Amino organocatalysts

The diastereoselectivities observed in aldol reactions of cyclic ketones catalysed by di- and tri-amino-organocatalysts is strongly influenced by the nature, size, and hydrogen-bond-donor ability of the Brpnsted acid additives employed. ... 

Xu LW, Shi ZH. Asymmetric synthesis with silicon-based bulky amino organocatalysts. Adv. Synth. Catal. 2010 352(2-3) 243-279. 

This bifunctionnal amino-thiourea organocatalyst led to high selectivity because it was activating both the nitrone and the malonate, in its enol form, due to the acidic hydrogen atoms of the thiourea. Thus, the amino-thiourea catalyst promoted the Michael reaction of malonates to various nitroolefins... 

Miller s biomimetic approach inspired Ishihara [234] to develop a minimal artificial acylase for the KR of mono-protected cw-l,2-diols and A-acylated 1,2-amino alcohols. Derived from (S)-histidine, Ishihara s organocatalyst contains only one stereogenic centre and incorporates a sulfonamide linkage in place of a polypeptide chain to allow the NH group to engage as an H-bond donor with the substrates (Fig. 13) [234]. 

Figure 6.44 Stereoselective organocatalysts derived from amino alcohols.

Optimized reaction conditions call for the use of Wilkinson s catalyst in conjunction with the organocatalyst 2-amino-3-picoline (60) and a Br0nsted add. Jun and coworkers have demonstrated the effectiveness of this catalyst mixture for a number of reactions induding hydroacylation and C—H bond fundionalization [25]. Whereas, in most cases, the Lewis basic pyridyl nitrogen of the cocatalyst ads to dired the insertion of rhodium into a bond of interest, in this case the opposite is true - the pyridyl nitrogen direds the attack of cocatalyst onto an organorhodium spedes (Scheme 9.11). Hydroamination of the vinylidene complex 61 by 3-amino-2-picoline gives the chelated amino-carbene complex 62, which is in equilibrium with a-bound hydrido-rhodium tautomers 63 and 64. 

Alkaloids, especially those from the Cinchona family, have proven popular as lead structures in the design of organocatalysts because they contain amino groups, which... 

When it comes to the development of an organocatalyst, the most thoroughly documented case is proline - an amino acid which can catalyze the asymmetric... 

The use of L-proline, amides derived from it, and related amino acids and small peptides as asymmetric organocatalysts for aldols - and indeed many other reactions mentioned elsewhere in this chapter - expanded hugely in 2006. A review deals with the direct aldol case.96... 

A new, metal-free protocol involving (heteroaryl)oxazoline catalysts for the enantioselective reduction of aromatic ketones (up to 94% ee) and ketimines (up to 87% ee) with trichlorosilane has been developed. The reaction is characterized by an unusual, long-ranging chiral induction.The enantiodifferentiation is presumed to be aided by aromatic interactions between the catalyst and the substrate.360 Asymmetric reduction of A-arylketimines with trichlorosilane is catalysed by A-methyl-L-amino acid-derived Lewis-basic organocatalysts with high enantioselectivity (up to 92% ee) 61... 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

The first catalytic asymmetric Strecker reaction was reported by the Upton group using the cyclic dipeptide 5 as an organocatalyst [4, 5, 15]. This diketopiperazine 5 was prepared starting from (S)-phenylalanine and (S)-a-amino-y-guanidinobutyric... 

It should be added that attempts to perform a direct Stacker reaction starting from benzaldehyde, ammonia, and hydrocyanide in the presence of the organocatalyst 5 were also made by the Lipton group [4]. The resulting amino nitrile, however, was found to be racemic [4]. 

A 3D-structure of the substrate-catalyst complex, which was supported by molecular modeling, revealed that the large group of the imine is directed away from the catalyst. This complex of the catalyst with the Z imine, and a solution structure of the organocatalyst, are shown in Figure 5.1 [12]. This explains the broad substrate tolerance which is independent of steric or electronic properties. A further important hypothesis is that addition of HCN occurs over the diaminocyclohexane framework in 10a this led to the prediction that a more bulky amino acid/amide portion should give a further improved catalyst. This conclusion led to (model-driven) optimization which resulted in the improved and highly enantioselective Strecker catalyst 10b (for preparative results with this catalyst see Scheme 5.8 and related text) [12]. 

Use of hydroxyacetone as donor in the asymmetric Mannich reaction led to the formation of optically active syn /i-amino alcohols bearing two stereogenic centers [22, 23], In the presence of 35 mol% L-proline as organocatalyst several types of syn / -amino alcohol syn-35 were successfully synthesized with enantioselectivity up to 99% ee and high diastereomeric ratio. For example, a high yield of 92%, a diaster-eomeric ratio of 20 1, and enantioselectivity >99% ee were observed by List et al. for formation of the syn yfi-amino alcohol 35a (Scheme 5.17) [23]. In addition to hydroxyacetone the methylated derivative methoxyacetone was also applied successfully in this reaction (93% yield, d.r. > 39 1, >99% ee). 

In addition to proline, other types of organocatalyst have been found to catalyze the Mannich-type reaction efficiently. The Jacobsen group developed an elegant and highly enantioselective route to N-Boc-/i-amino acid esters via nucleophilic ad-... 

The Jacobsen group have also focused on optimization of the organocatalyst, and the design of new, simpler catalysts [37], by systematic variation of each modular component of the catalyst, for example the salicylaldimine, diamine, amino acid, and amide. A new catalyst was found, a simple amino acid derivative 42 with less than half the molecular weight and fewer stereogenic centers than the thiourea catalyst 41. In the presence of this organocatalyst 42, benzaldimine was converted into the corresponding //-phenylalanine derivative (R)-40a with 100% conversion and 94% ee (Scheme 5.24) [37]. 

The asymmetric catalytic hydrophosphonylation is an attractive approach for the synthesis of optically active a-amino phosphonates [84]. The first example of this type of reaction was reported by the Shibasaki group in 1995 using heterobimetal-lie lanthanoid catalysts for the hydrophosphonylation of acyclic imines [85a]. This concept has been extended to the asymmetric synthesis of cyclic a-amino phosphonates [85b—d]. Very recently, the Jacobsen group developed the first organocatalytic asymmetric hydrophosphonylation of imines [86], In the presence of 10 mol% of thiourea-type organocatalyst 71, the reaction proceeds under formation of a-amino phosphonates 72 in high yield (up to 93%) and with enantioselectivity of up to 99% ee [86], A selected example is shown in Scheme 5.42. Di-o-nitrobenzyl phosphite 70 turned out to be the preferred nucleophile. 

A reaction mechanism was proposed in which the tertiary amino group of the alkaloid organocatalyst and the carboxylic acid group form a chiral ammonium... 

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