Enolization Lewis acid activated

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

The asymmetric aldol reaction is one of the most important topics in modern catalytic synthesis [54]. The products, namely />-hydroxy carbonyl compounds, have a broad range of applications and play a key role in the production of pharmaceuticals [55], Since the discovery of the catalytic asymmetric aldol reaction with enolsi-lanes by Mukaiyama et al. [56], steady improvements of the metal-catalyzed asymmetric aldol reaction have been made by many groups [57]. For this type of aldol reaction a series of chiral metal catalysts which act as Lewis acids activating the aldol acceptor have been shown to be quite efficient. It was recently shown by the Shibasaki group that the asymmetric metal-catalyzed aldol reaction can be also performed with unmodified ketones [57a], During the last few years, several new concepts have been developed which are based on use of organocatalysts [58], Enolates and unmodified ketones can be used as aldol donors. 

Lactols and their acetals can be transformed easily into their 2-arylsulfonyl derivatives 337 by reaction with a sulfinic acid under Lewis acid activation. The corresponding organolithiums are prepared by deprotonation with n-BuLi or LDA and, after reaction with electrophiles, a /(-elimination of sulfinic acid afforded a cyclic a-substituted enol ether514,547,548. 2-Lithio-2-(arylsulfonyl)tetrahydropyrans equilibrated to give mainly the anomer with the lithium atom at the equatorial position549. 

Treatment of the silyl enol ethers of IV-acyloxazolidinones with selected electrophiles that do not require Lewis acid activation similarly results in high induction of the same enolate face (eq 13). The facial bias of this conformationally mobile system improves with the steric bulk of the sUyl group. 

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. 

Low-valent Ru(II) [150] and Rh(I) complexes catalyze aldol and Michael reactions of 2-nitrilo esters. The sequence is thought to be initiated by nitrile complexation to the transition metal. This Lewis acid-activation is followed by an oxidative addition to give a metal hydride and a nitrile complexed enolate as shown in Sch. 36. Examples including diastereoselective Ru(II) catalyzed reactions [151] and enantioselective Rh(I)-catalyzed reactions [152-154] with the large trans-chelating chiral ligand PhTRAP are shown in Tables 8 and 9. 

Scheme 9 outlines the synthesis of a prostanoid intermediate (99) that relies on an intermolecular Nozaki process. It is important to note that unlike the intramolecular case described above, the intermolecular version of this protocol requires an aldehyde as the electrophilic trap however, it is interesting to note that there have been no reports of the addition of Lewis acid activated ketones (presumably, as a preformed complex which would be added via cannula at low temperature) to the preformed aluminum enolate. Finally, in this example, the conversion of enone (96) to adduct (98) is promoted by the less reactive dimethylaluminum phenyl thiolate and not the corresponding ate complex. 

The mechanism of the Mukaiyama aldol reaction largely depends on the reaction conditions, substrates, and Lewis acids. Linder the classical conditions, where TiCl4 is used in equimolar quantities, it was shown that the Lewis acid activates the aldehyde component by coordination followed by rapid carbon-carbon bond formation. Silyl transfer may occur in an intra- or intermolecular fashion. The stereochemical outcome of the reaction is generally explained by the open transition state model, and it is based on steric- and dipolar effects. " For Z-enol silanes, transition states A, D, and F are close in energy. When substituent R is small and R is large, transition state A is the most favored and it leads to the formation of the anf/-diastereomer. In contrast, when R is bulky and R is small, transition state D is favored giving the syn-diastereomer as the major product. When the aldehyde is capable of chelation, the reaction yields the syn product, presumably via transition state h. ... 

Finally, the Lewis acid activation of a,)6-unsaturated carbonyl compounds and Q -nitroalkenes is sufficient to induce productive Sr reactions with allenylstannanes (Scheme 5.2.70). Haruta and Kita have successfully achieved condensation reactions with 326 and 328 in the presence of TiCU, and cyclo-hexenones 330 and 332 also serve as synthetically effective substrates for the 1,4-conjugate addition. In the case of enone 332, activation with TBSOTf led to the isolation of silyl enol ether 333. ... 

As described in the sections above, it is well established that reactions of Lewis acid-activated aldehydes and ketones with silyl enolates afford -hydroxy or /7-sil-oxy carbonyl compounds (Mukaiyama aldol reactions). Occasionally, however, ene-type adducts, that is /-siloxy homoallyl alcohols, are the main products. The first example of the carbonyl-ene reaction of silyl enolates was reported by Snider et al. in 1983 [176]. They found that the formaldehyde-MesAl complex reacted smoothly with ketone TMS enolates to give y-trimethylsiloxy homoallyl alcohols in good yield. Yamamoto et al. reported a similar reaction of formaldehyde complexed with methylaluminum bis(2,6-diphenylphenoxide) [177]. After these early reports, Kuwajima et al. have demonstrated that the aluminum Lewis acid-promoted system is valuable for the ene reactions of several aldehydes [178] and for-maldimine [179] with silyl enolates bearing a bulky silyl group. A stepwise mechanism including nucleophihc addition via an acyclic transition structure has been proposed for the Lewis acid-promoted ene reactions. 

