faulkner and scheuer group meeting o'malley 10/12/2005 · pdf filegroup meeting...

Group Meeting10/12/2005O'Malley Faulkner and Scheuer

1

Paul J. Scheuer

BiographyPaul 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.CareerAfter receiving his doctorate and marrying, Prof. Scheuer joined the faculty of theUniversity of Hawaii at Manoa. His research initially focused on the natural productschemistry of terrestial Hawaiian plants, but quickly turned to the untapped resourcesof the surrounding Pacific Ocean. Before the work of Prof. Scheuer, marine naturalproducts 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.

D. John Faulkner

BiographyBorn 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.

CareerDuring 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.


9-isocyanopupukeanane: The First Marine Defensive SecretionThe 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.

CN

9-isocyanopupukeananeFirst 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. Thisis 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

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.

Maitotoxin

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 2

Maitotoxin


The Carbonimidic DichloridesIn 1977 and 1978, Faulkner reported the isolation of several natural productscontaining the carbonimidic dichloride functional group, which at that pointwas known only in synthetic compounds. (JACS, 1977, 99, 7367-8, TL, 1978,1391-4 and 1395-8).

Cl

OH

Cl

NCl

Cl HO

ClN Cl

Cl

N Cl

Cl

Cl

N Cl

Cl

Cl

Cl

NCl

Cl

ClCl

Proposed Biogenesis

Isonitrile (not isolated) or isothiocyanate (isolated)

None of these natural products have been synthesized

[O] [O]

Natural Products Gallery

• •

NO O

O

O

OH

ZoanthamineFaulkner, JACS, 1984, 106, 7983-4Synthesized (Norzoanthamine) by MisyashitaScience, 2004, 305, 495-9

N

NMe

H

O

O

OH

O

MeO

O

O

OMe

O

O

Renieramycin CFaulkner, JACS, 1982, 104, 265-9.JOC, 1989, 54, 5822-4 (stereochem reassigned)Several syntheses, as well as Saframycinsand Ecteinascidins.

N

N

NH

N

HNO

Eudistone AFaulkner, JOC, 1991, 5369-5371not synthesized

•

O

O

OH

H

DictyoxetaneFaulkner JOC, 1985, 50, 3665-6not synthesized

O

HO

CO2Me

O

OH

CO2Me

O

MeO2C

CO2Me

OMe

H

H

OH

HO

H

•

•

•

•

O

OHCO2Me

OH

O

O

Furanocembrane Diestersimilar compounds synthesizede.g. Pukalide (Scheuer isolation)

Mandapamatenot synthesized

Rameswaralidesynthesized by Trost(reported at ACS Meeting)

Faulkner Tet. Lett. 1998, 39, 8217-8220

3


N

HN

HN

NH

O

O

Br

BrN

HN NH2

NH

N

NH2

H•2HCl

SceptrinFaulkner JACS, 1981, 103, 6772-3Synthesized

O

O

O

O

O

O

O

O

OMe

OMe

H

H

MeO OMe

OMeMeO

H

H

O

O

Clavoside AFaulkner J. Nat. Prod. 2002, 65, 386-8Not Synthesized

N

•

O

N

OH

H

H

HO O

'UpenamideScheuer J. Org. Chem. 2000, 65, 8465-9Not Synthesized

AcO

Br

Br

OH

HO Cl

O

HO

H

Cl

Br

Algolane and IbhayinolFaulkner J. Nat. Prod. 2002, 65, 580-582Not Synthesized

O

O

CO2RMeO2C

HO

OO

O

OAc

O

O

H

O

R= Me: Didemnaketal BR= CH2CH2SO3Na: Didemnaketal CFaulkner Org. Lett. 2002, 4, 1699-1702Not Synthesized

O

NC

HO

CN

Kalihinol CScheuer JACS, 1987, 109, 6119-6123Synthezied by Wood Org. Lett. 2004, 6, 1123-6

