Recent Developments of the Morita-Baylis-Hillman Reaction

ecent Developments of the Morita-Baylis-illman eaction EWG 1 X 2 Catalyst 1 2 X! EWG X =, Erin Stache December 6, 2010 3rd Year Seminar

Basavaiah, D.; ao, A. J.; Satyanarayana, T. Chem. ev. 2003, 103, 811-891. Basavaiah, D.; eddy, B. S.; Badsara, S. S. Chem. ev. 2010, 110, 5447-5674.

rigins of the Morita-Baylis-illman (MB) eaction Morita 1968 C 2 PCy 3, 0.6 mol % dioxane, 125 C, 2h C 2 23% conversion Baylis and illman 1972 C 2 Et DABC 5 mol % neat, 7d, 23 C C 2 Et 93% conversion Morita, K.; Kobayashi, T. Bull. Chem. Soc. Jpn. 1968, 42, 2732. Baylis, A. B.; illman, M. E. D. German patent 2155113, 1972.

Features of the MB eaction EWG 1 X 2 Catalyst 1 2 X! EWG X =, 2 component coupling to form carbon-carbon bonds activated alkene component C 2 C C C 2 S 2 n X X = C 2,, S electrophiles are typically carbonyl components, but can also be Michael acceptors 2 2 = or C 2 aza-mb EWG catalysts consist of trialkyl amines or trialkyl, -aryl phosphines, although some Lewis acids are used in conjunction Basavaiah, D.; ao, A. J.; Satyanarayana, T. Chem. ev. 2003, 103, 811-891. Basavaiah, D.; eddy, B. S.; Badsara, S. S. Chem. ev. 2010, 110, 5447-5674.

Complications Associated with MB Very slow reaction rates C 2 DABC neat, 23 C, 6 d C 2 89% More electron rich aromatic aldehydes less reactive eactive substrates lead to dimerized products C DABC p- 2 C C C p- 2 DMF, 20 C 60-70 h C 76% 15% o traditional MB product observed Caubere, P.; Fort, Y.; Berthe, M. C. Tetrahedron 1992, 48, 6371-6384. Shi, M.; Ma, G.-.; Jiang, J.-J.; Wei, Y. Chem. Commun. 2009, 5496-5514.

Synthetic Challenges Associated with MB Asymmetric Induction S C, DABC C 2 Cl 2, 0 C, 12 h 85%, 99% ee Esoteric substrates give high selectivity Previous attempts with chiral amines, aldehydes, and acrylates unsuccessful Intramolecular MB C 2 Et PBu 3, 23 C, 1 d C 2 Et 75% conversion First example of an intramolecular MB Employing different electrophiles and exploring scope of the reaction Leahy, J. W.; Brzezinski, L. J.; afel, S. J. Am. Chem. Soc. 1997, 119, 4317-4318 Fráter, G.; oth, F.; Gygax, P. Tetrahedron Lett. 1992, 33, 1045-1048.

chanism of the MB eaction Initial chanistic ypothesis 1 3 1 3 2 DS 3 1 2 DS is addition into aldehyde, followed by an intermolecular proton transfer and catalyst expulsion 1 (D) stabilizing effect 2 k rel = 1 k rel = 7.4 1 KIE of 1.3 observed with D-hydroxyquinuclidine in CDCl 3 ill, J. S.; Isaacs,. S. Tetrahedron Lett. 1986, 41, 5007-5010. Kaye, P. T.; Bode, M. L. Tetrahedron Lett. 1991, 32, 5611-5614. Caubere, P.; Fort, Y.; Berthe, M. C. Tetrahedron, 1992, 48, 6371-6384.

chanistic ationale Does ot Explain... DABC (15 mol %) ' neat, 23 C ' t-bu Cl 3 C 7 d, 89% 20 h, 55% 6 d, 39% eaction rates dependent upon electronics and size of components PBu 3 (20 mol %) TF, 23 C, 1 h 1.5 equiv 23% Yield quantitative with addition of 2-naphthyl alcohol (20 mol %) offmann,. M..; abe, J. Angew. Chem. Int. Ed., Engl. 1983, 22, 795-796. Ikegami, S.; Yamada, Y. M. A. Tetrahedron Lett. 2000, 41, 2165-2169.

