Titanium ester enolates

Fujisawa et al. [89] have reported the stereodivergent synthesis of spiro-[S-1 act a ms 64, 65 (Scheme 17) by reaction of lithium or titanium ester enolates 62 with single chiral imines 63 by taking advantage of different coordination states of the enolate metals. Almost complete reversal of the diastereofacial-discrimination with respect to the C-4 of the (3-lactam skeleton has been attained in this reaction coupled with flexibility in the selection of the enolates and ready removal of the chiral auxiliary. 

Chiral syn-f-eecamo esters have been prepared by addition of titanium ester enolates to aldimines containing an (P)-a-methylbenzylamine moiety.32... 

The synthesis of chiral syn-fi-amino esters has been performed by the addition of titanium ester enolates to aldimines containing a chiral o -methylbenzylamine moiety.29 The reactions take place in high yields and diastereomeric ratios (up to 96 4). 

Aldol Reaction. In addition to the allyl derivatives (2) (eq 1), titanium ester enolates derived from chloride (1) react with aldehydes, affording aldol products after hydrolysis. Compared to the analogous reagents prepared from Chlow(cyclopentadienyl)bis[3-0-( 1,2 5,6-di-0-isopropylidene-a-D-glucofuranosyl)]-titanium the enantioselectivity of these... 

Titanium ester enolates are not only versatile reagents for asymmetric aldol additions but also function as starters of methacrylate polymerization. A representative titanium complex 24 was characterized by crystal structure and NMR spectroscopy and reveals the monomeric O-bound enolate character. The six-coordinated titanium atom in 24 is bound to two phenolic traws-oriented oxygen atoms and two sulfur donors the remaining ligands, methyl group, and enolate moiety are c/s-configured. Upon exposure to acetone, a spontaneous aldol occurs, and the aldolate 25 thus formed was also characterized by a crystal structure. Due to its coordinative saturation, the titanium obviously does not form a chelate with the carbonyl oxygen (Scheme 3.9) [57]. 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

More traditional carbon nucleophiles can also be used for an alkylative ring-opening strategy, as exemplified by the titanium tetrachloride promoted reaction of trimethylsilyl enol ethers (82) with ethylene oxide, a protocol which provides aldol products (84) in moderate to good yields <00TL763>. While typical lithium enolates of esters and ketones do not react directly with epoxides, aluminum ester enolates (e.g., 86) can be used quite effectively. This methodology is the subject of a recent review <00T1149>. 

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

Titanium(IV) enolates derived from a-diazo-/i-keto esters or ketones (28) efficiently add to T1CI4-activated A-tosylimines to give the corresponding 5-A-tosylamino derivative.76 Subsequent diazo decomposition - catalysed by rhodium(II) or light - yields useful pyrroles or y -lactams, respectively. 

The one-pot condensation of an ester enolate with an imine is a very powerful synthetic procedure toward azetidin-2-ones (Equation 183). Various types of esters and imines can be utilized. Although in the vast majority the reactions have been mediated by lithium, various other metals mediate the reaction as well. Some examples include zinc, aluminium, tin, boron, indium, and titanium <1996MI119>. Theoretical studies on these reactions have been reviewed <1998JCC1826>. 

Michael Addition. Titanium imide enolates are excellent nucleophiles in Michael reactions. Michael acceptors such as ethyl vinyl ketone, Methyl Acrylate, Acrylonitrile, and f-butyl acrylate react with excellent diastereoselection (eq 21 ). - Enolate chirality transfer is predicted by inspection of the chelated (Z)-enolate. For the less reactive unsaturated esters and nitriles, enolates generated from TiCl3(0-j-Pr) afford superior yields, albeit with slightly lower selectivities. The scope of the reaction fails to encompass p-substituted, a,p-unsaturated ketones which demonstrate essentially no induction at the prochiral center. Furthermore, substimted unsamrated esters do not act as competent Michael acceptors at all under these conditions. 

Amide Enolates. The lithium (Z)-enolate can be generated from (5)-4-benzyl-3-propanoyl-2,2,5,5-tetra-methyloxazolidine and Lithium Diisopropylamide in THF at —78 °C. Its alkylations take place smoothly in the presence of Hexamethylphosphoric Triamide with high diastereoselec-tivity (eq 3), and its Michael additions to a,(3-unsaturated carbonyl compounds are also exclusively diastereoselective (eq 4). Synthetic applications have been made in the aldol reactions of the titanium (Z)-enolates of a-(alkylideneamino) esters. ... 

These tri(alkoxy)titanium enolates, which have low Lewis acidity, are known to react chemoselective-ly with an aldehyde group in the presence of a ketone (equation 4). Other uses described by Reetz et al. include the diastereofacially selective additions of ketone and ester enolates to chiral a-alkoxy aldehydes with nonchelation control. - For example, aldol addition of the tri(isopropoxy)titanium enolate of pro-piophenone to the aldehyde (24) leads to only the two syn diastereomers, with the nonchelation adduct (25) favored (equation 5) i.e. Felkin-Anh selectivity is operating. In the case of aldol addition of t-butyl propionate to the same aldehyde (equation 6), highest stereoselectivity for the isomer (26) is obtained using the tri(diethylamino)titanium enolate. Very high levels of nonchelation stereoselectivity can also be obtained in the aldol addition to chiral a-siloxy or a-benzyloxy ketones if a titanium enolate of low Lewis acidity is employed, as in equation (7). ... 

