Titanium-Binol catalyst additives

Mikami et al. studied the Diels-Alder reaction between a-methylstyrene and n-butyl glyoxylate catalyzed by a titanium binolate catalyst.76-78 Addition of 0.5 equivalents of (Zf)-BINOL to 1 equivalent of the racemic catalyst accelerated the reaction and gave the product with 89.8% ee (Scheme 20). Enantiopure catalyst derived solely from (/ )-BINOL gave the product with 94.5% ee. Here the amplification originates from the creation of a new chiral complex 9 of higher efficiency (rate and enantioselectivity) with respect to each enantiomer of the original racemic catalyst. 

In a direct comparison, the CAB catalyst proved to be superior to the titanium binol catalyst in the reaction of branched aldehydes in both reaction times and selectivity. Finally, the CAB-promoted reaction of a chiral aldehyde with ( )-85 was examined (Scheme 10-48). When the aldehyde (7 )-106 reacts with the 2-bute-nylstannane in the presence of the CAB catalyst, a 98/2 mixture of diastereomers is obtained. The CAB-promoted reaction of the aldehyde (S)-106 with the (E)-85 affords a 90/10 mixture of diastereomers. This adduct is the minor isomer from the BF3-promoted addition of ( )-85 to aldehyde (S)-106. Thus, the CAB-promoted additions are strongly reagent controlled, essentially overriding the intrinsic facial preference of the aldehyde substrate. 

This explanation is described as a mnemonic rule [228], which can only be taken as a first approximation of reality. The same rule can be used to rationalize the topicity of other asymmetric Diels-Alder reactions, such as those employing titanium BINOLate catalysts (Figure 6.18i, [230]), or iron bisoxazoline catalysts (Figure 6.18j,k [206,215]). Although the explanation seems reasonable, the picture is not complete, since it does not account for a number of observations, including the fact that the dioxolane substituents exert an extraordinary effect on catalyst efficiency (c/ Table 6.6, entries 2 and 5). Additionally, both titanium TADDOLate [228] and BINOLate [230] complexes show a nonlinear relationship between enantiomeric purity of the catalyst and that of the product, which suggests that some sort of dimerization phenomenon is involved. 

The catalytic asymmetric Michael reaction using silyl enol esters (Mukaiyama-Michael reaction) as the pronucleophiles has been reported using a titanium/BINOL catalyst (in up to 90% ee). Considering furan (11.36) as a silyl enol ether, this has been shown to undergo nucleophilic addition to the Michael acceptor (11.37). The product (11.38) canbe obtained with excellent diastereocon-trol with the scandium complex of hgand (11.39), or with excellent enantiocontrol... 

Two other types of catalysts have been investigated for the enantioselective Strecker-type reactions. Chiral N-oxide catalyst 24 has been utilized in the trimethylsilyl cyanide promoted addition to aldimines to afford the corresponding aminonitriles with enantioselectivities up to 73% ee [14]. Electron-deficient aldimines were the best substrates, but unfortunately an equimolar amount of catalyst 24 was used in these reactions. The asymmetric Strecker addition of trimethylsilyl cyanide to a ketimine with titanium-based BINOL catalyst 25 gave fast conversions to quarternary aminonitriles with enantiomeric excesses to 59%... 

Immobilization of chiral ligands to effect asymmetric induction in alkylation of aromatic aldehydes by diorganozinc reagents promoted by PEG-im-mobilized ligands 54-57 can also be promoted by soluble polystyrene-bound species. A recent example of this is work where a polystyrene-bound BINOL was prepared [ 105]. This polymer 69 was used to form titanium-BINOLate and AlLibis(binaphthoxide) catalysts for Et2Zn reaction with benzaldehyde and for asymmetric Michael additions of stabilized carbanions to cyclohexenone. While good stereoselectivities were obtained with these catalysts, the synthetic yields were modest. 

