Recent Advances in Selective Olefin Metathesis Reactions

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1 Recent Advances in elective lefin tathesis Reactions DIPP TB s i Pr s s i Pr Jeffrey Lipshultz Group eting MacMillan Group January 22, 2015

2 lefin tathesis Initial Discoveries illips Triolefin Process (1964) (C) 6 Al 2, W 3 i 2 Chauvin first proposed metallacyclobutane intermediate (1971) Previously, coordinated quasicyclobutane was widely accepted intermediate W R R' W R R' W R R' W R R' W R R' W R R' Calderon,.; Chen, H.Y.; cott, K.W. Tetrahedron Lett. 1967, 34, Herisson, P.J.-L.; Chauvin, Y. Makromol. Chem. 1971, 141, 161. Heckelsberg, L.F.; Banks, R.L.; Bailey, G.C. Ind. Eng. Chem. Prod. Red. Dev. 1968, 7, 29. Banks, R.L.; Bailey, G.C. Ind. Eng. Chem. Prod. Res. Dev. 1964, 3, 170.

3 lefin tathesis Practical Developments Ring-opening tathesis Polymerization (RMP) orsorex Process for polynorbornene (1980) [W] R R [W] n Ring-closing tathesis (RCM) First applied with in situ prepared W/Ti mixed catalysts W 6 /Cp 2 Ti 2 18% yield R R Tsuji, J.; Hashiguchi,. Tetrahedron Lett. 1980, 21, hm, R.F. Chemtech 1980, 198.

4 lefin tathesis Well-defined Catalysts Ring-opening tathesis Polymerization with Tebbe's Reagent (1986) Living Polymerization Cp 2 Ti Al 2 P Cp 2 Ti Cp 2 Ti n First well-defined Tungsten alkylidene catalysts (1988) et the stage for detailed studies on structure and mechanism Ar Ar ethylene R R W t Bu R W R Gillion, L.R.; Grubbs, R.H. J. Am. Chem. oc. 1986, 108, 733. chrock, R.R.; DePue, R.T.; Feldman, J.; Chaverien, C.J.; Dewan, J.C.; Liu, A.H. J. Am. Chem. oc. 1988, 110, 1423.

5 lefin tathesis obel-prize Winning Catalysts Development of stable -carbene complexes (Grubbs) PCy 3 PCy 3 PCy 3 PCy 3 s s PCy 3 s i Pr s lybdenum and Tungsten alkylidenes (chrock, Hoveyda) DIPP DIPP F 6 - t Bu F 6 - t Bu t Bu DIPP DIPP W F 6 - t Bu F 6 - t Bu Grubbs, R.H. Tetrahedron 2004, 60, chrock, R.R.; Hoveyda, A.H. Angew. Chem. Int. Ed. 2003, 42, 4592.

6 obel Prize in Chemistry award jointly in 2005 lefin tathesis obel-prize Winning Catalysts Prof. Yves Chauvin Prof. Robert Grubbs Prof. Richard chrock "for the development of the metathesis method in organic synthesis"

7 lefin tathesis Talk Breakdown Part 1: Enantioselective (desymmetrizing) olefin metathesis Early asymmetric catalysts utilizing chiral ligands (pre-2008) Recent mechanistic understanding Chiral-at-metal catalysts achieve new success (post-2008) Part 2: Z-selective olefin metathesis Early successes with MAP catalysts The rise of carbometalated catalysts Bidentate anionic ligands unlock full potential of catalysts

8 lefin tathesis Talk Breakdown Part 1: Enantioselective (desymmetrizing) olefin metathesis Early asymmetric catalysts utilizing chiral ligands (pre-2008) Recent mechanistic understanding Chiral-at-metal catalysts achieve new success (post-2008) Part 2: Z-selective olefin metathesis Early successes with MAP catalysts The rise of carbometalated catalysts Bidentate anionic ligands unlock full potential of catalysts

9 lefin tathesis Early Asymmetric Catalyst ystems imple modification of the alcohol ligands on an -catalyst generate chiral catalysts Ar R R Ar t Bu t Bu *-1 Alexander, J.B.; La, D..; Cefalo, D.R.; Hoveyda, A.H.; chrock, R.R. J. Am. Chem. oc. 1998, 120, 4041.

