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Identification of an Unexpected 2-Oxonia[3,3]sigmatropicRearrangement/Aldol Pathway in the Formation of
Oxacyclic Rings. TotalSynthesis of (+)-Aspergillin PZ.
Current LitetatureJuraj Rehák10/8/2011
Stephen M. Canham, Larry E. Overman, Paul S. TanisTetrahedron 2011, ASAP,
DOI: 10.1016/j.tet.2011.09.079
Juraj Rehak @ Wipf Group Page 1 of 15 12/28/2011
(+)-Aspergillin PZ
NHOOHO
O
HH
H
H
(+)-Aspergillin PZ
The (+)-Aspergillin PZ was isolated from the soil fungus Aspergillus awamori.
The isolation and identification were reported by by Pei and coworkers in 2002.(1)
(1) Zhang, Y.; Wang, T.; Pei, Y.; Hua, H.; Feng, B. J. Antibiot. 2002, 55, 693–695.
The structure of aspergillin PZ was proved by 2D NMR studies and X-ray analysis. The aspergilin PZ has pentacyclic structure with isoindolone moiety and unusual 12-oxatricyclo[6.3.1.02,7]dodecane ring system.
Pei and coworkers also described morphological deformation of the conidia of Pyricularia oryzae at 0.089 µM induced by aspergillin PZ.(1)
Juraj Rehak @ Wipf Group Page 2 of 15 12/28/2011
Retrosynthetic analysis of (+)-Aspergillin PZ.
NHOOHO
O
HH
H
H
Aspergillin PZ
O
R1O
NR2
OO
O
R1O
O
OR3
Diels-Adlder
Prins-pinacolO
R1O OR4OR3
R5O
Juraj Rehak @ Wipf Group Page 3 of 15 12/28/2011
Stereochemical analysis of the Prins-pinacol reaction
O
OR3
OR5
R1O
R4OO OR5
Me
H
R1O
O OR5Me
H
R1O
OR5R''
H
HHC
O Me
R1O
OR3H
OR5
R3O R3O
O Me
R1O
H
OR5OR3
OR5H
R''
HHC
O
OR3
OR5
R1O
R4O
O
R1O
O
OR3
O
R1O
O
OR3
Pr ins chair
Pr ins boat
OR5
H
HO
R1O
R3O
OR5
H
H
Me
R3O
O
R1O
Me
Juraj Rehak @ Wipf Group Page 4 of 15 12/28/2011
Synthesis of the Prins-pinacol rac-precursors.
O CO2Me
1-r ac
m-CPBA, MeOH, 0 oC
90%, d.r.: 4:1 O CO2Me
HO
MeO2-r ac
O
TBSO
MeOO
1) TBSCl, imidazole, DMF
2) DIBAL-H, Et2O, -78 oC85%, 2 steps
i) n-BuLi, THF, -78 oC
OTBDPS
3-r ac
ii) 3-r ac, THF, -78 oC to rt
O
TBSO
MeOOH
TBDPSO
O
TBSO
MeO
TBDPSO
OH
O
TBSO
MeOOTBS
OTBDPS
O
TBSO
MeOOTBS
OTBDPS
1) TBSOTf, pyridine, DCM, -78oC2) Lindlar cat., H2, Et2O
82-95 %, 2 steps
d.r.: 1.3:195%
4a-rac 4b-r ac
5b-r ac5a-rac
Juraj Rehak @ Wipf Group Page 5 of 15 12/28/2011
Unexpected formation of the trans aldehydes
O
TBSO
MeOOTBS
OTBDPS
O
TBSO
MeOOTBS
OTBDPS
O
TBSO
O
5a-rac
5b-rac
6a-rac
SnCl4, DCM, 0oC
49%
SnCl4, DCM, 0oC
58%
O
TBSO
O
OTBDPS
6b-rac
O
TBSO
O
OH
7-r ac
1) NaBH4,2) p-BrBzCl, DMAP, TEA3) TBAF, AcOH
73%, 3 steps
OTBDPS
O
Br
Juraj Rehak @ Wipf Group Page 6 of 15 12/28/2011
Synthesis of the Prins-pinacol rac-glycosyl acetate.
O CO2Me1-r ac
i) DMDOii) EtSH, TFAA69%, d.r.: 7:1 O CO2Me
HO
EtS O
TBSO
EtSO
1) TBSCl, imidazole2) DIBAL-H, Et2O, -78 oC
70%, 2 steps
i) n-BuLi, THF, -78 oC
OTBDPS
ii) 9-r ac , THF, -78 oC to rt
O
TBSO
EtSOH
TBDPSO
O
TBSO
EtS
TBDPSO
OHO
TBSO
EtSOTBS
OTBDPS
84 %, 2 steps
98%, d.r.: 1.3:1
1) Swern oxid.2) DIBAL-H
60%, 2 steps
1) Pd/CaCO3, H2, quinoline2) TBSOTf, 2,6-lutidine
8-r ac 9-r ac
10-rac11-rac12-rac
Juraj Rehak @ Wipf Group Page 7 of 15 12/28/2011
Initiation of the Prins-pinacol cascade at low temperature from glycosyl acetate 13-rac
1) MeI, Ag2CO3, MeCN/H2O2) Ac2O, DMAP, pyridine
93 %, 2 steps O
TBSO
OTBS
OTBDPS
AcO
O
TBSO
O
OTBDPS
O
TBSO
O
OTBDPS
SnCl2, DCM, -78oC42%, d.r.: 1.3:1
13-r ac
14-r ac
6a-r ac
O
TBSO
EtSOTBS
OTBDPS
12-rac
Juraj Rehak @ Wipf Group Page 8 of 15 12/28/2011
Potential Prins-pinacol and 2-oxonia[3,3]sigmatropic/aldol pathways.
