Recent Progress on Enyne Metathesis: Its Application to Syntheses of Natural Products and Related Compounds

Olefin metathesis using ruthenium carbene complexes is a useful method in synthetic organic chemistry. Enyne metathesis is also catalyzed by these complexes and various carbo- and heterocycles could be synthesized from the corresponding enynes. Dienyne metathesis, cross enyne metathesis and ring-opening enyne metathesis have been further developed. Various complicated compounds, such as the natural products and the related biologically active substances, could be synthesized using these metatheses reactions. Skeletal reorganization using the transition metals and metallotropic rearrangement are also discussed.

Metathesis of enynes having alkene and alkyne moieties in a molecule is an extremely interesting reaction [23][24][25][26][27]. In this reaction, the double bond of enyne 2 is cleaved and a carbon-carbon bond is formed between the double and triple bonds, and the cleaved alkylidene part of the double bond migrates onto the alkyne carbon to produce a cyclic compound 3 having a 1,3-diene moiety (Scheme 1).
The first enyne metathesis was reported by Katz [28][29][30], who used a Fischer tungsten-carbene complex. Then Mori reported a chromium-catalyzed enyne metathesis [31][32][33][34]. It was later found that the ruthenium-carbene complex 1b or 1c was very effective for enyne metathesis [35][36]. The reaction would proceed via a [2+2] cycloaddition of a ruthenium-carbene complex with an alkyne part to produce ruthenacyclobutene 4, and ring-opening of this affords a ruthenium carbene complex 5, which reacts with an alkene part to produce ruthenacyclobutane 6, and ring-opening of this gives a cyclized compound 3 and a ruthenium-carbene complex is regenerated (Scheme 2, Route 1). In some cases, metathesis products via complexes 4' were obtained. The other mechanism also considered involves at first reaction of the alkene part of enyne 2 with ruthenium carbene complex to afford a new ruthenium carbene complex 7. The latter species reacts with the alkyne part to produce ruthenacyclobutene 8 and its subsequent ring-opening gives ruthenium carbene 9, that undergoes intermolecular [2+2] cycloaddition with the alkene part of enyne 2 to produce ruthenacyclobutane 10. Ring-opening of this gives cyclic compound 3 and ruthenium carbene complex 7 is regenerated (Scheme 2, Route 2).
Later, the detailed study on the reaction mechanism was shown by Lippstreu and Straub, who described that the reaction would proceeds via Route 2, and ruthenacyclobutene 4, generated from an alkyne part of enyne 2 and ruthenium carbene complex, do not exist as local minimum in the catalytic cycle [37].
Using ruthenium carbene complexes 1b and 1c, various carbo-and heterocycles could be synthesized from the corresponding enynes [35][36]. Furthermore, dienyne metathesis, cross enyne metathesis and ring-opening enyne metathesis have been developed. As the results, the novel route for the synthesis of various complicated compounds, such as the natural products and the related biologically active substances, were pioneered. Skeletal reorganization using the transition metals and metallotropic rearrangement will be discussed.

Ring-Closing Enyne Metathesis (RCM)
Mori reported the synthesis of heterocycles having a diene moiety using enyne metathesis [35][36]. Enynes 11 were treated with 1 mol % of Grubbs catalyst 1b at room temperature to afford heterocycles 12 in high yields. Using this procedure, five-to nine-membered heterocycles could be synthesized (Scheme 3). Scheme 3. Synthesis of heterocycles using ruthenium catalyst. In this reaction, enynes 11 (R = H), having a terminal alkyne, did not give a satisfactory result [38]. For example, RCM of enyne 11h afforded cyclic compound 12h in only 21% yield. It is reasoned that an alkene part in product 12h further reacts with ruthenium carbene methylidene complex 1l to afford ruthenium carbene 14, which would be coordinated by the alkene part to produce 15. Thus, the catalytic activity would decrease (Scheme 4). In fact, when the reaction of 11h using 1c was carried out under ethylene gas, the catalytic activity was much larger to afford 12h in 90% yield, even with the use of 1 mol % of the ruthenium catalyst 1c. The higher reactivity observed in enyne metathesis in the presence of ethylene gas has often been advantageous in applications to natural product synthesis.  When the second-generation ruthenium carbene complexes were used for enyne metathesis, unprecedented results were shown [39][40]. The reaction of enyne 16a or 16b was carried out using 5 mol % of 1f to afford expected metathesis product 17a or 17b along with six-membered compound 18a or 18b. Use of other second-generation ruthenium carbene complex 1g to the reaction of 16a gave a similar result. Presumably, when ruthenium carbene methylidene complex 1l reacts with the alkyne moiety in 16, two regiochemically different pathways are possible (Scheme 5, path A and B). Each carbene complex 19 or 20 gives a different product 17 or 18, respectively. On the other hand, if 1l reacts with an alkene moiety (path A'), compound 17 is formed. In this case, the path B' is a non-productive process. Thus, compound 18 should be formed via path B. However, it is not clear why two products 17 and 18 were formed when the second-generation ruthenium carbene complexes were used.
Metathesis of allene-yne 42 using molybdenum catalyst 1a gave cyclic compound 43 having an allene moiety. RCM of 42-D gave 43-D, which indicates that the vinylallene skeleton was constructed by a metathesis-type reaction between the alkyne moiety and the proximal carbon-carbon double bond of the allene moiety (Scheme 12) [56].