10 lefin tathesis Early Asymmetric Catalyst ystems imple modification of the alcohol ligands on an -catalyst generate chiral catalysts t Bu H H Tf Ar Tf R t Bu Ar t Bu t Bu *-1 Excellent stereochemical transfer to certain substrates Kinetic resolutions and desymmetrizations 3 mol% *-1 C 6 H 6, 22 C, 6h H 86% yield 93% ee Alexander, J.B.; La, D..; Cefalo, D.R.; Hoveyda, A.H.; chrock, R.R. J. Am. Chem. oc. 1998, 120, La, D..; Alexander, J.B.; Cefalo, D.R.; Graf, D.D.; Hoveyda, A.H.; chrock, R.R. J. Am. Chem. oc. 1998, 120, 9720.

11 ther chiral diols could be utilized lefin tathesis Early Asymmetric Catalyst ystems t Bu Ar DIPP Ar t Bu DIPP *-1 *-2 Different chiral diols were optimal for different substrate classes For example, 5 vs. 6 membered rings H 2 i H 2 i *-1 83% yield 99% ee *-2 77% yield 89% ee *-1 17% yield 65% ee *-2 98% yield >99% ee Zhu,..; Cefalo, D.R.; La, D..; Jamieson, J.Y.; Davis, W.M.; Hoveyda, A.H.; chrock, R.R. J. Am. Chem. oc. 1999, 110, 8251.

12 lefin tathesis Early Asymmetric Catalyst ystems imple proposed model DIPP Ar DIPP *-2 DIPP Ar DIPP R "The reason for the inefficiency of 1a in promoting the asymmetric formation of 7... is unclear." Weatherhead, G..; Houser, J.H.; Ford, J.G.; Jamieson, J.Y.; chrock, R.R.; Hoveyda, A.H. Tetrahedron Lett. 2000, 41, Zhu,..; Cefalo, D.R.; La, D..; Jamieson, J.Y.; Davis, W.M.; Hoveyda, A.H.; chrock, R.R. J. Am. Chem. oc. 1999, 110, 8251.

Chiral HCs allow for asymmetric catalysts lefin tathesis Early Asymmetric Catalyst ystems s s PCy 3 R i Pr i Pr PCy 3 R *-1: R=H *-2: R= i Pr -arenes are twisted, enforcing an open/closed geometry i

13 Chiral HCs allow for asymmetric catalysts lefin tathesis Early Asymmetric Catalyst ystems s s PCy 3 R i Pr i Pr PCy 3 R *-1: R=H *-2: R= i Pr -arenes are twisted, enforcing an open/closed geometry i Pr pointed up, away from olefin arene projected down, towards olefin eiders, T.J.; Ward, D.W.; Grubbs, R.H. rg. Lett. 2001, 3, Funk, T.W.; Berlin, J.M.; Grubbs, R.H. J. Am. Chem. oc. 2006, 128, 1840.

14 Chiral HCs allow for asymmetric catalysts lefin tathesis Early Asymmetric Catalyst ystems s s PCy 3 R i Pr i Pr PCy 3 R *-1: R=H *-2: R= i Pr catalysts have similar limited substrate scope but increased tolerance Projecting aryl group and axial ligand combine to enforce geometry i Pr 4 mol% *-1 ai, THF, 40 C H 64% yield 90% ee i Pr H R eiders, T.J.; Ward, D.W.; Grubbs, R.H. rg. Lett. 2001, 3, Funk, T.W.; Berlin, J.M.; Grubbs, R.H. J. Am. Chem. oc. 2006, 128, 1840.

