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. R = Me, Et, i-Pr, CH2CH2Ph, CH=CH2, Ph, (E)-CH=CHPh R JACS, 1981, 103, 2809 JACS, 1991, 113, 5354-5365 O Acc. Chem. Res., 1992, 25, 352-359 HN

CCl3 R1 11-2-2013 Rune Risgaard Larry E. Overman

- Synthesis of trisubstituted tetrahydropyrans Synthesis of oxacyclic ring systems - Stereochemistry of sidechains evolves from single stereocenter - Found in polyether antibiotics, marine toxins and pheromones - DCM not suitable (trapping of carbocation with halide competitive) - High enantiomeric purity obtained from nonracemic diols OH O COMe Me R 1) t-BuLi 2) CuCN O X X R SnCl Me RCHO (2 eq.) 4 Br 3) Ph O SnCl4 or TfOH o OH O MeNO2, -23 - 0 C Ph OH o Ph O R O 85% MeNO2, -25 C Me (S) 81-92%, >95% ee Me (50-81%) 6-18:1

X = NCO2Et, O, CH2; R = Me, Ph R = CH2CH2Ph, Me, Bn, i-Pr, t-Bu, Ph, (E)-CH=CHPh JOC, 2003, 68, 7143-7157 H OH - Ring-enlarging reactions (cis-fused octahydrobenzofurans and cycloheptatetrahydrofurans) COMe - In most cases both cis and trans fused diols gives cis-fused rings R OH O 1 1 1 O iPr-CHO (2 eq.) R R R 1 OH OH R SnCl4 SnCl4 OH Ph O (CH2)n (CH2)n MeNO , -25oC RCHO R 2 DCM, 1h (H C) 68% (2R,4S,6R) n 2 O Ph >99% ee OH 50-94% O H 1 R R/R = H, alkyl, aryl, vinyl JACS, 1999, 121, 1092-1093 n = 0, 1, 2 cis diols trans diols Synthesis of carbocyclic ring systems 1 R1 R - Oxocarbenium external to the ring formed upon Prins - Synthesis of attached rings with ring contraction R R HO O O MeO n n OH MeO MeO SnCl JOC, 1987, 52, 3711 4 H CHO OTIPS JACS, 1991, 113, 5365 DCM, 0 oC 50-84% m Hexahydroisobenzofuran synthesis m - Alkene contained in ring m = 1, 2, 3; n = 1,2 - Synthesis of ladiellin, briarellin and asbestinin diterpenes MeO

MeO MeO MeO SnCl4 H CHO H CHO BF Et O OTIPS 3 2 o OH OHC Ac H MeNO2, 0 C Ph 50-84% DCM, -55oC Ph OH (97%) O (1.4 : 1.0) (87% ee) (70% ee) JACS, 2001, 123, 9033 JOC, 2006, 71, 1581 11-2-2013 Rune Risgaard Larry E. Overman

Synthesis of hydrinans, hydroazulenes scaffolds containg functionalty in both rings - Keteniminium ion initiated cyclization-pinacol rearrangements O O OTMS R R R R O O SnCl4 RuO4 TESO R OTf R O n OMe DCM 55-72% n Tf2O, DTBMP o n N O -78 to -23 C overall H (75-82%) H DCE, -20 KHCO3 (aq) n (56-80%) Et O CH(OMe)2 nH 2 nH

R = H, Me; n = 1, 2, 3 O N JACS, 1989, 111, 1514 n = 0, 1, 2; R = H, Me N JOC, 2002, 67, 6421 DTBMP n TMSO n O o Ph 1) SnCl4, DCM, -78 to -23 C - Synthesis of tetrahydrothiophenes . - BF2 OEt2 performs best OMe O RCHO 2) RuO4, MeCN-H2O O OMe Me BF .OEt H (65-72 %) Me 3 2 Me H MgSO S R = H, Me; n = 0, 1 HO 4 Me S Tetrahedron, 2002, 58, 6473 DCM, -20oC R OH (51-71%) S Me SH Me HO Me - Allyl cation-initiated cyclization rearrangement to install 2-alkenyl substituent. R = CH2CH2Ph, Ar, (E)-CH=CHPh Me - Protodesilylation occurs under reaction conditions with TMS JACS, 2000, 122, 8672 Major byproduct R O TESO R

Tf2O

DCM, -78oC - In cases where oxonium fails sulfonium can work as alternative n n (54-80%) O H OTMS OTMS H >20:1 HO DMTSF O SPh SiMe3 o R CH(SPh)2 DCM, -45 C n = 1, 2, 3; R = H, Me OTES R1 SPh R1 (80%) H

n R n H H OTMS TMSO OTES Major S OTES SnCl4 OH O S BF4 R CH(OMe)2 DCM n R1 DMTSF n R R H JACS, 2001, 123,4851 R1 n 1 H R = H, Me, TMS; ds = 1.5:1, 10:1, 20:1 Minor JOC, 2002, 67, 6421 11-2-2013 Rune Risgaard Larry E. Overman

