Jaroslav Kalvoda

A convenient synthesis of 1α- and 1β-hydroxycholesterol

Abstract An efficient procedure for the preparation of 1α-hydroxycholesterol 3-acetate 4 is described, which starts from cholesterol and involves as key steps transannular cyclization of the ten-membered ring ontaining (E)-3β-acetoxy-5,10-seco-1(10)-cholesten-5-one 1 to the oxetane derivative 1α,5-epoxy-5α-cholestan-3β-ol acetate 3, and opening of the four-membered ether ring in the latter compound. 1β-Hydroxycholesterol diacetate 9 was obtained by oxidation of 4 to the 1-oxo derivative 8, followed by metal hydride reduction and acetylation.

Three novel mimics for the construction of sterically constrained protein turn models

Abstract 8-Amino-5,6,7,8-tetrahydro-2-naphthoic acid (1), 8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (2), and 8-aminomethyl-2-naphthoic acid (3) were synthesized in their protected forms for use in the construction of sterically constrained protein turn models.

Synthesis, structure and reactions of seco-steroids containing a medium-sized ring—IX : Reactions of Δ1(10)-unsaturated 5-oxo-5,10-seco-steroids with hydroxylamine and n-methylhydroxylamine

Abstract When treated with hydroxylamine or N-methylhydroxylamine, in the presence of proton donor catalysts, trans-Δ1(10)-unsaturated 5-oxo-5,10-seco-steroids, such as 3 (but not the corresponding diastereomeric cis-compounds), are converted stereospecifically and in good yield to isoxazolidine derivatives (e.g. 4 and 13), resulting from transannular 1,3-dipolar addition of the intermediately formed oximes and nitrones to the trans-double bond in the cyclodecene ring moiety of the seco-steroid system. Reactions are described and physical evidence is presented which establish the constitution and configuration of the isoxazolidine-containing cycloaddition products, and the mechanistic and steric course of this transannular ring closure process is discussed.

13,14-seco-steroids: A new type of modified steroids containing a nine-membered ring

Oxidations of 14 alpha-hydroxy-5 alpha-cholestan-3 beta-yl acetate (5) with lead tetraacetate under thermal or photolytic conditions or in the presence of iodine proceed mainly by fragmentation of the C(13)-C(14) bond to give as the primary products the 13,18-didehydro-13,14-seco derivative 6 and the (E)-Delta(12)-13,14-seco ketone 11, respectively. Further transformations of these compounds under conditions of their formation afforded, in addition, the acetoxy derivatives 7-9 (from 6), and the D-homo-C-nor compound 12 and (12R,13R)-epoxide 13 (from 11). Unexpectedly, the photolytic lead-tetraacetate oxidation of 5 resulted partly (to ca. 20%) in a reversible fragmentation involving scission and recombination of the C(8)-C(14) bond followed by formation of rite 14 beta,22-ether 10. Possible mechanisms for the observed transformations are discussed.

Synthese von 18-Methyl-Corticosteroiden

The synthesis of a representative (9α-fluoro-18-methyl-prednisolone) of the new class of 18-methylcorticosteroids is described.

Between basic and applied research: Ciba's involvement in steroids in the 1950s and 1960s

Through its collaboration with the ETH in Zurich (Ruzickas group) and later on with the University of Basel (Reichsteins group). Ciba became involved very early in steroid chemistry. The main task of the chemists consisted at that time of the synthesis of natural hormones and their derivatives. Cholesterol served for several years as the preferred starting material, and efficient procedures were developed for its degradation to suitable intermediates. Total syntheses of estrogenic substances were pursued independently. Up to the mid-1950s the search for alternative starting materials, like hecogenin were intensively investigated. In a later period, collaboration with various companies in the United States and in Europe stimulated Cibas involvement in the corticoids, especially the dermatocorticoids (Locorten, Sicorten, Miracortene/Ultravate). In line with Cibas traditionally strong engagement in process development, during the period described in this report a major effort, was directed towards the isolation and synthesis of aldosterone, the most active natural mineralocorticoid. In connection with its partial synthesis, new intramolecular radical reactions (e.g., the lead(IV) acetate and the hypoiodite reaction) were discovered and studied. Although, from the commercial point of view, aldosterone did not meet our expectations, the application of these new reactions to the synthesis of 19-norsteroids opened for Ciba the road to progestins and related compounds.

An unusual ozonolysis of the Delta(8(14))-unsaturated steroids

Ozonolysis of the Δ8(14)-unsaturated steroids 1a,b afforded, instead of the expected 8,14-dioxo-8,14-seco derivatives 2a,b two stereoisomeric Δ7-unsaturated ozonides 3a,b and 4a,b.

REACTIONS OF STEROIDAL 1,3-DIKETONES WITH SULFUR TETRAFLUORIDE

Steroidal 1,3-diketones of type 9 and 15 have been used as substrates in the study of the reaction of enolizable β-diketones with sulfur tetrafluoride in benzene. In a smooth reaction β-fluoro-(10; 17) and β-phenyl-(11; 18) enones are generated. In the case of the ring-A-dione 15 in addition, the alkynyl acyl fluoride 16 is formed in 35% yield. The different products formally derive from the corresponding activated tautomeric enols. A unifying mechanism involving vinyl cation-type species B and G is discussed.