Replicative durons: Stereoselective Synthesis of Oligo-Tetrahydrofuranic Lactones via C-Glyeosylation with [(Trimethylsilyl)oxy]furan

Full text of DOI:10.1021/jo970212n

3428
J . Org. Chem. 1997, 62, 3428-3429
Rep lica tive Ch ir on s: Ster eoselective
Syn th esis of Oligo-Tetr a h yd r ofu r a n ic
La cton es via C-Glycosyla tion w ith
[(Tr im eth ylsilyl)oxy]fu r a n
Bruno Figade`re,* J ean-Franc¸ois Peyrat, and
Andre´ Cave´
Laboratoire de Pharmacognosie, associe´ au CNRS
(BIOCIS), Universite´ Paris-Sud, Faculte´ de Pharmacie, rue
J ean-Baptiste Cle´ment, 92296 Chaˆtenay-Malabry, France
F igu r e 1.
Received February 5, 1997
Natural oligo-tetrahydrofuranic compounds such as the
antibiotic ionophores1 and annonaceous acetogenins2 are
widely found from several natural sources. These com-
pounds are of growing biological interest, particularly as
cytotoxic, antitumor, or antiparasitic agents, due to their
new mechanisms of action.3 Indeed, they all show
cytotoxicity ranging from 10-1 to 10-12 µg/mL, depending
both on the cancerous cell lines tested and the structure.2
However, poor specific cytotoxicity has been found for
such products. Therefore, tremendous efforts toward the
preparation of these bioactive products have appeared
in the literature,4 following different strategies dealing
with the stereocontrolled elaboration of contiguous oxy-
genated five-membered heterocycles.5,6 Most of these
approaches are limited to the preparation of stereode-
fined units due to the origin of the starting material(s)
and/or diastereoselective reactions used. Recently, Kein-
an’s group has shown that a large number of diastereo-
mers of a bis-tetrahydrofuranic butyrolactone, which can
be used as key intermediate in the total synthesis of
acetogenins of Annonaceae, could be obtained through
cross-coupling reactions between chiral aldehydes and
chiral phosphorus ylides, followed by a Kennedy oxida-
tion-Williamson cyclization sequence.7 In this paper, we
report that stereomers of these bis-tetrahydrofuranic
butyrolactones may be stereoselectively obtained by
replicative C-glycosylation of anomeric acetoxytetrahy-
drofurans with [(trimethylsilyl)oxy]furan (TMSOF). The
advantage of this approach is that it can also be used to
build up tris-tetrahydrofuranic butyrolactones as well as
to prepare natural acetogenins.
F igu r e 2.
Starting from the protected silyl ether of (-)-nor-
muricatacin 1, (4S,5S)-5-hydroxy-4-pentadecanolide, which
has been prepared in five steps from L-glutamic acid,8
the corresponding acetoxy derivatives 2 were prepared
by reduction of 1 with DIBAL-H at -78 °C in toluene
(96%), followed by treatment with 10 equiv of acetic
anhydride in the presence of triethylamine at room
temperature (92%). Then, addition at 0 °C in anhydrous
diethyl ether to the so obtained mixture of the anomeric
acetates 2, of 1 equiv of TMSOF, in the presence of 10%
molar of trityl perchlorate (TrClO4), afforded a separable
mixture of only two adducts, namely the erythro-trans
and threo-trans desired butenolides A and B in 92%
yields and 60:40 diastereomeric ratio (in favor of the
erythro compound A)9a (Figure 1). Use of different Lewis
acids and/or reaction conditions did not improve this
result. However, treatment of either diastereomer with
triethylamine led to the identical mixture of butenolides
in the same ratio (60:40), through epimerization at C-4.
The stereoselectivity of the reaction so observed may be
rationalized by stereodifferentiation of one face of the
intermediate cyclic oxonium ion due to the steric hin-
drance of the long alkyl chain, whereas the low facial
differentiation of the nucleophile is probably a result of
a thermodynamic equilibrium between both products, as
shown by the epimerization experiment.
* To whom correspondence should be addressed. Fax: (+33) 1 46
83 53 99.
(1) (a) Paterson, I.; Boddy, I. Tetrahedron Lett. 1988, 29, 5301-5304.
(b) Paterson, I.; Craw, P. A. Tetrahedron Lett. 1989, 30, 5799-5802.
(c) Paterson, I.; Boddy, I.; Mason, I. Tetrahedron Lett. 1987, 28, 5205-
5208. (d) Paterson, I.; Tillyer, R. D.; Smaill, J . B.; Paterson, I.; Boddy,
I. Tetrahedron Lett. 1993, 34, 7137-7140.
(2) Cave´, A.; Figade`re, B.; Laurens, A.; Cortes, D. In Progress in
the Chemistry of Organic Natural Products: Acetogenins From An-
nonaceae; Hertz, W., Ed.; Springer-Verlag: Wien, New York, 1997; Vol.
70, pp 81-288.
(3) (a) Espositi, M. D.; Ghelli, A.; Batta, M.; Cortes, D.; Estornell,
E. Biochemistry 1994, 301, 161-167. (b) Friedrich, T.; Van Heek, P.;
Leif, H.; Ohnishi, T.; Forche, E.; Kunze, B.; J ansen, R.; Trowitzsch-
Kienast, W.; Ho¨fle, G.; Reichenbach, H.; Weiss, H. Eur. J . Biochem.
