Titanium aldol addition catalyst

Summary of Facial Stereoselectivity in Aldol and Mukaiyama Reactions. The examples provided in this section show that there are several approaches to controlling the facial selectivity of aldol additions and related reactions. The E- or Z-configuration of the enolate and the open, cyclic, or chelated nature of the TS are the departure points for prediction and analysis of stereoselectivity. The Lewis acid catalyst and the donor strength of potentially chelating ligands affect the structure of the TS. Whereas dialkyl boron enolates and BF3 complexes are tetracoordinate, titanium and tin can be... 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Additional advantages of the formamide condensation protocol were observed performing the reaction in the presence of catalysts which decompose formamide to formaldehyde. Formaldeyde is the most important pre-biotic precursor of sugars through a series of enolization and aldol-like condensation processes catalyzed under acidic or basic conditions, known as the formose reaction [100]. When formamide was heated at 160 °C in the presence of titanium dioxide (a catalyst able to degrade amides to aldehydes) [101] a complex mixture of nucleobase derivatives was obtained including adenine 1, purine 12, cytosine 17, N9-formylpurine 28, N9, N6-diformyladenine 29, 5-hydroxymethyluracil 30, thymine 31 and three novel... 

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. 

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. 

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... 

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... 

Mikami reported that BINOL derived titanium complex efficiently catalyzed the aldol reaction of silyl enol ether with excellent control of both absolute and relative stereochemistry [106] (Scheme 14.37). The reaction was proposed to proceed via a prototropic ene reaction pathway that is different from that of Mukaiyama aldol condensation. A cyclic antiperiplanar transition-state model was proposed to explain the pref erential formation of the syn diastereomer from either (E)- or (Z)-silyl enol ethers [106]. Further modifications of the catalyst system include the use of perfluorophenols and other activating additives [107], or performing the reaction in supercritical fluids [108]. Furthermore, the nucleophile could be extended to enoxysilacyclobutane derivatives [109]. 

Under either the catalytic (eq 1) or the stoichiometric conditions (eq 2), the reagent undergoes addition to chiral aldehydes with complete reagent control , i.e. the stereochemistry of the aldol reaction is totally controlled by the chiral catalyst regardless of the inherent diastereofacial preference of the chiral aldehydes (eq 4). Titanium(IV) chloride and tm(TV) chloride mediate the addition of the title reagent to chiral a-alkoxy aldehydes and -alkoxy aldehydes with complete chelation control (eq 5), whereas the corresponding silyl ketene acetal is unselective. 4... 

Aldol Reactions Addition to Aldehydes and Imines. Since its discovery, the Mukaiyama aldol reaction. has attracted considerable attention and several improvements in reaction conditions have heen reported. Most useful catalysts for this reaction appear to he recently reported lanthanide triflates (eq 5), bis(cyclopentadienyl)titanium bis(trifluoromethanesulfonate), or Cp2Zr(OTf)2 THF. The metallocene salt also catalyzes additions to ketones (eq 6). This reaction can also be carried out under essentially neutral conditions by warming (70 °C) a stoichiometric mixture of the aldehyde and the KSA in acetonitrile (eq 7). When an optically active aldehyde is used, a slightly better stereochemical control is noticed under catalysis of zinc iodide. ... 

Tanabe and coworkers reported the first instances of additions of titanium enolates to ketones [8]. They reported moderate to excellent yields for several reactions. When the two substituents on the ketone were sufficiently sterically differentiated, good to excellent syn diastereoselectivity was observed. Representative examples of these crossed-aldol reactions are shown in Table 2.1. The initial method involved a catalytic (5 mol%) amount of trimethylsilyl trifiate in the reaction mixture it was suggested this generates a trichlorotitanium trifiate species in situ which is more effective at enoli-zation. This theory was, however, called into question by reports of additions of enolates to ketones with trimethylsilyl chloride as catalyst, which also provides moderate to good yields [9]. Additions of enolates of phenyl esters or phenyl thioesters to ketones were also shown to proceed in good yield and with syn diastereoselectivity in the absence of silyl additive [10]. 

---