Diastereoselective Ring-closing Metathesis Research Articles

A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)-Vallesamidine and (+)-14,15-Dehydrostrempeliopine.

The total synthesis of representative members of the schizozygine alkaloids, (+)-vallesamidine and (+)-14,15-dehydrostrempeliopine, were completed from a late-stage divergent intermediate. The synthesis took advantage of efficient nitro-group reactions with the A/B/C ring skeleton constructed concisely on a gram scale through an asymmetric Michael addition, nitro-Mannich/lactamisation, Tsuji-Trost allylation, and intramolecular C-N coupling reaction. Other key features of the synthesis are a novel [1,4] hydride transfer/Mannich-type cyclisation to build ring E and a diastereoselective ring-closing metathesis reaction to construct ring D. This approach gave access to a late-stage C14,C15 alkene divergent intermediate that could be simply transformed into (+)-vallesamidine, (+)-14,15-dehydrostrempeliopine, and potentially other schizozygine alkaloids and unnatural derivatives.

Diastereoselective Ring-Closing Metathesis as a Means to Construct Medium-Sized Cyclic Ethers: Application to the Synthesis of a Photoactivatable Gambierol Derivative.

This paper describes a concise synthesis of six- to eight-membered α,α'-substituted cyclic ethers by exploiting diastereoselective ring-closing metathesis (RCM) of 1,4-pentadien-3-yl ether derivatives. The RCM precursors could be efficiently prepared via a vinylation of the corresponding α-acetoxy ether derivatives using divinylzinc. Diastereoselective RCM of 1,4-pentadien-3-yl ether derivatives afforded a series of six- to eight-membered α,α'-substituted cyclic ethers with moderate to good diastereoselectivity. The stereochemical consequence of the diastereoselective RCM appeared to be dependent on the structure of the ring being forged. The diastereoselectivity of six- and seven-membered cyclic ethers appeared to be largely under kinetic control irrespective of the catalyst reactivity, whereas that of an eight-membered cyclic ether could be controlled by the catalyst reactivity. Finally, the diastereoselective RCM chemistry was applied to the synthesis of a biotin-tagged photoactivatable derivative of gambierol.

ChemInform Abstract: Total Synthesis of the Isodon Diterpene Sculponeatin N.

The total synthesis of sculponeatin N, a bioactive polycyclic diterpene isolated from Isodon sculponeatus, is reported. Key features of the synthesis include diastereoselective Nazarov and ring-closing metathesis reactions, and a highly efficient formation of the bicyclo[3.2.1]octane ring system by a reductive radical cyclization.

Total syntheses of leuconoxine, leuconodine B, and melodinine E by oxidative cyclic aminal formation and diastereoselective ring-closing metathesis.

Total syntheses of leuconodine B, melodinine E, and leuconoxine were accomplished via a divergent route. The [5.5.6.6]diazafenestrane skeleton was constructed from an indole-3-acetamide derivative via DMDO oxidation to hydroxylindolenine, TMSOTf/2,6-lutidine mediated cyclic aminal formation, and diastereoseletive ring-closing metathesis of a triene derivative.

Phosphate tethers in natural product synthesis.

Recent advances in phosphate tether-mediated natural product synthesis are reviewed. Synthetic approaches toward dolabelide C, (-)-salicylihalimide A, (-)-tetrahydrolipstatin, and (+)-strictifolione are included. In addition, current efforts in method development are briefly reviewed, including a detailed study on the effect of stereochemical complexity on the phosphate-mediated, diastereoselective ring-closing metathesis reaction and recent advances in multi-reaction, one-pot sequential processes mediated by the phosphate tether. Overall, this review seeks to highlight the utility of phosphate triesters to serve as multifunctional tethers with protecting group and latent leaving group characteristics and the ability to orchestrate multiple, orthogonal reaction pathways to allow for the facile synthesis of complex, bioactive small molecules and their analogs.

Synthesis studies on the Melodinus alkaloid meloscine

The pentacyclic Melodinus alkaloid (±)-meloscine was synthesized in 19 chemical steps from 2-bromobenzaldehyde through a route featuring an allenyl azide cyclization cascade to deliver the core azabicyclo[3.3.0]octane substructure. Peripheral functionalization of this core included a Tollens-type aldol condensation to set the quaternary center at C(20) and a diastereoselective ring-closing metathesis to forge the tetrahydropyridine ring.

Total Synthesis of (−)-Dactylolide and Formal Synthesis of (−)-Zampanolide via Target Oriented β-C-Glycoside Formation

The total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide via target oriented beta-C-glycoside formation is described. The two key reactions involved a stereoselective reduction of the appropriate oxocarbenium cation and a highly chemo- and diastereoselective ring-closing metathesis protocol for the formation of the macrocyclic core. In addition to the described chemistry, in vitro screening of the antipode of natural dactylolide against the NCI's 60 cancer cell line helped to illuminate the critical importance of the N-acyl hemiaminal side chain of natural zampanolide for its reported potent nanomolar cytotoxicities. Furthermore, by means of the in vitro screen of (-)-dactylolide, a promising cancer therapeutic lead has now emerged for a variety of carcinomas. More specifically, (-)-dactylolide exhibited GI50 values in the nanomolar (25-99 ng/mL) range against the four cell lines HL-60, K-562, HCC-2998, and SF-539, while displaying modest LC50 values.

