Dienolate addition

Catalytic enantioselective dienolate additions to aldehydes were realized by Tol-BINAP-Cu(ll) fluoride complexes as shown by an example in Equation (131). 

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. 

Another Mukaiyama-type dienolate addition was used in the synthesis of the C o-C]6 fragment 125. This time, enantioselective addition to benzyloxyacetalde-hyde, catalyzed by the chiral copper complex 126, gave 127 with >99% ee (Scheme 9-40). Subsequent manipulations, including an rmh-selective reduction, provided the C o-C 6 fragment 125. 

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... 

Singer RA, Carreira EM. Catalytic, enantioselective dienolate additions to aldehydes preparation of optially active acetoa-cetonate aldol adducts. J. Am. Chem. Soc. 1995 117(49) 12360-12361. 

The preferential exchange of the 6 -hydrogen under strongly acidic conditions is attributed to the formation of a A -dienol intermediate (29) which then undergoes deuterium attack from the -side at C-6. In contrast, in neutral or alkaline media the exchange proceeds via an enolate ion intermediate in which deuterium addition occurs in the following order C-4 >... 

Addition of bromine to the dienol acetate (49) gives the 6j5-bromo-A -3-ketone (50). Dehydrobromination of the crude bromo compound in DMF with lithium or calcium carbonate gives the title compound (51). ... 

In general, the Michael addition of a-substituted amide dienolates to a,/j-unsaturated esters is a method with great future potential for the diastereoselective construction of adjacent tertiary and quaternary stereogenic centers80. 

The asymmetric 1,4-addition of the dienolate of the optically active camphor derived 3-methyl-3-butenoate to 2-cyclopentenone gives a mixture of four diastereomers. The major adduct was applied in the synthesis of (—)-khusimone188. 

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. 

Addition of the lithium dienolate of 3-(tm-butyldimethylsilyloxy)-2,6-diinethyl-2-cyclohexenonc to ( + )-(.S )-4-( 3-methyl-3-butenyl)-3-(4-mcthylphenylsulfinyl)-2(5//)-furanonc in THF at — 95 °C for 2 hours gave an 88 12 mixture of diastereomeric adducts. A transition state has been proposed that involves chelation between both reacting partners20. 

TITANIUM-MEDIATED ADDITION OF SILYL DIENOL ETHERS TO ELECTROPHILIC GLYCINE A SHORT SYNTHESIS OF 4-KETOPIPECOLIC ACID HYDROCHLORIDE (Pipecolic acid, 4-oxo-, hydrochloride)... 

The reactivity of ethyl cyclopropylideneacetate (52b) has been exploited by Spitzner and Sawitzki in a new (formal) total synthesis of the diterpene ( + )-isoeremolactone 80 (Scheme 16) [25]. The key step of the synthesis is the addition of the enantiomerically pure dienolate 78 to the reactive acrylate 52b, to give a single isomer 79 in 92% yield. 

A simple two-step protocol for the generation of a terminal diene is to add allyl magnesium bromide to an aldehyde or a ketone and subsequent acid or base catalysed dehydration (equation 34)72. Cheng and coworkers used this sequence for the synthesis of some indole natural products (equation 35)72a. Regiospecific dienones can be prepared by 1,2-addition of vinyllithium to a,/l-unsaturated carbonyl compounds and oxidative rearrangement of the resulting dienols with pyridinium dichromate (equation 36)73. 

The effect of an ally lie hydroxy group was first observed in divinylglycol (1,5-hexadiene-cA-3,4-diol and 1.5-hexadiene-/raw.v-3,4-diol). It was shown that the hydroxy substitutions directed the addition of the osmium tetraoxide to syn addition, so that the cA-diol yielded allitol (all cA-hexaol) and the iraws-diol yielded mannitol42. The oxidation of the dienol 35 yielded a lactone ring 36 by cA-dihydroxylation and transesterification... 

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). 

Similarly, electrophilic cyclizations of dienols and trienols, such as homogeraniol and homonerol, were carried out without addition of strong acid, using benzeneselenenyl triflate18,144 as the organoselenium reagent (equations 145 and 146). 

The diastereoselective formation of dienol tricarbonyliron complexes on treating rf-2,4-pentadienal)Fe(CO)3 with functionalized zinc-copper reagents has been investigated (equation 49)66. Cyano-substituted complexes undergo intramolecular nucleophilic additions when treated with lithium diisopropylamide (LDA) as shown in equation 50. 

Table 1 summarizes the yields and selectivities of the addition of dienolate 2 to various aldehydes. It can be seen that the yield and enantioselectivity very much depend on the solvent, with THF being the best tested. The best results were obtained with pentanal (55% yield, 92% ee). On the other hand, when spiro dienolate 1 was used in these aldol reactions, benzaldehyde gave the best... 

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