Stereoselectivity nitronates

High-pressure promoted cycloadditions of nitroalkenes and enol ethers eliminate the use of Lewis acids (Eq. 8.106).162 Thus, even sterically hindered nitroalkenes react with 2,3-dihydro-furan to give the exo cyclic nitronates stereoselectively without using Lewis acids. 

Abstract This review is devoted to the stereoselectivity of intermolecular (intramolecular cycloadditions are not included) 1,3-dipolar cycloadditions of sugar-derived nitrones. Stereoselective cycloaddition (transformation of isoxazolidine followed by reduction of the N O bond to produce both an amino and a hydroxy function) allows the synthesis of tailor-made products of possible biological interest such as pol>4iydroxylated pyrrolidines, pyrrolizidines, indolizidines, fi-aminocarbonyl compounds, and disaccharides. Attention is focused on the preparation of isoxazolidinyl nucleosides and to the catalysis of the cycloaddition by Lewis acids. This review has concentrated on the new developments achieved from 1999 to February 2007. 

Reactions of nitroalkenes with electron-rich alkenes lead to cyclic nitrones stereoselectively. Besides thermal reactions Lewis acid-catalyzed additions employing SnCL, TiCl2( Pr)2 or bulky aluminum Lewis acids have been described. 

Such syn stereoselectivity also was observed for a number of additions of nitrones to fluoroallene, such as its reaction with N-phenyl-C-phenyl nitrone [25, 26, 27] (equation 19)... 

A model for the mechanism of the highly enantioselective AlMe-BINOL-cata-lyzed 1,3-dipolar cycloaddition reaction was proposed as illustrated in Scheme 6.13. In the first step nitrone la coordinates to the catalyst 11b to form intermediate 12. In intermediate 13, which is proposed to account for the absolute stereoselectivity of this reaction, it is apparent that one of the faces of the nitrone, the si face, is shielded by the ligand whereas the re face remains available... 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

Several approaches based on nitro-aldol for the synthesis of amino sugars have been reported Alumina-catalyzed reaction of methyl 3- nitropropanoate with O-benzyl-o-lactaldehyde gives the o-ribo-nitro-aldol fanti, and isomeri in 63% yield, which is converted into L-dannosamine fsee Secdon 3 3 Jager and coworkers have reported a short synthesis of L-acosamine based on the stereoselective nitro-aldol reaction of 2-O-benzyl-L-lactaldehyde with 3-nitropropanal dimethyl acetal as shovm in Scheme 3 10 The stereoselecdve nitro-aldol reacdon is carried ont by the silyl nitronate approach as discussed in Secdon 3 3... 

Stereoselective preparation of CEi-allyl alcohols via radical elimination from ruin -y-phenylthio-fi-nkro alcohols has been reported. The requisiteruin -fi-nitro sulfides are prepared by protonadon of nitronates at low temperanire Isee Chapter 4, and subsequent treatment v/ith Bu-vSnH induces and eliminadon to givelE -alkenes selecdvely IseeEq. 7.112. Unfortunately, it is difficult to get the pure syu-fi-nitro sulfides. Treatment of a rruxnire of syu- and ruin -fi-nitrosulfides v/ith Bu- SnH results in formadon of a rruxnire of (Ey and lZ -alkenes. 

I.3.5.6.4. Stereoselective Addition of Enantiomerically Pure Nitronates to Aldehydes... 

Another route to A-benzoyl-L-daunosamine is the 1,3-addition of silyl ketene acetal 4 to the chiral nitrone 5, accompanied by a silyl group transfer in acetonitrile under mild conditions. This reaction provides high stereoselectivity in favor of the tw -product 621. 

Wagner and co-workers explored the different selectivity of 1,3-dipolar cyclo additions of nitrones 140 and cinnamonitrile 139 leading to oxadia-zolines 141 derived from an exclusive CN attack instead of a C = C attack (Scheme 50). This behavior was observed when cinnamonitrile was coordinated to a transition metal like Ft or Pd [89]. A similar approach to platimun-promoted nitrile-nitrone cyclo additions was reported using cychc nitrones. In this case, the authors reported a higher stereoselectivity of cychc nitrones with respect to the acyclic nitrones, due to a rigid E conformation adopted by cyclic nitrones [90]. 

An in depth account of intramolecular 1,3-dipoIar cycloadditions involving dipoles such as nitrUe oxides, sUyl nitronates, H-nitrones, azides, and nitrUimines is presented with particular emphasis on the stereochemistry during the cycloaddition. Various methods employed for the generation of the dipoles and their applications to stereoselective synthesis are also discussed. 

Keywords Intramolecular 1,3-dipolar cycloadditions. Stereoselectivity, Nitrile oxides, SUyl nitronates. Oximes, H-Nitrones, Azides, NitrUimines... 

Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

High levels of diastereocontrol in an ISOC reaction were induced by a stereogenic carbon center that bears a Si substituent (Scheme 23) [55]. For instance, conversion of nitro alkenes (e.g., 199) to j3-siloxyketones (e.g., 203) has been accomplished via a key ISOC reaction-reduction sequence with complete control of 1,5-relative stereochemistry. The generality of the ISOC reaction of a silyl nitronate with a vinylsilane was demonstrated with seven other examples. Corresponding INOC reaction proceeded with lower stereoselectivity. 