chanism Also Does not Explain... C 2 5 equiv (cat) neat, 2-24 h, 23 C bservation of dioxanone product questions proton transfer C 2 = 0% 57% = i-pr = (1 equiv) 0% 95% 0% 52% 3 C 2 3 C 3 C C 2 - - 3 3 Perlmutter, P.; Puniani, E.; Westman, G. Tetrahedron Lett. 1996, 37, 1715-1718.

evised MB chanism Supported by Data 2nd order in aldehyde-2 equivalents in DS 1st order in acrylate-1 equivalent in DS 1st order in DABC-1 equivalent in DS Ar Ar Ar Ar Ar Ar Ar DS Ar Ar McQuade, D. T.; Price, K. E.; Broadwater, S. J.; Jung,. M. rg. Lett. 2005, 7, 147-150. McQuade, D. T.; Price, K. E.; Broadwater, S. J.; Walker, B. J. J. rg. Chem. 2005, 70, 3980-3987.

evised MB chanism Supported by Data 1 KIE of 5.2 in DMS with p-nitrobenzaldehyde 1 KIE of 2.2 in CCl 3 with p-nitrobenzaldehyde Decrease of 1 KIE a function of!pk a of alkoxide and "-proton (D) Ar Ar 1 KIE Ar Ar Ar Ar Ar DS Ar Ar McQuade, D. T.; Price, K. E.; Broadwater, S. J.; Jung,. M. rg. Lett. 2005, 7, 147-150. McQuade, D. T.; Price, K. E.; Broadwater, S. J.; Walker, B. J. J. rg. Chem. 2005, 70, 3980-3987.

Another Look at the MB chanism PBu 3 (20 mol %) TF, 23 C 1 h 1.5 equiv 23% Yield quantitative with addition of 2-naphthyl alcohol (20 mol %) 2 1 3 1 3 1 DS step 2 3 or C 2 1 3 1 EWG 3 DS step 3 Ikegami, S.; Yamada, Y. M. A. Tetrahedron Lett. 2000, 41, 2165-2169. Aggarwal, V. K.; Lloyd-Jones, G. C.; Fulford, S. Y. Angew. Chem. Int. Ed. 2005, 44, 1706-1708.

Another Look at the MB chanism 2 1 or 3 2 EWG Competition experiment between d-ethyl acrylate/ethyl acrylate Suggests DS is step 3 until 20% conversion, then DS is step 2 3 DS step 2 DS step 3 (D) Et Et 3 DS late stage C Et DS early stage - 3 3 Et Aggarwal, V. K.; Lloyd-Jones, G. C.; Fulford, S. Y. Angew. Chem. Int. Ed. 2005, 44, 1706-1708.

Complications Associated with MB Very slow reaction rates C 2 DABC neat, 23 C, 6 d C 2 89% More electron rich aromatic aldehydes less reactive Without limiting substrate scope, 3 ways to enhance rate Use Lewis acid catalysts to promote nucleophilic addition Find most reactive nucelophile to initiate reaction Employ protic additives or solvents to assist in DS 3 2 EWG Caubere, P.; Fort, Y.; Berthe, M. C. Tetrahedron 1992, 48, 6371-6384.

Lewis Acid for ate Enhancement of MB DABC (30 mol %) 2 C 2 La(Tf) 3 (1.5 mol %) chiral diamine (3 mol %) C 3 C, 23 C, 10 h 2 C 2 Bn 55% 97% 75% 88% = naphthyl, 20 min Bulky aryl acrylates give faster reaction times by stabilization of enolate 1.1 equiv TMEDA (10 mol %) MgCl 2 (10 mol %) DMAP (10 mol%), 23 C = (C 3 ) 2 C 15 h, 62% = p- 2 5 h, 94% = 15 h, 91% = p- 15 h, 67% 48 h, 83% S MgCl 2 /TMEDA work as Lewis acid, with DMAP as nucelophile 2h, 53% 1h, 92% Chen, K.; Yang, K.-S.; Lee, W.-D.; Pan, J.-F. J. rg. Chem. 2003, 68, 915-919. Connell, B. T.; Bugarin, A. J. rg. Chem. 2009, 74, 4638-4641.

