl propiolate as a strategic linchpin. In just two steps, three new bonds were formed to atoms derived from methyl propiolate and this ultimately enabled the construction of this structurally challenging natural product. An enantioselective formal total synthesis of aspergillide B has been accomplished using sequential Zn-catalyzed alkyne additions to a masked butane dialdehyde linchpin. This synthesis has led to the development of new conditions for Zn-ProPhenol-catalyzed alkynylation that provide excellent yield and enantioselectivity using just a single equivalent of alkyne. Ru-catalyzed trans-hydrosilylation provides the desired E alkene geometry and also allows chemoselective differentiation of the two double bonds in a subsequent hydrogenation step. This synthetic route provides access to aspergillide B in just 15 steps, using six highly efficient transition metal-catalyzed reactions. Labillarides E-H are a group of diastereomeric oxylipin natural products with very interesting structural features and spectroscopic properties. The development of a Pdcatalyzed allylic alkylation cascade has enabled the rapid construction of the furanopyrone core and alkenyl side chain of these compounds. The use of density functional calculations, in conjunction with spectroscopic data obtained from the truncated labillaride E-H structure, has provided good evidence that labillarides E and G have a 3,6-syn configuration, whereas labillarides F and H have a 3,6-anti configuration. Subsequent development of the Pd-AA cascade methodology has led to the discovery of a highly regioselective Pd-AA cascade with non-symmetric dihydropyran substrates. The combination of allylic carbonate and anomeric siloxy leaving groups in the dihydropyran substrate enables control of the many regiochemical possibilities in this reaction. Ultimately, annulation proceeds stereoconvergently to give a cisfused furopyran from either cis- or trans-substituted starting material. During the course of this research, the assignment of the remote relative stereochemistry of a number of 3,6-dihydro-2Hpyran starting materials and side products was achieved through a novel NMR-based analysis of axial shielding magnitudes.</p>

Cyanovinylation of Aldehydes: Organocatalytic Multicomponent Synthesis of Conjugated Cyanomethyl Vinyl Ethers

A novel organocatalytic multicomponent cyanovinylation of aldehydes was designed for the synthesis of conjugated cyanomethyl vinyl ethers. The reaction was implemented for the synthesis of a 3-substituted 3-(cyanomethoxy)acrylates, using aldehydes as substrates, acetone cyanohydrin as the cyanide anion source, and methyl propiolate as the source of the vinyl component. The multicomponent reaction is catalyzed by N-methyl morpholine (2.5 mol%) to deliver the 3-(cyanomethoxy)acrylates in excellent yields and with preponderance of the E-isomer. The multicomponent reaction manifold is highly tolerant to the structure and composition of the aldehyde (aliphatic, aromatic, heteroaromatics), and it is instrumentally simple (one batch, open atmospheres), economic (2.5 mol% catalyst, stoichiometric reagents), environmentally friendly (no toxic waste), and sustainable (easy scalability).

Vapor Sublimation and Deposition to Fabricate a Porous Methyl Propiolate-Functionalized Poly-p-xylylene Material for Copper-Free Click Chemistry

Conventional porous materials are mostly synthesized in solution-based methods involving solvents and initiators, and the functionalization of these porous materials usually requires additional and complex steps. In the current study, a methyl propiolate-functionalized porous poly-p-xylylene material was fabricated based on a unique vapor sublimation and deposition process. The process used a water solution and ice as the template with a customizable shape and dimensions, and the conventional chemical vapor deposition (CVD) polymerization of poly-p-xylylene on such an ice template formed a three-dimensional, porous poly-p-xylylene material with interconnected porous structures. More importantly, the functionality of methyl propiolate was well preserved by using methyl propiolate-substituted [2,2]-paracyclophane during the vapor deposition polymerization process and was installed in one step on the final porous poly-p-xylylene products. This functionality exhibited an intact structure and reactivity during the proposed vapor sublimation and deposition process and was proven to have no decomposition or side products after further characterization and conjugation experiments. The electron-withdrawing methyl propiolate group readily provided efficient alkynes as click azide-terminated molecules under copper-free and mild conditions at room temperature and in environmentally friendly solvents, such as water. The resulting methyl propiolate-functionalized porous poly-p-xylylene exhibited interface properties with clickable specific covalent attachment toward azide-terminated target molecules, which are widely available for drugs and biomolecules. The fabricated functional porous materials represent an advanced material featuring porous structures, a straightforward synthetic approach, and precise and controlled interface click chemistry, rendering long-term stability and efficacy to conjugate target functionalities that are expected to attract a variety of new applications.

