A new method for the synthesis of carba-sugar enones (gabosines) using a mercury(II)-mediated opening of 4,5-cyclopropanated pyranosides as the key-step

Article abstract of DOI:10.1016/j.tetlet.2006.07.023

The stereoselective transformation of the cyclopropyl derivative 2, stereoselectively obtained with the Simmons-Smith reaction of methyl 2,6-di-O-benzyl-α-l-threo-hex-4-enopyranoside (1), into gabosines and deoxy-carbahexoses is described. The treatment o

Full text of DOI:10.1016/j.tetlet.2006.07.023

Tetrahedron Letters 47 (2006) 6591–6594
A new method for the synthesis of carba-sugar enones
(gabosines) using a mercury(II)-mediated opening of
4,5-cyclopropanated pyranosides as the key-stepI
a
b
b
Antonino Corsaro,a, Venerando Pistara, Giorgio Catelani, Felicia D’Andrea,
*
`
Roberto Adamoa, and Maria Assunta Chiacchioa
a
`
Dipartimento di Scienze Chimiche, Universita degli Studi di Catania, viale A. Doria 6, Catania 95125, Italy
`
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita degli Studi di Pisa, via Bonanno 33, Pisa 56126, Italy
b
Received 9 June 2006; revised 6 July 2006; accepted 6 July 2006
Available online 31 July 2006
Abstract—The stereoselective transformation of the cyclopropyl derivative 2, stereoselectively obtained with the Simmons–Smith
reaction of methyl 2,6-di-O-benzyl-a-L-threo-hex-4-enopyranoside (1), into gabosines and deoxy-carbahexoses is described. The
treatment of 2 with mercuric trifluoroacetate in dry methanol gives the organomercuric chloride 3, which by demercuration with
lithium aluminum hydride affords the 4-C-deoxy-4-methyl-1,5-bis-glycoside 4. The acid hydrolysis of 4 produces a mixture of the
two diastereoisomeric 2-methyl-cyclohex-2-enones 6 and 7, catalytically reduced to carba-sugars 10 and 11. Structures and stereo-
chemistry of all isolated compounds were determined by 1D and 2D NMR experiments.
Ó 2006 Elsevier Ltd. All rights reserved.
McCasland et al.1a and Ogawa and Suami1b introduced
pseudo-sugars and carba-sugars terms, respectively, to
indicate a class of carbocyclic analogues of monosaccha-
rides containing a methylene group in the place of the
pyranose ring oxygen atom and showing very important
biological activities. Particularly, trihydroxylated cyclo-
hexanone and cyclohexenone carba-sugars, named
gabosines, were isolated from Streptomyces strains by
chemical screenings in the search of new secondary
metabolites from natural sources.2 Gabosines bearing
a methyl substituent, were detected, isolated and struc-
turally characterized, but initially no biological activity
could be found for them. Later, a variety of biological
activities such as plant growth regulating effects,3 and
inhibition of glyoxalase-I4 and glycosidases5 were found.
Recently, Thiericke and co-workers6 discovered weak
DNA-binding properties for A, B, F, N, and O gabo-
sines (Fig. 1) by their so-called biomolecular screening.7
Because of their interesting biological activities, the syn-
thesis of these compounds has stimulated a considerable
interest from organic chemists, who have followed
synthetic strategies involving the transformation of car-
bohydrates to carbocycles8a–c and chemical or enzymatic
elaboration of existing carbocycles.8d–h Furthermore,
gabosines reported in Scheme 1 could be devised as
direct chemical precursors of 6-deoxy-carba-pyranose
derivatives, such as carba-fucopyranose, a potential
Keywords: 4,5-Cyclopropanated sugars; Intramolecular aldol conden-
sation; Gabosines; 6-Deoxy-5a-carba-hexopyranosides.
q Part 21 of the series, ‘Chemical Valorisation of Milk-Derived
Carbohydrates’; for part 20, see Ref. 11.
*
Corresponding author. Tel.: +39 095 7385017; fax: +39 095
580138; e-mail: acorsaro@unict.it
Present address: Bijvoet Center, Department of Bio-organic Chem-
istry, Utrecht University Padualaan 8, 3584 CH Utrecht, The
Netherlands.
