Enantioselectivity alkene metathesis

Amir Hoveyda of Boston College has developed (J. Am. Chem. Soc. 2004,126, 12288) an elegant series of Ru catalysts for enantioselective alkene metathesis. The power of this approach is illustrated by the direct conversion of the easily-prepared prochiral alkene 13 into the enantiomerically-enriched... 

Catalytic enantioselective alkene metathesis has recently been developed as a powerful method for the synthesis of complex natural products [86]. The availability of various chiral catalysts for olefin metathesis provides more flexible and concise means to construct efficiently highly functionalized and enantiomerically pure frameworks than using achiral catalytic complexes with chiral nonracemic substrates. 

Hoveyda and Schrock s laboratories have pioneered in this field and developed a number of effective chiral Mo-based catalysts for enantioselective alkene metathesis [28]. A recent apphcation of catalytic enantioselective alkene ROM/RCM in the total synthesis of (+)-africanol (135) was reported by Hoveyda et al. (Fig. 36) [87]. Treatment of meso tertiary TBS ether (136) with 3 mol% chiral alkylidene [Mo] catalyst (137) smoothly afforded the desired bicycle (138) in 97% yield and 87% ee. 

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. 

Malcolmson SJ, Meek SJ, Sattely ES, Schrock RR, Hoveyda AH. Highly efficient molybdenum-based catalysts for enantioselective alkene metathesis. Nature 2008 456 933-937. 

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. 

Scheme 6.3. Zr-catalyzed enantioselective ethylmagnesation and metal-catalyzed alkene metathesis make effective partners. In the two cases shown here, the alkene substrate is synthesized and enantioselectively alkylated in the same vessel.

Distal C-C bond formation can also be used to construct cyclic ethers, but this demands that methods be developed for the enantioselective assembly of complex acyclic ethers. P. Andrew Evans of Indiana University has demonstrated (Angew. Chem. Jnt. Ed. 2004, 43,4788) that Rh-mediated coupling of secondary allylic carbonates such as 7 with secondary alcohols such as 8, both enantiomerically pure, proceeds with clean retention (double inversion) of absolute configuration. Alkene metathesis then delivers the cyclic ether 9 in high diastereomeric and enantiomeric purity. 

Chiral silver complexes bearing bidentate NHC ligands (24) have been synthesized. They are used in alkene metathesis and allylic alkylation reactions high diastereos- (g) electivity is observed induced by the chiral backbone on the prochiral biphenyl.27 Ruthenium-based complexes obtained from transmetalation with a Grubbs-Hoveyda complex exhibited high activities and enantioselectivities in ring-opening metathesis/ ... 

Beak P, Johnson TA, Kim DD, Lim SH (2003) Enantioselective Synthesis by Lithiation Adjacent to Nitrogen and Electrophile Incorporation. 5 139-176 Bien j, Lane GC, Oberholzer MR (2004) Removal of Metals from Process Streams Methodologies and Applications. 6 263-284 Blechert S, Connon SJ (2004) Recent Advances in Alkene Metathesis, if 93-124 Bottcher A see Schmalz HG (2004) 7 157-180... 

The enantioselective synthesis of azabicyclic y-lactams starting from 2-azanorbornenones after treatment of a catalytic amount of RuCl2(PCy3)2 (= CHPh) in the presence of ethylene or allyl acetate proceeds also via ring rearrangement—alkene metathesis (ROM-CM-RCM) [41] (Scheme 19). If n = 0 or 3, no RCM occurs and a cyclic dialkenyl compound is formed by cascade ROM-CM reactions. 

Hoveyda and co-workers have developed chiral catalysts for asymmetric alkene metathesis. They have demonstrated that with their chiral molybdenum catalyst asymmetric syntheses of dihydrofurans through catalytic kinetic resolution by RCM and enantioselective desymmetrization by RCM are feasible processes (Scheme 40) <1998JA9720>. The use of Schrock s molybdenum catalysts for asymmetric alkene metathesis has been reviewed <2001CEJ945>. 

SILP catalysis was introduced by Mehnert, in 2002, for slurry-phase hydrofornrylation and hydrogenation reactions [61, 62]. Shordy later, Riisager et al. published the first successful example of continuous gas-phase SILP catalysis [63]. Recendy, many technically relevant examples of SILP catalysis have been published, including exanples of hydroforntylation [64, 65], hydrogenation [66, 67], enantioselective hydrogenation [68, 69], water-gas shift reaction [70, 71], alkene metathesis [72, 73], hydroamination [74] and carbonylation of methanol [75]. Additionally, valuable information about SILP catalysis has been collected in reviews by Riisager et al. [76, 77], Gu and Li [78], van Doorslaer et al. [79] and Virtanen et al. [80fi... 

W. S. Knowles, R. Noyori, K. B. Sharpless enantioselective catalysis) 2005 Y. Chauvin, R. H. Grubbs, R. R. Schrock (alkene metathesis) 2007 G. Ertl chem. processes on solid surfaces/mechanisms of heterogeneous catalysts) 2010 R. F. Heck, E. Negishi, A. Suzuki Pd Catalyzed cross coupling reactions). 

Catalytic ring-closing metathesis makes available a wide range of cyclic alkenes, thus rendering a number of stereoselective olefin functionalizations practical. The availability of effective metathesis catalysts has also spawned the development of a variety of methods that prepare specially-outfitted diene substrates that can undergo catalytic ring closure. The new metathesis catalysts have already played a pivotal role in a number of enantioselective total syntheses. 

There are no mechanistic details known from intermediates of copper, like we have seen in the studies on metathesis, where both metal alkylidene complexes and metallacyclobutanes that are active catalysts have been isolated and characterised. The copper catalyst must fulfil two roles, first it must decompose the diazo compound in the carbene and dinitrogen and secondly it must transfer the carbene fragment to an alkene. Copper carbene species, if involved, must be rather unstable, but yet in view of the enantioselective effect of the ligands on copper, clearly the carbene fragment must be coordinated to copper. It is generally believed that the copper carbene complex is rather a copper carbenoid complex, as the highly reactive species has reactivities very similar to free carbenes. It has not the character of a metal-alkylidene complex that we have encountered on the left-hand-side of the periodic table in metathesis (Chapter 16). Carbene-copper species have been observed in situ (in a neutral copper species containing an iminophosphanamide as the anion), but they are still very rare [9],... 

Neutral catalysts or catalyst precursors based on fluorinated ligand systems have been applied in compressed CO2 to a broad range of transformations such as Zn- and Cr-catalyzed copolymerization of epoxides and CO2 [53, 54], Mo-catalyzed olefin metathesis [9], Pd-catalyzed coupling reactions [43, 55, 56] and Pd-catalyzed hydrogen peroxide synthesis [57]. Rhodium complexes with perfluoroalkyl-substituted P ligands proved successful in hydroformylation of terminal alkenes [28, 42, 44, 58], enantioselective hydroformylation [18, 59, 60], hydrogenation [61], hydroboration [62], and polymerization of phenylacetylene... 

Historically one of the first asymmetric methods to be explored, cyclopropanation came of age32 with box and salen ligands on Cu(I). Diazo compounds, particularly diazoesters 138, react with Cu(I) to give carbene complexes 140 that add to alkenes, particularly electron-rich alkenes to give cyclopropanes 141. The reaction is stereospecific with respect to the alkene -1runs alkenes giving trans cyclopropanes - and reasonably stereoselective as far as the third centre is concerned. Any enantioselectivity comes from the chiral ligand L. You have already seen the Ru carbene complexes are intermediates in olefin metathesis (chapter 15). 

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