The synthesis of cardenolide and bufadienolide aglycones, and related steroids bearing a heterocyclic subunit.

Covering: early studies through to March 2016Cardenolides and bufadienolides constitute an attractive class of biologically active steroid derivatives which have been used for the treatment of heart disease in traditional remedies as well as in modern medicinal therapy. Due to their application as therapeutic agents and their unique molecular structures, bearing unsaturated 5- or 6-membered lactones (or other heterocycles) attached to the steroid core, cardio-active steroids have received great attention, which has intensified during the last decade, in the synthetic organic community. Advances in the field of cross-coupling reactions have provided a powerful tool for the attachment of lactone subunits to the steroid core. This current review covers a methodological analysis of synthetic efforts to cardenolide and bufadienolide aglycones. Special emphasis is given to cross-coupling reactions applied for the attachment of lactone subunits at sterically very hindered positions of the steroid core. The carefully selected partial and total syntheses of representative cardio-active steroids will also be presented to exemplify recent achievements (improvements) in the field.

Chemoenzymatic approach to optically active 4-hydroxy-5-alkylcyclopent-2-en-1-one derivatives: an application of a combined circular dichroism spectroscopy and DFT calculations to assignment of absolute configuration.

A series of representative optically active derivatives of 4-hydroxy-5-alkylcyclopent-2-en-1-one were prepared from the respective 2-furyl methyl carbinols via the Piancatelli rearrangement followed by the enzymatic kinetic resolution of racemates. Applicability of chiroptical methods (experimental and calculated electronic circular dichroism [ECD] and vibrational circular dichroism [VCD] spectra) to determine the absolute configuration of both stereogenic centers in 4-hydroxy-5-methylcyclopent-2-en-1-one was demonstrated. It was also demonstrated that the concurrent application of ECD and VCD spectroscopy can be used for the determination of the configuration of two stereogenic centers.

Total synthesis of a CD-ring: side-chain building block for preparing 17-epi-calcitriol derivatives from the Hajos-Parrish dione.

An efficient synthesis of the key building block for 17-epi-calctriol from the Hajos-Parrish dione involving a sequence of diastereoselective transformation of the azulene core and the side-chain construction is presented.

Synthetic studies on dicyclopenta[a,d]cyclooctane terpenoids: construction of the core structure of fusicoccins and ophiobolins on the route involving a Wagner-Meerwein rearrangement.

The total diastereoselective synthesis of dicyclopenta[a,d]cyclooctane core skeleton of tricyclic terpenoids, fusicoccins, and ophiobolins is reported. The synthesis commences from 2-methylcyclopent-2-en-1-one and leads first to the easily accessible intermediary cyclopenta[8]annulene 18. The subsequent steps include two key transformations: shifting the angular methyl group from the angular to the neighboring position employing a carbocationic rearrangement (26 → 28) and construction of a quaternary stereogenic center via alkylation of α-methylcyclooctanone intermediate (38 → 48). In the context of the latter transformation, a series of model experiments on alkylation of 2-methylcyclooctan-1-one were conducted. The stereochemical assignments were verified by X-ray analyses of the key structures 39 and 50.

Ring-expanded bicyclic ß-lactams: a structure-chiroptical properties relationship investigation by experiment and calculations.

In the present work, the validity of the helicity rule relating the absolute configuration of the bridgehead carbon atom in bicyclic ß-lactams to the sign of the 220 nm band observed in their electronic circular dichroism (ECD) spectra is examined for ring-expanded cephalosporin analogues. To this end, a series of model compounds with a seven-membered ring condensed with the ß-lactam unit was synthesized. A key step of their synthesis was either the ring-closing metathesis (RCM) or the free radical cyclization leading to the seven-membered ring with an S, O, or C atom at the 6 position in the bicyclic skeleton. To investigate the scope and limitations of the simple, empirically established helicity rule, a combination of ECD spectroscopy, variable-temperature ECD measurements, X-ray analysis, and time-dependent density functional theory (TD-DFT) calculations was used. A comparison of the experimental ECD spectra with the spectra simulated by TD-DFT calculations gives a reasonable interpretation of the Cotton effects observed in the 240-215 nm spectral range. The results suggest that the helicity rule does not apply to the investigated compounds because of the planarity of their amide chromophore. Thus, these compounds do not constitute an exception to the rule that was established for bi- and polycyclic ß-lactams with the nonplanar amide chromophore only.

