TY - JOUR
T1 - A biosynthetically inspired synthesis of (−)-berkelic acid and analogs
AU - Bender, Christopher F.
AU - Paradise, Christopher L.
AU - Lynch, Vincent M.
AU - Yoshimoto, Francis K.
AU - De Brabander, Jef K.
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/3/1
Y1 - 2018/3/1
N2 - We describe a complete account of our total synthesis and biological evaluation of (−)-berkelic acid and analogs. We delineate a synthetic strategy inspired by a potentially biomimetic union between the natural products spicifernin and pulvilloric acid. After defining optimal parameters, we executed a one-pot silver-mediated in situ dehydration of an isochroman lactol to methyl pulvillorate, the cycloisomerization of a spicifernin-like alkynol to the corresponding exocyclic enol ether, and a subsequent cycloaddition to deliver the tetracyclic core of berkelic acid. Our studies confirm that the original assigned berkelic acid structure is not stable and equilibrates into a mixture of 4 diastereomers, fully characterized by X-ray crystallography. In addition to berkelic acid, C22-epi-berkelic acid, and nor-berkelic acids, we synthesized C26-oxoberkelic acid analogs that were evaluated against human cancer cell lines. In contrast to data reported for natural berkelic acid, our synthetic material and analogs were found to be devoid of activity.
AB - We describe a complete account of our total synthesis and biological evaluation of (−)-berkelic acid and analogs. We delineate a synthetic strategy inspired by a potentially biomimetic union between the natural products spicifernin and pulvilloric acid. After defining optimal parameters, we executed a one-pot silver-mediated in situ dehydration of an isochroman lactol to methyl pulvillorate, the cycloisomerization of a spicifernin-like alkynol to the corresponding exocyclic enol ether, and a subsequent cycloaddition to deliver the tetracyclic core of berkelic acid. Our studies confirm that the original assigned berkelic acid structure is not stable and equilibrates into a mixture of 4 diastereomers, fully characterized by X-ray crystallography. In addition to berkelic acid, C22-epi-berkelic acid, and nor-berkelic acids, we synthesized C26-oxoberkelic acid analogs that were evaluated against human cancer cell lines. In contrast to data reported for natural berkelic acid, our synthetic material and analogs were found to be devoid of activity.
KW - Cycloaddition
KW - Cycloisomerization
KW - Natural products
KW - Quinone methide
KW - Spiroketals
UR - http://www.scopus.com/inward/record.url?scp=85040685095&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040685095&partnerID=8YFLogxK
U2 - 10.1016/j.tet.2018.01.021
DO - 10.1016/j.tet.2018.01.021
M3 - Article
C2 - 29867257
AN - SCOPUS:85040685095
SN - 0040-4020
VL - 74
SP - 909
EP - 919
JO - Tetrahedron
JF - Tetrahedron
IS - 9
ER -