Enantioselective synthesis of furo[2,3-b]furans, a spongiane diterpenoid substructure

Article abstract of DOI:10.1021/ol051457m

(Chemical Equation Presented) A short and enantioselective synthesis of cis-fused 5-oxofuro[2,3-b]furans, being found in many spongiane diterpenoid natural products, is reported starting from inexpensive methyl 2-furoate. Moreover, the acid-catalyzed rear

Full text of DOI:10.1021/ol051457m

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5353-5356
Enantioselective Synthesis of
Furo[2,3-b]furans, a Spongiane
Diterpenoid Substructure
Roland Weisser, Weimin Yue, and Oliver Reiser*
Institut fu¨r Organische Chemie der UniVersita¨t Regensburg, UniVersita¨tsstr. 31,
D-93053 Regensburg, Germany
oliVer.reiser@chemie.uni-regensburg.de
Received June 22, 2005
ABSTRACT
A short and enantioselective synthesis of cis-fused 5-oxofuro[2,3-b]furans, being found in many spongiane diterpenoid natural products, is
reported starting from inexpensive methyl 2-furoate. Moreover, the acid-catalyzed rearrangement of the furo[2,3-b]furan framework A to B is
observed for some derivatives, suggesting a simple connection between natural products differing in the absolute configuration of the 3a,6a
ring junction.
Sponges are marine organisms expressing a large number
of natural compounds, which display interesting biological
properties such as antibacterial or cytotoxic activities.1 A
scarcely explored subgroup of spongiane diterpenoids shares
the structural motive of a cis-fused 5-oxofuro[2,3-b]furan
unit 1, found, e.g., in macfarlandin C (2)2 or in norrisolide
(3), which shows a unique interference with the Golgi
complex (Figure 1).3 Especially challenging in the latter two
structures is the placement of a bulky group in 3-position
on the concave face of the bicyclic system.
examined for biological activity at all, which is probably
due to their limited availability.
In contrast, the cheloviolenes A (4a) and B (4b),4 which
differ from all of the other known 5-oxofuro[2,3-b]furans
in their absolute stereochemistry at the 3a,6a ring junction,
and many other spongiane diterpenoids have not yet been
(1) Betancur-Galvis, L.; Zuluaga, C.; Arno´, M.; Gonza´lez, M. A.;
Zaragoza´, R. J. J. Nat. Prod. 2002, 65, 189-192.
(2) Molinski, T. T.; Faulkner, D. J.; He, C.-h.; Van Duyne, G. G.; Clardy,
J. J. Org. Chem. 1986, 51, 4564-4567.
(3) (a) Brady, T. P.; Wallace, E. K.; Kim, S. H.; Guizzunti, G.; Malhotra,
V.; Theodorakis, E. A. Bioorg. Med. Chem. Lett. 2004, 14, 5035-5039.
(b) Hochlowski, J. E.; Faulkner, D. J. J. Org. Chem. 1983, 48, 1141-
1142; Bergquist, P. R.; Bowden, B. F.; Cambie, R. C.; Craw, P. A.; Karuso,
P.; Poiner, A.; Taylor, W. C. Aust. J. Chem. 1993, 46, 623-632.
(4) Bergquist, P. R.; Bowden, B. F.; Cambie, R. C.; Craw, P. A.; Karuso,
P.; Poiner, A.; Taylor, W. C. Aust. J. Chem. 1993, 46, 623-632.
Figure 1. Natural products with 5-oxofuro[2,3-b]furan unit.
10.1021/ol051457m CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/03/2005

Few strategies for the synthesis of furo[2,3-b]furans have
been reported,5,6 with only one report making use of asym-
metric catalysis.5a Most related to our work, Theodorakis and
co-workers developed an elegant method to convert cyclo-
propanes 6 to the 5-oxofuro[2,3-b]furan 7 (Scheme 1);
As a proof of concept, 9 was hydrogenated, which
proceeded exclusively from the convex face of the bicyclic
framework to yield 10 as a single stereoisomer in 86% yield.
Subsequent rearrangement to 11 (74%) using 2 M hydro-
chloric acid in 1,4-dioxane gave rise to the parent 5-oxofuro-
[2,3-b]furan framework in only three steps from inexpensive
methyl 2-furoate (8) in enantiomerically pure form (Scheme
2).
Scheme 1
Scheme 2
however, in all derivatives reported subsituents in 3-position
are located on the conVex face of the bicyclic ring system.6
We report here a different strategy to compounds of type 6
and their subsequent rearrangement, giving not only access
to the 5-oxofuro[2,3-b]furan framework with substituents in
the 3-position on the concaVe face of the bicyclic framework,
a pattern being found in most spongiane diterpenoids such
as 2 or 3, but also to 3a,6a-epimers, a pattern being found
in the cheloviolenes 4.
We recently reported the copper-bisoxazoline-catalyzed,
enantioselective cyclopropanation of methyl 2-furoate (8) to
97 as a starting point toward the synthesis of γ-butyrolactone
natural products such as paraconic acids,8,9 xanthanolides,
guaianolides, and eudesmanolides.10 We envisioned 9 to be
a versatile building block toward a broad variety of deriva-
tives of 6, which could be subsequently converted to
5-oxofuro[2,3-b]furans.
(5) (a) Trost, B. B.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543-
3544. (b) Petit, F.; Furstoss, R. Synthesis 1995, 1517-1520. (c) Petit, F.;
Furstoss, R. Tetrahedron: Asymmetry 1993, 4, 1341-1352. (d) Uchiyama,
M.; Hirai, M.; Nagata, M.; Katoh, R.; Ogawa, R.; Ohta, A. Tetrahedron
Lett. 2001, 42, 4653-4656. (e) Clive, D. L. J.; Subedi, R. Chem. Commun.
2000, 237-238. (f) Jalali, M.; Boussac, G.; Lallemand, J.-Y. Tetrahedron
Lett. 1983, 24, 4307-4310. (f) Allegretti, M.; D’Annibale, A.; Trogolo, C.
Tetrahedron 1993, 49, 10705-10714. (g) Harrison, T.; Pattenden, G.;
Myers, P. L. Tetrahedron Lett. 1988, 29, 3869-3872. (h) Malanga, C.;
Mannucci, S.; Ladicci, L. J. Chem. Res., Synop. 2001, 97-99. (j) Enders,
D.; Vazquez, J.; Raabe, G. Chem. Commun. 1999, 701-702. (k) Enders,
D.; Vazquez, J.; Raabe, G. Eur. J. Org. Chem. 2000, 893-901. (l) Brady,
T. P.; Kim, S. H.; Wen, K.; Theodorakis, E. A. Angew. Chem., Int. Ed.
2004, 43, 739-742.
The structure of 11, having the carboxylic acid group
positioned on the concave face of the bicyclic system, was
unambiguously assigned by NOE experiments and by X-ray
structure analysis. Conversion of the carboxylic acid to the
acetoxy derivative 13, being typical in many spongiane
diterpenoids, was accomplished in a four-step sequence from
11 via its methyl ketone 12, which underwent diastereose-
lective Baeyer-Villiger oxidation under retention of con-
figuration. Alternatively, 11 could be photochemically
decarboxylated11 with lead tetraacetate under copper(II)
catalysis following a radical pathway to directly yield a
mixture of 13 and epi-13, which could be easily separated
by chromatography.
(6) (a) Kim, C.; Brady, T.; Kim, S. H.; Theodorakis, E. A. Synth.
Commun. 2004, 34, 1951-1965. (b) Kim, C.; Hoang, R.; Theodorakis, E.
A. Org. Lett. 1999, 1, 1295-1297.
(7) (a) Schinnerl, M.; Bo¨hm, C.; Seitz, M.; Reiser, O. Tetrahedron:
Asymmetry 2003, 14, 765-771. (b) Bo¨hm, C.; Reiser, O. Org. Lett. 2001,
3, 1315-1318. (c) Bo¨hm, C.; Schinnerl, M.; Bubert, C.; Zabel, M.; Labahn,
T.; Parisini, E.; Reiser, O. Eur. J. Org. Chem. 2000, 2955-2965.
(8) Chhor, R. B.; Nosse, B.; So¨rgel, S.; Bo¨hm, C.; Seitz, M.; Reiser, O.
Chem. Eur. J. 2003, 9, 260-270.
(9) ReView: Bandichhor, R.; Nosse, B.; Reiser, O. Top. Cur. Chem. 2005,
243, 43-72.
(10) (a) Nosse, B.; Chhor, R. B.; Jeong, W. B.; Bo¨hm, C.; Reiser, O.
Org. Lett. 2003, 5, 941-944. (b) Jezek, E.; Schall, A.; Kreitmeier, P.; Reiser,
O. Synlett 2005, 915-918.
Following this general strategy, we were next looking for
flexible ways to stereoselectively introduce substituents into
the 3-position of 5-oxofuro[2,3-b]furans (Scheme 3).
Thus, the vinylbromide 15, which we anticipated to be a
versatile building block for functionalization via palladium-
(11) Cf. Bacha, J. D.; Kochi, J. K. J. Org. Chem. 1968, 33, 88-93.
Org. Lett., Vol. 7, No. 24, 2005
5354

framework could again be initiated at room temperature.
However, the expected 28 was accompanied by uncyclized
compounds, and already by small amounts of 23 or 24.
Compound 28 could not be isolated in pure form but was
Scheme 3
1
identified by H NMR of the mixtures (Scheme 4). Upon
Scheme 4
catalyzed cross-coupling reactions, was synthesized from 9
by a bromination/dehydrobromination sequence. Indeed, 15
proved to be amenable for both Suzuki-couplings of aryl-
boronic acids and for Heck-coupling of styrene to give rise
to 16-19 in good yields. Subsequent hydrogenation of the
tetrasubstituted double bond was quite substrate dependent:
While 16 gave excellent yields already in ethyl acetate after
only 1 h, the use of methanol as a solvent and considerable
longer reaction times (2 d) were necessary to achieve at least
satisfying yields in the case of 17 and 19.
Hydrogenation of 18 failed completely under various
conditions, probably due to the additional steric hindrance
of the methoxy group. Nevertheless, in all successful cases
hydrogenation occurred exclusively from the exo-face of the
bicyclus, resulting in highly congested derivatives in which
the aryl and the ester group are forced on the concave side.
X-ray structure analyses of 20 (not shown) and 21 as well
as NOE experiments unambiguously proved these structural
assignments.
refluxing of these mixtures, 23 or 24, respectively, could be
isolated in high yields. Following these conversions by NMR,
signals were observed in agreement with the 2,3-dihydrofuran
26, which could explain the inversion of stereochemistry on
the centers 3a,6a.
The relative stereochemistry of 23 and 24 was assigned
from NOE data, and the absolute stereochemistry of 23 was
proved by an X-ray structure analysis of its (1R)-1-(4-
chlorophenyl)ethylammonium-salt. The latter analysis al-
lowed ruling out that instead of the centers at position 3a
and 6a the positions 2 and 3 were inverted, which would
have also been conceivable under the acidic reaction condi-
tions. Again, 23 could be converted to 30 in a straightforward
manner as previously described for the transformation of 11
to 13 (cf. Scheme 2).
The stereochemistry for the rearrangement of 22, having
a medium sized substituent in 3-position, could be controlled
to some extent (Scheme 5). At room temperature, along with
Similar to 10, acid-induced hydrolysis of 20 or 21 with
concomitant rearrangement to the 5-oxofuro[2,3-b]furan
Org. Lett., Vol. 7, No. 24, 2005
5355

later on.4,13 Our findings in the synthesis of 23, 24, 31, and
32 suggest the close relation between the two 5-oxofuro-
[2,3-b]furan frameworks found in nature and that under acidic
conditions their rearrangement, e.g., that of dendrillolide A
(34) to cheloviolene A (4a), should be feasible (Figure 2).
Scheme 5
Figure 2. Possible chemical relation between cheloviolene A and
dendrillolide A.
In conclusion, a synthetic strategy to 5-oxofuro[2,3-b]-
furans was developed that allows the versatile introduction
of carbon substituents in 3-position. The steric size of these
groups has a decisive influence on the stereochemistry of
the 3a,6a-ring junction, giving rise to bicyclic frameworks
found in spongian diterpenoids such as 2-4. The biological
evaluation of the analogues of these natural products
presented here and the application of the synthetic strategy
toward spongians is currently underway.
some ring opened, not lactonized products, mainly 31 was
formed, which could be isolated in pure form by crystal-
lization in moderate yield (37%). Under refluxing conditions
32 was predominantly formed, which unfortunately could
not be separated from 31. Moreover, refluxing 31 in 6 M
HCl and 1,4-dioxane resulted in the predominant formation
of 32 in quantitative yield.
Oxidative decarboxylation of 31 proceeded quantitatively
to give rise to 33 as an inseparable 1:3 R/â-mixture.
There had been considerable difficulties in the structure
elucidation of 5-oxofuro[2,3-b]furan natural products with
respect to the stereocenters at the 3a,6a ring junction. For
example, for both cheloviolene A (4a) as well as dendrillolide
A (33) the original structural assignment12 had to be revised
Acknowledgment. This work was supported by the
International Quality Network Medicinal Chemistry (DAAD/
BMBF), the Fonds der chemischen Industrie, and through
generous chemical gifts of Degussa AG. We are grateful to
Dr. M. Zabel for carrying out the X-ray structure analyses
presented in this paper.
Supporting Information Available: Analytical data, CIF
files of all X-ray structures, and copies of spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL051457M
(12) (a) Bobzin, S. C.; Faulkner, D. J. J. Nat. Prod. 1991, 54, 225-232.
(b) Sullivan, B.; Faulkner, D. J. J. Org. Chem. 1984, 49, 3204-3206.
(13) Bobzin, S. C.; Faulkner, D. J. J. Org. Chem. 1989, 54, 5727-5731.
5356
Org. Lett., Vol. 7, No. 24, 2005