Oct 12, 2005 ... Paul Josef Scheuer was born in Heilbronn, Germany in 1915. ... awarded the
Paul J. Scheuer Award in Marine Natural Products Chemistry in ...
O'Malley
Faulkner and Scheuer
Paul J. Scheuer Biography Paul Josef Scheuer was born in Heilbronn, Germany in 1915. Upon his graduation from high school in 1934, he was denied entrance to college by the racial policies of the National Socialist party. He served as a tanner's apprentice in Hungary and elsewhere before immigrating to the United States in 1938. His curiosity about the tanning process led him to study chemistry, and he obtained his BS from Northeastern University in 1943. He began graduate work at Harvard, but was drafted and served in the Chemical Warfare Service and Military intelligence. In 1946, he resumed his graduate work under R. B. Woodward. He defended his thesis on the structure and chemistry of strychnine in 1950.
Career
After receiving his doctorate and marrying, Prof. Scheuer joined the faculty of the University of Hawaii at Manoa. His research initially focused on the natural products chemistry of terrestial Hawaiian plants, but quickly turned to the untapped resources of the surrounding Pacific Ocean. Before the work of Prof. Scheuer, marine natural products were almost unexpolored; indeed, he is credited with coining the term in his 1973 book Chemistry of Marine Natural Products. During his prolific career, Prof. Scheuer published some 300 papers. Although he formally retired in 1983, he maintained an active research program unitl his death in January 2003. Notable projects in the Scheuer lab include work on the structure of ciguatoxin and palytoxin, studies on the chemical ecology of marine invertibrates, and the isolation of the peptide kahalalide F, which is presently in clinical trials as a treatment for cancer. Prof. Scheuer was also the first natural products chemist to utilize manned submersibles in sample collection. Interestingly, he had never even been to an aquarium before his arrival at Hawaii.
Group Meeting 10/12/2005
D. John Faulkner Biography Born in Bournemouth, England in 1942, John Faulkner received his Ph. D. in 1965 under Sir Derek Barton, then undertook postdoctoral research under R.B. Woodward at Harvard and William Johnson at Stanford. In 1968, he was appointed Assistant Professor at the Scripps Institute of Oceanography. He began a program of research directed at the isolation of marine natural products.
Career During Prof. Faulkner's prolific careeer, he published over 350 papers in the areas of natural products chemistry and chemical ecology. Among his most important discoveries are the realization that halogenation was a prominant biosynthetic pathway in the marine ecosystem. Indeed, he and his co-workers discovered more than 100 halogenated natural products. His studies on shell-less molluscs led to the theory that coevolution with toxic foods had allowed them to lose their shells over evolutionary time. His isolation of manoalide, a terpenoid that inhibits the inflammation enzyme Phospholipase A2 led to the discovery of a new class of antiinflamatory agents and investigations into the functions of PLA2. He was awarded the Paul J. Scheuer Award in Marine Natural Products Chemistry in 2000. He passed away in November 2002.
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Faulkner and Scheuer
O'Malley
9-isocyanopupukeanane: The First Marine Defensive Secretion The Scheuer group was responsible for the isolation of the first natural product identified as a marine feeding deterrent (JACS, 1981, 103, 2491-4). The nudibranch Phyllidia varicosa was identified as having a secretion that was toxic to fish and crustaceans. Subsequent investigation revealed that the active agent, 9-isocyanopupukeanane, was actually a secondary metabolite of the nudibranch's prey, the sponge Ciocalypta sp. This was the first observation of an organism concentrating a metabolite of another for its own use.
1989: pooling of world supply (1.1 mg) gives planar structure (Yasumoto) Careful study of toxic fish gut contents identified the benthic dinoflagellate Gambierdiscus toxicus as source organism. Culture of this organism proved very difficult and yielded only maitotoxin, not ciguatoxin. Eventually, a ciguatoxin analog was obtained (0.7 mg from 1,100 L culture broth). An antibody based stick test has been developed to detect ciguatoxin, but it is not known if this test is adequate for all related toxins. A false lead on the path to ciguatoxin led Scheuer to isolate palytoxin, whose planar structure was elucidated by Hirata and Moore, and stereochemistry by Kishi's synthesis of degradation products.
CN
9-isocyanopupukeanane First synthesized by Corey (JACS, 1979, 101, 1608-9) and Yamamoto (ibid. 1609-11)
Subsequent investigations on similar isocyano terpenoids reveled that the isocyano group was the biosynthetic precursor to the formamide and isothiacyano analogues. Other experiments revealed that cyanide served as the source of the isocyano group. This is in contrast to terrestial isocyanides, where the isocyano nitrogen is of peptidic origin.
