Titanium catalysts aldol reactions

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

BINOL-derived titanium complex was found to serve as an efficient catalyst for the Mukaiyama-type aldol reaction of ketone silyl enol ethers with good control of both absolute and relative stereochemistry (Scheme 8C.24) [57]. It is surprising, however, that the aldol products were obtained in the silyl enol ether (ene product) form, with high syn-diastereoselec-tivity from either geometrical isomer of the starting silyl enol ethers. 

Carreira et al. used a chiral BlNOL-derived Schiff base-titanium complex as the catalyst for the aldol reactions of acetate-derived ketene silyl acetals (Scheme 8C.29) [64a]. The catalyst was prepared in toluene in the presence of salicylic acid, which was reported to be crucial to attain a high enantioselectivity. A similar Schiff base-titanium complex is also applicable to the carbonyl-ene type reaction with 2-methoxypropene [64b], Although the reaction, when con-... 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Sllyl enol ethers react with aldehydes at -78°C, and with ketones near 0°C. Note that the aldol reaction of sllyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

In 1995 Carreira et al. [19] reported a catalytic variant of the asymmetric carbonyl-ene reaction (Scheme Ha). By treatment of the aldehyde 60 with 2 mol % of titanium catalyst 35, already used in the Mukaiyama aldol reaction, the / -hy-droxyketone 61 is formed in quantitative yield and with an excellent ee value. Here, the ene-compound, 2-methoxypropene, is used simultaneously as solvent in a large excess. The high en-antioselectivity is still limited to aldehydes similar to 60 benzaldehyde for instance is converted with an ee of only 66 %. 

Mukaiyama Aldol Condensation. The BINOL-derived titanium complex BINOL-T1CI2 is an efficient catalyst for the Mukaiyama-type aldol reaction. Not only ketone silyl enol ether (eq 25), but also ketene silyl acetals (eq 26) can be used to give the aldol-type products with control of absolute and relative stereochemistry. 

Mukaiyama Aldol Condensation. As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis. Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-ty pe aldol reaction of not only ketone si ly 1 enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11). ... 

Keck also investigated asymmetric catalysis with a BINOL-derived titanium complex [102,103] for the Mukaiyama aldol reaction. The reaction of a-benzyloxyalde-hyde with Danishefsky s dienes as functionalized silyl enol ethers gave aldol products instead of hetero Diels-Alder cycloadducts (Sch. 40) [103], The aldol product can be transformed into hetero Diels-Alder type adducts by acid-catalyzed cyclization. The catalyst was prepared from BINOL and Ti(OPr )4, in 1 1 or 2 1 stoichiometry, and oven-dried MS 4A, in ether under reflux. They reported the catalyst to be of BINOL-Ti(OPr% structure. 

A convergent total synthesis of polyene macrolide roflamycoin was achieved by S.D. Rychnovsky and co-workers." " In their approach, they introduced the C25 stereocenter via an asymmetric catalytic Mukaiyama aldol reaction utilizing Carreira s chiral titanium catalyst." ... 

Reetz et al. reported that a chiral Ti complex prepared from TiCL). and the dilithium salt of (S)-BINOL promoted the aldol reaction of 3-mefhylbutanal with KSA 48 with only poor enantioselectivity (60%, 8% ee) [115 b]. After this pioneering work, the titanium-based catalyst system has been intensively improved to attain an efficient catalytic cycle and high stereoselectivity [147-155]. 

The asymmetric carbonyl-ene reaction has been developed by using chiral aryloxy complexes, i.e, 64 [197,198] and 65 [199]. Titanium complexes bearing chiral diols such as 66 and 67 have been used as catalysts for various enantioselective reactions such as synthesis of cyanohydrin, aldol reactions [200], [2 + 2] cycloaddition reactions [201], the reaction of diketene with aldehyde [202], hydroboration [203], allylation of aldehydes [204], and Diels-Alder reactions [205]. 

