Synthesis 2017; 49(18): 4133-4136
DOI: 10.1055/s-0036-1588459
© Georg Thieme Verlag Stuttgart · New York

Scalable Syntheses of Chirally Pure Mono-protected and Orthogonally Di-protected cis-3,4-Diaminotetrahydrofurans

Franz J. Weiberth*a, Andre J. Bourqueb, Steven Elenbaasa, Reda Hannaa, Matthew R. Powersa, Craig S. Siegela, Jin Zhaoa
  • aSynthesis Development, Sanofi U.S. R&D, 153 Second Ave, Waltham, MA 02451, USA   Email:
  • bAnalytical R&D, Sanofi U.S. R&D, 153 Second Ave, Waltham, MA 02451, USA
Further Information

Publication History

Received: 03 May 2017

Accepted: 14 May 2017

Publication Date:
04 July 2017 (eFirst)


Scalable and chromatography-free syntheses of chirally pure and orthogonally protected cis-3,4-diaminotetrahydrofurans prepared from a single starting material, 3,4-epoxytetrahydrofuran, are presented.

Supporting Information

  • References

    • For recent reviews, see:
    • 1a Kalgutkar AS. Dalvie DK. Expert Opin. Drug Discovery 2012; 7: 561
    • 1b Kumalo HM. Bhakat S. Soliman ME. S. Molecules 2015; 20: 1984
    • 1c Singh J. Petter RC. Baillie TA. Whitty A. Nat. Rev. Drug Discovery 2011; 10: 307
    • 1d Baillie TA. Angew. Chem. Int. Ed. 2016; 55: 13408
    • 2a Fieldhouse C. Glen A. Robinson JS. Fujimoto T. PCT Int. Pat. Appl WO 2015/055994 A1, 2015
    • 2b Bifulco N. Dipietro L. Hodous BL. Miduturu CV. PCT Int. Pat. Appl WO 2015/061572, 2015
    • 2c D’Agostino LA. Sjin RT. T. Niu D. McDonald JJ. Zhu Z. Liu H. Mazdiyasni H. Petter RC. Singh J. Barrague M. Gross A. Munson M. Harvey D. Scholte A. Maniar S. PCT Int. Pat. Appl WO 2014/144737 A1, 2014
    • 2d Alexander MD. McDonald JJ. Ni Y. Niu D. Petter RC. Qiao L. Singh J. Wang T. Zhu Z. PCT Int. Pat. Appl WO 2014/149164 A1, 2014
    • 2e Qiao JX. Wang TC. Wang GZ. PCT Int. Pat. Appl WO 2004/082687 A1, 2004
    • 2f Kubo Y. Ando M. Tanaka H. Osaka S. Matsumoto T. Nakata H. Terada D. Nitabaru T. PCT Int. Appl WO 2015/030057 A1, 2015
    • 3a Martínez LE. Leighton JL. Carsten DH. Jacobsen EN. J. Am. Chem. Soc. 1995; 117: 5897
    • 3b Shaus SE. Larrow JF. Jacobsen EN. J. Org. Chem. 1997; 62: 4197
    • 4a Busse JK. Zook SE. Borer BC. PCT Int. Pat. Appl WO 2001/29013 A1, 2001
    • 4b Tulshian D. McKittrick BA. Xia Y. Chackalamannil S. US Patent 5939419, 1999
    • 4c Fukunaga K. Kohara T. Watanabe K. Usui Y. Uehara F. Yokoshima S. Sakai D. Kusaka S. Nakayama K. PCT Int. Pat. Appl WO 2007/119463 A1, 2001
  • 5 90–95% conversion and ca. 48:52 desired vs. undesired trans diastereomers as determined by 1H NMR spectroscopic analysis.
  • 6 Optical purities of enantiomers 2 and 3 were determined by HPLC-UV analyses of their N-benzoyl derivatives. Similarly, the absolute configuration of 2 prepared from 11 was correlated to 2 prepared independently by following references 2c and 3.
  • 7 Product isolated in the presence of 2-propanol was more crystalline and filtered better than the product crystallized directly from water.
  • 8 Theory is 0.47 mole H2; some debenzylation likely occurred during H2 purging. No unreacted 11 was observed by 1H NMR spectroscopic analysis.
  • 9 Additional 5% yield of a pure second crop was recovered from the filtrate.
  • 10 Analysis of extracts indicated some loss of 12 due to partial opening of the phthalimide ring by aqueous carbonate employed to wash out excess phthalimide. Although this degradation was minor, there was concern that losses would be higher at larger scale. In further improvements, the Mitsunobu reaction was run using 1.00–1.05 equiv of phthalimide at 40–50 °C to afford the same or higher conversions to 12. Elimination of the base wash afforded material that contained <6 wt% phthalimide, which was effectively removed by suspending crude 4 in toluene at 80 °C, then filtering.
  • 11 Ethylenediamine was employed because it is a less hazardous reagent on scale than hydrazine hydrate. Five equivalents were employed in initial batches. In subsequent batches, 1.0–1.5 equiv of ethylenediamine were successfully employed with good reaction performance and minimal caking onto reactor surfaces.
  • 12 Washes were employed to remove ethylenediamine. 1 N NaOH was chosen for these washes to enhance phase separations and minimize product loss in the aqueous phases.