Titanium homoenolates

The addition of a titanium homoenolate 115 to a proline derivative 114 proved to be a feasible approach for the formal synthesis of pumiliotoxin 251D. The addition proceeded with high stereoselectivity (Scheme 30) <1999JOC1410>. 

Various racemic titanium-homoenolate reagents have been successfully applied to O-protected (R)- and (5)-lactaldehydes (X = (5 )-2-(iV,iV-dibenzylamino)al-... 

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

An exothermic reaction between cyclopropane 1 and TiCl in methylene chloride produces a wine-red solution of a mixture of titanium homoenolate 2 and chlorotrimethylsilane [10, 19]. When the reaction is performed in hexane, the titanium species precipitates in the form of fine violet needles (approx 90% isolated yield, Eq. (9)). 

The chemical reactivities of such titanium homoenolates are similar to those of ordinary titanium alkyls (Scheme 2). Oxidation of the metal-carbon bond with bromine or oxygen occurs readily. Transmetalations with other metal halides such as SnCl4, SbClj, TeCl4, and NbCls proceed cleanly. Reaction with benzaldehyde gives a 4-chloroester as the result of carbon-carbon bond formation followed by chlorination [9]. Acetone forms an addition complex. No reaction takes place with acid chloride and tm-alkyl chlorides. 

The cyclopropane 1 reacts with none of the group 1 and 2 metal chlorides. Among early transition metal chlorides, NbCl reacted with i in moderate yield to give the same homoenolate obtained by the reaction of equimolar amounts of titanium homoenolate 2 and NbCl (Scheme 2). TaCl5, CrCl3, MoCls, and WC15 did not give any characterizable products. 

Two groups independently reported the formation of titanium homoenolates by the transmetalation reaction of 3-stannyl-propionate esters with TiCl, Eq. (48) [45, 46]. Amide homoenolates become available along this route [47], The trichlorotitanium species thus obtained have been shown ( H NMR) to be similar to that generated along the siloxycyclopropane route and indeed exhibit very similar reactivities. This method does provide a conventient alternative to the siloxycyclopropane route. 

The reaction of 1-isopropoxy-l-trimethylsiloxycyclopropane (1, R = i-Pr) with TiCl yields the titanium homoenolate of isopropyl propionate 2 (R = i-Pr) and Me3SiCl (Eq. see 9). That of 23, in contrast, yields a considerable fraction of the homoenolate of silyl propionate as well, Eq. (66) [19]. Apparently, the loss of an isopropyl group from an oxygen-stabilized cationic intermediate competes with that of the silyl group with bulky substituents. 

Scheme 8 Synthesis of 1-Hydroxyethylene Peptides by Addition of a Titanium Homoenolate to an a-Amino Aldehyde4 7 ...

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. 

Titanium homoenolates of alkyl propionates.18 Treatment of 1-alkoxy-l-trimeth-ylsiiyloxycyclopropanes (l)19 with TiCl4 results in moderately air-sensitive, thermally stable, purple solids formulated as 2, but probably dimeric. They are oxidized by air to alkyl p-hydroxypropionates in good yield. 

Ring-opening reactions of cyclopropanone hemiketals are well known. Under appropriate conditions, cleavage of trimethylsilyl protected hemiketals can provide a synthetically useful route to homoenolate anions as noted earlier (Scheme 20). The reaction of an isopropoxy-titanium homoenolate (128) derived from 127 with an aldehyde has recently been used as the key step in the stereocontrolled construction of the steroidal side-chain of depresosterol (Scheme 49) ... 

TMS-Cl or TMS-I, formed in situ, worics as the promoter in addition reactions of zinc homoenolates ((3-metallocarbonyl compounds), generated from 1-alkoxy-l-siloxycyclopropanes and ZnXz (equation 7). No reaction t es place with the purified zinc homoenolates. In contrast, titanium homoenolates are reactive enough to add to aldehydes in the absence of the Lewis acid promoter.Related reactions of zinc esters with aldehydes in the presence of (lVO)3TiCl have been reported (equation 8). ... 

As shown in Scheme 6.10, treatment of TiCl4 with trimethylsiloxycyclopropane affords the titanium homoenolate compound 62 [193-195], which is a chlorine-bridged dimer as revealed by X-ray analysis [196]. The enoiate 62 reacts with aldehydes, not... 

Ester homoenolates can be made from 3-chloroesters 20 with sodium in the presence of Me3SiCl which traps them as the cyclopropyl silyl ethers4 21, analogues of silyl enol ethers, in a step reminiscent of the acyloin condensation.5 Reaction with aldehydes and ketones again gives y-lactones 19 and Kuwajima has shown that the titanium homoenolate 22 is a true intermediate in this reaction.6... 

Titanium homoenolates can be prepared by transmetallation of 3-stannyl esters wiA TiCU (Scheme 13) 30,31 trichlorotitanium species (10), shows reactivity very similar to that obtained by the silyl-oxycyclopropane route. 

An attractive alternative to the chemistry of titanium homoenolates is the use of highly nucleophilic lanthanide homoenolates, which can be prepared by reduction of 3-halopropionates (Scheme 14). ... 

Optimization of the titanium homoenolate formation consisted of selecting the most appropriate titaninm ligands (i.e., the ratio of chloride to aUcoxide, as well as aUcoxide structure). In our original commnnication, we described the nse of ClTi(OiPr)3 as the transmetallation reagent. This selection was made partly based upon prior precedent, but also upon an observation made when employing... 

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