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Synthetic Efforts Toward Palau'amineDoug Behenna, Ryan McFadden
Eric Ashley, Jenn StockdillAkihiko Iwashita
August 9, 2004
N
N
NH
N
O
NH2
H
N
NH
H
H
OH
NH2
ClH2N
N
N
NH
N
O
NH2
H
N
NH
H
H
OH
NH2
ClH2N
R1R2
N NH
NHN
O
NH2
H
N
NH
H
H
OH
NH2
ClH2N
R2R1
R1 = R2 = H Palau'amine
R1 = H, R2 = Br 4-Bromo Palau'amine
R1 = R2 = Br Dibromo Palau'amine
R1 = R2 = H Styloguanidine
R1 = H, R2 = Br 3-Bromo Styloguanidine
R1 = R2 = Br Dibromo Styloguanidine
Isolation of Palau'amine and Congeners
Palau'amines
• Isolated from marine sponge Stylotella aurantium
• Structural determination by 1HNMR
• Cytotoxic against P-388 (0.1 µg/mL), A549 (0.2
µg/mL), HT-29 (2µg/mL) and KB (10 µg/mL)
• Antibiotic against Staphylococcus aureus and
Bacillus subtillus
• Antifungal against Penicillium notatum
• Kinnel, R. B. et. al. J. Am. Chem. Soc. 1993, 115,
3376-3377 and J. Org. Chem. 1998, 63, 3281-3886.
Styloguanidines
• Isolated from marine sponge Stylotella aurantium
• Structural determination by 1HNMR
• All three compounds are potent chitinase inhibitors
• First reported by Kato, T. et. al. Tetrahedron Lett.
1995, 36, 2133-2136.
• Also reported in Kinnel's second paper.
1
Biosynthesis of Palau'amine
CO2H
NH2
N
HN
Histidine
N
HN
NH2N
N
NH2H2N H2N
HN
CO2H
Proline
HN
CO2H
HN
CO2HBr
Br
N
N
NH2H2N
HN
CO2H+N
N
NH
H2N
O
HN
Mourabit, A. A.; Potier, P. Eur. J. Org. Chem., 2001, 237-243.
N
HN
NH2H2N
N
N
NH
H2N
O
HN+
NH
O
HN
NH2Cl
OH
N
HN
H2N
N
N
H2N
NH
O
HN
NH2
N
HN
H2N
HN
N
HN
HO
Cl
NH
OHN
NH2Cl
HN
NH2N
HO
N
N
H2N
Biosynthesis of Palau'amine
2
NH
OHN
NH2Cl
HN
NH2N
HO
N
N
H2N
NH2Cl
HN
NH2N
HO
N
OHN
N
NH
H2N
NH2Cl
HN
NH2N
HO
N
OHN
N
NH
HN
N
N
NH
N
O
H2N
H
N
HN
H
H
HO
H2N
ClNH2
Biosynthesis of Palau'amine
[O]
Palau'amine
Overman's Stereocontrolled Synthesisof the Tetracyclic Palau'amine Core
COOEt1. H2NCH2CO2Na, EtOH, reflux
2. H2SO4,EtOH, reflux3. CbzCl, TEA
EtO2C
CbzN
EtO2C
CbzN
EtO2C
HO
1. t-BuOK, THF, -78 oC
2. NaBH4, MeOH
CbzN
EtO2C
MeO2COTBS
1. MsCl, TEA, DMAP, PhH, 0 oC
2. O3, CH2Cl2; PPh3
3. LiCl, ACN, (MeO)POCH(OTBS)CO2Me
CsF, AcOH, ACN
CbzN
EtO2C
MeO2CO
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
Overman, L.E. et. al., J. Am. Chem. Soc. 1997, 119, 7159-7160.
3
CbzN
EtO2C
MeO2CO
NH2NHCSNH2
AcOH, 70 oC, 24h
CbzN
EtO2C
CO2MeHN
NHCSNH2
CbzN
EtO2C
N NHH2N
S
CO2Me
CbzN
N NH
CO2Me
HN
S
O
CbzN
EtO2C
HN
NH
H2NS
CO2Me -H+
Overman's Stereocontrolled Synthesisof the Tetracyclic Palau'amine Core
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
Overman, L.E. et. al., J. Am. Chem. Soc. 1997, 119, 7159-7160.
