Pre-organization induced synthesis of a crossed alkene-bridged nisin Z DE-ring mimic by ring-closing metathesis

An alkene-bridged mimic of the complex DE-bisthioether-ring system of the antibiotic nisin was prepared in one step from the linear precursor.     

Total synthesis of N-malayamycin A and related bicyclic purine and pyrimidine nucleosides

Methods are described for the total synthesis of bicyclic perhydrofuropyran nucleosides as N-analogues of the naturally occurring malayamycin A. Formation of the N-nucleosides relied on the activation of thioglycosides, proceeding via sulfonium intermediates. Ring closure metathesis was used in two approaches to build the bicyclic dioxa heterocycle. Another approach relied on the use of a sugar precursor and cyclization to the bicyclic thioglycoside.     

Ring-closing metathesis for the synthesis of side chain knotted pentapeptides inspired by vancomycin

A versatile method for the synthesis of bicyclic side chain knotted peptides inspired by vancomycin is described. The synthetic approach is based on the incorporation of a central amino acid derivative having two allylic groups-introduced by a Stille coupling-into pentapeptide 8 containing two allylated serine residues. Treatment of this bis-ring-closing metathesis precursor with 2nd generation Grubbs catalyst results in the formation of a bicyclic pentapeptide with the correct side chain to side chain connectivity pattern as observed in vancomycin: i- 2 --> i, i --> i + 2. Modelling studies using MacroModel hint at a cavity-like structure of the bicyclic pentapeptide which may bind suitable ligands.     

Stereoselective diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based polycyclic derivatives

A diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based tricyclic derivatives has been achieved from enantiomerically pure, natural product-like bicyclic scaffold. The solution synthesis of enantiopure bicyclic scaffold was developed by asymmetric hetero Michael reaction. Our approach for the synthesis of polycyclic derivatives utilized regio- and stereoselective hetero Michael reaction and ring-closing metathesis as key steps in solution and on solid phase.     

Ring-rearrangement metathesis of bicyclic amino acid derivatives

In this letter, we describe the ring-rearrangement metathesis (RRM) of bicyclic amino acid derivatives. The procedure is of use for the synthesis of constrained amino acid and peptide derivatives with potential as reverse-turn inducers.     

Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomycin through ruthenium-based cyclization chemistries

The synthesis of a bicyclic tripeptide that mimics the ABC ring system of vancomycin is described by using a ring closing metathesis (RCM) – peptide coupling – ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) strategy.     

Asymmetric total synthesis of bacillariolide III, a marine oxylipin

[reaction: see text] The asymmetric total synthesis of bacillariolide III has been achieved via 15 linear steps in 14.6% overall yield. The key feature of this synthetic route involves the highly stereoselective construction of the vinyl-substituted bicyclic lactone by an intramolecular Pd(0)-catalyzed allylic alkylation and its facile conversion to the hydroxy bicyclic lactone skeleton of bacillariolide III, induced by stereoselective vinylcerium addition to the aldehyde. In addition, the (Z)-pentenoic acid was efficiently introduced by the internal hydroxy group tethered ring-closing metathesis (RCM).     

Chiron approach strategy to the bicyclic oxazolidinylpiperidine: a building block for preparing mono- and bi-cyclic iminosugars

A chiron approach to the synthesis of bicyclic oxazolidinylpiperidine, a synthetically potential building block for preparing mono- and bi-cyclic iminosugars, is reported from d-glucose using ring closing metathesis as the key step.     

Ring-closing metathesis (RCM) based synthesis of the macrolactone core of amphidinolactone A

A convergent synthesis of the macrolactone core of amphidinolactone A has been achieved, in a 10 step linear sequence with 32% overall yield, through a ring-closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the union of acid and alcohol fragments derived from (R)-epichlorohydrin and (R)-2,3-O-isopropylidene glyceraldehyde, respectively.     

Studies toward Taxuspine X, a potent multidrug-resistance reversing agent, via ring closing metathesis strategy

The synthesis of bicyclic 3,8-secotaxane diterpenoids, which includes Taxuspine U and X, has been achieved through an approach that involves a ring closing metathesis reaction as key step for the macrocycle formation.     

Formal total synthesis of stigmatellin A

An efficient and stereoselective approach for the formal total synthesis of Stigmatellin A has been described. The key steps involved in this synthesis are desymmetrization of the bicyclic olefin to introduce two methyl and two hydroxyl chiral centers, Friedel Crafts acylation, regioselective demethylation, Baker-Venkataraman rearrangement and Grubbs cross metathesis.     

Solution- and solid-phase, modular approaches for obtaining different natural product-like polycyclic architectures from an aminoindoline scaffold for combinatorial chemistry

With the goal of developing a modular approach leading to different indoline alkaloid natural-product-like tricyclic derivatives having an unsaturated lactam (see compounds 13, 14, and 16), an aminoindoline-based bicyclic scaffold 10 was obtained from 9. The selective deprotection of the indoline NTeoc or benzylic NHAlloc in compound 10, followed by N-acryloylation and then subjection to a ring-closing metathesis reaction, successfully led to obtaining two different architectures (13/14 and 16) having an unsaturated lactam functionality. This modular solution-phase methodology was then developed on solid phase. To achieve this objective, the aminoindoline bicyclic scaffold having an additional hydroxyl group could be immobilized onto the solid support using alkylsilyl linker-based polystyrene macrobeads, giving 18. By applying a ring-closing metathesis approach, 20 (tricyclic derivative with seven-membered-ring unsaturated lactam) and 23 (tricyclic derivative with eight-membered-ring unsaturated lactam) were then obtained from 18 in a number of steps.     

