Enolates by conjugate addition

An alternative method of generating enolates by conjugate addition has been applied to aza Baylis-Hiltman reactions with low enantiocontrol (up to 44% ee) [96]. 

Fleming has generated enolates by conjugate addition of lithium bis(phenyldimethylsilyl)cuprate to a,p-unsaturated esters. The intermediate (Z)-enolates undergo stereoselective aldol addition, providing adducts having three contiguous stereocenters one example of this process is seen in equation (20). - ... 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

Wender and Dreyer have demonstrate that meta-areiw photocycloaddition chemistry can lead expediently to modhephene A( tate 7S>5, a photoproduct derived from indane and vinyl acetate was converted to tetracyclic ketone 797 (Scheme XCVI). Because the enolate of 797 partakes of the dynamic behavior of semibuUvalenes, it proved possible to trimethylate the substance to produce 798. A fourth methyl group was introduced by conjugate addition and the carbonyl was simultaneously converted to an olefinic center. Selective hydrogenation of799 provided modhephene in seven steps. 

If thioamide enolates are prepared by conjugate addition of Grignard reagents to a,/3-unsaturated thioamides of secondary amines, the reaction of these enolates with aldehydes affords anti aldols. These results are rationalized by the formation of a boat-like, chelate transition state" Representative examples are provided in equation 112 and Table 16. 

The use of aldehyde enolates for conjugate additions is precluded by competing polymerization and al-dolization processes however, introduction of the OfeCHO moiety is accomplished with aldehyde enolate equivalents. For example, dianions of nitroethanes, e.g. 3-phenylnitroethane (165) or methyl 3-nitropropionate (166), add exclusively in the 1,4-mode to ot,3- nones.,36a-b Similarly, the dianion of 4-nitro-1-butene (167) adds in a 1,4-mode exclusively unlike typical dienolates (Section 1.2.2.2.2) which react at the ot-position, this dianion is formally equivalent to the crotonaldehyde >-enolate (Scheme 64).l36c... 

Enol carbonates. Site-specific metal enolates, such as those generated by conjugate addition of cuprates to a./i-enones, can be trapped as the enol carbonates by a quench with methyl chloroformate. Unlike silyl enolates, enol carbonates are only weakly nucleophilic. Thus they are stable to ozone, peracids, and Wittig-like... 

The only new thing in this chapter is the combination of these two reagents so that a C-C bond is made by conjugate addition of an enolate to the enone 5 giving an enolate 6 of the product that gives the 1,5-diketone 1 on protonation. 

When the enones 1 were treated with the ai-haloalkanols 2 and base, the deformylated cfv-prod-ucts rac-3 were obtained exclusively13. Clearly this reaction is initiated by conjugate addition of the O-nucleophile. The diastereoselective step, however, is the subsequent intramolecular displacement of halide by the intermediate enolate anion. 

The formation of carbon-carbon bonds by conjugate addition of carbonucleophiles to a,/3-unsaturated systems has been studied intensively and reviewed over the past few years . Interestingly, applications with simple, unstabilized lithium enolates are relatively rare. Most reported examples are limited to the addition of stabilized enolates, such as those derived from malonates or acetoacetates. Nevertheless, some diastereo- and enantioselective versions of the conjugate addition, even with unstabilized lithium enolates, are well known. In 2004, Tomioka and coworkers studied the influence of a chiral diether (191) on the 1,4-addition of lithium ester enolates (189) to a,-unsaturated ketones (equation 51) . Their investigations showed that good enantioselectivities were obtained with cyclic enones, like 2-cyclopentenone (190) addition to a mixture of 189 and 191 gave the desired 1,4-adduct (R)-192 with 74% ee, but only 47% yield. Unfortunately, also the Peterson product 193 was formed in a yield of 22% by initial 1,2-addition of the enolate to the Michael acceptor. 

Thus, enones that exist preferentially as s-trans conformers will give rise to ( )-enolates, whereas conjugate addition of hydride to s-cis enones will lead to (Z)-enolates. These can be trapped by trimethylsilyl chloride (TMS-Cl) to give the corresponding silyl enol ethers (Scheme 32). "... 

Ketones 2 and 3 have two different a positions so there is a good chance that we can control eno-a formation directly from the ketone. Ketone 1 is different and enolate formation can he contraS j only by conjugate addition. The second enolate is thermodynamic and the third kinetic - poss-ilf methods are shown. 

Several problems in this chapter ask you to suggest ways to make molecules by conjugate additions of enols or enolates. We give one possible answer and sometimes comment on alternatives, but you should realize that there are many possible right answers to this sort of question. Make sure you have understood the principles behind each question and, if your answer is different from ours, check it with someone who knows. 

Suggest two different approaches to these compounds by conjugate addition of an enol(aT Which do you prefer ... 

One of the most important uses of DABCO is in the Baylis-Hillman reaction, discovered in 1972 by two chemists at the Celanese Corporation in New York. Their reaction is a modification of the aldol reaction (Chapter 27), except that, instead of the enolate being formed by deprotonation, it is formed by conjugate addition. You have seen the enolate products of conjugate addition being trapped by alkylating agents in Chapter 26, but in the Baylis-Hillman reaction, the electrophile is an aldehyde and is present right from the start of the reaction, which is done just by... 

Sammes and cowoikers devised a promising solution to the synthesis of substituted P-silyl sulfones, which has been exploited in a new approach to the antibiotic bicyclomycin (Scheme 44). In their approach the P-silyl sulfone (125) was prepared by conjugate addition of the lithium enolate of the mono-imino ether derivative (123) of a dioxopiperazine to the unsaturated P-silyl sulfone (124). After oxidative cyclization to the bicyclic system (126), the latent alkene functionality was unleashed in 89% yield on treatment with TBAF in THF at room temperature to give the basic skeleton of bicyclomycin. 

Patterson and Fried found that the clean lithium enolate (14), generated by conjugate addition of the lithium divinylcuprate (15) to cyclopentenone with subsequent trapping of the initial enolate with TMS-Cl and cleavage of the TMS enol ether with lithium amide in liquid ammonia-THF, could be alkylated in a reasonable yield with the (Z)-allylic iodide (16) to give the 11-deoxyprostaglandin derivative (17 ... 

A series of 16a-alkyl-17a -methylpregnan-20-ones has been prepared by conjugate addition of various Grignard reagents on to the 16-en-20-one system, followed by immediate in situ alkylation of the A -enolate with methyl iodide. Byproducts formed along with the 16a, I7a-dimethyl derivative include the 16a-methyl and 16a,21-dimethyl compounds. 21-Methylated corticosteroids have been obtained by base-catalysed methylation of the 17,21-acetonide (182). Acidic hydrolysis of the methylated acetonide (183) gave the product (184). 21-Trifluoroacetyl (185) and 2 -nitroethyl (186) derivatives were prepared similarly, as well as several other compounds with extended side-chains. ... 

Selenenyl halides also react similarly with copper enolates, aluminum enolates, and zirconium enolates [101]. Scheme 15.38 illustrates the selenenylation of copper enolates generated by conjugate addition of lithium diphenylcuprate to cyclo-pentenone [100 d]. 

Specific enolates by conjugate (Michael) addition An intermediate in Corey s ginkgolide synthesis A synthesis of jasmine ketolactone Tables of Enol Equivalents and Specific Enolates Modern Use of Specific Enolate Equivalents... 

---