TETRAHEDRON Pergamon Tetrahedron 54 (1998) 44134450

Tetrahedron report number 448

Recent Advances in Olefin Metathesis and Its Application in Organic Synthesis
Robert H. Grubbs" and Sukbok Chang

The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125

Received 22 September ! 997

Contents

1. 2. 3.

4. 5. 6.

Introduction Well-defined Catalyst Systems Ring-closing Metathesis 3.1. Medium sized (5-8) ring formation 3.2. Stereoselective RCM 3.3. Application to peptide chemistry 3.4. Macrocyclization using RCM 3.5. Tandem reactions 3.6. RCM of solid supported substrates 3.7. RCM mediated rearrangement Cross Metathesis Ring-opening Cross Metathesis Conclusions and Future Outlook

4414 4415 4418 4418 4423 4424 4427 4432 4435 4437 4438 4442 4445

E-mail: rhg@cco.caltech.edu FAX:626 564 9297 0040-40201981519.00 © 1998 Elsevier Science Ltd. All rights reserved. PH: S0040-4020(97) 10427-6

4414

R. H. Grubb s, S. Chang / Tetrahedron 54 (1998) 4413-4450

1.

Introduction

Olefin metathesis is a unique carbon skeleton redistribution in which unsaturated carbon-carbon bonds are rearranged in the presence of metal carbene complexes. 1 With the advent of efficient catalysts, this reaction has emerged as a powerful tool for the formation of C-C bonds in chemisu'y. The number of applications of this reaction has dramatically increased in the past few years. Of particular significance, this type metathesis utilizes no additional reagents beyond a catalytic amount of metal carbene and the only other product from the reaction is, in most cases, a volatile olef'm such as ethylene. The broad applicability of olefin metathesis has attracted attention from both academic and industrial scientists. Olefin metathesis can be utilized in three closely related type of reactions (Scheme 1): (A), ring-opening metathesis polymerization (ROMP); (B), ring-closing metathesis (RCM); and type (C), acyclic cross metathesis which when carried out on diolefins results in polymers (ADMET). It is now generally accepted that the mechanism of both cyclic and acyclic olefin metatheses proceeds through a series of metallacyclobutanes and carbene complexes. 2 Although the relative stability of the carbenes and metallacyclobutanes can change with reaction conditions, catalyst composition and alkene substitutions, the mechanism of olefm metathesis appears to be the same for all catalysts.

Scheme 1

)

~"

~

(A)

.
RI~ + R2~ ~.

©
RI~R2 ( C 3

R. H. Grubbs, S. Chang/Tetrahedron 54 (1998) 4413-4450

4415

Until recently, olefin metathesis was applied almost exclusively in ring-opening metathesis polymerization reactions (type A). ROMP is thermodynamically favored for strained ring systems such as 3-, 4,8- and larger-membered compounds. When bridging groups are present, e.g. when the compound is bicyclic, AG of polymerization for the particular ring will tend to be more negative as a result of increased strain energy in the monomer. In many cases, the ROMP of strained cyclic olefins initiated by metal carbene complexes shows the characteristic features of a living polymerization and therefore block copolymers can be made by sequential addition of different monomers. 3 Recently ring-closing olefin metathesis (RCM, type B) has received a great deal of attention for the synthesis of medium or large sized rings from acyclic diene precursors. This intensive study is primarily due to the development of well-defined metathesis catalysts which are tolerant to many functional groups as well as reactive towards a diverse range of substrates. Acyclic dienes may also be polymerized and whether a polymer or a cyclic compound is formed from any given diene is most often determined by thermodynamic rather than kinetic factors. lntermolecular olefin metathesis between two alkenes is the third reaction type (C). There are two issues that must be addressed in order for acyclic olefin metathesis to become generally useful in organic synthesis. The first requirement is to obtain high yields of the productive alkenes from cross metathesis while reducing formation of undesired self metathesis products. The second is to control the cis/trans olefin geometry in the newly formed double bond. The successful application of acyclic metathesis hinges on both the regio- and stereoselectivity of these reactions. In this review, important recent advances related to ring-closing metathesis (RCM) and cross-metathesis reactions will be discussed based on reports published up until the middle of 1997. involving the synthesis of small organic molecules will be reviewed. 2. Well-Defined Catalyst Systems. The number of catalyst systems that initiate olefin metathesis is very large, lc However, most early work in olefin metathesis was done using ill-defined multicomponent catalyst systems.4 It is only in recent years that well-defined single component metal carbene complexes have been prepared and utilized in olefin metathesis. Although a number of titanium and tungsten catalysts have been developed for metathesis and related reactions, the well-defined molybdenum complex I and ruthenium systems 2-3 (Scheme 2) have seen the most applications. Unlike the earlier olefin metathesis catalysts these highly active, long-lived catalyst systems do not require Lewis acidic co-catalysts or promoters. Scheme 2. Only those applications

c~,.. I

I~CY3 .,Ph
~

(FaC)2MeCO.... II
1

I~h

(FaC)2MeCOI~Q~MM;

Cff,,,,RI L~-/ PCy3
2

"Ph

IPCy3 c~,,.. ] ~Ph C¢,1~ PCy3
3

S.. but also because of their remarkable tolerance towards many different organic functional groups.Rlu~j ph 014 ] PPh3 2 PCy 3 -2 PPh3 CI.. 14 ...9 Scheme 3.doc_. Another closely related Rubenzylidene carbene complex 3 was prepared using phenyldiazomethane instead of cyclopropene.__i=< U Ph CI4 [ PPh'3 PCy3 PPh~ PCy3 RuCI2(PPh3)3 + ph~ N 2 CI. moisture or even to mace impurities present in solvents. however. In addition to the Mo. at high temperature.4416 R. moisture or minor impurities in solvents. H. its moderate to poor functional group tolerance. 12 This stable. 5 One of the major advantages of this system is its high reactivity towards a broad range of substrates with many steric or electronic variations.. They can be conveniently stored even under an air atmosphere without severe decomposition for several weeks... thermal instability on storage and expense of preparation. not only because they exhibit high reactivity in a variety of ROMP. The ruthenium vinylidene complex 2 can be easily prepared by reaction of RuCI2(PPh3) 3 with 3. 10 Catalytic activity is not reduced significantly in the presence of air. 6 Polymer-supported7 and water soluble8 versions of 2 have recently been described. The alkoxides in the [Mo] system can be readily altered to adjust their activities.. Efficiency of the cyclization. 11 especially with sterically bulky substrates when compared to the Mo-catalyst system.R]u~ ph CI 4 I PCy3 These Ru-carbene systems have drawn a lot of attention.3-diphenylcyclopropene followed by ligand exchange with PCy 3 (Scheme 3). Much work on the development of well-def'med metal carbenes that initiate olefin metathesis has been done by one of the coauthors and co-workers. RCM and cross-metathesis processes under mild conditions. a few other transition metal complexes have been investigated for application in these olefm metathesis reactions.Ph3 Ph o". varied depending on the steric demand of the substrates. their availability and ease of use have resulted in the catalyst of choice for all except the most difficult substrates. Grubbs.. high sensitivity to air.or Ru-based complexes discussed above. sterically crowded complex system has a d o metal center and has been shown to be an active catalyst system in various olefin metathesis reactions including ROMP... some diallyl compounds containing heteroatoms (O. Basset and co-workers have prepared a cyclometallated aryloxy tungsten carbene complex 4 by C-H bond activation of an arene substituent (Scheme 4)..PCy3 Ph 0. RCM and cross-metathesis.. Although the Ru-carbene system often exhibits relatively lower propagation rates. S.-=< Ph CI~' [ ~' -2 PPh3 . Chang / Tetrahedron 54 (1998) 4413-4450 One of the most important catalyst systems developed by Schrock and co-workers is the alkoxy imido molybdenum complex represented by 1. Ph Ph RuCl'(PPh3)3 + " ~' P. 13 As shown in Scheme 4. however. Critical drawbacks of this Mo-based carbene complex are. Si or P) were cyclized in the presence of the catalyst 4.