Figure 1. Structures of selected gabosines.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.023

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A. Corsaro et al. / Tetrahedron Letters 47 (2006) 6591–6594
Scheme 1. Reagents and conditions: (a) CH2I2, Et2Zn, Et2O; (b) Hg(OCOCF3)2, dry CH3OH, rt then NaCl/H2O; (c) NaBH4, THF, rt; (d)
CF3COOH, CH3CN/H2O, rt and (e) MCPBA, MeOH.
candidate for the inhibition of oligosaccharide process-
ing enzymes.9
meric 2-methyl-cyclohex-2-enones 616 and 7,17 was
obtained, which were isolated, after flash-chromato-
graphy, in 65 and 20% yield, respectively. It could be
reasonably supposed that, in the acid reaction medium,
after the expected formation of the dicarbonyl com-
pound 5, a fast intramolecular aldol condensation takes
place, affording two diastereoisomeric cyclohexanone
intermediates, which subsequently loose water with high
regiochemistry from 2,3-position, to give the a,b-unsat-
urated ketones 6 and 7, the structure and stereochemis-
try of which determined by 1D and 2D (NOE, COSY
and HETCOR) NMR experiments. The 1H NMR spec-
trum of 616 shows a double doublet centred at 6.58 ppm
for the unsaturated H-3 proton which couples with
methyl protons at 1.82 ppm (d, J = 1,5 Hz) and H-4
proton at 4.24 ppm (J = 2.5 Hz). The H-6 proton
Through a project on the elaboration of unsaturated
intermediated derivatives from lactose,10 we have re-
cently studied the cyclopropanation reactions of hex-4-
enopyranosides, such as 1, explaining the stereochemical
aspect of the reaction.11
In this letter, we describe, for the first time, a sequence of
reactions which allows the stereoselective transformation
of a cyclopropyl derivative into gabosines and 6-deoxy-
carbahexoses. To our best knowledge, until now, there
are no examples which use a cyclopropanation reaction
to transform an hexopyranose into a carba-sugar.
The cyclopropyl derivative 2 was obtained in a near
quantitative yield and with a high stereoselectivity11 in
the Simmons–Smith12 reaction of 4-hexenopyranoside
1 with diethyl zinc and diiodomethane, and was treated
with mercuric trifluoroacetate in dry methanol to give,
after exchange with NaCl, the organomercuric chloride
3 with high yield.13 It is noteworthy that the cyclo-
propane ring-opening takes place with the same high,
if not complete, regio- and stereoselectivity previously
reported for the methanolysis of analogous epoxide of
1 leading to 814a (Scheme 1). The crude reaction mixture
was used without purification in the reductive demercu-
ration with lithium aluminium hydride to afford, after
flash-chromatography, the 4-C-deoxy-4-methyl-1,5-bis-
glycoside 415 in 71% yield over three steps from 1. The
structure and the stereochemistry of compound 4 were
appears as a doublet at 3.85 ppm with a large Jax/ax =
11.0 Hz because of the coupling with the adjacent H-5
proton at 4.04 ppm (dd, Jax/eq = 8.0 Hz), which in its
turn couples with the H-4 proton. NOE experiments
confirmed the assigned stereochemistry, showing, in par-
ticular, an enhancement (6%) of the H-6 signal upon
1
irradiation of the H-4 proton, and vice versa. The H
NMR spectrum of 7,17 corresponding to the 2,6-di-O-
benzyl derivative of Gabosine A, shows a double dou-
blet (J = 1.5 and 4.0 Hz) centred at 6.66 ppm for the
unsaturated H-3 proton which couples with methyl pro-
tons at 1.74 ppm and H-4 proton at 4.33 ppm. A dou-
blet with a Jax/eq = 8.0 Hz centred at 4.06 ppm is
apparent for the H-6 proton owing to the coupling with
the adjacent H-5 proton which in its turn resonates as
double doublet at 4.17 ppm. Also in this case, NOE
experiments are in agreement with the assigned stereo-
chemistry, the irradiation of the H-4 proton giving rise
to enhancements of 4.5 and 3.6% of the H-5 and H-6 sig-
nals, respectively, and vice versa. When the hydrolysis of
bis-glycoside 4 was carried out by using a catalytic
amount of trifluoroacetic acid, it stops at the dicarbonyl
compound 5 as pointed out by the 1H NMR spectrum of
the unprocessed reaction mixture, which does not show
any evidence of condensation products, but signals for
the anomeric protons in the 5.20–5.70 ppm range are
characteristic of a complex mixture of tautomeric forms
in solution, which will be the object of further studies.
