Double addition of Grignard reagents to N-glycosyl nitrones: A new tool for the construction of enantiopure azaheterocycles

Article abstract of DOI:10.1021/ol047691e

(Chemical Equation Presented) C-Phenyl-N-erythrosylnitrone 3 behaves as a C1,C1′ bis-electrophile, undergoing a double addition of Grignard reagents in a domino fashion to afford acyclic hydroxylamines 4. The reaction proceeds at 0°C with variable degrees

Full text of DOI:10.1021/ol047691e

ORGANIC
LETTERS
2005
Vol. 7, No. 2
319-322
Double Addition of Grignard Reagents
to N-Glycosyl Nitrones: A New Tool for
the Construction of Enantiopure
Azaheterocycles
Marco Bonanni, Marco Marradi, Stefano Cicchi, Cristina Faggi, and Andrea Goti*
Dipartimento di Chimica Organica “Ugo Schiff”, UniVersita` di Firenze, ICCOM,
C.N.R., Via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy
andrea.goti@unifi.it
Received November 10, 2004
ABSTRACT
C-Phenyl-N-erythrosylnitrone 3 behaves as a C1,C1
to afford acyclic hydroxylamines 4. The reaction proceeds at 0
′
bis-electrophile, undergoing a double addition of Grignard reagents in a domino fashion
C with variable degrees of diastereoselectivity, from moderate to good, mainly
°
depending on the organomagnesium reagent used. The usefulness of compounds 4 has been exemplified with the synthesis of pyrroloazepine
12 through a ring closing metathesis key step.
Nitrones are very useful tools for the construction of
structurally complex molecules, and in particular, nitrogen-
containing biologically active compounds. This is because
of the high degree of diastereocontrol they often exhibit in
their reactions with various reagents. Their most well-studied
reactions, namely 1,3-dipolar cycloaddition1 and the addition
of organometallic reagents,2 have yielded a number of
extremely reliable synthetic procedures. Most recently, the
involvement of nitrones in a promising SmI2 mediated
pinacol-type coupling with carbonyl and R,â-unsaturated
carboxyl derivatives has also been disclosed.3
Considerable effort has also been devoted to the synthesis
and applications of nonracemic chiral nitrones, because of
their easy preparation and high versatility. Carbohydrate-
derived nitrones have turned out to be particularly useful
reagents for the synthesis of iminosugars and other hydroxy-
lated compounds.1d-h,2e-f,4 In this context, N-glycosylnitrones
1, readily available from the corresponding hydroxylamines
2,5 have been extensively used, both in 1,3-dipolar cyclo-
additions5,6 and nucleophilic additions,7 for enantioselective
syntheses, with the sugar moiety acting as a removable chiral
(1) (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; John Wiley & Sons: New York, 1984. (b) Confalone, P. N.; Huie,
E. M. Org. React. 1988, 36, 1-173. (c) Torssell, K. B. G. Nitrile Oxides,
Nitrones, and Nitronates in Organic Synthesis; Feuer, H., Ed.; VCH
Publishers: New York, 1988. (d) Frederickson, M. Tetrahedron 1997, 53,
403-425. (e) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863-
909. (f) Jones, R. C. F.; Martin, J. N. In Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: New York,
2002. (g) Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 585-
628. (h) Osborn, H. M. I.; Gemmell, N.; Harwood: L. M. J. Chem. Soc.,
Perkin Trans. 1 2002, 2419-2438.
(2) (a) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (b) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946. (c) Lombardo,
M.; Trombini, C. Synthesis 2000, 759-774. (d) Merino, P. In Science of
Synthesis; Padwa, A., Ed.; Thieme: Stuttgart, Germany, 2004; Vol. 27. (e)
Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synlett 2000, 442-454.
(f) Lombardo, M.; Trombini, C. Curr. Org. Chem. 2002, 6, 695-713.
(3) (a) Masson, G.; Py, S.; Valle´e, Y. Angew. Chem., Int. Ed. 2002, 41,
1772-1775. (b) Masson, G.; Cividino, P.; Py, S.; Valle´e, Y. Angew. Chem.,
Int. Ed. 2003, 42, 2265-2268. (c) Riber, D.; Skrydstrup, T. Org. Lett. 2003,
5, 229-231.
(4) (a) Kleban, M.; Hilgers, P.; Greul, J. N.; Kugler, R. D.; Li, J.; Picasso,
S.; Vogel, P.; Ja¨ger, V. ChemBioChem 2001, 2, 365-368. (b) Palmer, A.
M.; Ja¨ger, V. Eur. J. Org. Chem. 2001, 1293-1308. (c) Cardona, F.; Faggi,
E.; Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron Lett. 2003, 44, 2315-
2318.
10.1021/ol047691e CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/29/2004

