Nitrile oxide cycloadditions to olefinated sugars

Article abstract of DOI:10.1016/S0040-4039(02)02665-5

Carbohydrate derivatives with a spiro-isoxazoline moiety as present in psammaplysins and ceratinamides (metabolites isolated from marine sponges) were prepared in good yields and excellent regio- and diastereoselectivity by a route involving Wittig olefination and 1,3-dipolar cycloaddition as key steps.

Full text of DOI:10.1016/S0040-4039(02)02665-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1071–1074
Nitrile oxide cycloadditions to olefinated sugars
Pedro A. Colinas,a Volker Ja¨ger,b Albrecht Lieberknechta,b,* and Rodolfo D. Bravoa,*
aLaboratorio de Estudio de Compuestos Orga´nicos, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115,
1900 La Plata, Argentina
bInstitut fu¨r Organische Chemie der Universita¨t Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 22 October 2002; revised 18 November 2002; accepted 25 November 2002
Abstract—Carbohydrate derivatives with a spiro-isoxazoline moiety as present in psammaplysins and ceratinamides (metabolites
isolated from marine sponges) were prepared in good yields and excellent regio- and diastereoselectivity by a route involving
Wittig olefination and 1,3-dipolar cycloaddition as key steps. © 2003 Published by Elsevier Science Ltd.
1. Introduction
isoxazolines derived from carbohydrates by a sequence
involving the Wittig reaction and 1,3-dipolar cycloaddi-
tion as key steps (Scheme 1).
The psammaplysins and ceratinamides 1 are a unique
small family of bromostyrene metabolites isolated from
marine sponges of the order Verongida; they feature the
most unusual spiroketal ring system found in nature so
far.1 The psammaplysins were reported to exhibit
potent cytotoxicity against P388 murine leukemia cells
and anti-HIV activity against the Haitian RF strain of
HIV-1, while the ceratinamides display anti-fouling
activity.2
2. Synthesis of the
D
-lyxo-enitols
Wittig reactions of the phosphonium salt4 2 and several
aldehydes using n-BuLi in THF gave the exocyclic enol
ethers 3, which after filtration through silica gel, were
obtained spectroscopically pure in good yield (Scheme
2). The E and Z isomers could be separated by MPLC
on silica gel.6
In the last years we have developed the synthesis of
enol ethers derived from 2-deoxypentoses3a and
hexoses.4 Further interest is in the reactions of the ‘enol
ether’ function which offers numerous possibilities for
transformations and which can be regarded as a valu-
able intermediate in the synthesis of various new C-gly-
cosides.4 To the best of our knowledge, only one
example of nitrile oxide cycloaddition to 1-methylene
sugars is known, with few experimental details given.5
We wish to report a method for the synthesis of spiro-
3. Nitrile oxide cycloadditions
The cycloadditions of the olefinated sugars 3 were
performed with two nitrile oxides: mesitonitrile oxide
(stable monomer) and ethoxycarbonylnitrile oxide
(unstable; generated in situ using Huisgen’s method).
* Corresponding authors. Tel.: +54-221-422-6977; fax: +54-221-4222-6947; e-mail: rdb@exactas.unlp.edu.ar
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02665-5

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P. A. Colinas et al. / Tetrahedron Letters 44 (2003) 1071–1074
Scheme 1.
Scheme 2.
3.1. Mesitonitrile oxide cycloadditions
very slowly added at room temperature.3c,8 The normal
method involving the addition of triethylamine to the
solution could not be used due to very fast reaction
between the enol ether and the nitrile oxide precursor,
which afforded the addition product 7, probably cata-
lyzed by small quantities of HCl. The method reported
in the literature,5 involving the mixing of all reactants
at 0°C, was also employed but only led to a low yield of
the cycloadduct 6. Under these conditions the cycload-
ditions of the enol ethers (E)- and (Z)-3a were unsuc-
cessful and only the furoxan was obtained (Table 2).
