Synthesis of the fused polyether core of hemibrevetoxin B by two-directional ring-closing metathesis

The tetracyclic fused polyether core of the marine natural product hemibrevetoxin B has been prepared in an efficient manner by using a strategy in which ring-closing metathesis (RCM) reactions were employed for ring synthesis. Simultaneous construction of the A and D rings was accomplished by double two-directional RCM of a tetraene. [reaction: see text]     

Trisubstituted cyclooctene synthesis at the limits of relay ring-closing metathesis: a racemic difluorinated analogue of fucose

A telescoped sequence based on metallated enol acetal chemistry allowed the efficient delivery of a ring-closing metathesis (RCM) precursor, which was used to form a cyclooctenone product with a trisubstituted alkenyl group in moderate yield, though a high loading of second generation Grubbs' pre-catalyst was required. A relay RCM (RRCM) precursor was synthesised to deliver the key alkylidene at a higher rate; the catalyst loading required was high, and increasing the reaction temperature simply resulted in the loss of the cyclising alkylidene by a non-productive cross-metathesis pathway. We were forced to use high dilution conditions to suppress the unwanted CM and secure the cyclooctenone product. The cyclooctenone product could be progressed to analogues of fucose and 6-deoxyidose by UpJohn dihydroxylation.     

Metathesis studies to cyclic enol phosphonamidates

The development of cyclic, six membered enol phosphonamidates utilizing the ring-closing metathesis (RCM) reaction is discussed. Phosphonamidic monochloridates are generated and further functionalized to an array of acyclic, enol phosphonamidates. Subsequent metathesis affords both desired RCM product and corresponding cross metathesis (CM) dimer. Efforts to optimize formation of desired RCM product, while minimizing CM products are discussed, with interesting steric and electronic factors governing reactivity patterns. This strategy allows for generation of cyclic enol phosphonamidates, with ultimate application to C(6)-substituted analogs of the anti-cancer agent, cyclophosphamide.     

Olefin metathesis: remote substituents governing the stereoselectivity of 11-membered-ring formation

[reaction: see text] Stereospecific RCM reaction of 7 (R1 = Me) results in the formation of (Z)-11-membered macrocycle 9c. Cascade RCM/ROM/RCM transformation of 7 (R1 = H) affords the thermodynamically more stable spirocycle product 12.     

Ring-closing metathesis as a basis for the construction of aromatic compounds

The use of metathesis, especially in the context of ring-closing metathesis (RCM) to form five- and six-membered rings, is widespread in organic chemistry today. However, there are surprisingly few examples of the reaction being used to form aromatic compounds. The central place of aromatic compounds in both medicinal chemistry and natural products synthesis, coupled with the efficiency and functional group tolerance of RCM catalysts, means that there is now an interesting opportunity to use RCM for the synthesis of arenes. Although the formation of an aromatic compound was viewed in many early examples as an undesirable degradation product, several rationally designed methods towards the preparation of aromatic compounds by RCM have recently been developed.     

Getting Ring‐Closing Metathesis off the Bench: Reaction‐Reactor Matching Transforms Metathesis Efficiency in the Assembly of Large Rings

Reported is the first study of the influence of reactor configuration on the efficiency of a challenging ring‐closing metathesis (RCM) reaction. With the intention of increasing the generality of RCM scaleup and reducing its dependence on substrate modification, macrocyclization of an unmodified, low effective‐molarity diene was explored using different reactor types, in conjunction with a commercial, homogeneous Grubbs catalyst. Optimized performance is compared for a conventional batch reactor (BR), a continuous plug‐flow reactor (PFR), and a continuous stirred‐tank reactor (CSTR). In the PFR, maximum conversion is achieved most rapidly, but product yields and selectivity are adversely affected by co‐entrapment of ethylene with the catalyst, substrate, and product in the traveling “plug”. Use of the CSTR, in which ethylene is efficiently swept out, affords an order‐of‐magnitude increase in total turnover numbers, and reduces the required catalyst loadings by 25× relative to the BR (to 0.2 mol %), while improving RCM yields and selectivity to quantitative levels. Continuous‐flow methodologies that support liberation of the ethylene co‐product thus show great promise for industrial uptake of RCM.     

