Highly selective indium mediated allylation of unprotected pentosylamines

Article abstract of DOI:10.1021/ol3002656

A straightforward functionalization of d-pentoses is reported, which affords homoallylaminopolyols in two steps and uses ion exchange chromatography as the only purification operation. The key indium-mediated allylation is effected on unprotected glycosylamines and occurs with good to excellent syn stereoselection. Validation of the synthetic utility of the method was exemplified by a 3-step synthesis of an optically active 1,2,3,6- tetrahydropyridine from d-xylose.

Full text of DOI:10.1021/ol3002656

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1536–1539
Highly Selective Indium Mediated
Allylation of Unprotected Pentosylamines
Jean-Bernard Behr,* Audrey Hottin, and Alpha Ndoye
ꢀ
ꢀ
Universite de Reims Champagne-Ardenne, Institut de Chimie Moleculaire de Reims,
CNRS UMR 7312, UFR des Sciences Exactes et Naturelles, 51687 Reims Cedex 2,
France
jb.behr@univ-reims.fr
Received February 2, 2012
ABSTRACT
A straightforward functionalization of D-pentoses is reported, which affords homoallylaminopolyols in two steps and uses ion exchange
chromatography as the only purification operation. The key indium-mediated allylation is effected on unprotected glycosylamines and occurs with
good to excellent syn stereoselection. Validation of the synthetic utility of the method was exemplified by a 3-step synthesis of an optically active
1,2,3,6-tetrahydropyridine from D-xylose.
Allylation of carbonyl compounds using Indium as a
promoter is an efficient and versatile CÀC bond forming
reaction that has elicited considerable interest since its
discovery in 1988.1 The organoindium nucleophiles are
stable in both water and air, which allows very simple
experimental protocols for the allylation of unprotected
substrates in water or protic media.2 A remarkable appli-
cation of this reaction is the allylation of aldoses, a method
that permitted the protecting-group free synthesis of
higher-carbon sugars and biologically active polyols.3 At
least in the case of sugar-aldehydes, Barbier allylations
with indium metal afforded higher yields and selectivity
than the more standard Zn or Sn. In contrast to carbonyl
chemistry, the In-mediated allylation of CÀN double
bonds has been less explored mainly because of the lower
stability of imines in protic solvents and their poor electro-
philicity. Nevertheless, after a first communication on the
use of In as a promoter for allylation of aldimines in 1992,4
several reports described such a transformation, evaluating
its scopes and limitations.5 Glycosylamines are a class of
carbohydrate derivatives that are formed by condensation
(1) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831–
1833.
(2) (a) Yadav, J. S.; Antony, A.; George, J.; Reddy, B. V. S. Eur. J.
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Org. Chem. 2010, 591–605. (b) Auge, J.; Lubin-Germain, N.; Uziel, J.
Synthesis 2007, 1739–1764.
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5959–5960.
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Tetrahedron Lett. 2011, 52, 913–915. (b) Sugiura, M.; Hirano, K.;
Kobayashi, S. Org. Synth. 2006, 83, 170. (c) Lievens, S. C.; Molinski,
T. J. Am. Chem. Soc. 2006, 128, 11764–11765. (d) Hansen, F. G.;
Bundgaard, E.; Madsen, R. J. Org. Chem. 2005, 70, 10139–10142. (e)
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S.-K.; Lee, S.; Whitesides, G. M. J. Org. Chem. 1996, 61, 8739–8745. (g)
Gao, J.; Haerter, R.; Gordon, D. M.; Whitesides, G. M. J. Org. Chem.
1994, 59, 3714–3715. (h) Kim, E.; Gordon, D. M.; Schmid, W.; White-
sides, G. M. J. Org. Chem. 1993, 58, 5500–5507.
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hedron 2011, 67, 2617–2622. (b) Kim, S. J.; Jang, D. O. J. Am. Chem. Soc.
2010, 132, 12168–12169. (c) Kouznetsov, V. V.; Mendez, L. Y. V.
