Transmetallation aldol reactions

Conducting the aldol reaction at temperatures below —78 "C increases the diastereoselectivity, but at the cost of reduced yields45. Transmetalation of the lithium enolate 2 a by treatment with diethylaluminum chloride generated an enolate species that provided high yields of aldol products, however, the diastereoselectivity was as low as that of the lithium species45. Pre treatment of the lithium enolate 2a with tin(II) chloride, zinc(II) chloride, or boron trifluoridc suppressed the aldol reaction and the starting iron-acyl complex was recovered. 

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). 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

Transfer of chirality in aldol reactions has been attempted using / -allenyl ester enolates. These ambident nucleophiles have an axis of chirality, and such compounds have been less utilized in stereoselective reactions. They are prepared by transmetallation of the... 

Zinc bisenolate 136 (Figure 11) is prepared by the transmetallation of propiophenone lithium enolate with 0.5 equivalents of ZnBr2 136 reacts with aldehydes, both aliphatic and aromatic, in a domino aldol reaction which mimics the action of aldolases167. The first aldol reaction between 136 and the aldehyde produces zinc aldolate 137, which then undergoes a second intramolecular aldol addition to adduct 138. Spontaneous hemiacetalization affords 139, where all large substituents occupy equatorial positions168. 

For the propionate aldol reaction the Li enolate (7), generated by deprotonation of 2,6-dimethylphenyl propionate with Lithium Diisopropylamide in EtiO, was chosen. Transmetalation with 1.25 equiv of an ethereal solution of (1) takes 24 h at —78 °C. The completion of this step is evident by the disappearance of racemic anti-a do (9) in favor of optically active yw-isomer (10) (91-98% ee) upon reaction with an aldehyde (RCHO) and aqueous workup. At this point, 3-11% of anri-aldol (9) remaining in the reaction mixture is optically active as well (eq 2). This awri-isomer (9) (94-98% ee) becomes the major product if the reaction mixture, containing the putative ( )-titanium enolate derived from (7), is warmed for 4-5 h to —30°C before reaction with an aldehyde (RCHO) again at —78 °C. Isomerization to the (Z)-titanium enolate is a possible explanation of this behavior. Some substrates, aromatic and unsaturated aldehydes, behave exceptionally, as a high proportion of yn-isomer (10) (19-77%) of lower optical purity (47-66% ee) is formed in addition to (9) (94-98% ee). After hydrolysis of the acetonide (6) the products (9/10) are isolated and separated by chromatography in 50-87% yield. The reactions of pivalaldehyde (R = r-Bu) are sluggish at —78°C and have therefore been carried out at —50 to —30°C. 

Eluoride ion-catalyzed aldol reactions of silyl enolates are valuable for stereoselective carbon-carbon bond formation [19]. In this system fluoride ion works as an activator of silyl enolates to produce reactive metal-free enolates, which add to aldehydes as the actual nucleophiles. Similar aldol reactions via activation of silyl enolates by nucleophilic reagents and solvents have been reported in recent years. In addition, activation of silyl enolates by transmetalation has attracted much attention because of its possible application to diastereo- and enantioselective transformation. 

In contrast with the above Lewis acid-catalyzed asymmetric aldol reactions, chiral Pd and Pt cationic complexes have been found to catalyze the asymmetric process by a transmetalation mechanism involving a metal enolate intermediate (Section 10.2.1.3). 

The Tol-BINAP complexes of CuFa, CuF, and CuOt-Bu also work as efficient chiral catalysts of the aldol reactions of aromatic and a, -unsaturated aldehydes wifh dienolate 64 (Scheme 10.62) [164]. IR spectroscopy has revealed fhat the stoichiometric reaction of 64 wifh Cu(Ot-Bu)(S)-Tol-BINAP forms a Cu(I) enolate, and fhat subsequent reaction wifh an aldehyde gives a copper aldolate. The copper enolate is also obtained by stepwise treatment of 64 with Bu4NPh3SiF2 and Cu(C1O4)(S)-To1-BINAP. These results, with the known reduction of Cu(II) to Cu(I) by SEE, indicate that fhe Cu-catalyzed aldol reactions proceed fhrough a transmetalation mechanism involving a chiral Cu(I) enolate. 

