Stereochemical assignment of the fungal metabolite xestodecalactone A by total synthesis

Article abstract of DOI:10.1016/j.tetlet.2004.02.005

The first synthesis of the macrocyclic natural product xestodecalactone A, a metabolite of a sponge-derived fungus, is described. By the use of methyl 5-hydroxyhexanoate in its R- or S-configured form, or as its racemate as the precursors, both enantiomers of xestodecalactone A as well as the racemic compound were obtained. Comparison of these synthetic products with the natural product by circular dichroism (CD) spectroscopy and by HPLC on a chiral phase revealed the natural product to have the (R)-configuration.

Full text of DOI:10.1016/j.tetlet.2004.02.005

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2829–2831
Stereochemical assignment of the fungal metabolite
xestodecalactone A by total synthesisq
Gerhard Bringmann,* Gerhard Lang, Manuela Michel and Markus Heubes
Institute of Organic Chemistry, University of W€urzburg, Am Hubland, D-97074 W€urzburg, Germany
Received 9 December 2003; revised 29 January2004; accepted 3 February2004
Abstract—The first synthesis of the macrocyclic natural product xestodecalactone A, a metabolite of a sponge-derived fungus, is
described. By the use of methyl 5-hydroxyhexanoate in its R- or S-configured form, or as its racemate as the precursors, both
enantiomers of xestodecalactone A as well as the racemic compound were obtained. Comparison of these synthetic products with
the natural product bycircular dichroism (CD) spectroscopyand byHPLC on a chiral phase revealed the natural product to have
the (R)-configuration.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The xestodecalactones A (1), B (2a) and C (2b) are
secondarymetabolites of an isolate of the fungus Peni-
cillium cf. montanense obtained from the marine sponge
Xestospongia exigua.1 Structurally, they constitute
10-membered macrolides with a fused 1,3-dihydroxy-
benzene ring. Xestodecalactone B (2a) has been shown
to exhibit antifungal activityagainst Candida albicans.2
The constitutions and, in the case of 2a and 2b, relative
configurations of these compounds, initiallyassigned to
a far degree byusing hyphenated HPLC techniques like
LC–MS/MS and LC–NMR, were subsequentlycon-
firmed off line, after isolation of the compounds. The
stereostructures of the xestodecalactones were investi-
gated byHPLC coupled to circular dichroism (CD)
spectroscopyin combination with quantum chemical
CD calculations. The absolute configurations, however,
could not be unambiguouslyattributed, due to the
conformational flexibilityof the lactone ring and the
occurrence of pseudoenantiomeric conformations with
near-identical energetic contents but opposite CD con-
tributions, in combination with the unprecedented
structural type, thus not permitting a simple empirical
comparison with related compounds of known absolute
configuration.1–3
Previouslydescribed fungal metabolites structurally
related to the xestodecalactones are curvularin (3),4
which is the 12-ring homologue of 1, and sporostatin
(4),5 which differs from 1 onlybyhaving an additional
double bond in the lactone ring. While the former is
known to have the (S)-configuration,6 the configuration
of 4 has not yet been determined (Fig. 1).
OH
O
O
Me
HO
O
O
1
OH
OH
O
OH
OH
OH
O
9
9
O
O
11
11
Me
Me
Me
HO
HO
HO
HO
O
O
2b
2a
O
OH
O
*
O
4
Me
O
O
Keywords: Xestodecalactones; Total synthesis; Absolute configuration;
Natural products; Chiral phase; Circular dichroism spectroscopy.
q Supplementarydata associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.02.005
3
Figure 1. Macrocyclic benzo-annellated lactones from fungi: xesto-
decalactone A (1), B (2a) and C (2b), curvularine (3) and sporostatin
(4).
* Corresponding author. Tel.: +49-931-888-5323; fax: +49-931-888-
4755; e-mail: bringman@chemie.uni-wuerzburg.de
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved
doi:10.1016/j.tetlet.2004.02.005

