Cross-metathesis in Natural Products Synthesis

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]. 

This review is not comprehensive, but we have tried to select significant examples in each of the categories of CM reactions cited above, while at the same time emphasizing to which types [2] the olefins involved in the metathesis reactions belong. 

---

I 7 0 Cross-metathesis in Natural Products Synthesis 10.2.1.7 Vinyl Ketones... 

Gillingham DG, Hoveyda AH (2007) Chiral N-Heterocyclic Carbenes in Natural Product Synthesis Application of Ru-Catalyzed Asymmetric Ring-Opening/Cross-Metathesis and Cu-Catalyzed Allylic Alkylation to Total Synthesis of Baconipyrone C. Angew Chem Int Ed 46 3860... 

Gillingham DG, Hoveyda AH. Chiral N-heterocyclic car-benes in natural product synthesis application of Ru-catalyzed asymmetric ring-opening/cross-metathesis and Cu-catalyzed allylic alkylation to total synthesis of baconipyrone C. Angew. Chem. Int. Ed. 2007 46(21) 3860-3864. 

Cross-Metathesis in Biomolecule and Natural Product Synthesis.102... 

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. 

We will focus on the development of ruthenium-based metathesis precatalysts with enhanced activity and applications to the metathesis of alkenes with nonstandard electronic properties. In the class of molybdenum complexes [7a,g,h] recent research was mainly directed to the development of homochi-ral precatalysts for enantioselective olefin metathesis. This aspect has recently been covered by Schrock and Hoveyda in a short review and will not be discussed here [8h]. In addition, several important special topics have recently been addressed by excellent reviews, e.g., the synthesis of medium-sized rings by RCM [8a], applications of olefin metathesis to carbohydrate chemistry [8b], cross metathesis [8c,d],enyne metathesis [8e,f], ring-rearrangement metathesis [8g], enantioselective metathesis [8h], and applications of metathesis in polymer chemistry (ADMET,ROMP) [8i,j]. Application of olefin metathesis to the total synthesis of complex natural products is covered in the contribution by Mulzer et al. in this volume. 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Netherton M, Fu GC (2005)Palladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14 85-108 NicolaouKC, KingNP, He Y (1998) Ring-Closing Metathesis in the Synthesis of EpothUones and Polyether Natural Products. 1 73-104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11 81-92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11 155-171... 

Hydroxyhept-6-enoates have been key intermediates in the synthesis of a variety of natural products, especially of the arachidonic acid metabolic pathway, including prostaglandins, leukotrienes, and isoprostanes [105, 113-118]. The usage of two enantiocomplementary enzymes allowed convenient access to both enantiomers via an ADH-catalyzed reduction of 5-oxo-hept-6-enoate. Alcohol dehydrogenase from Lactobacillus brevis (ADH-LB) furnished the (S )-enantiomer, Thermoanaerobacter sp. ADH (ADH-T) the (7 )-enantiomer in excellent enantiomeric access respectively [119]. A cross-metathesis reaction followed by cyclopropanation led to the formal synthesis of constanolactones C and D (Fig. 16) [86, 120, 121]. 

A.B. Smith and co-workers have devised an efficient strategy for the synthesis of the cylindrocyclophane family of natural products. Olefin ring-closing metathesis was used for the assembly of the [7,7]-paracyclophane skeleton. During their investigations they discovered a remarkably efficient CM dimerization process, that culminated in the total synthesis of both (-)-cylindrocyclophane A and (-)-cylindrocyclophane F. They established that the cross metathesis dimerization process selectively led to the thermodynamically most stable member of a set of structurally related isomers. Out of three commonly used ROM catalysts, Schrock s catalyst proved to be the most efficient for this transformation. 

---