total synthesis of (+)-fendleridine and (+)-1 ...ccc.chem.pitt.edu/wipf/current...

Total Synthesis of (+)-Fendleridineand (+)-1-Acetylaspidoalbidine

Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger, D. L.J. Am. Chem. Soc. 2010, 132, 3009.

Kara GeorgeCurrent Literature

March 6, 2010

NH

N

H

O

(+)-Fendleridine

N

N

H

O

Ac

(+)-1-Acetylaspidoalbidine

Kara George @ Wipf Group of 13 4/26/2010

Isolation, Structural Features, & Previous Syntheses

• Parent members of the aspidoalbine family of alkaloids• Fendleridine (1) was first isolated in 1964 from the Venezuelan tree Aspidosperma fendleri

WOODSON by Burnell and co-workers• Only one total synthesis of 1 reported by Ban and co-workers in 1976• 1-Acetylaspidoalbidine (2) was first isolated in 1963 from Vallesia dichotoma RUIZ et PAV in

Peru• Ban reported the first total synthesis of 2 in 1975 and an improved formal synthesis in 1987• A formal synthesis of 2 was disclosed by Overman in 1991

Burnell, R. H.; Medina, J. D.; Ayer, W. A. Can. J. Chem. 1966, 44, 28.Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47.Ban, Y.; Ohnuma, T.; Seki, K.; Oishi, T. Tetrahedron Lett. 1975, 16, 727.Yoshido, K.; Sakuma, Y.; Ban, Y. Heterocycles 1987, 25, 47.Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598.

NH

N

H

O

(+)-Fendleridine (1)

N

N

H

O

Ac

(+)-1-Acetylaspidoalbidine (2)

N

N

H

O

Ac

HO

O

Aspidospermidin-21-oic acid

N

N

H

O

EtOC

HO

MeO

MeO

Aspidoalbine

N

N

H

O

R

HO

Haplocidine (R= H)Haplocin (R= COEt)

N

N

H

O

Ac

MeO

O

MeO

(-)-Aspidophytine


First Total Synthesis of(±)-Fendleridine and (±)-1-Acetylaspidoalbidine

Oishi, T.; Nagai, M.; Ban, Y. Tetrahedron Lett. 1968, 491.Ban, Y.; Ohnuma, T.; Seki, K.; Oishi, T. Tetrahedron Lett. 1975, 727.Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47.

NH O

NH2!HCl

O O

H

ONH

N

O

NH

N

H

O

O

NR

N

H OHNR

N

H OH

NR

N

H

O

(±)-Fendleridine (R=H)(±)-1-Acetylaspidoalbidine (R= Ac)

PtO2, HOAc, H2

Hg(OAc)2, 5% aq. AcOH

R= H or Ac R= H or Ac

1. basic aq. EtOH

2.

Cl Cl

O

O

N

N

O

OEt

O

NaH, DMSO

1. H+

2. K2CO3

3. Et3OBF4

Cl

O

O


Improved Formal Synthesis of(±)-1-Acetylaspidoalbidine by Ban and co-workers

Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am. Chem. Soc. 1981, 103, 6990.Yoshida, K.; Sakuma, Y.; Ban, Y. Heterocycles 1987, 25, 47.

N

N

OH

N

N

CO2CH3

THP

O

N

O

NH2

N

N

H

O

Ac

(±)-1-Acetylaspidoalbidine

h!, MeOH

N

NHO

H

N

NO

THP

N

N

THP

OH

OH

H+

N

N

H OHAc

1. LAH2. AcCl

LDA; then (CO2CH3)2

1. PhCOCl, Et3N2. THP protection3. LDA; then I(CH2)3Cl

4. NH2

N

NHO

THP

ClNaH, KI

18-crown-6

4 steps


Formal Synthesis of (±)-1-Acetylaspidoalbidine byOverman and co-workers

Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598.

OSiMe3NC

NHCOtBu

N

O

N

O

BuOtCHN

O

MeO2C

O

HNHHO

H2N

N

O

H2N

N

N

OBn

N

N

H OHAc

N

N

H

O

Ac

(±)-1-Acetylaspidoalbidine

OBn OBn OBn

OBn

n-BuLi, A, -70 °C; then HCl, -70 °C to rt

A

LiOH, MeOHN

BuOtCHN

OBn

MeO2C

HO

NCHO

1. Ph3P=CH22. KOH, H2O/EtOH (CH2O)n, Na2SO4

CSA, Na2SO4


Title Paper: Tandem [4+2]/[3+2] Cycloaddition Cascade

Tandem [4+2]/[3+2] cycloaddition cascade:• 4 C-C bonds• 3 rings• 5 stereogenic centers

NR

N

H

O

(+)-Fendleridine (R= H)(+)-1-Acetylaspidoalbidine (R= Ac)

N

N

O

HBn

O

OTBSCO2Me

N

NH

Bn

ON

N

CO2Me

N

N

Bn

ON

N

CO2Me

O

OTBS

HO

O

OTBS

N

N

N

O

O

OTBSCO2Me

NBn

-N2

[4+2][3+2]

N

O

OTBSNBn

O

CO2Me


Tandem Intramolecular Diels-Alder/1,3-DipolarCycloaddition Reactions of 1,3,4 Oxadiazoles

• Previously reported cycloaddition reactions of electron-deficient and symmetrical 1,3,4-oxadiazoles by Vasilíev, Sauer, Seitz, and Warrener:

Warrener, R. N. Eur. J. Org. Chem. 2000, 3363.Thalhammer, F.; Wallfahrer, U.; Sauer, J. Tetrahedron Lett. 1988, 29, 3231.Vasiliev, N. V.; Lyashenko, Y. E.; Patalakha, A. E.; Sokolski, G. A. J. Fluorine Chem. 1993, 65, 227.Elliot, G. I.; Fuchs, J. R.; Blagg, B. S. J.; Ishikawa, H.; Tao, H.; Yuan, Z.-Q.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10589.Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292.