Synthesis 2008, 491–506. (d) Law, M. C.; Cheung, T. W.; Wong,
K.-Y.; Chan, T. H. J. Org. Chem. 2007, 72, 923–929. (e) Vilaivan, T.;
Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org. Chem.
2005, 70, 3464–3471. (f) Ding, H.; Friestad, G. K. Synthesis 2005, 2815–
2829. (g) Yanada, R.; Kaieda, A.; Takemoto, Y. J. Org. Chem. 2001, 66,
7516–7518.
r
10.1021/ol3002656
Published on Web 02/24/2012
2012 American Chemical Society

of an aldose with an amine. As for sugars, they exhibit
mutarotation and might rearrange to a tautomeric imine
form. However, glycosylamines are usually considered as
unstablesubstrates:inproticsolvents, theymighthydrolyze
back to the parent aldose or might undergo Amadori
rearrangement, impeding their use for synthetic purpose.6
Nevertheless, it has been shown that protected glycosyla-
mines like 1 (Figure 1) react efficiently with allylzinc or
allylmagnesium species in a diastereoselective manner af-
fording diastereomeric aminopolyols like 2 and 3.7
using indium as a promoter and methanol as the solvent.
The scope of this transformation in the field of alkaloid
synthesis is exemplified by the straightforward synthesis of a
chiral dihydropyridine using subsequent RCM.
Among the few preparative procedures for obtaining
unprotected glycosylamines, the condensation between an
aldose and the appropriate amine using an alcohol as the
solvent isthe simplest.10 The stability of suchcompounds is
dependent on the nature of the starting sugar, the type of
the amine used (degree of substitution, basicity, hybridiza-
tion state) and the pH of the solution. To investigate a
simple and general preparation of glycosylamines, we used
D-xylose and benzylamine as models. When a suspension
of D-xylose in MeOH was stirred at 45 °C in the presence of
stoichiometric benzylamine, the insoluble carbohydrate
disappeared within 40 min, after which the reaction mix-
ture was evaporated to yield a colorless solid. NMR an-
alysis revealed a set of signals different from that of the
starting aldose with the presence of an aromatic system, a
supplementary methylene and a significant shielding of
anomeric proton and carbon compatible with the structure
of N-benzylxylosylamine 4a in a favored pyranose form.10a
NMR monitoring of a D2O solution of 4a showed that it
hydrolyzed back to xylose (t1/2 = 24 h at natural pH)
whereas a methanolic solution was more stable.11 By ap-
plying the same methodology, we were able to prepare
glycosylamines 4bÀg after reaction of D-xylose with one
equivalent of (R)- and (S)-R-methylbenzylamine, allyl-
amine, butylamine, cyclohexylamine and octylamine
respectively (Scheme 1).11 The reaction of the other
D-pentoses with benzylamine worked equally well and
afforded the corresponding D-arabino, D-lyxo and D-ribo
N-benzylglycosylamines 5, 6 and 7 (structures not shown).11
All of these glycosylamines were used in the next step
without further purification.
Figure 1. Protected glycosylamines in total synthesis.
These intermediates are key precursors of many biologi-
cally active compounds including iminosugars or sphingo-
sine derivatives.8 In view of this, allylation of unprotected
glycosylamines under Barbier conditions in “environmen-
tally preferable”9 solvents would expand the repertoire of
Green Chemist’s toolbox, bringing significative improve-
ments to the existing syntheses of aminopolyols in term of
atom economy and length, by avoiding the use of protection/
deprotection steps. We report here the protecting-group free
transformation of glycosylamines into homoallylaminols,
Scheme 1. Synthesis of Glycosylamines 4
(6) Isbell, H. S.; Frush, H. L. J. Org. Chem. 1958, 23, 1309–1319.
(7) (a) Rajender, A.; Rao, J.-P.; Rao, B. V. Tetrahedron: Asymmetry
2011, 22, 1306–1311. (b) Behr, J.-B.; Gainvors-Claisse, A.; Belarbi, A.
Nat. Prod. Res. A 2006, 20, 1308–1314. (c) Djebaili, M.; Behr, J.-B. J.
