Convenient and efficient synthesis of 2,4-dideoxy-levoglucosan

Article abstract of DOI:10.1080/00397911.2012.745158

A convenient and efficient synthesis of 1,6-anhydro-2,4-dideoxy-β-D- threo-hexopyranose (2,4-dideoxy-levoglucosan) from levoglucosan has been developed. The method uses cheap reagents and requires only crystallization and distillation for preparation of pure product on a multigram scale.

Full text of DOI:10.1080/00397911.2012.745158

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Convenient and Efficient Synthesis of 2,4-Dideoxy-
Levoglucosan
Mikhail S Ermolenko a
a Institut de Chimie des Substances Naturelles, Centre de recherche de Gif-sur-Yvette,
CNRS , 91198 Gif-sur-Yvette , France
Accepted author version posted online: 31 May 2013.
To cite this article: Mikhail S Ermolenko (2013): Convenient and Efficient Synthesis of 2,4-Dideoxy-Levoglucosan,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI:10.1080/00397911.2012.745158
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CONVENIENT AND EFFICIENT SYNTHESIS OF 2,4-DIDEOXY-
LEVOGLUCOSAN
Mikhail S Ermolenko1
1Institut de Chimie des Substances Naturelles, Centre de recherche de Gif-sur-Yvette,
CNRS, 91198 Gif-sur-Yvette, France
Abstract
A convenient and efficient synthesis of 1,6-anhydro-2,4-dideoxy-β-D-threo-
hexopyranose (2,4-dideoxy-levoglucosan) from levoglucosan has been developed. The
method uses cheap reagents and requires only crystallization and distillation for
preparation of pure product in multigram scale.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: Chiral pool, Carbohydrates, Epoxides, Deoxygenation, Mitsunobu
reaction
INTRODUCTION
1,6-Anhydro-2,4-dideoxy-β-D-threo-hexopyranose (2,4-dideoxy-levoglucosan) 1 is an
important and valuable intermediate for synthesis of polyene antibiotics,[1] avermectins,[2]
mevinic acids,[3] and other natural products and pharmaceuticals. As a consequence, a
large number of approaches to the synthesis of 1 from levoglucosan 3 has been developed
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in the past which can be divided into three groups. The first approach, based on the
complex metal hydrides reduction of derivatives involved in the cascade 4-7,[4–6] has the
disadvantage of not being regiospecific and giving inseparable mixtures of 1 and its
regioisomer 2 in (2-10):1 ratios (Scheme 1).
For small-scale synthesis, the reduction of ditosylate 4 with LiBHEt3 is by far the most
straightforward and popular method.[4] The crude ditosylate, available in a 90% yield and
containing ca. 15% of the tritosylate by-product, can be used in this reaction; however,
the resulting product must be subjected to chromatographic purification before
derivatization, required for separation of the isomers 1 and 2.[4d] This additional
purification step can be avoided by using pure ditosylate 4; unfortunately, it is available
from levoglucosan 3 only in a 50-60% yield.[7] The best overall result can be achieved by
reduction of the epoxide 5,[4a] which is easily available in an overall yield of 72-75% from
3 by treatment of the crude ditosylate with MeONa.[8] Regardless of the procedure, the
overall yield of pure 1 (or its derivative) from levoglucosan 1 never exceeds 50%.
Despite its apparent simplicity, this method suffers from several shortcomings. Namely, it
requires 6 equiv of expensive borohydride reagent, LiBHEt3, that must be destroyed by
alkaline peroxide oxidation resulting in a solution of water-miscible compounds 1 and 2
in a large volume of aqueous tetrahydrofuran (ca. 15 L/mol of the substrate). The lengthy
isolation of the mixture of 1 and 2 (several days)[4c] by continuous liquid-liquid
extraction, and their separation via derivatization is a laborious, unsafe and energy
consuming process which appears unsuitable for large-scale preparation of 1. To
circumvent the problem of regioselectivity, the radical deoxygenation of 2,4-di-O-
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phenylthionocarbonate 8 has been proposed.[9] This provided acceptable yields only when
tris(trimethylsilyl)silane was used as a hydrogen source. Subsequent modification of the
method[10] gave reasonable yields[11] with less expensive diphenylsilane. However, the
necessity of separating 1 from large amounts of byproducts also makes this approach
unpractical. The most attractive route from 3 to 1 appeared to be via hydrogenolysis of
the dithio derivative 10 in spite of the high-pressure hydrogenation conditions and the
large excess of the foul-smelling PhSH used for its preparation (Scheme 2).[12] We found
that the same yield of 10 can be obtained using only 2.5 equiv of thiophenol by simple
modification of the reaction conditions.[13] Unfortunately, numerous attempts to
reproduce the hydrogenolysis step with satisfactory yields failed.[14]
RESULTS AND DISCUSSION
In connection with several projects on natural product synthesis we needed a convenient
method to prepare 2,4-dideoxy-levoglucosan in large quantity. In searching for a solution
to this problem, a very simple and efficient synthesis of 1 from 3 was designed. Thus,
treatment of epoxide 5, readily available from 3 in 72-75% yield,[8] with LiBr in THF
gave rise to a mixture of epoxides 11 and 12 (11:12 = 1:5 at equilibrium), together with a
small quantity of 2,4-dibromo-derivative 13. Attempts to shift this equilibrium towards
13 were unsuccessful indicating kinetic instability of the intermediate lithium alkoxide of
13. To stabilize it, MgBr2 was added to the reaction mixture and the desired 13 could thus
be obtained in >90% isolated yield after crystallization from ethyl acetate-heptane. The
mother liquors, containing mainly the epoxides 11 and 12, were concentrated and
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repeatedly treated with MgBr2 in THF thus increasing the yield of 13 up to 97-98%
(Scheme 3).
