Carbohydrate-2-deoxy-2-phosphonates: Simple synthesis and horner-emmons reaction

Article abstract of DOI:10.1002/anie.200804725

Phosphorus meets carbohydrates: Dimethyl phosphite reacts with ceric(IV) ammonium nitrate (CAN) to give phosphonyl radicals that add to glycals 1. The derivatives 2 were isolated in high yields and during a subsequent Horner-Emmons reaction underwent an i

Full text of DOI:10.1002/anie.200804725

Angewandte
Chemie
DOI: 10.1002/anie.200804725
Carbohydrate Analogues
Carbohydrate-2-deoxy-2-phosphonates: Simple Synthesis and Horner–
Emmons Reaction**
Elangovan Elamparuthi and Torsten Linker*
À
À
À
À
Glycosyl phosphates play an important role in the biosynthe-
sis of oligosaccharides.[1] Therefore, there is ongoing interest
in hydrolytically stable analogues that can be used as enzyme
inhibitors.[2] Phosphonates that are linked by a methylene
group to the 1- or 5-position of carbohydrates have turned out
to be especially promising candidates.[2b,d,3] Phosphorus has
also been introduced at the 2-position of carbohydrates by
using 2,3-anhydrosaccharides as substrates, and the resulting
phosphines have found application as enantiomerically pure
ligands.[4] However, only less common altrose derivatives are
available by using this strategy, as ring-opening of the
intermediates always affords 2,3-diaxial products.
corresponding formation of C N, C S, C Se, and C halogen
bonds is well-established.[11]
We therefore investigated the transformation of dimethyl
phosphite (2) with CAN and the O-benzyl-protected glycals
1,[12] which are suitable precursors for radical C C bond
À
formation[9] and contain base-stable protecting groups
(Table 1). Indeed, the reaction proceeded smoothly in meth-
anol at 08C to afford carbohydrate-2-deoxy-2-phosphonates 3
Table 1: Synthesis of the carbohydrate-2-deoxy-2-phosphonates 3.[a]
The chemistry of phosphorus-containing carbohydrates
was described in several publications in the 1970s by Paulsen
and co-workers, who investigated the introduction of phos-
phonates at the 2-position of pyranoses.[5] Furthermore, the
great importance and current relevance of such compounds
was demonstrated in a study reported in 2008 by Leonelli
et al.[6] However, all previous syntheses required many steps
and afforded products with additional functional groups.
Carbohydrates in which only the oxygen atom at the 2-
position has been substituted with a phosphonate group were
hitherto unknown, although they best resemble naturally
occurring saccharides. Herein we describe a simple and
general synthesis of such analogues and their subsequent
Horner–Emmons reaction with benzaldehyde.
For many years, during the course of our investigations on
transition-metal-mediated radical reactions,[7] we have been
interested in the addition of CH-acidic compounds to
glycals.[8] Cerium (IV) ammonium nitrate (CAN) has
proven to be the reagent of choice for radical generation
and offers ready one-step access to C2-branched carbohy-
drates in good yields and high stereoselectivities. We recently
extended the synthetic potential of our methodology through
transformations of the side chain.[9] Surprisingly, despite the
pioneering azidonitration of carbohydrates by Lemieux and
Ratcliffe,[10] the addition of heteroatom radicals to glycals did
not attract any further attention. Furthermore, the generation
of phosphinyl radicals in the presence of CAN and their
reaction with alkenes was hitherto unknown, although the
Glycal
b-anti-3
a-anti-3
syn-3
(yield [%])[b]
(yield [%])[b]
(yield [%])[b]
glucal (1a)
galactal (1b)
xylal (1c)
b-gluco-3a
(64)
b-galacto-3b
(67)
b-xylo-3c
(61)
a-gluco-3a
(8)
a-galacto-3b
(7)
a-xylo-3c
(8)
a-manno-3a
(11)
a-talo-3b
(9)
a-lyxo-3c
(13)
arabinal (1d)[c]
maltal (1e)
lactal (1 f)
a-arabino-3d
b-arabino-3d
b-ribo-3d
(43)[c]
(32)[c]
(<5)[c]
b-malto-3e
(53)
b-lacto-3 f
(51)
a-malto-3e
(9)
a-lacto-3 f
(11)
a-epi-malto-3e
(12)
a-epi-lacto-3 f
(14)
[a] For reaction conditions, see the Experimental Section. [b] Yield of the
analytically pure product (isolated by column chromatography).