Syntheses of Natural Products and Related Compounds Using Ring-Closing Enyne Metathesis (RCM)
The first example of the total synthesis of a natural product using ring-closing enyne metathesis is the synthesis of (-)-stemoamide [57][58]. (-)-Pyroglutamic acid was converted into enyne 44 having an ester group on the alkyne, and RCM of enyne 44 was carried out in the presence of 4 mol % of ruthenium-carbene complex 1c to afford bicyclic compound 45 in 87% yield. Conversion of 45 into 46 smoothly proceeded. From this compound 46, (-)-stemoamide could be synthesized (Scheme 13).

Scheme 18.
Synthesis of (+)-ferruginine. Kozmin developed a highly efficient synthesis of cyclic compound bearing the methyl ketone functionality from enyne having a silyloxy group on the alkyne (Scheme 8) [46]. As an application of this method, they succeeded in the synthesis of eremophilane [68]. RCM of enyne 66a having a silyloxy group on the alkyne followed by treatment with HF gave cycloalkene 68b having the methyl ketone functionality. Hydrogenation of the double bond in compound 68b gave 69. From this compound 69, αand β-eremophilane could be synthesized (Scheme 19).
New allocolchinoids functionalized at C10 or C11 in the C ring were synthesized using the RCM of enyne 70 for the construction of the seven-membered ring. The reaction proceeded smoothly to give 71 using 1g in 92% yield. Deprotection followed by PCC oxidation gave 72, which was subjected to a Diels-Alder-aromatization sequence to form 73. Amination of 73 followed by acetylation gave allocholchicines (Scheme 20) [69]. The agalacto-spirolactone B subunit of quartromicins has been synthesized using the Claisen-Ireland/ RCM of enyne approach by Haudrechy et al. [70]. Enyne 74 was treated with 1g in toluene at 80 °C to afford 75 in 73% yield. From this compound 75, subunit B of quartromicin was synthesized (Scheme 21).
An enantioselective synthesis of (-)-galanthamine was realized in 11 steps starting from isovanillin (Scheme 22). The enyne 76 (92% ee) underwent an efficient RCM reaction in the presence of 3 mol % of 1c to give diene 77 in 85% yield. Hydroboration of the terminal alkene of 77 followed by oxidation gave homoallylic alcohol 78 in excellent yield, and palladium-catalyzed cyclization followed by SeO 2 oxidation gave 79. Mesylation of 79 followed by deprotection afforded (-)-galanthamine [71]. For the synthesis of angucyclinone-type natural products, a concise and highly enantioselective route was developed (Scheme 23). Chiral vinylcyclohexene derivative 81 was synthesized using RCM of enyne 80 under an atmosphere of ethylene in high yield. Intermolecular Diels-Alder reaction of 81 and 82 followed by aromatization gave compound 83 having benz[a]anthraquinone skeleton. Utilization of this strategy, total synthesis of YM-181741, (+)-ochromycinone, (+)-rubiginone B have been accomplished [72].
Stereoselective total synthesis of (+)-valienamine was reported utilizing ring-closing enyne metathesis (Scheme 24) [73]. An interesting acceleration effect of an allylic hydroxy group on ring-closing enyne metathesis has been demonstrated. Ring-closing enyne metathesis of terminal alkynes possessing an allylic hydroxy group proceeded smoothly. The synthesis of (+)-isofagomine with the aid of this efficient reaction has been demonstrated [74].
Grubbs demonstrated the synthesis of various fused polycyclic compounds using tandem metathesis reaction. A steroidal skeleton could be constructed using tandem enyne metathesis. Treatment of polyenyne 86 having double and triple bonds at the appropriate positions in the carbon chain gave compound 87 in high yield in one step, although many processes were contained in this reaction as shown in Scheme 25 [75].
Tandem ring-closing enyne metathesis followed by cross olefin metathesis is interesting and useful because the reaction process is shortened and the yield is raised compared with that of the stepwise reaction. One-pot RCM-CM reaction was realized by Royer et al. (Scheme 26). The RCM of 88 in the presence of an excess amount of methyl acrylate using ruthenium carbene complex 1g gave cyclic compound 89 in good yield. The reaction would proceed via the formation of 90 and subsequent CM with methyl acrylate to produce 89 [76]. Synthesis of anthramycine derivative 99a was achieved using RCM and CM (Scheme 27) [77]. L-Methionine was converted into enyne 91, and RCM of 91 using 1c gave pyrrolidine derivative 92. Deprotection followed by condensation with commercially available acid chloride 93 gave 94. Reductive cyclization of 94 using Zn-AcOH followed by treatment with dilute HCl gave pyrrolo-1,4-benzodiazepinone 95. To convert the vinyl group into an α,β-unsaturated ester group, olefin cross metathesis with ethyl acrylate was carried out using catalyst 1j [20][21]. The reaction proceeded smoothly to give compound 96 in 60% yield. Isomerization of the double bond in the pyrrolidine ring using RhCl 3  Morken and Evans succeeded in the synthesis of (-)-dihydroxanthatin using RCM and CM [78]. Enyne metathesis of 100 using 1g followed by methylation gave bicyclic compound 101. Cross metathesis of 101 and methyl vinyl ketone in the presence of 1g afforded (-)-dihydroxanthatin (Scheme 28).
Martin succeeded in the first total synthesis of the novel sesquiterpene 8-epi-xanthatin [79]. Palladium-catalyzed carbonylation of 102 followed by desilylation gave lactone 104. The total synthesis of 8-epi-xanthatin was directly achieved by tandem RCM-CM of lactone 104 using 1h in the presence of an excess amount of methyl vinyl ketone in one step (Scheme 29).

