Acetate aldol addition, stereoselective

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. 

Later, Yamamoto and coworkers developed the axially chiral ester 183 for asymmetric acetate aldol additions. After formation of the lithium enolate with LDA, the reaction with various aldehydes yielded P-hydroxy esters 184 in very high diastereoselectivity. It was shown, for two adducts, that a nearly quantitative saponification leads to P-hydroxy carboxylic acids 176 and liberates phenol 185 in nearly quantitative yield and undiminished optical purity (Scheme 4.40) [100]. The authors discuss a twist-boat as well as an open transition state for rationalizing the preferred Re-face attack to the aldehyde, observed with (R,R)-configured acetate 183. Yamamoto s procedure is impressive because of its stereoselectivity, but one has to be aware that the chiral auxiliary 185 is by far not as readily accessible as others also enabling the asymmetric acetate aldol addition. 

Remarkably, the induced stereoselectivity of enolates 303 and 306 is opposite despite the homochiral diazaborolidine skeleton cis-enolate 303 attacks predominantly from the Re-face to the aldehyde, whereas traws-enolate 306 approaches from the Si-face. The opposite stereochemical outcome was explained by Zimmerman—Traxler-like transition state models 308 and 309, respectively. It was assumed that transition state 308 is favored because it avoids repulsion between the phenylthio and the arylsulfonyl group, whereas 309 prevents steric hindrance between the arylsulfonyl moiety and the aldehyde (Scheme 4.68) [151d]. The chiral controller group 300 was also applied to acetates and thioacetates, but the reactions were found to be plagued by distinctly lower enantioselectivity of 52-80% ee with benzaldehyde - another example of the problematic asymmetric acetate aldol addition. 

Guided by the success of the Evans and related auxiliaries, several attempts were made to use enantiomerically pure a-bromoacyl oxazolidinones for stereoselective Reformatsky reactions. Fukuzawa and coworkers developed the reaction of various bromoacetyl oxazolidinones 323 as an alternative to an asymmetric acetate aldol addition. The conversion was mediated by samarium iodide and yielded P-hydroxy carbonyl compounds 325 with high diastereoselectivity in optimal combinations of auxiliary group and aldehyde. Among the different auxiliaries, the geminal dimethyl- and diphenyl-substituted ones performed better than the original Evans oxazolidinones. The stereochemical outcome was rationalized by assuming that an O-bound samarium(III) enolate reacts via a chair-like... 

For a recent comprehensive review on stereoselective acetate aldol additions, see Romea, P. and Urpi, F. (2013) in Modern Methods in Stereoselective Aldol Reactions (ed R. Mahrwald), Wiley-VCH Verlag GmbH, Weinheim,... 

In 1986, Nagao demonstrated the effectiveness of the acetyl thiazolidi-nethione 80 in combination with Sn(OTf)2 and N-ethylpiperidine for highly stereoselective acetate aldol additions (Scheme 4.9) [57]. It was proposed that the stereochemical outcome was the result of the intermediacy of a closed Zimmerman-Traxler-type transition state 81. This method was utilized in Romo s synthesis of the immunosuppressive agent (-)-pateamine A (84) [58]. The Nagao acetate aldol reaction was implemented twice in the route, giving excellent yields and superb diastereoselectivity. 

One of the pervasive problems in asymmetric synthesis has been the development of stereoselective acetate ester aldol reactions. Although a number of chiral auxiliaries perform superbly well in diastereoselective propionate aldol additions, these have, with rare exceptions, been unsuccessful in the corresponding additions of unsubstituted acetate-derived enolates [19, 63, 64). Braun s disclosure of a stereoselective acetate aldol addition reaction with 103 was an important milestone in the development of the field (Scheme 4.11) [63, 65]. The diol auxiliary can easily be prepared from mandelic acid esterification of the secondary alcohol is obsei ved, without interference from the tertiary counterpart. Its use has been showcased in a number of syntheses [53]. The high yield and diastereoselectivity generally obtained with 103 were highlighted by investigators at Merck in the construction of the chiral lactone fragment that is common in a number of HMG-CoA reductase inhibitors, such as compactin (105) [66]. 

