Optically active products Mannich reaction

In almost the same period, Uraguchi and Terada reported the direct Mannich reaction of N-Boc-protected imines with acetyl acetone (Scheme 11.2) [5]. In their direct Mannich reaction, phosphoric acid also worked as a dual functional catalyst the Br0nsted acidic moiety of phosphoric acid catalyst Ic activated aldimines 5, and the Lewis basic site (phosphoryl oxygen) interacted with the O-H proton of the enol form of 6. As a result, the reaction proceeded under a chiral environment created by phosphoric acid 1, acetyl acetone, and aldimine through hydrogenbonding interactions to furnish optically active products 7. 

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. 

Racemization of the Mannich ba.se may be caused by intrinsic instability " of the optically active final product, or it may occur during the synthesis or the optical resolution. The former case is fiequently observed in the preparation of cyclic derivatives of natural products and concerns Mannich reactions of different types, including the tandem aza-Cope-Mannich rearrangement, which affords more or less extensively ra-cemized products starting from optically active materials. -" -" - This finding is explained on the basis of the equilibrium involved in the 3,3-reanangement leading to ketones 201 (Fig. 72), key intermediates for the synthesis of alkaloids. 

The development of enantioselective Mannich-type reactions is an important subject in synthetic organic chemistry, because fhese reactions provide optically active nitrogen-containing compounds which are very valuable in syntheses of biologically active products and their derivatives. Until recently, this subject had been solved by use of chiral auxiharies [215]. In recent years, catalytic asymmetric Mannich-type reactions using chiral Lewis acids have been studied extensively [216]. This section deals wifh chiral Lewis acid-promoted reactions. 

Optically active trifluoromethyl-substituted tetrahydroimidazo[l, 5-c] quinazoline derivatives 44 were synthesized by Zhao and coworkers via a diastereo- and enantioselective Mannich-type cyclization cascade reaction of a-aryl isocyanoacetates and trifluoromethyl-substituted cyclic ketimines, using a multihydrogen-bonding donor squaramide/AgOAc cooperative catalytic system in THF at 0°C (Scheme 30) (140L4566). The products were obtained in 76—99% yield with a diastereomeric ratio of greater than 15 1 and 58-98% enantiomeric excess. 

Instead of using Br0nsted bases, chiral Br0nsted acids can also be utilized to enanti-oselectively acquire Mannich products. The acidic catalyst assists in the Mannich reaction by protonating the imine, thereby forming an iminium ion to which the deprotonated Brpnsted acid catalyst coordinates. This chiral counterion directs the incoming nucleophile and leads to an optically active Mannich product. 

Earlier, the same authors employed the same strategy to the synthesis of optically active amine compounds from alkenes through a three-component domino hydroformylation-Mannich reaction. The combination of rhodium catalyst hydroformylation with L-proline-catalysed asymmetric Mannich reaction worked well to afford the domino product in moderate yield and good enantioselectivity of 74% ee, as shown in Scheme 7.51. 

Shibasaki et al. also developed chiral barium catalysts prepared from barium alkoxide and optically active BINOL 3 or aryloxide 4 derivatives. These catalysts were applied to asymmetric Mannich reactions of p,y-unsaturated esters (Table 27) [101]. In this reaction, the initially formed Mannich adducts isomerized to afford aza-Morita-Baylis-Hillman-type products in moderate to good yields with good enantioselectivities. For four substrate examples, ayloxide 4 ligand worked well (entries 2—4). 

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