William Fenical and Satoshi Omura - The Scripps Research Institute

Baran Group Meeting
Wednesday,
May 19, 2004
Biography:
Professor Satoshi Omura
-Bachelors degree from Yamanashi University
-M.S. and Ph. D. from the Science University of Tokyo (1958)
-Ph. D. in Pharmacy from University of Tokyo
-Currently a professor and the president of the Kitasato Institute of Japan
-Research focuses on the isolation and discovery of microorganisms as well as
biologically interesting substances which they produce
William Fenical and Satoshi Omura
Antibacterial:
A-73A, aurantinins, factumycin, kinamycins,
KM-8, LA-1, leucomycins, takaokamycin
Bacterial cell wall synthesis inhibitor:
AM-5289, asukamycin, azureomycin,
nanaomycins, setomimycin, vineomycins
Antifolate:
AM-8402, diazaquinomycin
Antimycoplasmal:
2'-amino-2'-deoxyadenosine, cervinomycins,
frenolicin B, OM-173
Antianaerobic:
clostomicin, luminamycin, lustromycin,
thiotetromycin
Antiviral:
virantmycin, virustomycin
Antifungal:
AF-8 (albolleutin), cerulenin irumamycin,
O-2867, prumycin
Antiparasitic:
avermectins, hitachimycin (stubomycin),
setamycin
Anticancer:
OS-3256B, sporamycin
Herbicidal:
herbimycins, karabemycin
Penicillinase inhibitor:
KA-107
Adenosine deaminase inhibitor:
adechlorin
Elastase inhibitor:
elasnin
Antiplatelet:
OM-3209
Mike DeMartino
Biological diversity of Professor Omura's isolated chemicals
(Taken from Microbiological Reviews, 1986, 50, 259.)
Alkaloid (chemical screening):
AM-2504 (prolimycin), 1,3-diphenethylurea,
herquline, NA-337 A, neoxaline, pyrindicin,
quinoline-2-methanol, staurosporine, TM-64
(narcoactine)
Hybrid biosynthesis:
chimeramycins, mederrhodins
Chemical modification:
rokitamycin (3"-O-propionylleucomycin A,
5, 3,3",4"-tri-O-propionylspiramycin I,
motilides
Neuritogenesis inducer:
lactacystin
HMG-CoA synthase inhibitor:
1233A
Acyl-CoA synthetase inhibitor:
triacsins
Acyl-CoA:cholesterol acyl-transferase (ACAT)
inhibitor:
pyripyropenes, terpendole, purpactines,
glisoprenin
Glutamine synthetase inhibitor:
phosalacine, oxetin
Protein farnesyltransferase inhibitor:
pepticinnamin, gliotoxin
Cellulose biosynthesis inhibitor:
phthoramycin, phthoxazolin
Anticoccidial:
cytosaminomycin, fudecalone, hynapene
Gp-12-CD4 binding inhibitor:
chloropeptin, isochromophilones
Acetylcholine esterase inhibitor:
arisugacin
Others:
irumanolides, protylonolide

Baran Group Meeting
#29
Macrosphelides
#30
Staurosporine
#28
Madindolines
William Fenical and Satoshi Omura
#31
Trienomycins
and
Mycotrienins
#32
(+)-Lactacystin
HO 2C
AcHN
S
HO
O
HO
Me
#36
Nafuredin
N
H
Me
Me
O
#34
Hitachimycin
#35
Purpactins
#37
Avermectins
Mike DeMartino
#33
Pyripyropenes

Baran Group Meeting
Biography:
-Born in 1941, Chicago, Illinois
Professor William Fenical
-B.S. in Biochemistry from California State Polytechnic University (1963)
-M.S. in organic chemistry from San Jose State University (1965)
-Ph. D. with professor D. R. Radlick at University of California, Riverside
(1969)
-Began at Scripps Institute of Oeanography (SIO) as an assistant professor
in 1973
-Became a professor of oceanography at SIO in 1983
-Became Director of Marine Research in 1989
William Fenical and Satoshi Omura
#1
Scytalidamides
#3
Tamandarins
#4
Salinamides
Mike DeMartino
#2
Mangicols

Baran Group Meeting
O
#7
Ningalins
H
Cl
H
N
Me
OH
O
O
#5
Salinosporamide A
#8
Didemninides
William Fenical and Satoshi Omura
#6
Neomangicols
#9
Neoverrucosane
#12
Sterol Glycosides
#10
Trichodermamides
Me Me
HO
OH
#13
eunicellane diterpenoid; heterogorgiolide
Mike DeMartino
O
H
O
MeO
#11
Pestalone
OH
Cl
Cl
Me

