A Perspective on Professor Scott Eric Denmark: The Man, The Myth, The Chemist Si 3 2 C 2 S P (C 2 ) 5 2 n-c 5 9 ussell C. Smith Stoltz/eisman Group eting January 24, 2011 Si M
From umble Beginnings Born in Lynbrook, ew York on 17 June 1953 btained an S. B. degree from M.I.T. in 1975 Conducted research with both ichard. olm (ferredoxin analogs) and Daniel S. Kemp (functionalized cyclophanes). eceived D. Sc. Tech degree in 1980 Prof. Dr. Albert Eschenmoser ( n the Stereochemistry of the S eaction ). 1980 Independent career as assistant professor at the University of Illinois at Urbana-Champaign. 1986 Associate Professor 1987 Full Professor 1991 eynold C. Fuson Professor of Chemistry. steps S 2 S B B J. rg. Chem. 1981, 46, 3144
To A Thriving Career In rganic Chemistry: utline Silicon-Directed azarov Cyclization thexyl 2 Si Si 3 Bn BF 3 Et 2 C 6 5 Et, 125 C thexyl 2 Si Inter/Intramolecular [42]/[32] Cycloaddition of itro lefins 2 C 1. SnCl 4 C 2 Cl 2, -78 C 2. toluene, 80 C Lewis-Base Activation of Lewis Acids Enantioselective Carbon- Carbon Bond Formation C SiCl 4 Et TBS Bn 2 Si C P C 2 2 Bn 2 Si C 2 Et
To A Thriving Career In rganic Chemistry: utline Silicon-Directed azarov Cyclization thexyl 2 Si Si 3 Bn BF 3 Et 2 C 6 5 Et, 125 C thexyl 2 Si Inter/Intramolecular [42]/[32] Cycloaddition of itro lefins 2 C 1. SnCl 4 C 2 Cl 2, -78 C 2. toluene, 80 C Lewis-Base Activation of Lewis Acids Enantioselective Carbon- Carbon Bond Formation C SiCl 4 Et TBS Bn 2 Si C P C 2 2 Bn 2 Si C 2 Et
azarov Cyclization Background amed after the ussian chemist I.. azarov (1900-1957), 2 gs 4, 2 S 4 Proved later that the cyclization proceeds through a divinyl ketone 3 P 4, C 2 90 C Incorporation of nucleophile gave further insight into mechanism 2 S 4 Ac 2, 25-30 C a rg. eact. 1994, 45, 1-158
azarov Cyclization chanism * * * * * Promoted by thermal or photochemical initiation 254 nm, C 6 6 Ac, 3 P 4 50 C rg. eact. 1994, 45, 1-158
azarov Cyclization chanism * * * * * emote substituents can cause changes in the torquoselectivity of the cyclization clockwise 1 2 1 2 2 1 counterclockwise 1 2 1 2 rg. eact. 1994, 45, 1-158
Silicon-Directed azarov Cyclization C 3 Si MgBr 1. TF, -20 C 2. 4 Cl Si 3 i 2 Et 2, 0 C Si 3 FeCl 3 (1.05 equiv) Si 3 C 2 Cl 2 55%, 100% cis 84%, 100% cis 74%, 85/15 cis/trans 95%, 59/41 cis/trans Use of Si functionality directs collapse of cation J. Am. Chem. Soc. 1982, 104, 6242.
