Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B.
The total synthesis of the epidermal growth factor inhibitor reveromycin B (2) in 25 linear steps from chiral methylene pyran 13 is described. The key steps involved an inverse electron demand hetero-Diels-Alder reaction between dienophile 13 and diene 12 to construct the 6,6-spiroketal 11 which upon oxidation with dimethyldioxirane and acid catalyzed rearrangement gave the 5,6-spiroketal aldehyde 9. Lithium acetylide addition followed by oxidation/reduction and protective group manipulation provided the reveromycin B spiroketal core 8 which was converted into the reveromycin A (1) derivative 6 in order to confirm the stereochemistry of the spiroketal segment. Introduction of the C1-C10 side chain began with sequential Wittig reactions to form the C8-C9 and C7-C6 bonds, and a tin mediated asymmetric aldol reaction installed the C4 and C5 stereocenters. The final key steps to the target molecule 2 involved a Stille coupling to introduce the C21-C22 bond, succinoylation, selective deprotection, oxidation, and Wittig condensation to form the final C2-C3 bond. Deprotection was effected by TBAF in DMF to afford reveromycin B (2) in 72% yield.
School of Chemistry, The University of Melbourne, Victoria 3010, Australia.
A N
AN
Cuzzupe
C A
CA
Hutton
M J
MJ
Lilly
R K
RK
Mann
K J
KJ
McRae
S C
SC
Zammit
M A
MA
Rizzacasa
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D011714:Pyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D000903:Antibiotics, Antineoplastic; D011714:Pyrans; D013141:Spiro Compounds; C409389:reveromycin B; D004815:Epidermal Growth Factor