88%
Lancifodilactone G has eight rings with complicated cyclic connectivity. Paquette synthesized ABC segment 109 of lancifodilactones G using ring-closing enyne metathesis and then cross metathesis as the key steps (Scheme 30) [80]. Ring-closing enyne metathesis of 105 using 1g in CH 2 Cl 2 gave cycloheptene derivative 106, which was subjected to cross metathesis with methyl acrylate to give α,β-unsaturated ester 107. From this compound 107, target compound 109 was obtained.

Ring-Closing Dienyne Metathesis
Grubbs reported an ingenious method for synthesizing bicyclic compounds from dienynes taking advantage of the metathesis reaction (Scheme 31) [81][82]. When a benzene solution of dienyne 110a was stirred in the presence of 3 mol % of 1b, bicyclic compound 111a was obtained in 95% yield in one operation. In the case of 110b, two bicyclic compounds 111b and 112b were formed. Furthermore, dienyne 110c gave tricyclic compound 111c in a quantitative yield. Probably, ruthenium carbene methylidene complex 1l reacts with an alkene moiety in dienyne 110b to give ruthenium carbene complex 113 and/or 116, which reacts with an alkyne part to give ruthenacyclobutene 114 and/or 117. Ring opening of this complex gives ruthenium carbene complex 115 and/or 118, which reacts with the alkene part intramolecularly to give ruthenacyclobutane. Ring opening of this complex gives bicyclic compounds, 111 and/or 112.  The transformation of dienyne into the bicyclic vinylboronate is shown in Scheme 32. Alkynylboronate 119 cleanly underwent ruthenium-promoted metathesis in 70% yield. The resultant bicyclic dialkenylboronic ester 120 was efficiently oxidized to corresponding enoate 121 by treatment with Me 3 NO in refluxing THF. In the presence of CsF, reaction of 120 with 3-bromobenzonitrile under the catalysis of PdCl 2 (dppf) furnished cross-coupling product 122 (Scheme 32) [83].
A versatile route for the synthesis of a phosphorus oxide template was presented (Scheme 33). Dienyne metathesis using 1g on substrate 123 led to the formation of bicyclic phosphorus heterocycles 124 [84]. Base-promoted isomerization of propargyl amide 125 gave alkynyl amide 126, dienyne metathesis of which gave bicyclic compounds 127 and 128 in a ratio of 1:1 (Scheme 34) [85].