SDC Effect of Allylic Position Larger substituents promote increased levels of torquoselectivity (presence of vinyl silane) FeCl 3 Si 3 C 2 Cl 2 (C,T) (C,C) (C,T) (C,C) yield, % 78 22 99 C 2 =C 2 70 30 66 94 6 76 t-bu 94 6 63 C 2 90 10 76 Tetrahedron 1986, 48, 2821
SDC Effect of Silicon Functionality FeCl 3 Si 3 C 2 Cl 2 (C,T) (C,C) (C,T) (C,C) yield, % 2 Si 78 84 22 16 99 63 For Si 3 = 54/46 2 Si 3 Si 86 87 14 13 83 15 for Si(i-Pr) 3 = 79/21 I-Pr 3 Si 90 10 70 Tetrahedron 1986, 48, 2821
Formation of Enantioenriched Carbocycles Via SDC Si 3 FeCl 3 Br Br Br Br 2 C 2 Cl 2, -50 C 58%, 88% ee CCl 4 70% yield anti Si 3 M n Si 3 Si 3 M n Si 3 M n syn J. rg. Chem. 1990, 55, 5544
Total Synthesis of Silphinene: Application of SDC Bn = Si 2 thexyl Mn 2 C 2 Cl 2, 20 C 98% yield C Bn MgBr 3 Si TF, -30 C 80% yield Si 3 Bn Si 3 Mn 2 C 2 Cl 2, -40 C Bn BF 3 Et 2 C 6 5 Et, 125 C silphinene Presence of silicon functionality directs formation of cyclopentenone Tetrahedron 1997, 53, 2103
To A Thriving Career In rganic Chemistry: utline Silicon-Directed azarov Cyclization Inter/Intramolecular [42]/[32] Cycloaddition of itro lefins 2 thexyl 2 Si C Si 3 Bn BF 3 Et 2 C 6 5 Et, 125 C 1. SnCl 4 C 2 Cl 2, -78 C 2. toluene, 80 C Lewis-Base Activation of Lewis Acids Enantioselective Carbon- Carbon Bond Formation thexyl 2 Si C SiCl 4 Et TBS Bn 2 Si C P C 2 2 Bn 2 Si C 2 Et
Intramolecular Cycloaddition of itrosoalkenes eactivity of itrosoalkenes ' Cl base - ' uc ' uc Intermediate nitrosoalkene can act as 2π or 4π cycloaddition component 2 t-busi Cl CsF (3.0 equiv) C 3 C, 20 C 75/25 E/Z 70% yield 13% isomer 50/50 E/Z 32% yield (3.4/1 ratio of isomers J. rg. Chem. 1984, 49, 4714
itroolefins as 4π Components in Cycloadditions - SnCl 4 toluene, -29 C - 80% yield > 98/2 trans/cis J. Am. Chem. Soc. 1986, 108, 1306 itro groups serve as useful functionality for further elaboration - SnCl 4 C 2 Cl 2, -70 C - Kt-amyl -70 C Cl C 2 - SnCl 4 C 2 Cl 2, -70 C - C 2 2 C elv. Chim. Acta. 1986, 69, 1971
- Intramolecular [32] Cycloaddition Z Z' 1. SnCl 4 toluene, -78 C 2. toluene, 70 C Z' Z Z Z time, h [42] time, h [32] ds yield, % C 2 Et 7 0 >100:1 72 C 2 Et 8 3 20:1 78 - Z Z' 1. SnCl 4 C 2 Cl 2, -78 C 2. toluene, 80 C Z' Z Z Z time, min [42] time, h [32] ds yield, % C 2 Et 25 7 >100:1 93 C 2 Et 10 14 2.6:1 90 J. Am. Chem. Soc. 1990, 112, 311
Tandem Double Intramolecular [42]/[32] Cycloaddition Fused/bridged C(6) - 1. SnCl 4 toluene, -78 C C 2 2. ac 3 toluene, 80 C 82% yield 2 C a-i 2 (160 psi), rt 71% yield Fused/bridged C(5) - 1. SnCl 4 C 2 Cl 2, -78 C 2. ac 3 toluene, 100 C 79% yield 1. a-i 2 (160 psi), rt 2. Ac 2, py 82% yield Ac Ac Cycloaddition can be rendered diastereoselective by presence of chiral auxiliary rg. Lett. 2001, 3, 2907
