Enolate titanium-derived

Hayashi et al. have reported a novel Knoevenagel-type reaction with titanium enolate 70 derived from diketene 69 as the C4 unit source (Scheme 26).76 In contrast to the conventional Knoevenagel reaction (basic conditions), this transformation proceeds under mildly acidic conditions and provides higher yields and better E Z ratios. 

Bernadi and Scolastico, and later Evans in a more effective manner, indicated that the enantioselective addition reaction using silyl enol ethers can be catalyzed by Lewis acidic copper(II) cation complexes derived from bisoxazolines [38-40]. In the presence of the copper complex (S,S)-14 (10 mol %), silyl enol ethers derived from thioesters add to alkylidenemalonates or 2-alkenoyloxazo-lidone in high ees (Scheme 12). Bernadi, Scolastico, and Seebach employed a titanium complex derived from TADDOL for the addition of silyl enol ethers to nitroalkenes or 2-cyclopentenone [41-43], although these are stoichiometric reactions. 

The illustrative example is the synthesis of heptane-2,5-dione (Expt 5.105). A related reaction is the interaction of a silyl enol ether, derived from a ketone, with a nitro olefin in the presence of either titanium(iv) chloride or... 

Lilly has used an Evans auxiliary in its synthesis of LY309887 (32), a dideazafolate antitumor agent (Scheme 23.8).2 The de of the key step, reaction of the titanium-derived enolate, was >98%. It was noted that the auxiliary could be recycled after cleavage with lithium borohydride. 

If the 1,5-diearbonyl compound is required, then an aqueous work-up with either acid or base cleaves the silicon-oxygen bond in the product but the value of silyl enol ethers is that they can undergo synthetically useful reactions other than just hydrolysis. Addition of the silyl enol ether derived from aeetophenone (PhCOMe) to a disubstituted enone promoted by titanium tetrachloride is very rapid and gives the diketone product in good yield even though a quaternary carbon atom is created in the conjugate addition, This is a typical example of this very powerful class of conjugate addition reactions. 

Phenylthioalkylation of silyl enol ethers. Silyl enol ethers of ketones, aldehydes, esters, and lactones can be alkylated regiospecifically by a -chloroalkyl phenyl sulfides in fhe presence of a Lewis acid. Zinc bromide and titanium(IV) chloride are the most effective catalysts. The former is more satisfactory for enol ethers derived from esters and lactongs. ZnBr2 and TiCL are about equally satisfactory for enol ethers of ketones. The combination of TiCL and Ti(0-f-Pr)4 is more satisfactory for enol ethers of aldehydes. Since the products can be desulfurized by Raney nickel, this reaction also provides a method for alkylation of carbonyl compounds. Of more interest, sulfoxide elimination provides a useful route to a,B-unsaturated carbonyl compounds. 

For the sake of completeness, it should be mentioned that at variance with the corresponding silyl enolates, the oxidation of titanium bis(enolates) with a variety of oxidants does not show any diastereoselectivity in the formation of the enolate coupling product . On the basis of crossover experiments, it has been shown that the C—C bond formation occurs via an intramolecular route in the case of the silyl derivatives and intermolecularly in the case of the titanium derivatives. 

The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,y3-unsaturated carbonyl derivatives, the Mukaiyaraa Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [108], Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (/-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectiv-ity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from 5-diphenylmethyl ethanethioate proceeds highly enantioselectively. Sco-lastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectiv-ity (Sch. 44) [110]. 

The intrinsic difficulty in preparing various titanium derivatives with die desired alkyl group may be overcome by using reagent systems consisting of TiCU as the chelating agent, and a suitable nucleophile like dialkylzinc, allylsilanes, allylstannanes, etc. The utilization of other nucleophiles, like silyl enol ethers will be covert in Part 1 of Volume 2. 

The H NMR spectra (471, 472) of yttrium, lutetium, and titanium derivatives are consistent with structures in which the oxygen atom of the enolate bonds to the metal center. Resonances due to the =CH group appear as doublets of doublets. The signals due to the =CH2 protons appears as two doublets... 

A chiral aldehyde, attached through a silyl linker to a hydroxymethyl Merrifield resin, was employed for expanding polyketide diversity. Aldol reaction with preformed (H)-enol borinate derived from a suitable chiral (R)-ketone afforded the anti-anti aldol product. Titanium-mediated enolization of the enantiomer (S)-ketone afforded the syn-syn product. 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, and amides. Of particular importance are several modified amides, such as those derived from oxazolidinones, that can be used as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, tin, and titanium derivatives have all been used. Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.4.2.3, Part B), there has been a good deal of interest in the factors that control the stereoselectivity of enolate formation from esters. For simple esters such as ethyl propanoate, the E-enolate is preferred under kinetic conditions using a strong base such as EDA in THE solution. Inclusion of a... 

The mechanistic rationale for the dramatic Lewis acid effect on the course of the Engler indole/benzofuran synthesis involving styrenes is illustrated in Scheme 3. Whereas titanium forms a bidentate complex 11 with the C-1 carbonyl and C-alkoxy oxygens, which leads to the dihydroindole (equation 1), boron trifluoride engages in monodentate complexation 12 with the sulfonyl nitrogen, leading to dihydrobenzofuran formation (equation 2) [3, 4]. Likewise, the reaction between 11 and an enol ether derived from 4-piperidone is depicted in equation 3 [5]. 

