Tandem reactions lithium enolate aldol reaction

An intramolecular tandem Michael aldol reaction was described for esters that have an enolizable aldehyde in the molecule. The lithium ester enolate generated through the Michael reaction undergoes an intramolecular aldol reaction. Thus, the reaction of unsaturated esters 153 with lithium benzylthiolate provided the expected cyclization products 156 and 157 via (w-formylenolate 154 in an excellent cis stereoselectivity (Scheme 49)no. 

A remarkable example of tandem conjugate addition-aldol reaction has been recently reported by Tomioka and coworkers. The transient lithium enolate, generated by 1,4-addition of benzyl lithium thiolate onto the corresponding a,-unsaturated ester182,595, is followed by an intramolecular aldol tandem cyclization, resulting in a five-membered... 

Bodnar, P. M., Shaw, J. T., Woerpel, K. A. Tandem Aldol-Tishchenko Reactions of Lithium Enolates A Highly Stereoselective Method for Diol and Triol Synthesis. J. Org. them. 1997, 62, 5674-5675. 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

Both these silyl enol ethers 50 and 52 could of course be hydrolysed to the saturated aldehydes, but that would be to sacrifice the useful reactivity of these intermediates in aldol and other reactions explored in chapters 2-6. A more productive development is to react the silyl enol ether with an electrophile and hence develop a synthesis from three components in two consecutive reactions.23 This approach has formed the basis of many modern syntheses as it develops the target molecule so quickly and is discussed in chapter 37 under tandem reactions . It is not necessary to trap the enolate with Me3SiCl when lithium cuprates are used with ketones as the lithium enolate is the product of 1,4-addition. You may choose the lithium enolate or the silyl enol ether, whichever is more appropriate for the next step. 

Simple stereoselective aldol reactions (chapter 3) can also be controlled by tandem conjugate addition. Addition of Me2CuLi to the simple unsaturated ketone 27 gives the lithium enolate 28. It would be very difficult to produce this enolate from the parent ketone MhiCO.Me with regio- or stereoselectivity. The cyclic transition state 29 with zinc replacing lithium then shows the way to the anti-aldol7 30. 

Other fates are possible for the enolate formed in the initial conjugate addition and an obvious possibility is an aldol reaction. With an asymmetric catalyst, the combination of three simple molecules leads to one enantiomer of one diastereoisomer of the tandem Michael-aldol product14 83. The catalyst 84 is based on a BINOL A1 complex (see chapters 25, 26). It can be drawn either as a lithium salt with an aluminium cation or, better, as a lithium aryloxide with a Lewis-acidic aluminium atom. This is better because both basic ArCT and Lewis acidity are necessary for catalysis. 

The tandem aldol reaction simply involves adding an aldehyde to the lithium enolate before work-up. Since it is a Z-enolate we can expect a syn aldol. The Z -enolate 90 is indeed formed (we are drawing the molecules in a different way to make the aldol stereochemistry clearer) and it does give a syn-aldol with the added advantage that only one of the two possible. vyn-aldols 90 predominates. The two benzylic groups can be removed, the first with CAN , ceric ammonium nitrate, Ce(IV)(NH4)2(N03)6 and the second by reduction, to give one enantiomer of 95. 

An aluminum-lithiiun catalyst, (R)-ALB, prepared from (R)-BINOL, and lithium aluminium hydride promoted the addition of malonate to 23 giving (R)-44 in 99% ee. X-ray analysis of the ALB catalyst showed an aluminum ate complex structure with li coordination to the oxygen atom. The asymmetric tandem Michael-aldol reaction of 46 was conducted with this catalyst giving a single isomer 47 containing three asymmetric centers. The aluminum enolate under-... 

An aldol-Claisen tandem sequence is illustrated by the reaction of the cinnamaldehyde (211) with the chiral acetate (212) to give (88) followed by treatment with the lithium enolate (89) to give (90 equation 46 see equation 25, Section 3.6.3.4.2). ° ... 

Conjugate Addition. Conjugate addition-aldol tandem reaction of Q , S-unsaturated esters in the presence of catalytic amount of lithium phenylthiolate proceeds stereoselectively with the formation of aleohol (after protodesilylation). The aldol reaction of the lithium enolate with aldehyde takes place from the hottom face, anti to the phenylsulfenyl group in the thermodynamic enolate conformation (eq 30). ... 

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