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Biocatalytic synthesis of optically active tertiary alcohols

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Abstract

The enzymatic preparation of optically pure tertiary alcohols under sustainable conditions has received much attention. The conventional chemical synthesis of these valuable building blocks is still hampered by the use of harmful reagents such as heavy metal catalysts. Successful examples in biocatalysis used esterases, lipases, epoxide hydrolases, halohydrin dehalogenases, thiamine diphosphate-dependent enzymes, terpene cyclases, -acetylases, and -dehydratases. This mini-review provides an overview on recent developments in the discovery of new enzymes, their functional improvement by protein engineering, the design of chemoenzymatic routes leading to tertiary alcohols, and the discovery of entirely new biotransformations.

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References

  • Agger SA, Lopez-Gallego F, Hoye TR, Schmidt-Dannert C (2008) Identification of sesquiterpene synthases from Nostoc punctiforme PCC 73102 and Nostoc sp. strain PCC 7120. J Bacteriol 190:6084–6096

    Article  CAS  Google Scholar 

  • Ajikumar PK, Xiao WH, Tyo KEJ, Wang Y, Simeon F, Leonard E, Mucha O, Phon TH, Pfeifer B, Stephanopoulos G (2010) Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli. Science 330:70–74

    Article  CAS  Google Scholar 

  • Andexer JN, Langermann JV, Kragl U, Pohl M (2009) How to overcome limitations in biotechnological processes—examples from hydroxynitrile lyase applications. Trends Biotechnol 27:599–607

    Article  CAS  Google Scholar 

  • Avi M, Fechter MH, Gruber K, Bela F, Pochlauer P, Griengl H (2004) Hydroxynitrile lyase catalysed synthesis of heterocyclic (R)- and (S)-cyanohydrins. Tetrahedron 60:10411–10418

    Article  CAS  Google Scholar 

  • Bartsch S, Kourist R, Bornscheuer UT (2008) Complete inversion of enantioselectivity towards acetylated tertiary alcohols by a double mutant of a Bacillus subtilis esterase. Angew Chem Int Ed 47:1508–1511

    Article  Google Scholar 

  • Bassegoda A, Nguyen GS, Schmidt M, Kourist R, Diaz P, Bornscheuer UT (2010) Rational protein design of Paenibacillus barcinonensis esterase EstA for kinetic resolution of tertiary alcohols. ChemCatChem 2:962–967

    Article  CAS  Google Scholar 

  • Bohlmann J, Meyer-Gauen G, Croteau R (1998) Plant terpenoid synthases: molecular biology and phylogenetic analysis. Proc Natl Acad Sci U S A 95:4126–4133

    Article  CAS  Google Scholar 

  • Bosley JA, Casey J, Macrae AR, MyCock G (1994) Process for the esterification of carboxylic acids with tertiary alcohols. WO 95/01450

  • Brodkorb D, Harder J (2009) First enzymatic insight in anaerobic monoterpenes degradation. Characterization of the first initial steps. Biotrans 2009. Conference proceedings

  • Brodkorb D, Gottschall M, Marmulla R, Luddeke F, Harder J (2010) Linalool dehydratase-isomerase, a bifunctional enzyme in the anaerobic degradation of monoterpenes. J Biol Chem 285:30436–30442

    Article  CAS  Google Scholar 

  • Cane DE, Watt RM (2003) Expression and mechanistic analysis of a germacradienol synthase from Streptomyces coelicolor implicated in geosmin biosynthesis. Proc Natl Acad Sci U S A 100:1547–1551

    Article  CAS  Google Scholar 

  • Choi WJ (2009) Biotechnological production of enantiopure epoxides by enzymatic kinetic resolution. Appl Microbiol Biotechnol 84:239–247

    Article  CAS  Google Scholar 

  • Christoffers J, Baro A (2005) Quaternary stereocenters, challenges and solutions for organic synthesis. Wiley-VCH, Weinheim

    Book  Google Scholar 

  • Chipman D, Barak Z, Schloss JV (1998) Biosynthesis of 2-aceto-2-hydroxy acids: acetolactate synthases and acetohydroxyacid synthases. Biochim Biophys Act 1385:401–419

    Google Scholar 

  • Cozzi PG, Hilgraf R, Zimmermann N (2007) Enantioselective catalytic formation of quaternary stereogenic centers. Eur J Org Chem 2007(36):5969–5994

    Article  Google Scholar 

  • Crowell AL, Williams DC, Davis EM, Wildung MR, Croteau R (2002) Molecular cloning and characterization of a new linalool synthase. Arch Biochem Biophys 405:112–121

