Diaminal, proline-derived

Aldol additions of various lithium enolates performed in the presence of (S.S)-l, 4-bisdimethyl-amino-2,3-dimethoxypentane or (.SVS )-1,2,3,4-tctramethoxybutane display only modest reagent-induced stereoselectivity (<20% ee)21. Significant improvement results from the use of the proline derived diamines 2,3 and 4 as additives in tin(II) mediated aldol additions of silyl enol ethers22 23. 

The proline derived diamines 2 and 4 (vide supra) are also suitable chiral additives in enantiose-lective additions of a-unsubstituted enolates. Best results are obtained with the naphthyl derivative, as demonstrated in the tin(II) triflate mediated addition of the O-silylketene thio-acetal l-toT-butylthio-l-trimethylsilyloxyethane to aldehydes which delivers 3-hydroxythio esters in optical purities of up to 95% ee and chemical yields between 50 and 90 %24... 

As an alternative, tin enolates are very useful in these additions. Usually they are prepared in situ from the amide using tin(II) trifluoromethanesulfonate and a base. They are subsequently reacted with an enone, catalyzed by a Lewis acid47-48 (see Table 3). With triinethylsilyl trifluoromethanesulfonate as a catalyst, in the presence of proline derived diamines anti-adducts are formed exclusively49 (see Section 1.5.2.4.3.1.). 

Nakajima et al. (128) found that a number of diamines functioned as moderately effective ligands for Cu(II) in the catalytic aerobic oxidation of 2-naphthols. A series of proline derivatives were evaluated with the aniline ligand 187 providing optimal selectivities. Unfortunately, 2-naphthol affords only racemic binaphthol. With an isolated catalyst, formulated as 187 Cu(OH)Cl in analogy to the known TMEDA Cu(OH)Cl (TMEDA = A,A,A,A-tetramethylethylenediamine), oxidative... 

In addition, Oriyama was the first to provide a practical protocol for the ASD of mei( -l,2-diols [179-182], Thus, employing just 0.5 mol% of (5)-proline-derived chiral diamine 56 in conjunction with benzoyl chloride as the stoichiometric acyl donor in the presence of EtjN, asymmetric benzoylation of a variety of me o-diols could be achieved with good to excellent enantioselectivities (66-96% ee) and 80% yields (Scheme 24) [179-182],... 

Scheme 23 Oriyama s proline derived diamine catalyst [178] ...

Mukaiyama et al. 200) synthesized optically active 3-substituted succinialdehyde acid esters (204) via a Michael-addition. The methyl ester of fumaraldehydic acid was converted into the corresponding aminal (203) by treatment with the (S)-proline-derived chiral diamine (99). The Michael-addition of Grignard reagent to the aminal, followed by hydrolysis produced stereoselectivily 3-substituted succinaldehydic acid ester (204) in good yield. 

A range of proline derivatives have been employed as enamine-based organocatalysts of direct aldols in water, without organic co-solvent.111 Using the reaction of cyclohexanone with benzaldehydes as a test bed, lipophilic diamine (40) in the presence of TFA proved to be an excellent bifunctional catalyst system, giving performance up to 99/90/99% in terms of conversion/r/c/ee. Alkyl chains of (40) make an organic microphase likely. 

A direct organocatalytic Michael reaction of ketones or aldehydes with /3-nitrostyrene has been reported in brine solution, using a bifunctional catalyst system proline-derived diamine (70) and TFA.203 In some cases the conversion, yield, de, and ee all exceeded 95%. Results in water were poor, mainly due to polymerization, which is catalysed by amines. It is proposed that sodium cations stabilize the anionic intermediate formed from (70) and /3-nitrostyrene, thus minimizing polymer formation. While organic co-solvent is not required, an organic-rich phase is proposed to concentrate the Michael reactants and catalysts, thus accelerating the reaction. 

Diastereoselectivity and enantioselectivity were observed to increase substantially when proline-derived diamine salts were used as organocatalysts. In particular, the pyrrolidinium salt 41-2HC1 was found to be very useful, furnishing the target molecule 38 in 70% yield with diastereoselectivity of d.r. = 95 5 and enantioselec-... 

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). 

The asymmetric conjugate addition of diethylzinc with chalcone was also catalyzed by nickel and cobalt complex (Eq. (12.31)) [71]. A catalytic process was achieved by using a combination of 17 mol% of an aminoalcohol 34 and nickel acetylacetonate in the reaction of diethylzinc and chalcone to provide the product in 90% ee [72, 73]. Proline-derived chiral diamine 35 was also effective, giving 82% ee [74]. Camphor-derived tridentate aminoalcohol 36 also catalyzes the conjugate addition reaction of diethylzinc in the presence of nickel acetylacetonate to afford the product in 83% ee [75]. Similarly, the ligand 37-cobalt acetylacetonate complex catalyzes the reaction to afford the product in 83% ee [76]. 

