Stereoselective Cross-metathesis Research Articles

Synthesis of Z-gem-Cl,CF3-Substituted Alkenes by Stereoselective Cross-Metathesis and the Role of Disubstituted Mo Alkylidenes.

Stereochemically defined organofluorine compounds are central to drug discovery and development. Here, we present a catalytic cross-metathesis method for the synthesis of Z-trisubstituted olefins that contain a Cl- and a CF3-bound carbon terminus. Notably, the process is stereoselective, which is in contrast to the existing stereoretentive strategies that also involve a trisubstituted olefin as starting material. Reactions are catalyzed by a Mo monoaryloxide pyrrolide alkylidene, involve a trisubstituted alkene and gem-Cl,CF3-substituted alkene, and are fully Z-selective. Catalytic cross-coupling can be used to convert the C-Cl bond of the trisubstituted olefin to C-B, C-D, and different C-C bonds. We elucidate the role of Cl,CF3-disubstituted Mo alkylidenes. Experimental and computational (DFT) data show that in some instances a disubstituted alkylidene is formed and then transformed to a more active complex. In other cases, the Cl,CF3-disubstituted alkylidene is a direct participant in a catalytic cycle. The studies described shed new light on the chemistry of high oxidation-state disubstituted alkylidenes-scarcely investigated entities likely to be pivotal to approaches for stereocontrolled synthesis of tetrasubstituted alkenes through olefin metathesis.

4‐Hydroxy Enigmol, a 1‐Deoxyphytosphingolipid that Exhibit Good Activity against Prostate and Colon Cancer

AbstractIn the present work, 4‐hydroxy enigmol (1), an analogue of enigmol which is a known orally bioavailable 1‐deoxysphingolipid, effective against multiple cancer cell lines, has been synthesized with an additional hydroxy group for improved anti‐cancer activity. The additional group in compound (1) is likely to show enhanced activity due to improved cell permeability and hydrophilicity. The key steps involved are stereoselective cross metathesis reaction and OsO4/NMO mediated dihydroxylation. Further, analogues of 4‐hydroxy enigmol (1) with varying chain lengths (2, 3) have also been synthesized using the same synthetic strategy for varying hydrophobicity as an additional structural feature. To support the genesis in the design of compound (1–3), the pharmacokinetic studies and docking analysis has been done for calculating the polar surface area, binding affinity and hydrophobicity/hydrophilicity. The preliminary in‐vitro cytotoxicity on cancer cell lines displayed promising activity against the PC‐3 cell lines and HCT‐116 cell lines.

Synthesis of High-Oxidation-State Mo═CHX Complexes, Where X = Cl, CF3, Phosphonium, CN.

Reactions between Z-XCH=CHX where X = Cl, CF3, or CN and Mo(N-t-Bu)(CH-t-Bu)(OHIPT)Cl(PPh2Me) (OHIPT = O-2,6-(2,4,6-i-Pr3C6H2)2C6H3) produce Mo(N-t-Bu)(CHX)(OHIPT)Cl(PPh2Me) complexes. Addition of 2,2'-bipyridyl (Bipy) yields Mo(N-t-Bu)(CHX)(OHIPT)Cl(Bipy) complexes, which could be isolated and structurally characterized. The reaction between Mo(N-t-Bu)(CH-t-Bu)(OHMT)Cl(PPh2Me) (OHMT = O-2,6-(2,4,6-Me3C6H2)2C6H3) and Z-ClCH=CHCl in the presence of Bipy produces a mixture that contains both Mo(N-t-Bu)(CHCl)(OHMT)Cl(PPh2Me) and Mo(N-t-Bu)(CHCl)(OHMT)Cl(Bipy), but the relatively insoluble product that crystallizes from toluene-d 8 is the phosphoniomethylidene complex, [Mo(N-t-Bu)(CHPPh2Me)(OHMT)(Cl)(Bipy)]Cl. The Mo(N-t-Bu)(CHX)(OHIPT)Cl(PPh2Me) complexes (X = Cl or CF3) were confirmed to initiate the stereoselective cross-metathesis between Z-5-decene and Z-XCH=CHX.

Regio- and steroselective cross-metathesis of silylacetylenes with terminal olefins and α,ω-dienes

Second generation Grubbs catalyst [RuCl2(H2IMes)(PCy3)(CHPh)] initiates regio- and stereoselective cross-metathesis of silylacetylenes with 1-alkenes and α,ω-dienes leading to the formation of E-2-silyl-1,3-dienes and E-2-silyl-1,3,n-trienes, respectively. Efficient progress of the reaction is achieved by using 5–8 mol% of the benzylidene initiator and twofold excess of olefin (with respect to silylacetylene) as well as ethereal solution of HCl (10–20 mol% with respect to the catalyst) as an activator. The reaction is proposed to be catalysed by alkylidene complex [RuCl2(H2IMes)(PCy3)(CHR)] (where R = alkyl, n-alkenyl) generated from the benzylidene initiator, and proceed via initial interaction of a metal alkylidene with a triple bond.

Catalytic Z-selective cross-metathesis in complex molecule synthesis: a convergent stereoselective route to disorazole C1.

A convergent diastereo- and enantioselective total synthesis of anticancer and antifungal macrocyclic natural product disorazole C1 is reported. The central feature of the successful route is the application of catalytic Z-selective cross-metathesis (CM). Specifically, we illustrate that catalyst-controlled stereoselective CM can be performed to afford structurally complex Z-alkenyl–B(pin) as well as Z-alkenyl iodide compounds reliably, efficiently, and with high selectivity (pin = pinacolato). The resulting intermediates are then joined in a single-step operation through catalytic inter- and intramolecular cross-coupling to furnish the desired 30-membered ring macrocycle containing the critical (Z,Z,E)-triene moieties.

