Synthesis of chiral β-iodo-and vinylorganophosphorus(V) compounds by fragmentation of carbohydrate anomeric alkoxyl radicals

Article abstract of DOI:10.1021/ol302939z

A new general methodology for the synthesis of chiral vinylphosphonate and vinylphosphine oxide carbohydrate derivatives has been developed using the anomeric alkoxyl radical fragmentation reaction as the key step. The synthetic sequence proceeded via β-iodophosphonate and β-iodophosphine oxide intermediates, which may be interesting synthons for the introduction of phosphorus into organic molecules. These vinylphosphonates could be easily transformed into 2-methylene-1-phosphapentofuranoses (3-methylene-1,2- oxaphospholanes) and β-aminophosphonates, isosteres of biologically active α-methylene-γ-lactones and β-amino acids, respectively.

Full text of DOI:10.1021/ol302939z

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of Chiral β‑Iodo- and
Vinylorganophosphorus(V) Compounds
by Fragmentation of Carbohydrate
Anomeric Alkoxyl Radicals
ꢀ
Daniel Hernandez-Guerra, Marıa S. Rodrıguez,* and Ernesto Suarez*
ꢀ
´
´
´
Instituto de Productos Naturales y Agrobiologıa del CSIC, Carretera de La Esperanza 3,
38206 La Laguna, Tenerife, Spain
esuarez@ipna.csic.es; mrodriguez@ipna.csic.es
Received October 24, 2012
ABSTRACT
A new general methodology for the synthesis of chiral vinylphosphonate and vinylphosphine oxide carbohydrate derivatives has been developed
using the anomeric alkoxyl radical fragmentation reaction as the key step. The synthetic sequence proceeded via β-iodophosphonate and
β-iodophosphine oxide intermediates, which may be interesting synthons for the introduction of phosphorus into organic molecules.
These vinylphosphonates could be easily transformed into 2-methylene-1-phosphapentofuranoses (3-methylene-1,2-oxaphospholanes) and
β-aminophosphonates, isosteres of biologically active R-methylene-γ-lactones and β-amino acids, respectively.
Considerable attention has been focused on vinylphos-
phonates1 and vinylphosphine oxides2 because they are
useful synthetic intermediates in organic transformations
having in addition a wide range of biochemical applica-
tions in many areas. These organophosphorus compounds
due to the electrophilic double bond are used as key starting
materials in Michael and radical additions, 1,3-cycloadditions,
DielsÀAlder, Stetter, and metathesis reactions, among
others. In particular, Michael addition of amines to vinylpho-
sphonates has attracted special interest in the preparation of
β-aminophosphonic acids as isosteres of β-amino acids.3
Moreover, 1-(iodomethyl)alkylphosphineoxidesappear
to be practically unknown, with only one of the simplest
members of the family, (2-iodoethyl)(diphenyl)phosphine
oxide, having been synthesized.4 1-(Iodomethyl)alkyl-
phosphonates are also relatively rare compounds, and the
literature examples that we were able to uncover correspond
almost exclusively to diethyl 2-iodoethylphosphonate or sim-
ple alkyl-branched derivatives. They have been prepared by
halogen or OTs/I exchange under Finkelstein conditions5 or
by metallophosphorylation of zirconoceneÀalkene complexes
(1) For reviews, see: (a) Ananikov, V. P.; Khemchyan, L. L.; Belets-
kaya, I. P. Synlett 2009, 2375–2381. (b) Coudray, L.; Montchamp, J.-L.
Eur. J. Org. Chem. 2008, 3601–3613. (c) Gaumont, A. C.; Gulea, M. In
Science of Synthesis: HoubenÀWeyl Methods of Molecular Transforma-
tions; Molander, G. A., Ed.; Thieme: Stuttgart, 2006; Vol. 33, pp 665À694.
(d) Dembitsky, V. M.; Al Quntar, A. A. A.; Haj-Yehia, A.; Srebnik, M.
Mini-Rev. Org. Chem. 2005, 2, 91–109. (e) Maffei, M. Curr. Org. Chem.