    Article  CAS  Google Scholar 

  • Degenhardt J, Kollner TG, Gershenzon J (2009) Monoterpene and sesquiterpene synthases and the origin of terpene skeletal diversity in plants. Phytochemistry 70:1621–1637

    Article  CAS  Google Scholar 

  • Dominguez de Maria P, Carboni-Oerlemans C, Tuin B, Bargeman G, van der Meer A, van Gemert R (2005) Biotechnological applications of Candida antarctica lipase A: state-of-the-art. J Mol Catal B Enzym 37:36–46

    Article  CAS  Google Scholar 

  • Enders D, Balensiefer T, Niemeier O, Christmann M (2007) Enantioselective organocatalysis. Wiley-VCH, Weinheim

    Google Scholar 

  • Ericsson DJ, Kasrayan A, Johanssonl P, Bergfors T, Sandström AG, Bäckvall JE, Mowbray SL (2008) X-ray structure of Candida antarctica lipase A shows a novel lid structure and a likely mode of interfacial activation. J Mol Biol 376:109–119

    Article  CAS  Google Scholar 

  • Fechter MH, Gruber K, Avi M, Skranc W, Schuster C, Pochlauer P, Klepp KO, Griengl H (2007) Stereoselective biocatalytic synthesis of (S)-2-hydroxy-2-methylbutyric acid via substrate engineering by using “thio-disguised” precursors and oxynitrilase catalysis. Chem Eur J 13:3369–3376

    Article  CAS  Google Scholar 

  • Gall M, Kourist R, Schmidt M, Bornscheuer UT (2010) The role of the GGGX motif in determining the activity and enantioselectivity of pig liver esterase towards tertiary alcohols. Biocatal Biotransform 28:201–208

    Article  CAS  Google Scholar 

  • Hasegawa Y, Gridnev ID, Ikariya T (2010) Enantioselective and Z/E-selective conjugate addition of alpha-substituted cyanoacetates to acetylenic esters catalyzed by bifunctional ruthenium and iridium complexes. Angew Chem Int Ed 49:8157–8160

    Article  CAS  Google Scholar 

  • Heinze B, Kourist R, Fransson L, Hult K, Bornscheuer UT (2007) Highly enantioselective kinetic resolution of a tertiary alcohol using mutants of an esterase from Bacillus subtilis. Prot Eng Des Sel 20:125–131

    Article  CAS  Google Scholar 

  • Hellström H, Steinreiber A, Mayer SF, Faber K (2001) Bacterial epoxide hydrolase-catalyzed resolution of a 2,2-disubstituted oxirane: optimization and upscaling. Biotechnol Lett 23:169–173

    Article  Google Scholar 

  • Henke E, Pleiss J, Bornscheuer UT (2002) Activity of lipases and esterases towards tertiary alcohols: insights into structure-function relationships. Angew Chem Int Ed 41:3211–3213

    Article  CAS  Google Scholar 

  • Henke E, Bornscheuer UT, Schmid RD, Pleiss J (2003) A molecular mechanism of enantiorecognition of tertiary alcohols by carboxylesterases. Chembiochem 4:485–493

    Article  CAS  Google Scholar 

  • Herter S, Nguyen GS, Thompson ML, Steffen-Munsberg F, Schauer F, Bornscheuer UT, Kourist R (2011) Comparative analysis of tertiary alcohol esterase activity in bacterial strains isolated from enrichment cultures and from screening strain libraries. Appl Microbiol Biotechnol 90:929–939

    Article  CAS  Google Scholar 

  • Hiseni A, Arends IW, Otten LG (2011) Biochemical characterization of the carotenoid 1,2-hydratases (CrtC) from Rubrivivax gelatinosus and Thiocapsa roseopersicina. Appl Microbiol Biotechnol. doi:10.1007/s00253-011-3324-1

  • Holt J, Hanefeld U (2009) Enantioselective enzyme-catalysed synthesis of cynohydrins. Curr Org Synth 6:15–37

    Article  CAS  Google Scholar 

  • Holt J, Arends IWCE, Minnaard A, Hanefeld U (2007) Hydrolase-catalysed preparation of chiral alpha, alpha-disubstituted cyanohydrin acetates. Adv Synth Catal 349:1341–1344

    Article  CAS  Google Scholar 

  • Hotta Y, Ezaki S, Atomi H, Imanaka T (2002) Extremely stable and versatile carboxylesterase from a hyperthermophilic archaeon. Appl Environ Microbiol 68:3925–3931