1994, 219, 691-698. (c) Morre´, J .; De Cabo, R.; Farlay, C.; Oberlies,
N. H.; Mc Laughlin, J . L. Life Sci. 1995, 56, 343-348.
(4) (a) Figade`re, B. Acc. Chem. Res. 1995, 28, 359-365. (b) Hoppe,
R.; Scharf, H. D. Synthesis 1995, 1447. (c) For a recent work on
synthetic approaches to acetogenins, see: Marshall, J . A., Hinkle, K.
W. J . Org. Chem. 1996, 61, 4247.
After separation by flash chromatography, the two
butenolides A and B were independently and quantita-
tively hydrogenated over palladium on charcoal in tolu-
ene to lead to the desired butyrolactones 3, and 4. The
stereochemical relationships of the two diastereomers
were determined by NMR studies both on the butenolides
and their saturated analogues and confirmed both by
(5) Koert, U. Synthesis 1995, 115-132.
(6) Harmange, J .-C.; Figade`re, B. Tetrahedron: Asymmetry 1993,
4, 171.
(7) (a) Sinha, S. C.; Sinha, S; Yazbak, A.; Keinan, E. J . Org. Chem.
1996, 61, 7640-7641. (b) Sinha, S. C.; Sinha-Baghi, A.; Yazbak, A.;
Keinan, E. Tetrahedron Lett. 1995, 36, 9257-9260. (c) Sinha, S. C.;
Sinha-Baghi, A.; Keinan, E. J . Am. Chem. Soc. 1995, 117, 1447-1448.
(8) Figade`re, B.; Harmange, J .-C.; Laurens, A.; Cave´, A. Tetrahedron
Lett. 1991, 32, 7539-7542.
(9) (a) Figade`re, B.; Chaboche, C.; Peyrat, J . F.; Cave´, A. Tetrahedron
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S0022-3263(97)00212-0 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 11, 1997 3429
F igu r e 3.
F igu r e 4.
chemical correlation through an alternative and ste-
reospecific synthesis of 49a and comparison of the spec-
troscopic data of 4 with Keinan’s products.7b These
substrates were then separately used in a second se-
quence, namely the reduction-acetylation-C-glycosyla-
tion-hydrogenation transformations using the same
reagents and reaction conditions as described above (70%
overall yield for the four steps), in order to obtain the
corresponding lactones 7-10 possessing an extra tet-
rahydrofuran ring (Figure 2).
It is noteworthy that after the second C-glycosylations
only two adducts (among the four possible) are formed,
which possess the erythro-trans and threo-trans stereo-
chemical relationships across the butenolide-tetrahy-
drofuran pattern. Yields and diastereomeric ratios are
comparable to the former values obtained in the initial
sequence (85% combined chemical yield and dr ) 60:40
in favor of the erythro compound). The stereoselectivity
of the reaction may be rationalized again by invoking the
same effects as those described above. The stereomers
are easily separated by flash chromatography and may
be used, after hydrogenation, as starting material for the
same sequence. For instance, 7 and 9 were separately
used in a new reduction-acetylation-C-glycosylation
sequence (Figure 3).
The expected adducts were obtained in a 60:40 ratio
in favor of the erythro compound but in a lower yield
(60%). After hydrogenation, compound 16 was treated
with HF for removal of the protecting group to yield
alcohol 17 in 92% overall yield for the last two steps.
Even though we did not extend this methodology to
the preparation of tetrakis-tetrahydrofuranic butyro-
lactones, this strategy is probably not limited to the
preparation of the tris-tetrahydrofuranic butyrolactones
and could be extended to the synthesis of oligo-tetra-
hydrofuranic butyrolactones as well.
also be used with substituted TMSOF derivatives, lead-
ing after hydrogenation of the butenolides so obtained,
to 3,4-disubstituted tetrahydrofurans. Consequently, by
combining the different synthons, libraries of oligo-
tetrahydrofuranic butyrolactones may be thus obtained.
Indeed, because of the high cytotoxicity observed with
the natural acetogenins of Annonaceae, structurally
related analogues should be designed and synthesized
in order to obtain more specific chemotherapeutic agents.
In the annonaceous acetogenins field, we have used
compound 18 as a key building block for the preparation
of the C1-C34 fragment of natural deoxyasimicin. In-
deed, lactone 10 after reduction by DIBAL-H at -78 °C
led to the corresponding lactol 18 (94%), which can then
be treated with 1 equiv of the required phosphorus ylide
in the presence of potassium tert-butanolate to afford, via
a Wittig homologation, the desired ethylenic coupled
product 19 (Figure 4). Then this product will lead
through known procedures10 to the natural product
deoxyasimicin.2
In conclusion, the very efficient C-glycosylation of cyclic
oxonium ions with TMSOF allows a straightforward
access to oligo-tetrahydrofurans, due to this excellent
stereoselective and high-yielding reaction. The mild
reaction conditions allow one to prepare a large variety
of oligo-tetrahydrofuranic butyrolactones that can lead
to more elaborate compounds such as the acetogenins of
Annonaceae.
Ack n ow led gm en t. J .F.P. thanks the Ligue Natio-
nale contre le Cancer for a fellowship.
Su p p or tin g In for m a tion Ava ila ble: Physical data of
compounds 1-19 (10 pages).
J O970212N
(10) Vu Thi Tam; Chaboche, C.; Figade`re, B.; Chappe, B.; Bui Chi
It is noteworthy that theoretically this sequence could
Hieu; Cave´ A. Tetrahedron Lett. 1994, 35, 883-886.