Urea Catalyst for MB ate Enhancement C 2 catalyst (20 mol %) DABC (1 equiv) 23 C, neat C 2 (10 equiv) 88%, 20 h Catalyst k rel X none =, X = S = F, X = S 1.0 1.7 5.7 EWG urea promotes reaction = F, X = = CF 3, X = S 5.4 3.7 = CF 3, X = 6.7 2 C 2 C 2 C 2 C 2 93%, 1 h 88%, 2 h 81%, 3 d 71%, 4 d Urea catalyst enhances reaction rate through -bonding eactions employing MVK and catalyst resulted in decomposition Connon, S. J.; Maher, D. J. Tetrahedron Lett. 2004, 45, 1301-1305.

Exploration of MB Amine Catalysts Ac Cl pk a 8.7 11.3 9.9 9.3 8.9 6.9 k rel 1 9.0 4.3 0.15 0.04 0.006 eactions run neat; pk a measured in 2 More basic catalyst gives higher concentration of ammonium enolate pk a 8.7 9.3 Ac 8.9 Cl DABC higher pk a in aprotic solvents, higher rate of reaction k rel 1 0.15 0.04 C 2 1.2 equiv quinuclidine (25 mol %) methanol (75 mol %) 23 C C 2 time (h), yield = Et 7 h, 83% = 2-furyl 1 h, 84% = cinnamyl 3 h, 62% = p- 9 h, 82% previous best 14h, 83% 20h, 85% 24h, 43% 24h, 61% Catalytic aids in initial conversion and solubility of reactants Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. rg. Chem. 2003, 68, 692-700.

Exploration of MB Amine Catalysts C quinuclidine (25 mol %) methanol (75 mol %) 23 C C 1.2 equiv C C C C conditions previous best 3 h, 81% 5 min, 5kbar, 70% 1 h, 87% 4 h, 97% 20 min, 78% 5d, 74% 6 h, 76% 40 h, 66% quinuclidine (50 mol %) C 2 methanol (7.5-14M) 23 C C 2 C 2 C 2 C 2 C 2 conditions previous best 5 h, 83% 24 h, 89% 5 h, 66% 48 h, 61% 2 4 h, 65% 24 h, 95% 3 d, 55% n/a Very few acrylamide examples in literature Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. rg. Chem. 2003, 68, 692-700.

ctanol for ate Enhancement of MB 2 0% : 0% C DABC (15 mol %) 23 C, 12 h C Bu octanol C 3 (C 2 ) 11 28% : 12% 50% : 10% 65% : 8% 50% : 9% 2 equiv of octanol provided 90% yield MB adduct cyclohexanol 68% : 10% 2 F 3 C C C C C 3 ml 16% : 0% 20% : 0% 0% : 8% 7% : 7% octanol (2 equiv) 100% : 0% 100% : 0% 18% : 43% 91% : 9% eactions with MVK and challenging aldehydes unsuccessful stabilization of transition state through van der Waals 3 Chong, Y.; Choo,.; Park, K.-S.; Kim, J. Synlett 2007, 395-398.

p-itrophenol as a Promoter with P 3 P 3 (20 mol %) p-nitrophenol (30 mol %) DMS, 18 h, 23 C 52% 25% no additive p-nitrophenol acts as Lewis acid, promoting the conjugate addition step and proton transfer 2 35% 98% 72% B B 3 P enolate stabilization P 3 assisted deprotonation Shi, M.; Liu, Y.-. rg. Biomol. Chem. 2006, 4, 1468-1470.

The Double MB eaction 3 1 C 1 1 3 3 3 3 3 1 C 1 C 3 C 1 C 1 C 1 C 3 3 3 Treating PVK dimer with nucelophile and aldehyde does not provide double MB adduct Shi, M.; Ma, G.-.; Jiang, J.-J.; Wei, Y. Chem. Commun. 2009, 5496-5514.