Enz. Inihib. Med. Chem. 2005, 20, 123–127.
Next, we investigated the allylation reaction of xylosyl-
amine 4a under Barbier conditions (Table 1). Due to the
instability of our glycosylamines in water we used metha-
nol as the solvent for all our attempts. For the same reason,
TLC or HPLC monitoring of the reaction appeared
difficult. All the experiments were thus conducted over-
night and analysis of the crude mixture was operated after
suitable workup. In a first attempt (Table 1, entry 1), a
solution of N-benzylxylosylamine 4a was stirred in the
€
(8) (a) Schonemann, W.; Gallienne, E.; Compain, P.; Ikeda, K.;
Asano, N.; Martin, O. R. Bioorg. Med. Chem. 2010, 18, 2645–2650.
(b) Behr, J.-B.; Erard, A.; Guillerm, G. Eur. J. Org. Chem. 2002, 1256–
1262. (c) Behr, J.-B.; Guillerm, G. Tetrahedron: Asymmetry 2002, 13,
111–113. (d) Schweizer, F. Angew. Chem., Int. Ed. 2002, 41, 230–253. (e)
Cipolla, L.; La Ferla, B.; Peri, F.; Nicotra, F. Chem. Commun. 2000,
1289–1290. (f) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem.
Rev. 1995, 95, 1677–1716. (g) Liautard, V.; Desvergnes, V.; Itoh, K.; Liu,
H.-w.; Martin, O. R. J. Org. Chem. 2008, 73, 3103–3115. (h) Decroocq,
C.; Laparra, L. M.; Rodriguez-Lucena, D.; Compain, P. J. Carb. Chem
2011, 30, 559–574.
€
(9) Capello, C.; Fischer, U.; Hungerbuhler, K. Green Chem. 2007, 9,
(10) (a) Zhu, Y.; Pan, Q.; Thibaudeau, C.; Zhao, S.; Carmichael, I.;
Serianni, A. S. J. Org. Chem. 2006, 71, 466–479. (b) Chavis, C.;
De Gourcy, C.; Dumont, F.; Imbach, J.-L. Carbohydr. Res. 1983, 113, 1–20.
(11) See Supporting Information for NMR data.
927–934. For similar approaches, see: (a) Dangerfield, E. M.; Plunkett,
C. H.; Win-Mason, A. L.; Stocker, B. L.; Timmer, M. S. M. J. Org.
Chem. 2010, 75, 5470–5477. (b) Dangerfield, E. M.; Timmer, M. S. M.;
Stocker, B. L. Org. Lett. 2009, 11, 535–538.
Org. Lett., Vol. 14, No. 6, 2012
1537

allylindium intermediate (Allyl3In2Br3), a structure gener-
ally proposed as the active species in indium-mediated
allylation under Barbier conditions.13
Table 1. Conditions Screening
The ability of other metals to induce allylation of un-
protected glycosylamines was tried under the conditions
stated above (Table 1, entries 7 and 8). However, when 4a
was stirred for 12 h with allyl bromide in the presence of
either Sn or Zn, no reaction occurred and xylose was re-
covered quantitatively after acidic treatment.
The stereochemical outcome of the reaction was inves-
tigated next. Allylation of benzylxylosylamine 4a afforded
the sole diastereomer 8a, the absolute configuration of
which had to be determined. To this aim, we correlated the
structure of 8a to that of known L-xylo analogues 2 and 3
(Scheme 2).8b,c O-Debenzylation of formerly prepared 2
and 3 was performed in excellent yields with BCl3,14 lead-
metal
allyl-Br
equiv
entry
R
(equiv)
productayieldb (%)
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
In (1)
2
3
3
4
3
4
3
3
3
3
3
3
3
3
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
30
61
65
61
72
71
0
In (1)
In (1.5)
In (1.5)
In (2)
In (2)
ing to epimers ent-8a and 9, respectively. The 1H and 13
C
NMR spectra of 8a were strictly superimposable with that
of ent-8a, which permitted assignment of the absolute con-
figuration of 8a and establishment of the relative syn selec-
tivity for the indium mediated allylation of xylosylamines.
