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.
1
Group Meeting
10/12/2005
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)
3
Group Meeting
10/12/2005
Faulkner and Scheuer
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
6
Faulkner and Scheuer
O'Malley
Wittig
Nozaki-HiyamaKishi
Suzuki Coupling
Group Meeting
10/12/2005
7
Faulkner and Scheuer
O'Malley
HWE
Group Meeting
10/12/2005
8
O'Malley
Faulkner and Scheuer
Group Meeting
10/12/2005
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