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6 the Lf-diX Relationship AL But how are we to make the epoxide 617 The obvious route is by epoxidation of the alkene 63. The alkene 63 could be made by a Wittig reaction (chapter 15) on the ketone 64 or directly by sulfur ylid chemistry (chapter 30). é ~ 4} é ~ Now RCO _Me2S=CH_ Ce sulfur ylid 63 61 64 The ketone 64 still has a 1,2-diX relationship but at the carbonyl oxidation level, sa we discon- nect to another molecule of triazole 62 and the a-halo ketone 66 is easily made by a Friedel-Crafts reaction using available chloroacetyl chloride. This time we buy the 1,2-diX relationship in the form of chjoroacctyl chloride. ZA 0 co N é ns j oi ci ~coct v2 FO OGN F => 1,2 eae triazole “Crafts F F 64 65 66 The synthesis follows the analysis exactly giving fluconazole 60 in only 5 steps from available starting materials. This synthesis should demonstrate that important modern drugs are made by the style of reactions that you are meeting in this book.® The 1,1-diX Relationship The label ‘1,1-diX” may look strange but all it means is that the two functional groups are joined to the same carbon atom. You already know how to make acetals 68: you combine an aldehyde 67 with an alcohol, say methanol, in acidic solution. The disconnection 68a is therefore of both C-O bonds. This reveals a valuable truth: two heteroatoms joined to the same carbon atom are at the carbonyl oxidation level (two C—O bonds to the same C atom in both 67 and 68) and the TM is probably made from a carbonyl compound. Synthesis Analysis MeOH pe pom 4 t-aix HOMe R-cHO a> RL ak ===> r-cno He ‘OMe ‘OMe 2xC-O HOMe 67 68 68a 67 Again you may think that we are not using the two groups in cooperation. Bul we arc. The. key step in acetal formation and hydrolysis is the expulsion. of one OR group by the other. In the synthesis, protonation of the hemiacetal 69 is followed by expulsion of a molecule of water 70 and the addition of the second molecule of methanol 71 is possible because of the first. In the