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Synthesis directed towards Agelasines, Agelasimines, Asmarines and Analogs;
Bioactive Marine Natural Products
Lise-Lotte Gundersen
Department of Chemistry, University of Oslo, Norway
2
23. Organisk-kjemiske vintermøte, Geilo 2008
21:a Organikerdagarna, Åhus 2008
3
Marine organisms Algae and invertebrates (sponges, mollusks, tunicates etc)
Rich sources of bioactive compounds - Defence
•Antimicrobial
•Antineoplastic
4
Nature 2004, 430, 242
Nature 2004, 431, 892:
“Antibiotics are the worst
sort of pharmaceuticals
because they cure the
disease”
5
Agelasines Agelasimines Asmarines
N
N N
N
NHO
H
Asmarine A
N
N N
N
N
Agelasimine A
OH
H
Purine-Containing Natural Productsfrom Marine Sponges
•Total synthesis
•Synthesis of analogs
•Bioactivities
H
N
N N
N
NH2
Cl
Agelasine A
6
Marine Sponges?
7
Agelasines
•Isolated from marine sponges (Agelas sp.)
•11 comp. (Agelasine A - I, epiagelasine C and ageline B) known to date
•Total syntheses other groups: Agelasine A, B and C, and (±) agelasine F
•Bioactivities:
Cytotoxic
Antimicrobial
etc.
Brown Tube Sponge: Agelas sp. 2.5 feet long
H
N
N N
N
NH2
Cl
Agelasine A
7,9-dialkylated Adeninium salt
Terpenoid side chain at N-7
8
Synthesis of Trixagol and Agelasine E
Trixagol
OH
Isolated from Bellardia trixagoTL, 1978, 3491Isolated from Agelas sp.
Tetrahedron Lett. 1984, 2989
N
N N
N
NH2
CH3
CO2H
OH
Agelasine E
Geraniol
N
N NH
N
NH2
Helv. Chim. Acta, 1995, 539
Adenine
Cl
9
Synthesis of Trixagol and ent-Trixagol
Bakkestuen et al., Tetrahedron 2003, 59, 115
HO2C
HO2C
HO2C
O
H3CO2C
OOOCH3
OCH3
O
O
4 steps
+c.f. lit.
Synth. rac. acid: Helv. Chim. Acta, 1952, 1752 Resolution:Helv. Chim. Acta. 1995, 539
c.f. lit.
Trixagol
ent-Trixagol
Agelasine E
OH
3 steps
HO2C Litt. HOPhSSPh
Bu3P
pyridine
PhS
(S) 90%(R) 91%
oxone
MeOH, H2O0 oC
OTHP
OTHP
SO2Ph
PhSO2
OTs
OTHP
n-BuLiDMPU
THF
Na, Na2HPO4EtOH, THF
(S) 39%(R) 41%
two steps
PPTS
EtOH, 55 oC
OH
(S) 73% Trixagol(R) 82%
(S) 81%(R) 86%Tetrahedron 1997, 53, 3527
10
Synthesis of Agelasine E and ent-Agelasine E
N
N N
N
NH2
R
N
N N
N
NH
R
R'N
N N
N
NH2 R
N
N N
N
NH R
R'
Regioselectivity in dialkylation of adenines
R'X R'X
Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025
N
N N
N
Cl
HN
N N
N
NMeO
N
N N
N
NMeO
N
N N
N
NMeO
+
MeONH3Cl, Et3N
n-BuOH, Δ63%
DMA, 50 oC
1) Zn, AcOHMeOH / H2O
2) NaCl(aq)Cl
(R) Enantiomer shown(S), Trixagol
OH
82% (R)96% (S)
BrPBr3
Et2O, 0 oC
N
N N
N
NH2
48% (R)44% (S)
32% (R)26% (S)
54% (R) Agelasine E89% (S)
HN
N N
N
N
R
CH3O
HN
N N
N
N
R
CH3OR'
R'X N
N N
N
N
R
CH3O R'
+X
11
Synthesis of Agelasine D
Agelasine D Manool
Sclareol
Salvia sclarea (Clary Sage)
Isolated from Agelas sp.Tetrahedron Lett. 1984, 2989
N
N N
N
NH2
H
H
X
H
HO
H
HO
OHCl
12
Synthesis of Agelasine D - Initial Approach
Drawbacks: Lack of selectivity
Utenova et al., Tetrahedron Lett. 2004, 45, 4233
H
Br
HN
N N
N
NMeO
N
N N
N
N
N
N N
N
NMeO
+
DMA, 50 oC
Zn, AcOH
MeOH, H2O
H
N
N N
N
NH2
H
MeO
H
60% E:Z 8:243% pure E after cryst.