Metal compounds possessing Lewis acid character are often used in the Michael addition reaction, and the methodology is reasonably applied to the asymmetric reaction in the presence of chiral ligands. The mechanism could involve either purely Lewis acidic activation of the Michael acceptor or generation of new orga-nometallic species by the transmetalation or C-H activation, although they were not clear in many cases. The system of Sn(OTf)2 and chiral (S)-diamine developed by Mukaiyama promoted the asymmetric addition of trimethylsilyl enethi-olate 68 to P-arylvinyl ketones (Scheme 13) [70, 71]. The diamine-coordinated tin enolate was considered to be involved, and slow addition of 68 was essential to inhibit the racemate formation process. 

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. 

Phenols have been condensed with alkenoylesters to give chromans by an oxa-Michael addition/electrophilic aromatic addition sequence with magnesium(II)- or copper(II)-bis-oxazoline complexes as chiral Lewis acid catalysts (Scheme 17b) [97]. This reaction may be initiated by an oxa-Michael reaction, followed by a hydroarylation of a carbonyl group. The authors suggest that the initial stereodetermining oxa-Michael addition is followed by a fast diastereoselective aromatic substimtion [97]. A nickel Lewis acid, derived from Ni(hfacac)2 (hfacac = 1,LL5,5,5-hexafluoro-3,5-dioxopentane enolate) and chiral Al-oxide ligands, catalyzes the enantioselective oxa-Michael cyclization of 2-tert-butyloxycarbonyl-2 -hydroxy-chalcones to 3-ferf-butoxycarbonyl flavanones, which can be decarboxylated to flavanons in a separate step (Scheme 17c) [98]. A Lewis acid activation of the unsaturated p-ketoester unit can be assumed. 

Pd(OAc)2, combined with DPPE, catalyzes aldol condensation of aldehydes or ketones with ketene silyl acetal (Mukaiyama reaction) under neutral conditions. The ketene silyl acetal of methyl isobutyrate (10) reacted smoothly with methyl pymvate (9) or benzaldehyde (12) in THF or MeCN using 0.1 % of the catalyst. In this reaction the Pd enolate 14 is generated by transmetallation of the ketene silyl acetal with Pd(OAc)2, and the Pd moiety as a Lewis acid activates the carbonyl group to facilitate the attack by the enolate to provide 11 and 13 [2]. 

Highly functionalized tetrahydropyran-4-ones can be obtained through a silyl enol ether Prins cyclization promoted by a condensation reaction of hydroxy silyl enol ethers with Lewis-acid-activated aldehydes, with high diastereoselectivity (14JOC8733). Spirooxindole tetrahydropyran-4-ones are obtained from oxa-DA reaction of acyclic a,P-unsaturated methylke-tones and isatins mediated by a bifunctional enamine-metal Lewis acid catalyst, in good yields and moderate stereoselectivities (14S1339). 

In analogy t 0 the Cu(II) complex systems, the silver(I) -catalyzed aldol reaction is also proposed to proceed smoothly through a Lewis acidic activation of carbonyl compounds. Since Ito and co-workers reported the first example of the asymmetric aldol reaction of tosylmethyl isocyanide and aldehydes in the presence of a chiral silver(I)-phosphine complex (99,100), the catalyst systems of sil-ver(I) and chiral phosphines have been applied successfully in the aldol reaction of tin enolates and aldehydes (101), Mukaiyama aldol reaction (102), and aldol reaction of alkenyl trichloroacetates and aldehydes (103). In the Ag(I)-disphosphine complex catalyzed aldol reaction, Momiyama and Yamamoto have also examined an aldol-type reaction of tin enolates and nitrosobenzene with different silver-phosphine complexes (Scheme 15). The catalytic activity and enantioselectivity of AgOTfi(f )-BINAP (2 1) complex that a metal center coordinated to one phosphine and triflate were relay on solvent effect dramatically (Scheme) (104). One catalyst system solves two problems for the synthesis of different O- and AT-nitroso aldol adducts under controlled conditions. 

With the synergistic effect of Lewis base and Lewis acid, Denmark and coworkers have established several successful organic catalyst systems based on the strategy of Lewis acid activated Lewis base or Lewis base activation of Lewis acid, in which chiral phosphoramides expressed excellent diastereo- and stereoselectivity for the aldol reaction of silyl enolates and aldehydes (Scheme 65) (311-313). 

Kobayashi, S. and Hachiya L, Lanthanide triflates as water-tolerant Lewis acids. Activation of commercial formaldehyde solution and use in the aldol reaction of silyl enol ethers with aldehydes in aqueous media, /. Org Chem., 1994, 59, 3590-3596. 

Mukaiyama aldol reactions of silyl enol ethers are generally rationalized by a Lewis acid activation of the carbonyl group by in situ formation of a complex that reacts with the silyl enol ether or the silyl ketene acetal [99,167]. Transmetallation mechanisms according to which silicon is replaced under formation of a metal enolate have been discussed as well for catalytic versions of the reaction [168], in particular for late transition metals [169]. 

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