A new procedure for the preparation of β-keto-δ-lactones from sugars and their transformation into glycosyl acceptors in disaccharides synthesis

Article abstract of DOI:10.1021/ol991176c

(matrix presented) Glycals are effective starting materials for the synthesis of enantiopure β-ketone-δ-lactones. They are easily transformed, through a two-step, one-pot reaction, into the corresponding α,α′-dioxothiones which in turn can be quantitative

Full text of DOI:10.1021/ol991176c

ORGANIC
LETTERS
2000
Vol. 2, No. 3
251-253
A New Procedure for the Preparation of
â-Keto-δ-lactones from Sugars and
Their Transformation into Glycosyl
Acceptors in Disaccharides Synthesis
Alessandra Bartolozzi, Giuseppe Capozzi,* Stefano Menichetti, and
Cristina Nativi*
Centro CNR “Chimica dei Composti Eterociclici”, Dipartimento di Chimica Organica,
UniVersita’ di Firenze, Via Gino Capponi, 9 I-50121 Firenze, Italy
capozzi@chimorg.unifi.it
Received October 22, 1999
ABSTRACT
Glycals are effective starting materials for the synthesis of enantiopure â-ketone-δ-lactones. They are easily transformed, through a two-step,
one-pot reaction, into the corresponding r,r′-dioxothiones which in turn can be quantitatively trapped with dienophiles in inverse electron-
demand [4 + 2] cycloadditions. The reaction of dioxothione 8b with endo and exo glucals allowed the elaboration of a new protocol to prepare
2-thio- or 2-deoxydisaccharides stereoselectively.
â-Ketolactones are crucial compounds either as final products
or as precursors in the synthesis of challenging targets.1
Among the few procedures reported for their preparation,
the most common rely on aldol condensations2 or Dieckman
cyclizations.3 In the course of our research we had to face
the problem of preparing â-keto-δ-lactones with two ste-
reocenters in an enantiopure form, to be used as precursors
of heterodienes in Diels-Alder reactions, toward the syn-
thesis of an analogue of the GM3 ganglioside lactone4 (Figure
1).
stereocenters) made them unreliable for our purposes. In
dealing with our target, carbohydrates are highly attractive
Unfortunately, the drawbacks presented by known meth-
ods2,3 to synthesize â-keto-δ-lactones (undesired side lac-
tonizations or low selectivity in the formation of new
(1) (a) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle, F.
T. Synlett 1998, 869-872. (b) Evans, D. A.; Fu, G. C. J. Org. Chem. 1990,
55, 5678. (c) Seebach, D.; Meyer, H. Angew. Chem. 1974, 40, 86.
(2) (a) Sato, M.; Sugita, Y.; Abiko, Y.; Kaneko, C. Tetrahedron:
Asymmetry 1992, 3, 1157-1160. (b) Schlessinger, R. H.; Pettus, L. H. J.
Org. Chem. 1998, 63, 9089-9094. (c) Kashihara, H.; Shinoki, H.; Suemune,
H.; Sakai, K. Chem. Pharm. Bull. 1986, 34, 4527-4532.
(3) Ge, P.; Kirk, K. L. J. Org. Chem. 1996, 61, 8671-8673.
Figure 1. Structure of the GM3 ganglioside lactone (A) and of
the GM3 ganglioside lactone analogue (B).
(4) Regarding GM3 lactone and its biological role, see: (a) Hamilton,
W. B.; Helling, F.; Lloyd, K. O.; Livingston, P. O. Int. J. Cancer 1993, 53,
566. (b) Kojima, N.; Hakomori, S. J. Biol.Chem. 1991, 266, 17552-17558.
10.1021/ol991176c CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/13/2000

