The syntheses of aflastatin A and its C3-C48 degradation fragment are described. The syntheses feature several complex diastereoselective fragment couplings, including a C35-C36 anti-Felkin-selective boron-mediated oxygenated aldol reaction, a C15-C16 Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, and a C26-C27 chelate-controlled aldol reaction involving soft enolization with magnesium. Careful comparison of the spectroscopic data for the synthetic aflastatin A C3–C48 degradation fragment (2) to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. The cause of the mismatch was initially believed to be stereochemical in origin. Ultimately, the data reported for the naturally derived aflastatin A C3–C48 degradation lactol (2, R = H) was attributed to its derivative lactol trideuteriomethyl ether \((R = CD_3)\). Further, the absolute configurations of six stereogenic centers (C8, C9 and C28–C31) in aflastatin A (1) were formally revised by the isolation group prior to completion of its total synthesis. The synthesis of the aflastatin A C3–C48 lactol trideuteriomethyl ether and its spectroscopic match to the naturally derived C3–C48 degradation fragment confirm the stereochemical revision. The synthesis of a degradation product containing the tetramic acid and two overlapping stereocenters (C4 and C6) was also achieved. Its spectroscopic match to the corresponding naturally derived degradation fragment verified the absolute configuration of the aflastatin A C5' stereocenter. When combined with previous degradation fragment syntheses, and eventually the total synthesis of aflastatin A, the revised stereochemical assignment of aflastatin A was fully affirmed. / Chemistry and Chemical Biology
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/10974701 |
| Date | 07 June 2014 |
| Creators | Beiger, Jason James |
| Contributors | Evans, David A. |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | open |
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