Aldehydes conjugate homoenolate

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. 

The reactions discussed above have focused on an a1 to d1 umpolung, as exemplified by the reaction of the resulting d1 nucleophile with aldehydes (benzoin condensation [9]) or with Michael acceptors (Stetter reaction [38]) [3]. In contrast, a,/ -unsaturated aldehydes can react as d3 nucleophiles by utilizing a conjugated umpolung that involves a homoenolate reactivity. 

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... 

Corey s method20 relies on metal exchange with the bromocyclopropane 69 prepared by carbene addition. The extra stabilisation of cyclopropyl anions (chapter 8) makes both this lithium derivative and the ylid 63 more easily handled. Addition to aldehydes or ketones gives mixtures of adducts 70 [it turns out that none of the stereochemistry of 69 or 70 matters] which fragment under Lewis acid catalysis to give the thioacetal 71. Careful hydrolysis releases the 3,4-enal -72, the product of a homoaldol reaction with an aldehyde homoenolate and RCHO and a difficult compound to make as the double bond moves into conjugation very easily. 

The disconnections for this homoaldol are not obvious. Just as a conjugated (a,p-unsaturatcd) enal is derived from an aldol, we can consider deriving this unconjugated (p,y-unsaturated) enal 72 from a hydroxyaldehyde. We might initially prefer FGI to 73 as the 1,3-relationship is easy to make. But 73 will dehydrate to the conjugated (a,P-unsaturated) enal. Instead we must set up a 1,4-diO relationship 74 so that we can disconnect to an aldehyde RCHO and the homoenolate 75 of propanal. 

The reaction of a mercurio ketone with NaBRt produces a radical species which can be trapped in situ by a reactive acceptor such as a vinyl ketone. - Treatment of a mixture of a mercurio ketone and an electron-deficient terminal alkene (or fumarate) in CH2Q2 with concentrated aqueous NaBH4 gives a conjugate adduct (Scheme 19). Isomerization of such a homoenolate radical, presumably via an intermediate cyclopropanoxy radical, has been observed in the reaction of a mercurio aldehyde (Scheme 20).37.38 direction of the isomerization is opposite to that observed in the reactions of anionic ho-moenolates. Such a rearrangement has been used for a ring expansion reaction. ... 

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). 

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... 

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