Synthesis of (-)-citreoviral - 2,2-disubstituted 4-acyltetrahydrofurans containing different C2 substituents from unsymmetric ketone can be formed with high stereoselection SiMe Ph SiMe Ph - 4-acyl-3-(dimethylphenylsilyl)-tetrahydrofurans can serve as precusors of 4-acyl-3- i) TaCl , Zn, PhH-DME 2 2 5 hydroxytetrahydrofurans O Me Me 1) TBAF, THF, rt Org. Lett., 2000, 2, 223 SiMe2Ph Me ii) Me , THF OH 2) TMSCl, imidazole, OTMS o OTBDPS Me DCM, 0 C Me iii) aq. NaOH (81%, 3 steps) Me OTBDPS Me OTMS Me Selected targets acheived by Prins-Pinacol

SiMe2Ph MeO OMe Me O Me OTBDPS OMe N AcO SiMe2Ph Me H OH O Me TMSOTf O Me o DCM, -30 C O OTBDPS H H H Me O O H H H H Me Me OAc O (41%), >95% ee (47%) OTBDPS O OH O Me 1) aq. HF, ACN o H C7H15CO2 SnCl4, DCM, -78 C, (89%) H 2) p-TsOH, MeOH Briarellin F Magellanine (+)-Shahamin K HC(OMe)3 28 steps (0.7%) 25 steps (1.4%) 20 steps (2.9%) JACS., 2003, 125, 6650 JACS., 1993, 115, 2992 JACS., 2001, 20, 4851 PhMe2Si HO 1) Bz2O, DMAP, pyridine i) Li, NH3, THF-EtOH Me Me 2) (CF3CO)2, urea-H2O2 H O ii) TBAF, THF o O O O DCM, 0 C OMe iii) H2O2, KHCO3, MeOH OMe then aq. NaHCO3 O O O H Me Me (62%) Me Me (72% + Me Me O H O N 20% Acetate) H Br OH ( ± )-kumausallene (+)-Sieboldine A OBz OBz Me OBz 13 steps (5.4%) 20 steps Me DIBALH Me TPAP, NMO HO JACS., 1991, 113, 5378 JACS., 2010, 132, 7876 O O hexane-DCM,-78oC DCM, rt OH O Me (69%) O Me (81%) Me O Me HO Me O Me Me

(51%, dr = 4:1) Ph3P CO2Et PhH, reflux

Me OBz Me Me OH OH OH O HO HO HO CO Et 2 DIBALH BaMnO4 Me O Me hexane-THF Me O Me PhH, 80oC Me O Me Me 0oC to rt. Me (50%) Me (93%) (-)-citreoviral (15 steps) 11-2-2013 Rune Risgaard Larry E. Overman

Reaction of arylhalides through neutral pathway often gives lower %ee Intramolecular asymmetric Heck reaction Silver and Thallium salts (Ag2CO3, Ag2O, Ag3PO4, Tl2CO3, TlOAc) used to promote the cationic pathway. (JACS, 1998, 120, 6488) - Initial findings Common bases used (K2CO3, CaCO3, Et3N, i-Pr2NEt, PMP)

Pd(OAc)2 (3 mol%) Polar aprotic solvents are typically used (THF, ACN, DMF, DMA, NMP) Less basic silver salts (AgOAc, AgNO ) results in lower reaction rate and little asymmetric induction (JOC, CO Me (R)-BINAP (9 mol%) CO Me 3 2 Cyclohexene (6 mol%) 2 1992, 57, 4571) BINAP is by far the most widely used ligand. Depending on how HX is scavenged either enantiomer of the product can be formed using a single Ag2CO3 (2 eq.) enantiomer of a chiral diphosphine. I NMP, 60oC H The order of reactivity X = I>OTf>Br>>Cl 74% (46% ee) Catalyst loading 5-10%. Most common used precatalysts Pd(OAc)2, Pd2(dba)3 - Synthesis of spirocycles with quatenary centers OTf Pd(OAc)2 PPh2 (R,R)-DIOP PR2 MeO PPh2 O Et3N, Benzene, rt PR2 MeO PPh2 PPh2 PPh2 PPh O O O 2 90% (45% ee) J. Org. Chem., 1989, 54, 5846 (R)-(+)-BINAP R=Ph (R)-MeO-BIPHEP (R, R)-DIOP (R, R)-CHIRAPHOS (R)-(+)-Tol-BINAP R=p-tolyl General features - Two pathways proposed (Cationic and neutral) Synthesis of oxindoles, indolines, dihydrobenzofurans - Depending on how HI is scavenged each enantiomer can be obtained (cationic vs neutral pathway) - Which HI acceptor is optimal for achieving highest %ee is substrate dependent X Cationic pathway P Y Pd2(dba)3 Y X (R)-BINAP Pd O P PMP or Ag3PO3 ArOTf I Sol Ar O DMA or NMP, 100 oC O P Ar P Pd Pd O P P P X = N, O; Y = C=O, CH2 Pd P Ar (55-75%, 41-96% ee) P OTf (JACS, 1998, 120, 6477) ArX Pd OTf P X X = I, Br AgOTf AgX Intramolecular Heck reactions of (Z)-a,b-unsaturated 2-iodoanilides - Synthesis of oxindoles Ar R2 Pd O P P X 2 Neutral pathway Pd2(dba)3 R 1 N (R)-BINAP R P P Ar X 1 Pd Pd P Ar R I PMP or Ag3PO3 P P Ar P Ar P Pd ArX Pd Pd P o O P X DMA, 100 C P X X N JACS, 1998, 120, 6488 1 R = Me, Ph, t-Bu, CH2CH(OMe)2 (53-93%, 69-90% ee) R2 = H, OTIPS, OTBDMS, OMe (JACS, 1998, 120, 6488) 11-2-2013 Rune Risgaard Larry E. Overman