lefin tathesis Early Asymmetric Catalyst ystems Hoveyda explored BIL-derived bidentate HC ligands s s i Pr s R i Pr *-3: R=H *-4: R= Bidentate catalysts capable of RCM, mild success with RCM

15 lefin tathesis Early Asymmetric Catalyst ystems Hoveyda explored BIL-derived bidentate HC ligands s s i Pr s R i Pr *-3: R=H *-4: R= Bidentate catalysts capable of RCM, mild success with RCM Additionally, catalyst is recoverable by chromatography (up to 98%) 10 mol% *-3 Cy Cy THF, 50 C, 1h 60% yield >98% ee Van Veldhuizen, J.J.; Garber,.B.; Kingsbury, J..; Hoveyda, A.H. J. Am. Chem. oc. 2002, 124, Van Veldhuizen, J.J.; Gillingham, D.G.; Garbder,.B.; Kataoka,.; Hoveyda, A.H. J. Am. Chem. oc. 2003, 125,

16 lefin tathesis Theory Informs ynthethis Theoretical studies identify desired reactivity could be achieved thru asymmetrically bound metal R R 1: = 2: = Et R R R R R R R R relative rate = 18: R nfort-olans,.; ot, E.; Copéret, C.; Eisenstein,. J. Am. Chem. oc. 2005, 127, Poater, A.; nfort-olans,.; ot, E.; Copéret, C.; Eisenstein,. J. Am. Chem. oc. 2007, 129, 8207.

17 lefin tathesis Theory Informs ynthethis Theoretical studies identify desired reactivity could be achieved thru asymmetrically bound metal R R 1: = 2: = Et R R R olefins binds trans to better 3.4 σ-donor R 4.2 R R R R R nfort-olans,.; ot, E.; Copéret, C.; Eisenstein,. J. Am. Chem. oc. 2005, 127, Poater, A.; nfort-olans,.; ot, E.; Copéret, C.; Eisenstein,. J. Am. Chem. oc. 2007, 129, 8207.

18 lefin tathesis Theory Informs ynthethis Theoretical studies identify desired reactivity could be achieved thru asymmetrically bound metal R R 1: = 2: = Et R R 3.0 two metathesis R events per new bond = 3.4 double inversion R R R R R R nfort-olans,.; ot, E.; Copéret, C.; Eisenstein,. J. Am. Chem. oc. 2005, 127, Poater, A.; nfort-olans,.; ot, E.; Copéret, C.; Eisenstein,. J. Am. Chem. oc. 2007, 129, 8207.

19 lefin tathesis tate of the Art Chiral Catalysts noalkoxidepyrrolide (MAP) catalysts exhibit enhanced reactivity DIPP C 2 DIPP C 2 CF 3 CF 3 MAP-1 Capable of previously inefficient reactions 1 mol% MAP-1 H C 6 H 6, 1 h H 79% yield previous best: 61% yield, 6h Malcolmson,.J.; ek,.j.; attely, E..; chrock, R.R.; Hoveyda, A.H. ature 2008, 456, 933. attely, E..; ek,.j.; Malcolmson,.J.; chrock, R.R.; Hoveyda, A.H. J. Am. Chem. oc. 2009, 131, 943.

20 lefin tathesis tate of the Art Chiral Catalysts Utilizing an enantiopure monodentate alkoxide ligand generates chiral, diastereomeric catalyst DIPP DIPP C 2 TB MAP*-1 5:1 dr Enantioselective total synthesis of (+)-quebrachamine 1 mol% MAP*-1 H 10 steps C 6 H 6, 1 h H 84% yield, 96% ee 1 step to quebrachamine Malcolmson,.J.; ek,.j.; attely, E..; chrock, R.R.; Hoveyda, A.H. ature 2008, 456, 933. attely, E..; ek,.j.; Malcolmson,.J.; chrock, R.R.; Hoveyda, A.H. J. Am. Chem. oc. 2009, 131, 943.