Scheme 1. Synthesis of â-Keto-δ-lactones from Glycals
Scheme 3. Transfer of Disaccharides Synthesis
a t-BDMSOTf, py, 0 °C, 70% (gluco), >95% (galacto). b BnBr,
NaH, DMF, rt, 3h. c TBAF, DMF, rt, 4 h, 98% (gluco), 97%
(galacto) for two steps. d PivCl, py, CH2Cl2, rt., 8h, 74% (2a), 70%
(2b). e 3a: HCl, THF/H2O, 40 °C, 6 h, 69%. 3b: Bu4NHSO4,
CH3CN/H2O, 65 °C, 15 h, 72%. f Ag2CO3-Celite, benzene, 80 °C,
3 h, 74% (5a), 97% (5b). g DMSO, Et3N, (CF3CO)2O, -70 °C, 1
h, 86% (4a), 87% (4b).
chiral sources. To our knowledge there is only one literature
method regarding the preparation of â-keto-δ-lactones using
carbohydrates3 as “chirons”.5
In this Letter we describe a new procedure for the
preparation of â-keto-δ-lactones which takes advantage of
carbohydrates as starting materials and is used to carry out
a CHCl3, rt, 5 h (11, 76%; 14, 75%). b Ra/Ni, THF, rt, 1 h, 58%.
an easy and efficient transformation of the monosaccharide
moiety. Glycals 16 were selectively protected to give 2 which
smoothly afforded 3, the key intermediates to the desired
â-keto-δ-lactones 4 (Scheme 1).
Scheme 2. Oxothione for Cycloadditions with Ethyl Vinyl
Ether
The oxidation sequence of the two hydroxyl groups of the
lactols 3 was crucial for the successful formation of 4. In
fact, when 3 underwent oxidation under Swern conditions,
to be directly transformed into 4, the R,â-unsaturated lactones
6 were isolated as single products. On the other hand, when
the same oxidation was performed with PCC, PDC, or
SO3.py, we only observed decomposition of the starting
material.
To circumvent these problems, the two hydroxyl groups
were oxidized independently, selecting in the first step an
oxidant allowing the chemoselective transformation of the
anomeric hydroxyl group in the presence of the unprotected
OH at C-3. For this purpose the hydroxy lactols 3 were
(5) Hanessian, S. Total Synthesis of Natural Products: The ‘Chiron‘
Approach; Pergamon Press: Oxford, 1983.
(6) Glucal 1a and galactal 1b can be prepared from the corresponding
triacetyl derivatives or from the pentaacetylglucose and pentaacetylgalactose,
respectively.7
a PhthNSCl, rt, CHCl3, >95%. b Py, CHCl3. c Ethyl vinyl ether,
CHCl3, rt, 8 h, (9a, 79%; 9b, 88%).
(7) Somsa´k, L.; Ne´meth, I. J. Carbohydr. Chem. 1993, 12, 679-684.
252
Org. Lett., Vol. 2, No. 3, 2000

