A new approach to isolevoglucosenone via the 2,3-sigmatropic rearrangement of an allylic selenide

Article abstract of DOI:10.1081/CAR-120003745

A convenient method is described for the synthesis of isolevoglucosenone 5, via allylic selenide 3, and its rearrangement to allylic alcohol 4, followed by oxidation with manganese oxide. Isolevoglucosenone 5, is produced in 62% overall yield.

Full text of DOI:10.1081/CAR-120003745

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A NEW APPROACH TO ISOLEVOGLUCOSENONE VIA THE
2,3-SIGMATROPIC REARRANGEMENT OF AN ALLYLIC
SELENIDE
Zbigniew J. Witczak a , Peter Kaplon b & Mark Kolodziej b
a Department of Pharmaceutical Sciences , Nesbitt School of Pharmacy , Wilkes University ,
Wilkes-Barre, PA, 18766, U.S.A.
b Department of Pharmaceutical Sciences , School of Pharmacy , University of Connecticut ,
372 Fairfield Rd. U-92, Storrs, CT, 06269-2092, U.S.A.
Published online: 28 Oct 2011.
To cite this article: Zbigniew J. Witczak , Peter Kaplon & Mark Kolodziej (2002) A NEW APPROACH TO ISOLEVOGLUCOSENONE
VIA THE 2,3-SIGMATROPIC REARRANGEMENT OF AN ALLYLIC SELENIDE, Journal of Carbohydrate Chemistry, 21:1-2, 143-148,
DOI: 10.1081/CAR-120003745
To link to this article: http://dx.doi.org/10.1081/CAR-120003745
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J. CARBOHYDRATE CHEMISTRY, 21(1&2), 143–148 (2002)
A NEW APPROACH TO ISOLEVOGLUCOSENONE
VIA THE 2,3-SIGMATROPIC REARRANGEMENT
OF AN ALLYLIC SELENIDE
2
2
Zbigniew J. Witczak,1, Peter Kaplon, and Mark Kolodziej
*
1Department of Pharmaceutical Sciences, Nesbitt School of
Pharmacy, Wilkes University, Wilkes-Barre, PA 18766, USA
2Department of Pharmaceutical Sciences, School of Pharmacy,
University of Connecticut, 372 Fairfield Rd. U-92, Storrs,
CT 06269-2092, USA
ABSTRACT
A convenient method is described for the synthesis of isolevoglucosenone 5,
via allylic selenide 3, and its rearrangement to allylic alcohol 4, followed by
oxidation with manganese oxide. Isolevoglucosenone 5, is produced in 62%
overall yield.
INTRODUCTION
Levoglucosenone 1[1–4] and its isomer isolevoglucosenone 5[5–9] (Figure 1), are
excellent chiral precursors for the functionalization and introduction of biologically
important functional groups such as thio- azido- fluoro, fluoromethyl etc. The bicyclic
rigidity of 1 and 5 allows for the stereoselective functionalization of the ring system. An
efficient and economically feasible method to synthesize isolevoglucosenone is a
desirable goal in carbohydrate chemistry.
As part of our continuing studies on thiodisaccharides, [10,11] we required a
convenient, quick, and efficient way to produce both enones 1 and 5 for their further
stereoselective conversion into S-thiodisaccharides [10–12] and C-disaccharides. [13] Exist-
*Corresponding author. Fax: 570-408-7828; E-mail: witczak@wilkes.edu
143
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144
WITCZAK, KAPLON, AND KOLODZIEJ
Figure 1. Bicyclic rigidity of levoglucosenone 1 and isolevoglucosenone 5. Molecular models
generated by ACD ChemSketch 4.0, 3D (http://www.acdlabs.com).
ing methods of preparing isolevoglucosenone require multiple steps, and are labor
intensive. [5,6] Koll and coworkers reported the first chemical synthesis of enone 5 in
[5]
¨
six steps.
The second synthetic approach, reported by Furneaux and coworkers, [6] also
started from levoglucosenone 1 and produced isomeric enone 5 in low yield over seven
steps. The general methodology, developed by Horton and Roski [7] for the synthesis of 5
is based on the rearrangement of 3-mesyl-D-glucofuranose, but requires anhydrous
reaction conditions and an excess of the catalyst. A new approach to 5 from non-car-
bohydrate precursor 2-vinylfuran via an Achmatowicz rearrangement [8] was reported by
Ogasawara. [9] Recently, we developed a direct route to enone 5 from D-glucal through
the 2,3-allylic alcohol 4. [12] In this paper we report a new and convenient approach for
direct conversion of levoglucosenone 1 into its isomeric isolevoglucosenone 5 in 62%
overall yield.
RESULTS AND DISCUSSION
Our strategy for the functionalization of C-2 of levoglucosenone 1, required a
stereoselective reduction, followed by the selenium mediated functionalization and
oxidation of the allylic selenide. The practical synthesis of 5 is as follows (Scheme 1):
the carbonyl group of 1 was reduced with L-Selectride1 in THF at ꢀ78 ꢀC according to
the literature methodology [19] or alternatively with lithium aluminum hydride in ethyl
ether to give allylic alcohol 2 in 70% yield as a crystalline derivative, mp 53–54 ꢀC.
Scheme 1.

