Zirconium-BINOL

A spectacular activation of the chiral zirconium-BINOL Lewis acid complex was achieved by the addition of the (achiral ) r-butyl-calix[4]arene. Less than 2% of the catalyst were sufficient in the enantioselective allylation of various aldehydes by allyltributyltin to reach enantiomeric excesses of more than 90%, see Casolari, S. Cozzi, P. G. Orioli, P. Tagliavini, E. Umani-Ronchi, A. Chem. Commun. 1997, 2123-2124. 

To address the design criteria listed above, Kobayashi and co-workers prepared the mildly Lewis acidic zirconium[BINOL]2 complexes 78a,b from Zr(Of-Bu)4and (i )-BINOL and theimines 76 derived from 2-aminophenol [51a, 51b, 51c, 51d] (Scheme 26). In the presence of catalytic amounts of 78a the tri-methylsilyl ketene acetal of methyl 2-methylpropanoate (77) reacted with 76a to afford the adduct 79 quantitatively and with 34% ee. The use of N-methylim-idazole (NMI) in equal amoimts markedly improved the selectivity to 70% ee as did the use of 78b which provided 79 in 90% ee. By chemical correlation the products were shown to be of the i -configuration. The reaction displayed some generality with aromatic aldimines (83-98% ee), but the one enoHzable aldi-mine gave only modest results (56% yield, 80% ee) [51e]. 

The majority of metal-based Lewis acid catalysts used in the HDA reaction are moisture sensitive and are thus usually prepared in situ. The stable and storable zirconium-BINOL Lewis acids developed by Kobayashi and coworkers, effective in the aldol reaction (see Section 7.1) can also be used as asymmetric catalysts in the HDA reaction of aliphatic and aromatic aldehydes with dioxygenated dienes. Metal-free catalytic asymmetric HDA reactions have been developed, utilising enantiomerically pure protic molecules that activate the aldehyde component by hydrogen bonding to the carbonyl group. Rawal and coworkers have achieved up... 

Kobayashi has developed the zirconium-BINOL-derived complex 148 as a catalyst for enantioselective Strecker reactions with Bu3SnCN as the cyanide source [106], Subsequent investigations led to a protocol for the three-component in situ coupling of aldehydes, amines, and HCN (Equation 21) [107]. For example, aminonitrile 149 can be prepared in 99% yield and 94% ee in the presence of 5 mol% of zirconium catalyst 148. 

In parallel with the search for catalytic systems, has emerged an impressive amount of results in the field of enantioselective allylation. The pioneering work of Marshall using a chiral (acyloxy)borane (CAB) system [216] was readily followed by titanium/BINOL catalysts [217], leading to homoallylic alcohols with enantiomeric excess up to 98%. An extension of this work in fluorous phase was also developed with 6,6 -perfluoroalkylated BINOLs [218]. Replacing the titanium by zirconium (IV) salts, led to more reactive catalyst for the allylation of aromatic and aliphatic aldehydes [219]. One of the more active catalyst is the zirconium-BINOL system associated with 4-tert-butylcalix [4]arene, which remains active with only 2% of the chiral inductor [220]. The use of activators, such as iPrSSiMe3, iPrSBEt2,... 

Polymer-supported BINOLs thus prepared were treated with Zr(Ot-Bu)4 to form polymer-supported zirconium 20. In the presence of 20 mol% of various zirconium 20, the model aza Diels-Alder reactions of imine Id with Danishefsky s diene (7a) were performed results from selected examples are shown in Table 5.8. Whereas the 4-t-butylphenyl group resulted in lower enantiomeric excess (ee), higher ee were obtained when 3,5-xylyl, 4-biphenyl, 4-fluorophenyl, and 3-tri-... 