Chemoenzymatic total synthesis of stagonolide-E

Asymmetric total synthesis of small ring macrolide stagonolide-E has been described in this communication. The main highlight of our synthetic strategy is the application of ME-DKR (metal enzyme combo dynamic kinetic resolution) reaction, asymmetric reduction with Noyori’s BINAL-H reagent system, stereoselective cross metathesis, and RCM (ring closing metathesis) reaction at a late stage enables us to achieve the synthesis of the target molecule in an efficient way.

Synthesis of C1- and C8a-epimers of (+)-castanospermine from d-glucose derived γ,δ-epoxyazide: intramolecular 5- endo epoxide opening approach

A concise synthesis of two diastereomers of (+)-castanospermine namely 1- and 8a- epi-castanospermine 1b and 1c, respectively, is reported from d-glucose. The methodology involves stereoselective cross metathesis of d-glucose derived alkene 2 with 4-bromo-1-butene followed by azide displacement and m-CPBA oxidation to afford diastereomeric γ,δ-epoxyazides 5a/ 5b. The Staudinger reaction of epoxyazide 5a followed by reaction with benzylchloroformate (CbzCl) unexpectedly furnished 1,3-oxazinan-2-one derivative 7 whose stereochemistry was establish by single crystal X-ray. This helps to assign the stereochemistry in the epoxidation reaction. The reduction of 5a/ 5b was then carried out by transfer hydrogenation to provide γ,δ-epoxyamine that concomitantly undergoes intramolecular 5- endo-tet cyclization to afford hydroxypyrrolidine ring skeleton with sugar framework-a precursor to castanospermine analogues 1b/ 1c.

Highly effective synthesis of vinylfunctionalised cubic silsesquioxanes

A series of functionalised cubic monovinylheptaisobutylsilsesquioxanes and octavinylsilsesquioxanes were obtained via efficient and highly stereoselective cross-metathesis and silylative coupling with substituted styrenes.

ChemInform Abstract: Diastereoselective Ru‐Catalyzed Cross‐Metathesis—Dihydroxylation Sequence. An Efficient Approach Toward Enantiomerically Enriched syn‐Diols.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

An Efficient and Stereoselective Synthesis of the Monomeric Counterpart of Marinomycin A

[structure: see text] The monomeric counterpart of marinomycin A, an antitumor-antibiotic marine natural product, was synthesized efficiently in 11 steps from the commercially available ethyl (R)-(-)-3-hydroxybutyrate. The strategy was highlighted by a crucial regio- and stereoselective cross-metathesis to form the C20-C21 double bond, enantioselective allyltitanations to control the configuration of the C17, C23, and C25 stereogenic centers, and a stereocontrolled construction of the tetraene moiety based on an original Horner-Wadsworth-Emmons olefination followed by a Pd-catalyzed cross-coupling.

A microwave enhanced cross-metathesis approach to peptidomimetics

Functionalization of amino acid C- and N-termini with appropriate olefinic moieties allows for the generation of a peptidomimetic via a stereoselective cross-metathesis.

Tandem Sequence of Cross Metathesis—Ring‐Closing Metathesis Reaction of Alkynyl Silyloxy‐Tethered Enynes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Tandem Sequence of Cross Metathesis−Ring-Closing Metathesis Reaction of Alkynyl Silyloxy-Tethered Enynes

A tandem cross metathesis (CM)--ring-closing metathesis (RCM) sequence to form cyclic siloxanes is reported. This new enyne metathesis platform expands the scope and utility of the regio- and stereoselective cross metathesis reaction between silylated alkynes and terminal alkenes. The initial cross metathesis was directed to occur on the alkyne by employing sterically hindered mono-, di-, and trisubstituted alkenes tethered to the alkyne via silyl ether. The regio- and stereoselectivity feature of the initial CM step in this tandem CM-RCM process is identical to that of the CM reactions of silylated alkynes and alkenes. This tandem sequence provides both synthetically useful silylated 1,3-diene building blocks and insights into the reaction mechanism of the enyne metathesis reaction.

Concise Enantioselective Synthesis of (‐)‐Lasubine II.

Abstract An enantioselective synthesis of the quinolizidine alkaloid (−)-lasubine II 1 is reported. Two different pathways to the key intermediate 2 are described. The first case involving a sequence of ring rearrangement metathesis (RRM), simple functional group interconversion operations, followed by a stereoselective cross metathesis (CM) and in the second case a domino ring opening-/ring closing-/cross metathesis step is involved. In both cases, following the metathesis reactions, exclusively the E-isomer was obtained. The final cyclisation towards the quinolizidine skeleton is achieved by an intramolecular Michael reaction. This concept represents the first example of a highly stereoselective RRM-CM combination in the synthesis of a natural product.

Concise enantioselective synthesis of (−)-lasubine II

An enantioselective synthesis of the quinolizidine alkaloid (−)-lasubine II 1 is reported. Two different pathways to the key intermediate 2 are described. The first case involving a sequence of ring rearrangement metathesis (RRM), simple functional group interconversion operations, followed by a stereoselective cross metathesis (CM) and in the second case a domino ring opening-/ring closing-/cross metathesis step is involved. In both cases, following the metathesis reactions, exclusively the E-isomer was obtained. The final cyclisation towards the quinolizidine skeleton is achieved by an intramolecular Michael reaction. This concept represents the first example of a highly stereoselective RRM-CM combination in the synthesis of a natural product.