2 equiv 2 equiv 2 equiv The Double MB eaction DABC (10 mol %) DMF, 20 C 60-70 h = m- 2 C 76% 15% = trace 33% o MB product observed; challenging aldehydes give only PVK dimer 2 DABC (10 mol %) DMF, 20 C 40-50 h o dimerization or double MB adducts Shi, M.; Li, C.-Q.; Jiang, J.-K. Molecules 2002, 7, 721-733. Shi, M.; Ma, G.-.; Jiang, J.-K.; Wei, Y. Chem. Commun. 2009, 5496-5514. 3 (10 mol %) C DMF, 20 C 40-60 h DMAP DABC ucelophile used can affect formation of double MB adducts 85% 0% 63% 23% = m- 2 74% = 79%

Avoiding Dimerization: The Sila-MB TMS Ar Ar 2 TTMPP (5 mol %) C 3 7 C, 23 C TMS Ar 2 Ar P 1.5 equiv 3 TTMPP TMS = p-cl = = p- 99% 81% 55% TMS 69% TMS 72% Cl ormal MB adducts achieved with electron rich vinyl ketones TMS Ar Ar 2 TMS Ar TMS Ar 2 Ar -P 3 TMS Ar 2 Ar P 3 P 3 P 3 1,3-Brook rearrangement triggers elimination to provide product Gevorgyan, V.; Trofimov, A. rg. Lett. 2009, 11, 253-255.

Avoiding Dimerization: The Sila-MB 2 C C 2 TMS TTMPP (1 mol %), C (2 equiv) dioxane, 23 C 2 C C 2 TMS Inspiration for sila-mb of aryl vinyl ketones 2 C C 2 2 C C 2 2 C C 2 75% TMS TMS 65% 76% TMS 2 C C 2 2 C C 2 2 C C 2 TMS n-bu TMS CF 3 TMS 69% 86% 53% Steric bulk not an issue due to highly reactive substrate!-substitution well-tolerated; ketones function as electrophiles Gevorgyan, V.; Chuprakov, S.; Malyshev, D. A.; Trofimov, A. J. Am. Chem. Soc. 2007, 129, 14868-14869.

Complications Associated with MB Very slow reaction rates C 2 DABC neat, 23 C, 6 d 89% C 2 3 2 EWG Use protic additives to assist DS of proton transfer eactive substrates lead to dimerized products C DABC p- 2 C C C p- 2 DMF, 20 C 60-70 h C 76% 15% Sila-MB or change nucleophile Caubere, P.; Fort, Y.; Berthe, M. C. Tetrahedron 1992, 48, 6371-6384. Shi, M.; Ma, G.-.; Jiang, J.-J.; Wei, Y. Chem. Commun. 2009, 5496-5514.

Another Look at the MB chanism 2 1 or 3 2 EWG Competition experiment between d-ethyl acrylate/ethyl acrylate Demonstrates DS step 3 until 20% conversion, then DS step 2 3 DS step 2 DS step 3 Et Et 3 DS late stage C Et DS early stage - 3 3 Et Aggarwal, V. K.; Lloyd-Jones, G. C.; Fulford, S. Y. Angew. Chem. Int. Ed. 2005, 44, 1706-1708.

chanism Explains Difficulties in Asymmetric Induction 1 C LS 1!! fast slow slow 1! u! u! slow Past attempts unsuccessful due to incomplete understanding of mechanism Chiral amines or chiral lewis acids unlikely to control proton transfer step 4 diastereomeric intermediates possible before proton transfer/elimination With properly designed chiral catalysts, only one diastereomeric intermediate will proceed to product Aggarwal, V. K.; Lloyd-Jones, G. C.; Fulford, S. Y. Angew. Chem. Int. Ed. 2005, 44, 1706-1708.

