Deracemization strategies

An application of the deracemization strategy has provided efficient entry to a novel amino acid substituent of the antifungal agents, polyoxins and nikkomycins, as shown in Scheme 8E.20. The versatile five-carbon building block was obtained from phthalimidation of the hydroxymethyl-substituted epoxide in 87% yield and 82% ee. Straightforward synthesis of polyoxamic acid was then accomplished by subsequent dihydroxylation and selective oxidation of the alkylation product. 

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]. 

For instance, both (R)- and (S)-enantiomers of mexUetine, an orally effective antiarrhythmic agent, were synthesized from roc-mexiletme via a one-pot two-step deracemization process in 97% yield with >99% ee [146]. The pyruvate formed as side product of the transamination reaction using alanine as amine donor was in one deracemization strategy recycled back to L-alanine with AlaDH, in another approacdi... 

The kinetic resolution of amines was exploited first with co-TAs since the reaction is thermodynamically favored using pyruvate as acceptor [21]. Unfortunately, the inherent maximum 50% yield limits the practical applications of this approach and, therefore, will nof be considered in fhis confribufion. Thus, the other methodologies (stereoselective synthesis and deracemization) are preferred since a theoretical yield of 100% is possible. The asymmefric amination allows fhe preparation of enantiomer-ically pure amines at the expense of an amine donor, usually an amine or an AA (Scheme 2.2b). On the other hand, the combination of two stereocomplementary co-TAs enables to establish a deracemization process (Scheme 2.2c). Deracemization strategies are recommended when amines are readily available or the corresponding carbonyl compounds lack stability. 

The asymmetric amination of ketones is by far the most preferred approach for the preparahon of chiral amines using co-TAs. However, alternative methodologies may be considered if the carbonyl precursor is unstable or the synthesis of the racemic amine is easier to provide better results in economic and/or yield terms. Using racemic amines deracemization strategies allow the preparation of the desired amines in enantiopme form and a theoretical 100% yield [84- ]. This can be achieved by the combination of two stereocomplementary w-TAs. In the first step, the enantioselec-tive deamination of the racemic amine affords enantiopure untouched amine (50%) and the corresponding ketone (50%). In the second step, an enantiocomplementary -TA catalyzes the asymmetric amination of the ketone, leading to the optical pure amine in 100% theoretical yield (Scheme 2.18). 

Another deracemization strategy is stereoinversion, which involves one-pot two-step generation of stable nonchiral intermediates followed by as5onmetric synthesis. 

Biooxidative deracemization of racemic sec-alcohols to single enantiomers [47,48] is complementary to combined metal-assisted lipase-mediated strategies [49,50]. In general, deracemization can be realized by either an enantioconvergent, a dynamic kinetic resolution, or a stereoinversion process. The latter concept is particularly appealing, as only half of the substrate needs to be converted, as the remaining half already represents the product with correct stereochemistry. 

Such isolated enzyme approaches for deracemization have a clear disadvantage in that they require two operational manipulations with an intermediate recovery step. A one-pot strategy is offered by employing whole-cell biotransformations with strains containing set(s) of complementary dehydrogenases operating in both biooxidative and bioreductive modes. Trace amounts of the intermediate ketone species can be isolated in several cases. In order to lead to an efficient deracemization... 

Maerkle W, Liitz S (2008) Electroenzymatic strategies for deracemization, stereoinversion and asymmetric synthesis of amino acids. Electrochim Acta 53 3175-3180... 

The two more common strategies for achieving such an objective are deracemization by stereoinversion or deracemization by dynamic kinetic resoluhon DKR (Scheme 13.1). 

With their efficient procedure for deracemization of MBH adducts, Trost and coworkers have applied dynamic asymmetric kinetic transformation (DYKAT) to the total synthesis of furaquinodn E. As shown in Scheme 5.28, the asymmetric palladium-catalyzed alkylation of phenols combined with a reductive Heck reaction delivered an effident approach to the synthesis of the key synthon, which is the core structure of the furaquinocins. A general synthetic route to furaquinocin E was established in 14 steps from MBH adduct 159. Their work highlighted the ability to use racemic MBH adducts for asymmetric synthesis. They further extended the scope of their strategy by developing the synthesis of three more analogs of... 

To overcome these disadvantages by avoiding the occurrence of the undesired wrong enantiomer, several strategies are possible [67, 68]. AU of these processes which lead to the formation of a single stereoisomeric product from a racemate are called deracemizations [69]. 

Recently, this strategy was applied to the deracemization of propargylic alcohols that are important synthons for the preparation of biologically active compounds such as mifepristone, efavirenz, or petrosynol [63]. A one-pot two-step process employing whole cells from Candida parapsilosis ATCC 7330 was carried out in aqueous medium using short reaction times of 1—4h (Scheme 4.15). Biocatalyzed transformations afforded excellent enantiomeric excess (up to 99%) and isolated yields were from 60-81%. 

However, not only CALB but also other lipases have been fruitfully coupled in the deracemization of a wide variety of substrates, such as diols [26] a- [27], p- [28], and 8-hydroxyesters [29] benzoins [30] hydroxynitriles [31] haloalcohols [32] hydroxyalkanephosphonates [33] y-hydroxyamides [34] hydroxyacids and hydroxy-aldehydes protected with bulky groups [35] or cyclic allylic alcohols [36]. From those pioneer examples, many efforts have been attempted in order to design other ruthenium catalysts, which could decrease the reaction time and temperature, and improve the reaction conditions, to extend the applicability of this strategy to the resolution of other substrates. Some of those ruthenium catalysts that have led to relevant results are shown in Figure 14.5. 

The chiral synthesis of allylic alcohols has been the focus of many research works due to the high versatility of these molecules in the preparation of many active com-poimds [58,82], Allen and Williams reported the first example of DKR of allylic alcohols via lipase-palladium catalyst coupling deracemization of cyclic allylic acetates [83]. However, the accumulation of secondary products, as well as the long reaction times required, limited the use of this strategy. 

General synthesis strategies for transaminase-catalyzed reactions. (a) Asymmetric synthesis with transaminase, (b) Kinetic resolution with transaminase, (c) Dynamic kinetic resolution with transaminase, (d) One-pot two-step deracemization with transaminase. 

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