2830
G. Bringmann et al. / Tetrahedron Letters 45 (2004) 2829–2831
In this paper, we report on the assignment of the
absolute configuration of xestodecalactone A (1), byits
stereochemicallyunequivocal total synthesis, both as its
S- and its R-enantiomer, and as the respective racemate,
and comparison of these three synthetic products with
natural xestodecalactone A byCD spectroscopyand by
chromatographyon a chiral phase.
olytic O-debenzylation using Pd/C (10%) as the catalyst
eventuallycompleted the first synthesis of racemic xesto-
decalactone A (rac-1).
For the analogous synthesis of R- and S-xestodecalac-
tone A, (R)-1 and (S)-1, enantiopure methyl 5-hy-
droxyhexanoate (6) was required in both enantiomeric
forms. Compounds (S)-6 and (R)-6 were synthesized
from the acetonides of methyl (2R,3S)-dihydroxybuty-
rate, (2R,3S)-11, and of its enantiomer, (2S,3R)-11,
respectively(see Scheme 2), following a known proce-
dure.12 Reduction of the respective enantiomer of 11,
Swern oxidation, and Wittig reaction gave the aceto-
nides of the respective methyl 4,5-dihydroxy-2-hexeno-
ate, (4S,5S)- and (4R,5R)-12. In contrast to the
literature, these compounds could, even with an excess
of magnesium, not be completelyreduced to S- and R-6,
but onlyto a mixture of regioisomeric methyl 5-hydr-
oxy-2- and -3-hexenoates. Conversion of this mixture to
the respective enantiomer of 6 was achieved byhydro-
genation with Pd/C as the catalyst under atmospheric
pressure. As before for rac-6, S- and R-6 were smoothly
transformed to S- and R-1, respectively.
In analogyto a snythetic strategydeveloped for the
synthesis of the related, but larger ring system of cur-
7
vularin (3) byBracher et al. compound 1 was built up
from (3,5-dibenzyloxyphenyl)acetic acid (7) and methyl
5-hydroxyhexanoate (6). For a first, exploratorysny-
thesis of racemic xestodecalactone A (rac-1), rac-6 was
easilyobtained from 5-oxohexanoic acid ( 5) byreduc-
tion with sodium borohydride and treatment of the
product with a cation exchanger (Bayer, Lewatit SC108,
Hþ form) in methanol (see Scheme 1).8
Esterification of the aromatic acid building block 7 with
rac-6 gave the diester rac-8 in 79% yield.9 Since the ring
closure required the presence of a free terminal acid
function, the methyl ester group of 8 was selectively
7;10;11
cleaved byreaction with NaCN in HMPA,
deliv-
ering the carboxylic acid rac-9 in 80% yield. Ring closure
byintramolecular aclyation was achieved in TFA/
TFAA resulting in the dibenzylether rac-10 of xesto-
decalactone A. The yield of this reaction was 42%,
which was thus markedlyhigher than the 15% iyeld
reported for the corresponding cyclization reaction in
the synthesis of curvularin (3).7 Subsequent hydrogen-
With (R)-, (S)- and rac-1 available, these synthetic
products could now be stereochemicallycompared with
natural xestodecalactone A, byHPLC analsyis on a
chiral phase (Chiralcel OD-RH 4.6 · 150 mm; eluents:
water + 0.05% TFA (A) and MeCN (B); linear gradient:
O
O
O
O
O
Me S
Me R
R
S
CO2H
Me
CO2Me
CO2Me
(2R,3S)-11
(2S,3R)-11
5
according to lit.12
OBn
OH
CO2Me
+
Me
COOH
BnO
O
O
O
O
rac-6
7
S
R
Me S
Me R
CHCO2Me
CHCO2Me
i
(4S,5S)-12
(4R,5R)-12
1) 30 eq Mg, MeOH
2) Pd/C, H2
HO2C
O
MeO2C
O
OBn
OBn
ii
OH
OH
O
O
S
R
BnO
O
Me
Me
Me
BnO
O
Me
OMe
OMe
rac-9
rac-8
rac-1
(S)-6
(R)-6
iii
asin Scheme 1
OBn
O
O
OH
O
OH
O
iv
O
O
BnO
O
Me
R
S
Me
HO
Me
HO
O
O
rac-10
S-1
R-1
Scheme 1. Reagents and conditions: (i) DCC, DMAP, CH2Cl2, 79%;
(ii) NaCN, HMPA, 80%; (iii) TFA, TFAA, 42%; (iv) Pd/C, H2, 36%.
Scheme 2.

