Probing the SAR of dEpoB via chemical synthesis: a total synthesis evaluation of C26-(1,3-dioxolanyl)-12,13-desoxyepothilone B.
A practical total synthesis of 26-(1,3-dioxolanyl)-12,13-desoxyepothilone B (26-dioxolanyl dEpoB) was accomplished in a highly convergent manner. A novel sequence was developed to produce the vinyl iodide segment 17 in high enantiomeric excess, which was used in a key B-alkyl Suzuki merger. Subsequently, a Yamaguchi macrocyclization formed the core lactone, while a selective oxidation and a late stage Noyori acetalization incorporated the dioxolane functionality. Sufficient amounts of synthetic 26-dioxolane dEpoB were produced using this sequence for an in vivo analysis in mice containing xenograft CCRF-CEM tumors.
Chappell
Mark D
MD
Laboratories for Bioorganic Chemistry and Laboratories for Preclinical Pharmacology, The Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
Harris
Christina R
CR
Kuduk
Scott D
SD
Balog
Aaron
A
Wu
Zhicai
Z
Zhang
Fei
F
Lee
Chul Bom
CB
Stachel
Shawn J
SJ
Danishefsky
Samuel J
SJ
Chou
Ting-Chao
TC
Guan
Yongbiao
Y
D000818:Animals; D018450:Disease Progression; D034261:Epothilones / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D004852:Epoxy Compounds / Q000737:chemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D034261:Epothilones; D004852:Epoxy Compounds; C114026:desoxyepothilone B