Baran Group Meeting William Fenical and Satoshi Omura Mike ...Baran Group Meeting William Fenical...
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Mike DeMartino Baran Group Meeting William Fenical and Satoshi Omura Biography: -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 A n t i b a c t e r i a l: A-73A, aurantinins, factumycin, kinamycins, KM-8, LA-1, leucomycins, takaokamycin B a c t e r i a l c e l l w a l l s y n t h e s i s i n h i b i t or: AM-5289, asukamycin, azureomycin, nanaomycins, setomimycin, vineomycins A n t i f o l a t e: AM-8402, diazaquinomycin A n t i m y c o p l a s m a l: 2'-amino-2'-deoxyadenosine, cervinomycins, frenolicin B, OM-173 A n t i a n a e r o b i c: clostomicin, luminamycin, lustromycin, thiotetromycin A n t i v i r a l: virantmycin, virustomycin A n t i f u n g a l: AF-8 (albolleutin), cerulenin irumamycin, O-2867, prumycin A n t i p a r a s i t i c: avermectins, hitachimycin (stubomycin), setamycin A n t i c a n c e r: OS-3256B, sporamycin H e r b i c i d a l: herbimycins, karabemycin P e n i c i l l i n a s e i n h i b i t o r: KA-107 A d e n o s i n e d e a m i n a s e i n h i b i t o r: adechlorin E l a s t a s e i n h i b i t o r: elasnin A n t i p l a t e l e t: OM-3209 A l k a l o i d ( c h e m i c a l s c r e e n i n g ): AM-2504 (prolimycin), 1,3-diphenethylurea, herquline, NA-337 A, neoxaline, pyrindicin, quinoline-2-methanol, staurosporine, TM-64 (narcoactine) H y b r i d b i o s y n t h e s i s: chimeramycins, mederrhodins C h e m i c a l m o d i f i c a t i o n: rokitamycin (3"-O-propionylleucomycin A, 5, 3,3",4"-tri-O-propionylspiramycin I, motilides N e u r i t o g e n e s i s i n d u c e r: lactacystin H M G - C o A s y n t h a s e i n h i b i t o r: 1233A A c y l - C o A s y n t h e t a s e i n h i b i t o r: triacsins A c y l - C o A : c h o l e s t e r o l a c y l - t r a n s f e r a s e ( A C A T ) i n h i b i t o r: pyripyropenes, terpendole, purpactines, glisoprenin G l u t a m i n e s y n t h e t a s e i n h i b i t o r: phosalacine, oxetin P r o t e i n f a r n e s y l t r a n s f e r a s e i n h i b i t o r: pepticinnamin, gliotoxin C e l l u l o s e b i o s y n t h e s i s i n h i b i t o r: phthoramycin, phthoxazolin A n t i c o c c i d i a l: cytosaminomycin, fudecalone, hynapene G p - 1 2 - C D 4 b i n d i n g i n h i b i t o r: chloropeptin, isochromophilones A c e t y l c h o l i n e e s t e r a s e i n h i b i t o r: arisugacin O t h e r s: irumanolides, protylonolide Biological diversity of Professor Omura's isolated chemicals (Taken from Microbiological Reviews, 1986, 50, 259.) P r o f e s s o r S a t o s h i O m u r a Wednesday, May 19, 2004
Transcript of Baran Group Meeting William Fenical and Satoshi Omura Mike ...Baran Group Meeting William Fenical...
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
Biography:
-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
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
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
Biological diversity of Professor Omura's isolated chemicals(Taken from Microbiological Reviews, 1986, 50, 259.)
