mar_15 - 3/16/2010 The following reaction sequence cannot...

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Unformatted text preview: 3/16/2010 The following reaction sequence cannot be used to prepare A. A ~100% ~100% pKa = 19 ~0.1% ~100% A SN 2 A. Very sure this is true F. Very sure this is false N Li ~100% ~100% pKa = 19 ~0.1% ~100% A SN 2 aldol LDA ~100% ~0.1% ~100% ~0% pKa = 19 A SN 2 aldol How can these products be suppressed? The following reaction sequence can be used to prepare A. What are NSAIDs? NSAIDs? NSAID = non steroidal anti inflammatory drug = aspirin, ibuprofen, etc. What is a common steroidal anti inflammatory drug? O HO O N LDA Li H H H HO ~100% A coniine H 2N H2N O B cortisone HO H3C C ibogamine O OH O O D lysine E limonene F vanillin 1 3/16/2010 Identify the abused substance heroin and the NSAID aspirin. H3C O O H N CH3 O H3C O HO H O N CH3 O HO Identify the abused substance heroin and the NSAID aspirin. H3C O O N CH3 O H3C O H HO H O N CH3 O HO 1 2 heroin A. 2 B. 2 1 1 C. aspirin 3 4 4 3 heroin morphine O OH O CH3 O O OH OH O OH O CH3 O O OH OH D. 3 4 aspirin salicylic acid Identify the abused substance heroin and the NSAID aspirin. H3C O O H N CH3 O H3C O O HO Identify the abused substance heroin and the NSAID aspirin. H3C O O Ac2O base HO O H N CH3 O H3C O O H N CH3 heroin morphine heroin O OH O O OH OH OH Ac2O O CH3 base Felix Hoffmann 1897 O CH3 O Felix Hoffmann 1897 aspirin O salicylic acid aspirin Identify the abused substance heroin and the NSAID aspirin. H3C O O H N CH3 O H3C O O Are there other carboxylic acids found in nature? O O O O OH CO2H prostaglandin PGH2 platelet aggregation O OH O CH3 O arachidonic acid prostacyclins thromboxanes Felix Hoffmann 1897 G protein coupled receptors smooth muscle constraction other prostaglandins aspirin HO HO HO HO heroin cyclooxygenase (COX) O O 2 3/16/2010 Are there drugs that can control the harm done by the prostaglandins? (finger) O O OH CO2H Are there drugs that can control the harm done by the prostaglandins? (finger) O CO2H COX 1 COX 2 O COX 1 COX 2 O O OH prostaglandin PGH2 (stomach) O OH O CH3 O HO prostaglandin PGH2 arachidonic acid (stomach) arachidonic acid O NSAIDs inhibit COX enzymes CH3 S O O O inflammation, pain O inflammation, pain Rofecoxib (VIOXX) NSAIDs inhibit COX enzymes Are there drugs that can control the harm done by the prostaglandins? O C OH CRYSTAL STRUCTURE OF ARACHIDONIC ACID BOUND TO THE CYCLOOXYGENASE ACTIVE SITE OF COX-2 COXamino aci serine NH H N O O H CH3 H O H2N S O O N N F F F CH3 S O O O O amino acid tyrosine Celecoxib (Celebrex) Rofecoxib (VIOXX) NSAIDs inhibit COX enzymes Nature, 2000, 405, 97-101 97- amino acid serine NH H N NH amino acid serine H N arachidonic acid O H O protein prostaglandin O H O O protein O H O amino acid tyrosine H O amino acid tyrosine Nature, 2000, 405, 97-101 97- Nature, 2000, 405, 97-101 97- HO HO 3 3/16/2010 How does aspirin inactivate cyclooxygenase (COX)? CH3 O O O O amino acid serine NH H N O O aspirin H protein A. The carboxylate ion forms an ester with the OH of tyrosine. B. The carboxylate ion forms an ester with the OH of O serine C. The acetate forms an ester with the OH of serine CH3 O O amino acid serine NH H N O H O O H O amino acid tyrosine H O amino acid tyrosine Nature, 2000, 405, 97-101 97- Nature, 2000, 405, 97-101 97- H3C O O H O H3C O O H O H3C O O O H amino acid serine NH H N NH amino acid serine H N CH3 O O O H O O protein H3C O O O H O O protein O H O amino acid tyrosine O H O amino acid tyrosine Nature, 2000, 405, 97-101 97- Nature, 2000, 405, 97-101 97- How does ibuprofen prevent the COX enzyme from producing prostaglandin? amino acid serine NH H N O O amino acid serine NH H N O O arachidonic acid H3C O O O protein ibuprofen H protein H O amino acid tyrosine H O amino acid tyrosine Nature, 2000, 405, 97-101 97- 4 3/16/2010 Although both aspirin and ibuprofen inhibit COX enzymes one is an irreversible inhibitor whereas the other is a competitive inhibitor. From their mechanism of action choose the correct classification of aspirin and ibuprofen. aspirin amino acid serine NH H N H3C O O O ibuprofen amino a cid serine NH H N A. Aspirin = competitive inhibitor of COX. Ibuprofen = irreversible inhibitor of COX. B. Aspirin = irreversible inhibitor of COX. Ibuprofen = competitive inhibitor of COX. protein O H O O protein protein O H O amino acid tyrosine H O amino acid tyrosine irreversible inhibitor of COX competitive inhibitor of COX A synthesis of (f)-trisporol B. A mating phermone of mucoraceous fungi. O What is the mechanism of this reaction? O H H2O O O O H D H H2O Cl O O O H What What is the mechanism of this transformation? How could the alkyl bromide converted to the alcohol? O O H H2O O O O H H H2O O Br H O O O H O O O O O O H O O O PPh3 5 3/16/2010 Why is the alkyl bromide very reactive? How can the bromide be prepared? O O H H2O O Br or O O O O O Br H O H O O O H H H2O O O O O H O O How can this transformation be accomplished? Why is the top C=O more reactive? O O H H2O O O O H H H2O O O O H O + ? A synthesis of (f)-trisporol B. A mating phermone of mucoraceous fungi. O H H2O O O O H O Et3N 42 6 ...
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