60 min.4 moP/. 100% 4 (2. Cr ' / " ~ O A r 5 -2 Et3PbC/ E r / " "~OAr -C2H: ArID 6 Reaction Conditions: 5 (2 mol%).2. This promoter is presumed to replace the two chloride ligands in 5 with ethyl groups. 1000 8% Si(Ph)2 4 (1 moP/.16 Oxo-tungsten complex 5 itself does not perform any metathesis reaction. Grubbs. PbEt4 (4 mol%). ultimately leading to the catalytically active ethylidene complex 6 via a-hydride elimination.1013°/.R. it becomes an active metathesis catalyst.60 min. 130 °C. 1.). 4 80 °C X=S 0 P-Ph 4 4 (0. Chang/Tetrahedron 54 (1998) 4413-4450 4417 Scheme 4.).4-trichlorobenzeneor toluene. 15. Scheme 5. 2 h) . 300 min. 4 (5 mol%).5 moP/.120 min. S. but when activated by 2 equiv. 1 h 68Ol o 84.90 °C.). H.1 o I~C O2Et O2Et 86% NR ~'"~C O2M e MeO2~cO2M e 63% (no solvent. Another tungsten based complex system has been prepared and its viability as a metathesis catalyst has been examined by Nugent and co-workers (Scheme 5). of tetraethyllead.

and even more 2-3.. Scheme 6. H. .or tetrasubstituted cyclic alkenes have recently been disclosed (Scheme 7)..17 Although complex 5 readily performs RCM to yield carbocycles under these conditions. However.c. CHR n=1. the catalyst lacks the functional group compatibility which characterizes catalysts l.=. S.1. Chang / Tetrahedron 54 (1998) 4413-4450 Like the Basset system 4. Ring-Closing Metathesis Although the f'trst example was reported in 1980 by Tsuji. This review focuses mainly on reactions utilizing these metathesis catalysts.18 Although many different metal carbene systems have been prepared and investigated as olefin metathesis catalysts. 21 3. no 8-rnembered cyclic olefins (m+n=5) were formed with either catalyst mainly because dimer formation was found to be predominant even under high dilution conditions. 0. . 3.. Medium Sized (5-8) Ring Formation The modem use of olefin metathesis can be tracked to the series of papers 22 that demonstrated the high yielding closure of diolefins to provide 5. 23 Cyclization of mono gem-substituted dienes 7 afforded trisubstituted cyclic olefins 8 in excellent yield with both Mo-catalyst 1 and Ru-catalyst 3.° X= O. Grubbs. This section discusses the most recent advances (up to the mid 1997) in the RCM and its application in organic synthesis mainly published after the previous reviews. 6 and 7 membered rings with a diverse functionality and double bond substitution (Scheme 6). Differences in reactivity and functional group tolerance between the Mo-catalyst 1 and the Ru-complex 3 were observed in attempts of RCM with dienes having different steric and electronic properties. NR. high temperature is necessary to effect metathesis reactions with the precursor 5 and 2 equiv of PbEt4. 20 catalytic ring-closing metathesis (RCM) has only recently emerged as an effective strategy in organic synthesis and has been extensively employed in the preparation of a wide variety of complex molecules with multiple functionalities. Tetrasubstituted cyclic olefins 1 0 were efficiently obtained from the corresponding substituted dienes 9 only with the Mo-catalyst 1.3 Systematic studies on the RCM of dienes containing various gem-disubstituted olefins to yield tri.4418 R.2. 19 most significant examples of metathesis reported in the 1990s have utilized either the Mo-complex 1 or the Ru-based system 2 and 3.

(+ 40"1. 24 h 61-93% E E ~) ( n 8 E E (E = CO2Et) (m. It was observed that the Ru-carbene 2 which is more tolerant of allylic oxygen functions than the Mo-carbene 1 is less effective for the ring closure of diallylic sulfides. Chang / Tetrahedron 54 (1998) 4413-4450 4419 Scheme 7. 99% X = S-S. S. The cyclization yield was increased by slow addition of the catalyst and the substrate..R. 26 While the Mo-catalyst I rendered only intermolecular dimer. The key ring closing metathesis reaction was accomplished in 97% . 24 Monosulfide containing dienes 1 1 (X = S) were cyclized in excellent yields with catalyst 1. However.13) A highly convergent approach has been disclosed for the synthesis of carbocyclic nucleosides utilizing RCM as a crucial step (Scheme 10). no tetrasubstituted disulfide cyclic olefin was formed. including sulfide or disulfide containing dienes (Scheme 8). Scheme 9. ~ OBn 13 slow addition Csl'ls Y reflux. ~ 10 n (E = C02Et) (n = 1. 24h 93-100% 1 (5 moP/. 82% 12 RCM was utilized for the formation of 1. the Ru-carbene 2 was able to convert diene 13 to cycloheptene 14.) C6Hs m.2) The scope and limitations of RCM have been examined with respect to substrates containing second-row heteroatoms. 3) . For example. 65 °C. 25 Scheme 8. ~ 7 ~ y ~ 9 lor3(5moP/o) C H2CI2 or C6H6.) B n u.2. n = 1. rt. Grubb s. CZ~/ 11 l(10mol*/o) ~" C6H6. 35 n 14~OBn 40"1.~.4-difunctionalized cycloheptenes for eventual use in an enediyne system synthesis (Scheme 9). 990 X = NH. rt ~j~ x = S. 77% X = O. H. the yields for the formation of the disulfide cyclic olefins 12 (X = S-S) were strongly influenced by the substitution pattern around the double bonds. OBn 2 (I o moP/.

reflux ~' -R1 45-74% 18 R1 . It is a novel approach using a substrate where one of olefinic groups is an a. A variety of electronically or sterically .27.~R1 17 R2 . bicyclic diaza compounds 18 were prepared through the RCM of diallyl substituted hydantoins 17 which are readily made from amino acids and ureas. in the case of R2 = ailyl. no spirocyclic product was observed.31 The styrenyl allyl ether dienes 21 were easily prepared from salicylaldehydes in one pot and the cyclization reactions proceeded in excellent yields. ~ / ~ • 3(lmol%). (5* w/w). allyl.p/. alkyl.. Scheme 11. ~V OMe BnO~Nk ~ 2Ar.18 Scheme 10.30 min CH2CI2' O(~H ~ ~ H HO ~" H Ph 15 16 \ H Ph As shown in Scheme 11. N. 48h = Bn 70°/° BnO~'b 20 BnO'~B~ O 19 An efficient and practical method for the preparation of chromenes (2H-benzopyran derivatives) 22 has been described (Scheme 13). Grubbs.29 Cyclization of diene 19 with catalyst 2 afforded the bicyclic lactam 20 in 70% yield in refluxing toluene. . R2 . 30 This is a surprising result since unsaturated esters are not considered good substrates for RCM and reactions are normally not efficient at such high temperatures.aryl R2 .£) ~N.4420 R.. alkyl. S.9.O 3(10 mol%) I ~ CH2CI2.O ~ . benzyl RCM has been employed as a key step in the synthesis of a natural product castanospermine. H./gunsaturated ester. 28 Greater than 95% conversion was observed in all reactions using 10 mol% of catalyst 3 in refluxing methylene chloride. tolune 110°C. Scheme 12. a member of a large family of polyhydroxylated alkaloids (Scheme 12). . Interestingly. Chang/Tetrahedron 54 (1998)4413--4450 yield by exposure of a CH2C12 solution of diene 15 to 1% of the Ru-catalyst 3 to afford cyclopentenol 16.

. 33 It is particularly noteworthy that reaction of the tosylamide diene 26 with the Ru-catalyst 2 underwent a facile cyclization to generate a 8-membered ring 27 in 68% yield. Scheme 14. n=l) through RCM is also very efficient for silicon tethered alkenes.. ~ R 23 \/ 1 or 3 (2-5 moP/o) i. R1~ R3 21 R2 3 (2-6 moP/. the Mo-complex I was more effective for the cyclization of the more sterically hindered vinylsilyl substrates (n = 0). 0. . Chang / Tetrahedron 54 (1998) 4413--4450 4421 different substituents were introduced at the varying positions on the chromene framework. n = 0-2) In combination with an asymmetric ethylmagnesation of medium-sized heterocycles.34 Subsequent exposure of cycloolefm 27 to catalytic ethylmagnesation conditions delivers the unsaturated amide 28 in >98% ee.R. Et2N. Of particular interest is the tolerance of 3 to both the aryl amine and nitro substituents.15 M. ~ ~ m R 80-93=1o 25 (m = 1-3. It is noteworthy that formation of 8-membered rings (m=2. Tandem metathesis/carbomagnesation can be carried out in the same reaction vessel giving a similar overall yield. \/ ~"~nSi'o. NO2. Subsequent oxidative ring cleavage of the cyclic silyloxyalkenes 24 produced the corresponding cis-olefinic dihydroxy compounds 25 in excellent yields. 91% yield).5-5 h 73-96% 24 R OH KF/H202. One example has been reported in which silicon was used as the connecting atom between two olefins (Scheme 14). Alkyl RCM of temporarily connected dienes and subsequent removal of the tether can afford acyclic alkenes with various functionality. OMe. even in fairly concentrated solutions (0.vSko CH2CI2 °r 06H6 ~ ~ m rt. 5 mol% 3. CI. 32 While RCM of allyl. This result is presumably attributed to the presence of the sterically demanding tosyl group. which restricts the conformation of the diene leading to a more facile cyclization. H. Scheme 13.) CH2Cl 2 or C6Hs= ' 79-99% R3 Rlm R2 R 1 = Br. S. H C ~ . the Hoveyda group has illustrated an efficient procedure involving RCM to afford unsaturated alcohols or amides (Scheme 15). Grubbs.or 3-butenylsilyloxy dienes 23 (n >1) proceeded quantitatively with the Ru-catalyst 3.

