Ethers, silyl enol reaction with acetals

Table 5. Activation of acetals reactions with silyl enol ethers and ketene silyl acetals [44]. Entry Reaction...

A one-pot reaction between a tryptophan ester, benzotriazole, and 2,5-dimethoxytetrahydrofuran in acetic acid gives the diastereomeric benzotriazolyl tetracycles, 349, in good yield. Substitution of the benzotriazole by reaction with silyl enol ethers and boron trifluoride etherate gives the corresponding ketones 350 and 351, and reaction with allylsilanes gives the corresponding alkenes 352 and 353. If the boron trifluoride etherate is added to the mixture before the silane, elimination of benzotriazole from 349 is also observed (Scheme 83) <1999T3489>. 

Reaction of 4a with TiCl4 was carried out in the presence of siloxyalkene 3 as nucleophile and the results are summarized in Table III. In the reaction with ketene silyl acetals 3a and 3e at -78 °C, y-ketoesters 15a and 15e were obtained instead of chloride product 8 which is a major product in the absence of 3. Formation of product 15 is likely to result from trapping of alkylideneallyl cation 5 with 3 at the sp2 carbon. In contrast, the reactions with silyl enol ethers 3f and 3g gave no acyclic product 15, but gave cyclopentanone derivatives 16-18. The product distribution depends on the mode of addition of TiCl4 (entries 4-7). 

The reaction with silyl enol ethers 3f and 3g gave only the [3 + 2] cycloadducts in comparison with effective formation of acyclic adduct 15 in the reaction with ketene silyl acetals 3a and 3e at lower reaction temperature. This can be explained by the reactivity of cationic intermediates 19 the intermediates from 3f and 3g are more reactive owing to lower stabilization by the oxy group than those from 3a and 3e, and react with the internal allene more efficiently to give the cycloadduct(s). Cyclic product 17a could be obtained at higher temperature via the reaction of 3a (entry 2). 

Carbonyl activation and deactivation.1 Aldehydes, but not ketones, undergo aldol condensation with silyl enol ethers at —78° in the presence of dibutyltin bistriflate. In contrast, the dimethyl acetals of ketones, but not of aldehydes, can undergo this condensation (Mukaiyama reaction) with silyl enol ethers at -78° with almost complete discrimination, which is not observed with the usual Lewis-acid catalysts. Thus dibutyltin bistriflate activates aldehydes, but deactivates acetals of... 

Substitution of the acetate group at the C-3 position of the /3-sultam 105 can occur by reaction with silyl enol ethers in the presence of zinc iodide or zinc chloride. When the diazo compound is used, after desilylation with tetrabutyl-ammonium fluoride (TBAF), photochemical cyclization gives the bicyclic /3-sultam 106 as a mixture of two cis/ fra -diastereoisomers. When silyl enol ethers derived from cyclic ketones are used, the substitution product is stabilized by a retro-Michael-type reaction leading to open-chained sulfonamides 107 (Scheme 31) <1997LA1261>. 

Much more promising and synthetically versatile is the use of the bifunctional acetal stan-nane12. In this case, both reactive centers are activated under the same conditions and lead to clean [3 + 2] reactions with silyl enol ethers. The acetal stannane is readily available by Gri-gnard reaction of trimethylchlorostannane with the corresponding bromoacetal to afford the product in 76% yield. 

Ring expansion of cycloalkanones. 1-Trimethylsilyloxybicyclo[n.l.0]alkanes (1), prepared by Simmons-Smith reaction with silyl enol ethers of cycloalkanones, react with ferric chloride in DMF containing pyridine to form a 3-chlorocycIo-alkanone (2) in fair to high yield. Dehydrochlorination (sodium acetate) yields a 2-cycloalkenone (3) containing one more carbon atom than the starting cycloalkanone. 

As an extension of this new procedure for carbon-carbon bond formation, the reaction between silyl enol ethers and acetals 50, a typical protecting group of aldehydes, is performed to afford j5-alkoxy carbonyl compound 51 in the presence of titanium(IV) chloride (Eq. (24)) [27]. A variety of substituted furans are readily prepared by application of the TiCU-promoted reaction of a-halo acetals 52 with silyl enol ethers (Eq. (25)) [27]. 

Reductive aldol reaction of a,(5-unsaturated esters and enones with aldehyde mediated by a transition metal hydride complex and a hydride source, such as hydrosilane, is a versatile process to produce p-hydroxy carbonyl compounds (Scheme 15a) [21]. This reaction is thought to be an alternative transformation of Lewis acid-catalyzed Mukaiyama-type aldol reaction with silyl enol ethers or silyl ketene acetals (Scheme 15b). 

