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Total Synth GM Short.Pptx Total Synthesis New Methodology MacMillan Group Meeting 3-31-10 an opinion by Anthony Casarez What Classifies as Innovative? Innovation \i-nə-ˈvā-shən\ n: 1. The act of introducing something new. 2. A new idea, method, or device. Would introducing a new method in a total synthesis make it innovative? Yes but… Some innovations are considered to be more significant than others. How do we qualify these? In my view an innovation must dramatically change the landscape of our field or provide a method that is widely applicable. How Our Field was Born: UREA O H2N NH2 Isolated in 1773 from human urine (hence the name) by Hilaire M. Rouelle Intriguing to scientists who were eager to understand the mysteries of bodily functions . How Our Field was Born: UREA Friedrich Wöhler: 1800-1882; student of Jöns Jakob Berzelius. The synthesis of urea is known as the event that begot the field of synthetic organic chemistry. “I cannot, so to say, hold my chemical water, and must tell you that I can make urea, without thereby needing to have kidneys, or anyhow, an animal, be it human or dog.” Wöhlerʼs discovery shouldʼve refuted vitalism, the belief that organic molecules can only come from life which possesses a “vital force,” but the skeptics remained because he did not synthesize a C–C bond. O NH4Cl AgNCO AgCl H2N NH2 How Our Field was Born: UREA As if the birth of synthetic organic chemistry wasnʼt enough… Wöhler thought he was using AgOCN (silver cyanate) instead of AgNCO (silver isocyanate), both possessing the same formula as AgCNO (silver fulminate), studied by Justus von Liebig, but having different chemical properties. This gave rise to the notion of isomerism. O NH4Cl AgNCO AgCl H2N NH2 Convincing the Skeptics 15 years later Hermann Kolbe silenced (most) skeptics by synthesizing acetic acid, literally from elements. FeS2 C CS2 Fe 2Cl2 CS2 CCl4 2S pyrolysis Cl Cl 2CCl4 2Cl2 Cl Cl Cl Cl pyrolysis O 3HCl Cl Cl Cl3C OH O O 3H2 3HCl Cl3C OH H3C OH Retrosynthetic Application: Tropinone “By the imaginary hydrolysis at the points indicated by the dotted lines, the substance may be resolved into succinaldehyde, methylamine, and acetone, and this observation suggested a line of attack of the problem which has resulted in a direct synthesis.” –Sir Robert Robinson J. Chem. Soc. 1917, 762. Sir Robert Robinson NMe CO Sir Robertʼs analysis was one of the simplest yet most powerful suggestions of its time. The fact that it worked was a testament to his intuition. Tropinone Retrosynthetic Application: Tropinone “In Searching for a method of synthesis of any substance it is always convenient to be able to recognize the formation of traces of the desired product…tropinone is obtained in small yield by the condensation of succinaldehyde with acetone and methylamine in aqueous solution.” –Sir Robert Robinson J. Chem. Soc. 1917, 762-8. The forward synthesis only required a slight modification of starting materials. Me Me CO2H N N CHO CaCO3 CO2CaX HCl H2NMe O CHO H2O H2O O O CO2H XCaO2C Tropinone, 42% Tropinone: Mechanism CO2H CO2CaX CHO CaCO3 H2NMe O N Me OH CHO H2O CO2H OH CO2CaX Me N Me N CO2CaX CO2CaX OH O CO2CaX OH CO2CaX Me Me N N CO2CaX HCl XCaO2C O O 2CO2 “We have here a case where three rather simple molecules spontaneously unite into a complicated system, which earlier we could only build up step by step through a long series of reactions (13). We may suppose that here Sir Robert has found the key to natureʼs own way of working.” –A. Fredga: Robinsonʼs Nobel presentation speech (1947). Reserpine N MeO N H H H O H OMe MeO2C O OMe OMe (-)-reserpine OMe R. B. Woodward Known as one of the hallmarks of synthetic manipulation by a master of the field. One of the greatest achievements of Woodwardʼs career especially considering only IR and elemental analysis were used as guides. The dramatic conclusion taught chemists an invaluable lesson of thermodynamic engineering. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J; Kierstead, R. W. J. Am. Chem. Soc., 1956, 78, 2023. Reserpine: Retrosynthetic Analysis Reductive N O N amination MeO N MeO N H H H H H O Lactamization H H Bischler- OMe Napieralski MeO2C O MeO2C OAc OMe OMe OMe (+)-reserpine OMe O H Diels–Alder OAc O O H MeO2C OMe H CO2Me H O CO2Me O CO2Me NH2 p-benzoquinone MeO N H 6-methoxytryptamine Reserpine O OH H H PhH, ! Al(Oi-Pr)3 MeO2C O H i-PrOH H H O O CO2Me O O endo-TS H H H H MeONa Br2 O O H Br MeOH Br A Diels–AlderH sets the first three stereocentersH O O O O Meerwein–Pondorff–Verley reduction creates the next two causing a spontaneous lactonization with the nearby ester. H H H Br H H H O O H NBS O H OMe HO OMe H H OMe H H2SO4 (aq) O O O O O O Reserpine: Molecular Judo O OH H H PhH, ! Al(Oi-Pr)3 MeO2C O H i-PrOH H H O O CO2Me O O endo-TS H H H H Br MeONa O H 2 BromoetherificationO sets the next two. Br MeOH Br H H O O O O H H H Br H H H O O H NBS O H OMe HO OMe H H OMe H H2SO4 (aq) O O O O O O Reserpine: Molecular Judo O OH H H PhH, ! Al(Oi-Pr)3 MeO2C O H i-PrOH H H O O CO2Me O O endo-TS H H H H MeONa Br2 O O H Br MeOH Br H H O O O O H H H Br H H H O O O H H NSubstitutionBS of methoxide occurs with OMe HO OMe retention of configuration.H H OMe H H2SO4 (aq) O O O O O O Reserpine: Molecular Judo O OH H H PhH, ! Al(Oi-Pr)3 MeO2C O H i-PrOH H H O O CO2Me O O endo-TS H H H H MeONa Br2 O O H Br MeOH Br H H O O O O H H H Br H H H O O H NBS O H OMe HO OMe H H OMe H H2SO4 (aq) O O O O O O Reserpine H H Br Br H H H H Cr O Br H O H 2 2 7 O H Zn Zn O H HO OMe AcOH O OMe H H AcOH O OMe O O Zn H O O CO2H H H H OAc OH OsO 1. CH N 4 H 2 2 H NaClO3, O OMe 2. Ac2O O OMe H O H H 2 CO2Me CO2H OH O H H O N HO OAc MeO N OAc H H 1. HClO4 1. PhH, 1 H H MeO2C OMe H O OMe 2. CH2N2 2. NaBH4, H H CO Me MeOH MeO2C CO2Me 2 OAc OMe Reserpine O N N MeO N 1. POCl , ! MeO N H H 3 H H H 2. NaBH , H 4 H MeOH MeO2C OAc MeO2C OAc OMe OMe (+)-methyl-O-acetylisoreserpate H Reduction of theH iminium ion happens on the convex face providing the undesired epimer. N H H H N N OMe OAc H H CO Me MeO 2 CO2Me HN OMe OAc MeO Reserpine O N N MeO N 1. POCl , ! MeO N H H 3 H H H 2. NaBH , H 4 H MeOH MeO2C OAc MeO2C OAc OMe OMe (+)-methyl-O-acetylisoreserpate H H N H H H N N OMe OAc H H CO Me MeO 2 CO2Me HN OMe OAc MeO Thermodynamics favors the wrong conformation for an acid catalyzed epimerization. Reserpine O N N MeO N 1. POCl , ! MeO N H H 3 H H H 2. NaBH , H 4 H MeOH MeO2C OAc MeO2C OAc OMe OMe (+)-methyl-O-acetylisoreserpate H H H H H N H H H H N N N N N N OMe N ONAc H H H H HCO Me H H MeO 2 CO2Me HN OMe H OAc MeO N N N N H H H H Reserpine: Molecular Judo Hydrolysis and lactone formation lock the molecule in the thermodynamically unfavorable conformation. H H N H H H N N OMe OAc H H CO Me MeO 2 CO2Me HN OMe OAc MeO H H N H N H H H OAc O CO Me 1. KOH, MeOH MeO 2 MeO O HN HN 2. DCC, pyr MeO MeO Reserpine: Molecular Judo H H N H N H O H t-BuCO H O O 2 MeO O HN MeO H HN xylenes, ! OMe MeO NaOMe, Epimerization is now favored, correcting the stereochemistryMeO H, ! N MeO N H H H N Pyridine MeO N O H H H H O OMe OMe Cl MeO2C O H H OMe OMe MeO2C OH OMe OMe OMe OMe (+)-reserpine Reserpine H H N H N H O H t-BuCO H O O 2 MeO O HN MeO H HN xylenes, ! OMe MeO NaOMe, MeOH, ! N MeO N H H H N Pyridine MeO N O H H H H O OMe OMe Cl MeO2C O H OMe OMe MeO2C OH OMe OMe OMe OMe (+)-reserpine Reserpine (+)-reserpine 1. (+)-CSA 2. NaOH N MeO N H H H O H OMe MeO2C O OMe OMe (-)-reserpine OMe Woodward: Organic Ninja When defeated by both kinetics and thermodynamics, Woodward manipulated the system so that it worked in his favor.
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