Aldehydes preparation, directed aldol reaction

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

Following this exciting discovery Wittig, and subsequently others, then explored the scope and limitations of this process, and the development of a highly useful directed aldol reaction evolved for the preparation of a,3-unsaturated aldehydes (13 Scheme 3) some representative results are collected in... 

In 2013, the Rahman group studied the application of various polar tripeptides for the direct aldol reaction of substituted aromatic aldehydes and aliphatic ketones in an aqueous medium. In the course of their investigations histidine-containing peptide 35 showed the best results for the aldol reactions due to stabilising hydrogen bonding of the side chains of the peptide catalyst (Scheme 13.22b). This catalytic system could be further extended to aldoketoreductase-based mimetic octapeptides for the preparation of chiral p-hydro)yketones in excellent yield and diastereoselectivity and good enantioselectivity. ... 

In anticipation of the final carbon-carbon bond construction that is required to prepare the intact seco acid of erythronolide B using a directed aldol reaction to form the C(10)-C(l 1) bond, it was first necessary to prepare the requisite chiral aldehyde 80. Although the synthesis of 80 had been previously reported, we elected to devise an alternative route to access this material that commenced with the addition of the chiral boron enolate 37 0 to propionaldehyde to furnish 81 (Scheme 12). The sequential protection of the secondary hydroxyl group and removal of the chiral auxiliary gave 82, which was then converted to 80 by over-reduction followed by reoxidation under Swem conditions. 

The role of stoichiometric amount of zinc compounds in the aldol reaction was studied 30 years ago (107). The first study of asymmetric zinc-catalyzed aldol reaction was carried out by Mukaiyama and co-workers the chiral zinc catalyst was prepared from diethylzinc and chiral sulfonamides and was effective in the reaction of ketene silyl ethers with aldehydes (108). Among the subsequent studies on zinc-catalyzed aldol reactions, Trost s group gave important contribution to zinc/prophenol ligand complexes (109,110). The chiral dinuclear zinc catalyst promotes the direct aldol reaction of ketones, including a-hydroxyketones, and aldehydes with excellent enantioselectivity (Scheme 17). It is proposed that one zinc metal coordinated different substrates to form zinc enolate, and another zinc metal center provided the bridge between the interaction of donor and acceptor. 

In the same group, calcium, or barium, also played an acceptable catalytic activity in a certain aldol reaction. Early in 1998, Yamada and Shibasaki (145) have first found a chiral barium catalyst promoted a direct aldol reaction of aldehydes and unmodified ketones efficiently with good conversions (77-99% yield) and enantioselectivities (50-70% ee) (Scheme 30). The barium catalyst was prepared from Ba(0-fPr)2 and 2.5 equiv of ligand 96 (i2)-2-hydroxy-2 -methoxy-l,l -binaphthyl(BINOL-Me) in dimethyl ether, and the sideproduct of f-PrOH was removed by evaporation. 

Surprisingly, there was only one example of asymmetric calcium-catalyzed aldol reaction so far. In 2001, Noyori and Shibasaki (149) developed a chiral hy-drobenzoin/Ca complex for an asymmetric cataljdic direct aldol reaction of acetophenone and aliphatic aldehydes, in which the Ca catalyst system prepared from Ca[N Si(CH3)3 2](thf)2, (S,S)-hydrobenzoin 106, and KSCN (1 3 1 mol... 

Lanthanoid triisopropoxides are active catalysts for aldol reactions of aldehydes (209). In addition, it is useful reagent for the preparation of Ln-based heter-obimetallic catalysts, such as LLB 160. Shibasaki and co-workers contributed an important progress in the Ln-based heterobimetallic catalysts promoted organic transformations, including the aldol reactions (210-212). For example, early in 1997, they reported the (i )-LLB catalyzed direct aldol reaction with good enantioselectivities (up to 94% ee) and yields (up to 90%) for the direct aldol reaction of ketones to aldehydes (Scheme 55) (213). 

