Amides asymmetric aldol reactions

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

The conjugate addition of (K)-N-methyl-N-a-methylbenzyl amide 33 to tert-butyl cinnamate 34, followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination afforded the -substituted homochiral Baylis-Hillman product 39 in good yield (Scheme 7) [37]. This chemistry requires the use of stoichiometric rather than catalytic amounts of the chiral base. 

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

Asymmetric Aldol Reactions. Lithium enolates, derived from an ester, and LDA react with aldehydes enantioselectively in the presence of the chiral amide 2 (eq 3). When benzaldehyde is employed, the major diastereomer is the anrt-aldol with 94% ee, while the minor yn-aldol is only 43% ee. In this reaction, the lithium amide 2 coordinates to an additional lithium atom. There are four additional examples of aldehydes with the same ester enolate. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

The same group further developed the asymmetric aldol reaction of A -methoxy-A -methyl-a-isocyanoacetamide (a-isocyano Weinreb amide) with aldehydes (Sch. 25). The reaction of the Weinreb amide 96 with acetaldehyde in the presence of 86c Au(I) catalyst gives the optically active tram-oxazoline 98 (E = CON(Me)OMe R = Me) with high diastereo- and enantioselectivities similar to those of 95 [49], The oxazoline can be transformed into A,0-protected /3-hydroxy-a-amino aldehydes or ketones. 

Both syntheses made the bond between the two alkenes by a Stille coupling. One put the tin on the amide part by a Cu(I) catalysed conjugate addition of Bu3SnLi to the acetylenic ester 212 and Weinreb amide formation. Coupling this vinyl stannane with a single enantiomer of the iodide derived from the rest of the molecule gave crocacin C in good yield. The synthesis of the iodide uses an asymmetric aldol reaction and is described in the workbook.30... 

The development of the asymmetric aldol reaction [2] has been dominated by the stereo-controlled addition of chiral, amide-derived enolates to, mainly, aldehydes. This constitutes an excellent method for the first step of many NARC processes. The pamamycins [3] and the nactins [4] are two groups of naturally-occurring ionophores. They contain tetrahydrofuran sub-units which have proved to be suitable targets for the application of the NARC process. 

Ferrocenyldiphosphines 3.41 (R = Me2NCH2CH2) are used as ligands in gold-catalyzed asymmetric aldol reactions of a-isocyanoesters or -amides [408, 752, 858, 950], Silver complexes can also be used with the modified phosphine 3.41 (R = (CH2)5 or (CH g) [951, 952]. 

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. 

Chiral amides (222) and (223) and imides (224) and (225) have also been studied as reagents for asymmetric aldol reactions. These reagents show excellent diastereofacial preferences as their boron and zirconium enolates, but generally show poor selectivity as their lithium enolates. The reader is referred to other chapters in this volume for a discussion of these and related reagents. 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

Ellman and coworkers have shown that chiral sulfinate 14 can catalyse asymmetric aldol reactions of acetone, whereas proline itself gave poor results. However, more active and selective catalysts are prolinamides with general structure 16 containing two or more stereocentres in the molecule, and based on ot-alkylbenzylamines ISa," chiral (3-amino alcohols (16b-d, 16e-f, axially chiral amino hydroxyl-2,2 -binaphtyl amide 16i, ... 

The group of Moutevelis-Minakakis reported in 2014 the preparation and application of a series of tripeptides containing proline, phenylalanine and tert-butyl esters of different amino acids (see 36, Scheme 13.22c) for the asymmetric aldol reaction of aromatic aldehydes and various substituted ketones in both aqueous and organic medium. The authors assume in the proposed transition-state model, besides the well-known enamine activation, a stabilisation of the aldehyde via hydrogen-bond interactions of the two amide protons of the tripeptide with the carbonyl group of the aldehyde. The desired adducts were isolated in good to excellent yields and with very good diastereoselectivities and enantioselectivities. ... 

Asymmetric aldol reactions mediated by zirconium enolates with chiral auxiliary were reported (Equations 1 and 2). The zirconium enolate derived firom pseudoephedrine-based amide (1) and Cp2ZrCl2 was treated with a series of aldehydes to afford the corresponding aldol adducts (2) in high yields with excellent diastereoselectivity [2]. The high syn selectivity was explained by dinu-dear cyclic intermediates. In contrast, the aldol reactions with norephedrine-based ester (3) proceed with highly anti-selective manner (Equation 2) [3]. In both cases, 2 equivalent of Cp2ZrCl2 were necessary to achieve such high stereoselectivity. 

Prolinamide derivatives were found to be highly compatible with IL media. Asymmetric aldol reactions catalyzed by proline amide 18 [42], bis-amide 19 [43], or suUbnylated amide 20 [44] could be efficiently carried out in molten salts [bmim]... 

In 1999, Shibasaki et al. reported on the direct catalytic asymmetric aldol reaction (Scheme 8.36), which was not necessary to preconvert the ketone moiety into the more reactive species such as an enolate ion and enol ether." The addition of bulky aldehyde 248 into the mixture of ethyl methyl ketone 249 and LaLi3tris(/ -binaphthoxide) [(/ )-LLB)] afforded aldol adduct 250 in excellent stereoselectivity. However, this reaction required a large amount of ketones (50 equiv), and catalyst (20 mol%) were required. They improved the conditions to reduce the amount of ketone (5 equiv) and catalyst (8 equiv) by using the hetero-polymetallic asymmetric catalyst (Scheme 8.37). The addition of the catalytic amount of potassium bis(trimethylsilyl) amide (KHMDS) and H2O was found to be effective to the catalysis. Adduct 253 was converted into ester 254 by the... 

One of the most attractive options for asymmetric aldol reactions available to the synthetic chemist is to use enolates of carboxylic acid derivatives (inter alia ester, amide, or imide) with an appended chiral auxiliary (alcohol, amine, urethane). An early example of this approach dates back to 1938, when McKenzie reported that benzaldehyde undergoes addition by (-)-menthyl malonate (42) to give propanoic acid derivative 43 in 21 % ee (Equation 4) [43]. The modest selectivity was attributed to the conformational flexibility of ester enolates (cf. 44). 

Sawamura M, Nakayama Y, Kato T, Ito Y (1995) Gold(I)-catalyzed asymmetric aldol reaction of JV-methoxy-JV-meihyl-alpha-isocyanoacetamide (alpha-isocyano Weinreb amide)—an efBcient synthesis of optically-active beta-hydroxy-alpha-amino aldehydes and ketones. J Org Chem 60 1727-1732... 

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