A Synthesis of (+)-Saxitoxin James 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 Erikah Englund @ Wipf Group 2 4/3/2006 Saxitoxin • Isolated from: – Alaska butter clams, mussels, axenic cultures of Gonyaulax catanella 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 Erikah Englund @ Wipf Group 3 4/3/2006 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 distress and 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.htm FDA: http://www.cfsan.fda.gov/~mow/chap37.html Erikah Englund @ Wipf Group 4 4/3/2006 Kishi (JACS, 1977, 99, 2818) O CH3CO2 O S 1. CH3COCHBrCO2CH3 O NaHCO /CH Cl reflux HN P4S10 3 2 2 O O HN HN O 2.KOH, MeOH O OBn OBn 1. O 1.NH NH .H O O 2 2 2 CO2CH3 2. NOCl, CH Cl NHCONH silicontetraisothiocyanate HN 2 2 HN 2 O O 3. 90 oC, benzene 2. 110 oC, toluene S N S N O 4. NH3, benzene O OBn OBn H H H . H 1. Propanedithiol, BF OEt 1. Et3OBF4, NaHCO3 N 3 2 HN N HN O N 2. EtCO NH NH 2. AcOH, TFA S N NH 2 4 N N S S S S OH 1. BCl 3 H H 2. NBS, CH CN 3 HN N chlorosulfonylisocyanate N saxitoxin o 3. MeOH, 100 C N N NH OH OH Erikah Englund @ Wipf Group 5 4/3/2006 Jacobi (JACS, 1984, 106, 5594) H H CO Me N 2 O H CO2Me H N N O N O HN . N N N Bn 1. NaOMe, MeOH, NaBH4 HN Bn BF3 OEt2 HN Bn HN N O S OH S 2. BH3DMS S O S O S OMe S MeO O OH OH H OH OH O O H O H N N N S H H 1. Pd, formic acid OPh N N Bn N Na, NH3 HN NH HN N HN N HN O 2. NH OPh S S N N S S S S H S S S S PhO Cl S OAc OH H H N 1. Ac2O N EtCO NH N 1. NBS, wet CH3CN 2 4 N saxitoxin EtO H N N 2 2. chlorosulfonyl isocyanate 2. Et3OBF4, KHCO3 N SEt N N NH H H 2 S S S S Erikah Englund @ Wipf Group 6 4/3/2006 C-H Insertion • Du Bois, JACS, 2001, 123, 6935 • Du Bois, Angew.Chem.Int.Ed, 2001, 40, 598 Erikah Englund @ Wipf Group 7 4/3/2006 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) Erikah Englund @ Wipf Group 8 4/3/2006 Saxitoxin Retrosynthesis Erikah Englund @ Wipf Group 9 4/3/2006 Saxitoxin-1 • Synthesis of Starting Material (Du Bois, J. Am. Chem. Soc. 2003, 125, 2028) Erikah Englund @ Wipf Group 10 4/3/2006 Saxitoxin-2 O O O O O O 1. Me P S 3 S HN S 2. MeS(Cl)C=NMbs, i-Pr2NEt HN 1. H2, Pd/CaCO3/Pb PMBN 3. Tf O, pyridine, DMAP 2. NaN3, nBu4NI, DMF 2 4. NaN , DMF N OH 3. p-C6H4CH2Cl, nBu4NI, 3 3 OH 5. CAN MbsN K2CO3 (40%) OTs ( 77%) MeS N N3 H MbsN MbsN NH2 NH 1. KOtBuO, Cl2C=NMbs NH2 NH 1. Me3P then (Me3Si)2NH (70%) OH OH N 2. AgNO , Et N 2. aq. CH CN (95%) MbsN 3 3 3 NH 3 (65%) 2 NMbs MeS N C H MbsN MbsN NH2 NH NH2 NH O OH Cl CC(O)NCO 3 O NH2 NH NH then K2CO3, MeOH N NMbs 82% N NMbs H H Erikah Englund @ Wipf Group 11 4/3/2006 Oxidation • Plietker, JOC, 2004, 69, 8287 Undesired ketol (57%) afforded 13 (<5%) Erikah Englund @ Wipf Group 12 4/3/2006 Saxitoxin-3 MbsN MbsN NMbs NH2 NH O NH2 NH O HN NH O HO HO 2 O NH2 OsCl , oxone, Na CO O 3 2 3 O NH NH 2 O NH2 HO (57%) NH N NH N NMbs NMbs H N NMbs H H2N H2N O NH O HO NH HO HN DCC, C H N.HO CCF HN B(O2CCF3)3, TFA 5 5 2 3 HO O NH2 O NH2 (82%) N NH (70%) N NH NH2 NH2 Erikah Englund @ Wipf Group 13 4/3/2006 Conclusions • The stereoselective synthesis (+)-saxitoxin was accomplished in 16 steps and 3% overall yield from known starting material • The efficient synthesis of a 9 membered guanidine containing ring was demonstrated • Through ketohydroxylation condition optimization, the desired regioisomer could be obtained Erikah Englund @ Wipf Group 14 4/3/2006.