Furstner catalyst

One approach to synthesis of active Mo catalysts was reported by Furstner. Complex 40 is not an alkylidyne, but it is instead considered a precatalyst, which, when placed in CH2C12 solvent, actively promotes metathesis. There is some evidence that during the course of the reaction, the precatalyst converts to some ill-defined, high-oxidation-state Mo complex that could be an alkylidyne. One advantage of the Furstner catalysts is that they are tolerant of the presence of polar functional groups on substrates, which the Schrock alkylidynes are not.69... 

Scheme 53 Furstner s RCM-based synthesis of muscopyridine (264) with integrated selfclearance by proper choice of catalyst activity [122]...

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

In 2001, Furstner reported the preparation and characterisation of the NHC-Ru complex 22 containing iV,iV -bis[2,6-(diisopropyl)phenyl]imidazolidin-2-ylidene (SIPr) [29] (Fig. 3.6), which is the congener of complex 20. Subsequently, Mol and co-workers revealed that complex 22 was a highly active metathesis initiator [30]. More recent comparative studies showed that catalyst 22 could catalyse the RCM of 1 faster than any other NHC-Ru catalyst, while it was not stable enough to obtain complete conversion in the RCM of 3 and was inefficient for the construction of the tetrasubstituted double bond of cyclic olefin 6 [31]. 

As recently demonstrated by Furstner and Langemann, higher yields of the disubstituted olefin 83 can be obtained under high dilution conditions using la as the catalyst. Our experiments clearly illustrate that synthesis of trisubstituted macrocyclic alkenes is more complicated than that of their disubstituted analogues. See Furstner A, Langemann K (1996) J Org Chem 61 3942... 

The intramolecular iron-catalyzed Alder-ene reaction of enynes in the carbocy-clization reaction was recently reported by Furstner et al. (Scheme 9.8) [20], A low-valent cyclopentadienyliron catalyst, specifically the [CpFe(C2H4)2][Li(tmeda)] complex, is a reactive catalyst for enyne cydoisomerization reactions. Bicyclic products, also incorporating large ring systems, are thereby accessible, and the Thorpe-Ingold effect seems to be helpful for these types of reactions. 

Furstner and coworkers found that the McMurry coupling of aroylsilanes 147 gave silyl enol ethers 149 via the Brook rearrangement in addition to the normal McMurry coupling products 148 (equation 94)212. The product ratio 148/149 was dependent on the reaction conditions, especially on the catalyst. The coupling reactions of aliphatic acyltrimethylsilanes were unsuccessful. 

An alternative generation of a ruthenium catalyst has also emerged which is not based on the benzylidene structural motif. Easily accessible catalyst 8 is typical of a class of cationic catalyst from the groups of Furstner and Dixneuf [17]. This species can promote highly efficient RCM reactions and has the flexibility associated with both thermal and photochemical modes of activation [18]. 

In a related observation, Furstner and co-workers reported that while both the FMC and the MC2 lead to the same E Z alkene ratio in the case of 18-RCM, the use of the same conditions with 19 leads to product enriched selectively in either of the two isomers <02MI657> depending on catalyst selection (Scheme 9). Furstner notes that this "illustrates the subtle influence of remote substituents on the stereochemical outcome of RCM in the macrocyclic series." Studies concerning the effects of chelation of the reactivity of ruthenium carbene complexes were reported by Furstner and co-workers <02OM331>. Paquette and co-workers observed that the use of either the GMC or the MC2 led to different outcomes in the macrocyclization RCM of 1,2-amino-alcohol-templated ene-dienes <02HCA3033, 02MI615> hinting that catalyst selection is also an important consideration in those processes. 

A. Furstner and co-workers also showed that RCAM is indeed a very mild method, because during their stereoselective total synthesis of prostaglandin E2-1,15-lactone, the Mo[N-(f-Bu)(Ar)3]-derived catalyst tolerated a preexisting double bond and a ketone functionality. Chromatographic inspection of the reaction mixture revealed that no racemization took place before or after the ring closure, and the ee of the substrate and the product were virtually identical. 

A. Furstner and co-workers devised an efficient synthesis of (-)-gloeosporone, a fungal germination inhibitor. They utilized the Keck asymmetric allylation method to create the 7(R>homoallylic alcohol subunit. The reaction of the substrate aldehyde in the presence of the in situ generated catalyst provided the product with high yield and as the only diastereomer. It is important to note that it was essential to use freshly distilled Ti(/-OPr)4 for the preparation of the catalyst in order to get high enantioselectivity and reproducible results. 

Furstner, A., Guth, O., Rumbo, A., Seidel, G. Ring Closing Alkyne Metathesis. Comparative Investigation of Two Different Catalyst Systems and Application to the Stereoselective Synthesis of Olfactory Lactones, Azamacrolides, and the Macrocyclic Perimeter of the Marine Alkaloid Nakadomarin A. J. Am. Chem. Soc. 1999,121,11108-11113. 

Furstner, A., Ackermann, L., Gabor, B., Goddard, R., Lehmann, C. W., Mynott, R., Steizer, F., Thiel, O. R. Comparative investigation of ruthenium-based metathesis catalysts bearing N-heterocyclic carbene (NHC) ligands. Chem.- Eur. J. 2001, 7, 3236-3253. 

Benzylidene-bis-(tricyclohexylphosphine) dichlororuthenium (Grubbs catalyst) [172222-30-9] M 823.0. Wash it repeatedly with Me2CO and MeOH and dry it in a vacuum. Alternatively dissolve it in CH2CI2, concentrate it to half its volume, filter, add MeOH to precipitate it as purple microcrystals. Filter these off, wash several times with Me2CO and MeOH and dry them in a vacuum for several hours. [Scwab et al. / Am Chem Soc 118 100 1996, Miller et al. / Am Chem Soc 118 9606 1996, Furstner Langermann J Am Chem Soc 119 9130 7997.]... 

Metathesis with alkynes is also quite useful in synthesis,particularly for internal alkynes although terminal alkynes are not good partners in this reaction.358 internal metathesis reactions with alkynes are known,including the conversion of 439 to 440 (in 73% yield) in FUrstner s synthesis of prostaglandin E2-1,15-lactone.360 Note the use of a molybdenum metathesis catalyst for this reaction. Diynes also react with alkynes in an intermolecular reaction to form aromatic rings. An example is the conversion of 441 to a 6 1 mixture of 442/443, in 82% yield.36la a similar, palladium-catalyzed cycloaromatization is also known.362 The metathesis disconnections are... 

A. Furstner (2000) Angewandte Chemie International Edition, vol. 39, p. 3012 - Olefin metathesis and beyond a review that considers catalyst design and applications in alkene metathesis. 

Furstner, A., Guth. O.. Rumho, A., and Seidel, G. (1999) Ring closing alkyne metathesis. Comparative investigation of two different catalyst systems and application to the stereoselective synthesis of olfactory lactones, azamacrolides, and the macrocydic perimeter of the marine alkaloid nakadomarin A. y. Am, Chem. Soc., 121, 11108-11113. 

Transition metals are also useful catalysts for the title cycloaddition, and copper catalysts have proven especially effective. In an example from Furstner s lab, unactivated alkyne 17 undergoes an intramolecular Diels-Alder reaction catalyzed by copper thiophene 2-carboxylate (CuTC) to provide bicycle 18 in 95% yield. ... 

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