Olefin metathesis natural product synthesis

Sakaki S (2005) Theoretical Studies of C-H s-Bond Activation and Related by Transition-Metal Complexes. 12 31-78 Satoh T, see Miura M (2005) 14 1-20 Satoh T, see Miura M (2005) 14 55-84 Savoia D (2005) Progress in the Asymmetric Synthesis of 1,2-Diamines from Azomethine Compounds. 15 1-58 Schmalz HG, Gotov B, Bbttcher A (2004) Natural Product Synthesis. 7 157-180 Schmidt B, Hermanns J (2004) Olefin Metathesis Directed to Organic Synthesis Principles and Applications. 13 223-267... 

Metathesis reactions are now widely used in natural product synthesis. Novel retrosynthetic analyses were developed because a carbon-carbon single bond can be formed after hydrogenation of a double bond constructed by metathesis. Although many types of metathesis are now known, the reaction is classified by olefin, enyne, and alkyne metatheses in this chapter. 

These reactions involve metallate rearrangements , migratory insertion and transition metal-catalysed vinylic substitution reactions. They also perform well in applications in natural product synthesis . Many useful synthetic possibilities arise from application of ring-closing olefin metathesis (RCM) to unsaturated homoaldol products and their derivatives by means of the Grubbs catalyst 3942 4-286 Equation 105 presents some examples. ... 

Keywords Asymmetric synthesis, Chiral catalysis, Mo-based catalysts, Natural product synthesis, Olefin metathesis, Recyclable catalysts, Ru-based catalysts, Supported chiral catalysts... 

Olefin metathesis has become a very important reaction in polymer chemistry and natural product synthesis [47-49]. Garber et al. have used the physical properties of dendrimers in order to improve the separation between the dendritic metathesis catalyst and products on silica gel column chromatography [50]. The Van Koten group has reported on the synthesis of different generations of carbosilane dendrimers functionalized with ruthenium metathesis catalysts [51]. 

Schmalz HG, Gotov B, Bottcher A (2004) Natural Product Synthesis. 7 157-180 Schrock RR (1998) Olefin Metathesis by Well-Defined Complexes of Molybdenum and Tungsten. 1 1-36... 

Natural product synthesis and medicinal chemistry exist in a symbiotic relationship with the development of synthesis methodology. Noy-ori s asymmetric hydrogenations, Sharpless olefin oxidations, Grubbs olefin metathesis, Buchwald-Hartwig couplings and Jacobsen s hydrolytic kinetic resolution are illustrious examples with many practical applications. The key to the success of the above-mentioned reactions is that they have provided reliable shortcuts to more traditional synthetic... 

Because of the excellent performance of the new catalysts, many research groups use ringclosing metathesis as the key step in natural product synthesis [12]-[18]. Scheme 6 shows some examples. Via ring-closing metathesis of the olefin 37 to the hydroazulene 38, Blechert et al. [12] succeeded in synthesizing a cyclic system which is part of many sesquiterpenes. Cyclooctane derivatives, whose synthesis is the main problem in taxol synthesis, can be obtained in good yields (39 40), as demonstrated by Grubbs et al. [ 13]. 

Enyne metathesis/metallotropic [l,3]-shift domino processes are also valuable for natural product synthesis [33c,d]. Reaction of substrate 168 with cis-l,4-diacetoxy-2-butene in the presence of Grubbs catalyst 2 generated the intermediate ruthenium alkinyl carbene through a relay RCM with the hberation of 2,5-dihydrofuran followed by metallotropic [l,3]-shift and terminating (Z)-selective CM with the co-olefin to yield the conjugated enediyne 169 (Scheme 2.58) [33c]. The antitumor active Panax ginseng constituent (3R,9R,10R)-panaxytriol was readily synthesized from 169 in six steps. 

Olefin metathesis reaction that reorganizes carbon-carbon double bonds provides fundamentally new strategies for natural product synthesis and polymer chemistry. Hilvert and coworkers built up an artificial metalloenzyme by covalently tethering a Grubbs-Hoveyda-type Ru complex to a protein scaffold [78]. An /V-heterocyclic carbene (NHC) ligand, which has been reported as a suitable ligand for a number of water-soluble ruthenium-based metathesis catalysts, was derivatized with an electrophilic bromoacetamide. The Ru carbene complex (27 in Figure 10.16) was then attached by site-selective alkylation of the cysteine... 

The synthesis of manzamine A by Martin and co-workers using olefin metathesis - was one of the earliest demonstrations - of how this reaction could be applied as a strategy in natural product synthesis. The ring-closing metathesis in this synthesis was conducted with Schrock s molybdenum catalyst, as shown in Equation 21.8. 