The Ciguatoxin Odyssey (Terahedron, 1994, 50, 3-18) In 1957, Scheuer was invited to join an interdisciplinary task force of scientists studying ciguatera by Prof. A. H. Banner, a zoologist at the University of Hawaii. Ciguatera is the name for a diverse collection of symptoms displayed by those whoe have consumed contaminated fish, including vomiting, diarrhea, dizziness, tingling in the extremities, and a sensation of temperature reversal. The team planned four deceptively simple objectives: 1. Elucidate the molecular structure of the toxin 2. Discover the origin of the toxin 3. Devise a diagnotic test to distinguish toxic fish from non-toxic ones 4. Find an effective human therapy Difficulties: 1. Intermittent occurrence of toxicity in many species of fish/eels 2. Possible presence of >1 related toxin 3. Inability to distinguish toxic from non-toxic fish without bioassay 4. Low purity of extract (LD50 of extract 2 x 105 µg/kg, LD50 of ciguatoxin 0.45 µg/kg) 5. High molecular weight (1111.7 Da) History: 1961: Mouse bioassay replaces mongoose assay 1967 &1971: Identification of ciguatoxin (lipid soluble) and maitotoxin (water soluble) 1980: 1.3 mg ciguatoxin purified from 75 kg eel viscera (1100 kg of eels at ca. 5.5 kg each), mass spectrum, 600 MHz 1H NMR spectrum obtained 1989: Formula of C60H86O19 obtained by Yasumoto (former Scheuer postdoc) Disaster strikes: entire sample lost when pyridine solution transferred to plastic tube
Maitotoxin
1967 &1971: Identification of ciguatoxin (lipid soluble) and maitotoxin (water soluble) 1980: 1.3 mg ciguatoxin purified from 75 kg eel viscera (1100 kg of eels at ca. 5.5 kg each), mass spectrum, 600 MHz 1H NMR spectrum obtained 1989: Formula of C60H86O19 obtained by Yasumoto (former Scheuer postdoc) Disaster strikes: entire sample lost when pyridine solution transferred to plastic tube
Maitotoxin 2
Group Meeting 10/12/2005
Faulkner and Scheuer
O'Malley
The Carbonimidic Dichlorides In 1977 and 1978, Faulkner reported the isolation of several natural products containing the carbonimidic dichloride functional group, which at that point was known only in synthetic compounds. (JACS, 1977, 99, 7367-8, TL, 1978, 1391-4 and 1395-8).
O
O H •
HO
N O
O
O
N
Cl Cl OH
O
Renieramycin C Faulkner, JACS, 1982, 104, 265-9. JOC, 1989, 54, 5822-4 (stereochem reassigned) Several syntheses, as well as Saframycins and Ecteinascidins.
Zoanthamine Faulkner, JACS, 1984, 106, 7983-4 Synthesized (Norzoanthamine) by Misyashita Science, 2004, 305, 495-9
[O]
Cl
Cl
H
N
O
Cl
HN
N
Cl
Cl
OH O
Cl Cl
Cl
O
O
Cl
O
NMe MeO
N
Proposed Biogenesis
H
•
Cl
[O]
O
O
N Cl
OMe
Natural Products Gallery
N
Cl
O
•
Cl
OH N
N
O
Dictyoxetane Faulkner JOC, 1985, 50, 3665-6 not synthesized
NH
Eudistone A Faulkner, JOC, 1991, 5369-5371 not synthesized Cl N
CO2Me
Cl
OH
Cl
HO
O HO
OH
Isonitrile (not isolated) or isothiocyanate (isolated)
H
None of these natural products have been synthesized
H
O H
CO2Me
Furanocembrane Diester similar compounds synthesized e.g. Pukalide (Scheuer isolation)
•
OMe
MeO2C O
OH O
CO2Me
Mandapamate not synthesized
Faulkner Tet. Lett. 1998, 39, 8217-8220
• O
CO2Me •
OH
•
O
Rameswaralide synthesized by Trost (reported at ACS Meeting)
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O'Malley
OMe H N
H N
O N H
Br Br
MeO
NH2
HO O
N •2HCl
H N N H
H
HO
O
H O NH2
N H
O
O
O
N
O
OH OMe
OH
N
H
O
N
O
O
H
O
H
H
O
O H
O MeO
N H
Popolohuanone E Scheuer Tet. Lett. 1993, 34, 3727-3730 Not Synthesized
O OMe
Clavoside A Faulkner J. Nat. Prod. 2002, 65, 386-8 Not Synthesized
O
Cl
AcO O
HO
H3NH2C H
H
Br HO OH
O
Cl HO
H
O
Cl
Br
N
Br N
Algolane and Ibhayinol Faulkner J. Nat. Prod. 2002, 65, 580-582 Not Synthesized
'Upenamide Scheuer J. Org. Chem. 2000, 65, 8465-9 Not Synthesized
O O
OAc
O
CO2R
O
MeO2C
H
O
O O
R= Me: Didemnaketal B R= CH2CH2SO3Na: Didemnaketal C Faulkner Org. Lett. 2002, 4, 1699-1702 Not Synthesized
NH
H N
Cl
OAc AcO
H •
OH
O
Cl
AcO
O
•
O
Cl
Palau'amine Scheuer JOC, 1998, 63, 3281-6 Not Synthesized
O
O
NH
N
O
OAc
H
OH NH2
H N
O
Kapakahine D Scheuer JOC, 1996, 61, 7168-7173 Not Synthesized
NH2 NH
N H H
CN O
Cl H N
N O
H
OH
H
O • N
N
OMe
H
H N
N H
O
Sceptrin Faulkner JACS, 1981, 103, 6772-3 Synthesized
O
H
OH OCOCH2C HMe2
OAc
O
Nuiinoalide A Scheuer Heterocycles, 1996, 42, 325-331
Unnamed cladiellenol Faulkner J. Nat. Prod. 1994, 57, 574-580
O PrCOO
O
HO
H
O
HO
• O
Kalihinol C Scheuer JACS, 1987, 109, 6119-6123 Synthezied by Wood Org. Lett. 2004, 6, 1123-6
