A-Silyl enol

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

Moderate stereoselectivity is observed in the reaction of a glycine cation equivalent with a silyl enol ether86. 

The optically active ethoxylaetam 13 (see Appendix) gives similar results with an allylsilane102. The reaction with a silyl enol ether, however, proceeds with low diastereoselectivity. 

The final example concerns cyclization of a silyl enol ether, connected to yet another carbon atom. The (.Ej-enol ether 23 appears to be converted with high stereoselectivity into the aldehyde 24 in 70- 90% yield, while the (Z)-enol ether 23 affords the epimeric aldehyde 25 in similar yield and selectivity164. 

The enol acetates, in turn, can be prepared by treatment of the parent ketone with an appropriate reagent. Such treatment generally gives a mixture of the two enol acetates in which one or the other predominates, depending on the reagent. The mixtures are easily separable. An alternate procedure involves conversion of a silyl enol ether (see 12-22) or a dialkylboron enol ether (an enol borinate, see p. 560) to the corresponding enolate ion. If the less hindered enolate ion is desired (e.g., 126), it can be prepared directly from the ketone by treatment with lithium diisopropylamide in THE or 1,2-dimethoxyethane at —78°C. ... 

Longifolene has also been synthesized from ( ) Wieland-Miescher ketone by a series of reactions that feature an intramolecular enolate alkylation and ring expansion, as shown in Scheme 13.26. The starting material was converted to a dibromo ketone via the Mr-silyl enol ether in the first sequence of reactions. This intermediate underwent an intramolecular enolate alkylation to form the C(7)—C(10) bond. The ring expansion was then done by conversion of the ketone to a silyl enol ether, cyclopropanation, and treatment of the siloxycyclopropane with FeCl3. 

Scheme 3.31 Mechanism proposed by Jung and Murai for the reaction of DDQ with a silyl enol ether.

All alkyl halides used in the couplings were primary, although some of them were branched or had an ester functionality. Some of the dialkylzincs had a functional group without affecting the outcome of the reaction. For example, organozinc derivative 302 with a silyl enol ether group reacted with alkyl iodide 303, affording the desired product 304 in 65% yield (Scheme 153). 

Chromene acetals 39 are accessible from 2-vinyl-substituted phenols via the allylic acetals 38 through oxypalladation of benzyloxypropa- 1,2-diene and a subsequent Ru-catalysed RCM. 2-Substituted chromenes can be derived from the acetals 39 by conversion into the 1-benzopyrylium salts which are then trapped by nucleophiles (Scheme 26) <00TL5979>. In a like manner, 2-aIkoxychromans have been converted into various 2-substituted chromans by sequential treatment with SnCl4 and a silyl enol ether <00TL7203>. 

Palladium-catalyzed bis-silylation of methyl vinyl ketone proceeds in a 1,4-fashion, leading to the formation of a silyl enol ether (Equation (47)).121 1,4-Bis-silylation of a wide variety of enones bearing /3-substituents has become possible by the use of unsymmetrical disilanes, such as 1,1-dichloro-l-phenyltrimethyldisilane and 1,1,1-trichloro-trimethyldisilane (Scheme 28).129 The trimethylsilyl enol ethers obtained by the 1,4-bis-silylation are treated with methyllithium, generating lithium enolates, which in turn are reacted with electrophiles. The a-substituted-/3-silyl ketones, thus obtained, are subjected to Tamao oxidation conditions, leading to the formation of /3-hydroxy ketones. This 1,4-bis-silylation reaction has been extended to the asymmetric synthesis of optically active /3-hydroxy ketones (Scheme 29).130 The key to the success of the asymmetric bis-silylation is to use BINAP as the chiral ligand on palladium. Enantiomeric excesses ranging from 74% to 92% have been attained in the 1,4-bis-silylation. 

Judging from these findings, the mechanism of Lewis acid catalysis in water (for example, aldol reactions of aldehydes with silyl enol ethers) can be assumed to be as follows. When metal compounds are added to water, the metals dissodate and hydration occurs immediatdy. At this stage, the intramolecular and intermolecular exchange reactions of water molecules frequently occur. If an aldehyde exists in the system, there is a chance that it will coordinate to the metal cations instead of the water molecules and the aldehyde is then activated. A silyl enol ether attacks this adivated aldehyde to produce the aldol adduct. According to this mechanism, it is expected that many Lewis acid-catalyzed reactions should be successful in aqueous solutions. Although the precise activity as Lewis acids in aqueous media cannot be predicted quantitatively... 