2004, 1, 355–375. (f) Wang, H.-Q.; Liu, Z.-J. Chin. J. Org. Chem. 2003,
23, 321–330. (g) Minami, T.; Okauchi, T.; Kouno, R. Synthesis 2001,
349–357. (h) Minami, T.; Motoyoshiya, J. Synthesis 1992, 333–349.
(2) For a review, see: (a) Gaumont, A. C.; Gulea, M. In Science of
Synthesis, Houben Weyl Methods of Molecular Transformations; Georg
Thieme Verlag KG: Stuttgart, 2007; Vol. 33, pp 701À710. Selected repre-
sentative examples: (b) Ortial, S.; Montchamp, J.-L. Org. Lett. 2011, 13,
(3) For a review, see: Palacios, F.; Alonso, C.; de los Santos, J. M.
Chem. Rev. 2005, 105, 899–931.
(4) Shvchenko, V.; Engel, R. Heteroatom. Chem. 1998, 9, 495–502.
(5) (a) Kiyokawa, K.; Suzuki, I.; Yasuda, M.; Baba, A. Eur. J. Org.
ꢀ
ꢀ
Chem. 2011, 2163–2171. (b) Hockova, D.; Holy, A.; Masojıdkva, M.;
´
ꢀ
3134–3147. (c) Gonzalez-Nogal, A. M.; Cuadrado, P.; Sarmentero,
Keough, D. T.; Jersey, J.; Guddat, L. W. Bioorg. Med. Chem. 2009, 17,
6218–6232. (c) Balczewski, P.; Pietrzykowski, W. M. Tetrahedron 1997,
53, 7291–7304.
(6) (a) Lai, C.; Xi, C.; Chen, W.; Hua, R. Tetrahedron 2006, 62, 6295–
6302. (b) Xi, C.; Ma, M.; Li, X. Chem. Commun. 2001, 2554–2555.
M. A. Tetrahedron 2010, 66, 9610–9619. (d) Chernysheva, N. A.; Yas’ko,
S. V.; Gusarova, N. K.; Trofimov, B. A. Mendeleev Commun. 2010, 20,
20–21. (e) Kawaguchi, S.; Nagata, S.; Nomoto, A.; Sonoda, M.; Ogawa,
A. J. Org. Chem. 2008, 73, 7928–7933. (f) Oliana, M.; King, F.; Horton,
P. N.; Hursthouse, M. B.; Hii, K. K. J. Org. Chem. 2006, 71, 2472–2479.
r
10.1021/ol302939z
XXXX American Chemical Society

Scheme 1. Alkoxyl Radical β-Fragmentation of 2,3-Dideoxy-3-phosphorylhexopyranosesa
a ARF = alkoxyl radical β-fragmentation reaction; Z = Ph (phosphine oxides), Z = OEt (phosphonates).
with chlorophosphate using iodine as electrophile.6 Studies
on the chemical reactivity of these compounds have been
largely limited to diethyl 2-iodoethylphosphonate.5a,c,7
Previous work from our laboratory described the car-
bohydrate anomeric alkoxyl radical β-fragmentation reac-
tion (ARF) by treatment of the free anomeric alcohol with
hypervalent iodine in the presence of iodine.8 Exploiting
these sugar transformations, we set out to develop a new
methodology for elaboration of chiral vinylphosphine
oxide and vinylphosphonate derivatives of generalized
structure VII (Scheme 1). Regioselective introduction of
the CÀP bond into the carbohydrate skeleton was accom-
plished using two different protocols. 3-Phosphinyl deri-
vatives III (Z = Ph) were prepared from glycals I via an
anomalousFerrierreaction while a Michael addition tothe
readily available unsaturated lactones II was used for the
synthesis of 3-phosphonylated sugars IV (Z = OEt).
Subsequently, either the acid-catalyzed hydration of III
(Z = Ph) or the reduction of IV (Z = OEt) afforded the
required γ-hydroxyphosphorus compounds V which were
then submitted to the ARF reaction to give β-iodophosphorus
compounds VI. Dehydroiodination of VI provided the desired
vinylorganophosphorus VII.