An effective chiral catalyst for asymmetric allylation of aldehydes or ketones is the complex formed between the axially chiral l,l -bi-2-naphthol (BINOL) 164 and a titanium(IV) salt." Addition of allyltributylstannane to an aldehyde using this Lewis acid gives the product homoallylic alcohol with high optical purity. For example, allylation of iso-butyraldehyde gave the alcohol 165 as a 98 2 ratio of enantiomers (1.155). Use of (5)-BINOL gave the other enantiomer of the product. 

Another approach to facilitate the recovery of catalytic systems relies on the use of fluorinated analogues of classic chiral ligands. The recycling options offered by the fluorous catalysts have been explored in the field of asymmetric addition of dialkylzinc reagents to aldehydes in presence of titanium tetraisopropoxide. In 2000, the groups of Chan ° and Curran reported independently the synthesis of perfluoroallqrl-substituted BINOL ligands and their evaluation in the titanium-mediated enantioselective addition of diethylzinc to aromatic aldehydes in fluorous biphasic system (Scheme 7.27). 

To facilitate catalyst recovery, polymeric and dendrimeric TADDOL, and BINOL ligands have been used for the titanium-catalyzed diethylzinc addition reaction [49]. Moreover, ionic liquids and fluorous solvents have also been used as the reaction media to facilitate the separation of ligands [50]. The microporous metal-organic frameworks prepared from BINOL derivatives were applicable to heterogeneous diethylzinc addition to aldehydes in the presence of excess amount of Ti(O Pr)4 [51]. 

The addition of trimethylsilyl (TMS) cyanide to aldehydes produces TMS-protected cyanohydrins. In a recent investigation a titanium salen-type catalyst has been employed to catalyse trimethylsilylcyanide addition to benzaldehyde at ambient temperature1118]. Several other protocols have been published which also lead to optically active products. One of the more successful has been described by Abiko et al. employing a yttrium complex derived from the chiral 1,3-diketone (41)[119] as the catalyst, while Shibasaki has used BINOL, modified so as to incorporate Lewis base units adjacent to the phenol moieties, as the chiral complexing agent11201. 

Keck reported an asymmetric allylation with a catalytic amount of chiral titanium catalyst [24]. The enantioselective addition of methallylstannane to aldehydes is promoted by a chiral catalyst 13 prepared from chiral BINOL and Ti(0-i-Pr)4 (Scheme 9.10). An example of asymmetric amplification was reported by using (R)-BINOL of 50% ee, and the degree of asymmetric amplification was dependent on the reaction temperature. Tagliavini also observed an asymmetric amplification in the enantioselective allylation with a BIN0L-Zr(0-i-Pr)2 catalyst [25]. 

The activation of a racemic catalyst by a chiral additive was achieved by Mikami in a chiral titanium complex-catalyzed asymmetric carbonyl-ene reaction (Scheme 9.21) [39], The racemic catalyst ( )-BINOL-Ti-(0-i-Pr)2 37 (10 mol %) is activated by adding (R)-BINOL (5 mol %), and the ene product 38 with 90% ee is obtained. (R)-BINOL is selectively associated with (/f)-BIN0L-Ti-(0-i-Pr)2 to give a dimeric catalyst whose activity is kinetically calculated to be 25.6 times greater than that of the remaining (S)-BIN0L-Ti-(0-i-Pr)2. 

The vast majority of successful chiral catalysts to date are based on tartaric acid, BINOL, or oxazolidinone derivatives (Table 26.1). Because derivatives of both of these compounds are commercially available, scale up should not present a problem. If the observed asymmetric induction is found to be low with catalysts based on tartaric acid or oxazolidinones, the sterically hindered titanium BINAP-type complexes should allow for increased selectivity. In addition, nontoxic metal counterions, such as iron and aluminum, do not appear to compromise the asymmetric induction. 

Cyanosilylation. The chiral titanium reagent, prepared from the lithium salt of BINOL with TiCL, has been used as a catalyst for the asymmetric addition of cyanotrimethylsilane to aldehydes. In the example shown, the cyanohydrin is obtained with <82% ee (eq 9). 

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. 