The Fu and Vedejs catalysts are excellent and work with a range of substrates but good kinetic resolutions can be achieved even with some very simple chiral diamines. A catalyst derived from proline 21 was used at low temperature and low loading to resolve the secondary alcohol 22 very effectively.13 The use of the proline-derived catalysts has been extended to some primary alcohols.14... 

Additional catalysts have also been proposed for the reaction of Et2Zn with aromatic aldehydes, including (proline derivative 2.13 (R = CPh2OH) [110] and a four-membered analog [646], (1S,2R)-1.61 (R = S02Tol), 2.47, and pyridine-derived aminoalcohols [110, 644, 651, 1173]. Other catalysts include sulfur derivatives of ephedra alkaloids [645, 728], the Li diamide of piperazine 2.46, diamines 1.64 (R = 2-Py) and other related 2-aminopyridines [367, 648, 649, 1174], p-Hydroxysulfoximines have also been used as catalysts in these reactions [1175], as has an oxazaborolidine derived from ephedrine [1176],... 

An extensive study on Sn(OTf)2-catalyzed asymmetric aldol reactions " using chiral diamine ligands derived from proline has been carried out. Of particular significance is that the enantioselectivity can be switched completely by slight changes of the ligand structures. 

Aldol reactions. Asymmetric aldol reactions of ketene silyl acetals with catalytic systems consisting of Sn(OTf)2, a chiral diamine, and SnO or Bu2Sn(OAc)2 are very efficient." It is interesting that slight changes in the structure of the chiral diamine ligand (derived from proline) can have opposite effects on the enantio-selectivity."... 

In close analogy, many proline derived diamines were prepared by reduction of amides of proline2,7-l3. 

A number of alternatives to oxazolines based on other diamine or amino alcohol derivatives have been proposed, and in several cases good control over planar stereoselectivity can be achievecL The earliest, published before any work on fer-rocenyloxazolines, drew on Nozaki s early studies [3,39] on stereoselective lithiation of aminomethylferrocenes, and made use of the proline-derived amino ether 45 (Scheme 13) [40]. Substitution of 44 gave 46, whose lithiation proceeded with 93 7 stereoselectivity with w-BuLi in ether at -78°C and with 99 1 stereoselectivity with s-BuIi in ether at -78°C. Reaction of 47 with ClPPh2 gave 48 the enantiomer is available by silylation, re-lithiation, phosphination and deprotection in the manner of Scheme 9. Removal of the prolinol auxihary is achieved by acetylation and hydrolysis to 49 [41]. 

Addition of Chiral Ligands. If a chiral adjuvant is used to achieve asymmetric induction, it should preferentially be inexpensive, easily removed, efficiently recovered, and capable of inducing high stereoselectivity. Of these, 1,3-oxathianes based on (-l-)-camphor or (-l-)-pulegone, and proline-derived 1,3-diamines, have been accorded the greatest attention. 

First studies in relation to the conjugate addition of ketones with alkylidene malonates were performed by Barbas group initially using L-proline [107] and proline-derived diamines such as 31 [49, 138] (Fig. 2.4) as organocatalysts, showing that acetone, cyclohexanones, and cyclopentanone could add to various aryl- and alkylidene malonates with moderate yields and enantioselectivities. Very recently. 

For reactive aldehydes, proline-derived 7V-sulfonylcarboxamides were investigated as catalysts by Ley and co-workers [45], Berkessel et al. [46], and Kokotos and co-workers [47]. Not only did amino acid derivatives promote the aldol reaction, but also chiral diamines in the presence of an acid were also found to be effective [48]. The yield and enantioselectivity were the same as for the proline-catalyzed reactions. In combination with polyoxometalate acid, a diamine could be used in 0.33 mol%, but for less reactive aldehydes the yields are still low [49]. 

Gratifyingly, several catalysts were recently found to be selective for this transformation. A proline-derived diamine/polyoxometalate system generates the araft -aldol anii-79a with high enantioselectivity and reasonable diastereoselectivity, even with a... 

Furthermore, for the generation of quaternary carbon centers, the best results were obtained using proline-derived diamine 10 in the presence of TFA [119]. The (S)-enantiomer was formed predominantly as a result of an enamine attack to the 7 e-face of an aryl aldehyde. Other diamine-derived catalysts used for this reaction worked well but required longer reaction times (Table 3.8) [120-123]. 

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