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Asymmetric Synthesis of Chiral Oxazolidinone Phosphonates ⇑ ⇑ Maria Teresa Barros , Ana Maria Faísca Phillips

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Asymmetric Synthesis of Chiral Oxazolidinone Phosphonates ⇑ ⇑ Maria Teresa Barros , Ana Maria Faísca Phillips Tetrahedron: Asymmetry 21 (2010) 2746–2752 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy The first enantioselective [3+2] cycloaddition of epoxides to arylisocyanates: asymmetric synthesis of chiral oxazolidinone phosphonates ⇑ ⇑ Maria Teresa Barros , Ana Maria Faísca Phillips REQUIMTE, Department of Chemistry, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Caparica, Portugal article info abstract Article history: A [3+2] cycloaddition of diethyl 1,2-oxiranephosphonate to aryl isocyanates catalyzed by lanthanide cat- Received 19 October 2010 ions is described. The reaction is highly regioselective and 5-substituted 2-oxazolidinone phosphonates Accepted 27 October 2010 are obtained with a regioselectivity greater than 95:5 with respect to the 4-substituted regioisomer, Available online 20 November 2010 and in up to 84% yield. When 20 mol % of Pybox-Yb3+ is used as a catalyst, enantiomerically enriched products are obtained in up to 75% ee, depending on the reaction conditions, and the nature of the iso- cyanate. Low temperatures benefit asymmetric induction, but have an adverse effect on the regioselec- tivity for para-substituted aryl isocyanates. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction yphosphonates as antibacterials, nucleoside phosphonate ana- logues as antivirals, and bisphosphonates as drugs for the The oxazolidinone unit is rarely present in natural products, but treatment of numerous bone diseases. Only a few examples of oxa- compounds with this unit have many applications.1–3 Oxazolidi- zolidinone phosphonate derivatives could be found in the litera- nones are often used as chiral auxiliaries for a variety of asymmet- ture. Wyatt et al. converted a 2-amino-1-hydroxyphosphonate ric synthetic transformations4 (the so-called Evans’ auxiliaries), as into the corresponding oxazolidinone using 1,10-carbonyldiimidaz- protecting groups for 1,2-amino alcohols, and as building blocks in ole, as a means to elucidate the stereochemistry of the parent polymers. In recent years 5- and 4,5-disubstituted oxazolidinones phosphonate.12 Jung et al. have synthesized a few biologically ac- have attracted a lot of attention because they are one of a few tive oxazolidinone phosphonates via a multi-step synthesis, with new classes of antibiotics that have been discovered in the past the phosphoryl group separated from the ring by a three or more 30 years, after the quinolones.5,6 In 2000, Linezolid of Pharmacia/ atom tether.13–15 Starting from the oxazolidinone ring, it is also Pfizer became the first to be commercialized. possible to obtain N-(phosphonomethyl)oxazolidinones, via reac- This and related antibacterials are active against numerous tion with phosphorus trichloride and formaldehyde.16,17 We Gram-positive organisms, including methicillin-resistant Staphylo- decided to try an approach using the 1,3-cycloaddition of epoxides coccus aureus (MRSA), vancomycin-resistant enterococci (VRE) and to isocyanates, a reaction that to the best of our knowledge has not penicillin- and cephalosporin-resistant Streptococcus pneumoniae. been applied in phosphonate chemistry. The treatment of mycobacterial infections, which place at risk im- A number of halides are known to catalyze the 1,3-cycloaddi- muno-compromised populations, is a potential area of applica- tion of simple epoxides to isocyanates: tetraalkylammonium ha- 7 18,19 20 21 tion. These antibiotics inhibit bacterial protein synthesis, do not lides, LiBr-OPPh3, n-Bu-SnI Lewis base complexes, and 22 exhibit cross-resistance, and can be administered orally as well lanthanide chlorides. Also, Pd2(dba)3ÁCHCl3 and trialkyl phos- as intravenously. The synthesis of analogues is an active area of re- phite can also be used to convert substituted vinyl oxiranes stere- search. Modifications of the rings, ring-substituents, as well as the oselectively to cis-oxazolidinones.23 Some of these methods C-5 side chain, have given rise to libraries of compounds8,9 in a require high temperatures and trimerization or polymerization of search for higher activity, lower toxicity, or better properties. The the isocyanate may occur as a side reaction. To the best of our absolute configuration at C-5 is critical for the biological activity.9 knowledge, no catalytic asymmetric versions have been reported. We have been interested in biologically active phosphonate Herein we report our results on the synthesis of enantiomerically derivatives for a few years,10,11 and the possibility of a phosphoryl enriched oxazolidinone phosphonates B (Fig. 1) with potential substituent