全部 标题 作者
关键词 摘要

OALib Journal期刊
ISSN: 2333-9721
费用:99美元

查看量下载量

相关文章

更多...
PLOS ONE  2013 

A Highly Productive, Whole-Cell DERA Chemoenzymatic Process for Production of Key Lactonized Side-Chain Intermediates in Statin Synthesis

DOI: 10.1371/journal.pone.0062250

Full-Text   Cite this paper   Add to My Lib

Abstract:

Employing DERA (2-deoxyribose-5-phosphate aldolase), we developed the first whole-cell biotransformation process for production of chiral lactol intermediates useful for synthesis of optically pure super-statins such as rosuvastatin and pitavastatin. Herein, we report the development of a fed-batch, high-density fermentation with Escherichia coli BL21 (DE3) overexpressing the native E. coli deoC gene. High activity of this biomass allows direct utilization of the fermentation broth as a whole-cell DERA biocatalyst. We further show a highly productive bioconversion processes with this biocatalyst for conversion of 2-substituted acetaldehydes to the corresponding lactols. The process is evaluated in detail for conversion of acetyloxy-acetaldehyde with the first insight into the dynamics of reaction intermediates, side products and enzyme activity, allowing optimization of the feeding strategy of the aldehyde substrates for improved productivities, yields and purities. The resulting process for production of ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate (acetyloxymethylene-lactol) has a volumetric productivity exceeding 40 g L?1 h?1 (up to 50 g L?1 h?1) with >80% yield and >80% chromatographic purity with titers reaching 100 g L?1. Stereochemical selectivity of DERA allows excellent enantiomeric purities (ee >99.9%), which were demonstrated on downstream advanced intermediates. The presented process is highly cost effective and environmentally friendly. To our knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme. Finally, applicability of the presented process is demonstrated by efficient preparation of a key lactol precursor, which fits directly into the lactone pathway to optically pure super-statins.