Early Example of Asymmetric MB CF 3 catalyst (10 mol %) CF 3 TF or DMF, -55 C p- 2 2 3 equiv A CF 3 CF 3 p- 2 p- 2 B (+)-quinidine A : 12%, ee nd B : 22%, 33% ee A : 2%, ee nd B : 32%, 35% ee A : 63%, 35% ee B : 10%, 33% ee A : 58%, 91% ee B : 11%, 04% ee Less sterically hindered amine enhances rate of reaction CF 3 CF 3 = = isobutyl A : 57%, 95% ee B : n/a A : 51%, 99% ee B : 18%, 85% ee igh enantioselectivities for electron rich aromatic and aliphatic aldehydes atakeyama, S.; Iwabuchi, Y.; akatani, M.; Yokoyama,. J. Am. Chem. Soc. 1999, 121, 10219-10220.

chanistic ationale for Stereoinduction Et catalyst C(CF 3 ) 2 Et 1 C 1 C C 2 X C 2 Y 2 Et C 2 1 C 1 C 1 1 1 1 1 1 atakeyama, S.; Iwabuchi, Y.; akatani, M.; Yokoyama,. J. Am. Chem. Soc. 1999, 121, 10219-10220.

Thiourea Catalyst for Asymmetric MB catalyst (10 mol %) solvent, 0 C, 48 h 5 equiv 2 S CF 3 21%, 39% ee CF 3 S CF 3 CF 3 S CF 3 CF 3 56%, 73% ee 83%, 71% ee Binaphthyl amine essential for yield and enantioselectivity ptimized conditions with C 3 C provide 80% yield, 83% ee n-bu 84%, 81% ee 63%, 94% ee 71%, 90% ee 55%, 60% ee Cl Increased sterics improves enantioselecitivity; aromatic aldehydes provide moderate ee's Wang, W.; Wang, J.; Li,.; Yu, X.; Zu, L. rg. Lett. 2005, 7, 4293-4296.

Simple Thiourea for Asymmetric MB catalyst (20 mol %) DABC (20 mol %) 23 C CF 3 CF 3 CF 3 S S S CF 3 CF 3 CF 3 48h, 32%, 9% ee 65h, 56%, 46% ee 88h, 50%, 63% ee emoval of hydroxyl group results in lower conversion ptimized conditions use 4 equiv cyclohexenone, 20 mol% catalyst and 20 mol% Et 3 147h, 61%, 88% ee 120h, 45%, 81% ee 119h, 74%, 64% ee 119h, 86%, 56% ee Lattanzi, A. Synlett 2007, 2106-2110.

Thiourea Catalyst for MB with Aromatic Aldehydes C catalyst (20 mol %) DABC (20 mol %) 2 C 3, 23 C, 3 d 2 Aromatic aldehydes have proven difficult in asymmetric reactions S ' S ' = ' = 3,5-(C 3 ) 2 ' = 3,5-(CF 3 ) 2 53%, 39% ee 65%, 35% ee 67%, 72% ee 67%, 5% ee S ' S = 3,5-(CF 3 ) 2 More electron deficient thiourea provides highest levels of selectivity 99%, 81% ee Cl 90%, 85% ee F 79%, 88% ee Shi, M.; Liu, X.-B. rg. Lett. 2008, 10, 1043-1046.

Chiral Brønsted Acid Catalyzed MB catalyst (2 mol %) PEt 3 (0.5 equiv) TF, 0 C, 36 h X CF 3 X = X = CF 3 74%, 32% ee X = X = X 73%, 48% ee 69%, 86% ee 70%, 88% ee 84%, 86% ee 43%, 3% ee emoval of one Brønsted acid lowers catalyst activity and selectivity Et B B 71%, 96% ee 82%, 95% ee 72%, 96% ee Et 3 P Et 3 P stabilization of enolate and assisted deprotonation Schaus, S. E.; McDougal,. T. J. Am. Chem. Soc. 2003, 123, 12094-12095. Schaus, S. E.; McDougal,. T.; Trevellini, W. L.; odgen, S. A.; Kilman, L. T. Adv. Synth. Catal. 2004, 346, 1231-1240.

Lewis Acid Enhanced MB with Chiral Amine Catalyst catalyst (10 mol %) MgI 2 (50 mol %) i-pr, -20 C, 24 h 1.5 equiv Fu (+)-PPY Fu (+)-DMAP Taniaphos 2 2 P Fe Fe 2 P Fe 2 98%, 81% ee 96%, 94% ee 45%, 54% ee Less nucelophilic catalyst provides highest selectivity 87%, 94% ee 73%, 95% ee 94%, 98% ee 2 75%, 89% ee Electron deficient aromatic and aliphatic aldehydes gave moderate results All other Michael acceptors failed to produce product Connell, B. T.; Bugarin, A. Chem. Commun. 2010, 46, 2644-2646.