The enol ether 3 and mesitonitrile oxide were dissolved
in dichloromethane and allowed to react under the
conditions (temperature, time) indicated in Table 1. The
products were easily purified using chromatography on
silica gel.7 In all cases the d.r. determined from the
crude reaction mixtures was >95:5. The H NMR, 13C
1
NMR, 2D-COSY (H–H, H–C) and NOESY experi-
ments supported the proposed structures for com-
pounds 4. The lack of NOE between the H-4
(isoxazoline) and the H-7 (pyranosyl C-5 hydrogen)
confirms the configuration of the spiro-isoxazolines.
Also this configuration is in agreement with the attack
of the nitrile oxide to the less hindered a-face of the
exo-glycal.
In some cases, solvent-free conditions coupled with
microwave irradiation have proven useful for the gener-
ation of nitrile oxides and good yields were found with
sluggish dipolarophiles.9,10 Due to the low reactivity of
the 1-phenylenitols (E)- and (Z)-3a, we applied these
conditions to the reaction with the ethoxycarbonyl-
nitrile oxide, which was generated in situ using Al2O3 as
base (Table 3).11 Also the methyl derivate (E)-3b was
used for comparison.
3.2. Ethoxycarbonylnitrile oxide cycloadditions
The enol ether and triethylamine were dissolved in
dichloromethane and the hydroximoyl chloride 5 was
Table 1. Reactions of 3 with mesitonitrile oxidea
The reaction of trisubstituted alkenes with nitrile oxides
was accelerated under high pressure (10 kbar) using
potassium carbonate as base.12 Unfortunately, the reac-
tions of the exo-glycals 3a–b with the ethoxycarbonyl-
nitrile oxide did not proceed in reasonable yields under
these conditions.
The high stereoselectivity observed is in accord with the
steric approach control, which favors the attack to the
less hindered a-face of the enol ethers 3 leading to
products with
a b-oriented C-substituent at the
anomeric center (Fig. 1). This stereochemical outcome
was also found in other additions to exo-glycals (like
hydrogenation, hydroboration, etc.).4,5 The regioselec-
tivity, with the preference for the more substituted
carbon atom to end up at the 5-position of the hetero-
cycle, corresponds to the mode normally found in
nitrile oxide cycloadditions to trisubstituted alkenes.12
In conclusion, the method described here allows for the
regio- and diastereoselective preparation of such spiro-
Olefin
(E)-3a
(Z)-3a
(E)-3b
Product
trans-4a
cis-4a
Temp.
Time
Yield (%)
rt
reflux
rt
reflux
rt
20 d
36 h
20 d
30 h
12 h
85
80
86
78
76
trans-4b
a Dipole:dipolarophile 1:1.

P. A. Colinas et al. / Tetrahedron Letters 44 (2003) 1071–1074
Table 2. Reactions with ethoxycarbonylnitrile oxidea
1073
Reactants
Reagent added
Temperature
Yield (%)
6
7
Furoxan
(E)-3b+5
Et3N
rt 18 h
0°C, rt 18 h
rt 18 h
rt 18 h
rt 18 h
–
92
8
-
–
–
–
30
(E)-3b+5+Et3N
(E)-3b+Et3N
(E)-3a+Et3N
(Z)-3a+Et3N
–
5
5
5
30b,e (trans)
76e (trans)
–
–
10
70c
78d
a Dipole:dipolarophile 1:1.
b 50% of (E)-3b recovered.
c 80% of (E)-3a recovered.
d 76% of (Z)-3a recovered.
e d.r. >95:5 (determined by 1H NMR).
Table 3. Cycloadditions with microwave irradiationa,b
experimental help, Mr. J. Rebell for NMR measure-
ments, the DLR (Germany) and SETCIP (Argentina)
for financial support, and DAAD for granting a post-
doc fellowship to P.A.C.
Olefin
(E)-3a
Product
Power (W)
Time (min)
Yield (%)
trans-6a
400
400
700
400
400
15
30
15
15
15
42
40
35
45
70
(Z)-3a
(E)-3b
cis-6a
trans-6b
References
a Dipole:dipolarophile 1:1.
1. Perron, F.; Abizati, K. F. Chem. Rev. 1989, 89, 1617–
1661.
b d.r. >95:5.