Syntheses of Natural Products and Related Compounds Using Dienyne Metathesis
Dienyne metathesis is a useful method for the synthesis of fused bicyclic or polycyclic compounds in one step, and many bond fissions and bond formations occur during the dienyne metathesis. Therefore, when dienyne metathesis is used for the total synthesis of natural products, retro synthetic analysis for them is unique, and the reaction process is generally shortened.
A new approach to the synthesis of a linearly fused 6-8-6 tricarbocyclic ring system was realized using dienyne metathesis [87]. This ring system is a carbon framework analogous to the proposed transition state of isomerization of previtamin D 3 to vitamin D 3 . The starting dienyne 134, which was prepared by condensation of indenone 132 and alkyne 133 followed by deprotection and then introduction of an allyl group, was reacted with 1c to give target molecule 135 as a diastereomeric mixture at the C-10 position in 48% yield (Scheme 36). A concise route to a key intermediate in the total synthesis of guanacastepene A using dienyne metathesis was reported [88]. The main feature includes the construction of fused seven-and six-membered rings. Metathesis of dienyne 136 was carried out using 1g and a mixture of tricyclic compounds 137 was obtained in a ratio of 1 to 1. Selective epoxidation followed by introduction of an allyloxy group in the presence of Yb(OTf) 3 gave 138a and 138b. Protection of the hydroxyl group of 138a gave 139a, and then it was led to compound 140, which was already converted into (±)-guanacastepene A (Scheme 37).

Scheme 37.
Synthesis of (±)-guanacastephene A.  Krishna reported the synthetic study toward the stereoselective total synthesis of ilexlactone, the structure of which was already assigned as 143a. Bicyclic ring system was constructed from dienyne 142a using 5 mol % of 1g in 74% yield. Deprotection of the MOM group afforded the target molecule 143a. However, the spectral data of this compound was found to be different from those of ilexlactone reported in the literature. Thus, the authors further synthesized ent-143a and 143b from 142b in a similar procedure. However, the spectral data of ent-143a and 143b were found to be different from those of ilexlactone. Thus, the authors concluded that the structure proposed ilexlactone was incorrect (Scheme 38) [89].
Total synthesis of (±)-erythrocarine was achieved by Mori using dienyne metathesis [90]. Synthesis of trisubstituted alkene 146 was achieved with a regio-and stereoselective introduction of carbon dioxide and an alkynyl group onto the terminal alkyne of 145 followed by desilylation. Hetero-Michael reaction of 146 gave isoquinoline derivative 147, which was converted into dienyne 149. Since the tertiary amine of 149 coordinates to the ruthenium catalyst and the catalytic activity is decreased, dienyne metathesis of 149·HCl was carried out using ruthenium catalyst 1c to give tetracyclic compounds as a diastereomeric mixture in a ratio of 1:1 in quantitative yield. Deacetoxylation of α-isomer gave erythrocarine (Scheme 39). Hatakeyama succeeded in total synthesis of erythravine using a similar procedure [91]. Honda et al. succeeded in a diastereoselective total synthesis of (-)-securinine in an optically pure form by employing RCM of the corresponding dienyne 150 as a key step [92]. They synthesized dienyne 150 having terminal alkene and disubstituted alkene parts from (+)-pipecolinic acid, because ruthenium-carbene complex would at first react with the terminal alkene to form a furan ring. Thus, dienyne metathesis of 150 was carried out using 1i [18] to give bicyclic compound 151 in good yield. Oxidation of 151 with CrO 3 gave lactone 152, which was treated with NBS and then TFA to produce (-)-securinine (Scheme 40). They also synthesized viroallosecurinine in a similar manner [93]. Hatakeyama succeeded in the total synthesis of erythroidine [94]. Construction of C and D rings was begun from amino acid 153, which was led to dienyne 158. Dienyne metathesis was carried out using 1c to give erythroidine in 42 % yield along with compound 159 in 4% yield. In this case, 1g turned out to be less effective and gave erythroidine in less than 30% yield (Scheme 41).