To prevent the epoxide ring formation and increase its solubility, the dibromide 13 was
acetylated to 14 and then subjected to hydrogenolysis over Raney Ni (0.25 w/w, pre-
washed with AcOH-EtOH) in ethanol in the presence of AcONa as the acid scavenger.
The hydrogenolysis went to completion in 6 hours at room temperature and hydrogen
pressure of 4 atm (alternatively, in 24-30 h at 1 atm of H2) to give the regiomerically pure
acetate 15 in 93% yield (65-67% from levoglucosan 3) after simple filtration and
evaporation of solvents. Although this product still contained traces of volatiles, it proved
to be sufficiently pure (98% by capillary GLC) for most preparative purposes that
permitted the telescoping of subsequent steps. Bulb-to-bulb distillation of this product
gave analytically pure 15 (84% overall yield from 5) which represents a convenient shelf-
stable storage form of the sticky and very hygroscopic 2,4-dideoxy-levoglucosan 1. The
preparation of 15 according to this scheme was scaled up to 0.2 mol without any
alteration in the yield.
After deacetylation of 15 under mild conditions, the 2,4-dideoxy-levoglucosan 1 can be
isolated in pure state or directly used in a subsequent step without purification. For
example, deacetylation of 15 followed by the Mitsunobu reaction with 4-methoxyphenol
gave rise to highly crystalline erythro-derivative 16 in 86% unoptimized yield in one pot.
Since the anisyl protecting group is known to be very resistant towards hydrogenolysis,
basic, acidic, as well as organometallic reagents and can be removed under mild
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conditions,[15] the erythro-isomer 16 appears to be a promising synthon for synthesis of
mevinic acids, macrolide antibiotics, altohyrtin and other natural products. The acetate 15
has itself been previously used for the synthesis of an HMG-CoA reductase inhibitor by
the C-glycoside route.[16] Further use of these valuable intermediates in synthesis will be
reported in due course.
In conclusion, the convenient, efficient and scaleable synthesis of the valuable chiral
synthon, 1,6-anhydro-2,4-dideoxy-β-D-threo-hexopyranose (2,4-dideoxy-levoglucosan),
was elaborated from levoglucosan, the product of pyrolysis of renewable resources
(starch and wood). This method uses cheap reagents and requires only crystallization and
distillation for preparation of pure 1 in multigram scale.
Supporting Information: Full experimental detail, 1H and 13C NMR spectra for
compounds 1 and 13-16. This material can be found via the “Supplementary Content”
section of this article’s Web page.
REFERENCES
1. Beau, J.-M. In Recent Progress in The Chemical Synthesis of Antibiotics; G. Lukacs,
M. Ohno (Eds.); Springer-Verlag: Berlin, 1990; pp. 135–182.
2. Blizzard, T.; Fisher, M.; Mrozik, H.; Shih, T., In Recent Progress in The Chemical
Synthesis of Antibiotics; G. Lukacs, M. Ohno (Eds.); Springer-Verlag: Berlin, 1990; pp.
65–102.
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3. Chapleur, Y., In Recent Progress in The Chemical Synthesis of Antibiotics and
Related Microbial Products; G. Lukacs (Ed.); Springer-Verlag: Berlin, 1993; vol 2, pp.
829–937.