Lewis Acid for Asymmetric MB DABC (30 mol %) La(Tf) 3 (1.5 mol %) chiral diamine (3 mol %) C 3 C, 23 C, 10 h 2 C 2 C C 2 C 2 75%, 84% ee 70%, 67% ee Aliphatic aldehydes gave moderate selectivity 3 La 2 82%, 93% ee =!-naphthyl 35%, 95% ee Stereochem rationalization Chen, K.; Yang, K.-S.; Lee, W.-D.; Pan, J.-F. J. rg. Chem. 2003, 68, 915-919.

91%, 97% ee Asymmetric Synthesis of Substituted xindoles 81%, 98% ee 3 : 1 dr C C (10 mol %) C Bn 97%, 96% ee C 2 Cl 2, - 20 C, 4 d In previous examples, ketones unsuccessful F 96%, 98% ee C 92%, 96% ee C Differential substitution does not effect selectivity ab 4 (5.0 equiv) TF/ 2 (9:1 v/v) 0 C ne step derivatization of oxindole products LiAl 4 (5.0 equiv) TF, 23 C C 79%, 98% ee Br Br 96%, 93% ee Zhou, J.; Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang, C. J. Am. Chem. Soc. 2010, 132, 15176-15178. C 75%, 98% ee

Synthetic Challenges Associated with MB Asymmetric Induction S C, DABC C 2 Cl 2, 0 C, 12 h 85%, 99% ee Use bifunctional catalyst to control stereochemistry of addition into aldehyde and proton transfer Intramolecular MB C 2 Et PBu 3, 23 C, 1 d C 2 Et 75% conversion First example of an intramolecular MB Employing different electrophiles and exploring scope of the reaction Leahy, J. W.; Brzezinski, L. J.; afel, S. J. Am. Chem. Soc. 1997, 119, 4317-4318 Fráter, G.; oth, F.; Gygax, P. Tetrahedron Lett. 1992, 33, 1045-1048.

Early Demonstrations of Intramolecular MB SEt SEt solvent temp C time (h) additive yield % CCl 3 65 24 DMAP, DMAP!Cl (1.0, 0.25 equiv) 48 C 2 Cl 2 23 3 DBU (1 equiv) 25 DMF 78 5 DMAP, DMAP!Cl (1.0, 0.25 equiv) 43 Et 78 1 DMAP, DMAP!Cl (1.0, 0.25 equiv) 87 Et 78 1 DABC (1 equiv) 18 C 2 Cl 2 23 15 P 3 (0.1 equiv) 82 DMAP!Cl assists in stabilization of resulting alkoxide, pushing equilibrium to product P 3 (1.0 equiv) C or t-bu 20-30 C Bu 12 h, 98% 22 h, 99% 24 h, 83% 25 h, 83% DABC ineffective at inducing transformation Keck, G. E.; Welch, D. S. rg. Lett. 2002, 4, 3687-3690. Koo, S.; Yeo, J. E.; Yang, X.; Kim,. J. Chem. Commun. 2004, 236-237.

Intramolecular Asymmetric MB catalyst (10 mol %) CDCl 3 25 C, 48h Co-catalyst conditions necessary for reaction and selectivity C 2 C 2 C 2 C 2 60% ee <10% ee <10% ee 60% ee 32% ee Change of solvent to TF/ 2 (3:1) 80% ee 82%, 80% ee Cl 92%, 79% ee 94%, 51% ee S 83%, 74% ee rtho substitution lowers enantioselectivity Miller, S. J.; Aroyan, C. E.; Vasbinder, M. M. rg. Lett. 2005, 7, 3849-3851.

Thiourea Catalyzed Intramolecular Asymmetric MB catalyst (10 mol %) C 2 Cl 2, 25 C P 2 i-pr S 48 h, 72%, 18% ee Bn P 2 S 60 h, 50%, 67% ee Bn P 2 S CF 3 12 h, 83%, 76% ee CF 3 Bn P 2 S 84 h, 45%, 56% ee Electronics of thiourea have large effect on activity and selectivity Bn S 77%, 84% ee F 76%, 75% ee 99%, 45% ee 2 P Ar re-attack rtho substitution effects enantioselectivity Wu, X.-Y.; Gong, J.-J.; Yuan, K.; Song,.-L. Tetrahedron 2010, 66, 2439-2443.

