Kinetic resolution of racemic secondary

An efficient kinetic resolution of racemic secondary allyl carbamates was accomplished by the jw-butyllithium-(-)-sparteine complex76 131. Whereas the R-enantiomer (80% ee) is recovered unchanged, the 5-enantiomer is deprotonated preferentially. 

Recently, a similar reaction has been shown to affect the kinetic resolution of racemic secondary amines (Scheme 6) [15]. In this example, A7-oxyl radical (20) was utilized as the mediator. The rest of the reaction conditions remained the... 

In contrast, the HRP-catalyzed kinetic resolution of racemic secondary hydroperoxides in the presence of guaiacol afford the hydroperoxides and their alcohols in high enantiomeric excesses (Eq. 3) [69]. In the case of the aryl alkyl-substituted hydroperoxides and cyclic derivatives (Table 4, entries 1 -3,6-10), HRP preferentially accepts the (R)-enantiomers as substrates with concurrent formation of the (R)-alcohols the (S)-hydroperoxides are left behind, further-... 

Kinetic resolution of racemic secondary hydroperoxides rac-16 can be effected by selective reduction of one enantiomer with employing either chiral metal complexes or enzymes (equation 10). In this way hydroperoxides 16 and the opposite enantiomer of the corresponding alcohols 19 can be produced in enantiomerically enriched form. As side products sometimes the corresponding ketones 20 are produced. 

Horseradish peroxidase catalysed kinetic resolution of racemic secondary hydroperoxides has been described by Adam et al. [79]. The reaction yields (i )-hy-droperoxides up to ee>99% and (S)-alcohols up to ee>97%. Optically active hydroperoxides as potential stereoselective oxidants can be obtained by this process. 

Figure 1.10. Kinetic resolution of racemic secondary alcohols by BINAP-Ru catalyzed hydrogenation.

Within limits, an increase in the steric bulk at the olefin terminus of allylic alcohols of the type R1 CH(OH)CH=CHR2 causes an increase in the rate of epoxidation of the more-reactive enantiomer, and a decrease in the rate for the less-reactive enantiomer, resulting in enhanced kinetic resolution334. However, complexes of diisopropyl tartrate and titanium tetra-terf-butoxide catalyse the kinetic resolution of racemic secondary allylic alcohols with low efficiency335. Double kinetic resolution techniques can show significant advantages over the simple Sharpless epoxidation techniques336. 

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

High enantiomeric excess in organocatalytic desymmetrization of meso-diols using chiral phosphines as nucleophilic catalysts was achieved for the first time by Vedejs et al. (Scheme 13.21) [36a], In this approach selectivity factors up to 5.5 were achieved when the C2-symmetric phospholane 42a was employed (application of chiral phosphines in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). A later study compared the performance of the phos-pholanes 42b-d with that of the phosphabicyclooctanes 43a-c in the desymmetrization of meso-hydrobenzoin (Scheme 13.21) [36b], Improved enantioselectivity was observed for phospholanes 42b-d (86% for 42c) but reactions were usually slow. Currently the bicyclic compound 43a seems to be the best compromise between catalyst accessibility, reactivity, and enantioselectivity - the monobenzoate of hydrobenzoin has been obtained with a yield of 97% and up to 94% ee [36b]. 

The same group subsequently discovered that the loading of the chiral diamine catalyst can be reduced substantially if triethylamine is added in stoichiometric amounts as an achiral proton acceptor [37b]. As shown at the top of Scheme 13.23, as little as 0.5 mol% catalyst 45 was sufficient to achieve yields and ee comparable with the stoichiometric variant (application of the Oriyama catalysts 44 and 45 in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). Oriyama et al. have also reported that 1,3-diols can efficiently be desymme-trized by use of catalysts 44 or 45. For best performance n-butyronitrile was used as solvent and 4-tert-butylbenzoyl chloride as acylating agent (Scheme 13.23, bottom) [38]. 

Hoft E, Hamann H-J, Kunath A, Adam W, Hoch U, Saha-Moller CR, Schreier P (1995) Enzyme-catalyzed kinetic resolution of racemic secondary hydroperoxides. Tetrahedron Asymmetry 6 603-608... 