Another method for the asymmetric version of the Baeyer-Villiger reaction was presented by Lopp and coworkers in 1996 . By employing overstoichiometric quantities of Ti(OPr-t)4/DET/TBHP (1.5 eq./1.8 eq./1.5 eq.), racemic andprochiral cyclobutanones were converted to enantiomerically enriched lactones with ee values up to 75% and moderate conversions up to 40% (Scheme 171). Bolm and Beckmann used a combination of axially chiral C2-symmetric diols of the BINOL type as ligands in the zirconium-mediated Baeyer-Villiger reaction of cyclobutanone derivatives in the presence of TBHP (or CHP) as oxidant (Scheme 172) . With the in situ formed catalysts 233a-d the regioisomeric lactones were produced with moderate asymmetric inductions (6-84%). The main drawback of this method is the need of stoichiometric amounts of zirconium catalyst. 

The Stacker reaction has been employed on an industrial scale for the synthesis of racemic a-amino acids, and asymmetric variants are known. However, most of the reported catalytic asymmetric Stacker-type reactions are indirect and utilize preformed imines, usually prepared from aromatic aldehydes [24]. A review highlights the most important developments in this area [25]. Kobayashi and coworkers [26] discovered an efficient and highly enantioselective direct catalytic asymmetric Stacker reaction of aldehydes, amines, and hydrogen cyanide using a chiral zirconium catalyst prepared from 2 equivalents of Zr(Ot-Bu)4, 2 equivalents of (R)-6,6 -dibromo-1, l -bi-2-naphthol, (R)-6-Br-BINOL], 1 equivalent of (R)-3,3 -dibromo-l,l -bi-2-naphthol, [(R)-3-Br-BINOL, and 3 equivalents of N-methylimida-zole (Scheme 9.17). This protocol is effective for aromatic aldehydes as well as branched and unbranched aliphatic aldehydes. 

Kobayashi and co-workers. used zirconium-based bromo-BINOL complex for the catalytic enantioselective Mannich-type reaction. The o-hydroxyphenyl imine 3.36 chelates the Zr(IV)(BrBINOL)2 to form the activated chiral Lewis acid complex A. The ketone acetal 3.37 reacts with the Lewis acid complex A to give the complex B. The silyl group is then transferred to the 3-amino ester to form the product 3.38 and the catalyst Zr(BrBINOL)2 is regenerated, which is ready for binding with another imine molecule (Scheme 3.16). 

For the preparation of enantiomerically pure ebthi zirconium derivatives, an efficient procedure using optically pure binol can be used starting from racemic mixture. ... 

This asymmetric reaction was recently improved by using a Lewis acid system of BINOL, ZrCl4(THF)2 and 4-tert-calix[4]arene prepared in situ [19bj. The modified method required only 2 % BINOL and zirconium to obtain up to 96 % ee of the homoallylalcohols. 

A binuclear zirconium catalyst, prepared in situ from Zr(0-t-Bu)4, (/ )-6-Br-BINOL, and () )-3-Br-BINOL has been used in catalytic and enantioselective synthesis of a-aminonitriles 98 as shown in Eq. (45) [46]. 

Kobayashi has demonstrated that a chiral zirconium catalyst derived from 3,3 dibromo or 3,3 dichloro BINOL can catalyze the addition of substituted allyl stannanes to the imines derived from 2 hydroxyaniline and aryl or hetereoaryl substituted aldehydes (Scheme 1.25) [95]. The active catalyst is possibly generated by the bonding of the alcohol functionalities of the imine and of allylstarmane to the zirconium center. 

Various titanium or zirconium complexes have been shown to catalyze the addition of allyl(tri-M-butyl)tin [29,30,31] or allyltrimethylsilane [32,33] to aldehydes, giving good enantioselectivities and some asymmetric amplification. In all these examples the chiral auxiliary is derived from (R)- or (S)-BINOL. 

