Lewis mediated nucleophilic addition

Table 28 Formation of tetrahydropyrans 600 by Lewis-acid-mediated nucleophilic addition to resin bound isochromans 599...

Lewis acid-mediated nucleophilic additions to carbon-nitrogen double bond have been applied to the synthesis of homoallylic amines.1 3 Three-component syntheses of homoallylic amines starting from aldehydes, amines, and allyltributyltin are realized in the presence of Lewis acids such as La(OTf)3, Bi(OTf)3, LiClOa (Equation (47)).154-156... 

Our next concern was to affix the side chain at C2 position via a Lewis acid-mediated nucleophilic addition to A-acyliminium ion diastereoselectively using Ley s phenyl sulfone protocol. However, conversion of the hemiaminal (223) using PhSOjH... 

Group-transfer polymerizations make use of a silicon-mediated Michael addition reaction. They allow the synthesis of isolatable, well-characterized living polymers whose reactive end groups can be converted into other functional groups. It allows the polymerization of alpha, beta-unsaturated esters, ketones, amides, or nitriles through the use of silyl ketenes in the presence of suitable nucleophilic catalysts such as soluble Lewis acids, fluorides, cyanides, azides, and bifluorides, HF. ... 

In one of the earliest reports on enantioselective radical reactions, chiral Lewis acid mediated conjugate addition followed by enantioselective H-atom transfer a to a carbonyl was reported by Sato and co-workers (Scheme 3) [22], The single point binding chiral aluminum complex presumably coordinates to the carbonyl oxygen of the lactone as shown in 10. The strong Lewis acidity of the aluminum complex activates the substrate 7 to nucleophilic conjugate addition, which is followed by an enantioselective H-atom transfer from BuaSnH in a chiral environment provided by BINOL ligand in 8. Only 28% ee was observed for product 9. 

Protected (5)-ethyl lactate cleanly acylates methyllithium to afford the 2-butanone with essentially complete enantiomeric fidelity and in nearly quantitative yield. Various diastereoselective constructions were achieved by nucleophilic addition to the ketone (eq 5). For example, addition of vinyllithiums, followed by acetal formation and Lewis acid-mediated rearrangement, provided a ready entry into the indicated 3-acyltetrahydrofurans. 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

Activation of C=N double bonds by copper Lewis acids for nucleophilic addition has also been reported (Sch. 37) [73]. The a-imino ester 157 undergoes alkylation at the imine carbon with a variety of nucleophiles when catalyzed by copper Lewis acids. The presence of the electron-withdrawing ester group increases the reactivity of the imine and also assists in the formation of a stable five-membered chelate with the Lewis acid. Evidence for Cu(I) Lewis-acid catalysis and a tetrahedral chelate was obtained by FTIR spectroscopy, from the crystal structure of the catalyst, and from several control experiments. The authors rule out the intermediacy of a copper enol-ate in these transformations. The asymmetric alkylation of A,0-acetals with enol silanes mediated by a copper Lewis acid proceeding with high selectivity has been reported [74],... 

TiCl4 is used extensively as a Lewis acid in numerous organic transformations, forming adducts that mediate reactivity. Such reactions include Diels Alder, 54,355 hetero Diels Alder,356 cyclization of olefinic aldehydes,357 Flosomi Sakurai allylic coupling reactions,358 cyclopropanations,359 chal-cogen-Baylis Flillman,360 Mukaiyama Aldol reactions,36 363 reductions of ketones to alcohols 364 and stereoselective nucleophilic additions to aldehydes.365... 

Although the mechanism of the Mukaiyama reaction is not yet fully understood, several points have now been firmly established (a) a Lewis acid enolate is not involved (b) the Lewis acid activates the carbonyl group for the nucleophilic addition and (c) the Si—O bond is cleaved by nucleophilic attack of the anionic species, generally halide, on silicon. Point (a) has been established by the use of INEPT- Si NMR spectroscopy. Moreover, trichlorotitanium enolates have been synthesized, characterized and shown to give a completely different stereochemical outcome than the TiCU-mediated reactions of silyl enol ethers. Complexes between Lewis acids and carbonyl compounds have been isolated and characterized by X-ray crystallography and recently by NMR spectrometry. On the basis of these observations closed transition structures will not be considered here open transition structures with no intimate involvement between the silyl enol ether and the Lewis acid offer the best rationale for the after the fact interpretation of the stereochemical results and the best model for stereochemical predictions. 