References

[1]  Tobert JA (2003) Lovastatin and beyond: the history of the HMG-COA reductase inhibitors. Nat Rev Drug Discov 2: 517–526.
[2]  Istvan ES, Deisenhofer J (2001) Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292: 1160–1164.
[3]  Brautbar A, Ballantyne CM (2011) Pharmacological strategies for lowering LDL cholesterol: statins and beyond. Nat Rev Cardiol 8: 253–265.
[4]  Kidd J (2006) Life after statin patent expires. Nat Rev Drug Discov 5: 813–814.
[5]  Almuti K, Rimawi R, Spevack D, Ostfeld RJ (2006) Effects of statins beyond lipid lowering: potential for clinical benefits. Int J Cardiol 109: 7–15.
[6]  Switzer JA, Hess DC (2006) Statins in stroke: prevention, protection and recovery. Expert Rev Neurotherapeutics 6: 192–202.
[7]  Lahera V, Goicoechea M, de Vinuesa SG, Miana M, de las Heras N, et al. (2007) Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins. Curr Med Chem 14: 243–248.
[8]  Paraskevas KI, Tzovaras AA, Briana DD, Mikhailidis DP (2007) Emerging indications for statins: a pluripotent family of agents with several potential applications. Curr Pharm Des 13: 3622–3636.
[9]  Bersano A, Ballabio E, Lanfranconi S, Mazzucco S, Candelise L, et al.. (2008) Statins and stroke. Curr Med Chem 15: 2380–2392 and references cited therein.
[10]  Endo A, Kuroda M, Tsujita Y (1976) ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum.. J Antibiot 29: 1346–1348.
[11]  Endo A (1992) The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res 33: 1569–1582.
[12]  Endo A, Hasumi K (1993) HMG-CoA reductase inhibitors. Nat Prod Rep 10: 541–550.
[13]  Endo A (2008) A gift from nature: the birth of the statins. Nature Med 14: 1050–1052.
[14]  ?asar Z (2010) Historic overview and recent advances in the synthesis of super-statins. Curr Org Chem 14: 816–845.
[15]  ?asar Z, Steinbücher M, Ko?mrlj J (2010) Lactone pathway to statins utilizing the Wittig reaction. The synthesis of rosuvastatin. J Org Chem 75: 6681–6684.
[16]  Fabris J, ?asar Z, Gazi? Smilovi? I (2012) The use of a lactonized statin side-chain precursor in a concise and efficient assembly of pitavastatin. Synthesis 44: 1700–1710.
[17]  Vasi?-Ra?ki ? (2006) History of industrial biotransformations - Dreams and realities. In: Liese A, Seelbach K, Wandrey C, editors. Industrial Biotransformations 2nd ed. Weinheim: Wiley-VCH. 1–29.
[18]  Liese A, Villela Filho M (1999) Production of fine chemicals using biocatalysis. Curr Opin Biotechnol 10: 595–603.
[19]  Schulze B, Wubbolts MG (1999) Biocatalysis for industrial production of fine chemicals. Curr Opin Biotechnol 10: 609–615.
[20]  Wandrey C, Liese A, Kihumbu D (2000) Industrial biocatalysis: past, present, and future. Org Process Res Dev 4: 286–290.
[21]  Zaks A (2001) Industrial biocatalysis. Curr Opin Chem Biol 5: 130–136.
[22]  Koeller KM, Wong C-H (2001) Enzymes for chemical synthesis. Nature 409: 232–240.
[23]  Schmid A, Dordick JS, Hauer B, Kiener A, Wubbolts M, et al. (2001) Industrial biocatalysis today and tomorrow. Nature 409: 258–268.
[24]  Straathof AJJ, Panke S, Schmid A (2002) The production of fine chemicals by biotransformations. Curr Opin Biotechnol 13: 548–556.
[25]  Patel RN (2002) Microbial/enzymatic synthesis of chiral intermediates for pharmaceuticals. Enzyme Microb Technol 31: 804–826.
[26]  Bertau M (2002) Novel developments in biocatalytic organic chemistry. Curr Org Chem 6: 987–1014.
[27]  Schoemaker HE, Mink D, Wubbolts MG (2003) Dispelling the myths-biocatalysis in industrial synthesis. Science 299: 1694–1697.
