Titanium enolates enantioselectivity

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). 

As the t-butyl group can readily be removed upon acidic or basic hydrolysis, this method can also be used for //-hydroxyl acid synthesis. In analogy with allylation reactions, the enolate added preferentially to the Re-face of the aldehydes in aldol reactions. Titanium enolate 66 tolerates elevated temperatures, while the enantioselectivity of the reaction is almost temperature independent. The reaction can be carried out even at room temperature without significant loss of stereoselectivity. We can thus conclude that this reaction has the following notable advantages High enantiomeric excess can be obtained (ee > 90%) the reaction can be carried out at relatively high temperature the chiral auxiliary is readily available and the chiral auxiliary can easily be recovered.44... 

It was found that aryltitanium triisopropoxides 52 (ArTi(0 Pr)3) also participate in asymmetric conjugate addition to a,yS-unsaturated ketones in an aprotic solvent [38] (Scheme 3.20). The addition of 52 to 2-cyclohexenone la was complete within 1 h in the presence of 3 mol% of [Rh(OH)((S)-BINAP)]2 in THF at 20°C to give high yields of the titanium enolates 53 as conjugate addition products. The enantioselectivity is very high, 99.5, 99.0, and 99.8% enantiomeric excess, for Ar = Ph, 4-FC6H4, and... 

MeOC6H4, respectively. The titanium enolates were converted into silyl enol ethers 54 by treatment with chlorotrimethylsilane and lithium isopropoxide. Additionally, cyclic enones lb and Ic, and linear enones Id and le, are also good substrates for the asymmetric conjugate addition of phenyltitanium triisopropoxide, giving the corresponding arylation products with over 97% enantioselectivity. 

In addition to the simplified operation, this direct generation of titanium enolates has some advantages such as improved yields and enantioselectivities, and its compatibility with a wider range of electrophiles. One limitation is that it is less useful for unhindered ketones, because of self-condensation. 

Crimmins s TiCL -mediated asymmetric aldol condensation protocol was used in the enantioselective total synthesis of (9S)-dihydroerythronolide A (68)25 (Scheme 2.lx). Swern oxidation of the primary alcohol 69 provided the aldehyde 70 in almost quantitative yield, which underwent asymmetric aldol condensation with the titanium enolate of (A )-4-bcnzyl-3-propionyloxa/,olidin-2-onc (26M) in the presence of (-)-sparteine to afford the aldol adduct desired (71) as a single diastereomer. 

The most smdied O-bonded transition metal enolates are titanium enolates . The reason for their success has beeu recognized in the fact that titanium enolates show an enhanced stereochemical control in C—C bond-forming reactions over simple lithium enolates and the possibility of incorporating chiral ligands at the titanium centre, a possibility which has lead to enantioselective aldol reactions with excellent enantiomeric excess. Moreover, titanium euolates have been used in oxidation reactions with remarkable diastereoselectivity. 

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... 

The method is also successful for carboxyhc esters , and A,A-disubstituted amides, and can be made enantioselective by the use of a chiral oxaziridine. Dimethyldioxirane also oxidizes ketones (through their enolate forms) to a-hydroxy ketones. Titanium enolates can be oxidized with tert-butyl hydroperoxide or with dimethyl dioxirane and hydrolyzed with aqueous ammonium fluoride to give the a-hydroxy ketone. Ketones are converted to the a-oxamino derivative (0=C CH2- 0=C CHONHPh) with excellent enantioselectivity using... 

The first enantioselective total synthesis of (-)-denticulatin A was accomplished by W. Oppolzer. The key step in their approach was based on enantiotopic group differentiation in a meso dialdehyde by an aldol reaction. In the aldol reaction they utilized a bornanesultam chiral auxiliary. The enolization of A/-propionylbornane-10,2-sultam provided the (Z)-borylenolate derivative, which underwent an aldol reaction with the meso dialdehyde to afford the product with high yield and enantiopurity. In the final stages of the synthesis they utilized a second, double-dlastereoditferentiating aldol reaction. Aldol reaction of the (Z)-titanium enolate gave the anf/-Felkin syn product. The stereochemical outcome of the reaction was determined by the a-chiral center in the aldehyde component. 

Fluoride ion activation of aryltrimethylstannane is important for the enantioselective catalytic arylation of aldimine (16) (Scheme 3.43) [6]. Titanium enolates (20) of trifluo-romethyl ketones (19) are stable and can be alkylated anfi-selectively at the a-carbon in... 

The aldol reactions of titanium enolates have been the best studied of all the transition metal enol-ates."- In many cases they show higher stereoselectivity and chemoselectivity in their reactions than lithium enolates and are easily prepared using inexpensive reagents. They also promote high levels of diastereofacial selectivity in reactions of chiral reactants. The Lewis acidity of the titanium metal center can be easily manipulated by variation of the ligands (chloro, alkoxy, amino, cyclopentadienyl, etc.) attached to titanium, which leads to enhanced selectivity in appropriate cases. Moreover, the incorporation of chiral ligands on titanium makes possible efficient enantioselective aldol reactions. 

An important development is the use of D-glucose-derived alkoxy ligands on titanium in cyciopentadi-enyldi(alkoxy)titanium enolates, which undergo efficient enantioselective aldol reactions with aldehydes. The chiral titanium reagent (30), prepared from reaction of cyclopentadienyltitanium trichloride with two equivalents of (l,2 5,6)-di-0-isopropylidene-a-D-glucofuranose, can be used to transmetal late the lithium enolate of t-butyl acetate in ether solution (equation 10). The titanium enolate generated is then... 

Table 4 Enantioselective Aldol Reactions of the Chiral Titanium Enolate of t-Butyl Acetate...

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