Chiral a-methyl aldehydes (43) show exceptional diastereofacial preferences in their Lewis acid mediated reactions with enol silanes (equation 16) 21,25c>26-64 selected data are reported in Table 8. The reason for this selectivity may be due to an approach trajectory of the nucleophile closer to the stereocenter when the carbonyl group is bound to the Lewis acid.64 Additions to chiral a-alkoxy aldehyde (48) were studied with both nonstereogenic (equation 17 Table 9) and stereogenic enol silanes (equation 18 Table 10). (Stereogenic and nonstereogenic are defined according to Mislow and Siegel.)170... 

In terms of Lewis-base-mediated covalent catalysis, Birman has shown that the DKR of azlactones is possible using BTM 149 and bis(-naphthyl)methanol, providing di(l-naphthyl)methyl esters of a-amino acids with up to 96% ee. A mechanistic scheme, involving nucleophilic addition of BTM to the rapidly epimerizing azlactone, and preferential recognition through transition state 178 was advanced in order to account for the observed enantiose-lectivity (Scheme 31). ... 

The stereo- and enantio-controlled synthesis of L-arcanose (11) and L-olivomycose (12) by a Lewis acid-mediated reaction of l-TMS-2,3-butadiene with S-benzyl lactaldehyde has been disclosed (Scheme 4). The nucleophilic addition which led to the former sugar is concluded to have gone by way of a chelated transition state the major product in the latter case was produced by way of a non-chelated transition state. 

Diene)tricarbonyliron complexes are able to react with a variety of nucleophiles, mediated by a Lewis acid. The Darzens-Nenitzescu reaction was utilized to prepare i7" -dienetricarbonyliron complexes containing carbonyl groups. Lewis acid-catalyzed nucleophilic additions have been reported to occur at carbonyl functionalities adjacent to an iron-complexed diene. In a separate study, facile racemization or epimerization was observed... 

Finally, a synthesis of the 7,7,6,6-tetracyclic skeleton of hemibrevetoxin 138 has been accomplished (Scheme 28). Manipulation of D-mannose provided the [4.4.0]bicycle 136 and a Lewis acid-mediated intramolecular addition of an allyl stannane to a carbonyl unit (aldehyde or ketone) provided the vehicle for 7-membered ring formation. This is illustrated with aldehyde 137, although establishing the second of the two adjacent 7-membered rings involved addition of the allyl stannane nucleophile to a ketone moiety. 

The controlled polymerization of (meth)acrylates was achieved by anionic polymerization. However, special bulky initiators and very low temperatures (- 78 °C) must be employed in order to avoid side reactions. An alternative procedure for achieving the same results by conducting the polymerization at room temperature was proposed by Webster and Sogah [84], The technique, called group transfer polymerization, involves a catalyzed silicon-mediated sequential Michael addition of a, /f-unsaluralcd esters using silyl ketene acetals as initiators. Nucleophilic (anionic) or Lewis acid catalysts are necessary for the polymerization. Nucleophilic catalysts activate the initiator and are usually employed for the polymerization of methacrylates, whereas Lewis acids activate the monomer and are more suitable for the polymerization of acrylates [85,86]. 

Lewis acid-mediated addition of allylsilanes to carbon nucleophiles. Also known as the Hosomi-Sakurai reaction. The allylsilane will add to the carbonyl compound directly if it is not part of an a,P-unsaturated system (Example 2), giving rise to an alcohol. 

The reaction is based upon the two components condensation between an aldehyde or ketone 6 (or their synthetic equivalents) and alcohol 95, which contains an allylsilane (or vinylsilane) moiety. The IMSC reaction is mediated by Lewis or Bronsted acids, which activate the carbonyl group of 6 towards nucleophilic attack. After addition of alcohol 95 on the activated carbonyl, the oxonium cation 96 is formed, which is intramolecularly captured by the pendant allylsilane function, leading to oxygen-containing rings 97 (Scheme 13.38). This process typically requires a stoichiometric (or more) amount of Lewis acid. 

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