Aldol addition Lewis-base-catalyzed

TABLE 8B2.4. Lewis base-catalyzed aldol addition reactions (Eq. 8B2.9)0... 

Recently, the rapid preparation of carbohydrates has been facilitated by a synthetic route based on aldol coupling of three aldehydes used for the de novo production of polyol differentiated hexoses in only two chemical steps. The dimerization of alpha-oxyaldehydes, catalyzed by L-proline, is followed by a tandem Mukaiyama aldol addition-cyclization step catalyzed by a Lewis acid. Differentially protected glucose, allose, and mannose stereoisomers can each be selected, in high yield [46]. Microwave irradiation is becoming an increasingly popular method of carbohydrate synthesis and has been the subject of a recent review [47]. 

Denmark, S. E., Stavenger, R. A., Wong, K.-T. Lewis Base-Catalyzed, Asymmetric Aldol Additions of Methyl Ketone Enolates. J. Org. Chem. 1998, 63, 918-919. 

Recent developments in the field have also identified novel mechanistic pathways for the development of catalytic, asymmetric aldol processes. Thus in addition to Lewis acid catalysts that mediate the Mukaiyama aldol addition by electrophilic activation of the aldehyde reactant, metal complexes that lead to enolate activation by the formation of a metalloenolate have been documented. Additionally, a new class of Lewis-base-catalyzed addition reactions is now available for the asymmetric aldol addition reaction. 

Denmark et al. used non-linear effects to identify a higher order molecularity of the catalyst with respect to substrate in one of the pathways for a chiral Lewis base-catalyzed aldol addition reaction [60]. The reaction generates mainly a syn or an anti aldol, according to the catalysts used (A or B, Scheme 9). It was proposed that the formation of the anfi-adduct involved two molecules of a chiral phosphoramide A (the catalyst) bound to a cationic sihcon intermediate. In contrast, only one molecule of the more bulky catalyst B can bind to silicon, favoring the formation of the syw-adduct. This interpretation is in agreement with the NLE curve observed for catalyst A and the linear behavior observed with catalyst B. 

In a novel departure from the traditional approach to the asymmetric Mukaiyama aldol, Denmark has reported a Lewis base-catalyzed aldol addition reaction of enol trichlorosilanes and aldehydes. These unusual silyl ketene acetals are readily prepared by treatment of the tributylstannyl enolates 246 with SiC (Eq. 51). In the initial ground-breaking studies, the methyl acetate-derived trichlorosilyl ketene acetal 247 was shown to add rapidly to a broad range of aldehydes at -80 C to give adducts (89-99% yield, Eq. 52). 

Thus in the aldol addition, just as in the case of epoxide-opening reactions, the chloride ion, formed as a necessary consequence of the mechanism of Lewis base catalysis with chlorosilanes, is not innocuous. In fact, it is a competent nucleophile that can attack an aldehyde or an epoxide activated by the Lewis base-coordinated silicenium cation in an intermolecular fashion. The desire to understand these two seemingly inconsistent results obtained in our study of the Lewis base-catalyzed reactions of trichlorosilanes presented an opportunity for the development of novel catalytic processes. For example, if a chloride ion can capture these activated electrophiles, could other exogenous nucleophiles be employed to intercept these reactive intermediates If so, a wide variety of bond-forming processes mediated by the phosphoramide-bound chiral Lewis acid [LB SiCls]" would be feasible. At this point it remained unclear if (1) an exogenous nucleophile could compete with the ion-paired chloride and (2) what kinds of nucleophiles could be compatible with the reaction conditions. 

The results of the aldol additions with silyl enol ethers further refined our new model of a Lewis base-catalyzed-Lewis acid-mediated pathway. Use of the N value was clearly predictive of substrate scope, validating our mechanistic scheme and the role of the ionized chloride in the complex. Gratifyingly, the sense of asymmetric induction in all these reactions is the same using the chiral bisphosphoramide (RJi)-S. 

Demnark SE, Fan Y, Eastgate MD (2005) Lewis base catalyzed, enantioselective aldol addition of methyl trichlOTOsUyl ketene acetal to ketraies. J Org Chem 70 5235—5248... 

Denmark SE, Su X, Nishigaichi Y (1998) The chanistry of trichlorosilyl enolates. 6. Mechanistic duality in the lewis base-catalyzed aldol addition reaction. J Am Chem Soc 120 12990-12991... 

Denmark SE, Stavenger RA, Wong K-T (1998) Lewis base-catalyzed, asymmetric aldol additions of methyl ketone enolates. J Org Chem 63 918-919... 

