Acetate Aldol Additions

Some of the most impressive advances in the area of catalytic, enantioselective aldol addition reactions have taken place in the development of catalytic methods for enantioselective acetate aldol additions, a reaction type that has long been recalcitrant. Thus, although prior to 1992 a number of chiral-auxiliary based and catalytic methods were available for diastereo- and enantiocontrol in propionate aldol addition reactions, there was a paucity of analogous methods for effective stereocontrol in the addition of the simpler acetate-derived enol silanes. However, recent developments in this area have led to the availability of several useful catalytic processes. Thus, in contrast to the state of the art in 1992, it is possible to prepare acetate-derived aldol fragments utilizing asymmetric catalysis with a variety of transition-metal based complexes of Ti(IV), Cu(II), Sn(II), and Ag(I). 

TABLE 8B2.8. Catalytic, Enantioselective methyl acetate aldol addition reactions (Eq. 8B2.17)0... 

The acetate aldol addition reactions using catalyst 72 have found application in a number of syntheses. S imon and co-workers util ized aldol adduct 74 as a key building block in the total synthesi s... 

Highly diastereoselective acetate aldol additions using chlorotitanium enolates of mesityl-substituted JV-acetylthiazolidinethione 136 has been documented <07OL149>. These aldol reactions proceed in high yields and diastereoselectivities (94/6 to 98/2) for aliphatic, aromatic, and a,P-unsaturated aldehydes. Compound 136 also undergoes double diastereoselective aldol additions with chiral aldehyde 139 to give adduct 140 in high yields. 

In addition to the efficiency exhibited by catalyst 165 with a broad spectrum of aldehydes in acetate aldol addition reactions, this catalyst has been shown to function competently in enantioselective additions of dienol silane 87. The requisite dienolate is readily synthesized from 2,2,6-trimethyl-4H-l,3-dioxin-4-one 84 (diketene-i-acetone adduct) by deprotonation with LDA and quenching with MejSiCl (Eq. 24). Dioxinone 84 is commercially available at a nominal price in addition, the silyl dienolate 87 is easily purified by distillation and stable to prolonged storage. The addition reactions of 87 with aldehydes were conducted with 1-3 mol % of 165 at 0 °C (Eq. 25). A variety of aldehydes serve as substrates and give aldol adducts in 79-97% yields and up to 99% ee after a single recrystallization. 

A synthesis of atorvastatin calcium that used the acetate aldol addition of (5)-173 is shown in Scheme 4.38. Thus, the reaction of the enolate 174, transmetallated with magnesium bromide, with the aldehyde 177 at -78°C led to the triphenylglycol ester 178, isolated in 60% yield after recrystalUzation in a diastereomeric ratio of 97.8 2.2. The chiral auxiliary was cleaved by a... 

Scheme 4.38 Application of the acetate aldol addition of triphenylglycol ester (S)-173 for syntheses of HMG-CoA reductase inhibitors atorvastatin, lovastatin, and fluvastatin.

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. 

After Nagao, Fujita, and coworkers had introduced Af-acyl thiazolidinethiones for asymmetric acetate aldol additions in 1985 [34a, 115], the group of Crimmins... 

Aside from thiazolidinethione 234 various related Af-acylimides like 237a-d, also shown in Scheme 4.53, served for acetate aldol additions mostly through the titanium enolates and led to diastereomeric ratios in the range from 90 10 to 95 5 [35a, 120]. In most of these procedures, the diastereoselectivity is lower than that reached by Evans propionate aldol protocols [121]. 

Scheme 4.53 Unselective Evans N-acetyl oxazolidinone 231 and selected auxiliaries 232, 234, and 237 for acetate aldol additions.

Oppolzer s sultams also provided a solution to the problem of the asymmetric acetate aldol addition based upon a Mukaiyama reaction of sUyl ketene N,0-acetal 276, derived from N-acetylsultam 92 (R = H). In the titanium tetrachloride-mediated reaction with various aldehydes, the diastereoselectivity is not particularly high - as typical for aldol additions of a-unsubstituted enolates. 

Scheme 4.64 Acetate aldol addition with Iron acetyl complex 124b via Davies-Liebeskind enolates.

Scheme 4.65 Masamune s aldol reaction mediated by the Cj-symmetric borolane as a chiral controller in enolates 283. Transition state model for the propionate and acetate aldol additions 286 and 287, respectively.

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. 

Scheme 4.70 Acetate aldol additions mediated via titanium enolates with chiral ligands derived from diacetone glucose and TADDOL 312 and 313, respectively.

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 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]. 

Keck has reported a catalytic enantioselective acetate aldol addition reaction that utilizes a H(IV) catalyst 79 that is readily prepared in situ (Eq. 8B2.20) [26]. The reaction protocol is noteworthy as a consequence of its simplicity of execution thus BINOL, TiCl2( )2 ... 

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 addition to the advances in auxiliary-controlled acetate aldol addition reactions, a number of innovative solutions for the preparation of propionate-derived 1,2-anti products have also appeared using auxiliaries other than Evans oxazolidinone. The various successful approaches to anti aldol adducts stem from the design of novel auxiliaries coupled with the study of metal and base effects on the reaction stereochemistry. Masamune documented that the addition of optically active ester enolate 112 to aldehydes afforded anti aldol adduct 113 in superb yield and diastereoselectivity (Equation 10) [70]. After careful selection of the reaction conditions for the enolization of the ester [71], the aldol addition was successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. An attractive feature of this process is the subsequent facile removal of the auxiliary (LiOH, THF/H2O) to afford the corresponding acid without concomitant deterioration of the configurational integrity of the products [70]. 

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