Scheme 1. Known Reactivity of 1 and 2
Scheme 2. Planned Domino Double Addition
auxiliary (Scheme 1, A). More recently, Dondoni has used
N-glycosylhydroxylamines 2 as masked chiral nitrones in
additions with organolithium and magnesium derivatives,8
where the sugar framework remains embodied in the final
adducts (Scheme 1, B).
In consideration of the above-described reactions, we
envisaged the possibility of using N-glycosylnitrones 1 as
synthetic equivalents of chiral C1,C1′ bis-nitrone (or dication)
synthons in organometallic additions (Scheme 2). Indeed,
intermediates such as 5 (formed from the first nucleophilic
addition) should be in equilibrium with the open-chain
nitrones 5′, which can function as substrates for a further
nucleophilic attack.9 In this Letter, we report our findings
on the domino double addition of Grignard reagents to a
N-glycosylnitrone, and we show a synthetic application of a
resulting bis-adduct.
As a model substrate for the methodological study we
chose C-phenyl-N-erythrosylnitrone 3.5b Treatment of an ice-
cold THF solution of nitrone 3 with a 3-fold excess of a
Grignard reagent afforded the bis-adducts 4 in good to
excellent yields (Scheme 2 and Table 1).
Double addition at R,R′-positions10 to nitrogen generates
two new stereogenic centers (apart from addition of PhMgBr,
entry 3, Table 1). Hence, formation of four diastereoisomers
is possible. Taking into account the literature precedents
which show that nucleophilic additions occur usually with
good diastereoselection to both N-glycosylnitrones 17 and
N-glycosylhydroxylamines 2,8 we hoped that similar results
would accrue in the double additions to nitrone 3. In fact, a
predominant adduct, whose configuration is depicted in Table
1, was generally obtained with diastereoselectivities from
moderate to satisfactory. It is relevant that in all cases only
two or three out of the four possible bis-adducts have been
detected, which means that at least one of the two additions
is particularly stereoselective. The major products of the
additions from entries 1, 2, 5, and 6 show the (R,S) absolute
configuration, respectively, at the C1,C1′ newly created
stereogenic centers. Conversely, the major product of the
addition of allylmagnesium chloride (entry 4, Table 1) turned
out to have the opposite (S) configuration at C1, while the
minor had the expected (R) configuration.
Complete stereochemical characterization of both the bis-
adducts derived from the addition of allylmagnesium chloride
(entry 4, Table 1) was achieved by nOe experiments on a
derivative of the major adduct 4d (compound 10, see below).
These results were confirmed by an X-ray structural deter-
mination, and by a single-crystal X-ray analysis of the minor
adduct. The configuration of all the other major adducts 4
was also firmly ascertained. Single-crystal X-ray analyses
were performed on the adduct 4a and on the monoacetyl
derivative (at the hydroxylamine oxygen atom, see Support-
ing Information) of 4e. The configuration of adducts 4b and
(5) (a) Vasella, A. HelV. Chim. Acta 1977, 60, 426-446. (b) Cicchi, S.;
Marradi, M.; Corsi, M.; Faggi, C.; Goti, A. Eur. J. Org. Chem. 2003, 4152-
4160. (c) Cicchi, S.; Corsi, M.; Marradi, M.; Goti, A. Tetrahedron Lett.
2002, 43, 2741-2743.
(6) (a) Vasella, A. HelV. Chim. Acta 1977, 60, 1273-1295. (b) Vasella,
A.; Voeffray, R. J. Chem. Soc., Chem. Commun. 1981, 97-98. (c) Vasella,
A.; Voeffray, R. HelV. Chim. Acta 1982, 65, 1134-1144. (d) Vasella, A.;
Voeffray, R. HelV. Chim. Acta 1982, 65, 1953-1964. (e) Vasella, A.;
Voeffray, R.; Pless, J.; Huguenin, R. HelV. Chim. Acta 1983, 66, 1241-
1252. (f) Kasahara, K.; Iida, H.; Kibayashi, C. J. Am. Chem. Soc. 1986,
108, 4647-4648. (g) Mzengeza, S.; Whitney, R. A. J. Org. Chem. 1988,
53, 4074-4081. (h) Kasahara, K.; Iida, H.; Kibayashi, C. J. Org. Chem.
1989, 54, 2225-2233. (i) Machetti, F.; Cordero, F. M.; De Sarlo, F.; Guarna,
A.; Brandi, A. Tetrahedron Lett. 1996, 37, 4205-4208. (j) Tamura, O.;
Mita, N.; Kusaka, N.; Suzuki, H.; Sakamoto, M. Tetrahedron Lett. 1997,
38, 429-432. (k) Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.;
Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R. J. Org. Chem. 1999, 64,
9321-9327. (l) Chiacchio, U.; Rescifina, A.; Corsaro, A.; Pistara`, V.;
Romeo, G.; Romeo, R. Tetrahedron: Asymmetry 2000, 11, 2045-2048.
(m) Tamura, O.; Kanoh, A.; Yamashita, M.; Ishibashi, H. Tetrahedron 2004,
60, 9997-10003. (n) Tamura, O.; Iyama, N.; Ishibashi, H. J. Org. Chem.
2004, 69, 1475-1480.
(7) Phosphites: (a) Huber, R.; Knierzinger, A.; Obrecht, J.-P.; Vasella,
A. HelV. Chim. Acta 1985, 68, 1730-1747. (b) Bernet, B.; Krawczyk, E.;
Vasella, A. HelV. Chim. Acta 1985, 68, 2299-2311. (c) Huber, R.; Vasella,
A. HelV. Chim. Acta 1987, 70, 1461-1476. (d) Huber, R.; Vasella, A.
Tetrahedron 1990, 46, 33-58. Sulfoxonium ylides: (e) Lantos, I.; Flisak,
J.; Liu, L.; Matsuoka, R.; Mendelson, W.; Stevenson, D.; Tubman, K.;
Tucker, L.; Zhang, W.-Y.; Adams, J.; Sorenson, M.; Garigipati, R.; Erhardt,
K.; Ross, S. J. Org. Chem. 1997, 62, 5385-5391. Trimethylsilyloxyfuran:
(f) Mita, N.; Tamura, O.; Ishibashi, H.; Sakamoto, M. Org. Lett. 2002, 4,
1111-1114. Grignard reagents: (g) Mancini, F.; Piazza, M. G.; Trombini,
C. J. Org. Chem. 1991, 56, 4246-4252. (h) Rohloff, J. C.; Alfredson, T.
V.; Schwartz, M. A. Tetrahedron Lett. 1994, 35, 1011-1014. (i) Basha,
A.; Henry, R.; McLaughlin, M. A.; Ratajczyk, J. D.; Wittenberger, S. J. J.
Org. Chem. 1994, 59, 6103-6106. Zinc acetylides: (j) Fa¨ssler, R.; Frantz,
D. E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054-
3056. (k) Patel, S. K.; Py, S.; Pandya, S. U.; Chavant, P. Y.; Valle´e, Y.
Tetrahedron: Asymmetry 2003, 14, 525-528.
(8) (a) Dondoni, A.; Perrone, D. Tetrahedron Lett. 1999, 40, 9375-
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4273.
(9) This hypothesis was supported by the observation reported, only in
one of the previous studies (ref 7i), concerning the formation of a bis-
adduct.
(10) We designate with R (or C1) and R′ (or C1′) the positions adjacent
to phenyl and the dioxolane ring, respectively, following the sequential order
of the two consecutive additions.
320
Org. Lett., Vol. 7, No. 2, 2005