Professor Satoshi Omura
Wednesday, May 19, 2004
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
#28Madindolines
#29Macrosphelides
#30Staurosporine
#31Trienomycins
andMycotrienins
NH
Me
Me
O
MeHO
HO
O
SHO2C
AcHN
#32(+)-Lactacystin
#33Pyripyropenes
#34Hitachimycin
#35Purpactins
#36Nafuredin
#37Avermectins
Mike DeMartinoBaran Group Meeting
Professor William Fenical
Biography:
-Born in 1941, Chicago, Illinois
-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
#1Scytalidamides
#2Mangicols
#3Tamandarins
#4Salinamides
William Fenical and Satoshi Omura
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
#6Neomangicols
#7Ningalins
#8Didemninides #9
Neoverrucosane
#10Trichodermamides
#11Pestalone
#12Sterol Glycosides
#13eunicellane diterpenoid; heterogorgiolide
HN
O
O
O
Cl
Me
OH
H
#5Salinosporamide A
HO
OH
Cl
OH
Me
Cl
O
MeOH
O
Me Me
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
#14Arenaric Acid
#15LuisolsA & B
#16Cyclized Didemninide
NNH
Oi-Bu
H
N
NNH
O
Me
OO
NNH
Oi-Bu
H
N
NNH
O
Me
OOH
#17Fumiquinazolines H & I
#18Cyclomarins
Me
MeMe
H
H
O
Me
OMe
O
O
OAcOH
OH
O
O
NN Me
#19Eleutherobin
O
O
Me
O
Me
OH
O
HO
Me
O
O
Me
O
Me
OHHO
Me
#20Octalactins A & B
#21Diazonamides #22
Aspergilloxides
#23Aspergillamides
#24Labiatamides
#25Thraustochytrosides
#26Aplidiamine
#27Polycarpine
Dihydrochloride
Mike DeMartinoBaran Group Meeting 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!)
HO
OH
Cl
OH
Me
Cl
O
MeOH
O
Me Me
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
NMRProton: Two olefinic methyl groups One Aromatic resonance methoxy group three exchangable phenols aldehydeCarbon: Alhyde and ketone confirmed Lots of aromatic/vinylic quat carbons One aromatic double
2D NMR: Isoprene Fragment -other modest asignments
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
Me
MeOH
Ph(Me)2COOH
Ti(O-i-Pr)4,(+)-DIPT
82%
Me
MeOH
O
NaH
BnNCO
O NBn
O
OHMeMe
BnN O
O
HO
MeMe
NaHTHF
75% Total
A
AJones
O NBn
O
CO2HMeMe
1. CH2N2
2. KOHEtOH96%
O NBn
O
CO2HMeMe
1. 2N KOH
2. H2, Pd(OH)298% OH
Me
Me
NH2
CO2H
1. HCl(g),MeOH, 100%
2. PhC(OMe)382%
O N
Ph
CO2MeMeMe
1. LHMDS,H2CO, 85%
2. DMSO, DCCO N
Ph
CHOMeMe
CO2Me [Ipc-(+)]2B
O
N
PhMe
MeMeO2C
HO Me
70%, 4:1
1. O3, DMS
2. NaClO2,NaH2PO3
68% O
N
PhMe
MeMeO2C
CO2H
HO MePd,
NH4O2CH NH
MeO2C
MeMe
O
MeHO
HO
1. O.1 N NaOH82%
2. BOPCl, Et3N
79%
AcHNSH
CO2Allyl
NH
MeMe
O
MeHO
HO
O
SAllylO2C
AcHN
Pd(PPh3)4, HCO2H
Et3N, 81% NH
MeMe
O
MeHO
HO
O
SHO2C
AcHN
(+)-Lactacystin
NH
MeMe
O
MeHO
HO
O
SHO2C
AcHN
(+)-Lactacystin
-Total Synthesis of (+)-Lactacystin J. Am. Chem. Soc. 1996, 118, 3584.
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
TBDPSO
OMPM
MeHO
OMPM
MeOMMTr
OMPM
MeOMMTr
O
O
Me
O
Me
Me
Me
OH
O
HO
Me
O
O
Me
O
Me
Me
Me
OHHO
Me
Octalactin A Octalactin B
1. 9-BBN; H2O2
2. MMTrCl, Base3. TBAF
1. DMP
2. N2CHPO(OMe)2,t-BuOK
1. I2, Morpholine
2. CrCl2 (1.0% w/w NiCl2)
4hr, rt 75-90% (1:1)
TBDPSOCHO
Me
OMPM
MeOMMTrMe
TBDPSO OH
1. H2, Pd/CaCO32. Ac2O, DMAP, py
2. PPTS3. H2, Pd/C
1. DMP;NaClO2
2. K2CO3MeOH
1. 2,2' pyridinedisulfidePPh3;
AgBF4, Refluxing PhMe
63-75%2. TBAF
O
O
MeOH
MPMO
Me
O
O
Me
OH
Me
Me
Me
OTBSMPMO
Me
Me
TBDPSO OAc
Me
OMPM
OHMe
TBDPSO OH
Me
OMPMCO2H
1. DMP
2. CrCl2 (0.1% w/w NiCl2)
74% 1.5:1
I
Me
OTBS
Me
Me
1. DMP2. HF
3. DDQ, H2OO
O
Me
O
Me
Me
Me
OHHO
Me
Octalactin B
1. t-BuOOH, VO(acac)2
2. DMP3. HF
4. DDQ, H2OOctalactin A
-Total Synthesis of Octalins A & B Keith Buszek: J. Am. Chem. Soc. 1994, 116, 5511.
