Branched-chain functionalised carbohydrates via β-functionalised organolithium compounds

Article abstract of DOI:10.1016/S0957-4166(98)00411-X

The reaction of the epoxysugar 1 with an excess of lithium powder and a catalytic amount of DTBB (5 mol%) in THF at -78°C leads to the formation of the corresponding β-oxido functionalised organolithium intermediates 2, which by treatment with different electrophiles [H₂O, D₂O, Me₃SiCl, PhCHO, Me₂CO, (CH₂)₅CO] at -78°C to room temperature afford, after hydrolysis with water, the expected enantiomerically pure compounds 3. Starting from the epimeric epoxide 4 and following the same procedure, using water as electrophile, the compound 6 was isolated, the corresponding intermediate 5 having been involved in the process.

Full text of DOI:10.1016/S0957-4166(98)00411-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3939–3943
Branched-chain functionalised carbohydrates via β-functionalised
organolithium compounds
Tatiana Soler,a Abderrazak Bachki,a Larry R. Falvello,b,† Francisco Foubelo a and
Miguel Yus a,∗
aDepartamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
bDepartamento de Química Inorgánica, Instituto de Ciencia de los Materiales de Aragón, Facultad de Ciencias, Universidad
de Zaragoza-CSIC, 50009 Zaragoza, Spain
Received 22 September 1998; accepted 9 October 1998
Abstract
The reaction of the epoxysugar 1 with an excess of lithium powder and a catalytic amount of DTBB (5 mol%)
in THF at −78°C leads to the formation of the corresponding β-oxido functionalised organolithium intermediates
2, which by treatment with different electrophiles [H2O, D2O, Me3SiCl, PhCHO, Me2CO, (CH2)5CO] at −78°C
to room temperature afford, after hydrolysis with water, the expected enantiomerically pure compounds 3. Starting
from the epimeric epoxide 4 and following the same procedure, using water as electrophile, the compound 6 was
isolated, the correponding intermediate 5 having been involved in the process. © 1998 Elsevier Science Ltd. All
rights reserved.
From a biological point of view, carbohydrates play a vital role in molecular recognition, cell sig-
nalling, biomolecular transport, the immune system and, in fact, in virtually every essential biological
process.1 From a chemical point of view, carbohydrates have long been utilised as useful starting
materials in the synthesis of chiral natural products, D-glucose being probably the starting material most
extensively used;2 this is an example of the so called EPC-synthesis, which allows the preparation of
enantiomerically pure compounds using the pool of easily available chiral natural compounds.3 One im-
portant family of sugar derivatives are the corresponding branched-chain functionalised carbohydrates,4
which are glycosidic components of antibiotics. In nature, most of the branched-chain sugars contain
a polar substituent at the branching carbon atom, the alcohol functionality being the most commonly
found.4 On the other hand, in the last few years we have applied an arene-catalysed lithiation5 to
the preparation of functionalised organolithium compounds6 starting from different materials, such as
chlorinated compounds,7 ethers8 or thioethers,9 sulfones10 and heterocycles.11,12 Concerning this last
type of compound, the reductive opening of epoxides using lithium and a stoichiometric13 or catalytic14
∗
†
Corresponding author. E-mail: yus@ua.es
To whom the correspondence on X-ray structure should be addressed.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00411-X

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T. Soler et al. / Tetrahedron: Asymmetry 9 (1998) 3939–3943
amount of an arene is a useful methodology, which allows the generation of β-oxido functionalised
organolithium intermediates. In this paper we apply the aforementioned arene-catalysed lithiation to
the ring opening of epoxides derived from D-glucose in order to prepare branched-chain functionalised
carbohydrate derivatives.4
The reaction of the protected epoxy D-glucose 115 with an excess of lithium powder (1:14 molar ratio)
and a catalytic amount of 4,40-di-tert-butylbiphenyl (DTBB; 1:0.1 molar ratio, 5 mol%) in THF at −78°C
for 2 h followed by treatment with different electrophiles [E+=H2O, D2O, Me3SiCl, PhCHO, Me2CO,
(CH2)5CO] at temperatures ranging between −78°C and room temperature led, after hydrolysis with
water, to the expected products 3a–f, the corresponding intermediate 2 being probably involved in the
process (Scheme 1 and Table 1).
Scheme 1. Reagents and conditions: i, Li, DTBB (5%), THF, −78°C, 2 h; ii, E+=H2O, D2O, Me3SiCl, PhCHO, Me2CO,
(CH2)5CO, −78 to 20°C; iii, H2O
In the case of prochiral carbonyl compounds, such as benzaldehyde, a 2:3 diastereoisomeric mixture
was obtained (Table 1, entry 4), which was separated by column chromatography (silica gel, hexane/ethyl
acetate) giving the corresponding pure diastereoisomers, one of them (the most polar one) was recrys-
Table 1
Preparation of compounds 3 from the epoxide 1