Total Synthesis of ()-Crotanecine 2 C 2 i-pr Al 2 i-pr 2 C G* L-selectride Si 2 toluene, -14 C 73% yield Si 2 C 2 Cl, -78 C 91% yield i-pr 2 C G* Si 2 a-i 200 psi 2 Et 58% yield Si 2 94.9% ee 1. C()3 Ts 2. 2 S 2 Cl, Et 3 3. Ac, KBr AC, aac 4. 90% TFA 3 S B 3, TF 3 S B 3 Et 3, 120-130 C rosmarinecine (intra) hastanecine (inter) macronecine (inter) J. Am. Chem. Soc. 1997, 119, 125
1-Azafenestranes: Planarization of sp 3 Carbon Center 2 Cu(C)ZnI 2 Se 2 2 2 t-bu then SeBr Al 3 C 2 Cl 2, -78 C t-bu - t-bu 2.6 1 a-i, 2 10% 2 in EtAc P 3, DIAD then B 3 TF -78 C to rt B 3 B 3 BF 3 BF 3 Et 2 8 2 1 5 C(8)-C(1)-C(2) 120.7 121.2 121.9 -C(1)-C(5) 119.8 119.2 121.8 -ray quality
To A Thriving Career In rganic Chemistry: utline Silicon-Directed azarov Cyclization Inter/Intramolecular [42]/[32] Cycloaddition of itro lefins thexyl 2 Si 2 C Si 3 Bn BF 3 Et 2 C 6 5 Et, 125 C 1. SnCl 4 C 2 Cl 2, -78 C 2. toluene, 80 C Lewis-Base Activation of Lewis Acids Enantioselective Carbon- Carbon Bond Formation thexyl 2 Si C SiCl 4 Et TBS Bn 2 Si C P C 2 2 Bn 2 Si C 2 Et
Lewis-Base Activation of Lewis Acids P 3 B 3 P B stable Adduct mp = 100 C stable in 2 Preparative Examples I dioxolane t 1/2 = 80 min Li I dioxolane 4 eq. MPA t 1/2 = < 1 min Tf Tf Et ZnEt 2 Ti(i-Pr) 4 (1.2 equiv) 23 C, 12 h C ZnEt 2 Ti(i-Pr) 4 (1.2 equiv) -20 C, 1.5 h Et 98% ee EVIEW: Angew. Chem Int. Ed. 2008,47, 1560
L Lewis-Base Activation of Lewis Acids Principles Gutmann Analysis L L D A e.g. B 3 Lewis Base Lewis Acid increased negative charge! L! L D L A!! increased positive charge L L D L A cationic Lewis Acid L D L L A Lewis Base Lewis Acid! L! L D L! A! L L D A L cationic Lewis Acid e.g. SiCl 4 increased negative charge increased positive charge EVIEW: Angew. Chem Int. Ed. 2008,47, 1560
Lewis-Base Activation of Lewis Acids Principles ybridization of Silicon EVIEW: Angew. Chem Int. Ed. 2008,47, 1560
Aldol eaction of Silicon-Substituted Enolates Uncatalyzed SiCl 3 1. C 2 Cl 2, 0 C 2. sat. aq ac 3 Cy t-bu (E)-cinnamyl yield, % 98 96 99 89 SiCl 3 1. P 0.1 equiv C 2 Cl 2, -78 C = (E)-cinammyl 2. sat. aq. ac 3, anti/syn 65/1, 93% ee (E)-cinnamyl, anti/syn >99/1, 88% ee J. Am. Chem. Soc. 1996, 118, 7404
Addition to Ketones Silyl Ketene Acetals SiCl 3 ' t-bu Bu Bu 1. C 2 Cl 2, 0 C 2. sat. aq ac 3 t-bu ' Et F 3 C 95%, 83% ee 91%, 76% ee 94%, 68% ee 97%, 49% ee 86%, 8% ee 91%, 32% ee 90%, 80% ee 94%, 35% ee J. Am. Chem. Soc. 2002, 124, 4234
Vinylogous Aldol 1 4 TBS 5 P 2 SiCl 4, C 2 Cl 2, -78 C 3 C 2 2 1 4 5 3 2 Et Et 89%, >99:1!/", 98% ee 93%, >99:1!/", 99% ee 73%, >99:1!/", 95% ee t-bu t-bu 92%, >99:1!/", 89% ee, 98% de 71%, >99:1!/", 82% ee, 98% de chiral phosphoramide TBS SiCl 4, C 2 Cl 2, -78 C 92% yield, >99:1!/", 74% ee J. Am. Chem. Soc. 2003, 125, 2800
