A synthesis of aromatic five- and six-membered B-N heterocycles via ring closing metathesis

The ring closing metathesis on appropriate vinyl or allyl aminoboranes (1 or 2) gives azaboracycloalkenes (3 or 4) which can be converted to azaborolides (5) or azaborines (6).     

Total synthesis of patulolide A through ring closing metathesis

A simple and efficient total synthesis of patulolide A from readily available 7-octen-1-ol is reported by asymmetric synthetic approach. The key reactions involved are asymmetric dihydroxylation using AD-mix-β and Grubbs’ ring-closing metathesis reaction for the synthesis macrocyclic ring system.     

Catalytic enantioselective synthesis of naturally occurring butenolides via hetero-allylic alkylation and ring closing metathesis

An efficient catalytic asymmetric synthesis of chiral γ-butenolides was developed based on the hetero-allylic asymmetric alkylation (h-AAA) in combination with ring closing metathesis (RCM). The synthetic potential of the h-AAA-RCM protocol was illustrated with the facile synthesis of (-)-whiskey lactone, (-)-cognac lactone, (-)-nephrosteranic acid, and (-)-roccellaric acid.     

Efficient synthesis of 16-28 membered macrocyclic crown amides via ring closing metathesis

Ring closing metathesis of suitable diamides containing 1,ω-dienes led to efficient synthetic approaches towards macrocylic polyoxadiamides 1-18 with 16-28 membered ring sizes in good to excellent yields using Grubbs' catalyst.     

Asymmetric synthesis of unusual fused tricyclic beta-lactam structures via aza-cycloadditions/ring closing metathesis

Conveniently substituted bis-beta-lactams, pyrrolidinyl-beta-lactams, and piperidinyl-beta-lactams undergo ring-closing methatesis using Grubbs' carbene, Cl(2)(Cy(3)P)(2)Ru=CHPh, to give medium-sized rings fused to bis-2-azetidinone, pyrrolidinyl-2-azetidinone, or piperidinyl-2-azetidinone systems. The diolefinic cyclization precursors can be obtained from optically pure 4-oxoazetidine-2-carbaldehydes bearing an extra alkene tether at position 1 or 3 of the beta-lactam ring via [2 + 2] cycloaddition of imino 2-azetidinones, N-metalated azometine ylide [3 + 2] cycloaddition, and subsequent N-acylation of the pyrrolidinyl nitrogen atom, or through aza-Diels-Alder cycloaddition of 2-azetidinone-tethered imines. Under standard reaction conditions, the combination of cycloaddition reactions of 2-azetidinone-tethered imines with ring-closing methatesis offers an asymmetric entry to a variety of unusual fused tricyclic 2-azetidinones bearing two bridgehead nitrogen atoms.     

Alpha-phosphono lactone analogues of cytidine and cytosine arabinoside diphosphates: synthesis via ring closing metathesis

alpha-Phosphono lactone derivatives of the nucleosides cytidine and cytosine arabinoside have been prepared from the corresponding nucleoside aldehydes. The stereochemical outcome of allylation reactions with these aldehydes was found to be dependent upon both the choice of protecting groups for the 2'- and 3'-hydroxyl groups and, to some extent, the nature of the Lewis acid catalyst employed. Ultimately, conditions were found that favored either the 5'R or 5'S diastereomer from different cytidine aldehydes, and gave some stereoselectivity in additions to an aldehyde derivative of ara-C. The resulting homoallylic alcohols were used as substrates in attempted Knovenagel and Horner-Wadsworth-Emmons condensations, but elimination was found to predominate over lactone formation under the conditions employed. The desired alpha-phosphono lactones could be prepared through a reaction sequence that included ring-closing metathesis on acrylate esters of the homoallylic alcohols, followed by reduction of the resulting alpha,beta-unsaturated lactones and carbon-phosphorus bond formation on enolates generated from the saturated lactones.     