. the efficiency of the reaction was significantly influenced by the conformation of the substrate and the difference of the cyclization yields between two diastereomers is especially noteworthy.39 However. Chang / Tetrahedron 54 (1998) 4413--4450 Scheme 15._ ~ [Zr'] (10 moW°) I I ~ EtMgCI 77% " Ts 27 ....40 Again. Grubbs. S. . This approach to cyclic ether synthesis could be potentially useful in an iterative sense.~ rt... . C61--I 60-.H3 A r . ~.. While the mixture of diastereomers 29 was cyclized cleanly with the Mo-catalyst 1 to the trisubstiturzd bicyclic olefin 30. permitting sequential ring construction to yield multiply fused ring systems frequently found in natural products such as brevetoxins.v. .. 2h . Fused bicyclic allyl ethers such as 34 were also obtained by cyclization of the allyl ether precursors 33 with catalyst 1 under high dilution conditions. ~ N Ts ~ 2 (2 moP/. treatment of enol-ether precursors such as 31 with the Mo-catalyst 1 affords the bicyclic products 32 in good yields.. the same reaction with the Ru-catalyst 2 was very slow even at elevated temperature and yielded one diastereomer. v 28 l "NHTs I >98%e0 One pot: 54%: >98% e e RCM of monocyclic dienes containing a gem-disubstituted olef'm was utilized to obtain a trisubstituted cyclic olefin in a synthesis of coronafacic acid (Scheme 16).) C68% H2CI2. Early work by Grubbs and co-workers demonstrated that such systems could be prepared by combined olefination of an ester followed by cyclization. 91% CO2Me C O2Me 30 C O2H Coronafacic acid .36 the ketone was converted to a ketal group.. direct conversion of olefinic esters to cyclic enol ethers was also illustrated using stoichiomelric Tebbe-type reagents. numerous approaches have been disclosed for the synthesis of these cyclic structures...'N ° 1 (6 mol%). Recently.4422 R..-~. 38 As illustrated in Scheme 17.~...37 The Mo catalyst 1 must be used in the formation of vinylethers since the carbenes formed by the rapid reaction of vinyl ethers with 2-3 are unreactive for further metathesis reactions...- Since cyclic ether components are abundant in natural products. tetrasubstituted bicyclic enol ethers were not formed under these conditions. Presumably this is due to fact that the increased steric sensitivity of catalyst 2 allows it to cyclize only one diastereomer of 29. 35 Because the first attempt at cyclization with the corresponding keto ester of 29 was unsatisfactory.. Scheme 16. H.

c.~ ~ H ~ 1 (25 mol%) PiP Csl_ls..O_. S. Grubbs.41 metathesis occurs at the double bond of the chiral center and that the olefins of the prochiral center do not react with each other.R. Scheme 18.1 H" P-'G-'n IB IJ n conc(M) yield 1 H Et 0.003 14 2 H H 0.= U : H rv.2. . H. this surprising "catalyst-specificity" may be attributed to the different spatial arrangement of the respective ligands in each complex during the cyclization. whereas the syn-product 37 was preferentially obtained with the Mo-carbene 1. 42 Ru-catalyst 3 provided the anti-product 36 with remarkably high d.60oC PMP~"O . 1 1 (13 mol%). Stereoselective R C M Diastereoselective ring-closing metathesis reactions have been recently described in which an existing This strategy requires that initial chiral center controls the direction of cyclization of prochiral dienes.r ' ' " / i:.. R 1 = H. Chang/Tetrahedron 54 (1998)4413-4450 4423 Scheme 17.2. >90% R2 32 C5H12.25 °C R2--. n =1.. It was found that cyclization of enantiopure 35 did indeed proceed with a significant Even though no general diastereoselectivity (Scheme 18).n=l.TFA97% yield -~ ~'OTBS 37 syn/anti 8:92 R = CF3CO syn/anti 86:14 A chiral Mo-carbene catalyst 39 suitable for olef'm metathesis was prepared by the reaction of the dilithium salt of a novel chiral diol 38 with the Mo-alkylidene bis(tliflate) precursor in high yield (Scheme 19).~H.008 97% 2 H Et 0.. explanation was suggested. 3 (10 moP/.) ~ CsHs/80 00/4 d TFA'= CFaC O-N 98% (based on ~ 62°1oconversion) { ~ "~OTBS OTBS 36 ent-35 1 (10 mol%) / CsHs/80 °C/3 d /'~ . H.003 86 2 Et H 0.~ 31 R l=Et.43 Complex 39 may be stored under N2 at low temperature (-10 °C) for several months and its solution in frozen benzene is stable over 1 week.2. 42-73% El A R 1_2 R1 R2 . This is possible by a modification of the prochiral olefins from terminal to internal position so that the likelihood of ring closure between the stericaUy crowded double bonds at the prochiral center is minimized.003 58 R 1 R2 33 34 3. This observation demonstrates the complementality of the catalyst and suggests that new systems may yield further control of stereochemistry.

Chang/Tetrahedron 54 (1998)4413-4450 Scheme 19.~CO2M e CH2CI2. 93% R = CH2Fer.6-(i-Pr)2C6H 3 The chiral Mo-carbene 39 showed excellent catalytic activity both in ring-opening metathesis polymerization (ROMP) and in ring-closing metathesis (RCM) processes under the standard conditions. 44 Scheme 20. N. -40°C-r.~_. (PMB = p-MeO-C6H4CH2. Highly functionalized 6. R = PMB.45 Scheme 21. 38 OLi CF3 e.CF3 F3C. 18% R = Boc.4424 R.~ : CF3 CF3 39 Ar = 2.R=PMB. R = CH2Fer. asymmetric RCM (kinetic resolution) was for the first time accomplished by using this chiral catalyst (Scheme 20).. More significantly. Grubbs.t. RCM has recently extended its utility to the area of peptide chemistry. reflux=. .. 89% R 41 20% X=H2. 93% R = H.3. Application to Peptide Chemistry Due to the high activity and functional group tolerance of the metathesis catalysts 1-3.~OLi NAr n-pentane.and 7-membered amino esters or acrylic amides 41 were prepared from enantiopure amino acid-derived dienes 40 with the Ru-catalyst 3 (Scheme 21). H. I CO2Me R 40 X=O. 0% 54°/.R=H. Et3Si O• • 3g (2 reel%) toluene = -20 °C / 660 min oS ~ Et3Si (s + 38% Et3SiO"" 9 6~/o 48% ee 3.. Fer = Ferrocenyl-) .. S.

n k. Grubbs. Spiro bis-lactam ethers 45 were then hydrolyzed under mildly acidic conditions to furnish the cyclic amino ester 46.R. benzene or toluene H* ~ ..O2Me 45 RCM of a dienic amide 47 with the Ru-catalyst 2 led to a dehydro lactam 48. . 78% (1) m = 1. <5% ~' ~J" ~.50 It is interesting that the ferrocenylmethyl (Fcm) group was selected for nitrogen protection of the amide bond in the substrate 47 because apparently the steric bulk leads to the formation of the favorable conformation for closure. 47 Scheme 22. In addition. 6. CH2CI2 rt. H2 Me O ~ N ~ (~. X = N-Ts. 91% (1) 81% (3) Stereoselective synthesis of rigidified ct-amino acids where the ct-carbon of the amino acid is incorporated in a 5-. n = 1. a direct precursor of the Zethylenic dipeptide isostere 49 (Scheme 24). 48 RCM of the geminal diolefins in 44 was efficiently performed by the Ru. R m 42 43 m = 0 .53 -99% m + n = 5. cyclization of substrates containing an a-functional group (for instance. S.2. 12-84%(1) m=l. hydroxy-) has been shown to proceed in good yields. H. m=l-3. Chang/Tetrahedron 54 (1998) 4413-4450 4425 Olefin metathesis has shown to be an effective process for the functionalization of monocyclic ~lactams46 and for the preparation of bicyclic 13-1actams 43 via the ring closure of monocyclic diene precursors 42 (Scheme 22). .49 Scheme 23.X=S..catalyst 3 (2 mol%) in an aromatic solvent.or 7-membered ring has been described as shown in Scheme 23. 2-6 h . X=CH2. The cyclization appears to be sensitive to the steric interactions between the catalyst and the isopropyl group of the substrates. X=O.l 44 II 20-1005-23 h °C Me O ' ~ N ~ ` n 45 m.