A route involving trapping the enolate as a silyl enol ether, subsequent transme-tallation to the corresponding lithium enolate and alkylation turned out to be more efficient (Scheme 18.41) [123]. Thus, treatment of 120 with the cuprate 124 and chlorotrimethylsilane furnished the silyl enol ether 125, which was then converted into the desired enprostil derivative 127 with 68% yield over both steps by reaction with methyllithium and the allenic triflate 126. 

Ketones may direct lateral Uthiation even if the ketone itself is enoUzed enolates appear to have moderate lateral-directing ability. Mesityl ketone 522, for example, yields 523 after silylation—BuLi is successlnl here because of the extreme steric hindrance around the carbonyl group (Scheme 204). The lithium enolate can equally well be made from less hindered ketones by starting with a silyl enol ether . ... 

A number of steric effects on the rate of rearrangement have been observed and can be accommodated by the chairlike transition-state model.165 The A-silyl enol ethers... 

In parallel to the bismuth(III)-catalyzed three-component allylation reaction, we have reported the corresponding three-component bismuth(III)-catalyzed Mannich-type reaction. A major merit of the three-component reaction is indeed that many unique structures can be afforded rapidly when three or more reactants are combined in a single step to afford new compounds. The development of an efficient bismuth-catalyzed Mannich-type three-component reaction that combines an aldehyde, an amine, and a silyl enolate to give compounds with a (3-amino carbonyl core... 

Oxygen at the heterocyclic sulfur atom has been functionalized in two ways (1) by a TMSOTf-catalyzed Pummerer reaction in the presence of a silyl enol ether (Scheme 95) <1998TL9131> or (2) by reductive removal of the oxygen using Ac20/Zn/cat. 4-dimethylaminopyridine (DMAP) <1996SL885>. The formation of 1,3-dithiane from 1,3-dithiane 1-oxide proceeds efficiently in 95% yield (Equation 70). 

Sigmatropic rearrangements proceed via closed transition states in the Claisen-Ireland variation a silyl-enol ester, 27 or 28, is used, which may be selectively generated in (Z) or (E) configuration12 (Section A. 1.6.3.1.). As shown in the transition states 32 and 29, this results in the formation of 30/31 and 33/34. 

Fluoropyridinium triflate (la) exhibits high selectivity in fluorinations. In a steroid 8 with two reaction sites, a conjugated and a nonconjugated vinyl acetate moiety, 1-fluoropyridinium triflate (la) reacts at the conjugated site only. On the other hand, steroid 9 with a silyl enol ether and a conjugated acetate moiety affords the product resulting from reaction at the former site only.44,52... 

Formation of a silyl enol ether will generate an allyl vinyl ether which after rearrangement can be desilylated to give a carboxylic acid. 

We have just seen in a preceding scheme (see Section 4.2.1.5) an example of alkylation of a silylated enolate with phenylthiomethyl chloride. The Lewis acid-promoted phenylthioalkylation of O-silylated enolates of ketones, aldehydes, esters and lactones has been used by Paterson and Fleming as a convenient synthetic route to a-alkylated or alkylidenated carbonyl compounds [323-325] according to the accompanying scheme. 

The asymmetric catalytic aldol reaction of a silyl enol ether can be performed in a double and two-directional fashion to give the 1 2 adduct in the silyl enol ether form with >99% ee and 99% de in 77% isolated yield (Scheme 8C.25) [59]. The present catalytic asymmetric aldol reaction is characterized by a kinetic amplification phenomenon of the product chirality, going from the one-directional aldol intermediate to the two-directional product (Figure 8C.8). Further transformation of the pseudo C2 symmetric product, while still being protected as the silyl enol ether, leads to a potent analog of an HIV protease inhibitor. 

Having defined the types of commonly used carbon nucleophiles and carbon electrophiles, it would seem that if you react any of the carbon nucleophiles (electron donors) with any of the carbon electrophiles (electron acceptors), then a carbon-carbon bond should be formed. While this is theoretically true, it is unworkable from a practical point of view. If, for example, a carbanion nucleophile was reacted with a cationic electrophile, it is unlikely that the desired carbon-carbon bond formation would be detected, even after the smoke cleared. Or if a silyl enol ether nucleophile was reacted with an a, /f-unsaturated ester, no reaction could be observed to take place in any reasonable time frame. 

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