Transformation of D-Glucose into 1D-3-Deoxy-3-hydroxymethyl-myo-inositol by Stereocontrolled Intramolecular Henry Reaction

Article abstract of DOI:10.1021/ol035771x

(Equation presented) An intramolecular Henry cyclization provides a promising new strategy for the transformation of nitroheptofuranoses into deoxyhydroxy-methylinositols. This method has allowed a stereospecific transformation of D-glucose into 1D-3-deox

Full text of DOI:10.1021/ol035771x

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4457-4459
Transformation of D-Glucose into
1D-3-Deoxy-3-hydroxymethyl-myo-inositol
by Stereocontrolled Intramolecular
Henry Reaction
Raquel G. Soengas, Juan C. Este´vez, and Ramo´n J. Este´vez*
Departamento de Qu´ımica Orga´nica, UniVersidade de Santiago,
15782 Santiago de Compostela, Spain
qorjec@usc.es
Received September 13, 2003
ABSTRACT
An intramolecular Henry cyclization provides a promising new strategy for the transformation of nitroheptofuranoses into deoxyhydroxy-
methylinositols. This method has allowed a stereospecific transformation of D-glucose into 1D-3-deoxy-3-hydroxymethyl-myo-inositol.
The nitroaldol condensation, or Henry reaction, couples a
carbonyl compound to a nitroalkane bearing an R hydrogen
atom, thereby creating an R-nitroalkanol. It is one of the
classical methods for carbon-carbon bond formation and
can result in the formation of one or two chiral centers.1
Following the condensation reaction, the nitro group can be
subjected to a range of chemical transformations,2 including
its removal.3
(sphinganine analogues,5 cerebroside B1b,6 etc.) and, more
recently, in studies on the asymmetric synthesis of nitroal-
kanols, in which dendritic,7 lanthanum-lithium-binaphthol,8
La-Li-6,6′-disubstituted BINOL,9 and zirconium phosphate10
catalysts have been used to achieve enantioselectivity.
Nevertheless, to the best of our knowledge, nitroethanol has
been used in only one intramolecular Henry reaction11 and
in only one Henry reaction in which the substrate has been
a sugar (D-glyceraldehyde).12
Nitroethanol has been used as the nitroalkane of the Henry
reaction4 in several total syntheses of natural products
(5) (a) Kolter, T.; van Echten-Deckert, G.; Sandhoff, K. Tetrahedron
1994, 50, 13425. (b) Mori, K.; Funaki, Y. Tetrahedron 1985, 41, 2369.
(6) (a) Kodato, S.; Nakagawa, M.; Nakayama, K.; Hino, T. Tetrahedron
1989, 45, 7247. (b) Nakagawa, M.; Kodato, S.; Nakayama, K.; Hino, T.
Tetrahedron Lett. 1987, 28, 6281.
(7) Morao, I.; Cossio, F. P. Tetrahedron Lett. 1997, 38, 6461.
(8) Sasai, H.; Watanabe, S.; Shibasaki, M. Enantiomer 1997, 2, 267.
(9) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki,
M. J. Org. Chem. 1995, 60, 7388.
(1) (a) Henry, C. R. Acad. Sci. Paris 1985, 120, 1265. (b) Luzzio, F. A.
Tetrahedron 2001, 57, 915.
(2) (a) Pinnick, H. W. Org. React. 1990, 38, 655. (b) McMurry, J. E.;
Melton, J.; Padgett, H. J. Org. Chem. 1974, 39, 259. (c) McMurry, J. E.;
Melton, J. J. Org. Chem. 1973, 38, 4367. (d) Olah, G. A.; Gupta, B. G. B.
Synthesis 1980, 44. (e) Crosslay, M. J.; Crumbie, R. L.; Fung, Y. M.; Potter,
J. J.; Pegler, M. A. Tetrahedron Lett. 1987, 28, 2883.
(3) Baumberg, F.; Vasella, A. HelV. Chim. Acta 1983, 66, 2210.
(4) For the first reported example of a Henry reaction involving
nitroethanol, see: Grob, C. A.; Gadient, F. HelV. Chim. Acta 1957, 40,
1145.
(10) Costantino, U.; Curini, M.; Marmottini, F.; Rosati, O.; Pisani, E.
Chem. Lett. 1994, 2215.
(11) Lichtenthaler, F. W.; Leinert, H. Chem. Ber. 1968, 101, 1815.
(12) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67, 8783.
10.1021/ol035771x CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/14/2003