Baran Group Meeting
N
O
N
Me
NH
O
N
O
O
H
#18
Cyclomarins
NH
i-Bu
#15
Luisols
A & B
N
O
N
#17
Fumiquinazolines H & I
Me
N
NH
O
O
OH
H
Me
NH
William Fenical and Satoshi Omura
i-Bu
Me
H
H
Me
#14
Arenaric Acid
O
#19
Eleutherobin
O
#16
Cyclized Didemninide
O
Me
OMe
O
OAc
O
N
OH
OH
N Me
HO
Me
O
O
Me
#25
Thraustochytrosides
O
#20
Octalactins A & B
O
Me
OH
#21
Diazonamides
#26
Aplidiamine
#23
Aspergillamides
HO
Me
O
O
Mike DeMartino
Me
#22
Aspergilloxides
#27
Polycarpine
Dihydrochloride
O
Me
OH
#24
Labiatamides

Baran Group Meeting
LREIMS: m/z = 438/440/442
->C21 H20 O6 Cl2
-11 Degrees of Unsaturation
IR
-Benzaldehyde
-Ketone
-Hydroxyl groups
UV: Aromatic Ring with
extended chromophore
William Fenical and Satoshi Omura
Isolation of Pestalone
-"...potent antibacterial activity aganist drug-resistant bacteria."
-Isolated as yellow crystals (Yes you could just do crystallography, but that's no fun!)
Me Me
HO
OH
O
H
O
MeO
NMR
Proton: Two olefinic methyl groups
One Aromatic resonance
methoxy group
three exchangable phenols
aldehyde
Carbon: Alhyde and ketone confirmed
Lots of aromatic/vinylic quat carbons
One aromatic double
OH
2D NMR: Isoprene Fragment
-other modest asignments
Cl
Cl
Me
Mike DeMartino

Me
Me
Baran Group Meeting
-Total Synthesis of (+)-Lactacystin
J. Am. Chem. Soc. 1996, 118, 3584.
A
Jones
1. 2N KOH
2. H 2, Pd(OH) 2
98%
1. LHMDS,
H 2CO, 85%
2. DMSO, DCC
OH
Ph(Me) 2COOH
Ti(O - i - Pr) 4,
(+)-DIPT
82%
Me
Me
Me
Me
Me
Me
O NBn
O
OH
O N
Ph
HO 2C
NH 2
AcHN
Me
CO 2H
CO 2H
CO2Me CHO
Me
S
HO
HO
O
Me
(+)-Lactacystin
O
N
H
Me
OH
Me
1. CH 2N 2
2. KOH
EtOH
96%
William Fenical and Satoshi Omura
NaH
BnNCO
1. HCl (g),
MeOH, 100%
2. PhC(OMe) 3
82%
[Ipc-(+)] 2B
O
70%, 4:1
HO
Me
A
Me
BnN O
Me
Me
Me
O
O NBn
O
Me
75% Total
Me
Me
OH
O NBn
Me
O
O N
Ph
MeO2C Me
CO 2H
CO 2Me
O
N
NaH
THF
HO Me
Ph
1. O 3, DMS
2. NaClO 2,
NaH 2PO 3
68%
1. O.1 N NaOH
82%
2. BOPCl, Et 3N
AcHN
CO 2Allyl
79%
SH
MeO2C Me
Me
AllylO 2C
AcHN
HO Me
O
N
S
HO
CO 2H
Ph
HO
O
Me
N
H
Me
Me
O
Pd,
NH 4O 2CH
Pd(PPh 3) 4, HCO 2H
Et 3N, 81%
Mike DeMartino
HO 2C
MeO 2C
AcHN
HO
HO
Me
S
HO
N
H
Me
HO
O
Me
Me
(+)-Lactacystin
O
N
H
Me
Me
O

