Enamines proline-derived

Ketone donors bearing a-heteroatoms are particularly useful donors for the enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can be accessed in remarkably high enantioselectivities using either proline or proline-derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also described a syn selective variant with dihydroxyacetone donors [201], and the Barbas group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn selective reactions with both protected and unprotected dihydroxyacetone [202]. 

The Stork reaction between methylvinyl ketone and enamine (130) derived from (S)-proline derivatives (131) is of particular interest since chiral cyclohexenones can be obtained. These are useful in many natural product syntheses. Optical yields of 20-50% have been reported 147>. 

When (2S)-1-(1-cyclohexene-l-yl)-2-(methoxymethyl)pyrrolidine (206), enamine from cyclohexanone, and (S)-proline-derived (2S)-(methoxymethyl)pyrrolidine is added to the Knoevenagel condensation products (207), mainly one of the possible four diastereomers is formed. The diastereomeric purity was found to be excellent (d.s. > 90%) 203). The stereochemical course of this highly effective asymmetric synthesis allowed the synthesis of the optically active target molecules (208). A possible mechanism discussed by Blarer and Seebach 203). 

Asymmetric allylation.n The chiral enamine 1, derived from the allyl ester of (S)-proline, when treated with this Pd(0) complex at 25° in various solvents provides (S)-( — )-2-allylcyclohexanone (2) in 80-100% ee, the highest enantio-selectivity being observed in CHC13. 

Early investigations have demonstrated that aldehydes and ketones can be enantioselectiveiy a-alkyl-ated via Michael reactions of the corresponding enamines, prepared from proline-derived secondary amines.149-156 However, optical purities of the products were generally low and never exceeded 59% ee.iS1 This kind of asymmetric a-alkylation could later be improved, allowing for example the preparation of compound (141) with high ee (Scheme 51).156-160... 

In 2008 Resmini et al. [76] presented their work on the synthesis of novel molecularly imprinted nanogels with Aldolase type I activity in the cross-aldol reaction between 4-nitrobenzaldehyde and acetone. A polymerisable proline derivative was used as the functional monomer to mimic the enamine-based mechanism of aldolase type I enzymes. A 1,3-diketone template, used to create the cavity, was... 

A range of proline derivatives have been employed as enamine-based organocatalysts of direct aldols in water, without organic co-solvent.111 Using the reaction of cyclohexanone with benzaldehydes as a test bed, lipophilic diamine (40) in the presence of TFA proved to be an excellent bifunctional catalyst system, giving performance up to 99/90/99% in terms of conversion/r/c/ee. Alkyl chains of (40) make an organic microphase likely. 

Notwithstanding the progress in other reaction types, the main thrust in organo-catalysis research centers is on enantioselective catalysis applications [109,110], of which amine-based asymmetric catalysts form the majority [111]. Most of the reactions proceed via the enamine catalytic cycle (Figure 3.38a) or via imonium intermediates. The most common (and most successful) catalysts for such reactions are proline derivatives. Thanks to its secondary amine functionality and relatively high pKa value, proline (pyrrolidine-2-carboxylic acid) is a good... 

Of the several studies made of enolates derived from such a-aminoke-tones,37 the most interesting one from the point of view of this work came from Holladay and co-workers who studied alkylation reactions of pyrrolidine enamine 40 derived from protected 4-keto-L-proline 41 with allyl bromide (Scheme 10).38 A 44% yield of two diastereoisomers of allylated material 42 was obtained with a quoted isomer ratio of trans cis of 2 1. 

Prior to the work of Holladay and co-workers,38 there was good literature precedent for 4-keto-L-proline derivatives 39 giving the required 3,4-dehydro isomer of the enamine rather than the 4,5-dehydro isomer in a report by Friary and co-workers.46 It was found that the protected 4-keto-L-proline derivative 49 gave enamine 50 on treatment with morpholine in the presence of molecular sieves (Scheme 17). 

Repeating the enamine formation conditions of Holladay and coworkers38 using 4-keto-L-proline derivative 47 and pyrrolidine (1.2 equiv) in the presence of activated 5-A molecular sieves at room temperature gave essentially quantitative conversion to required enamine 51 after a reaction time of 16 h (Scheme 18). Analytical data were consistent... 