Cross Enyne Metathesis
A novel synthetic procedure of 1,3-diene from alkyne and ethylene using cross enyne metathesis was developed in 1997 by Mori [97][98]. When a CH 2 Cl 2 solution of alkyne 178a was stirred under an atmosphere of ethylene at room temperature in the presence of 1c, 1,3-diene 179a was obtained in 62% yield. It is interesting that, formally, the double bond of ethylene is cleaved and each methylene part of ethylene is introduced onto the alkyne carbon to produce 1,3-diene 179 (Scheme 44). The possible reaction course was shown in Scheme 45. Reaction of ruthenium carbene methylidene complex 1l, generated from 1c and ethylene, with alkyne 178 gives ruthenacyclobutene 180, ring-opening of which gives ruthenium carbene 181. It reacts with ethylene to afford ruthenacyclobutane 182, ring-opening of which gives 1,3-diene 179, and 1l is reproduced. If 1l reacts with ethylene, this is non-productive process and 1l would be reproduced. However, this method has a problem, that is: propargyl ester 178a or amide 178b gave good results, while homopropargyl amide 178c led to 1,3-diene 179c in only 11% yield (Scheme 44). Presumably, a heteroatom at the propargylic position is important, and the ruthenium catalyst would be coordinated by the heteroatom at first and then the reaction proceeds.
Scheme 44. Synthesis of 1,3-diene using cross metathesis. A short and efficient synthesis of highly substituted tetrahydropyridines was achieved from a monosubstituted alkyne, a terminal alkene, and an imine by a combination of cross enyne metathesis and aza-Diels-Alder reaction under high pressure. Cross metathesis of terminal alkyne and alkene afforded diene 185, which was reacted with imine to give pipecolinic acid derivative 186 in high yield (Scheme 47) [106]. Scheme 47. One-step synthesis of pipecolinic acid. The reaction was further extended to intramolecular Diels-Alder reaction, and cis-hexahydro-1H-indene 189 was synthesized from diene 187 and terminal alkyne in one operation [107]. Diver reported cross metathesis of terminal alkyne and cyclopentene using 1g [109]. Ruthenium-carbene complex 1l reacts with the terminal alkyne to produce ruthenium-carbene complex 194, which reacts with cyclopentene to produce ruthenium-carbene complex 195. It reacts with the alkene part to afford a cycloheptadiene derivative 193 (Scheme 50).

Synthesis of Natural Products and Related Compounds Using Cross Metathesis
Synthesis of natural products using cross metathesis is interesting because 1,3-diene moiety is constructed onto the alkyne carbons at the later step. Anolignans were synthesized using cross metathesis of enyne as a key step. 1,3-Diene 197 could be synthesized from alkyne 196 by treatment with 1g under ethylene gas. Palladium-catalyzed deacetoxylation followed by deprotection gave anolignan A. Anolignan B could be synthesized in a similar manner. It was interesting that two methylene parts of the anolignan skeleton could be introduced at a later stage of the total synthesis using cross metathesis (Scheme 51) [110].  A versatile strategy for the synthesis of C-aryl glycoside was successfully developed. An intermolecular enyne metathesis of C-alkynyl glycoside 205 with ethylene gave diene 206, which was followed by Diels Alder reaction and then aromatization to provide C-aryl glycoside 207 (Scheme 53) [112].
Lee succeeded in the total synthesis of (-)-amphidinolide E, whose side chain was constructed using cross enyne metathesis [113][114]. Alkyne 208 was first reacted with ethylene in the presence of 1g to give 209, which was further engaged in situ in a chemoselective cross metathesis with 2-methyl-1,4-pentadiene to give triene 210 in 65% yield along with diene 209 in 19% yield. Isolated diene 209 was further recycled and reacted with 2-methyl-1,4-pentadiene in the presence of 1g to afford triene 210, which was further elaborated into 211. Condensation of 211 and 212 afforded compound 213. From this compound 213, total synthesis of amphidinolide E was achieved (Scheme 54). Recently, same group succeeded in the total synthesis of amphidinolide K using intramolecular cross enyne metathesis in the key step [115].
Fürstner succeeded in the total synthesis of amphidinolide V using ring-closing alkyne metathesis for the construction of the macrocycle (Scheme 55). Dialkyne 214 was treated with molybdenum complex 215 to give macrocycle 216 in 84% yield. Then an intermolecular enyne metathesis of the resulting cycloalkyne 216 with ethene was used to set the vicinal exo-methylene branches. From this compound 217, amphidinolide V was synthesized. As the result, the absolute configuration of amphidinolide V was determined to be as 8R, 9S, 10S, 13R [116][117].

