Propionate aldol addition

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). 

Impressive advances in catalytic, enantioselective propionate aldol addition reactions have also been documented since 1992. Mikami has described a Ti(lV) catalyst readily prepared from BINOL and TiC O Pr. A propionate aldol addition process by Evans utilizes complexes prepared with bisoxazoline ligands and Sn(II) and Cu(II). In analogy to the acetate aldol... 

New auxiliaries and reaction methods are now available for the stereoselective synthesis of all members of the stereochemical family of propionate aldol additions. These also include improvements on previously reported methods that by insightful modification of the original reaction conditions have led to considerable expansion of the versatility of the process. In addition to novel auxiliary-based systems, there continue to be unexpected observations in diastereoselective aldol addition reactions involving chiral aldehyde/achiral enolate, achiral aldehyde/chir-al enolate, and chiral aldehyde/chiral enolate reaction partners. These stereochemical surpri.ses underscore the underlying complexity of the reaction process and how much we have yet to understand. 

Masamune has documented the addition of optically active ester enolates that afford lanfi-aldol adducts in superb yields and impressive stereoselectivity (Eq. (8.3)) [4]. The generation of a boryl enolate from 8 follows from groundbreaking studies of ester enolization by Masamune employing dialkyl boryl tri-flates and amines [5]. Careful selection of di-n-alkyl boron triflate (di-n-butyl versus dicyclopentyl or dicyclohexyl) and base (triethyl amine versus Hiinigs base) leads to the formation of enolates that participate in the <2u//-selective propionate aldol additions. Under optimal conditions, 8 is treated with 1-2 equiv of di-c-hex-yl boron triflate and triethyl amine at -78 °C followed by addition of aldehyde the products 9 and 10 are isolated in up to 99 1 antv.syn diastereomeric ratio. The asymmetric aldol process can be successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. 

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. 

The auxiliaries R) and (S)-triphenylglycol 172 were also applied to achieve anti-selective propionate aldol additions, as shown by Braun and coworkers. It turned out that, for this purpose, the tertiary hydroxyl group of the propionate (R)-204 had to be protected by silylation. This was easily accomplished by a one-pot procedure that delivered the ester (R)-205. After deprotonation with LICA, the lithium enolate was transmetallated with dichloro(dicyclopentadienyl)zirconium and reacted with aliphatic aldehydes to give predominantly anti-diastereomers 206, the diastereomeric ratio surpassing 95 5. Reduction with lithium aluminum hydride finally led to diols 207 under the release of the chiral auxiliary R)-172. After its removal by chromatography, diastereomerically pure diols 207 were isolated with >95% ee (Scheme 4.45) [107]. For the benzaldehyde adduct 206 (R = Ph), alkaline hydrolysis was also performed and found to lead to epimerization to only a small degree. 

Scheme 4.45 Propionate aldol addition via triphenylglycol ester (ff)-204.

Evans auxiliaries originally developed for the propionate aldol addition were found to be applicable to a range of a-hetero-substituted acyl imides, illustrated in Scheme 4.52 for the valine-derivatized oxazoUdinones 229, pars pro toto the phenylalanine and ephedrine-derived auxiliaries were also used analogously. The robust method, mostly via the boron but also tin and titanium enolates, tolerates inter alia alkoxy, chloro, bromo, alkylthio, and isothiocyanato substituents in a-position and yields Evans-syn diastereomers 230 in a predictable and reliable way with high stereoselectivity (Scheme 4.52) [117]. It is obvious that the extension from propionates to the cx-heterosubstituted carboxylates made Evans aldol method even more valuable. The individual protocols and apphcations have been treated in several overviews [32, 67d-f]. 

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]. 

The allylation and crotylation of aldehydes provide attractive alternatives to asymmetric acetate and propionate aldol addition reactions for the construction of /1-hydroxy aldehydes or ketones (Scheme 5.2 see also Chapter 4). In analogy to propionate aldol addition reactions, an important stereochemical feature involving the addition of substituted allylation reagents to aldehydes is simple diastereoselectivity namely, the formation of 1,2-syn versus 1,2-anti products. Although the underlying reasons for absolute and relative induction have yet to be studied in mechanistic detail for many of these processes, there are a collection of methods that reliably and predictably furnish optically active adducts. 

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. 

The predominant formation of ann -carboxylic esters and thioesters results when the additives 13 or 14 are used to mediate aldol additions of silylketene acetals derived from propionates and propanethioates37. The enantioselective addition of a-unsubstituted esters or thioesters is also feasible with the borane 1437. 

Catalysis with Bisoxazoline Complexes of Sn(II) and Cu(II). The bisoxazoline Cu(IT) and Sn(II) complexes 81-85 that have proven successful in the acetate additions with aldehydes 86,87, 88 also function as catalysts for the corresponding asymmetric propionate Mukaiyama aldol addition reactions (Scheme 8B2.8) [27]. It is worth noting that eithersyn or anti simple diastereoselectivity may be obtained by appropriate selection of either Sn(II) or Cu(II) complexes (Table 8B2.12). 