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SYNTHESIS OF ISOLEVOGLUCOSENONE
145
Scheme 2.
The hydroxy group of 2 was further functionalized by utilizing a combination of the
selenium reagent [20] o-nitrophenylselenocyanate/tributyl phosphine [21] in a tetrahydro-
furan solution with the formation of allylic selenate 3 in 94% yield. The oxidative
elimination reaction of the o-nitrobenzeneselenyl group with hydrogen peroxide in pyri-
dine at ꢀ20 ꢀC for 2 h produced the 1,3 rearranged allylic alcohol 4 in 89% yield (Scheme 1).
The oxidation of 3 with a stoichiometric amount of hydrogen peroxide performed at
low temperature (preferably at ꢀ20 ꢀC) produced the allylic alcohol 4 in good yield
(68%) along with the formation of o-nitrobenzeneselenenic acid o-NO2C6H4SeOH easily
separated from the reaction mixture. The stoichiometric amount of hydrogen peroxide is
critical as the o-nitrobenzeneselenenic acid formed by further oxidation will be converted
to o-nitro-benzeneseleninic acid, o-NO2C6H4Se(O)OH, which is known to catalyze the
epoxidation of allylic alcohols. [14] In the oxidation of 3, described above, the formation
of the epoxide 6[14] was not observed.
The [2,3]-sigmatropic shift leading to rearrangement of the allylic selenide via the
intermediate selenoxide during hydrogen peroxide oxidation is presumably catalysed by
evolved o-nitrophenylseleninic acid, as described by Kametani et. al. [14]
The mechanism of this sigmatropic rearrangement [15] is shown in Scheme 2. This
key-step results in double bond transposition and introduction of allylic functionality at
C-4 of isolevoglucosenone. To our knowledge, this is the first example of a [2.3]-sig-
matropic rearrangement of a functionalized carbohydrate selenide.
The 2,3-allylic alcohol 4, prepared by this method was identical to the product
synthesized by the Oberdorfer procedure. [16,17]
Oxidation of allylic alcohol 4 was performed with manganese oxide [18] in dichlo-
romethane solution to produce the enone 5 in high 89% yield. Alternatively, oxidation of
4 with pyridinium dichromate (PDC) in dichloromethane/acetic anhydride solution
produced enone 5 in comparable yield (88%) but required purification by column chro-
matography to remove residual colloidal chromium complex. In summary, isolevoglu-
cosenone was synthesized in four efficient steps from levoglucosenone, using a sig-
matropic rearrangement of an allylic selenoxide as the key step.