Ruthenium Metathesis Catalysts with Saturated Unsymmetrical N-Heterocyclic Carbene Ligands

The facile synthesis of two new unsymmetrical N-heterocyclic carbene (NHC) ligands from commercially available monosubstituted diamines is presented. The resultant unsymmetrical NHC ligands have been complexed to ruthenium to give novel olefin metathesis initiators. Of particular interest, the new complexes (7a and 8a) gave significantly different E:Z ratios in cross-metathesis reactions and gave an improved selectivity in diastereoselective ring-closing metathesis, in comparison to the corresponding Grubbs 2 (2) and Hoveyda−Grubbs (3) complexes.

Diastereoselective Ring-Closing Metathesis: Synthesis of P-Stereogenic Phosphinates from Prochiral Phosphinic Acid Derivatives

[reaction: see text] The preparation of phosphorus-containing trienes featuring two diastereotopic vinyl moieties followed by a diastereoselective ring-closing metathesis is described. This methodology allowed for the synthesis of novel highly functionalized P-stereogenic heterocycles featuring both an exo- and an endocyclic double bond. An investigation into the factors influencing the diastereochemical outcome of the ring-closing metathesis is also presented, revealing that the geometry of the double bonds conjugated to phosphorus is important and that 1,3-stereoinduction is superior to 1,4-stereoinduction for these reactions.

Diastereoselective Ring-Closing Metathesis to Build a Quaternary Carbon Center

Diastereoselective ring-closing metathesis (RCM) was used to create a quaternary stereogenic center induced by protected hydroxyl groups. The initial stereogenic center was conveniently installed by Sharpless asymmetric epoxidation. The chiral RCM product cyclohexene was converted into a key chiral precursor used for the total synthesis of indole-containing alkaloid (-)-eburnamonine.

Enantiocontrolled Synthesis of a Chiral Building Block via Diastereoselective Ring-Closing Metathesis

An enantiocontrolled construction of a chiral building block, which had been converted into an indole alkaloid (-)-eburnamonine, has been accomplished using a diastereoselective ring-closing metathesis for the construction of the quaternary stereogenic center.

A Formal Total Synthesis of (‐)‐Limaspermine.

An enantiocontrolled formal total synthesis of an aspidosperma indole alkaloid (-)-limaspermine has been accomplished using a diastereoselective ring-closing metathesis for formation of the quaternary stereogenic center.

A Formal Total Synthesis of (-)-Limaspermine

An enantiocontrolled formal total synthesis of an aspidosperma indole alkaloid (-)-limaspermine has been accomplished using a diastereoselective ring-closing metathesis for formation of the quaternary stereogenic center.

Diastereoselective ring-closing metathesis for the construction of a quaternary carbon stereogenic center

A diastereoselective ring-closing metathesis of the trienes 1 leading to the formation of a quaternary carbon stereogenic center on the cyclohexenes 2 has been developed.

Combining ring-closing metathesis and hydroformylation strategies: a novel approach to spirocyclic gamma-butyrolactones.

Di- or tetrahydropyrans with a vinyl side chain are obtained by diastereoselective ring-closing metathesis or by addition of vinylmagnesium chloride to an appropriately functionalized tetrahydropyranone. The resulting allylic alcohols are converted to spirocyclic hemiacetals under hydroformylation conditions. Oxidation yields the corresponding lactones.

ChemInform Abstract: Diastereoselective Ring-Closing Metathesis in the Synthesis of Dihydropyrans.

An investigation into the factors influencing the diastereochemical outcome of the ring-closing metathesis based synthesis of dihydropyrans is presented in this paper. Divinyl carbinols derived from α-hydroxy carboxylic acid esters are elaborated to trienes with two diastereotopic vinyl moieties. Depending on the steric demand of the oxo substituent of the divinyl carbinol moiety (either unprotected OH, TBDMS, or benzyl ether) different diastereomers are preferrably formed upon ring-closing metathesis. An extension to diastereoselective double ring-closing metathesis in the formation of spirocycles has also been investigated.

Diastereoselective Ring-Closing Metathesis in the Synthesis of Dihydropyrans

An investigation into the factors influencing the diastereochemical outcome of the ring-closing metathesis based synthesis of dihydropyrans is presented in this paper. Divinyl carbinols derived from alpha-hydroxy carboxylic acid esters are elaborated to trienes with two diastereotopic vinyl moieties. Depending on the steric demand of the oxo substituent of the divinyl carbinol moiety (either unprotected OH, TBDMS, or benzyl ether) different diastereomers are preferrably formed upon ring-closing metathesis. An extension to diastereoselective double ring-closing metathesis in the formation of spirocycles has also been investigated.

Expeditious tandem-metathesis route to the AB-ring fragment of ciguatoxin

Abstract The AB-ring fragment of ciguatoxin was synthesized in ten steps from tri-O-benzyl- d -glucal based on a highly diastereoselective ring-closing metathesis and subsequent cross metathesis.