Cyclization via MB Pathway Cl 1. PBu 3 (1 equiv) t-bu, 5h, 23 C 2. K, BnEt 3 Cl, 2h 80% PBu 3 Cl Cl Cl K -PBu 3 Bu 3 P Bu 3 P Second step needed to displace catalyst in absence of alkoxide Cl Cl 1 : 2 94%, >10 : 1 Treatment of allylic alcohol with SCl 2 provided mixture of regioisomers Cl Cl PBu 3 t-bu, 23 C, 5 h >90% recovery Suggests no allylic isomerization, S 2' or S 2 mechanism likely Krafft, M. E.; axell, T. F. J. Am. Chem. Soc. 2005, 127, 10168-10169.

Cyclization via MB Pathway 2 P 3 (1 equiv) t-bu, 23 C 2 2 endo exo 30h, 66% 72h, 60% 18h, 76% Sterics govern endo/exo selectivity 10 equiv P 3 72h, 92% n C 2 C 3 PBu 3 (1 equiv) Pd(P 3 ) 4 (1 mol %) t-bu, 60 C n EtS 92% 76% 73% Cyclopropanes untouched under these conditions Krafft, M. E.; Wright, J. A. Chem. Commun. 2006, 2977-2979. Krische, M. J.; Jellerichs, B. G.; Kong, J.-. J. Am. Chem. Soc. 2003, 125, 7758-7759. 66%

Synthetic Applications of MB EWG 1 X 2 Catalyst 1 2 X! EWG X =, 1 X EWG Conditions 1 EWG X Formation of tri-substituted olefins X =, X = C, Cl, Br, I,, ew method development using MB adducts simple starting materials EWG 1 X 2 Catalyst 1 2 X! EWG complex products Use MB adducts as synthetic intermediates en route to complex products Basavaiah, D.; ao, A. J.; Satyanarayana, T. Chem. ev. 2003, 103, 811-891. Basavaiah, D.; eddy, B. S.; Badsara, S. S. Chem. ev. 2010, 110, 5447-5674.

Synthesis of Tri-substituted lefins from MB Adducts Cl C 2 Cl (2.5 equiv) Cl DMF (2 M), C 2 Cl 2 23 C, 1.5 h C 2 Cl 89% Z-selective synthesis C 2 C 2 C 2 C 2 Et Cl Cl Cl Cl Cl 94% 2 97% 85% 92% Formation of Villsmeier reagent followed by attack and elimination provides Z-isomer C I 2 /P 3 C 2 Cl 2, 23 C 0.5-6 h 92% C I E-selective synthesis Cl 90% C I 2 58% C I n-hept 89% C I Li, J.; Li, S.; Jia, X.; Zhang, Y. J. Chem. es. 2008, 48-49. Das, B.; Majhi, A.; Banerjee, J.; Chowdhury,.; Venkateswarlu, K. Tetrahedron Lett. 2005, 46, 7913-7915.

Applications of Modified MB Adducts Ac X C 2 C 2 X S S a 2 S (1.5 equiv) DMS/ 2, 40 C 10 min - 1.5 h S X S 2- C 2 =5-, X = F =, X = F =, X = 2 C 2 34% 41% 43% S 2 C Thiochromenes have shown variable biological activity C 2 Et Ac C 2 Et 1. K 2 C 3, TF 23 C, 2-6 h 2 2. Fe/Ac reflux, 1.5 h 62% C 2 C 2 Et C 2 Br 68% 64% Lee, K.-J.; Cha, M. J.; Song, Y. S.; an, E.-G. J. eterocyclic Chem. 2008, 45, 235-240. Basavaiah, D.; Aravindu, K. rg. Lett. 2007, 9, 2453-2456. 63%

Butenolide Synthesis From an MB Adduct Ac 2 2-trimethylsiloxy furan (200 mol %) P 3 (20 mol %) TF 2 62-94%, >95 : 5 dr 88%, >95:5 dr 2 80%, 20:1 dr 88%, 24:1 dr 86%, >95:5 dr n-pr Br 2 94%, 96% ee 36h 85%, 95% ee 24h 98%, 91% ee 24h 60%, 72% ee 96h Chiral phosphine used to induce asymmetry Krische, M. J.; Cho, C.-W. Angew. Chem. Int. Ed. 2004, 43, 6689-6691. Shi, M.; Jiang, Y.-Q.; Shi, Y.-L. J. Am. Chem. Soc. 2008, 130, 7202-7203.