In pursuance of this goal we decided to prepare first
3-phosphinylated-glycals 1, 5, and 9 by reaction of the
corresponding perbenzylated D-glucal, D-galactal, and
D-lactal, respectively, with diphenylphosphenium cation
using a previously reported procedure developed by
Yamamoto et al. for perbenzylated D-glucal (Table 1).9
The extension of this methodology to perbenzylated
D-galactal afforded 5 as a sole stereoisomer. The reaction
was also expanded to disaccharide D-lactal, but a mixture
of the four Ferrier isomers, by P-nucleophilic attack at C-1
and C-3, were obtained as described in the Supporting
Information. For the present study, only the major
3R-isomer 9 (45%) has been used.
Hydration of these glycals by a modification of the
procedure of Falck et al.10 with catalytic amounts of
Ph3P HBr in refluxing THF/H2O gave hexopyranose
3
compounds 2, 6, and 10 in high yields. The ARF reactions
were performed under the conditions stated in Table 1,
with (diacetoxyiodo)benzene (DIB) and iodine in CH2Cl2.
The ARF proceeded smoothly and the β-iodo phosphine
oxides 3, 7, and 11 were obtained in good yields. In the
fragmentation of 10, the major product 11 (67%) was
accompanied by a side product identified as lactone 33S
(15%, see the Supporting Information). The dehydroiodi-
nation of the β-iodo phosphine oxides was effectively
accomplished with DBU in benzene to afford vinylpho-
sphine oxides 4, 8, and 12 in high yields.
In the iodide elimination of 11, partial hydrolysis of the
formate group was observed, and besides vinylphosphine
oxide 12, a small amount of the corresponding alcohol 34S
(13%, see the Supporting Information) was obtained, the
global yield of the vinylphosphine oxide reaching 96%.
Preliminary attempts to prepare 3-phosphonylated
sugar of general structure III (Z = OEt) using a modified
Yamamoto protocol by reaction of perbenzylated D-glucal
with (EtO)2PCl/AlCl3 proved to be unsuccessful; therefore,
an alternative route was sought. The phospha-Michael
addition of triethyl phosphite to readily accessible pent-
2-enono-1,4-lactones11 and hex-2-enono-1,5-lactones12 under
the conditions described by Kofoed and Pedersen,13 using
phenol as protonating agent, afforded the 3-phosphonylated
γ- and δ-lactones 13, 17, and 21. The reaction proceeded with
excellent regio- and diastereoselectivity for 13 and 21, but as
should be expected for a sterically less demanding substrate,
the glucose derivative 17 was obtained as an inseparable
(10) (a) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org.
Chem. 1990, 55, 5812–5813. (b) Koviach, J. L.; Chappell, M. D.;
Halcomb, R. L. J. Org. Chem. 2001, 66, 2318–2326.
(7) Takahashi, H.; Inagaki, S.; Yoshii, N.; Gao, F.; Nishihara, Y.;
Takagi, K. J. Org. Chem. 2009, 74, 2794–2797.
~
(11) Camps, P.; Cardellach, J.; Font, J.; Ortuno, R. M.; Ponsati, O.
ꢀ
(8) (a) de Armas, P.; Francisco, C. G.; Suarez, E. Angew. Chem., Int.
ꢀ
Tetrahedron 1982, 38, 2395–2402.
(12) Yadav, J. S.; Reddy, B. V. S.; Reddy, Ch. S. Tetrahedron Lett.
2004, 45, 4583–4586.
Ed. Engl. 1992, 31, 772–774. (b) de Armas, P.; Francisco, C. G.; Suarez,
ꢀ
E. J. Am. Chem. Soc. 1993, 115, 8865–8866. (c) Gonzalez, C. C.;
ꢀ
ꢀ
Kennedy, A. R.; Leon, E. I.; Riesco-Fagundo, C.; Suarez, E. Angew.
Chem., Int. Ed. 2001, 40, 2326–2328.
(13) For a review on phospha-Michael addition, see: (a) Enders, D.;
Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29–
49. (b) Kofoed, T.; Pedersen, E. B. Nucleosides, Nucleotides and Nucleic
Acids 1995, 14, 345–347.
