Aldehyde homoenolate equivalent

In place of a Grignard reagent, several homoenolate equivalents have also been employed. Kempt 1 7 reported the titanium-mediated addition of /V-alkylmethylacrylamide dianions to N-protected a-amino aldehydes (Scheme 8). Pyrolytic cyclization affords a 3-methylenetetrahydrofuran-2-one and the side chain of C3 is appended via conjugate addition. The resulting lactone can be converted into the 1-hydroxyethylene dipeptide by hydrolysis. The stereochemistry of the C6 atom is the same as that of the a-amino aldehyde. However, the stereoselectivities of the reactions regarding the C3 and C5 atoms are unsatisfactory. 

Kleinman and co-workers 20 synthesized a lactone precursor to the (2/ ,46, 56 )- -hydroxy-ethylene dipeptide stereoselectively in four steps using the lithium salt of ethyl propiolate as a homoenolate equivalent. As summarized in Scheme 11, addition of ethyl lithiopropiolate to a protected a-amino aldehyde affords hydroxy acetylenic esters as a mixture of dia-stereomers. Reduction of the acetylene group and subsequent lactonization gives a readily separable (4S)-lactone-enriched mixture. Direct alkylation with alkyl halide and lithium hexamethyldisilanazide yields the tram-lactone as the major stereoisomer. 

Employing a similar strategy, y-lactams could be synthesized by addition of the homoenolate equivalent to an appropriate imine (Scheme 9.20) [61]. A variety of functionalized a,/ -unsaturated aldehydes 62 and N-4-methoxybenzenesulfonyl imines 70 produced disubstituted y-lactams 71 in good yields and with a preference for the cis diastereomer. One crucial point is the reversibility of the addition of the catalyst to the imine to enable a reaction with the aldehyde. N-Aryl, N-alkyl, N-tosyl and N-phosphinoyl imines where either unreactive or inhibited any catalytic reaction due to the formation of a stable adduct with the catalyst. 

Recently, Bode et al. were able to demonstrate that the products formed after generation of the homoenolate equivalents 67 are determined by the catalytic base [64]. Strong bases such as KOt-Bu led to carbon-carbon bond-formation (y-butyrolactones), while weaker bases such as diisopropylethylamine (DIPEA) allowed for protonation of the homoenolate and the subsequent generation of activated carboxylates. The combination of triazolium catalyst 72 and DIPEA in THF as solvent required no additional additives and enabled milder reaction conditions (60 °C), accompanied by still high conversions in the formation of saturated esters out of unsaturated aldehydes (Scheme 9.21). Aliphatic and aromatic enals 62, as well as primary alcohols, secondary alcohols and phenols, are suitable substrates. a-Substituted unsaturated aldehydes did not yield the desired products 73. 

Allyl carbamates 19 are even more versatile, and the lithio derivatives 20 of allyl carbamates are the most important class of homoenolate equivalents.17 Lithiated allyl carbamates react reliably at the y-position with aldehydes and ketones but less regioselectively with alkylating and silylating agents. O-Benzyl carbamates 21 are readily deprotonated and can be quenched with electrophiles.17 20... 

Barluenga and Yus showed that reductive lithation with naphthalene was nonetheless an effective way of making functionalised organolithiums. The (3-oxygenated species such as 11 are stable below -78 °C provided the lithium is at a primary centre (above this temperature they decompose with elimination of Li20) and can be formed by reductive lithiation of the lithium alkoxide 10.22 25 The amide 12 behaves similarly,26 and protected aldehyde 14 yields homoenolate equivalent 15.27... 

The formation of the observed products can be explained by the following catalytic cycle (Scheme 8). Addition of the nucleophilic carbene leads to adduct I, followed by proton transfer to give conjugate enamine Ha. Homoenolate equivalent Ha (see also resonance structure lib) can add to the aldehyde reaction partner providing zwitterion III and after... 

The umpolung of a,p-unsaturated aldehydes promoted by /V-heterocyclic carbenes generating a homoenolate equivalent is the key procedure in a synthesis of 3-alkylcoumarins from salicylaldehydes carried out in ionic liquids (Scheme 31) <07EJO943>. 

Trimethylsiloxy cyanohydrins (9) derived from an a,3-unsaturatied aldehyde form ambident anions (9a) on deprotonation. The latter can react with electrophiles at the a-position as an acyl anion equivalent (at -78 C) or at the -y-position as a homoenolate equivalent (at 0 C). The lithium salt of (9) reacts exclusively at the a-position with aldehydes and ketones. The initial kinetic product (10) formed at -78 C undergoes an intramolecular 1,4-silyl rearrangement at higher temperature to give (11). Thus the initial kinetic product is trapped and only products resulting from a-attack are observed (see Scheme 11). The a-hydroxyenones (12), -y-lactones (13) and a-trimethylsiloxyenones (11) formed are useful precursors to cyclopentenones and the overall reaction sequence constitutes a three-carbon annelation procedure. 

