Silylation of Enolates

Electrostatic potential map for cyclohexanone lithium enolate shows negatively-charged regions (in red) and positively-charged regions (in blue). 

HOMO of cyclohexanone lithium enolate reveals the most nucleophilic sites. 

Enolate reactivity depends on the electrophile. Enolates generally form CC bonds with carbon electrophiles, and OSi bonds with silicon electrophiles. 

Obtain the energies of the products resulting from metihylation of cyclohexanone enolate the CCproduct (shown above) and the OCproduct. Does methylation give the more stable product Repeat this analysis for the CSi and OSi silylation products. 

Electrostatic and orbital interactions may steer reaction toward either carbon or oxygen. First, examine the electrostatic potential map for cyclohexanone lithium enolate. Which atom is more negatively charged, carbon or oxygen Is the difference significant If it is, what would be the favored mode of addition Does either methylation or silylation appear to be guided by electrostatics Explain. 

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They are generally prepared by silylation of enolate anions derived from a,(3-unsaturated carbonyl compounds (Equations Si3.9 and 3.10). 

Silylation of azaallyllithium reagents derived from hydrazones unlike silylation of enolates seems to occur mainly on cartwn. While chiral (S)-l-amino-2-methoxymethylpyrrolidine (SAMP) aldehyde hydrazones (c/. equation 4) alkylate to a greater extent on nitrogen to form an azaallylsilyl reagent, ketones give predominant C-silylation. In the case of chiral ketone hydrazones derived from (5)-(4), a-silylated ketone hydrazones are produced in these reactions with consistently high ee ( 6%) ... 

A useful catalyst for asymmetric aldol additions is prepared in situ from mono-0> 2,6-diisopropoxybenzoyl)tartaric acid and BH3 -THF complex in propionitrile solution at 0 C. Aldol reactions of ketone enol silyl ethers with aldehydes were promoted by 20 mol % of this catalyst solution. The relative stereochemistry of the major adducts was assigned as Fischer- /ir o, and predominant /i -face attack of enol ethers at the aldehyde carbonyl carbon atom was found with the (/ ,/ ) nantiomer of the tartaric acid catalyst (K. Furuta, 1991). 

Silylated cyanohydrins have also been prepared via silylation of cyanohydrins themselves and by the addition of hydrogen cyanide to silyl enol ethers. Silylated cyanohydrins have proved to be quite useful in a variety of synthetic transformations, including the regiospecific protection of p-quinones, as intermediates in an efficient synthesis of a-aminomethyl alcohols, and for the preparation of ketone cyanohydrins themselves.The silylated cyanohydrins of heteroaromatic aldehydes have found extensive use as... 

Selective fluonnation in polar solvents has proved commercially successful in the synthesis of 5 fluorouracil and its pyrimidine relatives, an extensive subject that will be discussed in another section Selective fluonnation of enolates [47], enols [48], and silyl enol ethers [49] resulted in preparation of a/phn-fluoro ketones, fieto-diketones, heta-ketoesters, and aldehydes The reactions of fluorine with these functionalities is most probably an addition to the ene followed by elimination of fluonde ion or hydrogen fluoride rather than a simple substitution In a similar vein, selective fluonnation of pyridmes to give 2-fluoropyridines was shown to proceed through pyridine difluondes [50]... 

Both the Af-fluorosulfonamides and the A -fluoroammonium salts are very effective in the fluormation of enol acetates, enamines, silyl enol ethers, and enolates (Table 2) The reactions are thought to proceed through a mechanism which involves Sf 2 attack on the fluorine atom, but contributions from electron-transfer pathways also exist [65, 68, 73, 75, 76, 79, 80, 81, 82]... 

Benzyloxy-2-fluoro-2-methylpropionaIdehyde was prepared in optically active form from (5)-monoethyl 2-fluoro-2-methylmalonate, which had itself been prepared by enzymatic hydrolysis A number of enol silyl ethers or enolates were added to the aldehyde in processes that occur with fair to good diastereoselectivity [6] (equation 6) (Table 2)... 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

Scheme 6a presents the synthesis of fragment 15. Intermediate 15 harbors two vicinal stereogenic centers, and is assembled in a very straightforward manner through the use of asymmetric aldol methodology. Treatment of the boron enolate derived from 21 with 3-[(p-methoxybenzyl)oxy]propanal (22) affords crystalline syn aldol adduct 34 in 87 % yield as a single diastereomer. Transamination to the A-methoxy-A-methylamide,20 followed by silylation of the secondary hydroxyl group at C-19 with triethylsilyl chloride, provides intermediate 15 in 91 % yield. 

The Ireland-Claisen reaction of ( )-vinylsilanes has been applied to the stereoselective synthesis of syn- and c/nti-2-substituted 3-silyl alkcnoic acids. a R-2-Alkyl-3-silyl acids are prepared by rearrangement of ( )-silyl ketene acetals which are generated in situ from the kinetically formed (Z)-enolate of the corresponding propionate ester40. Chelation directs the stereochemistry of enolization of heteroelement-substituted acetates in such a way that the syn-diastereomers are invariably formed on rearrangement403. 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

The addition of the lithium enolates of methyl acetate and methyl (trimelhylsilyl)acetate to ( + )-(S)-2-(4-methylphenylsulfinyl)-2-cycloalkenones gives, after desulfurization, (/ -substituted cycloalkenones. A higher level of selectivity is observed with the a-silyl ester enolate and in the cyclohexenone series13. The stereochemical outcome is rationalized by assuming attack on a ground-state conformation analogous to that in Section 1.5.3.2.1. 

Enolizable compounds can be used for Meerwein reactions provided that the keto-enol equilibrium is not too far on the side of the ketone for example, P-dicar-bonyl compounds such as acetylacetone are suitable (Citterio and Ferrario, 1983). The arylation of enol esters or ethers (10.12) affords a convenient route for arylating aldehydes and ketones at the a-carbon atom (Scheme 10-48). Silyl enol ethers [10.12, R = Si(CH3)3] can be used instead of enol ethers (Sakakura et al., 1985). The reaction is carried out in pyridine. 

C in CH2CI2, in the formation of enol ethers 404 in high yields [26] (Scheme 5.4). Likewise, silylated alcohols 13 and free 1,2- and 1,3-glycols react with ketones in the presence of TMSOTf 20 to cyclic ketals [27]. 

Likewise, addition of enol silyl ethers such as 980 to the intermediate 977 a furnish the 5-trimethylsilylmethylisoxazolidine 981 in 61% yield and 15% isoxazoline 982 [73, 74] whereas addition of 2-trimethylsilyloxyfuran 827 to 977 a affords, via the intermediates 983, on work-up with CF3CO2H, 96% yield of a mixture of lactones 984 and 985 [75] (Scheme 7.23). More recently it has also been reported that Danishefsky (trimethylsilyloxy)dienes add to intermediates such as 977 to give the corresponding products [76]. 

Fe(OTf)2-catalyzed aziridination of enol silyl ethers with PhlNTs followed by ring opening led to a-N-tosylamido ketones in good yields (Scheme 27) [81]. With silyl ketene ketal (R = OMe) as substrate, the N-tosyl-protected amino acid ester was obtained in 50% yield. In contrast, the copper (I) salt CuClOq was found not effective for this substrate [82]. 

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