Chemistry from the Boger Research Group A Synergy of Target-Oriented Synthesis and New Reaction Development: Cycloadditions for the Formation of Highly-Functionalized Ring Structures and Applications in Total Synthesis Troy E. Reynolds January 8, 2007 Dale L. Boger Education B.S. University of Kansas, 1975 Ph.D. Harvard University, 1980 - E. J. Corey "Part I: New annulation processes, Part II: Studies directed toward a biomimetic synthetic approach to prostaglandins" Professional Career Assistant Professor/Associate Professor, University of Kansas 1979-1985 Associate Professor/Professor, Purdue University, 1985-1991 Professor, The Scripps Research Institute, 1991-present Awards Searle Scholar Award 1981-1984 NIH Career Award 1983-1988 Alfred P. Sloan Fellow 1985-1989 ACS Arthur C. Cope Scholar Award, 1988 Japan Promotion of Science Fellow, 1993 ISHC Katritzky Award in Heterocyclic Chemistry, 1997 Honorary Member, The Lund Chemical Society (Sweden), 1998 ACS Aldrich Award for Creativity in Organic Synthesis, 1999 A. R. Day Award, POCC 1999 Honorary Ph.D. Degree: Laurea Honors Causa, Univ. of Ferrara, 2000 Smissman Lecturer, Univ. of Kansas, 2000 Yamanouchi USA Faculty Award, 2000 Paul Janssen Prize for Creativity in Organic Synthesis, 2002 oss Lecturer, Dartmouth College, 2002 Fellow, American Association for the Advancement of Science, 2003 Adrien Albert Medal, Royal Society of Chemistry, 2003 ISI Highly Cited (top 100 chemists) Alder Lecturer, University of Köln, 2005 Chemistry from the Boger Research Group Research Interests •Total synthesis •New synthetic methods •Bioorganic and medicinal chemistry •Combinatorial chemistry •DNA-agent interactions •Chemistry of antitumor antibiotics Cycloaddition Reactions I. Heteroaromatic Azadienes Roseophilin II. N-Sulfonyl-1-Azadienes •Mechanism/Reactivity Piericidin A1 •Scope/Limitations •Utility/Application III. Cyclopropenone Ketals Rubrolone Aglycon IV. Intramolecular [4+2]/[3+2] Cascades Vindoline II. Heteroaromatic Azadiene 1 R R R N R N 3 N N N N R N R R R R EDG 1,3,5-triazine N N 1,2,4-triazine R R pyridine 2 R pyrimidine N N N N R 1,2,4,5-tetrazine O O R R R2 N N Zn/HOAc N 2 NH N N R N R R1 R R1 1,2-diazine R pyrrole R indole •Electron-deficient azadienes ideally suited for inverse-demand Diels Alder reactions •Introduction of highly substituted heterocylcic systems I. Heteroaromatic Azadienes: 1,2,4-Triazine R R R N R N + ! N N N R R 1,2,4-triazine pyridine Mechanism N 1 N R1 N R N –N N N + 2 R1 N N N R1 N loss of R2 R2 2 N R 2 H R N Reactivity CO2Et CO2Et N N •Highly functionalized pyridines > > N N N N N •Rxns run at 25-80 ºC N N •Aromatization is slow