HO
•
NC
•
O O
• OH
Valdivone A FaulknerTetrahedron, 1993, 49, 7977-7984
B
OH OH O
• H O
OAc
Asbestinin 7 Faulkner JACS 1980, 102, 5088-5092
Unnamed Oxacembrene Faulkner J. Nat. Prod. 1993, 56, 2003-7
Proposed Biosynthetic Relationship
A
A
O
A
B
A
O
Me Shift
O
B
O
O
Briarein
Synthesis of Ciguatoxin CTX3C
H
Inoue/Hirama PNAS, 2004, 101, 12013-8 and references therein H
OH
O
SPh H
O
H
+
Cl3BzCl, Et3N; DMAP 35°C, 90%
ONAP H O O
H
O
O H H
NAPO Cl
ONAP H O O
HO2C
H O
H
H
O
ONAP H O O
H
Cp2Ti(P(OEt)3)2
O MOMO
H O
THF reflux, 80%
SPh
O
H
ONAP
O
O H MOMO H
H O O
TBDPSO TIPSO
H
O
H
H
O
H ONAP
H O
H
TBDPSO TIPSO
X=H, Y=OH X,Y= O
H
H
H
O
O H
H
1.TBAF, 35 °C, 85% 2. methyl propiolate NMM, 100%
ONAP
O O
O H MOMO H
1. LiBHEt3, THF, 0 °C, 90% 15:1 !-OH
H O O
H
O
2. DMP, 95% O H
TBDPSO TIPSO
H O
O H H ONAP
O
O
H
PhS
O
H
H
ONAP Y
X O H MOMO H
H O O
1. TfOH, (MeO)3CH, 62% Y
BF3•OEt2, TESH, -50 to -20 °C, 81% HF•py, 91% SO3•py, NEt3, 0 to rt
H O
O H H
O
H
H
OH
O H
O
H
O H
AgOTf, DTBMP -70 to 0 °C, 70%
H
O
H
X=OMe, Y=OTBDPS, H X=H, Y=OTBDPS, H X=H, Y=OH,H X=H, Y=O
O H
H OH
O
H
H O O H H
H
O H
H O H
H
3. Ph3PCH3Br, tBuOK, 0 °C, 92%
ONAP H O O
H
H
1. Grubbs I, 40 °C 90% 2. DDQ, 63%
H
H
H O
HO
H
1. Bu3SnH, AIBN, 85DIBAL, °C 54%-90 °C 2.
O H H
O H H ONAP
O H H
H H H
O H H
OTIPS
H O H
ONAP H O O
R=TIPS R= (E)-CH=CHCO2Me
H
H O
H
O H
H
ONAPH H O O
H
X
H O
H
O
RO
NAPO
DMDO, -78 to - 45 °C
H
MOMO
SPh
H
TBDPSO TIPSO
H
H
O H H PhS
H
OTIPS
PhS
NAPO
H O
O
+
O H
TIPSO
O
Asbestinin 4
Group Meeting 10/12/2005
Faulkner and Scheuer
O'Malley
TBDPSO
Eunicellin
Cembrane
H
Ciguatoxin 3C
O H
H O H
OH H O
O
H
1. allylSnBu3, MgBr2 73% (12% epimer) 2. NAPBr, TBAI, NaH NAPO 98%
H O
O H H
O
H
H
ONAP H O O O H
OTIPS
1.[O] 2. NaBH4, 0 °C, 81% 3. (PhS)2, Bu3P, py, 83% 4. NCS
5
NAP= CH2(2-Naphthyl)
Faulkner and Scheuer
O'Malley Kishi Palytoxin Synthesis JACS, 1989, 111, 7525-7530, 7530-3, JACS 1994, 116, 11205-6
Wittig/ [H]
Wittig/ [H]
Nozaki-HiyamaKishi
Group Meeting 10/12/2005
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O'Malley
Wittig
Nozaki-HiyamaKishi
Suzuki Coupling
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7
Faulkner and Scheuer