O
O
Me
O
Me
Me
Me
OH
O
HO
Me
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
O
O
Me
Me Me
MeO
O
NN Me
O
OAcOH
OH
OMe
H
H
Eleutherobin
Me
Me Me
H
H
CHO
OTBS
(+)-carvone derived
1. H2C=CHOEt,t-BuLi;Then A
2. H2SO4A
Me
Me Me
H
HOTBS
OH
Me
O
1. HCCMgBr
2. TBAF
Me
Me Me
H
HOH
OH OHMe 1. TESOTf
Et3N
2. PPTS
Me
Me Me
H
HOH
TESO OTESMe
1. TPAP,NMO
2. CNCH2CO2EtBase
Me
Me Me
H
H
TESO OTESMe
CN
CO2Et
Dibal
Me
Me Me
H
H
TESO OTESMe
CHO
OH
O SPhOH
OO
1. NaH; PMB-Cl2. TsOH
3. TBSOTf, Et3N
O SPhOPMB
OTBSTBSO
1. NBS, py
2. NaHCl3CCN
O OPMBOTBSTBSO
OC(NH)CCl3
Me
Me Me
H
H
TESO OTESMe
CHO
O
O
OPMBOTBS
OTBS
TMSOTf
b = 54%a = 28%
1. LHMDS
2. DMP
Me
Me Me
H
H
O
O
OPMBOTBS
OTBS
O
TESO MeOTES
1. DDQ, H2O
2. Ac2ODMAP, Et3N
Me
Me Me
H
H
O
O
OAcOTBS
OTBS
O
TESO MeOTES
1. Et3N•3HF
2. H2, Pd/CaCO3
O
O
Me
Me Me
MeOH
O
OAcOTBS
OTBS
OH
H
H
1. PPTS, MeOH
2. Et3N, DMAP
3. TBAF
O
O
NN Me
O
O
O
Me
Me Me
MeO
O
NN Me
O
OAcOH
OH
OMe
H
H
Eleutherobin
-Total Synthesis of Eleutherobin K.C. Nicolaou: Angew. Chem. Int. Ed. Engl. 1997, 36, 2520.
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
Me
MeMe
Cl3CCHOZn, 0°C,
Sonication
Cl
ClO
65%
Me
MeMe
ClCl
O
a-phellandrene
Zn,
MeOH
Me
MeMe
O
H
H
H
H
Me
MeMe
O
H
H
NMe2
t-BuOCH(NMe)2 TsOH,
MeOH
Me
MeMe
H
HCO2Me
OMe
OMe
1. H+, H2O
2. n-BuLi
1.3:13. TBDPSCl,Im., DMAP
O BrBr
Me
MeMe
H
HCO2Me
OTBDPS
OBr
1. Dibal2. MsCl
3. KCN4. Dibal
Me
MeMe
H
H
OTBDPS
OBrCHO
CrCl2 (5eq)NiCl2 (1eq)
74%, 15:1
Me
MeMe
H
H
O
OTBDPS
OH
1. PivCl, Et3NDMAP
2.TBAF
Me
MeMe
H
H
O
OH
OPv
DMDO/Acetone
94%
Me
MeMe
H
H
O
O
OHOPv
H Me
MeMe
H
H
O
OTMSOPv
HHO
Me
1. TMSOTf
2. MeLi
TsOH (cat)
MeOH90%
Me
MeMe
H
H
O
OH
OPv
Me
OMe
1. TBSOTf
2. TPAP,NMO
Me
MeMe
H
H
O
OTBS
O
Me
OMe
LHMDS;
Comins' Rgt.
Me
MeMe
H
H
O
OTBSMe
OMeOTf
Pd(PPh)3LiCl
50%
O
O
OAcO
O
Bu3Sn
Me
MeMe
H
H
O
OTBSMe
OMeO
O
OAcO
O
1. TBAF
2. DCC, DMAP
3. PPTS
HO
O
NN Me
Me
MeMe
H
H
O
Me
OMeO
O
OAcOH
OH
O
O
NN Me
Eleutherobin
-Total Synthesis of Eleutherobin Samuel Danishefsky: J. Am. Chem. Soc. 1999, 121, 6563.