Methyl (2E)-3-[3-Benzyl-2-(3-methoxy-3-oxoprop-1-yn-1-yl)-2-(1-naphthyl)imidazolidin-1-yl]acrylate

Compounds with propargylamine moiety are useful synthetic precursors of several important classes of nitrogen-containing heterocycles. The title compound, methyl (2E)-3-[3-benzyl-2-(3-methoxy-3-oxoprop-1-yn-1-yl)-2-(1-naphthyl)imidazolidine-1-yl]acrylate, has been prepared by domino-reaction, employing easily available 1-benzyl-2-(1-naphthyl)-4,5-dihydro-1H-imidazole and methyl propiolate in a high 92% yield. The structure of title compound was determined using 1H-NMR, 13C-NMR, UV, FT-IR and HRMS (High-Resolution Mass Spectrometry).

Huisgen [3 + 2] Dipolar Cycloadditions of Phthalazinium Ylides to Activated Symmetric and Non-Symmetric Alkynes

We present herein a straightforward and efficient pathway for the synthesis of pyrrolophthalazine cycloadducts via Huisgen [3 + 2] dipolar cycloaddition reactions of phthalazinium ylides to methyl propiolate or dimethyl acetylenedicarboxylate (DMAD). A thoroughly comparative study concerning the efficiency of synthesis, conventional thermal heating (TH) versus microwave (MW) and ultrasound (US) irradiation, has been performed. The cycloaddition reactions of phthalazinium ylides to methyl propiolate occur regiospecific, with a single regioisomer being obtained. Under conventional TH, the cycloaddition reaction of phthalazinium ylides with DMAD occurs to a mixture of inseparable partial and fully aromatized pyrrolophthalazine cycloadducts, while MW or US irradiation are leading only to fully aromatized compounds, with the reactions becoming selective. A feasible mechanism for formation of fully aromatized compounds is presented. Besides selectivity, it has to be noticed that the reaction setup under MW or US irradiation offer a number of other certain advantages: higher yields, decreasing of the amount of used solvent comparative with TH, decreasing of the reaction time from hours to minutes and decreasing of the consumed energy; consequently, these reactions could be considered environmentally friendly.

Influence of the Nucleophilic Ligand on the Reactivity of Carbonyl Rhenium(I) Complexes towards Methyl Propiolate: A Computational Chemistry Perspective

A comparative theoretical study on the reactivity of the complexes [ReY(CO)3(bipy)] (Y = NH2, NHMe, NHpTol, OH, OMe, OPh, PH2, PHMe, PMe2, PHPh, PPh2, PMePh, SH, SMe, SPh; bipy = 2,2′-bipyridine) towards methyl propiolate was carried out to analyze the influence of both the heteroatom (N, O, P, S) and the alkyl and/or aryl substituents of the Y ligand on the nature of the product obtained. The methyl substituent tends to accelerate the reactions. However, an aromatic ring bonded to N and O makes the reaction more difficult, whereas its linkage to P and S favour it. On the whole, ligands with O and S heteroatoms seem to disfavour these processes more than ligands with N and P heteroatoms, respectively. Phosphido and thiolato ligands tend to yield a coupling product with the bipy ligand, which is not the general case for hydroxo, alcoxo or amido ligands. When the Y ligand has an O/N and an H atom the most likely product is the one containing a coupling with the carbonyl ligand, which is not always obtained when Y contains P/S. Only for OMe and OPh, the product resulting from formal insertion into the Re-Y bond is the preferred.