2. (a) Ichiba, T.; Scheuer, P. J. J. Org. Chem. 1993, 58,
4149–4150; (b) Liu, S.; Fu, X.; Schmitz, F. J.; Kelly-
Borges, M. J. Nat. Prod. 1997, 60, 614–615; (c) Lacy, C.;
Scheuer, P. J. J. Nat. Prod. 2000, 63, 119–121.
3. (a) Lieberknecht, A.; Griesser, H.; Bravo, R. D.; Colinas,
P. A.; Grigera, R. J. Tetrahedron 1998, 54, 3159–3168; (b)
For other syntheses see: Somsa´k, L. Chem. Rev. 2001,
101, 81–135 and references therein; Griffin, F. K.; Pater-
son, D. E.; Murphy, P. V.; Taylor, R. K. Eur. J. Org.
Chem. 2002, 1305–1322; (c) Cf. Cycloadditions to furan:
Mu¨ller, I. Dissertation, Wu¨rzburg, 1984; Ja¨ger, V.;
Mu¨ller, I. Tetrahedron 1985, 41, 3519–3528.
Figure 1.
isoxazolines. The reactions with the phenyl-substituted
enol ethers afforded lower yields than the ones with the
methyl substituent, but the yields and/or reaction times
could be improved by using higher temperature (Table
1) or with the aid of microwave irradiation (Table 3).
4. Lieberknecht, A.; Griesser, H.; Kra¨mer, B.; Bravo, R. D.;
Colinas, P. A.; Grigera, R. J. Tetrahedron 1999, 55,
6475–6482.
Various transformations of the spiro-isoxazolines are
meanwhile in progress and will be presented in due
course.
5. RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51,
5458–5461.
6. The E and Z configurations were assigned on the basis of
the chemical shifts of the vinyl protons, according to
increment calculations done for related olefins: Pascual,
C.; Meier, J.; Simon, W. Helv. Chim. Acta 1969, 49,
164–168; Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W.
Strukturauflkla¨rung organischer Verbindungen, 3rd ed.;
Acknowledgements
We would like to thank Ms. I. Kienzle for valuable

1074
P. A. Colinas et al. / Tetrahedron Letters 44 (2003) 1071–1074
Springer: Berlin-Heidelberg-New York, 1986. Also the
assignment was confirmed by comparison with earlier
exo-glycals prepared by us: Refs. 3a and 4.
2H, J=11.8, PhCH6 2), 4.69 (AB, 1H, J=11.5, PhCH6 2),
4.93 (AB, 1H, J=11.5, PhCH6 2), 6.86 (s, 2H, Mst), 7.23–
7.36 (m, 20 H, Ph). 13C NMR (125 MHz) l=11.4
7. Preparation of 4a: A solution of 0.1 mmol of the enol
ether (E)- or (Z)-3a, (E)-3b and 0.1 mmol of the mesi-
tonitrile oxide in 1 mL of dry methylenchloride, under
nitrogen, was stirred at the temperature and time indi-
cated. The solution was concentrated in vacuo to afford
an oil, which was purified by chromatography on silica
gel (eluent: hexane/ethyl acetate 9:1) to give the products
4. Trans 4a: colorless syrup, IR (neat): 3062.4, 3030,
2918.2, 2360.1, 1495.4, 1454.1, 1364.1, 1104.0 1067.1,
(CH3-C4), 19.9, 21.1 (CH3 (Mst)), 29.7 (C-10), 55.3 (C-4),
69.0 (C-11), 70.8 (Ph-C
6 H2), 71.4 (C-8), 72.4 (C-7), 73.3
(Ph-CH2), 74.5 (Ph-CH2), 76.3 (C-9), 108.9 (C-5), 122.3–
6
6
128.6, 137.3–138.8 (Ph), 164.1 (C-3). Anal. calcd for
C39H43NO5: C, 77.33; H, 7.15; N, 2.31. Found: C, 77.20;
H, 7.04; N, 2.25.
