BINOL organocatalysts

After having proven that BINOL phosphates serve as organocatalysts for asymmetric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of electrophilic activation of imines by means of chiral phosphoric acids might be applicable to further asymmetric transformations. Other groups recognized the potential of these organocatalysts as well. They showed that various nucleophiles can be used. Subsequently, chiral phosphates were found to activate not only imines, but also other substrates. 

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

Chiral BINOL (60) is a bifunctional organocatalyst in addition to the phenolic Brpnsted acid groups, it has a Lewis base unit attached via a spacer moiety.167 This particular combination holds the groups in a conformational lock, where they can doubly activate a substrate while giving a high level of stereocontrol. For this example of an aza-Morita-Baylis-Hillman reaction of an enone and an imine, yields up to 100% and ees up to 96% have been achieved. 

S)-3-(A-Isopropyl-A-3-pyridinylaminomethyl)BINOL (4) has been established as an efficient asymmetric bifunctional organocatalyst for the aza-MBH reaction.23 The acid-base functionalities cooperate in substrate activation and fixing of the organocatalyst conformation to promote the reaction with high enantiocontrol. 

Another class of bifunctional organocatalysts for the enantioselective aza-Morita-Baylis-Hillman reaction of imines (112) with enones (113) (Scheme 6) is based on BINOL (115). The efficiency of the catalysts proved to be mainly influenced by the position of the Lewis basic moiety attached to the BINOL scaffold. The activation of the substrate by acid-base functionalities and the fixing of conformation of the catalyst (115) are apparently harmonized to maximize the enantiocontrol (<95% ee) 52... 

Bifunctional organocatalysts, particularly, (S)-3-(N-isopropyl-N-3-p5nidi-nylaminomethyl) BINOL for enantioselective aza-Morita-Baylis-Hillman (aza-MBH) reactions 07Y1089. 

A number of Bronsted acidic organocatalysts have been applied to the asymmetric hydrophosphonylation of aldimines. Thiourea catalysts related to (6.130) catalyse the asymmetric hydrophosphonylation of a range of aliphatic and aromatic aldimines with high ee and BINOL-derived phosphoric acid derivatives similar in structure to (6.131) are effective catalysts in the asymmetric phosphonylation of cinnamaldehyde-derived aldimines. Asymmetric hydrophosphonylation of aromatic aldimines can also be achieved with high ee using cheap, commercially... 

The metal-based Lewis acid derived from the camphor-derived Kgands such as (7.159) and La(OTf)3 is effective in the MBH reaction of aromatic aldehydes with a,P-unsaturated aldehydes mediated by l,4-diazabicyclo(2.2.2]octane (DABCO). The best ees (up to 95%) are obtained using sterically bulky acrylates such as a-naphthyl acrylate. More success has been obtained using Bronsted acidic organocatalysts. The partially reduced BINOL (7.160) has been used to effect enantioselective MBH reaction of aliphatic aldehydes such as (7.71) with 2-cyclohexen-l-one (7.161) mediated by triethylphosphine/ while bis(thio)ureas such as (7.163) provide up to 96% ee in the coupling of this ketone with cyclohex-anecarbaldehyde in the presence of DABCO. °... 

A number of BINOL-based bifunctional organocatalysts, for example (7.171-7.173), containing both Bronsted acidic and Lewis basic sites have been used to good effect in the asymmetric MBH reaction. The amine-thiourea (7.171) promotes the MBH reaction of aliphatic aldehydes with 2-cyclohexenone with ees ranging from 80 to 94% while both the (pyridinylaminomethyl)BINOL (7.172) and phosphine (7.173) catalyse the aza-Bayhs-Hilhnan reaction of simple a,p-carbonyls such as MVK and phenyl acrylate with N-tosyl arylaldmines with similar levels of enantioselectivity. 