CbzN
N NH
CO2Me
HN
S
OLiOH, HCl
CbzN
N NH
CO2H
HN
S
OPO(NCS)3
THF, reflux
CbzN
HN
NHHN NH
O O
S S
MeI, NaOH
H2O/MeOH, RT
CbzN
NNHHN
N
O O
SMe SMe
BnNH2, EtOH, 70 oC
CbzN
NNHHN
N
O O
NHBn NHBn
Overman's Stereocontrolled Synthesisof the Tetracyclic Palau'amine Core
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
Overman, L.E. et. al., J. Am. Chem. Soc. 1997, 119, 7159-7160.
4
Synthesis of Epimeric Cyclization Precursores
SESN
OH
EtO2C
SeO2, t-BuO2H
CH2Cl2, reflux
20%
SESN
OH
EtO2C
HO
1
largely (~90%) one stereoisomer
(56% recovered 1)
2
acetone, PPTS
Me2C(OMe)2
O
OSESN
EtO2C
3
columnchromatography
O
OSESN
H
EtO2C
4a, 50-55%
O
OSESN
H
EtO2C
4b, 15-20%
L. E. Overman et al. J. Org. Chem. 2002, 67, 7880-7883.
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
Synthesis of Epimeric Cyclization Precursores
SESN
OHEtO2C
TBDMSO
TBDMS-OTf,
Et3N, 0 °C
1. MsCl
2. O3, PPh3
3. (MeO)2POCH(OTBDMS)CO2Me
LiCl, DBU4
6a: !-TBDMS (75%)6b: "-TBDMS (48%)
SESN
EtO2C
TBDMSO
CO2Et
OTBDMS
7a: !-TBDMS (~35%)7b: "-TBDMS (~12%)
CsF, AcOH
MeCN
~100%
SESN
EtO2C
TBDMSO
CO2Et
O
8a: !-TBDMS8b: "-TBDMS
Dowex (resin)
MeOH, rtSESN
OHEtO2C
HO
5a: !-OH (74%)5b: "-OH (80%)
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
L. E. Overman et al. J. Org. Chem. 2002, 67, 7880-7883.
5
Intramolecular Cycloaddition Reactions
SESN
EtO2C
CO2Me
OH2N
NH
NH2
S
AcOH, 70 °C
SESN
HNN NH
CO2Me
S
O
89%10 11
SESN
EtO2C
CO2Me
O
H2NNH
NH2
SSESN
HNN NH
CO2Me
S
O
TBDMSO
OTBDMS
9a: !-TBDMS9b: "-TBDMS
AcOH, 70 °C
12a: !-TBDMS (49%)12b: "-TBDMS (58%)
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
L. E. Overman et al. J. Org. Chem. 2002, 67, 7880-7883.
The Pauson-Khand Approach
HO
OH
OO
O O
1,2:5,6-di-O-isopropylidene-D-mannitol
$$$
NaIO4, NaHCO3
4:1 MeOH/H2O, then
Ph3P
O
OMe
-60°C to 0°C
75%, 1 pot
OO O
OMe
16:1 Z/E
DIBAL, CH2Cl2 -78°C
PPh3, CBr4, CH3CN
0°C to r.t.OO
91% 97%
OH
OO
Br
Austin, D. J., et. al., Org. Lett. 2003, 5, 2203-2206.
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
6
The Pauson-Khand Approach
N
O
O
OH +
Br
TMS
DBU, DMF N
O
O
O
TMS
94%
H2NNH2, CH2Cl2
95%
H2N O
TMS
BOC2O, NaHCO3
1,4-dioxane
79%
BOC
HN O
TMS
OO
Br
1. A, then NaH then B, DMF, 50°C
A
B
2. K2CO3, MeOH
0°C to r.t.
O
O
O
N BOC
1. Co2(CO)8
CH2Cl2
2.
0°C to r.t.
Et3N O
83%
O
O
O
N
O
BOC
dr = 4:1
69%, 2 steps
Austin, D. J., et. al., Org. Lett. 2003, 5, 2203-2206.
