Asymmetric nitroolefination

Node and Fuji have developed a new chiral synthesis of various alkaloids using chiral nitroalkene, (S)-(-)-2-methyl-2-(2 -nitrovinyl)-S-valerolactone. Scheme 8.11 shows a total synthesis of (-)-physostigmine, a principal alkaloid of the Calabar bean.53 The key nitroalkene is prepared by asymmetric nitroolefination of a-methyl-8-lactone using a chiral enamine (see... 

A similar asymmetric nitroolefination reaction has been described that uses an optically active / -nitro-a,/ -unsaturated sulfoxide, e.g., 2-nitro-1-[(/ )-2-phenylpropylsulfmyl]cyclohexene, where the chiral sulfoxide moiety functions as a leaving group. Condensation oflactam enolates with this sulfoxide affords substituted lactams with high enantiomeric excesses and good yields27. 

The total synthesis of spirotryprostatin B was accomplished by K. Fuji et al using an asymmetric nitroolefination to establish the quaternary stereocenter." The conversion of the nitroolefin to the corresponding aldehyde was carried out under reductive conditions using excess titanium(lll) chloride in aqueous solution. The initially formed aldehyde oxime was hydrolyzed in situ by the excess ammonium acetate. 

The total syntheses of the potent glycosidase inhibitors (+)-castanospermine, (+)-6-epicas-tanosperimine, (+)-australine, and (+)-3-epiaustraline have been reported. These four natural products are derived from a single common intermediate, the nitroso acetal (as shown in Scheme 8.43), which is created in the key step by the asymmetric tandem [4+2]/[3+2] cycloaddition between silaketal nitroolefin and chiral vinyl ether.182 The strategy of the synthesis is outlined in Scheme 8.43. Scheme 8.44 presents a total synthesis of (+)-castanosperimine and (+)-6-epi-castanosperimine from the common intermediate prepared by tandem [4+2]/[3+2] cycloaddition. 

Nitroolefins are good Michael acceptors and their reactivity toward diethylzinc is different depending on the presence or absence of Lewis acids. Since the nitro group can be further transformed to a variety of useful containing functionalities,76,7641 the asymmetric 1,4-additions of nitroolefins may provide an easily accessible pathway to highly versatile optically active synthons. 

Hoveyda and co-workers presented the asymmetric addition of alkylzincs to small-, medium-, and large-ring nitroolefins with chiral peptide-based phosphines 57 as catalyst.87 The enantioselectivities were typically >90%. Ligand 57 also worked well in the asymmetric addition of dialkylzinc to acyclic disubstituted nitroalkenes (up to 95% ee Scheme 26).88... 

As early as 1977 Pracejus et al. investigated alkaloid-catalyzed addition of thiols to a-phthalimido acrylates, methylene azlactones, and nitroolefins [56a]. In the former approach, protected cysteine derivatives were obtained with up to 54% ee. Mukaiyama and Yamashita found that addition of thiophenol to diisopropyl mal-eate in the presence of cinchonine (10 mol%) proceeds in 95% yield and that the product, (S)-phenylthiosuccinate, was formed with 81% ee [56b]. The latter Michael adduct was used as starting material for preparation of (R)-(+)-3,4-epoxy-1-butanol. In the course of an asymmetric total synthesis of (+)-thienamycin Ike-gami et al. studied the substitution of the phenylsulfonyl substituent in the azetidi-none 69 by thiophenol in the presence of cinchonidine (Scheme 4.34) [56c]. This substitution probably proceeds via the azetinone 70. In this reaction the phenyl-thioazetidinone 71 was obtained in 96% yield and 54% ee. Upon crystallization, the optically pure substitution product 71 was obtained from the mother liquor... 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

Recently, a small library of novel axially chiral bis-arylthioureas 148-161 as chiral organocatalyst has been prepared and evaluated for the asymmetric addition of N-melhylindole to nitroolefins. Initial studies have shown that the relatively simple and readily prepared (S)-154 is the optimal structure (Scheme 40) [120]. 

Scheme 2.44 Asymmetric addition of aldehydes to nitroolefins catalyzed by Alexakis s aminopyrrolinines 5 and 29.

