Zinc-mediated domino elimination-alkylation of methyl 5-iodopentofuranosides: An easy route to unsaturated carbohydrates for transition metal-catalyzed carbocyclizations

Article abstract of DOI:10.1039/a906953d

5-Iodopentofuranosides are converted with zinc and allyl/propargyl bromide into dienes/enynes which are further used in carbohydrate annulation reactions.

Full text of DOI:10.1039/a906953d

Zinc-mediated domino elimination–alkylation of methyl
5-iodopentofuranosides: an easy route to unsaturated carbohydrates for
transition metal-catalyzed carbocyclizations
Lene Hyldtoft, Carina Storm Poulsen and Robert Madsen*
Department of Organic Chemistry, Technical University of Denmark, DK-2800 Lyngby, Denmark.
E-mail: okrm@pop.dtu.dk
Received (in Cambridge, UK) 27th August 1999, Accepted 16th September 1999
Table 1 Domino elimination–alkylation of methyl 5-iodofuranosidesa
5-Iodopentofuranosides are converted with zinc and allyl/
propargyl bromide into dienes/enynes which are further
used in carbohydrate annulation reactions.
Domino reactions are becoming a very attractive tool for
enhancing synthetic efficiency by allowing several bond-
forming transformations to be carried out in a single synthetic
operation.1 Such a strategy could be particularly important in
the area of carbohydrate chemistry: because carbohydrates are
densely functionalized, synthetic applications are often ham-
pered by the need for many reaction steps, usually for
manipulation of different protecting groups. In particular, the
conversion of carbohydrates into carbocycles is a major task
and has been the subject of intense study due to the biological
significance of the products.2 Herein, we report a zinc-mediated
domino elimination–alkylation of methyl 5-deoxy-5-iodopento-
furanosides to prepare carbohydrate-derived dienes and enynes.
These are important substrates for transition metal-catalyzed
carbocyclizations,3 and we demonstrate the use of the obtained
dienes in the ring-closing metathesis reaction.4,5
Entry
Furanoside
Alkyl Br
Yield (%) (S+R)b
Zinc-mediated reductive elimination of w-iodoglycosides is a
valuable reaction for introducing a terminal double bond in
carbohydrates,6 but the instability of the liberated aldehyde can
be a problem leading to side reactions and decomposition. We
reasoned that the aldehyde could be trapped in situ by a Barbier-
type alkylation7 (Table 1). Zinc would then serve a dual purpose
by promoting both the reductive elimination and reacting with
an alkyl halide to perform the Barbier reaction. Hereby, a C–C
double bond, a C–C single bond and a new stereocenter would
be generated in the same pot.
Allyl and propargyl bromide were selected as the alkyl
halides. Initial experiments were carried out on isopropylidene
ribofuranoside 1.8 When 1 was reacted with allyl bromide and
zinc, the desired diene was obtained in quantitative yield as a
4+1 diastereomeric mixture (entry 1, Table 1). Switching to
propargyl bromide gave rise to the corresponding enyne, but
now in an improved 9+1 diastereomeric ratio (entry 2). Notably,
no isomerization from alkyne to allene was observed under
these conditions. In general, for these sequential transforma-
tions to go to completion, 3 equiv. of allyl bromide was needed
while the reaction with propargyl bromide required 5 equiv.
Allyl bromide was added at the beginning of the reaction while
propargyl bromide was added during the course of the reaction
to minimize the formation of Wurtz coupling products. The
reactions were carried out under sonication in aq. THF.7 The
THF+H2O ratio influenced the rate, but had little effect on the
diastereoselectivity. Addition of more H2O generally enhanced
the rate of the overall transformation.
These conditions were then applied to substrates 2–5 (Table
1). Interestingly, the reaction of unprotected ribofuranoside 2
with allyl bromide now gave the opposite diastereomer as the
major product as compared to isopropylidene-protected 1
(entries 1 and 3). However, the reaction of 2 with propargyl
bromide failed to give any of the desired enyne. The reason for
this is not clear, but is probably associated with the unprotected
hydroxy groups. As a result, the remaining furanosides were
a
General procedure: To a solution of the iodofuranoside (1.6 mmol) and
allyl bromide (0.4 ml) in THF–H2O (4+1, 10 ml) was added zinc (1 g, pre-
activated with aq. HCl). The mixture was sonicated at 40 °C for 4 h under
Ar atmosphere, filtered through Celite, and worked up by extraction with
CH2Cl2 or stirring with ion-exchange resin followed by flash chromatog-
b
raphy. The stereochemistry of the enynes from the propargylations was
assigned after hydrogenation to the corresponding dienes with Lindlar
catalyst. In entry 10 the stereochemistry of the major enyne isomer was
determined after conversion into its known MEM-protected derivative (ref.
9). Hydrogenation with Lindlar catalyst subsequently showed that the major
diene isomer in entry 9 had the same absolute stereochemistry. c Protecting
group removed in the work-up by acidic ion-exchange resin.
Chem. Commun., 1999, 2101–2102
This journal is © The Royal Society of Chemistry 1999
2101