[28]  Yazbeck DR, Martinez CA, Hu S, Tao J (2004) Challenges in the development of an efficient enzymatic process in the pharmaceutical industry. Tetrahedron: Asymmetry 15: 2757–2763.
[29]  Panke S, Held M, Wubbolts M (2004) Trends and innovations in industrial biocatalysis for the production of fine chemicals. Curr Opin Biotechnol 15: 272–279.
[30]  Panke S, Wubbolts M (2005) Advances in biocatalytic synthesis of pharmaceutical intermediates. Curr Opin Chem Biol 9: 188–194.
[31]  Pollard DJ, Woodley JM (2006) Biocatalysis for pharmaceutical intermediates: the future is now. Trends Biotechnol 25: 66–73.
[32]  Hudlicky T, Reed JW (2009) Applications of biotransformations and biocatalysis to complexity generation in organic synthesis. Chem Soc Rev 38: 3117–3132.
[33]  Müller M (2005) Chemoenzymatic Synthesis of Building Blocks for Statin Side Chains. Angew Chem Int Ed 44: 362–365.
[34]  Liljeblad A, Kallinen A, Kanerva LT (2009) Biocatalysis in the Preparation of the Statin Side Chain. Curr Org Synth 6: 362–379.
[35]  Ma SK, Gruber J, Davis C, Newman L, Gray D, et al. (2010) A green-by-design biocatalytic process for atorvastatin intermediate. Green Chem 12: 81–86.
[36]  Schürman M, Wolberg M, Panke S, Kierkels H (2010) The development of short, efficient, economic, and sustainable chemoenzymatic processes for statin side chains. In: Dunn PJ, Wells AS, Williams MT, editors. Green Chemistry in the Pharmaceutical Industry 1st ed. Weinheim: Wiley-VCH. 127–144.
[37]  Whalen LJ, Wong C-H (2006) Enzymes in organic synthesis: aldolase-mediated synthesis of iminocyclitols and novel heterocycles. Aldrichim Acta 39: 63–71.
[38]  Dean SM, Greenberg WA, Wong C-H (2007) Recent Advances in Aldolase-Catalyzed Asymmetric Synthesis. Adv Synth Catal 349: 1308–1320.
[39]  Samland AK, Sprenger GA (2006) Microbial aldolases as C–C bonding enzymes-unknown treasures and new developments. Appl Microbiol Biotechnol 71: 253–264.
[40]  Bolt A, Berry A, Nelson A (2008) Directed evolution of aldolases for exploitation in synthetic organic chemistry. Arch Biochem Biophys 474: 318–330.
[41]  Clapés P, Fessner W-D, Sprenger GA, Samland AK (2010) Recent progress in stereoselective synthesis with aldolases. Curr Opin Chem Biol 14: 154–167.
[42]  Gijsen HJM, Wong C-H (1994) Unprecedented asymmetric aldol reactions with three aldehyde substrates catalyzed by 2-deoxyribose-5-phosphate aldolase. J Am Chem Soc 116: 8422–8423.
[43]  Gijsen HJM, Qiao L, Fitz W, Wong C-H (1996) Recent advances in the chemoenzymatic synthesis of carbohydrates and carbohydrate mimetics. Chem Rev 96: 443–474.
[44]  Greenberg W, Varvak A, Hanson SR, Wong K, Huang H, et al. (2004) Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proc Natl Acad Sci USA 101: 5788–5793.
[45]  Ikunaka M (2007) Catalytic asymmetric carbon-carbon bond formations: their evolution from biocatalysis to organocatalysis over the millennium. Org Process Res Dev 11: 495–502.
[46]  Yoshida Y, Noritake T, Watanabe M, Nakamoto Y (2005) Method for producing (4R,6S)-6-benzyloxymethyl-4-hydroxy-tetr?ahydro-2-pyrone.(Ube Industries, Ltd., Japan). Jap Pat Appl JP 2005229858 A Chem Abstr (2005) 143: 228047.
[47]  ?asar Z, Mesar M, Kopitar G, Mrak P, O?laj M (2008) Synthesis of statins. (Lek Pharmaceuticals d.d.). PCT Int Appl WO 2008119810 A2 Chem Abstr (2008) 149: 448104.
[48]  Machajewski TD, Wong C-H (2000) The catalytic asymmetric aldol reaction. Angew Chem Int Ed 39: 1352–1374.
