Synthesis 2021; 53(20): 3725-3734
DOI: 10.1055/a-1509-5655

Aldol–Tishchenko Reaction of α-Oxy Ketones: Diastereoselective Synthesis of 1,2,3-Triol Derivatives

Carlos Sedano
Cintia Virumbrales
Samuel Suárez-Pantiga
Roberto Sanz
This work was supported by the Ministerio de Ciencia e Innovación (CTQ2016-75023-C2-1-P), and Consejería de Educación, Junta de Castilla y León and FEDER (BU291P18, BU049P20). The project leading to these results has also received funding from the “la Caixa” Foundation, under agreement LCF/PR/PR18/51130007 (CAIXA-UBU001). Postdoctoral contracts (S.S.-P. and C.V.) and a predoctoral contract (C.S.) were funded by Consejería de Educación, Junta de Castilla y León and FEDER, and Ministerio de Educación (FPU), respectively.

To the memory of Prof. Dr. V. Snieckus


α-Oxy ketones, easily accessible by conventional routes, can be selectively deprotonated generating an enolate intermediate, which upon treatment with paraformaldehyde undergoes an aldol–Tishchenko reaction, leading to relevant 1,2,3-triol fragments in a totally diastereoselective manner. The excellent stereocontrol in the generation of a quaternary stereocenter is attributed to stereoelectronic effects in the Evans intermediate. This methodology allows overcoming some limitations of our previously reported strategy, based on the reaction of α-lithiobenzyl ethers with esters and paraformaldehyde, broadening the scope of the obtained polyols. Synthetic applications of this process include the preparation of a new dilignol model and some functionalized oxetanes.

Supporting Information

Publication History

Received: 15 April 2021

Accepted after revision: 17 May 2021

Publication Date:
17 May 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Perna FM, Salomone A, Capriati V. In Lithium Compounds in Organic Synthesis: From Fundamentals to Applications, Chap. 6 . Luisi R, Capriati V. Wiley-VCH; Weinheim: 2014: 153-189

    • For the carbenoid nature of α-functionalized organolithiums, see:
    • 2a Capriati V, Florio S. Chem. Eur. J. 2010; 16: 4152
    • 2b Pace V, Castoldi L, Monticelli S, Rui M, Collina S. Synlett 2017; 28: 879
    • 2c Castoldi L, Monticelli S, Senatore R, Ielo L, Pace V. Chem. Commun. 2018; 54: 6692
    • 2d Ielo L, Pillari V, Miele M, Castiglione D, Pace V. Synlett 2021; 32: 551

    • For a selected recent report, see:
    • 2e Cocco A, Rubanu MG, Sechi ML, Frongia A, Mastrorilli P, Degennaro L, Colella M, Luisi R, Secci F. Org. Biomol. Chem. 2021; 19: 1945
  • 3 For a recent review, see: Wang F, Wang J, Zhang Y, Yang J. Tetrahedron 2020; 76: 130857

    • For our previous work with oxygen-functionalized organolithiums, see:
    • 4a Barluenga J, Fañanás FJ, Sanz R, Marcos C, Trabada M. Org. Lett. 2002; 4: 1587
    • 4b Barluenga J, Fañanás FJ, Sanz R, Marcos C. Org. Lett. 2002; 4: 2225
    • 4c Sanz R, Miguel D, Martínez A, Pérez A. J. Org. Chem. 2006; 71: 4024

    • For other reports, see, for instance:
    • 4d Dammacco M, Degennaro L, Florio S, Luisi R, Musio B, Altomare A. J. Org. Chem. 2009; 74: 6319
    • 5a Velasco R, Feberero C, Sanz R. Org. Lett. 2015; 17: 4416
    • 5b Sedano C, Velasco R, Suárez-Pantiga S, Sanz R. Org. Lett. 2020; 22: 6365

      Lithiation of benzyl methyl ether:
    • 6a Azzena U, Demartis S, Fiori MG, Pisano L. Tetrahedron Lett. 1995; 36: 5641

    • Lithiation of benzyl methoxymethyl ether:
    • 6b Azzena U, Pisano L, Mocci S. J. Organomet. Chem. 2009; 694: 3619
  • 7 Velasco R, Silva-López C, Nieto-Faza O, Sanz R. Chem. Eur. J. 2016; 22: 15058
  • 8 Sedano C, Velasco R, Suárez-Pantiga S, Sanz R. Org. Lett. 2020; 22: 8070
    • 9a Mahrwald R. Curr. Org. Chem. 2003; 7: 1713
    • 9b Mlynarski J. Eur. J. Org. Chem. 2006; 4779
    • 9c Koskinen AM. P, Kataja AO. Org. React. 2015; 86: 105

      See, for instance:
    • 10a Baramee A, Chaichit N, Intawee P, Thebtaranonth C, Thebtaranonth Y. J. Chem. Soc., Chem. Commun. 1991; 1016
    • 10b Bodnar PM, Shaw JT, Woerpel KA. J. Org. Chem. 1997; 62: 5674
    • 10c Mascarenhas CM, Duffey MO, Liu S.-Y, Morken JP. Org. Lett. 1999; 1: 1427

    • For examples of the enantioselective aldol–Tishchenko reaction, see:
    • 10d Gnanadesikan V, Horiuchi Y, Ohshima T, Shibasaki M. J. Am. Chem. Soc. 2004; 126: 7782
    • 10e Horiuchi Y, Gnanadesikan V, Ohshima T, Masu H, Katagiri K, Sei Y, Yamaguchi K, Shibasaki M. Chem. Eur. J. 2005; 11: 5195
    • 10f Mlynarski J, Rakiel B, Stodulski M, Suszczyńska A, Frelek J. Chem. Eur. J. 2006; 12: 8158
    • 10g Stodulski M, Mamiska A, Mlynarski J. Tetrahedron: Asymmetry 2011; 22: 464
    • 10h Ichibakase T, Nakajima M. Org. Lett. 2011; 13: 1579
    • 11a Ichibakase T, Kaneko T, Orito Y, Kotani S, Nakajima M. Tetrahedron 2012; 68: 4210

    • For the enantioselective aldol–Tishchenko reaction of cyclic α-fluoro ketones, see:
    • 11b Asano T, Kotani S, Nakajima M. Org. Lett. 2019; 21: 4192
    • 12a Li W, Xu X.-F. Adv. Synth. Catal. 2015; 357: 3393
    • 12b Liu C, Huang W, Zhang J, Rao Z, Gu Y, Jérôme F. Green Chem. 2021; 23: 1447

      See, for instance:
    • 13a Mohapatra DK, Mondal D, Gonnade RG, Chorghade MS, Gurjar MK. Tetrahedron Lett. 2006; 47: 6031
    • 13b Reddy PS, Sharma GV. M. Synthesis 2014; 46: 1532

      See, for instance:
    • 14a Ouchi T, Arita Y, Imoto M. Polym. J. 1976; 8: 477
    • 14b Ishikawa S, Hamada T, Manabe K, Kobayashi S. J. Am. Chem. Soc. 2004; 126: 12236
    • 14c Liu C, Shen M, Lai B, Taheri A, Gu Y. ACS Comb. Sci. 2014; 16: 652
  • 15 See the Supporting Information for details.
  • 16 Schäfer H, Schöllkopf U, Walter D. Tetrahedron Lett. 1968; 6759 ; see also ref. 6a
  • 17 The reaction of 2-ethoxyheptan-3-one (SM11) under the established conditions only afforded unidentified products; see the Supporting Information for details.
  • 18 For a related dilignol compound, see: Rinesch T, Mottweiler J, Puche M, Concepción P, Corma A, Bolm C. ACS Sustainable Chem. Eng. 2017; 5: 9818

    • For the preparation of dilignol β-O-4 type model compounds, see:
    • 19a Buendia J, Mottweiler J, Bolm C. Chem. Eur. J. 2011; 17: 13877
    • 19b Dias RM. P, de Oliveira GP, Burtoloso CB. Org. Biomol. Chem. 2020; 18: 4815
    • 20a Kärkäs MD, Matsuura BS, Monos TM, Magallanes G, Stephenson CR. J. Org. Biomol. Chem. 2016; 14: 1853
    • 20b Gillet S, Aguedo M, Petitjean L, Morais AR. C, da Costa Lopes AM, Lukasik RM, Anastas PT. Green Chem. 2017; 19: 4200
    • 20c Das A, König B. Green Chem. 2018; 20: 4844
    • 21a Burkhard JA, Wuitschik G, Roger-Evans M, Müller K, Carreira EM. Angew. Chem. Int. Ed. 2010; 49: 9052
    • 21b Carreira EM, Fessard TC. Chem. Rev. 2014; 114: 8257
    • 21c Bull JA, Croft RA, Davis OA, Doran R, Morgan KF. Chem. Rev. 2016; 116: 12150