Ring-Opening Enyne Metathesis
Tandem metathesis of cycloalkene-ynes is a unique reaction because different cyclic compound is formed from the starting cycloalkene via many steps by a one operation. These reactions are contained ring opening metathesis (ROM), ring closing metathesis (RCM) and/or cross metatheses (CM). Mori reported the ROM of cycloalkene-yne [118]. When cycloheptene-yne 220a, the substituent of which was placed at the 3-position of cycloalkene, was reacted with the first generation ruthenium carbene complex 1c in CH 2 Cl 2 under ethylene gas at room temperature for 24 h, pyrrolidine derivative 221a was obtained in 56% yield ( Table 2, entry 1). Various cycloalkene-ynes 220 gave pyrrolidine derivatives 221 in high yields by a one-pot operation. Formally, in this reaction, the double bonds of ethylene and cycloalkene were cleaved and each methylene part of ethylene was introduced onto the alkyne and cycloalkene carbons, respectively, and a carbon-carbon double bond was formed between the alkyne and cycloalkene carbons to form a pyrrolidine ring (Figure 3). In each case, pyrrolidine ring is formed and the length of the substituent corresponds to the initial ring size minus 1. The possible reaction course for formation of 221 from 220 was shown in Scheme 56. Blechert reported the same type of ROM-CM. Reaction of cyclopentene derivative 222a having a propargyloxy group at the 3-position with 1c in the presence of diethyl allyl malonate afforded compound 223a in 75% yield [119][120]. In this reaction, the cleaved alkylidene part of diethyl allyl malonate is introduced onto the cyclopentene carbon, and the methylene part is introduced onto the alkyne carbon to form furan derivative 223a (Figure 4). Furthermore, the five-membered ring of estrone 222b or 222c is cleaved using 1c in the presence of an alkene to give 223b or 223c, and an alkene part is introduced onto the C-ring (Scheme 57). Ring-opening metathesis of 1-substituted cycloalkene-yne 224 with 1g afforded bicyclic compound 225 [121][122]. Reaction of an alkyne part of 224 with ruthenium carbene complex 1l gives ruthenacyclobutene 226. Ring opening of this gives ruthenium carbene complex 227, which reacts with cycloalkene to afford highly strained ruthenacyclobutane 228. Ring opening of this affords ruthenium carbene complex 229 and then it reacts with alkene part to afford ruthenacyclobutane 230, ring-opening of which gives bicyclic compound 225. When a CH 2 Cl 2 solution of cyclopentene derivatives 224a was stirred in the presence of 1g under ethylene gas for 26 h, bicyclic compound 225a was obtained in quantitative yield. In a similar manner, cyclopentene-yne 224b, the side chain of which was elongated, was reacted with 1g to give bicyclic compound 225b in 76% yield. These results indicated that the initial ring (n) was enlarged to (n + 2) ring and the size of the other ring corresponds to the carbon chain length from an alkyne carbon to an alkene carbon (Scheme 58).
To synthesize an isoquinoline derivative using this method, the initial cycloalkene would be cyclobutene and the chain length between alkyne and alkene carbons containing nitrogen would be four. Treatment of cyclobutene-yne 231a with 1g afforded isoquinoline derivative 232a in 60% yield in one step. Furthermore, glycine derivative 231b having a cyclobutene ring in a tether afforded cyclic amino acid 232b in 76% yield. This procedure was further extended to the synthesis of biaryl compound 232c from cyclobutene-yne 231c. It was interesting that in this case, an aryl group on the alkyne of 231c is placed at the 5-position of isoquinoline 232c (Scheme 59) [123].  [124][125]. The reaction proceeded stereoselectively to produce substituted cis-fused bicyclic ethers 234a-c. In a similar manner, indolizidinone derivative 234d was obtained from azabicyclo[2.2.1]heptenone 233d in high yield. Later, the substituent effect of this reaction was further investigated and pyrrolizidinone derivative 234e was obtained in 40% yield along with indolizidinone derivative 234e' in 30% yield when the toluene solution of 233e (R=Me) and 1g was warmed at 80 °C for 30 min under ethylene gas [126].
Surprisingly, in some cases, simple Lewis or Brønsted acids as the catalysts could replace PtCl 2 (Scheme 67). Treatment of 248 with BF 3 ·Et 2 O or HBF 4 gave skeletal reorganization product 249 in good yield [141]. Murai and Chatani group reported skeletal reorganization of enynes to 1-vinylcycloalkene by GaCl 3 [142]. The reaction of 250a proceeded in methylcyclohexene at 0 °C and was completed within 1 h to give 251a. It is interesting that highly strained cyclobutene derivative 251b was obtained from 1,7-enyne 251a in high yield (Scheme 68). Presumably, each skeletal reorganization reaction starts by coordination of the metal to the alkyne part, and then the alkene part would attack the cation center of the alkyne coordinated by metals. However, the reaction mechanism is still not clear, and it is thought that each reaction mechanism differs depending on the metal used [143].

