Chlorotitanium

The chlorotitanium enolate, generated by treatment of (S )-l-tm-butyldimethylsiloxy-l-cyclohexyl-2-butanone with titanium(iv) chloride and diisopropylethylamine, provides the syn-product upon reaction with benzaldehyde. The diastereoselectivity of 99 1 is defined as the ratio of the major isomer to the sum of all other isomers47bc. 

Substrate-induced diastereoselectivity is provided by the chlorotitanium enolate of 14a,b47b and the boron enolate of ketone 15S3 to give predominantly. wt-aldols. 

In a similar way. ft-keto imide 19 undergoes stereodivergenl aldol reactions. Thus, conversion of 19 into the tin enolate, and subsequent addition of aldehydes, give predominantly the diastereomers 20. On the other hand, hydroxy ketones 21 are the main products when the chlorotitanium enolate of 19 is reacted with aldehydes53. ... 

The best titanium mediator appears to be methyltitanium triisopropoxide, yet good yields are also obtained with titanium tetraisopropoxide and chlorotitanium triisopropoxide. The methyl group on titanium serves as a dummy alkyl ligand which is eliminated as methane after hydride transfer from the... 

The reactivity of acylzirconocene chlorides towards carbon electrophiles is very low, and no reaction takes place with aldehydes at ambient temperature. In the reaction described in Scheme 5.12, addition of a silver salt gave the expected product, albeit in low yield (22—34%). The yield was improved to 79% by the use of a stoichiometric amount of boron trifluoride etherate (BF3OEt2) (1 equivalent with respect to the acylzirconocene chloride) at 0 °C. Other Lewis acids, such as chlorotitanium derivatives, zinc chloride, aluminum trichloride, etc., are less efficient. Neither ketones nor acid chlorides react with acylzirconocene chlorides. In Table 5.1, BF3 OEt2-mediated reactions of acylzirconocene chlorides with aldehydes in CH2C12 are listed. 

Table 11.4. 1,2-Disubstituted cyclopropanols 22 from carboxylic acid esters 8 and 2-substituted ethyl-magnesium halides in the presence of titanium tetraisopropoxide or chlorotitanium triisopropoxide. Entry Starting Product Conditions Yield Ref. Ester R1 R3 [mol% (%) R2 Ti(OR)4] (d. r. Z/Eb) ...

M. T. Bilodeau, Ph.D. Thesis I. Studies on the Direct Formation of Chlorotitanium Enolates. II. The Development of the Copper-Catalyzed Aziridination Reaction, Harvard University, Cambridge, MA, 1993. 

The oxazolidinones have been used as chiral auxiharies for enolate alkylation and aldol reactions in enantioselective and total syntheses The interest in these substrates is largely known for iyw-diastereoselective aldol reactions with chlorotitanium or diaUcylboron oxazilidinone enolates (equation 114). 

DeCamp et al.t19l synthesized the lactone intermediate of the 1-hydroxyethylene isostere with high yields and stereoselectivity. As summarized in Scheme 10 (Section 10.6.2), the titanium homoenolate is prepared from ethyl 3-iodopropionate. The iodide is metalated with zinc/copper couple to give the iodozinc homoenolate species. The alkyltitanium homoenolate is then generated by transmetalation of the iodozinc precursor with one of the several chlorotitanium isopropoxide species. The resulting titanium homoenolate reacts with a N-protected a-amino aldehyde, leading to a mixture of 45-diastereomers. In the last step, the product is lactonized. 

Having noticed certain limitations of chlorotitanium aldol reactions on Evans et al. s chiral auxiliary,21 in 1997 Crimmins and others developed a brilliant protocol to achieve a highly diastereoselective aldol reaction.22 Asymmetric aldol... 

In subsequent investigations the generality of the above behavior was established for n-alkyltitanium compounds 21,22 77,78). For example, quenching ethyllithium 25 with chlorotitanium triisopropoxide 3 affords 9, which reacts in situ with a 1 1 mixture of 19 and 20 to afford essentially only the aldehyde adduct 23 (Equation 9) 77). 25 itself reacts at 0 °C almost statistically ... 