Catalysts (25) are the Lewis acid-Lewis base bifunctional catalysts in which Lewis acid-Al(III) moiety activates acyl iminium ion and the Lewis base (oxygen of phosphine oxide) does TMSCN, simultaneously (Scheme 5.7). Halogen atoms at the 6-position enhanced both yields and enantioselectivity in Reissert-type cyanation of the imino part of 26. However, the order for the activation is not parallel to the electronegativity of the halogen atoms and, moreover, the strong electron-withdrawing trifluoromethyl group provided unexpectedly the worst result for the activation [13]. It is not simple to explain this phenomenon only in terms of the increased Lewis acidity of the metal center. Trifluoromethylated BINOL-zirconium catalysts (28) for asymmetric hetero Diels-Alder reaction (Scheme 5.8) [14], trifluoromethylated arylphosphine-palladium catalyst (32) for asymmetric hydrosilylation (Scheme 5.9) [15], and fluorinated BINOL-zinc catalyst (35) for asymmetric phenylation (Scheme 5.10) [16] are known. 

Kobayashi has extended this chemistry and has reported a zirconium version of this binol catalyst.39 He has described binuclear catalyst 79 in which the optimized version, essential for asymmetric induction, made use of (7 )-6-bromobinol and (R)-3-bromobinol. 

Hetero-Diels-Alder reaction. The zirconium complexes of 3,3 -diaryl-BINOL are effective chiral catalysts for the smooth condensation of aldimines with a Danishefsky diene. Linkage of the BINOL moiety to polymer support also provides viable catalysts. 

The air stable and storable zirconium catalyst, formed from Zr(0 Bu)4, 3,3 -diiodo-l,l -binaphthalene-2,2 -diol (3,3 -l2-BINOL), -propanol and water, with the putative dimeric structure (7.33) also catalyses auft -selective asymmetric aldol reactions. While this process is beheved to proceed through an acyclic transition state, as depicted in Figure 7.2, it is postulated that the greatest steric interaction is now between the silyl enol ether substituent R3 and the bulky Lewis acid resulting in the formation of the fluft -diastereomer predominantly. 

The HDA reaction can also be performed using imines as dienophiles to give piperidinone derivatives as the cycloadducts. This aza-Diels-Alder process has been performed in an asymmetric fashion using a variety of enantiomerically pure metal-based Lewis acids. Early work in this area was carried out by Kobayashi and coworkers using zirconium catalysts derived from BINOL (8.150) in the cycload-dition of diene (8.123) with aryl imines derived from 2-hydroxyaniline such as (8.151). ° More recently aryl imines derived from 2-methoxyaniline (o-anisidine)... 

A variety of chiral, non-racemic zirconium complexes were explored in attempts to develop an enantioselective variant of this reaction (Scheme 3) [7-9]. Eor example, when allyUc amines lla,b were treated with EtMgCl and 10% of C2-symmetric BINOL-zirconium bis(tetrahydroindenyl)ethane (12, Brintzinger s catalyst [10], BINOL is l,l -binaphthalene 2,2 -dioate), chiral ethylated products 13a,b were obtained in 34-39% yield with enantiomeric excesses (ee) of ca. 26% [8]. Use of a (neomenthylindene)ZrCpCl2 catalyst 14, designed to improve the steric differentiation of the diastereomeric transition states, improved the chemical yields of amines at lower catalyst loadings (2-4%) and increased the ees of the reactions by a factor of three in the case of 11a [8,9]. Similar reactivity is observed in zirconocene dichloride-catalyzed cyclization of 1,6- and 1,7-enynes with 12.5% Cp2ZrCl2 using EtsAl as the stoichiometric reductant. For these substrates, the alkyne coordinates... 

ZnX2," " ZnCl2," ° Zn(0Tf)2-H20," ZnF2 with diamine complex,- Et2Zn with (S, S) linked BINOL,dinuclear zinc catalyst," chiral zirconium catalyst" (e.g., Zr(0-... 

In 2010, Vila and co-workers reported that chiral complexes of BINOL-based ligands with zirconium tert-butoxide could catalyze AFC alkylation reaction of indoles with p-trifluoromethyl-a,p-unsaturated ketones to give functionalized indoles with an achiral tertiary carbon center attached to a trifluoromethyl group in good yields with up to 99% ee (Scheme 6.53). ... 

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