Shibasaki and co-workers used a ring-closing metathesis approach to prepare a number of five-, six-, and seven-membered rings from electron-deficient olefins. Treatment of acyclic enol ether 18 with 7 mol % of 3 in refluxing benzene provided the corresponding cyclic enol ether 19 in 94% yield. Deprotection of the silyl ether 19 (not shown) resulted in the corresponding cyclic ketone, a valuable synthetic intermediate in natural products synthesis and a number of industrial processes. The authors reported additional examples of the synthesis of five-membered ring carbocycles as part of this study. 

Undheim and co-workers applied their olefin metathesis strategy for the synthesis of five-membered ring spirocyclic carbocycles to synthesize six-membered ring spirocyclic carbocycles for use as templates in natural product synthesis. Reaction of 198 with 2 mol % of 3 furnished the corresponding spirocycle 199 in greater than 95% yield. 

Krafft and co-workers used olefin metathesis to prepare several inside-outside medium-size rings as scaffolds for natural products synthesis. Reaction of bicyclic lactone 267 with 10 mol % of 4 in refluxing dicholormethane gave the corresponding tricyclic lactone 269 in 88% yield after only two hours. 

Undheim and co-workers employed their olefin metathesis strategy for the synthesis of five- and six-membered ring spirocyclic carbocycles to prepare seven-membered ring spirocyclic carbocycles for use as templates in natural product synthesis. Reaction of diene 295 with 2 mol % of 3 furnished the corresponding spirocycle 296 in only 60% yield. However when diene 297 was reacted under similar conditions, the desired spirocycle 298 was obtained in 90% yield. Although no specific reason is given for the lower yield of 296, it is possible that conformational constraints and/or sterics may have played a role. 

Alkene metathesis has significant advantages in natural product synthesis for several reasons. First, alkene moieties broadly exist in numerous natural products, and alkene metathesis allows facile access from the readily available or easily prepared olefins to those that are difficult to access. Second, alkene metathesis reactions either do not produce any by-product or only generate the volatile ethylene. Third, alkenes are relatively stable in the multistep synthesis, and are sufficiently reactive to be used in a wide range of transformations to generate other functionalities under specific reaction conditions. Finally, and most importantly, with the help of effective catalysts, alkene metathesis can provide remarkable selectivities (regio-, chemo-, and stereoselectivity) in the challenging synthetic operations. 

In summary, in this section we have reviewed some recent apphcations of relay olefin metathesis in the total synthesis of complex natural products. The collection of examples including both selective RRCM and relay cross metathesis demonstrates that the relay strategy has been broadly considered and implemented for complex natural product synthesis. The relay strategy will continue to provide possible solutions to the challenging synthesis where the limitations in classical metathesis methods are encountered. 

In summary, alkene cross metathesis has been successfully applied to numerous total syntheses of complex natural products. In most cases, this reaction can provide high yield, and good regio-, chemo-, and F-stereoselectivities. More importantly, the outcome of selective alkene cross metathesis can be predicted based on the propensity of different olefin for dimerization, making it a reliable transformation for design and implementation of complex natural product synthesis. 

In summary, the development of catalytic enantioselective alkene metathesis has become a fascinating new direction for olefin metathesis. In this rapidly emerging field, several elegant applications in complex natural product synthesis have been reported to date. We can certainly expect that more active and robust catalysts will be developed and applied to target-oriented synthesis in the near future. 

One of the most successful embodiments of this concept combined a metathetical step with the selective isomerisation of a terminal C=C double bond, and found applications in natural product synthesis. As discussed in Sections 7.3.2.2 and 7.3.2.3, it is indeed possible to convert the metathetically active benzylidene initiator 20 into hydrido complex 43, simply by adding trimethyl(vinyloxy)silane or methanol to the reaction mixture, thereby triggering a consecutive catalytic isomerisation process. Other methods for the decomposition of ruthenium metathesis catalysts for use in tandem with olefin isomerisation reactions include treatment with hydrogen, formic acid, sodium borohydride, or sodium hydroxide in isopropanol. ... 

Sattely ES, Meek SJ, Malcolmson SJ, Schrock RR, Hoveyda AH. Design and stereoselective preparation of a new class of chiral olefin metathesis catalysts and application to enantioselective synthesis of quebrachamine catalyst development inspired by natural product synthesis. J. Am. Chem. Soc. 2009 131 943 953. 

This chapter is divided into six sections. The first three sections loosely reflect the role of alkene cross-metathesis (CM) in the general plan of the synthesis of natural products, which can be the functionaHzation of terminal olefins appending a side chain to the core of a complex compound, or couphng two fragments to build the entire skeleton of the target molecule. Afterwards, tandem processes involving CM will be presented, followed by a few examples ofene-yne and alkyne CM in natural product synthesis [1]. 

Catalytic Enantioselective Olefin Metathesis and Natural Product Synthesis... 

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