Formation of Quaternary Centers Silyl Ketene Imines C 1 2 C TBS 5 mol% chiral phosphormaide SiCl 4 C 2 Cl 2, -78 C 1 2 C C Et C C Et 87%, 95/5 dr, 97% ee F 3 C 73%, 97/3 dr, 99% ee 74%, 87/13 dr, 89% ee C C TBS 5 mol% chiral phosphormaide SiCl 4 C 2 Cl 2, -78 C C dr ee, % yield, % 4-CF 3 >99:1 99 88 2- >99:1 99 84 1-naphthyl >99:1 97 76 2-furyl 99:1 90 92 J. Am. Chem. Soc. 2007, 129, 14864
-Silyl xyketene Imines Aldol Surrogates cross-benzoin 1 2 3 Si C 1 Pg 2 cat C Pg 1 2 glycolate-aldol 3 Pg 1 2
-Silyl xyketene Imines Aldol Surrogates C t-bu KMDS (1.2 equiv) i-pr 3 SiCl (1.1 equiv) TF, -78 C (i-pr) 3 Si C t-bu where =, Er, i-bu, Bn, allyl (i-pr) 3 Si C t-bu P SiCl 4, i-pr 2 Et C 2 Cl 2, -78 C C 2 2 t-bu C Aryl t-bu C t-bu C t-bu C 84%, 96:4 dr, 99% ee 93%, 99:1 dr, 99% ee 90%, 99:1 dr, 99% ee t-bu C C 2 91%, 98:2 dr, 97% ee t-bu C 93%, 99:1 dr, 97% ee t-bu C 91%, 99:1 dr, 99% ee at. Chem. 2010, 2, 937
Total Synthesis of K-397 Synthesis of Polyol Fragment Bn 2 Si Bn 2 Si 1. ed-al 2. DMS (CCl)2 Et 3 C 2 Et C KMDS Bn 2 Si Bn 2 Si C TBS Et C 2 Et SiCl 4 P C 2 2 75%, 96% ee 74%, 19/1 dr 1. TMSTf, DIPEA 1. -Cl i-prmgcl 2. MgBr Bn 2 Si C() 2. SiCl 4, g(ac) 2 3. PMB C P Bn 2 Si PMB 1. ab 4 2. C() 2 CSA Bn 2 Si PMB
Total Synthesis of K-397 Synthesis of Polyene Fragment Bn 2 Si Si 2 I TP 1. a 2. Pd 2 (dba) 3 CCl 3 Bn 2 Si TP 77%, 3/1 dr I C 2 Et TP Pd(dba) 2 Et 79%, 5/1 dr 1. Ts, I 2 2. PBr 3, py P(Et) 3 3. P(Et) 3 Et 93% 8 of 10 stereocenters were generated by substrate control
Eli Lilly esearch Grantee, 1983 Beckman Endowment esearch Award, 1983 University of Illinois Center for Advanced Study, Beckman Fellow, Spring 1985 A. P. Sloan Foundation Fellow, 1985-1987 SF Presidential Young Investigator Award, 1985-1990 Procter and Gamble University Exploratory esearch Program Award, 1986-89 University Scholar, University of Illinois, 1986-1989 School of Chemical Sciences Teaching Award, University of Illinois, 1986 Stuart armaceuticals Award in Chemistry, ICI Americas, 1987 A. C. Cope Scholar Award, American Chemical Society, 1989 Awards/ecognition Fellow, American Association for the Advancement of Science, 1990 eynold C. Fuson Professor of Chemistry, 1991 Pedler dal (oyal Society of Chemistry), 2002-2003 ACS Award for Creative Work in Synthetic rganic Chemistry, 2003 Yamada-Koga Prize (Japan esearch Foundation for ptically Active Compounds), 2006 Fellow, oyal Society of Chemistry (FSC), 2006 Prelog dal (ET-Zürich, Switzerland), 2007 obert obinson dal and Lectureship (oyal Society of Chemistry), 2009-2010. C. Brown Award for Creative esearch in Synthetic thods (ACS), 2009 Fellow, American Chemical Society, 2009 (inaugural year)