TETRODOTOXIN - Scripps Research · PDF fileTETRODOTOXIN Presentation by Neil Vasan Baran Lab...
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TETRODOTOXIN
Presentation by Neil Vasan
Baran Lab Group SeminarAugust 13, 2003
OHOH
HO
OO
NH2N N
H
H
O
OH
HO
TTX: Background• Toxic venom component of puffer fish or fugu (Spheroides
rubripes), a Japanese delicacy (1 fish = ~$400)• First isolated in 1909 and named after puffer fish order
Tetraodontidae• Structure first elucidated in 1964 by Woodward (confirmed by
Kishi in 1965)• First synthesis by Kishi, et. al. in 1972• Toxicity attributed to selective blockage of Na+ channels of
skeletal muscles• Lethal dose for adult human = .001 mg• Upon ingestion, one feels tingling and lightheadedness but is
lucid; paralysis and death ensue within 6-24 hours• 70-100 deaths each year, mostly in rural Japan• No known antidote exists
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TTX: Structure
OHOH
HO
OO
NH2N N
H
H
O
OH
HO
OHOH
HO
OO
NH2N N
H
H
OO
OHOH
HO
OOH
NH2N N
H
H
O
OH
HO
Equilibrium mixture among ortho ester, anhydride, and lactone forms
TTX: Kishi SynthesisSynthesis of Cyclohexane chiral core
, SnCl4
MeCN, rt(83%)
OMe
Me
NOH
OMe
NH
H
OAc
NaBH4MeOH
OMe
MeN OH
H
O
Me
NH
HOH
OAc
MsClO
Me
MeN Ms
H
O
Me
NH
HO
HOH
H
OAc
H
Et3N(quant.)
H2O, 100 oCBeckmann
(61%) (96%)
m-CPBAcamphorsulfonic acid
(75%)
O
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TTX: Kishi Synthesis
(90% in 2 steps)
(76% in 6 steps) (70% from diethyl ketal)
Towards Tetrodamine
Me
NH
HO
HOH
H
OAc
H Me
NH
HO
O
O
H
OAc
H Al OCHMe2
NH
HO
EtO
EtO
H
OAcAc
HOCH2OAc
H NH
HO H
OAcAc
HOCH2OAc
HEtOO
Me
NH
HO
O
O
H
OAcAc
H3
MPV-reduction
1)
2) O(COCH3)2, pyr.(95% in 2 steps)
1. o-DCB, reflux2. m-CPBA, K2CO3
CH2Cl2
AcOH, rt
TTX: Kishi SynthesisTowards Tetrodamine
O
O
O
AcO
HOHCH2OAc
HOAc
AcHNAcO
H
H
H
NH
HO H
OAcAc
HOCH2OAc
HOAcO
mCPBACH2Cl2, rt
NH
HO H
OAcAc
H
OCH2OAc
HOAcO
O
O
O
O
HOAcCH2OAc
HOAc
AcHNAcO
H
H
KOAc, AcOH90 oC, 2h
(quant.) (quant.)
1) O(COCH3)2, pyr.2) pyrolysis, 300 oC, vacuum (80% in 2 steps)
(acetylatedtetrodamine)
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TTX: Kishi SynthesisTetrodamine to Tetrodotoxin
O
O
O
HOAcCH2OAc
HOAc
AcHNAcO
H
HBF3 Et2OCH2Cl2
O
O
O
HOAcCH2OAc
HOAc
H2NAcO
H
HAcN
SEt
SEt
O
O
O
HOAcCH2OAc
HOAc
NAcO
H
H
CNH2
AcHN
HOHO
TTX O
O
O
HOAcCH2OAc
HOAc
NAcO
H
H
CNH2
AcHN
O
O
O
HOAcCH2OAc
HOAc
NAcO
H
H
CSEt
AcHN120 oC, 12h
OsO4
THF, -20 oC1) NaIO4, THF, 0 oC2) NH4OH, MeOH
(92%)
(acetylated tetrodamine)
(25% from mono-acetylguanidine)
(20% in 3 steps from tetrodamine)
TTX: Isobe SynthesisRetrosynthesis
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TTX: Isobe SynthesisSonogashira Coupling and Claisen Rearrangement
OMe
OHO
OH
Oi-Pr
OOTBS
O
Oi-Pr
TMS
O
OAcOAc
AcO
OAc
OOTBS
OH
Oi-Pr
I
OOTBS
Oi-Pr
TMS
OMe
TMS OOTBS
OH
Oi-Pr
TMS
OOTBS
Oi-Pr
OOTBDPS
BzO
Pd(OAc)2, Ph3P, CuI,Et3N, PhH
(99%)
PPTS/THF
(89%)
K2CO3
o-DCB150 oC(94%)
5(50% in 6 steps)
(61% in 4 steps)
(available in 2 steps from )
TTX: Isobe Synthesis
H2SO4MeOH
OOTBS
OMe
OTBDPS
BzO
O
OO
OOBzOHTBDPSO
HOMe
OOH
OTBDPS
BzO
OBOM
OH
OOTBS
OMe
OTBDPS
BzOO
OTBS
OTBDPS
BzO
OBOM
OHOO
and thenHgO (cat.)