G. Bringmann et al. / Tetrahedron Letters 45 (2004) 2829–2831
2831
€
tance with the synthesis, and Dr. E. Gunther, Zentaris
AG, for useful suggestions. This work was generously
rac-1
R-1
supported bythe BMBF (Bundesministerium f ur Bil-
€
dung, Wissenschaft und Forschung, project no.
03F0239A and Center of Competence BIOTECmarin)
and bythe Fonds der Chemischen Industrie.
S-1
References and notes
natural 1
1. Edrada, R. A.; Heubes, M.; Brauers, G.; Wray, V.; Berg,
€
€
A.; Grafe, U.; Wohlfarth, M.; Muhlbacher, J.; Schau-
mann, K.; Sudarsono; Bringmann, G.; Proksch, P. J. Nat.
Prod. 2002, 65, 1598–1604.
10
15
t [min]
Figure 2. HPLC of rac-1, (R)-1, and (S)-1, as well as natural xesto-
decalactone A on a chiral phase.
2. Bringmann, G.; Proksch, P.; Edrada, R.A.; Heubes, M.;
€
Gunther, E. U.S. Patent Appl. U.S. 2003216354 (2003).
3. Part of this work has been reported in preliminaryform:
Bringmann, G.; Lang, G. In Marine Molecular Biotech-
€
nology; Muller, W. E. G., Ed.; Springer: Berlin, 2003; pp
89–116.
0 min––20% B, 30 min––35% B; flow rate: 0.5 mL/min).
The racemic material, rac-1, gave two well separated
peaks for the two enantiomers (R)-1 and (S)-1 (see Fig.
2), eluting after 14.5 and 13.9 min, respectively, as clari-
fied bychromatographic comparison with the pure
synthetic enantiomers. By its retention time and with the
help of co-elution experiments, natural xestodecalactone
A was shown to possess the (R)-configuration. This
result was confirmed bythe identical CD spectra of ( R)-
1 and natural xestodecalactone A.13 The xestodecalac-
tones B and C (2a and 2b) both have similar CD spectra
as 1,1 so that an (11R)-configuration of these com-
pounds––and thus 9S,11R for 2a and 9R,11R for 2b––
can be tentativelyassumed.
4. Musgrave, O. C. J. Chem., Soc. 1956, 4301–4305.
5. Kinoshita, K.; Sasaki, T.; Awata, M.; Takada, M.;
Yaginuma, S. J. Antibiot. 1997, 50, 961–964.
6. Gerlach, H. Helv. Chim. Acta 1977, 60, 3039–3044.
7. Bracher, F.; Schulte, B. Liebigs Ann. Recl. 1997, 1979–
1982.
8. Machleidt, H.; Cohnen, E.; Tschesche, R. Liebigs Ann.
Chem. 1962, 655, 70–80.
9. All new compounds were fullycharacterized. For example
20
S-9: ½aŠ þ 4:1 (c 0.76, CHCl3); 1H NMR (400 MHz,
D
CDCl3) d ¼ 1:15 (d, J ¼ 6:2 Hz, 3H, OCHCH3), 1.50–1.70
(m, 4H, CH2), 2.25 (m, 2H, CH2), 3.45 (s, 2H, ArCH2),
4.85 (m, 1H, OCHCH3), 4.95 (s, 4H, OCH2Ar), 6.46 (m,
3H, ArH), 7.25–7.40 (m, 10H, ArH); 13C NMR (100 MHz,
CDCl3) d ¼ 20:2, 20.9, 33.9, 35.4, 42.3, 70.5, 71.4, 101.3,
108.9, 136.7, 137.2, 127.9, 128.4, 129.0, 160.4, 171.4, 178.7;
MS (ESI pos.) m=z 463 [M+H]þ; elemental analysis (%):
calcd for C28H30O6: C 72.71, H 6.54; found: C 72.51, H
6.79.
Interestingly, natural xestodecalactone A (1) thus pos-
sesses the opposite configuration at C-11 as compared to
6
its configurationallyassigned 12-ring homologue, (S)-
curvularin (3).
10. Caution! Formation of free HCN during acidic workup.
€
11. Muller, P.; Siegfried, B. Helv. Chim. Acta 1974, 57, 987–
994.
12. Lee, G. H.; Pak, C. S. Bull. Korean Chem. Soc. 1999, 20,
619–620.
Acknowledgements
€
€
We thank Professor P. Proksch, Universitat Dusseldorf,
for providing us samples of natural xestodecalactones,
G. Ocloo, Universityof Cape Coast, Ghana, for assis-
13. CD data of R-1 (c 0.1, MeOH): De197 þ6:6, De214 þ0:3,
20
De220 þ1:2, De264 )5.0, De314 þ6:3 cm2/mol; ½aŠ þ56:8 (c
D
0.24, CHCl3).