Electrophilic Ketones

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The combination of thionation by Lawesson s reagent [98] of oxoenamino-ketones 96 with normal electron-demand Diels-Alder reaction of conjugated aldehydes allows a variety of thiopyrans 97 to be synthesized by a regio-selective and chemoselective one-pot methodology [99] (Equation 2.28). Thionation occurred at the more electrophilic ketonic carbonyl group. O O... 

Removing the substituted hydrazine (58) leaves acetoacetic ester (57). Phenylhydrazine is available, so it is easier to make (59) and methylate afterwards. This removes the chemoselectivity problem as the more nucleophilic NH group attacks the more electrophilic ketone. 

Other ketones besides acetone can be used for in situ generation of dioxi-ranes by reaction with peroxysulfate or another suitable peroxide. More electrophilic ketones give more reactive dioxiranes. 3-Methyl-3-trifluoromethyldioxirane is a more reactive analog of DMDO.99 This reagent, which is generated in situ from 1,1,1-trifluoroacetone, can oxidize less reactive compounds such as methyl cinnamate. 

Dondoni pioneered the use of 2-(trimethylsilyl)thiazole (71) as a formyl anion equivalent for the homologation of aldehydes. Extension of this reaction to ketones would be very useful, but has thus far been restricted to tritluoromethyl cases. However, it has now been widened to include several a, a -alkoxy ketones, as demonstrated in a new route to branched-chain monosaccharides. Aldehydes catalyse the reaction, although the scope is still limited electrophilic aldehydes, such as 2-fluorobenzaldehyde, promote the addition of (71) to electrophilic ketones. 

High levels of iyn-diastereoselectivity have been achieved on reaction of lithiated chiral phosphine oxides [apparently existing as rapidly equilibrating diastereomeric lithiated species such as RCH(Me)CHLiP=0(Ph)2] with electrophilic ketones, esters or MesSiCl. ... 

In an attempt to move away from the hydroxamic acid zinc binding group, which is known to causes poor pharmacokinetics as a result of hydrolysis or glucuronidation, the group at Abbott searched for alternative zinc chelators culminating in the development of a series of electrophilic ketone HDACis (Figure 9.12) [64—66]. Subsequently, a group at IRBM developed a related series of thiophene trifluor-omethyl ketones and showed these to be selective class II HDACis [12]. 

In the metal-free epoxidation of enones and enoates, practically useful yields and enantioselectivity have been achieved by using catalysts based on chiral electrophilic ketones, peptides, and chiral phase-transfer agents. (E)-configured acyclic enones are comparatively easy substrates that can be converted to enantiomeri-cally highly enriched epoxides by all three methods. Currently, chiral ketones/ dioxiranes constitute the only catalyst system that enables asymmetric and metal-free epoxidation of (E)-enoates. There seems to be no metal-free method for efficient asymmetric epoxidation of achiral (Z)-enones. Exocyclic (E)-enones have been epoxidized with excellent ee using either phase-transfer catalysis or polyamino acids. In contrast, generation of enantiopure epoxides from normal endocyclic... 

How does an electrophilic ketone react with water ... 

Protecting groups have been mentioned occasionally in previous chapters in this chapter the ideas behind their use are systematically presented and a collection of protecting groups suitable for a range of functional groups is tabulated. Protection allows us to overcome simple problems of chemoselectivity. It is easy to reduce the keto-ester I to the alcohol 2 with a nucleophilic reagent such as NaBHU that attacks only the more electrophilic ketone. 

Since sclerotiorin, a member of the azaphilone family, was found to inhibit CETP activity, the effect of azaphilones on CETP activity was tested. A structure-specific CETP inhibition by azaphilones was shown. Electrophilic ketone(s) and/or enone(s) at both the C-6 and C-8 positions of the isochromane-like ring are neces-... 

The deprotonation step, either by the sensitizer radical anion or by some adventitious base, is essential for the formation of any amine derived products. This step can be prevented if the a-hydrogens are arranged in a plane orthogonal to the singly occupied nitrogen n-orbital a requirement which is met for the radical cation of l,4-diazabicyclo[2.2.2]octane (DABCO). The low oxidation potential, due to the interaction of the pair of transannular nitrogens, makes this an excellent electron transfer quencher. Yet, no product formation is observed as a result of these interactions, with the possible exception of the zwitterionic adducts formed with highly electrophilic ketones [193]. 

For instance, the preparation of isoxazole 4.17 is virtually regiospecific because the reaction commences with the more nucleophilic heteroatom (i.e. nitrogen) attacking the more electrophilic ketone (activated by the electron-withdrawing inductive effect of the adjacent ester group). The reader is encouraged to consider the regiochemical bias in the preparation of isoxazole 4.15 and pyrazole 4.16. 

As you would expect, simply adding phenylmagnesium bromide to ethyl acetoacetate leads mainly to addition to the more electrophilic ketone. 

The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making it no longer reactive towards nucleophilic addition. The Grignard then adds to the ester, and finally a deprotection step, acid-catalysed hydrolysis of the acetal, gives us back the ketone. An acetal is an ideal choice here—acetals are stable to base (the conditions of the reaction we want to do), but are readily cleaved in acid. 

The third molecule of acetyl CoA also functions as a nucleophilic enol and attacks the keto group of acetoacetyl CoA. This is not a Claisen ester condensation—it is an aldol reaction between the enol of a thiol ester and an electrophilic ketone. 

The mechanistic proposal for the formation of these p-laclonc products is related to that for the formation of y-lactones (Scheme 17). Initial formation of the conjugate enamine Ila is followed by a proton transfer from oxygen to carbon thereby forming the enolate V. In an aldol-type reaction this enolate attacks the electrophilic ketone providing zwitte-rions VI. The subsequent cyclization to the lac tone 18 then liberates the NHC catalyst. 

If the amine does not act as a base, it must act as a nucleophile. After addition to the electrophilic ketone to give a hemiaminal, OH leaves, and an iminium ion is obtained. The iminium ion, the key intermediate, cannot be formed from a 3° amine. 

Angelastro, M. R., Baugh, L. E., Bey, P., et al. (1994) Inhibition of human neutrophil elastase with peptidyl electrophilic ketones. 2. Orally active PG-Val-Pro-Val pentafluoroethyl ketones. J. Med. Chem., 37, 4538 1553. 

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