Synthesis of thiazolines linked to a difluoromethylphosphonate diester via dithioester chemistry.

Article abstract of DOI:10.1021/ol025544f

[reaction: see text] A two-step, high-yielding synthesis of delta(2)-thiazolines containing a difluoromethylphosphonate diester moiety has been devised using a building block approach. Racemic or chiral beta-amino alcohols and diols were coupled with meth

Full text of DOI:10.1021/ol025544f

ORGANIC
LETTERS
2002
Vol. 4, No. 5
843-846
Synthesis of Thiazolines Linked to a
Difluoromethylphosphonate Diester via
Dithioester Chemistry
Emmanuel Pfund, Thierry Lequeux, Serge Masson, and Michel Vazeux*
Laboratoire de Chimie Mole´culaire et Thio-organique UMR CNRS 6507 ISMRA,
UFR Sciences, UniVersite´ de Caen, 6 Bd Mare´chal Juin, 14050 Caen Cedex, France
Vazeux@ismra.fr
Received January 11, 2002
ABSTRACT
A two-step, high-yielding synthesis of ∆2-thiazolines containing a difluoromethylphosphonate diester moiety has been devised using a building
block approach. Racemic or chiral â-amino alcohols and diols were coupled with methyl difluoro(diethoxyphosphono)dithioacetate to give
predominantly the corresponding â-hydroxythioamides, which were then cyclized to provide a series of novel substituted ∆2-thiazolines.
Since the pioneering work of Blackburn,1 a very wide range
of structurally novel and biologically interesting difluoro-
methylenephosphonic acids and their phosphonate derivatives
have been synthesized.2 It has been demonstrated that the
isoelectronic and isosteric CF2/O transposition in phosphate
analogues confers metabolic stability and imparts important
features for receptor binding affinity or hydrogen bonding
interactions. Many R,R-difluoroorganophosphorus (V) de-
rivatives have been studied as potential enzyme inhibitors
and as useful probes for the elucidation of biochemical
processes.3 Among the more potent nucleotidyl inhibitors
are the Halazy’s acyclic nucleoside phosphonate I,4 to-
gether with its conformationally constrained analogues
developed recently by Shimeno and Yokomatsu’s groups,5
and the ribonucleoside 5′-difluoromethyl phosphonates II6
(Figure 1).
Figure 1. Structures of two representative nucleoside analogues
as PNP (I) and RNA polymerase (II) inhibitors.
(1) (a) Blackburn, G. M.; England, D. A.; Kolkmann, F. J. Chem. Soc.,
Chem. Commun. 1981, 930. (b) Blackburn, G. M.; Eckstein, F.; Kent, D.
E.; Perre´e, T. D. Nucleosides Nucleotides 1985, 4, 165.
Peptides containing difluorophosphonomethyl amino acids7
as well as difluoromethylene analogues of naturally occurring
(2) Reviews: (a) Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. ReV. 1996,
96, 1641. (b) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(3) For recent leading references, see: (a) Halazy, S.; Ehrhard, A.;
Eggenspiller, A.; Berges-Gross, V.; Danzin, C. Tetrahedron 1996, 52, 177.
(b) Kawamoto, A. M.; Campbell, M. M. J. Chem. Soc., Perkin Trans. 1
1997, 1249. (c) Caplan, N. A.; Pogson, C. I.; Hayes, D. J.; Blackburn, G.
M. J. Chem. Soc., Perkin Trans. 1 2000, 421. (d) Yokomatsu, T.; Hayakawa,
Y.; Kihara, T.; Koyanagi, S.; Soeda, S.; Shimeno, H.; Shibuya, S. Bioorg.
Med. Chem. 2000, 8, 2571.
(5) Yokomatsu, T.; Hayakawa, Y.; Suemune, K.; Kihara, T.; Soeda, S.;
Shimeno, H.; Shibuya, S. Bioorg. Med. Chem. Lett. 1999, 9, 2833.
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60, 2563.
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1989, 30, 7013. (b) Wrobel, J.; Dietrich, A. Tetrahedron Lett. 1993, 34,
3543. (c) Berkowitz, D. B.; Shen, Q.; Maeng, J.-H. Tetrahedron Lett. 1994,
35, 6445. (d) Chetyrkina, S.; Estieu-Gionnet, K.; La¨ın, G.; Bayle, M.;
De´le´ris, G. Tetrahedron Lett. 2000, 41, 1923.
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315.
10.1021/ol025544f CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/13/2002

