Enantioselective enamine-imine

In enantioselective enamine catalysis, the enamine can control the approach of the electrophile either by the steric bulk of the enamine or by directing the electrophile with an activating group. As can be readily observed with relatively unreactive electrophiles, such as aldehydes, ketones or imines, additional assistance for catalysis can be provided by suitably positioned hydrogen bond donors and/or other acids (Scheme 6) [46]. 

Recently, A(-sulfinyl L-proline amides have been used for the enantioselective reduction of a range of A(-aIkyl (i-enamino esters (Scheme 15.8) [32]. In this case, the use of water an additive is crucial for high reactivity and enantioselectivity, accelerating enamine-imine tautomerization and increasing the eletrophilicity of the imine thought protonation of the nitrogen atom. 

Synthetic highlight Diastereoselective production of rac-menthol from its aromatic precursor is achieved by site-selective isopropylation and diastereoselective hydrogenation to the all-trans racemate. Enantioselective allylic amine-enamine-imine rearrangement of an acyclic diene-allylic amine, catalyzed by an Rh(I)-(—)-BINAP complex, affords (—)-menthol the process has been scaled-up to production of 1,000 tons/year. 

Enantioselective Allylic Amine-Enamine-Imine Rearrangement... 

Next to be investigated were the members of the homologous series, namely, P-imino nitriles 133 and P-imino esters 134, existing predominantly in the conjugated enamine forms 131 and 132, which cannot be reduced with trichlorosilane (Scheme 15.27) [97d]. However, Maikov and Kocovsky found that Bronsted acids can facilitate the enamine-imine equiUbrium and provide sufficient concentration of the desired imine form, whose reduction can now be accomphshed. In the case of Sigamide 114b, acetic acid (1 equiv) was identified as an optimal additive the reduction, carried out in its presence, afforded the expected P-amino nitriles 135 and P-amino esters 136 in high yields and enantioselectivities (Table 15.12, entries 1 and 2). 

Recently, the methodology was successfully employed for the enantioselective reduction of indoles 137 into indolines 138 using catalysts 113c and 118b (Scheme 15.28) [98gj. To faciUtate the enamine/imine tautomeric equiUbrium, the required Br0nsted acid was generated by a controlled hydrolysis of excess trichlorosilane with water. 

When either or both of the reaction components has a chiral substituent, the reaction can be enantioselective (only one of the four diastereomers formed predominantly), and this has been accomplished a number of times. Enantioselective addition has also been achieved by the use of a chiral catalyst and by using optically active enamines instead of enolates. Chiral imines have also been used. ... 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

The optically active Schiff bases containing intramolecular hydrogen bonds are of major interest because of their use as ligands for complexes employed as catalysts in enantioselective reactions or model compounds in studies of enzymatic reactions. In the studies of intramolecularly hydrogen bonded Schiff bases, the NMR spectroscopy is widely used and allows detection of the presence of proton transfer equilibrium and determination of the mole fraction of tautomers [21]. Literature gives a few names of tautomers in equilibrium. The OH-tautomer has been also known as OH-, enol- or imine-form, while NH tautomer as NH-, keto-, enamine-, or proton-transferred form. More detail information concerning the application of NMR spectroscopy for investigation of proton transfer equilibrium in Schiff bases is presented in reviews.42-44... 

Early transition-metal complexes have been some of the first well-defined catalyst precursors used in the homogeneous hydrogenation of alkenes. Of the various systems developed, the biscyclopentadienyl Group IV metal complexes are probably the most effective, especially those based on Ti. The most recent development in this field has shown that enantiomerically pure ansa zirconene and titanocene derivatives are highly effective enantioselective hydrogenation catalysts for alkenes, imines, and enamines (up to 99% ee in all cases), whilst in some cases TON of up to 1000 have been achieved. 

Generally, the imine substrates are prepared from the corresponding ketone and amine and are hydrogenated as isolated (and purified) compounds. However, reductive animation where the C = N function is prepared in situ is attractive from an industrial point of view, and indeed there are some successful examples reported below [18, 19]. It is reasonably certain that most catalysts described in this chapter catalyze the addition of H2 directly to the C=N bond and not to the tautomeric enamine C = C bond, even though enamines can also be hydrogenated enantioselectively. 

Table 34.4 Selected results for the enantioselective hydrogenation of N-alkyl imines and enamines (for structures, see Fig. 34.7) Catalytic system, reaction conditions, enantioselectivity, productivity and activity.

Despite the remarkable enantioselectivities observed with the Ti-ebthi catalyst for the imine and enamine hydrogenation, we consider its technical potential rather low. The ligand is difficult to prepare, the activation of the catalyst precursor is tricky, for the moment the catalytic activity is far too low for preparative purposes, and last - but not least - its tolerance for other functional groups is low. 

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). 

In 2008, the same group employed chiral dicarboxylic acid (R)-5 (5 mol%, R = 4- Bu-2,6-Me2-CgHj) as the catalyst in the asymmetric addition of aldehyde N,N-dialkylhydrazones 81 to aromatic iV-Boc-imines 11 in the presence of 4 A molecular sieves to provide a-amino hydrazones 176, valuable precursors of a-amino ketones, in good yields with excellent enantioselectivities (35-89%, 84-99% ee) (Scheme 74) [93], Aldehyde hydrazones are known as a class of acyl anion equivalents due to their aza-enamine structure. Their application in the field of asymmetric catalysis has been limited to the use of formaldehyde hydrazones (Scheme 30). Remarkably, the dicarboxylic acid-catalyzed method applied not only to formaldehyde hydrazone 81a (R = H) but also allowed for the use of various aryl-aldehyde hydrazones 81b (R = Ar) under shghtly modified conditions. Prior to this... 

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]. 

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-... 

The Zr-catalyzed asymmetric alkylation shown in Eq. (2) [8] illustrates two important principles (1) The catalytic asymmetric protocol can be readily applied to the synthesis of non-aryl imines to generate homochiral amines that cannot be prepared by any of the alternative imine or enamine hydrogenation protocols. (2) The catalytic amine synthesis involves a three-component process that includes the in situ formation of the imine substrate, followed by its asymmetric alkylation. This strategy can also be readily applied to the preparation of arylamines. The three-component enantioselective amine synthesis suggests that such a procedure maybe used to synthesize libraries of homochiral amines in a highly efficient and convenient fashion. 

Enantioselective exocyclic, endocyclic, and acyclic a-p-tolylsulfinyl ketimines have been reacted with Et2AlCN 45 The cyclic substrates exhibit good yield and diastere-oselectivity, but the acyclic cases are complicated by imine-enamine equilibria. 

In order to form the anti-products enantioselectively, the reaction face of either the enamine or the imine must be opposite that utilized in the proline-catalyzed reactions. In the reactions catalyzed by 13 (Scheme 2.15b), the methyl group at 5-position of the pyrrolidine ring acts to fix the conformation of the enamine and the acid functionality at the 3-position controls the enamine and imine face selection in the transition state (Scheme 2.15b). In order to avoid steric interactions between the substituent at the 5-position of this catalyst and the imine in the transition state, catalyst 13 has a trans configuration for substituents at the... 

Fig. 2.3 Catalysts for the Mannich-type reactions of aldehydes and glyoxylate imines that use m-s/tu-gene rated enamine intermediates and that selectively afford (a) syn-products or (b) ont/ -products with high enantioselectivities.

---