Table 1. Double Additions of Grignard Reagents to Nitrone 3a
Scheme 3. Interconversions for Chemical Correlation
amine.8c A more strict diastereocontrol in the second addition
seems to be operative in all additions.
The anomalous diastereoselection shown by allylmagne-
sium chloride is to be underlined. Possibly this is due to the
peculiar nature of allyl metals. On the other hand, the
precedent of an addition occurring with an opposite diaste-
reofacial preference already has been reported.7e Furthermore,
this result should be compared to those reported for the
analogous addition (1 equiv) to a N-mannosyl nitrone,7g
where only monoadducts were obtained, albeit in moderate
yield, with a low 1.5 dr and with the same diastereofacial
preference, while the D-mannosyl moiety should give the
opposite induction.5b
a Reactions were carried out in a 0.1 M solution of 3 in THF at 0 °C for
1 h. b Total yields considering all the adducts recovered after chromatog-
raphy. Yields in parentheses are those of isolated major diastereoisomers.
1
c Based on integration of H NMR spectra of the crude reaction mixtures.
The effects of varying the solvent and reagent concentra-
tions and ratios and reaction temperature have been studied
and are discussed in the Supporting Information.
From a practical point of view, it is interesting that the
additions with unsaturated Grignard reagents (entries 4-6,
4f was determined to be the same as that for 4e by chemical
correlation, as reported in Scheme 3 (see Supporting
Information for details). Only the configuration of compound
4c was based on analogy.
The major bis-adducts 4a, 4b, 4e, and 4f appear to derive
from preferential attack of the Grignard reagent at the re
face of N-glycosylnitrone 3 (first attack) and the si face of
open-chain nitrone 5′ (second attack). These preferred modes
of approach were predicted according to the models proposed
by Vasella for the nucleophilic addition to N-glycosylnitrones7d
and Dondoni for those to N-glycosylhydroxylamines8 (Figure
1). The second attack of phenylmagnesium bromide (entry
3, Table 1) is also in agreement with the latter model.
In the addition of allylmagnesium chloride, where only
two bis-adducts were detected, whose configuration was
established unequivocally, a further consideration can be
inferred. Both adducts displayed the (S) configuration at C1′,
thus showing that complete diastereofacial differentiation was
attained in the second addition. This result is in agreement
with the 96:4 diastereoselectivity observed for the addition
of allylmagnesium bromide to N-erythrosyl-N-benzylhydroxyl-
Figure 1. Preferred transition state models for the two consecutive
attacks of Grignard reagents to nitrone 3.
Org. Lett., Vol. 7, No. 2, 2005
321