4426 R.]. Grubbs. .~ H2 HO2 49 .. 48 h 65% yield Q MeMeQ Q M. S. . Ghadiri and a co-worker have shown that the 8-residue cyclic peptide cyclo[-(L-Phe-D-MeNAla-L-Hag-D-MeNAla)2]. . eMeg ./'" 6H oY "--x • ~. containing two L-homoallylglycine residues.. Ph FcrrkN O ~ 47 06H6. N ~ ~XN#'% H . Chang I Tetrahedron 54 (1998) 4413-4450 Scheme 24. . 0 Me MeQ - 0 Me MeQ - I i i i i i l i i i I i I I 9. self assembles to form two interconverting hydrogen-bonded diastereomeric ensembles. H A66~ . ct and tO isomers. N.6 MeO 0 Me MeO 0 Me 2 (20-25 moP/°) CDCI3. . This covalent capture stlategy may be useful in stabilizing kinetically labile (z-helical and ~-sheet peptide secondary structures. . Scheme 25. rt. rl = 85-90% 0-# v 48 Ph . .V M~J ~ Ivle . 51 It contains two pairs of double bonds in sufficiently close proximity that each pair undergoes RCM in the presence of 2 to give tlicyclic cylindrical product 51 (38-membered ring) with a mixture of three (cc. one of which is represented as 50 in Scheme 25.Ph The wide range of functional group tolerance shown by the Ru-carbenes 2-3 has enabled researchers to apply RCM methodology to the synthesis of biologically relevant macrocyclic peptides which contain many polar functional groups and acidic protons.~. H.~/X.N ~ M-~¥~ e~ 0 Me 51 N~" yN.

This suggests that although interactions increasing rigidity of the system helps to favor cyclization.~ 53 _m 3. RCM is becoming recognized as one of the most straightforward and reliable methods for the formation of large ring systems and compares favorably to all current synthetic alternatives. both of these factors..R. . The key competing reactions are shown below (Scheme 27).. in which both the Pro and Aib residues are replaced with leucines. However. Therefore. Bn " ~ _ . Macrocyclization Using RCM One of the major considerations for RCM in the synthesis of highly flexible large (>9) ring systems is the conformational predisposition of starting material for favorable intramolecular cyclization. RCM of additional peptides having no such a conformational restriction in the backbone was examined in order to explore the scope of this chemistry (Scheme 26). it has been demonstrated that macrocyclization metathesis is highly efficient not only with substrates having suitable restrictions but also with substrates devoid of any rigorous conformational constraints by modification of the reaction conditions (usually by slow addition)..52 In a later study. . closure of larger rings usually requires higher catalyst loading. it is not a strict requirement for the synthesis of many peptide macrocycles by RCM. The ratio of cyclic products 54 to oligomers 55 is determined by the ratio of kclosure / koligo[diolefin ]. where the naturally occurring disulfide bridge is replaced with a carbon-carbon double bond. As the rate of closure decreases due to ring size and conformational effects. As a result. Me Me Me. the competing reactions interfere with the desired reaction. The rate of oligomerization can be decreased by lowering the concentration of the diene or using slow addition of the substrate.. with the catalyst 3 afforded the 14-membered cyclic tetrapeptide 53 in modest yield. Grubbs.. 53 Reaction of tetrapeptide 52. Chang/Tetrahedron 54 (1998)4413-4450 4427 Another notable example is the facile synthesis of a cyclic [3-turn analogs by RCM.4. Initially it was believed that the ProAib sequence was required to restrict the conformation of the peptide backbone and subsequently allow facile macrocyclization. S. 21h " I~ ~ L = O HN eft'/. However. . H. Scheme 26. low concentrations and high temperature. BocN "-. / M e O \ OBn N H I ~ BocN O HNk ~O C H2CI2 (0. which favor closure also allow catalyst decomposition to start to compete with the desired reaction. Higher temperatures also favor ring closure. :.004M) M I~ 40°C.

Scheme 28. metal fragment p. 54 It is surprising that RCM of diene 58 containing a methyl remote to the terminal olefm provided the 14-membered lactone 59 with a remarkably high stereoselectivity (96:4... The reaction was essentially quantitative affording the 12-membered product as a mixture of E and Z isomers.. H. E/Z). a valuable perfumery ingredient.todiene 56 (with 2) under the slow addition conditions afforded the 16-membered lactone 57 which is an olefinic precursor of exaltolide. 55 Cyclization was cleanly achieved by slowly combining two solutions of the diene 60 and the Ru-catalyst 2 via dropping funnels. O O 2 (4 tool%) CH2CI2. .4428 R. S./x 55 LnM=C H R )~ 54 + LnM=CH2 Scheme 28 illustrates macrocyclization of acyclic dienes using RCM. Cyclization of highly flexible ct. rt O slow addition 72% (E/Z= 96/4) O 58 58 A 12-membered bicyclic macrolide 61 was synthesized via a RCM reaction (Scheme 29)...~M Ln ~o + + LnM=CH2 " ~. This result is in stark contrast to the almost statistical ratio obtained in the cyclization of 56 and suggests that the stereochemistry is kinetically controlled. Grubbs.. Chang /Tetrahedron 54 (1998) 4413-4450 Scheme 27. rt slow addition 79% (Z/E = 54/46) 56 b"t O CH2CI2.

. Chang/Tetrahedron 54 (1998) 4413-4450 4429 Scheme 29. S. slow addition 94*/0 "°?9 = M e ~ 61 (E/Z = 2. as seen in many examples of conformationally unrestricted acyclic olefins..) (R =/-Pr.0005 M) 40 °C.311) M e O" ~ ' ~ v 60 Bridged calix[4]arene derivatives were efficiently prepared by RCM as shown in Scheme 30. 62%) tB tBu tBu tB tBu tBu The tricyclic core of roseophilin has been prepared using RCM as a key step (Scheme 31). Me0 0 = . While metathesis of 62 (X = H) with 3 afforded only macrocyclic dimer as a major product even under the extremely dilute concentrations. 3 (4 tool%) CsHs. 25 h 63 60% (single diastereomer) 3 (30 moP/. X = OTIPS) Hoveyda and co-workers have completed the direct synthesis of the antifungal agent Sch 38516 through the RCM of a fully functionalized acyclic precursor in contrast to their previous report..R. 58 Mo-catalyzed ring closing metathesis of diene 64 led to the 14-membered trisubstituted olefin 65 in excellent yield (Scheme 32). cyclization of the diene 62 (X = OTIPS) containing a bulky restraint group on the hexenyl moiety provided the desired ansa-bridged silylether product 6 3 in good yield. 57*/0 R = OMe.-~ // % CH2CI2 (0. H.. 2 (6 mol%). 59 . Scheme 30. only with appropriate structural restraints. Scheme 31. Grubbs. 56 Similar yields of cyclic compounds were obtained for dienes with free hydroxyl or dimethyl ethers. rt (R = OH.57 Cyclization was shown to proceed..

.'¢ CH2C12 solution to afford the 16-membered macrocyclic Z-olefin 67 in 50% yield together with its separable E-isomer (35%).13-double bond. It is interesting that the flexibility in the synthesis of the isomeric macrolides by RCM was claimed to potentially allow the generation of a diverse epothilone library for further biological investigations. H. Chang/Tetrahedron 54 (1998) 4413-4450 Since the Ru catalysts are more sensitive to bond substitution than the Mo catalyst.. The same group has reported a similar approach to the same compounds based on solid-phase RCM (vide ip~'a). 8 h ~TJ. H . . L 66 67 (50% + 35% E-isomer) Another approach to the synthesis of epothilone A was reported by Schinzer et al. OAc OAc OAc OAc ~ -O 1 1 .61 The olefin metathesis reaction of acyclic diene 66 having an unprotected hydroxyl group at C7 was effected by the Ru-catalyst 3 in dilu. was protected with t-butyldimethylsilyl (TBS) and RCM of the diene precursor with 3 gave the cyclic epothilone A intermediate in 94% yield as a 1:1 mixture of diastereomers. . The C-7 hydroxyl group. .4430 R. M e H N.63 . 60. CtH 6 60"C.62 Almost the same strategy was employed as in the Nicolaou synthesis.~ 65 3 MeHNv~ 64 Me I The power of olefin metathesis in forming macrocycles has culminated in the synthesis of biologically active epothilone A and its derivatives by several research groups.. site of the olefin formation by RCM was chosen to be the A12. Macrocyclic olefm metathesis was also efficiently utilized in a separate report for the construction of a basic skeleton of epothilone A. Grubb s. 10 h =. the [Mo] system appears to be more generally useful for the closure of macrocyclic trisubstituted double bonds (see above for an exception).. Scheme 32. ~ '~NHCOCF ~ ( . Nicolaou and co-workers first reported a RCM based approach to the macrocyclic skeleton of the epothilones (Scheme 33).~ • Me 1 (20 rnol%). Scheme 33. in which RCM was also used as a key step for the cyclization.~ O 3 (15 mol%) CH2CI2 (0.006 M 2 rt. in this case... S.

