Dienolates aldol addition

Ti(IV). Carreira has reported a novel class of tridentate ligands whose complexes with Ti(IV) 48 serve as catalysts for a variety of enantioselective aldehyde additions [20J. The reactions that have been examined include acetate and dienolate aldol additions as well as ene-like reactions of 2-methoxy propene [21], The salient features of these catalytic systems include the fact that a wide range of aldehyde substrates may be utilized, the ability to carry out the reaction employing 0.2-5 mol% catalyst loading, and the experimental ease with which the process is executed. The typical experimental procedure prescribes the use of an in situ generated catalyst, at -10 to 23 °C in a variety of solvents, employing as little as 0.5 mol% catalyst. 

Kim, Y.. Singer, R.A., and Carreira, E.M., Total synthesis of macrolactin A with versatile catalytic, enantioselective dienolate aldol addition reactions, Angew. Chem., 110, 1321, 1998 Angew. Chem. Int. Ed. Engl., 37, 1261, 1998. 

Several other chiral Lewis acids have also been reported to effect asymmetric aldol reactions. Kruger and Carreira59 reported a catalytic aldol addition of silyl dienolate to a range of aldehydes in the presence of a bisphosphanyl-Cu(II) fluoride complex generated in situ from (iS )-Tol-BINAP, Cu(OTf)2, and (Bu4N)Ph3SiF2. Aromatic, heteroaromatic, and a,/ -unsaturated aldehydes provided the aldol adducts with up to 95% ee and 98% yield (Scheme 3-33). 

Oxamborolidenes. There are noteworthy advances in the design, synthesis, and study of amino acid-derived oxazaborolidene complexes as catalysts for the Mukaiyama aldol addition. Corey has documented the use of complex 1 prepared from A-tosyl (S)-tryptophan in enantioselective Mukaiyama aldol addition reactions [5]. The addition of aryl or alkyl methyl ketones 2a-b proceeded with aromatic as well as aliphatic aldehydes, giving adducts in 56-100% yields and up to 93% ee (Scheme 8B2.1, Table 8B2.1). The use of 1-trimethylsilyloxycyclopentene 3 as well as dienolsilane 4 has been examined. Thus, for example, the cyclopentanone adduct with benzaldehyde 5 (R = Ph) was isolated as a 94 6 mixture of diastereomers favoring the syn diastereomer, which was formed with 92% ee, Dienolate adducts 6 were isolated with up to 82% ee it is important that these were shown to afford the corresponding dihydropyrones upon treatment with trifuoroacetic acid. Thus this process not only allows access to aldol addition adducts, but also the products of hetero Diels-Alder cycloaddition reactions. 

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. 

Regio-, enantio-, and diastereo-selective vinylogous aldol additions of silyl dienol ethers to aldehydes use a Lewis base (a chiral bis-BINAP-phosphoramide) to activate a Lewis acid (silicon tetrachloride).139... 

Figure 9.32 adds the information of how enol ethers are normally produced, i.e., enol ethers with no conjugation between the C=C- and the neighboring C=0 double bond 0,0-Acetals are subjected to an acid-catalyzed elimination of one equivalent of alcohol, via an El mechanism, that is, via an oxocarbenium ion intermediate that is deprotonated to give the respective enol ether (i.e., the product presented in the first line of Figure 9.32) or dienol ether (the product shown in the second line of Figure 9.32). Among other things, enol ethers are required for the Mukaiyama aldol addition (example Figure 12.23).

Following the mechanism given in Figure 12.23, the addition of an acetal to a simple enol ether (in contrast to the dienol ether B shown above) leads to a /3-alkoxy acetal. This reaction is known as the Mukaiyama aldol addition. If this is followed by a hydrolysis (of the... 

A catalytic, enantioselective approach towards the synthesis of polyol chains has recently been reported by Carreira et al. and has been applied in a synthesis of the polyol subunit of amphotericin B (Scheme 5) [13]. Aldol addition of the silyl dienolate 26 to furfural (27) catalyzed by the Tol-BlNAP-CuF -complex (2 mol-%) gives rise to the addition product 28 in 95 % yield and >99 % ee after one recrystallization. Spectroscopic evidence indicates that a copper dienolate is formed in situ from the silyl dienolate 26 and is actually the active nucleophile [14], Standard transformations including a j-yw-selective reduction of the ft-hydroxy ketone by the method of Prasad and the oxidative conversion of the furan ring to the car-... 

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. 