Construction of the tricyclic 5-7-6 scaffold of fungi-derived diterpenoids. Total synthesis of (±)-heptemerone G and an approach to Danishefsky's intermediate for guanacastepene A synthesis.

An efficient and operationally simple synthesis of the neodolestane diterpenoids (±)-heptemerone G and (±)-guanacastepene A is reported. The common tricyclic scaffold (±)-4 was prepared from 2-methylcyclopent-2-en-1-one via 23 isolated intermediates in 5.1% yield. The key features include a novel annulation sequence combining tandem conjugate addition, methylenation, and metathesis reaction and completely diastereoselective transformation of the azulene derivative 23 into rings AB building block 32. Stereochemistry of alkylation of both saturated trans-azulene enolate 38 and its α,ß-unsaturated counterpart 48 was examined. Rather surprisingly, a different facial selectivity was recorded. Several synthetic methods were modified or developed, including an alternative methodology for the Wharton-type rearrangement, ketalization of epimerizable ketone under mild conditions, and efficient alkylation of a ketone via its kinetic enolate.

Rearrangement of 2,3-epoxy alcohol dimethylthiocarbamate derivatives. Synthesis of 2,3-epithio alcohol derivatives under mild conditions.

Transformation of representative 2,3-epoxy alcohols, including 3-trimethylsilyl- and 3-triphenylsilylglycidols, into the corresponding 2,3-epithio alcohol dimethylthiocarbamate derivatives under mild alkaline conditions is reported.

Steric control of alpha- and beta-alkylation of azulenone intermediates in a guanacastepene a synthesis.

The origins of different stereoselectivities observed experimentally in the alkylations of azulenone precursors in the guanacastepene A synthesis have been determined through density functional theory investigations. The optimized transition structures of methylation of two different guanacastepene A precursors show that steric effects, rather than torsional factors that often determine such stereoselectivities, dictate the preferred products observed.

Synthesis and evaluation of Na+/K+-ATP-ase inhibiting and cytotoxic in vitro activities of oleandrigenin and its selected 17ß-(butenolidyl)- and 17ß-(3-furyl)- analogues.

Natural cardiac-active principles built upon the 14,16ß-dihydroxy-5ß,14ß-androstane core and bearing a heterocyclic substituent at 17ß, in particular, a cardenolide - oleandrin and a bufadienolide - bufotalin, are receiving a great deal of attention as potential anticancer drugs. The densely substituted and sterically shielded ring D is the particular structural feature of these compounds. The first synthesis of oleandrigenin from easily available steroid starting material is reported here. Furthermore, selected 17ß-(4-butenolidyl)- and 17ß-(3-furyl)-14,16ß-dihydroxy-androstane derivatives were en route synthesized and examined for their Na+/K+-ATP-ase inhibitory properties as well as cytotoxic activities in normal and cancer cell lines. It was found that the furyl-analogue of oleandrigenin/bufatalin (7) and some related 17-(3-furyl)- derivatives (19, 21) show remarkably high Na+/K+-ATP-ase inhibitory activity as well as significant cytotoxicity in vitro. In addition, oleandrigenin 2 compared to derivatives 21 and 25 induced strong apoptosis in human cervical carcinoma HeLa cells after 24 h of treatment.

Synthesis and evaluation of cytotoxic and Na+/K+-ATP-ase inhibitory activity of selected 5α-oleandrigenin derivatives.

Oleandrin, the major biologically active constituent of shrub Nerium oleander preparations of which have been used in traditional Mediterranean and Asian medicine, attracts a great deal of attention due to its pronounced anticancer activity. The synthesis of oleandrigenin model, 16ß-hydroxy-3ß-methoxy-5α-card-20(22)-enolide 16-acetate, from androstenolone acetate through 17ß-(3-furyl)-intermediates has been developed. Several related 17ß-(butenolidyl)- and 17ß-(furyl)-androstane derivatives were synthesized and tested for in vitro cytotoxic and Na+/K+-ATP-ase inhibitory activities. Comparison of Na+/K+-ATP-ase inhibitory and cytotoxic activity underlines complex nature of the relationship.

