Cycloaddition reactions of carbohydrate derivatives. Part 7: [3+2] cycloadditions of chiral nitrilimines

Article abstract of DOI:10.1016/S0957-4166(98)00356-5

The diastereoselective 1,3-dipolar cycloaddition reactions of chiral alkenes with a nitrilimine derived from D-galactose phenylhydrazone were studied. The best stereoselectivity was observed with N-acryloyl-(-)-camphor sultam 9, as the chiral inductor, to

Full text of DOI:10.1016/S0957-4166(98)00356-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3359–3363
Cycloaddition reactions of carbohydrate derivatives. Part 7: [3+2]
cycloadditions of chiral nitrilimines
Attila Agócs,a Attila Bényei,b,† László Somogyi a and Pál Herczegh a,∗
aResearch Group for Antibiotics of the Hungarian Academy of Sciences, Kossuth Lajos University, PO Box 70,
H-4010 Debrecen, Hungary
bDepartment of Physical Chemistry, Kossuth Lajos University, H-4010 Debrecen, Hungary
Received 18 August 1998; accepted 3 September 1998
Abstract
The diastereoselective 1,3-dipolar cycloaddition reactions of chiral alkenes with a nitrilimine derived from D-
galactose phenylhydrazone were studied. The best stereoselectivity was observed with N-acryloyl-(−)-camphor
sultam 9, as the chiral inductor, to produce compound 8. © 1998 Elsevier Science Ltd. All rights reserved.
Although nitrilimines represent an intensively studied class of 1,3-dipoles,1 until very recently no data
on their diastereoselective cycloaddition reactions have been reported, and chiral nitrilimines have not
been prepared.2 After completing the present work, the first diastereoselective cycloaddition reaction of
an achiral nitrilimine with a chiral dipolarophile was described.3 When the preparation of this manuscript
was finished, a paper on the diastereoselective [3+2] cycloaddition of nitrilimines with Fisher carbene
complexes16 appeared. In continuation of our studies on the cycloaddition reactions of carbohydrates4
it was decided to study the preparation and investigation of sugar-derived nitrilimines, as potential
precursors to the analogs of some important alkaloid antibiotics.
The simplest access to nitrilimines is based on the dehydrohalogenation of hydrazonoyl halides.5
For the generation of the carbohydrate-derived hydrazonoyl bromide 2, D-galactose phenylhydrazone
penta-O-acetate6 1 was treated with an excess of N-bromosuccinimide and dimethyl sulfide (Corey–Kim
reagent7) according to the method of Patel et al.8 (Fig. 1). Dehydrohalogenation of 2 with triethylamine
in the presence of methyl acrylate gave the nitrilimine 3, which was immediately transformed into the
4-bromophenylpyrazoline 4 as a 1:1 mixture of diastereomers, and one of them could be isolated by crys-
tallization from ether/hexane. Compound 4 could also be obtained from the 4-bromophenylhydrazone
10 with the same reaction sequence. Interestingly enough, Patel et al.8 did not report on the aromatic
bromination of the phenylhydrazones of aryl or aralkyl aldehydes when the reagent was employed in
excess.
∗
†
Corresponding author. E-mail: herczeghp@tigris.klte.hu
OTKA postdoctoral fellow.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00356-5

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A. Agócs et al. / Tetrahedron: Asymmetry 9 (1998) 3359–3363
Fig. 1.
We expected to enhance the stereoselectivity of the cycloadditions of 3 with the use of chiral acrylic
esters and amides as dipolarophiles9 (Fig. 3). Thus, reaction with (−)-menthyl acrylate10 gave an
isomeric mixture of 5 (double stereoselection of a mismatching pair of reagents), while the corresponding
enantiomer ensured higher diastereoselectivity (6, matching pair). With (1R)-endo-fenchyl acrylate11
a
mixture of isomers (7) was also obtained. In the latter three cases, the ratios of diastereoisomers were
determined by HPLC.
Contrary to the above results, when the Oppolzer’s camphor sultam derivative12,13 9 was applied as the
chiral inductor, compound 8 was detectable exclusively in the reaction mixture, the structure of the adduct
being elucidated by X-ray crystallography14 (Fig. 2). The observed selectivity of this latter reaction is in
good accordance with the model of Kim and Curran for asymmetric nitrone cycloadditions.15
As expected, N-acryloyl-(+)-camphor sultam had a poorer selectivity (constituting a mismatching pair
Fig. 2. X-Ray structure of 8.

