Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino

Wednesday,
May 19, 2004
Biological diversity of Professor Omura's isolated chemicals
(Taken from Microbiological Reviews, 1986, 50, 259.)

Antibacterial: Alkaloid (chemical screening):

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

#32 HO Me
(+)-Lactacystin O

HO2C
#28 S O
Madindolines N
HO H
AcHN
Me

Me

#31
Trienomycins #33
and Pyripyropenes
Mycotrienins

#34
Hitachimycin

#29
Macrosphelides

#35
Purpactins

#37
#36 Avermectins
Nafuredin

#30
Staurosporine
 Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino

#2
Mangicols

#1
Scytalidamides

Professor William Fenical

Biography:
#3
-Born in 1941, Chicago, Illinois Tamandarins

-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 #4

Salinamides
Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino

OH

H O
N

O
O
#10
Trichodermamides
Me

#5 Me Me #11
Salinosporamide A Pestalone
Cl
#6
Neomangicols
O OH

HO Cl

#7
Ningalins H
MeO Me

OH O Cl

#12
Sterol Glycosides

#8
Didemninides
#9
Neoverrucosane

#13
eunicellane diterpenoid; heterogorgiolide
Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino
O #20 O
#14 Octalactins A & B
Arenaric Acid HO HO
O O OH O O OH

Me Me
O
Me Me Me Me

#21
Diazonamides #22
Aspergilloxides

#15
Luisols
A&B

Me Me
N N
NH NH
O
N N
O O
O O OH
#16
H H
Cyclized Didemninide
NH NH
N N
#23 #24
i-Bu i-Bu
#17 Aspergillamides Labiatamides
O O
Fumiquinazolines H & I

Me O Me
N #25
H Me
N Thraustochytrosides

H OMe

Me Me O OAc #27
#26 Polycarpine
OH Aplidiamine Dihydrochloride
#18 #19 O
Cyclomarins Eleutherobin OH
Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino
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

O OH

HO Cl

H
MeO Me

OH O Cl

LREIMS: m/z = 438/440/442 NMR

->C21 H20 O6 Cl2 Proton: Two olefinic methyl groups
One Aromatic resonance
-11 Degrees of Unsaturation
methoxy group
IR three exchangable phenols
-Benzaldehyde aldehyde
-Ketone Carbon: Alhyde and ketone confirmed
-Hydroxyl groups Lots of aromatic/vinylic quat carbons
One aromatic double

UV: Aromatic Ring with

extended chromophore 2D NMR: Isoprene Fragment
-other modest asignments
 Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino
-Total Synthesis of (+)-Lactacystin
J. Am. Chem. Soc. 1996, 118, 3584.

HO Me
HO Me HO Me
O 1. O3, DMS Pd, MeO2C
MeO2C O
HO2C CO2H N
S Me N NH4O2CH HO H
N O 2. NaClO2,
HO H Me
AcHN NaH2PO3 O
Me 68% Me Ph Me
Me
(+)-Lactacystin
Me HO Me HO Me
Me 1. O.1 N NaOH O O
82% Pd(PPh3)4, HCO2H
AllylO2C HO2C
HO S S
N O N O
2. BOPCl, Et3N HO H Et3N, 81% HO H
AcHN AcHN
Me Me BnN O CO2Allyl Me Me
Ph(Me)2COOH NaH
OH OH AcHN Me Me
Me Me O
Ti(O-i-Pr)4, O BnNCO NaH SH (+)-Lactacystin
(+)-DIPT THF 79%
Me
82%
Me OH

O NBn
A
O
75% Total
Me Me
Jones Me CO2H 1. CH2N2 Me CO2H
A
O NBn 2. KOH O NBn
EtOH
O 96% O

Me
Me NH2 1. HCl(g), Me CO2Me
1. 2N KOH MeOH, 100%
Me CO2H O N
2. H2, Pd(OH)2 2. PhC(OMe)3
OH
98% 82% Ph

HO Me
Me
CO2Me MeO2C
1. LHMDS, Me [Ipc-(+)]2B
CHO Me N
H2CO, 85%
O N
70%, 4:1 Me O Ph
2. DMSO, DCC
Ph
 Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino
-Total Synthesis of Octalins A & B
Keith Buszek: J. Am. Chem. Soc. 1994, 116, 5511.
O O O
1. DMP
HO HO 2. HF HO
O O OH O O OH O O OH
Me Me 3. DDQ, H2O Me
Me Me Me
O
Me Me Me Me Me Me Me Me Me
Octalactin B
Octalactin A Octalactin B