step, not initial [4+2] and loss of N CO2Et 2 CO2Et 1,2,4-Triazines CO2Et R1 CO2Et N N + N N N R2 CHCl3, 45 ºC R1 R CO Et 2 R2 1,2,4-triazine Dienophile Conditions product yield (%) EtO2C N CO2Et N CHCl3, 60 ºC, 18 h 79 EtO2C Ph Ph EtO2C N CO2Et N CH3 CHCl3, 45 ºC, 8 h 73 EtO C CH Ph 2 3 Ph TMSO EtO2C N CO2Et CHCl3, 60 ºC, 22 h 84 Ph EtO2C Ph TMSO CH 3 CHCl3, 60 ºC, 16 h No Product 0 Ph EtS CH3 CHCl3, 80 - 160 ºC, 16 h No Product 0 Ph Catalytic 1,2,4-Triazines Diels Alder H N O R1 N + R2 R1 N N N 2 CHCl3, 45 ºC R 1,2,4-triazine R –N2 Ketone time (h) equiv of product yield (%) pyrollidine O 22 0.2 N 52 O 58 0.2 86 N O 96 2.0 93 N O 84 4.0 36 N O 36 1.0 N 19 I. Heteroaromatic Azadienes: 1,2,4-Triazine Utility O MeO O N CO2H H2N N N CO2H O H2N N CH3 H2N O OH CH3 H2N OMe OMe Lavendamycin Streptonigrin Lavendamycin (J. S. Panek, S. R. Duff, M. Yasuda), J. Org. Chem. 1985, 50, 5782-5789, 5790-5795 Streptonigrin (J. S. Panek), J. Am. Chem. Soc. 1985, 107, 5745-5754 1,2,4,5-Tetrazines CO2CH3 CO2CH3 R EDG R N N N + N N N R R CO2CH3 CO2CH3 Mechanism CO2CH3 CO2CH3 CO2Et N R EDG CO2CH3 R R N N N R N N + N R EDG N N ! N N EDG N N R -N2 R -H-EDG H3CO2C CO2CH3 CO2CH3 CO2Et Reactivity CO2CH3 SCH3 SCH3 NHCOR N N N N N N N N > > > R = CH3, OCH3 N N N N N N N N CO2CH3 SCH3 NHCOR NHCOR 1,2,4,5-Tetrazines Utility CO2CH3 CO2CH3 CO2CH3 R EDG R R N N N Zn/HOAc + N N N NH R R R CO2CH3 CO2CH3 CO2CH3 1,2,4,5-Tetrazine 1,2-Diazine Pyrrole Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D.; J. Org. Chem. 1984, 4405; Mechanism CO2Et CO2Et CO2Et CO2CH3 CO2CH3 R R R R R N Zn N H+ O -H2O H N NH NH N HN N 2 H2N R R CO2CH3 CO2CH3 CO2Et CO2Et CO2Et Kornfield, E. C. et. al.; J. Med. Chem. 1980, 23, 481. 1,2,4,5-Tetrazines!1,2-Diazine!Pyrrole CO2CH3 CO2CH3 CO2CH3 R EDG R R N N N Zn/HOAc + 25 ºC N N N NH dioxane 25 ºC R R R CO2CH3 CO2CH3 CO2CH3 Dienophile Diazine Yield Pyrrole Yield Et3SiO H CO C CO CH 87 H CO C 63 3 2 2 3 3 2 N CO2CH3 N N H N H CO C CO CH 85 52 3 2 2 3 H CO C 3 2 N CO2CH3 N N H O Ph Ph N H3CO2C CO2CH3 87 65 H CO C CO CH N N 3 2 N 2 3 H Ph O O OCH OCH3 3 OCH3 H CO C CO CH O OCH3 3 2 2 3 71 H CO C 56 3 2 N CO2CH3 N N H Total Synthesis of Roseophilin Retrosynthesis SEMN RCM N Acyl Radical SEMN O Alkene Cyclization CO2Me O N OMe + SEM O OMe O HN HN Cl Cl Wittig N N OBn MeO2C CO2Me OBn N N CO Me + MeO2C N 2 MeO2C CO2Me SEM [4+2] N N OMe 1,2,4,5-tetrazine Reductive Ring Contraction OBn Total Synthesis of Roseophilin 1. TiCl , (iPr) NH, 1. TPAP, NMO O O 4 2 BnOCH2Cl, 99% 100% OMe 2. LiAlH , 54% 2. CH3OCH=PPh3 N 4 HO OBn OBn Bn N N MeO2C CO2Me OBn Zn/TFA, 25 ºC, OBn N N 1 h, 52% 25 ºC, 60 h MeO2C CO2Me 91% for 2 steps MeO C