Palladium-catalysed coupling of vinyl triflates with enynes and its application to the synthesis of 1α,25-dihydroxyvitamin D3

doi:10.1016/S0040-4020(01)86410-3

Tetrahedron

Volume 47, Issues 20–21, 1991, Pages 3485-3498

Dedicated to Prof I. Ribas on the occasion of his 89th birthday.

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Abstract

We describe a general approach, based on the palladium-catalysed coupling of enynes with vinyl triflates, for the construction of dienynes related to vitamin D metabolites and analogues. As an application of this method, an efficient convergent synthesis of 1α,25-dihydroxyvitamin D₃ starting from the Inhoffen-Lythgoe diol (6a) and natural carvones has been carried out (11 steps, 28% overall yield from 6a). This strategy allows labelling of the side chain in the final steps of the synthesis

An efficient route to 1α,25-dihydroxyvitamin D₃ (1b) is described.

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1α,25‐Dihydroxyvitamin D₃ (1,25D₃), the hormonally active form of vitamin D₃, regulates mineral homeostasis, cell growth, cell differentiation‐proliferation, apoptosis, and immune responses. 1,25D₃ activates more than 229 genes associated with several diseases, including arthritis, diabetes and cancer, suggesting its implications in a broader range of biological functions than originally thought. Despite the wide range of biological activities, the clinical applications of 1,25D₃ have been limited due to its collateral hypercalcemic effects. This problem has boosted intense synthetic activity in the vitamin D area in the last decades aimed at the development of highly active and non‐calcemic analogs for treatment of hyperproliferative diseases. This review covers the most useful synthetic approaches to 1,25D₃ analogs containing the natural vitamin D triene system with emphasis on the Pd(0)‐catalyzed transformations involved in the formation of the vitamin D triene system and A‐ring synthons.
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The reaction however proceeds in a maximum of 60% yield whereas other attempted procedures were found to be irreproducible, often leading to the thermodynamic enolate. Notably, the use of phenyl triflimide as reported by Mouriño et al.22,23 and used by other groups18,24–27 proved capricious in my hands. Boronation of the enol triflate 11 following Takagi et al. procedure28 was successful in securing 12, an alternative platform for Suzuki-type couplings (Scheme 3).
The described semi-synthetic route differs from the previously published approaches by an original C-7–C-8 disconnection. The kinetic enol triflate of Grundmann ketone was chosen as the CD-ring platform on which to couple an A-ring synthon via a challenging sp²–sp³ cross-coupling. A range of A-ring synthons was synthesized to allow the investigations of various conditions of metal-catalyzed couplings. Suzuki-type chemistry provided a useful (89% yield) answer. Whereas the last step of the designed route—a regioselective opening of the epoxide obtained from the alkene, product of the coupling reaction—proved more challenging than expected, a hydroboration endgame route completed a formal synthesis of (−)-astrogorgiadiol.
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The 1α,25-dihydroxy-2-methylene-vitamin D3 (6) and its 20-epimer 7 were successfully synthesized according to the reaction sequence shown in Scheme 3. The vinyl triflates 27 [11] and 28 [12] were separately coupled with the A-ring synthon 19 in the presence of bis(triphenylphosphine)palladium (II) acetate-copper (I) iodide as a catalyst and Et2NH in DMF, following the procedure elaborated by Mouriño [13]. The obtained trienynes 29 and 30 were then subjected to careful catalytic hydrogenation, in the presence of Lindlar catalyst and quinoline, to give previtamin D compounds 31 and 32.
As a continuation of our studies on structure–activity relationship of vitamin D compounds we synthesized new calcitriol analogs characterized by the presence of an exomethylene substituent at C-2. The A-ring dienyne synthon was prepared from commercially available quinic acid by two different synthetic routes, and it was then coupled with the triflate enol derived from the corresponding (20R)- and (20S)-Grundmann ketone by palladium catalyzed Sonogashira reaction.
The obtained 1α,25-dihydroxy-2-methylene-vitamin D₃ analogs, epimeric at C-20, were biologically evaluated by in vitro and in vivo studies. Both isomers exhibited unique activity profiles and greater biological potency than 1α,25-(OH)₂D₃. It was established that the biological profiles of the newly obtained vitamin D compounds depend on the configuration at C-20. Thus, introduction of 2-methylene substituent to the calcitriol molecule together with alteration of stereochemistry of its side chain induces remarkable changes in a VDR-mediated signaling response and enhances biological activity.
This article is part of a Special Issue entitled ‘Vitamin D Workshop’.
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Enantioselective synthesis of steroids
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^☆: For preliminary communications describing part of this work, see: (a) Castedo, L.; Mascareñas, J. L.; Mouriño, A. Tetrahedron Lett. 1987, 29, 2099. (b) Castedo, L.; Mascareñas, J.L.; Mouriño, A.; Sarandeses, L. A. Tetrahedron Lett. 1988, 29, 1203. (c) Mouriño, A.; Castedo, L.; Fernández, B. R.; Granja, J.; Maestro, M. A.; Mascareñas, J. L.; Sarandeses, L. A. Vitamin D. Molecular, Cellular and Clinical Endocrinology; Norman, A. W., Schaefer, K., Grigoleit, H.-G., Herrath, D. v., Eds.; Walter de Gruyter & Co: Berlin-NY, 1988; pp 34–42.

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Palladium-catalysed coupling of vinyl triflates with enynes and its application to the synthesis of 1α,25-dihydroxyvitamin D3☆

Abstract

J. Org. Chem.

Tetrahedron

J. Chem. Soc.

J. Chem. Soc. (C)

J. Org. Chem.

Top. Curr. Chem.

Prog. Chem. Org. Nat. Prod.

Nature

Biochem. Biophys. Res. Commun.

Proc. Natl. Acad. Sci. USA

Endocrinology

Steroids

Chem. Soc. Rev.

Bull. Soc. Chim. Fr.

Synform

Synform

Synform

Tetrahedron Lett.

Chem. Pharm. Bull.

Chem. Pharm. Bull.

J. Chem. Soc.

Helv. Chim. Acta

Chem. Pharm. Bull.

J. Chem. Soc.

Helv. Chim. Acta

Helv. Chim. Acta

J. Org. Chem.

J. Am. Chem. Soc.

J. Org. Chem.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

J. Org. Chem.

Tetrahedron Lett.

Palladium-catalysed coupling of vinyl triflates with enynes and its application to the synthesis of 1α,25-dihydroxyvitamin D₃☆