Possibility of [1,5] sigmatropic shifts in bicyclo[4.2.0]octa-2,4-dienes.

The thermal equilibration of the methyl esters of endiandric acids D and E was subject to a computational study. An electrocyclic pathway via an electrocyclic ring opening followed by a ring flip and a subsequent electrocyclization proposed by Nicolaou [ Nicolaou , K. C.

Synthesis of 1alpha,25-dihydroxyvitamin D analogues featuring a S(2)-symmetric CD-ring core.

Three analogues of 1a,25-dihydroxyvitamin D(3) (calcitriol), featuring a trans-fused decalin C,D-core with local S(2)-symmetry, and possessing identical side-chain and seco-B,A-ring structures, have been synthesized starting from readily available (4aR,8aS)-octahydronaphthalene-1,5-dione (7). The very short sequences involve the simultaneous introduction of the side-chain and seco-B,A-ring fragments via Suzuki and Sonogashira coupling reactions. The analogues are devoid of relevant biological activity.

Nonenzymic polycyclization of analogues of oxidosqualene with a preformed C-ring.

Some nonenzymic epoxide-initiated polyolefin cyclization are reported. The presented molecules are partially constrained analogues of (3S)-oxidosqualene, the natural substrate to many important cyclase enzymes. These model compounds feature a preformed C-ring with built-in stereochemical information.

Asymmetric synthesis of (7aS)-7a-methyl-4,5,7,7a-tetrahydro-1H-indene-2,6-dione and useful derivatives thereof.

The enantioselective synthesis of the title compound, using Meyers' bicyclic lactam methodology, is described. This compound and a few of its derivatives are useful intermediates in natural product synthesis.

Application of the solid-phase Julia-Lythgoe olefination in vitamin D side-chain construction.

An example of the Julia-Lythgoe attachment of the vitamin D side chain to a solid-phase linked Inhoffen-Lythgoe diol derived CD-ring fragment is reported.

Asymmetric synthesis of the epimeric (3S)-3-((E)-hex-1-enyl)-2-methylcyclohexanones.

The asymmetric rhodium-catalysed 1,4-addition of alkenylzirconium reagents to 2-cyclohexenone can be useful in the synthesis of 3-alkenyl-2-methylcyclohexanones, provided that formaldehyde is used in trapping the intermediate zirconium enolates. In this manner a four-step sequence leading to the two epimeric 3-hexenyl-2-methylcyclohexanones in enantiomeric form was developed.

Synthesis of 3,4,7,8-tetrahydronaphthalene-1,5(2H,6H)-dione.

A short and high yielding route for the preparation of the title compound, starting from commercially available 1,5-dihydroxynaphthalene, is described. The key step in the sequence is the air oxidation of a bis(trimethylsilyloxy)diene precursor.

The development of CD-ring modified analogs of 1alpha,25-dihydroxyvitamin D.

During a 20-year collaboration the laboratories of UGent and KU Leuven have developed different series of Vitamin D analogs characterized by structural modifications in the central CD-ring system. Modifications have first involved the introduction of substituents at C11 and the epimerization at C14, and subsequently more drastic changes consisting in both ring deletion and enlargement relative to the natural CD-ring system. Lately, the focus has shifted towards the synthesis of analogs featuring a symmetrical CD-ring core.

Application of the B-alkyl suzuki-miyaura cross-coupling reaction to the stereoselective synthesis of analogues of (3S)-oxidosqualene.

[reaction: see text] A general method is described for the direct and stereoselective synthesis of epoxypolyenes via Suzuki-Miyaura cross-coupling reaction of 1-iodoalkenes with B-alkylboron compounds. It allows for the straightforward and convergent assembly of compounds that are structurally similar to (3S)-oxidosqualene, an important intermediate in steroid biosynthesis.

Synthesis of spiro[4.5]decane CF-ring analogues of 1 alpha,25-dihydroxyvitamin D3.

A novel series of analogues of calcitriol (1) is developed featuring a spirocyclic central core resulting from C18/C21-connection and C15/C16-deletion (2a, 2b). The synthesis of the key intermediate involves an Eschenmoser rearrangement of an enantiomerically pure bromo-substituted cyclohexenol.

Biological activity and conformational analysis of C20 and C14 epimers of CD-ring modified trans-decalin 1alpha,25-dihydroxyvitamin D analogs.

In the context of our ongoing study of vitamin D structure-function relationships and in an attempt to obtain a better dissociation of their prodifferentiating (HL-60) and/or antiproliferative (MCF-7) activities and their calcemic activity, further 20-epi and 14-epi modifications were made to three trans-decalin CD-ring analogs of 1,25-dihydroxyvitamin D(3), the hormonally active metabolite of vitamin D(3), possessing a natural 20R side chain and featuring additional structural modifications in the seco-B-ring and in the A-ring. Following a previously observed trend and in agreement with the conformational analysis results, all three 20-epi derivatives show substantially lower biological activities, opposite to what is usually observed for analogs having the natural CD-ring. The 14-epi modification (cis-decalins) has little effect on the biological activity of the ynediene type and the saturated derivative, but results in an approximate 10-fold reduction in activity of the previtamin derivative.

Synthesis and biological activity of 22-oxa CD-ring modified analogues of 1alpha,25-dihydroxyvitamin D3: spiro[5.5]undecane CF-ring analogues.

The synthesis and biological activity of novel CD-ring modified analogues of 22-oxa-1alpha,25-dihydroxyvitamin D(3), lacking the D-ring and featuring a connection between C-18 and C-21 (spiro[5.5]undecane CF-ring analogues), is described. The central ring system is conveniently synthesised from an achiral intermediate.

