total synthesis of tremulenolide a
TRANSCRIPT
Total synthesis of tremulenolide A
1st Literature review presentation
Grenning Group
Ouidad LAHTIGUI
Synthesis of tremulenolide A
Cruz, E. R., Can. J. Chem., 1997, 75, 834.
tremulenolide A
Isolated from fungus Phellinus tremulae
Tremulane core and its posi4onal isomers
lactarane merulane tremulane
OO
H
Synthesis of tremulenolide A Biosynthesis of tremulane core
Tremulane sesquiterpenes
Tremulenediol A
PPO
H
B H
- H + H
H
H
H
HH
HH
H
HH
H H
H2O
HO
H
OH
OH
humulene
re
si
farnesyl diphosphate
Ayer W. A.; Cruz, E. R. J. Org. Chem. 1993, 58, 7529.
Synthesis of tremulenolide A
Ying, Y-M.; Shan, W-G.; Zhang, L-W.; Zhan, Z-J., Phytochemistry, 2013, 95, 360. Wu, X.; Lin, S.; Zhu, C.; Yue, Z.; Yu, Y.; Zhao, F.; Liu, B.; Dai, J.; Shi, J.. J. Nat. Prod., 2010, 73, 1294.
Tremulane derivatives
HOH
H
HO
HO
ceriponol A
OOH
OH
ceriponol B
H
OH
OOMe
ceriponol G
H
OH
OOMe
O
ceriponol H
Phellinus ignarius
Conocybe siliginae
H H
AcO
HOOH
H
OH
OH
AcO
AcO
OH
HO H
OH OH
AcO
Ceriporia lacerate
H H
HOOH
H
OH OH
H
OH OH
OH
HO
HO HO
OH
H
OH
Synthesis of tremulenolide A
Davies, H. M. L.; Doan, B. D., J. Org. Chem., 1999, 64, 8501.
Former tremulenolide A synthesis attempt
Retrosynthesis strategy
(+)-5 – epi- tremulenolide A
OO
HH
HO
O
N2
MeOH
CO2H
Synthesis of tremulenolide A Formation of cis/ trans-vinyldiazoacetate
N3SO
OHN
O
p-ABSA:
CO2Me
LiOH
MeOH/H2O 96%
CO2H OHO
O
p-ABSA
DBU, 45 °C55%
O
ON2
DCC, DMAP
CH2Cl2, 0 °C, 88%
Davies, H. M. L.; Doan, B. D., J. Org. Chem., 1999, 64, 8501.
Synthesis of tremulenolide A
Regitz, M., Angew. Chem. int. Ed., 1967, 6, 733.
Regitz diazo-transfer reaction - mechanism
O
OB O
O
BH
N N
O
NHO
OSN
O
O
N
NSO OAr
NH
O
O
N
NHSO OAr
N
O
O
HB
NN
O
ON2
NH2
SO OAr
+ B
Synthesis of tremulenolide A Cyclopropanation/cope rearrangement
R
SN
OO
O
O Rh
Rh
4R = C12H25
Rh2(R-DOSP)4
(+)-5 – epi- tremulenolide A
O
O
N2
Me
-78 °C 69%
35% ee
Rh2(R-DOSP)4
OO
HH
H
O
O
N2
Me
H
-78 °C 65%
98% ee
Rh2(R-DOSP)4O
O
Me
o-xylene -140 °C 85%
H2 / RhCl(PPh3)3
EtOH, 76%
OO
HH
H
Davies, H. M. L.; Doan, B. D., J. Org. Chem., 1999, 64, 8501.
Synthesis of tremulenolide A
Ashfeld, B. L.; Martin, S. F., Org. Lett., 2005, 7, 4535.
