Total Synthesis of and Studies Surrounding

Batrachotoxinin A

Aaron C. Smith

April 27, 2005

Kurosu, M.; Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 6627.
Grinsteiner, T. J.; Kishi, Y. Tetrahedron Lett. 1994, 35, 8333.
Grinsteiner, T. J.; Kishi, Y. Tetrahedron Lett. 1994, 35, 8337.

Structure and Biological Activity

- Isolated from skins of the green-banded poison dart
frog, phyllobates aurotaenia, as well as from feathers of a
New Guinea bird, Pitohui

- Recent data proposes source of the batrachotoxins is a
melyrid beetle that is a dietary source for the birds

- Among the most toxic natural substances, 250 times
more potent than strychnine

- Bind with high affinity to voltage-gated sodium channels
in nerve and muscle membranes, locking them in an
open state

- Structures of bachratoxinin A and bachratoxin
determined through X-ray analysis and chemical
correlation, respectively

- Structural features include steroid-based pentacyclic
core, a seven-membered oxazapane ring, and a
hemiketal moiety

O

HO

H

O

OR

HO

N

Batrachotoxinin A: R = H

Batrachotoxin: R =

NH

O

Retrosynthetic Analysis

Synthesis of Ketone

O

OTBS

TBSO

H

OAc

O

OH

OH

1. naph-SO

3

H 75%

2. Na

2

CO

3

-H

2

O

2

TFAA 87%

OAc

O

O

O

OAc

O

OH

1. HCl (aq)
2. DBU 95%

OAc

HO

OH

H

1. H

2

, Pd/C

2. Me

4

NB(OAc)

3

H

76%

1. TBSCl, imid 97%
2. DIBAL
3. Swern w/ Et

3

N, 76%

w/ iPr

2

NEt, 85%

Synthesis of Diels-Alder Precursor

entry

R

X

Y

yield, %

ratio (X:X)

a

TBS

H

OTBS

70-75

>25:1

b

TBDPS

H

H

75-80

>3:1

c

TBDPS

OPMB

H

40-50

1.4:1

O

OTBS

TBSO

H

OTBS

TBSO

H

O

Y

RO

H

S

S

O

Y

TBSO

H

S

S

O

+

1. Ethyl Formate, NaH
2. nBuSH, TsOH 88%
3. Me

3

SI, NaHMDS

4. HgCl

2

54%

1. DMF
(COCl)

2

84%

2. CSA

72%

Y

RO

H

O

S

S

OH

OTBS

TBSO

H

O

S

S

X

X

X

1. tBuLi, HMPA
2. TBAF 52%

Br

TBSO

SH SH

O

O

H

H

MnO

2

Stereoselectivity of the Diels-Alder

Y

TBSO

H

S

S

O

O

+

Y

RO

H

O

S

S

O

X

X

Me

H

TBSO

X

Y

O

R

Me

H

X

Y

TBSO

O

R

TBSO

H

H

H

H

Me

H

Me

TBSO

H

H

H

H

H

H

H

OTBS

TBSO

H

S

S

O

O

H

H

Synthesis of Methyl Ketal

OTBS

TBSO

H

S

S

O

O

1. NaCNBH

3

, AcOH

2. Ac

2

O, pyr.

TBSO

NH

2

OTBS

TBSO

H

S

S

O

N

Ac

TBSO

H

1. (CF

3

CO

2

)

2

IPh

CaCO

3

, MeOH

2. PPTS, acetone
3. DBU 68%

OTBS

TBSO

H

HO

N

Ac

TBSO

O

1. p-NO

2

PhCO

3

H 90%

2. MOMCl, iPr

2

NEt 93%

OTBS

TBSO

H

MOMO

N

Ac

TBSO

O

X

O

X = H

2

X = O

1. KHMDS, Davis' oxiziridine 93%
2. TFAA, DMSO, Et

3

N 88%

1. (Me

2

N)

3

S(Me

3

SiF

2

)

2. PhNTf

2

, Et

3

N 95%

OTBS

TBSO

H

MOMO

N

Ac

OTf

O

O

O

O

O

H

MOMO

N

Ac

O

O

O

1. Pt

2

O, H

2

2,6-di-t-Bupyr. 90%
2. NaBH

4

3. TBAF
4. DMP

1. DBU
2. CSA, MeOH 85%

O

MeO

H

MOMO

N

Ac

O

O

O

Completion of Synthesis

O

MeO

H

MOMO

N

Ac

O

O

O

1. NaBH

4

, CeCl

3

2. PBu

3

S(2-pyr)

MeO

H

MOMO

N

Ac

OH

O

O

MeO

H

MOMO

N

Ac

O

O

O

1. Raney Ni, H

2

2. DMP 73%

N

S

2

1. KHMDS, PhNTf

2

90%
2. Pd(PPh

3

)

4

, CO

morpholine 96%

MeO

H

MOMO

N

Ac

O

O

O

N

O

MeO

H

MOMO

N

O

O

O

HO

H

HO

N

O

O

OH

1. CeCl

3

, MeLi

2. NaHCO

3

, MeI

80%

1. Zn(BH

4

)

2

80%

2. TsOH, wet acetone
83%

batrachotoxinin A

Synthesis of an Advanced Intermediate

Br

O

OMe

O

O

OMe

O

O

OMe

O

H

O

O

O

MeO

H

O

O

O

O

O

MeO

H

O

O

OMe

H

O

O

MeO

2

C

1. NaH
2. BuLi 77%

3. Lindlar's cat. 95%

1. KOH, PhI(OAc)

2

MeOH
2. h! 60%

1. Mg, MeOH
" 74%
2. DMAP

75%

HO

O

O

+

1. MeOH, 105

o

C

sealed tube 95%
2. MVK, K

2

CO

3

92%

1. pyrrolidine, "
2. NaOAc, AcOH, H

2

O

" 70%
3. Pb(OAc)

2

, 150

o

C

sealed tube 72%

OMe

H

O

MeO

2

C

AcO

Me

2

PhSi

O

SEt

O

OMe

H

O

MeO

2

C

AcO

O

R

H

Me

2

PhSi

R = C(O)SEt

O

OMe

H

MeO

2

C

AcO

O

R

H

Me

2

PhSi

O

OH

H

R = C(O)SEt

OMe

H

O

MeO

2

C

AcO

O

O

OAllyl

Me

2

PhSi

O

O

OMe

H

O

MeO

2

C

AcO

O

R

H

Me

2

PhSi

R = CHO

R = CH

2

OH

R = CH

2

OAc

OMe

H

MeO

2

C

AcO

O

R

H

Me

2

PhSi

R = CH

2

OAc

O

O

H

H

H

H

H

OH

OMe

H

O

MeO

2

C

AcO

O

R

H

Me

2

PhSi

O

H

OMe

H

MeO

2

C

O

R

H

Me

2

PhSi

O

H

OH

H

OMe

H

O

MeO

2

C

AcO

O

O

OAllyl

1.

Cs

2

CO

3

16%

2. Pd(PPh

3

)

4

,

morpholine 81%

1.

Cs

2

CO

3

97%

2. Pd(PPh

3

)

4

,

morpholine 62%

Ac

2

O DMAP 94%

LiAl(OCEt

3

)

3

H

72%

KHMDS, !
37%

Cs

2

CO

3

, ! 38%