Acetate aldol addition/reaction

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... 

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. 

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 ... 

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]. 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

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. 

Z-vinyl iodide was obtained by hydroboration and protonolysis of an iodoalkyne. The two major fragments were coupled by a Suzuki reaction at Steps H-l and H-2 between a vinylborane and vinyl iodide to form the C(ll)-C(12) bond. The macrocyclization was done by an aldol addition reaction at Step H-4. The enolate of the C(2) acetate adds to the C(3) aldehyde, creating the C(2)-C(3) bond and also establishing the configuration at C(3). The final steps involve selective deprotonation and oxidation at C(5), deprotection at C(3) and C(7), and epoxidation. 

The group of Samuel Danishefsky at the Sloan-Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of these syntheses also uses the olefin metathesis reaction (not shown). The synthesis in Scheme 13.51 uses an alternative approach to create the macrocycle. One of the key steps is a Suzuki coupling carried out at step H-(l,2) between a vinylborane and vinyl iodide. The macrocyclization is an aldol addition reaction at step H-4. The enolate of the acetate adds to the aldehyde, creating the C(2)-C(3) bond of the macrolactone and also establishing the stereocenter at C-3. 

Cu(II) and Sn(II) Bisoxazolinc Complexes. Evans has prepared and studied a family of Cu(II) complexes prepared from bisoxazoline ligands [8]. Utilizing these complexes a number of different addition reactions can be successfully conducted on pyruvate, benzyloxyacetalde-hyde, and glyoxylates. Whereas the focus of the work in the context of aldol addition reactions has been on the use of silyl ketene acetals (vide infra), the addition of ketone-derived enoxy silanes 8a-b with methyl pyruvate has been examined (Eq. 8B2.1). The additions of 8a-b proceed in the presence of 10 mol % Cu(II) catalyst at -78°C in CH2Cl2, affording adducts of acetophenone 9a and acetone 9b with 99% and 93% ee, respectively. 

Yamamoto has recently described a novel catalytic, asymmetric aldol addition reaction of enol stannanes 19 and 21 with aldehydes (Eqs. 8B2.6 and 8B2.7) [14]. The stannyl ketones are prepared solvent-free by treatment of the corresponding enol acetates with tributyltin methoxide. Although, in general, these enolates are known to exist as mixtures of C- and 0-bound tautomers, it is reported that the mixture may be utilized in the catalytic process. The complexes Yamamoto utilized in this unprecedented process are noteworthy in their novelty as catalysts for catalytic C-C bond-forming reactions. The active complex is generated upon treatment of Ag(OTf) with (R)-BINAP in THF. Under optimal conditions, 10 mol % catalyst 20 effects the addition of enol stannanes with benzaldehyde, hydrocinnamaldehyde, or cinnamaldehyde to give the adducts of acetone, rerf-butyl methyl ketone (pinacolone), and acetophenone in good yields and 41-95% ee (Table 8B2.3). 

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... 

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. 

Table 9 Uncatalyzed aldol addition reactions of silacyclobutyl ketene acetals to aliphatic and aromatic aldehydes...

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. 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) 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, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

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. 

As part of a series of studies on the use of BINOL-Ti(IV) complex 53 as a catalyst in a number of C-C bond-forming reactions, Mikami has reported the aldol addition reactions of thioacetate-derived silyl ketene acetals 55, 56 to a collection of highly functionalized aldehydes (Eq. (8.13)) [28]. As little as 5 mol% of the catalyst mediates the addition reaction and furnishes adducts 57 in excellent yields and up to 96% ee. One of the noteworthy features of the Mikami process is the fact that aldehyde substrates containing polar substituents can be successfully employed, a feature exhibited by few other Lewis-acid-catalyzed aldehyde addition reactions. 

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. 

Recently, Chen has synthesized and resolved chiral suberyl carbenium ions and utilized these as catalysts for enantioselective Mukaiyama aldol addition reactions (Eq. (8.22)) [34]. Thus the reaction of the ethyl acetate-derived silyl ketene acetal with benzaldehyde in the presence of 10-20 mol% of catalyst afforded the corresponding adduct in 50% ee. The enantioselectivity of the process proved sensitive to the nature of the cation, consistent with observations previously highlighted by Denmark in related studies [35]. Although at the current level of development the selectivities are modest, the study documents a novel class of metal-free Lewis acidic agents. 

In a landmark study of Mukaiyama aldol addition reactions, Heathcock proposed that the observed stereochemical outcome of the products in the Lewis acid-mediated addition of silyl ketene acetals to aldehydes was consistent with extended, open transition-state structures [38a, 38b]. This analysis has gained wide acceptance as a consequence of its predictive power. Alternative models involving cyclic, closed structures have also been postulated, in particular, the latter have been invoked with increasing regularity in the analyses of catalytic, enantioselective aldol addition reactions [7,30b,39a,39b. ... 

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 catalytic process has found successful application in several natural product total syntheses. In 1996, Simon reported a synthesis of the antitumor dep-sipeptide FR-9001,228 in which the aldol addition reaction of 168 and the ethyl acetate-derived enol silane furnished a key synthetic intermediate (Eq. 23). The enantioselective aldol addition reaction of 168 was conducted with 165 and its enantiomer ent-165 to separately provide both enantiomers of the aldol adducts 169 and 170 (Scheme 14). These were then utilized in the preparation of diastereomeric seco acids 171 and 172 [101]. Macrocyhzation of 172 through a Mitsonobu reaction yielded the desired natural product 173. 

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]. 

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). 

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