    Article  CAS  Google Scholar 

  • Hou CT, Adachi S (2005) Handbook of industrial biocatalysis. CRC Taylor & Francis, Boca Raton

    Book  Google Scholar 

  • Komatsu M, Tsuda M, Omura S, Oikawa H, Ikeda H (2008) Identification and functional analysis of genes controlling biosynthesis of 2-methylisoborneol. Proc Natl Acad Sci U S A 105:7422–7427

    Article  CAS  Google Scholar 

  • Kourist R, Bartsch S, Bornscheuer UT (2007a) Highly enantioselective synthesis of arylaliphatic tertiary alcohols using mutants of an esterase from Bacillus subtilis. Adv Synth Catal 349:1393–1398

    Article  CAS  Google Scholar 

  • Kourist R, Krishna SH, Patel JS, Bartnek F, Hitchman TS, Weiner DP, Bornscheuer UT (2007b) Identification of a metagenome-derived esterase with high enantioselectivity in the kinetic resolution of arylaliphatic tertiary alcohols. Org Biomol Chem 5:3310–3313

    Article  CAS  Google Scholar 

  • Kourist R, Dominguez de Maria P, Bornscheuer UT (2008a) Enzymatic synthesis of optically active tertiary alcohols: expanding the biocatalysis toolbox. Chembiochem 9:491–498

    Article  CAS  Google Scholar 

  • Kourist R, Nguyen GS, Strübing D, Böttcher D, Liebeton K, Naumer C, Eck J, Bornscheuer UT (2008b) Hydrolase-catalyzed stereoselective preparation of protected alpha, alpha-dialkyl-alpha-hydroxycarboxylic acids. Tetrahedron Asymmetry 19:1839–1843

    Article  CAS  Google Scholar 

  • Kourist R, Jochens H, Bartsch S, Kuipers R, Kumar Padhi S, Gall M, Böttcher D, Joosten H-J, Bornscheuer UT (2010a) The alpha/beta-hydrolase fold 3DM database (ABHDB) as a tool for protein engineering. Chembiochem 11:1635–1643

    Article  CAS  Google Scholar 

  • Kourist R, Brundiek H, Bornscheuer UT (2010b) Protein engineering and discovery of lipases. Eur J Lipid Sci Technol 112:64–74

    Article  CAS  Google Scholar 

  • Krishna SH, Persson M, Bornscheuer UT (2002) Enantioselective transesterification of a tertiary alcohol by lipase A from Candida antarctica. Tetrahedron Asymmetry 13:2693–2696

    Article  Google Scholar 

  • Landmann C, Fink B, Festner M, Dregus M, Engel KH, Schwab W (2007) Cloning and functional characterization of three terpene synthases from lavender (Lavandula angustifolia). Arch Biochem Biophys 465:417–429

    Article  CAS  Google Scholar 

  • Larkov O, Zaks A, Bar E, Lewinsohn E, Dudai N, Mayer AM, Ravid U (2008) Enantioselective monoterpene alcohol acetylation in Origanum, Mentha and Salvia species. Phytochemistry 69:2565–2571

    Article  CAS  Google Scholar 

  • Lehwald P, Richter M, Rohr C, Liu HW, Müller M (2010) Enantioselective intermolecular aldehyde-ketone cross-coupling through an enzymatic carboligation reaction. Ang Chem Int Ed 49:2389–2392

    CAS  Google Scholar 

  • Lutz S, Bornscheuer UT (eds) (2008) Protein engineering handbook. Wiley-VCH, Weinheim

    Google Scholar 

  • Majeric-Elenkov M, Hoeffken HW, Tang L, Hauer B, Janssen DB (2007) Enzyme-catalyzed nucleophilic ring opening of epoxides for the preparation of enantiopure tertiary alcohols. Adv Synth Catal 349:2279–2285

    Article  Google Scholar 

  • Majeric-Elenkov M, Tang LX, Meetsma A, Hauer B, Janssen DB (2008) Formation of enantiopure 5-substituted oxazolidinones through enzyme-catalysed kinetic resolution of epoxides. Org Lett 10:2417–2420

    Article  Google Scholar 

  • Mihovilovic MD, Leisch HG, Mereiter K (2004) Microwave-mediated intramolecular Diels–Alder cyclization of biodihydroxylated benzoic acid derivatives. Tetrahedron Lett 45:7087–7090