[49]  Mestres R (2004) A green look at the aldol reaction. Green Chem 6: 583–603.
[50]  Sukumaran J, Hanefeld U (2005) Enantioselective C-C bond synthesis catalysed by enzymes. Chem Soc Rev 34: 530–542.
[51]  Mlynarski J, Paradowska J (2008) Catalytic asymmetric aldol reactions in aqueous media. Chem Soc Rev 37: 1502–1511.
[52]  Heine A, DeSantis G, Luz JG, Mitchell M, Wong C-H, et al. (2001) Observation of covalent intermediates in an enzyme mechanism at atomic resolution. Science 294: 369–374.
[53]  Heine A, Luz JG, Wong C-H, Wilson IA (2004) Analysis of the class I aldolase binding site architecture based on the crystal structure of 2-deoxyribose-5-phosphate aldolase at 0.99 A° resolution. J Mol Biol 343: 1019–1034.
[54]  Racker E (1952) Enzymatic synthesis and breakdown of deoxyribose phosphate. J Biol. Chem. 196: 347–365.
[55]  Pricer WE, Horecker BL (1960) Deoxyribose aldolase from Lactobacillus plantarum. J Biol Chem 235: 1292–1298.
[56]  Barbas CF, Wang Y-F, Wong C-H (1990) Deoxyribose-5-phosphate aldolase as a synthetic catalyst. J Am Chem Soc 112: 2013–2014.
[57]  Gijsen HJM, Wong C-H (1995) Sequential three- and four-substrate aldol reactions catalyzed by aldolases. J Am Chem Soc 117: 7585–7591.
[58]  Chen L, Dumas PD, Wong CH (1992) Deoxyribose-5-phosphate aldolase as a catalyst in asymmetric aldol condensation. J Am Chem Soc 114: 741–748.
[59]  Kierkels JGT, Mink D, Panke S, Lommen FAM, Heemskerk D (2003) Process for the preparation of 2,4-dideoxyhexoses and 2,4,6-trideoxyhexoses. (DSM N.V.). PCT Int Appl WO 2003006656 A2 Chem Abstr (2003) 138: 112523.
[60]  Greenberg W, Wong K, Varvak A, Swanson R (2004) Chemoenzymatic methods for the synthesis of statins and statin intermediates. (Diversa Corporation). , PCT Int Appl WO 2004027075 A2 Chem Abstr (2004) 140: 302423.
[61]  Jennewein S, Schürmann M, Wolberg M, Hilker I, Luiten R, et al. (2006) Directed evolution of an industrial biocatalyst: 2-deoxy-D-ribose 5-phosphate aldolase. Biotechnol J 1: 537–548.
[62]  Habeeb AFSA, Hiramoto R (1968) Reaction of proteins with glutaraldehyde. Arch Biochem Biophys 126: 16–26.
[63]  Franke D, Hsu C-C, Wong C-H (2004) Directed evolution of aldolases. Methods Enzymol 388: 224–238.
[64]  Suau T, Calveras J, Clapés P, Benaiges MD, álvaro G (2005) Immobilization of fuculose-1-phosphate aldolase from E. coli to glyoxal-agarose gels by multipoint covalent attachment. Biocatal Biotransfor 23: 241–250.
[65]  Suau T, álvaro G, Benaiges MD, López-Santín J (2009) Performance of an immobilized fuculose-1-phosphate aldolase for stereoselective synthesis. Biocatal Biotransfor 27: 136–142.
[66]  Wang A, Wang M, Wang Q, Chen F, Zhang F, et al. (2011) Stable and efficient immobilization technique of aldolase under consecutive microwave irradiation at low temperature. Bioresour Technol 102: 469–474.
[67]  Faber K (2011) Biotransformations in Organic Chemistry: A Textbook 6th ed. Berlin: Springer: 9–10.
[68]  Ishige T, Honda K, Shimizu S (2005) Whole organism biocatalysis. Curr Opin Chem Biol 9: 174–180.
[69]  Fukuda H, Hama S, Tamalampudi S, Noda H (2008) Whole-cell biocatalysts for biodiesel fuel production. Trends Biotechnol 26: 668–673.
[70]  Wohlgemuth R (2009) The locks and keys to industrial biotechnology. New Biotechnol 25: 204–213.
[71]  Xiao Z, Lv C, Gao C, Qin J, Ma C, et al. (2010) A novel whole-cell biocatalyst with NAD+regeneration for production of chiral chemicals. PLoS ONE 5: e8860.
[72]  Yuryev R, Liese A (2010) Biocatalysis: the outcast. ChemCatChem 2: 103–107.