To see whether it was possible to control the orienta-
tion of the addition with a chiral N-auxiliary, we subjected
(R)- and (S)-R-methylbenzylglycosylamines 4b and 4c to this
In-mediated allylation (Table 1, entries 9 and 10). The
reaction was expected to afford mixtures of diastereomers
reflecting the directing effect of both stereogenic units.15 We
anticipated, at least in one case, a significant drop in
selectivity due to the conflicting influence of mismatch
relationships. However, the allylation of 4b and 4c gave
comparable results affording mainly a single diastereoi-
somer 8b or 8c respectively. The isolated yields were sig-
nificantly lower, certainly because of steric effects hindering
the approach of the allylindium species. The same (R)
configuration was determined for the new stereocenter in
8b and 8c, after their respective hydrogenolysis which
led to the same compound 10, which correlated with a sample
of 10 obtained from 8a by an analogous reaction (Scheme 2).
Thus, the orientation of the addition could not be mediated
by the chiral auxiliary, and the syn diastereoisomer was the
major compound obtained in each case. This is in good
agreement with the well-known 1,2-syn stereoprefer-
ence in indium-promoted allylations of aldohexoses.3f
A set of reactions was performed to widen the scope of
this transformation to other amines (Table 1, entry 11À14)
or pentoses (Scheme 3). Thus homoallyl amines 8dÀg were
prepared featuring allyl, butyl, cyclohexyl or octyl sub-
stituents on nitrogen. Yields were good (57À79% for two
steps), except for the N-cyclohexylglycosylamine (23%),
which reflects the sensitivity of the reaction to steric
hindrance. In the same manner, N-benzylglycosylamines
derived from D-arabinose, D-lyxose or D-ribose reacted as
Sn (2)
Zn (2)
0
(R) CH(CH3)Ph In (2)
37c
55d
79
77
23d
57
10 (S) CH(CH3)Ph In (2)
11 allyl
In (2)
In (2)
In (2)
In (2)
12 butyl
13 cyclohexyl
14 (CH2)7CH3
8g
a All diastereoisomeric ratios were determined by 13C NMR analysis
of the crude reaction mixture. b Isolated yield. c de = 64%. d de = 68%.
presence of allylbromide (2 equiv) and powdered indium
(1 equiv) at room temperature under air atmosphere. After
10 min a slightly exothermic reaction started, which ceased
rapidly and the mixture was left to react for 16 h. Analysis
of the crude reaction mixture and isolation of the com-
pound proved somewhat difficult because of complexation
of the aminopolyol with indium.12 Only the addition of
1 M hydrochloric acid permitted to liberate the product,
obtained as a colorless mixture after concentration. Grat-
ifyingly, NMR analysis showed the presence of the ex-
pected homoallylamine 8a in addition with almost equal
amount of xylose (provided by hydrolysis of unreacted
glycosylamine). Purification was simply reduced to ion-
exchange chromatography: application of the crude on a
Dowex50W-X8 column followed by elution with 0.8 M
NH4OH yielded aminopolyol 8a in 30% yield.
To optimize the reaction conditions (Table 1, entries
2À6), we varied the relative quantities of either indium
(1, 1.5, 2 equiv) or allyl bromide (2, 3, 4 equiv). Best condi-
tions used 2 equiv of indium with 3 equivalents of allyl
bromide, resulting in 72% isolated yield of 8a (overall yield
for the two steps). The optimal 2:3 ratio of indium and allyl
bromide is consistent with the formation a sesquihalide
(13) (a) Bowyer, W. J.; Singaram, B.; Sessler, A. M. Tetrahedron
2011, 67, 7449–7460. (b) Koszinowski, K. J. Am. Chem. Soc. 2010, 132,
6032–6040. Haddad, T. D.; Hirayama, L. C.; Singaram, B. J. Org. Chem.
2010, 75, 642–649.
