Metallo enolates

A great majority of the catalytic aldol processes that have been developed over the last two decades involve Lewis acids derived from complexes of titanium, boron, tin, and, more recently, copper as well as silver. A recent, exciting area of rapid development for aldehyde addition reactions is represented by the catalytic aldol methods that utilize soft-metal and lanthanide coordination complexes which mediate addition reactions through metalloenolate intermediates. 

Ba(II). Shibasaki and co-workers have also described a catalytic system that utilizes the mono 0-methyl ether of (/ )- or (5)-binol and BalO/Pr) (Eq. (8.24)) [38]. A complex consisting of a 2 1 adduct of ligand and Ba(ll) (94) is suggested to mediate the addition of acetophenone to aldehydes affording adducts in 77-99% yield and up to 70% ee. This sy.stem is reported to have a number of advantages over the Ln-based catalysts discussed previously fewer equivalents of ketone are necessary and the reaction times are considerably shorter. 

Carreira and co-workers have documented a class of Cu-mediated dieno-late aldol addition reactions that are postulated to proceed through an intermediate metalloenolate (Eq. (8.26)) [40]. The active catalyst is generated upon dissolution of p-tolbinap and Cu(OTf)2 in THE followed by addition of Bu4NPh3Sip2 as an anhydrous fluoride source. The putative Cu-fluoride complex initiates the formation of a Cu-dienolate that subsequently participates in a catalytic, enantioselec-tive addition reaction. Using as little as 0.5 mol% catalyst, the protected acetoace-tate adducts are isolated in up to 94% ee [41]. The use of the corresponding p-tol-binap-Cu(OrBu) complex prepared in situ from Cu(OfBu) and binap functions as a competent catalyst. This feature is consistent with an intermediate metal alkox-ide in the catalytic cycle, namely, the first-formed metal aldolate adduct. The 

Pt(II). Fujimura has developed a Pt(II)-catalyzed process for the addition of iso-butyrate-derived silyl ketene acetal 97 to aldehydes (Eq. (8.27)) [43]. The process utilizes a readily available Pt(Il) complex (98) that is generated in situ and can be easily handled in the laboratory [44]. In the presence of 5 mol% each of 98, triflic acid, and lutidine, 97 undergoes addition to aldehydes to afford a mixture of tri-methylsilyl-protected 99 and free alcohol 100 products in up to 95% ee. A thorough examination of the reaction conditions and their effect on the product selec-tivities has revealed that the addition of water and oxygen to the catalyst mixture leads to significant improvement in the optical purity of the products. A number of spectroscopic studies by P NMR and IR has led Fujimura to postulate that the reaction involves a carbon-bound platinum enolate intermediate in the catalytic cycle. 

Lewis Basic Phosphoramides. In a series of elegant investigations, Denmark has documented an aldol process that utilizes trichlorosilyl enolates such as 101 and 105 in catalytic, enantioselective addition reactions (Eqs. (8.28) and (8.29)) [45]. These unusual enoxysilanes are prepared by treatment of the corresponding tribu-tylstannyl enolates with SiCl4. Trichlorosilyl enolates are sufficiently reactive to add to aldehydes at -78 °C, but their addition can be substantially accelerated by the addition of Lewis basic phosphoramides. The use of catalytic amounts of chiral phosphoramides leads to the formation of optically active products. Thus, treatment of the cyclohexanone or propiophenone-derived trichloroenolsilanes 101 and 105 with a variety of aldehydes afforded adducts displaying high levels of simple diastereoselectivity and up to 96% ee. On the basis of the stereochemical outcome of the reaction, Denmark has postulated that the reaction proceeds through an or- 

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Zinc enolates have been shown to react with chiral /V-acylpyridinium salts with high diastereo-selectivity (Scheme 24) (93JOC5035). Other metallo enolates gave products with lower diastereoselectivity. Titanium enolates react with /V-acylpyridinium salts to yield 1,4-dihydropyridines, which on subsequent oxidation (aromatization) give 4-(2-oxoalkyl)pyridines (84TL3297). 