CO Me N N 2 N 2 H 1. Pd/C, H2 2. CSA, PhH 1. SEMCl, 92% 1. ClCO2Et, Et3N 77% for 2 steps 2. LiI, 74% 2. NaBH4, 90% O O O MeO2C HO2C N N HOH2C H O SEM O N SEM O Total Synthesis of Roseophilin 1. MnO2 BnO + - 1. Pd/C, H2, 97% 2. BnO(CH2)4PPh3 Br , NaHMDS, 2. TPAP, NMO 96% for 2 steps 3. CH2=PPh3 67–85% for two steps O O O HOH C 2 N N SEM N SEM O SEM O O 1. LiOH O + - 2. TMSCHN2 CH2=CH(CH2)2PPh3 Br , 3. TPAP, NMO NaHMDS CO Me 91% for 4 steps N 2 SEM CO Me N 2 SEM PCy3 Cl Ru CHPh Cl 1. NaOH, 49% 2. (EtO) P(O)Cl; PCy3 2 PhSeNa, 83% Bu3SnH, AIBN CH2Cl2, 40 ºC, 72 h 83% SEMN 72–88% SEMN CO2Me SEMN (1:1 E:Z) COSePh O Intramolecular Acyl Radical Cyclizations (EtO)2P(O)C, PhSeNa Bu3SnH, AIBN 83% 83% SEMN SEMN SEMN CO2H COSePh O Other Examples 5-exo-dig Bu3SnH, AIBN COSePh 80% O SEMN CN H H O Bu3SnH, AIBN COSePh 62% O CH2CN O O Bu3SnH, AIBN O ( )n SePh 46 - 74% n = 2 - 11 ( )n Boger Isr. J. Chem. 1997, 37, 119 O O Total Synthesis of Roseophilin 1. n-BuLI, -78 ºC 2.CeCl , –55 ºC 30 min PtO , H 3 SEMN 2 2 3. -78 C OH 100% OMe OMe SEMN SEMN O O O O TIPSN Cl Cl TIPSN 1. Bu4NF 2. HCl ClH•N OMe O HN Cl ent–Roseophiline•HCl Intramolecular Diels-Alder: Preperation of Indoles and O Indolines O R2 2 N R N –N2 N N N N 1 R R1 1,2-Diazine Conditions Product Yield CH3 N N 230 ºC, 12 h 85% N N CO CH 2 3 CO2CH3 H3C CH3 N N 230 ºC, 18 h 77% N N CO2CH3 CO2CH3 CH OTBS TBSOH2C 2 N N 230 ºC, 18 h 92% N N CO2CH3 CO2CH3 Et Et H3COS N • N 120 ºC 50 -55% N N CO2CH3 CO2CH3 Intramolecular Diels-Alder: Preperation of Indoles and Indolines Utility NH2 N N HO2C O HO2C O O OH O OH OMe OMe PDE-I PDE-II H2N N O Me OH HN OMe NH N N O O O O OH OMe (+)-CC-1065 1,3,5-Triazines R N R N R EDG N N + N R R 1,3,5-triazine pyrimidine Ynamines Diels-Alder R N R CH3 N Me N R R R –RCN N N + Me N N N Bn2N Bn N R NBn2 2 R R pyrimidine 1,3,5-triazine R = H, 40 - 90 ºC, 81% Amidine Diels-Alder R = CO2Et, 40 - 90 ºC, 95% R = SCH3, 160 ºC, 93% R R = S(O)CH , >25 ºC, 50% NH2•HCl 3 HN H2N Me N N R R R N R Me N R N -NH3 R -RCN N N + H2N N N N R H N R 2 NH2•HCl NH N R 2 R R H2N N R = H,125 ºC, 64% H2N N R R = CO2Et, 100 ºC, 85% N R R = SCH3, 150 ºC, 0% 1,3,5-Triazine H N O H N O 2 2 NH2 NH2 H H N N CONH2 CONH2 N N O CH3 N N H N H2N N CO2H H2N CO2H H Me O Me N NH (–)-Pyrimidolblamic Acid P-3A H O N H2N O S NH2 H N N CONH2 O S H HO N N N O NH N H N H2N N HO S H H bleomycin A2 Me O N O OH HO O NH O OH OH O OH OCONH OH 2 Heteroaromatic Azadiene Diels-Alder Reactions 1 R R R N R N 3 N N N N R N R R R R EDG 1,3,5-triazine N N 1,2,4-triazine R R pyridine 2 R pyrimidine N N N N R 1,2,4,5-tetrazine O O R R R2 N N Zn/HOAc N 2 NH N N R N R R1 R R1 1,2-diazine R pyrrole R indole I.