Table 1), which furnish more synthetically useful products,
occur with excellent yields and are also the most diastereo-
selective. To demonstrate the synthetic potential of this novel
double addition procedure, hydroxylamine 4d was trans-
formed into pyrroloazepine 12 (Scheme 4), which displayed
tected in situ to the corresponding hydroxylamine, which was
reduced with zinc dust to the azepine 10. Cyclization to 11
was induced by treatment with triflic anhydride. Final
deprotection of the hydroxy groups was achieved in an acid
medium, which afforded the desired product as its am-
monium salt 12 (Scheme 4).
In conclusion, our preliminary results demonstrate the
feasibility of the bis-addition of Grignard reagents to
N-glycosylnitrones. The reaction can be performed at 0 °C
fairly rapidly and affords in nearly quantitative yield the
desired bis-adducts with moderate to good diastereoselec-
tivity. The usefulness of the method has been demonstrated
by the construction of a biologically active polyhydroxylated
azepine system. The present reaction seems to have high
synthetic potential and versatility for a range of applications.
In consideration of this, possible structural variation at the
nitrone carbon atom, in the Grignard reagent, and in the
glycosyl moiety makes the method especially attractive.
Further studies are currently underway in our laboratory to
extend the methodology along these lines and to improve
the diastereoselectivity of the reaction.
Scheme 4. Synthesis of Pyrroloazepine 12 through a Key
RCM
Acknowledgment. We are grateful to MIUR-Italy for
financial support (PRIN 2002) and Ente Cassa di Risparmio
di Firenze-Italy for granting a 400-MHz NMR spectrometer.
We also thank Brunella Innocenti and Maurizio Passaponti
for technical assistance.
Supporting Information Available: Experimental pro-
cedures, analytical and spectroscopic characterization of all
1
new compounds, H and 13C NMR spectra of compounds
4a, 4c, 4d, 4d′ (minor isomer), 4f, and 6-13, and X-ray
crystallographic data of compounds 4a, 4d′, monoacetylated
4e (i.e. 13), and 10. This material is available free of charge
via the Internet at http://pubs.acs.org.
good inhibition of R-glucosidase from yeast (90% at 1
mM).11 After acetylation of hydroxylamine 4d, a ring-closing
metathesis with the second generation Grubbs’ catalyst gave
9 in nearly quantitative yield. The product was then depro-
OL047691E
(11) Details will be given in a full paper. We thank Prof. P. Vogel
(University of Lausanne) for enzyme inhibition experiments.
322
Org. Lett., Vol. 7, No. 2, 2005