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Biocatalyst and Green Chemistry

Environmental chemistry in Bsc 5 th sem .. This is the 4th unit of environmental chemistry. Named as biocatalysis and role of biocatalysis in green chemistry.

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38 views7 pages

Biocatalyst and Green Chemistry

Environmental chemistry in Bsc 5 th sem .. This is the 4th unit of environmental chemistry. Named as biocatalysis and role of biocatalysis in green chemistry.

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seema26456
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1.5 THE ROLE OF CATALYSIS The waste generated in the manufacture of fine chemicals and pharmaceuticals is largely due to the use of stoichiometric inorganic and organic reagents that are partially incorporated or not incorporated into the product. Typical examples include oxidations with inorganic oxidants such as chromium (V1) salts, permanganates, manganese dioxide, and stoichiometric reductions with metals (Na, Mg, Zn, Fe) and metal hydrides (LiAIH [,, NaBH,). Similarly, stoichiometric amounts of mineral acids (H,SO,, HE, and H,PO,) and Lewis acids (AICI, ZnCl, BF,) are major sources of waste. The solution is evident: the substitution of antiquated stoichiometric method- ologies with cleaner catalytic alternatives [43-45]. This is true elegance and efficiency in organic synthesis [46]. For example, catalytic hydrogenation, oxidation, and car- bonylation are highly atom-efficient processes. Similarly, the use of recyclable solid (heterogeneous) acids and bases as catalysts results in substantial reductions in waste in industrial organic synthesis [47, 48]. Indeed, several pharma companies have developed reagent guides for particular reaction types with the aim of improving the greenness and sustainability of their processes [41]. The ultimate in step and AE is the development of catalytic cascade processes whereby several catalytic steps are integrated in one-pot procedures without the need for isolation of intermediates [49]. Such “telescoping” of multistep syntheses into catalytic cascades has several advantages—fewer unit operations, less solvent and reactor volume, shorter cycle times, higher volumetric and space-time yields, and less waste (lower E factor)—that afford substantial economic and environmental benefits. Furthermore, coupling of reactions can be used to drive equilibria toward product, thus avoiding the need for excess reagents. 1.6 BIOCATALYSIS AND GREEN CHEMISTRY Biocatalysis has many attractive features in the context of green chemistry and sus- tainable development: 1. The catalyst (an enzyme) is derived from renewable resources and is biocom- patible (sometimes even edible), biodegradable, and essentially nonhazard- ous, that is, it fulfills the criteria of sustainability remarkably well. 1.6 BIOCATALYSIS AND GREEN CHEMISTRY 2. Biocatalysis avoids the use of, and contamination of products by, scarce precious metals such as palladium, platinum, and rhodium. The long-term commercial viability of many “endangered” elements, such as various noble metals, is questionable. Moreover, the costs of removing traces of noble metals, toan acceptable level, from end products can be substantia 3. Reactions are performed in an environmentally compatible solvent (water) tunder mild conditions (physiological pH_and ambient temperature and pressure) 4. Reactions of multifunctional molecules proceed with high activities and chemo, regio-, and stereoselectivties and generally without the need for functional group activation, protection, and deprotection steps required in traditional omganie syntheses. This affords processes that are more step eco nomic and more efficient in energy and raw material consumption, generate less waste, and are, therefore, both environmentally and economically more attractive than conventional routes. 5. Asa direct result of the higher selectivities and milder reaction conditions, biocatalytic processes often afford products in higher purity than traditional chemical or chemo-catalytic processes. 6. Enzymatic processes (but not fermentations) can be conducted in standard multipurpose batch eactors and, hence, do not require any extra investment, for example, for high-pressure equipment. 7. Biocatalytc reactions are conducted under roughly the same conditions of temperature and pressure, and, hence, is relatively easy to integrate multiple reactions into eco-effcient catalytic eascade processes [50] Inshort biocatalyss its very well with the principles of green chemistry and sustainabi- ity. As Barry Commoner, the doyen of industrial ecology, observed [51]: in nature there {sno such thing as waste, everything is recycled.” As shown in Table 12, biocatalysis conforms with 10 ofthe 12 principles of green chemistry and is not really relevant for the other two (principles 4 and 10), which are concerned with the design of safer, ioegradable products. Consequently, since the mid-1950',biocatalyss has emerged {as an important technology for meeting the growing demand for green and sustainable chemical manufacture [52,53], particularly in the pharmaceutical industry {54,55} ‘Thanks to advances in biotechnology and protein engineering techniques such as in vitro evolution [56], it is now possible to produce most enzymes for commercially TABLE 1.2 Biocatalysis and the Principles of Green Chemistry {Green Chemistry Principles Biocatalysis 1. Waste prevention Enables more sustainable routes with sigficantiy rexluced waste 2. Atom economy Enables more atom and step economic routes 5. Less hazardous syntheses General low toxicity 4. Design for safer products Not relevant 5. Safer solventsand auxiliaries Usually performed in water or Class 3 solvents 6: Energy efficient ‘Mild eomuitions ar conducive with enengyelicieney 7 Renewable fedstocks Eneymesare renewable 8 Reduce derivatization Biocatlysscviates the nee for prtetion/ protection 9. Catalysis Enzymes ae catalysts 10, Design for degradation [Not realy relevant but enzymes themselves are biodegradable 11. Realtime analysis for pollution Camb applicable in biocatalytic processes prevetion 12. Inherently safer processes Performed under mild and safe conditions 1 BIOCATALYSIS AND GREEN CHEMISTRY acceptable prices and to manipulate them such that they exhibit the desired properties with regard to, inter alia, substrate specificity, activity, selectivity, stability, and pH. ‘optimum [57, 58]. This has made it eminently feasible to optimize the enzyme to fita predefined optimum process that is genuinely benign by design. Furthermore, the development of effective immobilization techniques has paved the way for optimiz~ ing the storage and operational stability and the recovery and recycling, of enzymes [58]. In addition, the coimmobilization of two or more enzymes can afford multifunc- tional solid biocatalysts capable of catalyzing biocatalytic cascade processes [60] Biocatalytic processes are performed with isolated enzymes or as whole-cell bio- transformations. Isolated enzymes have the advantage of not being contaminated with other enzymes present in the cell. The use of whole cells, on the other hand, is less expensive as it avoids the separation and purification of the enzyme. Inthe case ‘of dead cells, E factors of the two methods are essentially the same: the waste cell debris is separated before or after the biotransformation, respectively. In contrast, substantial amounts of waste biomass can be generated when using growing micro- bial cells in the fermentation processes. We note, however, that this waste is generally ‘easy to dispose of, or example, as animal feed o can, in principle, be used as.a source ‘of enengy for the process. Many fermentation processes also involve the formation of copious amounts of inorganic salts that may even be the major contributor to waste E factors have generally not been calculated for fermentations, but published data [61] regarding mass balances can be used to calculate E factors. The E factor for the bulk fermentation product—citric acid, for example—is 1.4, which compares well with the E factor range of <1-5 typical of bulk petrochemicals. Interestingly, ca. 75% ‘of the waste is accounted for by an inorganic salt, calcium sulfate. If water is included im the calculation, the E factor becomes 17. In contrast, small-volume fermentation [processes for low-volume, high-added-value biopharmaceuticals can have extremely hhigh E factors, even when compared with those observed in the production of small- molecule drugs. The fermentative production of recombinant human insulin [15] for ‘example, involves an E factor of ca. 6600 and inclusion of water affords an astronomi- ‘al E factor of 50000! In contrast, biocatalysis with isolated enzymes tends to involve significantly higher substrate concentrations and combines a higher product with a lower water usage compared to fermentations, 1.7 EXAMPLES OF GREEN BIOCATALYTIC PROCESSES 1.7.1 A Chemoenzymatic Process for Pregabalin Pfizer scientists have described [62] a second-generation chemoenzymatic process (Figure 1.3) for the manufacture of pregabalin, the active ingredient of the CNS drug Lyrica. Itrepresented a dramatic improvement in process efficiency compared tocar. lier routes. The stereocenter was set early in the synthesis in accordance with the ‘golden rule of chirotechnology [63], and the wrong enantiomer could be easily race- mized and reused. The key enzymatic step was conducted with an inexpensive, read- ily available laundry detergent lipase at a staggering substrate concentration of 7658/1. Organic solvent usage was dramatically reduced in a largely aqueous pro- ‘ess. Compared to the first-generation manufacturing process, the new process afforded a higher yield and a fivefold reduction inthe E factor from 86 to 17. 1.7.2 A Three-Enzyme Process for Atorvastatin intermediate Codexis scientists developed and commercialized a green-by-design, three-enzyme process for the synthesis of a key intermediate (Figure 1.4) in the manufacture of atorvastatin, the active ingredient of the cholesterol-lowering drug Lipitor [64,65]. In the first step, ethyl-4-chloroacetoacetate undergoes highly enantioselective reduction 1.7 EXAMPLES OF GREEN BIOCATALYTIC PROCESSES NOB, PACH isha J Rocenication — coor: Tipe HOA) ‘coor 8709 2h 1 Ren. 88°C, con, ee ex 6590 ‘Chemoenzymatic process for pregabalin. 