1
deduced from its H and 13C NMR, COSY and NOE
1
spectra. Particularly, in the H NMR spectrum of 4,
diagnostic signals were doublet (J4,Me = 7.0 Hz) centred
at 0.98 ppm for the methyl protons in 4-position, and a
double quartet for the H-4 proton at 2.44 ppm (J3,4
=
5.0 Hz).
When the bis-glycoside
4 was submitted to the
same hydrolytic conditions (CF3COOH/H2O/CH3CN
0.1:0.5:1, rt, 12 h) as that reported for the transforma-
tion of the bis-glycoside 8 into the corresponding 1,5-
dicarbonyl-hexose 9,14 a mixture of the two diastereoiso-

A. Corsaro et al. / Tetrahedron Letters 47 (2006) 6591–6594
6593
3. Grabley, S.; Wink, J.; Hammann, P.; Giani, C.; Huetter,
K.; Zeeck A. (Hoechst A. G., Fed. Rep. Ger.), PCT Int.
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4. (a) Takeuchi, T.; Chimura, H.; Hamada, M.; Umezawa,
H. J. Antibiot. 1975, 28, 737–742; (b) Douglas, K. T.;
Shinkai, S. Angew. Chem., Int. Ed. Engl. 1985, 24, 31–44.
5. (a) Iwasa, T.; Yamamoto, H.; Shibata, M. J. Antibiot.
1970, 23, 595–602; (b) Suami, T.; Ogawa, S.; Chida, N. J.
Antibiot. 1980, 33, 98–102.
Scheme 2. Reagents and conditions: (a) Pd/C, H2, MeOH; and (b)
Raney/Ni, H2, EtOH.
6. Grabley, S.; Thiericke, R.; Zeeck, A. In Drug Discovery
from Nature; Grabley, S., Thiericke, R., Eds.; Springer:
Berlin, 1999; pp 124–148.
7. (a) Tang, Y.-Q.; Maul, C.; Hofs, R.; Sattler, I.; Feng, S.;
Zeeck, A.; Thiericke, R. Eur. J. Org. Chem. 2000, 149–153;
(b) Hofs, R.; Schoppe, S.; Thiericke, R.; Zeeck, A. Eur. J.
Org. Chem. 2000, 1883–1887.
With the aim of chemically supporting the structure of
6, it was reduced with hydrogen and Pd/C to give, as
unique product, the tri-hydroxy-methylcyclohexanone
10,18 a diastereoisomer of the naturally occurring Gabo-
sines B, F and O (Scheme 2).19 Furthermore, the cata-
lytic hydrogenation of 6 with Ni-Raney determines the
complete reduction of the conjugate system, leading
with high stereoselectivity to a partially debenzylated
carba-sugar isolated with 71% yield and identified
(NMR) as the benzyl 5a-carba-b-L-fucopyranoside
1120 (Scheme 2). The position of the benzyl group was
unequivocally assured with NOE experiments; in partic-
ular, the irradiation of CH2 protons determines the
enhancement of the equatorial H-7 proton (2.1%) and
H-2 proton signals (1.5%), and vice versa.
8. (a) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93,
2779–2831; (b) Lubineau, A.; Billault, I. J. Org. Chem.
1998, 63, 5668–5671; (c) Dalko, D. I.; Sinay, P. Angew.
¨
Chem., Int. Ed. 1999, 38, 773–777; (d) Shing, T. K. M.; Li,
T. Y.; Kok, S. H.-L. J. Org. Chem. 1999, 64, 1941–1946;
(e) Banwell, M. G.; Bray, A. M.; Wong, D. J. New J.
Chem. 2001, 25, 1351–1354; (f) Shinada, T.; Fuji, T.;
Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 8,
1341–1343; (g) Ramana, G. V.; Rao, B. V. Tetrahedron
Lett. 2005, 46, 3049–3051; (h) Alibes, R.; Bayon, P.; De
March, P.; Figueredo, M.; Font, J.; Marjanet, G. Org.
Lett. 2006, 8, 1617–1620.
In conclusion this letter describes a new route for the
preparation of 6-deoxy-carbasugars from a cyclopropa-
nated D-galactose derivative. The key steps of this
synthesis are the stereocontrolled cyclopropanation of
4-hexenopyranoside, the stereoselectivity of the mer-
cury-mediated cyclopropane ring opening and the stereo-
selective reduction of the carbonyl group, which allows
to obtain different isomers of the title compound in a
stereocontrolled manner.
9. Wilkox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108,
3102–3104.
10. Catelani, G.; Corsaro, A.; D’Andrea, F.; Mariani, M.;
`
Pistara, V.; Vittorino, E. Carbohydr. Res. 2003, 338, 2349–
3258.
`
11. Corsaro, A.; Chiacchio, U.; Adamo, R.; Pistara, V.;
Rescifina, A.; Romeo, R.; Catelani, G.; D’Andrea, F.;
Mariani, M.; Attolino, E. Tetrahedron 2004, 60, 3787–
3795.