The development of a catalytic enantioselective process has received much attention and, in common with the all-carbon Diels-Alder reaction, most success has been achieved using metal-based Lewis acids and, most recently, organocatalysts/ The earliest work on an enantioselective variant of this reaction was performed by Danishefsky/ The enantiomerically pure europium complex Eu(hfc)3 provided moderate enantioselectivities for the hetero-Diels-Alder reaction between derivatives of diene (8.123) and benzaldehyde (8.125), performed under solvent-free conditions. Higher ees have been obtained using the hindered BINOL ligand (8.126), as its aluminium complex. Yamamoto s CAB catalysts (see Section 8.1) such as (8.129), with the appropriate substituent on boron, have also been used to good effect. 

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. ... 

Asymmetric addition of diorganozincs to aldehydes and ketones has been reviewed, focusing on bifunctional catalysts such as those prepared from salens or BINOLs. Regioisomeric chiral amine-sulfonamide organocatalysts give >99% yield and up to 98% ee in addition of diethylzinc to aldehydes. Switching between regioisomers effectively switches the direction of selectivity. Amino-acid-derived (15,l 5)-4,4 -biquinazoline primary amines catalyse ethylation of aryl aldehydes in up to 95%... 

In 2009, Gong s group reported the dynamic kinetic transfer hydrogenation reaction of 2-methyl-2,4-diaryl-2,3-dihydrobenzo[ )][l,4]diazepines, using chiral phosphoric acids as organocatalysts and Hantzsch ester as the hydride source. ° A 3,3 -H8-BINOL-derived phosphoric acid was identified as the optimal chiral catalyst for this process, affording the corresponding 1,3-diamine derivatives with moderate diastereoselectivities of up to 78% de, and enan-tioselectivities of up to 94% ee, as shown in Scheme 2.107. 

It worth to mention that despite the importance of the Kabachnik-Fields reaction, stereoselective versions for the synthesis of enantioenriched a-aminophosphonates are scarce [212, 213], and only few enantioselective examples have been published to date (for reviews on enantioselective catalytic direct hydrophosphonylations of imines, see Refs. [162a-c]). Organocatalytic examples use well-known chiral binol-derived phosphoric acid organocatalysts (Fig. 12.6,80 and 81) [214], and regarding metal catalysis, chiral scandium(III)-A,A -dioxide and... 

Finally, a BINOL-derived phosphoric acid was demonstrated by Rueping and Antonchick to be an efficient organocatalyst to promote the asymmetric... 

However, in contrast to the relatively well-developed cyanation of aldimines, limited reports were related to the cyanation of ketoimines. In this context, Feng et al. have designed a novel Ai, A -dioxide catalyst derived from BINOL and prolinamide in order to be applied as organocatalyst for the asymmetric Strecker reaction of ketoimines with fairly wide substrate scope and excellent enantioselectivities of up to 99% ee (Scheme 3.34)." A low catalyst loading of 2 mol % combined with mild reaction conditions and an operational simplicity made this strategy facile to be used for the synthesis of pharmaceutically important chiral disubstituted a-amino nitriles. 

The first example of 1,3-dipolar cycloaddition of nitrones catalysed by a chiral organocatalyst was that developed by Yamamoto et al, concerning the cycloaddition with ethyl vinyl ether promoted by a chiral BINOL-derived phosphoramide. These reactions yielded the endo products as the major diastereomers with high diastereoselectivities of up to 94% de, excellent yields and high enantioselectivities of up to 93% ee, as shown in Scheme 6.14. 

This phosphoric acid derived from (i )-BINOL was also applied by Akiyama et al. as an organocatalyst to promote the highly enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes, generating the corresponding Friedel-Crafts adducts with high yields and excellent enantioselectivities of up to 94% ee for a broad range of substrates in the presence of 3-A molecular sieves (Scheme 10.2). ... 

The Biginelli synthesis shows considerable flexibility. Thus, it has been extended to other N-C-N systems like thioureas [267] or guanidines [268] in the presence of a BINOL-derived phosphoric acid as chiral organocatalyst, formation of dihydropyrimidi-nones or -thiones can be conducted enantioselectively [269]. 

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