Titanium aldol type addition

Recent developments of aldol-type reactions with titanium enolates include the a- and /3-C-glycosidation of glycals73 and the diastereoselective addition to 2-acetoxytetrahydrofurans.74 Mukaiyama and co-workers have developed a one-pot procedure for the preparation of unsymmetrical double aldols.75... 

In addition to enol silyl ethers, an optically active boryl enolate underwent the highly anri-stereoselective aldol reaction with a wide variety of aldehydes in the presence of TiCU (Eq. 34) [120]. The vinyl sulfides shown in Eq. (35) reacted with a,fi-unsaturated ketones via the 1,4-addition pathway in the presence of a titanium salt, but the reaction was followed by the cleavage of a carbon-carbon bond in the cycloalkane to give open chain products in a stereoselective manner [121]. The 1,2-type addition was observed, if the olefinie acetal was used instead of the corresponding carbonyl compound, as shown in Eq. (36) [121], The successive scission of the carbon-carbon bond took place analogously to give the same type of products as shown in Eq. (35). 

Trimethylsilyloxy)furan can also be used as a functionalized silyl enol ether for the asymmetric catalytic aldol-type reaction. Figadere has reported that the reaction of aliphatic aldehydes with the siloxyfuran catalyzed by BINOL-derived titanium complex provides the diastereomeric mixtures with high enantioselectivity (Sch. 42) [107], The addition reaction proceeds at the y position of the siloxyfuran to give butenolides of biological and synthetic importance. 

Keywords Ene reaction, Hetero-Diels-Alder reaction, Ene cyclization, Desymmetrization, Kinetic resolution. Non-linear effect. Asymmetric activation, Metallo-ene, Carbonyl addition reaction, Aldol-type reaction. Titanium, Aluminum, Magnesium, Palladium, Copper, Lanthanides, Binaphthol, Bisoxazoline, Diphosphine, TADDOL, Schiff base. 

The Mukaiyama reaction is an aldol-type reaction between a silyl enol ether and an aldehyde in the presence of a stoichiometric amount of titanium chloride. The reaction, which displays a negative volume of activation, could be performed without acidic promoter under high pressure [58]. In this case, the major product is the syn hydroxy ketone, not as for the TiCl4-promoted reactions which lead mostly to the anti addition product. Since the syn or anti selectivity is the result of two transition states with different activation volumes (AV n < AVfnti), it was of great interest to investigate the aldol reaction in water. Indeed, the reaction of the silyl enol ether of cyclohexanone with benzaldehyde in aqueous medium was shown to proceed without any catalyst and under atmospheric pressure, with the same syn... 

The influence of Lewis acids on the diastereoselectivity of the cycloaddition of /f-alkoxyalde-hydes has also been studied35. Magnesium bromide, highly effective for a-alkoxyaldehydes, fails in the case of the cycloaddition of aldehyde 10 to diene 2 and the reaction does not exhibit any selectivity, probably due to a change of mechanism to Mukaiyama s aldol type. One reason may be the change of solvent from tetrahydrofuran to a mixture of benzene and diethyl ether. The additions of aldehyde 10 to other dienes are more selective but diastereoselectivity is still much lower than for the a-alkoxy aldehydes. Boron trifluoride-diethyl etherate complex also leads to a mixture of four possible products. Excellent selectivity is achieved for the titanium(IV) chloride catalyzed addition of aldehyde 10a to diene 2b, 11c is obtained as the only product. 

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

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],... 

Further process optimization by Thiruvengadam and co-workers (Thimvengadam et al., 1999), led to a novel, stereoselective, scalable two-step process devoid of chromatography for chiral 2-azetidinone construction (Scheme 13.4). As above, the titanium-enolate of chiral oxazolidinone 11a was preformed, but now when reacted with well behaved imines of type 16, affords the unexpected anti-addition product. This surprising result was further supported by careful comparison to minor antiproducts obtained in the earlier aldol-addition methodology and determination that the major product was indeed 17a (undesired RSR series). Adjustment of the oxazolidinone absolute stereochemistry to the fortuitously less expensive 2S-series afforded the desired diastereo-mer 17b in 95% de and in 50-70% yield. Recrystallization improved the stereochemical purity to >99% de. 

Carreira employed a chiral BINOL-derived Schiff base-titanium complex as a catalyst for aldol reactions with acetate-derived ketene silyl acetals (Sch. 38) [100]. The catalyst was prepared in toluene in the presence of salicylic acid, which was reported to be crucial to achieving high enantioselectivity. A similar Schiff base-titanium complex is also applicable to the carbonyl-ene type reaction with 2-methoxypropene (Sch. 39) [101]. Although conducting the reaction in toluene or ether solution provided no addition product, excellent chemical yield and enantioselectivity were attained by the use of 2-methoxypropene as a solvent. 

Titanium enolates have also been obtained by direct deprotonation from ketones and imides upon treatment of titanium tetrachloride in the presence of tertiary amines, preferably, Hiinig s base. As they have been found to be efficient in syn-selective aldol additions [120], their configuration has been assumed to be cis, but they were rarely characterized by NMR spectroscopy. For the titanium enolate derived from Evans-type auxiliaries, the relative ratio of base to titanium tetrachloride was found to have a distinct impact on the selectivity in the addition to aldehydes. This effect has been rationalized by postulating an equilibrium between the tetrachlorotitanate 106/titanium tetrachloride and the titanium enolate 107/pentachlorotitanate, as supported by NMR studies (Scheme 2.30) [121]. Several chiral ketones have been converted into the corresponding cis-enolates by treatment with TiClgOiPr in the presence of Hiinig s base [122]. Titanium tetrachloride and trialkylamines also lead to aldehyde enolates and enable directed aldol additions between aldehydes. This is remarkable in view of the fact that preformed enolates of aldehydes are not readily accessible [123]. 

Scheme 5.62 Enantioselective Mukaiyama aldol additions mediated by titanium-BINOL complexes 196 according to Mikami and Keck. Proposed Zimmerman-Traxler-type transition state model.

Chiral haloacetates of the Evans and Oppolzer type are highly potent and versatile synthons for the preparation of a broad variety of e.p. intermediates. The boron enolates of Evans haloacetates and the titanium enolates of Oppolzer s derivatives undergo aldol additions with aliphatic and aromatic aldehydes to provide syn 2-halo-3-hydroxy carboxylic acid derivatives with excellent diastereoselectivities, generally exceeding syn/anti ratios >50 1 . In the Oppolzer series, only with acetaldehyde (diasteromeric ratio... 

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