Diastereoselection directed aldol reaction

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Marhwald reported that ligand exchange of Ti(rac-BINOLate)(Of-Bu)2 with optically active a-hydroxy acids presents an unexpected and novel approach to enantio-selective direct aldol reactions of aldehydes and ketones (Scheme 12.19). The aldol products have been isolated with a high degree of syn diastereoselectivity. High enantioselectivities have been observed when using simple optically pure a-hydroxy acids. 

Unlike most enantio- and diastereoselective direct aldol processes, the enamine-catalyzed aldol reactions are also feasible with aldehyde donors. In a milestone paper, Northrup and MacMillan reported in 2002 that aldehyde-aldehyde aldol... 

The MgX2/R3N systems offer another useful synthetic interest. Recently, Evans and coworkers have demonstrated that substoichiometric amounts of magnesium halides in the presence of an amine and chlorotrimethylsilane catalyze the direct aldol reaction of A-acyloxazolidinones and A-acylthiazolidininethiones with high diastereoselectivity (equation 59). 

Trost et al. have discovered a novel design of dinuclear zinc catalyst that can catalyze diastereoselective and enantioselective direct aldol reactions [17]. The dinuclear zinc catalysts 5a-7a are generated in situ by exposing the appropriate ligands 5-7, respectively, to 2equiv. diethylzinc in THF (Scheme 3). 

First, chemoselective (Chapter 24) conjugate addition of the silyl ketene acetal on the enone is preferred to direct aldol reaction with the aldehyde. Then an aldol reaction of the intermediate silyl enol ether on the benzaldehyde follows. The stereoselectivity results, firstly, from attack of benzalde-hyde on the less hindered face of the intermediate silyl enol ether, which sets the two side chains trans on the cyclohexanone, and, secondly, from the intrinsic diastereoselectivity of the aldol reaction (this is treated in some detail in Chapter 34). This is a summary mechanism. 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

Acetals are a versatile alternative to aldehydes and ketones which have wide applicability in the titanium-mediated aldol reaction [51], Equation (10) shows the difference between an acetal and the parent aldehyde in the diastereoselective aldol reaction [52]. In this example the latter results in better diastereoselectivity than the former. The reactivity of an aldehyde and its acetal have been compared (Eq. 11) [53]. More examples of the directed aldol reaction starting from enol derivatives of aldehydes and ketones are summarized in Table 1. 

As discussed above, all of the cinchona-based quaternary ammonium salts used as catalysts gave only poor to moderate diastereoselectivities and enantioselectivities for direct aldol reactions. Quite recently, a highly enantioselective, catalytic, direct aldol reaction was realized by adopting the enamine catalysis approach [12], in which 9-amino-epi-cinchona alkaloids are employed as aminocatalysts [13, 14]. 

Scheme 11.20 Highly diastereoselective and enantioselective direct aldol reactions.

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. ... 

The mechanism of enamine catalysis has been established the enamine is the active form of nucleophile. Other modes of activation are less developed and are limited to a certain group of donors and acceptors. Quinidine was found to catalyze the reaction of hydroxyacetone with aldehydes to yield the desired 5y -aldols with moderate diastereoselectivity and low enantioselectivity [169]. This represents the first example of a tertiary amine catalyzing the direct aldol reaction. Even (3, y-unsaturated a-keto ester 154 was successfidly coupled with protected hydroxyacetone 51 in the presence of 20 mol% of 9-amino-9-deoxy-cpi-cinchonine 155 and a small amount of TEA (Scheme 3.27). 

A methodologically similar approach was successfully utilized independently for the synthesis of the oviposition attractant pheromone of the female Culex mosquito (—)-(5/ ,6S )-6-acetoxyhexadecanolide (28), by Kotsuki et al. 45) and Li et al. 46). While the Li group carried out a direct aldol reaction between undecanal (23) and cyclopentanone (24) to obtain the desired isomer 25 in excellent enantio- and diastereoselectivity, the Kotsuki group introduced the stereogenic centers by a reaction between 24 and the dithiane 26 under solvent-free conditions (Scheme 7). 

The most versatile and the most frequently applied among the enantioselective catalytic aldol protocols is based upon the Mukaiyama s directed aldol reaction the addition of silicon enolates to aldehydes or ketones [86], in its classic version under activation of the carbonyl group by a chiral Lewis acid. More recently, base-promoted versions of the Mukaiyama reaction were elaborated and also procedures that involve a transmetallation of the silicon enolate. Over the years since the discovery of the reaction, numerous protocols for enantioselective and diastereoselective additions of silicon enolates to aldehydes or ketones under activation by chiral catalysts were elaborated [87], after the group of Mukaiyama itself had made seminal and substantial contributions [88]. 

Another proUne-based catalyst was also tested in solvent-free aldol reactions under baU-miUing conditions, for example, derivatives of l,T-binaphthyl-2,2 -diamine or proUne-based dipeptides. Nijera [62] and coworkers used a combination of (SJ-binam-bis-L-prolinamide and benzoic acid to catalyze a direct aldol reaction under solvent-free conditions using conventional magnetic stirring. In addition, comparative studies with ball milling (400 rpm) were carried out for the reaction of cyclohexanone and 4-nitrobenzaldehyde but no improvement was observed. After 1.5 h quantitative conversion and similar diastereoselectivity and enantioselectivity were obtained using these methods [62]. Moreover, a study... 

The real catalytic potential of primary amino acids was disclosed by Barbas in the asynunetric direct aldol reactions of a-hydroxyketones such as hydroxyacetone and dihydroxyacetone (DHA) catalyzed by 0-t-Bu-L-threonine 14 [15]. The reactions gave unprecedentedly 5yn-selectivity, to note that most chiral secondary amine catalysts like L-proline are anfi-selective in these reactions (Scheme 5.4). A Z-enamine was proposed to account for the iyn-diastereoselectivity and in this model the secondary enamine A-H would participate in intramolecular hydrogenbonding with OH group, contributing the Z-enamine (Scheme 5.4). Very recently. 

The catalysis of 24-TfOH conjugate not only reached much improved efficiency and stereoselectivity over L-proline in the typical direct aldol reactions of acetone, but enabled the first 5yn-diastereoselective aldol reactions of linear aliphatic ketones (Scheme 5.6) [17a],... 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

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],... 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

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