Ketone Enantioselective Mannich

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

Kobayashi and co-workers. used zirconium-based bromo-BINOL complex for the catalytic enantioselective Mannich-type reaction. The o-hydroxyphenyl imine 3.36 chelates the Zr(IV)(BrBINOL)2 to form the activated chiral Lewis acid complex A. The ketone acetal 3.37 reacts with the Lewis acid complex A to give the complex B. The silyl group is then transferred to the 3-amino ester to form the product 3.38 and the catalyst Zr(BrBINOL)2 is regenerated, which is ready for binding with another imine molecule (Scheme 3.16). 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones and esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds. In recent years, various enantioselective Mannich reactions have been developed. Among them, catalytic enantioselective additions of silicon enolates to imines have been elaborated into one of the most powerful and efhcient asymmetric Mannich-type reactions, primarily because sihcon enolates can be prepared regio- and stereoselectively from various carbonyl compounds. ... 

Carretero and coworkers have successfully employed a copper(I)-Fesulphos complex as a Lewis acid for enantioselective Mannich-type reactions of N-sulfonyl imines [43]. A combination of [151 CuBr]2 and AgCl04 does efficiently catalyze the addition of silyl enol ethers of ketones, esters, and thioesters (150) to N-(2-thienyl)sulfonyl aldimines (Scheme 17.30). The corresponding P-amino carbonyl derivatives (152) were isolated in good yields with generally good enan-tioselectivity. 

Completely different reaction conditions for the synthesis of enantiopure quinazolines 1153 relied on Lewis acid catalysis. In particular, treatment of quinazoline 1163 with cyclopropyl acetylene and Zn(OTf)2 in the presence of chiral additive 1164 (Scheme 247) [706] was extended to enantioselective diynylation of quinazolines [707]. An example of using organocatalysis included enantioselective Mannich-type reaction of 1166 or its analogues with ketones in the presence of chiral diamine 1167 and L-dibenzoyltartaric acid (L-DBT) (Scheme 248) [708]. In the latter case, the enantioselectivity was moderate, it might be improved to >99 % by a single recrystallization of the product. 

Recently, Xu et al. describled a highly enantioselective Mannich-type three-component reaction of diazoacetophenones 315, alcohols 311, and imines 148 under the cocatalysis of Rh COAc) and phosphoric acid 5 m (Scheme 2.86). In the presence of RhjCOAc), diazoacetophenones and alcohols formed oxonium ylides to serve as the enol equivalents of a-alkoxyl aryl ketones, which then underwent Mannich-type reaction with phosphoric acid-activated imines to produce enantioenriched p-amino-a-hydroxyl ketone products 316 [119],... 

A number of chiral catalysts originally devised for aldol reactions (see Chapter 4) have also successfully been deployed in enantioselective Mannich additions. One such example is the dinuclear zinc complex 220 developed by Trost (Equation 18) [154]. The complex is generated in situ from Et2Zn and the corresponding chiral diamino triol ligand derived from prolinol. Excellent enantio- and diastereoselectivity were obtained in reactions with a-hydroxyketones such as 218. From imine 219, the syn a-hydroxy-/l-amino ketone 221 was isolated in > 99% ee and > 15 1 dr. Additional investigations revealed that appropriate choice of the N-substituent on the imine could selectively provide either the anti or the syn a-hydroxy- -amino ketones [155]. 

Addition of enantiomerically pure cnamines derived from (.Y -jmethoxymethyfipyrrolidine (SMP) and ketones (cyclohexanone, cycloheptanone, propiophenone) to AGY-dimethylmethylene-iminium tetrachloroaluminate11,42 give the corresponding Mannich bases in moderate to good yields (56 -79%) and low to moderate enantioselectivities (30-66% ce)12, l3. The (-)-isomer is the major enantiomer in each case. The absolute configuration of the major enantiomer has not been determined. The auxiliary can be recovered. 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

Later in 2007, Gong utilized If and saturated derivative 2 in a direct Mannich reaction between in situ generated N-aryl imines and cyclic ketones as well aromatic ketones (Scheme 5.3) [10], It was found that electron poor anilines as coupling partners gave the highest enantioselectivities. The authors postulate that acid promoted enolization of the ketone forms the reactive enol which adds to the protonated aldimine. 

Dixon reported that saturated BINOL 45 sufficiently activates various N-Boc aryl imines toward Mannich reaction with acetophenone-derived enamines to yield P-amrno aryl ketones in good yields and enantioselectivities (Scheme 5.62) [116]. The same group applied a BINOL-derived tetraol catalyst to the addition of meth-yleneaminopyrroHdine to N-Boc aryl imines. Interestingly, appendage of two extra diarymethanol groups to the BINOL scaffold resulted in a marked increase in enantiomeric excess [117]. 

