Ketones, silyloxy

Hydrosilylation of fi-hydroxy ketones.1 (3-Silyloxy ketones (2), prepared by silylation of (3-hydroxy ketones with 1 under the usual conditions (DMAP or Py), on treatment with a Lewis acid form a mixture of siladioxanes, 3a and 3b, which on desilylation with HF is converted into a mixture of anti- and syn-diols (4). The... 

In a related study of the Lewis acid catalyzed intramolecular hydrosilylation of 3-silyloxy ketones, anti selective hydrosilylation has been observed. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

In a cross-coupling benzoin condensation of two different aldehydes, usually a mixture of products is obtained, with the ratio being determined by the relative stabilities of the four possible coupling products under thermodynamic control. If, however, an acyl silane, e.g. 5, is used as the donor component, the a-silyloxy-ketone 6 is obtained as a single product " ... 

The nucleophilic acylation of 2-phenylpropanal or 3-phenyI-2-butanone with cyano(trimethyl-silyloxy)phenylmethyllithium proceeds with high Cram selectivity6. The primary addition product 7, after silyl migration and loss of lithium cyanide, gives the a-silyloxy ketones 86. 

Silyl enol ethers have been prepared via a Brook rearrangement from the reaction of phenyldimethylsilyllithium with a-silyloxy ketones (see Scheme 68). The comparison of the rate of the base-catalysed Brook rearrangement in -substituted... 

The ozonolysis of substituted-allyl silyl ethers or allyl esters followed by treatment with bases or Ph3P give the corresponding a-silyloxy ketones or a-acyloxy ketones.116 The reaction is proposed to proceed via an ene-diol rearrangement of the corresponding a-silyloxyaldehyde or a-acyloxyaldehydes intermediates. 

Oxygenation of silyl enol ethers. Oxygenation of a silyl enol ether under the conditions cited above results in a silyloxy epoxide, which rearranges spontaneously to an a-silyloxy ketone. The preferred Ni catalyst for this epoxidation is bis(3-methyl-2,4-pentanedionato)nickel(II), Ni(mac)2. The a-silyloxy ketone is converted... 

Electrophilic hydroxylationReaction of this peroxide (1) with Grignard reagents affords the corresponding silyloxy derivatives in 70-90% yield. The reaction with vinyl Grignard reagents results in silyl enol ethers or a-silyloxy ketones. 

Reduction of a-silyloxy ketones. a-Hydroxy ketones are reduced by zinc boro-hydride with the expected anf/-selectivity, the extent of which varies somewhat with the substitution pattern. Preparation of the isomeric, v /i-diols can be effected by reduction of the a-r-butyidiphenylsilyloxy ketones with SMEAH in toluene at —78° followed by desilylation (equation I). Again, the selectivity varies with the nature of R and R-, and is low when R is a bulky alkyl group. 

Heathcock has reported an anomalous case of ozonolysis of a silyl enol ether. Usually these substrates undergo facile oxidative cleavage in the same manner as alkoies. However, in this instance the a-silyloxy ketone (61) was obtained in quantitative yield. The inteimediacy of a silyloxy epoxide was suggested. A more recent leport has indicated that a similar process is competitive with the simple cleavage reaction, (63a) versus (63b), in the ozonolysis of the steroidal enol ether (62). 

Enol ethers, and in particular silylated ends (see Volume 2, Chapter 2.3), react with peroxy acid reagents to give initially a silyloxy qpoxide, which rearranges with silyl migration to yield an a-silyloxy ketone, " as in Scheme 3. The net result is that a ketone is converted to a protected a-hydroxy ketone, and the stereochemistry b determined by the least hindered approach of the peroxy acid to the enol. 

Deprotonation of a-silyloxy ketones with LDA furnishes (Z)-lithium enolates, whereas treatment of ketones with n-Bu2BOTf in the presence of /-Pr2EtN gives the corresponding (Z)-(0)-boron enolates. Interestingly, reaction of the Li-enolates with r-PrCHO proceeds with opposite facial preference to that of the boron enolates. Thus, the Si face of the Li-enolate adds to the Si face of the aldehyde and the Si face of the boron enolate adds to the Re face of the aldehyde to furnish the chiral P-hydroxy ketone enantiomers shown below. The reason for the different face selectivity between the lithium enolate and the boron enolate is that lithium can coordinate with three oxygens in the aldol Zimmerman-Traxler transition state, whereas boron has only two coordination sites for oxygen. 