12. Simmons, H. E.; Cairns, T. L.; Vladuchik, S. A.; Hoiness,
C. M. Org. React. 1973, 20, 1–131.
Recently, this reaction route is carried out with a cyclo-
propanated lactose analogue to 2;11 preliminary results
are like those reported in this letter for the monosaccha-
ride derivative, and therefore they outline a new route
for the stereoselective transformation of lactose into
new and biologically interesting carba-sugars, expand-
ing, thus, the series of applications directed towards an
economical valorisation of this natural disaccharide, a
by-product of the cheese-industry. The results of these
studies will be the object of a next publication.
13. Methyl 2,6-di-O-benzyl-4-deoxy-5-C-methoxy-4-(methyl-
chloromercurio)-b-D-galactopyranoside 3: syrup, 98% yield,
25
½aꢀD +110.5 (c 0.1, CHCl3). Selected NMR data: 1H
(500 MHz, CDCl3) d: 1.29 (t, 1H, J = 12.5 Hz, H7a), 1.54
(dd, 1H, J = 5.5, 12.5 Hz, H7b), 2.58 (dt, 1H, J = 5.5,
12.5 Hz, H4), 3.21 (dd, 1H, J = 7.5, 10.0 Hz, H2), 3.23 (s,
3H, C5OCH3), 4.32 (dd, 1H, J = 5.0, 10.0 Hz, H3), 4.45 (d,
1H, J = 7.5 Hz, H1); 13C (50 MHz, CDCl3) d: 20.11 (C7),
42.65 (C4), 48.37 (C5–OCH3), 56.91 (C1–OCH3), 65.37
(C6), 66.97 (C3), 78.52 (C2), 101.07 (C1), 102.47 (C5).
14. (a) Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F.
`
Gazz. Chim. Ital. 1992, 122, 135–142; (b) Pistara, V.;
Barili, P. L.; Catelani, G.; Corsaro, A.; D’Andrea, F.;
Fisichella, S. Tetrahedron Lett. 2000, 41, 3253–3256.
Acknowledgements
15. Methyl 2,6-di-O-benzyl-4-deoxy-5-C-methoxy-4-methyl-b-
The authors are grateful to MIUR (Ministero dell’Ist-
25
D-galactopyranoside 4: syrup, 96% yield, ½aꢀD ꢁ26.7
`
ruzione, dell’Universita e della Ricerca, Roma) for par-
(c 0.3, CHCl3). Selected NMR data: 1H (500 MHz,
CDCl3) d: 0.98 (d, 3H, J = 7.0 Hz CH3), 2.44 (dq, 1H,
J = 5.0, 7.0 Hz, H4), 2.58 (d, 1H, J = 2.5 Hz, OH), 3.26 (s,
3H, C5–OCH3), 3.33 (dd, 1H, J = 8.0, 9.5 Hz, H2), 3.53 (s,
3H, C1–OCH3), 4.17 (ddd, 1H, J = 2.5, 5.0, 9.5 Hz, H3),
4.49 (d, 1H, J = 8.0 H1); 13C (125 MHz, CDCl3) d: 8.39
(CH3), 38.74 (C4), 47.95 (C5–OCH3), 56.70 (C1–OCH3),
65.65 (C6), 68.92 (C3), 79.58 (C2), 101.01 (C1), 101.65 (C5).
16. (4R,5S,6R)- and (4S,5R,6S)-4,6-bis(benzyloxy)-5-hydr-
tial financial support in the frame of the COFIN 2004
program.
References and notes
1. (a) McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org.
Chem. 1966, 31, 1516–1521; (b) Suami, T.; Ogawa, S. Adv.
Carbohydr. Chem. Biochem. 1990, 48, 21–90.
25
oxy-2-methylcyclohex-2-enone 6: syrup, 65% yield, ½aꢀD
1
2. Bach, G.; Breiding-mack, S.; Grabley, S.; Hammann, P.;
+7.7 (c 0.5, CHCl3). Selected NMR data: H (500 MHz,
Hutter, K.; Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A.
¨
Liebigs Ann. Chem. 1993, 241–250.
CDCl3) d: 1.82 (dd, 3H, J = 1.5, 2.5 Hz, CH3), 3.85 (d, 1H,
J = 11.0 Hz, H6), 4.04 (dd, 1H, J = 8.0, 11.0 Hz, H5), 4.24

6594
A. Corsaro et al. / Tetrahedron Letters 47 (2006) 6591–6594
(dq, J = 2.5, 8.0 Hz, H4), 6.58 (dd, 1H, J = 1.5, 2.5 Hz,
not always follow the standard prioritisation rules. We
have attributed (Scheme 2) to compounds 6 and 10 the
numbering system used in the literature for Gabosine
analogues (Ref. 8), and that used for carba-sugar deriv-
atives for compound 11 (Ref. 21).