N

N

Me

OAc

HO CO2Me

MeO

Vindoline

N

NO

R

R

R1

R1

N

NO

R

R

R1

R1

O

R

R

R1

R1

R1

R1

O

R1

R1

R

R

- N2

slow [4+2] fast [3+2]

fast

1, R= CF3, SO2Et, CO2Me

1

NMe

N

ON

N

MeO2C

O

RERZ

NMe

N

RZ

O

CO2Me

O

RE

NMe

N

O

N

NO

RE

RZ

CO2Me

NMe

N

O

O

RE

RZ

MeO2C

[4+2] [3+2]

- N2


Tandem Intramolecular Diels-Alder/1,3-DipolarCycloaddition Reactions of 1,3,4 Oxadiazoles

O

HRE

RZ

N

O

H

N

Me

E

• Single diastereomer with relative stereochemistry set by: (1) dienophile geometry (2) Exclusive indole endo [3+2] cycloaddition sterically directed to the α-face of the 1,3-dipole• Forms: 3 rings 4 C-C bonds 6 stereocenters 4 quaternary centers

Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10596.Elliot, G. I.; Fuchs, J. R.; Blagg, B. S. J.; Ishikawa, H.; Tao, H.; Yuan, Z.-Q.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10589.Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292.

NMe

N

ON

N

MeO2C

O

RERZ

NMe

N

RZ

O

CO2Me

O

RE

NMe

N

O

N

NO

RE

RZ

CO2Me

NMe

N

O

O

RE

RZ

MeO2C

[4+2] [3+2]

- N2

1a, R=H o-Cl2C6H4, 180 °C, 3 h 87% 1b

(E)- 2a, RE = Me o-Cl2C6H4, 180 °C, 24 h 65% 2b

(E)- 3a, RE = OBn TIPB, 230 °C, 19 h 88% 3b

(Z)- 4a, RZ = OBn TIPB, 230 °C, 38 h 41% 4b

AB


Total Synthesis of(+)-Fendleridine and (+)-1-Acetylaspidoalbidine

NR

N

H

O

(+)-Fendleridine (R= H)(+)-1-Acetylaspidoalbidine (R= Ac)

N

N

O

HBn

O

OTBSCO2Me

N

NH

Bn

ON

N

CO2Me

N

N

Bn

ON

N

CO2Me

O

OTBS

HO

O

OTBS

O

O

m-CPBAO

O

O

K2CO3, MeOH

91%

TBSCl, imid

88%

Ph3P CH2

88%

R= MeR= HLiOH, 96%

RO

O

OTBS

MeO

O

O

OH

MeO

O

O

OTBS



N

NH2

Bn

N

NH

Bn

N

O

NN

NH

Bn

NH

O

H2N

HN

O

O

O HN

O

O

O

N

NH

Bn

ON

N

CO2Me

CDI

97% HOAc, THF

TsCl, Et3N

81% (2 steps)

N

NH2

H

N

N

H

Phth

N

N

Bn

Phthphthalic anhydMePh, !

93%

NaH, BnBrDMF, 55 °C

99%

N2H4"H2OEtOH, !

95%



HOOTBS

O

N

NH

Bn

ON

N

CO2MeEDCI, DMAP

74% N

N

Bn

ON

N

CO2Me

O

OTBS

o-Cl2C6H4, 180 °C

71%N

N

O

HBn

O

OTBSCO2Me

1. NH3, MeOH2. TFAA, pyr

90%N

N

O

HBn

O

OTBSCN

HF-pyridine, THF

quant.N

N

O

HBn

O

CNHO

N

N

O

HBn

O

OH

Na-selectride

85%



N

N

O

HBn

O

OH

N

N

O

HBn

O

O

SMe

S

NaH, CS2; MeI

92%N

N

X

HBn

O

AIBN, Bu3SnHPhCH3, 100 °C

77%

X= OX= S

Lawesson'stoluene, 85%

Ra-Na

80%

N

N

HBn

O

Na, NH3t-BuOH, THF, -78 °C

quant.

NH

N

H

O

Ac2O, pyridine

81%

N

N

H

O

Ac

(+)-Fendleridine (+)-1-Acetylaspidoalbidine


Conclusions & Future Directions• Total synthesis of (+)-fendleridine and (+)-1-acetylaspidoalbindine was

achieved• The pentacyclic core and all necessary stereochemistry of the natural

products are assembled in one step via intramolecular [4+2]/[3+2]cycloaddition cascade

• Tandem [4+2]/[3+2] cycloaddition cascade reaction can be applied to avariety of natural products containing a similar pentacyclic ring core

• Extension of this methodology to alternative tethering and/ortransannular cycloadditions provides access to other interesting ringsystems

N

N

ON

N

O

N

N

O

O

O N

Me

MeMe

NO

Me

HC6H6, 80 °C, 40 h

70%

N

N

ON

N

O

N

N

O

O

O N

Me

Me MeNO

Me

o-Cl2C6H4, 180 °C, 144 h

53% (93% brsm)

H


total synthesis of (+)-fendleridine and (+)-1 ...ccc.chem.pitt.edu/wipf/current...

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