Ketone lithium enolates

Posner recently reported a very simple and fast way to activate epoxides towards nucleophilic opening by ketone lithium enolate anions by use of BF3 Et20 (1 equiv.) [73]. The application of this procedure to the nucleophilic opening of propene oxide with the lithium enolate of 2-cycloheptanone, obtained by the conjugate addition of trimethylstannyllithium to 2-cycloheptenone, afforded the stan-... 

Reaction with Methyl Ketone Lithium Enolates. 83... 

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

Evidence for chair-like transition states in aldol reactions of methyl ketone lithium enolates has been obtained from deuterium-labelled enolates.121... 

As emphasized in Section IV of this chapter, the lithiotropy is of much consequence in the reactivity of enolates, the O and C sites competing toward electrophiles. This problem has been examined recently by Meneses and coworkers202, who described a local hardness parameter that can be used as a selectivity index, in particular for a set of ketone lithium enolates. 

The mixed (heterogeneous) complexes of a lithium amide (LDA or LiTMP) and a ketone lithium enolate (acetone, cyclohexanone or diisopropyl ketone) have been examined by semiempirical methods (MNDO) by Romesberg and Collum48. If the stabilization associated with these mixed complexes was not determined, the solvation (by THF and HMPA) of the mixed cyclic dimers and trimers was calculated to be generally exothermic (but decreasingly with the steric demand of the enolate) and led to disolvated entities. A set of solvated dimers, trimers and tetramers, cyclic or not, has thus been identified... 

SCHEME 59. Various types of solid-state mixed aggregates involving ketone lithium enolates (A) pinacolone enolate/lithium amide [LiHMDS/CH2C(OLi)Bu-i, 2 DME]230 (B) pentan-3-one enolate/2 chiral lithium amide232 (C) pinacolone enolate/lithium amide/LiBr [LiHMDS/2 Cl HCtOI.ijBu-f/LiBr, 2 TMEDA]235... 

Enantioselective Michael Additions. Amine 1 has also been used as an effective ligand for enantioselective Michael reactions of ketone lithium enolate donors with various benzylidene acceptors. As representative examples, the lithium enolates of aryl methyl ketones were reacted with dimethyl benzylidene-malonate in the presence of 1 (eq 9). The lithium enolate was generated from the corresponding ketone by treatment with hex-amethyldisilazide in the presence of lithium bromide in toluene. The resulting enolate was then exposed to 1 and allowed to stir for 30 min to form the desired ternary complex. After addition of the benzylidene acceptor, the desired products were isolated in acceptable yields and with high % ee. 

Transmetallation of a lithium enolate to a copper enolate in Davies iron carbonyl system [(t) -C5H5)Fe(CO)(PPh3)COEt] allows for highly stereoselective additions to symmetrical ketones. Lithium enolates (83) alone give 2 1 to 6 1 ratios of (84a, RR S) and (84b, RS R), and additives e.g. SnCh, BF3, Et2AlCl, ZnCh) either completely suppress the 1,2-addition or do little to influence the dia-stereoselectivity. Addition of CuCN (1 equiv.), however, gives in most cases 10 1 to 60 1 product ratios (Scheme 14). 

Several ketone lithium enolates and dianions of jS-dicarbonyl substrates similarly undergo highly selective 1,4-addition to a variety of a-enones. Thus, tandem inter- and intramolecular Michael addition using the enolates of a,/l-unsaturated ketones as Michael donors was achieved successfully (Scheme 6.88) [111] treatment of 111-ATPH complex in toluene with a THF solution of the benzalacetone lithium enolate at -78 °C, then heating under reflux for 13 h gave the stereo-chemically homogeneous annulation product in 50% yield almost exclusively. 

Alkylation of a ketone lithium enolate with dialkyl 2-ethoxy-2-(bromo or iodo)-l-propenylphos-phonates gives the corresponding 2,5-dioxophosphonates after hydrolysis - ... 

The reaction between an aryl vinyl selenoxide and ketone lithium enolates provides a convenient preparation of cyclopropyl ketones/ Further details have appeared concerning the bicycloannulation of cyclohexenones by reaction of a -enolates with vinylphosphonium salts, to form tricyclo[3.2.1.0 ]octan-6-ones [equation (43)]/ The method has been used to synthesize the trachylobane carbon skeleton. The reaction can also be carried out with vinyl sulphones, but with this reagent HMPA is required for the cyclization to be successful. ... 

The formation of diastereomeric product 67 from the substrate E)-65 is plausibly rationalized by a twofold inversion firstly in the formation of the Jt-complex 66 and secondly by an approach of the nucleophilic enolate. In this case, there is no need for a thermodynamically controlled (Z)- to ( )-interconversion, and thus, a net retention in the allylic alkylation results (Scheme 5.22). Analogous stereochemical outcome was observed for the reaction of the lithium enolate of cyclohexanone with the allylic substrates (Z)-60 and ( )-65. The results shown in Schemes 5.21 and 5.22 clearly prove the outer-sphere mechanism for the Tsuji-Trost reaction of ketone lithium enolates [16c]. 

Notwithstanding a prior claim that methylthio esters react only sluggishly under these conditions, such a variant proved effective for a short synthesis of the 4-demethoxy-11-deoxyanthracycline skeleton (eq 72). This is especially significant because methylthio esters are available by an efficient C-C connective process involving C-acylation of ketone lithium enolates with Carbon Oxysulfide (COS) followed by S-methylation with lodomethane. For the deoxyanthracycline synthesis, the requisite enolate was generated by 1,4-addition of a silyl-stabilized benzyllithium derivative to 2-cyclohexenone. 

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