The key step in the total synthesis of the furanoditerpene c/,/-isospongiadiol by P.A. Zoretic and co-workers was an oxidative free-radicai cyciization, which gave rise to the tricyclic skeleton of the natural product.The last stereocenter at C2 was introduced using the Rubottom oxidation on the fully elaborated tetracyclic intermediate. The product was a mixture of a-hydroxy and silyloxy ketone and the last step was a global deprotection with TBAF to afford the natural product. 

Xin, L., Johnson, J. S. Kinetic control in direct -silyloxy ketone synthesis A new regiospecific catalyzed cross silyl benzoin reaction. Angew. Chem., Int. Ed. Engl. 2003,42, 2534-2536. 

This approach can use the inherent regioselectivity of silyl enol ether formation (chapter 3) using kinetic or thermodynamic enolisation. Hence kinetic enolisation of enones (chapter 11) occurs on the a side leading to 2-Me3SiO-butadienes such as 222. Epoxidation of this silyl enol ether gives the unstable silyloxy ketone 223 which can be desilylated by fluoride ion and hence transformed into the hydroxyketone 225 or acetoxy ketone 224. These transformations are useful because the hydroxy ketones can be unstable34 (see below). 

It is well established that one way of reducing the ability of an oxygen atom to coordinate to a metal is to attach an organosilyl protecting group, especially one which is relatively bulky. Thus, certain a-silyloxy ketones have been found to be useful substrates for hydride reduction under Felkin-Anh control. In one example, which complements the reduction discussed immediately above, (S)-( )-2-/m-buty]dipheny]silyloxy-4-methyl-4-hepten-3-one was reduced with lithium aluminum hydride in tetrahydrofuran at —20 C to give the xvw-product with d.r. 95 523. 

Cyclization of epoxydienes. Corey and Sodeoka2 have examined in detail the optimum conditions for cyclization of the epoxydiene I. Of several Lewis acids, CH3AICI2 was found to increase the rate of cyclization more than (CH3)2A1CI or (CH3)2AIOTf, but the yield was comparable in all cases. Methylene chloride is superior to CICH2CH2CI, CH3NO2, or toluene as solvent. Under optimal conditions the cyclization was carried out at -78° for 1 hour followed by silylation. The principal products are the silyloxy ketone 2 and the monocyclic silyloxy methyl ketone 3, formed under all conditions as a minor product... 

The first examples of enolsilane oxidations were described independently by Brook,lb Hassner,lc and Rubottom in late 1974-early 1975. Brook reported that oxidation of enolsilanes derived from cyclic and acyclic ketones with w-CPBA affords a-silyloxy ketones in good yields subsequent hydrolysis of these products provided the corresponding alcohols. Rubottom noted that either a-silyloxy ketones or a-hydroxy ketones could be obtained depending on the nature of the workup (nonaqueous vs. aqueous). Hassner observed that enolsilanes derived from both aldehydes and ketones are suitable substrates for these transformations. Subsequent studies by Rubottom and others led to significant expansions of this methodology along with a more complete understanding of the mechanism of these reactions.2,3... 

The mechanism initially proposed for the Rubottom oxidation involved epoxidation of the enolsilane to afford intermediate silyloxyoxirane 4. It was suggested that this intermediate undergoes acid-mediated cleavage to afford stabilized carbocation 5, which is transformed to the a-silyloxy ketone 6 via 1,4-silicon migration. Hydrolysis of 6 by aqueous acid in a subsequent step generates the a-hydroxy ketone 7.lb 15 Attempts to provide support for this mechanism via isolation of intermediate silyloxyoxiranes derived from simple ketones proved difficult due to the lability of these compounds. However, Brook demonstrated that the related heterocyclic silyloxyoxirane 8 was isolable and was transformed to ketone 9 upon treatment with /j-TsOH. 

Further support for the mechanism described above was obtained in subsequent studies by several groups. Direct evidence for the initial epoxidation event in the Rubottom oxidation of an acyclic enolsilane was first obtained by Weinreb, who described the isolation of silyloxyoxirane 10 and demonstrated its conversion to a-silyloxy ketone 11 upon treatment with PPTS.4 The isolation of a macrocyclic bis(silyloxyoxirane) has also been reported.5... 

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