Chiral nitroolefination

Chiral nitroolefins prepared in Eqs. 4.96 and 4.97 are converted into various natural products as summarized in Scheme 4.16.121-123... 

A total synthesis of (-)-physostigmine is accomplished from a chiral nitroolefin of Eq. 4.101 (Scheme 4.17).128... 

Using l-(2-nitrovinyl)pyrrolidines 108 or 111 as Michael acceptors, the addition of the Reformatsky reagent is followed by amine elimination. A formal vinylic substitution ensues, which can take advantage of the presence of stereocenters in the pyrrolidine moiety, affording new chiral nitroolefins 110151 and 113152, as reported in equations 64 and 65, respectively. In both cases, zinc enolates 109 and 112 are prepared by lithia-tion/transmetallation of the parent ester. 

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... 

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. 

The enantioselective conjugate addition of dialkylzinc to nitroalkenes using other phosphoramidite,79,79a 83a sulfonamide,84 and binaphthol-based thioether ligands65 has also been studied in the past few years. Particularly noteworthy are the efficient chiral monodentate phosphoramidite ligands (S,R,R)-29 and (A,A)-55 developed by Feringa et al. and Alexakis et al., respectively, for this reaction. (S,R,R)-29 provided excellent enantioselectivities (up to 98% ee) for acyclic nitroalkenes (Scheme 25).80 It also worked well for other nitroolefin substrates such as 3-nitrocoumarin 7068 and methyl 3-nitropropenoate 7185. 

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... 

Some additional examples, where the stereochemical outcome of the cycloaddition to chiral alkenes has been explained in terms of the Honk—Jager model, should also be mentioned. The diastereomer ratio found in the reaction of y-oxy-a,p-unsamrated sulfones (166), with Morita-Baylis-Hillman adducts [i.e., ot-(a -hydro-xyalkyl)-acrylates (167)] (Scheme 6.27), with dispiroketal-protected 3-butene-l,2-diol (168), and with a,p-unsamrated carbonyl sugar and sugar nitroolefin (169) derivatives, all agree well with this model. 

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. 

Based on this gathered experience the diastereoselective alkylation of enantio-pure a-lithiated sulfonates was extended to the Michael addition with aliphatic nitroolefins [95]. Thus the Michael adducts 118 could be achieved in excellent yields (84-99%) with high diastereoselectivities de of 80-88% (84 to >98% after recrystallization or chromatography). Cleavage of the chiral auxiliary and treatment with diazomethane furnished the anti-configured a,j3-disubstituted y-nitro-methyl sulfonates 119 in overall yields of 41-70% and with excellent de- and ee-values (Scheme 1.1.32). 

The chiral monoacetates now available are useful multiple coupling reagents16-18 for syntheses of enantiomerically pure target molecules. They can be converted to nitroolefinic allylic esters, achiral or racemic analogues of which we have previously shown16-18 to combine sequentially with two (different) nucleophiles (see 1-2 in Scheme 1). 

The enantioselective aldol and Michael additions of achiral enolates with achiral nitroolefins and achiral aldehydes, in the presence of chiral lithium amides and amines, was recently reviewed354. The amides and amines are auxiliary molecules which are released on work-up (equation 90 shows an example of such a reaction). 

Nitroolefins are attractive alternative acceptors to enones. In 1999, Barnes and Ji reported an efficient catalyst system for reaction of nitroolefins with 1,3-dicarbonyl compounds with high enantioselectivity (up to 97% ee Scheme 19) [22], Using this method, a highly functionalized nitro compound 38, an important intermediate in the synthesis of an endothelin-A antagonist, was prepared on a large scale in 88 % ee. In this case, the formation of a chiral Mg enolate as a reactive intermediate was proposed. 

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]. 

Chiral bis-sulfonamides 162-163 are a new group of organo catalysts for the enantioselective Friedel-Crafts alkylation of indoles to nitroolefins. The hy-... 

The Tang group combined the chiral pyrrolidine core with a thiourea function (Scheme 2.43) [29]. Optimal reaction conditions were obtained with 26 under solvent-free conditions and in the presence of n-butyric acid as additive (10 mol%) at 0 °C (Scheme 2.43). The high selectivity of the addition was attributed to the formation of a rigid three-dimensional H-bonded structure in the transition state, in which the enamine was positioned at the correct distance compared to the nitroolefin and allowed an addition from the Re-face of the enamine. 

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... 

In the same year, Connon and coworkers [63] reported that the chiral bifunctional cinchona alkaloid-based thiouea 81a is also able to catalyze the addition of dimethyl chloromalonate 196 to nitroolefins 124, leading to the Michael adduct that cyclizes to form the cyclopropane 197 in the presence of DBU. Almost single diastereomeric nitrocyclopropanes (>98% de) were obtained in good yields. However, the enantios-electivity obtained with this type of catalyst was poor (<47% ee) (Scheme 9.69). 

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