Proline organo catalysts

Under the reaction conditions used in the one-pot Mannich reaction described above, L-proline (S)-27 was clearly found to be the preferred organocatalyst. As is apparent from Scheme 5.14, the best yield (90%) and enantioselectivity (93% ee) were obtained by use of this organocatalyst [23]. The suitability of all other organo-catalysts used in this one-pot reaction, using 3-methylbutanal as aldehyde, was poor. Remarkably lower yields and poor enantioselectivity were obtained when the thiazolidine catalyst (S)-31 and other pyrrolidine-based organocatalysts were used. 

Amino acids and peptides (including proline derivatives) as asymmetric organo-catalysts 02T2481. 

Two representative organocatalytic reaction systems can be considered for nucleophilic a-substitution of carbonyl compounds, the issue of this chapter. One involves the in situ formation of a chiral enamine through covalent bond between organo-catalyst (mainly a chiral secondary amine such as proline) and substrate (mainly an aldehyde), followed by asymmetric formation of new bond between the a-carbon of carbonyl compound and electrophile. Detachment of organocatalyst provides optically active a-substituted carbonyl compound, and the free organocatalyst then participates in another catalytic cycle (Figure 6.1a) [2]. 

Table 27.1 Direct aldol reaction of cyclohexanone and aromatic aldehydes in the presence of proline-substituted organo-catalysts(Clx-Pr-l-4, Ph-Pr-1 and -2)... 

Notably, proline was unique for this transformation, as all the other chiral secondary amines tested failed to promote the reaction. Another well-estabhshed organo-catalyst (4), invented by MacMillan [27], and unable to form secondary interactions with electrophiles like proUne, was used in the addition of aldehydes to indolyl and other carbocations derived from alcohols. The formation of stable carbenium ions from alcohols and their compatibility with water, generated by the organocatalytic cycle (formation of enamines from the corresponding carbonyl derivatives), was estabUshed by Cozzi in a SnI nucleophilic substitution of alcohols in the presence of water [28]. The enamine formed in situ by the MacMUlan catalyst approaches the carbocation from the less hindered side and the hindrance of the incipient carboca-tion controls the stereoselectivity of the reaction (Scheme 26.2) [29]. 

Very recently, Zhu and Cheng reported an organocatalytic Michael-type addition of phosphorus ylides 93 to a,(i-unsaturated ketones 94 using a chiral dual organo-catalyst system composed of 9-amino-(9-deoxy)-epi-quinine with Boc-L-proline (Scheme 43.20) [31]. The Michael-type/Wittig reactions proceeded smoothly to provide chiral a-methylene-6-ketoesters 95 with good to excellent enantioselectivi-ties (up to 95% ee). 

Knudsen KR, Mitchell GET, Ley SV. Asymmetric organo-catalytic conjugate addition of malonates to enones using a proline tetrazole catalyst. Chem. Commun. 2006 1 66-68. 

In addition to the many intermolecular asymmetric (organo)catalytic aldol reactions, analogous intramolecular syntheses are also possible. In this connection it is worthy of note that the first example of an asymmetric catalytic aldol reaction was an intramolecular reaction using an organic molecule, L-proline, as chiral catalyst. This reaction - which will be discussed in more detail below - is the so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction [97-101], which was discovered as early as the beginning of the 1970s. 

Notwithstanding the progress in other reaction types, the main thrust in organo-catalysis research centers is on enantioselective catalysis applications [109,110], of which amine-based asymmetric catalysts form the majority [111]. Most of the reactions proceed via the enamine catalytic cycle (Figure 3.38a) or via imonium intermediates. The most common (and most successful) catalysts for such reactions are proline derivatives. Thanks to its secondary amine functionality and relatively high pKa value, proline (pyrrolidine-2-carboxylic acid) is a good... 

Methyl-4-hydroxy-2-pentanone (diacetone alcohol) could be used as nucleophile instead of acetone (3a) [15], giving the expected aldol products 4 (R =H) with lower enantioselectivities (48-86% ee). A tandem organo- and biocatalytic process has been designed [16], with the aim of improving the achieved enantioselectivities for the a-hydroxy ketones 4 (R =H), using Pseudomonas cepacia lipase (Amano 1) as catalyst for the kinetic resolution of the mixture of aldol adducts obtained after the proline-catalyzed reaction. 

Hayashi and co-workers applied the asymmetric direct aldol reaction for the synthesis of chiral building block 75 for (+)-cytotrienin A 76," which is a microbial antitumor secondary metabolite. The diol 75 was synthesized with high enantioselectivity by means of the organo-catalytic aldol reaction of furfural 55 and propanal 39 in the presence of a catalytic amount of 4-acyloxy proline 74 (Scheme 27.13). The original procedure, i.e., with proline as a catalyst, was not effective for large-scale synthesis of 75 because of low yield and low diastereoselec-tivity. Total synthesis of (+)-cytotrienin A 76 was achieved in another 32 steps from diol 75. 

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