Oguni has reported asymmetric amplification [12] ((-i-)-NLE) in an asymmetric carbonyl addition reaction of dialkylzinc reagents catalyzed by chiral ami-noalcohols such as l-piperidino-3,3-dimethyl-2-butanol (PDB) (Eq. (7.1)) [13]. Noyori et al. have reported a highly efficient aminoalcohol catalyst, 2S)-3-exo-(dimethylamino)isobomeol (DAIB) [14] and a beautiful investigation of asymmetric amplification in view of the stability and lower catalytic activity of the het-ero-chiral dimer of the zinc aminoalcohol catalyst than the homo-chiral dimer (Fig. 7-5). We have reported a positive non-linear effect in a carbonyl-ene reaction [15] with glyoxylate catalyzed by binaphthol (binol)-derived chiral titanium complex (Eq. (7.2)) [10]. Bolm has also reported (-i-)-NLE in the 1,4-addition reaction of dialkylzinc by the catalysis of nickel complex with pyridyl alcohols [16]. 

Other use of the functionalized chiral BINOL includes the 5,5, 6,6, 7, 7, 8,8 -octahydro derivative developed by Chan and coworkers, the titanium complex of which is more effective than BINOL in the enantioselective addition of triethylaluminum and diethylzinc a 4,4, 6,6 -tetrakis(perfluorooctyl) BINOL ligand developed for easy separation of the product and catalyst using fluorous solvents for the same zinc reaction an aluminum complex of 6,6 -disubstituted-2,2 -biphenyldiols used by Harada and coworkers in the asymmetric Diels-Alder reaction a titanium complex of (5 )-5,5, 6,6, 7,7, 8,8 -octafluoro BINOL employed by Yudin and coworkers in the diethylzinc addition, in the presence of which the reaction of the enantiomeric (/f)-BINOL is promoted . 

During the past two decades the homogeneous and heterogeneous catalytic enan-hoselective addition of organozinc compounds to aldehydes has attracted much attention because of its potential in the preparation of optically active secondary alcohols [69]. Chiral amino alcohols (such as prolinol) and titanium complexes of chiral diols (such as TADDOL and BINOL) have proved to be very effective chiral catalysts for such reactions. The important early examples included Bolm s flexible chiral pyridyl alcohol-cored dendrimers [70], Seebach s chiral TADDOL-cored Frechet-type dendrimers [28], Yoshida s BINOL-cored Frechet-type dendrimers [71] and Pu s structurally rigid and optically active BlNOL-functionalized dendrimers [72]. All of these dendrimers were used successfully in the asymmetric addition of diethylzinc (or allyltributylstannane) to aldehydes. 

Keck almost simultaneously reported two procedures using chiral titanium catalysts 6A and 6B for the enantioselective addition of allyltributyltin to aldehydes [11]. In the first procedure, the catalyst 6A is prepared from a 1 1 mixture of (R)-binaphthol and titanium tetraisopropoxide. The second procedure for the preparation of 6B, in contrast, requires a 2 1 mixture of BINOL, Ti(0 Pr)4, and a catalytic amount of CF3SO3H or CF3CO2H. Using 10 mol % of the catalyst 6A or 6B, a variety of aromatic, aliphatic, and a,P-unsaturated aldehydes are efficiently transformed into the corresponding optically active homoallylic alcohols with high enantioselectivity. An improved procedure was later published for the catalytic asymmetric allylation reactions using the 2 1 BINOL/Ti catalytic system [12]. 

Three new substituted BINOL ligands, (i )-3-[4,6-bis(dimethylamino)-l,3,5-triazin-2-yl]-l,10-bi-2-naphthol (R)-(72), (i )-3,3 -bis[4,6-bis(dimethylamino)-l,3,5-triazin-2-yl]-l,10-bi-2-naphthol (R)- 73), and 2,4-bis(2,2 -dihydroxy-1,10-binaphthalen-3-yl)-6-(/i-tolyl)-l,3,5-triazine iR,R)-74), have been obtained by directed ort o-lithiation and a Suzuki cross-coupling process (Scheme 10) <2005TA3667>. The titanium complex of (R)-72 was found to be an effective catalyst in the asymmetric addition of diethylzinc to a variety of aromatic aldehydes. 

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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