27% E:Z 8:2
Cl
51%81% E:Z 8:2
PBr3, pyridine
Et2O, -35 oC
H
HO
(+) Manool
(+) Agelasine D
13
Improved Synthesis of Agelasine D
Synthesis of geometrically pure allyl bromide
Vik et al., J. Nat. Prod. 2006, 69, 381
H
AcO
90% E:Z 92:8
Ac2O, DMAP, Et3N
THF, Δ
H
AcO
PdCl2(MeCN)2
THF, 0 oC
K2CO3
MeOH
H
HO
76% Pure E
PBr3, pyridine
Et2O, 0 oC
H
Br
76% Pure E
Anticopalol
H
Br
81% E:Z 8:2
PBr3, pyridine
Et2O, -35 oC
H
HO
(+) Manool
14
Improved Synthesis of Agelasine D - Regioselective N-alkylation
Vik et al., J. Nat. Prod. 2006, 69, 381
H
Br
HN
N N
N
NMeO
N
N N
N
N
N
N N
N
NMeO
+DMA, 50 oC
H
MeO
H
60% E:Z 8:2 27% E:Z 8:2
H
Br
HN
N N
N
NO
N
N N
N
N
DMA, 50 oC
Zn, AcOH
MeOH, H2O
H
N
N N
N
NH2
H
O
Cl
49%
(+) Agelasine D
90%
Only isomer observed
HN
N N
N
NRO
DMA, 50 oC
PhCH2Br N
N N
N
NRO Ph
A
+ N
N N
N
NRO
Ph
B
R- Ratio A : B Yield (%) A Yield (%) B
CH3- 60 : 40 55 30
t-Bu- 90 : 10 86 9
PhCH2- 80 : 20 72 13
15
Synthesis of Agelasine F
Isolated from Agelas sp.Tetrahedron Lett. 1984, 2989J. Am. Chem. Soc. 1984, 106, 1819
N
N N
N
NH2
CH3
Agelasine F(Ageline A)
Cl
Asao et al., Synthesis 1990, 382Asao et al., Tetrahedron Lett. 1989, 30, 6397
Asao et al., Tetrahedron Lett. 1989, 30, 6401
O
CO2Me
BnOBr
+9 steps
(±)
HO
11 steps Br
(±)2 steps
(±) Agelasine F
16
Synthesis of Agelasine F
Isolated from Agelas sp.
Isolated from pennyroyal
(Mentha Pulegium)
N
N N
N
NH2
CH3
Agelasine F(Ageline A)
Cl OH
Geraniol
N
N NH
N
X
X(S)-Pulegone
17Proszenyak et al., Manuscript
BrO
(R)-Pulegone Side chain ent-Agelasine F
O
(R)-Pulegone
O TMSO
TMSCl, Et3N
DMF
1) LDA2) MeI
THF- 78 oC
O
KOH (aq)
48% from pulegone
Cl SPh
O
PhS
57%
O
PhS
33%
+TiCl4, CH2Cl2, -23 oC
TMSO
Cl SO2Ph
O
PhS
O
PhS
oxone
MeOH, H2OO
PhSO2
O
PhSO2
87%
85%
oxone
MeOH, H2O
X-ray; minor isomer sulfone
18Proszenyak et al., Manuscript
PhSO2
PhSO2
Agelasine E Agelasine F
More reactive
O
PhSO21) MeMgI
Et2O, 0 oC - rt
82%
2) HCO2H, 80 oC
PhSO2
1) BuLi
2) THPO
THF, 50 oC
THPO
SO2Ph
THPONa, Na2HPO4
EtOH, THF
PPTs
EtOH, 55 oC
HO
I
54%(Two steps)
82%
PBr3
Et2O, 0 oCBr
93%
O
(R)-Pulegone
19
Intermediate in synthesis of other natural products ?