Cp2Zr(Me)Cl, respectively. Their NMR spectra clearly reveal that the O-bond character of the enolate, indicated by the carbon-carbon double bond, is maintained in solution (Scheme 3.8) [53]. Crystal structures were also obtained for O-bound zirconium acetophenone enolate 21 [55], titanium ketone enolate 22, derived from/) r -methylacetophenone, and amide enolate 23 [56]. Whereas the latter readily added to benzaldehyde, the ketone enolate 22 (X = Ph) failed to undergo an aldol addition. This difference in reactivity was explained - based on a computational study - by a higher electron density at the methylene carbon atom in the amide compared to the ketone enolate [56]. 

Silyl enol ethers derived from acetone undergo ene reactions rather than aldol reactions to give a-fimctionalyzed enol silyl ethers. Lewis acidic chiral titanium, chiral chromium, and chiral palladium catalysts have been developed to allow synthesis of silyl enol ethers having a chiral center (Scheme 3-60). 

Titanium Complexes of Unsaturated Alcohols. TetraaHyl titanate can be prepared by reaction of TYZOR TPT with aHyl alcohol, followed by removal of the by-product isopropyl alcohol. EbuUioscopic molecular weight determinations support its being the dimeric product, octaaHoxydititanium. A vinyloxy titanate derivative can be formed by reaction of TYZOR TPT with vinyl alcohol formed by enolization of acetaldehyde (11) ... 

Titanium(IV) is a powerful but selective Lewis acid which can promote the coupling of allylsilanes with carbonyl compounds and derivatives In the presence of titanium tetrachlonde, benzalacetone reacts with allyltnmethylsilane by 1,4-addition to give 4-PHENYL-6-HEPTEN-2-ONE. Similarly, the enol silyl ether of cyclopentanone is coupled with f-pentyl chloride using titanium tetrachlonde to give 2-(tert-PENTYL)CYCLOPENTANONE, an example of a-tert-alkylation of ketones. 

Ghosh and co-workers have recently used the indanyl-derived auxiliary 69 (Table 1.9) in titanium enolate condensations with a range of aldehydes [34], Of the four possible diastereomers, only the anti 71 and syn TL were produced (the alternative anti and syn diastereomers were not detected by 1H or 13C NMR). The use of monodentate aliphatic aldehydes resulted in the formation of anti diastereomers... 

Carbohydrate-derived titanium cnolates also provide yvn-x-amino-/l-hydroxy esters of high diastcrcomeric and enantiomeric purity. For this purpose, the lithium enolate derived from ethyl (2,2,5,5-tetramcthyl-2,5-disilapyrrolidin-l-yl)acetate is first transmctalated with chloro(cy-clopentadienyl)bis(1,2 5,6-di-0-isopropylidene-a-D-glucofuranos-3-0-yl)titanium and subsequently reacted with aldehydes.. vj-n-a-Amino-/ -hydroxy esters are almost exclusively obtained via a predominant /te-side attack (synjanti 92 8 to 96 4 87-98% ee for the xvn-adducts)623-b. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

A combination of diethylzinc with sulfonamides 18 or 19 offers another possibility for the enantioselective acetate aldol reaction39,41. The addition of silyl enol ethers to glyoxylates can be directed in a highly enantioselective manner when mediated by the binaphthol derived titanium complex 2040. 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

The chiral (V-camphanoyl iminium ion 7, prepared by hydride abstraction from 2-camphanoyl-l,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline 6 (see Appendix) with triphenylcarbenium te-trafluoroborate, reacts with silyl enol ethers to give 1-substituted tetrahydroisoquinoline derivatives with reasonable diastereoselectivity, 0°. On addition of titanium(IV) chloride, prior to the addition of the silyl enol ether, the diastereoselectivity gradually rises to an optimum at 2.5 equivalents of the Lewis acid, but the yield drops by 20%. 

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium, titanium, zirconium, and tin, ° silyl enol ethers, enol borinates,and enol borates, R CH=CR"—OB(OR)2. The nucleophilicity of silyl enol ethers has been examined. In general, metallic Z enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. The ( ) isomers generally react nonstereoselectively. However, anti (or threo) stereoselectivity has been achieved in a number of cases, with titanium enolates, with magnesium enolates, with certain enol bor-inates, and with lithium enolates at — 78°C. ... 

Reaction conditions that involve other enolate derivatives as nucleophiles have been developed, including boron enolates and enolates with titanium, tin, or zirconium as the metal. These systems are discussed in detail in the sections that follow, and in Section 2.1.2.5, we discuss reactions that involve covalent enolate equivalents, particularly silyl enol ethers. Scheme 2.1 illustrates some of the procedures that have been developed. A variety of carbon nucleophiles are represented in Scheme 2.1, including lithium and boron enolates, as well as titanium and tin derivatives, but in... 

Entry 8 in Scheme 2.1 is an example of this method. Titanium enolates are frequently employed in the synthesis of complex molecules and with other carbonyl derivatives,... 

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