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
The Pauson-Khand Approach
O
O
O
N
O
BOC
Hydrogenation
Na(Hg)
SmI2, THF/EtOH
O
O
NH
O
BOC
OH
O
O
HO
N
O
BOC
49%
O
O
O
N
O
BOC
Pd/C
57 psi H2
EtOH (95%)
LiBH4, THF
0°C (80%)
O
O
O
N
HO
BOC
0.1M SmI2
THF/H2O
(70%)
or
Na(Hg),
Na2HPO4
EtOH, 0°C
(77%)
O
O
NH
HO
BOC
OH
Austin, D. J., et. al., Org. Lett. 2003, 5, 2203-2206.
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
7
Studies on Absolute Configurationof a Pyrrolopyrazinone related to
Palau'amine
Lindel, T., et. al., Chem. Eur. J. 2004, 10, 1141-1148.
N
N
O
BrBr
HRO
N
N
O
BrBr
HRO
CD Spectral Features of two synthetic models:
10
10a
10
10a
Positive Elipticityat 250nm, due tostereocenter 10a
Strong Band thatsits at 285nm, dueto stereocenter 10
Positive Elipticityat 250nm, due tostereocenter 10a
Weak shoulder thatsits at 285nm, dueto stereocenter 10
CD Features
N
N
O
BrBr
? HN
N?
H
H2N
(-)-Dibromophakellin
Negative Elipticityat 250nm, so thestereocenter at 10ais R.
Weak Shoulder isobserved at 285nmindicating that thestereocenter at 10is S.
10
10a
Whether R is Ac, R-MTPA, S-MTPA or just H,the CD spectrum is virtually unchanged!
N
N
O
BrBr
HN
N
H
H2N
Circular DichroismStudies
The authors arecurrently investigating
the CD features ofPalau'amine.
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
Another Biosynthetic Hypothesis Driven Synthetic Effort
The Hypothesis:
N
N
O
HN
NH2N
X X
X = Br Dibromophakellins
NH2
X = H Proposed
Romo(Texas A&M) Org. Lett. 2001, 3, 1535-1538
HN
N
H2N
2-amino-1-(2-aminoimidazolyl) prop-1-ene (AAPE) --a known metabolite
(4 +2)
N
N
O
HN
NH2N
X X
HN
N
H2N
NH2
H
HChloroperoxidase
Mediated Oxidationand Rearrangement
Cl+
N
N
O
HN
NH2N
X X
H
HN
N
NH2Cl
H2NN
N
O
HN
NH2N
X X
H
H
HN
N
NH2Cl
H2N
OHH H2O
8
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
Building the Diels-Alder Fragments
(S)-pyroglutamic acid
N
HO
HOO 5 -Steps N
Ts
TIPSOO
HN
NH
O
O
OH
BnN
NBn
OOH
BnN
NBn
OO
OEt
BnN
NBn
OOH
1. NaH BnBr DMF 41%
2. DIBAL-H DCM -78 °C 84 %
1. MnO2 DCM 98%
2. (EtO)2P(O)CH2CO2Et, NaH
DIBAL-H DCM -78 °C 78 %
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
Key Diels-Alder / Ring Contraction Sequence
N
Ts
TIPSOO
BnN
NBn
OOH
Ph-H, 2,6 Lut
95 °C, 4 d
N
BnN
NBn
O
O
OTIPSTs
OH
NO
OTIPSTs
NBn
NBn
HO
O64 % 15 %
N
BnN
NBn
O
O
OTIPSTs
OH2. DMDO, MgSO4
DCM, -45°C
then DMS, 99 %
N
BnN
NBn
O
O
OTIPSTs
OTBSHO
NCS,
DCM, 75%
NO
OTIPSTs
BnN
NBn
O
OCl
OTBS
1. TBSCl
9
Palau'amine Retrosynthetic Summary
N
N
HN
N
H2N
O
NH2
Cl
N
HN
H2N
HO
O
O
NHR
OH
HO
O
O
O
NR
O
Austin
NO
OTIPSTs
BnN
NBn
O
OCl
OTBS
N
BnN
NBn
O
O
OTIPSTs
OTBSHO
Romo
CbzN
N NH
CO2Me
HN
S
O
Overman
H2NNH
NH2
S
CbzN O
O
OMeO
OMe
CbzN
NNHHN
N
O O
NHBn NHBn
10
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