Silyl dienolates Mannich reactions

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). 

Scheme 27 Vinylogous Mannich reaction of silyl dienolates 2.3.5 Aza-Ene-Type Reaction...

In this review we will attempt to highlight the most important contributions toward the realization of a catalytic, enantioselective, vinylogous Mannich reaction and show the current state of the art. This chapter is organized in such a way that vinylogous Mannich reactions of preformed silyl dienolates in Mukaiyama type reactions will be discussed first followed by direct vinylogous Mannich reactions of unmodified substrates. 

Vinylogous Mukaiyama Mannich Reactions of Silyl Dienolates 159... 

The first systematic investigation toward Lewis acid catalyzed vinylogous Mukaiya ma Mannich reactions was reported by the group of Ojima in 1987 who showed that acyclic vinylketene silyl 0,0 acetals 10 reacted with imines activated by stoichio metric amounts of TiCU to furnish either 5 amino 2 alkenoates 11 or 5,6 dihydro pyridones 12 selectively in excellent yields depending upon the substitution of the silyl dienolate employed (Scheme 5.4) [5]. Although 2 methyl substituted vinylketene acetal 10a gave rise to acyclic 5 amino 2 alkenoates 11 exclusively, 3 methyl substi tuted vinylketene acetal 10b furnished 5,6 dihydropyridones 12 as the sole products. 

Vinylogous Mukaiyama Mannich Reactions of Silyl Dienolates I 165 Table 5.4 Brens ted acid catalyzed vinylogous Mannich reaction according to Akiyama et al. [10],... 

In 2008 our group reported the first example of a catalytic, enantioselective, vinylogous Mannich reaction of acyclic silyl dienolate 30 with imines (Table 5.5) [14]. 

Aromatic and heteroaromatic aldimines were effectively converted into vinylogous Mannich products 31 with complete y regioselectivity and with typically 80 90% ee. The reaction could easily be run in a three component fashion, starting directly from an aldehyde, para anisidine, and silyl dienolate 30 obviating the need to prepare the imine in a separate reaction. In contrast to most other protocols that required a salicyl imine moiety in the substrate for selectivity issues, here the amine component within the imine could just be a phenyl group or any para substituted phenyl group. 

Scheme 5.10 Enantioselective, vinylogous Mannich reaction of silyl dienolate 30 catalyzed by...

The catalytic, enantioselective, vinylogous Mannich reaction has recently emerged as a very powerful tool in organic synthesis for the assembly of highly functionalized and optically enriched 6 amino carbonyl compounds. Two distinctly different strategies have been developed. The first approach calls for the reaction of preformed silyl dienolates as latent metal dienolates that react in a chiral Lewis acid or Bronsted acid catalyzed Mukaiyama type reaction with imines. Alternatively, unmodified CH acidic substrates such as a,a dicyanoalkenes or 7 butenolides were used in vinylo gous Mannich reactions that upon deprotonation with a basic residue in the catalytic system generate chiral dienolates in situ. 

Phosphoric acids 32 and 35 have been successfully employed as chiral Bronsted acid catalysts for vinylogous Mannich reactions of acyclic silyl dienolates with imines (Table 5.5 and Scheme 5.10). Why does the exchange of a para methyl group for a tert butyl group on the 3,3 aryl groups within the BINOL backbone have such a pronounced effect on the enantioselectivity of the reaction although this position appears to be quite remote from the reaction center ... 

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). ... 

For the reaction of the 3-pyridine aldimine 16e, the first equivalent of zinc chloride is coordinated to the more nucleophilic pyridine nitrogen and thus is inactivated. Only the second equivalent activates the imine. However, the zinc chloride coordinated to the more nucleophilic pyridine nitrogen, logically exposes more nucleophilic chlorine ligands for the interaction with the silyl dienol ether 19. Therefore, in this case the nucleophile 19 is introduced from the free back side of 16e (Formula C) and furnishes selectively the Mannich base 28 with opposite stereochemistry compared to the compounds 27. 

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... 

The use of silyl dienolates in additions to iminium ions is known as the vinylogous Mannich reaction and constitutes an important expansion of this classic. Inter- and intramolecular versions of this transformation have been studied in great detail by Martin in the context of numerous total syntheses [110, 117]. As an example, silyl dienolate 128 intercepted iminium ion 127 to yield adduct 129 in 69% yield (Scheme 11.20) [118]. Subsequently, this adduct could be efficiently converted into 131 by addition to methyl vinyl ketone and intramolecular Michael reaction. Further elaborations of this key intermediate afforded the indole alkaloid (-)-ajmalicine (132). 

---