A ring-closing metathesis approach to the bicyclo[4.3.1]decane core of caryolanes

A synthesis of highly substituted and sterically congested bicyclo[4.3.1]decenes, a structure embedded in the core 4,7,6-tricyclic system of natural caryolanes, was successfully achieved via a ring-closing metathesis (RCM) reaction of syn-1,3-diene substituted cyclohexanols. The construction of the diene substrates, starting from 4-acetoxy-3-methyl-2-cyclohexen-1-one, employed diastereoselective copper-mediated conjugate addition and Grignard reactions. An X-ray crystal structure determination of a key synthetic intermediate confirmed the relative stereochemistry of the RCM bicyclic product.     

Effects of temperature and concentration in some ring closing metathesis reactions

Ring closing metathesis (RCM) has emerged as a powerful tool to construct macrocyclic ring systems. However, the product distribution of monomer and oligomers is often a problem in the formation of medium to large rings. In the course of synthetic studies on the natural product radicicol and its analogs, we have found that the reaction temperature, along with concentration, has significant impact on the outcome of the product ratio. Specifically, carrying out the RCM reaction in refluxing toluene (110°C) at higher dilution affords improved yields of the monomeric macrocycle. Similar observations for another family of macrolactone natural products, the epothilones, are also reported.     

Ring-Closing Metathesis of Ene-Ynamide: Application to the Synthesis of Medium-Sized Cyclic Dienamide

Summary: Ring-closing metathesis (RCM) of ene-ynamide, which could be applied to the synthesis of various heterocycles containing 7- and 8-membered rings, was investigated. Ene-ynamides are easily synthesized by the known method. When a toluene solution of ene-ynamide was stirred in the presence of a catalytic amount of second-generation ruthenium carbene complex 1 under an ethylene atmosphere, RCM proceeded smoothly to provide a heterocyclic compound having a diene moiety in good to high yield. A substituent of the ynamide moiety affected the yield of the cyclized product.     

Stereoselective synthesis of the phorboxazole A macrolide by ring-closing metathesis

[Structure: see text] Described is a regio- and stereoselective ring-closing metathesis (RCM) to form the C2-C3 alkene of the macrolide-containing domain of phorboxazole A. This work demonstrates a dramatic effect of reaction solvent on RCM product (E/Z)-selectivity. This process offers an alternative assembly of the macrolide-containing domain of phorboxazole A, one of the most potent anticancer agents known.     

Stereoselective total synthesis of decarestrictine-J via Ring Closing Metathesis (RCM)

Stereoselective total synthesis of decarestrictine-J, a polyketide natural product is described. The synthesis involves the Prins cyclisation and Ring Closing Metathesis (RCM) as key steps.     

An RCM‐Based Total Synthesis of the Antibiotic Disciformycin B

The total synthesis of the potent new antibiotic disciformycin B ( 2 ) is described, which shows significant activity against methicillin‐ and vancomycin‐resistant Staphylococcus aureus (MRSA/VRSA) strains. The synthetic route is based on macrocyclization of a tetraene substrate to the 12‐membered macrolactone core by ring‐closing olefin metathesis (RCM). Although macrocyclization was accompanied by concomitant cyclopentene formation by an alternative RCM pathway, conditions were established to give the macrocycle as the major product. Key steps in the construction of the RCM substrate include a highly efficient Evans syn‐aldol reaction, the asymmetric Brown allylation of angelic aldehyde, and the stereoselective Zn(BH₄)₂‐mediated 1,2‐reduction of an enone. The synthesis was completed by late‐stage dehydrative glycosylation to introduce the d ‐arabinofuranosyl moiety and final chemoselective allylic alcohol oxidation.     