Synthesis of 3-alkyl-3-aryl oxindoles Synthesis of (+)-Minfiensine - A broad range of indole alkaloids contain a diarylsubstituted quatenary center - Strychnos alkaloid

1) p-TsOH, PhH, 50oC 1) Methyl propagylic ether o OTf OMe O O 2) LHMDS, NCCO2Me, n-BuLi, -78 to -25 C OTf Bu3SnH TfO O O THF, -78oC 2) PhNTf , -25 oC to rt O Pd(PPh3)4 NH2 N O 2 3) NaHMDS, Comins' reagent (59 %) 0 oC, (84 %) N N N N H OTIPS 69 %, 3 steps Bn H OMe SnBu 3 TIPSO CO2Me

Pd(OAc)2 OMe Pd2dba3 BocHN BocHN Ar (R)-BINAP OTf OMe O P(2-furyl)3, CuI NHBoc PMP ArI, NMP, rt i) 9-BBN, , 0oC - rt. (51-93 %) O THF, 80 oC CsF,CsCO3, ii) NaOH, rt N iii) PdCl (dppf), THF, rt. N H Comins' reagent 2 H Ar N N (48-91%; 71-98% ee) DMF, rt, 85 % 71 % TfO CO2Me TIPSO CO2Me Ar = Ph, 4-MeO-C6H4, 3-pyridyl, 4-AcNH-C6H4, 1-naphthyl, 2-NO2-C6H4, N N Bn Boc JACS, 2003, 125, 6261 10 %, Pd(OAc)2, ligand 1 o PMP, toluene, microwave 170 C O (75-87%, 99% ee) TBDMSO O OTBDMS Ph2P N Pd(OAc) 2 t-Bu (R)-BINAP NHBoc 1 N halide salt X O 1) 9-BBN, THF, 100 oC, DMF, 100 oC N H2O2, NaOH TFA, DCM 2) TPAP, NMO, DCM X = OTf or I 75 %, 2 steps 63 %, 2 steps N N Triflates can be diverted to neutral pathway Compound( Addi+ve( Oxindole( %ee( N - Higher enantioselection without presence of silver salt MeO C yield( CO2Me 2 Boc - Identical low ee in presence of AgOTf OTf$ %$ 72$ 43$ - Addition of halide salts to the triflate enhanhced ee

OTf$ nBu4NI" 62$ 90$

OTf$ nBu4NBr" 59$ 93$ O 1) TFA, DCM, rt O 2) K CO , ACN, OTf$ nBu4NCl" 52$ 93$ 2 3 Br OTf$ nBu4NOTf" 70$ 42$ I OTf$ PMPHI$ 40$ 91$ N N 65 %, 2 steps N OTf$ PMPHBr$ 62$ 92$ N MeO2C MeO2C Boc OTf$ PMPHCl$ 60$ 88$ I I$ %$ 76$ 91$ I$ PMPHI$ 62$ 91$ I$ PMPHBr$ 45$ 95$ O I$ PMPHCl$ 75$ 94$ NaHMDS 10 % PdCl2(dppf), Comins' reagent I$ AgOTf$ %$ 43$ K2CO3

N o Angew. Chem. 1997, 36, 518 o THF, -78 C, (86 %) MeOH, 70 C, 74 % N MeO2C 11-2-2013 Rune Risgaard Larry E. Overman

