Ethyl Ketone-derived Enolates

The addition of ketone-derived enol silanes and aldehydes in the presence of 184 at -78 °C in propionitrile afforded the aldol adducts in excellent yields as well as diastereo- and enantioselectivity (Eq.29) [106]. The versatility of this catalyst is evidenced by the fact that enol silanes derived from aliphatic methyl and ethyl ketones as well as acetophenone are substrates for the aldol addition reaction. 

Denmark SE, Pham SM (2003) Stereoselective aldol additions of achiral ethyl ketone-derived trichlorosilyl enolates. J Org Chem 68 5045-5055... 

Preparation of the requisite side chain starts by alkylation of ethyl acetoacetate with 1,3-dibromopen-tane the initially formed bromoketone (shown as the enol 97) undergoes O-alkylation under the reaction conditions to give the dihydropyran 98. Reaction of that masked hydroxy ketone derivative with hydrogen... 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

E -Enolates often react with lower stereoselectivity than those of the corresponding Z-enolates. A classic example to illustrate this point is a study carried out by Heathcock et al.6 (Scheme 2.IV). When the carbonyl compounds 1 were deprotonated with lithium diisopropylamide (LDA) and the resulting enolates were subsequently treated with benzaldehyde at -72° C, the aldol products desired (2) were obtained in 83 to 99% yield. The Z-enolates derived from t -butyl and 1-adamantyl ethyl ketones afforded syn -products in excellent levels of diastereoselectivity. The fact that the syn/anti ratios directly reflect the isomeric purity of the reacting enolates hints that the Z-enolates in these cases undergo aldol reaction through a chairlike six-membered transition state (Scheme 2.III,... 

Enol acetates and corresponding derivatives constitute another class of unsaturated compounds that can advantageously be hydrogenated with high enantiomeric excess. This reaction is related to the enantioselective reduction of ketones. Acylated enol carboxy-lates (as an equivalent of a-keto carboxylic acid) can likewise be successfully reduced with rhodium(I) catalysts based on (5,5)-ethyl-DuPHOS (eq 8). Subsequent deprotection of the hydroxyl group or reduction of the carboxylic acid derivatives so obtained deliver chiral a-hydroxy carboxylates and 1,2-diols, respectively. 

The tributyltin enolates 74 are readily prepared from the corresponding enol acetates and tributyltin methoxide in the absence of solvent [34]. The tin enolates thus obtained occur in the 0-Sn form and/or the C-Sn form, and both species can be used for the aldol reaction of this system. Although the tin enolates themselves have adequate reactivity toward aldehydes [34c], in the presence of the BINAP silver(I) catalyst the reaction proceeds much faster even at -20 °C. Optimum conditions entail the use of THF as solvent and the results employing these conditions in the catalytic enan-tioselective aldol reaction of a variety of tributyltin enolates with typical aromatic, a,/3-unsaturated, and aliphatic aldehydes are summarized in Table 2. TTie characteristic features are (i) All reactions proceed to furnish the corresponding aldol adducts 75 in moderate to high yield in the presence of 10 mol % (i )-BINAP AgOTf complex at -20 °C for 8 h, and no dehydrated aldol adduct is observed (ii) with an a,j3-unsaturated aldehyde, the 1,2-addition reaction takes place exclusively (entry 3) (iii) a bulky alkyl substituent of tin enolate increases the enantioselectivity of the aldol reaction. For instance, the highest ee (95 % ee) is obtained when the tin enolate prepared from pinacolone 77 or rert-butyl ethyl ketone 79 is added to aldehydes (entries 2, 7, and 8) (iv) addition of the cyclohexanone-derived enol tributylstannane 78 (( )-... 

An early prediction about the structure of a nnagnesium ketone enolatewas subsequently modified when the diethyl ether solvated, magnesium bromide enolate derived from r-butyl ethyl ketone was characterized as the dimer (160) with bridging enolate residues. 

The two faces of a chiral aldehyde are diastereotopic, and reaction with an achiral enolate can therefore give two diastereomeric products. Qualitatively, the major and minor products of such a reaction are determined by the intrinsic diastereofacial preference of the chiral aldehyde, which may be evaluated by the use of Cram s rule or one of its more modem derivatives. Quantitatively, the diastereomeric ratio in such a reaction is a function of the enolate. An example is seen in Scheme 8. 2-Phenylpropanal reacts with the lithium enolates of acetone, pinacolone, methyl acetate and N,N-dimethylacetamide to give 3,4-syn and 3,4-ant diastereomers in ratios of 3 1 to 4 1. With ethyl ketones and propionate esters, the diastereofacial ratio is approximately 6 1 and with methyl isobutyrate only a single isomeric product is produced. This tendency of more bulky nucleophiles to give higher diastereofacial ratios in reactions... 

The first highly enantioselective construction of a-methyl-p-hydroxycarbonyl units, described by Masamune et al., used alkenyloxyboranes (29) prepared by enolization of ethyl ketone (30) derived in three steps from enantiomerically pure mandelic acid. Various dialkylboryl triflates are used with diiso-propylethylamine for enolization. The alkenyloxyboranes (29) exhibit striking stereoselectivity as chiral reagents in reactions with representative aldehydes. With judicious choice of the alkyl ligands on the... 

Several reports by Gennari et a/. describe the generation of enolates directly from carbonyl compounds by using ethylenedioxychloroborane (B-chloro-2,5-dioxaborolane 118) in the presence of diiso-propylethylamine. Reactions of these enolates, derived from ketones and thiol esters, with aldehydes provide good yields (60-85%) of aldol adducts, whereas esters give unsatisfactory yields (-30%). V en ethyl ketones or propanethioates are employed, Z )-enolates (119) can be formed exclusively using specific reaction conditions, and excellent syn selectivities (92 8 to 99 1) ate observed (Scheme 48). 

The asymmetric catalysis using SiCU and (107) is effective also in enantioselective Mukaiyama aldol reaction of TMS enolates derived from methyl ketones [164]. Addition of i-Pr2NEt improves the yield of adducts. The amine probably acts as a proton scavenger to suppress the protodesilylation of the enolates with adventitious HCl. The reaction of TMS enolates derived from ethyl ketones shows high anti diastereoselectivity as in the case of the TBS enolate of t-butyl propanoate. 

Thus the sodio derivative (I) of the enol form of ethyl acetoacetate is obtained. This mechanism can clearly apply also to the condensation of an ester with a suitable ketone or nitrile, as in the above reactions (ii) and (iii) respectively. 

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... 

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