monosaccharide phosphates8 have also been the subject of
great interest as bioactive molecules.
routes to thiazoline-based difluoromethylphosphonate di-
esters. To test this, dithioester 1 was conveniently prepared
on a large scale (up to 15 g), according to a slightly modified
procedure described by Blackburn et al.17 and coupled with
some achiral or enantiopure â-amino alcohols. A summary
of these reactions is presented in Table 1.
The most common approaches to this class of phos-
phonates usually involve PCF2-based nucleophilic synthons
or radicals,9 although the gem-difluorination and phos-
phonyl radical addition techniques may also offer alternative
routes.10 A number of difluorophosphonylated systems have
also been prepared following the building block approach.11
Representative examples using simple carbocyclic acids
include phosphoenol pyruvate and sparfosic acid analogues;
the latter, also referred to as PALA, is a potent inhibitor of
ATCase.12
Table 1. Synthesis of Difluoromethylphosphonate Diesters
Linked to an N-â-Hydroxythioamido Group from Dithioester 1
In connection with our studies on the chemistry of
bifunctional organic compounds containing both phosphorus
and dithioester moieties,13 we anticipated that the methyl
difluoro(diethoxyphosphono)dithioacetate 1 should provide
a new synthesis of thiazolines appended with a PCF2-
function. Many biologically active natural products, including
derived peptides, incorporate thiazoline (and/or thiazole)
motifs in their structures,14 and consequently, the construction
of these rings has aroused considerable interest, as shown
by the number of methods available.15,16
We report herein utilization of the methyl ester of difluoro-
(diethoxyphosphono)dithioacetic acid 1 as an efficient N-
thioacylating reagent in order to open facile and flexible
(8) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Sloss, D. G. J. Org. Chem.
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1996, 52, 165. (c) Arnone, A.; Bravo, P.; Frigerio, M.; Viani, F.; Zappala,
C. Synthesis 1998, 1511. (d) Boivin, J.; Ramos, L.; Zard, S. Z. Tetrahedron
Lett. 1998, 39, 6877. (e) Blades, K.; Butt, A. H.; Cockerill, G. S.; Easterfield,
H. J.; Lequeux, T. P.; Percy, J. M. J. Chem. Soc., Perkin Trans. 1 1999,
3609. (f) Butt, A. H.; Percy, J. M.; Spencer, N. S. Chem. Commun. 2000,
1691. (g) Yokomatsu, T.; Katayama, S.; Shibuya, S. Chem. Commun. 2001,
1878.
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1992, 48, 9841. (b) Ben-Bari, M.; Dewynter, G.; Aymard, C.; Jei, T.;
Montero, J.-L. Phosphorus, Sulfur Silicon Relat. Elem. 1995, 105, 129. (c)
Morris, A. D.; Cordi, A. A. Synth. Comm. 1997, 27, 1259.
(13) (a) Masson, S. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 95-
96, 127. (b) Leflemme, N.; Marchand, P.; Gulea, M.; Masson, S. Synthesis
2000, 1143.
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Am. Chem. Soc. 1977, 99, 8078. (b) Carmeli, S.; Moore, R. E.; Patterson,
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1994, 59, 4733. (f) Wipf, P.; Xu, W. J. Org. Chem. 1996, 61, 6556. (g)
Onoda, T.; Shirai, R.; Koiso, Y.; Iwasaki, S. Tetrahedron 1996, 52, 14543.
(h) Wipf, P.; Venkatraman, S. Synlett 1997, 1. (i) White, J. D.; Kim; T.-S.;
Nambu, M. J. Am. Chem. Soc. 1997, 119, 103. (j) Kuriyama, N.; Akaji,
K.; Kiso, Y. Tetrahedron 1997, 32, 8323. (k) Akaji, K.; Kiso, Y.
Tetrahedron 1999, 55, 10685. (l) Ramasamy, K. S.; Bandaru, R.; Averett,
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a Reactions conducted with 1 equivalent of triethylamine.
The reactions were carried out routinely at room temper-
ature by adding dithioester 1 dropwise to a stirred solution
of commercially available â-amino alcohols in dried di-
chloromethane (THF is also a suitable solvent). The excep-
tional reactivity18 of free amines was clearly evidenced by
the color change from red to orange-yellow shortly after
the addition was completed (entries 1-4, Table 1). Use of
triethylamine as a dehydrohalogenating agent allowed â-
hydroxyamine hydrochlorides to be similarly coupled, albeit
in longer reaction times (entries 5 and 6). The reaction rates
(15) (a) North, M.; Pattenden, G. Tetrahedron 1990, 46, 8267. (b)
Fukuyama. T.; Xu, L. J. Am. Chem. Soc. 1993, 115, 8449. (c) Boyce, R. J.;
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A. B.; Chua, P. J. Org. Chem. 1998, 63, 908. (e) Ino, A.; Murabayashi, A.
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Lett. 2000, 2, 3289. (g) Wuts, P. G. M.; Northuis, J. M.; Kwan, T. A. J.
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844
Org. Lett., Vol. 4, No. 5, 2002

