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We describe an efficient convergent synthesis of vitamin D3 metabolites and analogues. The synthetic strategy relies on a tandem Pd-catalyzed A-ring closure and Suzuki-Miyaura coupling to the CD-side chain component to set directly the vitamin D triene system under protic conditions. This strategy enables rapid access to vitamin D3 and 3-epi-vitamin D3 metabolites and analogues modified at the side chain for biological evaluation and structural and metabolic studies.

Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D3 bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5a–c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen–Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization–Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D3 analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D3 but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects. © 2012 American Chemical Society., We thank the Spanish Ministry of Education and Innovation (SAF2007-67205 and SAF2010-15291 to A. Mouriño, SAF2010-18302 to A. Muñoz, and SAF2009-07631 to RPF) for financial support.

A convergent synthesis of an analogue of (1α)-1,25-dihydroxyvitamin D 3 (1b) with a C 7 side chain at C(12), i.e., of 5 (Fig.), is described. A key step of the synthesis is the assembly of the triene system by a Pd II-catalyzed ring closure of an enol triflate ('bottom' fragment) followed by coupling of the resulting Pd II intermediate with an alkenylboronate ('upper' fragment) (Scheme 2). The synthetic strategy allows isotopic labelling at the end of the synthesis. Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zurich, Switzerland.

An efficient convergent synthesis of nonadeuterated 1α,25-dihydroxyvitamin D2 (1) by Pd(0)-catalyzed coupling between the boronate ester (upper fragment) and the enol triflate (A-ring fragment) is described. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Two novel vitamin D analogues of the hormone 1α,25-(OH)2D3 modified at C-7, namely, 7-methyl-1α,25-(OH)2D3 (12) and 7-methyl-1α,25-(OH)2-19-nor-D3 (26), were synthesized and biologically evaluated to gain further insights into the structure-function relationships of vitamin D. Key steps in the synthesis of 12 include the functionalization at C-7 by an efficient regioselective hydrostannylation of an allene precursor, and the construction of the triene framework by a palladium-catalyzed intramolecular cyclization-Suzuki-Miyaura coupling cascade. Since the calcitriol analogue 12 was prone to conversion into its previtamin D form by thermal equilibration, the corresponding 19-nor-compound 26 was also synthesized. The diene moiety of compound 26 was constructed by a modified Julia coupling. UV data as well as X-ray analysis indicate that introduction of the methyl group at C-7 results in a significant deviation from planarity of the 5,7-diene moiety. The new vitamin D analogues 12 and 26 retained good VDR binding ability.

Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D₃ bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5a-c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen-Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization-Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D₃ analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D₃ but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects.

Convergent syntheses of three new analogues of 1α,25-dihydroxyvitamin D 3 with α-hydroxyalkyl substituents at C12 ( 4a – c ) are described. The A-ring and triene system of each analogue were assembled by a tandem Pd-catalysed intramolecular cyclization and Suzuki–Miyaura coupling process. The stereoselective introduction of substituents at C12 was achieved by Johnson–Claisen rearrangement on allylic alcohol 15 as the key step. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.