Diastereoselectivity nitrones/nitronates

The electronic character of aromatic groups at the a-C of nitrones affects both, the yields and the stereoselections (Table 2.28). Electron-rich aromatic groups increase enantioselectivities but decrease the yields (entries 1-3). Electron-deficient ones slightly decrease enantioselectivities but increase the reaction rates (entries 4 and 5). The electronic properties of A-bound aromatic groups of nitrones has almost no obvious impact on the enantio-selections (entries 6-10). Both, electron-deficient and electron-rich aromatic groups afford good enantioselectivities and diastereoselectivities. Nitrone with a A-bound furyl group furnishes, in moderate yield, the best ee but the lowest diastereoselectivity (entry 9). a-Alkyl and A-alklyl nitrones fail to react (entries 11 and 12). 

For diastereoselective nitrone intramolecular cycloaddition to conjugated esters, see R. Annunziata, M. Cinquini, F. Cozzi and L. Raimondi, Tetrahedron Lett., 1988, 29, 2881. 

On the basis of this successful application of 23d, this catalyst was applied in a series of reactions (Scheme 6.22). For all eight reactions of nitrones 1 and alkenes 19 in which 23d was applied as the catalyst, diastereoselectivities >90% de were observed, and most remarkably >90% ee is obtained for all reactions involving a nitrone with an aromatic substituent whereas reactions with N-benzyl and N-alkyl nitrones led to lower enantioselectivities [65]. 

I.4.I.7.I. Acyclic Nitrones 1.4.1.7.1.1. Substrate-Induced Diastereoselection Stereogenic Center at Carbon... 

Deacetylanisomycin (4) is synthesized using L-tartaric acid (1) as a precursor in 12% overall yield16. The key step is the diastereoselective addition of (4-methoxybenzyl)magnesium chloride to the C — N double bond of nitrone 2 at 0°C in the presence of 1 equivalent of ethylmagncsium-bromide diethyl ether complex in dichloromethane. This procedure affords a chromatograph-ically separable mixture of the hydroxylamines 3 a and 3 b in a diastereomeric ratio [(2R,35,4R)/ (25,35,47 )] 70 30 and 60% yield from 2. 

The diastereoselectivity of the nucleophilic addition to nitrone 2 may be rationalized by assuming that magnesium bromide preferentially coordinates with the nitrone oxygen. The Grignard reagent is therefore forced to interact with the acetal oxygen in position 3. 

The model is supported by the fact that in the absence of magnesium bromide 4-methoxyben-zylmagnesium chloride reacts with nitrone 2 at 0°C in THF with an inverse diastereoselectivity [3a/3b d.r. (2R,35,4R)/(25,35,4R) 40 60]I6. 

The reactions of the lithium enolates of substituted 2-cyclohexenones and 2-cyclopentenones with ( )-l-nitropropene give a mixture of syn- and ami-products3. The lithium enolate of 3,5,5-trimethyl-2-cyclohexenone gives a mixture of the syn- and //-3.5,5-trimethyl-6-(l-methyl-2-nitroethyl)-2-cyclohexcnoncs in modest diastereoselection when the reaction mixture is quenched with acetic acid after. 30 minutes at —78 =C. When the reaction mixture is heated to reflux, tricyclic products are obtained resulting from intramolecular Michael addition of the intermediate nitronate ion to the enone moiety. 

The initial nitronate anion intermediates formed from the addition of trimethylaluminum to nitroalkenes having a /i-phenylthio substituent, however, undergo a highly diastereoselective protonation to give awn -products19. 

While a different explanation for the diastereoselection in these protonation reactions has been proposed, the stereochemical sense of protonation can be rationalized as arising from protonation of the chelated intermediate from the least hindered diastereotopic face of the nitronate anion (i.e. anti to the /i-methyl group)20-21. 

Like the nitronate ion, the cyanide ion is synthetically equivalent to the aminomethyl carbanion (CH2NH2) , because of the possible reduction of - CN to the - CH2NH2 group. Consequently, the addition of cyanide ion to imines to give a-aminonitriles (Strecker-type reaction) is a viable route to 1,2-diamines. As a matter of fact, a number of diastereoselective and catalytic... 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

As previously described, in basic conditions the proUne-derived a-sulfonyl amide 141 generates the imine function, which afterwards undergoes addition by a nucleophile, e.g., a nitronate ion see the diastereoselective synthesis of the diamino nitroalkane derivative 172, which is the precursor of the piperazine-2-carboxyUc acid 173, through a Nef reaction [45]. Similarly, the addition of the Uthium enolate of ethyl acetateto the a-sulfonyl amide 174 gave the diamino ester derivative 175, wich was then converted to (-)-l-aminopyrrolizidine 176 (Scheme 27). 

Scheme 21 summarizes further reactions leading to phosphonic acid analogues of amino acids. Treatment of the nitrone (138 R =Me or Pr ) with a dialkyl hydrogen phosphonate (best as the Li derivative which shows greater diastereoselectivity than the Na or K salts), and subsequent steps involving acidolysis of the oximino compound (139) lead to the free (ot-aminoalkyl)-phosphonic acids (140)(phosphonoalanine, phosphonova1ine). 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

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