    Article  CAS  Google Scholar 

  • Molinaro C, Guilbault AA, Kosjek B (2010) Resolution of 2,2-disubstituted epoxides via biocatalytic azidolysis. Org Lett 12:3772–3775

    Article  CAS  Google Scholar 

  • Nguyen GS, Kourist R, Paravidino M, Hummel A, Rehdorf J, Orru RVA, Hanefeld U, Bornscheuer UT (2010) An enzymatic toolbox for the kinetic resolution of 2-(pyridinyl)but-3-yn-2-ols and tertiary cyanohydrins. Eur J Org Chem 14:2753–2758

    Google Scholar 

  • O'Hagan D, Zaidi NA (1992) Hydrolytic resolution of tertiary acetylenic acetate esters with the lipase from Candida cylindracea. J Chem Soc Perkin Trans 1:947–949

    Article  Google Scholar 

  • Özdemirhan D, Sezer S, Sonmez Y (2008) Enzyme-catalyzed resolution of aromatic ring fused cyclic tertiary alcohols. Tetrahedron Asymmetry 19:2717–2720

    Article  Google Scholar 

  • Paravidino M, Holt J, Romano D, Singh N, Arends I, Minnaard AJ, Orru RVA, Molinari F, Hanefeld U (2010) Microbial-catalysed resolution of sterically demanding cyanohydrins. J Mol Catal B Enzym 63:87–92

    Article  CAS  Google Scholar 

  • Pleiss J, Fischer M, Peiker M, Thiele C, Schmid RD (2000) Lipase engineering database—understanding and exploiting sequence-structure-function relationships. J Mol Catal B Enzym 10:491–508

    Article  CAS  Google Scholar 

  • Pogorevc M, Faber K (2000) Biocatalytic resolution of sterically hindered alcohols, carboxylic acids and esters containing fully substituted chiral centers by hydrolytic enzymes. J Mol Catal B Enzym 10:357–376

    Article  CAS  Google Scholar 

  • Purkarthofer T, Skranc W, Schuster C, Griengl H (2007) Potential and capabilities of hydroxynitrile lyases as biocatalysts in the chemical industry. Appl Microbiol Biotechnol 76:309–320

    Article  CAS  Google Scholar 

  • Rashamuse K, Magomani V, Ronneburg T, Brady D (2009) A novel family VIII carboxylesterase derived from a leachate metagenome library exhibits promiscuous beta-lactamase activity on nitrocefin. Appl Microbiol Biotechnol 83:491–500

    Article  CAS  Google Scholar 

  • Seebach D (2011) Generation of secondary, tertiary, and quaternary centers by geminal disubstitution of carbonyl oxygens. Angew Chem Int Ed 50:96–101

    Article  CAS  Google Scholar 

  • Sonawane RP, Jheengut V, Rabalakos C, Larouche-Gauthier R, Scott HK, Aggarwal VK (2011) Enantioselective construction of quaternary stereogenic centers from tertiary boronic esters: methodology and applications. Angew Chem Int Ed 50:3760–3763

    Article  CAS  Google Scholar 

  • Steinreiber A, Faber K (2001) Microbial epoxide hydrolases for preparative biotransformations. Curr Opin Biotechnol 12:552–558

    Article  CAS  Google Scholar 

  • Stymiest JL, Bagutski V, French RM, Aggarwal VK (2008) Enantiodivergent conversion of chiral secondary alcohols into tertiary alcohols. Nature 456:778–783

    Article  CAS  Google Scholar 

  • Wiggers M, Holt J, Kourist R, Bartsch S, Arends I, Minnaard AJ, Bornscheuer UT, Hanefeld U (2009) Probing the enantioselectivity of Bacillus subtilis esterase BS2 for tert. alcohols. J Mol Catal B Enzym 60:82–86

    Article  CAS  Google Scholar 

  • Yoshikuni Y, Martin VJ, Ferrin TE, Keasling JD (2006) Engineering cotton (+)-delta-cadinene synthase to an altered function: germacrene D-4-ol synthase. Chem Biol 13:91–98

    Article  CAS  Google Scholar 

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Acknowledgments

RK is grateful to the “Fonds der Chemischen Industrie” (Frankfurt, Germany) for the financial support.

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Correspondence to Uwe T. Bornscheuer.

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Kourist, R., Bornscheuer, U.T. Biocatalytic synthesis of optically active tertiary alcohols. Appl Microbiol Biotechnol 91, 505–517 (2011). https://doi.org/10.1007/s00253-011-3418-9

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