metathesis reaction on the major dienes from the allylations by
the use of 5–10% Grubbs catalyst [RuCl2(CHPh){PCy3}2]13 in
CH2Cl2 (Table 2). These reactions also allow the ster-
eochemical outcome of the allylations to be determined. The
unprotected dienes in entries 1–4 all gave the desired cyclohex-
enes 7–10 in near quantitative yields. When the ammonium salt
of diene 6 (Scheme 1) was subjected to Grubbs catalyst,
significant decomposition took place and only a moderate yield
of the cyclohexene could be obtained. However, when 6 was N-
acetylated the ring-closing metathesis reaction went smoothly
to give 11 in very high yield (entry 5, Table 2).
In conclusion, we have developed a zinc-mediated elimina-
tion–alkylation of 5-iodopentofuranosides which permits ‘one-
pot’ formation of several bonds and a stereocenter in a
controlled manner. The obtained dienes and enynes are valuable
in carbohydrate annulation by transition metal catalysis, and we
have processed the dienes in the ring-closing metathesis
reaction. Hereby, a range of complex carbocyclic structures are
easily available as chiral building blocks from cheap sugar
starting materials by two consecutive organometallic trans-
formations.
Scheme 1
protected as triethylsilyl (TES) ethers 3–5. The reaction of these
in the presence of allyl/propargyl bromide proceeded smoothly
to give the dienes/enynes in good to excellent yields (entries
5–10). Unfortunately, the 2-deoxyribose substrate 5 gave a poor
diastereoselectivity in the alkylation. For the protected furano-
sides 1, 3 and 4, on the other hand, the selectivity for addition to
the intermediate aldehyde generally followed the Felkin–Anh
model.10
The intermediate aldehyde can potentially be intercepted
with an amine prior to the alkylation (Scheme 1). The alkylation
would then take place on the formed imine resulting in the
introduction of an amino group. In fact, treatment of 1 with zinc,
benzylamine and allyl bromide succeeded in giving the amino
diene product 6 in both good yield and diastereoselectivity. To
prevent significant allylation of the intermediate aldehyde, it
was important to add allyl bromide slowly during the course of
the reaction.
We thank the Danish Natural Science Research Council for
financial support.
Notes and references
1 L. F. Tietze, Chem. Rev., 1996, 96, 115; L. F. Tietze and U. Beifuss,
Angew. Chem., Int. Ed. Engl., 1993, 32, 131.
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4 For recent reviews, see: U. K. Pandit, H. S. Overkleeft, B. C. Borer and
H. Biera¨ugel, Eur. J. Org. Chem., 1999, 959; D. L. Wright, Curr. Org.
Chem., 1999, 3, 211; A. Fu¨rstner, Top. Organomet. Chem., 1998, 1,
37.
Dienes and enynes are useful in transition metal-catalyzed
carbocyclizations.3 Hydroxylated enynes have previously been
used in palladium-catalyzed coupling of the A-ring in vitamin D
derivatives9,11 and in cobalt-mediated Pauson–Khand reac-
tions.12 Hydroxylated dienes are useful for carbocyclization by
ring-closing olefin metathesis. We have carried out the
Table 2 Ring-closing olefin metathesis of the major diene products from the
allylations
5 For recent applications of ring-closing olefin metathesis in carbohydrate
chemistry, see: P. Kapferer, F. Sarabia and A. Vasella, Helv. Chim.
Acta, 1999, 82, 645; H. Ovaa, J. D. C. Code´e, B. Lastdrager, H. S.
Overkleeft, G. A. van der Marel and J. H. van Boom, Tetrahedron Lett.,
1999, 40, 5063; A. Kornienko and M. d’Alarcao, Tetrahedron:
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C. Strehler and J. Eustache, Tetrahedron Lett., 1999, 40, 853.
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M. Nakane, C. R. Hutchinson and H. Gollman, Tetrahedron Lett., 1980,
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Chem., 1991, 56, 2213.
Entry
Diene
Cyclohexene
Yield (%)
7 J.-L. Luche, L. A. Sarandeses, in Organozinc Reagents—A Practical
Approach, ed. P. Knochel and P. Jones, OUP, Oxford, 1999, p. 307.
8 L. M. Lerner, Carbohydr. Res., 1977, 53, 177.
9 R. M. Moriarty, J. Kim and H. Brumer III, Tetrahedron Lett., 1995, 36,
51.
10 M. Che´rest, H. Felkin and N. Prudent, Tetrahedron Lett., 1968, 2199;
N. T. Anh, Top. Curr. Chem., 1980, 88, 145.
11 B. M. Trost, J. Dumas and M. Villa, J. Am. Chem. Soc., 1992, 114, 9836;
R. M. Moriarty and H. Brumer III, Tetrahedron Lett., 1995, 36, 9265.
12 C. Mukai, J. S. Kim, M. Uchiyama and M. Hanaoka, Tetrahedron Lett.,
1998, 39, 7909.
13 P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996, 118,
100.
14 Structure confirmed by acetylation to the known triacetate: J. Bange,
A. F. Haughan, J. R. Knight and J. Sweeney, J. Chem. Soc., Perkin
Trans. 1, 1998, 1039.
15 T. Hudlicky, H. Luna, H. F. Olivo, C. Andersen, T. Nugent and J. D.
Price, J. Chem. Soc., Perkin Trans. 1, 1991, 2907.
16 The structure of enantiomeric 9 and 10 was determined by OsO4
catalyzed dihydroxylation to the same symmetrical quercitol,
(1b,2b,3a,4b,5b)-pentahydroxycyclohexane: S. J. Angyal and L. Odier,
Carbohydr. Res., 1982, 100, 43.
17 Structure assigned after hydrogenation of the double bond and 1H NMR
analysis of the resulting cyclohexane.
a Ref, 14, b Ref. 15. c Ref. 16. d Ref. 17.
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Chem. Commun., 1999, 2101–2102