O
(S)-Pulegone
O
O
O
OculatolideO
Subersin
S
NHH2N
HN
OO
(-) Agelasidine CAgelasidine D
OH
S
NHH2N
HN
O
O
PhSO2
O
(R)-Pulegone
O
O
O
Sollasin D
O
Sollasin A(Fulvanin 1)
O
S
NHH2N
HN
OO
S
HN
H2NNH
OO
(+) Agelasidine C
Agelasidine B
PhSO2
O
O
Microcionin 2
O
O
O
O
Striatol
OH
20
Proszenyak et al., Manuscript
Asao et al., Synthesis 1990, 382Asao et al., Tetrahedron Lett. 1989, 30, 6397
Asao et al., Tetrahedron Lett. 1989, 30, 6401
BrO
10 steps
O
CO2Me
BnOBr
+9 steps
(±)
HO
11 steps Br
(±)
21Proszenyak et al., Manuscript
O
(R)-Pulegone
Br
HN
N N
N
NRO
N
N N
N
NRO
76%, R = t-Bu
49%, R = Me
+ N
N N
N
NRO
11%, , R = t-Bu
23%, R = Me
N
N N
N
NH2
48%
Cl
DMA, 50 oC
ent-Agelasine F
Zn, AcOH
MeOH, H2O75 oC
22
Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025
Vik et al., J. Nat. Prod. 2006, 69, 381
Vik et al., Bioorg. Med. Chem. 2007, 15, 4016
Proszenyak et al., Arch. Pharm. Chem. Life Sci. 2007, 340, 625
HN
N N
N
N
R''
RO
orHN
N N
N
N
R''
OR
syn anti
HN
N N
N
NMeO
H2N
OHO
HO
NOE
Hill et al. Nucl. Acids Res. 1998, 26, 1144
HN
N N
N
N
R''
RO
HN
N N
N
N
R''
RO R'
N
N N
N
NH2
R''
R'
ClR'-CH2-Br
N
N N
N
NH
R''
RO
A
B
RONH2N
N N
N
Cl
R''
R''XN
N NH
N
Cl[red]
Base
N
N N
N
N
R''
RO R'
X
HX
1H NMR: A : B, ca 8 : 2 (CDCl3, CD3OD, DMSO-d6), 25 oC
Only minor variations depending on R and R''
23
X % Amine B in DMSO-d6
40 oC25 oC 70 oC
H 20 25 32
Me 18 21 29
CF3 100 100 100
Cl 100 100 100
NO2 100 100 100
OMe 92 92 92
OEt 94 93 94
NHMe 28 33 37
NMe2 100 100 100
1H NMR data Roggen et al. Manuscript
N
N
Cl
X N
N
Me
N
N
NH
X N
N
Me
MeO
HN
N
N
X N
N
Me
MeO
H, CH3, CF3, Cl, NO2 H, CH3, CF3, Cl, NO2
OMe, OEt, NHMe, NMe2
A B
MeONH2
HXR
24Roggen et al. Manuscript
X Yield (%) 1 Yield (%) 2
H 51 35
Me 57 29
CF3 <2 _
Cl 4 _
NO2_ _
OMe _11
OEt 52 20
NHMe 61 7
NMe2 56 22
Yields of isolated compounds
% Start. mat. recov
8
5
66
86
95
14
22
12
_
N
N
NH
X N
N
Me
MeO
HN
N
N
X N
N
Me
MeO
H, Me, CF3, Cl, NO2
OMe, OEt, NHMe, NMe2
A B
HN
N N
N
N
Me
MeO
N
N N
N
N
Me
MeO
+
X X
Ph
BrBnBr
DMA, 50 oC
1 2
Ph
N
N N
N
NH
Me
MeO
19%
O
Ph**
25
Bioactivities•Antibacterial (incl. Mycobacterium tuberculosis)•Antifungal•Antiprotozoal (incl. several causing tropical diseases;
i.e. Chagas disease, Viceral Leichmaniasis)•Antifouling•Antineoplastic
HN
N N
N
N
R''
RO
HN
N N
N
N
R''
RO R'
N
N N
N
NH2
R''
R'
ClR'-CH2-Br [red]
Base
N
N N
N
N
R''
RO R'
X
HX
X X X
X
Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025
Vik et al., J. Nat. Prod. 2006, 69, 381
Vik et al., Bioorg. Med. Chem. 2007, 15, 4016
Proszenyak et al., Arch. Pharm. Chem. Life Sci. 2007, 340, 625Sjögren et al., Biofouling. 2008, 24, 251
26
•Generally broad spectrum activity
•Type A more active than type B structure ( otherwise same subst.)
•R’ must be relatively long and preferably contain unsaturation(s)
•R, R’’ and X; some modifications of activity spectrum
Structure - Activity Relationships
HN
N N
N
N
R''
RO R'
N
N N
N
NH2
R''
R'
XX X
Type A Type B
X
HN
N N
N
N
CH3
MeO
HO
geranylgeraniol
Agelasine analog
X
27
WHO (1993): Tuberculosis - TB a “global emergency”
•AIDS
•Resistant strains
•Migration
•Powerty
Ca. 3 mill deaths / year
R MIC M. tuberculosis (μg/mL)
Type A Type B
3.13
1.56
3.13
3.13
n.d.