Baran Group Meeting
-Total Synthesis of Octalins A & B
Keith Buszek: J. Am. Chem. Soc. 1994, 116, 5511.
HO
Me
1. DMP
2. N 2CHPO(OMe) 2,
t-BuOK
1. H 2, Pd/CaCO 3
2. Ac 2O, DMAP, py
2. PPTS
3. H 2, Pd/C
O
O
1. 2,2' pyridinedisulfide
PPh 3;
AgBF 4,
Refluxing PhMe
63-75%
2. TBAF
Me
O
TBDPSO
Me
O
Me
Me
OMPM
OH
OMPM
Me
Me
HO
Octalactin A Octalactin B
TBDPSO OAc
MPMO
Me
Me
Me
1. 9-BBN; H 2O 2
2. MMTrCl, Base
3. TBAF
1. I 2, Morpholine
HO
OMMTr
2. CrCl2 (1.0%
w/w NiCl2) CHO
TBDPSO
O
O
Me
Me
Me
4hr, rt 75-90% (1:1)
OMPM
OH
I
OH
1. DMP;
NaClO 2
2. K 2CO 3
MeOH
1. DMP
2. CrCl 2 (0.1%
w/w NiCl 2)
Me
OTBS
74% 1.5:1
Me
William Fenical and Satoshi Omura
O
O
Me
Me
O
OMPM
Me
TBDPSO OH
MPMO
Me
Me
Me
OH
OMMTr
TBDPSO OH
Me
O
O
Me
Me
Me
OH
Me
OMPM
Me
Me
OMPM
OMMTr
CO 2H
OTBS
Me
Me
1. DMP
2. HF
3. DDQ, H 2O
1. t-BuOOH,
VO(acac) 2
2. DMP
3. HF
4. DDQ, H 2O
HO
Me
HO
Me
O
O
O
O
Me Me
Octalactin B
O
Me
O
O
Me
Octalactin A
OH
OH
Me
Me
Me
Me
Mike DeMartino

Baran Group Meeting
-Total Synthesis of Eleutherobin
K.C. Nicolaou: Angew. Chem. Int. Ed. Engl. 1997, 36, 2520.
O
O
1. HCCMgBr
2. TBAF
1. TPAP,
NMO
2. CNCH 2CO 2Et
Base
O SPh
OH
Me
H
H
Me Me
A
Me
H
H
Me Me
CHO
OTBS
(+)-carvone derived
Me
H
H
Me Me
OH OH
Me
OH
Me TESO
H
H
Me Me
1. NaH; PMB-Cl
2. TsOH
3. TBSOTf, Et 3N
CN
OTES
Me
CO 2Et
O
O
O
Me
OMe
O OAc
O
Eleutherobin
N
1. H 2C=CHOEt,
t-BuLi;
Then A
2. H 2SO 4
1. TESOTf
Et 3N
2. PPTS
Dibal
O SPh
OPMB
OTBS
TBSO
OH
OH
William Fenical and Satoshi Omura
N Me
Me
H
H
Me Me
1. NBS, py
2. NaH
Cl 3CCN
OH
O
Me
OTBS
Me TESO
H
H
Me Me
OH
Me TESO
H
H
Me Me
O
OTBS
TBSO
OTES
Me
CHO
OTES
Me
OH
OC(NH)CCl3 OPMB
TMSOTf
b = 54%
a = 28%
1. DDQ, H 2O
2. Ac 2O
DMAP, Et 3N
Me TESO
H
H
Me Me
O
CHO
OTES
Me
O
OPMB
OTBS
O
TESO
Me Me
H
OTES
H
Me Me
1. PPTS, MeOH
2. Et 3N, DMAP
O
O
N
3. TBAF
O OAc
O
O
N Me
OTBS
OTBS
OTBS
1. LHMDS
2. DMP
1. Et 3N•3HF
2. H 2, Pd/CaCO 3
Me
H
H
Me Me
O
O
O
Me
Mike DeMartino
TESO
Me Me
H
OTES
H
Me Me
OMe
O OAc
O
Eleutherobin
Me
H
H
Me Me
N
OH
OH
O
N Me
O
OPMB
OTBS
O
O
OH
Me
OH
O OAc
O
OTBS
OTBS
OTBS