(82%)
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1) TBS-OTf Et3N, lutidine
2) TBS-Cl imid., DMF
1) TBAF THF H2O
2) Cl3CCOCl DMAP, pyr.(74% in 4 steps)
(67% in 6 steps)
1) NaBH4, MeOH, rt2) Me2C(OMe)2, CSA, acetone3) PPTS, MeOH(93% in 3 steps)
Cyclohexenone and Exoolefin Synthesis
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TTX: Isobe SynthesisPrevious Overman Rearrangement Problem with Overman Rearrangement
TTX: Isobe SynthesisInstallation of Nitrogen Functionality: Conjugate Carbamate Addition
OTBDPS
BzO
OBOM
OHOO
OMMTr
OTBDPS
O
OBOM
OO
O
NH
COOMe
OTBDPS
HO
OBOM
OO
OTBDPS
HO
OBOM
OO
NHBoc
OMMTr
COOMe
OTBDPS
O
OBOM
OO
O
H2N
1) DIBAL-H2) TEMPO, NCS3) NaClO2, NaH2PO4, Me2C=CHMe-H2O4) TMS-CHN2 (78% in 4 steps)
1) Cl3CCONCO CH2Cl22) Et3N, MeOH(99% in 2 steps)
(88% in 3 steps)
1) t-BuOK, THF2) LiBH4, THF3) MMTrCl, pyr.
(84% in 2 steps)
1) Boc2O, Et3N DMAP, THF2) LiOH, MeOH (CH2Cl)2-H2O
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TTX: Isobe Synthesis
OTBDPS
HO
OBOM
OO
NHBoc
OMMTr
(70% in 7 steps)
Construction of Lactone Bicycle
TTX: Isobe Synthesis
OAcOBz
O
OOAc
NN N
Ac
OBz
O
AcO
Ac
Ac
Me
Introduction of Guanidine
OHOBz
O
OOAc
O
BOM
OO
Me
Me
HOH
BocHN
OAcOBz
O
OO
OBz
Ac
OO
Me
Me
AcO
BocHN
OAcOBz
O
OO
OBz
Ac
HOHO
AcO
NH
BocHN
BocN
OAcOBz
O
OO
NN N
H
H
OBz
OH
AcO
Boc
Ac
BocN
NHBoc
SMe
(96% in 4 steps)
1) TFA, MeOH2) CAN MeCN-H2O3) HgCl2 Et3N-DMF(53% in 3 steps)
1) NaIO4
MeOH-H2O2) TFA, MeOH(90% in 2 steps) (50% in 3 steps)
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TTX: Isobe SynthesisDeprotection and Final Conversion
OAcOBz
O
OOAc
NN N
Ac
OBz
O
AcO
Ac
Ac
Me
OHOHO
OOH
NH2N N
H
O
O
HOMe
H
H
OHOH
HO
OO
NH2N N
H
O
OH
HO
OHOHO
OOH
NH2N N
H
O
H
O
Et3NMeOH-H2O
(85%)+
TFA-d/D2O
(TTX-anhydride)
(TTX-ortho ester)
(-) TTX
TTX: Du Bois Synthesis
OHOH
OH
OO
OH
HO
NHNH
NH2
OHOH
OH
OO
OH
HO
HO
OH
OH
HOOH
HO
OHCHCO2HHO
O
OO
Me
Me
OR1O
O
OR2
O
OO
Me
Me
OR1O
O
OR2
HN2
OH
OH
HOOH
HO
OHCHCO2HHO
stereospecific C-Hamination
Rh-catalyzedC-H insertion
Retrosynthesis
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TTX: Du Bois SynthesisRh-carbene C-H insertion
O OH
OH
O
HOOH
O
OO
Me
Me
Ot-BuO2C
O
OTBS
H
OOO
MeMe
OTBS
CO2Bn
OHBnO2CO
O
MeMe
TBSO
OO
COOt-Bu
ON2
O
OOMe
Me
O Me
MeHO
O CO2t-Bu
(53% in 4 steps)(64% in 5 steps)
1) Rh2(tpacam)4, CCl42) NH3 BH3, CH2Cl2-MeOH
(75% in 2 steps)
1) H2 (1200 psi), Rh-C, CF3CO2H-MeOH2) p-TsOH, 2,2-DMP; then t-BuCOCl, pyr., THF (77% in 2 steps)
TTX: Du Bois SynthesisConstruction of Lactone Bicycle
O
OO Me
O Me
MeHO
O CO2t-Bu
Me
O
OO Me
O Me
MeH
Me2NOCCO2t-Bu
Me
O
OO Me
O Me
MeH
Me
HO
Me2NOCOt-Bu
O
O
OO Me
O Me
MeH
Me2NOCCO2t-Bu
Me
O
OO Me
O Me
Me
Me
HOH
O
(56% in 3 steps)
Ph2Se2, PhIO2
100 oC, pyr., PhCl(70%)
(77% in 2 steps)
1) t-BuCO2H PhCl, 200 oC2) NaOMe, THF-MeOH (78% in 2 steps)
O
O
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TTX: Du Bois Synthesis
O
OO Me
O Me
Me
Me
HOH
O
OO
O
OO
MeMe
HO
MeMe
OH
OO
O
OO
MeMe
OMe
Me
Cl
NH
OO
OO
O
OO
MeMe
HO
MeMe
O
Cl
O
NH2
OO
O
OO
MeMe
OMe
Me
NHBoc
OH
(66% in 3 steps)
Rh2(tfacam)4, PhI(OAc)2, MgO, DCE, 50 oC
