Ring-closing Enyne Metathesis Research Articles

Enantioselective total synthesis of (-)-acylfulvene and (-)-irofulven.

We report our full account of the enantioselective total synthesis of (-)-acylfulvene (1) and (-)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular framework of these antitumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing metathesis cascade reaction in a challenging setting, (3) the reagent IPNBSH for a late-stage reductive allylic transposition reaction, and (4) the final RCM/dehydrogenation sequence for the formation of (-)-acylfulvene (1) and (-)-irofulven (2).

Efficient Generation of Highly Functionalized Fused Oxazepine Frameworks Based on a CAN-Catalyzed Four-Component Tetrahydropyridine Synthesis/Ring-Closing Metathesis Sequence

1-Allyl(propargyl)-6-allyl(propargyl)oxy-1,4,5,6-tetrahydropyridines, obtained through a CAN-catalyzed four-component reaction, were transformed into highly functionalized pyrido[2,1-b][1,3]oxazepines by ring-closing metathesis (RCM) and ring-closing enyne metathesis (RCEYM) processes, which constitute the first examples of the preparation of 1,3-oxazepine systems using metathesis reactions.

Ring-Size-Selective Enyne Metathesis as a Tool for Desymmetrization of an Enantiopure C2-Symmetric Building Block

The enantiomerically pure C(2)-symmetrical hexa-1,5-diene-3,4-diol is selectively monopropargylated. The products undergo ring-closing enyne metathesis to give exclusively dihydropyrans as single stereoisomers. An unprotected hydroxy group is identified as the factor controlling the ring-size selectivity.

Structure and reactivity of alkyne-chelated ruthenium alkylidene complexes.

The isolation and structural characterization of alkyne-bound Ru alkylidene complexes has been elusive. However, a sequential enyne ring-closing metathesis of a diyne moiety and metallotropic [1,3]-shift followed by a second enyne ring-closing metathesis allowed the formation of a highly stable alkyne-chelated ruthenium complex. The full characterization of this complex was realized by NMR spectroscopy and X-ray crystallography.

Synthesis of macrocyclic scaffolds suitable for diversity-oriented synthesis of macrolides

Synthesis of macrocyclic glycal-based scaffolds for diversity-oriented synthesis was studied and demonstrated using macrocyclic enyne ring-closing metathesis. The roles of ring size, alkyne substitution, and orientation relative to the glycal were studied. In all cases, the cyclization showed preference for the thermodynamically favored endo-mode of closure and a trans-double bond at the ring-closure site, leaving macrocyclic scaffolds all containing multiple orthogonal functional groups available for further diversification.

Observations in the synthesis of the core of the antitumor illudins via an enyne ring closing metathesis cascade

Observations concerning the synthesis of the core spirocyclic AB-ring system of illudins using an enyne ring closing metathesis (EYRCM) cascade are discussed. Substituent effects, in addition to optimization of the reaction conditions and the olefin tether for the key EYRCM reaction, are examined.

Endo-selective enyne ring-closing metathesis promoted by stereogenic-at-Mo monoalkoxide and monoaryloxide complexes. Efficient synthesis of cyclic dienes not accessible through reactions with Ru carbenes.

Stereogenic-at-Mo monoalkoxide and monoaryloxide complexes promote enyne ring-closing metathesis (RCM) reactions, affording the corresponding endo products with high selectivity (typically >98:<2 endo:exo). All catalysts can be prepared and used in situ. Five-, six-, and seven-membered rings are obtained through reactions with enyne substrates that bear all-carbon tethers as well as those that contain heteroatom substituents. The newly developed catalytic protocols complement the related exo-selective Ru-catalyzed processes. In cases where Ru-based complexes deliver exo and endo products nondiscriminately, such as when tetrasubstituted cyclic alkenes are generated, Mo-catalyzed reactions afford the endo product exclusively. The efficiency of synthesis of N- and O-containing endo diene heterocycles can be improved significantly through structural modification of Mo catalysts. The modularity of Mo-based monopyrrolides is thus exploited in the identification of the most effective catalyst variants. Through alteration of O-based monodentate ligands, catalysts have been identified that promote enyne RCM with improved efficiency. The structural attributes of three Mo complexes are elucidated through X-ray crystallography. The first examples of catalytic enantioselective enyne RCM reactions are reported (up to 98:2 enantiomer ratio and >98% endo).