Baran Group Meeting
-Total Synthesis of Eleutherobin
Samuel Danishefsky: J. Am. Chem. Soc. 1999, 121, 6563.
Me
Me
Me
a-phellandrene
Me
Cl 3CCHO
Zn, 0°C,
Sonication
Cl
O
Cl
65%
Me
H
H
Me
NMe 2
O
Me
Me
H
H
Me
Cl
Cl
t-BuOCH(NMe) 2 TsOH,
1. H + , H 2O
2. n-BuLi
Br
O
Br
1.3:1
3. TBDPSCl,
Im., DMAP
CrCl 2 (5eq)
NiCl 2 (1eq)
74%, 15:1
DMDO/Acetone
94%
Me
Me
H
Me
Me
H CO O
2Me
Me
Me
H
H
Me
Me
H
H
Me
OTBDPS
O
O
Br
OTBDPS
OH
O
MeOH
1. Dibal
2. MsCl
3. KCN
4. Dibal
1. PivCl, Et 3N
DMAP
2.TBAF
William Fenical and Satoshi Omura
Zn,
MeOH
Me
Me
Me
Me
Me
H
Me
H
H
Me
Me
H
H
Me
Me
H
O
H Me
H
OH
OPv
1. TMSOTf
2. MeLi
Me
H
Me
H
Me
Me
O
H CO 2Me
OMe
OMe
OTBDPS
O
CHO
OH
O
O
OPv
HO
H Me
OTMS
OPv
Br
HO
TsOH (cat)
MeOH
90%
LHMDS;
Comins' Rgt.
1. TBAF
2. DCC, DMAP
O
3. PPTS
N
Me
N Me
Me
Me
H
H
Me
Me
H
H
Me
Me
OH
Me
O
OMe
OPv
OTBS
Me
O
OMe
OTf
Me
H
H
Me
O
O
Bu 3Sn
O
Me
OMe
O OAc
O
Eleutherobin
1. TBSOTf
2. TPAP,
NMO
Pd(PPh) 3
LiCl
O OAc
O
50%
N
OH
OH
O
N Me
O
Mike DeMartino
Me
Me
Me
H
H
Me
Me
H
H
Me
OTBS
Me
O
O
O
OMe
OTBS
Me
OMe
O OAc
O
O
O

Me
Baran Group Meeting
-Total Synthesis of Eleutherobin
Jeffery Winkler: Org. Lett. 2003, 5, 1805.
Me
O
MeO 2C
AgNO 3
SiO 2
79%
BaMnO 4
1. Dibal, 96%
2. VO(acac) 2
t-BuOOH
66%
Br
Br
Me
S
O
O
Me
SnCl 2
NaI
86%
SnCl 2, NaI
72%
S
O
O
Me
CHO
Me
H
Me
H
S
O
O
Me
Me
O
O
Me
Me
O
H
O
Me Me OH
Me
H
Me
O
Me
OH
H
OH
O
Me Me OTBS
Me
OH
OH
Me
CO 2Me
NaHCO 3
PhMe
Reflux
94%
A
TBSOTf
51%
William Fenical and Satoshi Omura
DMP
1. NaOH (aq)
2. NaIO 4
66%
Dibal
S
O
O
Me
Me
O
Me Me
A
Me
Me
Me
H
O
Me
OH
Me
O
O OH
Me
O
H
O
Me Me OTBS
Me
H
Me
O
H
OH O
Me Me OH
OH
SmI 2
NiI 2(cat)
72%
VO(acac) 2
t-BuOOH;
Et 3N, SiO 2
MeI, Ag 2O
CaCO 3, 76%
Me
H
Me
OH
H
OH O
Me Me OH
Me Me
H OH OH
H
O
Me Me O
Me
Me
H
H
Me
O
O
OH Me
O O
Me
OMe
Me
H
H
Me
O
O
O
Me
OMe
O OAc
O
Eleutherobin
(COCl) 2
py, 79%
K 2CO 3
MeOH
N
OH
OH
Mike DeMartino
N Me
Me Me
H OH
H
O
Me Me O
Me
Me
H
H
Me
O
O
OH Me
O O
OH

