KR of secondary alcohols

in a modification to the above system, we reported the use of an indenylruthenium complex 2 as a racemization catalyst for the DKR of secondary alcohols, which does not require ketones but a weak base hke triethylamine and molecular oxygen to be achvated. The DKR with 2 in combination with immobilized Pseudomonas cepacia lipase (PCL, trade name. Lipase PS-C ) was carried out at a lower temperature (60°C) and provided good yields and high optical purities (Table 2). This paved the way for the omission of ketones as 

DKR of secondary alcohols with indenyl mthenium complex 2 

40°C (Table 3). A noticeable feature of this catalyst system was that allylic alco-  

DKR of allylic alcohols with cymene-ruthenium catalyst 4  

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The KR of secondary alcohols by some hydrolytic enzymes has been well known. The combinations of these hydrolytic enzymes with racemization catalysts have been explored as the catalysts for the efficient DKR of the secondary alcohols. Up to now, lipase and subtilisin have been employed, respectively, as the R- and 5-selective resolution enzymes in combination with metal catalysts (Scheme 2). 

During their studies on kinetic resolution (KR) of secondary alcohols, Connon et al. found that chiral pyridine catalyst 177 and its optimized analogue 178 promoted the synthetically useful KR of MBH adducts 179 derived from deactivated precursors (which were difficult to synthesize using catalytic asymmetric MBH reactions), allowing the convenient preparation of 179 in 62-90% ee and 82-97% ee, respectively (Scheme 2.87). This study also represents the first examples of effective non-enzymatic acylative KR of sec-sp -sp ... 

Scheme 41.37 Silylation-based KR of secondary alcohols by Wiskur et al.

For the resolution of a secondary alcohol, forming an optically active alcohol enantiomer and the corresponding ester antipode, purification is usually carried out by silica gel chromatography because of the chemical nature of both final products, and adequate derivatization can be carried out, facilitating the isolation of the final products by filtration or distillahon [50]. Some elegant and more sophisticated acyl donors have been described for the KRs of secondary alcohols, which allow an easy purification of the final products and the removal of the acyl donor by simple extraction protocols. These include the use of cyclic anhydrides such as succinic anhydride [51,52] or vinyl esters with amino acid tags [53]. 

In 2004, Birman et al. began their quest to develop an easily accessible and highly effective acylation catalyst for the KR of secondary alcohols. The first chiral derivative to be prepared and tested was based on the 2,3-dihydroimidazo[l,2-a]-pyridine (DHIP) core, itself derived from (R)-2-phenylglycinol (Figure 41.2). (R)-2-Phenyl-2,3-dihydroimidazo[l,2-a]pyridine (35, H-PIP) [27a] afforded the KR of ( )-phenylethylcarbinol in a promising 49% ee (enantiomeric excess) albeit with a low conversion (21% conversion, s = 3.3). To increase the electrophihcity of the acylated intermediate and thus improve the reactivity of the catalyst, an electron-withdrawing... 

The enzymatic KR between racemic amines and nonactivated esters using a lipase as biocatalyst is shown in Scheme 7.15. In the same manner as in the transesterification of secondary alcohols, this process fits Kazlauskas rule [32], where normally if the large group (L) has larger priority than medium group (M), the (R)-amide is obtained. In general, major size differences between both groups result in better enantios-electivities ( ). 

In an alternative application of asymmetric alcohol oxidation, Rychnovsky has reported the use of the chiral nitroxyl radical 34 (Fig. 12.14) along with bleach, allowing kinetic resolution of secondary alcohols [89]. The best substrates were simple benzylic alcohols, for which S factors (= ks/kR) were in the range 3.9 to 7.1 (Scheme 12.22). Other chiral C2-symmetric nitroxyl radicals reported recently give lower selectivities [90]. 

Heumann et al. reported KRs of racemic alcohols and carboxylic acids through dicyclohexylcarbodiimide (DCC)-esterification methodology with enantiopure carboxylic acids (Equation 2.15) or secondary alcohols (Equation 2.16), respectively. Among various carboxylic acids tried, O-arylsubstituted (R)-lactic acids were the most effective for resolution of secondary alcohols, whereas (R)-l-(4-pyridyl)ethanol was chosen as the best enantioselective chiral reagent for carboxylic acids (34, 35]. 

In addition, Shiina et al. [34] have developed the first KR of secondary benzyhc alcohols with free carboxyhc acids as acylation agents catalysed by (-l-)-benzotetramizole 10, which allowed good selectivity factors of up to 94 to be... 

