11-2-2013 Rune Risgaard Larry E. Overman - Born in 1943 in Chicago, Illinois Awards/Honours include: - Raised in Hammond, Indiana ACS Arthur. C. Cope Award (2003) - B.A., Earlham College 1965 ACS Creative work in Synthetic Organic Chemistry (1995) - Ph.D., University of Wisconsin 1969 with Professor Howard W. Whitlock 2011 - UCI Medal, University of California, Irvine, American Chemical - NIH postdoctoral fellowship with Professor Society, Ronald Breslow at Columbia University 2010 - Herbert C. Brown Award for Creative Research in Synthetic - He joined University of California, Irvine in 1971 Methods, where he is Distinguished Professor of Chemistry 2008 - Tetrahedron Prize for Creativity in Organic Chemistry, 2007 - The Nagoya Medal of Organic Chemistry, 2005 - International Society of Heterocyclic Chemistry Senior Award, 2004 - Ta-shue Chou Lectureship Award, 2003 - American Chemical Society Arthur C. Cope Award, 362 publications: 2002-2003 U.C. Irvine Distinguished Faculty Lectureship Award for - 128 JACS Research, - 74 JOC 2002 - Yamada Prize - 12 Angew. Chem. 1999 - Japan Society for the Promotion of Science Fellowship, - 117 papers with the term "total synthesis" - S. T. Li Prize for Achievements in Science and Technology, - Earlham College Distinguished Faculty Award, 1997 - Centenary Medal, Chemical Society, U.K. 1995 - American Chemical Society Award for Creative Work in Synthetic Organic Chemistry, 1993 - 1994 - Guggenheim Fellowship, 1993 - C.S. Hamilton Award, University of Nebraska 1985 - 1992 - Javits Neuroscience Investigator Award 1989 - American Chemical Society Arthur C. Cope Scholar Award Research Interests: Organic, Inorganic, Organometallic and Chemical Biology - Visiting Miller Research Fellow, U.C. Berkeley 1985 - 1987 - Alexander von Humboldt U.S. Senior Scientist Award, - Professor Overman's research interests center on the invention of new reactions 1976-1981 Camille and Henry Dreyfus Teacher-Scholar Award and strategies in organic synthesis and the total synthesis of natural products and 1981 - U.C. Irvine School of Physical Sciences Distinguished Teaching their congeners. Award, 1979 - U.C. Irvine Alumni Association Distinguished Research Award 1975-1977 - Alfred P. Sloan Foundation Fellow 11-2-2013 Rune Risgaard Larry E. Overman Charge in rearrangement reactions Synthesis of cis-fused octahydroindoles and cycloheptapyrrolidines - One carbon ring expansion - Present in alkaloids of the Amaryllidaceae, Aspidosperma, and Strychnos familes Cope R3 R3 R3 O OH OH OH R3 Oxy-Cope Ar N Ar N Aza-Cope R2CHO [3,3] Mannich R2 O O NH EtOH, reflux, N R2 N R2 N (66-78 %) H H H 1 rate acceleration up to1017 rate acceleration up to1010 R1 R1 R1 R relative to Cope relative to Cope Charged atom can distort the reaction pathway of concerted toward nonconcerted R3 R3 Rate acceleration due to delocalization in transition state H H R2 R2 The aza-Cope rearrangement N N o - Mild conditions (100-200 C below the corresponding Cope rearrangement) 1 1 - Usually occurs near rt. OH R OH R - Reversible (Driven by aryl conjugation of the product iminium ion) 1 2 3 R = H, Me; R = H, Me, n-C6H13; R = Ph - Charged intermefiate lowers free energy of activation JACS 1981, 103, 