Diamines aldol reaction

In 1991, Kobayashi el al. prepared novel chiral S/N ligands for the tin-mediated aldol reaction of silyl enol ethers with aldehydes. As an example, the reaction of benzaldehyde afforded the expected syn aldol product as the major product with a good yield and an enantioselectivity of up to 92% ee (Scheme 10.26). Moreover, other aldehydes such as substituted benzaldehydes or aliphatic unsaturated aldehydes were converted into their corresponding aldol products with enantioselectivities of more than 90% ee. It was checked that the corresponding diamine ligands provided less active complexes for the same reactions. 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

Ligands for catalytic Mukaiyama aldol addition have primarily included bidentate chelates derived from optically active diols,26 diamines,27 amino acid derivatives,28 and tartrates.29 Enantioselective reactions induced by chiral Ti(IY) complex have proved to be one of the most powerful stereoselective transformations for synthetic chemists. The catalytic asymmetric aldol reaction introduced by Mukaiyama is discussed in Section 3.4.1. 

In the presence of a chiral promoter, the asymmetric aldol reaction of pro-chiral silyl enol ethers 71 with prochiral aldehydes will also be possible (Table 3-6). In this section, a chiral promoter, a combination of chiral diamine-coordinated tin(II) triflate and tributyl fluoride, is introduced. In fact, this is the first successful example of the asymmetric reactions between prochiral silyl enol ethers and prochiral aldehyde using a chiral ligand as promoter. 

As depicted in Scheme 3-25, the aldol reaction carried out at —78°C can give the corresponding aldol adduct 72 in 78% yield with 82% ee. The combination of chiral diamine-coordinated tin(II) triflate and tributyltin fluoride is so essential that the enantioselectivity cannot be obtained without tributyltin flu-... 

Perfect stereochemical control in the synthesis of sy -a-methyl-/ -hydroxy thioesters has been achieved by asymmetric aldol reaction between the silyl enol ether of. S -ethyl propanethioate (1-trimethylsiloxy-l-ethylthiopropene) and aldehydes using a stoichiometric amount of chiral diamine-coordinated tin(II)... 

In the synthesis of D-eryt/zro-sphingosine (78 without BOC protection), the key step is the asymmetric aldol reaction of trimethylsilylpropynal 75 with ke-tene silyl acetal 76 derived from a-benzyloxy acetate. The reaction was carried out with 20 mol% of tin(II) triflate chiral diamine and tin(II) oxide. Slow addition of substrates to the catalyst in propionitrile furnishes the desired aldol adduct 77 with high diastereo- and enantioselectivity (syn/anti = 97 3, 91% ee for syn). In the synthesis of protected phytosphingosine (80, OH and NH2 protected as OAc and NHAc, respectively), the asymmetric aldol reaction is again employed as the key step. As depicted in Scheme 3-27, the reaction between acrolein and ketene silyl aectal 76 proceeds smoothly, affording the desired product 80 with 96% diastereoselectivity [syn/anti = 98 2) and 96% ee for syn (Scheme 3-27).50... 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

Enanantioselective aldol reactions. Divalent tin enolates of aldehydes and aryl ketones generated with tin(II) triflate undergo aldol condensation with aldehydes to form aldols.2 The reaction is highly enantioselective if conducted in the presence of chiral diamines derived from (S)-proline, such as l.3... 

Other groups beside nitro can be reduced in the same step. So the diamine 19, needed for polyamine manufacture, could come from the unsaturated nitro compound 20 that would in turn come from an aldol reaction between the anion of nitromethane 1 and the aldehyde 21. This has a 1,5-diX relationship and acrylonitrile 23 is excellent at conjugate addition (chapter 21) so we can use isobutyraldehyde 24 as a starting material. 

Asymmetric aldol reactions.1 This diamine (1) when coordinated with tin(II) triflate and dibutyltin diacetate promotes highly stereoselective aldol-type reactions between silyl enol ethers and aldehydes. 

Their previous screening of catalysts for of aldol reactions and Robinson annu-lations suggested the possibility that chiral amines might also be able to catalyze the Mannich reaction [30, 31]. Thus, screening of catalysts for Mannich-type reactions between N-OMP-protected aldimines and acetone revealed that chiral diamine salt 10, L-proline 11, and 5,5-dimethylthiazolidine-4-carboxylic acid (DMTC) 12 are catalysts of Mannich-type reactions affording Mannich adducts in moderate yields with 60-88 % ee. To extend the Mannich-type reactions to aliphatic imines, the DMTC 12-catalyzed reactions are performed as one-pot three-component procedures. The o-anisidine component has to be exchanged with p-anisidine for the one-pot reactions to occur. The DMTC 12-catalyzed one-pot three-component direct asymmetric Mannich reactions provide Mannich adducts in moderate yield with 50-86 % ee. 