Due to the increased reactivity of the aldehyde, alkyl-substituted nitroolefins can also be used as substrates. Nevertheless, these reactions are usually low-yielding and afford moderate selectivity. Alexakis has shown, however, that the bispyrrolidine 5-catalyzed additions may be used in multistep synthesis. The addition of propionaldehyde 34 to nitroolefin 33 resulted an approximate 2 3 mixture of anti/syn isomers in 92% yield and in high ee (93%), allowing the asymmetric synthesis of (—)-botryodiplodin (Scheme 2.46) [23b]. 

Modified cinchona alkaloids 18 and 19, derived from quinine and quinidine, respectively, were utilized by Deng and co-workers for the catalytic asymmetric Michael additions of malonates to nitroolefins [49]. These catalysts effectively promoted the conjugate additions of methylmalonate to a variety of aromatic (90-99% yield 96-98% ee), heteroaromatic (97-99% yield 96-98% ee) and aliphatic (71-86% yield 94% ee) -substituted nitroolefins (Table 6.7). As the two alkaloids... 

Jorgensen and co-workers employed chiral bis-sulfonamide catalyst 27, a proven ligand for metal-based asymmetric catalysis, for the Friedel-Crafts alkylations of N-methylindoles (24) using -substituted nitroolefins [52]. Using optimized conditions, 2 mol% 27 gave the desired indole alkylation products of substituted aryl and heteroaryl nitroolefins in moderate to high yields (20-91%) and moderate enantiopurities (13-63% ee Scheme 6.3). Aliphatic -substitution... 

Dixon and co-workers independently reported the asymmetric hydrogenbonding catalyzed 1,4-additions of dimethyl malonate to nitroolefins using a cinchonine-derived thiourea catalyst 30 [54]. Catalyst 30 gave good to high yields (81-99%) and good to high enantioselectivities (82-97% ee) for a variety of aromatic, heteroaromatic and aliphatic nitroolefins (Scheme 6.4). Optical purity... 

The epi-quinine urea 81b was also found by Wennemers to promote an asymmetric decarboxylation/Michael addition between thioester 143 and 124 to afford the product 144 in good yield and high enantioselectivity (up to 90% ee) (Scheme 9.49). Here, malonic acid half-thioesters serve as a thioester enolate (i.e., enolate Michael donors). This reaction mimics the polyketide synthase-catalyzed decarboxylative acylation reactions of CoA-bound malonic acid half-thiesters in the biosynthesis of fatty adds and polyketides. The authors suggested, analogously with the enzyme system, that the urea moiety is responsible for activating the deprotonated malonic add half-thioesters that, upon decarboxylation, read with the nitroolefin electrophile simultaneously activated by the protonated quinuclidine moiety (Figure 9.5) [42]. 

In 2007, Connon and McCooey developed highly efficient, asymmetric syn-selective addition reactions of enolizable carbonyl compounds to nitroolefins by adopting the enamine catalysis approach [48]. The 9-epi-amino cinchona alkaloid derivative (160,9 -epi-DHQDA) as an aminocatalyst promoted the addition ofa variety... 

Sharpless bis-cinchona alkaloids such as [DHQD]2PYR (163a) have proved to serve as highly efficient catalysts for the asymmetric vinylogous Michael addition of the electron-deficient vinyl malonitriles 164 as the nucleophilic species to nitroole-fins 124 [50], This process exhibited exclusive y-regioselectivity and high diastereo-and enantioselectivity. Only the anti-products 165 were observed in all reactions (Scheme 9.57). Of note, 1-tetralone did not react with nitroolefins under these... 

With chiral diamine 24, in the form of a trifluoroacetate salt, the classic aqueous biphasic protocol has been successfully applied to the asymmetric Michael reaction of ketones with both aryl and alkyl nitroolefins. Brine is used as the aqueous phase. ... 

However, despite the rapid design of news CILs, successful applications in synthesis remained elusive for some time. Only in the last 2-3 years have some significant results been obtained. Leitner and co-workers in 2006 reported a high enantiomeric excess (84% ee) by using a chiral anion containing ionic liquid for an aza-Baylis-Hillman reaction (Scheme 4.11), whereas CILs with an imidazolium or a benzimidazolium unit attached to (5)-pyrrolidine have been used with success as solvents or catalysts for asymmetric aldol reactions and Michael additions to nitroolefins (ee up to 99%). ... 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Chiral heterocychc amines as organocatalysts for asymmetric conjugate addition to nitroolefins and vinyl sulfones via enamine activation 07CC3123. 

A number of enantiomerically pure amines catalyse the asymmetric Michael reaction of ketones with nitroolefins. Amongst these some of the most successful... 

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