1 Problem session (1) Answer 2015.10.2 Daiki Kuwana Topic : A Total Synthesis of ( )-Basiliolide B by Lee et al. CO 2 Me O O ( )-basiliolide B O MeO O H Introduction 1. About basiliolide O O ( )-basiliolide A1 (transtaganolide D) O MeO O H O O ( )-basiliolide A2 (transtaganolide C) O MeO O H R S R CO 2 Ac O O ( )-basiliolide C O MeO O H R Isolation : A plant Thapsia garganica Appendino, G. et al., J. Nat. Prod. 2005, 68, 1213. Bioactivity : Mobilization of intracellular Ca 2+ and NFAT activation in the leukemia T-cell line Jurkat Navarrete, C. et al., J. Pharmacol. Exp. Ther. 2006, 319,422. Features : Tetracyclic core including a seven-membered ring, a trans-decalin framework, a lactone bridge 2. Total synthesis by Stoltz's group R O O O MeO O H C B A D 8 9 1 common structure I CO 2 Me O O H OTBS O Pd(Pt-Bu 3 ) 2 DMF, then water n-Bu 3 Sn OMe CO 2 Me O O H OTBS O OMe H 2 O CO 2 Me O O ( )-basiliolide B O MeO O H 8 + CO 2 Me O O ( )-epi-8-basiliolide B O MeO O H 8 (5%) (14%) 8 8 Nelson, H. M. et al., Angew. Chem. Int. Ed. 2011, 50, 3688. 9 9 9 9 MeO 2 C HO 3 steps 3. Approaches by authors CO 2 Me O O O O O H Me X H CO 2 Me O O O MeO O H CO 2 Me O O H O LG MeO O H 0-1 0-2 0-3 O-methylation O-acylation (Problem 3) Min, L. et al., Angew. Chem. Int. Ed. 2014, 53, 1294. Stille coupling H Claisen rearrangement Diels-Alder reaction 14 0-4 0-5
Transcript
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Problem session (1) Answer 2015.10.2 Daiki Kuwana
Topic : A Total Synthesis of ( )-Basiliolide B by Lee et al.
CO2Me
O
O
( )-basiliolide B
O
MeO
O
H
Introduction
1. About basiliolide
O
O
( )-basiliolide A1
(transtaganolide D)
O
MeO
O
H
O
O
( )-basiliolide A2
(transtaganolide C)
O
MeO
O
H
R S R
CO2Ac
O
O
( )-basiliolide C
O
MeO
O
H
R
Isolation : A plant Thapsia garganica
Appendino, G. et al., J. Nat. Prod. 2005, 68, 1213.
Bioactivity : Mobilization of intracellular Ca2+ and NFAT activation in the leukemia T-cell line Jurkat
Navarrete, C. et al., J. Pharmacol. Exp. Ther. 2006, 319, 422.
Features : Tetracyclic core including a seven-membered ring, a trans-decalin framework, a lactone bridge
2. Total synthesis by Stoltz's group
R
O
O
O
MeO
O
H
C
BAD
891
commonstructure
I
CO2Me
O
O
H
OTBSO
Pd(Pt-Bu3)2
DMF, then water
n-Bu3Sn OMe
CO2Me
O
O
H
OTBSO
OMe
H2O
CO2Me
O
O
( )-basiliolide B
O
MeO
O
H
8+
CO2Me
O
O
( )-epi-8-basiliolide B
O
MeO
O
H
8
(5%) (14%)
88
Nelson, H. M. et al., Angew. Chem. Int. Ed. 2011, 50, 3688.
9 9
9 9
MeO2C
HO3 steps
3. Approaches by authors
CO2Me
O
O
O
O
O
H
Me X
H
CO2Me
O
O
O
MeO
O
HCO2Me
O
O
H
O LG
MeOO
H
0-1 0-2 0-3
O-methylation O-acylation
(Problem 3)
Min, L. et al., Angew. Chem. Int. Ed. 2014, 53, 1294.
Stille coupling
H
Claisen rearrangement
Diels-Alder reaction
14
0-4 0-5
2
O
O
N2H
O
O
O
O
N2H
O
O O
N2
O
O
O
O
N2
O
O
OI
O
O
H
O
O
N2
O
O
step 1)
O
O
N2
A
1) 1, DBU (10 mol%), IBX,
DMSO, rt, 65%
2) 2 (10 mol%), toluene,
80℃, 74%,single diastereomer
3) NaBH4, MeOH,-78℃ to 20℃77%, d.r. = 10:1
4) 4N KOH, EtOH, 90℃;allyl bromide, DMF,rt, 98%
5) PPh3, I2, imidazole,THF, 0℃, 85%
6) n-BuLi, THF, <-80℃,97%
OH
OO
O
1
Establishment of the stereogenic centers at C8 and C9
H
O
O
1
OCu
N
N
O
2
1-1 1-3 1-4
1-6
1-7
N
N
Cu(TBS)2
8
9
O
N2
OH
O
O
I
O
OOH
N
N
H
O
N2
OH
O
1-5N
N
IBX
OI
O
OH
-H2O
1-1 1-2
H
3
O
O O
O
OH
O O
O
OH
Cu(TBS)2
O
L2Cu
O
O
1-10
O
O O
O
1-10
BH3H
KOH
O
O O
OH
1-11
H OMe
HO
O O
OH
step 3)
A
OH
O O
O
O
H
1-12
CuL2
O
O
N2
O
O
1-7
O
O
N
O
O
N
CuL2
O
O
N
O
O
1-8
N
CuL2
1-9
O
OO
OO
step 2)
OH
O O
O
OHBr
OH
O O
O
OH
step 4)1-13 1-14
N2
II II
II
II
H
II
4
Ph3P I I
Ph3P I
OH
OO
OH
OH
O O
O
OH
Ph3P I + I
I
OH
O O
O
OPPh3
nBuLi
nBuLi
step 5)
step 6)
H
step 4)
OH
O O
O
I
1-14 1-16
1-17
1-2
OH
O O
O
1-15
OPPh3H
NHN
halogen-lithium
exchange
Ph3P O
OLi
OOLi
O
1-19
1-18
X
Appel reaction
imidazole
Discussion
1. Cyclopropanation / ring opening vs. Claisen rearrangement
Cyclopropanation / ring opening Claisen rearrangement
temperaturelower higher
diastereoselectivityhigh low
steric repulsonlarge small
steps 1 stepat least 2 steps
Larsson, R. et. al., Org. Lett. 2009, 11, 658
1-20
Controlling relative configuration of C8 and C9 using Claisen arrangement
O
O
IOO
OTMS
NTMS
Et3N
toluene, 120℃
1-21
O
O
IOHO
84%, d.r = 2:1
89
O
O
Li
OLi
OH
5
3. Diastereoselectivity at protonation・Transition state half-chair conformation
OH
OO
OH
step 6)1-2
2. Diastereoselectivity in NaBH4 reduction
H3B
O
O O
O
BH3H
1-10
NH4ClH2O
1-19-1
(favored)
1-19-2
(disfavored)
OH
OO
OH
1-2'
work-up
O
Ar
(L)
H
O
O
(M)
(S)
convex face
concave faceO
H
BH3
H
O
Ar
H
O
O
O
H
O
O O
OH
1-11
O
Li
O
O
RO
H
Li
O
O
Li O
O
R
H
Lisyn-pentaneinteraction
O
OOLi
O
1-19
Li
・Negative hyperconjugation - proposed by authors -
