The “BASTADINS” Project
Objectives
 Development of a general synthetic route towards bastadins.
 Preparation of designed analogues and evaluation of their biological activity.
 Discover and evaluate new and/or existing synthetic methodology for the construction of
polyhalogenated diaryl ethers.
Project Summary
The development of a general methodology leading to efficient preparation of all members of
the bastadin famisly of natural products constitutes a challenge; the two successful total
syntheses of macrocyclic bastadins previously reported are restricted in the preparation of,
symmetrically brominated, bastadin-6. Furthermore, most of the available methodology for
the synthesis of diaryl ethers is either inappropriate or presents serious shortcomings for the
preparation of polybrominated substrates. Thus, continuing our ongoing investigation in the
area of biaryl ether natural products, we have initiated the “Bastadins” project with the
objective to address the aforementioned unresolved synthetic issues and facilitate further
biological studies on this class of natural products.
Some macrocyclic Bastadins
Z
Br
W
O
HO
NOH
H
N
O
Br
O
Y1
Y2
OH
3
Br
Y
O
N
H
NOH
Y1
Y2
Y3
H
Br
Br
8
H
Br
H
10
Br
Br
H
H
H
Br
17
H
Br
Br
4
H
Br
H
7
H
H
Br
11
Br
Br
H
14
H
Br
Br
5
Br
Br
Br
6
H
H
Br
9
Br
Br
H
15
Br
H
Br
16
W–Z
OH
Bastadin
12
Batadins are a family of natural products isolated from the marine sponges Ianthella basta
and Psammaplysilla purpurea. Structurally, they are linear or macrocyclic bis-biaryl ether
tetrapeptides possessing brominated aryl units and a unique -oximino amide bond. They
exhibit antibacterial, cytotoxic and anti-inflammatory activity. Furthermore, they constitute a
new class of chemical probes for studying immunophin/ryanodine-sensitive Ca2+ channel
interactions in skeletal muscle albeit their supply from natural sources is limited.
Z
W
Br
O
NOH
H
N
O
2
Y
Br
Br
O
OH
3
Y
1
Y Br
HO
NOPr
PrHN
MeO2C
OPr
O
O
1
Y
HO
+
Br
Br
OH
3
Y
O
N
H
NH 2
western part
NOH
HO 2C
NOPr
eastern part
Pr = Protective group
OH
OH
OBn
Y1
Br
OPr
CHO
NHPr
1
OH
Y
3
Br
O
Br
O
2
Retrosynthetic Analysis Disconnection of the macrocyclic bastadins structure at the two
amide bonds leads to two biaryl ether segments: a monoprotected diamine (western part) and
a methyl diacid monoester (eastern part). Further disconnection of these advanced
intermediates at the diaryl ehter linkages and functional group manipulation leads to an
optically active hydroxylamine and a racemic diol respectively. These key intermediates can
be prepared in multi-gram scale starting from commercially available p-benzyloxybenzaldehyde and p-bromo-phenol. For establishing the correct absolute stereochemistry of
key intermediate (1), which would determine the chirality of the final product, we rely on
Sharples’s assymetric dihydroxylation methodology.
OR
Br
OR
OR
I
CHO
OAr
NaOAr
CHO
CHO
OH
NHBoc
Ar
I2, Ph3P
I
Ar
NHBoc
NaBH 4
Ar
DBU
NHBoc
Ar
NHBoc
Model studies have indicated the iodonium salt method as the more appropriate for the
construction of the diaryl ether linkages. We have also demonstrated the suitability of the
hydroxyl functionality as a flexible common progenitor of all structural variants of bastadins
in the W–Z region.
References.
For the isolation and biological activity of bastadins.
Kazlauskas, R.; Lidgard, R. O.; Murphy, P. T.; Wells, R. J. Tetrahedron Lett. 1980, 21, 22772280.
Kazlauskas, R.; Lidgard, R. O.; Murphy, P. T.; Wells, R. J.; Blount, J. F. Austr. J. Chem.
1981, 34, 765-786.
Miao, S.; Andersen, R. J. J. Nat. Prod. 1990, 53, 1441-1446.
Pordesimo, E. O.; Schmitz, F. J. J. Org. Chem. 1990, 55, 4704-4709.
Butler, M. S.; Lim, T. K.; Capon, R. J.; Hammond, L. S. Austr. J. Chem. 1991, 44, 287-296.
Dexter, A. F.; Garson, M. J. J. Nat. Prod. 1993, 56, 782-786.
Park, S. K.; Jurek, J.; carney, J. R.; Scheuer, P. J. J. Nat. Prod. 1994, 57, 407-410.
Mack, M. M.; Molinski, T. F.; Buck, E. D.; Pessah, I. N. J. Biol. Chem. 1994, 269, 2323623249.
Franklin, M. A.; Penn, S. G.; Lebrilla, C. B.; Lam, T. H.; Pessah, I. N.; Molinski, T. F. J. Nat.
Prod. 1996, 59, 1121-1127.
Pessah, I. N.; Molinski, T. F.; Meloy, T. D.; Wong, P.; Buck, E. D.; Allen, P. D.; Mohr, F. C.;
Mack, M. M. Am. J. Physiology-Cell Physiology 1997, 41, C601-C614.
Chen, L.; Molinski, T. F.; Pessah, I. N. J. Biol. Chem. 1999, 274, 32603-32612.
For previous synthetic efforts directed towards members of the bastadin family.
Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1982, 23, 1281–1284.
Nishiyama, S.; Suzuki, T.; Yamamura, S. Tetrahedron Lett. 1982, 23, 3699–3702.
Nishiyama, S.; Suzuki, T.; Yamamura, S. Chem. Lett. 1982, 1851–1852.
Noda, H.; Niwa, M.; Yamamura, S. Tetrahedron Lett. 1981, 22, 3247–3248.
Guo, Z.-W.; Machiya, K.; Salamonczyk, G.M.; Sih, C.J. J. Org. Chem. 1998, 63, 4269–4276.
For our own, already published, work on bastadins.
Couladouros, E.A.; Moutsos, V.I. Tetrahedron Lett. 1999, 40, 7023–7026.
Couladouros, E.A.; Moutsos, V.I. Tetrahedron Lett. 1999, 40, 7027–7030.
For synthetic methodology for diaryl ether synthesis.
Sawyer, J. Scott Tetrahedron 2000, 56, 5045–5065.
Chakraborty, T.K.; Reddy, G.V. J. Org. Chem. 1992, 57, 5462–5469.
Financial Support
ALCHIMICA
UNIPHARMA S.A.
National Scholarship Foundation of Greece (I.K.Y.)