Asymmetric Hydrolysis of Epoxides

A recent discovery that has significantly extended the scope of asymmetric catalytic reactions for practical applications is the metal-complex-catalyzed hydrolysis of a racemic mixture of epoxides. The basic principle behind this is kinetic resolution. In practice this means that under a given set of conditions the two enantiomers of the racemic mixture undergo hydrolysis at different rates. The different rates of reactions are presumably caused by the diastereo-meric interaction between the chiral metal catalyst and the two enantiomers of the epoxide. Diastereomeric intermediates and/or transition states that differ in the energies of activation are presumably generated. The result is the formation of the product, a diol, with high enantioselectivity. One of the enantiomers of 

Asymmetric hydrolysis has several specific advantages to offer. First of all it uses water as one of the reagents. Water is cheap, safe, and environmentally benign Second, chiral 1,2 diols are versatile building blocks for complex organic molecules. Finally, asymmetric catalytic epoxidation does not work for alkenes such as propylene. However, by this method a racemic mixture of 

The precatalyst used in these water-based kinetic resolution reactions is the cobalt Schiff-base complex 9.40. Its structural similarity to the asymmetric epoxidation catalysts 9.38A and 9.38B is to be noted. In the actual catalytic system 9.40 is activated with small amounts of acetic acid and air to give a cobalt(III) complex where CH3C02 and H20 are additional ligands. The mechanistic details of this reaction are as yet unknown. 

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For the corresponding asymmetric hydrolysis of epoxides using a chiral Co-saien complex see [560],... 

The /M ) )-nitrite (or formate) esters of v/c-diols obtained via enzymatic ring-opening of epoxides in presence of nitrite (or formate) are unstable and undergo spontaneous (nonenzymatic) hydrolysis to furnish the corresponding diols. This protocol offers a useful complement to the asymmetric hydrolysis of epoxides. Depending on the type of substrate and the enzymes used, enantio-complementary epoxide hydrolysis can be achieved [1851]. 

The asymmetric hydrolysis of epoxides, which was impeded by the lack of readily available sources of microbial enzymes, is now possible on a preparative scale. This method offers a valuable alternative to the asymmetric epoxidation of olefins, particularly for those substrates where chemical methods fail due to the absence of directing functional groups. 

Chiral epoxides and their corresponding vicinal diols are very important intermediates in asymmetric synthesis [163]. Chiral nonracemic epoxides can be obtained through asymmetric epoxidation using either chemical catalysts [164] or enzymes [165-167]. Biocatalytic epoxidations require sophisticated techniques and have thus far found limited application. An alternative approach is the asymmetric hydrolysis of racemic or meso-epoxides using transition-metal catalysts [168] or biocatalysts [169-174]. Epoxide hydrolases (EHs) (EC 3.3.2.3) catalyze the conversion of epoxides to their corresponding vicinal diols. EHs are cofactor-independent enzymes that are almost ubiquitous in nature. They are usually employed as whole cells or crude... 

The above-mentioned facts have important consequences on the stereochemical outcome of the kinetic resolution of asymmetrically substituted epoxides. In the majority of kinetic resolutions of esters (e.g. by ester hydrolysis and synthesis using lipases, esterases and proteases) the absolute configuration at the stereogenic centre(s) always remains the same throughout the reaction. In contrast, the enzymatic hydrolysis of epoxides may take place via attack on either carbon of the oxirane ring (Scheme 7) and it is the structure of the substrate and of the enzyme involved which determine the regioselec-tivity of the attack [53, 58-611. As a consequence, the absolute configuration of both the product and substrate from a kinetic resolution of a racemic... 

FIGURE 10.26 (See color insert following page S88.) ZSM-5/Anodisc membrane system used in the enantioselective asymmetric hydrolysis of racemic epoxides. (Adapted from Choi, S.D. and Kim, G.J., Catal. Lett., 92, 35, 2004.)... 

Kinetic resolutions. A chiral alcohol is obtained on. selective removal of one enantiomer by acetylation using a chiral analog 1 of DMAP, or by oxidation based on hydrogen transfer to acetone mediated by a Ru complex 2. Benzylic secondary alcohols are resolved by selective pivaloylation with optically activeA-pivaloyl-4-t-butylthiazolidine-2-thione. A kinetic resolution of sulfoxides is based on asymmetric oxidation with (i-PrO)4Ti-cumyl hydroperoxide in the presence of a tartrate ester. Kinetic resolution of 1,3-diarylallenes is realized by selective oxidation with NaClO catalyzed by a chiral (salen)manganese(III) complex, whereas asymmetric hydrolysis of terminal epoxides with the aid of a chiral (salen)cobalt(II) catalyst solves the problem of their accessibility. 