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HWE
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Faulkner and Scheuer
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1. AcOH O
2
R1 =
2.
HO
O HO
N H
N H
N H
NH2
Palytoxin
36%, 62% BSM
SePh
3. Davis Oxaziridine 43% 9
Group Meeting 10/12/2005
Faulkner and Scheuer
O'Malley Gin Synthesis of Batzelladine D
Snider Synthesis of Batzelladine E
JACS, 2005, 127, 6924-5 isol: Faulkner, JOC, 1997, 62, 1814-9
Tet. Lett. 1998, 39, 5697-5700
BnO2C
TMGN3 84%, 2:1 E:Z
OTBDPS
N H
N N H
66%
NHPMB
(CH2)7CH3
N N H
O
C5H11
DMAP, 80 °C, 85%
+
PPh3
O
CHO
C H O
65%
1. O-methylisourea, iPr2EtN 55 °C 2. NH3, NH4OAc, 60 °C 14% 3. NaCNBH3, NaH2PO4, 88%
piperdine (0.33 eq) AcOH (0.3 eq) -20 °C
O BocHN O
H
H
O
N N H
1.I2, K2CO3 70% BocHN 2. Pd/C, Et3N, H2 (1 atm), 89%
N H
O
NPMB BocHN
H
1. TFA, 93% 2. NEt3
H
O
N N
NHPMB(CH2)7CH3
N H
O
N
S N H
BocHN
NBoc 4O
NHB oc
O
64%
HO
2
N OH PMB
OHC
O
BuLi, -78 °C PPh31-Br-2-Z-hexene
1. DCE, rt 86% (E) 88% (Z) 2. TBAF, 99%
H 1.[Ir(cod)pyr(PCy3)2]PF6 H H (400 psi), 80%;BnO2C
NBoc
O
NPMB
2.IBX, DMSO, 98%
2. Me(CH2)8PPh3 50 °C, 72% (BocHN)2C=N(CH2)4OMs Cs2CO3, 40 °C, 93%
N H
C
OTBDPS
N
1. Pd(OH)2, H2 H (1 atm), 80% BnO2C
H
H
BocHN
N
Cp2ZrHCl, -20 °C
O
HO2C
N3
1. PPh3 75% (E) 58% (Z) 2. PMBNCO
OH
BnO2C
O
OMe
C5H11
BocHN
CO2Bn
O
O
N Me NHBoc
3. TFA, 90% 4O
H
H
O
N N H
HN (CH2)8CH3 N PMB
H N NH2
O
H
H
O
N N
N H
Batzelladine E
6 4 %
Batzelladine E
HN
O
H N
H
TFA, 82%
H
O
N
NH2
N H
(CH2)8CH3
N H
Batzelladine D
1 0
Group Meeting 10/12/2005
Faulkner and Scheuer
O'Malley
Danishefsky Synthesis of Varacin JACS, 1993, 115, 7017-8. (Isolated by Ireland, similar to compounds isolated by Faulkner)
Overman Synthesis of Briarellins E and F JACS, 2003, 125, 6650-2 1. TsOH -78 to -20°C
H OMe MeO
isoamyl nitrite, isoamyl alcohol, CS2
NH2
OMe MeO
S O
75 °C, 40%
CO2H
TBDPSO
TIPSO
HO
CHO OH HO
3. hydrazine 4. Boc2O, DMAP, 55%
S
OTBDPS
1. TBAF, 93% 2. pthalimde, DEAD, PPh3
OTBDPS
R
2. SnCl4 -78 to rt 84%
O R
R
TMS OH H
OMe
OMe MeO
S
S2Cl2
O
S S
S
BocN
NHBoc
H H
TIPSO
S S
MeO
S
CHO
H CHO H
HCl; RP HPLC
O
46% TMS
TBDPSO
OMe S S
O S
S S
H H
H H O
