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OXIDATIVE COUPLING

OXIDATIVE COUPLING. OXIDATIVE COUPLING OF PHENOLS. PHENOLIC RINGS COUPLE EVEN WITH MILD OXIDIZING REAGENTS. FeCl 3. Fe 2+. Pt anode. (- e - ). K 2 S 2 O 8. . ( ). . ( ). . ( ). COUPLING PROCEEDS VIA RADICALS FORMED FROM THE CONJUGATE BASE. anion. . -. K 3 Fe(CN) 6.

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OXIDATIVE COUPLING

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  1. OXIDATIVE COUPLING OXIDATIVE COUPLING OF PHENOLS

  2. PHENOLIC RINGS COUPLE EVEN WITH MILD OXIDIZING REAGENTS FeCl3 Fe2+ Pt anode (- e- ) K2S2O8

  3. . ( ) . ( ) . ( ) COUPLING PROCEEDS VIA RADICALS FORMED FROM THE CONJUGATE BASE anion .. - K3Fe(CN)6 ferricyanide : .. KOH FeIII(CN)6-3 - e- FeII(CN)6-4 .. ferrocyanide . COUPLING ! .. at any of the indicated positions radical (has resonance) Even mild oxidizing agents (like O2 )can initiate coupling.

  4. . . O=O . HOO PUMMERER’S KETONE THOUGHT (INCORRECTLY) FOR MANY YEARS TO BE A MODEL FOR MORPHINE BIOSYNTHESIS O2 Pummerer’s ketone . one-electron oxidation Michael addition . . couple enolization : H+ : OH2 H+

  5. PHENOLS ARE VERY SENSITIVE TO OXIDATION Mild oxidizing agents, including oxygen, cause oxidative coupling. Stronger oxidants, cleave (destroy) the phenolic ring, especially if there are multiple phenolic groups, or the phenolic groups are ortho. EXAMPLE [O] [O] sidechains or other rings may survive as acids [O] [O] R-COOH etc + n CO2

  6. OXIDATIVE COUPLING MAKES SIMPLE COMPOUNDS MORE COMPLEX VERY QUICKLY

  7. APORPHINES (TWO TYPES) standard benzylisoquinoline 2 tyrosine Note how the benzene ring can rotate around its attachment to make a different substitution pattern. [O] . . . . rotate coupling, rearomatization via enolization, SAM coupling, rearomatization via enolization, SAM (+)-glaucine (+)-corydine

  8. ORIENTALINONE From a poppy-relative that grows in China. standard benzylisoquinoline 2 tyrosine [O] . . coupling (S)-orientalinone NADPH -H2O + orientalinol (S)-isothebaine H+

  9. CULARINE . . SAM cularine

  10. AMARYLLIS ALKALOIDS THREE TYPES oxidative coupling + other steps A fold B rotate C Compounds can “fold”, twist rings around, and adopt other conformations before oxidative coupling takes place. This makes interesting bicyclics and some variations in the substitution pattern.

  11. ERYTHRINA ALKALOIDS Erythrina crista-galli H+ . .. . H+

  12. (Chondodendron spp) Arrow poison of South American Indians (“pot curare”); another variety , “calabash curare”, is made from plants that have steroidal sapogenins. There are about 30-40 different plants in the mixture, not all active. Potency: one-tree, two-tree and three-tree (does not kill) curares are made, depending on how many trees a monkey will travel to before falling. It works by paralyzing muscles, including those necessary for breathing. (S)-N-methylcoclaurine . coupling SAM [O] enolizations . . . + [O] tubocurarine (R)-N-methylcoclaurine

  13. NOT JUST ALKALOIDS

  14. GRISEOFULVIN (discussed earlier) POLYKETIDE SAM .. Cl+ OXIDATIVE COUPLING reson. [O] . . . . FADH2 SAM griseofulvin

  15. . HYPERICIN ACETOGENIN emodin-anthrone . . NADPH [O] x2 oxidative coupling more oxidative coupling and oxidation hypericin

  16. MORPHINE

  17. BIOSYNTHESIS OF MORPHINE (details will be given later) tyrosine oxidative coupling ring formation thebaine norlaudanosoline reticuline morphine

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