The first asymmetric synthesis of (+)-cannabisativine was achived by D.L. Comins et al. using the addition of metallo enolates to a chiral 1-acylpyridinium salt as one of the key steps.The amide bond was created under the Schotten-Baumann conditions from a bicyclic acid chloride and a 1,4-amino alcohol. 

Kuethe, J. T., Comins, D. L. Addition of Metallo Enolates to Chiral 1-Acylpyridinium Salts Total Synthesis of (+)-Cannabisativine. Ora. Lett. 2000, 2, 855-857. 

Crotonic esters and certain homologues, when converted to their enolates with LDA and treated with stannyl and germyl chlorides, afford the y-metallo derivatives (Table 10)57. In contrast, silylation of these enolates leads to the 0-silyl derivatives. Interestingly, the halostannane derivatives show a strong preference for the (Z) geometry suggestive of a donor-acceptor interaction between the carbonyl oxygen and the electropositive tin atom,... 

Scheme 22.7 Catalytic addition of metallo-aldehyde enolates to ketones.

Perhaps the most elusive variant of the aldol reaction involves the addition of metallo-aldehyde enolates to ketones. A single stoichiometric variant of this transformation is known [29]. As aldolization is driven by chelation, intramolecular addition to afford a robust transition metal aldolate should bias the enolate-aldolate equilibria toward the latter [30, 31]. Indeed, upon exposure to basic hydrogenation conditions, keto-enal substrates provide the corresponding cycloal-dol products, though competitive 1,4-reduction is observed (Scheme 22.7) [24 d]. 

Intermolecular cross aldolization of metallo-aldehyde enolates typically suffers from polyaldolization, product dehydration and competitive Tishchenko-type processes [32]. While such cross-aldolizations have been achieved through amine catalysis and the use of aldehyde-derived enol silanes [33], the use of aldehyde enolates in this capacity is otherwise undeveloped. Under hydrogenation conditions, acrolein and crotonaldehyde serve as metallo-aldehyde enolate precursors, participating in selective cross-aldolization with a-ketoaldehydes [24c]. The resulting/ -hydroxy-y-ketoaldehydes are highly unstable, but may be trapped in situ through the addition of methanolic hydrazine to afford 3,5-disubstituted pyridazines (Table 22.4). 

A method for the stoichiometric addition of metallo-aldehyde enolates to ketones has recently been reported K. Yachi, H. Shinokubo, K. Oshima, /. Am. Chem. 

On the other hand, the use of [Rh(CO)2Cl]2 as a catalyst results in ring opening of the siloxycyclopropanes 13 to the silyl enol ethers 14 with high stereoselectivity [10]. The 2-siloxyrhodacyclobutane 15a is proposed to undergo j8-elimination to give jr-allylrhodium 16a followed by reductive elimination to the silyl enol ether 14a. 1-Trimethylsiloxybicyclo[n.l.0]alkanes serve as / -metallo-carbonyl compounds via desilylation with a variety of transition metals [11]. The palladium-catalyzed reaction of the siloxycyclopropanes 17 under carbon monoxide in chloroform provides a route to the 4-keto pimelates 18. In the presence of aryl triflates, the 1,4-dicarbonyl compounds 19 are... 

Treatment of the /J-hydroxy complex 15 with two equivalents of strong base followed by alkylation produces a mixture of the diastereomers 20 and 21 with an anomalously low d.r.27. The low degree of diastereofacial discrimination has been rationalized by invoking the formation of both rotamers of the initially formed alkoxide, 16 and 17. Rotamer 16 undergoes a-proton abstraction by a second equivalent of base to form the chelated dianionic Tf-enolate 18 which upon alkylation affords the usual diastereomer 20. Rotamer 17 is thought to rapidly transform to a metallo-lactone species by intramolecular attack of the alkoxide upon the proximate carbon monoxide ligand, which must occur faster than conversion to the less sterically encumbered conformer 16. Subsequent deprotonation to generate dianion 19, which is constrained to exist as the unusual Z-enolate, followed by alkylation provides the other diastereomer 21, which is formed in an amount nearly equal to 20. 