(12) Direct evaporation of the volatiles afforded a white precipitate
with unanalyzable broad NMR signals. Alternatively, when aqueous
ammonia was added both to neutralize the acidic reaction mixture and
to precipitate indium hydroxyde, evaporation of the liquor yielded only
trace amount of material, most of the organic fraction being incorpo-
rated into the insoluble solid. In(III) forms stable complexes with N-
containing ligands: Mahmoud, S. A.; Issa, I. M.; El-Gyar, S. A. Mon-
atsh. Chem. 1980, 111, 431–438.
(14) (a) Behr, J.-B.; Kalla, A.; Harakat, D.; Plantier-Royon, R.
ꢀ
J. Org. Chem. 2008, 73, 3612–3615. (b) Desvergnes, S.; Vallee, Y.;
Py, S. Org. Lett. 2008, 10, 2967–2970.
€
(15) Veith, U.; Jager, V. Chem. Commun. 1996, 329–330.
1538
Org. Lett., Vol. 14, No. 6, 2012

Interestingly, the two-step transformation to 11 could be
performed in a single pot, by first stirring D-arabinose with
BnNH2 at 45 °C and adding AllylBr and In0 at rt, which
afforded 11 in excellent 82% yield. All the compounds were
purified by ion exchange chromatography as the only pu-
rification operation, and could be used as such in subsequent
chemical transformations. In several cases, small amounts of
the corresponding stereoisomer were also present, the separa-
tion of which was not attempted here, but could be per-
formed later in a synthetic route.
Scheme 2. Absolute Configurations of 8aÀc via Chemical Cor-
relation
To exemplify the utility of the prepared homoallyla-
mines as synthetic intermediates, we explored the possibi-
lity of accessing, in very few steps, the core structure of
chiral tetrahydropyridines, a remarkable class of precur-
sors of bioactive compounds.16 To this aim, unprotected
N-allylhomoallylamine 8d was subjected to ring-closing
metathesis (Scheme 4). Gratifyingly, the reaction worked in
the presence of Hoveyda-Grubbs II catalyst (2.5%) and
toluenesulfonic acid (1 equiv) as a transient protecting group
for nitrogen.17 Tetrahydropyridine 14 was obtained in 55%
yield after purification by silica-gel chromatography.
Scheme 4. Synthesis of 14 by Direct RCM of 8d
Scheme 3. Synthesis of Homoallylamines 11À13
In conclusion, indium-mediated allylation was applied to a
variety of glycosylamines deriving from “naked” pentoses,
which afforded functionalized homoallylaminopolyols in
good yield and high syn selectivity. The transformation
might be performed in a single pot directly from pentoses.
The compounds obtained after ion-exchange chromato-
graphy were almost pure and might be used as such
in subsequent transformations, as exemplified by the
synthesis of an optically active 1,2,3,6-tetrahydropyridine
in very few steps.
Acknowledgment. Financial support by Ministry of
Higher Education and Research (MESR), CNRS, Conseil
Regional Champagne Ardenne, Conseil General de la
Marne, and EU-programme FEDER to the PlAneTCPER
project is gratefully acknowledged.
well affording the corresponding homoallylamines 11À13
in good yield and selectivity. By analogy with the results
obtained with xylosylamines 4aÀc (this work) or more
generally with arabinose, lyxose or ribose (syn addition in
all cases),3e,h the formation of 11À13 is assumed to be
syn-directed, but this has to be confirmed by further
experiments.
Supporting Information Available. Experimental pro-
cedures and analytical data of final compounds 8À14,
copies of NMR spectra for compounds 4À14, hydrolysis
experiments of glycosylamine 4a. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(16) Toyooka, N. In Asymmetric Synthesis of Nitrogen Heterocycles;
Royer, J. Ed.; Wiley: Weinheim, 2009; pp 98À107.
(17) Woodward, C. P.; Spiccia, N. D.; Jackson, W. R.; Robinson,
A. J. Chem. Commun. 2011, 47, 779–781. For a review, see: Compain, P.
Adv. Synth. Catal. 2007, 349, 1829–1846.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1539