A Stereoselective Synthesis of (-)-Tetrodotoxin

O HO O HO HN H2N (-)-tetrodotoxin Tetrodotoxin is found in the livers and ovaries of puffer fish (first isolated in 1909). One of the most toxic natural products. The structrue was independently determined by three groups (Hirata-Goto, Tsuda, and Woodward) in1964. Essential tool in the research area of brain and neuroscience due to its specific inhibition of voltage depended sodium ion-channels. O OH

OH NH OH

O O HN H2N 4,9-anhydro-TTX OH HO O O O O O HO O OH HO HN H2N

O O HO O OH HO HN H2N

O OH OH OH

OH NH OH

OH NH OH

NH OH

(-)-tetrodotoxin

lactone form

O OH

OH H2N OH tetrodamine Dioxa-adamantane

First Total Synthesis

H O 1. MsCl, NEt3 2. Beckmann rearrangement O H O

N OH CH3CN 83%

N O H O

SnCl 4 O H O O O H H O OAc HO HN H2N

HO O

OH

OH NH OH

+ N O

HO

AcO NHAc OAc

()-tetrodotoxin

Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am.Chem. Soc. 1972, 94, 9219.

First Asymmetric Total Synthesis of Tetrodotoxin

O HO O HO HN H2N (-)-tetrodotoxin OR O OH O O HN Cl 3C Overman rearrangement O H OBOM O Cl 3C OBz RO
5

OR OR OR OR O

OH NH OH

O Cl 3C O H O NH O NH OBOM
5

Cl 3C OBz OR OBz RO
5

HN

O O NH 2
5

O OMe H OBOM O

H OBOM O

RO

Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798

First Asymmetric Total Synthesis of Tetrodotoxin

O O RO
5

O O NH 2 H OBOM O OMe RO t-BuOK O

5

NH CO 2Me OBOM O O

OH HO O O O OH O O MeO 2C HO
5

OR OR

OH H2N OH tetrodamine

HN Boc

Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798

Synthetic Approach to Tetrodotoxin

O HO O HO HN H2N (-)-tetrodotoxin OH CO 2H HO OH O OH OH OH H2N OH HO OHC OH OH N MeO 2C O NH O TBSO O OMe O OH

OH NH OH

HO 2C core skeleton

OH NH 2 OH

MeO

OMe LiAl(t-BuO)4 ; I2 O O N H O Bn TBSO

TBSO

OMe

I O

NCbz O

TBSO

Itoh, T.; Watanabe, M.; Fukuyama, T. Synlett 2002, 8, 1323

A Stereoselective Synthesis of (-)-Tetrodotoxin

O HO O HO HN H2N (-)-tetrodotoxin OH O OH HO O O O OH

OH NH OH H2N OH

OH tetrodamine

Hinman, A.; J. Du Bois J. Am. Chem. Soc. 2003, 125, 11510

Iminoiodanes and C-N Bond Formation

PhI=NSO2Ph I N

SO 2R

[N-(Arylsulfonyl)imino]phenyliodane ArO2S N R1 R2

R1 R2

R3

PhI=NSO2Ar

Cu(I) or Cu(II)

R3

CH 3 CH 3 H C 3 H3C I Ph NH H N SO 2NH 2 PhI(OAc) 2 SO 2 Rh2(OAc)4 SO 2 KOH/MeOH 86%

Beslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105, 6728. Review: Dauban, P.; Dodd, R. H. Synlett 2003, 11, 1571

Iminoiodanes and C-N Bond Formation

O O O H2N S O O NH 2 PhI(OAc) 2, MgO HN O O O O PhI(OAc) 2, MgO HN S O O Cbz NH N

Rh2(tpa)4

Rh2(OAc)4

Espino, C. G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 589 Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 935.

Retrosynthetic Analysis
O HO O HO HN H2N (-)-tetrodotoxin OH O OH HO O O O OH O OO O OP OP OP NH 2 OP

OH NH OH HN OH

OH tetrodamine O O N2 O R1O H O O O O O OR 2 O

O O O NH 2 O

Preparation of -Diazoketone
O O O H n-BuLi DIBAL O O H Me 2N OTBS O O H N2 O PivO 1. t-BuCOCl O 2. Pd/C, H2 OTBS 3. (COCl) , CH N 2 2 2 cat. DMF O O overall 56-60% O O H BnO 2C HO OTBS O O H OTBS O BnO O NaOAc, THF O OBn H BnO 2C O O O O OTBS O OBn 10:1

Rh-Catalyzed C-H Insertion: the Cyclohexane Skeleton

O O H N2 O O PivO PivO O OTBS Rh2(HNCOCPh3)4 O O O O O OTBS 1. BH3, NH3 2. H2 (1200 psi) Rh/C HO H PivO 58% (4 steps) O O OTBS O O TsOH 2,2-DMP

O O O O O O OPiv NMe 2 Ph2Se2, PhIO2 cat. PbCl2 70%

O O O O O OPiv NMe 2

1. Me2NH 2. TPAP, NMO 3. Zn, TiCl4, CH2I2 ~50% O O

O O O O H OPiv

Formation of Lactone Ring

O O O O O O OPiv NMe 2 O 1. vinylMgBr CuI 2. BH3, t-BuNH2 77% O NMe 2 O HO O t-BuCO 2H O Cl OPiv O 200 C OPiv O O O O O

O O O Cl O O O O O NH 2 1. O3; NaBH4 2. MsCl, Pyridine 84%

O O O O O O O O NH 2 2. Cl 3C 1. NaOMe O NCO PivO O

O OP OP OP OP

; Zn, MeOH ~70% (three steps)

C-H Amination: Nitrene Insertion

O O O Cl O O O O O O O O O OH OH HO O O O OH NH 2 1. Boc2O, NEt3 DMAP 2. K2CO3, MeOH 3. H2O, 110 C 84% O O O O NH O O O NH 2 Rh(HNCOCF 3)4 PhI(OAc) 2, MgO 79% Cl O O O O NH O Cl O O O O N H OP OO O OP OP OP

1. PhSeNa 71% 2. mCPBA, Py O O O

HO O

O OP OP OP

H2N OP

OH H2N OH tetrodamine

Introduction of Guanidine and Completion of Synthesis

O BocN OP OP OP H2N OP HgCl 2 80% SMe NHBoc BocHN BocN 65% 1. O3; SMe2 2. aq. CF3CO2H HO O O OP OP OP NH OP

HO O

O HO O HO HN H2N (-)-tetrodotoxin O OH

OH NH OH

Conclusion
C-H Functionalization as a useful strategy for complex target molecules Demonstration of Rh-catalyzed nitrene insertion as powerful new tool in organic synthesis O O

O O O O O Cl O O O O O NH 2

NH 2

PhI(OAc) 2, MgO Rh2(tpa)4

HN

O O Rh(HNCOCF 3)4 PhI(OAc) 2, MgO 79% O Cl O O O O NH O