C7H15CO2
AcO
H
OH
H H
H H O
1. MsCl, NEt3; LAH, 89% 2. Bu8Sn4Cl4O2 isopropenylOAc 50°C, 95% 3. C7H15COCl py, 80%
AcO
H
MeO
O
OH
1. Bu3SnAlEt2, CuCN -30 °C, 78% (1 rec.) 2. I2, 84%
O
C7H15CO2
OH
1. (tBu)2(OH)ClSn,
H MeOH, 93% H
H H
2. DMP, 80%
O I
AcO
NH3•TFA
AcO
Varacin
H
O
H
OH
H H
H H
CrCl2, NiCl2
O
C7H15CO2
O
OH
H H
H H O X
79% C7H15CO2
I CHO
Briarellin E: X= "-OH, !-H Briarellin F: X= O
DMP, 79%
1 1
Trauner Synthesis of Crispatene
Kobayashi Synthesis of Bastadin 6 Tetrahedron, 2005, 61, 7211-8 isolation: Scheuer, J. Nat. Prod., 1993, 56, 153-157
NHBoc
NHBoc OH Br
Br
Group Meeting 10/12/2005
Faulkner and Scheuer
O'Malley
O HO
Br O
NHBoc
Carbonate incorporation: "yellow pigments" 19%, pyrones 21%, "green pigments" 6% "baseline" 42% "light pulse" experiments show formation of [3.1.0] system from cyclohexadiene system In Vivo
Na2S2O4, 100%
O O
14C
Br
Br
CAN, 0 °C, 53%
Br
O
PNAS, 2004, 101, 12019-12023 Isolation: Faulkner Tetrahedron, 1981, 37, 233-240 In Vivo photochemistry: Scheuer Science, 1979, 205, 922-3.
Br OTBS
Br
1. Me2AlCl, 83%
NH
NH2
1:1.5 dr 2. MeNHOMe•HCl CO2Et iPrMgCl, 76%
+ BnON
OH
OH
1, BnONH2, NaOAc 2. NBS, 91%
Br
Br
NOBn
OTBS
O Br
Br H
Br
NH2 O
CO2H
N(OMe)Me
EtMgBr, 0 °C 87%
NOBn
NOH
AlClMe2
O
+
O
1. EDCI, HOBt, 82% 2. Na2S2O4, 99% 3. TFA H N
O
OTBS
O
NOBn
O
EtO
O
Br
CAN, 0 °C, 52% HO2C
HO2C
HO2C
O
R
OTBS O
Cl
O
H
N(OMe)Me
O OMe
OTBS O O
DBU, 60 °C
O
Br
Br
O
O HO Br
Br OH Br
Br
Br
N H
O
O
2. BCl3•SMe2, 76% HO
O
LiHMDS, -78 °C 74%, 94% bsm
H
1. EDCI, HOBt, Et3N, 86%
Br
O N H
NOH
Br
OMe
OH Br
Br
Br
87%
O
H
O
OTBS
1. FSO3Me, -5 °C 32% OTBS, 17% OH
O NOBn
2. HF•py, 77% (OTBS only) OH
H
Bastadin 6
OMe
OH O
DMP, 86%
H O
OMe
O O H
Crispatene
Faulkner and Scheuer
O'Malley Suggested Reading O
H
HO
O
O O
OH
OH
H
H
H
OH O
O H
H
OH
O
H
Okadaic Acid Stucture Elucidation: Scheuer JACS, 1981, 103, 2469-2471 Synthesis: Forsyth JACS, 1997, 119, 8381-2 Isobe Tetrahedron, 1987, 43, 4767-4776 N N S
N H
AcHN
Kuoniamines and Dercitins isolation: Scheuer, JOC, 1990, 55, 4426 Synthesis: Ciufolini JACS, 1992, 114, 10081-2 JACS, 1995, 117, 12460-9 O
N N
OMe O
OMe
O
OAc
CHO
O
1 2
Group Meeting 10/12/2005