The kinetic resolution of racemic secondary alcohols via enantioselective benzoylation using Ph3Bi(OAc)2, CO, AgOAc, and a chiral Pd(n) catalyst has been investigated (Equation (135)).220,220a Of the chiral P- and A-ligands tested, the planar chirality of an optically active oxazolynylferrocenylphosphane has shown some positive effects on the enantioselectivity. 

So far, chiral imidazolium precatalysts have been used successfully for kinetic resolutions of racemic secondary alcohols via enantioselec-tive acylation (Kano et al. 2005 Suzuki et al. 2004). 

Figure 7.2 The structure of the faster reacting enantiomer in lipase-catalyzed esterification in kinetic resolution of racemic secondary alcohols or hydrolysis of the corresponding esters. Small and large refer to the relative size of the groups and not to the R/S notation.

The titanium-tartrate system is also effective for kinetic resolution of racemic secondary alcohols34. This is a diastereoselective epoxidation and is dealt with elsewhere in this volume. 

Kinetic Resolution of Racemic Secondary Alcohols. Racemic cyclic and acyclic secondary alcohols and p-halohydrins are kinetically resolved in good chemical yields with modest-to-excellent enantioselectivity (eqs 2 and 3). 

The kinetic resolution of racemic secondary alcohols by enzymatic acylation is a well-established method for obtaining optically pure alcohols or their esters in near-50% yield [293]. Coupling the enzymatic method with a catalytic redox ability of a Ru complex makes the process a dynamic kinetic resolution, increasing the theoretical yield from 50 to 100% [294]. Thus, a reaction system consisting of an achiral Ru catalyst for the chemical racemization of an alcoholic substrate, a suitable enzyme,... 

Asymmetric lactonization of prochiral diols has been performed vsdth chiral phosphine complex catalysts (Ru2Cl4((-)-DIOP)3 and [RuCl((S)-BINAP)(QH6)]Cl [17, 18]. Kinetic resolution of racemic secondary alcohol was also carried out with chiral ruthenium complexes 7 and 8 in the presence of a hydrogen acceptor, and optically active secondary alcohols were obtained with >99% e.e. (Eqs. 3.7 and 3.8) [19, 20]. 

A polyethylene-bound soluble recoverable dirhodium(II) tetrakis(2-oxapyrrolidine-(55 )-carb-oxylate) was also highly efficient in enantioselective intramolecular cyclopropanation of allyl diazoacetates and could be used repeatedly without significant loss of enantiocontrol. Some enantiomerically pure, secondary allylic diazoacetates showed the expected substrate-induced diastereofacial selectivity in intramolecular cyclopropanation, when they were decomposed with bis(A-n-r/-butylsalicylamidinato)copper(II). ° This selectivity could be significantly enhanced or reversed with the chiral catalyst 30 or its antipode. Furthermore, catalysts 30 and 32 allowed a highly efficient kinetic resolution of racemic secondary allylic diazoacetates. 

Dehydrogenative oxidation of secondary alcohols in the presence of acetone is the reverse process of transfer hydrogenation of ketones with 2-propanol [87b, 95b]. Kinetic resolution of racemic secondary alcohols is possible using this process with an appropriate chiral catalyst and suitable reaction conditions. As exemplified in Scheme 45, a variety of racemic aromatic or unsaturated alcohols can be effectively resolved in acetone with a diamine-based Ru(II) complex 42 or 50 [129]. Chiral alcohols with an excellent optical purity are recovered at about... 

R ) protrudes into an open quadrant and, therefore, frans-allylic alcohols always show standard enantioselectivity, irrespective of the bulkiness of the E-substituent. On the other hand, the C2-substituent (R ) exists in the vicinity of the tartrate ligand and the bulky substituent affects the conformation, causing depression of enantioselectivity to some extent. The Z-substituent (R ) is directed toward the ligand. Thus, the presence of a bulky Z-substituent makes it dffi-cult for the substrate to take the desired conformation, decreasing enantioselectivity to a considerable extent. The loaded substrate suffers from steric hindrance when R iH (see 8) and epoxidation of such a substrate is strongly retarded. This explains the kinetic resolution of racemic secondary allylic alcohols (see section 3). The enantiomer (R H, R =H) reacts much slower than the other enantiomer (R H, R =H). The poor reactivity of tertiary allylic alcohols can also be explained for the same reason. 