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
MeBr
S
MeOH
MeOO
S
MeO
OO H
SnCl2NaI86%
DMPS
MeO
MeOO
S
Me
OO
AgNO3SiO2
79% O
NaHCO3PhMeReflux
94% O
MeMe
A
MeO2C
Br
Me
Me
CHO
SnCl2, NaI72%
Me
Me
OH
CO2Me DibalMe
Me
OH
OH
BaMnO4
Me
Me
O
OHA
Me
Me
O
OOH
Me
O
OOHMe Me
Me
H
HTBSOTf
51%
Me
O
OOTBSMe Me
Me
H
H
1. Dibal, 96%
2. VO(acac)2t-BuOOH
66%
Me
O
OHOTBSMe Me
Me
H
H
O
1. NaOH(aq)
2. NaIO466%
Me
O
O
OHOHMe Me
Me
H
H
Me
OOHOHMe Me
Me
H
HSmI2
NiI2(cat)72%
OH(COCl)2
py, 79%
Me
OOOMe Me
Me
H
H OH
O
VO(acac)2t-BuOOH;
Et3N, SiO2
Me
OOOMe Me
Me
H
H OH
O
OHK2CO3
MeOHO O
OHMe
OH
H
HMe
Me
Me
MeI, Ag2O
CaCO3, 76% O O
OHMe
OMe
H
HMe
Me
Me
Me
MeMe
H
H
O
Me
OMeO
O
OAcOH
OH
O
O
NN Me
Eleutherobin
-Total Synthesis of Eleutherobin Jeffery Winkler: Org. Lett. 2003, 5, 1805.
Me
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
NH
CO2Me
TrocHN 1. BH3•THF/TFA2. Cbz-L-Leu, DCC
3. DDQ82-95% N
CO2Me
TrocHN
O i-Bu
NHCbz
1. Hg(OTFA)2,KI
2. I2 N
CO2Me
TrocHN
O i-Bu
NHCbz
I
Pd2(dba)3, P(o-tolyl)3
K2CO3, PhMe, reflux N
CO2MeTrocHN
NCbz
Oi-Bu
1. Zn, AcOH
2. Anthranilic AcidEDCI
DMDO
MeOH, 45% N
CO2Me
TrocHN
NCbz
Oi-Bu
HOOMe NaBH4
AcOH, 80% N
CO2Me
TrocHN
NCbz
Oi-Bu
HOH
A
A1. H2, Pd
2. SiO2 N
O
NH
Oi-Bu
H
OTrocHN
FmocCl
Hunig's Base N
O
NFmoc
Oi-Bu
H
OTrocHN
N
O
NFmoc
Oi-Bu
H
OHN
O
NH2
EDCI
Fmoc-L-NHCH(CH2SePh)CO2H
N
O
NFmoc
Oi-Bu
H
OHN
O
HN
O
SePh
NHFmoc
PPh3, Br2Et3N
O
NNHFmoc
N
O
NFmoc
Oi-Bu
H
ON
SePh
NH
N
O
NFmoc
Oi-Bu
H
OHN
O
N
NNH2
SePh
CH3CNReflux
N
OH
NH
Oi-Bu
H
N
NNH
OO
34%
NNH
Oi-Bu
H
N
NNH
O
Me
OO
A
1. SiO22. Zn, HOAc
3. Antrhanilic AcidEDCI
4. Fmoc-L-Ala N
O
NFmoc
Oi-Bu
H
OHN
O
HN
O
MeNCbz
1. PPh3, Br2Et3N
2. piperdine
3. CH3CNReflux
4. H2, Pd NNH
Oi-Bu
H
N
NNH
O
Me
OOH
Fumiquinazoline H
Fumiquinazoline I
NNH
Oi-Bu
H
N
NNH
O
Me
OO
Fumiquinazoline H
NNH
Oi-Bu
H
N
NNH
O
Me
OOH
Fumiquinazoline I
-Total Synthesis of Fumiquinazolines H & I Barry Snider: J. Org. Chem. 2003, 68, 545.
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
The Baran Lab's Retrosnythetic Analysis of Luisols A and/or B:
Mike DeMartinoBaran Group Meeting William Fenical and Satoshi Omura
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.
References