21 lefin tathesis tate of the Art Chiral Catalysts Utilizing an enantiopure monodentate alkoxide ligand generates chiral, diastereomeric catalyst DIPP DIPP C 2 TB MAP*-1 5:1 dr Very limited scope H 91% yield, 93% ee 89% yield, 67% ee 98% yield, 92% ee 86% yield, 93% ee 7 years later, this remains state of the art Malcolmson,.J.; ek,.j.; attely, E..; chrock, R.R.; Hoveyda, A.H. ature 2008, 456, 933. attely, E..; ek,.j.; Malcolmson,.J.; chrock, R.R.; Hoveyda, A.H. J. Am. Chem. oc. 2009, 131, 943.

22 lefin tathesis Talk Breakdown Part 1: Enantioselective (desymmetrizing) olefin metathesis Early asymmetric catalysts utilizing chiral ligands (pre-2008) Recent mechanistic understanding Chiral-at-metal catalysts achieve new success (post-2008) Part 2: Z-selective olefin metathesis Early successes with MAP catalysts The rise of carbometalated catalysts Bidentate anionic ligands unlock full potential of catalysts

23 lefin tathesis First Z-selective Catalysts Bulky aryloxide ligand of MAP complexes imparts excellent steric control TB DIPP TB Adm MAP*-1 5:1 dr MAP*-2 3:1 dr ize differential between aryloxide and imido substituent key factor Adm<DIPP better kinetic control Malcolmson,.J.; ek,.j.; attely, E..; chrock, R.R.; Hoveyda, A.H. ature 2008, 456, 933. Ibrahem, I.; Yu, M.; chrock, R.R.; Hoveyda, A.H. J. Am. Chem. oc. 2009, 131, 3844.

24 lefin tathesis First Z-selective Catalysts Bulky aryloxide ligand of MAP complexes imparts excellent steric control TB DIPP TB Adm MAP*-1 5:1 dr MAP*-2 3:1 dr ize differential between aryloxide and imido substituent key factor no observed product 5 mol% MAP*-1 10 eq. styrene C 6 H 6, 1h TB 1 mol% MAP*-2 2 eq. styrene C 6 H 6, 1h TB 80% yield, 90% ee > 98% Z Malcolmson,.J.; ek,.j.; attely, E..; chrock, R.R.; Hoveyda, A.H. ature 2008, 456, 933. Ibrahem, I.; Yu, M.; chrock, R.R.; Hoveyda, A.H. J. Am. Chem. oc. 2009, 131, 3844.

25 lefin tathesis First Z-selective Catalysts difiable monodentate alkoxide and -substituent allow for substantial catalyst diversity Br TB DIPP Br Br TB Adm Br Br TB DMP Br MAP*-3 5:1 dr MAP*-4 3:1 dr MAP*-5 5:1 dr Extension of RCM chemistry to CM, including with enol ethers Bu 10 equiv. 2.5 mol% cat. Bn Bu C 6 H 6, 2h substantial enol ether and α-olefin scope cat conv Z % MAP*-3 47 >98 MAP*-4 37 >98 MAP* % yield Malcolmson,.J.; ek,.j.; attely, E..; chrock, R.R.; Hoveyda, A.H. ature 2008, 456, 933. ek,.j.; 'Brien, R.V.; Llaveria, J.; chrock, R.R.; Hoveyda, A.H. ature 2011, 471, 461.

26 lefin tathesis First Z-selective Catalysts difiable monodentate alkoxide and -substituent allow for substantial catalyst diversity Br TB DIPP Br Br TB Adm Br Br TB DMP Br MAP*-3 5:1 dr MAP*-4 3:1 dr MAP*-5 5:1 dr Extension of RCM chemistry to CM, including with protected allylic amines Bn Bn Boc 2 Bn Bn Bn C 14 H 29 5 equiv. C 14 H 29 8 mol% MAP*-4 C 6 H 6, 22 C, 5h, 1 torr H H H C 25 H 51 H H H H H 29 C 14 Boc 2 Bn Bn Bn 4 steps, 74% yield 85% yield 96% Z KR7000 Malcolmson,.J.; ek,.j.; attely, E..; chrock, R.R.; Hoveyda, A.H. ature 2008, 456, 933. ek,.j.; 'Brien, R.V.; Llaveria, J.; chrock, R.R.; Hoveyda, A.H. ature 2011, 471, 461.