O
1. t-BuOOH,
OMPM OMPM HO
1. 9-BBN; H2O2 VO(acac)2 O O OH
TBDPSO HO OMMTr Me
2. MMTrCl, Base 2. DMP Me
Me 3. TBAF Me O
3. HF Me Me Me
4. DDQ, H2O
Octalactin A
TBDPSO OH
OMPM 1. I2, Morpholine
1. DMP OMPM
OMMTr 2. CrCl2 (1.0%
2. N2CHPO(OMe)2, Me OMMTr
t-BuOK Me w/w NiCl2)
CHO Me
TBDPSO
Me
4hr, rt 75-90% (1:1)

1. H2, Pd/CaCO3 1. DMP;

2. Ac2O, DMAP, py TBDPSO OAc OMPM NaClO2 TBDPSO OH OMPM
CO2H
OH 2. K2CO3
2. PPTS
3. H2, Pd/C Me Me MeOH Me Me

O O
1. 2,2' pyridinedisulfide
PPh3; MPMO 1. DMP MPMO
O O OH OTBS
AgBF4, 2. CrCl2 (0.1% Me
Me OH Me
Refluxing PhMe w/w NiCl2)
63-75% Me Me Me Me
OTBS
2. TBAF
I Me

Me Me
74% 1.5:1
 Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino
-Total Synthesis of Eleutherobin TESO
K.C. Nicolaou: Angew. Chem. Int. Ed. Engl. 1997, 36, 2520. Me TESO Me Me
H OTES H OTES
Me
O TMSOTf CHO 1. LHMDS

Me O b = 54% H 2. DMP H
H Me N Me O
N a = 28% O OPMB
Me Me Me Me
OTBS O OPMB
O
O OTBS
OTBS
H OMe O
OTBS
Me Me O OAc
OH
O TESO
OH Me Me Me OH Me
H OTES H
Eleutherobin
1. DDQ, H2O 1. Et3N•3HF O
Me Me OH
H 1. H2C=CHOEt, H O H
CHO 2. Ac2O O 2. H2, Pd/CaCO3 H OH
t-BuLi; DMAP, Et3N Me Me Me Me O OAc
Then A Me O OAc OTBS
OTBS OTBS OTBS
H 2. H2SO4 H O
A O OTBS
Me Me Me Me OTBS
(+)-carvone derived
O
Me OH OH Me TESO OTES
H 1. TESOTf H
Me Me Me O
1. HCCMgBr Et3N H Me N Me
1. PPTS, MeOH N
2. TBAF OH 2. PPTS OH 2. Et3N, DMAP O
H H
Me Me Me Me O O H OMe
Me Me O OAc
O
N Me OH
N
O
3. TBAF OH
Me TESO OTES Me TESO OTES
H H Eleutherobin
1. TPAP, Me Me
NMO Dibal
CN CHO
2. CNCH2CO2Et
H H
Base CO2Et OH
Me Me Me Me

1. NaH; PMB-Cl 1. NBS, py

O SPh O SPh O OC(NH)CCl3
OH 2. TsOH OPMB OPMB
O OTBS 2. NaH OTBS
O 3. TBSOTf, Et3N TBSO TBSO
Cl3CCN
 Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino

-Total Synthesis of Eleutherobin

Samuel Danishefsky: J. Am. Chem. Soc. 1999, 121, 6563. Me OH Me OTBS
H Me H Me
TsOH (cat) 1. TBSOTf
Me Me Me O O
Cl3CCHO H Cl H MeOH 2. TPAP,
Zn, 0°C, Cl Zn, 90% H OMe
NMO H OMe
Sonication OPv O
Me Me Me Me
Cl O MeOH O
H H
Me Me O
Me Me Me Me
Cl
a-phellandrene
65%

Me NMe2 Me OTBS
OMe Me Me OTBS
H H H Me H Me
Pd(PPh)3
t-BuOCH(NMe)2 TsOH, LHMDS; LiCl
OMe
O O
O MeOH CO2Me Comins' Rgt.
H H H OMe Bu3Sn O OAc H OMe
Me Me Me Me OTf O
Me Me Me Me O OAc
O O
O
50% O
Me OTBDPS Me OTBDPS O
H H
1. H+, H2O 1. Dibal
2. MsCl O
O O
2. n-BuLi CO2Me Br 3. KCN CHO Br Me O
H H 1. TBAF N Me
4. Dibal H Me
Br O N
Br Me Me Me Me
2. DCC, DMAP
O
O
1.3:1 H OMe
3. TBDPSCl, HO Me Me O OAc
N Me
Im., DMAP N OH
3. PPTS O
OH
Me OTBDPS Me OH Eleutherobin
H H
CrCl2 (5eq) 1. PivCl, Et3N
NiCl2 (1eq) O DMAP O
74%, 15:1 H 2.TBAF H
OH OPv
Me Me Me Me

