Diastereoselectivity reactions, nitroaldol

Scheme 6.170 Suggested transitions states for the anti-diastereoselective Henry (nitroaldol) reaction promoted by (R,R)-catalyst 186 (TS 1) and its (S,S)-isomer 183 (TS 2) to demonstrate the match/mismatch relationship between guanidine-thiourea catalyst and (S)-a-aldehyde.

Scheme 6.171 Product range of the 186-catalyzed anti-diastereoselective Henry (nitroaldol) reaction of a-chiral aldehydes with nitromethane.

Keywords HeterobimetaUic lanthanoid catalysts. Asymmetric nitroaldol reaction, Henry reaction, Enantioselective and diastereoselective reactions, syn-Selectivity... 

Diastereoselective Catalytic Nitroaldol Reaction Starting from Chiral Aldehydes... 

Aluminum oxide catalyzed addition of ethyl nitroacetate to racemic 2,3-cpoxy aldehydes 7 affords substituted 4,5-dihydroisoxazole 2-oxides through a regio- and stereospecific tandem nitroaldol cyclization process. High diastereoselectivities are observed in the reaction of cis-epoxyaldehydes to yield the ethyl, vi7 -4.5-dihydro-4-hydroxy-5-( I -hydroxyalkyl)-3-isoxazole-carboxylate 2-oxides, with tram configuration at the ring positions, whereas reactions of trans-and 3,3-disubstituted 2,3-epoxyaldehydes proceed with lower selectivities28. 

H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shibasaki, Efficient Diastereoselective and Enantiose-lective Nitroaldol Reactions from Prochiral Starting MaterialsStUtilization of La-Li-6,6 -Disubstituted BINOL Complexes as Asymmetric CatalystsUtJ. Org Chem 1995, 60, 7388-7389. 

Use of an organocatalyst in a highly diastereoselective nitroaldol reaction was reported by the Corey group in the synthesis of 123 [128]. This compound is a key building block in the synthesis of the HIV-protease inhibitor amprenavir. The alkaloid-based fluoride salt, 122, was used as an efficient chiral phase-transfer catalyst (this type of catalyst was developed by the same group [129-131]) and led to formation of the (2R,3S) diastereomer (2H,3S)-123 in 86% yield and with a diastereo-meric ratio of d.r. = 17 1 (Scheme 6.53) [128], It is worthy of note that a much... 

Nitroaldol reactions of enantiomerically pure a-amino aldehydes with nitromethane using a catalytic amount of LLB were found to proceed in a highly diastereoselective manner.35 The adducts (3-amino-2-hydroxy-l-nitro derivatives) are attractive intermediates for the synthesis of unnatural erythro-amino-2-hydroxy acids, which are important components of several biologically active compounds. As an example, the promising HIV-protease inhibitor KNI-272 (65)36 37... 

LLB-type catalysts were also able to promote diastereoselective and enantioselective nitroaldol reactions starting from substituted nitroalkanes. In preliminary work, however, LLB itself gave unsatisfactory results in terms of both diastereoselectivity (syn/anti ratio 63 37 to 77 23) and enantioselectivity (<78% ee).32 To address the problem of modest enantio- and diastereoselectivities with... 

Figure 21. Proposed transition states of diastereoselective and enantioselective nitroaldol reactions.

The results from the analysis indicated that nitroaldol intermediate 461 was resolved by crystallization from the dynamic system (36 possible diastereomers). This shows the advantage of DSR using diastereoselective crystallization technique to identify the optimal constituent from large and diverse dynamic systems in one-pot processes. After the resolution process, the reaction conditions of the single nitroaldol reaction of 4-pyridinecarboxyaldehyde 451 was further optimized in... 

As reported in Figure 2.5, nitroolefins (26), easily obtained by nitroaldol condensation between 5-nitro ketones (24) and aldehydes (25), are converted directly into the spiroketals (29) by reduction with sodium boronhydride in methanol. The one-pot reduction-spiroketalization of nitroalkenes (26) probably proceeds via the nitronate (27) that by acidification is converted into carbonyl derivatives, which spontaneously cyclize to emiketals (28). Removal of the tetrahydropyranyl group, by heating the acidic mixture during the workup, affords, in a one-pot reaction from (26), the desired spiroketals in 64-66% overall yields. The spiroketalization of (26)-(29b) proceeds in high ( )-diastereoselectivity. 

With more effective asymmetric catalysts in hand, we next applied the most efficient catalysts 27 and 28 to diastereoselective nitroaldol reactions. We were very pleased to find that high syn selectivity and enantioselectivity were always obtained by use of 3.3 mol % catalyst [58]. Representative results are listed in Table 14. 

Highly diastereoselective nitroaldol reactions <2003TL8681> and Lewis acid-catalyzed reactions with furan derivatives <2000PAG1589> on enantiopure glyoxylic acid derivative 586 (R = H, X = 0) were performed. 

The nitroaldol condensation with nitromethane (Henry s reaction), followed by Nef decomposition of the resultant nitronate under strongly acidic conditions, has been used to elongate aldehydes. For instance, A-acetyl-D-mannosamine has been converted into A-acetylneuraminic acid applying this method iteratively [69]. Chikashita and coworkers [70] have reported good levels of anti diastereoselectivity better than 99% in an iterative homologation sequence using 2-lithio-l,3-dithiane [71] with 2,3-O-cyclohexylidene-D-glyceraldehyde R)-62. In the case of the BOM-protected tetrose derivative, the addition of 2-lithio-l,3-dithiane was syn selective (synlanti 82 18) (Scheme 13.30). 

First encouraging results for a stereoselective synthesis in general were reported by Seebach in 1982, who investigated the syn/anti-diastereoselectivity starting from achiral aldehydes and nitroalkanes [4,5]. Barrett et al. examined the influence of nonchiral Lewis acids on the syn/anti diastereoselectivity [6]. Stoichiometric amounts of an enantiomerically pure aldehyde were used in a di-astereoselective reaction with 3-nitropropionate by Hanessian et al. [7]. However, an approach to enantioselective synthesis of nitroalcohols via the route of the asymmetric Henry reaction could not be carried out until almost one hundred years after the discovery of the nitroaldol reaction. 

A further example of a diastereoselective nitroaldol reaction using heterobimetallic lanthanoid complexes as catalysts was recently reported by Okamoto et... 

Schemes. Diastereoselective nitroaldol reaction as key step in the synthesis of erythro-AHPA 34...

Scheme 9. Catalytic diastereoselective nitroaldol reaction promoted by the LPB type catalyst...

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