Dienolates addition reactions

In the study of catalytic, dienolate addition reactions, the use of stannyl prope-nal 50 as a substrate in aldol methodology has been introduced (Scheme 8-4). The adduct 51 produced from the process is isolated in 92% ee and, importantly, serves as a useful building block for subsequent synthetic elaboration. It is amenable for further manipulations such as Stille cross-coupling reactions to give a diverse family of protected acetoacetate adducts 52. 

Sato and co-workers have also investigated the dienolate addition reactions of 49 with benzaldehyde and pentanal (Scheme 8-5). When 20 mol% of Mikami catalyst 53 was employed the aldol adducts were isolated in 38 and 55% yield and 88-92% ee [27], The use of Yamamoto s oxazaborolidene catalyst 54 afforded the products with diminished optical purity. 

A general type of chemical reaction between two compounds, A and B, such that there is a net reduction in bond multiplicity (e.g., addition of a compound across a carbon-carbon double bond such that the product has lost this 77-bond). An example is the hydration of a double bond, such as that observed in the conversion of fumarate to malate by fumarase. Addition reactions can also occur with strained ring structures that, in some respects, resemble double bonds (e.g., cyclopropyl derivatives or certain epoxides). A special case of a hydro-alkenyl addition is the conversion of 2,3-oxidosqualene to dammara-dienol or in the conversion of squalene to lanosterol. Reactions in which new moieties are linked to adjacent atoms (as is the case in the hydration of fumarate) are often referred to as 1,2-addition reactions. If the atoms that contain newly linked moieties are not adjacent (as is often the case with conjugated reactants), then the reaction is often referred to as a l,n-addition reaction in which n is the numbered atom distant from 1 (e.g., 1,4-addition reaction). In general, addition reactions can take place via electrophilic addition, nucleophilic addition, free-radical addition, or via simultaneous or pericycUc addition. 

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. 

Lead tetra-acetate oxidation of the allylic alcohols (170)—(172) and (182) leads to the formation of the epoxides (183)—(186), products of a novel internal addition reaction of the electron-deficient alcohol oxygen to the allylic double bond. In some cases, (171) and (172), the formation of a new type of acetoxylated enol ether (173) and (174) is observed. Oxidation of the allylic dienols (175) and (176) gives the epoxyacetates (187) and (188). A variety of cyclization products was also isolated. Their formation requires an isomerization of the allylic trans double bond to cis.69 Lead tetra-acetate oxidation of dihydro-y-ionol (189) gives the new bicyclic ether... 

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... 

The catalytic system using 62 is applicable to highly enantioselective preparation of acetoacetate aldol adducts (Scheme 10.55) [152]. The use of 1-3 mol% 62 and 0.4 equiv. 2,6-lutidine promotes the aldol reaction of a variety of aldehydes with silyl dienolate 64 in good to high optical yields. The dienolate addition provides a convergent and enantioselective route to 1,3-polyols by appending a protected acetoacetate in a single step. The 62-catalyzed aldol reactions of methyl acetate TMS enolate and dienolate 64 have been used in the total syntheses of Rofla-mycoin [153] and Macrolactin A [154], respectively. In the latter both enantiomers... 

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. 

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. 

Carreira and co-workers have described a Cu-mediated process that effects the catalytic, enantioselective addition of silyl dienolates 87 to aldehydes [24]. The active complex that is believed to initiate the reaction is readily prepared in situ upon mixing optically active bisphosphine, Cu(OTf)2 and (Bu4)NPh3SiF2 in THE (Eq. 58). The addition reactions catalyzed by this system proceed with a broad range of aldehydes to afford adducts 88 in up to 95% ee and 98% yield. Moreover, the reaction may be conducted on a preparative multigram scale utilizing as little as 0.5 mol % of 273 without deleterious effects on the product enantiomeric excess or yields. 

Moving forward from 59, six steps were required to convert this compound to 60. Vicinal dihydroxylation of the olefin was followed by oxidative cleavage of the intermediate diol using lead tetraacetate. Reductive amina-tion of the resulting aldehyde with methylamine, followed by acylation of the intermediate secondary amine gave the desired carbamate. Swern oxidation of the secondary alcohol, followed by enol ether formation gave 60. Elimination of -toluenesulfinic acid from 60 provided 61. Oxidation of this dienol ether to dienone 62 was followed by release of the secondary amine, followed by a conjugate addition reaction to establish the critical C-N bond. The remainder of the synthesis followed known chemistry. The mixture of enones 63 was converted to codeinone (35), codeine (3) and then morphine (1). 

Catalysis with BINAP-CuFz, Carreira and co-workers have recently reported a novel aldol addition reaction using a putative Cu(I) fluoride complex as catalyst [32]. The cmiqilex is readily assembled in situ upon dissolving BINAP and CufOTflj, in THF followed by addition of Bu4NPh3SiF2, as an anhydrous fluoride source. Dienolate 105 undergoes addition to a wide range of aldehyde substrates at -78°C with 5 mol % catalyst, giving the protected acetoacetate adducts with up to 94% ee. The reaction has been mechanistically examined in some detail, leading to the postulation that the addition process includes a metalloenolate in the catalytic cycle as relevant reactive intermediate (Scheme 8B2.11) [33]. This perspective contrasts the more traditional role of transition-metal catalysis of the Mukaiyama aldol addition reaction wherein the metal functions as a Lewis acid and activates the electrophilic aldehyde partner. 

Addition reactions of dienolates and aldehydes can also be effected through the use of bisphosphine copper(I) complexes [145, 146]. A mixture of p-Tol-BINAP, Cu(0Tf)2, and (Bu4N)Ph3Sip2 leads to a complex that efficiently promotes rapid aldol addition reactions of acetoacetate-derived dienolates to give adducts with high yields and selectivities. The addition to crotonaldehyde served as an important launch point in Carreira s total syn-... 

An important mechanistic aspect of the Cu-bisphosphine-catalyzed addition reactions of dienolates to aldehydes is worth highlighting. Infra-red spectroscopic studies have collectively provided insight into the details of this process. In this respect, these processes have been suggested to proceed through metaloenolate intermediates [146]. As such, the process complements the traditional Mukaiyama aldol addition reaction, which typically proceeds through Lewis activation of the electrophilic aldehyde partner. 

Optically active bicyclo[2.2,2]octanes can be obtained via diastercoselective MIMIRC reaction of lithium dienolates and a,/ -unsaturated esters of various chiral alcohols. Good yields (70-90%), high endo selectivities (> 95%) and diastereomeric ratios that depend on the auxiliary alcohol are found in these additions. The highest diastereomeric ratio reached was 18 82 using a camphor derived sulfonamide. The diastereomeric ratio could be improved (up to 9 91) by titanium(IV) chloride catalyzed addition of the corresponding silylenolates with the chiral a,/J-unsaturated esters358. 

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