SmI2-mediated reactions of diethyl iodomethylphosphonate with esters and lactones: A highly stereoselective synthesis of a precursor of the C-glycosyl analogue of thymidine 5′-(β-L-rhamnosyl)diphosphate

Article abstract of DOI:10.1016/S0040-4039(02)01540-X

In the presence of samarium iodide diethyl iodomethylphosphonate reacts with esters to afford β-ketophosphonates. The protocol has been applied to sugar lactones to afford in fairly good yields intermediates that are useful precursors for a variety of potentially bioactive compounds, such as the C-glycosyl analogue of thymidine 5′-(β-L-rhamnosyl)diphosphate.

Full text of DOI:10.1016/S0040-4039(02)01540-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7259–7261
SmI2-mediated reactions of diethyl iodomethylphosphonate with
esters and lactones: a highly stereoselective synthesis of a
precursor of the C-glycosyl analogue of thymidine
5%-(b- -rhamnosyl)diphosphate
L
Fulvia Orsini* and Alessandro Caselli
Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, Via Venezian 21 20133 Milano, Italy
Received 24 July 2002; accepted 25 July 2002
Abstract—In the presence of samarium iodide diethyl iodomethylphosphonate reacts with esters to afford b-ketophosphonates.
The protocol has been applied to sugar lactones to afford in fairly good yields intermediates that are useful precursors for a
variety of potentially bioactive compounds, such as the C-glycosyl analogue of thymidine 5%-(b-L-rhamnosyl)diphosphate. © 2002
Elsevier Science Ltd. All rights reserved.
b-Ketophosphonates are quite important organic com-
pounds for their metal-complexing ability1 and for their
many applications as organic intermediates in the syn-
thesis, for example, of a,b-unsaturated compounds (via
the Horner–Emmons reaction);2 of chiral b-hydroxy-
acids and chiral b-aminophosphonic acids, both
endowed with interesting biological properties,3,4 for
which several methods of preparation have been
reported, albeit not fully satisfactory ones.5
In the present work we have investigated the ability of
samarium iodide to promote the reaction between a-
halophosphonates and esters to produce b-ketophos-
phonates. Once this possibility had been verified, we
were particularly interested to extend the reaction to
sugar lactones, as easy available and convenient precur-
sors of a variety of potentially bioactive compounds
such as C-glycosyl phosphonates and aminophospho-
nates inserted on a sugar anomeric carbon.9
Also, C-glycosylphosphonates are quite interesting
compounds as they can act as stable biomimetics of the
corresponding glycosyl phosphates (which play a cru-
cial role in the biosynthesis of oligo- and polysaccha-
rides, and glycoconjugates) and are important as
enzymatic inhibitors.6 Therefore they have been the
subject of significant efforts in synthetic chemistry7 and
the development of new efficient methodologies for
their synthesis is an appealing target.
The reactions have been tested in tetrahydrofuran solu-
tion, using the convenient, commercially available
diethyl iodomethylphosphonate. As observed in the
synthesis of b-hydroxyphosphonates reported in the
preceding paper, the best results have been obtained by
simultaneous addition of the organic reagents to the
solution of samarium iodide (0.1
M
in tetra-
hydrofuran), the latter being used as at least 2.0
(usually 2.2) molar equivalents.
Samarium iodide has been found to be a very versatile
and mild reagent, useful in a wide variety of new types
of electron transfer reactions (such as radical cycliza-
tion, pinacol coupling reactions, ketyl–olefin coupling
reactions, Reformatsky-type and aldol type reactions)
which are quite superior for efficiency and selectivity to
the traditional ones.8
Addition to esters produced the expected b-ketophos-
phonates, and in reasonable to moderate yields (30–
49%) depending on the ester structure (Table 1). In all
cases unreacted starting ester was recovered in generally
comparable amounts with respect to the b-ketophos-
phonate, but it was easily separated by chromatography
and recycled (in most cases a simple filtration on a very
short column of silica gel was enough: a procedure
easily applicable also if the reaction has to be scaled
up). Methanephosphonate was also formed, a side
product that a priori could derive from different path-
Keywords: b-ketophosphonates; C-glycosylphosphonates; samarium
iodide.
* Corresponding author. Tel.: +39-02-5031411; fax: +39-02-50314106;
e-mail: fulvia.orsini@unimi.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01540-X