O OH

H

H

O

O

HO

HO

Popolohuanone EScheuer Tet. Lett. 1993, 34, 3727-3730Not Synthesized

N N

NH

HN

N

O

O

O NHO

N

HN

O

NHN

H

H

OH

O

OH

O

O

Kapakahine DScheuer JOC, 1996, 61, 7168-7173Not Synthesized

N

N NH

N

NH

HN NH2

ClH3NH2C

H

H

H

O

NH2

OH

Cl

H

Cl

Cl

Palau'amineScheuer JOC, 1998, 63, 3281-6Not Synthesized

O

OAc

H OHCl

AcO

OAc

O

Nuiinoalide AScheuer Heterocycles, 1996, 42, 325-331

•

•O

OAc

OCOCH2CHMe2

H

H

OH

Unnamed cladiellenolFaulkner J. Nat. Prod.1994, 57, 574-580

O

AcO

•

•O

OH

O

O

O

Valdivone AFaulknerTetrahedron,1993, 49, 7977-7984

• •

O

•

O OAc

PrCOO

OH

H

H

Asbestinin 7Faulkner JACS1980, 102, 5088-5092

O

HO

OH O

Unnamed OxacembreneFaulkner J. Nat. Prod.1993, 56, 2003-7

Proposed Biosynthetic Relationship

A AB

4

O

O

O

O

A

B

AB Me

Shift

Briarein Cembrane Eunicellin Asbestinin


Synthesis of Ciguatoxin CTX3CInoue/Hirama PNAS, 2004, 101, 12013-8 and references therein

O

O

TBDPSO

TIPSO

HOH

HH

SPh

SPh

OO

MOMO

H

HO2C

ONAP

OO

TBDPSOTIPSO

H

O

HHPhS SPh

OO

MOMO

HONAP

OO

O

TBDPSOTIPSO

H

HH

O

O O

H

H

MOMO

ONAP

OO

TBDPSOTIPSO

H

HH

O

O O

H

H

MOMO

ONAP

O

OO

TBDPSOTIPSO

H

HH

O

O O

H

H

MOMO

ONAPH

X

Y

X=H, Y=OHX,Y= O

OO

YOTIPS

H

HH

OH ONAPHH

O

O O

H

X H

X=OMe, Y=OTBDPS, H

X=H, Y=OTBDPS, H

X=H, Y=OH,H

X=H, Y=O

+Cl3BzCl, Et3N; DMAP

35°C, 90%

Cp2Ti(P(OEt)3)2

THF reflux, 80%

DMDO, -78 to - 45 °C1. LiBHEt3, THF, 0 °C, 90% 15:1 !-OH

2. DMP, 95%

1. TfOH, (MeO)3CH, 62%

BF3•OEt2, TESH, -50 to -20 °C, 81%

HF•py, 91%

SO3•py, NEt3, 0 to rt

OO

OTIPS

H

HH

OH ONAPH

O

O O

H

H HNAPO

Cl

PhS

O

OO

O

O

OH

HONAP

H HH H

H H HH H

+

AgOTf, DTBMP

-70 to 0 °C, 70%

O

OO

O

O

O

HONAP

H HH H

H H HH H

O

O

RO

H

HH

OH

ONAP

H

OO

O

H

HH

NAPO

PhS

R=TIPSR= (E)-CH=CHCO2Me

1.TBAF, 35 °C, 85%2. methyl propiolateNMM, 100%

1. Bu3SnH, AIBN,85 °C 54%2. DIBAL, -90 °C3. Ph3PCH3Br, tBuOK, 0 °C, 92%

O

O

H

HH

OH

ONAPH

OO

O

H

HH

O

OO

O

O

HONAP

H H

H H

H H HH

HH

H

H

NAPO

O

O

H

HH

OH

OHH

OO

O

H

HH

O

OO

O

O

HOH

H H

H H

H H HH

HH

H

H

HO

1. Grubbs I, 40 °C 90%

2. DDQ, 63%

Ciguatoxin 3C

5

OO

OTIPS

H

HH

OH ONAPH

O

O O

H

H HNAPO

1. allylSnBu3, MgBr2 73% (12% epimer)

