Mannich BINOL derivatives

Dixon reported that saturated BINOL 45 sufficiently activates various N-Boc aryl imines toward Mannich reaction with acetophenone-derived enamines to yield P-amrno aryl ketones in good yields and enantioselectivities (Scheme 5.62) [116]. The same group applied a BINOL-derived tetraol catalyst to the addition of meth-yleneaminopyrroHdine to N-Boc aryl imines. Interestingly, appendage of two extra diarymethanol groups to the BINOL scaffold resulted in a marked increase in enantiomeric excess [117]. 

Phosphorodithioic adds have been prepared according to an improved synthesis of 3,3 -disubstituted BINOL derivatives (226-231). In preliminary experiments, these new Bronsted adds were tested as organocatalysts in three reactions. They promoted the Nazarov cyclisation with mixed selec-tivities, the Mannich reaction with good enantioselectivity and they catalyzed efficiently the alkylation of iV-acyliminium with enol silyl ether. ... 

The first catalytic enantioselective nitro-Mannich-type reaction was developed by Shibasaki by the use of chiral BINOL-derived heterobimetallic complex 90 (Scheme 2.51). The catalyst prepared from Yb(0/-Pr)3, KOt-Bu, and (/ )-BINOL in a ratio of 1 1 3 gave the best result (82-91% ee) in the reaction of aldimines with nitromethane, while the conventional ratio (Yb K BINOL = 1 3 3) was much less effective (52% ee) in the same reaction. Moreover, the complex with a ratio of Yb K BINOL=l l 2 did not promote the reaction. Therefore, the complex YbK((I )-BINOLate)2 itself or its aggregated complex [YbK((I )-BINOLate)2] was not likely to be tbe actual catalyst. The active catalyst might be 90, a complex of YbK((I )-BINOLate)2... 

The aza-Morita-Baylis-HiUman reaction is known to be a useful and atom-economical C-C bond-forming reaction of electron-deficient alkenes with imines usually catalyzed by Lewis bases [202]. It formally involves a sequence of reactions including a Michael addition, a Mannich reaction, a proton transfer, and a retro-Michael reaction ( -elimination). Although there are many reports in the field of the enantioselective aza-Morita-Baylis-Hilhnan reaction, only rare examples of asymmetric domino reactions initiated by this reaction have been reported. In 2010, Sasai et al. [203] developed the first organocatalyzed asymmetric domino aza-Morita-Baylis-Hillman/aza-Michael reaction of a,p-unsaturated carbonyl compounds with N-tosylimines, allowing an easy access to chiral cis-1,3-disubstituted isoindolines as single diastereomers. The process was induced by a Hg-BINOL-derived catalyst and provided these products in high yields and enantioselectivities, as shown in Scheme 10.18. 

Later, these authors reported the utilisation of a combination of Rh2(OAc)4 with a chiral BINOL-derived phosphoric acid to induce an enantioselective three-component Mannich-type reaction of diazo compounds, carbamates and imines, providing a rapid and efficient access to... 

Akiyama and coworkers, who had pioneered BINOL-derived phosphoric acids, noticed that aldimines 365 available from 2-aminophenol and aromatic, heteroaromatic, and cinnamyl aldehydes can be activated by the chiral acid catalyst 367, so that they are electrophilic enough to react with silyl ketene acetals 366 in diastereoselective and enantioselective Mannich reactions. Thus, P-amino esters 368 are formed with a high preference for the syn-diastereomers that are obtained in high enantiomeric excess (Scheme 5.96) [182]. 

Similar BINOL-derived phosphoric acids were also found to effectively catalyze the asymmetric vinylogous Mannich reaction. Sickert and Schneider reported that various /V-PMP-protected imines react with acyclic silyl dieno-lates in the presence of the Brpnsted acid catalyst 137 to afford the desired 5-amino a,p-unsaturated carboxylic esters (139) in good yields (83-94%) with complete regi-oselectivity and high enantioselectivities (80-92% ee) (Scheme 11.29) [96], Remarkably, the one-pot three-component process (i.e., imine is formed in situ) is comparable... 

In general, bulky substituents at the 3,3 -position of the BINOL backbone are required to achieve good selectivities in asymmetric catalysis. This laborious catalyst fine-tuning can be simplified when chiral l,r-binaphthyI-2,2 -disulfonic acid (BINSA, 141) is used instead of the aforementioned BINOL-derived chiral phosphoric acids. Complexation with a suitable achiral amine enables to tune the bulkiness and Brpnsted acidity in situ [98]. Based on this approach, Ishihara and coworkers combined various A-Boc- or A-Cbz-protected imines and acetyl acetone in the presence of BINS A (1 mol%) and 2,6-diphenylpyridine (142, 2mol%) to afford the corresponding Mannich products in excellent yields and enantioselectivities (Scheme 11.31) [98]. However, the cata-... 

