Enolates of a,p-Unsaturated Carbonyl Compounds

Adapted from Sasidharan and Kumar (257). Reaction conditions catalyst, 150 mg methyl trimethylsilyl dimethylketene acetal (silyl enol ether), 10 mmol a,(3-unsaturated carbonyl compounds, 10 mmol dry THF, 10 mmol reaction temperature, 333 K reaction time, 14 h. Structures of a, p-unsaturated carbonyl compounds (2a-2g) and products (3a-3g) are shown in Scheme 24. 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

Conjugate addition of enolate to a, p-unsaturated carbonyl compounds... 

The stable, well-characterized copper(I) hydride cluster [(PPh3)CuH]6 is a useful reagent for conjugate reduction of a,p-unsaturated carbonyl compounds. o This hydride donor is chemically compatible with chlorotrimethylsilane, allowing formation of silyl enol ethers via a reductive silation process (Scheme 53). 

This chapter is based on the total synthesis of cylindramide (1), developed by Laschat and coworkers, comprising a novel method for the synthesis of a,p-unsaturated carbonyl compounds from the corresponding silyl enol ethers. 

This chapter concentrates on a novel type of IBX oxidation of silyl enol ethers 8 for the synthesis of a,P-unsaturated carbonyl compounds 9. 

Ito, Y., Hirao, T., Saegusa, T. Synthesis of a,P-unsaturated carbonyl compounds by palladium(ll)-catalyzed dehydrosilylation of silyl enol ethers. J. Org. Chem. 1978, 43, 1011-1013. 

In 1974,Mukaiyama and co-workers reported the first examples of Lewis acid-catalyzed Michael reactions between silyl enolates and a,p-unsaturated carbonyl compounds [33]. Evans and co-workers developed a catalytic asymmetric Michael reaction of silyl enol ethers of thiol esters to alkylidene malonates. For example, the reaction of alkylidene malonate 23 with 2.2 equiv of silyl enol ether 22 was carried out in the presence of 10 mol % of catalyst 25 and 2 equiv of hexa-fluoro-2-propanol (HFIP) in PhMe/CH2Cl2 (3 1) at -78 °C to give the expected adduct 24 in 93% ee (Scheme 5) [34]. Borane complex-catalyzed asymmetric Michael addition has also been reported [35]. 

Enolate anions with extended conjugation can be formed by proton abstraction of a,p-unsaturated carbonyl compounds (1.9). Kinetically controlled alkylation of the delocalized anion takes place at the a-carbon atom to give the p,7-unsaturated compound directly. A similar course is followed in the kinetically controlled protonation of such anions. 

The Michael addition reaction involves the conjugate addition of enolates to a,p-unsaturated carbonyl compounds. The reaction can be catalysed either by activation of the nucleophile or activation of the Michael acceptor. In some cases,... 

Hetero Diels-Alder cycloaddition of a,p-unsaturated carbonyl compounds and dioxygenated alkenes in the presence of a chiral bisoxazoline-Cu(OTf)2 complex as Lewis add catalyst furnished hexopyranose precursors in good yields and high enantomeric excess. In the synthesis of the precursor 6 of ethyl tetra-0-acetyl-P-D-mannopyranose outlined in Scheme 1, for example, a 69% overall yield and 99% ee were achieved. A new route to hex-2-uloses involving boron-or, preferably, lithium-enolates is exemplified in Scheme 2. Only 3,4-trans-... 

Conjugate reduction of a, 3-unsaturated carbonyl compounds and subsequent carbon-carbon bond formation provides a versatile domino process of carbocyde and heterocyle synthesis [20]. These reactions proceed by the formation of enolate 49 through conjugate reduction of a,P-unsaturated carbonyl compound 48 with a reducing agent (M-H) followed by trapping of the enolate with an electrophile 50 to give 51 (Scheme 9.11). 

To minimize the risk of accessory reactions during silylation of a,p-unsaturated carbonyl compounds and, hence, the uncertainty in the structures of derivatives, some original recommendations have been proposed. One of them implies the use of mixed reagent MSTFA + I2, that provides silylation of carbonyl enols accomplished by entering of A-containing fragment from TMS-carrier in the a-position of carbonyl compound in the result of nucleophilic substitution (it is recommended just for steroidal 3-ketones with C=C double bond in the position 4). However, this proposition remains discussible at first in respect of the yield of the derivatization and regioselectivity of the reaction. 

Problem 9.28. It has recently been pointed out (Yasuda, M. Chiba, K. Ohigashi, N. Katoh, Y. Baba, A. J. Am. Chem. Soc., 2003,125,7291) that of the four possible reaction patterns between enolates and a,P-unsaturated carbonyl compounds, as shown below, only the last ( Type D below) is rare. Why should Type D be disfavored relative to the other three ... 

Dang L, Lin Z, Marder TB. DFT studies on the borylation of a,P-unsaturated carbonyl compounds catalyzed by phosphine copper(I) boryl complexes and observations on the interconversions between O- and C-bound enolates of Cu, B, and Si. Organometallics. 2008 27 4443-4454. 

FIGURE 17.70 Addition of enols/enolates to a,p-unsaturated carbonyl compounds and related... 

So far in this section we have combined enolate anions with other carbonyl compounds by direct attack at the carbonyl group. We can expand the scope of this reaction by using a,p-unsaturated carbonyl compounds as the electrophiles. This is the Michael reaction. Remind yourself of tliis by writing out the mechanism of a Michael reaction such as ... 

Ordinarily nucleophilic addition to the carbon-carbon double bond of an alkene is very rare It occurs with a p unsaturated carbonyl compounds because the carbanion that results IS an enolate which is more stable than a simple alkyl anion... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

The key features of the catalytic cycle are trapping of the radical generated after cycliza-tion by an a,P-unsaturated carbonyl compound, reduction of the enol radical to give an enolate, and subsequent protonation of the titanocene alkoxide and enolate. The diaster-eoselectivity observed is essentially the same as that achieved in the simple cyclization reaction. An important point is that the tandem reactions can be carried out with alkynes as radical acceptors. The trapping of the formed vinyl radical with unsaturated carbonyl compounds occurs with very high stereoselectivity, as shown in Scheme 12.21. 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

The general usefulness of the developed methodology can be verified also in different areas. Thus chemoselec-tive reactions could be also carried out with p-unsubsti-tuted a-phenylthio substituted a, p-unsaturated carbonyl compounds and enol ethers as outlined in Scheme 6 (21). Naturally occuring 2,3,6-trideoxy and 4-amino-2,3,4,6-tetradeoxy sugars are obtained quite readily from this methodology. 

The inverse type hetero-Diels-Alder reaction of functionally substituted a, p-unsaturated carbonyl compounds was also possible with -alkyl substituted enol ethers (Scheme 9) (25). This was demonstrated in the synthesis... 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

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