Aldol alkyl ketone donors

Alkyl-alkyl ketones are particularly challenging in enamine-catalysis due to reactivity and regioselectivity issues. These ketones are bad donors in the direct aldol reaction because the equihbrium constants for their formation are low (Scheme 3.9)... 

In the general context of donor/acceptor formulation, the carbonyl derivatives (especially ketones) are utilized as electron acceptors in a wide variety of reactions such as additions with Grignard reagents, alkyl metals, enolates (aldol condensation), hydroxide (Cannizzaro reaction), alkoxides (Meerwein-Pondorff-Verley reduction), thiolates, phenolates, etc. reduction to alcohols with lithium aluminum hydride, sodium borohydride, trialkyltin hydrides, etc. and cyloadditions with electron-rich olefins (Paterno-Buchi reaction), acetylenes, and dienes.46... 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

A popular and useful application of the conjugate addition reaction is the combined conjugate addition-intramolecular aldol strategy, commonly known as the Robinson annulation. When the Michael donor is a ketone and the Michael acceptor an a,p-unsaturated ketone, the product is a 1,5-diketone which can readily undergo cyclization to a six-membered ring. Typical Michael donor substrates are 2-substituted cyclohexanones, which condense with alkyl vinyl ketones to give the intermediate conjugate addition products 42 (1.52). The subsequent intramolecular... 

The asymmetric Michael addition of nonstabilised ketone enolates has proved difficult, with most success achieved using 1,3-dicarbonyls as donors. However, Shibasaki and coworkers have achieved high ees in the addition of a-hydroxyketones with both aromatic Michael acceptors such as (11.32) and also cyclic enones and alkyl vinyl ketones, using bifiinctional zinc catalysts prepared from linked BINOL (11.33). These catalysts are also effective in the asymmetric aldol reaction (see Section 7.1) and incorporate two zinc atoms, one of which activates the acceptor carbonyl group and the other forms a zinc enolate with the donor. In addition, catalysts of this type have been used to good effect in the addition of P-ketoesters to cyclic enones. 

Carolinoside (1), isolated from Solanum carolinense as the host plant specific feeding induction factor for Manduca sexta, has been further characterised and shown to incorporate a 2,6-dideoxy-3-C-methyl- -L-flra6/ o-hexopyranose unit. Alkylation (LDA/Mel) of ketone (2) has afforded the 3-C-methyl derivative (3) which was converted to the A/ -benzylformamide compound (4), an TV-forraylkanosamine glycosyl donor. Aldol condensation (LDA/THF) of ester (5) with aldehyde (6) produced predominantly the isomer (7) which was converted into L-cladinose (8). An aldol condensation of mi s-but-2-enal with a ketene thioacetal has been employed with a chiral catalyst in a preparation of 4-C-methyl-D-ribose/... 

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