Synthetic Approach to the Core Structure of Oleandrin and Related Cardiac Glycosides with Highly Functionalized Ring D.

The first synthetic approach to the core structure of cardiac glycoside oleandrin exhibiting a potent cytotoxic activity, starting from a common androstane derivative, has been accomplished. The synthesis is focused on stereoselective transformations in the densely substituted and sterically shielded five-membered ring (steroid ring D). The developed synthesis paves a route to the synthesis of related bufadienolides, i.e., constituents of traditional drug Ch'an Su, bufotalin, and cinobufagin.

Studies towards the total synthesis of di- and sesterterpenes with dicyclopenta[a,d]cyclooctane skeletons. Three-component approach to the A/B rings building block.

Sesqui- and sesterterpenes of ophiobolin and fusicoccin families are important synthetic targets because of complexity of structure and potentially useful physiological activities, including anti-tumor activity. A synthesis of versatile building blocks for these terpenoids is described. Cyclopenta[8]annulene rings system with properly dislocated substituents was constructed using as key steps ring closing metathesis reaction and Wagner - Meerwein rearrangement. Ring closing metathesis reaction leading to cyclopenta[8]annulene was studied in detail.

Synthesis of 17-epi-calcitriol from a common androstane derivative, involving the ring B photochemical opening and the intermediate triene ozonolysis.

An efficient synthesis of 17-epi-calcitriol 2, an epimer of natural hormone, via 17-epi-cholesterol 5a is described. Synthesis of 5a includes palladium-catalyzed cyclopropanation of the common androstane derivative 7 with an alkyl diazoacetate, reductive fission of the less shielded side of cyclopropane carboxylic acid esters 6, oxidation of the products into acid 11a, and alkylation of ester 11b. Photolysis of 7,8-dedydro-17-epi-25-hydroxycholesterol 19b and consecutive thermal rearrangement gave a mixture of several products that was subjected to ozonolysis to provide, after chromatography, hydroxy ketone 3a. The silyl derivative 3b was coupled with the respective ring A building block.

Relation between QRS amplitude and left ventricular mass in the initial stage of exercise-induced left ventricular hypertrophy in rats.

The aim of the study was to analyze the relationship between QRS amplitude and left ventricular mass (LVM) in early stages of two different experimental models of left ventricular hypertrophy (LVH) in rats: in exercise-induced hypertrophy and pathological hypertrophy due to genetically conditioned pressure overload. Three groups of experimental animals were studied: healthy control Wistar-Kyoto rats (WKYs), spontaneously hypertensive rats (SHRs), and WKY rats exposed to training by intermittent swimming (SWIM). Orthogonal electrocardiograms were recorded in each group at the age of 12 and 20 weeks, and the maximum spatial QRS vector (QRSmax) was calculated. Then the animals were sacrificed and LVM was measured. The specific potential of myocardium (SP) was calculated as a ratio of QRSmax to LVM. The QRSmax values did not follow the changes in LVM. At the end of the follow-up period, the highest values of QRSmax were recorded in the control WKY rats (0.80 +/- 0.05 mV). The QRSmax values in both groups with experimental LVH were significantly lower as compared with control animals (SHR 0.44 +/- 0.02 mV, p < 0.001; SWIM 0.53 +/- 0.04 mV, p < 0.001). Similarly, the SP values were significantly lower in both groups with experimental LVH as compared with control animals (SHR 0.42 +/- 0.02 mV/g, p < 0.001; SWIM 0.55 +/- 0.05 mV/g, p < 0.001). A decrease in QRSmax and SP was observed in both models of experimental LVH. We attributed these findings to the changes in electrogenetic properties of myocardium in the early stage of developing LVH. In other words, it is changes of nonspatial determinants that influence the resultant QRS voltage in terms of the solid angle theory.