Olefins enynes

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. 

The metathesis reactions of olefins/ enynes and alkynes, has been the process, together with palladium-catalysed cross-coupling reactions, that has had the most profound impact on the formation of carbon-carbon bonds and the art of total synthesis in the last quarter of the 20th century. 

In the last quarter of the 20th century a new family of C-C forming reactions based on transition metal catalysts evolved as powerful tools in synthesis. Palladium-catalyzed cross-coupling reactions (Heck, Stile, Suzuki) and metathesis of olefins, enynes, and alkynes have had a profound impact on the art of total synthesis. 

Metathesis reactions are very powerful tools to create C—C bonds and provide synthetic chemists with synthetic design based on an unprecedented retrosynthetic analysis of complex compounds in very elegant and efficient ways. As the impact of metathesis in modern synthetic chemistry of drug and natural product is evidenced by a number of publications and reviews, in this chapter, we describe the most illustrative strategies of metathesis and their applications to drug and natural product syntheses in line with types of olefin, enyne, and alkyne metathesis reactions. 

In general, hydroboration—protonolysis is a stereoselective noncatalytic method of cis-hydrogenation providing access to alkanes, alkenes, dienes, and enynes from olefinic and acetylenic precursors (108,212). Procedures for the protonolysis of alkenylboranes containing acid-sensitive functional groups under neutral or basic conditions have been developed (213,214). 

Fluonnated ylides have also been prepared in such a way that fluonne is incorporated at the carhon P to the carbamonic carbon Vanous fluoroalkyl iodides were heated with tnphenylphosphine in the absence of solvent to form the necessary phosphonium salts Direct deprotonation with butyUithium or hthium dusopropy-lamide did not lead to yhde formation, rather, deprotonation was accomparued by loss of fluonde ion Flowever deprotonation with hydrated potassium carbonate in thoxane was successful and resulted in fluoroolefin yields of45-S0% [59] (equation 54) P-Fluorinated ylides may also be prepared by the reaction of an isopropyli-denetnphenylphosphine yhde with a perfluoroalkanoyl anhydnde The intermediate acyl phosphonium salt can undergo further reaction with methylene tnphenylphosphorane and phenyUithium to form a new yhde, which can then be used in a Wittig olefination procedure [60] (equation 55) or can react with a nucleophile [6/j such as an acetyhde to form a fluonnated enyne [62] (equation 56)... 

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. 

Grubbs et al. reported that the ruthenium-catalyzed RCM of a conjugated diene proceeds in such a way that the less hindered olefin moieties participate in the reaction. Consequently, RCM of 115 gives exo-methylene compound 116, and not exo-vinyl compound 117 (Scheme 24) [105]. This regioselectivity is complementary to that observed for enyne metathesis of 118, which gives exclusively 117 (Scheme 24) [106a]. 

Hexacarbonyldicobalt complexes of alkynes have served as substrates in a variety of olefin metathesis reactions. There are several reasons for complex-ing an alkyne functionality prior to the metathesis step [ 125] (a) the alkyne may chelate the ruthenium center, leading to inhibition of the catalytically active species [125d] (b) the alkyne may participate in the metathesis reaction, giving undesired enyne metathesis products [125f] (c) the linear structure of the alkyne may prevent cyclization reactions due to steric reasons [125a-d] and (d) the hexacarbonylcobalt moiety can be used for further transformations [125c,f]. 

II, while 9 failed. For substrates with H, both catalysts were found to be effective providing preferentially the rrawi-configured products 15a. Enynes carrying trisubstituted olefin moieties failed to react. 

The olefin cross metathesis (CM) can be described as the intermolecular metathesis of alkylidene fragments between two different olefins [133]. It can be farther divided into three main subtypes cross metathesis, ring opening cross metathesis (ROCM) and enyne cross metathesis (ECM) (Scheme 3.9). 

Enynes 71 react with aldehydes 61 in the presence of the [Ni(COD)J/SIPr catalytic system to afford two distinct products 72 and 73 (Scheme 5.20) [20b], The enone 72 is derived from aldehyde addition with the alkyne moiety while the adduct 73 arises from the aldehyde addition with the alkene moiety. The product distribution is dependent on the substituent on either the alkyne or alkene moieties. The reaction between 71 and ketones 74 led to the unprecedented formation of pyrans 75 (Scheme 5.20). The reaction showed to be highly regioselective in aU the cases, the carbonyl carbon was bound to the olefin. 