(9) Takano, A.; Fukuhara, H.; Ohno, T.; Kutsuma, M.; Fujimoto,
T.; Shirai, H.; Iriye, R.; Kakehi, A.; Yamamoto, I. J. Carbohydr. Chem.
2003, 22, 443–457.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Synthesis of β-Iodo- and Vinylorganophosphorus(V) Compounds
a Reagents and conditions per mmol of substrate: Ph2PCl (2 mmol), AlCl3 (2 mmol), DCM (5 mL), 0 °C f reflux. b Ph3P HBr (0.12À0.46 mmol),
3
THF (21.5 mL), reflux. c PhI(OAc)2 (1.1À1.5 mmol), I2 (0.6À1.1 mmol), DCM (25 mL). d DBU (1.1À2.6 mmol), PhH (25 mL), 9À10 °C. e For brevity β-
D-Gal refers to the perbenzylated moiety of β-D-galactose. f 15% of oxidized lactone (33S, see the Supporting Information) is also obtained. g 13% of
i
hydrolyzed compound (34S, see the Supporting Information) is also obtained. h P(OEt)3 (5 mmol), PhOH (4.2 mL), 100 °C. DIBAL-H (4 mmol),
PhCH3 (33 mL), À78 °C.
mixture of isomers (dr 3β/3R, 4.5:1). Separation of the
isomers was chromatographically accomplished in the next
step after the DIBAL-H reduction of the carboxylate group
and the reaction sequence was continued only with the major
β-diastereoisomer 18.
The synthetic usefulness of these compounds has
been preliminarily assessed, and the results are summar-
ized in Scheme 2. We were interested in the formation of
2-methylene-1-phosphapentofuranoses (3-methylene-1,2-
oxaphospholanes) (e.g., 26 and 27), which are isosteres
of R-methylene-γ-butyrolactones.14 The R-methylene-γ-
butyrolactone is an important structural motif found in a
great variety of natural products, many of which exhibit
useful significant biological activities.15 We have found
Thus, the other β-hydroxyphosphonates 14 and 22 were
also obtained and submitted to the ARF radical reaction.
Analogously to the β-iodophosphine oxides prepared be-
fore, β-iodophosphonates 15, 19, and 23 were obtained in
good to excellent yield and when chemically pure are also
stable compounds which can be stored atÀ20 °C for a long
time and handled at room temperature without any ap-
parent deterioration. Finally, base-mediated elimination
of the iodide compounds afforded vinylphosphonates 16,
20, and 24 in high yields. The series 18À20 was efficiently
conducted on a large scale: starting from 8.3 mmol (3.86 g)
of 18, 7.3 mmol of 19 (88%) and 7.3 mmol of 20 (100%)
were obtained.
(14) The C-isostere of 26 and 27 (2-deoxy-2-methylene-D-erythro-
pentono-1,4-lactone) has been prepared; see: Porto, R. S.; Coelho, F.
Synth. Commun. 2004, 34, 3037–3046and references cited therein.
(15) For recent reviews, see: (a) Janecka, A.; Wyrebska, A.; Gach, K.;
Fichna, J.; Janecki, T. Drug Discovery Today 2012, 17, 561–572. (b)
Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem., Int. Ed.
2009, 48, 9426–9451.
(16) (a) Collard, J.-N.; Benezra, C. Tetrahedron Lett. 1982, 23, 3725–
3728. For a related 3-methylene-1,2-oxaphospholane derivative from
dialkylphosphinic acid, see: (b) Xu, Y.; Li, Z. Tetrahedron Lett. 1986, 27,
3017–3020.
Org. Lett., Vol. XX, No. XX, XXXX
C

and 27 (Scheme 2). The reaction stereochemistry could be
ascribedto steric hindranceby the two vicinal ether groups.
Exclusive 1,4-conjugate addition on the β-side of the
molecule was observed in 28, whereas the sterically less
demanding substrate 27 afforded a separable mixture of
R- and β-isomers 30. The stereochemistry at C-2 was
assigned by NOESY experiments, with some of the ob-
served interactions also confirming the phosphorus
stereochemistry assigned previously for 26 and 27 (for
details, see the Supporting Information).20 In both cases,
the conjugate elimination of the vicinal benzyl ether was
observed as a side reaction, leading to the formation of
29 and 31.
