Synthesis of sugar-fused isoxazoline N-oxides from 2-nitroglycals

Article abstract of DOI:10.1002/ejoc.201000397

A new type of sugar-fused isoxazoline N-oxides was synthesized from 2-nitroglycals via [1+4] condensation with bromomalonate under the action of DBU. In addition, 1,3-dipolar cycloaddition of these isoxazoline N-oxides with alkene and alkyne dipolarophiles were also investigated.

Full text of DOI:10.1002/ejoc.201000397

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000397
Synthesis of Sugar-Fused Isoxazoline N-Oxides from 2-Nitroglycals
Qingju Zhang,[a,b] Jiansong Sun,*[a] Fuyi Zhang,[b] and Biao Yu*[a]
Keywords: Synthetic methods / 2-Nitroglycal / Isoxazoline N-oxide / 1,3-Dipolar cycloaddition
A new type of sugar-fused isoxazoline N-oxides was synthe-
sized from 2-nitroglycals via [1+4] condensation with bromo-
malonate under the action of DBU. In addition, 1,3-dipolar
cycloaddition of these isoxazoline N-oxides with alkene and
alkyne dipolarophiles were also investigated.
Introduction
Results and Discussion
2-Nitroglucal and -galactal derivatives, firstly introduced
It is well documented in the literature that the addition of
by Lemieux et al. in 1968,[1] have been employed in the syn- chloro- or bromomalonate to α,β-unsaturated nitroalk-
thesis of 2-amino-2-deoxyglycosides by Schmidt and co- enes can provide nitrocyclopropanes in good yields and excel-
workers, in which the thermodynamically favored α-gly- lent enantioselectivity.[5] We conjectured that 2-nitroglycals
cosidic products were predominantly formed in the pres- might also adopt a similar reaction pathway to afford 1,2-
ence of a strong inorganic base, such as KOtBu.[2] Recently, cyclopropanated sugar 3a (Scheme 1, route a), which could
we found that under the action of a weak Lewis base, i.e., be used as glycosyl donor to couple with nucleophiles.[6] Thus,
DMAP [4-(dimethylamino)pyridine] or PPY [4-(1-pyrrolid- 2-nitrogalactal 1a was treated with bromomalonate 2 in the
ino)pyridine], the addition of a nucleophile onto 2-nitrogly- presence of DBU (1.2 equiv. based on 2-nitroglycal) in
cals led to β-glycosidic products.[3] Considering that nitro CH2Cl2 at room temperature. The reaction proceeded rapidly,
olefins are versatile reagents in organic synthesis[4] and the and the putative adduct 3a was obtained in excellent yield
1
nitro olefin unit incorporated in a sugar scalffold may bring (91%). However, after scrutinizing carefully the H and 13C
about new chemical properties, we continued our program NMR spectra, we found that there were evident discrepancies
to investigate new reactions of 2-nitroglycals.
between the spectra and those of the proposed structure. In
Scheme 1. Condensation of 2-nitroglycals and bromomalonate.
[a] State Key Laboratory of Bioorganic and Natural Products
the 13C NMR spectrum, besides signals from the two ester
Chemistry, Shanghai Institute of Organic Chemistry, Chinese carbonyl carbon atoms, there were another two signals from
Academy of Sciences,
quaternary carbon atoms at δ = 109.56 and 84.21 ppm; these
Shanghai 200032, China
two signals should be assigned to C-2 and C-7 in compound
3a; nevertheless, the chemical shift values of these two carbon
atoms were in sharp difference to those of carbon atoms in
known compounds with similar chemical environments. Re-
garding C-2 incorporated in a cyclopropane and substituted
with NO2, its chemical shift should be δ ≈ 60 ppm,[5b,7] and
the signal of C-7 should appear at δ ≈ 50 ppm.[5b]
Fax: +86-21-64166128
E-mail: jssun@mail.sioc.ac.cn
byu@mail.sioc.ac.cn
[b] Chemistry Department, The Key Laboratory of Chemical
Biology and Organic Chemistry of Henan Province, Zhengzhou
University,
Zhengzhou 450052, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000397.
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Q. Zhang, J. Sun, F. Zhang, B. Yu
SHORT COMMUNICATION
An alternative reaction pathway for the condensation of
To further corroborate the proposed structure of 4a,
2-nitroglycals and bromomalonate is route b, which would chemical derivatizations were undertaken subsequently
lead to isoxazoline N-oxide derivative 4a. In fact, the struc- (Scheme 2). It is well documented that isoxazoline N-oxides
ture of 4a agrees with all the spectra quite well. The 13C can be easily reduced to ketone oxime derivatives by hydro-
signals at δ = 109.6 and 84.2 ppm were therefore well as- genolysis.[9] Thus, compound 4a was subjected to hydro-
signable to C-2 and C-7.[8] A characteristic 1H NMR singlet genolysis (H2, 1 atm) in the presence of Pd/C. A new com-
at δ = 5.78 ppm was assigned to the anomeric proton; pound, which was assigned to ketone oxime 5, was obtained
HMBC correlations between this proton and the two ester in good yield (77%), while all the benzyl groups remained
1
carbonyl carbon atoms were observed. The configuration intact. The structure of 5 correlated well with the H and
of the anomeric proton was determined to be β based on 13C NMR spectra; to this end, two deuterable proton sig-
the strong NOE correlation with one proton on C-6 (Fig- nals corresponding to ketone oxime proton and hydroxy
ure 1).
proton were found at δ = 8.31 and 4.10 ppm, and the na-
scent ketone oxime carbon signal appeared at δ =
150.1 ppm. Subsequent acetylation of 5 (Ac2O, pyridine,
room temp.) led to N-OAc derivative 6 quantitatively. In-
