Isoxazoline library

Studer A, Curran DP, A strategic alternative to solid phase synthesis preparation of a small isoxazoline library by fluorous synthesis . Tetrahedron, 53 6681-6696, 1997. 

Synthesis of the isoxazoline library [59] was performed on 2-chlorotritylchloride resin. The resin was loaded with diethylphosphonoacetic acid and the polymer-bound phospho-nate reacted with aldehydes to yield substituted E-cinnamic esters or substituted E-acrylic esters. This was followed by a 1,3-dipolar cyclo-addition with nitrileoxides, synthesized via the method of Mukaiyama and Floshinoc [60] (Fig. 17.18). In this reaction, two regioi-somers are formed, each of which exist in two enantiomeric forms. Table 17.4 shows the building blocks used in the library synthesis. 

Table 17.4. Building blocks for the isoxazoline library synthesis...

Appendix 17.2. Mass spectrometric data of the isoxazoline-library ISO-4. ... 

The selected examples by Studer et al. [159-161] reported the synthesis of two small discrete libraries of isoxazolines (eight compounds) and of amides derived from a Ugi 4CC reaction (ten compounds). The synthesis of the tagging silicon derivative and the scheme for isoxazoline synthesis are reported... 

The use of a triphasic extraction system, where an organic solvent, an aqueous phase and FC-72 [163] were used, allowed after any reaction step the isolation of the pure intermediates and eventually of the clean reaction products. The switch caused by the fluorous tag allowed the total partition of the library intermediates in the fluorous phase, where any other component of the reaction mixture was not dissolved, while after final deprotection the products were cleanly recovered from the organic phase and the tag moiety remained trapped by the fluorous phase. The eight isoxazoline alcohols were recovered with extremely high GC purities (> 91 %, average > 95%) and with moderate to good yields (from 29% to 99%). The low yields were probably due to the volatility of some of the final products. 

The same technique was also applied to the synthesis of a 10 member Ugi 4CC-derived solution library, where the fluorous tag was embedded into the carboxylic acid structure. The synthesis of the tag and the library synthetic scheme is shown in Figure 7.22. The tag was derived from a bromosilyl perfluorinated compound (C10F21CH2CH2, rather than C6Fi3CFI2CF[2, as for the isoxazolines) reacted with an orthothiobenzoate [164] and further elaborated with trivial chemistry. The library was produced using classical Ugi 4CC conditions and the tag detachment was obtained via treatment with... 

Multi-component couplings open up an economic and straightforward route to very different compound libraries. For example, 1,3-dipolar cycloaddition reactions of nitrones with alkenes furnish isoxazolines, which can be transformed reductively to hydroxyketones or )8-amino alcohols. In 1997, two groups reported on the synthesis of isoxazolines by rare earth metal-catalyzed [3 + 2] cycloadditions (Scheme 4) [13,14]. 

L13 LI 2 reacted with NH2OH library size 1,280x1=1,280 discrete isoxazolines... 

Additional examples of libraries of isoxazolines prepared by 1,3-dipolar cycloaddition of Wang resin-<1998TL939> or chlorotrityl resin- <1998TL2447> supported dipolarophiles, generated in the presence of a variety of dipolarophiles, have been reported. The achiral hydantoin- and isoxazoline-substituted bis-spirocyclobutanoids 458 and 459 were produced using SPS (Scheme 105) <2000CC1835>. 

Each isoxazoline subunit is built up starting from a resin-bound olefin submitted to a 1,3-dipolar cycloaddition of a nitrile oxide, followed by a selenide oxidation/elimination reaction to regenerate the olefin functionality [69]. Using different nitroseleno ethers and nitroalkanes, a library of triisoxazolines has been prepared and characterized by mass spectrometry. This flexible method to create heterocyclic oligomers via C-C bond ring closure is then versatile to combinatorial syntheses. 

In the following section we focus our attention on library analysis, and especially on libraries which are not related to oligomers. To demonstrate the possibilities and limits of this analysis, two typical compound libraries were chosen. The first group of libraries contains an aromatic scaffold, pyrroles, which were synthesized by the Hantzsch pyrrole synthesis. The second class of compounds are heterocyclic isoxazolines synthesized via a 1,3-dipolar cyclo-addition. In both cases the reaction conditions were first established on single compounds. Supporting mass spectrometric data are presented in Section 17.7 (Appendix). 

The selected examples by Studer et al. [97-99] reported the synthesis of two small, discrete libraries of isoxazolines (eight compounds) and of amides derived from a Ugi 4CC reaction (10 compounds). The synthesis of the tagging silicon derivative and the scheme for isoxazoline synthesis are reported in Figure 16. A known silane [100] was coupled quantitatively with bromine in the fluorinated solvent FC-72 [101] and the tagging reagent was used to protect and label the allyl alcohols in THF. After the cycloaddition of the fluorinated dipolarophiles with the nitrile oxides, the protected isoxazolines were finally cleaved with HF/pyridine complex in ethyl ether. The scheme of the purification for each synthetic step is depicted in Figure 17. 

Kurth and co-workers prepared libraries of polyisoxazolines 39,40 by solid-phase combinatorial synthesis utilizing polymer-bound olefin 34, nitro-selenoethers 13c and nitroalkanes 13d,e (Scheme 11) [103]. An iterative application of nitrile oxide 1,3-dipolar cycloaddition followed by selenide oxida-tion/elimination steps was employed to afford polymer boimd tri-isoxazolines which could be liberated from the resin via trans-esterification to afford 39,40. 

Chandrasekhar et al. synthesized a library of 15 isoxazolines 61 from ni-troalkanes 13 and polymer-bound electron-deficient olefins 60 under Hassner conditions (B0C2O, DMAP) (Scheme 18) [112]. The isoxazoline carboxylic acids 62 were then liberated from the resin on treatment with TFA in CH2CI2 (1 4). 

The method was developed further for the diastereoselective synthesis of isoxazoline derivative (Scheme 11.49). Later, a similar method was applied to the preparation of a diverse 990-member library of hydantoin and isoxazoline heterocycles with multipin technology. ... 

As mentioned so far, methylnitroisoxazolone 10 serves as a precursor of carbamoylnitrile oxide 6 upon treatment with only water under mild conditions, in which any special reagents, conditions, and manipulations are not necessary. The nitrile oxide 6 reacts with alkynes 15, alkenes 17, nitriles 29, and 1,3-dicarbonyl compounds 34 to afford corresponding carbamoyl-substituted isoxazoles 16, isoxazolines 18, 1,2,4-oxadiazoles 28, and isoxazoles 33, respectively (Scheme 9.17). The electron-withdrawing carbamoyl group realizes the cycloaddition with electron-rich dipolarophiles, which is inverse electron-demand 1,3-dipolar cycloaddition. Furthermore, the carbamoyl group also plays a role of an activator of the dipolarophile. This mefliodology will be useful for the construction of a new library of functionalized compounds. 

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