First total synthesis of a polyunsaturated chromone metabolite isolated from the brown algae Zonaria tournefortii

Article abstract of DOI:10.1021/ol802635a

(Chemical Equation Presented) Starting from the ethyl ester of eicosapentaenoic acid, the first total synthesis of the marine natural product all-(Z)-5,7-dihydroxy-2-(4Z,7Z,10Z,13Z,16Z-nonadecapentaenyl)chromone has been achieved in six steps and in 14% o

Full text of DOI:10.1021/ol802635a

ORGANIC
LETTERS
2009
Vol. 11, No. 3
587-588
First Total Synthesis of a
Polyunsaturated Chromone Metabolite
Isolated from the Brown Algae Zonaria
tournefortii
Hany F. Anwar and Trond Vidar Hansen*
School of Pharmacy, Department of Pharmaceutical Chemistry, UniVersity of Oslo,
P.O. Box 1068 Blindern, N-0316, Oslo, Norway
t.V.hansen@farmasi.uio.no
Received November 14, 2008
ABSTRACT
Starting from the ethyl ester of eicosapentaenoic acid, the first total synthesis of the marine natural product all-(Z)-5,7-dihydroxy-2-
(4Z,7Z,10Z,13Z,16Z-nonadecapentaenyl)chromone has been achieved in six steps and in 14% overall yield.
Marine organisms have proven to be a rich source of biologi-
cally interesting secondary metabolites.1,2 In 1982, Plattelli and
Tringali reported the isolation and structural elucidation of
all-(Z)-5,7-dihydroxy-2-(4Z,7Z,10Z,13Z,16Z-nonadecapen-
taenyl)chromone (1) from the pacific brown algae Zonaria
tournefortii.3 This natural product has also been isolated
recently from two other Zonaria species.4 Compound 1
contains the same number of methylene interrupted cis
double bonds as those present in eicosapentaenoic acid (2a,
EPA). To the best of our knowledge, no total synthesis or
biological data of this polyunsaturated natural product have
been reported. As part of our ongoing efforts on the synthesis
and biological evaluation of polyunsaturated natural prod-
ucts,5 we report herein a stereoselective and efficient
synthesis of 1 from the ethyl ester of EPA (Figure 1).
Our total synthesis of 1 started with the preparation of
aldehyde 3 in 97% yield as previously described.6 Aldehyde
3 was transformed to the terminal alkyne 4 in a Colvin
rearrangement7 in 58% yield. Alternatively, compound 4 was
obtained by using the Corey-Fuchs reaction8 in 52% yield.
To the anion of 4 at -78 °C, obtained after reaction with
n-butyllithium, a THF solution of 2,4,6-trihydroxybenzal-
dehyde (5a) was added. Unfortunately, the desired secondary
alcohol 6a was not obtained, even after several attempts with
either 3, 4, or 6 equiv of the anion of 4. On the other hand,
when a THF solution of commercially available 2,4,6-
trimethoxybenzaldehyde (5b) was added to the anion of 4
at -78 °C, the secondary alcohol 6b was obtained in 58%
yield.
Oxidation of 6b with activated MnO29 yielded ketone 7b
in 96% yield. We envisioned that deprotection of 7b,
followed by an intramolecular Michael addition, would yield
(1) Rinehart, K. L.; Tachibana, K. J. Nat. Prod. 1995, 58, 344
(2) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1
(3) Tringali, C.; Piattelli, M. Tetrahedron Lett. 1982, 23, 1509.
(4) (a) Blackman, A. J.; Rogers, G. I.; Volkman, J. K. J. Nat. Prod.
1988, 51, 158. (b) El Hattab, M.; Piovetti, L.; Chitour, C. E. J. Soc. Alger.
Chim. 2006, 16, 69.
.
.
(6) Holmeide, A. K.; Skattebøl, L.; Sydnes, M. J. Chem. Soc., Perkin
Trans. 1 2001, 1942.
(7) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973,
151.
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(9) (a) Manganese Dioxide. In Encyclopedia of Reagents for Organic
Synthesis; John Wiley & Sons: New York, 1995; Vol. 5, pp 3229-3235.
(b) Fatiadi, A. J. Synthesis 1976, 65. (c) Fatiadi, A. J. Synthesis 1976, 133.
(5) (a) Hansen, T. V.; Stenstrøm, Y. Synth. Commun. 2000, 30, 2549.
(b) Hansen, T. V.; Stenstrøm, Y. Tetrahedron: Asymmetry 2001, 12, 1407.
(c) Hansen, T. V.; Skattebøl, L. Tetrahedron Lett. 2004, 45, 2809.
10.1021/ol802635a CCC: $40.75
Published on Web 12/23/2008
2009 American Chemical Society

Scheme 1. Synthesis of Chromone 1
Figure 1. Chromone 1 and retrosynthetic analysis.
the natural product 1. However, decomposition of the starting
material associated with formation of polymeric material was
observed with most common deprotection methods.10 We
then prepared the known 2,4,6-tris(methoxymethoxy)ben-
zaldehyde 5c according to a literature procedure.11 Addition
of aldehyde 5c in THF to the anion of 4 at -78 °C yielded
the secondary alcohol 6c in 60% yield. Oxidiation of 6c with
MnO2 yielded MOM-protected ketone 7c in 88% yield. Mild
deprotection of 7c with HCl in EtOH at ambient temperature,
followed by intramolecular Michael addition under lenient
basic conditions (K2CO3, acetone), afforded the natural
product 1 in 49% yield for the latter two steps (Scheme 1).
All spectral data were in agreement with those previously
reported.3,4
from 2,4,6-trihydroxybenzaldehyde and ethyl ester of eicosa-
pentaenoic acid with an overall 14% yield. The synthesis
confirmed the assigned structure of 1 and provided sufficient
material for biological testing. These efforts will be reported
in due course.
Acknowledgment. Financial support to H.F.A. from the
University of Oslo (The Quota Scheme) is gratefully
acknowledged. Helpful discussions with Professor Lars
Skattebøl, Department of Chemistry, University of Oslo, are
gratefully acknowledged.
In conclusion, we have reported the first total synthesis
of the naturally occurring chromone derivative 1 in six steps
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in
Organic Synthesis, 4th ed.; John Wiley & Sons: Hoboken, NJ, 2007; pp
370-382.
(11) Graybill, T. L.; Casillas, E. G.; Pal, K.; Townsend, C. A. J. Am.
Chem. Soc. 1999, 121, 7729.
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