In the mid 1980s, Voronkov, Lukevics, and coworkers published results demonstrating the strong preference of terminal alkynes to react in platinum catalyzed hydrosilylation in the presence of 1-olefinic groups [10, 11], Enynes were found to give hydrosilylation products predominantly by addition of silanes across the triple bond. To check the versatility of these promising results, 2-allyloxy-3-butyne was chosen as an enyne to be reacted with an a, ui-dihydropoly(dimethylsiloxane) under normal hydrosilylation conditions (10"3 mole percent Pt, 120°C) (Eq. 3). 

These results clearly demonstrate a remarkable regioselectivity in the hydrosilylation of enyne compounds and that this approach works well for syntheses of siloxane polymers with reactive olefinic groups. 

Zhang54 published the first and only account of a non-asymmetric rhodium-catalyzed Alder-ene cycloisomerization of 1,6-enynes.55 The conditions developed by Zhang and co-workers are advantageous in that, similar to the ruthenium conditions developed by Trost, selectivity for 1,4-diene products is exhibited. The rhodium conditions are dissimilar from many other transition metal conditions in that only (Z)-olefins give cycloisomerization products. 

Stereoinduction was observed, as in the formation of 74 (Equation (46)) as a single diastereomer 1,3-stereo-induction was not successful. Most substrates contained only methyl-substituted olefins, leading to terminal alkenes. In the case of the cycloisomerization of an //-propyl-substituted enyne, a modicum of selectivity with respect to olefin geometry was exhibited 73 was produced in an isomeric ratio of 1 3.5. The authors do not specify whether the (E)- or (Z)-geometry was preferred. 

An intramolecular palladium-catalyzed cycloisomerization of enyne 170 was used to access the antifungal agent, chokol C (Scheme 43).102 The choice of ligand and catalyst was essential to the efficiency of the Alder-ene reaction. Enone 171 was obtained as a single olefinic isomer resulting from migration of only Ha during the cycloisomerization reaction. 

A hydrosilylation/cyclization process forming a vinylsilane product need not begin with a diyne, and other unsaturation has been examined in a similar reaction. Alkynyl olefins and dienes have been employed,97 and since unlike diynes, enyne substrates generally produce a chiral center, these substrates have recently proved amenable to asymmetric synthesis (Scheme 27). The BINAP-based catalyst employed in the diyne work did not function in enyne systems, but the close relative 6,6 -dimethylbiphenyl-2,2 -diyl-bis(diphenylphosphine) (BIPHEMP) afforded modest yields of enantio-enriched methylene cyclopentane products.104 Other reported catalysts for silylative cyclization include cationic palladium complexes.105 10511 A report has also appeared employing cobalt-rhodium nanoparticles for a similar reaction to produce racemic product.46... 

In turn, the propensity of 1 to respond to steric hindrance can be used to control the site of initiation of an RCM reaction in a polyene substrate (Scheme 9) [20]. Thus, dienyne 25 reacts with the catalyst regioselectively at the least substituted site the evolving ruthenium carbene 26 undergoes a subsequent enyne metathesis leading to a new carbene 27, which is finally trapped by the disubsti-tuted olefin to afford the bicyclo[4.4.0]decadiene product 28. By simply reversing the substitution pattern of the double bonds, the complementary bicyclo [5.3.0] compound 32 is formed exclusively, because the cyclization cascade is then triggered at the other end of the substrate. Note that in both examples tri-substituted olefins are obtained by means of a ruthenium based metathesis catalyst [20] ... 

Enyne metathesis is caused by transition metals. There are two types of enyne metathesis one is caused by a carbene complex, as is olefin metathesis, via [2+2] cocyclization and the other type is a reaction that proceeds via oxidative cycli-zation by a low-valent transition metal complex (Scheme 2). 

Intermolecular-enyne metathesis, if it is possible, is very unique because the double bond of the alkene is cleaved and each alkylidene part is then introduced onto each alkyne carbon, respectively, as shown in Scheme 9. If metathesis is carried out between alkene and alkyne, many olefins, dienes and polymers would be produced, because intermolecular enyne metathesis includes alkene metathesis, alkyne metathesis and enyne metathesis. The reaction course for intermolecular enyne metathesis between a symmetrical alkyne and an unsym-metrical alkene is shown in Scheme 9. The reaction course is very complicated, and it seems impossible to develop this reaction in synthetic organic chemistry. 

Subsequently, high chemoselectivity and enantioselectivity have been observed in the asymmetric epoxidation of a variety of conjugated enynes using fructose-derived chiral ketone as the catalyst and Oxone as the oxidant. Reported enantioselectivities range from 89% to 97%, and epoxidation occurs chemoselectively at the olefins. In contrast to certain isolated trisubstituted olefins, high enantioselectivity for trisubstituted enynes is noticeable. This may indicate that the alkyne group is beneficial for these substrates due to both electronic and steric effects. 

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