O
TBSO
OTBSR2O
X
SnCl4, DCMO
OTBS
OR2
OTBS
OOTBS
OR2
OTBS
OOTBS
OR2
OTBS
OOTBS
OTBS
OR2
OOTBS
OR2
TBSO
O
TBSO
O
O
TBSO
O
OR2
OR2
Prins-pinacol pathway
2-oxonia[3,3]sigmatropic/aldol pathway
epimerization
X = OMeX = OAc
Juraj Rehak @ Wipf Group Page 9 of 15 12/28/2011
Deuterium labeling experiments and epimerization of cis aldehyde epimer 14-rac under various reaction conditions
O
TBSO
OTBS
OTBDPS
AcOO
TBSO
O
OTBDPS0.5 eq., SnCl2,DCM, -78oC
D
D
D
D
O
TBSO
OTBS
OTBDPS
AcOO
TBSO
O
OTBDPS
2.1 eq., SnCl2,1.5 eq., CD3ODDCM, -78oC
H
13-rac 6a/14-r ac
15-rac 16-rac
O
TBSO
O
OTBDPS
H
14-rac
O
TBSO
O
OTBDPS
H
O
TBSO
O
OTBDPS
H
14-rac 6a-rac
Conditions
syn anti
Entry Conditions cis trans
1 BDU, toluene, r.t. 12 h - 100%
2 TEA, DCM. -78 °C→r.t. 12 h 100% -
3 0.5 eq. SnCl4 , DCM, -78 °C, 30 min 100% -
4 0.5 eq. SnCl4 , DCM, 0 °C, 15 min 34% 66%
5 0.15 eq. HN(Tf)2, DCM, -78 °C→ 0 °C, 30 min 100% -
6 0.15 eq. HN(Tf)2, DCM, 0 °C, 30 min 20% 80%
Ratio of cis/trans determined by integration of 1H NMR spectra
Juraj Rehak @ Wipf Group Page 10 of 15 12/28/2011
Synthesis of enantioenriched trans-8-oxabicyclooctyl aldehyde.
O CO2Me
1-(+) (92% ee)
O
TBSO
MeOO
42%, 3 steps
Zn(OTf)2, TEA,(+)-N-methylephedrine
OTBDPS O
TBSO
MeOOH
TBDPSO
O
TBSO
MeOOTBS
OTBDPS
1) TBSOTf, pyridine,DCM, -78oC2) Lindlar cat., H2, Et2O
80 %, 2 steps
92%
O
TBSO
O
SnCl4, DCM, 0oC49%
1) m-CPBA, MeOH2) TBSCl, imidazole3) DIBAL-H
OTBDPS
3 4a
5a6a
Juraj Rehak @ Wipf Group Page 11 of 15 12/28/2011
Preparation of cis-8-oxabicyclooctyl aldehyde.
O
TBSO
O
OH17
O
TBSO
O
O1) NaClO2, NaH2PO42-methyl-2-butene2) EDCl, HOBt, DMAP
66% 2 steps
O
TBSO
O
O
DBU, benzenereflux
83%
1) LiAlH42) TBDPSCl, DMAP, pyridine
65% 2 steps
O
TBSO
OHO
TBSO
O TPAP, NMO,4Å MS
97%
18
192014
cis-aldehyde 14 in 27% overallyield from its trans epimer 6a.
O
TBSO
O
TBAF, AcOH77%
OTBDPS6a
OTBDPS OTBDPS
Juraj Rehak @ Wipf Group Page 12 of 15 12/28/2011
Preparation of Diels-Alder precursor.
O
TBSO
O
14OTBDPS
O
TBSO
I
CrCl2, CHI344%
O
TBSO
(HO)2B
PdCl2(dppf), KOH, THF, H2O
93%
O
TBSOO
1) TBAF, AcOH2) Swern oxid.88% 2 steps
O
TBSO
NBz
OHO
BzNO
ii) 23
Dess- MartinperiodinaneNaHCO3
90%
36-57%
OTBDPS21
OTBDPS22
2324
i) LiHMDS
O
TBSO
NBz
O O
H
25
Juraj Rehak @ Wipf Group Page 13 of 15 12/28/2011
Completion of the (+)-Aspergillin PZ.
25
O
TBSO
NBz
OO
H O
TBSO
NBz
OO
PhSe
i) LiHMDSii) PhSeCl
83%
NHO
OHO
O
HH
H
H
(+)-Aspergillin PZ
NBzO
OTBSO
O
HH
H
H
1) H2O2, m-CPBA-50 oC to 0 oC2) toluene 100 oC
56%, 2 steps
1) NaOH, H2O,MeOH2) TBAF, THF67%, 2 steps
26 27
Juraj Rehak @ Wipf Group Page 14 of 15 12/28/2011
Conclusion.
NHO
OHO
O
HH
H
H
(+)-Aspergillin PZ
O
HO
O
HO
O
HO
O
OH
Prins
[3,3]sigmatropic
Pinacol
aldol
Autors showed evidence that the cascade transformation can take place by a 2-oxonia[3,3]sigmatropic/aldol pathway as well as by the more common Prins-pinacol mechanism.
The (+)-Aspergillin PZ was synthesized in owerall 0.23 % yield after 25 steps.
The syntetic sample of (+)-Aspergillin PZ was tested against two highly invasive tumor lines (A2058 melanoma and DU145 prostate cancer) and no useful activity (IC 50 >10 µM) was found in either cell line.
Juraj Rehak @ Wipf Group Page 15 of 15 12/28/2011