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146
WITCZAK, KAPLON, AND KOLODZIEJ
EXPERIMENTAL
General Methods. Unless otherwise noted, starting materials were obtained from
commercial suppliers and used without purification. Organic extracts were dried with
MgSO4 and concentrated with a rotary evaporator under reduced pressure (aspirator).
Flash column chromatography was carried out with Silica Gel 60 (70-213 mesh, Merck
No. 7734). Thin-layer chromatography (TLC) was performed with Merck F-254 TLC
plates. All melting points were uncorrected and were measured in open capillary tubes.
Optical rotations were measured with a Jasco DIP-370 polarimeter. 1H NMR spectra were
recorded at 250 MHz and 13C NMR spectra at 50 MHz, with TMS as an internal standard
on a Bruker DPX250 spectrometer. Levoglucosenone was produced according to the
convenient published methodology [4,5] and 1,6-anhydro-3,4-dideoxy-b-D-threo-hex-3-
enopyranose [2] was prepared according to the method of Shafizadeh et al. [1]
1,6-Anhydro-3,4-dideoxy-2-Se-(o-nitrobenzyl)-b-D-erythro-hex-3-enopyran-ose
(3). A solution of 2 (0.72 g, 5.6 mmol) in 15 mL of dry THF containing o-nitro-
benzeneselenylcyanate, (1.28 g, 5.6 mmol) under nitrogen was treated dropwise with tri-
n-butylphosphine (300 mg, 1.48 mmol) at room temperature. After the reaction was
stirred for 30 min the solvent was removed in vacuo. Column chromatography of the
residue on silica gel using hexane–ether (3:1) gave 1.72 g (94%) of o-nitrophenylsele-
nide 3, crystallized as white–yellow crystals mp 160–161.5 ꢀC, 94%, Rf =0.52 (EtOAc),
[a]D ꢀ238ꢀ (c 1.0 CHCl3), 1H NMR (CDCl3): d 3.72–3.84 (2H, m H-6 and H-60), 4.85–
4-82 (1H, m, H-5), 5.0 (1H, d, J= 4.0 Hz, H-2), 5.69 (1H, br, H-1), 5.9 (1H, ddd, J= 9.8,
4.0, 2.0 Hz, H-3), 6.38 ddd (1H, J =9.5, 4.8, 1.1 Hz, H-4), 8.24–8.32 (4H, m, aromatic
H). 13C NMR: (CDCl3) d 65.10 (C-2), 118.68, 125.90, 127.4–128.6 (CH-arom), 137.8–
138.8 (C-arom), 99.36 (C-1), 71.85 (C-5), 130.24 (C-4), 66.0 (C-6), 132.56 (C-3). HRMS
(M)+ m/z: Calcd for C12H11NO4Se: 312.9853. Found: 312.6195.
Anal. Calcd for C12H11NO4Se: C, 46.17; H, 3.55; N, 4.49. Found: C, 46.56, H,
3.53, N, 4.55.
1,6-Anhydro-2,3-dideoxy-b-D-erythro-hex-2-enopyranose (4). To a cooled sol-
ution of 3 (1.25 g, 3.9 mmol) in dry pyridine (35 mL), a solution of 32 wt.% water
solution of hydrogen peroxide 25 mL was added dropwise at ꢀ20 ꢀC. The resulting
solution was warmed to ambient temperature and stirred for 4 h. The solution was added
to saturated aqueous sodium hydrogen carbonate (100 mL) and the mixture was extracted
with chloroform (3ꢁ30 mL). The organic layer was washed with water, dried (MgSO4),
and concentrated to a yellow oil. Column chromatography on silica gel with hexane/ethyl
acetate (5:1) as eluant yielded compound 4 (0.45 g in 89% yield) which crystallized (mp
61–62 ꢀC) upon refrigeration. Compound 4 was independently prepared by the Ober-
dorfer [16,17] method. Rf = 0.59 (EtOAc), mp 60–61.5 ꢀC, Lit. 58–59 ꢀC, [16] [a]D +318ꢀ
(c 1.0 CHCl3), [a]D +318ꢀ (c 1.0 CHCl3): for NMR data see (16, 17). For 13C NMR see
(17).
1,6-Anhydro-2,3-dideoxy-b-D-glycero-hex-2-enopyranos-4-ulose (5) (Isolevo-
glucosenone). (a) A mixture of the crude allylic alcohol 4 (2.56 g, 20 mmol) was
dissolved in dry chloroform or dichloromethane (300 mL) and manganese dioxide
(MnO2), (29 g, 334 mmol) was stirred at room temperature for 6 h. After filtration,

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SYNTHESIS OF ISOLEVOGLUCOSENONE
147
the mixture was concentrated to a syrup and the crude product was purified by flash
chromatography with 5:1, n-pentane-Et2O, to give enone 5, (2.25 g, 89%) as a pale
yellow oil.
(b) The crude allylic alcohol 4 (2.56 g, 20 mmol) was dissolved in dichloromethane
(30 mL). Pyridinium dichromate (PDC), (9.63 g, 25.6 mmol) was added to the mixture
while stirring at room temperature for 40 h. Filtration through a column of silica/sand/
Celite and concentration afforded a brown syrup (1.5 g, 59.5%) which was purified by
flash chromatography using 5:1, n-pentane-Et2O, to produce the enone 5, as a pale yellow
oil (2.22 g, 88%).
Enone 5 could be obtained as an analytically pure colorless syrup after a second
chromatographic purification using 5:1, n-pentane-Et2O. ([a]D + 319.6 o (c 1.0 CHCl3)
lit. [a]D+321ꢀ (c 1.1 CHCl3). [9] The 1H NMR and 13C NMR spectra of 5 were identical
with those published in the literature. [5–9]
ACKNOWLEDGMENTS
Financial support from the American Cancer Society, Institutional Grant to the
University of Connecticut Health Center #ACSIN 152L-132 is gratefully acknowledged.
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Received November 16, 2000
Accepted December 31, 2001