O HO
Me H Me H Me
H H

DMDO/Acetone O 1. TMSOTf O

94% H OH 2. MeLi H OTMS

OPv OPv
Me Me Me Me
 Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino
-Total Synthesis of Eleutherobin
Jeffery Winkler: Org. Lett. 2003, 5, 1805.
Me Me Me Me Me
O H OH H OH
Me Me SmI2 (COCl)2
S H OH O
O DMP
Br O NiI2(cat) py, 79%
S S 72% H H
Me SnCl2 O O OH O O O
O Me O Me Me Me OH Me Me O
NaI
86% O

NaHCO3 Me
AgNO3 Me Me Me
Me
Me Me
OH OH H OH
PhMe VO(acac)2 H
SiO2 Reflux Me
t-BuOOH; K2CO3
S O O O
79% O 94% MeOH O
O A Et3N, SiO2 H
H
O O
Me Me O Me Me OH

Me O

OH
MeO2C Me CHO Me CO2Me Me
Dibal
Me
Me Me H OH
Br SnCl2, NaI Me
OH OH MeI, Ag2O
72%
O
CaCO3, 76% O
H
Me
Me Me OMe
OH Me
BaMnO4 Me A

Me O
O
O
OH
O

Me O
N Me
H Me
N
Me Me Me Me
H H O
TBSOTf
O O H OMe
51% O OAc
Me Me
H H OH
O O
Me Me OH Me Me OTBS O
OH
Eleutherobin

Me Me Me Me
H H
1. NaOH(aq)
1. Dibal, 96%
O O
2. VO(acac)2 2. NaIO4
t-BuOOH H O 66% H
OH OH O
66% Me Me OTBS Me Me OH
 Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino
SePh
-Total Synthesis of Fumiquinazolines H & I NH2
Barry Snider: J. Org. Chem. 2003, 68, 545.
H O NHFmoc
Me Me H
N N
N N 1. Zn, AcOH EDCI
NH NH O O HO O
O N
N N 2. Anthranilic Acid H Fmoc-L-NHCH(CH2SePh)CO2H
O O
EDCI NFmoc O O
O O OH N H
H H
i-Bu NFmoc
NH NH O N
N N
i-Bu
i-Bu i-Bu O
O O SePh SePh
Fumiquinazoline H Fumiquinazoline I
N N
NHFmoc NH2
O N
CO2Me
CO2Me
PPh3, Br2 O NH H O
TrocHN Et3N N N
1. BH3•THF/TFA
TrocHN 2. Cbz-L-Leu, DCC O O O
H H
3. DDQ
82-95% N NFmoc NFmoc
NHCbz N
N N
H
O i-Bu i-Bu
i-Bu O O
CO2Me CO2Me
TrocHN TrocHN Me
1. Hg(OTFA)2, Pd2(dba)3, P(o-tolyl)3 N N
KI NH NH
I O
K2CO3, PhMe, reflux NCbz CH3CN N N
2. I2 N N O O
NHCbz Reflux OH
i-Bu O O
O O H 34% H
i-Bu
NH NH
N N
CO2Me CO2Me i-Bu i-Bu
O O
TrocHN TrocHN
HO HO Fumiquinazoline H
DMDO OMe NaBH4 H

MeOH, 45% NCbz AcOH, 80% NCbz

N N
Me
i-Bu i-Bu Me
NCbz
O A O H
N N
1. PPh3, Br2 NH
HO O
1. SiO2 N Et3N N
O O 2. Zn, HOAc 2. piperdine O
TrocHN TrocHN
A O O O OH
O O 3. Antrhanilic Acid H 3. CH3CN H
EDCI Reflux
1. H2, Pd H H 4. Fmoc-L-Ala NFmoc NH
FmocCl N 4. H2, Pd N
A NH NFmoc
2. SiO2 N N i-Bu i-Bu
Hunig's Base O
i-Bu i-Bu O
Fumiquinazoline I
O O
Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino

The Baran Lab's Retrosnythetic Analysis of Luisols A and/or B:

Baran Group Meeting William Fenical and Satoshi Omura Mike DeMartino

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.