2. NAPBr, TBAI, NaH98%

NAP= CH2(2-Naphthyl)

1.[O]2. NaBH4, 0 °C, 81%3. (PhS)2, Bu3P, py, 83%

4. NCS


Wittig/ [H] Wittig/ [H] Nozaki-Hiyama-Kishi

Kishi Palytoxin SynthesisJACS, 1989, 111, 7525-7530, 7530-3,

JACS 1994, 116, 11205-6

6


Wittig Nozaki-Hiyama-Kishi

Suzuki Coupling

7


HWE

8


9

2

1. AcOH

2.

HO NH

NH2

SePh

O

36%, 62% BSM

3. Davis Oxaziridine 43%

R1 =HO N

HNH

O

Palytoxin


Gin Synthesis of Batzelladine DJACS, 2005, 127, 6924-5

isol: Faulkner, JOC, 1997, 62, 1814-9

CO2BnBnO2C

N3

BnO2C

N

NH

OOTBDPS N OTBDPS

NH

N

H

HO

BnO2C

NPMB

CNPMB

NH

N

NPMB

H HBnO2C

OHNH

N

NHPMB

H HHO2C

(CH2)7CH3

NH

N

NHPMB

HH

O

O

NH

BocHN

NBoc

(CH2)7CH3NH

N

H HO

O

NH

BocHN

NBoc

NPMB

(CH2)8CH3

4 4

TMGN3

84%, 2:1 E:Z

1. PPh3 75% (E) 58% (Z)

2. PMBNCO

Cp2ZrHCl, -20 °C

66%

1. DCE, rt86% (E)88% (Z)2. TBAF, 99%

1.[Ir(cod)pyr(PCy3)2]PF6

H2(400 psi), 80%;2.IBX, DMSO, 98%

1. Pd(OH)2, H2

(1 atm), 80%

2. Me(CH2)8PPh3

50 °C, 72%

(BocHN)2C=N(CH2)4OMsCs2CO3, 40 °C, 93%

1.I2, K2CO3 70%

2. Pd/C, Et3N, H2 (1 atm), 89%

N

N

H HO

O

NH

HNHN

NH2

Snider Synthesis of Batzelladine ETet. Lett. 1998, 39, 5697-5700

BocHNOH

C5H11 OMe

O O

DMAP, 80 °C, 85%C5H11 O

NHBoc

O O

O

PPh3PPh3

O O

CHO

CHOOHC

+

O O

BocHN

O

N

N

H HO

O

NH

BocHN

BuLi, -78 °C

1-Br-2-Z-hexene64%

65%

piperdine (0.33 eq)AcOH (0.3 eq)-20 °C1. O-methylisourea, iPr2EtN 55 °C

2. NH3, NH4OAc, 60 °C 14%3. NaCNBH3, NaH2PO4, 88%

1. TFA, 93%2. NEt3

NMe

BocHN

S

NHBoc

3. TFA, 90%

64%

Batzelladine E

10

NH

N

H HO

O

NH

(CH2)8CH3

HNHN

NH2

TFA, 82%

Batzelladine E

Batzelladine D


Overman Synthesis of Briarellins E and FJACS, 2003, 125, 6650-2

TIPSO

H

TMS

HOOH

CHO

TBDPSO

O

R

R

HO

R

O

H H

H

CHOHTIPSO

TMSTBDPSO

1. TsOH -78 to -20°C

2. SnCl4 -78 to rt84%

O

H H

H

HH

O

AcO

OH

OH

AcO

O

H H

H

HH

O

OH

C7H15CO2

O

H H

H

HH

O

OH

C7H15CO2 I

1. MsCl, NEt3; LAH, 89%2. Bu8Sn4Cl4O2

isopropenylOAc

50°C, 95%3. C7H15COClpy, 80%

1. Bu3SnAlEt2, CuCN-30 °C, 78% (1 rec.)

2. I2, 84%

1. (tBu)2(OH)ClSn,MeOH, 93%

2. DMP, 80%

Danishefsky Synthesis of VaracinJACS, 1993, 115, 7017-8.(Isolated by Ireland, similar to compounds isolated by Faulkner)