[73]  de Carvalho CCCR (2011) Enzymatic and whole cell catalysis: finding new strategies for old processes. Biotechnol Adv 29: 75–83.
[74]  Matsuyama A, Yamamoto H, Kobayashi Y (2002) Practical application of recombinant whole-cell biocatalysts for the manufacturing of pharmaceutical intermediates such as chiral alcohols. Org Process Res Dev 6: 558–561.
[75]  Gr?ger H, Rollmann C, Chamouleau F, Sebastien I, May O, et al. (2007) Enantioselective reduction of 4-fluoroacetophenone at high substrate concentration using a tailor-made recombinant whole-cell catalyst. Adv Synth Catal 349: 709–712.
[76]  Domínguez de María P, Stillger T, Pohl M, Kiesel M, Liese A, et al. (2008) Enantioselective C-C bond ligation using recombinant Escherichia coli-whole-cell biocatalysts. Adv Synth Catal 350: 165–173.
[77]  Ema T, Ide S, Okita N, Sakaia T (2008) Highly efficient chemoenzymatic synthesis of methyl (R)-O-chloromandelate, a key intermediate for clopidogrel, via asymmetric reduction with recombinant Escherichia coli. Adv Synth Catal 350: 2039–2044.
[78]  ?asar Z (2008) Straightforward and efficient synthesis of (4R,6S)-4-(tert-butyldimethylsiloxy)-6-(?hydroxymethyl)tetrahydropyran-2-one.Synlett: 2036–2040.
[79]  ?asar Z, Tram?ek M, Gor?ek A (2010) Calorimetric insight into coupling between functionalized primary alkyl halide and vinylic organocuprate reagent: experimental determination of reaction enthalpies in the synthesis of (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoa?te– a key lactonized statin side chain precursor. Acta Chim Slov 57: 66–76.
[80]  Troiani V, Cluzeau J, ?asar Z (2011) Application of chemoselective pancreatin powder-catalyzed deacetylation reaction in the synthesis of key statin side chain intermediate (4R,6S)-4-(tert-butyldimethylsilyloxy)-6?-(hydroxymethyl)tetrahydropyran-2-one. Org Process Res Dev 15: 622–630.
[81]  ?asar Z, Ko?mrlj J (2009) The first convenient entry to δ-formyl-δ-valerolactone precursor for the synthesis of statins via lactonized side chain. Synlett: 1144–1148.
[82]  Alcaide B, Almendros P (2008) Organocatalytic reactions with acetaldehyde. Angew Chem Int Ed 47: 4632–4634.
[83]  Udovi? M, Tram?ek M, Plantan I, Cluzeau J (2011) Synthesis of acetoxyacetaldehyde. (Lek Pharmaceuticals d.d.). PCT Int Appl WO 2011064249 A1 Chem Abstr (2011) 154: 617792.
[84]  Cluzeau J, ?asar Z, Mrak P, O?laj M, Kopitar G (2009) ((2S,4R)-4,6-Dihydroxytetrahydro-2H-pyra?n-2-yl)methylcarboxylate and process for the production thereof. (Lek Pharmaceuticals d.d.). PCT Int Appl WO 2009092702 A2 Chem Abstr (2009) 151: 218948.
[85]  DASGIP Technology (2002) DASGIP Application Note on High Density E. coli Fermentation. (DASGIP Information and Process Technology GmbH, an Eppendorf Company) Available: http://www.dasgip.com/media/content/page?s/downloads/Application_DASGIP_E.Coli_20?02.pdf Accesed 2012 November 15.
[86]  Shiloach J, Fass R (2005) Growing E. coli to high cell density–A historical perspective on method development Biotech Adv. 23: 345–357.
[87]  Shojaosadati SA, Kolaei SMV, Babaeipour V, Farnoud AM (2008) Recent advances in high cell density cultivation for production of recombinant protein. Iran J Biotech 6: 63–84.
[88]  Sharma A, Schulman SG (1999) Introduction to Fluorescence Spectroscopy. New York: Wiley Interscience. 174 p.
[89]  Craig EA, Eisenman HC, Hundley HA (2003) Ribosome-tethered molecular chaperones: the first line of defense against protein misfolding? Curr Opin Microbiol 6: 157–162.
