Cyclization Of Enynes Research Articles

Synthesis of Eupalinilide E, a Promoter of Human Hematopoietic Stem and Progenitor Cell Expansion.

Improving the ex vivo and in vivo production of hematopoietic stem and progenitor cells (HSPCs) has the potential to address the short supply of these cells that are used in the treatment of various blood diseases and disorders. Eupalinilide E promotes the expansion of human HSPCs and inhibits subsequent differentiation, leading to increased numbers of clinically useful cells. This natural product represents an important tool to uncover new methods to drive expansion while inhibiting differentiation. However, in the process of examining these effects, which occur through a novel mechanism, the natural product was consumed, which limited additional investigation. To provide renewed and improved access to eupalinilide E, a laboratory synthesis has been developed and is reported herein. The synthetic route can access >400 mg in a single batch, employing reactions conducted on useful scales in a single vessel. Key transformations enabling the approach include a diastereoselective borylative enyne cyclization and a late-stage double allylic C-H oxidation as well as adapted Luche reduction and aluminum-mediated epoxidation reactions to maximize the synthetic efficiency. Retesting of the synthetic eupalinilide E confirmed the compound's ability to expand HSPCs and inhibit differentiation.

Gold(I)-Catalyzed Enyne Cyclizations: Studies Toward the Total Synthesis of (+)-Aureol

We report a modular synthetic approach toward the total synthesis of (+)-aureol based on a bioinspired gold(I)-catalyzed enyne cascade cyclization reaction. First, we investigated an array of catalysts to promote a 6-<i>endo</i>-dig cyclization of a highly advanced enediyne precursor. Since these studies result exclusively in the formation of the 5-<i>exo</i>-dig product, we synthesized and investigated a dienyne cyclization precursor in order to form the benzo[<i>d</i>]xanthene skeleton in a stepwise fashion.

Mechanistic Information from Nonstationary Points.

The thermal cyclization of enyne-carbodiimides substituted at both the alkyne and carbodiimide terminus showed two curved Hammett correlations (log k/k0 against σp) that were fully reproduced by DFT (density functional theory) computational results. The latter suggest a concerted mechanism, but the transition state (TS) analysis failed to reveal any mechanistic insight about the reason for a curved Hammett correlation. Instead a preTS inspection, i.e., examination of the electronic and steric details on route between reactant and TS, furnished a detailed picture of the mechanism.

The Missing C1-C5 Cycloaromatization Reaction: Triplet State Antiaromaticity Relief and Self-Terminating Photorelease of Formaldehyde for Synthesis of Fulvenes from Enynes.

The last missing example of the four archetypical cycloaromatizations of enediynes and enynes was discovered by combining a twisted alkene excited state with a new self-terminating path for intramolecular conversion of diradicals into closed-shell products. Photoexcitation of aromatic enynes to a twisted alkene triplet state creates a unique stereoelectronic situation, which is facilitated by the relief of excited state antiaromaticity of the benzene ring. This enables the usually unfavorable 5-endo-trig cyclization and merges it with 5-exo-dig closure. The 1,4-diradical product of the C1-C5 cyclization undergoes internal H atom transfer that is coupled with the fragmentation of an exocyclic C-C bond. This sequence provides efficient access to benzofulvenes from enynes and expands the utility of self-terminating aromatizing enyne cascades to photochemical reactions. The key feature of this self-terminating reaction is that, despite the involvement of radical species in the key cyclization step, no external radical sources or quenchers are needed to provide the products. In these cascades, both radical centers are formed transiently and converted to the closed-shell products via intramolecular H-transfer and C-C bond fragmentation. Furthermore, incorporating C-C bond cleavage into the photochemical self-terminating cyclizations of enynes opens a new way for the use of alkenes as alkyne equivalents in organic synthesis.

Bisallylation of Zirconacyclopentenes and Ring-Closing Metathesis: A Route to Eight-Membered-Ring Compounds

The cyclization of various enynes with the Negishi reagent provides the corresponding bicyclic zirconacyclopentenes, which after exposure to allyl chloride in the presence of a catalytic amount of copper(I) chloride, undergo bisallylation to furnish 1,9-decadienes in good yields (42–89%). The dienes are subjected to ring-closing metathesis to afford bicyclic compounds with [6.3.0]bicycloundecane (8,5-fused ring system) or [6.4.0]bicyclododecane (8,6-fused ring system) frameworks in good to excellent yields (52–92%). Selective monoallylation of a selected zirconacyclopentene followed by carboxyethylation with ethyl chloroformate gives rise to the corresponding ester, which after metalation and reaction with allyl bromide, furnishes a 1,9-decadiene. Ring-closing metathesis then yields the expected eight-membered cyclic product in 92% yield. This procedure constitutes a new pathway to bicyclic carbocyclic systems starting from 1,ω-enynes.