Dichloroindium hydride, generated by transmetallation between tributyltin hydride and indium trichloride, predominantly reduces unsaturated ketones (enones) with 1,4 selectivity in the presence of aldehydes. Under anhydrous conditions, the successive aldol reaction between the resulting enolates and the remaining aldehydes proceeds with high anti-selectivity. The stereochemistry, however, is reversed to be syn-sclccti vc by the use of water and methanol as an additive and solvent, respectively [12 b]. 

An important development is the use of D-glucose-derived alkoxy ligands on titanium in cyclopentadi-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,22 can be used to transmetallate the lithium enolate of f-butyl acetate in ether solution (equation 10).23 The titanium enolate generated is then... 

Heterocycles. A route to 2,3-disubstituted furans takes advantage of the Cu-Zn-transmetallation (with ZnCl2) from enolates derived from conjugate organocuprate addition to enones, and aldol reaction of zinc enolates to an alkoxyacetaldehyde. ... 

Asymmetric aldol reactions. The chiral N-propionyloxazolidinone (1), prepared in several steps from (lR)-(—)-camphorquinone, undergoes highly diastereoselective aldol reactions with the additional advantage of high crystallinity for improving the optical purities of crude aldols. Either the lithium enolate or the titanium enolate, prepared by transmetalation with ClTi(0-(-Pr)3, reacts with aldehydes to form syn-adducts with diastereomeric purities of 98-99% after one crystallization. The observed facial selectivity is consistent with metal chelation of intermediate (Z)-enolates (supported by an X-ray crystal structure of the trapped silyl enol ether). The lithium enolate also exhibits... 

The o. o -disubshtuted thioglycolate amide was successfully Incorporated in highly diastereoselecUve aldol reaction with aromatic and aunsaturated aldehydes through transmetallation of the enolates with dicyclohexylboron bromide (eq 4). ... 

The early tvork in the field of titanium enolate acetate aldol reactions tvas conducted by Braun in a general investigation of acetate aldol reactions [12]. The enoiates tvere generated from chiral acetamide 16 by transmetalation of the lithium enolate tvith triisopropoxytitanium chloride or titanium tetrachloride, as sho vn in Table 2.3. They reported moderate selectivity for the reaction vith benzaldehyde. 

As described above, optically active aldol adducts are easily obtained by using a stoichiometric amount of chiral diamine, tin(II) triflate, and dibutyltin acetate. To perform the enantioselective aldol reaction by using a catalytic amount of the chiral catalyst, transmetalation of initially formed tin(II) alk-oxide 91 to silyl alkoxide 92 tvith silyl triflate is an essential step (Figure 3.6). When the aldol reaction vas conducted simply by reducing the amount of the chiral catalyst, aldol adducts vere obtained vith low stereoselectivity because Sn-Si exchange occurs slovrly and undesired Me3SiOTf-promoted aldol reaction affords racemic aldol adducts. 

After the first reports of the above-mentioned highly eflident catalytic enantioselective aldol reaction, some groups independently reported catalytic symmetric aldol reactions of silicon enolates vith aldehydes using chiral boron [72], titanium [73], zirconium [74], and copper Le vis acids [75], or by transmetalation to chiral Pd(II) enolates [44]. Chiral phosphoramide-promoted aldol reactions of trichlorosilyl enol ethers have been reported as Le vis base-catalyzed asymmetric aldol reactions [76]. 

Mukaiyama aldol reactions of silyl enol ethers are generally rationalized by a Lewis acid activation of the carbonyl group by in situ formation of a complex that reacts with the silyl enol ether or the silyl ketene acetal [99,167]. Transmetallation mechanisms according to which silicon is replaced under formation of a metal enolate have been discussed as well for catalytic versions of the reaction [168], in particular for late transition metals [169]. 

The most versatile and the most frequently applied among the enantioselective catalytic aldol protocols is based upon the Mukaiyama s directed aldol reaction the addition of silicon enolates to aldehydes or ketones [86], in its classic version under activation of the carbonyl group by a chiral Lewis acid. More recently, base-promoted versions of the Mukaiyama reaction were elaborated and also procedures that involve a transmetallation of the silicon enolate. Over the years since the discovery of the reaction, numerous protocols for enantioselective and diastereoselective additions of silicon enolates to aldehydes or ketones under activation by chiral catalysts were elaborated [87], after the group of Mukaiyama itself had made seminal and substantial contributions [88]. 

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