Denmark SE, Su X (1999) Solid state and solution structural studies of chiral phosphoramide-tin complexes relevant to lewis base catalyzed aldol addition reactions. Tetrahedron 55 8727-8738... 

Denmark SE, Fujimori S (2002) The effects of a remote stereogenic center in the lewis base catalyzed aldol additions of chiral trichlorosilyl enolates. Oig Lett 4 3477-3480... 

Denmark SE, Eklov BM, Yao PJ, Eastgate MD (2009) On the mechanism of lewis base catalyzed aldol addition reactions kinetic and spectroscopic investigations using rapid-injection NMR. J Am Chem Soc 131 11770-11787... 

Scheme 7.21 Lewis-base catalyzed aldol addition...

Aldolases are part of a large group of enzymes called lyases and are present in all organisms. They usually catalyze the reversible stereo-specific aldol addition of a donor ketone to an acceptor aldehyde. Mechanistically, two classes of aldolases can be recognized [4] (i) type I aldolases form a Schiff-base intermediate between the donor substrate and a highly conserved lysine residue in the active site of the enzyme, and (ii) type II aldolases are dependent of a metal cation as cofactor, mainly Zn, which acts as a Lewis acid in the activation of the donor substrate (Scheme 4.1). 

The mechanisms for metal-catalyzed and organocatalyzed direct aldol addition reactions differ one from another, and resemble the mode of action of the type 11 and type I aldolases, respectively. Some metal-ligand complexes, for example, 1-4 and 9 are considered to have a bifunctional character [22], embodying within the same molecular frame a Lewis acidic site and a Bronsted basic site. Whereas base would be required to form the transient enolate species as an active form of the carbonyl donor, the Lewis acid site would coordinate the acceptor aldehyde carbonyl, increasing its electrophilicity. By this means, both transition state stabilization and substrates preorganization would be provided (see Scheme 5 for a proposal). 

This concept of Lewis base catalysis has been widely developed by Denmark and coworkers in the asymmetric aldol additions of trichlorosilyl enolates on aldehydes. These reactions were shown to be highly susceptible to acceleration by catalytic quantities of chiral phosphoramides [69-77]. In particular, a phos-phoramide derived from (S,S)-stilbenediamine was remarkably effective not only in accelerating the reaction but also in modulating the diastereoselectivity and in providing the aldol addition products in good to excellent enantioselec-tivity. For example, trichlorosilyl enolate 61 reacts with benzaldehyde in very high enantio- and diastereoselectivity with 10 mol% of phosphoramide 62 in favor of the anti diastereomer (antifsyn 60/1). The catalyzed aldol reaction depends on the bulkiness and loading of the catalyst. On the other hand, the hindered phosphoramide (S,S)-63 afforded the syn aldol product in excellent diastereoselectivity (anti syn 1/97) but with modest enantioselectivity. 

In order to reverse the diastereoselectivity in the aldol reaction, the Lewis acid-catalyzed silyl enol ether addition (73) (Mukaiyama aldol reaction) was examined. Since the Mukaiyama aldol reaction is assumed to be proceeded via an acyclic transition state, a chelation controled aldol reaction of the a-alkoxy aldehyde should be possible (74). In the presence of TiCU, the silyl enol ether derived from 14 was reacted with aldehyde 13, followed by desilylation to afford the desired anti-Felkin product 122a as a single adduct (Scheme 21). Based on precedents for chelation-controlled Mukaiyama aldol reaction (74), the exceptional high selectivity in this reaction would be accounted for by chelation of TiCl4 with the C23-methoxy group of the aldehyde 13 (eq. 13). On the other hand, when the lithium enolate derived from 14 was treated with the aldehyde 13, followed by desilylation, it gave a 1 4 ratio of the two epimers in favour of the undesired (22S)-aldol product... 

This review covers the catalytic literature on condensation reactions to form ketones, by various routes. The focus is on newer developments from the past 15 years, although some older references are included to put the new work in context. Decarboxylative condensations of carboxylic acids and aldehydes, multistep aldol transformations, and condensations based on other functional groups such as boronic acids are considered. The composition of successful catalysts and the important process considerations are discussed. The treatment excludes enantioselective aldehyde and ketone additions requiring stoichiometric amounts of enol silyl ethers (Mukaiyama reaction) or other silyl enolates, and aldol condensations catalyzed by enzymes (aldolases) or catalytic antibodies with aldolase activity. It also excludes condensations catalyzed at ambient conditions or below by aqueous base. Recent reviews on these topics are those of Machajewski and Wong, Shibasaki and Sasai, and Lawrence. " The enzymatic condensations produce mainly polyhydroxyketones. The Mukaiyama and similar reactions require a Lewis acid or Lewis base as catalyst, and the protecting silyl ether or other group must be subsequently removed. However, in some recent work the silane concentrations have been reduced to catalytic amounts (or even zero) this work is discussed. 