Significant efforts have extended the scope of catalytic enantioselective Mukaiyama aldol addition reactions beyond the acetate and propionate enoxysilanes and have been used traditionally. Recent reports describe novel addition reactions of silyl dienolates along with isobutyrate-derived enol silanes. 

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

For the propionate aldol reaction the Li enolate (7), generated by deprotonation of 2,6-dimethylphenyl propionate with Lithium Diisopropylamide in EtiO, was chosen. Transmetalation with 1.25 equiv of an ethereal solution of (1) takes 24 h at —78 °C. The completion of this step is evident by the disappearance of racemic anti-a do (9) in favor of optically active yw-isomer (10) (91-98% ee) upon reaction with an aldehyde (RCHO) and aqueous workup. At this point, 3-11% of anri-aldol (9) remaining in the reaction mixture is optically active as well (eq 2). This awri-isomer (9) (94-98% ee) becomes the major product if the reaction mixture, containing the putative ( )-titanium enolate derived from (7), is warmed for 4-5 h to —30°C before reaction with an aldehyde (RCHO) again at —78 °C. Isomerization to the (Z)-titanium enolate is a possible explanation of this behavior. Some substrates, aromatic and unsaturated aldehydes, behave exceptionally, as a high proportion of yn-isomer (10) (19-77%) of lower optical purity (47-66% ee) is formed in addition to (9) (94-98% ee). After hydrolysis of the acetonide (6) the products (9/10) are isolated and separated by chromatography in 50-87% yield. The reactions of pivalaldehyde (R = r-Bu) are sluggish at —78°C and have therefore been carried out at —50 to —30°C. 

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. 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of apoptolidinone. This synthesis features three thiazolidinethione propionate aldol reactions for controlling the configuration of 6 of 12 stereogenio centers <05JA13810>. For example, addition of aldehyde 146 to the enolate solution of A -propionyl thiazolidinethione 145 produces aldol product 147 with excellent selectivity (>98 2) for the Evans syn isomer. Compound 145 also undergoes diastereoselective aldol addition with bisaryl aldehyde 148 to give the Evans syn product 149, which is converted to eupomatilone-6 in 6 steps <05JOC9658>. 

The use of these boryl complexes in catalytic, enantioselective additions to aldehydes by silyl ketene acetals has also been the subject of intense investigation by Yamamoto (Eq. 30) [108]. Although ethyl and benzyl acetate-derived enol silanes furnished racemic products, the phenyl acetate-derived trimethylsilyl ketene acetals proved optimal, giving adducts in up to 84% ee. Additionally, Yamamoto has documented the use of 184 in aldol addition reactions of propionate- and isobutyrate-derived enol silanes (Eqs. 31 and 32). Thus, the addition of the phenyl acetate derived (E)-enol silane afforded adducts as diastereomeric mixtures with the syn stereoisomer displaying up to 97% ee (Eq. 32). 

In analogy to the Yamamoto and Kiyooka catalysts, Mukaiyama aldol addition reactions catalyzed by 202a and 202b are optimal for 0-phenyl acetate-derived enol silanes under conditions wherein the aldehyde substrates are added slowly to the reaction mixture in propionitrile at -78 C. The aldol adducts are isolated for a broad range of aldehydes in excellent yields and up to 92% ee (Eq. 40). The propionate aldol adducts are isolated in good yields, with preference for the syn diastereomer in up to 98% ee (Eq.41) [117]. 

These tri(alkoxy)titanium enolates, which have low Lewis acidity, are known to react chemoselective-ly with an aldehyde group in the presence of a ketone (equation 4). Other uses described by Reetz et al. include the diastereofacially selective additions of ketone and ester enolates to chiral a-alkoxy aldehydes with nonchelation control. - For example, aldol addition of the tri(isopropoxy)titanium enolate of pro-piophenone to the aldehyde (24) leads to only the two syn diastereomers, with the nonchelation adduct (25) favored (equation 5) i.e. Felkin-Anh selectivity is operating. In the case of aldol addition of t-butyl propionate to the same aldehyde (equation 6), highest stereoselectivity for the isomer (26) is obtained using the tri(diethylamino)titanium enolate. Very high levels of nonchelation stereoselectivity can also be obtained in the aldol addition to chiral a-siloxy or a-benzyloxy ketones if a titanium enolate of low Lewis acidity is employed, as in equation (7). ... 

During the 1980s, one of the major thrusts of asymmetric synthesis was the development of chiral auxiliaries for the alkylation and aldol addition of propionates. The following paragraphs describe some of the methods that evolved, beginning with two examples of propionate ester alkylations developed by Helmchen using chiral alcohols as the auxiliary and ending with propionic imide auxiliaries developed by Evans and Oppolzer. 

Kinetic control. The Zimmerman-Traxler model, as applied to propionate and ethyl ketone aldol additions, is shown in Scheme 5.7 (note the similarity to the boron-mediated allyl additions in Scheme 5.3). Based on this model, we would expect a significant dependence of stereoselectivity on the enolate geometry, which is in turn dependent on the nature of X and the deprotonating agent (see section... 

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