Rate and equilibrium constants have been measured for representative intramolecular aldol condensations of dicarbonyls. For the four substrates studied (32 n — 2, R = Me = 3, R = H/Me/Ph), results have been obtained for both the aldol addition to give ketol (33), and the elimination to the enone (34). A rate-equihbrium mismatch for the overall process is examined in the context of Baldwin s rules. The data are also compared with Richard and co-workers study of 2-(2-oxopropyl)benzaldehyde (35), for which the enone condensation product tautomerizes to the dienol (i.e. ) -naphthol). In all cases, Marcus theory can be apphed to these intramolecular aldol reactions, and it predicts essentially the same intrinsic barrier as for their intermolecular counterparts. 

Oxazaborolidenes. Corey has reported the use of a novel oxazaborolidene complex 41 prepared from borane and A-tosyl (5)-tryptophan. This complex functions in a catalytic fashion in enantioselective, Mukaiyama aldol addition reactions (Scheme 8-3) [17]. The addition of ketone-derived enol silanes 42-43 gives adducts in 56-100% yields and up to 93% ee. The use of 1-trimethylsilyloxycyclo-pentene 43 in the addition reactions to benzaldehyde affords adducts 46 as a 94 6 mixture of diastereomers favoring the syn diastereomer in 92% ee. Addition reactions with dienol silanes 44 furnishes products 47 in up to 82% ee. Corey also demonstrated the use of these adducts as important building blocks for the synthesis of corresponding dihydropyrones treatment of 47 with trifluoroacetic acid affords the cyclic product in good yields. 

Cu(I). Carreira and co-workers have documented a class of Cu-mediated dieno-late aldol addition reactions that are postulated to proceed through an intermediate metalloenolate (Eq. (8.26)) [40]. The active catalyst is generated upon dissolution of p-tolbinap and Cu(OTf)2 in THE followed by addition of Bu4NPh3Sip2 as an anhydrous fluoride source. The putative Cu-fluoride complex initiates the formation of a Cu-dienolate that subsequently participates in a catalytic, enantioselec-tive addition reaction. Using as little as 0.5 mol% catalyst, the protected acetoace-tate adducts are isolated in up to 94% ee [41]. The use of the corresponding p-tol-binap-Cu(OrBu) complex prepared in situ from Cu(OfBu) and binap functions as a competent catalyst. This feature is consistent with an intermediate metal alkox-ide in the catalytic cycle, namely, the first-formed metal aldolate adduct. The... 

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. 

The catalytic version of this type of reaction was realized by using acetoacetate derived O-silyl dienolate as nucleophiles in the presence of Carreira s catalyst, giving acetoacetate y-adducts in high yields and enantiomeric excesses [119] (Scheme 14.42). The products are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotic and medicinally important HMG-CoA reductase inhibitors. This aldol addition can also be catalyzed by BINOL-Ti complex in the presence of 4A MS with moderate to good enantioselectivity [120]. The same catalyst system was also efficient in the asymmetric aldol reaction between the aldehydes and Chan s diene [ 1,3-bis-(trimethylsilyloxy)-l-methoxy-buta-1,3-diene] and other related silyl enol ethers [121, 122] (Scheme 14.43) or the functionalized silyl enol ether such as 2-(trimethylsilyloxy)furan with good to excellent enantioselectivities [123]. 

Denmark SE, Heemstra JR Jr (2004) Lewis base activation of lewis acids vinylogous aldol additions of dienol ethers to aldehydes. Synlett 2411-2416... 

Scheme 5.63 Vinylogous aldol addition of silyl dienolate 203a mediated by titanium-BINOL complex enantioselective synthesis of phorbaside A building block 205.

Moreover, the protocol could be used for a vinylogous Mukaiyama aldol addition and offered a solution to the problem of the asymmetric acetoacetate aldol reaction. Thus, 2 mol% of the catalyst 198 is enough to promote the addition of silyl dienolate 214 to various aldehydes to give, after desilylation, O-protected P-keto-5-hydroxy esters [113]. The protocol is illustrated for an addition to P-stannylpropenal 213. Depending on the enantiomer of the catalyst 198 or ent-198 chosen to mediate the aldol addition, enantiomeric products 215 and ent-215 were obtained in 92% ee. In an elegant convergent total synthesis, both enantiomers were incorporated into macrolactin A, as shown in Scheme 5.65 [114,115]. 

The bench-stable dihydrate of the copper PYBOX catalyst 217 served to mediate the vinylogous Mukaiyama aldol addition of dienolate 224 to para-methoxybenzyloxyacetaldehyde 219b. After first attempts were discouraging... 

Scheme 5.77 Carreira s copper-catalyzed vinylogous aldol addition of silyl dienolate 214 postulated catalytic cycle.

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