Evans et al. applied the Mukaiyama aldol reaction to the total synthesis of the squalene synthase inhibitor zaragozic acid C (Scheme 8.23). ° Di-f-butyl tartrate 135 was protected as acetal 137, which was converted into silyl enol ether 138. The partner aldehyde 141 was synthesized by the Evans aldol reaction (139 —> 140). The Mukaiyama aldol reaction with silyl enol ether 138 and aldehyde 141 in the presence of (i-PrO)TiCl3 gave adduct 142 as a single isomer. These transformations gave the desired stereochemistry at the C3 to C7 positions. 

Preparation of o,/3-Unsaturated Carbonyl Compounds by the Reactions of Silyl Enol Ethers and Enol Acetates with Ally Carbonates... 

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

Table 3. Reaction of (5)-3-Ben2yloxy-2-fIuoro-2-methylpropionaldehyde with Silyl Enol Ethers and Silyl Ketene Acetals [6]...

The Lewis acid induced reaction of silyl enol ethers and silyl ketene (thio)acetals with 4-acetoxyazetidinones is often used for introduction of a carbon substituent in the 4-position of the jS-lactam ring. Numerous examples are known, both with and without substituents at nitrogen, some of which are shown. 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

Scheme 2.9 gives some examples of use of enantioselective catalysts. Entries 1 to 4 are cases of the use of the oxazaborolidinone-type of catalyst with silyl enol ethers and silyl ketene acetals. Entries 5 and 6 are examples of the use of BEMOL-titanium catalysts, and Entry 7 illustrates the use of Sn(OTf)2 in conjunction with a chiral amine ligand. The enantioselectivity in each of these cases is determined entirely by the catalyst because there are no stereocenters adjacent to the reaction sites in the reactants. 

On the other hand, the method of Mukaiyama can be succesfully applied to silyl enol ethers of acetic and propionic acid derivatives. For example, perfect stereochemical control is attained in the reaction of silyl enol ether of 5-ethyl propanethioate with several aldehydes including aromatic, aliphatic and a,j5-unsaturated aldehydes, with syir.anti ratios of 100 0 and an ee >98%, provided that a polar solvent, such as propionitrile, and the "slow addition procedure " are used. Thus, a typical experimental procedure is as follows [32e] to a solution of tin(II) triflate (0.08 mmol, 20 mol%) in propionitrile (1 ml) was added (5)-l-methyl-2-[(iV-l-naphthylamino)methyl]pyrrolidine (97b. 0.088 mmol) in propionitrile (1 ml). The mixture was cooled at -78 °C, then a mixture of silyl enol ether of 5-ethyl propanethioate (99, 0.44 mmol) and an aldehyde (0.4 mmol) was slowly added to this solution over a period of 3 h, and the mixture stirred for a further 2 h. After work-up the aldol adduct was isolated as the corresponding trimethylsilyl ether. Most probably the catalytic cycle is that shown in Scheme 9.30. 

The cationic iridium complex [Ir(cod)(PPh3)2]OTf, when activated by H2, catalyzes the aldol reaction of aldehydes 141 or acetal with silyl enol ethers 142 to afford 143 (Equation 10.37) [63]. The same Ir complex catalyzes the coupling of a, 5-enones with silyl enol ethers to give 1,5-dicarbonyl compounds [64]. Furthermore, the alkylation of propargylic esters 144 with silyl enol ethers 145 catalyzed by [Ir(cod)[P(OPh)3]2]OTf gives alkylated products 146 in high yields (Equation 10.38) [65]. An iridium-catalyzed enantioselective reductive aldol reaction has also been reported [66]. 

Recently it was found that the aldol reaction of silyl enol ethers with acetals or aldehydes is effectively promoted by a catalytic amount of trityl perchlorate to give the corresponding aldols in good yields (44,45). Polymer-bound trityl perchlorate also successfully catalyzed the aldol reaction (45). 

Tin enolates of ketones can be generated by the reaction of the enol acetate 733 with tributyltin methoxide[601] and they react with alkenyl halides via transmetallation to give 734. This reaction offers a useful method for the introduction of an aryl or alkenyl group at the o-carbon of ketones[602]. Tin enolates are also generated by the reaction of silyl enol ethers with tributyltin fluoride and used for coupling with halides[603]. 

Cross aldol reactions of silyl enol ethers with acetals (25 - 26, and 27 - 28) are also mediated by EGA. The reaction runs smoothly at —78 °C in a CH2CI2— —LiClO —Et NClO —(Pt) system. At an elevated temperature protonation of both enol ether and acetal occurs competitively to give 28 in a poor yield. Table 5 summarizes yields and diastereoselectivities of 28 obtained by EGA, TiCl TMSOTf and TrtClO 5 . The EGA method is superior to TiCl with regard to the stereocontrol, and comparable with TMSOTf and TrtClO in both stereocontrol and yield. 

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