In 1974 Marumo and coworkers synthesized the enantiomers of JH II by microbial asymmetric hydrolysis of the epoxy ring of ( )-JH II (prepared by Mori) with a fungus Helminthosporium sativum 23 The hydrolysed diol was converted to (+)-JH II, while the epoxide remained intact was (—)-JH II. Their enantiomeric purities, however, were rather low (66-73% ee), and no definite biological data could be obtained. 

Recently, encouraging progress was made in the hydrolysis of cyclopentene oxide and cyclohexene oxide using the yeast Rhodotonda glutinis195L The corresponding (R,R)-trans-diols were obtained in over 90% optical and chemical yields. However, asymmetric hydrolysis of meso-epoxides by bacterial and fungal epoxide hydrolases is still impeded by insufficient selectivities. 

An enzymatic production process for Diltiazem (54), a coronary vasodilator and calcium channel blocker, was started in 1993 by Tanabe Seiyaku, Japan [7, 77]. The epoxide (2i, 3S)-52 is a key intermediate in this synthesis (Scheme 17) and can be produced via asymmetric hydrolysis of rac-52 catalyzed by Serratia marescens lipase immobilized on spongy layers. The whole process takes place in a polyacrylonitrile hollow fiber membrane reactor and produces (2i, 3S)-52 in yields of 40-45%. The hydrolyzed product (2S,3i )-53 is not stable under the prevailing reaction conditions and decarboxylates to aldehyde 55, a strong enzyme deactivator. The aldehyde needs therefore to be removed, which is achieved by continuous filtration of its bisulfite adduct 56. Using this enzymatic process it was possible to bring down the number of required steps en route to 54 from nine to five. This process is also carried out by other companies (e.g., DSM) with a worldwide annual production of 1001. 

Mischitz, M., Kroutil, W., Wandel, U., and Faber, K. (1995) Asymmetric Microbial Hydrolysis of Epoxides. Tetrahedron Asymmetry 6,1261-1272. 

A comparative study was made of asymmetric hydrolysis of styrene epoxide to (R)-l-phenyl-l,2-ethanediol by mung bean epoxide hydrolase in a biphasic system (n-hexane-buffer) containing hydrophilic ionic liquids (ILs). Compared to the biphasic system alone, the introduction of a small amount of hydrophilic ILs decreased the degree of non-en matic hydrolysis and increased the reaction rate by 22%. The ILs with a cation containing an alkanol group,... 

Highly active oligomeric (salen)Co complexes such as (198) were designed for asymmetric hydrolysis of meso-epoxides and kinetic resolution of terminal epoxides, based on cooperative bimetallic mechanism postulated for epoxide ring-opening reactions (Scheme 16.59) [83, 84]. 

W-J Ghen, W-Y Lou, M-H Zong, Asymmetric hydrolysis of racemic styrene oxide to (R)-l-phe-nyl-l,2-ethanediol catalyzed by Mung bean epoxide hydrolase. Am. Chem. Soc., pp. ORGN-667, 2011. 

Chen, W.-J., Lou, W.-Y. and Zong, M.-H. (2012) Efficient asymmetric hydrolysis of styrene oxide catalyzed by mung bean epoxide hydrolases in ionic liquid-based biphasic systems. Bioresour. Technol., 115,58-62. 

Morisseau, C., Nellaiah, H., Archelas, A., Furstoss, R. and Baratti, J.C. (1997) Asymmetric hydrolysis of racemic para-nitrostyrene oxide using an epoxide hydrolase preparation irom Aspergillus niger. Enzyme Microb. Technol., 20, 446-452. 

A number of insect pheromones are epoxides. Asymmetric hydrolysis of meso-diacetate 3 (Figure 24.2) witii pig pancreatic lipase (PPL) gives (2S,3P)-4-acetoxy-2, 3-epoxy-l-butanol (4, 90% ee) in 71% yield [4], Various epoxide pheromones were synthesized from (2S,3K)-4, which could be purified to give enantiopure material by recrystallizing tiie corresponding 3,5-dinitrobenzoate. 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

An alternative method for generating enriched 1,2-diols from meso-epoxides consists of asymmetric copolymerization with carbon dioxide. Nozaki demonstrated that a zinc complex formed in situ from diethylzinc and diphenylprolinol catalyzed the copolymerization with cyclohexene oxide in high yield. Alkaline hydrolysis of the isotactic polymer then liberated the trans diol in 94% yield and 70% ee (Scheme 7.20) [40]. Coates later found that other zinc complexes such as 12 are also effective in forming isotactic polymers [41-42]. 

Lee, E.Y. and Shuler, M.L. (2007) Molecular engineering of epoxide hydrolase and its application to asymmetric and enantioconvergent hydrolysis. Biotechnology and Bioengineering, 98, 318-327. 

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