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A novel synthesis of 19-nor analogs of vitamin D

Anita Pietraszek ,  Michał Chodyński ,  Agnieszka Ciesielska ,  Krzysztof Krajewski ,  Małgorzata Krupa ,  Marek Kubiszewski ,  Jerzy Winiarski ,  Andrzej Kutner 

Instytut Farmaceutyczny (PRI), Rydygiera 8, Warszawa 01-793, Poland


In our continous search for new vitamin D analogs of therapeutic potential in hyperproliferative diseases we have synthesized a new series of analogs of 25-hydroxy vitamin D with truncated methylene unit at carbon atom C-10. The resulting new 19-nor vitamins D are analogous to the existing therapeutic agent from this group. Known syntheses of 19-nor analogs started from 25-hydroxy vitamin D2 or from quinic acid. However, these syntheses were designed to prepare a selected single analog and did not allowed for the preparation of a series of structurally related compounds to be used for structure-activity analysis. In addition, 25-hydroxy vitamin D2 is practically unavailable from commercial sources. Our retro-synthetic analysis showed that the target molecule might be conveniently constructed from 19-nor-A-ring synthon, CD-ring system and a side-chain fragment. In our approach the A-ring synthon is first coupled with the indane CD-ring system and then connected with variety of side-chain fragments. This way a series of side-chain modified analogs of 19-nor vitamins D might be obtained in a convergent manner. The yields of key synthetic steps allowed for the synthesis of selected analogs in preparative quantities. Our initial approach of combining first the CD-ring system with the respective side-chain fragment did not gave the intermediates in a yield high enough as for synthesis of potential pharmaceutical substances. The structure of new key intermediates: the CD-ring synthon and the ACD synthon was confirmed by spectroscopic and diffraction methods. The phosphine oxide of A-ring synthon was synthesized from the respective alcohol. This was prepared from an achiral precursor, 1,3,5-trihydroxybenzene. CD-Ring synthon was synthesized by a photolytic degradation of the commercial vitamin D2.  The key diol SCD-2 was converted into the new ketosulfone - synthon CD. Wittig-Horner condensation of this synthon with the A-ring synthon gave the new 19-nor synthon ACD, as the advanced key intermediate. Julia olefination of this synthon with the side-chain aldehydes, followed by dehydroxy-desulfonylation and desilylatioin gave a series of  target 19-nor analogs with various alkyls at C-26, C-27 and C-28. New analogs are screened for their cell differentiation  and calcemic activity.


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Related papers

Presentation: Poster at VII Multidyscyplinarna Konferencja Nauki o Leku, by Anita Pietraszek
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-10 08:27
Revised:   2010-03-10 08:27