Elsevier

Tetrahedron Letters

Volume 58, Issue 36, 6 September 2017, Pages 3568-3570
Tetrahedron Letters

Modified Julia olefination and α aminoxylation reactions mediated convergent synthesis of 1α, 24 (R)-dihydroxyvitamin D3 (tacalcitol)

https://doi.org/10.1016/j.tetlet.2017.07.103Get rights and content

Highlights

  • A convergent synthesis of tacalcitol.

  • Cheap and commercially available starting material.

  • Vitamin D analogue for the treatment of psoriasis.

Abstract

A convergent synthesis of tacalcitol has been achieved starting from inexpensive and commercially available isovaleraldehyde and easily available Inhoffen-Lythgoe diol. Key steps include a proline catalyzed α aminoxylation and a Julia-Kocienski olefination.

Introduction

1α, 25-Dihydroxyvitamin D3 (calcitriol, 1) (Fig. 1), the hormonally active form of vitamin D3 (2) is involved in the regulation of calcium homeostasis, cell differentiation, immune system regulation and gene transcription.1

1α, 24 (R)-Dihydroxyvitamin D3 (tacalcitol, 3) and calcipotriol (4) (Fig. 1) are active analogues of vitamin D3, potent inhibitors of cancer cell proliferation both in vitro and in vivo, with less hypercalcemic activity.2

1α, 24(R)-Dihydroxyvitamin D3 (tacalcitol, 3) has been previously synthesized by the classical photochemical ring opening of steroidal Δ5,7-dienes bearing a suitably functionalized side chain,3 and recently by asymmetric catalytic reduction of a prochiral ketone followed by photocatalytic double-​bond isomerization.4 The first convergent synthesis of 3 was published in 1995 by Tanaka and co-workers, via a diastereoselective isopropylation and alkylative enyne cyclization.5 Two years later a novel synthetic approach to 3, based on an asymmetric nitroaldol reaction was described by Okamoto and co-workers.6 The same year, we reported an efficient synthesis of 3,7 based on the dienyne route and “the nitrile approach” methodology developed in our research group.8 Since then, to the best of our knowledge no new convergent synthesis of this important vitamin D analogue has been published. 1α, 24(R)-Dihydroxyvitamin D3 (tacalcitol, 3) is already used clinically for the treatment of psoriasis and the development of new convergent syntheses which could lead to A-ring modified analogues of 3 is indeed necessary.

Section snippets

Results and discussions

We anticipated that the side chain of target analogue 3 could be synthesized from sulfone 5 and aldehyde 6, via modified Julia olefination9 followed by a catalytic hydrogenation of the double bond (Scheme 1).

Sulfone 5 would be easily available from Inhoffen-Lythgoe diol 7.10 Aldehyde 6 could result from a proline catalyzed α aminoxylation11 of inexpensive and commercially available aldehyde 8. Accordingly, sulfone 5 was prepared as shown in Scheme 2.

Treatment of Inhoffen-Lythgoe diol 7 with

Conclusion

In summary, we have developed a new and convergent synthesis of tacalcitol which will pave the way to unprecedented A ring modified analogues of this commercially available drug used as treatment for psoriasis.

Acknowledgements

This work was supported financially by the Xunta de Galicia (CN 2012/184). The work of the NMR and MS divisions of the research support services of the University of Vigo (CACTI) is also gratefully acknowledged. A. M. thanks the University of Vigo for a fellowship.

References (18)

  • G.A. Leyes et al.

    J Am Chem Soc

    (1982)
    F. Sardina et al.

    J Org Chem

    (1986)
  • A. Pietraszek et al.

    J Pharm Sci

    (2013)
  • A. Glebocka et al.

    Arch Biochem Biophys

    (2012)
  • Fall Y, et al., Spanish Patent ES...
  • B. López-Pérez et al.

    Chem Commun

    (2017)
    D. Feldman et al.

    Vitamin D

    (1997)
    R. Pardo et al.

    Bull Soc Chim Fr

    (1985)
    H. Dai et al.

    Synthesis

    (1994)
    G.-D. Zhu et al.

    Chem Rev

    (1995)
    G.H. Posner et al.

    Eur J Org Chem

    (2003)
  • A. Opolski et al.

    Anticancer Res

    (1999)
    A. Opolski et al.

    Curr Pharm Des

    (2000)
    J. Wietrzyk et al.

    Steroids

    (2004)
    J. Wietrzyk et al.

    Anticancer Res

    (2007)
    J. Wietrzyk et al.

    Cancer Chemother Pharmacol

    (2008)
    J. Wietrzyk et al.

    Anticancer Drugs

    (2007)
  • M. Morisaki et al.

    J Chem Soc, Perkin Trans I

    (1975)
    P. Koch et al.

    Bull Soc Chim Fr

    (1983)
    M. Okamoto et al.

    Tetrahedron Asymmetry

    (1995)
  • H. Zhang et al.

    Tetrahedron Asymmetry

    (2017)
  • M. Okamoto et al.

    Tetrahedron

    (1995)
There are more references available in the full text version of this article.
View full text