Scheme 2. Synthesis of 2-Methylene-1-phosphapentofuranoses
and Their Addition Products with Glycine
In summary, we have developed a simple and effective
methodology for the synthesis of chiral 1-alkylvinylpho-
sphonate and -phosphine oxide building blocks with two
or three carbon tethers possessing one or two stereogenic
centers, respectively. The method utilizes inexpensive car-
bohydrates as starting materials and is amenable for large-
scale synthesis. The fragmentation reaction proceeded
under very mild conditions allowing the isolation of the
1-(iodomethyl)alkylphosphonate and -phosphine oxide
intermediates. Moreover, the method can be applied to
disaccharides such as the perbenzylated D-lactal derivative
9 without great loss of efficiency. Prior structural modifi-
cations and protection patterns of the carbohydrate in-
crease the potential of the method, e.g., 16 where selective
deprotection and derivatization of the alcohols may be
attempted.
scant information on the synthesis of 3-methylene-1,2-
oxaphospholanes derivatives.16
The preparation of 2-methylene-1-phosphapentofura-
noses 26 and 27 was achieved starting from the vinylpho-
sphonate 20. Basic hydrolysis of the formate ester afforded
alcohol 25, which was subsequently subjected to intramo-
lecular transesterification using PPTS. The diastereomeric
mixture of 26 and 27 was separated by chromatography.
The phosphorus stereochemistry was tentatively assigned
by the small but significant deshielding effect of the PdO
bond on all syn related protons (e.g., 26/27 Δδ 0.2 ppm for
H3β and À0.15 ppm for H4R).17 The value of the NMR
ring coupling constants (3JP,H3, 3JP,H4, and 3JH3,H4) differ
markedly in both isomers. Since all of them depend on the
dihedral angle in a Karplus-type relationship these differ-
ences are attributable to different conformations of the
ring.18 Indeed, molecular mechanics models indicate that
in 26 the 1,2-oxaphospholane ring preferentially adopts an
E4 conformation with phase angle P = 52°, while 27 shows
a preference for an E3 (P = 204°).17b,c,19
The ease with which these relatively complex 1-
(iodomethyl)alkylphosphonates can be synthesized on a
large scale may prompt further research to gain more
insight into their chemical reactivity.
Acknowledgment. This work was supported by the In-
vestigation Programs (CTQ2010-18244 and CTQ2007-67492)
of the Ministerio de Economı
(SolSub20081000192 and ProID20100088) of the Gobierno
de Canarias. D.H.-G. thanks the Ministerio de Economıa y
Competitividad for a fellowship.
´
a y Competitividad and
´
Finally, the use of these vinylphosphonates as scaffolds
was exemplified by the addition of Gly-OMe HCl to 26
3
(17) The deshielding effect of the PdO bond is well established: (a)
Quin, L. D. The Heterocyclic Chemistry of Phosphorus; Wiley-Inter-
Supporting Information Available. Experimental pro-
cedure and spectral data for all pure compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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science: New York, 1981; pp 350À353. (b) Wroblewski, A. E. Tetrahedron
1983, 39, 1809–1816. (c) Piotrowska, D. G. Tetrahedron: Asymmetry
2008, 19, 279–287.
(18) Coxon, B. Adv. Carb. Chem. Biochem. 2009, 62, 17–82.
(19) Studies on conformational analysis of 1,2-oxaphospholanes are
(20) Due to the expected flexibility conformational of 1,2-oxapho-
spholane rings, the NOESY studies of 28 and 30 were made on
minimized structures.
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scarce: (a) Wroblewski, A. E.; Konieczko, W. T.; Skoweranda, J.;
Bukowska-Strzyzewska, M. J. Crystallogr. Spectrosc. Res. 1991, 21,
ꢀ
581–587. (b) Wroblewski, A. E. Phosphorus, Sulfur Silicon Relat. Elem.
1991, 6, 97–117. (c) Bergesen, K. Acta Chem. Scand. 1970, 24, 1122–
1123. See also ref 17b,17c.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX