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d-Aminoacylase-initiated cascade Aldol condensation/Robinson annulation for synthesis of substituted cyclohex-2-enones from simple aldehydes and acetone

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Abstract

As an important building block, developing efficient and green synthesis strategy of cyclohex-2-enones is of great importance. In this present work, a general approach to the mild synthesis of substituted cyclohex-2-enones derivatives starting fro m simple aldehydes and acetone have been achieved via d-aminoacylase-initiated Aldol condensation/Robinson annulation cascade reaction using imidazole as an additive in organic media. The influences of reaction conditions including solvents, enzyme concentration, additives type, molar ratio of enzyme to additive, and substrate scopes were systematically investigated. Furthermore, some experiments were designed to explore the catalytic roles of d-aminoacylase and imidazole in the multistep cascade process, and one possible mechanism was proposed.

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References

  • Aleu J, Bustillo AJ, Hernandez-Galan R, Collado IG (2006) Biocatalysis applied to the synthesis of agrochemicals. Cur Org Chem 10(16):2037–2054

    Article  CAS  Google Scholar 

  • Authority EFS (2011) Scientific opinion on flavouring group evaluation 212: α,β-unsaturated alicyclic ketones and precursors from chemical subgroup 2.6 of FGE. 19. EFSA J 9(3):1923

    Google Scholar 

  • Baas BJ, Zandvoort E, Geertsema EM, Poelarends GJ (2013) Recent advances in the study of enzyme promiscuity in the tautomerase superfamily. Chem Biol Chem 14(8):917–926

    Article  CAS  Google Scholar 

  • Busto E, Gotor-Fernandez V, Gotor V (2010) Hydrolases: catalytically promiscuous enzymes for non-conventional reactions in organic synthesis. Chem Soc Rev 39(11):4504–4523

    Article  CAS  PubMed  Google Scholar 

  • Cai JF, Guan Z, He YH (2011) The lipase-catalyzed asymmetric C–C Michael addition. J Mol Catal B Enzym 68(3–4):240–244

    Article  CAS  Google Scholar 

  • Carlqvist P, Svedendahl M, Branneby C, Hult K, Brinck T, Berglund P (2005) Exploring the active-site of a rationally redesigned lipase for catalysis of Michael-type additions. Chem Biol Chem 6(2):331–336

    Article  CAS  Google Scholar 

  • Chai SJ, Lai YF, Xu JC, Zheng H, Zhu Q, Zhang P (2011) One-pot synthesis of spirooxindole derivatives catalyzed by lipase in the presence of water. Adv Synth Catal 353(2–3):371–375

    Article  CAS  Google Scholar 

  • Chen X, Liu BK, Kang H, Lin XF (2011) A tandem Aldol condensation/dehydration co-catalyzed by acylase and N-heterocyclic compounds in organic media. J Mol Catal B Enzym 68(1):71–76

    Article  CAS  Google Scholar 

  • Dhake KP, Tambade PJ, Singhal RS, Bhanage BM (2010) Promiscuous candida antarctica lipase B-catalyzed synthesis of β-amino esters via aza-Michael addition of amines to acrylates. Tetrahedron Lett 51(33):4455–4458

    Article  CAS  Google Scholar 

  • Feng XW, Li C, Wang N, Li K, Zhang WW, Wang Z, Yu XQ (2009) Lipase-catalysed decarboxylative aldol reaction and decarboxylative Knoevenagel reaction. Green Chem 11(12):1933–1936

    Article  CAS  Google Scholar 

  • Guan Z, Fu JP, He YH (2012) Biocatalytic promiscuity: lipase-catalyzed asymmetric aldol reaction of heterocyclic ketones with aldehydes. Tetrahedron Lett 53(37):4959–4961

    Article  CAS  Google Scholar 

  • He YH, Li HH, Chen YL, Xue Y, Yuan Y, Guan Z (2012) Chymopapain-catalyzed direct asymmetric Aldol reaction. Adv Synth Catal 354(4):712–719

    Article  CAS  Google Scholar 

  • Horning EC, Field RE (1946) Preparation of 3-methyl-5-aryl-2-cyclohexen-1-ones. J Am Chem Soc 68(3):384–387

    Article  CAS  Google Scholar 

  • Horning EC, Denekas MO, Field RE (1944) The preparation of 4-carbethoxy-3-methyl-5-alkyl-2-cyclohexen-1-ones and 3-methyl-5-alkyl-2-cyclohexen-1-ones. J Org Chem 9(6):547–551

    Article  CAS  Google Scholar 

  • Kazlauskas RJ (2005) Enhancing catalytic promiscuity for biocatalysis. Curr Opin Chem Biol 9(2):195–201

    Article  CAS  PubMed  Google Scholar 

  • Khersonsky O, Tawfik DS (2010) Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biophys Biomol 79:471–505

    CAS  Google Scholar 

  • Kitazume T, Ikeya T, Murata K (1986) Synthesis of optically active trifluorinated compounds: asymmetric Michael addition with hydrolytic enzymes. J Chem Soc Chem Comm 17:1331–1333

    Article  Google Scholar 

  • Li K, He T, Li C, Feng XW, Wang N, Yu XQ (2009) Lipase-catalysed direct Mannich reaction in water: utilization of biocatalytic promiscuity for C–C bond formation in a “one-pot” synthesis. Green Chem 11(6):777–779

    Article  CAS  Google Scholar 

  • Lin XF, Xu JM, Zhang F, Liu BK, Wu Q (2007) Promiscuous zinc-dependent acylase-mediated carbon–carbon bond formation in organic media. Chem Commun 20:2078–2080

    Google Scholar 

  • Lin XF, Wu Q, Xu JM, Li X, Wang JL (2009) Promiscuous zinc-dependent acylase-mediated one-pot synthesis of monosaccharide-containing pyrimidine derivatives in organic medium. Adv Synth Catal 351(11–12):1833–1841

    Google Scholar 

  • Liu ZQ, Xiang ZW, Wu Q, Lin XF (2013) Unexpected three-component domino synthesis of pyridin-2-ones catalyzed by promiscuous acylase in non-aqueous solvent. Biochimie 95(7):1462–1465

    Article  CAS  PubMed  Google Scholar 

  • Lou FW, Liu BK, Wu Q, Lv DS, Lin XF (2008) Candida antarctica lipase B (CAL-B)-catalyzed carbon-sulfur bond addition and controllable selectivity in organic media. Adv Synth Catal 350(13):1959–1962

    Article  CAS  Google Scholar 

  • Martínez R, Mendoza HM, Angeles E (1998) 5-Aryl-3-methyl-2-cyclohexen-1-ones from 4-aryl-1, 4-dihydropyridines (Hantzsch esters). Synth Commun 28(15):2813–2820

    Article  Google Scholar 

  • Mori K, Tamada S, Uchida M, Mizumachi N, Tachibana Y, Matsui M (1978) Synthesis of optically active forms of seudenol, the pheromone of douglas fir beetle. Tetrahedron 34(13):1901–1905

    Article  CAS  Google Scholar 

  • Nakayachi T, Yasumoto E, Nakano K, Morshed S, Hashimoto K, Kikuchi H, Nishikawa H, Kawase M, Sakagami H (2004) Structure-activity relationships of α,β-unsaturated ketones as assessed by their cytotoxicity against oral tumor cells. Anticancer Res 24(2B):737–742

    CAS  PubMed  Google Scholar 

  • Plummer EL, Stewart TE, Byrne K, Pearce GT, Silverstein RM (1976) Determination of the enantiomeric composition of several insect pheromone alcohols. J Chem Ecol 2(3):307–331

    Article  CAS  Google Scholar 

  • Pollard DJ, Woodley JM (2007) Biocatalysis for pharmaceutical intermediates: the future is now. Trends Biotechnol 25(2):66–73

    Article  CAS  PubMed  Google Scholar 

  • Pollini GP, Benetti S, De Risi C, Zanirato V (2010) Hagemann’s ester: a timeless building block for natural product synthesis. Tetrahedron 66(15):2775–2802

    Article  CAS  Google Scholar 

  • Renard G, Lerner DA (2007) First simple and mild synthesis of 2-alkylbenzimidazoles involving a supported enzymatic catalyst. New J Chem 31(8):1417–1420

    Article  CAS  Google Scholar 

  • Ross DW, Gibson KE, Thier RW, Munson AS (1996) Optimal dose of an antiaggregation pheromone (3-methylcyclohex-2-en-1-one) for protecting live douglas-fir from attack by dendroctonus pseudotsugae (Coleoptera: Scolytidae). J Econ Entomol 89(5):1204–1207

    CAS  Google Scholar 

  • Schmid A, Dordick JS, Hauer B, Kiener A, Wubbolts M, Witholt B (2001) Industrial biocatalysis today and tomorrow. Nature 409(6817):258–268

    Article  CAS  PubMed  Google Scholar 

  • Smith WT, Eftax DSP (1956) Analogs of “piperonyl cyclonene”. J Org Chem 21(2):174–176

    CAS  Google Scholar 

  • Svedendahl M, Hult K, Berglund P (2005) Fast carbon–carbon bond formation by a promiscuous lipase. J Am Chem Soc 127(51):17988–17989

    Article  CAS  PubMed  Google Scholar 

  • Torre O, Alfonso I, Gotor V (2004) Lipase catalysed Michael addition of secondary amines to acrylonitrile. Chem Commun 15:1724–1725

    Article  Google Scholar 

  • Vité JP, Pitman GB, Fentiman AF Jr, Kinzer GW (1972) 3-Methyl-2-cyclohexen-1-ol isolated from dendroctonus. Naturwissenschaften 59(10):469

    PubMed  Google Scholar 

  • Wang JL, Xu JM, Wu Q, Lv DS, Lin XF (2009) Promiscuous enzyme-catalyzed regioselective Michael addition of purine derivatives to α,β-unsaturated carbonyl compounds in organic solvent. Tetrahedron 65(12):2531–2536

    Article  CAS  Google Scholar 

  • Wang L, Li C, Wang N, Li K, Chen X, Yu XQ (2010) Enzyme-mediated domino synthesis of 2-alkylbenzimidazoles in solvent-free system: a green route to heterocyclic compound. J Mol Catal B Enzym 67(1–2):16–20

    Article  CAS  Google Scholar 

  • Wang JL, Liu BK, Yin C, Wu Q, Lin XF (2011a) Candida antarctica lipase B-catalyzed the unprecedented three-component Hantzsch-type reaction of aldehyde with acetamide and 1,3-dicarbonyl compounds in non-aqueous solvent. Tetrahedron 67(14):2689–2692

    Article  CAS  Google Scholar 

  • Wang L, Gong QP, Liu XJ, Li YH, Huang P, Wang BQ, Zhao KQ (2011b) Organocatalyst-mediated Aldol-robinson cascade reactions: a convenient synthesis of substituted cyclohex-2-enones. Chem Lett 40(2):138–139

    Google Scholar 

  • Wu WB, Wang N, Xu JM, Wu Q, Lin XF (2005) Penicillin G acylase catalyzed Markovnikov addition of allopurinol to vinyl ester. Chem Commun 18:2348–2350

    Article  Google Scholar 

  • Wu WB, Xu JM, Wu Q, Lv DH, Lin XF (2006) Promiscuous acylases-catalyzed markovnikov addition of N-heterocycles to vinyl esters in organic media. Adv Synth Catal 348(4–5):487–492

    Article  CAS  Google Scholar 

  • Wu Q, Liu BK, Lin XF (2010) Enzymatic promiscuity for organic synthesis and cascade process. Curr Org Chem 14(17):1966–1988

    Article  CAS  Google Scholar 

  • Wu MY, Li K, He T, Feng XW, Wang N, Wang XY, Yu XQ (2011) A novel enzymatic tandem process: utilization of biocatalytic promiscuity for high stereoselective synthesis of 5-hydroxyimino-4,5-dihydrofurans. Tetrahedron 67(14):2681–2688

    Article  CAS  Google Scholar 

  • Xiang ZW, Liu ZQ, Liang YR, Wu Q, Lin XF (2013) l-Lysine/imidazole-catalyzed multicomponent cascade reaction: facile synthesis of C5-substituted 3-methylcyclohex-2-enones. Chin J Chem 31(8):997–1002

    Article  CAS  Google Scholar 

  • Xu JM, Zhang F, Liu BK, Wu Q, Lin XF (2007) Promiscuous zinc-dependent acylase-mediated carbon–carbon bond formation in organic media. Chem Commun 20:2078–2080

    Article  Google Scholar 

  • Zhou J, Wakchaure V, Kraft P, List B (2008) Primary-amine-catalyzed enantioselective intramolecular aldolizations. Angew Chem Int Ed 47(40):7656–7658

    Article  CAS  Google Scholar 

  • Zhou LH, Wang N, Zhang W, Xie ZB, Yu XQ (2013) Catalytical promiscuity of α-amylase: synthesis of 3-substituted 2H-chromene derivatives via biocatalytic domino oxa-Michael/aldol condensations. J Mol Catal B Enzym 91:37–43

    Article  CAS  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the financial support from National Natural Science Foundation of China (No. 21072172, 21272208).

Conflict of interest

We declare that we have no competing financial interests.

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Authors and Affiliations

  1. Department of Chemistry, Zhejiang University, 310027, Hangzhou, People’s Republic of China

    Ziwei Xiang, Yiru Liang, Xiang Chen, Qi Wu & Xianfu Lin

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  1. Ziwei Xiang
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  2. Yiru Liang
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  3. Xiang Chen
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  4. Qi Wu
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  5. Xianfu Lin
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Correspondence to Qi Wu or Xianfu Lin.

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Xiang, Z., Liang, Y., Chen, X. et al. d-Aminoacylase-initiated cascade Aldol condensation/Robinson annulation for synthesis of substituted cyclohex-2-enones from simple aldehydes and acetone. Amino Acids 46, 1929–1937 (2014). https://doi.org/10.1007/s00726-014-1747-6

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