Enolization chemoselectivity

We shall also extend the scope of established reactions. We hope you would recognise the aldol disconnection in TM 10, but the necessary stereochemical control might defeat you. An early section of this book describes how to control every aspect of the aldol reaction how to select which partner, i.e. 11 or 12, becomes an enolate (chemoselectivity), how to control which enolate of the ketone 12 is formed (regioselectivity), and how to control the stereochemistry of the product 10 (stereoselectivity). As we develop strategy, we shall repeatedly examine these three aspects of control. 

C-Silylation. 2-Silyloxazoles can be prepared by deprotonation and quenching the resulting ambident oxazole anion (isocyano enolate) chemoselectively with trialkylsilyl triflates (eq 46). Trialkylsilyl chlorides generally give the product of O-silylation. ... 

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

The chemoselective desilylation of one of the two different silyi enoi ethers in 10 to give the monosilyl enol ether II is realized by the Pd-catalyzed reaction of Bu3SnF. The chemoselectivity is controlled by steric congestion and the relative amount of the reagent[7,8]. An interesting transformation of the 6-alkoxy-2,3-dihydro-6//-pyran-3-one 12 into the cyclopentenone derivative 13 proceeds smoothly with catalysis by Pd(OAc)2 (10 mol%)[9]. 

A synthetically useful virtue of enol triflates is that they are amenable to palladium-catalyzed carbon-carbon bond-forming reactions under mild conditions. When a solution of enol triflate 21 and tetrakis(triphenylphosphine)palladium(o) in benzene is treated with a mixture of terminal alkyne 17, n-propylamine, and cuprous iodide,17 intermediate 22 is formed in 76-84% yield. Although a partial hydrogenation of the alkyne in 22 could conceivably secure the formation of the cis C1-C2 olefin, a chemoselective hydrobora-tion/protonation sequence was found to be a much more reliable and suitable alternative. Thus, sequential hydroboration of the alkyne 22 with dicyclohexylborane, protonolysis, oxidative workup, and hydrolysis of the oxabicyclo[2.2.2]octyl ester protecting group gives dienic carboxylic acid 15 in a yield of 86% from 22. 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

Scheme 24) [38]. Chemoselective enolization of the less substituted enone moiety under hydrogenation conditions accompanied by subsequent aldol reaction provided the corresponding hydroxyl-enones, such as 87-89, which could be converted to various building blocks for polypropionate synthesis. p-Me2N styryl vinyl enone also was employed successfully as an enolate precursor, as demonstrated by the formation of hydroxy enone 90. 

The initially formed titanium enolate 80 adds, in a diastereoselective fashion, to the electrophilic center of the activated oxime. The generated adduct 81 cyclizes chemoselectively to afford the desired /f-azetine, which is converted, with retention of configuration, to the corresponding /3-amino carbonyl compounds 82 via 3V-acetylation followed by hydrolysis. 

These initial forays verified the utility of the process and provided mechanistic information which set the stage for further exploration into the scope of the process. Successful reactions with a variety of substrates demonstrated the generality of the process, with 6- and 7-membered cyclic enol ethers being most accessible (Scheme 19). Preservation of the trisubstituted olefin present in the complex substrate 132 indicates the chemoselective nature of the process [34a]. 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

The synthesis of the non-racemic cyclopentanone (+)-93 is outlined in Scheme 15. Starting with 2-methyl-cyclopent-2-enone (90), sequential cuprate addition and enolate alkylation afforded the racemic cyclopentanone rac-92 as a single diastereomer. The double bond was cleaved by ozonolysis, the resulting aldehyde chemoselectively reduced in the presence of the keto function and the primary hydroxyl function was subsequently protected as a silyl ether to provide racemic rac-93. This sequence has been applied fre-... 

Iron acyl complexes bearing an a,/ -unsaturated acyl ligand possess multiple sites of electrophilic reactivity. Strong bases may be induced to react with the acyl ligand, and in Section 1.1.1.3.4.1.1. the chemoselective y-deprotonation of Z-a,/i-unsaturated acyl ligands to generate enolate species was addressed. The profoundly different reactivity of the unsubstituted complex 1 and E-a,/ -unsaturated acyl complexes, such as 2, is discussed here. 

However, the more hindered, less basic lithium hexamethyldisilazamide reacts slowly with 1 at 0 °C to provide chemoselectively the desired enolate species 5. The a-protons of these rhenium-acyl complexes are believed to have a lower pKa than the cyclopentadienyl protons, but unless treated with hulky, selective hases the cyclopentadienyl protons exhibit greater kinetic acidity due to statistical factors and an earlier, reactant-like transition state since minimal rchybridiza-tion is required at the anionic center after cyclopentadienyl deprotonation. Equilibration of the cyclopentadienyl anion to the thermodynamically more stable enolate species cannot compete with the rapid acyl migration84. 

Trimethylsilyloxy-substituted alkenes are by far the most widely used enol ethers because of their straightforward preparation from the corresponding ketones (equation 20)78-82 -pjjg electron-rich character of silyl enol ethers allows for highly chemoselective cyclopropanations in the presence of additional double bonds (eqnation 21). ... 

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