lefin Metathesis MP: ing-opening metathesis polymerization Thermodynamically favored for 3,4, 8, larger ring systems Bridging groups (bicyclic olefins) make ΔG polymerization more favorable as a result of strain. MP n L n u= MP L n u= n CM:ing closing Metathesis CM L n u= dilute + 2 C=C 2 The reaction can be driven to the right by the loss of ethylene igh dilution conditions favor CM vs. olefin polymerization. The development of well-defined metathesis catalysts tolerant of many functional groups yet reactive toward a diverse array of substrates has led to to rapid aceptance of the CM reaction as a powerful tool for C-C bond formation and macrocyclization. Where the thermodynamics of ring closure are unfavorable, olefin polymerization takes place.
F 3 C F 3 C Mo 3 C F 3 C F 3 C C 3 C 3 C 3 P(c-ex) 3 u P(c-ex) 3 P(c-ex) 3 u P(c-ex) 3 1-Mo 2-u 3-u 1-Mo, 2-u, and 3-u are the most widely used catalysts for olefin metathesis Schrock s 1-Mo is more reactive toward a broad range of substrates, but has poor functional group tolerance, sensitivity to air, moisture, solvent impurities, and thermal instability. Grubb s 2- and 3-u have high reactivity in MP and CM and show a remarkable tolerance to a wide variety of functional groups asily prepared: u 2 (P 3 ) 3 + 2 = C 2 2 P 3 u P 3 P(c-ex) 3 C 2 2 3-u little sensitivity to air or moisture requires electron-rich ligands (P(c-ex) 3 )for increased activity JACS, 1993, 9858
A Dissociative Mechanism has been proposed: JACS, 1997, 3887. JACS, 1975, 3265. t 2 C C 2 t P(c-ex) 3 u P(c-ex) 3 5 mol% CD 2 2, 25 C t 2 C C 2 t P(c-ex) 3 u P(c-ex) 3 18e complex -P P(c-ex) 3 P(c-ex) 3 P(c-ex) 3 u u u 16e complex [2+2] metallacyclo butane -C 2 4 P(c-ex) 3 P(c-ex) 3 u P(c-ex) 3 vidence for phosphine dissociation: addition of one equivalent of phosphine decreases rate by 20 times u [2+2] P(c-ex) 3 u P(c-ex) 3 +P P(c-ex) 3 u P(c-ex) 3 u
Catalytic CM of dienes by 2-u substrate product yield Boc Boc 91 5,6,7-membered oxygen and nitrogencontaining heterocycles and cycloalkanes are formed efficiently 84 72 catalyst 2-u is stable to acids, alcohols, and aldehydes Free amines are not tolerated by ruthenium catalysts; the corresponding hydrochloride salts undergo efficient CM with 2-u 2 C - + 2-u C 2 2 a =C 2 87 =C 82 =C 2 88 Conditions: substrate + 2-4mol% 2-u, C 6 6, 20 C
For Tri- and Tetrasubstituted lefins, Catalyst 1-Mo is better substrate product yield 3-u yield 1-Mo =C 3 93 100 = 96 = 25 97 3 C C 3 93 3 C C 3 3 C C 3 C 3 C 3 conditions, 5mol% catalyst, 0.1M, C 6 6 61 JC, 1997, 7310 The standard "Thorpe-Ingold" effect favors cyclizations with gem-disubstituted substrates: 1mol% 1-Mo 25 C = 0% =C 3 95% JACS, 1992, 10978
ecyclable and Water-Soluble Catalysts u P(c-ex) 3 4-u JACS, 1999, 791 P u P (C 3 ) 3 + - 5-u (C 3 ) 3 + - P u P C 3 C 2 C 3 C 3-6-u - JC, 1998, 9904 Catalyst u-4 offers excellent stability to air and moisture and can be recycled in high yield by silica gel chromatography. Alkylidenes 5-u and 6-u are water-soluble u-based metathesis catalysts that are stable for days in methanol or water at 45 C. Although 3-u is highly active for CM of dienes in organic solvents, it has no catalytic activity in protic media: t 2 C C 2 t 5 mol% 3-u 25 C t 2 C C 2 t solvent: C 2 2 100% C 3 <5%