In general, chiral propanoates providing simple diastereoselectivity (in favor of yyn-aldols), combined with a reasonable degree of auxiliary-induced stereoselectivity, are rare. Numerous terpenoid- and carbohydrate-derived propionates do not display satisfactory syn selectivity60. Similarly, the titanium(IV) chloride promoted aldol addition of the following JV-metbylephe-drine derived silylketene acetal leads to the formation of the. mi-adduct in the moderate diastereomeric ratio of 78 22 (syn-adduct sum of the other stereoisomers)61. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

The induced stereoselectivity in these aldol additions with (///S)-2Tiydroxy-l,2,2-triphenylethyl acetate is improved by the use of an excess of base (e.g.. 3 equiv of lithium diisopropylamide or lithium hexamethyldisilazane) in the deprotonation step89. 

A somewhat tedious extension of this methodology, which guarantees good induced stereoselectivity, relies on the reversible introduction of an a-substituent which is removed after the aldol addition is performed. For this purpose, the corresponding derivative of (methyl-thio)acetic acid is converted into the boron enolate and subsequently reacted with aldehydes. The... 

The Mukaiyama aldol reaction can provide access to a variety of (3-hydroxy carbonyl compounds and use of acetals as reactants can provide (3-alkoxy derivatives. The issues of stereoselectivity are the same as those in the aldol addition reaction, but the tendency toward acyclic rather than cyclic TSs reduces the influence of the E- or Z-configuration of the enolate equivalent on the stereoselectivity. 

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.)... 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

Ester Enolate Aldol Additions to Aldehydes. Among the first examples of aldol additions employing chiral Lewis bases as catalysts were the additions of trichlorosilyl ketene acetals to aldehydes. Silyl ketene acetal 7 could be generated by metathesis of methyl tributylstannylacetate with SiCL. Treatment of 7 with benzaldehyde and 10 mol % of a phosphoramide in CH2CI2 at —78°C afforded aldol products in good to high yields with moderate enantioselectivities for all phosphoramides employed. Reaction of 7 with pivalaldehyde provided aldol products in similar yields and with slightly improved enantioselectivities. The increase in stereoselection is presumably attributed to a less com-... 

Stereoselective Aldol Reactions. The (R)- and (S)-2-hydroxy-1,2,2-triphenylethyl acetates (HYTRA) offer a simple soludon for a stereoselecdve aldol addition of a-unsubstituted enolates. When a suspension of HYTRA is treated in THF with 2 equiv of Lithium Diisopropylamide, a clear soludon of the enolate forms (eq 1). Subsequent dilution with 2-methylbutane followed by the addition of 2-methylpropanal affords predominantly the (R,R)-diastereomeric adduct. Alkaline hydrolysis not only delivers (/ )-3-hydroxy-4-methylpentanoic acid in 86-94% ee but also liberates the optically pure auxiliary reagent (/ )-1,2,2-triphenylethane-1,2-diol, which can be removed and reused (eq 1). - ... 

The pioneering discovery by Mukaiyama in 1974 of the Lewis acid mediated aldol addition reaction of enol silanes and aldehydes paved the way for subsequent explosive development of this innovative method for C-C bond formation. One of the central features of the Mukaiyama aldol process is that the typical enol silane is un-reactive at ambient temperatures with typical aldehydes. This reactivity profile allows exquisite control of the reaction stereoselectivity by various Lewis acids additionally, it has led to the advances in catalytic, enantioselective aldol methodology. Recent observations involving novel enol silanes, such as enoxy silacyclobutanes and O-si-lyl M(9-ketene acetals have expanded the scope of this process and provided additional insight into the mechanistic manifolds available to this versatile reaction. 

The same bisoxazoline Cu(II) and Sn(II) complexes have been utilized successfully in the corresponding propionate aldol addition reactions (Scheme 8-7). A remarkable feature of these catalytic processes is that either syn or anti simple dia-stereoselectivity may be accessed by appropriate selection of either Sn(II) or Cu(II) complexes. The addition of either - or Z-thiopropionate-derived silyl ke-tene acetals catalyzed by the Cu(II) complexes afford adducts 78, 80, and 82 displaying 86 14-97 3 syn anti) simple diastereoselectivity. The optical purity of the major syn diastereomer isolated from the additions of both Z- and i -enol silanes were excellent (85-99% ee). The stereochemical outcome of the aldol addition reactions mediated by Sn(Il) are complementary to the Cu(U)-catalyzed process and furnish the corresponding anp -stereoisomers 79, 81, and 83 as mixtures of 10 90-1 99 syn/anti diastereomers in 92-99% ee. 