Table 2.7 Diamine 8-CF3C02H-catalyzed aldol reactions of a,a-disubstituted aldehyde donors to afford hydroxyaldehydes with a quaternary carbon atom [29].

For the aldol reactions of aldehyde donors using (S)-proline or diamine (S)-8-CF3C02H, the major products and the proposed most suitable transition state that explains the stereochemistries of the products are also shown in Scheme 2.12 [8, 29a]. 

Scheme 2.12 The proposed most suitable transition states of the (S)-proline-catalyzed and diamine 8-CF3C02H-catalyzed aldol reactions of aldehyde donors [29b].

Aldol reactions. In the presence of these two promoters and in combination with the chiral diamine (S)-l-methyl-2-[(piperidinyl)methyl]pyrrolidine (13, 302),... 

Mukaiyama and co-workers developed a chiral Lewis acid complex 15 consisting of tin (II) triflate and a chiral diamine. An aldol reaction of enol silyl ether 16 and octanal is promoted by 15 to give 17 in a highly diastereo-and enantioselective manner. The enantioface of the aldehyde is selectively activated by coordination with 15. This method is similar to method 3, in that an aldehyde-chiral Lewis acid complex can be regarded as a chiral electrophile. An advantage of method 4 over method 3 is the possible catalytic use of a chiral Lewis acid. In the reaction of Scheme 3.6, 20 mol% of 15 effects the aldol reaction in 76% yield with excellent selectivity.9... 

Highly enantioselective cross aldol reactions of 3-acetylthiazolidine-2-thione with aliphatic aldehydes can be effected by use of the chiral diamine 1, derived from (S)-proline, as a ligand for the tin(II) enolate (equation II). 

This protocol has been successfully applied to the reactions of carboxylic acid derivatives such as thioamides and thione esters (cqs 3 and 4). 3-Acetylthiazolidine-2-thiones are quite suitable substrates for the tin(ll) enolate mediated asymmetric aldol reaction and various optically active p-hydroxy 3-acetylthiazolidine-2-thiones are obtained by using chiral diamine 1 (eq 5). ... 

Because tin(ll) enolates of thioesters are generated upon reaction of tin(ll) thiolates with ketenes, the optically active p-hydroxy thioesters are also easily synthesized by way of the aldol reaction with aldehydes in the presence of tin(Il) trifluoromethanesulfonate and chiral diamine 1 (eq 7)7... 

The asymmetric aldol reaction of enol silyl ethers of thioesters with aldehydes is performed in high enantiomeric excess by employing a chiral promoter, tin(II) trifluoromethanesulfonate coordinated with chiral diamine 1 and tri-n-butyltin fluoride (eqs 20 and 21). Highly enantioselective aldol reactions of achiral ketene silyl acetals with achiral aldehydes are carried out by means of the same chiral promoter (eq 22). ... 

Denmark further applied this concept of chiral diamine-derived phosphoramide bases to catalytic diastereo- and enantioselective aldol reactions (Sch. 60) [103] and enantioselective ring opening of epoxides (Sch. 61) [104]. For instance, catalytic 84 effectively promotes aldol coupling of aldehydes and enoxytrichlorosilane at -78 °C with predominant formation of anti or syn aldols from ( )- or (Z)-enolates, respee-tively. 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

Diamine protonic acids have been used for catalytic asymmetric aldol reaction.Boron triflate derivatives, R2BOTf, have been used for the condensation of ketals and ketone to give (3-alkoxy ketones. 

This procedure provides a good method for the construction of l,2-a ft-aldol moieties that are less accessible by the Sharpless asymmetric dihydroxylation (see Scheme 37,0 Scheme 58, O Scheme 92,0 Sect. 11) [138] because the corresponding Z-oleflns are difficult to obtain and show reduced enantioselectivity. The first demonstration of the use of the biologically significant substrate dihydroxyacetone as a donor in organocatalyzed aldol reaction was reported by Barbas 111 and co-workers [139]. The reactions of DHA with protected glyoxal and glycer-aldehydes, in aqueous media and in the presence of enantiomerically pure diamine 24, provide access to pentuloses and hexuloses, respectively (O Scheme 19). 

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