Proline derivatives, such as (2S,4R)-4-hydroxyproline (2), (2S,4R)-4-tert-butoxy-proline, (2S,3S)-3-hydroxyproline [71b] and tetrazole-containing pyrrolidine 9 [75] also catalyzed the Mannich-type reactions using aldehydes as nucleophiles via enamine intermediates, and afforded the syn-isomer as the major diaster-eomer with high enantioselectivity at room temperature. On the other hand,... 

More recently, Tardella and co-workers disclosed the use of this reagent in the synthesis of Af-(ethoxycarbonyl)-a-amino ketones from enamines and nitrene 18 [12b]. Their attempts to obtain asymmetric induction started with the use of proline-derived optically active enamines of cyclohexanone. Slow addition of sulfonyl-oxycarbamate 6e (1 equiv.) to a stirred solution of the enamine 19 and triethylamine (1 equiv.) in dichloromethane at room temperature, followed by work-up with petroleum ether and silica gel chromatographic purification afforded the aminated product 20 in low yield and good enantiomeric excess [12c] (Scheme 8). 

Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral enamines52-54. For example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%52. 

ENAMINE-BASED ORGANOCATALYTIC CROSS-ALDOL REACTIONS USING PROLINE DERIVATIVES... 

Analogous additions were later reported by Ito and co-workers (Scheme 9) (20). The enamines for these additions were prepared from the corresponding aminals using a mild base in the presence of trimethylsilyl chloride. In turn, the aminals used are available from (— )-ephedrine and (S)-prolinol. The byproduct amine hydrochloride was removed either by distillation or by precipitation from a benzene solution. Enamines prepared by this method were found to be unreactive toward unsaturated carbonyl compounds in a variety of solvents. Importantly, it was found that use of a mild Lewis acid such as anhydrous MgCl2 or ZnCl2 in THF promoted the reactions. Thus, the addition of enamines 9.1 and 9.2 to methyl acrylate is achieved. Of the two enamines, the proline-derived 9.1 is the more effective auxiliary. The... 

Addition of Proline-Derived Enamines of Phenylpropionaldehyde to Methyl Vinyl... 

Proline derivatives form enamine intermediates to activate the HOMO of a nucleophile. In contrast, iminium salts are generated with MacMillan s catalyst to activate the LUMO of an electrophile. The formation of the enamine intermediate from proline is reminiscent of the general catalysis of class 1 aldolase in enzymatic catalysis [21]. 

An alternative catalyst design consists of the introduction of bulky groups at the pyrrolidine ring, which would exert their stereochemical influence via steric shielding of one of the diastereotopic faces of the enamine intermediate. In this context, a wide variety of different proline derivatives have been employed in this transformation, including prolinol silyl ether homoprolinol silyl... 

Planarization in the pyrrolidine enamines increases p-character in the lone pair and renders nitrogen a stronger donor. Enamines derived from imidazolidinones are 10 -1(P times less reactive than those based on the proline-derived Hayashi-Jprgensen catalyst. ... 

From shape to stereoselectivity The difference between syn and anti conformations of proline-derived enamine of acetaldehyde is only O.lkcahmol (B3LYP-PCM/6-311++G(3df,2p)//B3LYP-PCM/6-31G(d,p) level. Figure 6.123). ° Not only are the two conformers essentially isoenergetic but the barrier for their inter-conversion (9.5 kcal/mol) is much lower than it is in amides. Henee, the lower energy of n jt resonance in enamines means that both conformers readily intercovert at the ambient conditions and both can participate in reactions with electrophiles. 

Figure 6.123 The syn-conformations of proline-derived enamine of acetaldehyde is only 0.1 kcal/mol more stable than the anti conformations.

Figure 6.125 Role of substituents in selectivity of reactions of proline-derived enamines.

In 1969 Yamada and Otani reported an stereoselective stoichiometric synthesis of 4,4-disubstituted 2-cyclohexenones through an asymmetric Robinson annula-tion between preformed chiral aldehyde L-proline-derived enamines 20 and methyl vinyl ketone (Scheme 2.12) [33]. Surprisingly, only few examples of organocatalyzed Michael additions of aldehydes to enones have been reported since then. 

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