a synthesis of (+)-saxitoxin-fccc.chem.pitt.edu/wipf/current literature/erikah_7.pdf · saxitoxin...

A Synthesis of (+)-SaxitoxinJames J. Fleming and J. Du Bois

J. Am. Chem. Soc., 128 (12), 3926 -3927, 2006

Erikah Englund, Current Lit. (4/06)

Erikah Englund @ Wipf Group 1 4/3/2006

Outline:• Introduction to Saxitoxin• Biological Activity• Previous Syntheses

– Kishi– Jacobi

• C-H activation in the Du Bois Group• Current Paper• Conclusions


Saxitoxin• Isolated from:

– Alaska butter clams, mussels, axenic cultures of Gonyaulaxcatanella and aged scallop extracts during G. tamarensis bloom

• Characterization:– Structure elucidated by single crystal X-ray diffraction (Schantz,

JACS, 1975, 97, 1238)

• Biological Activity:– neurotoxin– One of most toxic non-protein poisons (LD50 5-10 μg/kg)– Saxitoxin and ricin are only two natural toxins classified as

Schedule 1 Chemical Warfare Agents

ricin


Biological Activity:• Paralytic shellfish poisoning (PSP)

– All 20 compounds responsible for PSP are derivatives of STX• Death occurs within 2-12 hours in untreated cases• Symptoms include:

– dizziness, diarrhoea vomiting, disorientation, respiratory distressand eye irritation

• Effects on Na Channels– Potent and selective sodium channel blocker– No effect on potassium or calcium channels, chloride ion flux or

acetylcholine release.– Saxitoxin has been used for labelling, characterisation and

isolation of various sodium channel components,

University of Sussex at Brighton: http://www.chm.bris.ac.uk/motm/stx/saxi.htmFDA: http://www.cfsan.fda.gov/~mow/chap37.html


Kishi (JACS, 1977, 99, 2818)

HN

O

O

OP4S10

HN

S

O

O

HNO

O

CH3CO21. CH3COCHBrCO2CH3

NaHCO3/CH2Cl2 reflux

2.KOH, MeOH

OO

silicontetraisothiocyanate

2. 110 oC, toluene

1.

HN

NO

O

S

OBn

CO2CH3HN

NO

O

S

OBn

NHCONH2

1.NH2NH2.H2O

2. NOCl, CH2Cl2

3. 90 oC, benzene

4. NH3, benzene

HN

NS

OBn

HN

O

SS

NH

1. Propanedithiol, BF3.OEt2

2. AcOH, TFA

1. Et3OBF4, NaHCO3

2. EtCO2NH4

HN

NN

OBn

HN

N

SS

NH

1. BCl32. NBS, CH3CN

3. MeOH, 100 oC

HN

NN

OH

HN

N

OHOH

NH

chlorosulfonylisocyanate

saxitoxin

H H

H


Jacobi (JACS, 1984, 106, 5594)

HN

HN

O

SS O

HN

HN

Bn

O

OMe

OH

MeO

BF3.OEt2 HN

HN

O

SS O

N NBn

CO2Me

HN

HN

NN

O

Bn

O

SS

CO2Me

1. NaOMe, MeOH, NaBH4

2. BH3DMS

HN

HN

NN

O

Bn

SS

OH

1. Pd, formic acid

2.S

PhO Cl

HN

HN

NN

O

SS

OH

S

OPh Na, NH3HN

HN

NH

HN

O

SS

OH

S

OPhN

NH

HN

NH

O

H

OH

S

SS

1. Ac2O

2. Et3OBF4, KHCO3 N

NN

NH

EtO

H

OAc

SEt

SS

N

NN

NH

H2N

H

OH

NH2

SS

EtCO2NH41. NBS, wet CH3CN

2. chlorosulfonyl isocyanate

saxitoxin


C-H Insertion• Du Bois, JACS, 2001, 123, 6935

• Du Bois, Angew.Chem.Int.Ed, 2001, 40, 598


Application of CH Insertion Chemistry• Tetradotoxin (Du Bois, J. Am. Chem. Soc., 125, 11510 -11511, 2003)

• Manzicidin A and C (Du Bois J. Am. Chem. Soc. 2002; 124; 12950-12951)


Saxitoxin Retrosynthesis


Saxitoxin-1• Synthesis of Starting Material (Du Bois, J. Am. Chem. Soc. 2003, 125, 2028)


Saxitoxin-2

HNS

OH

OTs

O O

1. H2, Pd/CaCO3/Pb2. NaN3, nBu4NI, DMF

3. p-C6H4CH2Cl, nBu4NI, K2CO3

( 77%)

PMBNS

OH

O O

N3

1. Me3P2. MeS(Cl)C=NMbs, i-Pr2NEt3. Tf2O, pyridine, DMAP

4. NaN3, DMF5. CAN (40%)

HNS

O O

NH

MbsN

MeS

N3

1. KOtBuO, Cl2C=NMbs then (Me3Si)2NH (70%)

2. aq. CH3CN (95%)

NH

NH

MbsN

MeS

N3

OH

MbsN

NH2

1. Me3P

2. AgNO3, Et3N (65%)

NH

NH2

OH

MbsN

NH2

CNMbs

NH

NH

NH

OH

MbsN

NH2

NMbs

Cl3CC(O)NCO

then K2CO3, MeOH82% N

H

NH

NH

MbsN

NH2

NMbs

O

O

NH2


Oxidation• Plietker, JOC, 2004, 69, 8287

Undesired ketol (57%) afforded 13 (<5%)


Saxitoxin-3

NH

NH

NH

MbsN

NH2

NMbs

O

O

NH2 OsCl3, oxone, Na2CO3

(57%)

NH

NH

NH

MbsN

NH2

NMbs

O

O

NH2

N NH

NMbs

HOHN

HO

NMbs

NH2

O

O

NH2

B(O2CCF3)3, TFA

(82%) N NH

NH2

HO

O

O

NH2

NHHN

H2N

DCC, C5H5N.HO2CCF3

(70%) N NH

NH2

HO

O

O

NH2

NHHN

H2N

HO

O

HO


Conclusions• The stereoselective synthesis (+)-saxitoxin was

accomplished in 16 steps and 3% overall yieldfrom known starting material

• The efficient synthesis of a 9 memberedguanidine containing ring was demonstrated

• Through ketohydroxylation conditionoptimization, the desired regioisomer could beobtained


a synthesis of (+)-saxitoxin-fccc.chem.pitt.edu/wipf/current literature/erikah_7.pdf · saxitoxin...

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