Latest tremulenolide A synthesis
OO
H H
OHOH
OBn
OHC H
H
EE
O
CO2MeMeO2C OBn
OH
HO
O
N2
HO OH
Synthesis of tremulenolide A Synthesis of cyclic synthon: cyclopropyl lactone
O OHO
O
O
O O
O
O
N2O
OH
H
n-BuLi, Me3SI
DMAP, NaOAc, THF 93%
THF, 84%
p-TsN3, Et3N, CH3CN
then LiOH.H2O, 97%
Rh2[5-(R)-MEPY]4
CH2Cl2, 99%dr = 1:1, 94% ee
Rh Rh
NN
N
CO2Me
O
O
N
O
OMeO2C
Rh2[5-(R)-MEPY]4
Ashfeld, B. L.; Martin, S. F., Org. Lett., 2005, 7, 4535.
Synthesis of tremulenolide A Mechanism of cyclopropanation
H
HH
[Rh]
HO
O
Davies, H. M. L.; Doan, B. D., J. Org. Chem., 1999, 64, 8501.
[Rh]
O
O
NN
[Rh]
O
O
[Rh]
O
O
[Rh]
O
H
H
O
Rhodium carbene intermediate
Synthesis of tremulenolide A
HO OH
BnBr, TBAI
NaH, DMF, 53% HO OBnMsCl. Et3N
CH2Cl2, 92%MsO OBn
CH2(CO2Me)2, NaHTHF, 97%
CO2MeMeO2C OBn
Synthesis of linear synthon: malonate
Ashfeld, B. L.; Martin, S. F., Org. Lett., 2005, 7, 4535.
Synthesis of tremulenolide A Formation of fused ring via a 5+2 cycloaddition
O
OH
H +CO2Me
MeO2C OBnPd(PPh3)4, PPh3
NaH, THF, 71% OBn
HO2C H
H
MeO2CMeO2C
1. (COCl)2, DMF, CH2Cl2
2. LiAlH(OtBu)3, THF, -78 °C 84%
OBn
OHC H
H
MeO2CMeO2C
CHO
H
OBn
[Rh(CO)2Cl]2, PhMe
110 °C 84%MeO2C
MeO2C
Ashfeld, B. L.; Martin, S. F., Org. Lett., 2005, 7, 4535.
Synthesis of tremulenolide A
Wender, P. A.; Dyckman, A. J., Org Lett., 1999, 1, 2089.
Mechanism of 5+2 cycloaddition
BnO
CO2MeMeO2C
CHOH
[Rh]
BnO
CO2MeMeO2C
CHOH
H[Rh]
H
H
CHO
H[Rh]
H
HCHO
H[Rh]
H
H CHO
H
Oxidation addition
H
Rotation around C-C bond
Syn alignment of hydrogen atomsRing expansion
CHO
H
OBn
MeO2CMeO2C
[Rh]
Reductive elimination
OBn
OBn
OBn
MeO2CCO2Me
MeO2C
MeO2CMeO2C
MeO2C
Synthesis of tremulenolide A Functionalization of fused ring system leading to natural product
CHO
H
OBn
MeO2CMeO2C
1. NaBH4, THF2. TBSCl, ImH, DMF
81%
H
OBn
MeO2CMeO2C
OTBS
1. LiAlH4, THF2. MsCl, Et3N, CH2Cl2 72%
H
OBn OTBS
MsO
OMs
1. LiBHEt3, THF
2. TBAF, THF, 70%
H
OBn OH
H
OH
H2, Pd/C
84%
OH
MnO2, CH2Cl2
86%
OO
H
Ashfeld, B. L.; Martin, S. F., Org. Lett., 2005, 7, 4535.
Synthesis of tremulenolide A Two previous methods:
Cyclopropana4on: -‐ Precursor of fused rings simple to synthesize
-‐ Key step genera4ng 3 stereocenters … Epimer! 5+2 cycloaddi4on: -‐ Rela4vely long synthesis to obtain the cycloaddi4on
precursor
-‐ Key step genera4ng 3 stereocenters with right stereochemistry
…Natural product!
Acknowledgements
✴ Dr A. J. Grenning
✴ Grenning Group ✴ University of Florida ✴ Chemistry Department
✴ Thank you all for your attention