27 lefin tathesis First Z-selective Catalysts BIL-derived catalysts still find use for selective formation of Z-vinyl boronates via CM Br TB DIPP Br Br TB Adm Br Br TB DMP Br MAP*-3 5:1 dr MAP*-4 3:1 dr MAP*-5 5:1 dr Different -substituent for differnt α-olefin coupling partners (pin)b B(pin) R 60%, 97% Z Bu B(pin) 5 mol% MAP*-5 5 equiv. vinyl-bpin 1 equiv. R B(pin) 3 mol% MAP*-4 1 equiv. vinyl-bpin 5 equiv. Ar B(pin) R=, 69%, 93% Z 80%, 93% Z R= CF 3, 93%, 95% Z Kiesewetter, E.T.; 'Brien, R.V.; Yu, E.C.; ek,.j.; chrock, R.R.; Hoveyda, A.H. J. Am. Chem. oc. 2013, 135, 6026.

28 lefin tathesis First Z-selective Catalysts Catalytic generation of Z-alkenyl boronate esters to enable a total synthesis disorazole C 1 H H Br TB DMP Br MAP*-5 5:1 dr TB 10 mol% MAP*-5 7 equiv. vinyl-bpin TB B(pin) I I 91% yield, >98% Z peed, A.W.H.; Mann, T.J.; 'Brien, R.V.; chrock, R.R.; Hoveyda, A.H. J. Am. Chem. oc. 2014, 136,

29 lefin tathesis impler MAP Catalysts If sterics of the alkoxide vs. imide are determining factor, why use chiral alcohols? Br TB Adm Br Trip Adm M Trip MAP*-4 3:1 dr M=, MAP*-6 M= W, MAP*-7 teric bulk of 2,6-Trip phenoxide ligand is sufficient for Z control 2 C 2 mol% MAP*-6 2 C C 2 2 C 2 C C 2 >99% Z, >99% syndiotactic Flook, M.M.; Jiang, A.J.; chrock, R.R.; Müller, P.; Hoeyda, A.H. J. Am. Chem. oc. 2009, 131, 7962.

30 lefin tathesis impler MAP Catalysts Application towards the total synthesis of nakadomarin A by Z-selective RCM Adm Ar M M=, MAP*-6 M= W, MAP*-7 Ar W t Bu MAP*-8 H H 5 mol% MAP*-8 tol (1 mm), 8h nakadomarin A 63% yield, 94% Z Wang, C.; Yu, M.; Kyle, A.F.; Jakubec, P.; Dixon, D.J.; chrock, R.R.; Hoveyda, A.H. Chem. Eur. J. 2013, 19, 2726.

31 lefin tathesis Cyclometalated Catalysts CH activation leads to a surprisingly active and selective class of catalysts s s 2 PivAg Piv s Piv -PivH s Piv i Pr i Pr i Pr CMR-1 Endo, K.; Grubbs, R.H. J. Am. Chem. oc. 2011, 133, 8525.

32 lefin tathesis Cyclometalated Catalysts CH activation leads to a surprisingly active and somewhat selective class of catalysts s Piv s Piv i Pr CMR-1 i Pr CMR-2 Highly promising levels of Z selectivity in CM and homodimerization Ac Ac 5 mol% CMR-2 THF/H 2, reflux, 4h Ac 64% conv 87% Z (pin)b 2 mol% CMR-2 THF, 35 C, 4h (pin)b B(pin) 74% yield >95% Z Endo, K.; Grubbs, R.H. J. Am. Chem. oc. 2011, 133, Keitz, B.K.; Endo, K.; Herbert, M.B.; Grubbs, R.H. J. Am. Chem. oc. 2011, 133, 9686.

