Aldehydes asymmetric diethylzinc addition

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. 

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]. 

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

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... 

Using these ligands, the Davis group has reported the as)mimetric additions of diethylzinc to aromatic aldehydes as the initial exploration of the asymmetric induction realized by amino sugar-based ligands [180]. As shown inO Scheme 49, three aromatic aldehydes 198 were treated with diethylzinc in the presence of 194 or 195. The addition products 199 were obtained in... 

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. 

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]. 

A large number of chiral a,a -orz/zo-disubstituted diphenyldiselenides with hydroxy and amino functions (e.g., 244 and 245) have been prepared by Wirth and co-workers. They were used as electrophiles for a number of asymmetric addition and cyclization reactions including the total synthesis of the lignan derivatives (-l-)-samin and (-l-)-membrine as well as catalysts in the asymmetric diethylzinc addition to aldehydes. 

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. 

A variety of C2-symmetric diphenyl-phosphoramides, -thiophosphoramides and -selenophosphoramides have been used as chiral catalysts in alkylation reactions. ° " ° Compounds (350) and (351) ° and the selenophosphoramidates (352), (353), and (354) " act as ligands in Ti(IV)-catalysed asymmetric addition reactions of diethylzinc to aldehydes to give secondary alcohols with e.e. values of 40 to 83%. The diphenylthiophosphoramidates(351), (355), and (356) similarly act as ligands in Ag(I)-promoted enatioselective allylation of aldehydes with... 

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... 

The tremendous success in the catalytic asymmetric addition of organozinc reagents to aldehydes spurred Itsuno and co-workers to examine the reactivity of diethylzinc with silyl imines in the presence of chiral amino alcohols and diols. Unfortunately, this type of azomethine function failed to react [23a]. The use of activated N-acyl- and iV-phosphinoylimines turned out to be crucial as evidenced by the following reports on the alkylation of these functions using di-... 

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). 

A direct synthesis of chiral propargylic alcohols from 1-alkynes and aldehydes in the presence of Zn(OTf)2, EtjN, and (+)-A-methylephedrine has a broad scope. Several new ligands are found suitable for inducing asymmetric addition of R2Zn (mostly diethylzinc) to aldehydes. These include 42, 43, 44, 45, and Other (3-amino alcohols that show desirable features are S-ew-morpholinoisoborneol, which is more stable in air than the dimethylamino analogue, (S)-2-(pyrrolidin-l-yl)-l,2,2-triph-enylethanol, and a polymer-supported A-alkyl-a,a-diphenyl-L-prolinols. A,A-Dibutyl-norephedrine is useful in a solvent-free reaction. ... 

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. 

BINOL is an effective ligand in the titanium-catalysed asymmetric addition of alkynylzinc reagents to aldehydes. Aromatic, aliphatic and a,P-unsaturated aldehydes such as (6.35) are converted into the propargylic alcohol with 91-99% ee using the alkynylzinc, generated from phenylacetylene and diethylzinc. Carriera and coworkers have developed an enantioselective alkynylzinc addition that is also... 

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. 

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. 

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). 

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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