Phenoxy-Linked Mesoionic Triazol-5-ylidenes as Platforms for Multinuclear Transition Metal Complexes

The preparation and full characterization of a variety of mono- ([L1-H]), di- ([L2-H2], [L2A-H2]), and tri- ([L3-H3]) 1,2,3-triazolium salts constructed form “clicked” hydroxybenzene derivatives are reported. Deprotonation with potassium hexamethyldisilazide, followed by in situ metalation, allowed for the synthesis of a series of mono- (L1·[M]), di- (L2·[M]2, L2·[M]2), and trinuclear (L3·[M]3) group 9–11 (M = [Rh(CO)2Cl], [Pd(allyl)Cl], and [AuCl]) triazol-5-ylidene metal complexes. In solution, all metal complexes feature symmetrical patterns displaying C2 and C3 fold axes when supported by di- and tritriazol-5-ylidene ligands. The vibration frequencies of Ln·[Rh(CO)2Cl]n (n = 1–3) complexes indicate that the electron-donor properties of the new ligands are comparable to those for previously reported MIC complexes and superior to classical NHCs. Prompting coordination of the vicinal phenoxy group to the metal centers proved unsuccessful after treatment of the Ln·[Rh(CO)2Cl]n and Ln·[Pd(allyl)Cl]n (n = 1–3) precursors with AgBF4; the expected chelated cationic complexes were highly unstable, indicating a weak or no coordination availability through the oxygen atom. Crystal structures of the complexes L1·[AuI] and L2A·[Pd(allyl)I]2 illustrated the metal center geometrical environment and confirmed the lack of coordination through the phenoxy moiety of the ligand. Preliminary catalytic trials established the enhanced performance of di- and trimetallic palladium complexes in cross-coupling reactions and the intramolecular cyclization of enynes catalyzed by gold complexes.

N‐Heterocyclic Carbene–Phosphinidene Complexes of the Coinage Metals

Coinage metal complexes of the N-heterocyclic carbene-phosphinidene adduct IPr⋅PPh (IPr=1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) were prepared by its reaction with CuCl, AgCl, and [(Me2 S)AuCl], which afforded the monometallic complexes [(IPr⋅PPh)MCl] (M=Cu, Ag, Au). The reaction with two equivalents of the metal halides gave bimetallic [(IPr⋅PPh)(MCl)2 ] (M=Cu, Au); the corresponding disilver complex could not be isolated. [(IPr⋅PPh)(CuOTf)2 ] was prepared by reaction with copper(I) trifluoromethanesulfonate. Treatment of [(IPr⋅PPh)(MCl)2 ] (M=Cu, Au) with Na(BAr(F) ) or AgSbF6 afforded the tetranuclear complexes [(IPr⋅PPh)2 M4 Cl2 ]X2 (X=BAr(F) or SbF6 ), which contain unusual eight-membered M4 Cl2 P2 rings with short cuprophilic or aurophilic contacts along the chlorine-bridged M⋅⋅⋅M axes. Complete chloride abstraction from [(IPr⋅PPh)(AuCl)2 ] was achieved with two equivalents of AgSbF6 in the presence of tetrahydrothiophene (THT) to form [(IPr⋅PPh){Au(THT)}2 ][SbF6 ]2 . The cationic tetra- and dinuclear complexes were used as catalysts for enyne cyclization and carbene transfer reactions.

Chiral [2.2]paracyclophane-based NAC- and NHC-gold(I) complexes

From enantiomerically pure, planar chiral [2.2]paracyclophane amines a series of nitrogen acyclic carbenegold(I) complexes and nitrogen heterocyclic carbenegold(I) complexes are prepared by a modular template synthesis using isonitriles and amines. These chiral catalysts are tested in two reactions, the enantiotopos-selective furanyne cyclization and the enantioselective enyne cyclization. While excellent conversions could be achieved with these new catalysts, the enantioselectivities in only some cases are in the range of best known catalysts for these conversion.

Synthetic Strategies for Oligoynes

AbstractOligoynes with alternating carbon–carbon single and triple bonds and with suitable end groups are interesting compounds for materials science and molecular electronics. Here we present recent synthetic strategies for the preparation of oligoynes as well as a few oligoenynes, in both linear and cyclic scaffolds, with different end groups, which are present either to incorporate additional functionality and properties to the molecule (such as redox properties) or to sterically shield the oligoyne chain. The strategies involve a variety of metal‐catalyzed reactions as well as procedures in which the oligoyne is prepared in the final step of the synthesis from related conjugated precursors. End‐capping of terminal alkynes with phosphine‐gold(I) complexes presents a way to enhance the stability and has been used not only to construct oligoynes, but also cyclic radiaannulene structures from stable and isolable tetraethynylethene building blocks (see frontispiece); upon ready reduction, these cyclic enynes can form cumulenic structures.

Air-stable cationic gold(I) catalyst featuring a Z-type ligand: promoting enyne cyclizations.

An air-stable cationic Au(I) complex featuring a Z-type ligand (boron atom) as a σ-acceptor was developed for elucidating the effect of B on catalytic reactions. An enyne cyclization in the presence of either [Au→B](+) or [Au](+) showed that [Au→B](+) promotes the reactivity, which enabled the effective construction of not only five- and six-membered rings, but also seven-membered rings.

