Synthesis of 25-hydroxyvitamin D(3) and 26,26,26,27,27,27-hexadeutero-25-hydroxyvitamin D(3) 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.

Novel synthetic approach to 1alpha,25-dihydroxyvitamin D3 and analogues.

A mild and stereoconvergent synthesis of 1alpha,25-dihydroxyvitamin D(3) (calcitriol, 1a) is described. The key step is a cascade process consisting of two consecutive transformations: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflate 4 followed by a Negishi cross-coupling reaction with alkenyl zinc 3. This approach is of interest for the rapid synthesis of a variety of new vitamin D(3) analogues of therapeutic potential, especially those modified at the triene and ring-A. The mildness of the method also allows the preparation of thermal sensitive vitamin D(3) analogues.

Strained polycycles by H5C5x free-radical cascades.

[reaction: see text] An H(5)C(5x)-type free-radical chain reaction selectively generates up to three new bonds and three new stereocenters in one pot. This previously unexploited strategy provides a straightforward route to the tricyclic cyclopenta[c]indene skeleton, present in a wide range of pharmacologically active natural products, and can significantly simplify the synthesis of other strained polycyclic structures by sidestepping protection, deprotection, and functional group interconversion steps.

Oxidative Cyclization of Iodo Ketones. Synthesis of 6-Oxa-5alpha-pregnane-3,20-dione.

The steroidal delta- and gamma-iodo ketones 1 and 9 were converted to the cyclic hemiketals 3 and 10, by oxidation to the iodoso derivatives with m-CPBA. Spontaneous cyclization of the latter intermediates to the corresponding oxocarbenium ions, followed by stereoselective addition of water, rendered the hemiketals. Depending on the reaction conditions, the five-membered oxocarbenium ion derived from the gamma-iodo ketone 9 may add H(2)O or m-CPBA to give either the hemiketal or a Baeyer-Villiger type product 12, while the oxocarbenium derived from 1 gives exclusively the hemiketal. When the reaction was carried out in dry methanol, methyl ketals were formed. Use of this methodology allowed us to synthesize 6-oxa-5alpha-pregnanes with and without functionalization at C-19.

Synthesis, structure, and biological activity of des-side chain analogues of 1α,25-dihydroxyvitamin†D3 with substituents at C18.

An improved synthetic route to 1α,25-dihydroxyvitamin D(3) des-side chain analogues 2 a and 2 b with substituents at C18 is reported, along with their biological activity. These analogues display significant antiproliferative effects toward MCF-7 breast cancer cells and prodifferentiation activity toward SW480-ADH colon cancer cells; they are also characterized by a greatly decreased calcemic profile. The crystal structure of the human vitamin D receptor (hVDR) complexed to one of these analogues, 20(17→18)-abeo-1α,25-dihydroxy-22-homo-21-norvitamin D(3) (2 a) reveals that the side chain introduced at position C18 adopts the same orientation in the ligand binding pocket as the side chain of 1α,25-dihydroxyvitamin D(3).

A short practical approach to 24R,25-dihydroxyvitamin D3.

A synthesis of the vitamin D3 metabolite 24R,25-dihydroxyvitamin D3 (1) by Lythgoe's Wittig-Horner approach is described. The key step of the synthesis is the stereocontrolled introduction of the 24-hydroxyl group by a palladium(0)-induced [3,3]-sigmatropic rearrangement on a 22R-allylic acetate (7).

Synthesis of novel analogues of 1alpha,25-dihydroxyvitamin D(3) with side chains at C-18.

Novel analogues of the hormone 1alpha,25-(OH)(2)-D(3) with side chains attached to C-18 were synthesized by a versatile route in which key steps were the remote radical-induced functionalization of the 18-methyl by the C-8beta-hydroxyl group and the introduction of the side chains by Wittig reactions on a C-18-aldehyde. The triene system of the novel analogues was constructed by the convergent Lythgoe-Hoffmann la Roche approach, which involves reaction of a phosphine oxide (the ring A fragment) with a ketone (the upper fragment).