Efficient synthesis of 18-40 membered macrocyclic polyoxadiamides and polyoxatetraamides via ring closing metathesis

Ring closing metathesis of the appropriate 1,ω-dienes led to efficient synthetic approaches towards the corresponding macrocyclic polyoxadiamides and tetraamides with 18-40 membered ring sizes in good to excellent yields using Grubbs' catalyst.     

A general,enantioselective synthesis of 2-substituted thiomorpholines and thiomorpholine 1,1-dioxides

In the course of our drug discovery programs, we had need to access chiral, 2-substituted thiomorpholines and their oxidized congeners, thiomorpholine 1,1-dioxides. Here, we disclose a high-yielding, general protocol for the enantioselective synthesis of C2-functionalized thiomorpholines and thiomorpholine 1,1-dioxides.     

Synthesis of bruguierol A employing ring closing metathesis

An expedient synthesis of bruguierol A encompassing a novel 2,3-benzo-8-oxabicyclo[3.2.1]octane ring system is described employing ring closing metathesis to generate the oxa-bridged tricyclic core.     

Efficient synthesis of 19-31 membered macrocyclic tetralactones via ring closing metathesis in ionic liquids

The ring closing metathesis reaction in the presence of Grubbs catalyst was demonstrated using several ionic liquids to synthesize a range of macrocyclic tetralactones having ring size of 19 to 31 membered with different spacers. The ionic liquid [mmim][PF₆] was found to be an excellent solvent and the recovery of the catalyst was demonstrated. X-ray analysis of a representative macrocyclic tetralactone was also reported.     

Novel cycloalkene indole carbazole alkaloids via the ring closing metathesis reaction

Methodology for the synthesis of a series of carbocyclic indole carbazole natural product analogs is presented. The chemistry involves construction of the core indole, followed by attachment of double bond tethered side chains of three and four carbon lengths. The bottom carbocyclic ring system is formed through a ring closing metathesis reaction, and allows the installation of four, five, and six member ring sizes.     

A general solid phase synthesis of 4-substituted quinolinones via Pd-catalyzed cross coupling

A general method for the solid phase synthesis of 4-hydroxy quinolinones and subsequent Pd-catalyzed cross coupling to afford 4-substituted quinolinones has been developed. Conversion of support-bound 4-hydroxy quinolinones to 4-tosyl quinolinones and subsequent treatment with alkyl, aryl, benzylzinc halides, or arylboronic acids in the presence of catalytic amount of Pd(PPh₃)₄ provides 4-alkyl, aryl, or benzyl quinolinones. This method allows for the introduction of alkyl, aryl, and benzyl groups at the 4-position of the quinolinone ring, and is ideal for parallel and combinatorial chemistry library synthesis.     

Synthesis of cholaphanes by ring closing metathesis

The synthesis of cholaphanes by ring closing metathesis (RCM) of 3α,7α,12α,24-tetraol allyl derivatives, obtained from cholic acid, was attempted. The reactions of tetraol 3,24-diallyl ether or 3,24-diacrylate were not satisfactory. However, diallyl derivatives of disteroidal 3,3′- or 24,24′-ortho-phthalates reacted smoothly affording cyclic dimers in good yields. In all the reactions studied, the E isomers of the macrocycles were obtained in excess.     

Template-directed synthesis of kinetically and thermodynamically stable molecular necklace using ring closing metathesis

