Allyl alcohols nitrile synthesis

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

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). 

The key step in the stereoselective total synthesis of erythronolide A is the Mg(II)-mediated 1,3-dipolar cycloaddition of the functionalized nitrile oxide (45) with the allylic alcohol (46) to produce the isoxazoline (47) as a single diastereomer in high... 

Allene, perfluoro-, cycloaddition to phenylsydnone, 59, 12 Allene, phenylsulfinyl-, cycloaddition of nitrile oxides, 60, 276 Alloxan, structure, 55, 133 Alloxazines, synthesis, 55, 186 Allyl alcohols, ethers, chiral,... 

Enantiopure isoxazolines were synthesized using both chiral nitrile oxides and chiral dipolarophiles. For example Mg(ll)-directed 1,3-dipolar cycloaddition of nitrile oxides with chiral allylic alcohols 482 generated isoxazolines 483 (Scheme 111) <2001AGE2082>. Later, this cycloaddition was applied in a total synthesis of erythronolide A 484 (Scheme 111) <2005AGE4036>. 

The enantioselective total synthesis of the 13-membered macrolide fungal metabolite (+)-brefeldin A was accomplished using a triple chirality transfer process and intramolecular nitrile oxide cycloaddition in the laboratory of D. Kim. To set the correct stereochemistry at C9, the stereoselective ortho ester Claisen rearrangement was applied on a chiral allylic alcohol precursor. The rearrangement was catalyzed by phenol and it took place at 125 °C in triethyl orthoacetate to give 84% isolated yield of the desired diester. 

The a,P-unsaturated nitriles can be converted to the corresponding a,P-unsaturated alcohols by two successive treatments with DlBAL-H. This reaction has been used in the synthesis of sarco-phytols A and T to produce the allylic alcohol in 71% yield " ... 

Of the five positional isomers of the four-carbon saccharinic acids theoretically possible, 3-hydroxy-2-(hydroxymethyl)propanoic acid (VI) is the only one that lacks an asymmetric carbon atom and is optically inactive and unresolvable. The first attempt at its synthesis, by Glattfeld and cowork-ers, " was by a direct method. The reaction of 2-chloro-2-deoxyglyceritol (LII) [prepared from allyl alcohol (LI) by reaction with hypochlorous acid] with cyanide ion and subsequent hydrolysis of the anticipated nitrile (LIII) should have produced the desired 3-hydroxy-2-(hydroxymethyl)-... 

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. 

Kim et al. have reported a facile one-pot stereoselective synthesis of ( )-cinnamyl alcohols 113 via the treatment of MBH adducts, derived from aryl aldehydes and ethyl acrylate, with TFA. However, a similar reaction of MBH adducts derived from aryl aldehydes and acrylonitriles with TFA gave the ( )-allyl alcohols 111 in low yields (Scheme 3.40). " Since Basavaiah s method works well for nitrile-containing adducts [for ( )-selective nitriles] and the trifluoroacetic acid method works well with ester-containing adducts [for ( )-selective esters], these two methods are considered to be complementary for the preparation of stereochemically defined cinnamyl alcohols. 

The double bond is elaborated into the allylic alcohol functionality via the epoxide, as described above for our shikimate synthesis. Strongly alkaline hydrolysis of the nitrile ester then provides the hydroxy diacid, predominantly as the exo isomer. 

An asymmetric solid-phase synthesis of isoxazolines was reported by Zou and Jiang. Cycloaddition of resin-bound nitrile imines with an allyl alcohol in the presence of a chiral diisopropyl tartrate (DIPT) gave isoxazoles with good regio- and enantioselectivity (Scheme 11.33). Ether-linked cycloadducts were released from the Wang resin as phenols with 10% trifluoroacetic acid. 

Acetamides have been prepared in moderate to good yield from alcohols by reaction with acetonitrile and sulphuryl chloride. It has been found that the hydrolysis of nitriles to amides can be effected in excellent yield using potassium hydroxide in t-butanol if the amide produced is relatively insoluble in water. Experimental details for the large scale anodic oxidation of iV-formyl derivatives of amines to a-methoxyalkylamides have been recorded, and an interesting synthesis of trichloroacetamides from allylic alcohols via a thermal [Att + 2a] rearrangement has been described (Scheme 50). ... 

This result prompted us to first apply the strategy to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides, which had not been developed when our research project started. The idea was presented as follows when nitrile oxide is generated in situ from hydroximoyl chloride by treatment with ethylzinc moiety as abase, the stereochemical course of nitrile oxide coordinated to the chiral zinc species 5 was anticipated to be controlled efficiently. In accordance with this hypothesis, the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to allylic alcohols was realized to afford the corresponding 2-isoxazolines 6 with excellent enantioselectivity (Eq. 11.3). Even when a catalytic amount (0.2 equiv) of diisopropyl (R,/f)-tartrate [(R,/ )-DlPT] was employed, the 2-isoxazolines 6 were obtained with the selectivity of up to 93% ee by the addition of a small amount of 1,4-dioxane (Eq. 11.4). This method was the first catalytic enantioselec-tive 1,3-dipolar cycloaddition of nitrile oxides with alkenes. The method was efficiently applied to the total synthesis of (—)-Lasubine 11 (Scheme 11.2) [11]. 

The asymmetric 1,3-dipolar cycloaddition of nitrones instead of nitrile oxides was also realized The nitrones 7 possessing an amide moiety were reacted with allylic alcohols 1 (R, R = H) by the use of a catalytic amount of (R,R)-DIPT as a chiral auxiliary to afford the corresponding 3,5-cw-isoxazolidines 8 with high regio-, diastereo-, and enantioselectivity up to over 99% ee (Eq. 11.5). This asymmetric 1,3-dipolar cycloaddition was applied to the synthesis for the (25,4R)-4,5-dihydroxynorvaline derivative 10, which is a key component of polyoxin E, via amino alcohol intermediate 9 (Scheme 11.3) [12]. 

Carreira has demonstrated that the hydroxy-directed nitrile oxide cycloaddition reaction is a general synthetic approach to polyketide fragments, with the intermediate isoxazolines functioning as latent, masked aldol adducts [65], The 1,3-dipolar cycloadditions have been shown to tolerate a large variety of alcohol substrates, including aliphatic allylic, homoallylic, and cyclic allylic alcohols [65-67], A demonstration of the versatility of the approach was reported in the synthesis of erythronolide A (58, Scheme 18.12) [67], This synthetic effort took advantage of two sequential hydroxy-directed nitrile oxide cycloadditions to provide fragments 55 and 57, both of which were obtained with excellent yields and diastereoselectivity (dr2 98 2). 

A one pot synthesis of isoxazolines 78a-f involves base mediated 1,4-addition of malonate or alcohol 76 possessing an allylic substituent, conversion of the resulting nitronate to the a-chloroaldoxime (hydroxymoyl chloride 77) and its subsequent dehydrohalogenation to the nitrile oxide intermediate which cyclizes to isoxazoline 78 (Eq. 7, Table 6) [32]. 

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