Cycloadditions chiral phosphoric acids

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

Chiral phosphoric acids mediate the enantioselective formation of C-C, C-H, C-0, C-N, and C-P bonds. A variety of 1,2-additions and cycloadditions to imines have been reported. Furthermore, the concept of the electrophilic activation of imines by means of phosphates has been extended to other compounds, though only a few examples are known. The scope of phosphoric acid catalysis is broad, but limited to reactive substrates. In contrast, chiral A-triflyl phosphoramides are more acidic and were designed to activate less reactive substrates. Asymmetric formations of C-C, C-H, C-0, as well as C-N bonds have been established. a,P-Unsaturated carbonyl compounds undergo 1,4-additions or cycloadditions in the presence of A-triflyl phosphoramides. Moreover, isolated examples of other substrates can be electrophil-ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found utility as specific acid catalysts of selected asymmetric transformations. 

The asymmetric, catalytic, three-component 1,3-dipolar cycloaddition which have been reported by Gong and co workers, of a broad range of methyleneindolinones with aldehydes and amino esters, in the presence of the chiral phosphoric acid (137) produced spirooxindole derivatives in high yield with unusual regiochemistry and excellent stereoselectivities (up to 98% ee), under mild conditions (Scheme 36). ... 

The first catalytic asymmetric formal [3h-3] cycloaddition of isatin-3-indolyhnethanol derivatives and in situ generated azomethine ylides was recently developed to synthesize structurally diverse spiro[indoline-3,4 -pyridoindoles] 228 bearing one all-carbon quaternary stereogenic center [109]. The reaction takes place with a range of A(-substituted isatin-derived 3-indolylmethanols, aromatic aldehydes 4, and diethyl 2-aminomalonate 221 and is catalyzed with chiral phosphoric acid 227 with the bulky 9-phenanthrenyl group at the 3,3 -positions of the BINOL moiety (Scheme 2.78). 

Chiral oxazaborolidine catalysts were applied in various enantioselective transformations including reduction of highly functionalized ketones/ oximes or imines/ Diels-Alder reactions/ cycloadditions/ Michael additions, and other reactions. These catalysts are surprisingly small molecules compared to the practically efficient chiral phosphoric acids, cinchona alkaloids, or (thio)ureas hence, their effectiveness in asymmetric catalysis demonstrates that huge substituents or extensive hydrogen bond networks are not absolutely essential for successful as5unmetric organocatalysis. 

In 2010, Gong et al. reported a highly enantioselective three-component domino reaction, consisting of an enantioselective aza-Diels-Alder cycloaddition catalysed by a chiral phosphoric acid and a subsequent intramolecular hydroamination catalysed by a gold complex. The domino reaction occurred between aldehydes, an enamide, and 2-(2-propynyl)aniline... 

The first catalytic asymmetric homo-1,3-dipolar cycloadditions have been estatlished via SPINOL-derived chiral phosphoric acid (189)-catalysed reactions of aldehydes (186) and 2-aminomalonates (187). This protocol provided an easy access to synthetically and pharmaceutically important chiral imidazolidines (188) with two stereogenic centers, and four new bonds in a single step (Scheme 50). ... 

A one-pot, three component 1,3-dipolar cycloaddition reaction of aldehydes (289), a-aminomalonate (290), and nitroalkenes (291) has been developed through 3,3 anthiyl substituted hinaphthol derived chiral phosphoric acids (292) (Scheme 78). ... 

Chiral phosphoric acids also catalyze [4+2] cycloadditions. Gong and colleagues showed that 99c activates aromatic aldehydes 207, anisidine (119), and cyclohex-enone (206) to give the hetero-Diels-Alder products 208 and 209 with good yield and enantioselectivity, along with moderate endo-selectivity (Scheme 42.48) [104]. 

Scheme 42.48 Chiral phosphoric acid-catalyzed [4+2] cycloaddition of cyclohexenone and aromatic aldimines via three-component methodology.

Very recently, as a consequence of their continuing interest in combining metal/ organic catalysis, Han et al. expanded the chemistry combining chiral phosphoric acid and gold catalysis. By incorporating an Au complex-catalyzed Danishefsky diene formation and chiral phosphoric acid-promoted enantioselective [4h-2] cycloaddition into the tandem reaction [69], they obtained pentacyclic frameworks in high yields and selectivities (Scheme 9.66). 

The same group expanded the scope of the aza-Diels-Alder reaction of electron-rich dienes to Brassard s diene 97 (Scheme 37) [60]. In contrast to Danishefsky s diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phosphate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4 + 2] cycloaddition of A-arylated aldimines 94 and Brassard s diene 97. Subsequent treatment with benzoic acid led to the formation of piperidinones 98. Interestingly, the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of 72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,P-unsaturated, and aliphatic precursors 94 in satisfactory yields (63-91%) and excellent enantioselectivities (92-99% ee). NMR studies revealed that Brassard s diene 97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h), but comparatively stable in the presence of its pyridinium salt (25% decomposition after 1 h). This observation can be explained by the fact that the pyridinium salt is a weak Brpnsted acid compared to BINOL phosphate 3m. 

