Acetate aldol problem

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

Extensive investigations have been directed toward the development of chiral ester enolates that might exhibit practical levels of aldol asymmetric induction. Much of the early work in this area has been reviewed (111). In general, metal enolates derived from chiral acetate and propionate esters exhibit low levels of aldol asymmetric induction that rarely exceed 50% enantiomeric excess. The added problems associated with the low levels of aldol diastereoselection found with most substituted ester enolates (cf. Table 11) further detract from their utility as effective chiral enolates for the aldol process. Recent studies have examined the potential applications of the chiral propionates 121 to 125 in the aldol condensation (eq. [94]), and the observed erythro-threo diastereoselection and diastere-oface selection for these enolates are summarized in Table 31. For the six lithium enolates the threo diastereoselection was found to be... 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

The next task was to form the C2-C3 aldol bond stereoselectively. However, asymmetric coupling of acetate derivatives to aldehydes is often accompanied by poor / -induction [89]. Moreover, the C3-C4 bond is particularly sensitive to retro-aldol reaction, especially under basic conditions. In the natural products, this was observed to be the main decomposition reaction. The first total syntheses of epothilones circumvented this problem by constructing this part of the molecule in an indirect manner, e.g., by using reduced forms at Cl or C5. We decided to employ our chromium-Reformatsky methodology, which avoids these problems and allows the direct use of reagents in the correct oxidation state. The non-basic reaction conditions, the intermediacy of a chromium(III) aldolate that is resistant to retro-aldol reaction, and the potential of a direct asymmetric carboxymethyl ( acetate ) transfer favor the use of this method [90]. 

An interesting problem in stereoisomerism is found in the aldol reactions of the achiral aldehydes which are obtained by ozonolysis of the homoallylic alcohols 174. After stereospecific conversion by the FruA [230], the products can be readily induced to form an intramolecular glycoside 175 by acidic (R=OH) or alkaline treatment (R=C1), under which conditions the two equatorial ring hydroxyl groups completely direct the stereogenic acetal formation [234]. The corresponding RhuA catalyzed reactions deliver the enantiomeric... 

The base One equivalent, at least, of a base relative to the aryl halide must be present to achieve the alkene substitution catalytically. Most often a tertiary amine is employed. Secondary amines also appear to be suitable but primary amines usually are not. The base strength of the amine is important since only quite basic amines such as triethylamine work well. Acetate salts, carbonates and bicarbonates also are suitable bases but solubility may cause difficulties in some instances. The addition of a phase transfer agent such as a quaternary ammonium salt has often solved this problem. The inorganic bases, of course, may cause other problems such as ester hydrolysis, aldol condensations and other undesired side reactions. 

The syntheses of the Cl -C6 aldol fragment (C) and similar building blocks with defined stereochemistry at C3 reveal several general problems. On one hand, it is difficult to transfer an acetate unit to an aldehyde with good ) -induc-tion, this usually is referred to as the aeetate-problem [44]. On the other hand the CI-C5... 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles proceed smoothly in the presence of 2 mol % B(CgF5)3 [151a,c]. The following characteristic features should be noted (i) the products can be isolated as j8-trimethylsilyloxy ketones when crude adducts are worked-up without exposure to acid (ii) this reaction can be conducted in aqueous media, so that the reaction of the silyl enol ether derived from propiophenone with a commercial aqueous solution of formaldehyde does not present any problems (iii) the rate of an aldol reaction is markedly increased by use of an anhydrous solution of B(C6Fs)3 in toluene under an argon atmosphere and (iv) silyl enol ethers can be reacted with chloromethyl methyl ether or trimethylorthoformate hydroxymethyl, methoxy-methyl, or dimethoxymethyl Cl groups can be introduced at the position a to the carbonyl group. These aldol-type reactions do not proceed when triphenylborane is used (Eq. 92). 

In Kiyooka s approach to acetate aldols by use of a stoichiometric amount of 3f, the enantiomeric excess obtained in the reaction with silyl ketene acetals derived from a-unsubstituted acetates was much lower (ca 10-20 %) than that obtained in the reaction with l-ethoxy-2-methyl-l-(trimethylsiloxy)-l-propene (> 98 % ee). Introduction of an removable substituent, e.g., a methylthio or bromo substituent, after aldol reaction at the a-position of chiral esters, resolved this problem [43e], Asymmetric synthesis of dithiolane aldols was achieved in good yield by using the silyl ketene acetal derived from l,3-dithiolane-2-carboxylate in the 3f-promoted aldol reaction, and desulfurization of the dithiolane aldols resulted in production of the acetate aldols in high enantiomeric purity (Eq. 56). 