2° a KK, Heomtame, oR _aenmie eT NADPHSH' —NADP* >995% ce msec no Gaon detyaopenae ‘catalyzed by a ketoreductase (KRED), Cofactor regeneration was achieved with ‘glucose as the hydrogen donor and an NADP-dependent glucose dehydrogenase (GDH) as the catalyst. The (5) ethybtchlorohydroxybutyrate product was ‘obtained in 96% isolated yield and >99.5% ee. In the second step, a halohydrin dehal- ‘ogenase (HHDH) was employed to catalyze a nucleophilic substitution of chloride by cyanide using HCN at neutral pH and ambient temperature. ‘Al previous manufacturing routes tothe hydroxynitile product employed, as the fina step a standard S, substitution of halide with cyanide ton in alkaline solu- tion at elevated temperatures. This resulted in extensive by product formation owing tothe base sensitivity of both substrate and product. Since the product is high-boiling ‘ll, troublesome and expensive highvacuum fractional distillation is required to recover product of acceptable quality, resulting in further yield losses and more waste. Hence, the key to designing an economically and environmentally attractive process was lo conduct the cyanation reaction at ambient temperature and neutral DpH using the enzyme, HHDH as the catalyst. Overall this afforded an elegant two- step, three-enzyme process for the hydroxynitrle product. ‘Unfortunately, the wild-type KRED and GDH exhibited prohibitively low activi- ties, and large enzyme loadings were required to obtain an economically viable reac- tion ate. This resulted in troublesome emulsion formation and associated yield losses in downstream processing. Fortunately, the enzyme loadings could be drasti- «ally reduced by employing in vitro evolution via DNA shuffling [66] to improve the activity and stability of KRED and GDH. The GDH activity was improved by a factor ‘of 13 and the KRED activity by a factor of 7 while maintaining the nearly perfect ‘enantioselectvity (>99.5%) ofthe wild-type KRED. With the improved enzymes, the reaction was complete in 8h with a substrate loading of 160 g/l and phase separation required <1 min, providing the chlorohydrin in >95% isolated yield and >99.9% ee FIGURE 1.4 ‘Atwostept for atonasta 0 1 BIOCATALYSIS AND GRE! Similarly, the activity of the wild-type HHDH in the nonna reaction was extremely low, and the enzyme exhibited severe produc poor stability under operating conditions. However, after many iter 1 BIOCATALYSIS AND GREEN CHEMISTRY Similarly, the activity of the wild-type HHDH in the nonnatural cyanation reaction was extremely low, and the enzyme exhibited severe product inhibition and poor stability under operating condition, However, after many iterative rounds of (A shulfling, the inhibition was largely overcome and the HHDH activity was increased more than 2500-old compared tothe wild-type enzyme. The greenness of process was assessed according to the 12 principles of green chemistry ‘Principle 1—twaste prevention: The highly selective biocatalytic reactions afforded «substantial reduction in waste, and by avoiding by product formation, the neo for yield -sacrificing fractional cision was Crcumvented. The but) ‘scctate and ethyl acetate solver, used in the extraction ofthe product fom the aqueous layer in the first and second steps, respectively, were recycled with an efficiency of 85%. The E factor forthe overall process is 58 if proves water isexcluded (23 for the reduction and 35 for the eyanation)- If process water is included, th E factor forthe whole process is 18 (for the reduction and TL forthe cyanation). The main contributors tothe E factor (Table 13) are salvent losses (1%), sodium gluconate (25%), and the innocuous inorganic salts, NaCl and Na,SO, combined ea. 22%). The three enzymes and the NADP cofactor account for<1% of the waste. Furthermore, the main waste streams are aqiae- ‘ous and directly biodegradable. Principle —AE: The use of glucose asthe reductant for cofactor regeneration is ‘costeffective, bul the AE is poor (57). However, glucose isan inexpensive renewable raw material and the gluconate coproduct i flly Biodegradable. Principle 3—toss hazardous hema sythees: The reduction reaction uses exsentally nontoxic string materials and avoids the we of potentially hazardous hydrogen and heavy metal catalysts obviating concer for their removal from waste streams {nd /or contamination ofthe prod While cyanide must be used inthe second ‘Step, a in all practical routes to the product its sed more efcenty (higher Yield) and under less harsh conditions compared to previous processes. Principle +—design sofer chemicals: This isnot applicable as the hydroxynitile products the target molecule Principle S—sufersotcens and auritaris: Sate and environmentally aceptable ‘thy acetate and butyl acetate are used, together with water, as Coolvent in the biocatalytic eduction reaction and extraction ofthe hydroxynitile prod ‘uct No auniiaries are cede Principles 6nd 9—desgn for energy efconcy ond catalysis: The process constitutes ‘very efficient biocatalysis with turnover numbers of >10” for KRED and GDH tnd 95:10" for HHH. In contrast with previous proceses, which employ levated temperatures forthe cyanation step and high-pressure hydrogenation ‘TABLE 13 _E Factor of the Process for Atorvastatin Intermediate Waste ‘Quantity gig product) ‘eof (Exc Water) “wo (nck Water) 009 2 a 08 a a 12 2 a7 8 ars as 046 os a3 290 as au ona a a 0.008 on

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