total% synthesisof jiadifenolide - ccc/upcmldccc.chem.pitt.edu/wipf/current...
TRANSCRIPT
Ian Paterson,* Mengyang Xuan, and Stephen M. Dalby
Angew. Chem. Int. Ed. 2014 May 23. doi: 10.1002/anie.201404224.
Total Synthesis of Jiadifenolide
Raffaele Colombo – 6/7/2014
O
OTES
O
O
O
OO
R
OSmLn
O
O
O
OHO
O
OH
A
C
A
C
BB
A
C
Sm
Jiadifenolide
Jiadifenolide
Jiadifenolide is a complex sesquiterpenoid first isolated from the fruit of the Chinese plant Illicium jiadifengpi
by Fukuyama and coworkers in 2009.
Potent neurotrophic ac<vi<es: potenKal therapeuKc treatment of neurodegeneraKve diseases. Low natural abundance (1.5 mg/kg plant material) Unkown structure–acKvity relaKonship (SAR)
A?rac<ve target for total synthesis
O
O
O
OHO
O
OH
Jiadifenolide
Jiadifenolide and related compounds
Natural products from Illicium species with potent neuropharmacological acKviKes containing a seco-‐prezizaane core
O
O
O
OHO
O
OH
Jiadifenolide
Theodorakis 2011,Sorensen 2014, Paterson 2014
O
O
O
OHO
O
Jiadifenoxolane A
HO
O
O
O
OHO
O
Jiadifenoxolane B
HO
O
O
O
OH
HOO
HO
Neomajucin
HO
O
OH
HOO
HO
AnisatinYamada 1990,
Fukuyama 2012
HO O
O
O
O
OH
HOO
JiadifeninDanishefsky 2006,Theodorakis 2011,
Zhai 2012
O
OMeH
Previous total synthesis – Theodorakis (2011)
O
OH
O
O
O
O
OH
O
OH
O
OTES
O
O
O
OH
O
O
OH
O
O
O
OH
O
TBSOO
O
O
O
TBSOO
O
O
OH
O
O
O
O
OH hemiacetal formation
Pd0-mediated
methylation
asymmetric Robinson annulation
Pd0-mediated
carbomethoxylation
translactonization
Angew. Chem. Int. Ed. 2011, 50, 3672 –3676
Previous total synthesis – Theodorakis (2011)
Angew. Chem. Int. Ed. 2011, 50, 3672 –3676
O
O63%
O
OO
D-prolinamide
PPTS, MeCN,40 °C, 14 days
74%
O
O
( > 90% ee )
1) NaBH4 (0.25 eq)
2) TBSCl
TBSO
O
92%
TBSO
O37%
5 steps
OTBS
1) KHMDS, PhNTf2, -78°C, 1h
2) CO (1 atm), Pd(PPh3)4, MeOH, DM, Et3N, 50°C, 1hthen TFA, DCM, rt, 5h
TBSO
O
O
69%
H2O2, 3M NaOH,
THF, 0°C to rt, 5h
99%
TBSO
O
O
O
1) OsO4 (1 mol%), NaIO4
2) Jones reagent
TBSO
O
O
O
OH
70%
O
1) [Pd(allyl)Cl]2
O
2)
HO
O
O
O
OH
OTBAF mCPBAHO
O
O
O
OH
O
O
Dess-MartinO
O
O
O
OHO
OH
38%(over 2 steps)
95%
1) H2 (6 atm), Pd(C),
2) TESOTf
O
O
O
O
OHO
OTES
O
O
O
OHO
OTES1) KHMDS, Comins reag.