1. Hg(OTFA) 2,
KI
2. I 2
Baran Group Meeting
-Total Synthesis of Fumiquinazolines H & I
Barry Snider: J. Org. Chem. 2003, 68, 545.
Me
A
DMDO
MeOH, 45%
TrocHN
1. H 2, Pd
CO 2Me
N
H
TrocHN
TrocHN
HO
TrocHN
N
O
N
2. SiO 2 N
1. BH 3•THF/TFA
2. Cbz-L-Leu, DCC
O
N
CO 2Me
N
CO 2Me
O
O
O
NH
O
O
O
N
H
3. DDQ
82-95% N
I
OMe
NHCbz
i-Bu
NCbz
NH
H
NH
i-Bu
O
Fumiquinazoline H
i-Bu
i-Bu
N
O
William Fenical and Satoshi Omura
TrocHN
O
Pd 2(dba) 3, P(o-tolyl) 3
K 2CO 3, PhMe, reflux
NaBH 4
N
CO 2Me
NHCbz
i-Bu
TrocHN
TrocHN
HO
AcOH, 80% N
FmocCl
Hunig's Base
Me
N
NH
O
OH
H
NH
i-Bu
O
Fumiquinazoline I
TrocHN
N
O
O
A
O
H
CO 2Me
N
O
CO 2Me
O
H
NFmoc
i-Bu
NCbz
NCbz
i-Bu
i-Bu
A
1. Zn, AcOH
2. Anthranilic Acid
EDCI
PPh 3, Br 2
Et 3N
CH 3CN
Reflux
1. SiO 2
2. Zn, HOAc
3. Antrhanilic Acid
EDCI
4. Fmoc-L-Ala
NH2 H
N
O
N
N
N
O
H
N
O
N
O
N
O
O
Me
N
O
O
O
HO
N
H
NFmoc
i-Bu
SePh
NHFmoc
O
N
H
NFmoc
NH
O
OH
O
H
NCbz
N
O
O
O
i-Bu
NH
H
EDCI
Fmoc-L-NHCH(CH 2SePh)CO 2H
i-Bu
NFmoc
i-Bu
NH
34%
1. PPh 3, Br 2
Et 3N
2. piperdine
3. CH 3CN
Reflux
4. H 2, Pd
Mike DeMartino
N
H
N
N
O
O
HO
N
H
N
N
O
N
O
SePh
N
O
O
SePh
N
NH 2
N
N
NHFmoc
O
O
Me
N
O
O
O
H
H
NH
O
O
Me
N
NH
NFmoc
i-Bu
NFmoc
H
O
OH
H
NH
Fumiquinazoline H
NH
i-Bu
i-Bu
i-Bu
O
Fumiquinazoline I

Baran Group Meeting
William Fenical and Satoshi Omura
The Baran Lab's Retrosnythetic Analysis of Luisols A and/or B:
Mike DeMartino

Baran Group Meeting
William Fenical and Satoshi Omura
References
Selected Natural Products:
1. J. Org. Chem. 2003, 68, 8767.
2. J. Org. Chem. 2000, 65, 4843.
3. J. Org. Chem. 2000, 65, 782.
4. J. Org. Chem. 1999, 64, 1145.
5. Angew. Chem Int. Ed. 2003, 42, 355.
6. J. Org. Chem. 1996, 63, 8346.
7. J. Org. Chem. 1997, 62, 3254.
8. J. Org. Chem. 1997, 62, 1486.
9. J. Nat. Prod. 2003, 66, 818.
10. J. Nat. Prod. 2003, 66, 423.
11. J. Nat. Prod. 2001, 64, 1444.
12. J. Nat. Prod. 2000, 63, 1427.
13. J. Nat. Prod. 1999, 62, 1322.
14. J. Nat. Prod. 1999, 62, 605.
15. J. Nat. Prod. 1999, 62, 608.
16. J. Nat. Prod. 1999, 62, 389.
17. Chem. Eur. J. 2000, 6, 1355.
18. J. Am. Chem. Soc. 1999, 121, 11273.
19. J. Am. Chem. Soc. 1997, 119, 8744.
20. J. Am. Chem. Soc. 1991, 113, 4682.
21. J. Am. Chem. Soc. 1991, 113, 2303.
22. Org. Lett. 2002, 4, 1583.
23. Tetrahedron 1998, 54, 13459.
24. Tetrahedron 1996, 52, 2735.
25. Tetrahedron Lett. 1999, 40, 7637.
26. Tetrahedron Lett. 1997, 38, 941.
27. Tetrahedron Lett. 1996, 37, 2369.
28. J. Am. Chem. Soc. 2000, 122, 2122.
29. J. Am. Chem. Soc. 1997, 119, 10247.
30. Bioorg. Med. Chem. Lett. 1996, 16, 1893.
31. J. Am. Chem. Soc. 1996, 118, 8308.
32. J. Am. Chem. Soc. 1996, 118, 3584.
33. J. Am. Chem. Soc. 1994, 116, 12097.
34. J. Am. Chem. Soc. 1992, 114, 8003.
35. J. Org. Chem. 1992, 57, 1271.
36. Org. Lett. 2001, 3, 2289.
37. Tetrahedron Lett. 2004, 45, 2507.
Mike DeMartino