Intramolecular nitrone cycloadditions often require higher temperatures as nitrones react more sluggishly with alkenes than do nitrile oxides and the products contain a substituent on nitrogen which may not be desirable. Conspicuously absent among various nitrones employed earlier have been NH nitrones, which are tautomers of the more stable oximes. However, Grigg et al. [58 a] and Padwa and Norman [58b] have demonstrated that under certain conditions oximes can undergo addition to electron deficient olefins as Michael acceptors, followed by cycloadditions to multiple bonds. We found that intramolecular oxime-olefin cycloaddition (lOOC) can occur thermally via an H-nitrone and lead to stereospecific introduction of two or more stereocenters. This is an excellent procedure for the stereoselective introduction of amino alcohol functionality via N-0 bond cleavage. 

Cycloadditions of nitrones, nitrile oxides or diazo compounds to thiete dioxides do not show the high stereoselectivity observed with acyclic vinyl sulfones, and mixtures of the two possible adducts are formed . The charge-transfer stabilization energy calculated according to the Klopman-Salem perturbational approach is able to account for the experimental trends of the isomer ratio in terms of the major stereochemical structural differences between the acyclic vinyl sulfones and the four-membered ring sulfones (see Section IV.B.3). 

N-donor ligand. The reaction appears to proceed via an acyclic iminoplatinum(II) intermediate that undergoes a subsequent intramolecular cyclization. Some mechanistic aspects of this versatile reaction have been elucidated.225,226 A4-l,2,4-oxadiazolines have been prepared by the [2+3] cycloaddition of various nitrones to coordinated benzonitrile in m-[PtCl2( D M SO)(PhCN)] precursors.227,228 Racemic and chiral [PtCl2(PhMeSO)(PhCN)] complexes have also been used in order to introduce a degree of stereoselectivity into the reaction, resulting in the first enantioselective synthesis of A4-l,2,4-oxadiazolines, which can be liberated from the complexes by the addition of excess ethane-1,2-diamine. 

Bicyclic trimethylsilyl nitronates undergo stereoselective Henry reactions with benzalde-hyde in the presence of fluoride ion to give cyclic hemiacetals in good yield with high diastereo-selectivity (95% ds) (Eq. 3.68).110... 

An experimentally simple procedure for stereoselectively preparing P-nitro alcohols has been developed. The alkyl nitronates, formed by the action of n-butyllithium on nitroalkanes in THF solution, react with aldehydes in the presence of isopropoxytitanium trichloride at room temperature to give the P-nitro alcohols enriched in the anri-diastereoisomers (Eq. 3.71).112... 

The heterobimetallic asymmetric catalyst, Sm-Li-(/ )-BINOL, catalyzes the nitro-aldol reaction of ot,ot-difluoroaldehydes with nitromethane in a good enantioselective manner, as shown in Eq. 3.78. In general, catalytic asymmetric syntheses of fluorine containing compounds have been rather difficult. The S configuration of the nitro-aldol adduct of Eq. 3.78 shows that the nitronate reacts preferentially on the Si face of aldehydes in the presence of (R)-LLB. In general, (R)-LLB causes attack on the Re face. Thus, enantiotopic face selection for a,a-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. The stereoselectivity for a,a-difluoroaldehydes is identical to that of (3-alkoxyaldehydes, as shown in Scheme 3.19, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... 

The addition of alkyl nitronate anions to imines in the presence of a Lewis acid proceeds in high yield with up to 10 1 diastereoselection favoring the anti isomer. This reaction is used for the stereoselective synthesis of 1,2-diamines (Eq. 4.121).167 Scandium triflate catalyzes the addition of 1-trimethylsilyl nitropropanoate to imines with a similar selectivity.35... 

Stereoselective preparation of ( )-allyl alcohols via radical elimination from anti-j-phenylthio-P-nitro alcohols has been reported.154 The requisite anti-P-nitro sulfides are prepared by protonation of nitronates at low temperature (see Chapter 4), and subsequent treatment with Bu3SnH induces anti elimination to give (E)-alkenes selectively (see Eq. 7.112). Unfortunately, it is difficult to get the pure yyw-P-nitro sulfides. Treatment of a mixture of syn- and anti-P-nitrosulfides with Bu3SnH results in formation of a mixture of (E)- and (Z)-alkenes. 

Cycloaddition of the cyclic nitrone derived from proline benzyl ester with alkenes proceeds readily to give isoxazolidines with good regio-and stereoselectivity (Eq. 8.47).68 The reaction favors exo-mode addition. However, certain cycloadditions are reversible and therefore the product distribution may reflect thermodynamic rather than kinetic control. 

Alkenylboronic esters undergo regio- and stereoselective 1,3-dipolar cycloadditions with nitrones. These reactions lead to boronic ester-substituted isoxazolidines, which can be converted by oxidation with H202 to the corresponding 4-hydroxy derivatives (Eq. 8.48).69 The high selectivity could be the result of a favorable interaction between the boronic ester and the amino group. 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

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