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