In the course of our work on nitrosugars,13 and more
specifically in relation to the synthesis of inositols from
sugars, we have prepared deoxyhydroxymethylinositol 10
(Scheme 1) by a synthetic sequence involving two Henry
aqueous sodium bicarbonate solution gave the enantiomeri-
cally pure compound 5.
The stereochemistry of compound 5 was easily established
from that of its derivative 6, which was obtained by treatment
1
of 5 with acetic anhydride and p-toluenesulfonic acid. H
NMR experiments on compound 6 showed NOEs between
the methylene group on the CH2OBn substituent and H2
(2.6%) and H4 (1.9%) and between H1 and H3 (5.5%).
Accordingly, the favored chair conformation for this com-
pound (Figure 1) is that in which the CH2OBn and NO2
Scheme 1. Synthesis of Deoxyhydroxymethylinositols
Figure 1. NOESY diagrams of compounds 6 and 9.
substituents at C6 are axial and equatorial, respectively, the
OBn groups at C3 and C5 are equatorial and axial, respec-
tively, and the OAc groups at C1, C2, and C4 are all
equatorial. The coupling constants between H4 and H5 (J )
2.2 Hz, typical of an axial-equatorial interaction) and
between H2 and H3 (J ) 9.6 Hz, typical of a diaxial
interaction) provide further evidence of the axial orientation
of the protons H1, H2, H3, and H4 and the equatorial
disposition of H5.
The fact that reaction of the isomeric mixture 4 afforded
5 but not its diastereomer 13 may be attributed to the former,
in which the bulky groups at C5 and C6 are trans to each
other, presumably being significantly more stable than the
latter, in which they are cis (Scheme 2). Because of this,
whereas carbanion 11, the reaction intermediate derived from
reactions. The first couple nitroethanol and D-glucose deriva-
tive 1 and the second use the coupled nitroalkane in an
intramolecular reaction converting the furanose into a cy-
clohexane.
Scheme 2. Mechanism of the Transformation of Compounds 4
into Cyclohexane 5
Condensation of D-glucose derivative 114 with nitroethanol
under typical Henry reaction conditions gave a 3:2 mixture
of epimers 2 in 75% yield (Scheme 1). To protect hydroxy
groups at C5 and C7, 2 was then treated with benzyl
trichloroacetimidate and triflic acid, giving the epimeric
mixture 3, from which the acetonide protecting group was
removed by treatment with a 1:1:1 mixture of trifluoroacetic
acid, dioxane, and water. Surprisingly, immediate treatment
of the resulting unstable mixture of compounds 4 with 2%
(13) (a) Soengas, R. G.; Este´vez, J. C.; Este´vez, R. J.; Maestro, M.
Tetrahedron: Asymmetry 2003, 14, 1653. (b) Soengas, R. G.; Este´vez, J.
C.; Este´vez, R. J. Org. Lett. 2003, 9, 1425.
(14) Paulsen, H.; Brieden, M.; Sinwell, V. Liebigs Ann. Chem. 1985,
113.
4458
Org. Lett., Vol. 5, No. 23, 2003

nitrosugar 4a, proceeds easily to 5, its epimer 12 (the
intemediate derivative of 4b) finds isomerization to 11 and
subsequent conversion to 5 to be more favored than conver-
sion to 13.
groups at C1, C2, and C4 with respect to those borne by C3,
C5, and the methylene group at C6. This possibility is of
significant interest for phosphorylation of specific OH groups
for biological studies.
Nitrocyclohexane 5 was transformed into inositol 10 as
follows (Scheme 1). After protection of the OH groups of 5
as OEE by reaction with ethyl vynyl ether, the nitro group
was removed by treating the product, compound 7, with
n-Bu3SnH and AIBN,15 a process that brought about inver-
sion of the configuration at C6. The OEE protecting groups
were then removed with PPTS, and the benzyloxy groups
were removed by catalytic hydrogenation.
We are currently applying the new strategy systematically
to sugars other than D-glucose in order to prepare all the
possible deoxyhydroxymethylinositol derivatives of D-hex-
oses with the aim of studying their chemical and biological
properties. The interest of these studies is supported by the
recent observation that deoxyhydroxymethyl-scillo-inositol,
which should be possible to obtain from D-mannose by our
approach, is a potent agonist of the receptor of the classical
inositol known as Ins(1,4,5)P3, which influences the transport
of Ca2+ in several types of cells.17,18 This finding suggests
that replacement of the C6 hydroxy group of inositols with
a hydroxymethyl group can result in an increase in biological
activity.
The absolute stereochemistry of deoxyhydroxymethyl-
1
inositol 10 was deduced from the H NMR spectrum of its
precursor 9, which shows NOEs between H1 and H3 (6.0%),
H3 and H5 (7.1%), and between H4 and the OH groups at C1
(1.6%), C4 (2.2%), and C5 (1.9%). These NOEs show that,
in the cyclohexane chair conformation favored in 9 (Figure
1), the three OH groups are equatorial, the OBn groups at
C2 and C6 are axial and equatorial, respectively, and the CH2-
OBn group is equatorial. This stereochemistry was confirmed
by the presence in the 1H NMR spectrum of a triplet at δ )
3.46 ppm due to proton H5 (J5,4 ) J5,6 ) 9.0 Hz) and a
doublet of doublets at δ ) 3.73 ppm due to H4 (J4,3 ) 10.7
Hz, J4,5 ) 9.0 Hz), which clearly indicate the axial orientation
of protons H3, H4, H5, and H6.
In conclusion, we have developed a promising novel
strategy for the transformation of nitrosugars into deoxyhy-
droxymethylinositols. This process has allowed the first total
synthesis of deoxyhydroxymethylinositol 10 with total ster-
eochemical control. The new route to these targets constitutes
a simpler and more efficient approach than the few previously
described routes16 and has the additional advantage of
offering the possibility of orthogonal protection of the OH
Acknowledgment. We thank the Spanish Ministry of
Science and Technology for financial support and for an FPI
grant to Raquel G. Soengas, as well as Prof. George W. J.
Fleet for useful suggestions and discussions.
Supporting Information Available: General experimen-
tal procedure, 1H and 13C NMR spectra for compounds 5, 7,
8, 10, 11, 13, 15, 17, and 18, and characterization data for
all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL035771X
(16) (a) Paulsen, H., Ro¨ben, W. Liebigs Ann. Chem. 1983, 1073. (b)
Riley, A. M.; Guedat, P.; Schlewer, G.; Spiess, B.; Potter, B. V. L. J. Org.
Chem. 1998, 63, 295.
(17) Riley, A. M., Murphy, C. T., Lindley, C. J.; Westwick, J.; Potter,
B. V. L. Bioorg. Med. Chem. Lett. 1996, 6, 2197.
(15) See ref 3.
(18) Berridge, M. J. Nature 1993, 361, 315.
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