Many of the classical methods grew out of the earliest synthesis of imidazole, which was achieved in 1858 by Debus [1] when he allowed glyoxal, formaldehyde and ammonia to react together. Although the earliest modifications of this method used a-diketones or a-ketoaldehydes as substrates [2, by the 1930s it was well established that a-hydroxycarbonyl compounds could serve equally well, provided that a mild oxidizer (e.g. ammoniacal copper(ll) acetate, citrate or sulfate) was incorporated [3. A further improvement was to use ammonium acetate in acetic acid as the nitrogen source. All of these early methods have deficiencies. There are problems associated with the synthesis of a wide range of a-hydroxyketones or a-dicarbonyls, yields are invariably rather poor, and more often than not mixtures of products are formed. There are, nevertheless, still applications to the preparation of simple 4-alkyl-, 4,5-dialkyl(diaryl)- and 2,4,5-trialkyl(triaryl)imidazoles. For example, pymvaldehyde can be converted quite conveniently into 4-methylimidazole or 2,4-dimethylimidazole. However, reversed aldol reactions of pyruvaldehyde in ammoniacal solution lead to other imidazoles (e.g. 2-acetyl-4-methylimidazole) as minor products [4]. Such... 

Despite the impressive developments in asymmetric aldol processes, a number of gaps have remained in the field. Thus, for example, stereoselective acetate additions that produce /i-hydroxy a-unsubstituted carbonyl adducts as well as propionate additions that produce anri-substituted aldol adducts constitute synthetic problems that remained elusive and intractable. Recently, however, a number of innovative independent solutions have been crafted involving novel chiral-auxiliaries and asymmetric catalysis. 

In addition to the acetate aldol problem, stereoselective aldol additions of substituted enolates to yield 1,2-anti- or f/treo-selective adducts has remained as a persistent gap in asymmetric aldol methodology. A number of innovative solutions have been documented recently that provide ready access to such products. The different successful approaches to anri-selective propionate aldol adducts stem from the design of novel auxiliaries coupled to the study of metal and base effects on the reaction stereochemistry. The newest class of auxiliaries are derived from A-arylsulfonyl amides prepared from readily available optically active vicinal amino alcohols, such as cw-l-aminoindan-2-ol and norephedrine. 

The solution to the chemoselectivity problem is minimal protection ap-mcthoxybcnzyl group for the hydroxyaldehyde and an acetal 158 for the diol unit in the product 157 of the enzyme-catalysed aldol reaction. The solution to the alkene geometry problem is going to be intramolecular trapping by the one remaining free OH group. 

The development of a catalytic, enantioselective Mannich-type reaction of si-lyl ketene acetals lagged far behind the now-well-established enantioselective Mukaiyama directed aldol addition. The major consideration for the invention of such a transformation is obviously the selection of an appropriate Lewis acid activator. This is a challenging problem in view of the basicity of the imine nitrogen, the ambiguity in complexation geometry, and most importantly the release of the catalyst to effect turnover. Thus, it is not surprising that the first successful catalytic, enantioselective Mannich reaction was reported only in 1997. 

Oxidative Cleavage Reactions. Among the numerous methods for 1,2-diol cleavage there exist only a few that involve catalytic ruthenium reagents, for example Ruthenium(III) Chloride with Sodium Periodate Attempted selective monooxidation of a 1,2-diol to the hydroxy aldehyde with catalytic TPAP and NMO resulted in carbon-carbon bond cleavage to provide the aldehyde (eq 11). Furthermore, attempted oxidation of an anomeric a-hydroxy ester failed instead, in this case decarboxy-lation/decarbonylation and formation of the lactone was observed (eq 12). However, Dimethyl Sulfoxide-Acetic Anhydride provided the required a-dicarbonyl unit. Retro-aldol fragmentations can also be a problem. ... 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles like chloromethyl methyl ether and trimethylorthoformate proceed smoothly in the presence of 2 mol% of 1 (eq 1) (3, 5). These reactions can be carried out in aqueous media, so that the reaction of silyl enol ethers with an aqueous solution of formaldehyde does not present any problems. Triphenylboron catalyzes no aldol-type reactions. 

The problem occurs in aldol additions of methyl ketones and all kind of acetic acid derivative, esters, amides, and thioamides [53, 54]. 

The formation of an active complex 81 consisting of three components, tin(II) trifiate, chiral diamine 80, and dibutyltin acetate is assumed in these aldol reactions. The three-component complex would activate both aldehyde and silyl enolate (double activation), i.e. the chiral diamine-coordinated tin(II) trifiate activates aldehyde while oxygen atoms of the acetoxy groups in dibutyltin acetate interact with the silicon atom of the silicon enolate. Because it has been found that the reaction does not proceed via tin(II) or tin(IV) enolates formed by silicon-metal exchange, silicon enolate is considered to attack the aldehydes directly [65]. The problem of this aldol reaction is that (Z) enolates [63] react with aldehydes more slowly, consequently affording the aldols in lower yield and with lower diastereo- and enantio-selectivity. 

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