Enantioselective deracemization

Two equivalents of a 1 1 molar mixture of CuCl andbipy are needed for a highly efficient dechlorinative Surzur-Tanner rearrangement of 2,2,2-trichloroethyl carboxylates to 1-chloroethenyl carboxylates. Highly enantioselective deracemization of linear and vaulted hiaryl ligands, VANOL and VAPOL, is also achieved in the presence of a cortplex of (—)-sparteine and CuCl (eq 16). ... 

Foulkes, J.M., et al., Engineering a biometalUc whole cell catalyst for enantioselective deracemization reactions. ACS Catal, 2011.1(11) 1589-1594. 

Assuming that the enzymatic reaction is highly enantioselective, then even after only four cycles the enantiomeric excess will have reached 93.4% whereas after seven catalytic cycles the enantiomeric excess is >99% (Figure 5.3). This type of deracemization is really a stereoinversion process in that the reactive enantiomer undergoes stereoinversion during the process. One of the challenges of developing this type of process is to find conditions under which the enzyme catalyst and chemical reactant can coexist, particularly in the case of redox chemistry in which the coexistence of an oxidant and reductant in the same reaction vessel is difficult to achieve. For this... 

Faber et al. have reported a novel process for the overall deracemization of racemic mandelic acid derivatives using a combination of an enantioselective lipase and a mandelate racemase activity from Lactobacillus paracasei (Figure 5.19) [32]. 

Asymmetric synthesis can refer to any process which accesses homochiral products. We will focus on asymmetric synthesis from racemic or prochiral starting materials in the presence of an enantioselective catalyst (enzyme). There are four general methodologies commonly applied kinetic resolution, dynamic kinetic resolution, deracemization and... 

Figure 11.1 Enzymatic deracemization of racemic amines via a two-step, one-pot process utilizing an enantioselective amine oxidase in combination with ammonia-borane.

J )-Mandelic acid 3 is a useful chiral synthon for the production of pharmaceuticals such as semi-synthetic penecillins, cephalosporins and antiobesity agents and many methods have been reported for the preparation of the optically pure material. A method to deracemize the racemate which is readily available on a large scale was developed by Ohta et al. using a combination of two biotransformations. The method consists of enantioselective oxidation of (S)-... 

The results actually showed a deracemization of the racemic hydroxyester 10 as opposed to enantioselective hydrolysis with formation of optically pure (R)-hydroxyester 10 and only 20 % loss in mass balance. Small quantities of ethyl 3-oxobutanoate 9 (<5%) were also detected throughout the reaction, leading the authors to suggest a multiple oxidation-reduction system with one dehydrogenase enzyme (DH-2) catalysing the irreversible reduction to the (R)-hydroxy-ester (Scheme 5). 

Scheme 2.31 Deracemization of amines via combined use of an enantioselective amine oxidase and ammonia borane.

Chemoenzymatic processes involving oxidizing enzymes have been reported particularly for specific chemical syntheses. For example, industrially important amino acids can be deracemized by exploiting the enantioselectivity of amino acid oxidases a commercial process has recently been developed in which efficient... 

Recently, Turner et al. described the synthesis of the alkaloid (R)-(-t-)-crispine A, which shows cytotoxic activity against HeLa human cancer cell lines, using in the final step a deracemization procedure with the combination of an enantioselective amine oxidase obtained by directed evolution methods and a chemical non-selective reducing agent (Scheme 10.20) [48]. 

Similarly to the case of amino acids, hydroxy acids can also be deracemized by combining an enantioselective oxidation with a non-enantioselective reduction with sodium borohydride. For example, the group of Soda has reported the transformation of DL-lactate into D-lactate in >99% (Scheme 5.38) [78]. 