5579 Acc. Chem. Res., 1992, 25, 352-359 Tetrahedron Lett. 1982, 2733 The aza-Cope-Mannich rearrangement - Cycloheptapyrrolidine moiety present in Gelsemine - Directing the rearrangement by intramolecular trapping - Double bond incorporated in a suprafacial sense Ph OH O Ph CH O Synthesis of 3-Acyl-pyrrolidines O 2 3 R Benzene, reflux, H NH (66-78 %) 2 CSA H N R1 CHO NH2R 1 H 1 R 1 R3 o R = H, CHPh2 R OH X Benzene, 80 C, 24h Tetrahedron Lett. 1982, 2737 (54-97 %) R1 N R2 Mannich 2 2 Cyanomethyl as a source for the iminium equivalent R R - Also functions as protection group N R1 N R1 [3,3] Ph O OH Ph R3 R3 AgNO3 HO HO EtOH, 1h rt. N R1 = alkyl, phenyl, thiophene, pyridine; R2 = alkyl, benzyl; R3 = H, Me N CN 60 % H H JACS, 1979, 101, 1310 Tetrahedron Lett. 1982, 2741 JACS, 1983, 105, 6622 11-2-2013 Rune Risgaard Larry E. Overman OBut Synthesis of (± )pancracine - Amaryllidaceae alkaloid N Ar 1) HCHO, KCN 2) Swern OH 1) NaH, Benzene, 100oC 3) t-BuLi, O H (CH O) , Na SO . 2) KOH, EtOH:H O, 60oC N 2 n 2 4 OH vinylbromide AgNO3 BF3 OEt2 2 O o (62%) MeCN, 80 C O OBut O EtOH, rt DCM, -20oC (98%) N (87%) (97%) NH N N HO N N CN H O N 1) LDA, NCCO2Me, THF Bn O Bn Bn o O N -78 C N O 2) HCl in MeOH, reflux O O (70 %, 2 steps) 1) HCl, Pd/C, H2, O MeOH 1) Zn, H SO , MeOH, reflux O O O N 2 4 N H 2) Formalin, Et3N, 2) NaOMe, MeOH, rt. aq. 6N HCl 7 steps OH H 3) DIBAL, DCM, -78 oC (65%, 2 steps) O H N N N NH H OH OH N OH H Bn ( ± )pancracine H 7% overall yield CO2Me (17 steps) N JOC. 1993, 58, 4662 CH2(CO2H)2, Ac2O, NaOAc, HOAc, 110oC H O H Enantioselective total synthesis of (-)-Strychnine N H OTIPS O OH 7 steps JACS, 1993, 115, 9293-9294 (-)-Strychnine 20 steps, (3% yield) AcO (39%) Me3Sn (1R, 4S) 1 OBut Selected targets acheived with the Aza-Cope-Mannich reaction O H N O N OTIPS H N N 1) t-BuO H, Triton-B, THF 2.5% Pd2dba3 O 2 HN N 22% Ph As, LiCl 2) Ph3P=CH2, THF 1 3 t HN MeO N OBu N I CO (50 psi) (84% 2 steps) HO2C O H R2N CO Me NMP 70 oC 2 O O dl-16-Methoxytabersonine (80%) 11 steps OH ( ± )-Gelsimine JOC, 1983, 48, 2685 (-)-Actinophyllic acid 26 steps, (1.4%) 1) TBAF, THF, -15oC 9 steps, (8%) Angew. Chem., 1999, 38, 2934 NHCOCF3 JACS, 2010, 132, 4894-4906 OTIPS 2) MsCl, Hünigs base, N N H o O O DCM, -23 C OH 3) NH2COCF3, NaH t t DMF, rt. OBu OBu O H R N R2N 2 (83%) H N N H N O O CO2Me H (-)-Crinine ( ± )-Akuammicine ( ± )-Meloscine 10 steps, (6%) 10 steps, (8%) 24 steps, (3%) Helv. Chim. Acta., 1985, 68, 745 JACS, 1993, 115, 3966 JACS, 1991, 113, 2598 11-2-2013 Rune Risgaard Larry E. Overman Conversion of allylic alcohols into a cis-vicinal diol Initial asymmetric Pd(II) catalyst developed - Conventional oxymercuration-demercuration gives trans-1,3-diol - Only useful for N-arylbenzimidates - Coordination of the basic trichloroacetimidate nitrogen to the palladium center H H - Competing elimination reactions 2+ CCl3 CCl3 OH O O SiMe3 t-Bu O O O N N N HgX2 NaBH4 Pd Pd CCl3CHO X Fe Cl R R HgX R 2 (BF )2- 2 4 JACS, 1999, 121, 2933-2934 JOC, 1997, 62, 1449-1456 t OH (35-97% yield, 57-93% ee) (25-68% yield, up to 60% ee) R = H, Bu ; X = OCOCF3 OH Na, Et O, rt J.C.S. Chem. Comm., 1972, 1196 2 Ar Ar Zn, AcOH, reflux 1 1 (79 and 88%) Ar Ar 5 % catalyst R N O N O DCM, rt Synthesis of amines