Among the many metal ion templates tested. 39"1o (38:62 Z/E) n = 1. 67 Complex 73.selectivity of the cyclic products is gready changed (Scheme 35). R = TBS X = I~-OH. remote side chain effects in macrolide formation by RCM were extensively investigated by the Danishefsky group in the synthesis of epothilone A and its derivatives (Scheme 34).02 M. Y = a-OTPS. R = T B S X = ct-OH. obtained by complexation of the 2 .selectivity in RCM based macrocyclization.001 rt. LiCIO 4 (5 equiv). (Z/E = 1/3) 80% (Z/E = 1/5) 8 6 0 ( Z / E = 1. 65 Scheme 35. no template. 66 Catenanes. Grubbs.R. more importantly. Chang / Tetrahedron 54 (1998) 4413--4450 4431 Recendy. LiC104 effected a quantitative conversion Of an acyclic diene 70 to the cis ring-closed crown ether 71. 1 h 71 n = 1. interlocked molecular rings. Y = O. R = TBS 81% (Z/E = 1/9) 88% (Z/E = 1/2) An important advance has been disclosed regarding the control of stere. stere. Y = O. have been shown to be synthesized by the combination of threedimensional template effects and RCM reaction (Scheme 36).7/1) 6 5 % ( Z / E = 1/2) X = 13-OH. (o-1--" 78 CH2CI2. Y = O. 64 Cyclization of the acyclic dienes 68 with the Ru-catalyst 3 afforded the 16-membered macrolactones 69 having an E C12-C13 double bond as the major isomer in most cases. Similarly. S.THF (0. Template directed RCM of linear oligooxy ethylenic dienes devoid of other conformational constraints has demonstrated that an appropriate metal-ion template significantly promotes not only product yields but. Y = a-OTPS.control. R = H 86*/. >95% (100:0 Z/E) It is presumed that preorganization of polyether olef'm around a complementary metal ion provides a favorable conformation to enhance the rate of cyclization and stere. H. Scheme 34. 12 C6H6(0.) M)~. Y = ot-OTPS. 24 h Y X 68 3(50moP/. With all protecting groups identical. Y " ~" ~ X 69 "]1~ O O L i~/-~ 0 X = a-OH. R _ ~ r e . 45 *C. R = TBS X = ot-OTBS. the proportion of E product increases up to 9:1 upon changing from the 3S to 3R series. keeping the C-3 and C-7 groups constant but varying C-5 affords more of the Z olefin product. R = TBS X = (x-OTES.

H.CH2CI 2 (0. 2.oj 73 . Tandem Reactions = 98:2) In addition to the ring-closing metathesis (RCM) of acyclic dienes. Scheme 36.0~0 O O KCN o --~+ PFs" q ~o~_ro~ 75 Co ~ k. Mo. S. j / / ~ + PFs- Cu(MeCN)4PFs I= Lo\ joJ 72 ( . A new strategy for the formation of bicyclic ring systems has been developed in which intramolecdar ring-opening/ring-closing metathesis of cyclic olefins .and Ru-carbene complexes 1-3 also promote the ring opening metathesis of strained cyclic olefms.f R_ ~o. 6 h. k J o_-ou. (.5. Grubbs.. Chang/Tetrahedron 54 (1998)4413-4450 equiv of the bidentate diene 72 with a copper complex. g0% yield ~. 3 (5 tool%).01M) rt. For all [n] catenates synthesized by this strategy.4432 R. was cleanly cyclized to form a 32-rnembered catenate complex 74 in remarkably high yield and subsequent demetallation gave the catenane 75.o~_foJ 74 (trans/cis 3. . the energetically favored trans configuration at the double bond predominates..

and seven° membered rings in a highly selective manner. in which the acetylene positioned between the two olefins acts as an olef'm metathesis relay.R. With the bulky t-Bu substituent. ~O. 60°C. I. Also substrates containing heteroatoms directly attached to the acetylene were not cyclized by the Ru-catalyst 2.~O~ 76 3 (5 tool%) C6H6 (0. Among the two possible sites. trealrnent of bis(alkenyl) ethers of several cycloolefin diols such as 76 or 78 with complex 3 afforded the respective bicyclic products 77 and 79 in good to excellent yields. 3 h) CO2Me.1 M) CsDe OSiEt3 X=H.m. Chang / Tetrahedron 54 (1998) 4413-4450 4433 containing two alkenyl side chains is performed in a tandem manner.i~'. the acetylenic substituent is transformed into a vinylic pendent which could subsequently be manipulated into more diverse functionality. six-... 60 ~. however. NR Ph. This family of reactions allows for the rapid synthesis of complex molecules from simple substrates.05-0. OSiEt3 2 (3-5 moWo) ~ (0. X 80 X 81 96% (60 °(3. initial metathesis at the disubstituted ring olefin. 4 h) t-Bu. no cyclization product 8 1 was observed. >95% (rt. TMS. initial metathesis at the mono-substituted acyclic olefin was postulated to predominate over the other possibility. To this end. Grubbs.. the effects of various acetylenic substituents on the RCM of dienynes 80 were examined (Scheme 38).69 This strategy provides functionalized fused bicyclics containing five-..O] ring systems was previously developed via Ru-carbene catalyzed double RCM of acyclic dienynes. CI. 2 h 917'1o 77 ~. was circumvented by conducting these reactions at low concentrations or by using disubstituted acyclic olefin side chains. H. SnBu3. In the proposed mechanism of the dieneyne RCM. 68 As shown in Scheme 37. Br.1 M). 15 rain) 95% (rt. Competing intermolecular metathesis has been frequently observed with less strained ring systems such as 6-8 membered cycloolefins. 70 With alkyl substitution.Ph = CO2Me). Me. S. Scheme 38. 82% (60 °C./O~ 76 O ~ 3 (3 moP/o) C6H6(0.~T. 8 h) .07 M). steric effects are important and reaction rates follow the expected trend (X = H > Me > i-Pr -. Scheme 37. This undesirable pathway. 6h 7(71o 79 The formation of fused bicyclic [n.

1= 0 H 0 82 R = Me: 83 2 (5 mol%).2-polybutadiene 88 was treated with the Ru-carbene catalyst 3 to cleanly afford the cyclopolymer product 89.4-vinyl units of the polymer backbone occurs during the ring-closing process. stemoamide (Scheme 39). both fused and nonfused tricyclic triene systems were produced in the presence of the Ru-catalyst 3. the tandem reactions can be extended to "multi-cyclization" by attaching additional metathesis relays such as acetylenes or cyclic olefins. 0 0 .1 M) 45 °C. 50 °C. C6H6 (0. the kinetic .4434 R.2-poly(Z-pentadiene) 90 yielded the trans-diisotactic cyclopolymer 91 in a quantitative yield. Grubbs. Recently this has been realized. H. 73% (-)-Stemoamide R = CO=Me: 3 (4 mol%). rt. 4 h 40=/0 87 RCM of simple ot. 11 h. S. one step tricyclization was accomplished by the metathesis of dienediynes (Scheme 40). The lower molecular weight (Mn) and broader polydispersity (PDI) of the polycyclopentene 89 compared to the starting material 88 suggests that metathetical degradation of the infrequent 1. A substrate with a cyclic olefin relay such as 86 leads to a nonconjugated diene moiety in the tfiene product 87. 71 Cyclic eneynes 82 were smoothly converted to the 5. C6H6. 72 Depending on the dienediynes utilized. 5 h. As a dramatic illustration of the reversibility of RCM. CH2CI2.05 M) It f 86 45 °C.ordienes has been extended to polymeric substrates containing suitably-spaced olefins (Scheme 41). Scheme 40.7-fused compounds 83 in the presence of Ru-carbene catalysts 2 or 3. The reaction proceeds to 90% conversion in the first 30 min and then continues much more slowly to 97% conversion in over 3 h. 87% In principle. 73 Atactic 1. Chang/Tetrahedron 54 (1998) 4413-4450 lntramolecular enyne metathesis has been applied in the total synthesis of a natural product.. Reaction of the Mo-alkylidene complex 1 with syndiotactic 1. 4 h 600 O a4 It 86 Ts CsH 6 (0. Scheme 39.