The group of Turner has reported the deracemization of amines [79]. The wild type of Type II monoamine oxidase from Aspergillus niger possesses very low but measurable activity toward the oxidation of L-a-methylbenzylamine. The oxidation of the D enantiomer is even slower. In vitro evolution led to the identification of a mutant with enhanced enantioselectivity, showing high E values (>100) for a variety of primary and secondary amines. An example is shown in Scheme 5.39. 

An important breakthrough was made very recently in this area. A chemoenzymatic method developed by Turner has allowed the cyclic deracemization of tertiary amines [80]. Enantiopure tertiary amines cannot be obtained via DKR. One of the variants obtained by directed evolution of the monoamine oxidase from Aspergillus niger showed high activity and enantioselectivity toward cyclic tertiary amines (Scheme 5.40). 

The thiolester group was used for deracemization of terpenic esters [254]. Racemic 5-phenyl thiocyclogeranate was deprotonated by n-BuLi, and the resulting enolate was protonated by a chiral aminoalcohol, ( )-N-isopropylephedrine. The thiolester was obtained with the highest enantioselectivity (99% e.e.) reported for such a process (carried out on a 40 g scale). With a sulfur group a selective (Z)-enolate was formed and protonation was slower than for esters. 

E.3.2.1. Deracemization of Acyclic Substrates When chiral allylic substrates generate meso 71-allyl intermediates, the two allylic termini of such intermediates are enantiotopic. Thus, enantioselectivity is derived from the regiochemistry of the nucleophilic addition (a vs. b), and the alkylation process corresponds to a deracemization event (Eq. 8E,2). One of the prototypical reactions, which has been studied in extensive detail, is the 1,3-diphenylallyl system. Since its introduction as a different mechanistic motif in contrast with the 1,1,3-triphenylallyl system, this reaction has become a benchmark for design and comparison of a variety of different ligands in recent years [73]. 

An allylic halide has been used to give a better result than the corresponding allylic acetate (Scheme 8E.21) [134]. Notably, only 0.05 mol% of catalyst was sufficient to produce the enantiopure product in 96% yield. To achieve high enantioselectivity, the reactivity of the substrate had to be modulated by slow addition of the nucleophile, This deracemization strategy offers an efficient alternative method for the preparation of hydroxylactone, which has served as a synthetically useful building block for various natural product syntheses [135,136]. 

The alkylation products are synthetically useful because simple subsequent transformations furnishes precursors of important natural products as illustrated in Scheme 8E.23. Simple oxidative cleavage of allylic phthalimide 45 generates protected (5)-2-aminopimelic acid, whose dipeptide derivatives have shown antibiotic activity. The esterification via deracemization protocol is not limited to the use of bulky pivalic acid. The alkylation with sterically less hindered propionic acid also occurs with high enantioselectivity to give allylic ester 116, which has been utilized as an intermediate towards the antitumor agent phyllanthocin and the insect sex excitant periplanone. Dihydroxylation of the enantiopure allylic sulfone gives diol 117 with complete diastereoselectivity. Upon further transformation, the structurally versatile y-hydroxy-a,(f-un-saturated sulfone 118 is readily obtained enantiomerically pure. 

The obligatory enantiofacial exchange for efficient deracemization also occurs in a very congested allylic system giving high enantioselectivity (86% ee) as shown in Eq. 8E.8 [145]. The silyl groups in the alkylation product could be removed without loss of stereochemical integrity to effect a nct-benzylic substitution. 

Racemic acid was deracemized using Nocardia diaphanozonaria (Figure 29(f)).30tg In this reaction, subtle difference in the structure of the substrate determined the enantioselectivity.30 ... 

The deracemization of a number of pharmaceutically valuable building blocks has been carried out by biocatalytic processes. This includes epoxides, alcohols, amines and acids. DKR involves the combination of an enantioselective transformation with an in situ racemisation process such that, in principle, both enantiomers of the starting material can be converted to the product in high yield and ee. The racemization step can be catalysed either enzymatically by racemases, or non-enzymatically by transition metals. 

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