Application of Tandem Ring-Closing Enyne Metathesis: Formal Total Synthesis of (−)-Cochleamycin A

A tandem ring-closing metathesis of a silaketal-based dienyne substrate proceeded efficiently to provide a bicyclic siloxane, which upon removal of the silicon tether afforded an (E,Z)-1,3-dienediol. Further manipulation of this key functional motif rendered synthesis of the entire C1-C19 linear skeleton of (-)-cochleamycin A, a late-stage intermediate employed in the previous total synthesis of (+)-cochleamycin A by Roush and co-workers.

Ring-Closing Enyne Metathesis (RCEYM) for the Synthesis of Cyclic Sulfoximines

Heterocyclic sulfoximines have been synthesized by RCEYM reactions starting from N-alkynyl-S-alkenyl sulfoximines in up to 79% yield. The products can be converted to tricyclic derivatives by a domino Diels-Alder/aromatization reaction sequence.

Cyclic poly(ε‐caprolactone) synthesized by combination of ring‐opening polymerization with ring‐closing metathesis, ring closing enyne metathesis, or “click” reaction

AbstractThis article described the synthesis of cyclic poly(ε‐caprolactone) (PCL) via ring‐closing metathesis (RCM), ring closing enyne metathesis (RCEM), and “click” reaction of different difunctional linear PCL. Linear PCL precursors were prepared by ring‐opening polymerization (ROP) of ε‐caprolactone in bulk using 10‐undecen‐1‐ol or propargyl alcohol as the initiator, followed by reacting with corresponding acyl chloride containing vinyl or azido end group. The subsequent end‐to‐end intramolecular coupling reactions were performed under high dilution conditions. The successful transformation of linear PCL precursor to cyclic PCL was confirmed by Gel permeation chromatography, 1H NMR, and Fourier transform infrared measurements. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3022–3033, 2009

Synthesis of Carbocyclic Aromatic Compounds Using Ruthenium-Catalyzed Ring-Closing Enyne Metathesis

General synthetic methods of substituted carbocyclic aromatic compounds are reported. Ring-closing enyne metathesis (RCEM)/dehydration of 1,5-octadien-7-yn-4-ols 6 and RCEM/tautomerization of 1,5-octadien-7-yn-4-ones 7 furnished a wide variety of substituted styrenes 4 and 4-vinylphenols 8, respectively. Acyclic precursors 6 and 7 were readily prepared from beta-halo-alpha,beta-unsaturated aldehydes 9 or 3-halo-2-propene-1-ols 13 by utilizing combinations of the Sonogashira coupling, allylation, and the Dess-Martin oxidation. The RCEM/dehydration for the synthesis of 1,3,5-tris(1-phenylethenyl)benzene derivative 4r and the RCEM/RCM/dehydration for the synthesis of 1,1'-binaphthyl derivative 19a are also presented as applications of this method.

Stereoselective Total Synthesis of (+)-Valienamine and (+)-4-epi-Valienamine via a Ring-Closing Enyne Metathesis Protocol

Stereoselective total synthesis of (+)-valienamine is reported utilizing Sharpless asymmetric dihydroxylation, diastereoselective Carreira alkynylation, and ring-closing enyne metathesis (RCEYM) as key steps from l-serine. A similar strategy is also reported for the first total synthesis of (+)-4-epi-valienamine.

閉環メタセシスを利用する置換芳香族化合物の合成

The demand for functionalized aromatic compounds is growing rapidly in many research fields. Therefore, the efficient synthesis of desired aromatic compounds is a critical issue in organic synthesis. In this account, we describe new synthetic approaches to versatile aromatic compounds, such as phenols, benzenes, 3-hydroxypyridines, and styrenes, by ring-closing olefin metathesis (RCM)/aromatization and ring-closing enyne metathesis (RCEM)/aromatization of acyclic precursors. The advantages in terms of simplicity, flexibility, and avoidance of the formation of regioisomers are proof of the versatility of this method for the synthesis of aromatic compounds.