The aza-Petasis-Ferrier rearrangement is not a true concerted sigmatropic reaction, since it is thought to proceed via C-O bond cleavage of a hemiaminal vinyl ether by the action of an acid catalyst to afford a reactive iminium cation and the enol form of an aldehyde these two intermediates combine subsequently in a Mannich-type process, leading to 3-amino aldehydes (Scheme 40.45) [54]. Recently, Terada and Toda used a BINOL-derived phosphoric acid diester as a catalyst for this interesting reaction [55]. 

The first catalytic enantioselective Mannich reaction was documented by Kobayashi, using the conveniently assembled BINOL-derived Zr catalyst 212 (Scheme 11.32) [150]. This catalyst was highly effective in enantioselective additions of silyl ketene acetals to N-(o-hydroxyphenyl)-aldimines such as 210. In a further expansion of the reaction scope, ( )- and (Z)-substituted a-alkoxy silyl enol ethers were observed to undergo diastereoselective additions to aldimines, giving syn and anti amino alcohols, respectively [151]. These processes were utilized in the rapid assembly of (2R,3S)-3-phenyliso-serine (214), a precursor of the C,3 side chain of paclitaxel, known to be essential for its anticancer activity. 

In 2004, Akiyama s and Terada s groups independently pioneered the development of chiral BINOL-derived phosphoric acids 197, which have subsequently found wide resonance as catalysts in various asymmetric transformations [33, 41, 42]. Akiyama reported that silyl ketene acetals such as 237 participate in additions to aromatic aldimines with high diastereo- and enantioselectivity in the presence of catalyst 238 (Equation 21) [146]. In parallel studies, Terada demonstrated that the chiral phosphoric acid 242 readily catalyzes direct asymmetric Mannich reactions between acetylacetone (241) and N-Boc-protected aromatic aldimines such as 240 (Equation 22) [145]. 

The Akiyama group tested various BINOL phosphates 3 as catalysts for the indirect Mannich reaction of aldimines 8 derived from 2-aminophenol with silyl ketene acetals 9 (Scheme 4). All of these Brpnsted acids furnished P-amino ester 10a in (nearly) quantitative yields. Both the reaction rates (4-46 h) and the enantioselectivities (27-87% ee) were strongly dependent on the nature of the substituents at the 3,3 -positions. 

Mannich reaction. A complex derived from (r-BuOjaHf, imidazole and 6,6 -dibromo-BINOL is air-stable. It is capable of asymmetric induction in catalyzing the Mannich reaction (80-90% ee). ... 

Zirconium(rV) t-butoxide, Zr(OtBu)4 is a widely used component of various in situ catalysts. BINOL, its 3,3 -dibromo and 6,6 -dibromo derivatives, and TAD-DOL have been used as chiral ligands (138). These types of catalysts have been used for enantioselective Strecker reactions and Mannich-type reactions (139). 

BINOL-Ti catalyst has also been applied to the Mannich-type reaction by using nitrone as the nucleophile, affording the corresponding P-amino acid ester derivatives in up to 92% ee (Scheme 14.45). It was found that the addition of phenolic additive is essential for obtaining high enantioselectivity of the reaction [125]. 

Shibasaki et al. also developed chiral barium catalysts prepared from barium alkoxide and optically active BINOL 3 or aryloxide 4 derivatives. These catalysts were applied to asymmetric Mannich reactions of p,y-unsaturated esters (Table 27) [101]. In this reaction, the initially formed Mannich adducts isomerized to afford aza-Morita-Baylis-Hillman-type products in moderate to good yields with good enantioselectivities. For four substrate examples, ayloxide 4 ligand worked well (entries 2—4). 

The use of a zirconium catalyst derived from BINOL (Lj in Scheme 11.4 10 mol%) as promoter for the three-component Mannich-type reaction of 5-hexynal, 2-amino-m-cresol and the ketene silyl ketal derived from phenyl propionate provided an efficient and simple protocol for the preparation of a new p-amino acid derivative (>99% yield, 82% de, 99% ee), which was essential for the total synthesis of onchidin, a cytotoxic, C2-symmetric, cyclic decadepsipeptide isolated from a marine mollusk [16]. 

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

Our group has synthesized chiral cyclic phosphoric acid diesters (41), derived from (P)-BINOL, and studied their catalytic activity in the Mannich-type reaction of ketenesilylacetal with aldimines (Scheme 2.83). Although (41a) was not effective as... 

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