Also, Gong and co-workers reported a Brpnsted add catalyzed three-component asymmetric 1,3-dipolar cycloaddition reactions between aldehydes 213, amino esters 214, and dipolarphiles 215 by catalyst 216, providing pyrrolidines 217 in high yields with excellent enantioselectivity. Scheme 3.69 [86], The methodology introduced a concept that stereochemistry can be controlled by use of a chiral Br0nsted acid (BH), e.g., phosphoric acid. The chiral BH provided sufficient acidity... 

The trienamine-catalysed asymmetric Diels-Alder cycloaddition reaction of 2,4-dienals (77) with chiral phosphorous dienophiles (78) produced densely functionalized phosphonocyclohexene adducts (79) with excellent enantioselectivity (up to 99% ee) and good to high diastereoselectivity (up to >99 1) (Scheme 22). The thermal Diels-Alder reaction of l-phosphono-(3,4)-disubstituted-1,3-butadienes with maleimides and 4-phenyl-l,2,4-triazoline-3,5-dione produced polycyclic phosphonic acid derivatives. ... 

The catalytic asymmetric /-selective Diels-Alder annulation of a, -unsaturated /-butyrolactams with enones provided a synthesis of, y-functionalized bridged bi-or tri-cyclic dihydropyranopyrrolidin-2-ones in one step (up to 98% yield, >20 1 dr, and 99% ee) The inverse-electron-demand aza-Diels-Alder cycloaddition 0 of A-aryl-a,/0-unsaturated ketimines with enecarbamates in the presence of chiral bifunctional phosphoric acids produced 4,5,6-trisubstituted 1,4,5,6-tetrahydropyridines having three contiguous stereogenic centres in up to 84% yield, 95 5 dr, and 95% 5-Alkenylthiazoles react as in-out dienes with e-poor dienophiles in polar 44-2- 0 cycloaddition reactions. The cycloadditions are site selective. The mechanism is thought to lie between a concerted but highly asynchronous process and a stepwise process. 

Scheme 42.44 Synthesis of chiral pyrrolidines 193 by enantioselective domino 1,3-dipolar cycloaddition of azomethine ylides formed in situ and dialkyl fumarates 192 catalyzed by phosphoric acid catalyst 106.

The same group reported a chiral Br0nsted acid-catalyzed 1,3-dipolar cycloaddition reaction converting aldehydes 199 (2 equivalents), amino esters 198, and anilines 200 into chiral imidazolidines 201 with high levels of stereoselectivity (up to 82% de and 98% ee. Scheme 42.46). Again, aromatic aldehydes were needed to achieve high enantioselectivity induced by phosphoric acid 100b [102]. 

The use of chiral Bronsted acids as catalysts for enantioselective hetero-Diels-Alder reactions has also been examined by Akiyama [132, 133]. A BINOL-derived phosphoric acid [19,128, 134] was found to promote enantioselective cycloadditions of Brassard s diene 265 [135] to imines (Equation 27). Use of the corresponding pyridinium phosphate 266 resulted in higher yields along with high enantioselectivity for a range of imines, as exemplified by the formation of 267 (97% ee, 90% yield) [132]. 

Ester-based chiral auxiliaries have also beat used in other settings. P-Alk-oxyesters 1.27 of (R)-1 -phenylethanol 1.1 (R = Me, Ar = Ph) or (5)-1-naphthyl-ethanol 1.1 (R = Me, Ar = 1-Np) are transformed into dural synthons by reactions with a lithiated carbanion a to phosphorous followed by hydrogenolysis [194], Ethers 1.28 of chiral alcohols 1.1 undergo selective alkylations or hydroxyalkyla-tions [169]. The auxiliaries can be removed by hydrogenolysis. Enol or dienol ethers 1.29 and 1 JO suffer [2+2] [195, 196] or [4+2] cycloadditions [49, 197,198, 199], The best stereoselectivities are obtained when the chiral auxiliary is 1.1 (R = r-Pr, Ar=Ph), 1.4 (R=Ph), 1.5 (R = Ph), 1.10 or 1.13. These auxiliaries are cleaved either by acid treatment [199] or by other means in subsequent steps. Acetylene ethers G OC=CR derived from 1.5 (R=Ph) [199a] can undergo stereoselective Pauson-Khand reactions [200, 201], The auxiliaries are removed by treatment of the products with Sml2 in THF-MeOH. 

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