Synthesis of Natural products Using Skeletal Reorganization
Skeletal reorganization is a useful tool for the synthesis of complicated natural products. Fürstner achieved formal total syntheses of the antibiotics metacycloprodigiosin and streptorubin B by a platinum-catalyzed skeletal reorganization reaction (Scheme 69) [144]. The key step leading to the meta-bridged pyrrole core structures consisted of a metathesis reaction of electron-deficient enynes 252a and 252b catalyzed by PtCl 2 . The skeletal reorganization products 253a and 253b were converted into the respective target molecules.

Scheme 69.
Formal total synthesis of streptorubin B and metacycloprodigiosin. Trost succeeded in formal total synthesis of roseophilin [145]. Macrocyclic compound 260 was synthesized from enyne 259 by platinum-catalyzed skeletal reorganization. Compound 260 was converted into 261, which was led to pyrrole derivative 258 and it was already converted into roseophilin (Scheme 70).

Synthesis of Natural Products Using Metallotropic Rearrangement
The metallotropic [1,3] shift of a transient ruthenium carbene complex is involved in the enyne ring-closing metathesis of diyne containing substrates. Ring-closing metathesis followed by metallotropic [1,3]-shift and cross metathesis allowed for the development of novel strategy for the total synthesis of conjugated 1,3-diyne-containing natural product (3R,9R,10R)-panaxytriol [151]. When compound 268 was treated with 1g in the presence of 2.0 equiv. of alkene 269, the expected product 270 was obtained in 61% yield as a mixture of Z/E-isomers (5:1) together with 268 (10%). Metathesis of diene in 268 gave ruthenium carbene complex 271, metallotropic [1,3]  Total synthesis of (+)-asperpentyn and (-)-tricholomenyn A have been accomplished by implementing this metathesis-based tandem reaction sequence as the key step [152]. Compound 276, which was prepared from 275 and diyne, was treated with 1g under ethylene atmosphere gave 279a and 279b via 277 and 278. From 279a, asperpentyn was synthesized. When compound 280 was reacted with ethylene in the presence of 1g, the reaction did not proceed. In a similar method, compound 281 was treated with 1g under ethylene to give 282, which was led to (+)-tricholomenyn. Scheme 74. Synthesis of (+)-asperpentyn and (+)-tricholomenyn A using tandem enyne metathsis.

Perspective
Since the discovery of stable and isolable catalysts for metathesis by Schrock and Grubbs, a wide range of olefin metatheses have been reported, and olefin metathesis now plays an important role in natural product syntheses. Enyne metathesis, dienyne metathesis, cross enyne metathesis, and ROM of cycloalkene-yne have also been developed. Furthermore, skeletal reorganization using the transition metals or metallotropic rearrangement is a unique reaction. Novel procedures for the synthesis of the natural products and related compound, various complex molecules and macrocyclic compounds would be further developed using these various enyne metatheses. The retrosynthetic analysis of the natural products using these enyne metatheses would be completely different from that of the previous synthesis and the steps for the synthesis of these compounds would be shortened.