[c] Opposite configurations at C2 and C3. Bn=benzyl.
in high yields in only one step. Complete conversion required
10 equivalents of the phosphite. However, 2 is one of the
cheapest phosphorus reagents available and can be removed
readily with a Kugelrohr apparatus after the reaction. All
products were characterized unequivocally on the basis of the
coupling constants in their 1H NMR spectra and were isolated
by column chromatography in analytically pure form (see the
Supporting Information).
From a mechanistic point of view, the reaction evidently
proceeds via phosphonyl radicals generated from dimethyl
phosphite and CAN. Orbital control is responsible for the
highly regioselective attack at the 2-position of the glycal, and
the methyl glycosides are formed by oxidation of the
anomeric center to a cation and subsequent trapping by the
solvent methanol. Importantly, addition reactions of dialkyl
phosphites to glycals under acidic conditions proceed exclu-
[*] E. Elamparuthi, Prof. Dr. T. Linker
Institute of Chemistry, University of Potsdam
Karl-Liebknecht-Strasse 24–25, 14476 Potsdam (Germany)
Fax: (+49)331-977-5056
E-mail: linker@chem.uni-potsdam.de
[**] This research was generously supported by the Deutsche For-
schungsgemeinschaft (Li 556/7-3).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804725.
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sively at the 1-position with an allylic shift;[13] thus, it is clear
that the present reaction in the presence of CAN indeed
occurs through a radical mechanism.
The stereoselectivities of the reactions are interesting,
since two new stereogenic centers are formed in one step. In
all examples, the phosphonyl radical attacked the double
bond of the glycal 1 preferentially anti to the 3-O-benzyl
group (Table 1). This preference can be rationalized on the
basis of steric interactions. Carbohydrate-2-deoxy-2-phospho-
nates syn-3, obtained as by-products, were separated readily
by column chromatography. Overall, the stereoselectivities of
the radical reactions with dimethyl phosphite (2) are some-
what lower than those observed in the addition of malona-
tes;[9b] however, they are in accordance with transformations
with nitromethane,[9c,d] probably owing to the similar steric
demand of the radical precursors.
Scheme 1. Horner–Emmons reactions of the carbohydrate-2-deoxy-2-
phosphonates 3 (see the Experimental Section).
In contrast to the anti/syn selectivities, the formation of
anomeric methyl glycosides was initially surprising (Table 1).
No a-gluco or a-galacto isomers were observed during the
addition of malonates or nitromethane.[9] This difference can
be rationalized by a weaker neighboring-group participation
of the phosphonate substituent, which can not stabilize and
shield the anomeric cation in a four-membered ring as
effectively as an ester or a nitro group in a five-membered
ring. Despite the product mixtures, all reactions afforded one
main product, and the isomers could be separated by column
chromatography and isolated in analytically pure form (see
the Supporting Information).
Scheme 2. Proposed mechanism of the elimination during the
Horner–Emmons reaction (shown for xylo-3c).
Subsequently, we investigated the Horner–Emmons reac-
tion of the isolated main products b-anti 3 and selected
À
benzaldehyde (4), which is very reactive in such C C bond
formations, as the carbonyl compound.[14] Despite the CH
acidity of the 2-position, the reaction conditions had to be
optimized carefully, as bases that were too strong led to
decomposition products as a result of the lability of the
carbohydrate. On the other hand, no conversion was observed
with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), which has
been applied in Horner–Emmons reactions of carbohydrate
phosphonates previously.[15]
benzaldehyde. This cleavage of a neighboring protecting
group is in accordance with transformations of carbanions at
an anomeric center.[16] Because of the vinylogous phospho-
nate, the resulting unsaturated carbohydrate 7c has an acidic
hydrogen atom in the 4-position; deprotonation generates the
intermediate 8c. Only now does the Horner–Emmons
reaction with benzaldehyde (4) occur to afford the final
product 5b. The preferential formation of the E-configured
double bond can be rationalized on the basis of steric
interactions with the methoxy group and supports the
postulated elimination of the 3-O-benzyl substituent prior
The best conditions found for the deprotonation of the
carbohydrate-2-deoxy-2-phosphonates 3a–d were treatment
with sodium hydride at 08C, which afforded two compounds 5
in good yields (Scheme 1). Interestingly, irrespective of the
configuration of the starting material (gluco/galacto or xylo/
arabino), product 5a or 5b, respectively, was obtained. This
result is in accordance with the degradation of several
stereogenic centers during the Horner–Emmons reaction.