We report the template-directed synthesis of a well-defined, kinetically stable [5]molecular necklace with dialkylammonium ion (R(2)NH(2)(+)) as recognition site and DB24C8 as macrocycle. A thread containing four dialkylammonium ions with olefin at both ends was first synthesized and then subjected to threading with an excess amount of DB24C8 to form pseudo[5]rotaxane, which in situ undergoes ring closing metathesis at the termini with second generation Grubbs catalyst to yield the desired [5]molecular necklace. The successful synthesis of [5]molecular necklace is mainly attributed to the self-assembly and dynamic covalent chemistry which allows the formation of thermodynamically most stable product. The self-assembly of the DB24C8 ring onto the recognition site known as templating effect was driven by noncovalent stabilizing interactions like [N(+)-H···O], [C-H···O] hydrogen bonds as well as [π···π] interactions which is facilitated in non-polar solvents. The reversible nature of olefin metathesis reaction makes it suitable for dynamic covalent chemistry since proof-reading and error-checking operates until it generates thermodynamically the most stable interlocked molecule. Riding on the success of [5]molecular necklace, we went a step further and attempted to synthesize [7]molecular necklace using the same protocol. This led to the synthesis of another thread with olefin at both ends but having six dibenzylammonium ions along the thread. However, the extremely poor solubility of this thread containing six secondary ammonium ions limits the self-assembly process even after we replaced the typical PF(6)(-) counter anion with a more lipophilic BPh(4)(-) anion. Although the poor solubility of the thread remains the bottleneck for making higher order molecular necklaces yet this approach of "threading-followed-by-ring-closing-metathesis" for the first time produces kinetically and thermodynamically stable, well-defined, homogeneous molecular necklace which was well characterized by one-dimensional, two-dimensional, variable temperature proton NMR spectroscopy and ESI mass spectroscopy.     

Asymmetric synthesis of cyclic β-amino acids and cyclic amines via sequential diastereoselective conjugate addition and ring closing metathesis

Diastereoselective conjugate addition of lithium (S)-N-allyl-N-α-methylbenzylamide to a range of α,β-unsaturated esters followed by ring closing metathesis is used to afford efficiently a range of substituted cyclic β-amino esters in high d.e. Alternatively, conjugate addition to α,β-unsaturated Weinreb amides, functional group conversion and ring closing metathesis affords cyclic amines in high d.e. The further application of this methodology to the synthesis of a range of carbocyclic β-amino esters via conjugate addition, enolate alkylation and ring closing metathesis is also described. Application of this methodology affords, after deprotection, (S)-homoproline, (S)-homopipecolic acid, (S)-coniine and (1S,2S)-trans-pentacin.     

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.     

Asymmetric synthesis of cyclic β-hydroxyallylsilanes via sequential allyltitanation-ring closing metathesis

Highly enantioenriched cyclic β-hydroxyallylsilanes have been prepared via enantioselective allylation of unsaturated aldehydes using a chiral allyltitanium reagent, followed by a ring-closing metathesis. Functionalized rings of various sizes have been synthesized and the electronic effect of the silicon group in the RCM reaction has been studied. The resulting cyclic β-hydroxyallylsilanes reacted stereoselectively with a variety of electrophilic reagents. A first application of this method to the synthesis of a highly functionalized dihydropyrane is reported.     

A formal synthesis of (-)-englerin A by relay ring closing metathesis and transannular etherification

A bicyclization approach to englerin A has culminated in a formal asymmetric total synthesis. Key transformations in the 10-step sequence are a regiospecific epoxide opening and a relay ene-yne-ene metathesis that converts linear substrates specifically to Δ(4,6)-guaiadiene-9,10 diol derivatives. Regiospecific functionalization of the diene moiety installs the oxygen bridge required for the englerin tricyclic core.     

A tandem aza-Claisen rearrangement and ring closing metathesis reaction for the synthesis of cyclic allylic trichloroacetamides

A one-pot tandem palladium(II)-catalyzed aza-Claisen rearrangement and ring closing metathesis process has been developed for the efficient synthesis of cyclic allylic trichloroacetamides. The use of chiral Pd(II) catalysts such as (S)-COP-Cl during the rearrangement stage results in the preparation of these compounds in excellent yields and in high enantiomeric excess.     

Benzoylureas as removable cis amide inducers: synthesis of cyclic amides via ring closing metathesis (RCM)

Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.