Nitrile oxides polyols

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

A strategy based on the diastereoselective dipolar cycloaddition reaction of nitrile oxides and allylic alcoholates, has been applied to the synthesis of bis-(isoxazolines) that are precursors to polyketide fragments. These intermediates can be elaborated into protected polyols, for example, 439, by sequential chemos-elective reductive opening of each isoxazoline or, alternatively, by simultaneously, providing access to all stereoisomers of this carbon skeleton (479). 

Substituted 4,5-dihydro-5-vinylisoxazoles (40), obtained by regio- and stereospecific cycloaddition of nitrile oxides to dienes, undergo smooth osmium-catalyzed c/s-hydro-xylation to give amino-polyol precursors (equation 28)45. The reaction is anti selective, the diastereomeric ratios ranging from 73 27 up to 99 1. Highest stereoselectivities were observed when R3 was methyl. Thus, whereas osmylation of 40a afforded a 78 22 mixture of 41a and 42a, respectively, in 80% overall yield, similar treatment of 40b resulted in a 92 8 mixture of 41b and 42b, respectively, in 70% overall yield. The cycloaddition-osmylation sequence allows control of the relative configuration of up to 4 contiguous asymmetric centers. 

Talaromycin B is a spiro-acetal produced by the fungus Talaromyces stipitatus, the toxicity of which may be due to its ability to block outward potassium fluxes. In an elegant synthesis, the requisite open-chain polyol with hydroxy groups in the y-and y -positions was assembled from nitrile oxide and olefin building blocks 50 and 51, both of which carry a f>w(hydroxyethyl) moiety protected as a cyclohexanone acetal (284). Hydrogenolysis of the N O bond of isoxazoline 52 using Raney nickel, followed by treatment with aqueous acid, gave the spiroketal 53, which was further transformed into racemic talaromycin B (54) (Scheme 6.54) (284). 

Aminoalcohol Ring Cleavage of Nitrile Oxide Cycloadducts Synthesis of Amino Polyols, Amino Sugars, and Amino Acids... 

Uses of Nitrile Oxide Cycloadditions in the Isoxazoline Route Toward Mono- and Bicyclic Imino Acids and Imino Polyols... 

It is worthy to note that four of the eight possible diastereomeric pyrrolidine-polyols are accessible by this method. The configuration at C(l) (nitrile oxide part) depends on the enantiomeric aldehyde precursor chosen. The 5-epimers were obtained as a separable 1 1 mixture and were derived from the nonselective cycloaddition (see Section 6.2.3.4). 

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