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Reductive Amination Without the Aldehyde: Use of a Ketolactol as an Aldehyde Surrogate

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Abstract

To overcome stability issues associated with the use of an aldehyde in a catalytic reductive amination reaction, a cyclic ketolactol (ω-hydroxylactone) was employed as an aldehyde surrogate to form a γ-aminoacid. The reaction proceeded most favorably over a Pt/C catalyst. The thermodynamics of each step were evaluated using density functional theory calculations, which correctly predicted the dominance of the ring-closed lactol reactant, yet suggested a preference for a ring-opened iminium intermediate upon the initial, slightly endoergic addition of amine substrate. Exoergic hydrogenation of this intermediate provided the thermodynamic driving force for the overall transformation. During development, the reaction was observed to depend significantly on the volumetric gas to liquid mass transfer coefficient (kLa) and this parameter was optimized to ensure successful scale up in a 400 L stirred tank reactor.

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Notes

  1. Brief unoptimized catalyst screening suggested Pt/C provided better yield than Pt on other supports (Al2O3, graphite) or “poisoned” Pt (S, Bi) or a variety of Pd catalysts. Interestingly, select “homogeneous” Ir based catalysts were evaluated and found to exhibit an intriguing inverse dependence on ligand concentration, consistent with nanoparticle catalyzed reduction see Ref. [15].

  2. The relative stabilities of the aminolactone and iminium forms of seven exhibit a basis set dependence. PCM-B3LYP/6-31G* total energies actually predict a reversed preference, in favor of the aminolactone species (∆E = 1.9 kcal/mol.) However, inclusion of zero-point energy and TΔS terms from the PCM-B3LYP/B3LYP/6-31G* vibrational frequencies result in an energetic preference (∆G = 1.7 kcal/mol) in favor of the iminium form, reinforced by the PCM-B3LYP/cc-PVTZ energy evaluations (Fig. 3.) The enamine tautomer (not shown) of seven is predicted to lie >10 kcal/mol on the B3LYP potential energy surface, and thus is not expected to play a significant role in this chemical transformation.

  3. Other mixing parameters have been compared for the reactors described in this work, including Reynold’s number, tip speed and energy dissipation per reaction volume following literature methodology. While these parameters are critical to understanding scale-up of a variety of processes, kLa was the most relevant parameter to consider in this process.

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Acknowledgments

The authors thank Amgen Inc. for permission to publish this work.

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Authors and Affiliations

  1. Central Research and Development, E.I. duPont de Nemours and Company, Wilmington, DE, 19880, USA

    Alan M. Allgeier

  2. Threshold Pharmaceuticals, South San Francisco, CA, 94080, USA

    Denise Andersen

  3. Amgen Inc, Thousand Oaks, CA, 91320, USA

    Michael D. Bartberger & Jason S. Tedrow

  4. Argonne National Laboratory, Lemont, IL, 60439, USA

    Emilio E. Bunel

  5. Alcon, Fort Worth, TX, 76134-2001, USA

    Robert D. Larsen

  6. Incyte Corporation, Wilmington, DE, 19880, USA

    Pingli Liu

  7. Ironwood Pharmaceuticals, Cambridge, MA, 02142, USA

    Thomas Storz

Authors
  1. Alan M. Allgeier
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  2. Denise Andersen
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  3. Michael D. Bartberger
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  4. Emilio E. Bunel
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  5. Robert D. Larsen
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  6. Pingli Liu
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  7. Thomas Storz
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  8. Jason S. Tedrow
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Correspondence to Alan M. Allgeier or Michael D. Bartberger.

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Allgeier, A.M., Andersen, D., Bartberger, M.D. et al. Reductive Amination Without the Aldehyde: Use of a Ketolactol as an Aldehyde Surrogate. Top Catal 57, 1335–1341 (2014). https://doi.org/10.1007/s11244-014-0300-x

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  • DOI: https://doi.org/10.1007/s11244-014-0300-x

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