Asymmetric additions of diethylzinc to aldehydes

Liu et al. 43) prepared chiral BINOL ligands bearing dendritic Frechet-type polybenzyl ether wedges ((J )-41-(J )-44), which were assessed in enantioselective Lewis acid-catalyzed addition of Et2Zn to benzaldehyde. 

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The direct strong steric interaction between substrate substituents and ligand substituents has been demonstrated in asymmetric addition of diethylzinc to aldehydes catalysed by sterically congested ferrocenyl aziridino alcohol derivatives.114 In addi- tion, this non-bonded steric repulsion influenced enantioselectivities significantly, and even led to inversion of the absolute configuration. This fact was further confirmed by theoretical calculations and the design of a new chiral ferrocenyl aziridino alcohol ligand. 

Table 4. Asymmetric addition of diethylzinc to aldehydes in the presence of chiral ferrocenyl compounds...

Cyclopropylcarbinols are prepared from dicyclopropylzinc, and t)ie use of mixed diorganozincs such as MejSiCHjZnEt for the addition has also been explored. Chiral tertiary alcohols are obtained from organozinc addition to ketones in the presence of functionalized isobomeols. (15,2/f)-2-(A -piperidinyl)-l-phenylpropane-l-thiol acetate is a ligand prepared from (+)-norephedrine ° and it catalyzes asymmetric addition of diethylzinc to aldehydes very effectively. 

Enantioselective addition of (C2Hs)2Zn to ECHO. Of a variety of chiral N-sulfonylamino alcohols, 1 was found to be the most effective ligand for asymmetric addition of diethylzinc to aldehydes catalyzed by titanium(IV) isopropoxide in methylene chloride. Addition of calcium hydride or 4 A molecular sieves does not affect the enantioselectivity but can increase the yield. 

Oxazaborolidines have also been used as catalysts in atrop enantioselective ring-opening (49), asymmetric addition of diethylzinc to aldehydes (50), asymmetric Diels-Alder reactions (57, 52), aldol reactions (55), Rh catalyzed hydroboration (54), etc. 

A macrocyclic triangular trinuclear Pt complex composed of an optically active biaryl group and cis-dialkynylplatinum(ii) group 851 has been prepared. The macrocycle containing Ti at the binaphthyl group shows high catalytic activity toward asymmetric addition of diethylzinc to aldehydes. 

The synergistic effect of achiral quaternary ammonium salt on asymmetric additions of diethylzinc to aldehydes catalysed by chiral phosphoramide-Zn(II) complex has been demonstrated. The addition of 10mol% NBU4X can dramatically reduce the loading amount of chiral ligand (up to 0.5 mol%) without loosing the excellent reactivity and enantioselectivity of the asymmetric reaction. 

On the other hand, S/O ligands have been developed to a lesser extent, but their efficient use as chiral ligands was proven in the enantioselective addition of diethylzinc to aldehydes and also in the copper-catalysed asymmetric conjugate addition. 

Chiral quaternary ammonium salts in solid state have also been used as catalysts for the enantioselective addition of diethylzinc to aldehydes (Scheme 2-45).112 In most cases, homogeneous chiral catalysts afford higher enantio-selectivities than heterogeneous ones. Scheme 2-45 presents an unusual asymmetric reaction in which chiral catalysts in the solid state afford much higher enantioselectivities than its homogeneous counterpart.112... 

The most fully understood system in this class of reactions, however, is the DAIB-catalyzed addition of diethylzinc to aldehydes, due to the very detailed mechanistic studies performed by Noyori et al.32-37 They were able to determine the structure of several intermediates involved in the reaction and established the kinetic law. Part of the catalytic cycle is depicted in Scheme 13. The origin of the asymmetric amplification lies in the formation of dimers of DAIB-zinc alkoxides. The heterochiral dimer is quite stable in the concentration range of the experiment (2 x 10 1 to 5 x 10 1 M in toluene for DAIB), whereas the homodimers are prone to dissociation and react further with diethylzinc to give a di-zinc complex that is the active species in the catalytic cycle. They react with benzaldehyde and give rise to the asymmetric transfer of the ethyl group. The final product, as a zinc alkoxide, does not interfere with the reaction (and hence there is no autoinduction), since it... 

D. The use of chiral oxazaborolidines as enantioselective catalysts for the reduction of prochiral ketones, imines, and oximes, the reduction of 2-pyranones to afford chiral biaryls, the addition of diethylzinc to aldehydes, the asymmetric hydroboration, the Diels-Alder reaction, and the aldol reaction has recently been reviewed.15b d The yield and enantioselectivity of reductions using stoichiometric or catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13 The above procedure demonstrates the catalytic use of the oxazaborolidine-borane complex for the enantioselective reduction of 1-indanone. The enantiomeric purity of the crude product is 97.8%. A... 

Chiral bis(oxazolines) 51 with an oxalylic acid backbone were used for the Ru-catalyzed enantioselective epoxidation of tran5-stilbene yielding franx-l,2-diphenyloxirane in up to 69% ee [24]. The asymmetric addition of diethylzinc to several aldehydes has been examined with ferrocene-based oxazoline ligand 52 [25], resulting in optical yields from 78-93% ec. The imide 53 derived from Kemp s triacid containing a chiral oxazoline moiety was used for the asymmetric protonation of prochiral enolates [26]. Starting from racemic cyclopentanone- and cyclohexanone derivatives, the enantioenriched isomers were obtained in 77-98 % ee. 