33 lefin tathesis Cyclometalated Catalysts Computational and mechanistic understanding elucidates important aspects of Z selective catalysts s Piv CMR-2 i Pr Liu, P.; u,.; Dong,.; Keitz, B.K.; Herbert, M.B.; Grubbs, R.H.; Houk, K.. J. Am. Chem. oc. 2012, 134, 1464.

clash with -s methyl Liu, P.; u,.; Dong,.; Keitz, B.K.; Herbert, M.

34 lefin tathesis Cyclometalated Catalysts ide-bound transition state favors Z geometry over E geometry steric clash with -s methyl Liu, P.; u,.; Dong,.; Keitz, B.K.; Herbert, M.B.; Grubbs, R.H.; Houk, K.. J. Am. Chem. oc. 2012, 134, 1464.

35 lefin tathesis ptimized Cyclometalated Catalysts wapping bidentate ligands and varying arenes on HC yielded ideal catalyst Ar Ar t Bu i Pr i Pr Ar=s, CMR-3 Ar=DIPP, CMR-4 CMR-2 itrate ligand proved to be key to unlocking full potential Z-selective RMP 0.3 mol% CMR-3 THF, -20 C 80% yield, 91% Z Rosenbrugh, L.E.; Herbert, M.B.; Marx, V.M.; Keitz, B.K.; Grubbs, R.H. J. Am. Chem. oc. 2013, 135, Marx, V.M.; Herbert, M.B.; Keitz, B.K.; Grubbs, R.H. J. Am. Chem. oc. 2013, 135, 94. Keitz, B.K.; Fedorov, A.; Grubbs, R.H. J. Am. Chem. oc. 2012, 134, Keitz, B.K.; Endo, K.; Patel, P.R.; Herbert, M.B.; Grubbs, R.H. J. Am. Chem. oc. 2012, 134, 693.

36 lefin tathesis ptimized Cyclometalated Catalysts wapping bidentate ligands and varying arenes on HC yielded ideal catalyst Ar Ar t Bu i Pr i Pr Ar=s, CMR-3 Ar=DIPP, CMR-4 CMR-2 itrate ligand proved to be key to unlocking full potential Z-selective homodimerization H 0.1 mol% CMR-4 H H THF, 35 C 77% yield, >95% Z Rosenbrugh, L.E.; Herbert, M.B.; Marx, V.M.; Keitz, B.K.; Grubbs, R.H. J. Am. Chem. oc. 2013, 135, Marx, V.M.; Herbert, M.B.; Keitz, B.K.; Grubbs, R.H. J. Am. Chem. oc. 2013, 135, 94. Keitz, B.K.; Fedorov, A.; Grubbs, R.H. J. Am. Chem. oc. 2012, 134, Keitz, B.K.; Endo, K.; Patel, P.R.; Herbert, M.B.; Grubbs, R.H. J. Am. Chem. oc. 2012, 134, 693.

37 lefin tathesis ptimized Cyclometalated Catalysts wapping bidentate ligands and varying arenes on HC yielded ideal catalyst Ar Ar t Bu i Pr i Pr Ar=s, CMR-3 Ar=DIPP, CMR-4 CMR-2 itrate ligand proved to be key to unlocking full potential Z-selective macrocyclic RCM 7.5 mol% CMR-3 DCE, 60 C, 20 mtorr 75% yield 94% Z Rosenbrugh, L.E.; Herbert, M.B.; Marx, V.M.; Keitz, B.K.; Grubbs, R.H. J. Am. Chem. oc. 2013, 135, Marx, V.M.; Herbert, M.B.; Keitz, B.K.; Grubbs, R.H. J. Am. Chem. oc. 2013, 135, 94. Keitz, B.K.; Fedorov, A.; Grubbs, R.H. J. Am. Chem. oc. 2012, 134, Keitz, B.K.; Endo, K.; Patel, P.R.; Herbert, M.B.; Grubbs, R.H. J. Am. Chem. oc. 2012, 134, 693.

