Mercedes Torneiro

Efficient and versatile synthesis of a-ring precursors of 1α,25-dihydroxy-vitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide

Abstract An efficient, versatile synthesis of Lythgoe-Phosphine Oxide has been developed starting from l-carvone. The key steps are rupture of protected epoxide 7 to give dicarbonyl compound 8, preparation of vinylic triflate 2, and palladium-catalysed cyclization-carbonylation of vinylic triflate 2.

An efficient stereoselective synthesis of 1α,24(R)-dihydroxyvitamin D3 by the dienyne route

Abstract 1 α ,24( R )-Dihydroxyvitamin D 3 ( 5e ) was synthesized. The key step in the preparation of the side-chain was opening of the chiral epoxide 10 by the α-anion of the nitrile 9 . The triene system was synthesized by the dienyne route.

An efficient route to 1α,25-dihydroxyvitamin D3 functionalized at C-11

Abstract An efficient route to vitamin D 3 analogues functionalized at C-11 is described. Key features of this synthesis are: (i) the development of a novel and efficient route for the introduction of the 25-hydroxylated side chain, present in the most important metabolites of vitamin D 3 , and (ii) the stereoselective functionalization of the C-ring of 1α,25-(OH) 2 -D 3 at C-11.

A nitrile approach to the synthesis of the side chain of vitamin D metabolites and analogues

Abstract An efficient new method for the construction of vitamin D hydroxylated side chains is described which is based on the alkylation and opening of epoxides by the ga-anions derived from nitriles 6 and 7 .

Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D3 Analogues with a Long Side Chain at C12 and Short C17 Side Chains

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.

Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D(3) analogues hydroxymethylated at C-26.

We designed by docking and synthesized two novel analogues of 1α,25-dihydroxyvitamin D(3) hydroxymethylated at C-26 (2 and 3). The syntheses were carried out by the convergent Wittig-Horner approach via epoxide 12a as a common key intermediate. The antiproliferative and transactivation potency of the compounds was evaluated in colon and breast cancer cell lines. The analogues showed a similar but reduced activity compared to 1,25(OH)(2)D(3). Analogue 3 was more potent than analogue 2, and in some assays it exhibited potency similar to that of the natural ligand.

Synthesis of 25-Hydroxyvitamin D3 and 26,26,26,27,27,27-Hexadeutero-25-hydroxyvitamin D3 on Solid Support

A convenient five-step route to 25-hydroxylated vitamin D(3) compounds on (hydroxymethyl)polystyrene support is reported. A CD-side chain fragment was anchored to the solid phase through an ester group at C25 and coupled to an A ring building block to assemble the vitamin D triene system by the Wittig-Horner approach. Deprotection of the hydroxy group was carried out on the support, prior to functionalization at C25. The title compounds were released from the resin in excellent global yield by nucleophilic attack on the ester carbonyl group using commercially available organometallic reagents. This key last step offers an opportunity for the efficient generation of 26,27-labeled compounds and also for diversification at the side chain without need for a pool of side chain fragments.

Divergent Synthesis of Porous Tetraphenylmethane Dendrimers

Tetraphenylmethane-ethynylene-based shape-persistent dendrimers are a new class of nanoobjects with an intriguing 3D architecture. We report an efficient divergent strategy for their synthesis based on the Sonogashira Pd-catalyzed coupling of terminal alkynes with aryl iodides. As repeat unit, we prepared a tetraphenylmethane derivative bearing a terminal alkyne and three triazene moieties. Coupling of this building block to tetrakis(p-iodophenyl)methane afforded, after triazene activation, a dodecaiodo-terminated first generation dendrimer, which was transformed by another Sonogashira coupling into a methoxy-terminated second generation dendrimer with persistent globular shape and well-defined cavities. This work also unveils new aspects of triazene chemistry, i.e., the unprecedented efficient generation of an azo compound by mixing of a triazene with phenol.

Shape-persistent fluorescent tetraphenylmethane dendrimers

We report the first examples of a new class of rigid dendrimers made of three-dimensional tetraphenylmethane units connected by ethynylene linkers. Designed to obtain a persistent globular shape, minimal backfolding of terminal groups and well-defined cavities at low generations, the dendrimers were synthesized until the second generation by a convergent strategy based on Sonogashira couplings. Their structure and size were confirmed by NMR, MALDI-TOF-MS and SEC among other techniques. The dendrimers showed intrinsic fluorescence with quantum yields of ∼0.6.

Copolymers with acetyl-protected thiol pendant groups as highly efficient stabilizing agents for gold surfaces

Multifunctional sulfur-containing homo, block and random copolymers with a modulable number of noble metal affine groups were efficiently prepared by the atom transfer radical polymerization of S-(4-vinylbenzyl)thioacetate, in case with styrene. Their potential as model ligands for the stabilization of sub-5 nm noble metal nanoparticles is demonstrated through the one-step fabrication of well-controlled stable gold dispersions, in spite of working with a gold precursor to ligand concentration ratio considerably lower than those typically used in the presence of more traditional mono-functional terminated polymers.