Total Synthesis and Biomimetic Studies of Nine-Membered Enediynes
Martin J. Lear*, Keiichiro Hirai, Kei Yamada, Ryo Takahashi, Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578
[email protected]
The kedarcidin and C1027 chromophores are formidable targets of total synthesis. During our
20-year study of these nine-membered enediyne chromophores, several powerful, yet
chemoselective methods have been developed: stereoselective epoxyalkyne formation,
atropselective Pd/Cu-Sonogashira coupling, 2-deoxy-α-glycosylation, CeX3-mediated
enediyne cyclisation, and SmI2-based reductive olefination. Besides their total syntheses,
application of these methods to the biomimetic study of the putative enediyne-precursors of
the cyanosporasides, sporolides, and fijiolides will be presented. In particular, we disclose
biomimetic evidence of a p-benzyne diradical species reacting in either a radical mode
(hydrogen abstraction) or ionic mode (chloride attack) at the same sterically exposed site,
leading to either monochlorinated cyanosporaside A/F or cyanosporaside B–E, respectively.
The ionic monochlorination of the cycloaromatized p-benzyne of the C1027 enediyne core to
generate the fijiolide aglycon framework will also be presented.
Cl
OH
OH
3
O
N
OH
O
OH
O
"H", "Cl"
incorporation
6
OH
O
Cl
NHR
Fijiolide A: R = COCH3
Fijiolide B: R = H
N
OH
O
Biomimetic Studies
and Total Synthesis
of Natural Enediynes
O
O
OH
O
OH
O
O
Cl
MasamuneBergman
cyclization
NHR
Pre-fijiolide
(C1027-like)
i-PrO
[Sugar]
OH
1
O R
CN
HO
"H", "Cl"
incorporation
OH
O
[Sugar]
O
MeO
O
OOH / Ac
OMe
Cl N
NH
O
O
O
O
NMe2
OH
O
CN
R2
Cyanosporaside A/F: R1= Cl, R2= H
Cyanosporaside B-E: R1= H, R2= Cl
OH
Pre-cyanosporaside
(proposed)
HO
HO
O
O
O
Kedarcidin chromophore
*Dedicated to the lasting contributions of Professor Emeritus Masahiro Hirama to Total Synthesis
CV of Attendant: Martin J. LEAR (マーティン・リアー ).
Picture of Speaker
Education: University of Glasgow, Scotland, UK (B.Sc., 1991; Ph.D., 1996).
(35 mm × 45 mm)
Professional career: Since Jan 2013, he has been a Lecturer and then Associate
Professor at Tohoku University (Sendai, Japan). During 2005 to 2012, he was as
a Lecturer and core-member of the Medicinal Chemistry Group at the National
University of Singapore (NUS). During 2000 to 2004, he was an Assistant
Professor at Tohoku University with Masahiro Hirama (Sendai, Japan).
Awards / other information: Postdoctoral fellowships include Parke-Davis (Cambridge, UK, 1996),
ICSN-CNRS (Gif-sur-Yvette, France, 1997) and Tohoku University (JSPS and CREST, 1997-2000).
Dr. Lear is also a Co-founder and Director of www.BioLynxTech.com (Singapore, since March 2011).