The demand for environmentally friendly chemistry and its widespread applicability have made water an increasingly popnlar solvent for organic transformations. Mixtures of water and other solvents snch as tetrahydrofnran are now commonly anployed for a number of organic transformations. For instance, the Lewis acid catalysed aldol reaction of silyl enol ethers, commonly known as the Mnkaiyama aldol reaction, which was firstly reported in the early seventies, can be carried ont in snch media. With titanium tetrachloride as the catalyst this reaction proceeds regioselectively in high yields, but the reaction has to be carried ont strictly nnder non-aqneons conditions in order to prevent decomposition of the catalyst and hydrolysis of the sUyl enol ethCTS. In the absence of the catalyst it was observed that water had a beneficial influence on this process (Table 4, entry D) . Nevertheless, the yields in the nncatalysed version WCTe still unsatisfactory. Improved results were obtained with water-tolerant Lewis acids. The first reported example for Lewis acid catalysis in aqueous media is the hydroxymethylation of silyl enol ethers with commercial formaldehyde solution using lanthanide trillates. In the meantime, the influence of several lanthanide triflates in cross-aldol reactions of various aldehydes was examined " " ". The reactions were most effectively carried out in 1 9 mixtures of water and tetrahydrofnran with 5-10% Yb(OTf)3, which can be reused after completion of the reaction (Table 19, entry A). Although the realization of this reaction is quite simple, the choice of the solvent is crucial (Table 20). 

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... 

Tridentate BINOL catalysts can be derived from titanium tetra(isopropoxide), BINOL ligands, and hindered amine bases. These catalysts have also been shown to provide good yields and ee s for the aldol reactions at low temperatures of 2-methoxypropene with several aldehydes to the P-hydroxyketones, but an acid workup of the products is required. 

The reaction can be applied to silyl enol esters as well. Good asymmetric induction can be achieved in the Mukaiyama aldol reaction. The reaction of silyl enol thioether 246 and nonanal, for example, gave 247 in 60% yield and in 93% ee when the (/ )-BINOL-titanium catalyst shown was used. In this work, the reaction was also done in supercritical fluoroform and in supercritical carbon dioxide. A similar reaction was reported using catalysts closely related to 244 and dichloromethane as the solvent.Chiral oxazaborolidine catalysts have also been shown to be effective for enantioselective Mukaiyama aldol reactions. 

The titanium tetrachloride (TiCl4)-mediated aldol reaction of silyl enol ethers with aldehydes was first reported by Mukaiyama and co-workers [22]. Following this report, several other Lewis acids such as BF3 Et20, and SnCl4, or fluoride anions such as BU4F were found to be effective promoters or catalysts in this reaction. 

Carriera and coworkers employed titanium SchifFbase catalysts such as (7.189) (see Section 7.1) in an ene reaction of 2-methoxypropene (7.190) with various aldehydes (7.01) (not especially reactive ones). The overall synthetic strategy of using 2-methoxypropene (7.190) has significant merit in comparison with aldol reactions, because it is a cheap starting material, and means that a silyl enol ether does not have to be prepared prior to an aldol reaction. The Schiff base chromium complexes such as (7.192) developed by Jacobsen and coworkers is effective with both aliphatic and aromatic aldehydes providing up to 96% ee in the reaction of the latter type of substrate with 2-methoxypropene (7.190). This complex also catalyses the ene reaction with 2-silyloxypropene with high ee. ... 

Mechanistically related to the Mukaiyama aldol reaction, the carbonyl ene reaction is the reaction between an alkene bearing an allylic hydrogen and a carbonyl compound, to afford homoallylic alcohols. This reaction is potentially 100% atom efficient, and should be a valuable alternative to the addition of organometallic species to carbonyl substrates. However, the carbonyl ene reaction is of limited substrate scope and works generally well in an intermolecular manner only with activated substrates, typically 1,1-disubstituted alkenes and electron-deficient aldehydes (glyoxylate esters, fluoral, a,p-unsaturated aldehydes, etc.), in the presence of Lewis acids. The first use of chiral catalyst for asymmetric carbonyl ene was presented by Mikami et al. in 1989. ° By using a catalytic amount of titanium complexes prepared in situ from a 1 1 ratio of (rPrO)2titaniumX2 (X = Cl or Br) and optically pure BINOL, the homoallylic alcohols 70a,b were obtained in... 

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