Stereoselective indium-mediated allylation of erythrulose derivatives in aqueous media

Article abstract of DOI:10.1016/S0957-4166(98)00103-7

A range of erythrulose derivatives has been allowed to react with allyl bromide and metallic indium in THF or aqueous THF. Some of these allylations are highly stereoselective.

Full text of DOI:10.1016/S0957-4166(98)00103-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1117–1120
Stereoselective indium-mediated allylation of erythrulose
derivatives in aqueous media
M. Carda«,a,∗ E. Castillo,a S. Rodríguez,a J. Murga a and J. A. Marco«, b
aDepart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, E-12080 Castellón, Spain
bDepart. de Q. Orgánica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
Received 16 February 1998; accepted 11 March 1998
Abstract
A range of erythrulose derivatives has been allowed to react with allyl bromide and metallic indium in THF or
aqueous THF. Some of these allylations are highly stereoselective. © 1998 Published by Elsevier Science Ltd. All
rights reserved.
The allylation of carbonyl compounds with allyl halides and activated metals under Barbier type
conditions is an established method for the synthesis of homoallylic alcohols.1 Within these nucleophilic
additions, those conducted in aqueous media have been a particularly active research topic in recent years.
Either in pure water or in water-containing organic solvents, allyl halides are able to add to carbonyl
compounds under promotion of metals such as tin, zinc, indium and others.2 The use of indium in
organic synthesis is a quite recent development.1b,2,3 The physicochemical properties of this element,
most particularly its low ionization potential, make it very prone to insertion into carbon–halogen
bonds.3 The first example of an indium-mediated allylation in an aqueous solvent was reported in
1991, when Li and Chan described allylations of various aldehydes and methyl ketones in water. They
showed that indium gave rise to a smooth reaction without the need of a promoter and that yields were
consistently better with indium than with tin.4 A further interesting feature, pointed out by several
groups,5 is that indium-mediated allylations are equally successful with carbonyl compounds bearing
free hydroxyl groups. In addition, chiral α- or β-hydroxy and α-acylamino aldehydes often react in
these conditions with a high stereoselectivity. Interestingly, protection of the free hydroxyl groups causes
marked variations in the degree and/or sense of the stereoselectivity.5 This has been attributed by some
authors to chelate formation between the substrate and the indium atom of an intermediate organometallic
reagent. According to their opinion, chelation is still operative in water and acquires its maximum
efficiency when a free hydroxyl group in the immediate vicinity of the carbonyl function is involved.5a,b,d
More recently, it has been found that indium-mediated stereoselective allylations are also possible with
α-alkoxy ketones.6
∗
Corresponding author. E-mail: alberto.marco@uv.es
0957-4166/98/$19.00 © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00103-7

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The ketotetrose L-(S)-erythrulose 1 and protected derivatives thereof 2 are useful precursors for
the synthesis of many types of chiral, polyfunctionalized compounds.7 We have recently shown that
nucleophilic additions of organometallic reagents, including allylmetal derivatives, display a high stere-
oselectivity under chelation-control conditions.7a,b,d These additions were performed, however, on fully
protected erythrulose derivatives 2 (R1–R3=silyl or benzyl) under anhydrous conditions. The excellent
diastereoselectivity displayed by some allylating reagents in aqueous media2 prompted us to try the same
type of reaction on derivatives 2 with both free and protected hydroxyl groups. Aside from the synthetic
utility, we further desired to test once more the possible concurrence of α- versus β-chelation, a question
which has not yet received a satisfactory answer.7d
In addition to 1 itself, erythrulose derivatives 3–12 were selected for the purpose of our work. The
syntheses of most of these protected derivatives have been recently described,7c,d while those of the
remaining ones will be reported in due course. Allyl bromide was allowed to react with these ketones
in the presence of metallic indium either in THF, aqueous THF or pure water. Table 1 shows the
observed diastereomeric ratios (d.r.). The two diastereoisomeric allylation products have been arbitrarily
designated as syn or anti.8 The syn product is that predicted by Cram’s cyclic chelation model.7d
Whenever possible, all reactions were performed in the three solvent systems. Exceptions were products
4–8, 11 and 12, which were not assayed in water because of their very low solubility in this solvent.
It is noteworthy that compounds 4–8 and 12, where all hydroxyl groups are protected, displayed a low
diastereoselectivity. In contrast, compounds 9–11, which have free hydroxyl groups, behaved in a quite
syn stereoselective way. The case of 9 is particularly worth mentioning, as it displays one of the highest
d.r. values registered to date in indium-mediated allylations (>19:1). Erythrulose acetonide 3, which has a
free hydroxyl on the α0 side of the carbonyl group, showed also an appreciable stereoselectivity but with
the opposite sense. In contrast, the parent sugar 1, which displays three free hydroxyl groups, behaved in
an almost stereorandom way.
In principle, the high syn stereoselectivity of 9 and 11 is in a good agreement with an α-chelation
control.7d Further support of the involvement of α-chelation comes from the results of a competition

M. Carda et al. / Tetrahedron: Asymmetry 9 (1998) 1117–1120
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Table 1
Stereoselective allylations of erythrulose derivatives 1, 3–12a
experiment, which showed that 9 is much more reactive than 7.9 However, β-hydroxy ketone 10 reacts
with the same sense of stereoselectivity as 9, a fact which cannot be so easily reconciled with a putative
β-chelation model. As we have recently shown for erythrulose derivatives in anhydrous media,7d no clear-
cut evidence exists to date which supports without any doubt the participation of chelates in nucleophilic
additions to β-oxygenated carbonyl groups. Very recently, Paquette has postulated the existence of β-
chelation control in order to explain the high stereoselectivity of indium-mediated allylations of β-
hydroxy aldehydes in aqueous media.5d However, support of his proposal relies mainly on the high
stereoselectivity and not on additional data. Furthermore, his results have been obtained in reactions with
β-chiral β-hydroxy aldehydes with no stereogenic centre at Cα. Substrate 10, however, is an α-chiral
α-alkoxy β-hydroxy ketone and its features may not be comparable with those of the aforementioned
aldehydes.7d Although a high stereoselectivity suggests in fact a reduced internal mobility of the bonds
around the carbonyl group, the true origin of this enhanced rigidity is not quite clear in reactions such
as those under study, which occur on a heterogeneous system. Single electron transfer (SET) from the
metal surface to either the carbonyl substrate or the allyl halide has been suggested to be the initial step.5
Very recently, the mechanism of the allylation of β-keto esters with zinc in THF/aq NH4Cl has been
investigated.10 The data presented seem to indicate the intermediacy of free radicals, generated most
likely through SET processes on the metal surface, but the origin of the stereoselectivity is still unclear.
More data have still to be collected for a sound mechanistic view to be feasible. Work in this direction is
in progress.

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Acknowledgements
The authors wish to acknowledge the financial support by the DGICYT (Projects PB95-1089 and
PB96-0760) and by BANCAJA (Project P1B95-21). E.C. thanks the Consellería de Cultura de la
Generalitat Valenciana for a pre-doctoral fellowship.
References
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8. (a) The configurations of the allylation products have been determined from a network of mutual chemical correlations via
interchange of protecting groups, as well as through chemical correlations with previously described allylation products.7d
All details are part of the projected Ph.D. Thesis of E.C. and will be described in due course.
9. When 7 and 9 (1 equiv. each) were allowed to compete for 1 equiv. of indium and 1.5 equiv. of allyl bromide, 9 reacted
completely at room temperature whereas 7 was almost quantitatively recovered.
10. Ahonen, M.; Sjöholm, R. Acta Chem. Scand. 1997, 51, 785–790.