appeared to correlate, as shown in the last entry, with the
nucleophilicity of the amino group. After careful flash
chromatography on silica, the desired N-â-hydroxylated
difluorophosphonoethanethioamides 2a-f were isolated in
satisfactory yields.
Table 2. Dehydrocyclization of Ν-â-Hydroxylated Thioamides
to Thiazolines at 20 °C in CH2Cl2
In most cases, however, the yields of 2 were significantly
depressed by competing formation of the monofluoro
dithioester 3 (5-12% yield). A plausible mechanism to
account for this side product is shown in Scheme 1 and
Scheme 1. Proposed Mechanism for the Formation of the
Monofluorophosphono Dithioacetate 3
involves presumably initial thiophilic addition of methane-
thiol (or its anion) liberated during the reaction onto the
starting difluoro dithioester 119 followed by elimination of
hydrogen fluoride. Subsequent displacement of the methyl-
thio group upon an intermediately formed ketenedithioacetal
disulfide with methanethiol would afford the unwanted 3 and
dimethyl disulfide. Further investigations to confirm this
hypothesis are currently underway.20
At this stage, the reagents and reaction conditions neces-
sary to effectively mediate the formal cyclodehydration
process were examined. Over the years, a number of
â-hydroxythioamide-based syntheses of ∆2-thiazolines have
been reported.16 Initial application of the Mitsunobu condi-
tions21 (PPh3, DEAD, THF) to thioamido alcohol 2a as a
model substrate showed that the byproducts of this reaction
have Rf values similar to those of thiazoline 4a, thus
preventing an easy final purification.
Therefore, we turned our attention to inducing the intra-
molecular cyclodehydration with alternative protocols such
as thionyl chloride.22 As evident from Table 2, method A
(SOCl2/pyridine) provides a mild access within 30-60 min
to thiazolines 4 and the yields were good to excellent.
Remarkably, primary thioamido alcohols 2 (entries 1-3 and
6) cyclize as well as a secondary one (entry 5) and no 1,2-
dehydration of the R-thioamido â-hydroxy ester 2f is
observed. In addition, the norephedrin adduct 2e was easily
cyclized without detectable epimerization or racemization.
However, in the case of the 2-thioamido-1,3-diol 2d, this
method failed to produce the expected thiazoline and instead
a (A) 1.1 equiv of SOCl2 and pyridine; (B) 2 equiv of MsCl and Et3N.
led to a cyclic sulfite derivative.23 Nevertheless, the desired
cyclization of 2d was achieved with MsCl/Et3N (method B,
entry 4), and the expected thiazoline was recovered as its
mesylate 4d after the reaction.
Having fully characterized all compounds listed in Tables
1 and 2 and noticed that thioamido alcohols 2 proved to be
somewhat difficult to purify, we further carried out the two-
step sequence in the same flask. The N-thioacylation
followed by cyclodehydration in a “one-pot” procedure was
found to provide a rapid access and an efficient route to chiral
thiazolines 4b,c,e with overall yields ranging from 75 to 80%
after standard flash chromatography performed on silica gel.
Interestingly, the resulting thiazolines preserved the high
enantiomeric purity of the starting â-amino alcohols sub-
strates, as demonstrated by HPLC analysis (97.4% ee).
In view of the current interest focused on the syntheses
of novel types of nucleoside analogues, we next sought to
study the possibility of introducing nucleobase derivatives
onto either our primary mesylate-containing thiazoline 4d
or, even better, its thioamido-1,3-diol precursor 2d. Recent
literature reports24 dealing with the synthesis of pseudoaza-
nucleosides and thionucleosides suggest that primary alcohols
are or would be superior substrates for our purpose. On the
other hand, Mitsunobu-type procedures have been reported
to cyclize 2-thioamido alcohols16,25 and to link nucleic acid
(19) (a) Viola, H.; Hartenhauer, H.; Mayer, R. Z. Chem. 1988, 269. (b)
Bulpin, A.; Masson, S. J. Org. Chem. 1992, 57, 4507.
(20) For example, the following ketenedithioacetal disulfide (EtO)2P-
(O)CFdC(SMe)S-S-t-Bu was prepared in high yield and fully characterized
from a CH2Cl2 solution containing difluorodithioester 1 and t-BuSH in the
presence of triethylamine. Its further conversion to the monofluorodithioester
3 was easily achieved by using lithium ethylthiolate in THF.
(23) Review: Byun, H.-S.; He, L.; Bittman, R. Tetrahedron 2000, 56,
7052.
(21) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
(22) (a) Crawhall, J. C.; Elliott, D. F. J. Chem. Soc. 1951, 2071, 2075.
(b) Tomalia, D. A.; Paige, J. N. J. Org. Chem. 1973, 38, 3949.
(24) (a) Deng, L.; Scha¨rer, O. D.; Verdine, G. L. J. Am. Chem. Soc.
1997, 119, 7865. Reviews: (b) Yokoyama, M.; Momotake, A. Synthesis
1999, 1541. (c) Yokoyama, M. Synthesis 2000, 1637.
Org. Lett., Vol. 4, No. 5, 2002
845