5 mol% Substrate Product solvent catalyst yield recovered catalyst% TBS TBS C 2 2 4-u 90 75 Ts Ts C 2 2 4-u 99 88 Ts Ts C 2 2 4-u 72 88 C 3 5-u 6-u 80 95 C 3 6-u >95 Boc Boc C 3 5-u 30 6-u >95 Alkylidene 6-u is a significantly more active catalyst than alkylidene 5-u, because of the more electron-rich phosphines in 6-u Substitution of one of the two terminal olefins in the substrate with a phenyl group leads to regeneration of the benzylidene catalyst, which is far more stable than the methylidene catalyst in methanol cis-olefins are more reactive in CM than the corresponding trans-olefins
xample: (C 3 ) 3 + - 10 mol% 6-u (C 3 ) 3 + - Mechanism: 2 90% L n u= methylidene, = benzylidene, = L n u L n u= ul n L n u enyl substitution within the starting material can also greatly increase the yield of CM in organic solvents: - - 5 mol% 3-u C 2 2 = 60% = 100%
Macrocyclizations and pre-organization n=1,2 n 5 mol% 3-u "template" C 2 2, 45 C n n template yield cis:trans 1 none 39 38:62 1 Li 4 >95 100:0 2 none 57 26:74 2 Li 4 89 61:39 Preorganization of the linear polyether about a complementary metal ion can enhance CM In general, ions that function best as templates also favor formation of the cis isomer. ACI, 1997, 1101. Although interactions that increase substrate rigidity (i.e. intramolecular hydrogen bonding) and reduce the entropic cost of cyclization can be beneficial in CM, it is not a strict requirement for macrocyclization by CM. See: JACS, 1996, 9606.; JACS, 1995, 2108; JACS, 1995, 5855.
CM of enol ethers: 3 C 12 mol% 1-Mo 88% 12 mol% 1-Mo 97% nly catalyst 1-Mo is effective for metathesis of these substrates JC, 1994, 4029 JACS, 1996, 10335 ing-opening, ing osing Metathesis 3-u 3mol% 0.1M 90% JACS, 1996, 6634. 3-u 6mol% 0.04M 68% 6 mol% 3-u 0.12 M 16% 0.008M 73% Without sufficient strain in the starting olefin, competing oligomerization can occur igher dilution favors the intramolecular reaction
Mechanism: L n u=c L n u=c 2 L n u ul n ul n Initial Metathesis of the acyclic olefin is supported by the fact that substitution of this olefin decreases the rate of metathesis
Catalytic, nantioselective CM Sit 3 5mol% Sit 3 Sit 3 3 C Mo C 3 3 C 3 C C 3 C 3 8-Mo 8-Mo JC, 1998, 824 JACS, 1996, 2499 19%, >99%ee + 43%, 93%ee JACS, 1998, 4041 Diastereodifferentiation occurs during formation or breakdown of the metallabicyclobutane intermediates 3 C Ar 3 C Mo 3 C C 3 3 C 3 C Favored Sit 3 3 C Ar 3 C Mo 3 C C 3 3 C 3 C Disfavored Sit 3
3 C C 3 3 C 3 C Mo C 3 C 3 8-Mo =ipr 9-Mo =Me 3 C Catalytic, nantioselective Desymmetrization: 5mol% 8-Mo 3 C + 3 C % conversion SM ee (%) n-c 5 11 63 92% c-c 6 11 62 98% C 6 5 56 75% increasing the size of the alpha-substitutent leads to greater selectivity; neither 8-Mo nor 9-Mo resolve disubstituted alkenes 3 C C 3 1-2mol% 9-Mo Works for tertiary allylic ethers with 9-Mo: 3 C 3 C =, 85%, 93%ee =C 3, 93%, 99%ee 5 mol% 9-Mo 91%, 82%ee JACS, 1998, 4141 JACS, 1998, 9720
Dienyne Metathesis n m L n M n m n m ML n n m Sit 3 3-5mol% 2-u Sit 3 yield >98 C 3 95 ipr 78 96 reaction rates decrease as the size of the alkyne substituent increases JC, 1996, 1073. substrate product yield M Sit 3 83% 0.03M Sit 3 C 3 Sit 3 C 3 t 3 Si 78% 0.001M ote: regiochemical control within unsymmetrical substrates is achieved by substitution of the olefin required to undergo metathesis last. Unsymmetrical substrates containing equally reactive olefins produce mixtures of products: Sit 3 Sit 3 + t 3 Si C 3 C 3 C 3 C 3 86%, 1:1 C 3
Cross Metathesis Bz 7 + "olefin" 5 mol% 3-u Bz 7 "olefin" yield :Z Ac Ac Ac 89 4.7:1 tbu tbu 90 7:1 The use of disubstituted olefins in cross-metathesis minmizes the formation of a methylidene intermediate (Lnu=C 2 ) which is a less stable catalyst. The disubstituted alkene may be used as solvent to increase the yield of cross metathesis Procedure: a. homodimerize the more readily available terminal olefin, and b. use two equivalents of this homodimer in cross metathesis with the more valuable terminal olefin Ac Bn Bn Bn Bn 7 0.3 mol% 3-u + Ac 7 7 Ac Ac 7 7 Ac Bn Bn 5 mol% 3-u Bn Bn TL 1998, 7427. 73%; :Z 3:1 Ac
ew u-based Catalysts Mes Mes u P(c-ex) 3 Mes Mes u P(c-ex) 3 Mes Mes u P(c-ex) 3 most reactive u-based catalysts to date 10-u 11-u 12-u substrate product 10-u 11-u 12-u tbu 100 100 100 3 C C 3 40 31 55 3 C 3 C C 3 95 90 87 C 3 C 3 C 3 L, 1999, 953 TL, 1999, 2247
Metathesis of Alkynes and Diynes 3 C Mo C 3 3 C C 3 14-Mo C 3 C 3 C 2 2 3 C Mo C 3 3 C C 3 15-Mo C 3 C 3 C 3 14-Mo (10mol%) C 2 2, toluene Substrate Product Yield (%) C 3 C 3 91 88 = 60% =C 58% Catalyst 15-Mo is tolerant of diverse functional groups: esters, amides, thioethers, and basic nitrogen atoms. JACS, 1999, 9453.
Cross-Metathesis of Functionalized lefins Mes Mes Bn A Ac B u P(c-ex) 3 C 3 C 3 13-u Functionalized lefin Alkene Product Yield :Z A B B B Bn Ac Ac Ac Si(t) 3 B Ac 91 4.5:1 C 3 92 >20:1 62 1.1:1 55 5:1 Si(t) 3 81 11:1 JACS, 2000, 3783.
CM of Functionalized dienes Diene Product Yield C 3 86 93 97 conditions: 5 mol% 13-u JACS, 2000, 3783. Substrates containing both allyl and vinyl ethers provide CM, while no products are observed if vinyl ethers alone are present!,"-unsaturated lactones and enones of various ring sizes are produced in good to excellent yields
Cross Metathesis of thylene and Alkynes 11-u outperforms 3-u in both rate and overall conversion: Substrate Product Yield = 73 =Ac 92 =TBS 91 Ac Ac Ac Ac 69 Ts Ts 91 conditions: 5mol% 11-u at 60 psi of ethylene pressure 11-u can tolerate free hydroxyl groups and coordinating functionality at propargylic and homopropargylic positions Chiral propargylic alcohols afford chiral diene products without loss of optical purity: 99%ee 11-u (5 mol%) ethylene (60 psi) 99%ee
nyne Metathesis eactions Catalyzed by Pt 2 Substrate Product Yield 2 S S 2 2 S S 2 96% Me 2 C 70% C 3 Ts Ts 80% conditions: 4-10mol% Pt 2, 80 C, toluene JACS, 2000, 6785. emote alkenes are not affected commercial Pt 2 used.