Amino)cinnamoyl compounds 79 can be regarded as primary products they may arise from an aldol condensation catalyzed by base, add, or (most frequently) by Lewis acids [173]. Alternatively, quinoline formation may result from primary cross aldol addition, subsequent cydocondensation to an imine(4-hydroxy-3,4-dihydroquinoHne), and aromatization by H2O elimination [174]). 

In the catalytic cycle, a simplified version of which is shown in Scheme 5.72 for the acetate aldol addition of 246, the highly electrophilic silyl cation 251 plays a key role, as assumed by the authors. It forms from the reaction of tetrachlorosilane with the corresponding phosphoramide ((Me2N)3PO symbolizing the catalyst 235). When loaded with benzaldehyde, silicon enlarges its coordination sphere and adopts an octahedral geometry in 252. After the carbon-carbon bond has been established, cation 253 forms. It then decomposes to liberate phosphoramide 235, chlorotrialkylsilane, and the aldolate 254. By NMR studies, it was shown that the intermediate of this procedure is the tric/i/orosilyl-protected aldolate 254. This makes a substantial mechanistic difference to conventional Lewis acid-catalyzed Mukaiyama aldol protocols that deliver tri /Ay/silyl-protected aldolates. In accordance with the catalytic cycle shown in Scheme 5.72, tetrachlorosilane is consumed and therefore required to be used in stoichiometric amounts. Thus, the reaction is catalyzed by phosphoramides and mediated by tetrachlorosilane or, more generally, by Lewis base-activated Lewis acids [126]. 

This class of chiral Lewis base catalysts was also applicable to the enantioselective aldol reactions of trichlorosilyl enol ethers (Scheme 7.14) [24, 25). As included in Scheme 7.14, Denmark devised chiral bipyridine N.N -dioxide 8 and demonstrated that it smoothly catalyzed the aldol addition of methyl acetate-derived trichlorosilyl ketene acetal to a series of ketones with good to high enantioselectivi-ties [25],... 

According to Mayr s nucleophilicity scale (N), silyl enol ethers derived from aldehydes (N > 3.5) and ketones (N > 5) and, in particular, silyl ketene acetals (N > 8) [70] represent powerful nucleophihc reagents. Indeed, the aldol-type addition of trichlorosilyl enol ethers 76a-d to aldehydes 1 proceeds readily at room temperature without a catalyst (Scheme 15.14), which is in contrast with the lack of reactivity of allyl silanes in the absence of a catalyst. As a result, the reaction exhibits simple first-order kinetics in each component [71, 72]. Nevertheless, the reaction is substantially accelerated by Lewis bases, which provides a sohd ground for the development of an asymmetric variant The required trichlorosilyl enol ethers 76 can be generated in various ways, for example (i) from the corresponding trimethylsilyl enol ethers on reaction with SiCLt, catalyzed by (AcO)2Hg,... 

Researchers fundamentally interested in C-C bond-forming methods for polyketide synthesis have at times viewed allylation methods as alternatives, and maybe even competitors, to aldol addition reactions. Both areas have dealt with similar stereochemical problems simple versus absolute stereocontrol, matched versus mismatched reactants. There are mechanistic similarities between both reaction classes open and closed transition states, and Lewis acid and base catalysis. Moreover, there is considerable overlap in the prominent players in each area boron, titanium, tin, silicon, to name but a few, and the evolution of advances in both areas have paralleled each other closely. However, this holds for an analysis that views the allylation products (C=C) merely as surrogates of or synthetic equivalents to aldol products (C=0). The recent advances in alkene chemistry, such as olefin metathesis and metal-catalyzed coupling reactions, underscore the synthetic utility and versatility of alkenes in their own right. In reality, allylation and aldol methods are complementary The examples included throughout the chapter highlight the versatility and rich opportunities that allylation chemistry has to offer in synthetic design. 

The mechanism is similar to that of the barium-catalyzed direct aldol reaction (Scheme 16). The reaction commences with deprotonation of the ketone (2) by the Br0nsted base unit of the catalyst under generation of the enolate 81. After addition of the aldehyde 1 the Lewis acid-base adduct 82 is formed. Then the reaction of the aldehyde and the enolate occurs (82 83). After... 

---