Identification of an Unexpected 2-Oxonia[3,3]sigmatropic Rearrangement/Aldol Pathway in the ...

15 Pages·2011·0.61 MB·English

Identification of an Unexpected 2-Oxonia[3,3]sigmatropic
Rearrangement/Aldol Pathway in the Formation of
Oxacyclic Rings. Total
Synthesis of (+)-Aspergillin PZ.
Stephen M. Canham, Larry E. Overman, Paul S. Tanis
Tetrahedron 2011, ASAP,
DOI: 10.1016/j.tet.2011.09.079
Current Litetature
Juraj Rehák
10/8/2011

Juraj Rehak @ Wipf Group Page 1 of 15 12/28/2011
(+)-Aspergillin PZ
H
H
O H NH
O
O
H
HO
(+)-Aspergillin PZ
The (+)-Aspergillin PZ was isolated from the soil fungus Aspergillus awamori.
(1)
The isolation and identification were reported by by Pei and coworkers in 2002.
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
2,7
12-oxatricyclo[6.3.1.0 ]dodecane ring system.
Pei and coworkers also described morphological deformation of the conidia of
(1)
Pyricularia oryzae at 0.089 µM induced by aspergillin PZ.
(1) Zhang, Y.; Wang, T.; Pei, Y.; Hua, H.; Feng, B. J. Antibiot. 2002, 55, 693–695.

Juraj Rehak @ Wipf Group Page 2 of 15 12/28/2011
Retrosynthetic analysis of (+)-Aspergillin PZ.
H
H
Diels-Adlder NR2
O H NH O
O
HO H O R1O O O
Aspergillin PZ
R5O
O
Prins-pinacol
O
O OR3
OR3
R1O OR4 R1O

Juraj Rehak @ Wipf Group Page 3 of 15 12/28/2011
Stereochemical analysis of the Prins-pinacol reaction
OR3
O
R1O R1O R1O
R4O O O MOeR5 O MOeR5 O OR3
OR5 R3O H R3O H R1O
Prinschair
R1O
R''
OR5 Me
HC H O OR5
H
H
R3O
H
OR3
O
R1O R1O R1O
R4O O OR3 O HMOeR5 OR3 O HMOeR5 O OR3
OR5 R1O
Prinsboat
R3O H
H
OR5 H
HC H OR5
R'' R1O
Me
O
Juraj Rehak @ Wipf Group Page 4 of 15 12/28/2011
Synthesis of the Prins-pinacol rac-precursors.
HO TBSO
m-CPBA, MeOH,0oC 1)TBSCl, imidazole,DMF
O
O CO2Me 90%, d.r.: 4:1 MeO O CO2Me 2)DIBAL-H, Et2O,-78oC MeO O
85%,2 steps
1-rac 2-rac 3-rac
OTBDPS
i) n-BuLi,THF,-78oC
ii)3-rac, THF,-78oCto rt
95% d.r.: 1.3:1
TBDPSO TBDPSO
TBSO TBSO
MeO O MeO O
OH OH
4a-rac 4b-rac
1)TBSOTf,pyridine,DCM, -78oC
2)Lindlar cat.,H ,Et O
2 2
82-95 %, 2steps
OTBDPS OTBDPS
TBSO TBSO
MeO O MeO O
OTBS OTBS
5a-rac 5b-rac

Juraj Rehak @ Wipf Group Page 5 of 15 12/28/2011
Unexpected formation of the trans aldehydes
Br
O
OTBDPS
O 1)NaBH4, O
TBSO 2)p-BrBzCl, DMAP,TEA
SnCl4,DCM, 0oC O 3)TBAF,AcOH O
MeO O 49% 73%, 3steps OH
TBSO TBSO
OTBS
OTBDPS
5a-rac 6a-rac 7-rac
OTBDPS
O
TBSO
O
SnCl ,DCM, 0oC OTBDPS
4
MeO O
OTBS 58% TBSO
5b-rac 6b-rac

Juraj Rehak @ Wipf Group Page 6 of 15 12/28/2011
Synthesis of the Prins-pinacol rac-glycosyl acetate.
HO 1)TBSCl, imidazole TBSO
i) DMDO
o
ii) EtSH,TFAA 2)DIBAL-H, Et2O, -78 C
O
O CO Me 69%, d.r.: 7:1 EtS O CO Me 70%, 2steps EtS O
2 2
1-rac 8-rac 9-rac
OTBDPS
o
i) n-BuLi,THF, -78 C
ii) 9-rac,THF,-78 oCto rt
98%, d.r.: 1.3:1
OTBDPS
TBDPSO TBDPSO
TBSO 1) Pd/CaCO3,H2,quinoline TBSO 1) Swernoxid. TBSO
2) TBSOTf,2,6-lutidine 2) DIBAL-H
EtS O 84 %,2steps EtS O 60%,2steps EtS O
OTBS OH OH
12-rac 11-rac 10-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
O
O
OTBDPS
OTBDPS OTBDPS
TBSO
1)MeI,Ag CO ,MeCN/H O
TBSO 2 3 2 TBSO 6a-rac
o
2)Ac O, DMAP,pyridine SnCl ,DCM,-78 C
2 2
93 %, 2steps 42%, d.r.: 1.3:1
EtS O AcO O O
OTBS OTBS
12-rac 13-rac
O
OTBDPS
TBSO
14-rac

Juraj Rehak @ Wipf Group Page 8 of 15 12/28/2011
Potential Prins-pinacol and 2-
oxonia[3,3]sigmatropic/aldol pathways.
Prins-pinacolpathway
OTBS
OTBS
OR2 OR2 O
O
O
O
OTBS
OTBS
TBSO
OR2
R2O epimerization
OTBS
OTBS
SnCl ,DCM OR2 O
O 4
O
O
TBSO X OTBS
TBSO
OR2
X =OMe
X =OAc
OTBS
TBSO
OR2 OR2
O O
OTBS OTBS
2-oxonia[3,3]sigmatropic/aldol pathway

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 O O
H H H
O OTBDPS Conditions O OTBDPS O OTBDPS
TBSO TBSO TBSO
14-rac 14-rac 6a-rac
syn anti
OTBDPS
O
TBSO 2.1eq.,SnCl2, H Entry Conditions cis trans
1.5eq.,CD3OD
DCM,-78oC O OTBDPS
1 BDU, toluene, r.t. 12 h - 100%
AcO O
OTBS TBSO
13-rac 6a/14-rac
2 TEA, DCM. -78 °C→r.t. 12 h 100% -
3 0.5 eq. SnCl , DCM, -78 °C, 30 min 100% -
4
OTBDPS
O
TBSO D D 4 0.5 eq. SnCl4 , DCM, 0 °C, 15 min 34% 66%
0.5eq.,SnCl ,
AcO O D DCM,-78oC 2 O OTBDPS 5 0.15 eq. HN(Tf)2, DCM, -78 °C→ 0 °C, 30 min 100% -
OTBS TBSO D
15-rac 16-rac 6 0.15 eq. HN(Tf) , DCM, 0 °C, 30 min 20% 80%
2
Ratio of cis/trans determined by integration of 1H NMR spectra

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