Pinacol coupling diastereoselectivity

A variety of such ternary catalytic systems has been developed for diastereoselective carbon-carbon bond formations (Table). A Cp-substituted vanadium catalyst is superior to the unsubstituted one,3 whereas a reduced species generated from VOCl3 and a co-reductant is an excellent catalyst for the reductive coupling of aromatic aldehydes.4 A trinuclear complex derived from Cp2TiCl2 and MgBr2 is similarly effective for /-selective pinacol coupling.5 The observed /-selectivity may be explained by minimization of steric effects through anti-orientation of the bulky substituents in the intermediate. 

Based on these observations [18,19,23], a variety of modified catalytic systems have been reported for the diastereoselective reductive carbon-carbon bond formation (Scheme 8). A complex 5 derived from Cp2TiCl2 and MgBr2 is proposed to be an efficient catalyst for the DL-diastereoselective pinacol coupling of aromatic aldehydes [24], Addition of a solution of benzalde-... 

The above-mentioned results indicate the additive effect of protons. Actually, a catalytic process is formed by protonation of the metal-oxygen bond instead of silylation. 2,6-Lutidine hydrochloride or 2,4,6-collidine hydrochloride serves as a proton source in the Cp2TiCl2-catalyzed pinacol coupling of aromatic aldehydes in the presence of Mn as the stoichiometric reduc-tant [30]. Considering the pKa values, pyridinium hydrochlorides are likely to be an appropriate proton source. Protonation of the titanium-bound oxygen atom permits regeneration of the active catalyst. High diastereoselectivity is attained by this fast protonation. Furthermore, pyridine derivatives can be recovered simply by acid-base extraction or distillation. 

The 1,5- and 1,6-dialdehydes 22 and 24 undergo the annulative pinacol coupling to give the cyclic vzc-diols 23 and 25, respectively (Scheme 13) [29]. The vanadium-catalyzed intramolecular coupling reaction of 1,5-diketone 26 also proceeds with excellent selectivity (Scheme 14) although the intermolecular coupling of ketones such as acetophenone results in low diastereoselectivity under these conditions [21]. 

Diastereoselectivity of a catalytic pinacol coupling using TiCU, zinc, and acetic anhydride at room temperature for 24 h in DME is low (dljmeso = 60/40). The ratio improves a little by changing the reductant to aluminum. ... 

Treatment of alkanedials with the reagent for pinacol coupling causes intramolecular cyclization leading to 1,2-cycloalkanes. The diastereoselectivity depends on the ring size formed (Equation (16)). ... 

I, 5-dithioniabicyclo[3.3.0]octane bis(trifluoromethanesulfonate) 7 in acetonitrile at 50°C. The salt promotes pinacol coupling of aromatic ketones even at —40 °C. In addition, the diastereoselectivity dl meso) of the coupling reaction of acetophenone in acetonitrile at —40°G is 94 6. "... 

Although yields and diastereoselectivities are moderate, a cross-pinacol coupling reaction between a 1,2-diketone and an aldehyde is accomplished with Sml2 in the presence of HMPA. ... 

Low-valent niobium and tantalum are also effective for homocoupling of aldehydes leading to 1,2-diols. " Not only commercially available NbClglDME) but also a combination of NbCls and zinc can be used for the pinacol coupling. Reactions in a mixed solvent of 1,4-dioxane and toluene (1 4) give better diastereoselectivity than those in DME or THE (Equation (52)). ... 

Stilbene diols such as 3 are gaining prominence both as synthetic intermediates and as effective chiral auxiliaries. While the diols can be prepared in high by Sharpless dihydroxylation, it would be even more practical to prepare them by direct asymmetric pinacol coupling. N. N. Joshi of the National Chemical Laboratory in Pune reports (J. Org. Chem. 68 5668,2003) that 10 mol % of the inexpensive Ti salen complex 2 is sufficient to effect highly enantioselective and diastereoselective pinacol coupling of a variety of aromatic aldehydes. Most of the product diols are brought to >99% by a single recrystallization. 

Cross pinacol coupling of aldehydes. Pedersen et al.2 have reported the first general method for stereoselective pinacol coupling of aldehydes by use of this vanadium(II) reagent. Aryl aldehydes couple in the presence of 1 to pinacols in >90% yield and with high diastereoselectivity (dllmeso = 12-100 1). Aliphatic aldehydes under similar conditions couple only slowly, but depending on the struc-... 