(55% with 38% reactant) (59% in 4 steps)
Rh-nitrene C-H insertion
TTX: Du Bois SynthesisGuanidine Insertion and Final Steps
OO
O
OO
MeMe
OMe
Me
NHBoc
OH
OHOH
OH
OO
OH
HO
NHNHH2N
HO
OO
O
OO
MeMe
OMe
Me
NH2
OH
OHOH
OH
OO
OH
NHNHH2N
O
NBoc
BocHN SMe
H2O-CF3CO2H5 days
(4:1 mixture)(65% from
after deprotection)
OO
O
OO
MeMe
OMe
Me
N
OHNHBoc
NHBocH2O, 110 oC
(95%) HgCl2, Et3N, MeCN-CH2Cl2
(80%)
O3, Me2S, CH2Cl2-MeOH;
then H2O-CF3CO2H(1:1 mixture)
([-] TTX-ortho ester) ([-] TTX-anhydride)
(-) TTX
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Comparisons and Contrasts
0.49%1.22%0.66%Yield326729# of Steps
Rhodium-catalyzed carbene and nitrene
C-H insertions; Ph2Se2-promoted allylic oxidation; Shows power of organometallic
chemistry in total synthesis
Claisenrearrangement;
Sonogashiracoupling;
Intramolecularcarbamate-ester
conjugate addition; All OH groups
differently protected for future analog
synthesis
Diels-Alder synthesis of skeleton; 6 chiralcenters established on cyclohexane core ring; Only ketal and
acetyl protecting groups; Common
reagents employed to carry out elegant
chemistry
HighlightsAsymmetricAsymmetricRacemicTypeJune 2003Jan. 2003Sept. 1972DateDU BOISISOBEKISHIChemist
TTX: References
Structure: Woodward, R. B. Pure. Appl. Chem. 1964, 9, 49-74. Tsuda, K., et. al. Chem. Pharm. Bull. 1964, 12, 1357-1374. Goto, T.; Kishi, Y.; Takahashi, S.; Hirata, Y. Tetrahedron 1965, 21, 2059-2088.
Absolute stereochemistry: Furusaki, A., et. al. Bull. Chem. Soc. Jpn. 1970, 43, 3332-3341.
Bioorganic studies: Narahashi, T.; Moore, J. W.; Scott, W. R. J. Gen. Physiol. 1964, 47, 965-974. Hucho, F. Angew. Chem, Int. Ed. Engl. 1995, 34, 39-50. Numa, S.; Noda, M. Ann. N.Y. Acad. Sci. 1986, 479, 338-355.
Other analog syntheses: Nishikawa, T., et. al. Angew. Chem., Int. Ed. 1999, 38, 3081-3084.Asai, M., et. al. Tetrahedron 2001, 57, 4543-4558. Nishikawa, T., et. al. J. Am. Chem. Soc. 2002, 124, 7847-7852.
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TTX: References Kishi synthesis: Kishi, Y., et. al. Tetrahedron Lett. 1970, 59, 5127-5128.
Kishi, Y., et. al. Tetrahedron Lett. 1970, 59, 5129-5132.Kishi, Y., et. al. J. Am. Chem. Soc. 1972, 94, 9217-9219. Kishi, Y., et. al. J. Am. Chem. Soc. 1972, 94, 9219-9221.
Isobe synthesis: Isobe, M., et. al. J. Am. Chem. Soc. 2003, 125, 8798-8805.
Overman Rearrangement: Overman, L. E. Acc. Chem. Res. 1980, 13, 218-224.Sonogashira Coupling: Sonogashira, K., et. al. Tetrahedron Lett. 1975, 16, 4467-4470. α-hydroxyl Lactone: Corey, E. J.; Ghosh, A. K. Tetrahedron Lett. 1988, 26, 3205-3206.
Du Bois Synthesis: Hinman, A.; Du Bois, J., personal communication. (to be published in JACS)
Rh-carbene C-H insertion: Espino, C. G.; Du Bois, J. Angew. Chem., Int. Rd. Engl. 2001, 40, 598-600.Rh-nitrene C-H insertion: Guthikonda, K.; Du Bois, J., J. Am. Chem. Soc. 2002, 124, 13672-13673.Ph2Se2 allylic oxidation: Barton, D. H. R.; Crich, D. Tetrahedron 1985, 41, 4359-4364.
TTX: Acknowledgements
• Prof. Justin Du Bois, Stanford University
• The Baran Laboratory, TSRI