Alkyne Partners Research Articles

Toward the synthesis of amphidinolide P: optimization of a model ene–yne metathesis fragment coupling

Ene–yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene–yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda–Grubbs carbene complexes.

From Understanding to Prediction: Gold- and Platinum-Based π-Acid Catalysis for Target Oriented Synthesis

During the last century, conceptual advances in organometallic chemistry were often rapidly embraced by target oriented synthesis. Feedback provided by such preparative scrutiny has greatly benefitted method development; particularly prominent are examples from the entire cross coupling arena, as well as olefin metathesis. Seen against this backdrop, it is somewhat surprising that the explosive growth of research into π-acid catalysis has not yet yielded a matching number of implementations into the synthesis of structurally complex targets of biological significance. In contrast to the massive output of methodological and mechanistic investigations, few studies illustrate the strategic use of gold, silver, or platinum catalysis in late stages of such multistep endeavors. These elaborate and highly precious compounds demand utmost confidence in the reliability and robustness of the method to be applied. In this Account, we analyze the possible reasons for this imbalance, after a short summary of the conceptual basis of carbophilic activation of π-bonds with the aid of soft transition metal cations or complexes. We pinpoint mechanistic subtleties, which, at least in part, produce a great deal of structural diversity but can jeopardize predictive power. With the advances in the understanding of π-acid catalyzed processes in general, however, this uncertainty is gradually vanishing and the entire field is transitioning from comprehension to prediction. This is expected to foster advanced applications, while recent progress in asymmetric gold catalysis further improves the preparative significance. The presented work in this Account illustrates our own commitment to the field as well as our growing confidence in the maturity of platinum and gold catalysis. The carbophilic activation of π-bonds, particularly of alkynes, provides a method to manipulate functional groups that is orthogonal to traditional carbonyl chemistry. We illustrate this notion by presenting a new approach to hydroxypyrone derivatives that has enabled the total synthesis of the fragile polyunsaturated cyclophane derivative neurymenolide A. The synthesis of the pyrrole alkaloid streptorubin by an enyne cycloisomerization is equally instructive. In addition, different manifestations of transannular hydroxyl addition reactions across alkyne partners mark the late stages of our conquests of amphidinolide F, polycavernoside A, and spirastrellolide F. Together with a few model studies and a personal selection of recent highlights from other groups, these examples augur well for future applications of π-acid catalysts in the realm of target oriented synthesis.

ChemInform Abstract: Homo‐ and Heterocoupling of Terminal Alkynes Using Catalytic CuCl2 and DBU.

Homocoupling of terminal alkynes has been efficiently achieved using catalytic amounts of CuCl2 and DBU. This methodology could be extended to couple two different terminal alkynes together by taking one of the alkyne partners, preferably the electron rich alkyne, in five fold excess than the other.

Synthesis of trans-A2B2-Porphyrins Bearing Phenylethynyl Substituents

Efficient and convenient conditions for the preparation of trans-A(2)B(2)-porphyrins bearing two phenylethynyl moieties directly from phenylpropargyl aldehydes and dipyrromethanes of diversified lipophilicity and reactivity have been developed. This new procedure allows the preparation of a library of porphyrins of this architecture with a wide range of substituents. Thanks to the identification of the reagent solubility as one of the key factors influencing the yield of the porphyrinogens, we were able to improve yields to ca. 30%. The scope and limitations of two sets of conditions have been explored. The methodological advantage of this approach is its straightforward access to building blocks and the formation of the porphyrin core in the last step without the need for deprotection of the triple bond or bromination and consecutive coupling reaction, which often demands copper salts to proceed smoothly, especially with electron-deficient alkyne partners. Therefore, it prevents undesired copper porphyrin formation, as well as the need for utilizing expensive alkynes. A two-step method for the preparation of phenylpropargyl aldehydes has also been refined.

A Regio‐ and Diastereoselective Platinum‐Catalyzed Tandem [2+1]/[3+2] Cycloaddition Sequence

Platinum complexes bearing phosphinous acids have efficiently promoted a tandem intermolecular sequence of [2+1]/[3+2] cycloaddition reactions. This process gave access to novel tricyclic systems and the cascade reactions were regio- and diastereoselective (see scheme; Cy=cyclohexyl). The [3+2] cycloaddition reaction was investigated further and two different alkyne partners were used.

Homo and Heterocoupling of Terminal Alkynes Using Catalytic CuCl2 and DBU

Homocoupling of terminal alkynes has been efficiently achieved using catalytic amounts of CuCl2 and DBU. This methodology could be extended to couple two different terminal alkynes together by taking one of the alkyne partners, preferably the electron rich alkyne, in five fold excess than the other.

Nucleoside and nucleotide analogues by catalyst free Huisgen nitrile oxide–alkyne1,3-dipolar cycloaddition

An efficient, catalyst free, 1,3-dipolar cycloaddition strategy to conjugate nucleosides and nucleotides with isoxazoles under atmospheric conditions and in an aqueous environment is reported. The protocol involves chloramine-T as a practical reagent to induce in situ nitrile oxide formation and the alkyne partner is attached to the sugar residue or the nucleobase. The reactions are regiospecific, fast and high yielding.

Ambient Temperature Hydrophosphination of Internal, Unactivated Alkynes and Allenyl Phosphineoxides with Phosphine Borane Complexes

Phosphine boranes have been found to hydrophosphinate internal, unactivated alkynes at room temperature under basic conditions without the need for catalysts or radical initiators. The use of air-sensitive secondary phosphines is avoided in this facile process. Broad scope in both the phosphine borane and alkyne partners leads to excellent diversity in the phosphine products. Asymmetric hydrogenation of these species then provides one of the shortest possible routes to chiral monodentate phosphines. Hydrophosphination of allenyl phosphine oxides under similar conditions followed by hydrogenation of the exomethylene moiety yields a wide variety of bis-phosphine derivatives.

Ru-catalyzed alkene-alkyne coupling. Total synthesis of amphidinolide P.

A coordinatively unsaturated ruthenium complex catalyzed the formation of a carbon-carbon bond between two judiciously chosen alkene and alkyne partners in good yield, and in a chemo- and regioselective fashion, despite the significant degree of unsaturation of the substrates. The resulting 1,4-diene forms the backbone of the cytotoxic marine natural product amphidinolide P. The alkene partner was rapidly assembled from (R)-glycidyl tosylate, which served as a linchpin in a one-flask, sequential three-components coupling process using vinyllithium and a vinyl cyanocuprate. The synthesis of the alkyne partner made use of an unusual anti-selective addition under chelation-control conditions of an allyltin reagent derived from tiglic acid. In addition, a remarkably E-selective E2 process using the azodicarboxylate-triphenylphosphine system is featured. Also featured is the first example of the use of a beta-lactone as a thermodynamic spring to effect macrolactonization. The oxetanone ring was thus used as a productive protecting group that increased the overall efficiency of this total synthesis. This work was also an opportunity to further probe the scope of the ruthenium-catalyzed alkene-alkyne coupling, in particular using enynes, and studies using various functionalized substrates are described.

Ethylene metathesis of sulfur-containing alkynes

Enyne metathesis of sulfur-containing alkynes and ethylene has been achieved. High yields were obtained by use of thiol esters in the alkyne partner for the cross metathesis with ethylene. The necessary reactivity and functional group compatibility were achieved through the use of the Grubbs’ second generation benzylidene carbene catalyst.