Asymmetric Butenolide Synthesis from an MB Adduct Ac 2 TMS 2.5 equiv 10 mol % catalyst C 3, 2 (6 equiv) 23 C 2 C P 2 P 2 TMS P 2 Si 3 [4+2] 2 Grob-type C 2 P C Si 3 [4+2] cycloaddition with Grob-type fragmentation Shi, M.; Jiang, Y.-Q.; Shi, Y.-L. J. Am. Chem. Soc. 2008, 130, 7202-7203.

MB in Total Synthesis Corey 2004 - Salinosporamide A PMB Bn quinuclidine (1 equiv) DME, 0 C, 7 d 90% PMB C 2 Bn 1 : 9 PMB C 2 Bn steps Diastereoselective intramolecular MB Cl Porco Jr. 2006 - (-)-Kinamycin C Br (C 2 ) n, La(Tf) 3 Br steps Ac Ac TBS (C 2 C 2 ) 3 PEt 3, C 2 Cl 2-20 C, 6 h, 70% TBS Ac Triethanolamine sequesters lewis acid to liberate nucleophile Corey, E. J.; eddy, L..; Saravanan, P. J. Am. Chem. Soc. 2004, 126, 6230-6231. Porco Jr., J. A.; Lei, X. J. Am. Chem. Soc. 2006, 128, 14790-14791.

Concluding emarks Morita-Baylis-illman reaction is an atom economical process that results in high levels of molecular complexity EWG 1 X 2 Catalyst 1 2 X! EWG X =, Despite the slow nature of the reaction, many methods have been developed to enhance reaction rate Asymmetric induction can be achieved using bifunctional catalysts or combinations of organocatalysts and lewis acids MB products have many applications in total synthesis as well as new method development

Concluding emarks Morita-Baylis-illman reaction is an atom economical process that results in high levels of molecular complexity Despite the slow nature of the reaction, many methods have been developed to enhance reaction rate Asymmetric induction can be achieved using bifunctional catalysts or combinations of organocatalysts and lewis acids MB products have many applications in total synthesis as well as new method development

Concluding emarks Morita-Baylis-illman reaction is an atom economical process that results in high levels of molecular complexity Despite the slow nature of the reaction, many methods have been developed to enhance reaction rate Asymmetric induction can be achieved using bifunctional catalysts or combinations of organocatalysts and Lewis acids S CF 3 i-pr catalyst (10 mol %) C 3 C, 0 C, 48-120h i-pr CF 3 94% ee MB products have many applications in total synthesis as well as new method development

Concluding emarks Morita-Baylis-illman reaction is an atom economical process that results in high levels of molecular complexity Despite the slow nature of the reaction, many methods have been developed to enhance reaction rate Asymmetric induction can be achieved using bifunctional catalysts or combinations of organocatalysts and Lewis acids MB products have many applications in new method development and total synthesis Ac 2 TMS 10 mol % catalyst C 3, 2 (6 equiv) 23 C p-tol CC 3 P 2 96% ee

Future utlook A general method for asymmetric induction still needed Current methods are very specific to substrates!-substitution very limited to special substrates 2 Si 1 2 1. Sc(Tf) 3 (10 mol %) C 2 Cl 2, -78 C, 15min-18h 2. Cl, TF 1 2 20:1 Z:E Compatible with extremely hindered and electron rich substrates Intramolecular variant still in infancy Scheidt, K. A.; eynolds, T. E.; Bharadwaj, A.. J. Am. Chem. Soc. 2006, 128, 15382-15383.

Acknowledgements Eric Ferreira Ferreira Group