R. . A diene which contains a variety of functional groups (for instance. 76 . 40 °C.) may be covalently bound by a linker to a solid support and heterogeneous RCM can be carried out on the resultant solidbound substrates (equation A). Chang / Tetrahedron 54 (1998) 4413-4450 4435 prof'des suggest that the catalyst randomly closes adjacent olefins until only isolated olefins remain and then the catalyst migrates up and down the chain until all olefins are cyclized. There are two potential strategies depending on the olefin's position on the solid support as depicted in Scheme 42.6. Olefm metathesis methodology has been also shown to be compatible on solid support bound substrates.15 M) ~.21) gO 1 (5 moP/.90. Grubbs. alcohol. conversion 91 (Mn 5180..) C6H6 (0. o-(3+..04) 3 (2 moP/o) CH2CI2(0"12M)_ 35 °C.75 Despite the conceptual merit that RCM of dienes such as 94 directly releases the desired cycloolef'mic product.12) 3. Examples of each strategy have been recently documented (Scheme 43). Poly-styrene bound diene 9 2 was converted quickly to the cycloolefin 93 which remains bound to the resin. S. PDI 2. 21 h >97% conversion ~ 89 (Mn 3150. PDI 1.52) RCM of Solid Supported Substrates Performing organic transformations on a solid support has seen increased uses during the past few years. the actual metathesis of these substrates has been found to be quite sluggish under standard reaction conditions to afford 95. Scheme 42.74. A different approach (B) is the "cyclizatlon/cleavage method" in which the desired cyclic olefm is directly liberated from RCM of a diene attached at one end to solid support and therefore no additional step for removing the linker from the resin is necessary. Scheme 41. ~ 88 (Mn 25000. .. 16h >99*/. carboxylic acid. (Mn 46. PDI 3. PDI 1. amine etc. H.

Desilylafion and epoxidation of the cyclic olef'ms affords the biologically important epothilone A and its derivatives. TH = 2-methylthiazole . "" ii _~1~°~ I j~ TH ~ O O OR O 96 OR O 97 + ORO 98 O OR O 9g O OR O 100 O Merryfieldresin(0. presumably by detaching the immobilized catalyst to provide a recyclable active carbene intermediate. C2H4. Addition of a terminal olefin such as ethylene or 1-octene largely obviated this problem.75 equiv of catalyst 3 in methylene chloride. 23 °C.Bn I 95 o NHBoc I~NHBoc 14 mol%. 5% 30 rnol%.7s ~uiv) H .' ~ Oo. 7 d. 48 h 52*/o (97:g8:$9:100 = 3:3:1:3) 3(o. 23 °C. CH2CI2. C2H4. Chang / Tetrahedron 54 (1998) 4413--4450 Scheme 43. Nicolaou and co-workers have reported a solid-phase synthesis of epothilone A incorporating RCM (Scheme 44). 50 °C. Grubbs.. 12 h 70*/. 2 d.3 mrnolg-l) R = TBS. O °-3_e a C O ~ 3 (13 moP/. CH2CI2 reflux. and therefore the catalyst is not available for further reaction. S.rt. 1-octene. Scheme 44. resin = tritylpolystyrol ~ O C FaCO . o toluene 94 9~ . 44% 12 moP/.4436 R. 2 h.. H. 4 olefinic compounds 97-100 were released from the resin in total 52% yield as a separable mixture of 4 diastereomers.37% The authors attribute this low rate of RCM mainly to immob'dization of the metal carbene complex on the resin during the course of the metathesis. 77 Upon treating solid support bound olefm 96 with 0.).

the yields of the desired rearranged-products were dramatically improved under an ethylene atmosphere as dimer formation was minimized. n = 2.R. 84*/.) Q CH2CI2 (0. H.5 equiv). the feasibility of performing the RCM on solid support hound peptides was considered (Scheme 45).allylglycine~ ly-Fmoc lm 3.or 8-membered ring systems. 35% 92% R = OMe. with substrates containing small size rings (103. substrates commonly suffer from poor solubility in usual non-polar organic solvents where the metal carbene complexes display their highest activities. 104 . 10-14h • 1 atm of C2H4 R . the rearrangement proceeds less efficiently than for 7. n < 1). cyclopentenyl styrenyl ether (103. For instance. Scheme 45. ~ j ~ = ~ ' ~ O ~ n = 1.1 M) 22 °C. CH2CI2. RCM Mediated Rearrangement Recently olefin metathesis catalysts have been employed for the rearrangement of styrenyl ethers to yield isomeric heterocyclic products (Scheme 46).~ne-Gly-Fmoc II 1= II 3 (0. However. Chang/Tetrahedron 54 (1998)4413--4450 4437 In the RCM of peptidic olefms containing greater than five amino acid residues. 78 Surprisingly. ~N--Val-allylg~ne-Tyr-Pro-allyig ~. R = H. 53 Peptidic dienes were prepared by the standard solid phase peptide synthesis on a Tentagel resin. 86% n=3. R = H. Scheme 46. 90% R = NO2.40 °C. n = 0) gave no rearranged product. and heterogeneous RCM of 101 was effected under the conditions analogous to the solution phase RCM reaction. Grubbs. RCo 10B 2 (5 moP/.7. As a result. efficiency of the solid phase reaction was revealed to be analogous to the solution phase cyclization. R=H. 22 h 65% (after removingthe beads) I~N--Valallylglycine--Tyr-Pro. Chromenes 104 with different lengths of side chain and with diverse substituents were prepared in exceUent yields from reaction of styrenyl ethers 103 with the Ru-carbene 2. Upon cleavage of the cyclic peptide from the resin bound product 102. S.100% R = F.

Scheme 47.. a mechanism for the above Ru-catalyzed rearrangement of styrenyl ethers has been proposed (Scheme 47).R2 + R I ~ (desired) R1 + R 2 . there are only a few examples of selective cross-metathesis in the presence of functional groups.. 79 This unique acyclic C-C double bond "interchanging strategy". With ethylene present. dimer formation is reduced likely because the ethylene competitively reacts with 109 to deliver both 110 and the active ruthenium methylidene LnRu=CH2 which goes on to form 106 in the catalytic cycle. Efficiency of the cross metathesis depends on the selectivity In addition to the observed in the couplings. therefore. Minimization of unproductive alkenes from "self-metathesis" and consequently maximization of productive cross-metathized alkenes is a crucial issue to be optimized.~. The lower reactivity of the smaller ring systems probably results from strain in the formation of the metallacycle 108. 109 may react with 110 to afford the undesired dimer 111.. Cross Metathesis Metal carbene catalyzed intermolecular coupling between two different olefins potentially yields 3 new types of alkenes as depicted in Scheme 48. Rl. H.o ~" 1 108 d 109 111 107 4.4438 R.= .-'~ + R2""~ M=CH2(cat)= RI. Scheme 48. S. . Grubbs... stereocontrol of the newly formed double bonds is another important consideration in this chemistry. as increasing amounts of 110 are produced. However. has not found widespread application in organic synthesis because of the fact that general conditions giving high selectivity have not been discovered. " ' ~ "R2 (undesired) In contrast to the vast number of successful accounts of ring-closing metathesis reactions. regioselecfivity. Reaction of the intermediate carbene 109 with a second equivalent of styrenyl ether 105 yields the desired product 110. Chang/Tetrahedron 54 (1998) 4413-4450 In light of added olefin (ethylene) effects. .