4. (a) Kelly, A. G.; Roberts, J. S. Carbohydr. Res. 1983, 77, 231–233; (b) Baker, R.;
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M. J.; Swain, C. J. J. Chem. Soc., Perkin Trans. 1, 1987, 1613–1621; (e) Paquette, L. A.;
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Warrier, U.; White, J. D. Tetrahedron Lett. 1988, 29, 2923–2926 ; (g) White, J. D.;
Bolton, G. L.; Dantanarayana, A. P.; Fox, C. M. J.; Hinter, R. N.; Jackson, R. W.;
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Ducharme, Y.; Brideau, C.; Chan, C.-C.; Chauret, N.; Desmarais, S.; Dubé, D.;
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McAuliffe, M.; McFarlane, C. S.; Nicoll-Griffith, D. A.; Riendeau, D.; Yergey, J. A.;
Girard, Y. J. Med. Chem. 1996, 39, 3951–3970.
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6. Halbych, J.; Trnka, T.; Cerny, M. Collect. Czech. Chem. Commun. 1973, 38, 2151–
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7. Cerny, M.; Kalvoda, L.; Pacak, J. Collect. Czech. Chem. Commun. 1968, 33, 1143–
1156.
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8. (a) Cerny, M.; Gut, V.; Pacak, J. Collect. Czech. Chem. Commun. 1961, 26, 2542–
2550; (b) Grindley, T. B.; Reimer, G. J.; Kralovec, J.; Brown, R. G.; Anderson, M. Can. J.
Chem. 1987, 65, 1065–1071.
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1992, 33, 1997–2000. See also Tolstikov, G. A.; Miftakhov, M. S.; Valeev, F. A.;
Ibragimova, I. R.; Gareev, A. A. J. Org. Chem. USSR (Engl. Transl.) 1991, 27, 355–358.
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7214.
11. The yield reported in ref. 10 has been determined by NMR. In our hands, in 10-mmol
scale preparation, the isolated yield of 1 was 65% after careful chromatography of the
acetate derivative 15.
12. David, C.; Gesson, J. P.; Jacquesy, J. C. Tetrahedron Lett. 1989, 30, 6015–6018.
13. Reaction of 5, PhSH (2.5 equiv) and NaOH (2.5 equiv) in dioxane-H2O (1:1, 0.4 mL
per mmol of 5) at 100°C for 3 h gave, after work-up and crystallization from ether-
pentane (1:1), pure 10 in 82% yield. An additional portion (10%) of 10 was obtained after
chromatographic purification of the mother liquors.
14. Three lots of commercial Ra-Ni (Aldrich, Janssen) of various ages, as well as fresh
catalyst, prepared according to Burgstahler's procedure (Fieser, L. M.; Fieser, M.,
Reagents for Organic Synthesis, vol.1; John Wiley: New York, 1967; p. 729), were used
for attempted hydrogenolysis in a rocking steel autoclave at 10-20 atm. H2 at rt. Reaction
was incomplete even after 2 weeks. Similar results were reported by a Merck group
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(Belyk, K. M.; Leonard, W. R.; Bender, D. R.; Hughes, D. L. J. Org. Chem. 2000, 65,
2588–2590).
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16. Ermolenko, M.S.; Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 715–718.
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Scheme 1.
O
O
O
O
S
S
S
S
PhO
O
O
OPh PhO
O
O
OPh
8
9
OSiMe3
OH
70%
86%
[9]
85% (by NMR) [10]
O
O
O
O
O
O
HO
OH
O
OH
1
2
OH
OH
3
(5-10:1)
[4]
(4.5:1)
[4a]
(4:1)
[5]
(1.7:1)
[6]
O
O
O
O
O
O
O
TsO
OTs
OTs
OTs
O
O
4
5
7
6
OH
OH
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Scheme 2.
PhSH (10 equiv)
NaOH (10 equiv)
O
O
H2 (10 atm)
Ra-Ni
O
O
O
O
Dioxane-H2O
65°, 24 h
92%
EtOH
85%
PhS
SPh
OTs
O
OH
OH
5
10
1
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Scheme 3.
O
O
O
O
O
O
O
LiBr
5
THF, ∆
Br
O
Br
Br
Br
O
11
12
OLi
p-MeOC6H4OH
Ph3P, DEAD
H2, Ra-Ni
O
O
O
O
O
MgBr2
AcONa
97%
from 5
EtOH, r.t.
93%
(see text)
CH2Cl2, r.t.
84% from 15
Br
Br
OR
OR
OAn
R = H 13
R = Ac 15
16
Ac2O, Et3N
quant.
MeONa/MeOH
93%
An = p-MeOC6H4O-
R = Ac 14
R = H 1
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