Enantioselectivity nitrile oxide cycloadditions

Sibi et al. reported that substoichiometric chiral Mg(II) complexes catalyzed regio- and enantioselective nitrile oxide cycloadditions to electron-deficient alkenes (Scheme 4.8) [6]. For an achiral template, bulky pyrazolidinone (20) was essential for high regio- and enantioselectivity in (22) and (23), while oxazolidinone crotonate and 3,5-dimethylpyrazole gave the adducts, but with poor results. In particular, mesityl nitrile oxide (21), a stable dipole, was chosen as the reagent due to steric interactions of that group with either a bulky achiral template and/or a bulky Lewis acid center. Aliphatic (t-Bu and i-Bu) nitrile oxides also provided cycloaddition... 

Kanemasa and coworkers have has also developed the effective use of MS 4A for the rate-controlled slow generation of nitrile oxide 1,3-dipoles from hydroximoyl chlorides in alcohol media. Less than 3 equiv of MS 4A was sufficient enough for the quantitative generation of nitrile oxides in a few hours. This MS 4A-mediated generation method of nitrile oxide can be effectively applied to the catalytic enantioselective nitrile oxide cycloadditions with l-acryloyl-3,5-dimethylpyrazole as dipolarophile in the presence of the nickel(II) aqua complex (10mol%) of R, 7 -DBFOX/Ph ligand [36]. As shown in Table 7.18, the highest yield of cycloadduct was 94% and the maximized enantioselectivity was up to 97% ee. 

Control of reaction selectivities with external reagents has been quite difficult. Unsolved problems remaining in the held of nitrile oxide cycloadditions are (a) Nitrile oxide cycloadditions to 1,2-disubstituted alkenes are sluggish, the dipoles undergoing facile dimerization to furoxans in most cases (b) the reactions of nitrile oxides with 1,2-disubstituted alkenes nonregioselective (c) stereo- and regiocontrol of this reaction by use of external reagents are not yet well developed and (d) there are few examples of catalysis by Lewis acids known, as is true for catalyzed enantioselective reactions. 

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. 

Kim and Lee also developed another enantioselective synthesis of methyl (-)-8-epinonactate (Scheme 18) (30) based on the same nitrile oxide cycloaddition product 127 used in their earlier synthesis. The enantiomerically enriched alcohol 127 (>98%e.e.e.) was converted to its iodide... 

The 1,3-DC of nitrile oxides and alkenes leads to the formation of 2-isoxazolines, which are useful building blocks in organic chemistry. While the diastereoselective nitrile oxide cycloadditions have been investigated extensively, the development of enantioselective variants is quite rare. 

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Most of the approaches outlined in Figure 15.10 have been successfully realized on insoluble supports, either with the alkene or alkyne linked to the support, or with support-bound 1,3-dipoles (Table 15.16). Nitrile oxides are highly reactive 1,3-dipoles and react smoothly with both electron-poor and electron-rich alkenes, including enol ethers [200]. The addition of resin-bound nitrile oxides to alkenes (Entries 5 and 6, Table 15.16) has also been accomplished enantioselectively under catalysis by diisopropyl tartrate and EtMgBr [201], The diastereoselectivity of the addition of nitrile oxides and nitrones to resin-bound chiral acrylates has been investigated [202], Intramolecular 1,3-dipolar cycloadditions of nitrile oxides and nitrones to alkenes have been used to prepare polycyclic isoxazolidines on solid phase (Entries 7 and 9, Table 15.16). 

A chiral zinc(II) complex derived from Et2Zn and diisopropyl (/ ,/ )-tartrate as a chiral auxiliary is applied to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to an achiral allylic alcohol, giving the corresponding (R)-2-isoxazolines with high enantioselectivity. Addition of a small amount of ethereal compounds such as DME and 1,4-dioxane is crucial for achieving the high asymmetric induction in a reproducible manner [71] (Eq. 8A.47). 

Magnesium ion-mediated nitrile oxide 1,3-DC reactions to allylic alcohols have been reviewed <02SL1371>. New examples have been recently reported, in particular, cycloadditions of aromatic and aliphatic nitrile oxides with optically active a-silylallyl alcohols in the presence of magnesium cations. The substituted isoxazolines, which were obtained with high diastereo- and enantioselectivity, were smoothly converted to [1,2]-oxazine derivatives by treatment with TBAF. For example, oxazin-3-one (S)-58 was obtained in 81% ee starting from dipolarophile (S)-55 <02T9613>. 

The Brown allylboration was used in the enantioselective total synthesis of (-)-calicheamicinone 3318 (Scheme 3.1o). Thus the lactol 34, readily prepared from tetronic acid, was treated with the allylborane d35 to give 36 in a highly stereoselective manner (95% ee, > 98% de). Compound 36 was converted to the aldoxime 37 by standard chemistry. Generation of the nitrile oxide with aqueous sodium hypochlorite was accompanied by spontaneous [3 + 2]-dipolar cycloaddition to afford 38 in 65% yield. 

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