Prepared from chlorotitanium triphenoxide and CH3Li in situ reaction with 124 in ether at... 

We have prepared a number of titanium enolates by quenching the lithium analogs withchlorotitanium triisopropoxide 3, chloro- or bromotitanium tris(diethylamide) 15 or chlorotitanium tris(dimethylamide) 103 25). In mqst cases the solutions can be freed from the ether or THF and the stable liquid titanium enolates studied by NMR if so desired. In case of the amino derivative 186 flash distillation is possible. The H-NMR spectra of the distilled and non-distilled compound are identical and... 

If carbanions are to be titanated, alkoxy or amino ligands at titanium are most likely to ensure success. Sulfur or phosphorus ligands have not been tested. In rare cases electrontransfer instead of titanation sets in, forming Ti(III) species which are generally unsuitable for useful chemistry. This is most likely to occur if the carbanion is very electron rich, e.g., in case of dianions or extended anionic K-systems. We have noticed that this undesired property decreases in going from chloro to alkoxy and finally to amino ligands at titanium. For example, dianions derived from carboxylic acids reduce chlorotitanium triisopropoxide 3 to some extent, whereas quantitative double titanation occurs with chloro- or bromotitanium tris(diethylamide) 15 77>. Addition of amines to the reaction mixture has similar effects 77). 

Highly diastereoselective acetate aldol additions using chlorotitanium enolates of mesityl-substituted JV-acetylthiazolidinethione 136 has been documented <07OL149>. These aldol reactions proceed in high yields and diastereoselectivities (94/6 to 98/2) for aliphatic, aromatic, and a,P-unsaturated aldehydes. Compound 136 also undergoes double diastereoselective aldol additions with chiral aldehyde 139 to give adduct 140 in high yields. 

We speculated earlier whether a fluoride ligand could add catalytic properties to our chiral dialkoxy cyclopentadienyltitanium complexes. Chlorotitanium-TADDOLate 17 - an excellent template for controlling the stereochemistry of stoichiometric additions also to chiral aldehydes... 

The chlorotitanium enolates derived from AT-acyloxazolidinones 3.17, N-acyloxazolidinethiones 3.18 and iV-acylthiazolidinethiones 3.19 undergo highly selective and efficient aldol reactions with aldehydes. The iST-acyloxazolidinethione 3.18 and N-acylthiazolidinethione 3.19 auxiliaries are also easier to cleave. 

Consequently, various Grignard reagents have been shown to be effective for the intramolecular cyclopropanation reactions with insignificant differences in yields. Whereas several titanium alkoxides and aryloxides can also be employed, chlorotitanium triisopropoxide and methyltitanium triisopropoxide have often been found to be the titanium reagent of choice. Ether, THE, toluene, or even dichloromethane are generally appropriate reaction solvents. 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

Sydowic acid (100) was prepared as outlined in Scheme 10. ° The crucial transformation of ketone (101) to cafbinol (102) was accomplished by stereoselective 1,2-addition of trimethylaluminum, which afforded superior facial selectivity for the re-face compared to Grignard reagents. In contrast, methyltri-chlorotitanium addition resulted in a 5i -face stereoselectivity. 

Allyltitanium complexes (22) readily add to carbonyl compounds with high regio- and stereo-selection. They are prepared by reaction of a chlorotitanium complex (21) with an allyl-magnesium or -lithium derivative (equation 13). Some of these unsaturated Ti complexes, like (23)-(25) in Scheme 2, obtained from allylmagnesium halides or allyllithium by reaction with titanium tetraisopropoxide or titanium tetramides, are known as titanium ate complexes . The structure of these ate complexes, at least from a formal point of view, can be written with a pentacoordinate Ti atom. Some ate complexes have synthetic interest, as is the case of (allyl)Ti(OPr )4MgBr which shows sharply enhanced selectivity towards aldehydes in comparison with the simple (allyl)Ti(OPr )3. ... 

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