Soft enolization

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

Simultaneous treatment of a carbonyl compound with a Lewis acid and a tertiary amine or another weak base ( soft enolization ) can sometimes be used to generate enolates of sensitive substrates which would have decomposed under strongly basic reaction conditions [434]. Boron enolates, which readily react with aldehydes at low temperatures, can also be prepared in situ from sensitive, base-labile ketones or carboxylic acid derivatives [293, 295, 299]. Unwanted decomposition of a carbanion may also be prevented by generating it in the presence of an electrophile which will not react with the base (e.g. silyl halides or silyl cyanides [435]). 

For related palladium-catalyzed cyclizations of enolates, see Ciufolini, M.A. Qi, H.B. Browne, M.E. Intramolecular arylations of soft enolates catalyzed by zerovalent palladium. J. Org. Chem. 1988, 53, 4149 151. Muratake, H. Natsume, M. Nakai, H. Palladium-catalyzed intramolecular -arylation of aliphatic ketone, formyl, and nitro groups. Tetrahedron 2004, 60, 11783-11803. Muratake, H. Natsume, M. Palladium-catalyzed intramolecular -arylation of aliphatic ketones. Tetrahedron Lett. 1997, 38, 7581-7582. 

The first attempts to use transition metal-catalyzed cross-coupling methodology to couple enolates with aryl halides were far from being broadly applicable, and involved less-attractive preformed zinc- or tin-enolates [210]. In addition, only ketones or acetates could be employed as enolate precursors. At that time, nickel was the predominant transition metal to mediate these couplings [211]. In an early contribution, CiufoHni arylated soft enolates in an intramolecular fashion with aryl halides using Pd(PPh3)4, along with NaH, in DMF at elevated temperatures [212]. This represented one of the first palladium-catalyzed arylations of enolates. 

In summary, the Pd-catalyzed allylic substitution reaction between allyl acetates (and related electrophiles) with soft enolates has a wide scope and continues to attract considerable interest as a synthetic tool. 

Our studies commenced with exploring various catalysts and promoters of the aldol reactions (Table 2). To simplify the analysis, only diastereomerically pure Michael adduct 14a was used in the screening of reaction conditions. Initially, the intramolecular double-cyclization proved to be difficult as pro-line catalysis (entry 1), soft enolization (entry 2), and tertiary amines (entries 3 and 4) were unsuccessful. Acidic conditions (pTSA) provided a positive result as the steroid diol 24 with the unnatural C13/C14 configuration was formed. Unfortunately, the formation of significant side products along with 24 complicated isolation of this product. 

Evans and coworkers also brought about ti-selective aldol additions based upon Af-propionyl oxazolidinones and thiazolidinethiones, which is surprising in view of the fact that these auxiliaries seems to be predestined for providing sy -selectivity [116]. However, the soft enolization of oxazolidinone 73 with magnesium chloride in the presence of a tertiary amine and chlorotrimethylsUane induced an addition to various aromatic and a,P-unsaturated aldehydes that led to a ti-configured sUyl-protected aldols 225 in a highly diastereoselective manner. 

A remarkable utilization of an Evans enolate is shown in Scheme 4.95. The soft enolization of oxazolidinone 439 occurs selectively in favor of the imidic... 

Crimmins MT, King BW, Tahet EA, Chaudhary K. Asymmetric aldol additions use of titanium tetrachloride and (-)-sparteine for the soft enolization of iV-acyl oxazoUdi-nones, oxazolidinethiones, and thiazoUdinethiones. J. Org. Chem. 2001 66 894-902. 

Evans has disclosed that oxazolidinone enolates can also be generated under mild conditions through the use of titanium tetrachloride and tertiary amine bases (Equation 11) [84]. These conditions have been referred to as "soft enolization and permit the use of electrophiles in enolate alkylations that are predisposed for Sml-type reactions [85]. As a demonstration of the synthetic utility of such conditions, the titanium enolate of oxazolidinone... 

Soft electrophiles will prefer carbon, and it is found experimentally that most alkyl halides react to give C-alkylation. Because of the n character of the HOMO of the anion, there is a stereoelectronic preference for attack of the electrophile approximately perpendicular to the plane of the enolate. The frontier orbital is ip2, with electron density mainly at O and C-2. The tpi orbital is transformed into the C=0 bond. The transition state for an 8 2 alkylation of an enolate can be represented as below. 

Ferrocen-l,l -diylbismetallacycles are conceptually attractive for the development of bimetal-catalyzed processes for one particular reason the distance between the reactive centers in a coordinated electrophile and a coordinated nucleophile is self-adjustable for specific tasks, because the activation energy for Cp ligand rotation is very low. In 2008, Peters and Jautze reported the application of the bis-palladacycle complex 56a to the enantioselective conjugate addition of a-cyanoacetates to enones (Fig. 31) [74—76] based on the idea that a soft bimetallic complex capable of simultaneously activating both Michael donor and acceptor would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol due to a highly organized transition state [77]. An a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd(II)-center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid [78],... 

Carreira and Kruger reported facile transmetallation of silicon enolates to other soft metal enolates including Gu derivatives.499 They reasoned that the use of soft metal fluoride complexes enabled silyl metal transmetallation with catalytic use of a soft metal source. The concept is illustrated in Scheme 103. Normal Lewis acid-catalyzed reactions of silicon enolates with aldehydes proceed via activation of aldehydes by carbonyl oxygen coordination to Lewis acids, as shown in the upper equation of Scheme 103. A key step for catalytic turnover is the desilyation of 233 by the... 

Besides direct nucleophilic attack onto the acceptor group, an activated diene may also undergo 1,4- or 1,6-addition in the latter case, capture of the ambident enolate with a soft electrophile can take place at two different positions. Hence, the nucleophilic addition can result in the formation of three regioisomeric alkenes, which may in addition be formed as E/Z isomers. Moreover, depending on the nature of nucleophile and electrophile, the addition products may contain one or two stereogenic centers, and, as a further complication, basic conditions may give rise to the isomerization of the initially formed 8,y-unsaturated carbonyl compounds (and other acceptor-substituted alkenes of this type) to the thermodynamically more stable conjugated isomer (Eq. 4.1). 

The central feature of the mechanism is the 3-cuprio(III) enolate Cpop, of an open, dimeric nature, as shown by comparison of theory with experimentation involving NMR and KIEs [80, 81]. This species serves as the direct precursor to the product (Scheme 10.5, top box). In this critical CPop complex, copper/olefin (soft/soft) and a lithium/carbonyl (hard/hard) interactions are present. The open complex may be formed directly, by way of an open cluster (bottom left of Scheme 10.5), or by complexation of a closed cluster with the enone (CPcl). Experiments have shown that the enone/lithium complex (top left of Scheme 10.11) is a deadend species [60, 74]. 

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