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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).

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.

The design and synthesis of vitamin D(3) dimers 2 and 3 and 1 alpha, 25-dihydroxyvitamin D(3) (calcitriol) dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin D receptor (VDR) and inducing the receptor homodimerization. In the dimers the units are linked through the C-11 position in ring C by an alkyl side chain of six or 10 carbon atoms, far from the hydroxy groups responsible for the VDR binding. The linker is formed by olefin metathesis of an olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The synthesis, which is both short and convergent, uses the Wittig-Horner approach to construct the vitamin D triene system and allows the preparation of dimers with a linker of modulated length with the purpose of optimizing the vitamin D(3)-VDR interaction.

The synthesis of four new analogues of calcitriol (1α,25-(OH)2-D3)possessing aromatic and conjugated double bond units at the side chain are described. The triene system is introduced using the Lythgoe−Hoffmann La Roche convergent Wittig−Horner approach. The key steps in the preparation of the requisite upper fragments are the introduction of the side chain with the E-conjugated aromatic system and its photochemical conversion to the Z counterpart.

Two synthetic routes to the nonnatural hormone 1α,25-dihydroxyergocalciferol [2b, 1α,25-(OH)2-D2] and analogs modified at C-24 have been developed both starting from aldehyde 7b. Key steps in route A (eight steps, ≈38% overall yield from 7b) are (1) stereoselective addition of (E)-vinyllithium reagent 8c to aldehyde 7b; and (2) SN2‘ anti-displacement of the allylic phosphate of 5e by organocuprates derived from Grignard reagents and CuCN in the presence of LiCl. Key steps in route B (eight steps from 7b, 48% overall yield) are (1) Wittig−Horner type coupling between ketone 22, which bears an allylic phosphate group on the side chain, and the ylide derived from the Lythgoe−Roche phosphine oxide to form the vitamin D triene unit; and (2) efficient SN2‘ anti-displacement of the phosphate group of 23 by the organocuprate derived from MeMgCl, CuCN, and LiCl, without affecting the labile vitamin D triene system, to give, after deprotection, 1α,25-(OH)2-D2. Route B is particularly attractive as an approach to di...

3-Hydroxy-4-pyridones, which are easily prepared from commercially available 3-hydroxy-4-pyrones, can be readily transformed into 4-methoxy-3-oxidopyridinium ylides by treatment with methyl trifluoromethanesulfonate and subsequent deprotonation with a non-nucleophilic base. These ylides are capable of undergoing cycloaddition to several electron-deficient alkenes, thus allowing the synthesis of highly functionalized azabicyclo[3.2.1]octane moieties. The rich substitution patterns of these frameworks might allow their divergent conversion to a variety of natural and non-natural tropane alkaloids.

A versatile method for the rapid construction of fragments related to the upper part of vitamin D3 from the Lythgoe-Inhoffen diol is described. The key feature of the strategy is a new zinc-copperinduced conjugate addition of iodo triflate 10a to electron-deficient olefins under sonochemical aqueous conditions. These fragments are rapidly and efficiently transformed via the dienyne convergent approach to several derivatives of the hormone 1α,25-(OH)2-D3 modified at C-25. © 1993, American Chemical Society. All rights reserved.

The Lewis-acid-mediated nucleophilic substitution of dioxanone and acetal templates for the construction of 25-hydroxylated side chains of vitamin D 2 metabolites and analogs has been studied. As an application a highly stereoselective synthesis of 1α,25-dihydroxyvitamin D 2 by the dienyne route is described

Total synthesis of A-ring fragments of 10(S),19-dihydrovitamins D and 10(R),19-dihydro-(5E)-epivitamins D from (+)-(S)-carvone and (-)-(R)-carvone is described. These fragments were used for convergent synthesis of dihydrotachysterol 2 (DHT 2 ), 25-hydroxydihydrotachysterol 2 , 10(R),19-dihydro-(5E)-3-epivitamin D 2 , and 25-hydoxy-10(R),19-dihydro-(5E)-3-epivitamin D 2

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.

Six new calcitriol analogues, conformationally restricted at their side chain by the introduction of both a cyclopropane ring at C17−C20 and a double or triple bond at C22, were synthesized using the Wittig−Horner approach to construct the triene system. The six CD-ring and side-chain bearing fragments were prepared from ketone 14 by a divergent route to generate both series of epimers at C20, followed by stereoselective cyclopropanation. The (E)-alkenyl side chain was synthesized by means of a Wittig reaction. The alkynyl side chain was prepared by Corey−Fuchs homologation, followed by alkylation. The (Z)-alkenyl side chain was prepared from the previous alkyne by partial hydrogenation. The 20-epi analogues bind more strongly to VDR than the corresponding analogues with the C20 natural stereochemistry. These results can be reasoned by conformational analysis and hydrophobic interactions with the VDR ligand-binding domain.

Temporary connection of alkenes to 3-alkoxy-4-pyrones via sulfur or silicon tethers allows their thermal [5 + 2] cycloaddition and ensures complete regio- and stereochemical control. © 1993, American Chemical Society. All rights reserved.

A general method for the synthesis of the principal vitamin D3 metabolites whether unlabeled or with radiolabeled side chains is described. The synthesis of the key de-A,B-(ethylenedioxy)cholestanone derivative 7d is based on the coupling between the iodide 4c and 3-(trimethylsilyl)-3-buten-2-one (5b) via cuprate chemistry. The synthesis of 25-ketovitamin D3 (a suitable intermediate compound for radiolabeling) was achieved by coupling between 7d and the n-butyllithium-induced carbanion of the phosphine oxide 8c using Lythgoe’s strategy and deprotection. As an example of the utility of this route, 25-hydroxyvitamin D3 was synthesized. © 1986, American Chemical Society. All rights reserved.

On introduit le centre chiral en C 24 par deplacement stereo- et regiospecifique d'un carbamate allylique par un cuprate