Recently, analogues of nucleosides [60], natural products Huperzine-A [61] and Hydroartemisinin [62], and inhibitors of metallo-/ -lactamases have been synthesised [63]. With acylsilane electrophiles, the initial adducts undergo Brook rearrangement which is interrupted by -Si bond fission with loss of fluoride anion (Eq. 16), leading to the formation of extremely useful difluoro-enol silanes [64]. Of the various fluoride sources employed, the tetrabutylam-monium triphenyldifluorostannate described by Gingras appears to be particularly effective. The numerous other methods for trifluoromethylation formed the subject of an exhaustive review [65]. More recently, the Olah group described a chlorodifluoromethyl trimethylsilane which is expected to have a rich chemistry [66]. 

This work raises the possibility that some eryfAro-selective aldol condensations with metal enolates may actually involve the a-metallo ketone. 

The precursor to the cofactor is an a-phosphoiylated ketone (commonly drawn in its enol form). It has been demonstrated that a-substituted ketones (including a-phosphoiylated ketones) are viable precursors to 1,4-dithiines [68,69] and metallo-l,2-enedithiolates [70-73], These chemical conversions require... 

Porous 1D-, 2D-, 3D-Metallo-Coordination Polymers - Tetrazolyl Enolate-,... 

Coverage in this chapter is restricted to the use of alkenes or alkynes as enophiles (equation 1 X = Y = C) and to the use of ene components in which a hydrogen is transferred. Coverage in Sections 1.2 and 1.3 is restricted to ene components in which all three heavy atoms are carbon (equation 1 Z = C). Thermal intramolecular ene reactions of enols (equation 1 Z = O) with unactivated alkenes are presented in Section 1.4. Metallo-ene reactions are covered in the following chapter. Use of carbonyl compounds as enophiles, which can be considered as a subset of the Prins reaction, is covered in depth in Volume 2, Chtqiter 2.1. Addition of enophiles to vinylsilanes and allylsilanes is covered in Volume 2, Chapter 2.2, while addition of enophiles to enol ethers is covered in Volume 2, Chapters 2.3-2.S. Addition of imines and iminium compounds to alkenes is presented in Volume 2, Part 4. Use of alkenes, aldehydes and acetals as initiators for polyene cyclizations is covered in Volume 3, Chapter 1.9. Coverage of singlet oxygen, azo, nitroso, S=N, S=0, Se=N or Se=0 enophiles are excluded since these reactions do not result in the formation of a carbon-carbon bond. 

Analogous boion-ene addition to enol ethers (36) requires 110-140 C. Under these harsh conditions die initially formed 2-alkoxyboranes (37).undergo a spontaneous -eliInination to furnish 1,4-dienes (38) in good yields (Scheme 9 Table 5) Application of this cu-metallo-allylation/syR-elimination sequence to cyclic enol ethers provides a stereocontrolled access to 1,4-dienols containing a trisubstituted alkenic bond, as illustrated by the transformation (39) + (40) - (42) (Scheme 9). 

In this manner, both C- and 0-metallo derivatives of keto-enol systems were shown not to be in tautomeric ketone enolate equilibrium (in benzene), thus differing from ketones and enols themselves where ketone enol equilibria exist. Metal enolates, however, are transformed by substitution to the derivatives of the ketone species, while our C-mercury derivatives of ketones or aldehydes have been shown to produce the enol compounds. A conventional scheme (in which ketones, not their metallic derivatives, are shown) thus becomes somewhat unsatisfactory ... 

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