8. Preparation of trans-6b: To a solution of 0.1 mmol of
(E)-3b and 0.15 mmol of triethylamine in 2 mL of dry
methylenchloride was added, under argon and at room
temperature, 0.1 mmol of the hydroximoyl chloride 5
dissolved in 10 mL of methylenchloride during 18 h. The
reaction mixture was filtrated, washed with brine and
dried. The residue, after removal of the solvent in vacuo,
was chromatographed on silica gel (eluent: hexane/ethyl
acetate 8:2) to give the product trans-6b as a colorless oil
in 76% yield. [h]2D0: +99.5 (c 0.8, CHCl3) IR (neat) 2871.8,
2359.9, 1720.7, 1586.1, 1496.5, 1454.3, 1372.2, 1254.2,
1060.9, 860.3, 822.4, 738.7, 697.0. 1H NMR (500 MHz)
l=1.17 (d, 3G, J=7.5, CH3-C4), 1.35 (t, 3H, J=7.2,
1
1027.4, 812.8, 737.0, 698.1 H NMR (500 MHz) l=1.94
(dd, 1H, J=4.4, J=12.6, H-10), 2.04 (t, 1H, J=12.6,
H-10), 2.18 (s, 9H, 3×CH3 (Mst)), 3.55 (dd, 1H, J=5.4,
J=8.7, H-11), 3.71 (t, 1H, J=8.7, H-11), 4.03 (s, 1H,
H-7), 4.06 (m, 1H, H-9), 4.35 (t, 1H, J=6.4, H-8), 4.38 (s,
1H, H-4), 4.45 (AB, 1H, J=11.6, PhCH
J=11.6, PhCH2), 4.50 (AB, 1H, J=11.6, PhCH2
(AB, 1H, J=11.6, PhCH2), 4.64 (AB, 1H, J=11.5,
6
2), 4.49 (AB, 1H,
6
6
), 4.57
6
PhCH6 2), 4.87 (AB, 1H, J=11.5, PhCH6 2), 6.73 (s, 2H,
Mst), 7.16–7.37 (m, 20H, Ph). 13C NMR (125 MHz)
l=20.3, 20.9 (CH3, Mst), 30.0 (C-10), 67.0 (C-4), 68.9
CH6 3CH2), 2.06 (dd, 1H, J=4.2, J=12.6, H-10), 2.36 (t,
1H, J=12.6, H-10), 3.27 (c, 1H, J=7.5, H-4), 3.45 (dd,
1H, J=5.3, J=9, H-11), 3.60 (t, 1H, J=9, H-11), 4.05
(m, 1H, H-9), 4.17 (dd, 1H, J=5.8, J=7.8, H-8), 4.32 (m,
(C-11), 70.8 (Ph-C
6
H2), 71.4 (C-8) 71.9 (C-7), 72.2 (Ph-
C
6
H2), 73.3 (Ph-C
6
H2), 74.4 (C-9), 109.9 (C-5), 125.1–
131.9, 137.3–138.7(Ph), 163.4 (C-3). Anal. calcd for
C44H45NO5: C, 79.13; H, 6.79; N, 2.10. Found: C, 79.03;
H, 6.80; N, 2.06.
2H, CH3CH2
CH2), 4.64 (d, 1H, J=11.4, Ph-CH2
11.4, Ph-CH
MHz) l=11.9 (C
50.1 (C-4), 62.0 (CH3C
72.0, 72.1 (C-7, C-8), 73.3 (PhC
(C-9), 111.9 (C-5), 127.3–128.5 (Ph), 137.9–138.7 (Ph),
157.5 (C-3), 160.2 (C(O)OEt). Anal. calcd for
6
), 4.42 (s, 2H, Ph-CH2
6
), 4.61 (m, 2H, PH-
), 4.91 (d, 1H, J=
6
6
6
2), 7.25–7.38 (m, 15H, Ph). 13C NMR (125
cis-4a: colorless oil, IR (neat): 3087.6, 2921.5, 2360.3,
2349.8, 2288.6, 1454.4, 1256.1, 1210.9, 1169.5, 1069.3,
6
H3-C4), 14.1 (C
H2), 68.3 (C-11), 70.6 (PhC
H2), 74.5 (PhCH2), 75.6
6
H3CH2), 29.4 (C-10),
H2),
1
6
6
736.6, 697.9 H NMR (500 MHz) l=2.18 (s, 3H, 1×CH3
6
6
(Mst)), 2.24 (s, 6H, 2×CH3 (Mst)), 2.38 (dd, 1H, J=4.6,
J=12.5, H-10), 2.52 (t, 1H, J=12.5, H-10), 3.47 (dd, 2H,
J=5.4, J=3.2, H-11), 3.92 (s, 1H, H-7), 4.07 (m, 1H,
H-9), 4.27 (t, 1H, J=6.6, H-8), 4.37 (AB, 1H, J=11.8,
6
C33H27NO7: C, 72.12; H, 4.95; N, 2.55. Found: C, 71.98;
H, 4.86; N, 2.51.