by rearrangement of allylic trichloroacetimidates R R (Overman rearrangement) Allylic imidate rearrangement discovered in 1937 Works for 1o, 2o and 3o allylic alcohols Large enthalpic driving force (imidate to amide functionality 15 kcal/mol) Useful for synthesis of hindered amines Catalytic asymmetric rearrangement of allylic trichloroacetimidates Mild cleavage of the trichloroacetyl group - Catalyzed by monomeric cobalt oxazoline palladacycles (COP) Trichloroacetimidates often used directly without purification - >90% ee Preparation typically invole DBU in aprotic solvents or alkali metal hydrides - COP-Cl superior in DCM but low solubility - COP-hfacac soluble in a wide variety of solvents. Higher solubility EWG (CCl3 or CF3) results in more facile rearrangment compared to imidates High stereoselection (preference for E isomer) R2 CCl CCl CCl CN [3,3] 1 3 3 3 1 3 1 R R 5 mol % COP R OH R O CCl3 25-140 oC NaH 38 C, 18 h. HN O HN O NH2 R2 R3 Et O R2 R3 NH Xylene O NH 2 (93%, 93% ee) R R R R = H. alkyl 1 Dilute NaOH R H CCl3 CCl3 (60-83% overall) R = H, alkyl, aryl 2 R R3 R2 F3C CF3 HN O R1 R3 Cl O O six-membered transition state for thermal rearrangement Pd Pd NH2 Hg(II) and Pd(II) salts catalyze rearrangement N N Mechanism proceeds through a iminomercuration-deoxymercuration Catalytic effect greater then 1012 Ph Co Ph Co MX O Ph Ph O R R R MX2 Ph Ph Ph Ph MX2 HN O N O HN O COP-Cl (1) COP-hfacac (2) HX CCl3 CCl3 CCl3 JACS, 2003, 125, 12412-12413 JOC, 2004, 69, 8101 JACS, 1976, 98, 2901-2910 JACS, 1974, 96, 597 11-2-2013 Rune Risgaard Larry E. Overman Prins pinacol rearrangement Catalytic asymmetric synthesis of chiral allylic esters and aryl ethers - Allylic acetals into highly substituted tetrahydrofurans . O - Catalyzed by lewis (EtAlCl2, BF3 OEt2, SnCl4) (SnCl4 is generally superior) R - Reaction occurs via chair topography with (E)-oxonium ion NH 1mol% COP-OAc R1COOH O R1 - Incoporation of doublebond in suprafacial sense - Both diastereoisomers gives the same product DCM, rt O CCl3 (60-100%, 87-99%ee) R CH3 O R1 JACS, 2005, 127, 2866-2867 CH3 CH 2 R2 3 R O SnCl R 4 H3C CH3 CH NH 1mol% COP-OAc Ar 1 o 3 ArOH R DCM, -78 - 0 C O H C O O DCM, 38oC 3 (73 and 90 %) H3C O CCl R 1a or b 3 (45-88%, 80-98%ee) Org Lett., 2007, 9, 911-913 1 2 1 2 a) R = H, R = CH3; b) R = CH3, R = H JACS, 1987, 109, 4748 N N Mechanism: AcO Pd C -OAc NH Pd C 1 Cl3C OH R HO R1 O R1 NH CH3 R2 Cl3C H C H C R2 O 3 2 Prins 3 Pinacol O R R H3C O O H3C CH3 CH R1 O H C O CH 3 R CH3 3 3 O H3C R H NH Cl C N 1 3 R O Cannot undergo C-C O R N bond formation (5-endo-trig) AcO Pd C HOAc 3 NH Pd C R Cl3C 1 OH O O R O R2 OCOR1 O 3 O R R1 R R 2 O Cl C NH R 1 3 2 R OH Can undergo C-C 3 R bond formation (6-endo-trig) Thermal rearrangement of propagylic trichloroacetimidates O - Synthesis of trichloroacetamido-1,3.dienes R2 - High stereoselectivity observed, (1Z,3E) isomer formed R R R MgBr CH CH3 O CH CCl3 3 CSA 3 H3C O O O CH2 O OH 1 R CHO 1 SnCl4 H3C RH C HN H N R R O NH [3,3] 2 tautomerice PhH, 80oC THF, rt O DCM, -78 to -23oC 1 RH2C CCl CCl3 H C OH (41-95%) OH (64-70%) H C O H 3 3 H3C 3 (60-77%) H3C xylene, reflux 1 1 H H (38-92%) H R H R R1 R = H, Me, Ph [1,5] 1 R = H, alkyl,benzyl; R1 = H, alkyl, phenyl, TMS.