Systematic investigations of the catalyst structure-enantioselectivity profile in the Mannich reaction [72] led to significantly simplified thiourea catalyst 76 lacking both the Schiff base unit and the chiral diaminocyclohexane backbone (figure 6.14 Scheme 6.88). Yet, catalyst 76 displayed comparable catalytic activity (99% conv.) and enantioselectivity (94% ee) to the Schiff base catalyst 48 in the asymmetric Mannich reaction of N-Boc-protected aldimines (Schemes 6.49 and 6.88) [245]. This confirmed the enantioinductive function of the amino acid-thiourea side chain unit, which also appeared responsible for high enantioselectivities obtained with catalysts 72, 73, and 74, respectively, in the cyanosilylation of ketones (Schemes 6.84 and 6.85) [240, 242]. 

After the successful asymmetric synthesis of a-substituted P-amino ketones (R)-14, we envisaged the diastereo- and enantioselective synthesis of a,P-disubstituted Mannich bases. As shown in Scheme 1.1.4, we were able to use benzaldehyde-N-phenylimine [11] as well as a-alkoxycarbonylaminosulfones [12] as Mannich electrophiles to synthesize in good overall yields and high de- and ee-values the anti-configured P-amino ketones (R,S)-15 and (R,S)-16, respectively [13]. 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

It was reported that proline catalyzed the direct catalytic asymmetric Mannich reactions of hydroxyacetone, aldehydes, and aniline derivatives [(Eq. (10)] [40-44]. Not only aromatic aldehydes but also aliphatic aldehydes worked well in this reaction, and good to excellent enantioselectivity and moderate to excellent yields were observed. Mannich reactions of glyoxylate imines with aldehydes or ketones were also successfully performed [45,46]. 

An important feature of this reaction is that in contrast to most other catalytic asymmetric Mannich reactions, a-unbranched aldehydes are efficient electrophiles in the proline-catalyzed reaction. In addition, with hydroxy acetone as a donor, the corresponding syn-l, 2-aminoalcohols are furnished with high chemo-, regio-, diastereo-, and enantioselectivities. The produced ketones 14 can be further converted to 4-substituted 2-oxazolidinones 17 and /i-aminoalcohol derivatives 18 in a straightforward manner via Baeyer-Villiger oxidation (Scheme 9.4) [5]. 

In conclusion, this new organocatalytic direct asymmetric Mannich reaction is an efficient means of obtaining optically active //-amino carbonyl compounds. It is worthy of note that besides the enantioselective process, enantio- and diastereose-lective Mannich reactions can also be performed, which makes synthesis of products bearing one or two stereogenic centers possible. Depending on the type of acceptor or donor, a broad range of products with a completely different substitution pattern can be obtained. The range of these Mannich products comprises classic / -amino ketones and esters as well as carbonyl-functionalized a-amino acids, and -after reduction-y-amino alcohols. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

Trost and coworkers recently reported that these dinuclear zinc complexes catalyze Mannich reactions with unmodified aromatic hydroxy ketones as donors with excellent enantioselectivity [18]. Mannich-type reactions between an N-para-meth-oxyphenyl (PMP)-protected a-ethyl glyoxalate and hydroxyacetophenone in the presence of a catalytic amount of catalyst 5a afford the desired N-PMP protected amino acid derivative in 76 % yield with a dr of 7 1 and 95 % ee (Eq.5). 

S)-Proline also catalyzed Mannich reactions of ketone donors in a three-component (donor ketone, 4-methoxyaniline, aryaldehyde) protocol, as shown in Table 2.16 [84b, 90, 91]. In these three component reactions, the C-C bond formation occurred at both a-positions of unsymmetrical alkyl ketones (entry 3), and the ratio of the regioisomers depended on the reactant ketones and aldehydes. When the reaction was performed using a ketone donor possessing an a-hydroxy or methoxy group, C-C bond formation occurred exclusively at the oxy-substituted a-carbon (entries 5-7) the major diastereomer was again the syn-product. The enantioselectivities of (S)-proline-catalyzed three-component... 

Enders D, Seki A (2002) Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett 2002 26-28 Enders D, Vrettou M (2006) Asymmetric synthesis of (+)-polyoxamic acid via an efficient organocatalytic Mannich reaction as the key step. Synthesis 13 2155-2158... 

List B, Lerner RA, Barbas CF 3rd (2000) Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 122 2395-2396 List B, Pojarliev P, Martin HJ (2001) Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org Lett 3 2423-2425 List B, Pojarliev P, Biller WT, Martin HJ (2002) The proline-catalyzed direct asymmetric three-component Mannich reaction scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J Am Chem Soc 124 827-833... 

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