[90]  Tyedmers J, Mogk A, Bukau B (2010) Cellular strategies for controlling protein aggregation. Nat. Rev. Mol. Cell Bio (11) 777–788.
[91]  Chiang SM, Schellhorn HE (2012) Regulators of oxidative stress response genes in Escherichia coli and their functional conservation in bacteria. Arch Biochem Biophys 525: 161–169.
[92]  Guisbert E, Yura T, Rhodius VA, Gross CA (2008) Convergence of molecular, modeling, and systems approaches for an understanding of the Escherichia coli heat shock response. Microbiol Mol Biol Rev 72: 545–554.
[93]  Gutsulyak DV, Nikonov GI (2012) Chemoselective Ruthenium-Catalyzed Reduction of Acid Chlorides to Aldehydes with Dimethylphenylsilane. Adv Synth Catal 354: 607–611.
[94]  Chuang C-Y, Vassar VC, Ma Z, Geney R, Ojima I (2002) Electronic effects on the regio- and enantioselectivity of the asymmetric aminohydroxylation of O-Substituted 4-hydroxy-2-butenoates. Chirality 14: 151–162.
[95]  Crestia D, Guerard C, Bolte J, Demuynck C (2001) Rabbit muscle aldolase (RAMA) as a catalyst in a new approach for the synthesis of 3-deoxy-D-manno-2-octulosonic acid and analogues. J Mol Cat B: Enz 11: 207–212.
[96]  Sakuraba H, Yoneda K, Yoshihara K, Satoh K, Kawakami R, et al. (2007) Sequential aldol condensation catalyzed by hyperthermophilic 2-deoxy-D-ribose-5-phosphate aldolase. Appl Environ Microbiol 73: 7427–7434.
[97]  Schmidt RR, Zimmermann P (1986) Synthesis of D-erythro-sphingosines. Tetrahedron Lett 27: 481–484.
[98]  Wild R, Schmidt RR (1994) Sphingosine and phytosphingosine from D-threose: Synthesis of a 4-keto-ceramide. Tetrahedron: Asymmetry 5: 2195–2208.
[99]  lamparuthi E, Ramesh E, Raghunathan R (2012) InCl3 as an efficient catalyst for cyclotrimerization of aldehydes. Synthesis of 1,3,5-trioxane under solvent-free conditions. Synth Commun 35: 2801–2804.
[100]  Park CP, Lee JH, Yoo KS, Jung KW (2010) Efficient Diacetoxylation of Alkenes via Pd(II)/Pd(IV) Process with Peracetic Acid and Acetic Anhydride. Org Lett 12: 2450–2452.
[101]  O’Connor CJ, Barton RH (1998) Acyl transfer isomerization of Glycerol 1,2-Dibutyrate and Propane-1,2-diol 1-Butyrate. Aust J Chem 51: 455–459.
[102]  Steinfeld JI, Francisco JS, Hase WL (1989) Chemical Kinetics and Dynamics. Englewood Cliffs: Prentice Hall. 548 p.
[103]  Pravdic N, Fletcher HG (1971) The oxidation of 2-acetamido-2-deoxyaldoses with aqueous bromine. Two diastereoisomeric 2-acetamido-2,3-dideoxyhex-2-enono-1,4-l?actonesfrom 2-acetamido-2-deoxy-D-glucose, -mannose, and -gallactose. Carbohydr Res 19: 339–352.
[104]  Lee T-J (1985) An expeditious chiral route to analogs of mevinolin and compactin. Tetrahedron Lett 26: 4995–4996.
[105]  Clive DLJ, Murthy KSK, Wee AGH, Prasad JS, da Silva GVJ, et al. (1988) Total synthesis of both (+)-compactin and (+)-mevinolin. A general strategy based on the use of a special TiCl3/C8K mixture for dicarbonyl coupling. J Am Chem Soc 110: 6914–6916.
[106]  Sharma M, Bernacki RJ, Paul B, Korytnyk W (1990) Fluorinated carbohydrates as potential plasma membrane modifiers. Synthesis of 4- and 6-fluoro derivatives of 2-acetamido-2-deoxy-D-hexopyranoses. Carbohydr Res 198: 205–221.
[107]  Rajagopal S, Vancheesan S, Rajaram J, Kuriacose JC (1992) RuCl2(PPh3)3-catalyzed transfer hydrogenation of D-glucose. J Mol Cat 75: 199–208.
[108]  Mori Y, Suzuki M (1990) Synthetic study on 1,3-polyols. An efficient enantioselective synthesis of tarchonanthuslactone. J Chem Soc Perkin Trans 1: 1809–1812.

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133