Synthesis and applications of sulfur-substituted cis-hexahydro-2-quinolinones

An efficient synthesis of sulfur-substituted cis-hexahydro-2-quinolinones has been achieved by an aza-Diels^_Alder reaction of p-toluenesulfonyl isocyanate with a diene precursor derived from a bicyclic 3-sulfolene via ring-closing metathesis. Some synthetic tranformations have also been carried out.     

Total synthesis of (+/-)-mycoepoxydiene,a novel fungal metabolite having an oxygen-bridged cyclooctadiene skeleton

[reaction: see text] The first total synthesis of (+/-)-mycoepoxydiene has been accomplished. A ring-closing olefin metathesis (RCM) approach was employed for the construction of the oxygen-bridged eight-membered bicyclic skeleton. The RCM product was converted to the target natural product featuring the oxidative rearrangement of a furfuryl alcohol introduced as the side chain and the stereoselective 1,2-reduction of a delta-keto-beta,gamma-unsaturated alpha-lactol intermediate.     

Synthesis of biologically active dicarba analogues of the peptide hormone oxytocin using ring-closing metathesis

Facile synthesis of cis and trans olefinic analogues of oxytocin 1 that have carbon in place of sulfur is achieved via ring-closing metathesis (RCM) on a resin-bound linear precursor peptide. Hydrogenation of the cis olefin, 3, proceeds selectively to generate the previously reported saturated derivative 5. Biological testing on rat uterus strips shows that cis compound 3 has an EC50 value of 38 ng/mL (EC50 for oxytocin is 2.7 ng/mL) whereas 5 and trans olefin 4 are less active. [reaction--see text]     

3',4'-trans-linked bicyclic nucleosides locked in S-type conformations

A novel class of 3',4'-trans-linked bicyclic nucleosides with locked S-type furanose conformations is introduced by synthesis of two model derivatives; one was obtained by cyclic ether formation and the other by ring-closing metathesis methodology.     

Anodic Amide Oxidation/Olefin Metathesis Strategies: Developing a Unified Approach to the Synthesis of Bicyclic Lactam Peptidomimetics

In connection with efforts to build constrained peptidomimetics for the endocrine hormone TRH, a general strategy for the construction of bicyclic lactam peptide building blocks has been developed. This strategy used an anodic amide oxidation to selectively functionalize proline and then an olefin metathesis to build the desired lactam constraint. The route described provides a single approach for synthesizing both fully functionalized TRH analogs having seven- and eight-membered ring lactam constraints, as well as six- and seven-membered ring lactam analogs without the sidechain on the central amino acid.     

Part 1. modular approach to obtaining diverse tetrahydroquinoline-derived polycyclic skeletons for use in high-throughput generation of natural-product-like chemical probes

A practical synthesis of a tetrahydroaminoquinoline scaffold (12) was developed that used a stereocontrolled aza Michael as the key reaction. Three tetrahydroquinoline alkaloid-like, tricyclic derivatives 16, 18, and 19 with different medium to macrocyclic ring skeletons were obtained, using this scaffold as the starting material, in a modular manner. The macrocyclic compounds with an isolated olefin and an electron-deficient olefin were obtained by ring-closing metathesis approaches. Compounds 16 and 18 are unique and contain bridged 10- and 12-membered functionalized rings. The NMR studies of these compounds revealed interesting information on the conformation of the bicyclic scaffolds that was dependent on the nature and the size of the macrocyclic rings. Finally, this modular methodology, using compound 21 anchored onto the solid support, successfully led to the generation of different macrocyclic derivatives, 23, 25, and 27 in solid-phase synthesis. The solid-phase synthesis approach outlined in this article has the potential to generate tetrahydroquinoline-based tricyclic compounds containing different medium to macrocyclic architectures.     

Diversity-oriented synthesis of bicyclic ring systems via a conjugate addition/aldol/RCM process

Diversity-oriented synthesis(DOS) has been widely applied in the generation of a large collection of highly functionalized molecules with diverse chemical skeletons.Herein,we report the diversity-oriented synthesis of a series of structurally diverse bicyclic substrates via an efficient tandem conjugate addition/aldol process followed by ring-closing metathesis(RCM).This approach allows us to efficiently prepare a number of structurally complex molecules for the further chemical biology studies.     

A new approach to (-)-swainsonine by ruthenium-catalyzed ring rearrangement

A new enantioselective synthesis of the idolizidine alkaloid (-)-swainsonine 1 in 40% overall yield starting from the known oxazolidinone 6 is described. Throughout the synthesis, the high efficiency of metal-catalyzed reactions is illustrated. The key step is a new ruthenium-catalyzed metathesis rearrangement reaction. In this ring-closing/ring-opening tandem process, stereocenters are transferred from a ring to the olefinic side chain of the formed heterocycle. The metathesis precursor was obtained by palladium-catalyzed desymmetrization of cyclopentenediol. The synthesis was completed by functionalization of the terminal double bond, cyclization of the second ring, and diastereoselective dihydroxylation.