corporation of the Ac group on the ketone oxime resulted
in a downfield shift of the ketone oxime carbonyl carbon
signal from δ = 150.1 ppm to δ = 158.4 ppm and disappear-
ance of the proton signal at δ = 8.31 ppm.
Isoxazoline N-oxide derivatives are frequently used as in-
termediates in the synthesis of natural products and biolo-
gically active compounds.[10] The preparation methods of
Figure 1. Key correlations observed by 2D NMR spectroscopy.
Scheme 2. Derivatization of compound 4a.
Table 1. [4+1] cycloaddition of 2-nitroglycals and 2-bromo-1,3-dicarbonyl compounds.
[b]
[a] Isolated yields. 2 equiv. of 9 and DBU were used.
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Synthesis of Sugar-Fused Isoxazoline N-Oxides from 2-Nitroglycals
isoxazoline N-oxides can be divided into three categories: along the [4+1] pathway to yield 11; however, inferior yields
(1) intramolecuar O-alkylation of aliphatic nitro com- and stereoselectivity (11a/11b = 3.6:1) were registered be-
pounds;[11] (2) [3+2] cycloaddition;[12] (3) [4+1] cycload- cause of the lower reactivity of 1b. These results were in
dition.[13] Nevertheless, compared to the former two meth- accordance with our previous finding on the nucleophlic
ods, the [4+1] cycloaddition strategy was less explored and addition to 2-nitroglucal.[3]
reported only once, in which a Michael addition was in-
With these sugar-fused isoxazoline N-oxides in hand, we
volved, and the Michael donor was attached to cinconidine tested their synthetic utility in the 1,3-dipolar cycloaddition
to secure a high enantioselectivity.[13] The present synthesis to form nitroso acetals with three fused rings. Nitronates,
of 4a belongs to this [4+1] strategy as well, but the high both in cyclic and acyclic form, have been proved to be
stereoselectivity was realized through the chiral Michael ac- versatile 1,3-dipoles that undergo reactions with neutral,
ceptor.
electron-rich or -poor dipolarophiles.[4b,9] In addition, the
Then the scope of this reaction was briefly examined regiochemical course of the dipolarophile approach is such
(Table 1). Under the above-mentioned conditions that the carbon atom bearing the substituent always be-
(1.2 equiv. of bromomalonate, 1.2 equiv. of DBU, CH2Cl2, comes attached to the oxygen atom of the dipole.[4b]
room temp.), the condensation of 2-nitroglycal 1a with ethyl
Indeed, when isoxazoline N-oxide 8 was treated with
bromomalonate 7 gave isoxazoline N-oxide 8 in excellent ethyl acrylate 12 (as co-solvent with dichloroethane in a 1:1
yield (98%), and only the α-isomer was obtained (Table 1, ratio) at room temperature, two diastereoisomers 13a and
Entry 2). With 3-bromo-2,4-pentanedione 9 as the Michael 13b were obtained in good yield (57%, 13a/13b = 1.2:1)
donor, the desired product was obtained in 54% yield. Nev- (Table 2, Entry 1), indicating that 12 approached 8 with a
ertheless, the stereoselectivity was maintained (Entry 3). high facial selectivity (from the β-face exclusively) and a
The reaction of 2-nitroglucal 1b with 2 also proceeded low endo/exo (exo product 13a was weakly favored) dis-
Table 2. [3+2] cycloaddition of isoxazoline N-oxides with dipolarophiles.
[a] Isolated yields.
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Q. Zhang, J. Sun, F. Zhang, B. Yu
SHORT COMMUNICATION
crimination manner. Similar results were obtained when 4a kyne dipolarophiles led to nitroso acetals with three fused
was treated with methyl methacrylate 14, but the yield and rings in good yields.
exo selectivity were enhanced (88%, 15a/15b = 1.8:1)
Supporting Information (see footnote on the first page of this arti-
(Table 2, Entry 2). Next, dimethyl acetylenedicarboxylate
(16) was examined as dipolarophile. Notably, 8 reacted with
16 facial-selectively to form 17 in an excellent 91% yield 19.
(Entry 3). Although the facial discrimination decreased
when 16 reacted with 4a (18a/18b = 4.5:1), the yield was
still excellent (98%, Entry 4). Glucosylisoxazoline N-oxide
11b was also a good substrate for the cycloaddition with
16; a good yield (78%) and an excellent facial selectivity
were obtained (Entry 5). It is worthy to note that the facial
discrimination of olefins 12/14 and acetylene 16 (compare
Entries 1, 2 with Entries 3, 4, 5) is opposite. In addition, to
the best our knowledge, this is the first report that an al-
kyne is used as dipolarophile in the 1,3-dipolar cycload-
dition with isoxazoline N-oxides. All these compounds were
characterized spectroscopically. X-ray diffraction analysis
of a single crystal of 19[14] further confirmed the proposed
structure (Figure 2).
cle): Experimental details and reproductions of the NMR spectra
for all new compounds and X-ray diffraction data for compound
Acknowledgments
This work was financially supported by the National Basic Re-
search Program of China (2010CB833202) and the National Natu-
ral Science Foundation of China (20932009 and 20902097).
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Conclusions
A new type of sugar-fused isoxazoline N-oxides was syn-
thesized from 2-nitroglycals by [4+1] condensation with
bromomalonate in the presence of DBU. 1,3-Dipolar cyclo-
addition of these isoxazoline N-oxides with alkenes and al-
Received: March 24, 2010
Published Online: May 21, 2010
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Eur. J. Org. Chem. 2010, 3579–3582