Reagents titanium

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

Another chiral titanium reagent, 11, was developed by Corey et al. [17] (Scheme 1.24). The catalyst was prepared from chiral ris-N-sulfonyl-2-amino-l-indanol and titanium tetraisopropoxide with removal of 2-propanol, followed by treatment with one equivalent of SiCl4, to give the catalytically-active yellow solid. This catalyst is thought not to be a simple monomer, but rather an aggregated species, as suggested by NMR study. Catalyst 11 promotes the Diels-Alder reaction of a-bro-moacrolein with cyclopentadiene or isoprene. 

Mikami et al. have reported that the chiral titanium reagent 12 derived from bi-naphthol and TiCl2(0-i-Pr)2 catalyzes the Diels-Adder reaction of a-bromoacrolein or methacrolein with isoprene or 1-methoxy-l,3-butadiene to afford the cycloadducts with high enantioselectivity [18] (Scheme 1.25). 

Another issue important to the success of this chiral titanium reagent 31 was the discovery of a marked solvent effect. When the fumaric acid derivative is reacted with isoprene in the presence of 10 mol% of the titanium reagent 31 in toluene, poor optical purity results (36-68% ee). Interestingly the optical purity of the adduct greatly increased in the order benzene, toluene, xylenes, and mesitylene, with 92% ee obtained in the last. Mesitylene is difficult to remove, because of its high boiling point, and other solvents were screened in detail. As a result, the mixed solvent system toluene petroleum ether (1 1) was discovered to be very effective. 

Application of this catalytic process was extended to asymmetric intramolecular Diels-Alder reactions. Synthetically useful intermediates with octalin and decalin skeletons were obtained in high optical purity by use of a catalytic amount of the chiral titanium reagent [45] (Scheme 1.57, Table 1.25). The core part of the mevi-nic acids was enantioselectively synthesized by use of this asymmetric intramolecular reaction [46] (Scheme 1.58). 

The reaction is limited to allylic alcohols other types of alkenes do not or not efficiently enough bind to the titanium. The catalytically active chiral species can be regenerated by reaction with excess allylic alcohol and oxidant however the titanium reagent is often employed in equimolar amount. 

In contrast to the results obtained with the jS-alkoxy-a-alkyl-y-lactol 16 (vide supra), a chelation-directed, anti-Cram selective nucleophilic addition to the a-methyl-y-lactol 1 was not only observed with methyllithium and methylmagnesium bromide but also with (triisopropoxy)methyl-titanium72. In fact, the highest diastereoselectivity (> 98 % de) was observed with the titanium reagent in dichloromethane as reaction solvent. A seven-membered chelate 3 with the a-methyl substituent in a pscudoequatorial position has been postulated in order to explain the stereochemical outcome. 

Enantiomerically enriched l-(diisopropylaminocarbonyloxy)allyllithium derivatives (Section 1.3.3.3.1.2.) add to carbonyl compounds with syn-l,3-chirality transfer21, giving good evidence for a pericyclic transition state in the main reaction path (Section 1.3.3.1.). However, since the simple diastereoselectivity and the degree of chirality transfer are low, for synthetic purposes a metal exchange with titanium reagents or trialkyltin halides (Section D.1.3.3.3.8.2.3.) is recommended. 

Reagents of type 1 are the most important and exhibit the highest reactivity towards carbonyl compounds. The reactivity can be further tuned by altering the substitution on titanium. Reagents of type 2 show lower reactivity, but higher selectivities, but have, so far, only been used occasionally (Section 1.3.3.3.8.2.1.2.). Reagents of type 3, derived from chiral alcohols, accomplish efficient enantioselective allyl transfer (Section 1.3.3.3.8.2,3.3.). 

The corresponding zirconium allyl derivatives have also been investigated6,7, but, in general, do not have any particular advantages over the titanium reagents. In addition, the starting materials are often more expensive and more difficult to purify. 

The corresponding titanium reagent can be similarly prepared from (H,fl)-2,3-0-isopropylidcne- 1,1,4,4-te-traphenyl-1.2.3,4-butanctctrol36. 

Ammonium fluoride solution is also recommended for aqueous workup56. Most homoallylic alcohols also survive a workup with 2N hydrochloric acid56 (3-5 mL per mmol of titanium reagent). 

Alkene R1 Ketone Titanium Reagent Temp. (°C) d.r. (anti/syn) Yield (%) Ref... 

Allyltrialkoxy- or -tris(dialkylamino)titanium reagents are not capable of chelation-controlled addition reactions with oxy- or amino-substituted carbonyl compounds due to their low Lewis acidity87. To attain chelation control, the application of allylsilanes (Section 1.3.3.3.5.2.2.) and allylstannanes (Section I.3.3.3.6.I.3.2.) in the presence of bidentate Lewis acids like titanium(IV) chloride, tin(lV) chloride or magnesium bromide are the better options. 

High nonchclation-controlled induced and simple diastereoselectivity are also reported for a 2-butenyl titanium reagent for example65 92 ... 

The enantiomeric compositions of the titanium reagents are monitored easily by the reaction with enantiomerically pure chiral aldehydes, such as 2-(fer/-butyldimethylsilyloxy)propanal104. Here, the ratio of diastereomeric products reflects the ratio of enantiomers of the reagent, although a small error arises from double stereodifferentiation95 104. 

Very high levels of induced diastereoselectivity are also achieved in the reaction of aldehydes with the titanium enolate of (5)-l-rerr-butyldimethylsiloxy-1-cyclohexyl-2-butanone47. This chiral ketone reagent is deprotonated with lithium diisopropylamide, transmetalated by the addition of triisopropyloxytitunium chloride, and finally added to an aldehyde. High diastereoselectivities are obtained when excess of the titanium reagent (> 2 mol equiv) is used which prevents interference by the lithium salt formed in the transmetalation procedure. Under carefully optimized conditions, diastereomeric ratios of the adducts range from 70 1 to >100 1. 

Narasaka K., Iwasawa N. Asymmetric Reactions Promoted by Titanium Reagents... 

Keywords asymmetric Diels-Alder reactions, chiral titanium reagent... 

The titanium reagent also dimethylates aromatic aldehydes." Triethylaluminum reacts with aldehydes, however, to give the mono-ethyl alcohol, and in the presence of a chiral additive the reaction proceeds with good asymmetric induction." A complex of Me3Ti-MeLi has been shown to be selective for 1,2 addition with conjugated ketones, in the presence of nonconjugated ketones." ... 

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