>6.25(38% inhib. at 6.25 μg/mL)
>6.25(21% inhib. at 6.25 μg/mL)
>6.25(30% inhib. at 6.25 μg/mL)Agelasine E
>6.25(38% inhib. at 6.25 μg/mL)
3.13Agelasine F
MIC Rifampin 0.25 μg/mL Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025Mangalindan et al. Planta Med. 2000, 66, 364; Agelasine F
N
N N
N
NH2
Cl
R
N
N N
N
N RMeO
Type A Type B
28Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025Vik et al., Bioorg. Med. Chem. 2007, 15, 4016
N
N N
N
N
CH3
MeO
Staphylococcus aureus
MIC (μg/mL)
Mycobacterium tuberculosisMIC (μg/mL)
4.0 3.13
N
N N
N
N
CH3
MeO > 32 >6.25(86% inhib. at 6.25 μg/mL)
N
N N
N
NHMeO > 32 >6.25
(74% inhib. at 6.25 μg/mL)
N
N N
N
NH2
CH3
Cl
32 >6.25(38% inhib. at 6.25 μg/mL)
N
N N
N
NH2 > 32 1.56
29Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025Vik et al., Bioorg. Med. Chem. 2007, 15, 4016Vik et al., Planta Med. 2007, 73, 1410
N
N N
N
N
CH3
MeO
Staphylococcus aureus
MIC (μg/mL)
Mycobacterium tuberculosisMIC (μg/mL)
HO
(Geranylgeraniol)
O
O
O
4.0 3.1
3.1n.d.
> 32 1.6
n.d. n.d.(0% inhib. at 6.25 μg/mL)
30
N
N N
N
NH2
H
Cl Sjögren et al., Biofouling. 2008, 24, 251
Antifouling activity - Barnacles
Agelasine D and analogs inhibit settlement of Balanus improvisus cypris larvae,
low tox. to cyprids
31
Agelasines Agelasimines Asmarines
N
N N
N
NHO
H
Asmarine A
N
N N
N
N
Agelasimine A
OH
H
Purine-Containing Marine Natural Productsfrom Marine Sponges
H
N
N N
N
NH2
Cl
Agelasine A
32
Asmarines
•Isolated from marine sponges (Raspailia sp.)
•11 comp. (Asmarine A - J)
•No total syntheses
•Bioctivities: Cytotox.
N
N N
N
NR
H
Asmarine A: R = OHAsmarine B: R = OH (epi at C'-5)Asmarine G: R = OMeAsmarine H: R = HAsmarine K: R = H (epi at C'-5)
N
N N
N
NR
H
O
* *
Asmarine D: R = OHAsmarine C: R = OH (epi at C'-5)Asmarine E: R = OMe (epi at C'-5)Asmarine F: R = OMe
N
N N
N
NR
H
Asmarine I: R = OHAsmarine J: R = H
33
Previous strategies for construction of the 7-membered ring
No ex. of formation of bond c or d
N
N
N
N
NX
R1R2
a
b cd
e
N
N
N
N
Cl
HNMOM
N
HN
N
N
NRO
N
N
NH
N
NX
OH
N
N
N
N
NR
SOCl2Et3N, BuOH
R1Br
N
HN
N
N
NRO
R1R2
R1 = R2 = H
R2
1. I2, NaHCO32. Bu3Sn
HBr, AcOH
34
Formation of bond d - Initial attempts
Vik et al.Tetrahedron. Lett. 2007, 48, 1931
Co-complex
NCo
N
N
N
OH2
O O
O
H
OH
N
N N
N
NR
R'' R'
N
N N
N
NR
R'' R'
RCM ?
7
d
N
N N
N
Cl
HXCH2CH=CH2
Pyridine, 100 oCN
N N
N
X
a: X = NH, 89%b: X = NMe, 92%c: X = Od: X = NBoc, 65%
(Boc)2ODMAP, CH2Cl2
N
N N
N
NBocGrubbs II or
Hoveyda-Grubbs II
DCE, Δ
54% (Grubbs II) 73% (How.-Grubbs II) Compds a-c: n.r.
N
N N
N
HN
HCl(aq)
MeOH81%
N
N N
N
HN
N
N NH
N
Cl I-CH2CH=CH2, K2CO3, Co-complex, CH3CN
(c.f. Dalby et al. Angew. Chem. Int. Ed. Engl. 1993, 32, 1696)
8
H2, Pd/C
H2SO2MeOH
85%
35
N
N N
N
NR
R'' R'
N
N N
N
NR
R'' R'
RCM ?
7
N
N N
N
NH
(Boc)2O, DMAP
MeCN
Hoveyda-Grubbs II
DCE, ΔN
N N
N
NH
N
N N
N
NBoc
68%
N
N N
N
NBoc7
95%
K2CO3
MeCN, Δ
100%
N
N N
N
HN
76%
1) H2, Pd/C, EtOAc
2) HCl, MeOH
Vik et al.
Tetrahedron. Lett. 2007, 48, 1931
N
N N
N
HN
H
Asmarine H
36
Acknowledgements
Synthesis•Dr. Anne Kristin Bakkestuen
•Anthony James
•Dr. Agnes Prozenyak
•Heidi Roggen
•Linda W. Tangen
•Dr. Bibigul T. Utenova
•Dr. Anders Vik
Bioactivities•Prof. Lars Bohlin & co-workers
•Dr. Colin Charnock•Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF)
•WHO - TDR
Financial Support•NFR (FRINAT & KOSK)
•UiO