2) AlMe3, Pd(PPh3)43) H2 (90 atm), PtO2
57%
NaHMDS,
O
N
PhO2S
Ph
Davis reagent
O
O
O
OHO
OTES
OHO
O
O
OHO
O
OH
Jones reagent
33% (2 steps)
(conditions employed by the Danishefsky group toward the synthesis of jiadifenin)
(-)-jiadifenolide 1.5% overall yield (25 steps in total)
Previous total synthesis – Sorensen (2014)
Angew. Chem. Int. Ed. 2014, 53, 5332 – 5335
O
OH
O
O
O
OOH
OR
DG
O
O
O
CO2Me O
(R)-(+)-pulegone
DG
O
O
C-H oxidation
JOC 1975, 40, 1602
3 steps
(ca. 1$/g)
1) Br2
2) NaOEt, Et2OFavorskii ring contraction
3) O3, Zn, AcOH
57% overall yield
Previous total synthesis – Sorensen (2014)
O
CO2Me 1) DBU,O
2) pTsOH
CO2CH3
O
CH3I, KOtBuCO2CH3
O
3 steps
69%
CHO
O
O
KOtBu, THF, -50 °C
then MeOH, 65 °C
O
O
CN
90%82%
91%
H2SO4, MeOH, H2O, 100 °C O
O
O
73%
1) NH2OH
2) Pd(OAc)2PhI(OAc)2, 1:1 Ac2O/AcOH100°C, 12 h
N
O
O
20%
OAc
OAc
1) Fe, AcOH, TMSCl2) KHMDS, Comins reagent
3) Pd(OAc)2, Ph3P, Et3N, CO (1 atm), MeOH
44%
O
O
OAc
CO2Me
Van Leusen homologation
Ts NC:
SanfordC-H oxidation
Weinreb deprotection
K2CO3,
MeOH
O
O
O
O
H2O2,
NaOH
O
O
O
OO
61% (2 steps)
1) Me3SiCl, LiHMDS, THF, -78 °Cthen NIS
2) DMDO
O
O
O
O
O
O
LiOH
O
O
O
OHO
O
OH
(-)-jiadifenolide 0.4% overall yield (21 steps in total)
40% (3steps)
for Sanford's C-H oxidation see: J. Am. Chem Soc. 2004, 126, 9542-9543Org. Lett. 2010, 12, 532-535Acc. Chem. Res. 2012, 45, 936-946.
for Weinreb acetyl-oxime deprotection see:Tetrahedron Lett. 2010, 51, 3555-3557
Angew. Chem. Int. Ed. 2014, 53, 5332 – 5335
Current work – retrosynthe<cal analysis
O
OH
O
O
O
OOH
O
H
O
O
HO
reductivecyclization
O
O
O
aldol
O
O
OO
H
Ireland-Claisen
oxidation OR
+
O
ca. 1$/g
Paterson et al., Angew. Chem. Int. Ed. . 2014 May 23. doi: 10.1002/anie.201404224.
Synthesis – first steps
O
1) NaBH4, CeCl32) mCPBA
3) TBSCl, imid
65%OTBS
O BF3Et2O, DCM
OTBS
O
19:1 dr
78%
(MeO)2P-CH2CO2Me
O
NaH, THF
73%OTBS
CO2Me 1) LiAlH4
2) Ac2O
77%
OTBS
OAc LDA, TBSCl, -78 °C
OTBS
COOR
R = OTBS, H
then Benzenereflux
OTBS
O
TBSO
LiAlH4
OTBS
OH63%
10:1 dr
1) HCl/MeOH
2) Swern [O]
74%
Ireland-Claisen
O
OO
OTES
+
M
O
OTESBr
M = Li, ZnBr, MgBr, SmI2,
Unsuccessful Sm-‐mediated coupling
O
1) NaBH4, CeCl32) mCPBA
3) TBSCl, imid
65%OTBS
O BF3Et2O, DCM
OTBS
O
19:1 dr
78%
(MeO)2P-CH2CO2Me
O
NaH, THF
73%OTBS
CO2Me 1) LiAlH4
2) Ac2O
77%
OTBS
OAc LDA, TBSCl, -78 °C
OTBS
COOR
R = OTBS, H
then Benzenereflux
OTBS
O
TBSO
LiAlH4
OTBS
OH63%
10:1 dr
1) HCl/MeOH
2) Swern [O]
74%
Ireland-Claisen
Bu2BOTf, iPr2NEt
THF, -78°C to -20 °C
98%O
OH
O
O
2:1 dr
Dess-Martin
O