MeO

OMe

NH2

CO2H

OTBDPS

MeO

OMe

OTBDPS

S

S

O

MeO

OMe

NHBoc

S

S

O

MeO

OMe

BocN

S S

S

SS

CHO

MeO

OMe

S S

S

SS

isoamyl nitrite, isoamyl alcohol, CS2

75 °C, 40%

1. TBAF, 93%2. pthalimde, DEAD, PPh3

3. hydrazine4. Boc2O, DMAP, 55%

S2Cl2 HCl; RP HPLC

46%

11

AcO AcO

O

H H

H

HH

O

CHO

OH

C7H15CO2 I

O

H H

H

HH

O

OH

C7H15CO2

X

CrCl2, NiCl2

79%

Briarellin E: X= "-OH, !-HBriarellin F: X= O

DMP, 79%

NH3•TFA

Varacin


Kobayashi Synthesis of Bastadin 6Tetrahedron, 2005, 61, 7211-8

isolation: Scheuer, J. Nat. Prod., 1993, 56, 153-157

OH

Br Br

NHBoc

NHBoc

Br

O

Br

NH

O

O

O

Br

NHBoc

Br

O

BrHO

Br

NH2

OH

Br Br

OH

HO2C

O

HO2C

NOBnBr

BrHO2C

NOBnO

O

BnON O

Br

O

NH2

NOBn

CO2H

HN

Br O

NOH

CAN, 0 °C, 53%

1, BnONH2, NaOAc2. NBS, 91% CAN, 0 °C, 52%

Na2S2O4, 100%

+

1. EDCI, HOBt, 82%2. Na2S2O4, 99%3. TFA

Trauner Synthesis of CrispatenePNAS, 2004, 101, 12019-12023

Isolation: Faulkner Tetrahedron, 1981, 37, 233-240

In Vivo photochemistry: Scheuer Science, 1979, 205, 922-3.

14C 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

CO2Et

OTBSR

O

EtOAlClMe2

H

O

N(OMe)Me

OTBS

O

N(OMe)Me

OTBS

H

OOTBS O

OTBS

O

1. Me2AlCl, 83%

1:1.5 dr2. MeNHOMe•HCliPrMgCl, 76%

+

EtMgBr, 0 °C87%

Cl OMe

O O

DBU, 60 °C

12

Br

O

BrHO

Br

NH

O

Br Br

O

OH

Br

NOBn

Br

O

BrHO

Br

NH

O

Br Br

O

OH

Br

NOH

O

1. EDCI, HOBt, Et3N, 86%

2. BCl3•SMe2, 76%

Bastadin 6

HH O

OMe

H

OTBS

O

O

OH H

OH

O

OMe

O

H

O

OMe

O

O

LiHMDS, -78 °C74%, 94% bsm

87%

1. FSO3Me, -5 °C32% OTBS, 17% OH

2. HF•py, 77%(OTBS only)

DMP, 86%

Crispatene


Suggested Reading

O

OHO

O

O

O

OOH

H H

OHH

HH

H

OHH

OH

O

Okadaic AcidStucture Elucidation: Scheuer JACS, 1981, 103, 2469-2471Synthesis: Forsyth JACS, 1997, 119, 8381-2Isobe Tetrahedron, 1987, 43, 4767-4776

N

NH

N

S

AcHN

Kuoniamines and Dercitinsisolation: Scheuer, JOC, 1990, 55, 4426Synthesis: Ciufolini JACS, 1992, 114, 10081-2JACS, 1995, 117, 12460-9

N

O NCHO

O OOMe OMe OAc

faulkner and scheuer group meeting o'malley 10/12/2005 · pdf filegroup meeting...

Documents