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F. Orsini, A. Caselli / Tetrahedron Letters 43 (2002) 7259–7261
correlation between one or both the methylenic hydro-
gens adjacent to the carbonyl carbon and the hydrogen
at C-2.
ways: acid–base exchange between an unreacted
organosamarium and water during work-up; or by
acid–base exchange between the organosamarium itself
and the b-ketophosphonate,10 this last assumption
being strongly supported by the higher acidity of the
latter.
Lactol 3 is a particularly valuable compound, because it
is a precursor of the C-glycosyl analogue of thymidine
5%-(b-
L
-rhamnopyranosyl diphosphate),
a
potential
inhibitor of rhamnosyltransferase, a quite important
enzyme for the biosynthesis of mycobacterial cell wall.
Therefore inhibitors of this enzyme have a potential
therapeutic interest.11
The partly disappointing results (maximum 50% yields)
obtained with esters prompted us to investigate the
reaction of diethyl iodomethylphosphonate with gly-
conolactones. For this purpose 2,3,5-tri-O-benzyl-b-
D
-arabinono-1,4-lactone,
2,3,4,6-tetra-O-benzyl-
D-
In summary, the protocol reported above allows the
synthesis of b-ketophosphonates under mild and neu-
tral conditions, and with some advantages with respect
to known procedures: easily available substrates; no
strong bases, acids or heat required; no side products
deriving from the attack on the carbonyl carbon of the
b-ketophosphonate.
mannono-1,5-lactone and 2,3,4-tri-O-benzyl-
L
-rham-
nono-1,5-lactone (easily prepared from the parent
sugars by oxidation with pyridinium chlorochromate,
in 3.5 molar ratio, in methylene chloride in the pres-
ence of molecular sieves) were reacted with diethyl
iodomethylphosphonate in tetrahydrofuran in the pres-
ence of 2.2 equiv. of samarium iodide, according to the
protocol used with esters. The reaction worked better in
these cases, affording the expected addition compounds
with yields ranging from 45 to 82% depending on
the starting lactone which was recovered in 10 to 40%
yield, and was easily separated by chromatography
and recycled (Scheme 1).
When the protocol is applied to glyconolactones, in
particular six-membered 1,5-lactones, the reaction pro-
ceeds in high yields and stereoselection and may repre-
sent a convenient entry to a variety of bioactive
compounds of therapeutic potential.
The reaction was stereoselective and afforded only one
stereomer for the mannono- and rhamnono-lactone,
whereas the lactone from 2,3,5-tri-O-benzyl-arabino-
furanose afforded the two diastereomers in a 3/1 ratio.
The anomeric configuration of the lactols 1–3 was
determined by NOE experiments, which evidenced a
Typical procedure. In a typical procedure a THF solu-
tion (2 mL) of diethyl iodomethylphosphonate (0.5
mmol) and carbonyl compound (0.5 mmol) was added
dropwise over a 20 min period to a room temperature
stirred solution of SmI2 in tetrahydrofuran (0.1 M, 12
mL). Soon after the addition the original blue solution
Table 1. Reactions between diethyl iodomethylphosphonate and estersa
a
All new compounds gave satisfactory 1H, 13C NMR and MS spectroscopic analyses.
b Yields refer to % of isolated products, unless otherwise stated; yields between parentheses refer to diethyl methanephosphonate formed under
the reaction conditions.
c Yields refer to % of recovered unreacted carbonyl compound.

F. Orsini, A. Caselli / Tetrahedron Letters 43 (2002) 7259–7261
7261
Scheme 1.
turned to a yellowish suspension. The reaction mixture
was stirred at room temperature for 12 h, monitored by
TLC (EtOAc/n-hexane), treated with aqueous HCl
(0.1N solution, 3 mL) and extracted with ethyl acetate
(3×4 mL); the organic layer was washed with a satu-
rated Na2SO3 aqueous solution (2 mL), dried with
sodium sulfate, filtered, the solvent was evaporated and
the crude was purified by column flash-chromatography
(Scheme 1).
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Acknowledgements
The National Research Council (CNR) and Ministero
della Ricerca Scientifica e Tecnologica (MURST) are
thanked for financial support.
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