The stereoselectivity of Sml2-mediated pinacol couplings depends highly on the substrates used. In contrast to the intermolecular cases, high levels of diastereoselectivity can be attained in the cyclisation of a variety of 1,5- and... 

Another example of the impact of neighbouring protected hydroxyl groups on the diastereoselectivity of pinacol couplings can be found in d Alarcao s studies on the synthesis of the myo-inositol derivative 10 (Scheme 5.10).21... 

The use of this protocol provided good to excellent diastereoselectivities in a range of intermolecular and intramolecular pinacol coupling reactions. 

The Sml2-mediated intramolecular pinacol coupling reactions of carbonyls 151 were found to afford heterocyclic diols 152 in diastereoselective... 

Samarium diiodide has also been utilized as a reductant to promote pinacolic coupling reactions mediated by low-valent titanium species (equation 71). Utilizing this protocol, high diastereoselectivity can be achieved, although the yields for Ais particular process were not reported. 

Cerium isopropoxide catalyzes the highly diastereoselective pinacol coupling of aliphatic and aromatic aldehydes (eq. (15)) [139]. 

Intramolecular pinacolic coupling reactions have also proven successful with Stnl2. Yields with simple diketones are relatively low. i> However, excellent yields and diastereoselectivities are achieved in intramolecular pinacolic coupling reactions of P-keto ester and P-ketoamide substrates (equation 72). A variety of substitution patterns can be tolerated in these reactions to generate five-membered carbo-cycles. Six-membered rings can also be generated by this process, but substantially lower yields and diastereoselectivities are observed (equation 73). Yields obtained for p-ketoamide substrates are also lower than those observed in the P-keto ester series. 

Pinacol formation from carbonyl compounds promoted by Smij continues to interest chemists. In the presence of methyl chloroformate the products are cyclic carbonates. In a cyclitol synthesis the diastereoselectivity for cyclization is found to be dependent on the a-substituents of the aldehyde groups. Lithium halides (chloride, bromide) have a profound effect on the reactivity of Sml2 and the pinacol coupling is favored. The reduction and pinacol coupling of ketones in THF is accelerated by MejSiCl (reaction time from hours reduced to a few minutes)." ... 

Shikonin. Torii has accomplished an efficient intermolecular pinacol coupling reaction, en route to the total synthesis of shikonin, a compound with antiinflammatory, antibacterial, and antitumor activity (Eq. 3.11) [29], Because the aromatic aldehyde possessed a substituent capable of chelating to vanadium, Torii anticipated, based on precedent, that selective cross-coupling would be possible. The pinacol reaction proceeded in 73% yield and with good diastereoselectivity (5.5 1). 

Indium. Kim has developed an indium-mediated pinacol coupling of aromatic aldehydes that proceeds in water or in water/t-BuOH (Eq. 3.14) [33]. Sonication greatly enhances the rate of the reaction. The diastereoselectivity of the pinacol coupling is variable, with d,l meso ratios ranging from 6 1 to 1 2. Aliphatic aldehydes, as well as ketones, are inert to these conditions. 

Manganese. Li and Chan [34] and Rieke [35] have independently reported that manganese reagents can accomplish the pinacol coupling of aromatic carbonyl compounds. In the Li/Chan study, reaction of an array of aromatic aldehydes proceeded in good to excellent yield in the presence of Mn/Ac0H/H20, albeit with poor diastereoselectivity (Eq. 3.15). Under these conditions, aliphatic aldehydes are reduced to the corresponding alcohol, and ketones (aromatic or aliphatic) do not react. 

Niobium. Szymoniak has developed a niobium-based method for the pinacol coupling of aliphatic aldehydes, aromatic aldehydes, and aromatic ketones (Eq. 3.18) [37]. In the presence of NbCl3, intermolecular couplings proceed with consistently high diastereoselectivity. In many cases, the diol forms an acetal with the remaining aldehyde, and this is isolated at the end of the reaction. The stereoselection of... 

In contrast, mrramolecular pinacol couplings mediated by NbCl3 proceed in lower yield and with essentially no diastereoselectivity (Eq. 3.19). 

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