85% 40% 76% 45% 60*/0 37"1o + R~R 1 1 6 a.. varying amounts of the self-metathesis dimers were formed in these cases. (c/s/ffans = 9:1 ) 17. The yields are generally lower for alkyl-substituted olefins beating electron-withdrawing groups.8:1 E/Z = 4. Grubbs. 19"/. H.and stere.~v. Increasing the size of the alkyl group (i. Even though the coupling with alkylsubstituted olefins afforded modest tram-selectivity (ca. 80 The reaction efficiency was found to be dependent on the type of the second substrate 112. from trimethylsilyl.4:1 116. Chang / Tetrahedron 54 (1998) 4413-4450 4439 Cross metathesis in which acrylonitrile is used as one olef'm is one of the few examples affording high selectivity (Scheme 49).selectivity. Scheme 50.e. 20% <1% 60%(cis/trans=7.6:l) 56% (cisdrans = 9:1 ) 76% (cis/trans = 3:1 ) 4% 0% 4°/.to triisopropylsilyl-) on the silyl alkenes led to increased trans selectivity without diminishing the overall yields. 4*/. 3 h N C'~ 113 I R + R" I ~ ' " 114 (undesired) R = (CH2)sCH 3 (CH2) Br (CH2)3OBn ( C H2)5C H 3 CH2TMS ( C H2)5C H 3 (C H2)6CH=CH2 (CH2)2C(O)OBn R 113. 4 h R = Ph. 56% (cisA~ans = 9:1 ) 53%(cis/trans=8:1) 44*/0 (cis/trans = 5.6:1 ) Allylsilane coupling with terminal olefins is another example of regio.R. the high cis-selectivity exerted with acrylonitrile is especially noteworthy because other metathetical coupling reactions between two different olefins invariably proceed with a high degree of o'atts pathway.selective cross metathesis demonstrated by Crowe and co-workers (Scheme 50). 3-5:1). More significantly. S.0% 0% 0% 12% 26"/o 15"/o . NC I~ + ~'R 112 1 (5 mol%) CH2CI2 = rt. 6*/. Even though its origin is not clear at present.. R~. 81 Reaction of allyltrimethylsilane with various para-subsfituted styrenes in the presence of Mo-catalyst 1 generated excellent stere. Scheme 49. 56*/.5% (cis/trans = 9:1 ) 114.TMS 115 115.7 E/'Z = 2. R = 0-NO2C6H4 R =CN R = (CH2)2Br R = (CH2)3OBn R = (0H2)20 N E/Z= 100:0 E / Z = 100:0 E/Z = 1:4. R~ + ~TMS 1 (2 rnol%) D M E ~. unproductive self-metathesized products were not formed.6:1 E/Z = 4.

A steady stream of N2 across the reaction mixture increased yields. unproductive self-metathesized products were also formed in similar ratios. 40 '~3 R ~. it is noteworthy that derivatives of various synthetically useful allyl stannanes can be prepared by this simple procedure.1.~/SnR'3 (2 equiv) R . Chang/Tetrahedron 54 (1998) 4413-4450 Cross metathesis of various terminal olef'ms with allyltriphenyl. 30 h. With the exception of acrylonitrile.3:1). ~ j S n B u 3 R'= Ph.~. 22% (E/Z= 1. 74% (E/Z= 2..2:1). 83 Even though high Estereoselectivity (>10/I) for the productive cross metathesis alkenes 118 was obtained with styrene.~'~.SnPh3 or R~ .4440 R. considerably lower coupling yields were obtained when a ketonic ester was employed in cross metathesis instead of the acetal ester 119. 11 3 N = Ph.. R' = Bu. 67% (E/Z= 2.~ + ~. R'= Bu.0:1) R' = M~O'~'~CH2 O NCCH 2 O=C=N-CH2 AcO.--~ 0 0 Ph. R' = Bu. all olefins were coupled with 119 to afford a moderate Eselectivity.. H. trans/eis = 4/1. N2 4366°/= t. no reaction. 84 Despite the broad functional tolerance of Mo-I and Ru-3 catalysts.or alkylsubstituted terminal alkenes has recently been illustrated (Scheme 52). R 1H N . 82 Even though the stereoselectivity observed is low to moderate. derivatives of jasmonic acid 120 containing modified olefinic side chains were prepared to study their biological activities (Scheme 53). R' = Bu.PhCH2 1 (5-10m01%) = CH.or allyltributyl stannane has been reported by Blechert and co-workers (Scheme 51). R' = Bu. R~. . 74%(E/Z= 1.tCI2. 72%(E/Z= 1.43-55% R = alkyl. Scheme 51.4:1) R' = Ph. 55% (F_/Z. Grubbs..2:1) R' = Ph. trans/ais = >10/1. ~ C 02R 2 R3 ~ 117 ClCH~H~l= rt. S c h e m e 52. S. .. 21% (Eonly) Ru-carbene catalyzed cross metathesis of protected forms of unnatural amino acid homoallylglycine 1 17 with aryi.55-66% Using cross metathesis. It is possible that the ketone coordinates with the intermediate carbene complexes.8:1). 78% (E/Z= 2.7:1). no reaction R'= Ph.

1:1 mixture of . Scheme 54. Chang / Tetrahedron 54 (1998) 4413-4450 4441 Scheme 53..3-0. cross metathesis involving polymer-bound olefins could give one potential benefit. immunosuppressant FK 506 (124) was dimerized in 49% yield with the Ru-catalyst 3 (Scheme 55).5 mrnol/g of 121) (0.~C O2Me (1.5 equiv) 1 (5 tool%) (65%.34 mmol/g of 121) ~ 3% TFA/CH2CI2 ~7"~ R (<0..E/Z= 6:1) (2 equiv) 1 (5 tool%) (92%..6 mmol) polystyrene CH2CI2 40 °C. O••C•O 119 ~.5 equiv) 2M e + 1 (5 moP/. Indeed high efficiency was obtained in the cross coupling of a immobilized alkene 121 with various aliphatic olefins giving new immobilized olefin products 122 (Scheme 54).) (73%.. E/Z= 2:1 ) ~. 85 Products 122 were subjected to electrophilic cleavage to yield homologated alkenes 123..R. The yield of the dimeric product 125 (ca.O ../. Grubbs..~ co2M e 120 (83%..1 mmol/g of121) In an interesting and biologically relevant application of cross metathesis.OAc ~ O ~"C N (2 equiv) 3 (5 moP/.5 equiv) 3 (8 mol%) (70%.E/Z = 2:1) H (1. 86 The potentially coordinating alcohol functionality at C-24 or C-32 were not protected. self metathesis of solid support bound olefins could be theoretically prevented due to the site isolation on the solid support. H. ~).. 5 h.) C H2CI2 ~40 °C.._. S.Z only) (1. ~'R (0.E/Z= 4:1 ) In comrast to the coupling of two alkenes in solution. 18 h122 (1% Divinylbenzene) 121 (300 rag) product isolated yield (0.

2a Ring-opening cross metathesis of strained norbomene derivatives with various types of olefins has been illustrated by Biechert and co-workers (Scheme 56).A.-~ 0==~ )=o O.D Me r..' ~ e ~"bMe Me MeOMeo" ."~ ~ / ~ t M. Ringopening metathesis of strained ring systems and subsequent coupling with acyclic alkenes provides new types of diene products. control of regio...-) .Me ~ HO.O ~ / ~ ~ ~. Chang I Tetrahedron 54 (1998) 4413~14 50 alkene isomers) was improved (58%) by increasing the concentration of the diene 124 and replenishing the catalyst 3 (total 10 mol%) once during the reaction. (.DMe " Me( H. H. Me.1 M) and an excess of acyclic alkenes is added.. /.22h HQk .. In fact the formation of scrambled cross products as the kinetic products with classical catalysts was one of the fn'st clues implying that the mechanism involves carbenoid intermediates. ~ 0 Me L'v~oH O . Improved Z-selectivity (3:1 Z/E) was obtained by TBS Scheme 55..OH o Me )..( M ex )=o o( ) OMe k~'-~OH O==~ ~ M /~. This modified cross metathesis uses the ring-opening of strained cyclic olefins as a driving force for the reaction.... 0.¢ 5. 125 Ring-Opening Cross Metathesis Another area of cross metathesis has been recently re-investigated from synthetic points of view.. the reaction is usually performed in relatively dilute concentrations (ca.. 87 With symmetrical norbornenes such as 127. modest E-selectivity (4:1 E/Z) was obtained in refluxing t-BuOH (23% yield). The recent successful application of these reactions is surprising in light of the rapid equilibration of the end groups in cross metathesis reactions with classical catalysts.o. ~ . S... protection of the C-24 hydroxyl group. Grubbs. Even though the stereoselectivity of the metathesis was relatively insensitive to both common organic solvents and reaction temperature.4442 R. As in cross-metathesis. To avoid polymerization of the cyclic olefins.and stereoselectivity of the newly forming double bonds appears to be the most important issue in order to make this reaction an appealing strategy in organic synthesis. 124 H'i ~n ~ "-Me Me."~N . reaction . rt....--( ~r~ Ill ~=0 ....:e L~Me 3(10mol%) CH2CI2.

