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Total Synthesis of Rapamycin
Author(s) -
Nicolaou K. C.,
Piscopio Anthony D.,
Bertinato Peter,
Chakraborty Tushar K.,
Minowa Nobuto,
Koide Kazunori
Publication year - 1995
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.19950010509
Subject(s) - swern oxidation , chemistry , stille reaction , total synthesis , sulfonium , aldol reaction , iodide , palladium , intramolecular force , aldehyde , amide , coupling reaction , organic chemistry , catalysis , salt (chemistry) , dimethyl sulfoxide
Details of the total synthesis of rapamycin (1) are reported. The synthesis required the preparation of intermediates 4 – 9 in nonracemic form; key coupling reactions included a chromium‐mediated addition of vinyl iodide 8 to aldehyde 7 and an Evans aldol reaction to couple fragments 62 and 9 . Intermediates 4 and 6 were joined through an amide bond formation to afford advanced intermediate 71 . Swern oxidation of the diol in 71 was followed by a selective removal of the TES groups and a second Swern oxidation. Finally, removal of the remaining silyl protecting groups provided fully deprotected, penultimate intermediate 2 in which all carbons were in their proper oxidation state. Macrocyclization was achieved through a tandem inter/intramolecular palladium‐mediated Stille coupling reaction between distannylethene 3 and bis(vinyl iodide) 2 . This latter process accomplished in one step the installation of the remaining two carbons of the natural product and the completion of its total synthesis.