H3); 13C (125 MHz, CDCl3) d: 15.16 (CH3), 29.21, 73.14
and 73.99 (CH2), 76.55, 77.80, 82.60 (C4, C5 and C6),
135.05 (C2), 142.85 (C3), 197.04 (C@O).
17. (4R,5R,6R)- and (4S,5S,6S)-4,6-bis(benzyloxy)-5-hydr-
25
oxy-2-methylcyclohex-2-enone 7: syrup, 20% yield, ½aꢀD
20. Benzyl 5a-carba-b-L-fucopyranoside 11: syrup, 71% yield,
25
ꢁ89.7 (c 0.8, CD3CN). Selected NMR data: 1H (500 MHz,
CDCl3) d: 1.74 (t, 3H, J = 1.5 Hz, CH3), 4.06 (d, 1H,
J = 8.0 Hz, H6), 4.17 (m, 1H, H5), 4.33 (ddd, 1H, J = 1.5,
2.5, 4.0 Hz, H4), 6.66 (dd, 1H, J = 1.5, 4.0 Hz, H3); 13C
(125 MHz, CDCl3) d: 15.58 (CH3), 29.68, 71.42, 72.61
(CH2), 72.99, 73.49 (CH2), 80.18, 136.39 (C2), 139.02 (C3),
196.63 (C@O).
½aꢀD +7.70 (c 1.3, CHCl3). Selected NMR data: 1H
(500 MHz, CD3CN) d: 0.95 (d, 1H, J = 6.8 Hz, CH3), 1.34
(dd, 1H, J = 11.5, 12.6 Hz, H7ax), 1.54 (m, 1H, H5), 1.71
(dt, 1H, J = 3.8, 4.6, 12.6 Hz, H7eq), 3.20 (ddd, 1H,
J = 4.6, 9.5, 11.5 Hz, H1), 3.23 (dd, 1H, J = 3.0, 9.5 Hz,
H3), 3.48 (t, 1H, J = 9.5 Hz, H2), 3.60 (br t, 1H,
J = 3.0 Hz, H4); 13C (50 MHz, CDCl3) d: 17.3 (CH3),
30.9 (CH2), 31.4, 71.1, 72.5, 74.2, 74.9, 80.1. For previous
synthesis of 5a-carbafucopyranoside derivatives, see Ref.
21.
18. (2R,3S,4R,6R)- and (2S,3R,4S,6S)-2,3,4-trihydroxy-6-
25
methylcyclohexanone 10: syrup, 92% yield, ½aꢀD ꢁ55.6 (c
1.1, CHCl3). Selected NMR data: 1H (500 MHz, CD3OD)
d: 1.04 (d, 1H, J = 6.5 Hz, CH3), 1.20 (ddd, 1H, J = 5.0,
5.5, 13.5 Hz, H5b), 2.13 (ddd, 1H, J = 5.5, 12.5, 13.5 Hz,
H5a), 2.61 (ddd, 1H, J = 5.5, 6.5, 12.5 Hz, H6), 3.21 (d,
1H, J = 9.5 Hz, H3), 3.85 (m, 1H, J = 9.5 Hz, H4), 4.03
(dd, 1H, J = 0.9, 9.5 Hz, H2); 13C (50 MHz, CD3OD) d:
13.81 (CH3), 38.99 (CH2), 40.13, 71.77, 79.37, 81.39, 194.6
(C@O).
21. (a) Carpintero, M.; Jaramillo, C.; Fernandez-Mayoralas,
A. Eur. J. Org. Chem. 2000, 1285–1296; (b) Carpintero,
M.; Bastida, A.; Garcia-Junceda, E.; Jimenez-Barbero, J.;
Fernandez-Mayoralas, A. Eur. J. Org. Chem. 2001, 4127–
4135; (c) Calderon, F.; Carpintero, M.; Garcia-Junceda,
E.; Fernandez-Mayoralas, A.; Bastida, A. Lett. Org.
Chem. 2005, 2, 247–251; (d) Verduyn, R.; van Leeuwen,
S. H.; van der Marel, G. A.; van Boom, J. H. Rec. Trav.
Chim. Pays-Bas 1996, 115, 67–71.
19. The generally adopted numbering for carbacycles of
naturally occurring derivatives or their analogues does