O Vinylsilane terminated cyclization reactions OTf - Hyperconjugation stabilizes beta carbonium ion OMe - Carbon-silicon bond is strongly polarized (Electronegativity 2.35 vs. 1.64) Pd(OAc)2, PPh3, Et3N - Electrophile directed to silicon bearing carbon - Complete regiocontrol of the double bond N CO, MeOH, DMF (89%) N - Two mechanisms can be considered: Direct cyclization through beta silyl cation N N or via [3,3] aza-cope rearrangement. MeO2C MeO2C R1 1 1) LiAlH , THF, -78 oC R 2 R R1 = TMS R OH 4 R = TMS R R2 N 2) NaOH, MeOH, N N o H endocyclic H2O, 100 C exocyclic N R2 H N R1 85 %, 2 steps TMS R TMS (+)-Minfiensine R N N JACS, 2008, 130, 5368 R2 H H Ph H N N Vinylsilane-terminated cyclizations occur with preference for carbocation in sequence: tertitary trialkyl > secondary beta-silyl >tertiary alfa-silyl > O HN secondary dialkyl > primary beta-silyl cations H H H H Chemical Reviews, 1986, 86, 857 N N N N O H Synthesis of unsaturated azacycles (1,2,5,6-tetrahydropyridine) - Found in several alkaloids H O - A cyanomethyl amine can be used as formaldehyde equivalent. N H HN Ph CSA R = nC3H7, Ph, PMB R1CHO R1 = H, nC H NH TMS ACN, reflux 6 13 N N 1 HN (68-92 %) R N (+)-Asperazine H H H 22 steps O R R Tetrahedron, 2007, 63, 8499 N N n n R = H, Br O 1) NaBH4, MeOH H H H O R n = 1,2 N N R 2) TFA N O OH Quadrigemine C O 19 steps (2% yield) (90-92%) JACS, 2002, 124, 9008 OH TMS O JACS, 1983, 105, 6994 HN O O N N Preparation of enantioenriched tetrahydropyridines from silylpentenylamine O (-)-Morphine TMS ( ± )-Gelsemine (17 steps) H JACS, 1993, 115, 11028 N 26 steps (1,1% yield) O CH2O, p-TsOH JACS, 2005, 127, 18054 5 steps or AgBF4 L-alanine N O H ACN N Me Ph N Me (-)-Spirotryprostatin B Bn (10 steps, 9% yield) R = H, CH2CN R Angew. Chem., 2000, 39, 4596 (33-69 %, 92-99 %ee) Tetrahedron Lett., 1993, 34, 5243 11-2-2013 Rune Risgaard Larry E. Overman

Synthesis of indoloquinolizidine ring system found in a variety of indole alkaloids O 1) KOH, EtOH, H O, 90 oC Both (E) and (Z)-trisubstituted vinylsilanes can be cyclized with >98% retention 2 N 2) Formalin, MeOH N SiMe3 Me SiMe Me O H O 3 H CH2OBn CH2OBn H H NH NH Me SiMe3 SiMe3 CHO, CSA, ACN O (60 %, 3 steps) Me H H CHO CH2OBn OTBDPS H H Me Me o CSA, (79 %) H ACN, 80 C Me (83 %) (CH2O)n H O 1) Li/NH Me PPh 3 3 N 2) Swern ox. N OTBDPS DCM, reflux (53 %, 2 steps) N N N (71 %) Me OH Me OH Me H OH ( ± )-Deplancheine Me Me JOC, 1982, 47, 5297 H Me Enantioselective totalsynthesis of Pumiliotoxin B and 251D LiAlH4, THF, HO - Pulimiotoxin B isolated from Panamanian poison frog Dendrobates pumilio in 1967 and pumiliotoxin 251 D -20 oC - rt. OH from skin extracts of the Ecuadorian poison frog (74 %) - Dendrabatid alkaloids - Poison used in blowdarts H - Cardiotonic agent Me R OH H CH3 H3C R = Pumiliotoxin B N H CH3 OH N CH OH 3 R = n-Pr Pumiliotoxin 251 D Me JACS, 1981, 103, 1851 JACS, 1984, 106, 4192 OH Pumiliotoxin B 1) 2 eq. MeMgI 2) SOCl2, pyridine, THF N COOBn 3) m-CPBA, DCM N COOBn N COOBn L-proline 54 % 3 steps OH H COOMe N H H H OH O (2:1) O CH N N H 3 H O H H O N 1) i-Bu2AlH, hexane O H CO C OH Me H 2) MeLi, Et O/hexane 3 2 2 N (+)-Streptazolin d,l-Epielwesine (+)-Geissoschizine 3) CH2OBn N COOBn O SiMe3 10 steps (4.2% yield) 6 steps (30% yield) 11 steps, (7.5% yield) JACS, 1987, 109, 6115-6118 Tett Lett., 1984, 25, 5739-5742 JACS, 1989, 111, 300-308 H CH2OBn TMS O H