O
O
O SmI2
O
O O
O
+
83%
SmI2
Key step: Sm-‐mediated reduc<ve cycliza<on
O
1) NaBH4, CeCl32) mCPBA
3) TBSCl, imid
65%OTBS
O BF3Et2O, DCM
OTBS
O
19:1 dr
78%
(MeO)2P-CH2CO2Me
O
NaH, THF
73%OTBS
CO2Me 1) LiAlH4
2) Ac2O
77%
OTBS
OAc LDA, TBSCl, -78 °C
OTBS
COOR
R = OTBS, H
then Benzenereflux
OTBS
O
TBSO
LiAlH4
OTBS
OH63%
10:1 dr
1) HCl/MeOH
2) Swern [O]
74%
Ireland-Claisen
Bu2BOTf, iPr2NEt
THF, -78°C to -20 °C
98%O
OH
O
O
2:1 dr
TESCl, imid
O
OTES
O
O
O
O O
O
+
O
OTES
O
O+
65% 29%
Proposed mechanism: chelated intermediate
O
OTES
O
O
O
OTES
O
O
SmI2, THF
65°C, 2hHO
OTES
O
O
H
OO
O R
OSmLn
51%
O
O
O ROSmI2
PPTS, MeOH
HO
OH
O
O
H
88%
SmLn
1 ring, 3 stereocenters
O
O
OSmIII
H
O
O
H
SmI2, MeOH
THF, rt, 2 min 57%O
HO
H
O
O
NH
OOH
OH
HO2C
(-)-platensimycin
Nicolaou et al., Angew. Chem. Int. Ed. 2008, 47, 944
OTBSO
O
O
OTBSO
O
HO
HH
SmI2, LiBr,
THF, tBuOH
Reisman et al., J. Am. Chem. Soc. 2013, 135, 11764
57%O
OH
OO
H
O
(-)-trichorabdal A
O
H
TBSO
H
SmIII
O
O
OO
HSmI2, LiBr
THF, -78 °C
O
O
OO
H
SmIII
O
HO
H
OOH O
HO
H
OO
OAc
H
maoecrystal Z
Reisman et al., J. Am. Chem. Soc. 2011, 133, 14964
51%
Previous Sm-‐mediated cycliza<on
Final steps – oxidase phase
O
OTES
O
O
O
OTES
O
O
SmI2, THF
65°C, 2hHO
OTES
O
O
H
OO
O R
OSmLn
51%
O
O
O ROSmI2
PPTS, MeOH
HO
OH
O
O
H
88%
SmLn
1 ring, 3 stereocenters
HO
OH
O
O
HPCC
HO
O
O
O
H
HO
O
O
O
OH+
81% 11%
1) TMSOTf,2) OsO4, NMO 99%
1) NH4BH(OAc)3
2) TESCl, imidHO
OTES
O
O
OH
84%> 19:1 dr
OsO4, NMO, py
84%
HO
OTES
O
O
OH
OH
OH
TPAP, NMOO
OTES
O
O
OH
OO
HF.Py
O
O
O
OHO
O
OH
jiadifenolide 2.3% overall yield (23 steps in total)
88% 86%
NMR spectra comparison
Fukuyama (2009) Theodorakis (2011) Sorensen (2014) Paterson (2014)
O
O
O
OHO
O
OH
Paterson future work
O
1) Br2, Et3N
2) NaBH4, CeCl3HO
Br
Lipase PS, vinily acetate
HOBr
AcOBr
(S)(S)HO
(R)(R)HO
tBuLi
tBuLi
(-)
(+)
37.5% yield96% ee
42.5% yield96% ee
EnanKomeric version of the synthesis Analogues for biologiacal screening
X. Zhou, P. J. De Clercq, J. Gawronski, Tetrahedron: Asymmetry, 1995, 6, 1551.
Conclusion Total synthesis of Jiadifenolide: -‐ 23 steps, 2.3 % overall yield -‐ Sm-‐mediated reduc<ve cycliza<on as key step -‐ 2:1 mixture of diasteroisomers in the aldol reac<on -‐ Tedious oxida<on-‐oxida<on-‐reduc<on-‐oxida<on-‐oxida<on in the last steps -‐ Racemic synthesis
Wipf Group
Van Leusen
Sanford’s C-‐H ac<va<on
Favorskii ring contrac<on
O O
Br
Br
O
Br
O
Br
O
MeO-
MeO-
O
O
Br2
Theodorakis – key step
O
O
O
O
OHO
OHHO
O
O
O
OH
O
8 14
Jiadifenin – Danishefsky approach