Mannich Asymmetric vinylogous

The Schneider group independently reported an asymmetric vinylogous Mannich reaction (Scheme 27) [47]. Addition of silyl dienolates 73 to A-PMP-protected imines 74 was promoted by phosphoric acid (R)-3g (5 mol%, R = Mes) with mesityl substituents to afford tra i -a,p-nnsatnrated 8-amino esters 75 in high yields (66-94%) together with good enantioselectivities (80-92% ee). 

Under similar conditions, the same authors were able to control two stereogenic centers in an asymmetric vinylogous Mannich reaction. Indeed, treatment of imines derived from aryl a-ketoesters with siloxyfuran under related conditions gave functionalized y-butenolides with high diastereo- and enantioselectivities (Scheme 10.21 ).40... 

Similar BINOL-derived phosphoric acids were also found to effectively catalyze the asymmetric vinylogous Mannich reaction. Sickert and Schneider reported that various /V-PMP-protected imines react with acyclic silyl dieno-lates in the presence of the Brpnsted acid catalyst 137 to afford the desired 5-amino a,p-unsaturated carboxylic esters (139) in good yields (83-94%) with complete regi-oselectivity and high enantioselectivities (80-92% ee) (Scheme 11.29) [96], Remarkably, the one-pot three-component process (i.e., imine is formed in situ) is comparable... 

SCHEME 11.51 Asymmetric total synthesis of (-)-anabasine and (-)-coniine employing an asymmetric vinylogous Mannich reaction as key step. 

Based on the Br0nsted add-catalyzed asymmetric vinylogous Mannich reaction, the lab of Schneider developed a highly flexible approach to access a variety of naturally and nonnaturally occurring indolizidine alkaloids, in general, in 11 steps in overall yields exceeding 36% (Scheme 11.52)... 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Intramolecular [ 2 + 2] photoadditions often proceed very efficiently with good stereochemical and regiochemical control. The vinylogous amide (96) is converted in this way into the adduct (97) with a high level of asymmetric induction retro-Mannich fragmentation of this adduct affords the imine (98), a useful intermediate in a synthesis of vindorosine. Intramolecular [ 2 + 2] photoadditions have also been observed in the N -( -alkenyl)-pyrimidines (99) and afford the diazatricyclodiones (100) as the sole photoproducts. 

The Mannich reaction and its variants have been reviewed, mainly focussing on asymmetric catalysis thereof. Catalytic, enantioselective, vinylogous Mannich reactions have also been reviewed, covering both direct and silyl dienolate methods. Another review surveys Mannich-type reactions of nitrones, oximes, and hydrazones. A pyrrolidine-thiourea-tertiary amine catalyses asymmetric Mannich reaction of N-Boc-imines (e.g. Ph-Ch=N-Boc) with ethyl-4-chloro-3-oxobutanoate to give highly functionalized product (16). Addition of triethylamine leads to one-pot intramolecular cyclization to give an 0-ethyl tetronic acid derivative (17). ... 

Zhang, Q., Hui, Y, Zhou, X., Lin, L., Liu, X., Feng, X. (2010). Highly efficient asymmetric three-component vinylogous Mannich reaction catalyzed by a chiral scandium(III)-lV,lV -dioxide complex. Advanced Synthesis Catalysis, 352, 976-980. 

As shown in Fig. 8, the Ni2-lb complex was applicable to broad range of catalytic asymmetric reactions under simple proton transfer conditions [19-30]. As donors in direct Mannich-type reactions, not only a-nitroacetates, but also malonates, p-keto esters [22], p-keto phosphonates [23], and a-ketoaniUdes [24] gave excellent enantioselectivity and diastereoselectivity. It is noteworthy that the Ni2-lb complex also promoted vinylogous direct catalytic asymmetric Mannich-type reaction of an a,p-unsaturated y-butyrolactam, giving synthetically versatile functionalized a,p-unsaturated y-butyrolactam in 99% ee [25]. Because the Ni2-lb... 

SCHEME 11.29 Vinylogous asymmetric Mannich reaction catalyzed by chiral phosphoric acids. 

SCHEME 11.30 Vinylogous asymmetric Mannich reaction between y-substituted silyl dienolates and imines. 

An asymmetric version of the vinylogous Mannich reaction has also been implemented in the total synthesis of various alkaloids. For example, Schneider and coworkers combined A-p-methoxyphenylnicotinimine 230 and the acyclic silyl dienolate 229 in the presence of 3mol% of a chiral... 

---