PhCH
J=12.2, PhCH
11.8, 2×PhCH
6
2), 4.43 (AB, 1H, J=11.8, PhCH2
6 ), 4.48 (AB, 1H,
9. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathe´, D. Synthesis 1998, 9, 1213–1234.
10. (a) Touaux, B.; Klein, B.; Texier-Boullet, F.; Hamelin, J.
J. Chem. Res. (S) 1994, 116–117; (b) Touaux, B.; Texier-
Boullet, F.; Hamelin, J. Heteroatom Chem. 1998, 9, 351–
354.
11. General procedure for the cycloadditions with microwave
irradiation: 0.1 mmol of the enol ether and 0.1 mmol of
5 were adsorbed on 1 g of Al2O3 previously dried. The
mixture was then irradiated for the given time and power.
Then the mixture was extracted with methylenchloride,
and, after removal of the solvent, the residue was purified
by chromatography on silica gel (eluent: hexane/ethyl
acetate 9:1).
6
2), 4.60 (s, 1H, H-4), 4.62 (AB, 2H, J=
6
2), 4.85 (AB, J=11.5, PhCH6 2), 6.74 (s, 2H,
Mst), 6.94–7.33 (m, 20 H, Ph). 13C NMR (125 MHz)
l=20.7, 21.0 (CH3, Mst), 31.8 (C-10), 65.2 (C-4), 68.9
(C-11), 70.5 (Ph-C
6 H2), 71.6 (C-8), 71.9 (C-7), 73.1 (Ph-
C
6
H2), 73.2 (Ph-CH2), 75.7 (C-9), 107.6(C-5), 125.6–131.4,
6
138.1–139.3(Ph), 162.7(C-3). Anal. calcd for C44H45NO5:
C, 79.13; H, 6.79; N, 2.10. Found: C, 79.10; H, 6.75; N,
2.05.
trans-4b: colorless oil, [h]2D0 +135.2 (c 1.1, CHCl3) IR
(neat): 3029.9, 2918.3, 2361.2, 1610.1, 1496.5, 1454.4,
1365.3, 1211.3, 1166.4, 1111.2, 1069.6, 1027.9, 850.7,
1
823.9, 734.8, 696.6. H NMR (500 MHz) l=1.03 (d, 3H,
J=7.6, CH3-C4), 2.14 (dd, 1H, J=4.3, J=12.2, H-10),
2.23 (s, 6H, 2×CH3(Mst)), 2.27 (s, 3H, 1×CH3(Mst)), 2.42
(t, 1H, J=12.2, H-10), 3.31 (c, 1H, J=7.6, H-4), 3.50
(dd, 1H, J=5.5, H=9.0, H-11), 3.66 (t, 1H, J=9.0,
H-11), 4.04 (s, 1H, H-7), 4.11 (m, 1H, H-9), 4.30 (t, 1H,
12. Ja¨ger, V.; Colinas, P. A. Nitrile Oxides. In The Chemistry
of Heterocyclic Compounds, Vol. 59: Synthetic Applica-
tions of 1,3-Dipolar Cycloaddition Chemistry Toward Het-
erocycles and Natural Products; Padwa, A.; Pearson, W.,
Eds.; Wiley, 2002.
J=6.6, H-8), 4.44 (AB, 2H, J=11.7, PhCH6 2), 4.64 (AB,