bases to skeletons bearing a free hydroxyl group.5,26
Therefore, this approach was applied to the thioamido-1,3-
diol 2d.
As outlined in Scheme 2, Mitsunobu cyclization and
condensation with 3-benzoylthymine27 and 6-chloropurine
fluorophosphonomethyl)-∆2-thiazolines using â-amino al-
cohols. This method has the advantages of simplicity and
brevity and provides the possibility of linking preformed
nucleic base derivatives to the thiazoline backbone if a
â-amino-1,3-diol is employed. The principles of the approach
delineated here should find further applications in modified
nucleotide synthesis, and other ring systems should also be
accessible via dithioester chemistry in a near future.
Scheme 2. Synthesis of
2-(Difluorophosphonomethyl)Thiazoline-Based Nucleotide
Analogues under Mitsunobu Conditions
Acknowledgment. We appreciate the financial support
provided by the “Centre National de la Recherche Scienti-
fique” and acknowledge the “Ministe`re de la Recherche et
de la Technologie” for a doctorate grant to E.P. (1999-
2002).
Supporting Information Available: Detailed description
of experimental procedures and full characterization data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL025544F
in a one-pot process afforded compounds 5 and 6, respec-
tively. The likely intermediates for these transformations are
related to oxyphosphonium species. Experimentally, the two
thiazolines appended with a methylene base unit were
produced in yields ranging from 58 to 66% by simply treating
a suspension of the diol 2d, the nucleobase derivative, and
Ph3P in THF with DEAD (dropwise addition in THF at 0
°C) for 4 days. Deprotection of the thymine adduct occurred
during the purification.
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Here we have reported a new building block approach for
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846
Org. Lett., Vol. 4, No. 5, 2002