treated with Ag2CO3 on Celite8 to obtain the hydroxy lactones
5 in high yield (5a, 74%; 5b, 97%). The subsequent oxidation
of 5 using Swern’s conditions gave the enantiomerically pure
â-keto-δ-lactones 49 (4a, 86%; 4b, 87%).10
In conclusion, we have devised a new procedure to prepare
enantiopure â-keto-δ-lactones from carbohydrates which
makes them available for use as new glycosyl acceptors for
the synthesis of 2-thio- or 2-deoxydisaccharides.16
To test whether â-keto-δ-lactones could be employed as
precursors of disaccharides through cycloaddition reactions,
derivatives 4 were converted to 1,4-oxathiins 9 by means of
ethyl vinyl ether. By following a previously described
procedure,11 treatment of 4 with phthalimidosulfenyl chloride
afforded sulfenamides 7; upon addition of pyridine the latter
gave the transient R,R′-dioxothiones 8 which were directly
trapped in situ by ethyl vinyl ether. The inverse electron-
demand Diels-Alder reaction between 8 and ethyl vinyl
ether allowed for isolation of the cycloadducts 9 as single
regioisomers,11,12 in a 1/1 diasteromeric ratio (Scheme 2).
As depicted in Scheme 3, the cycloaddition of oxothione 8b
with tribenzyl glucal 10 afforded 11 as a single regio- and
stereoisomer. Desulfurization of 11, carried out with Raney/
Ni at room temperature,11 gave the corresponding 2-deoxy
disaccharide 12.
Acknowledgment. This research was carried out within
the framework of the National Project Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni supported by
the Ministero dell’Universita’ e della Ricerca Scientifica e
Tecnologica, Rome, and by the University of Firenze.
Supporting Information Available: EA as well as 1H and
13C NMR data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL991176C
again to -78 °C. A solution of 5b (0.17 mmol) in dry CH2Cl2 (2.0 mL)
was added and the reaction mixture stirred at -60 °C for 45 min. After
this time Et3N (1.36 mmol) was slowly added and the solution so obtained
was gently warmed to room temperature, dissolved in dichloromethane,
washed with brine, and dried over Na2SO4. The organic solvent was removed
under reduced pressure, and the crude material was purified on a silica gel
column (hexane/ethyl acetate 2/1) to yield 4b (50 mg, 87%): 1H NMR
(CDCl3) δ 7.38-7.26 (m, 5H), 4.93-4.87 (A part of an AB system, J )
12.1 Hz, 1H), 4.68 (m, 1H), 4.61-4.54 (B part of an AB system, J ) 12.1
Hz, 1H), 4.36 (AB part of an ABX system, J ) 12.1 Hz, 2H), 4.09 (d, J )
The procedure was also successfully employed with the
exoglucal 13,13 affording the spiro derivatives 14a and 14b,
which were obtained as a 2/1 mixture of stereoisomers.14 It
is readily apparent that 14b constitutes the core structure of
the GM3 ganglioside lactone analogue B.4,15
1
4.4 Hz, 1H), 3.56 (AB system, J ) 20.5 Hz, 2H), 1.14 (s, 9H); H NMR
(8) Fetizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972, 4445-
4448.
(9) No C-4 epimerization product was ever detected under the reported
reaction conditions.
(DMSO) δ 11.95 (s, 1H), 7.39-7.28 (m, 5H), 5.01 (s, 1H), 4.76-4.55 (m,
3H), 4.38-4.24 (m, 2H), 4.03 (d, J ) 2.5 Hz, 1H), 1.12 (s, 9H); 13C NMR
(CDCl3) δ 197.6 (C-3), 177.8, 165.8 (C-1), 135.9, 128.8, 128.7, 128.6, 128.4,
128.3, 74.8, 74.6, 72.9, 61.7, 44.7, 38.7, 26.9. Anal. Calcd for C18H28O6:
C, 63.49; H, 8.30. Found: C, 63.80; H, 8.01.
(10) Representative Procedure. Oxidation of 4-O-Benzyl-2-deoxy-5-
O-pivaloyl-D-galactopyranoside (3b) to the â-Ketolactone 4b. To a
solution of 3-hydroxylactol 3b (0.41 mmol) in dry benzene (4 mL) was
added 683 mg of silver carbonate on Celite. The mixture was refluxed under
vigorous stirring for 2.5 h. After the reaction was completed, the reaction
was cooled to room temperature and filtered through a pad of Celite. After
removal of the solvent, the crude oil was chromatographed on silica gel
(ethyl acetate/hexane 1/1) to yield the â-hydroxylactone 5b (97%) which
was fully characterized as the acetyl derivative: 1H NMR (CDCl3) δ 7.38-
7.26 (m, 5H), 5.16 (td, J ) 10.0, 2.0 Hz, 1H), 4.71 (AB system, J ) 11.4
Hz, 2H), 4.50 (td, J ) 6.0, 2.0 Hz, 1H), 4.39-4.19 (m, 2H), 4.08 (t, J )
2.0 Hz, 1H), 2.94 (d, J ) 9.1 Hz, 2H), 2.05 (s, 3H), 1.01 (s, 9H); 13C NMR
(CDCl3) δ 178.0, 170.0, 167.4 (C-1), 137.0, 128.6, 128.3, 127.9, 76.8, 74.8,
71.1, 69.0, 62.3, 38.7, 31.9, 27.1, 20.9. Trifluoroacetic anhydride (1.03
mmol) was added dropwise to a mixure of DMSO (3.6 mmol) and dry
CH2Cl2 (1.0 mL) previously cooled to -78 °C; a white precipitate formed.
The suspension was warmed to -70 °C, stirred for 15 min, and then cooled
(11) (a) Capozzi, G,; Franck, R. W.; Mattioli, M.; Menichetti, S.; Nativi,
C.; Valle, G. J. Org. Chem. 1995, 60, 6416-6426. (b) Capozzi, G.; Dios,
A.; Franck, R. W.; Geer, A.; Marzabadi, C.; Menichetti, S.; Nativi, C.;
Tamarez, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 777-779.
(12) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.; Raffaelli, B.
Chem. Eur. J. 1999, 5, 1748-1754.
(13) Bartolozzi, A.; Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.;
Paolacci, B. A. J. Org. Chem. 1999, 64, 6490-6494.
(14) Compunds 14a and 14b were perfectly separated by chromatography
on silica gel.
(15) For other examples of GM3 ganglioside lactone analogues, see: (a)
Ray, A. K.; Nilsson, U.; Magnusson, G. J. Am. Chem. Soc. 1992, 114,
2256-2257. (b) Tietze, L. F.; Keim, H. Angew. Chem., Int. Ed. Engl. 1997,
36, 1615-1617.
(16) All new compouds had EA and proton and carbon NMR data
consistent with their structures.
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