38 lefin tathesis ptimized Cyclometalated Catalysts wapping bidentate ligands and varying arenes on HC yielded ideal catalyst Ar Ar t Bu i Pr i Pr Ar=s, CMR-3 Ar=DIPP, CMR-4 CMR-2 itrate ligand proved to be key to unlocking full potential Z-selective and chemoselective cross metathesis H 7 1 mol% CMR-4 THF, rt, 5h 7 H 1 equiv. 7 equiv. 5 equiv. 1 equiv. 45% yield, >95% Z 66% yield, >95% Z Cannon, J..; Grubbs, R.H. Angew. Chem. Int. Ed. 2013, 52, 9001.

39 lefin tathesis ptimized Cyclometalated Catalysts Highly enabling technology for total synthesis of complex molecules Vanderwal's synthesis of myltilipin A in 7 steps H 1. 2, Et 4 2. DMP H ; Br AlEt 2 ah 45% yield (3 steps) 30 mol% Br 1. Mg; DMF 2. Cr 2 s 51% yield (2 steps) i Pr BF 3, Et 4 2. Et pyr 5 58% yield (3 steps) 32%, >95% Z Chung, W.; Carlson, J..; Bedke, D.K.; Vanderwal, C.D. Angew. Chem. Int. Ed. 2013, 52,

40 lefin tathesis Enantiopure Carbometalated Catalysts Chirality at center can be resolved by classical resolution s I i Pr s i Pr s i Pr separation of diastereomers CMR*-3 Chiral-at- CMR catalysts can provide excellent asymmetric induction Z-selective enantioselective RCM Bn Bn 7 equiv. HBoc 1 mol% CMR*-3 THF, 23 C Bn Bn HBoc brand new technology, still developing 41% yield, 95% Z, 94% ee Hartung, J.; Grubbs, R.H. J. Am. Chem. oc. 2013, 135, Hartung, J.; Dornan, P.K.; Grubbs, R.H. J. Am. Chem. oc. 2014, 136,

lefin tathesis Bidentate Anionic LIgands thenium catalysts with aryl thiolate ligand show promise for Z-selective CM s s K s Ar s i Pr i Pr Very mild Z-selectivities, and only at low conversion 5 0.

41 lefin tathesis Bidentate Anionic LIgands thenium catalysts with aryl thiolate ligand show promise for Z-selective CM s s K s Ar s i Pr i Pr Very mild Z-selectivities, and only at low conversion mol% cat THF, 40 C % conv, 86% Z 45% conv, 81% Z 64% conv, 75% Z Rate-limiting cyclobutane reversion, favors cis by ~ 1.2 kcal/mol s s s s Ar R Ar R R R cchipinti, G.; Hansen, F.R.; Tornroos, K.W.; Jensen, V.R. J. Am. Chem. oc. 2013, 135, cchipinti, G.; Koudriavtsev, V..; Tornroos, K.W.; Jensen, V.R. Dalton Trans. 2014, 43, elson, J.W.; Grundy, L.M.; Dang, Y.; Wang, Z.-.; Wang,. rganometallics 2014, 33, 4290.

i Pr DT-2 Design principle: tie back small anionic ligands, allow for bulky HC

42 lefin tathesis Bidentate Anionic LIgands Utilizing dithiolate (bidentate) ligands proves to be key for control s s C C i Pr DT-1 a C a C s i Pr s a a s s i Pr DT-2 Design principle: tie back small anionic ligands, allow for bulky HC to control DT-2 Khan, R.K.M.; Torker,.; Hoveyda, A.H. J. Am. Chem. oc. 2013, 135,