Synthesis and biological activity of 22-oxa CD-ring modified analogues of 1alpha,25-dihydroxyvitamin D3: cis-perhydrindane CE-ring analogues.

The synthesis and biological activity of novel CD-ring modified analogues of 22-oxa-1alpha,25-dihydroxyvitamin D(3), lacking the D-ring and featuring a connection between C-12 and C-21 (cis-perhydrindane CE-ring analogues), is described. The synthesis of the CE-ring system follows Meyers' methodology for the preparation of enantiomerically pure hydrinden-2-ones. The analogues show a complete lack of binding affinity for the vitamin D receptor (pig nVDR) and of antiproliferative activity (MCF-7 cells), as compared to calcitriol.

Synthesis, biological activity, and conformational analysis of CD-ring modified trans-decalin 1 alpha,25-dihydroxyvitamin D analogs.

A novel series of analogs of 1,25-dihydroxyvitamin D3, the hormonally active metabolite of vitamin D3, characterised by the presence of a trans-fused decalin CD-ring system, possesses surprising biological activities in combination with specific structural modifications in the flexible parts of the molecule, when compared with the natural hydrindane derivatives. (1) A large difference in biological activity is observed between the 20-epimeric trans-decalin analogs that follows a pattern opposite to what is usually observed for the natural ring size. (2) Several trans-decalin analogs that are modified in the seco-B-ring region, including previtamin derivatives, possess a pronounced vitamin D-like activity, whereas the corresponding hydrindane derivatives are inactive.

Previtamin D3 with a trans-fused decalin CD-ring has pronounced genomic activity.

Deletion of C19 in the structure of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] does not substantially alter the biological potency but prevents the conversion between the vitamin and the previtamin form. Hence, this modification allows the study of locked previtamin and vitamin forms. The locked 19-nor-1,25(OH)2-previtamin D3 analog (19-nor-previtamin D) had a low biological activity and was a rather weak activator of the genomic signal transduction pathway.

Synthesis and affinity studies of himbacine derived muscarinic receptor antagonists.

A series of himbacine (1)-related analogues has been prepared featuring three different isomeric configurations with respect to the B-ring (a, b and natural c) and three different interconnecting two-carbon unsaturated units [natural (E)-ene, (Z)-ene, and yne]. The study of the binding affinities of the nine resulting compounds, including synthetic (+)-himbacine (3c), towards the M(1)-M(4) muscarine receptor subtypes revealed that analogues 3a and 5c display a promising 10-fold selectivity for the M(2) receptor as compared to the M(1) receptor.

A novel short convergent entry into himbacine derivatives.

[reaction: see text]. The IMDA reaction of 9 leads with good stereoselectivity to exo-adduct 10b. The functionalized ABC-ring core in 10 is well suited for the convergent synthesis of analogues of himbacine, a naturally occurring M2 selective muscarine receptor antagonist, as illustrated with the further synthesis of the dehydro-derivative 5.

A pentaerythritol-based molecular scaffold for solid-phase combinatorial chemistry.

A convergent synthesis has been developed for the preparation of solid-phase bound construct 1, consisting of an orthogonally protected trifunctional core structure that is attached to TentaGel via a photocleavable linker. [structure: see text]

Stepwise Approach toward First Generation Nonenzymatic Hydrolases.

The synthesis and reactivity study of a first generation serine protease mimic is described. Central in the design stands the possibility of stabilization of the transition state by an amino triol such as 8t. En route to 8t, a series of amino alcohols (4-8) was obtained, the reactivity of which was studied toward esterification by acetylimidazole (AcIm) and by p-nitro-2,2,2-trifluoroacetanilide (PNTFA).

Application of Combinatorial Procedures in the Search for Serine-Protease-Like Activity with Focus on the Acyl Transfer Step.

Recursive deconvolution of a 729-membered peptide library has identified three active sequences, in which both Ser and His are present in one of the two tripeptidic chains generated on a steroidal scaffold (see structural formula), for the cleavage of an activated p-nitrophenyl ester. This combinatorial approach aims at searching for serine-protease-like activity.

Synthesis, biological activity, and conformational analysis of four seco-D-15,19-bisnor-1alpha,25-dihydroxyvitamin D analogues, diastereomeric at C17 and C20.

The synthesis of four CD-ring-modified 19-nor-1alpha, 25-dihydroxyvitamin D(3) derivatives lacking C15, referred to as 6C analogues, and diastereomeric at C17 and C20 is described. The synthesis involves an Ireland-Claisen rearrangement of a 3-methyl-substituted ester of (1R)-3-methyl-2-cyclohexen-1-ol as the key step, followed by elaboration of the side chain, transformation into a C8 cyclohexanone derivative, and final Wittig-Horner coupling with the 19-nor A-ring phosphine oxide. Despite possessing a more flexible side chain than the parent hormone, biological evaluation showed an unexpected superagonistic antiproliferative and prodifferentiating activity (10-50 times higher as compared to that of 1alpha,25(OH)(2)D(3)) for the diastereomer with the "natural" configuration at C17 and C20.

On the use of volume maps in the conformational analysis of vitamin D analogs.

Dot maps used to represent the calculated conformations of the side chain of vitamin D derivatives are improved by replacing dots by coloured balls to create volume maps and to identify particular energy windows. Two procedures to define a relative activity volume, based on a pair of analogs with distinctly different biological activity and conformational behaviour, are presented.