The most sophisticated homoenolate equivalents, and the first to allow some control over stereochemistry, are the lithium derivatives 160 of allyl carbamates 159 introduced by Hoppe.1 They are particularly valuable for reaction with an aldehyde or a ketone in a homoaldol reaction. 

Synthesis of Homoenolate Equivalent. The samarium iodide-induced coupling of carbonyl derivatives with methoxyal-lene provides 4-hydroxy 1-enol ethers in high yields (eq 58). An almost equimolar mixture of the two enol ethers are usually observed but acid hydrolysis leads to the aldehyde. 

The Scheidt group reported a highly diastereo- and enantioselective NHC-catalyzed reaction of a,p-unsaturated aldehydes with nitrones to afford y-amino esters. It is postulated that a rare six-membered heterocycle is generated as the initial product of the reaction, which gives the final y-amino ester product upon the addition of an alcohol. The mechanism for this reaction involves the addition of the homoenolate equivalent to the nitrone as the stereochemical-determining step, and catalyst turnover is promoted by an intramolecular acylation after the tautomerization of enol to acyl azolium (Scheme 7.60). 

The Bode group have documented an NHC-catalyzed enantioselective synthesis of ester enolate equivalents with a,p-unsaturated aldehydes as starting materials and their application in inverse electron demand Diels-Alder reactions with enones. Remarkably, the use of weak amine bases was crucial DMAP (conjugate acid = 9.2) andN-methyl morpholine (NMM, conjugate acid pAa = 7.4) gave the best results. A change in the co-catalytic amine base employed in these reactions could completely shift the reaction pathway to the hetero-Diels-Alder reaction, which proceeded via a catalytically generated enolate. An alternative pathway that occurred via a formal homoenolate equivalent was therefore excluded. It is demonstrated that electron-rich imidazolium-derived catalysts favor the homoenolate pathways, whereas tri-azolium-derived structures enhance protonation and lead to the enolate and activated carboxylates (Scheme 7.71). 

Scheldt and coworkers reported the addition of amide enolates to acylsilanes for generation of p-silylojq homoenolate equivalents 62, based on the fact that less electrophilic p-carbonyl groups disfavor the formation of cyclopropanolates 63 by internal carbanion attack (Scheme 6.30). Instead, the carbanion generated in situ can be trapped by allq l halides, aldehydes, ketones, and imines. The use of optically active amide enolates delivers p-hydroxy amides with high levels of diastereoselectivity. 

It is proposed that primarily a nucleophilic carbene 24 (cf. p. 221) is generated by deprotonation of 22, which adds to the a,f -unsaturated aldehyde to give a homoenolate equivalent 25 as umpoled R-CH=CH-CH=0 synthon. Protonation of 25 in P-position leads to the 2-substituted imidazohum ion 26 on reaction with 26, the sahcylalde-hyde is O-acylated 27), the imidazohum ion 22 is regenerated, and (base-induced) intramolecular Claisen condensation of 27 provides the coumarin (23). 

From the first reports by Glorias and Bode on the NHC-catalyzed generation of homoenolate equivalents, it was recognized that conjugate additions of these species to unsaturated carbonyls could lead to cyclopentanones (Scheme 14.16). This was first achieved by Nair, who made the surprising finding that imi-dazolium-catalyzed additions of a,p-unsaturated aldehydes to chalcones led to... 

The choice of imidazolium vs. triazolium pre-catalyst is subtler. Triazolium-derived NHCs are nearly always preferred, with the exception of certain processes proceeding via catalytically generated homoenolate equivalents. For example, the y-lactone forming annulations of a,p-unsaturated aldehydes and aromatic aldehydes give extremely poor conversion with triazolium-derived pre-catalysts but proceed in excellent yield with IMes-HCl 19. When more reactive electrophiles, such as a-trifluoromethylketone or saccharine-derived imines, ° are employed, other catalyst classes including N-mesityl substituted triazoliums and thiazoliums again become viable pre-catalysts. This can be attributed to the increased electron donating... 

A-heterocyclic carbenes (NHC) are also efficient organocatalytic tools for generating homoenolate equivalents from a,P-unsaturated aldehydes. These reactive intermediates display a versatile reactivity in a number of catalytic transformations attesting to an important synthetic potential [38]. Recently, Scheldt et al. [39a] accomplished the first enantioselective protonation of a homoenolate species generated by a chiral NHC precursor 93 in the presence of DIE A and an excess of ethanol as the achiral proton source (Scheme 3.46). The suggested mechanism involves an initial addition of NHC 93 to the enal 89 followed by a formal 1,2-proton shift resulting in the formation of the chiral homoenolate equivalent 91. A diastereose-lective P-protonation/tautomerization sequence leads to the acyl triazolinium inter-... 

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