Stereoselective synthesis of tarchonanthuslactone via the Prins cyclisation

The stereoselective total synthesis of tarchonanthuslactone, a polyketide natural product, has been achieved. The synthesis exploits the high stereochemical control in the Prins cyclisation along with ring closing metathesis (RCM) as a key step.     

Experimental and theoretical study on the olefin metathesis of alkenyl Baylis-Hillman adducts using second-generation Grubbs catalyst

[reaction: see text] We have investigated the olefin metathesis from alkenyl Baylis-Hillman adducts using second-generation Grubbs catalyst. In the experiment, the ring-closing metathesis (RCM) product could not be found, while the cross-metathesis (CM) products were found. The computational studies provided consistent explanations for the experimental result. The most limiting factor for the RCM process using second-generation Grubbs catalyst is caused by the high strain and steric effect in the metallacyclobutane intermediates.     

Rapid synthesis of the A-E fragment of ciguatoxin CTX3C

The A-E fragment of the marine natural product CTX3C has been prepared in an efficient manner by using a strategy in which two-directional and iterative ring-closing metathesis (RCM) reactions were employed for ring construction.     

Total syntheses of (S)-(-)-zearalenone and lasiodiplodin reveal superior metathesis activity of ruthenium carbene complexes with imidazol-2-ylidene ligands

Total syntheses of the bioactive orsellinic acid derivatives zearalenone 3 and lasiodiplodin 1 are reported based on a ring-closing metathesis (RCM) reaction of styrene precursors as the key steps. These and closely related macrocyclizations are catalyzed with high efficiency by the "second generation" ruthenium carbene catalyst 5 bearing a N-heterocyclic carbene ligand, whereas the standard Grubbs carbene 4 fails to afford any cyclized product. Only the (E)-isomer of the macrocyclic cycloalkene is formed in all cases. The substrates for RCM can be obtained either via a Stille cross-coupling reaction of tributylvinylstannane or, even more efficiently, by Heck reactions of the aryl triflate precursors with pressurized ethene. Furthermore, the synthesis of 1 via RCM is compared with an alternative approach employing a low-valent titanium-induced McMurry coupling of dialdehyde 47 for the formation of the large ring. This direct comparison clearly ends in favor of metathesis which turned out to be superior in all preparatively relevant respects.     

Electrochemical partial fluorination of organic compounds. 80. Synthesis of cyclic alpha-arylthio-alpha-monofluorophosphonate esters

[Reaction: see text]. Seven-membered cyclic alpha-monofluorophosphonate esters such as 2-allyloxy-3-fluoro-3-phenylthio-4,7-dihydro-[1, 2]-oxaphosphinine-2-oxide were successfully synthesized in moderate total yield as 41% from open-chain allyl phosphonates having an alpha-arylthio group as an electroauxiliary using an alternative sequence of anodic fluorination and ring-closing olefin metathesis (RCM). On the other hand, in an attempt to synthesize an eight-membered analogue, a different type of seven-membered fluorinated cyclic product was formed predominantly by the RCM reaction between the allyloxy groups.     

Total synthesis of 1-deoxygulonojirimycin. Revision of the absolute configuration of the natural product

A concise, stereoselective synthesis of 1-deoxygulonojirimycin was achieved and the absolute configuration of the natural product was revised. Key features involve diastereoselective oxazoline formation catalyzed by palladium(0), RCM and dihydroxylation.     

Enantiospecific total synthesis of the putative structure of cryptopyranmoscatone B2

Total synthesis of THP tethered pyrone containing natural product cryptopyranmoscatone B2 was accomplished from commercially available 2-deoxyribose. The key THP unit was assembled by FeCl₃ catalyzed cyclization of an allyl alcohol. Brown allylation and RCM reactions were employed to construct the lactone unit. The synthesis represents the first total synthesis of the putative structure of the natural product.