Air‐Stable Cationic Gold(I) Catalyst Featuring a Z‐Type Ligand: Promoting Enyne Cyclizations

AbstractAn air‐stable cationic AuI complex featuring a Z‐type ligand (boron atom) as a σ‐acceptor was developed for elucidating the effect of B on catalytic reactions. An enyne cyclization in the presence of either [Au→B]+ or [Au]+ showed that [Au→B]+ promotes the reactivity, which enabled the effective construction of not only five‐ and six‐membered rings, but also seven‐membered rings.

ChemInform Abstract: Base‐Promoted One‐Pot Sequential Phosphite Addition and 5‐exo‐dig Cyclization of Enynals: A Facile Route to Trisubstituted Furans.

An easy route for the synthesis of trisubstituted furans has been demonstrated. One-pot sequential phosphite (H-phosphonate) addition to alkynylaldehydes (enynals) promoted by tripotassium phosphate leads to trisubstituted furans (phosphono-furans) via 5-exo-dig cyclization of the phosphono-alkynol intermediates. In contrast, in the presence of silver(I) tetrafluoroborate, the reaction using the same substrates leads to a diene product.

Rerouting radical cascades: intercepting the homoallyl ring expansion in enyne cyclizations via C-S scission.

The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3-exo-trig/fragmentation) ring expansion to afford the benzylic radical necessary for the final aromatizing C-C bond fragmentation. The interception of the intermediate 5-exo-trig product via β-scission of a properly positioned weak C-S bond provides direct mechanistic evidence for the 5-exo cyclization/ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild synthesis of Bu3Sn-functionalized naphthalenes.

ChemInform Abstract: Copper‐Catalyzed Trifluoromethylation—Cyclization of Enynes: Highly Regioselective Construction of Trifluoromethylated Carbocycles and Heterocycles.

Regioselective trifluoromethylation-cyclization: A method for copper-catalyzed trifluoromethylation-cyclization of simple enynes using the C-C triple bond as a nucleophile is reported for the first time (see scheme). The reaction proceeds efficiently in a highly regioselective manner to give various 5- or 6-exo-dig carbocycles and heterocycles in moderate to high yields.

Base-Promoted One-Pot Sequential Phosphite Addition and 5-exo-dig Cyclization of Enynals: A Facile Route to Trisubstituted Furans

An easy route for the synthesis of trisubstituted furans has been demonstrated. One-pot sequential phosphite (H-phosphonate) addition to alkynylaldehydes (enynals) promoted by tripotassium phosphate leads to trisubstituted furans (phosphono-furans) via 5-exo-dig cyclization of the phosphono-alkynol intermediates. In contrast, in the presence of silver(I) tetrafluoroborate, the reaction using the same substrates leads to a diene product.

Highly active phosphite gold(i) catalysts for intramolecular hydroalkoxylation, enyne cyclization and furanyne cyclization

New and highly active mononuclear phosphite gold(I) catalysts are described. Turn-over numbers up to 37,000 for the furan-yne reaction and up to 28,000,000 for the two-fold hydroalkoxylation of alkynes are reported.

ChemInform Abstract: Oxidant‐Dependent Chemoselectivity in the Gold‐Catalyzed Oxidative Cyclizations of 3,4,6,6‐Tetrasubstituted 3,5‐Dien‐1‐ynes.

AbstractIn contrast to the reaction of 3,5‐dienynes with methylquinoline N‐oxide giving fused cyclopropane derivatives, treatment with less active dichloropyridine N‐oxide is found to result in formation of cyclopentadienyl aldehydes via prior enyne cyclization and subsequent carbene oxidation.

Drawing from a Pool of Radicals for the Design of Selective Enyne Cyclizations

Despite the possibility of intermolecular attack at four different locations, the Bu3Sn-mediated radical cyclization of aromatic enynes is surprisingly selective. The observed reaction path originates from the least stable of the equilibrating pool of isomeric radicals produced by intermolecular Bu3Sn attack at the π-bonds of substrates. The radical pool components are kinetically self-sorted via 5-exo-trig closure, the fastest of the four possible cyclizations. The resulting Sn-substituted indenes are capable of further transformations in reactions with electrophiles.

Palladium(II)-catalyzed oxidative annulation of alkenylindoles with alkynes initiated by C–H activation

A palladium(II)-catalyzed annulation of alkenylindoles with diarylethynes initiated by C–H bond activation was developed. This method provided a convenient way for the synthesis of dihydrocyclopenta[b]indoles by enyne cyclization initiated by C–H bond activation.

ChemInform Abstract: Selective Construction of Aliphatic Polycycles Utilizing Platinum‐Catalyzed Cyclization of 2‐(Enynyl)cycloalkenals.

AbstractOptimized reaction conditions including PtCl2 as the catalyst are developed for the cyclization of enynals to give tricyclic cycloheptadienone derivatives.