We established unequivocally by two-dimensional NMR
spectroscopy that the products 5 had a 3,6-dihydro-2H-
pyran structure with a 3-benzylidene group. E/Z isomers
were separated by column chromatography and isolated in
high yields in analytically pure form, and the configuration at
the double bond was determined by NOE measurements (see
the Supporting Information).
À
to the C C coupling step.
To suppress fragmentation reactions during the Horner–
Emmons reaction, the O-benzyl protecting groups were
removed from b-gluco-3a by catalytic hydrogenation,[17] and
the free carbohydrate-2-deoxy-2-phosphonate was isolated in
87% yield in analytically pure form (see the Supporting
Information). However, even the deprotonation of this
substrate with sodium hydride resulted only in decomposition
products. This decomposition can be explained by the
required excess of base and poor solubility of the tetraanion
in organic solvents. All the same, this deprotection gave a
water-soluble carbohydrate–phosphorus analogue: an impor-
tant compound for future biological studies.
À
We explain the surprising formation of the C C coupling
products 5 by the mechanism depicted for xylo-3c in
Scheme 2. In the initial step, the anion 6c is generated by
deprotonation. As a result of steric hindrance, 6c eliminates
the O-benzyl group in the 3-position faster than it reacts with
In summary, we generated phosphonyl radicals with
cerium(IV) ammonium nitrate and succeeded in their addi-
tion to glycals for the first time. Thus, carbohydrate-2-deoxy-
2-phosphonates became available in only one step in good
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Chemie
[2] For a review, see: “Synthesis of Glycosyl Phosphate Mimics”: F.
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charides could be used in this procedure, and all products
were isolated in analytically pure form. An interesting
fragmentation took place during the Horner–Emmons reac-
tion with benzaldehyde, which afforded multiply unsaturated
products by a mechanism involving consecutive deprotona-
tion–elimination steps. The conjugated p systems obtained
should be suitable for further transformations and have
promising photophysical properties. Since glycals can be
synthesized on a multigram scale or are even commercially
available, and dimethyl phosphite is one of the cheapest
phosphorus reagents, relatively large amounts of the carbo-
hydrate–phosphorus derivatives are accessible. The biological
activity of these carbohydrate analogues will be investigated
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Experimental Section
General procedure for the synthesis of 3: A solution of 1 (1.0 mmol)
and dimethyl phosphite (2; 1.1 g, 10.0 mmol) in methanol (5 mL) was
cooled to 08C under an argon atmosphere, and a solution of
cerium(IV) ammonium nitrate (2.2 g, 4.0 mmol) in methanol
(15 mL) was added dropwise until conversion was complete (TLC,
approximately 4 h). The reaction mixture was stirred for a further
30 min at 08C, and then an ice-cold dilute solution of sodium
hydrogen sulfite (50 mL) was added, and the mixture was extracted
with dichloromethane (3 ꢀ 80 mL). The combined organic extracts
were dried (Na2SO4) and concentrated, and the excess of dimethyl
phosphite was removed at 0.01 mbar and 1208C with a Kugelrohr
apparatus. The crude product 3 was purified by column chroma-
tography on silica gel (cyclohexane/ethyl acetate/methanol 4:2:1).
General procedure for the Horner–Emmons reactions: A solu-
tion of 3 (1.0 mmol) in anhydrous THF (5 mL) was cooled to 08C
under an argon atmosphere. Sodium hydride (70 mg, 3.0 mmol) was
added at this temperature, and stirring was continued for 10 min. A
solution of benzaldehyde 4 (320 mg, 3.0 mmol) in anhydrous THF
(5 mL) was then added dropwise until conversion was complete
(TLC, 1 h). The reaction mixture was stirred for a further 30 min at
08C and then quenched with a dilute solution of ammonium chloride
(30 mL) and extracted with diethyl ether (3 ꢀ 30 mL). The combined
organic extracts were dried (Na2SO4) and concentrated. The crude
product 5 was purified by column chromatography (cyclohexane/
ethyl acetate 8:1). All compounds 3 and 5 were isolated in analytically
pure form and characterized completely (see the Supporting Infor-
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Received: September 26, 2008
Revised: December 2, 2008
Published online: January 23, 2009
À
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Keywords: C C coupling · carbohydrates · phosphorus ·
radical reactions · synthetic methods
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