“Click, Click, Cyclize”: A DOS Approach to Sultams Utilizing Vinyl Sulfonamide Linchpins

A diversity-oriented synthesis (DOS) strategy termed "Click, Click, Cyclize" is reported. This approach relies on functional group (FG) pairing between a vinyl sulfonamide and an array of functional groups to synthesize skeletally diverse sultams. Several FG pairing pathways on central tertiary vinyl sulfonamide linchpins have been developed including intramolecular Heck, aza-Michael, ring-closing enyne metathesis, Pauson-Khand, and chemoselective oxidation/Baylis-Hillman reactions.

Structure and Reactivity of Alkynyl Ruthenium Alkylidenes

The isolation and structural characterization of alkynyl Ru-alkylidene species has been elusive owing to their rapid metallotropic shift and fast turnover. The enyne ring-closing metathesis and relay metathesis provides the platform to form a variety of alkynyl Ru-alkylidene species possessing a sterically and electronically different substituent on the carbenic carbon, which allowed their regio-controlled trapping and structural characterization.

Acceleration Effect of an Allylic Hydroxy Group on Ring‐Closing Enyne Metathesis of Terminal Alkynes: Scope, Application, and Mechanistic Insights

An interesting acceleration effect of an allylic hydroxy group on ring-closing enyne metathesis has been found. Ring-closing enyne metathesis of terminal alkynes possessing an allylic hydroxy group proceeded smoothly without the ethylene atmosphere generally necessary to promote the reaction. The synthesis of (+)-isofagomine with the aid of this efficient reaction has been demonstrated. Mechanistic studies of the acceleration effect were also carried out. Results of NMR studies suggested that the reaction proceeded via an "ene-then-yne" pathway. Kinetic studies indicated switching of the rate-determining step as a consequence of the presence of an allylic hydroxy group. These results suggest acceleration of the reentry step of Ru-carbene species by the allylic hydroxy group.

Efficient synthesis of 4-vinyl α,β-unsaturated γ-lactams by ring-closing enyne metathesis reactions

The ring-closing enyne metathesis reaction of alkyl 2-substituted-2-( N-alkynyl acrylamido)esters using the first-generation Grubbs’ catalyst afforded five-membered lactams bearing a 1,3-diene moiety in high isolated yields. In the reaction process, the presence of ethylene gas is essential.

Synthesis of a Conformationally Constrained Phenylalanine Derivative by a Strategic Combination of Ring-Closing Enyne Metathesis and Diels-Alder Reaction

An efficient route towards the synthesis of a conformationally constrained phenylalanine derivative is demonstrated using the strategic combination of ring-closing enyne metathesis and Diels-Alder reaction as key steps.

The Joy and Challenge of Small Rings Metathesis

Recent decades have seen a burgeoning of interest in olefin metathesis, as witnessed by a rapidly growing number of elegant applications. Using this tool, chemists can now efficiently synthesize an impressive range of molecules that only a decade ago required significantly longer and tedious routes.[1] Several types of olefin metathesis have been identified so far, among them ring-closing metathesis (RCM) and cross-metathesis (CM) being widely and successfully applied in the synthesis of biologically active complex compounds (Scheme 1). Ring closing metathesis occurs when a diene undergoes intramolecular metathesis affording a cyclic olefin. Analogous intramolecular reaction of an enyne is sometimes called enyne cycloisomerisation or enyne RCM.[2] Ring-closing metathesis reactions of dienes and enynes represent an attractive and powerful tool for formation of medium and large cycles (≥5 members). However, it is generally acknowledged that small rings (threeand four-membered) and strained cannot be formed by RCM.[3] In such cases, the ring opening process can be far more thermodynamically favourable than ring closing. Indeed, various strained molecules, such as norbornene derivatives, are well known substrates for ring-opening metathesis polymerization (ROMP) reactions (Scheme 1).[4]

Synthesis of Styrenes Using Ruthenium-Catalyzed Ring-Closing Enyne Metathesis

The synthesis of substituted styrenes was achieved by ring-closing enyne metathesis (RCEM)/elimination of enyne substrates 12. The synthetic approach was also effective for a different type of enyne substrate 14, yielding corresponding styrene 15.