Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of P-Stereogenic, Z-Configured Bicyclo[7.3.1]- and Bicyclo[8.3.1]phosphates.
ABSTRACT: A phosphate tether-mediated ring-closing metathesis (RCM) study to the synthesis of Z-configured, P-stereogenic bicyclo[7.3.1]- and bicyclo[8.3.1]phosphates is reported. Investigations suggest that C3-substitution, olefin substitution, and proximity of the forming olefin to the bridgehead carbon of the bicyclic affect the efficiency and stereochemical outcome of the RCM event. This study demonstrates the utility of phosphate tether-mediated desymmetrization of C2-symmetric, 1,3-anti-diol-containing dienes in the generation of macrocyclic phosphates with potential synthetic and biological utility.
Project description:A phosphate tether-mediated ring-closing metathesis study towards the synthesis of P-stereogenic bicyclo[6.3.1]-, bicyclo[7.3.1]-, and bicyclo[8.3.1]phosphates is reported. This study demonstrates expanded utility of phosphate tether-mediated desymmetrization of C2-symmetric, 1,3-anti-diol dienes in generating complex medium to large, P-stereogenic bicyclo[n.3.1]phosphates..
Project description:The development of P-stereogenic bicyclo[4.3.1]phosphite borane tether systems for the desymmetrization of C2-symmetric dienediols is reported. This report highlights preliminary studies including tether installation and removal as well as chemoselective functionalization of the exocyclic olefin via diimide reduction or cross-metathesis. Most notably, a divergent oxidation strategy allows for the transformation of the bicyclic phosphite borane complexes to the corresponding phosphate or thiophosphate systems, highlighting the electronic attenuation of this P-tether system.
Project description:The first synthesis of dolabelide C (1), a cytotoxic marine macrolide, is reported utilizing a phosphate tether-mediated approach. Bicyclic phosphates (S,S,S(P))-5 and (R,R,R(P))-5 serve as the central building blocks for the construction of two major 1,3-anti-diol subunits in 1 through selective cleavage pathways, regioselective olefin reduction, and cross-metathesis. Overall, phosphate-mediated processes provided copious amounts of both major subunits allowing for a detailed RCM macrocyclization study to the 24-membered macrolactone 1.
Project description:A phosphate tether approach to the C1-14 subunit of dolabelide is described. The phosphate tether serves a multifaceted role mediating several processes, including (i) diastereotopic differentiation via RCM, (ii) selective CM by imparting Type III behavior to the exocyclic olefin, (iii) regioselective hydrogenation, and (iv) regioselective Pd(0)-catalyzed reductive opening of the bicyclic phosphate. Overall, this strategy uses orthogonal protecting- and leaving-group properties innate to phosphate esters to rapidly assembly the titled subunit.
Project description:An array of examples of diastereoselective, phosphate-tether-mediated ring-closing metathesis reactions, which highlight the importance of product ring size and substrate stereochemical compatibility, as well as complexity, is reported. Studies focus primarily on the formation of bicyclo[n.3.1]phosphates, involving the coupling of C?-symmetric dienediol subunits with a variety of simple, as well as complex, alcohol partners.
Project description:Ruthenium(II) alkylidene complexes such as the Grubbs' 1st and 2nd generation catalysts undergo a ligand substitution with 2,2'-bipyridine, which readily leads to the common photoredox catalyst Ru(bpy)3 2+ . The application of this catalyst transformation in sequential olefin metathesis/photoredox catalysis is demonstrated by way of ring-closing metathesis (RCM)/photoredox ATRA reactions.
Project description:Macrocyclic compounds occupy an important chemical space between small molecules and biologics and are prevalent in many natural products and pharmaceuticals. The growing interest in macrocycles has been fueled, in part, by the design of novel synthetic methods to these compounds. One appealing strategy is ring-closing metathesis (RCM) that seeks to construct macrocycles from acyclic diene precursors using defined transition-metal alkylidene catalysts. Despite its broad utility, RCM generally gives rise to a mixture of E- and Z-olefin isomers that can hinder efforts for the large-scale production and isolation of such complex molecules. To address this issue, we aimed to develop methods that can selectively enrich macrocycles in E- or Z-olefin isomers using an RCM/ethenolysis strategy. The utility of this methodology was demonstrated in the stereoselective formation of macrocyclic peptides, a class of compounds that have gained prominence as therapeutics in drug discovery. Herein, we report an assessment of various factors that promote catalyst-directed RCM and ethenolysis on a variety of peptide substrates by varying the olefin type, peptide sequence, and placement of the olefin in macrocycle formation. These methods allow for control over olefin geometry in peptides, facilitating their isolation and characterization. The studies outlined in this report seek to expand the scope of stereoselective olefin metathesis in general RCM.
Project description:A facile substrate-encapsulated RCM-based synthesis of 7-membered lactones is reported. Coordination of the alpha,omega-dienyl ester precursor to the bulky Lewis acid (LA) aluminum tris(2,6-diphenylphenoxide) (ATPH) provides a protective extended steric pocket to the olefin moieties, thereby favoring intramolecular RCM over intermolecular ADMET oligomerization. The LA-encapsulated esters undergo ring-closure in the presence of Ru-based olefin metathesis catalysts to give previously difficult-to-access 7-membered beta,gamma- and gamma,delta-unsaturated lactones in good yields.
Project description:1(st) Generation Hoveyda-Grubbs olefin metathesis catalyst was purposely decomposed in the presence of ethylene yielding inorganic species that are inactive in the ring-closing metathesis (RCM) of benchmark substrate diethyldiallyl malonate (DEDAM). The decomposed catalyst was treated with 1-(3,5-diisopropoxyphenyl)-1-phenylprop-2-yn-1-ol (3) to generate an olefin metathesis active ruthenium indenylidene-ether complex in 43 % yield. This complex was also prepared independently by reacting RuCl(2)(p-cymene)(PCy(3)) with organic precursor 3. The activity of the isolated reactivated catalyst in the RCM of DEDAM is similar to that of the independently prepared complex.
Project description:8-Allylcoumarins are conveniently accessible through a microwave-promoted tandem Claisen rearrangement/Wittig olefination/cyclization sequence. They serve as a versatile platform for the annellation of five- to seven-membered rings using ring-closing olefin metathesis (RCM). Furano-, pyrano-, oxepino- and azepinocoumarins were synthesized from the same set of precursors using Ru-catalyzed double bond isomerizations and RCM in a defined order. One class of products, pyrano[2,3-f]chromene-2,8-diones, were inaccessible through direct RCM of an acrylate, but became available from the analogous allyl ether via an assisted tandem catalytic RCM/allylic oxidation sequence.