Based on the hypothesis that the generation of a boron enolate intermediate would be possible through the cooperative intramolecular interaction between a basic and a boronate function, Whiting and co-workers (239) prepared a series of bifunctional aminoboronate systems and examined the catalytic activities in a direct aldol reaction of aldehydes and hydroxyacetone. Of the several analogues for the aminoboronate catalyst examined, an ate complex 169, the... 

Later on, a fluorous organocatalyst 27 with a perfluorooctyl propanoxyl group on the aromatic ring was prepared from i-tyrosine by the same group (Scheme 7.26) [41]. It efficiently catalyzed the direct aldol reaction of aromatic aldehydes with cyclohexanone. In accordance with previous results, catalyst 27 showed higher efficiency than its non-fluorinated analog which is probably because the fluorous tag created a hydrophobic reaction field in brine. The catalyst 27 was easily recovered with FSG extraction and reused without further purification. 

As practiced in the preceding syntheses by Evans and Nishiyama and Yamamura, the A-ring fragment 43 is formed through substrate-directed vinylogous aldol reaction of the Brassard-type diene 19 and the chiral aldehyde 42, which is prepared using Brown s protocols for enantioselective allylation [53], followed by hydroxy-directed nnn-diastereoselective reduction of the C3 ketone (Me4NB(OAc)3H) [41],... 

Simple enamines cannot be deprotonated directly at the a-position due to their low acidity, but starting from a-chloroenamines 685, a-lithioenamines 686991 have been prepared by chlorine-lithium exchange using an arene-catalyzed lithiation992. The treatment of compounds 685 with an excess of lithium and a catalytic amount of 4,4 -di-tert-butylbiphenyl (DTBB) in THF at —90 °C allowed the preparation of intermediates 686, which were trapped with a variety of electrophiles (Scheme 177). For aldol reactions, the arene-catalyzed lithiation has to be performed in the presence of aldehydes (Barbier conditions) at —40 °C. These adducts were transformed into a-hydroxy ketones after acid hydrolysis with hydrochloric acid or silica gel. 

Inspired by the biosynthesis of carbohydrates we envisaged a direct de novo synthesis of carbohydrate derivatives by using the DHA-equivalent 4 in a C3+Cn-sirategy. As can be seen from the retrosynthetic analysis, the desired building blocks 5 should be prepared from the dioxanone (4) and an aldehyde component 6 in an organocatalytic aldol reaction... 

The most direct method for the preparation of polyol frameworks is without doubt the aldol reaction. The diastereofacial selectivity of the reaction can be controlled by /J-alkoxy groups in both the methylketone enolate and the aldehyde. As investigations by Evans [6] and Paterson [7] and their groups have demonstrated, the correct selection of enolization conditions and the protective group for the )8-hydroxy group are important for the stereocontrol of the reaction. 

To utilize the aldol reaction in synthesis, you must be able to determine which aldehyde or ketone is needed to prepare a particular P-hydroxy carbonyl compound or a,P-unsaturated carbonyl compound—that is, you must be able to work backwards, in tbe retrosynthetic direction. 

Trichlorotitanium enolates are directly prepared from a ketone, TiCU, and a tertiary amine [122,123] and undergo aldol reactions with aldehydes [124-129], ketones [129], and imines [130,131], Intramolecular condensation with esters is also known [132-137], Although these reactions, based on a titanium enolate [16], which often results in high diastereoselectivity in aldol and related reactions [122], will not be discussed in detail in this article, the success of the alkylation of this titanium enolate with SNl-active electrophiles should be discussed owing to the high Lewis acidity of the metal center [123], Equation (37) shows stereoselective alkylation with an orthoacetate, which is usually inert to alkali metal enolates [138], Aminoalkylation of trichlorotitanium enolates with (a-chloroalkyl)amine has been performed analogously [139,140],... 

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