Several other examples of this [2 + 2 + 2] procedure with chiral nitriles have been reported32. Highly stereocontrolled construction of 3-alkoxy-2-azctidinones are obtained via formal [2 + 2] cycloaddition of imincs and ester enolates in the presence of chirally modified titanium(IV) salts33-34. 

These four examples do not seem to comply with a consistent mechanistic model. The dilithioprolinol amide enolate in Scheme 5.31a is attacked on the enolate Si face, in accord with the sense of asymmetric induction observed in alkylations of this enolate [166,167]. On the other hand, the structurally similar dilithiovalinol amide enolate, while being attacked on the same face (as expected), reverses top-icity. Furthermore, the S,S-pyrrolidine enolate in Scheme 5.31c is attacked from the Si face by Michael acceptors, but from the Re face by alkyl halides [168] and acid chlorides [169]. The titanium imide enolate in Scheme 5.31d adds Michael acceptors from the Si face, consistent with the precedent of aldol additions of titanium enolates (c/. Table 5.4, entry 2, [88]). An intramolecular addition (Scheme 5.3le) seems to follow a clear mechanistic path [165] the Si face is attacked by the electrophile, and the cis geometry of the product implicates intramolecular complexation of the acceptor carbonyl. This coordination of the acceptor carbonyl is probably a function of the metal recall the lithium ester enolates illustrated in Scheme 5.30c and d, but also metal chelation in titanium aldol additions (Table 5.4, entry 2). 

The cycloaddition of ester enolates with imines is of continuing interest and potassium rert-butoxide may be used to generate the enolate (94S805) but more usually tin, titanium or zinc enolates are employed. When enolates are generated from 2-pyridylthioesters, the stereochemistry of the tin enolate may be greater than and, in some cases, opposite to that for titanium enolates (94T5821). The effect of the lithium, zinc or titanium on the diastereoselectivity in addition reactions of the enolates of a-... 

Reactions of a-selenoacetate enolates have been reported to give excellent selectivity and yield in the presence of triphenylphosphine or triphenyl-phosphine oxide, as shotvn in Table 2.12 (entries 7-11) [30]. This tvork tvas extended to a-selenopropionate esters (Table 2.12, entries 12 and 13) and a-selenoketones (Table 2.12, entries 14-20) [31]. As for a-sulfur substituents, the a-selenopropionate ester enolates gave excellent yield and selectivity for aldols in vhich the a-heteroatom and j5-hydroxyl group vere syn to each other. These papers highlighted the importance of the presence of 1 equiv. bulky phosphine or amine to coordinate to titanium to improve the yield and the selectivity. 

Gosh independently reported another anti-selective aldol addition process employing aminoindanol-derived esters 114 (Equation 11) [72]. These were subjected to enolization with excess TiCl, and Hiinig s base to furnish titanium 2-enolates, as determined by NMR spectroscopy. Addition reactions with a variety of aliphatic and unsaturated aldehydes, precomplexed with TiCl4, furnished the anti aldol adducts such as 116 in 44—97% yields and up to 99 1 anti/syn ratios of diastereomers. The stereochemical outcomes of the reactions have been attributed to chelated Zimmerman-Traxler transition state structures, such as 115. It is interesting to note that benzaldehyde, as the only aromatic aldehyde examined, yielded a 1 1.1 mixture of antijsyn products. 

Enols and alkoxides give chelates with elimination of alcohol. For example, in the reaction of the enol form of acetylacetone [123-54-6] all four alkoxide groups attached to zirconium can be replaced, but only two of the four attached to titanium (Fig. 3). Acetoacetic esters react similarly. 

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. 

The svn/anti ratio of the product ester is high, and the enantiomeric excess is 94%62b. The titanium enolates are believed to be -configurated. 

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. 

These oxazolidinones can be acylated and converted to the lithium, boron, tin, or titanium enolates by the same methods applicable to ketones and esters. For example, when they are converted to boron enolates using di-n-butylboron triflate and triethyl-amine, the enolates are the Z-stereoisomers.125... 

Additionally, it has been shown that novel benzylidene titanium complexes of type 74 react with polymer-bound carboxylic esters to form the corresponding enol ethers (Scheme 28).79... 

Scheme 17. Titanium-mediated metathesis strategy for the conversion of olefinic esters (118) to cyclic enol ethers (123) (Nicolaou et al.) [34]...

Scheme 19. Titanium-mediated metathesis strategy for the conversion of olefinic esters to 6- and 7-mem -bered cyclic enol ethers, (a) 4.0 equiv of Tebbe reagent (93), THF, 25°C, 20 min then reflux, 2-8 h, 64% (129), 45% (131a), 32% (131b), 45% (133) (Nicolaou etal.) [34a]...

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

---