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
HO N HO O O H OR

Batrachotoxinin A: R = H Batrachotoxin: R = O NH

Retrosynthetic Analysis

Synthesis of Ketone

OAc OH OH O 1. naph-SO3H 75% 2. Na2CO3-H2O2 TFAA 87% O O O

OAc 1. HCl (aq) 2. DBU 95% O

OAc 1. H2, Pd/C 2. Me4NB(OAc)3H 76% OH

OAc 1. TBSCl, imid 97% 2. DIBAL 3. Swern w/ Et3N, 76% w/ iPr2NEt, 85%

HO

TBSO

OH

OTBS

Synthesis of Diels-Alder Precursor

O 1. Ethyl Formate, NaH 2. nBuSH, TsOH 88% 3. Me3SI, NaHMDS 4. HgCl254% 1. DMF (COCl)2 84% 2. CSA OTBS 72% SH SH

S S TBSO

Br 1. tBuLi, HMPA 2. TBAF 52%

TBSO

TBSO

OTBS

TBSO

OTBS

OH O O S S RO RO H Y X H Y X MnO2 O S H S + TBSO O S H Y X O H S

entry a b c

R TBS TBDPS TBDPS

X H H OPMB

Y OTBS H H

yield, % 70-75 75-80 40-50

ratio (X:X) >25:1 >3:1 1.4:1

Stereoselectivity of the Diels-Alder

O O O S S RO TBSO H Y X H OTBS O S H S + TBSO O O S H Y X H S

Me X H TBSO Y

O H Me Y TBSO

R X

H H

H H H TBSO H

H Me H

H Me TBSO H H

Synthesis of Methyl Ketal

O O S TBSO H H S 1. NaCNBH3, AcOH NH2 TBSO 2. Ac2O, pyr. TBSO H OTBS TBSO Ac N S O S 1. (CF3CO2)2IPh CaCO3, MeOH 2. PPTS, acetone 3. DBU 68%

OTBS

TBSO HO

Ac N O

TBSO 1. p-NO2PhCO3H 90% 2. MOMCl, iPr2NEt 93% TBSO MOMO O

Ac N

X O 1. (Me2N)3S(Me3SiF2) 2. PhNTf2, Et3N 95%

TBSO

OTBS

OTBS 1. KHMDS, Davis' oxiziridine 93% 2. TFAA, DMSO, Et3N 88% Ac N Ac N 1. DBU 2. CSA, MeOH 85% MeO MOMO O O H O

X = H2 X=O O OTf

Ac N MOMO O O TBSO H OTBS

1. Pt2O, H2 2,6-di-t-Bupyr. 90% 2. NaBH4 3. TBAF 4. DMP O

MOMO O O H O

Completion of Synthesis
Ac N MOMO O O MeO H O O 1. NaBH4, CeCl3 2. PBu3 MeO 2 MOMO O O N S H S(2-pyr) Ac N OH 1. Raney Ni, H2 2. DMP 73%

Ac N MOMO O O MeO H

O 1. KHMDS, PhNTf2 90% 2. Pd(PPh3)4, CO morpholine 96% MeO MOMO

Ac O N O O H

O 1. CeCl3, MeLi 2. NaHCO3, MeI 80%

N MOMO O O MeO H

O 1. Zn(BH4)2 80% 2. TsOH, wet acetone 83% HO HO

N O O H batrachotoxinin A

OH

Synthesis of an Advanced Intermediate

1. NaH 2. BuLi 77% O O OMe Br 3. Lindlar's cat. 95% O O OMe 1. KOH, PhI(OAc)2 MeOH 2. h! 60% O O OMe H 1. Mg, MeOH " 74% 2. DMAP O O HO 75%

O O O O + H MeO O O O

O O 1. MeOH, 105 C sealed tube 95% 2. MVK, K2CO3 92%

o

1. pyrrolidine, " MeO2C O OMe H 2. NaOAc, AcOH, H2O " 70% 3. Pb(OAc)2, 150 oC sealed tube 72%

H MeO

AcO O

MeO2C

OMe H

O OMe H 1. Me2PhSi

O SEt AcO MeO2C O R Me2PhSi H O O OMe H AcO MeO2C O R H H Me2PhSi H R = C(O)SEt O O AcO MeO2C O R Me2PhSi H O O OMe H KHMDS, ! 37% Me2PhSi AcO MeO2C O R H H H OH O OMe H OH O OMe H

AcO MeO2C

O O O OAllyl

Cs2CO3 16% 2. Pd(PPh3)4, morpholine 81%

R = C(O)SEt

AcO MeO2C

OMe H

1. Me2PhSi Cs2CO3 97% 2. Pd(PPh3)4, morpholine 62%

O O O OAllyl

LiAl(OCEt3)3H 72%

R = CHO R = CH2OH R = CH2OAc AcO MeO2C O R OMe H Cs2CO3, ! 38% Ac2O DMAP 94%

R = CH2OAc

H MeO2C R H OH O

OMe H

Me2PhSi

H O O

Me2PhSi