Homoenolate equivalent

Stereoselectivity of chiral homoenolate equivalents in reactions of heterocycles 99S365. 

Scheme 12.9 Generation of homoenolate equivalents from a-hydroxyenones...

Allyltitanium complexes derived from a chiral acetal have been reacted with carbonyl compounds and imines [63], While the chiral induction proved to be low with carbonyl compounds, high induction was observed with imines. This complex represents the first chiral homoenolate equivalent that reacts efficiently with imines. Finally, the reactions with electrophiles other than carbonyl compounds and imines, namely a proton source, NCS, and I2, furnished the corresponding alkene, chloro, and iodo derivatives in good yields [64]. 

An alternative formation of titanated alkoxyallenes could be achieved by reaction of 3-alkoxy-2-propyn-l-yl carbonates 78 with (r/2-propene)titanium diisopropoxylate (79). Successive addition of 80 to benzaldehyde afforded the corresponding addition products 81 in high yield (Scheme 8.22) [70]. The results demonstrate that titanium species 75 and 80 can serve as easily available ester homoenolate equivalents. Notably, conversion of lithiated alkoxyallenes to the magnesium species by treatment with MgBr2 followed by addition to chiral carbonyl compounds resulted in a mixture of a- and y-products [71]. 

No other synthetic method Is known that achieves the equivalent transformation. Rather elaborate procedures using an allylic anion type of the homoenolate "equivalents" or homoenolate radicals have been reported, but their tolerance to the structure of the enone acceptor is much narrower. 

Aminoallyl carbanions, obtained by deprotonation of enamines or allylamines, are well-known homoenolate equivalents, since electrophilic attack occurs, in most cases, highly regiose-lectively to give the 3-substituted enamines, hydrolysis of which leads to the corresponding carbonyl compounds15 24,25. 

Nonetheless, homoenolates have been much talked about as a species useful for carbon-carbon chain extension, and a number of "homoenolate equivalents have been prepared and used for organic synthesis. Reviews on these species have been published [6]. 

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. 

Tetr 36 2531 (1980) (carbonyl homologation and masked homoenolate equivalents)... 

Alternatively, the ambident oi-hetero substituted allyl anions have been utilized as homoenolate equivalents. For example, in the presence of HMPA, allyl phenyl sulfides (251),192 allyl phenyl sulfones (252)192b c and allyl phenyl selenides (253)192d e add to a,(3-enones in a l,4(0)-mode, while allyl phenyl sulfoxides (254) and allyl phosphine oxides (255) afford 1 A j-addition exclusively, irrespective of solvent used.193 Hua has shown that additions of either chiral sulfoxide (254 R1 = R2 = R3 = R4 = H, R5 = p-tolyl) or allyl oxazaphospholidine oxide (256) occur with excellent enantioselectivity (>95% ee).194 Similarly, Ahlbrecht reports that the a-azaallyl (257) adds exclusively in a 1 A j-mode to acceptor (59) to afford 1,5-diketones (Scheme 86).195... 

A CH-group, which bears vinyl and sulfide substituents, is acidic enough to be metallated by strong bases. Other d3-synthons may contain two activating functional groups in Imposition ( homoenolate -equivalents). Only one of the a-carbons is deprotonated under appropiate conditions (e.g. succinic diesters). Ano ther possibility is an acidic carbon and a non-acidic functional group in 1,3-positions (e.g. propargyl derivatives). Silyl ethers of a, -unsaturated alcohols can also be converted to anions, which react as d3-synthons (W. Oppolzer, 1976). 

Whisler, M. C. Beak, P. Synthetic applications of lithiated N-Boc allylic amines as asymmetric homoenolate equivalents./. Org. Chem. 2003, 68, 1207-1215. 

Martin, S. F. DuPriest, M. T. Reactions of allylpyrrolidine carbanions with electrophiles. A new homoenolate equivalent. Tetrahedron Lett. 1977, 3925-3928. 

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... 

Therefore acceptor cyclopropanes 1 will be ring opened by nucleophiles N to provide products like 2 (homo Michael addition) as depicted in Eq. 1. On the other hand, electrophiles E+ cleave donor activated cyclopropanes 3 affording adducts 4 or 5 which demonstrates that the cyclopropane serves as a homoenolate equivalent in this sequence (Eq. 2). Seebach consequently classified these methods as umpolung with the cyclopropane trick 4. ... 

Their reactivity should reflect charge distribution as shown in the mesomeric formula 8. This intuitive view is supported by MNDO calculations8). It is therefore to be expected that nucleophiles and/or electrophiles add to 7 affording products with the general structure 9 or derivatives thereof. Thus 7 should combine the features of a homo Michael system and those of a homoenolate equivalent. 

From the reactions shown in Scheme 93, we can conclude that telluride 159 behaves as a homoenolate equivalent 160a (Figure 6). 

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>. 

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