at C-5 seemed to be an attractive option. Many biological activity. phosphonates have applications in medicine, such as epox- 2. Results and discussion ⇑ Corresponding authors. Tel.: +351 212948300; fax: +351 212948550. E-mail addresses: [email protected] (M.T. Barros), [email protected] (Ana As a test reaction, the [3+2] cycloaddition of phenyl Maria Faísca Phillips). isocyanate to diethyl 1,2-epoxyphosphonate, a simple terminal 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.10.028 M. T. Barros, A. M. F. Phillips / Tetrahedron: Asymmetry 21 (2010) 2746–2752 2747 F O O corresponding proton on a carbon atom attached to nitrogen, a less electronegative atom, which in similar 4-substituted oxazolidinon- R 25 31 ON NO NO es appears near 4.5 ppm. In P NMR spectra, a single signal was observed for the oxazolidinone phosphonate. In 1H NMR spectra, NHAc OR two additional small multiplets centered at 4.41 and 4.72 ppm P OR could usually be seen, suggesting that the other regioisomer may O have formed albeit in low amounts: usually 65%. There were no A B : Linezolid : Targets other signals present that could help identify this substance, which was difficult to separate chromatographically from the oxazolidi- Figure 1. none, another indication of structural similarity. It is generally thought19,22 that the mechanism of the reaction epoxyphosphonate analogous to the well-known antibiotic fosfon- with halides involves ring opening to form a 1,2-alkoxy halide, omycin, was selected. The required substrate could be obtained in which subsequently adds to the isocyanate, a process which would high yield by a modification of the method of Sturtz and Pondaven- be facilitated by epoxide coordination to the metal. This mecha- 26 Raphalen,24 with t-BuOK in t-BuOH being used to cyclize the inter- nism is supported by computational studies. The chlorohydrin mediate halohydrin obtained from the reaction of diethyl allyl found in reaction mixtures is consistent with this type of mecha- phosphonate with NaOCl formed from bleach-HCl. When the epox- nism. However, it was also found that if the reactions were allowed yphosphonate and isocyanate were mixed in the absence of a cat- to proceed longer than their endpoints, more chlorohydrin is alyst, there was no reaction at room temperature, or even after formed. refluxing for 3 h in dichloromethane. Tetrabutylammonium alkyl As for the nature of the metal, the hard Lewis acid TiCl4 gave halides did not give the desired [3+2] cycloadducts either. How- only the halohydrin after 3 h of reflux, and there was no reaction ever, several metal halides were found to catalyze the reaction, when SnCl2 was used as a catalyst. However, BiCl3 gave 28% of with different degrees of success. The results obtained are shown the oxazolidinone under the same conditions. Catalyst RuCl3 also in Table 1. The reactions were regioselective: the 5-substituted worked in this transformation, but its activity was low (entry 2). 2-oxazolidinone was obtained in preference to the 4-substituted The lanthanides, which are mild Lewis acid catalysts, are highly regioisomer, either with none or with some b-chlorohydrin, in a ra- oxophilic anions and usually attain association-dissociation equi- 27 tio that varied with the nature of the metal and the reaction condi- libria rapidly in ligand substitution reactions; due to the liability tions. The regiochemistry of the product is in accordance with that of the Ln–O bond, product dissociation is also fast. All the lantha- expected, considering the inductive effect of the phosphonate nide chlorides that we tested, irrespective of their position in the group and the steric effects on the terminal epoxide. The 1H NMR periodic table, were active in this [3+2] cycloaddition. The triflate spectrum of the compound has a multiplet at 5.49 ppm due to (entry 11) did not yield the desired product, which supports the the methine proton, whose corresponding carbon atom is attached theory that the reaction between epoxides and isocyanates is initi- to the oxygen. A chemical shift of greater than 5 ppm is consistent ated by the reaction of a chloride ion at the epoxy ring. Both the with 2-oxazolidinones substituted at the 5-position by electron anhydrous and the hydrated metal chlorides yielded a product. withdrawing groups. It is further downfield than the signal of the The hydrated catalysts reacted faster, for example, CeCl3 versus Table 1 Screening of potential metal catalysts for the [3+2] cycloaddition of epoxyphosphonate 1 to arylisocyanates O O Cl O O Catalyst O O P P OEt Ar-N=C=O P OEt OEt OEt OEt Solvent; reflux OEt N OH Ar 12 3 4 Entry Catalyst Reagents Conditionsa Resultsb Epoxide (mmol) Isocyanate (R, mmol) Metal (mmol) Solvent Time (h) Conv. (%) Oxazolidinonec (%) Chlorohydrin (%) 1 TiCl4 1.0 Ph, 1.10 0.47 Toluene 3 100 0 100 (52) 2 RuCl3 1.0
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