T. Soler et al. / Tetrahedron: Asymmetry 9 (1998) 3939–3943
3941
Figure 1.
tallised and analysed by X-ray difraction, confirming the stereochemistry at both formed stereocentres
(Fig. 1).16
When the epimeric epoxide 417 was submitted to the same procedure as shown in Scheme 1, and using
water as electrophile, the expected ‘reduced’ product 618 was obtained, consistent with the intermediate
5 being involved in the process (Scheme 2).
Scheme 2. Reagents and conditions: i, ii as in Scheme 1 with E+=H2O
Just to confirm the stereochemistry of the new stereocentre in 6 we performed the addition of
methyllithium to the ketone II15 in THF at temperatures ranging between −78°C and room temperature,
thus generating the same compound 6.19,20
From the results reported here we conclude that the epoxysugars 1 and 4 are convenient precursors
for the generation of enantio- and regiochemically pure β-functionalised organolithium compounds,
which are versatile intermediates for the preparation of branched-chain functionalised sugars. We are
now studying the synthetic scope of this reaction using different sugar derivatives. Note that the use of
oxosugars, such as compound II15 as an electrophilic component, opens the door for obtaining dimeric
structures having two monosaccharide units (disaccharide type molecules).

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T. Soler et al. / Tetrahedron: Asymmetry 9 (1998) 3939–3943
Acknowledgements
This project was financially supported by the DGICYT from the Spanish Ministerio de Educación y
Cultura (MEC; project nos. PB94-1514 and PB95-0792). T.S. thanks the Generalitat Valenciana for a
predoctoral fellowship.
References
1. See, for instance: Borman S. Chem. Eng. News 1998, 76, July 20, 49.
2. See, for instance: (a) Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach; Pergamon Press: Oxford,
1983. (b) Lichtenthaler, F. In Modern Synthetic Methods 1992; Scheffold, R., Ed.; VCA Publishers: New York, 1992; p.
273. (c) Bols, M. Carbohydrate Building Blocks; John Wiley & Sons: New York, 1996.
3. Seebach, D.; Hungerbühler, E. In Modern Synthetic Methods 1980; Scheffold, R., Ed.; Salle+Sauerländer-Verlag: Aarau,
1980; p. 91.
4. Sato, K.; Suzuki, K.; Ueda, M.; Katayama, M.; Kajihara, Y. Chem. Lett. 1991, 1469.
5. (a) For the first account of this reaction, see: Yus, M.; Ramón, D. J. J. Chem. Soc., Chem. Commun. 1991, 398. (b) For a
review, see: Yus, M. Chem. Soc. Rev. 1996, 155.
6. (a) Nájera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155. (b) Nájera, C.; Yus, M. Recent Res. Devel. Org. Chem. 1997, 1,
67.
7. Last paper on this topic from our laboratory: Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1998, 39, 3303.
8. Last paper on this topic from our laboratory: Bachki, A.; Foubelo, F.; Yus, M. Tetrahedron Lett. 1998, 39, 7759.
9. Last paper on this topic from our laboratory: Foubelo, F.; Gutierrez, A.; Yus, M. Tetrahedron Lett. 1997, 38, 4837.
10. Last paper on this topic from our laboratory: Alonso, D. A.; Alonso, E.; Nájera, C.; Ramón, D. J.; Yus, M. Tetrahedron
1997, 53, 4835.
11. Last paper on this topic from our laboratory: Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1997, 53, 5563.
12. For a review, see: Yus, M.; Foubelo, F. Rev. Heteroatom. Chem. 1997, 17, 73.
13. (a) Bartman, E. Angew. Chem., Int. Ed. Engl. 1986, 25, 653. (b) Barluenga, J.; Fernández-Simón, J. L.; Concellón, J. M.;
Yus, M. J. Chem. Soc., Chem. Commun. 1987, 915. (c) Barluenga, J.; Fernández-Simón, J. L.; Concellón, J. M.; Yus, M.
J. Chem. Soc., Perkin Trans. 1 1988, 3339. (d) Dorigo, A. E.; Houk, K. N.; Cohen, T. J. Am. Chem. Soc. 1989, 111, 8976.
(e) Cohen, T.; Jeong, I.-H.; Mudryk, B.; Bhupathy, M.; Awad, M. M. A. J. Org. Chem. 1990, 55, 1528. (f) Conrow, R. E.
Tetrahedron Lett. 1993, 34, 5553.
14. (a) Bachki, A.; Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1995, 6, 1907. (b) Bachki, A.; Foubelo, F.; Yus, M.
Tetrahedron: Asymmetry 1996, 7, 2997.
15. Compound 1 was prepared from 1,2;5,6-di-O-isopropylidene-α-D-glucofuranos-3-ulosa (II) [prepared by oxidation of
the corresponding commercially available alcohol I with PCC in a mixture of acetic anhydride and CH2Cl2 at room
RT
temperature for 30 min: 73%; Rf 0.31 (silica gel, hexane/ethyl acetate: 4/1); [α]D 131.5 (CH2Cl2; c 1.27)] by treatment
with equimolecular amounts of potassium tert-butoxide and trimethylsulfoxonium iodide in tert-butanol at 50°C for 2.5 h,
RT
followed by hydrolysis with water: 82%; Rf 0.48 (silica gel, hexane/ethyl acetate: 4/1); [α]D 55.4 (CH2Cl2; c 1.08).
16. (a) Crystal data (to be deposited at the Cambridge Crystallographic Data Centre): C20H28O7, M=380.42; monoclinic,
a=14.5447(13), b=6.6448(10), c=21.591(3) Å, β=91.129(9); U=2086.3(5) Å; space group P21; Z=4; Dc=1.211 Mg m−3
;
λ=0.71073 Å; µ=0.091 mm−1; F(000)=816; T=24–25ꢀ1°C. Intensity data were measured on a CAD-4 diffractometer.
The data were reduced by routine methods.16b The structure was solved by direct methods16c and refined to all 3037
2
unique Fo by full matrix least squares.16d Most of the hydrogen atoms were seen in difference Fourier maps, but for
the final refinement all H atoms were placed at idealised positions and refined as rigid atoms, with the exception of

