Alkylation of ketone enolate

Scheme 1.5 gives some examples of alkylation of ketone enolates. Entries 1 and 2 involve formation of the enolates by deprotonation with LDA. In Entry 2, equilibration... 

Scheme 1.8 shows some intramolecular enolate alkylations. The reactions in Section A involve alkylation of ketone enolates. Entry 1 is a case of a-alkylation of a conjugated dienolate. In this case, the a-alkylation is also favored by ring strain effects because y-alkylation would lead to a four-membered ring. The intramolecular alkylation in Entry 2 was used in the synthesis of the terpene seychellene. 

Several examples of alkylation of ketone enolates are given in Scheme 1.7. 

Substrate-induced diastereoselection is the most common principle in alkylations of enolates derived from ketones. There are numerous successful applications reported in the literature (for extensive reviews, see refs 1, 3, and 79). The following account does not cover this extensive field with all its applications in detail, but rather presents representative examples which provide a general overview of the different synthetic methods available for alkylations of ketone enolates of various structural types, as well as demonstrating that remote asymmetric induction can be efficient and predictable. 

Baldwin, J. E. Kruse, L. I. Rules for ring closure. Stereoelectronic control in the endocyclic alkylation of ketone enolates./. Chem. Soc. Chem. Commun. 1977, 233-235. 

T. Norin, Alkylation of Ketone Enolates, in Stereoselective Synthesis (Houben-Weyl) 4th ed. 1996, (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), 1996, Vol. E 21 (Workbench Edition), 2, 697-722, Georg Thieme Verlag, Stuttgart. 

The efficiency of the palladium-catalyzed asymmetric alkylation of ketone enolates was shown by Trost and coworkers in their synthesis of hamigeran B (50), a potent antiviral agent with low cytotoxicity to host cells (equation 15). The quaternary center... 

The resulting derivatives were applied with success in the standard asymmetric allylic alkylation (up to 97 % ee) [134, 136] or in transformations involving either specific allylic substrates (2-cycloalkenyl derivatives, up to >99% ee) [135, 137], unsymmetrical substrates (monosubstituted allyl acetate, up to 83% ee) [140], or especial nucleophiles (nitroalkanes [141], iminoesters [138 a], or diketones [139, 140, 142]). Such ligands were also effective in the formation of quaternary chiral carbon through allylic substitution (eq. (6)) [138, 143], deracemiza-tion of vinyl epoxides (up to 99% ee) [144], or alkylation of ketone enolates [138 b], and deracemization of allylic derivatives [145]. 

Miscellaneous. Acylation of unprotected amino acids, desilylation of TBS-ethers, alkylation of ketone enolates with (iso)/quinolinium salts, Wolff rearrangement, bromination of active arenes with NBS, and dichloroketene formation from Zn and CI3CCOCI (for cycloaddition to alkynes) have all been promoted with ultrasound. 

Cyclic Ketones.—Baldwin has developed his rules for ring-closure reactions to explain the experimental observation that six- but not five-membered cyclic ketones can be synthesized by endocyclic intramolecular alkylation of ketone enolates (Scheme 28). ... 

Shortly after our initial report, Doyle and Jacobsen disclosed the use of prochiral tin enolates in a salen-chromium complex-catalyzed asymmetric alkylation reaction [45, 46], It is noteworthy that this reaction was the first example of an asymmetric metal-catalyzed a-alkylation of ketone enolates that utilizes a variety of alkyl halides and is not limited to allylic electrophiles. While this mechanistically interesting reaction does not proceed via a metal 7i-allyl complex, it is a rare example of a catalytic reaction that provides access to enantioenriched a-quatemary ketones. 

M. W. Rathke and A. Lindert. The alkylation of ketone enolates in the presence of triethanolamine borate. Synth. Comm., 1978, 8, 9. 

Trost and Schroeder made pioneering contributions in developing the asymmetric catalytic alkylation of ketone enolates. This methodology was applied successfully in... 

Trost BM, Schroeder GM. Palladium-catalyzed as3mimetric alkylation of ketone enolates. J. Am. Chem. Soc. 1999 121 (28) 6759-6760. 

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