Hantzsch esters catalysis

In 2001, we reasoned that this catalysis strategy might be applicable to the conjugate reduction of a, 3-unsaturated carbonyl compounds if a suitable hydride donor could be identified (Scheme 18). Hantzsch ester 11 seemed to be particularly promising since its reaction with preformed a, 3-unsaturated iminium ions had already been established (Makino et al. 1977 Baba et al. 1980). 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

Selected recent developments in the area of asymmetric organocatalysis in our laboratory have been briefly summarized. Enamine catalysis, Brpnsted acid catalysis, and iminium catalysis turn out to be powerful new strategies for organic synthesis. Using Hantzsch ester as the hydride source, highly enantioselective transfer hydrogenantion reactions have been developed. We have also developed an additional new con-... 

A brief discussion of some aspects of alcohol dehydrogenase will be used to illustrate the potential for catalysis. This system is chosen for illustration because it has been studied so extensively. Lessons drawn can be applied in a broader context. The 1,4-dihydropyridine (2a) is the reductant and this affords a nico-tinium ion (1) on transfer of hydride, as illustrated in equation (1). This process is mimicked in many abiotic systems by derivatives of (2 R = alkyl or benzyl), by Hantzsch esters (7), which are synthetically readily accessible, and 1,4-dihydro derivatives (8) of pyridine-3,5-dicarboxylic acid. A typical abiotic reaction is the reduction of the activated carbonyl group of an alkyl phenylglyoxylate (9), activated by a stoichiometric amount of the powerful electrophile Mg(CI04)2, by, for example, (2b equation 8). After acrimonious debate the consensus seems to be that such reactions involve a one-step mechanism (i.e. equation 5), unless the reaction partner strongly demands a radical intermediate, as in the reduction of iron(II) to iron(III). 

Ramachary and Reddy developed one of these sequences using an amino acid-catalyzed three-component reductive alkylation (TCRA) as the first reaction of their MCC. This multicomponent reaction involved an aldehyde 21, a malonate 22, and the Hantzsch ester 24 under amino acid catalysis starting with a Knoevenagel condensation, which was followed by hydrogenation of the formed olefin 23 to form... 

Fukuzumi S, Kondo Y, Tanaka T (1983c) Evidence for a single electron transfer activation in the hydride transfer from an NADH model compound to tetracyanoethylene. Chem Lett 751-754 Fushimi M, Baba N, Oda J, Inouye Y (1980) Asymmetric reduction of a-keto-esters and trifluoroacetophenone with N-anionized Hantzsch ester. Bull Inst Chem Res Kyoto Univ 58 357-365 Gase RA, Boxhoorn G, Pandit UK (1976) Metal-complex mediated catalysis of reduction of 2-benzoylpyridine by an NADH-model. 

In 2007, Ramachary et al. reported an asymmetric Knoevenagel/hydrogenation/Robinson annulation sequence to obtain Wieland-Miescher ketone 189 [88] (Scheme 2.62). The reaction of 5 equiv of aldehyde 9 with the 1,3-dicarbonyl compounds 186 (with CH acid) and Hantzsch ester 187 under proline catalysis furnished the expected cyclo-hexane-1,3-dione B in good yields. Once the solvent was removed by vacuum pump, the crude reaction mixture was diluted with DMF and treated with methyl vinyl ketone 188 in the presence of (S)-proline (1) furnishing the expected... 

Based on previous studies where the imines were reduced with Hantzsch dihydropyridines in the presence of achiral Lewis [43] or Brpnsted acid catalysts, [44] joined to the capacity of phosphoric acids to activate imines (for reviews about chiral phosphoric acid catalysis, see [45-58]), the authors proposed a reasonable catalytic cycle to explain the course of the reaction (Scheme 3) [41]. A first protonation of the ketimine with the chiral Brpnsted acid catalyst would initiate the cycle. The resulting chiral iminium ion pair A would react with the Hantzsch ester lb giving an enantiomerically enriched amine product and the protonated pyridine salt B (Scheme 3). The catalyst is finally recovered and the byproduct 11 is obtained in the last step. Later, other research groups also supported this mechanism (for mechanistic studies of this reaction, see [59-61]). 

A successful asymmetric organocatalytic based C=0 reduction with the Hantzsch ester was not reported until very recently. Terada and Toda developed a relay catalysis that combined Rh(ll) and a chiral phosphoric acid catalyst in a one-pot reaction (Scheme 32.15). In this reaction sequence, a rhodium carbene (I) forms in the first step and is followed with an intramolecular cyclization to afford carbonyl ylide intermediate II or oxidopyrylium III. These intermediates are protonated by 7 to yield the chiral ion pair between isobenzopyrylium and the conjugate base of 7 (IV). Intermediate IV is further reduced in situ by Hantzsch ester Id to produce the isochroman-4-one derivative 67, which is finally trapped with benzoyl chloride to afford the chiral product 68. Surprisingly, the reaction sequence proceeds well to give racemic product even without the addition of chiral 7, while giving rise to the desired product with high enantioselectivity in the presence of chiral Br0nsted acid 7 [38]. 

Au(l)/Br0nsted Acid System Han et al. developed an unprecedented protocol to synthesize tetrahydroquinolines 332 directly from 2-(2-propynyl)aniline derivatives 365 in one pot under relay catalysis of an achiral Au complex 368 and a chiral phosphoric acid 5j [131]. The Au -catalyzed intramolecular hydroamination of 2-(2-propynyl)aniline provided the 1,4-dihydroquinolines 366, followed by isomerization into imine-like 3,4-dihydroquinoliniums 367 with 5j. This active intermediate then underwent asymmetric transfer hydrogenation with Hantzsch ester to produce enantioenriched tetrahydroquinoUne products (Scheme 2.97). 

Very recently, Toda and Terada reported an elegant example of a cascade reaction by combining Rh catalysis and chiral phosphoric acid catalysis [60]. The reaction comprised a Rh-catalyzed yUde formation through an Rh-carbene intermediate and chiral phorphoric acid-catalyzed asymmetric reduction of a Hantzsch ester toward the newly formed oxonium (Schane 9.63), affording chiral building blocks 194 with satisfactory results. For the first time, this chemistry showed the trapping of oxonium ylide with reductants in asymmetric synthesis. 

Almost at the same time, Liu and Che published a cascade intermolecular hydroamination/asymmetric reduction sequence, which included achiral Au complex-catalyzed hydroamination of aryl amines and chiral phosphoric acid-promoted Hantzsch ester reduction to afford secondary aryl amines [70], More recently, the same group reported a tandem one-pot assembly of functionalized tetrahydroquino-lines from amino aldehyde and alkynes by combining Au and chiral phosphoric acid catalysis [71], The reaction was initiated by Au-promotedquinololine 210 generation, followed by an enantioselective HEH-incorporated transfer hydrogenation process (Scheme 9.67). 

Asymmetric hydride reduction using Hantzsch ester has recently been extensively explored in organocatalysis using iminium-based catalysts or Brpnsted acid catalysts [72a-c], As an advance to their asymmetric conterion-directed catalysis (ACDC), List and coworkers found that the combination of simple primary amino acids such as L-valine with a chiral phosphoric acid led to an effective primary aminocatalyst for asymmetric transfer hydrogenation of a,P-unsaturated ketones (Scheme 5.43) [72d]. The catalysis could be applied to a range of substrates with good yields and excellent enantioselectivity. 

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