KRs based on the oxidation of a chiral secondary alcohol to a prochiral ketone has been of considerable interest as the later can be usually recycled into the racemic starting material by simple hydride reduction [2d, 55]. The first broadly applicable method for this purpose was reported by Noyori et al. [56], under catalytic hydride transfer conditions similar to those employed for the asymmetric hydrogenation of ketones. For example, excellent results (s>50) have been reported for the KR of benzyhc alcohols by using a chiral diamine-ruthenium complex in the... 

An empirical rule was postulated by Jing and Kazlauskas to predict the enantiomer that reacts more quickly in a lipase-catalysed esterification reaction of a racemic secondary alcohol. The relative sizes of the two substituents determine the KR product [6]. X-ray structures of Upases revealed that the alcohol-binding pocket possesses a large hydrophobic pocket that is accessible to solvent along with a second, smaller pocket. The enantiopreference of lipases therefore allows for the determination of the absolute configuration of secondary alcohols. Clearly, the reliability of this method is dependent on how similar the molecule under study is to a molecule with a known absolute configuration in KR. The empirical rule to date only applies... 

Rychnovsky has reported an alternative method for the oxidation of secondary alcohols, using chiral nitroxyl radical 42 (Figure 19.14) in the presence of bleach [128]. By analogy to TEMPO oxidations [129], this chemistry is hkely to proceed via an oxoammonium ion as the active oxidant. The best substrates were found to be simple benzylic alcohols, giving S factors (= kj/kr) in the range 3.9-7.1 (Scheme 19.21). Chiral azabicyclo-N-oxyl 43 has also been used for the enantioselective electrooxidation of sec-alcohols, giving S factors of up to 21 [130]. 

Subsequently, Birman et al. tested various amidine-based catalysts, including commercially available tetramisole (45) and its benzanneUated analog benzote-tramisole (BTM) (23) in the KR of secondary aryl aUcyl alcohols and propargyUc alcohols (Eigure 41.3). Both catalysts displayed far superior enantioselectivity although BTM proved to be more reactive [27c, 50, 51[. 

Building upon the results obtained by Birman and coworkers. Smith et al. set out to develop an isothiourea-based catalyst that could promote the KR of secondary aryl alkyl alcohols [58]. After screening a range of DHIP catalysts, (2S,3R)-2-phenyl-3-isopropyl-substituted isothiourea (56) proved to be ideal as it afforded high levels of selectivity (s > 17) under low catalyst loadings (<1 mol%) (Scheme 41.12). To explain the enantiodiscrimination, the authors proposed a model where the N-acylated catalyst adopts a conformation that places the phenyl substituent in a pseudo-axial position to minimize 1,2-strain, resulting in a preferential attack of the (R)-enantiomer of the alcohol due to favorable n-n and/or cation-Jt interactions of the TT-system of the alcohol with the acylated isothiouronium catalyst intermediate. 

Table 41.3 KR of secondary aryl alkyl alcohols by Richards et al...

Unfortunately, as none of these catalysts induced useful levels of selectivity in the KR of secondary aryl alkyl alcohols. Miller et al. set out to identify specific peptide-catalysts for specific applications using automated peptide synthesis and high-throughput fluorescent screening. This allowed them to unveil some particularly effective catalysts for various transformations such as the KR of an intermediate in the synthesis of aziridomitosane [22h, k], the KR of a series of tertiary alcohols [22i], the regioselective acylation of carbohydrates [22k], and the KR of N-acylated tert-amino alcohols [22ij. 

In 2011, Bode et al. reported a unique dual-catalysis redox approach to the KR of secondary amines based on the catalytic generation of an acyl azolium species [132]. Indeed, these species, which can undergo rapid acyl transfer in the presence of various nucleophiles such as water, alcohols, or thiols, are absolutely inert in the presence of amines except if an additive such as imidazole or l-hydroxy-7-azabenzotriazole (HOAt) is added to the reaction mixture [133]. 

Carbery et al. also used the DMAP scaffold to develop the first hehcenoidal asymmetric organocatalyst, which proved to be a particularly selective acylation catalyst for the KR of secondary aryl alkyl alcohols [64]. Catalyst 67 offered good to excellent selectivity factors ranging from s = 17 to 116 at catalyst loadings as low as 0.5mol% (Scheme 41.18). 

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