Asymmetric addition of diorganozincs to aldehydes catalyzed by chiral -amino alcohols provides a general method for the preparation of chiral secondary alcohols. Oguni, Noyori, and co-workers found that the aminoalcohol, (2S)-3-exo-(dimethylamino)isobornenol ((2S)-DAIB), acts as a particularly efficient promoter for this asymmetric reaction [9, 10]. Reaction of benzalde-hyde with diethylzinc in the presence of 2 mol% of (2S)-DAIB gives, after aqueous workup, (S)-l-phenylpropanol in high yield with 99% ee as shown in Scheme 8. Detailed mechanistic and theoretical studies of the (2S)-DAIB-pro-moted asymmetric addition have been reported [11]. 

Among DASF derivatives examined, the compound 32 prepared from the diselenide 2 and cyclohexene oxide was revealed to be the best catalyst for this addition, giving up to 94 % ee. It is noteworthy that the sulfur (33) and tellurium analogues (34) of 32 also catalyzed the reaction to afford the alcohol, but with lower enantioselectivity (52% and 46% ee, respectively). Related compounds 35 and 36 do not act at all as a catalyst for the reaction, indicating that the presence of both hydroxyl and dimethylamino groups in 32 are indispensable to act as an efficient asymmetric catalyst. Typical results of enantioselective addition of diethylzinc to aldehydes other than benzaldehyde catalyzed by 32 are also summarized in Table 4. 

Chiral polymer-supported catalysts have been utilized in asymmetric addition of dialkylzinc to aldehydes because of the easy product isolation and workup [26]. In the previous section, a highly enantioselective addition of diethylzinc to aldehydes was described using M-(l-ferrocenylalkyl)-iV-alkylnorephedrines as effective catalysts. We then examined incorporation of the catalyst into polymeric systems. 

The asymmetric addition of diethylzinc to heptanal, a straight-chain aliphatic aldehyde, was catalyzed by compound 20 (Table 3-6). All R,S catalysts 20, except 20s and 20u, afforded (S)-3-nonanol in moderate enantiomeric excess, regardless of the stereochemistry of the asymmetric carbon bearing the hydroxyl group. Cyclo-hexanol derivative 20g, which is less bulky around the carbinol center than catalysts... 

On the other hand, chiral o-hydroxyarylphosphine oxides such as 52 have been widely applied as catalysts in the asymmetric addition of diethylzinc to a series of aromatic aldehydes [52-54]. 

Their 3,3 -substituents are utilized not only for their steric bulk, but also for the coordination to metals. Yamamoto and coworkers employed a boron complex of 3,3 -bis(2-hydroxyphenyl) BINOL in the asymmetric Diels-Alder reaction of cyclopentadiene and acrylaldehyde (equation 70) . The ligand possesses two additional hydroxy groups and forms a helical structure on coordination. The catalyst is considered to function as a chiral Brpnsted acid and a Lewis acid. The complex was also used in the Diels-Alder reactions and aldol reactions of imines. Although addition of diethylzinc to aldehydes gives low ee using BINOL itself or its 3,3 -diphenyl derivative, the selectivity can be increased when coordinating groups are introduced at the 3,3 -positions. Katsuki and... 

Seebach et al. have comprehensively examined the use of a chiral diol (TAD-DOL) derived from tartaric acid as a chiral ligand [22]. The titanium-TADDOL system also catalyzes the asymmetric addition of diethylzinc to various aldehydes (Scheme 8) [23,24]. This system is applicable to the alkylation of various... 

Asymmetric addition of diethylzinc to RCHO.2 In the presence of 5 mol % of this ( -symmetric 2,2 -bipyridinc, (R,R)-1, diethylzinc adds to a wide variety of aldehydes with high cnantiosclcctivity (equation I). 

Solvent precipitation is widely used with polymers other than poly(ethylene glycol) and polystyrene too. For example, the chiral polymer copolymer catalyst 72 developed by Pu, containing both BINOL and BINAP groups in the polymer main chain, is recovered by precipitation in methanol after its use in a tandem asymmetric reaction where it catalyzes both the asymmetric addition of diethylzinc to an aromatic aldehyde and asymmetric hydrogenation of the aryl methyl ketone (Eq. 26) [109]. 

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. 

The same group also reported that when cadmium nitrate or perchlorate salts were used in the preparation of the MOF, two different MOF structures can be obtained with the same chiral binaphthyl ligand [130]. This diversity in crystal structures seemed to arise from the participation of the anion accompanying Cd " " in the structure. The chiral MOF prepared from nitrate acts as an efficient heterogeneous catalyst for the room-temperature asymmetric addition of diethylzinc to a series of aromatic aldehydes, with ee values up to 90% at 100% substrate conversion. Conversely, the MOFs derived from the perchlorate salt were inactive under the same conditions. 

The five chiral polymers 128 and 132-135 were then tested in asymmetric addition of diethylzinc to benzaldehyde. Good enantioselectivities were obtained with chiral polymers 133-135 in opposite to the two others polymers 128 and 132. In the case of p-chlorobenzaldehyde, an excellent ee of 99% was obtained with polymer 134 in oposite to o-alkoxybenzaldehydes (21-54%) and longer reaction times were necessary to have satisfactory conversions with aliphatic aldehydes. 

Zhang H, Xue F, Mak TCW, Chan KS (1996) Enantioselectivity increases with reactivity electronically controlled asymmetric addition of diethylzinc to aromatic aldehydes catalyzed by a chiral pyridylphenol. J Org Chem 1996(61) 8002-8003... 

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