A. Agócs et al. / Tetrahedron: Asymmetry 9 (1998) 3359–3363
3361
with 9), and in fact two diastereomers 11 were isolated in an 8:2 ratio (Fig. 3). To estimate the extent
of chiral induction exerted by the sugar moiety, the achiral benzaldehyde p-bromophenylhydrazone 12
was selected as the nitrilimine source (Fig. 4) and a d.e. of 54% 13 was observed. This finding suggests
that the contribution of the sugar portion to the stereocontrol is smaller than that of an appropriate chiral
inductor built in the alkene reaction partner. It is interesting to note that despite its close structural analogy
with the camphor grouping, the fenchyl group is not an efficient inductor at all, as yields for the three-
and four-step one-pot reaction sequences leading to the chiral pyrazolines were in the range of 30–40%
(60–70% for each step). Further chemical transformations of the cycloadducts are being studied.
Fig. 3.

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A. Agócs et al. / Tetrahedron: Asymmetry 9 (1998) 3359–3363
Fig. 4.
Acknowledgements
The authors thank the Hungarian Scientific Research Fund for financial support (Grant Nos. T 019338,
T 014205 and D 25136), and Mr. Tamás Menyhárt for his skillful technical assistance.
References
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2H-pyrazole-3-yl]carbonyl]-bornane-2,10-sultam 8: N-bromosuccinimide (NBS, 2.4 g) and dimethyl sulfide (2 ml) were
dissolved in dry CH2Cl2 at 0°C. Ten minutes later, 3.4 g (1.7 mM) of the p-bromophenylhydrazone 10 was added to the
yellow suspension at 0°C. One hour later, N-acryloyl-(−)-camphor sultam (9; 0.7 g) and triethylamine (6 ml) were added
to the orange suspension at 0°C. After 30 min the mixture was washed with sat. aq. NaHCO3, dried and evaporated.
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1H-NMR (360 MHz, CDCl3): δ 1.0 and 1.2 (6H, 2s, 2 methyl), 1.33, 1.44 and 1.9 [7H, 3m, 6, 8, 9 –CH2– and H-7 (–CH–)
of sultam], 1.9–2.1 (15H, m, 5 acetyl), 3.08 (1H, dd, H-2b (pyr. ring) J2a,2b=18 Hz, J3,2b=6 Hz), 3.28 (1H, dd, H-2a,
J
2a,3=12.5 Hz (pyr. ring)), 3.48 and 3.58 (2H, 2d, –CH2SO2–), 3.9 (1H, dd+dd, NCH, (sultam) J5,6a=J5,6b=6.5 Hz, H-50b
(CH2 sugar) J4 ,5 b=5.5 Hz, J5 a,5 b=11.5 Hz), 4.26 (1H, dd, H-50a (CH2 sugar)), 50.24 (1H, ddd, H-40, J3 ,4 =1.5 Hz), 5.35
0
0
0
0
0 0
(1H, dd, H-3 (pyr. ring)), 5.45 (1H, dd, H-30, J2 ,3 =9.5 Hz), 5.67 (2H, d+dd, H-1 and H-2 , J1 ,2 =2.5 Hz), 6.82 and 7.3
0
0
0
0 0
(4H, 2d, aromatic Jortho=9 Hz).
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14. Colorless block crystals (0.4×0.2×0.1 mm) of C35H44BrN3O13S, grown from dichloromethane/ether, M=826.7,
monoclinic, a=10.230(5) Å, b=14.174(4) Å, c=14.08(1) Å, β=105.81°, V=1964(1) Å3, Z=2, space group: P21, ρcalc=1.398
g cm−3. Data were collected at 293(1) K, Enraf–Nonius MACH3 diffractometer, MoKα radiation, λ=0.71073, ω−2θ
motion, θmax=25.24°, 4022 reflections of which 2927 were unique with I>2σ(I), decay: 4%. The structure was solved

A. Agócs et al. / Tetrahedron: Asymmetry 9 (1998) 3359–3363
3363
using the SIR-92 software (Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J. Appl. Cryst. 1993, 26, 343–350)
and refined on F2 using the SHELX-97 program (Sheldrick, G. M. SHELXL-93, Universität Göttingen, Germany, 1993),
R(F)=0.0466 and wR(F2)=0.0992 for 4022 reflections, 478 parameters, H atoms were fixed, Flack parameter: −0.00(1)
(Flack, H. D. Acta Cryst. A 1983, 39, 876–881).
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