S. Hashiguchi, A. Fujii, K.-J. Haack, K. Matsumura, T. Ikariya, R. Noyori, Kinetic resolution of racemic secondary alcohols by Ru-catalyzed hydrogen transfer, Angew. Chem. Int. Ed. Engl., 1997, 36, 288-290. 

The SCCO2/IL flow process developed for hydroformylation is applicable to other homogeneous catalysis reactions, including enzymatic reactions. For instance, two groups independently reported the kinetic resolution of racemic secondary alcohols via transesterification by Upase in an scC02/[bmim][NTf2] system (Scheme 82). The reaction is advantageous with respect to the conventional process because of the ease of the product/enzyme and product/solvent separations. 

Fantin, G., Fogagnolo, M., Medici, A., Pedrini, A., and Fontana, S. (2000) Kinetic Resolution of Racemic Secondary Alcohols Via Oxidation with Yarrowia lipolytica Strains, Tetrahedron Asymmetry 11, 2367-2373. 

One of the typical applications of chiral DMAP catalysts is the atylative kinetic resolution of racemic secondary alcohols. Two landmark catalj ts, planer chiral DMAP catalyst 7 and chiral bicyclic PPY catalyst 10, were developed independently by Fu and Kawabata, respectively (Schemes 22.1 and 22.2). Catalysts 7 showed excellent properties as chiral nucleophilic catalysts. In the presence of 2 mol% of 7b, a variety of racemic secondaiy alcohols possessing aryl (or vinyl) and allg l groups such as 8 and 9 were kinetically resolved with acetic anhydride to give the acetates and the recovered starting materials in high enantioselectivity (s = 12-52) (Scheme 22.1). ... 

Scheme 22.6 Acylative kinetic resolution of racemic secondary alcohols with Miller s peptide-based iV-methylimidazole catalysts.

The second example involves the kinetic resolution of racemic secondary alcohols, a process that also has been used in a total synthesis. As illustrated in Figure 14.27, the naturally occurring tricyclic diamine sparteine, in combination with palladium dichloride and oxygen as the terminal oxidant, catalyzes the oxidation of one enantiomer of the race mic benzylic alcohol to the ketone faster than it oxidizes the other enantiomer. The desired unreacted alcohol was isolated in 47% yield with 99% ee (s > 47) and was subsequently transformed to (+)-amurensinine. ... 

Sato, Y., Kayaki, Y., and Ikariya, T. (2012) Efficient dynamic kinetic resolution of racemic secondary alcohols by a chemoenzymatic system using bifunctional iridium complexes with C-N chelate amido ligands. Chem. Commun. (Cambridge, UK), 48 (30), 3635-3637. 

Chiral N-sulfonyldiamine ligands are used to create effective chiral bifunctional amidoiridium catalysts for the asymmetric aerobic oxidation of meso- and prochiral diols to give up to >99% ee of hydroxyl ketones and 50%ee oflactones. " These catalysts can be also applied for an efficient oxidative kinetic resolution of racemic secondary alcohols affording R enantiomers with >99% ee and with 46—50% yields. 

Arita S, Koike T, Kayaki Y, Ikariya T. Aerobic oxidative kinetic resolution of racemic secondary alcohols wdth chiral bifunctional amido complexes. Angew Chem Int Ed Engl. 2008 47 2447-2449. 

In 1996, Rychnovsky et al. used optically active binaphthyl-based nitroxyl radicals as catalysts for the kinetic resolution of racemic secondary alcohols (Table 7.36) [346]. They achieved a fair selectivity factor ( 5=7.1) for the preferred oxidation of one enantiomer. 

Iwabuchi et al. use chirally modified 2-azaadamantane A -Oxyls (AZADOs) 525-533 for the enantioselective oxidative kinetic resolution of racemic secondary alcohols instead of TEMPO (Table 7.38). TEMPO is inefficient in the oxidation of structurally hindered secondary alcohols. The modified AZADOs exihibit superior catalytic activity and high enantioselectivities for the oxidation of structurally hindered secondary alcohols. A further alternative to TEMPO is the readily available 9-azabicyclo[3.3.1]nonane A-oxyl (ABNO, 534) which is kinetically more efficient than AZADO (Table 7.38) [350-352]. 

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