T. Soler et al. / Tetrahedron: Asymmetry 9 (1998) 3939–3943
3943
the OH and the methyl group hydrogens, which were located in Fourier calculations; these groups were refined as rigid
rotators. Final wR2=0.1440 for all data and 499 parameters; R1=0.0547 for 2366 Fo>4α(Fo). The enantiomorph was
fixed according to the known stereochemistry of four of the chiral centres in the molecule. (b) Data were processed on an
AlphaStation 200 4/166 (OpenVMS Alpha V6.2), using the program XCAD4B (K. Harms, University of Marburg) and
the commercial package SHELXTL-PLUS Release 5.05/V. © 1996 Siemens Analytical X-Ray Instruments, Inc., Madison,
WI. (c) SHELXS-97: Fortran program for crystal structure solution. © 1997 G. M. Sheldrick. (d) SHELXL-97: Fortran
program for crystal structure solution. © 1997 G. M. Sheldrick.
17. Compound 4 was prepared from ketone II15 by reaction with chloroiodomethane (1:2 molar ratio) and lithium bromide
in THF at −78°C for 10 min, followed by treatment with n-butyllithium at −78°C to room temperature: ca. 30% overall
RT
yield; Rf 0.15 (silica gel, hexane/ethyl acetate: 4/1); [α]D 85.6 (CH2Cl2; c 1.2).
RT
18. >95%; Rf 0.13 (silica gel, hexane/ethyl acetate: 4/1); [α]D 23.7 (CH2Cl2; c 1.26).
RT
19. 48%; Rf 0.11 (silica gel, hexane/ethyl acetate: 4/1); [α]D 25.8 (CH2Cl2; c 1.10).
20. In the literature has been reported that nucleophilic addition to the C-3 carbonyl group of II15 takes place to the convex
β-position by the preferential control due to the rigid bicyclic structure. See, for instance: (a) Peterson, M. A.; Mitchell, J.
R. J. Org. Chem. 1997, 62, 8237. (b) Yamauchi, N.; Kishida, M.; Sawada, K.; Ohashi, Y.; Eguchi, T.; Kakinura, K. Chem.
Lett. 1998, 475. (c) See also Ref. 4.