Evans has recently reported the use of structurally well-defined Sn(II) Lewis acids 119 and 120 (Fig. 9)for the enantioselective aldol addition reactions of a-heterosubstituted substrates [83]. These complexes are easily assembled from Sn(OTf)2 and C2-symmetric bisoxazoline Hgands 124 and 126 (Fig. 10). The facile synthesis of these ligands commences with optically active 1,2-amino alcohols 122, which are themselves readily available from the corresponding a-amino acids 121 [84, 85]. The Sn(II) bis(oxazoHne) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, using 10 mol % of 119, thioacetate and thiopropionate derived silyl ketene acetals add at -78 °C in CH2CI2 to glyoxaldehyde to give hydroxy diesters 130 in superb yields and enantioselectivities as well as diastereo-selectivities (Eq. 12). The process represents an unusual example wherein 2,3-anti-aldol adducts are obtained in a stereoselective manner. 

The addition reaction of fert-butyl thioacetate-derived silyl ketene acetal produces the corresponding aldol adducts in 84% yield and up to 96% enantiomeric excess (Eq. 16). The enantioselectivity of the products was observed to be optimal with toluene as solvent the use of the more polar dichloromethane consistently produced adducts with 10-15% lower enantiomeric excess. The bulkier ferf-butylthioacetate-derived enol silane was found to lead to uniformly higher levels of enantioselectivity than the smaller S-ethyl thioketene acetal. This process is impressive in that it tolerates a wide range of aldehyde substrates for instance, the aldol addition reaction has been successfully conducted with aldehydes substituted with polar functionaUty such as N-Boc amides, chlorides, esters, and 0-benzyl ethers. A key feature of this system when compared to previously reported processes was the abiUty to achieve high levels of stereoselectivity at 0 °C, in contrast to other processes that commonly prescribe operating temperatures of -78 °C. 

The aldol reaction is one of the most useful carbon-carbon bond forming reactions in which one or two stereogenic centers are constructed simultaneously. Diastereo-and enantioselective aldol reactions have been performed with excellent chemical yield and stereoselectivity using chiral catalysts [142]. Most cases, however, required the preconversion of donor substrates into more reactive species, such as enol silyl ethers or ketene silyl acetals (Scheme 13.45, Mukaiyama-type aldol addition reaction), using no less than stoichiometric amounts of silicon atoms and bases (Scheme 13.45a). From an atom-economic point of view [143], such stoichiometric amounts of reagents, which afford wastes such as salts, should be excluded from the process. Thus, direct catalytic asymmetric aldol reaction is desirable, which utilizes unmodified ketone or ester as a nucleophile (Scheme 13.45b). Many researchers have directed considerable attention to this field, which is reflected in the increasing... 

Michael addition of the reagent to enoates and enones occurs at low temperature (—50 to —78 °C) in the presence of catalytic amounts of various Lewis acids. A catalytic amount of triph-enylmethyl perchlorate (5 mol %) effectively catalyzes the tandem Michael reaction of ethyl acetate-derived silyl ketene acetal to a, -unsaturated ketones and the sequential aldol addition to aldehydes with high stereoselectivity.HgL mediates the Michael addition to chiral enones, followed by Lewis acid-mediated addition to aldehydes. The Michael-aldol protocol has been used for the stereoselective synthesis of key intermediates on the way to prostaglandins, compactin, and ML-236A (eq 19). ... 

Synthesis of (R)-3-hydroxy-4-pentenoic acid 88 by stereoselective aldol addition of the chiral acetate (R)-83. 

Enolates or their neutralized equivalents (silyl enol ethers or enol acetates) play a central role in stereoselective reactions [97]. They can be employed in C-C-bond forming reactions, such as alkylations or aldol additions or in C-hetero bond formations, for example, oxygenation. Stereocontrol can be exerted via substrate control by preexisting stereocenters or via chiral auxiliaries, which are temporarily attached to the substrate. 

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