Diastereoselectivity nitroalkane

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). 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

Correspondingly, the catalytic 1,4-addition of dialkylzinc reagents to 3-nitro-coumarin 89 (Scheme 7.24), with a fixed trans orientation of the aryl and nitro groups, proceeds with excellent yields (90-99%), high diastereoselectivity (d.r. up to 20 1), and enantioselectivities of up to 92%. Hydrolysis of the lactone moiety in 90 was accompanied by decarboxylation, providing an asymmetric synthesis of 8-aryl-nitroalkane 91. 

In 2008, the Rueping group reported the addition of nitroalkanes 78 to A-PMP-protected a-imino esters 79 in the presence of chiral phosphoric acid (R)-14r (10 mol%, R = SiPhj) (Scheme 29) [51]. This transformation provided P-nitro-a-amino esters 80 in good yields (57-93%), anrt-diastereoselectivities (2 1-13 1) and enan-tioselectivities (84-92% ee). 

Scheme 6.74 Typical N-Boc-protected syn-P-nitroamines obtained from the enantio- and diastereoselective aza-Henry (nitro-Mannich) reaction between N-Boc-protected (hetero) aromatic aldimines and nitroalkanes in the presence of biflinctional thiourea catalyst 12.

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... 

Significant levels of syn diastereoselectivities (5 1 to 16 1) were observed for all substrates, with the exception of an ortho-chloro-substituted aryl imine, which provided only 2 1 syn selectivity. The catalyst was viable for a variety of nitroalkanes, and afforded adducts in uniformly high enantioselectivities (92-95% ee). The sense of enantiofacial selectivity in this reaction is identical to that reported for the thiourea-catalyzed Strecker (see Scheme 6.8) and Mannich (see Tables 6.18 and 6.22) reactions, suggesting a commonality in the mode of substrate activation. The asymmetric catalysis is likely to involve hydrogen bonding between the catalyst and the imine or the nitronate, or even dual activation of both substrates. The specific role of the 4 A MS powder in providing more reproducible results remains unclear, as the use of either 3 A or 5 A MS powder was reported to have a detrimental effect on both enantioselectivities and rates of reaction. 

Matsumoto et al. have reported the first example of a diastereoselective nitro-aldol reaction of optically active A,(V-dibenzyl a-amino aldehydes 150 with nitroalkanes 151 under high pressure without a catalyst (Scheme 7.38). The reactions occurred at 0.8 GPa (room temperature, 12h) and gave mixtures of diastereomers 152 and 153 in good yields and with high optical purity under atmospheric pressure 150 did not react with 151. Very high diastereoselectivity (152/153 = 99) was observed in the reaction of 150a with 2-nitropropane (151c). 

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. 

Catalytic enantio- and diastereoselective nitroaldol reactions were explored by using designed guanidine-thiourea brfunctional organocatalysts like 15 (Figure 4.4) under mUd and operationally simple biphasic conditions. These catalytic asymmetric reactions have a broad substrate generality with respect to the variety of aldehydes and nitroalkanes [43]. On the basis of studies of structure and catalytic activity relationships, a plausible guanidine-thiourea cooperative mechanism and a transition state of the catalytic reactions are proposed. 

Silyl nitronates undergo aldol condensation with aldehydes in the presence of a catalytic amount of anhydrous TBAF to form highly diastereoselective erythro products, which can be elaborated to give synthetically useful 1,2-amino alcohols (eq 22). A one-pot procedure has been developed for direct aldol condensation of nitroalkanes with aldehydes by using TBAF trihydrate with Triethylamine and tert-ButyldimethylchlorosilaneP It appears that silyl nitronates are not reactive intermediates in this case, and the reactions proceed by a different mechanism... 

Enantioselective synthesis of N-protected aminodiols 235 and 239 via dia-stereoselective inter- and intramolecular cycloaddition of optically active nitrile oxides 233 and 237 followed by cleavage of the isoxazoHnes 234 and 238 has been reported by Enders and co-workers (Schemes 55 and 56) [156]. The nitrile oxides 233 and 237 were generated from nitroalkanes 232 and 236, respectively, which in turn were obtained by diastereoselective oxa-Michael addition of (IR, 2S)-(-)-N-formylnorephedrine 231 to ahphatic nitroalkenes 75b,c. The LiAIH4-mediated cleavage of isoxazolines 234 and 238 to aminoal-cohols 235 and 239, respectively, proceeded with >96% diastereoselectivity. 

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