0] ring systems in excellent yields. reaction of unsymmetrically substituted olefins introduces new regio. ~.2 eq) 0H2CI2.and stereoselective ring-opening cross metathesis of cyclobutene-containing substrates with suitable terminal olefins has been recently investigated by Snapper and co-workers (Scheme 57). Chang/Tetrahedron 54 (1998)4413-=.07 mol% of the Ru-catalyst 3 being sufficient to complete the reaction in 15 min at room temperature. 129 Me3SiCH2~. Moreover. the diastereomer of 139. ""--OTBS 128 (F_/Z=1/5) /•.3. 88 S c h e m e 56..90 Unlike syrrmaetrical alkenes (for instance. -° v "~.~ 0 "~1"0"~ 0 (E...~iM e3 H "~ (1 eq) 94% Me3SiCH!~" ~30 (~Z = 5/1) I (E only) (130/131 =3: 1) / ~ ~ O + ~ (10 eq) 2 (2 moP/.. In fact.R.5:1) (R = CH2CH3) 1_. ~'~'~---O 127 ~'. no ring-opening metathesis occurred with cyclobutene 142..E/E. While cross-metathesis of 136 with TBS protected 4-penten-1-ol provided ring-opened products with little regiocontrol (137/138 = 1.Z= 3.450 4443 with a slight excess of terminal alkene produced only one regioproduct 128 in excellent yield using the Rucatalyst 3.5:1). .~-----~ CH2CMe3 + ~. . + ~". H.--OTBS =. Indeed.. reaction of dicyclopentadiene 129 with allylsilane afforded a 3:1 mixture of two regioisomeric products 130-131. subtle variations in substrate structure also play a critical role in the reactivity profde for ringopening cross metathesis.... however..Q.. would be formed from the reaction of unsymmetrical norbornenes. This increased efficiency is apparently due to the high reactivity of the strained olefins. Two regioisomeric products. cycloadducts having substituents on the furan ring led to higher levels of regioselectivity (140/141 = 8:1).25 °C 1.. As was observed for intramolecular ringclosing metathesis.=) CH2CI 2.~ Regio. The efficiency of the reaction is truly remarkable..... with only 0... Grubbs. 89.. ethylene). the newly formed olefin of the major regioisomer 140 was obtained with excellent E-selectivity (>20:1).. 25 °C =.. 2h 96*/0 .and stereochemical questions.. S. .... Stereospecific Cope rearrangement of the metathesis products affords bicyclo [6. If a disubstituted aikene is added to a strained cyclic olefin 132... a new type of ring-opened internal olef'm 133 is formed as a isomeric mixture.~Me3 (1.5 h 96% 3 (5 mol%) TBSO--.

Chang I Tetrahedron 54 (1998) 4413-4450 Scheme 57.- H.o~ Cy3 + e 143 3 CDCI~ 70°/o H ~ C l /. hi... R + (8 : 1) H'. HC L.. M e "Ph 144 ...0.. The stable (even on silica gel) complex 144 has been found to have a catalytic activity in beth ROMP and RCM. NR During the above study.. H 3 + H2C==CH2 617'/o 138 134 H + ~R 3 .. °°" H + ~"" R e 139 H ...5 : 1) 138 pp. 3 136 (R = (CH2)3OTBS) (1.. Scheme 58.4444 R. 84% 137 I~. a new ruthenium alkylidene intermediate 144 was isolated from the reaction of cyclobutene adduct 143 with stoichiometric Ru-complex 3 and its structure was characterized (Scheme 58). 72% IP HI.' ~'O" ~M e 140 141 + ~'R "~O''M e 142 3 =. 91 One of the phosphine ligands is replaced by a tethered olefin and the alkylidene hydrogen is syn-periplanar to the ruthenium-phosphine bond as shown by both NMR spectroscopy and an X-ray structure. S. Grubbs.).

102. Trost. 109. 2. Rooney. Ring-closing metathesis (RCM) reactions are simple. M. L. Block Coploymers. References 1.. and Pine. Parlier. A. J. (a) Herdson.. Grubbs. Makromol. The authors acknowledge the support of the National Institute of Health for support for the preparation of this review and the research which provided much of the basis of the research discussed. Osborn. H. Sci. Makromol. through either development of new selective catalyst systems or discovering more optimized reaction conditions including modification of substrate types. Rooney. 874-876. A. J.. Osborn. considering the remarkable speed of progress in the area of RCM in the recent years. (d) Kress. Y. 1985. Acknowledgment.. The successful application of olef'm metathesis reactions hinges on the selectivity of the carbon-carbon bond formation.. J. 1991. J. Vol. 5. Chapter 9.. and Mol. V. A. S. and McGrath. 1997. 1983. in The Strem Chemiker. (a) Noshay. Rudler. Although control of stereoselectivity in macrocyclization and cross metathesis is one issue that is yet to be addressed in order to make this strategy more valuable. 1971. J. high-yielding and truly friendly to the environment. 1-6.. 3151. C. Gundiah.. K. J.. Fontanille. Rapid Commun. J.. Olefin Metathesis and Metathesis Polymerization. Grubbs.. M. S. Chem. . Siekermann.. J. Makromol. With improved selectivity. J. some reaction conditions have been disclosed that reduce this selectivity problem. 55. Adv. Ind. reactions involving cross metathesis. J.. 1987..and stereoselectivity can be reliably predicted in ring-opening cross metathesis. 190.. Chang/Tetrahedron 54 (1998) 4413-4450 4445 At this time there are no general rules by which regio. J. Polymer.. Ivin. H. Greene..-L. 1. more significantly in. ring-opening cross metathesis could be a promising area for metathesis chemistry in the near future. J. B. J. C. H. Chauvin. 47. 141. (b) Novak. New York. However. Conclusions and Future Outlook Olefin metathesis is quickly emerging as one of the most powerful strategies for carbon-carbon bond formation. J. Greene. Polymer Sci. Ivin. (c) Kress. (b) Leymet. Newburgport. C. Chem. this selectivity issue should find its solution. Fleming. S. B. Lin. E. 1992. 4. Am. J. (a) Grubbs. p. 1992. (b) Sehrer. Chem. (c) Ivin. Eds. However. J. Soc. Risse. A. W. Chem. R. Chem. 161-176. I. L.. R. Pergamon: New York. No. (a) Warwel. the reactions are highly efficient and provide diverse types of new alkenes which can not be easily obtained with any known chemistry.. J. Commun. I.. Academic Press. H. Res. Paquette. Soc. 2397. therefore.. San Diego. XIV. Academic. M. Vol. R.. R. 3. 6. E. M. A. K. Siove. A. H.-J.R. J. K. R.. S. 1989. R. 899-901. M. in Comprehensive Organic Synthesis. Chem. Strem Chemicals. in some cases. E. 4. Sci. With the advent of the well def'med [Mo] and [Ru] catalyst the early promise of olefm metathesis as a new synthetic strategy is being realized and numerous new aspects of this chemistry have been discovered. J. (b) Schrock. A. Although introduction of substituents on the substrates results in different degrees of cisltrans preferences. The examples discussed above demonstrate that RCM catalysts show the scope and activity required for a generally useful synthetic approach to complex molecules. 1993. (c) Liaw. 1983..3. 31. 250. it is too early to correctly predict the outcomes of the stereoselectivity. Polymer Chem.423. 1977. D. The stereoselectivity of the reaction often varies dramatically rather in a seemingly unpredictable way.

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H. degrees from the University of Florida working with M. from Columbia University for work with Ron Breslow. He received his B. and M. working with Robert H.A. Seoul) under the guidance of Sunggak Kim. Battiste and his Ph.S. Korea.4450 R. His research interests lie in the area of organic and organometallic chemistry. degree from Korea Advanced Institute of Science and Technology (KAIST. S. in 1942. Grubbs Sukbok Chang Robert H. from Korea University and M. After a postdoctoral year with Jim Collman at Stanford he joined the faculty at Michigan State University (1969). Grubbs.S. In 1996. He worked in a chemical company for few years in Korea. KY.D. Grubbs was born near Possum Trot. Chang / Tetrahedron 54 (1998) 4413--4450 Biographical sketch Robert H. . he earned a Ph.S.D. where he is now the Victor and Elizabeth Atkins Professor of Chemistry. In 1978 he moved to California Institute of Technology. Sukbok Chang was born in 1962 in Kangweon Do. degree in chemistry at Harvard University under the guidance of Eric N. He received his B. Grubbs. Jacobsen. He is currently a postdoctoral fellow at Caltech.