43 lefin tathesis Bidentate Anionic LIgands Utilizing dithiolate (bidentate) ligands proves to be key for control s s C C i Pr DT-1 a C a C s i Pr s a a s s i Pr DT-2 Excellent reactivity and perfect selectivity for RMP 0.1 mol% cat DCM, rt, 1h DT-1: 90% yield, >98% Z DT-2 : 93% yield, >98% Z 0.1 mol% cat DCM, rt, 24h DT-1: 75% yield, >98% Z DT-2: 75% yield, >98% Z Khan, R.K.M.; Torker,.; Hoveyda, A.H. J. Am. Chem. oc. 2013, 135,

44 lefin tathesis Bidentate Anionic LIgands Utilizing dithiolate (bidentate) ligands proves to be key for control s s C C i Pr DT-1 a C a C s i Pr s a a s s i Pr DT-2 Z-selective RCM are also highly efficient H H 20 equiv. 1 mol% DT-2 THF, rt, 1h H H 92% yield 97% Z H H 10 equiv. 2 mol% DT-2 DCM, rt, 2h H H = Bu, 95%, 98% Z = Et, 80%, 92% Z Koh, M.J.; Khan, R.K.M.; Torker,.; Hoveyda, A.H. Angew. Chem. Int. Ed. 2014, 126, Khan, R.K.M.; Torker,.; Hoveyda, A.H. J. Am. Chem. oc. 2013, 135,

45 lefin tathesis Bidentate Anionic LIgands Utilizing dithiolate (bidentate) ligands proves to be key for control s s C C i Pr DT-1 a C a C s i Pr s a a s s i Pr DT-2 Computational support for simple stereochemical model Khan, R.K.M.; Torker,.; Hoveyda, A.H. J. Am. Chem. oc. 2013, 135,

46 lefin tathesis Bidentate Anionic LIgands Limited in ability to perform CM with allyl alcohols - only can do RCM efficiently 3 mol% s s H H H i Pr 9h, 50% conv 42% yield, 98% Z o further conversion implies decomposition of catalyst... s s s s 1,2 shift likely deactivates catalyst R 1 H R 1 R strong σ-donor (HC) = large trans inf large trans inf = electron rich apical R electron deficient groups on -arene? Koh, M.J.; Khan, R.K.M.; Torker,.; Yu, M.; Mikus, M..; Hoveyda, A.H. ature 2015, /nature14061.

47 lefin tathesis Bidentate Anionic LIgands re stable dithiolate catalysts allow for broader substrate scope 5 mol% s s H H H DT-3 i Pr 9h, 84% conv 71% yield, 96% Z Excellent scope - extremely broad functional group tolerance H H 8 H H 3 H 4h, 72% conv 64% yield, 96% Z 4h, 86% conv 80% yield, 94% Z 4h, 85% conv 70% yield, 96% Z H Ac H 4h, 77% conv 68% yield, 98% Z H 8h, 72% conv 63% yield, 92% Z H c 12h, 85% conv 70% yield, 98% Z H Koh, M.J.; Khan, R.K.M.; Torker,.; Yu, M.; Mikus, M..; Hoveyda, A.H. ature 2015, /nature14061.

48 Current tate-of-the-art: lefin tathesis What's ext? enantioselective Z-selective TB DIPP s s i Pr decomposes readily very poor generality What's coming in the next 5 years? s Is kinetic E-selecitivity possible? i Pr broader scope for ee?

49 lefin tathesis Useful references Marx, V.M.; Rosebrugh, L.E.; Herbert, M.B.; Grubbs, R.H. Top. rganomet. Chem. 2014, 48, 1. Hoveyda, A.H. J. rg. Chem. 2014, 79, Fürstner, A. cience, 2013, /science

New perspectives in metal-catalyzed metathesis: Alkyne and Z-selective olefin metathesis, new powerful tools for total synthesis

New perspectives in metal-catalyzed metathesis: Alkyne and Z-selective olefin metathesis, new powerful tools for total synthesis Ophélie Quinonero Literature - Group Meeting 31/03/2014 1 Introduction Metathesis: