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Our work was started with the aromatic halogenation of 13α-estrone. 3-O-Methyl- and 3-O-benzyl-protected 13α-estrone were successfully reacted with N-iodo-, N-bromo- or N-chlorosuccinimide to afford 2-, 4- and 2,4-bis-substituted derivatives at ring A. These were formed in short reaction times and good yields. Conversions could be significantly influenced by changing the solvent of the reaction and varying the quantity of the reactant. The presence of the phenolic OH group facilitates both mono- and double substitution. 3-Protected compounds yielded only monosubstituted derivatives. The 3-O-benzyl ether showed reduced reactivity, only bromination and chlorination occurred in this case. Similar halogenations of 17-deoxy-13α-estrone with N-halosuccinimide were carried out to synthesize 2-, 4- and 2,4-bis-substituted derivatives. A comparison of the results obtained in the halogenation of 17-oxo and 17-deoxy starting compounds allowed the conclusion that analogous derivatives were formed in different ratios. In the 17-deoxy series in some cases major changes in conditions were required to have the desired compounds.  We have developed a convenient synthetic microwave procedure for Sonogashira coupling using the synthesized halogen compounds as starting materials. The reaction of 2-iodo-3-O-methyl-13α-estrone with phenylacetylene could efficiently be achieved using Pd(PPh3)4 catalyst and CuI cocatalyst in dimethylformamide in the presence of Et3N as a base, at 50 °C in 20 min in a microwave reactor. After establishing the most favourable reaction conditions using phenylacetylene as the alkyne partner, the method was successfully adapted to compounds with phenolic 3-OH function by the change of solvent to acetonitrile. We extended the scope of the steroid component to 4-iodo derivatives. We found that elevation of the reaction temperature to 80 °C and the change of catalyst to Pd(PPh3)2Cl2 facilitated substitution at C-4. Iodo compounds bearing phenolic OH required the changing of solvent to tetrahydrofuran. We isolated the desired 4-phenethynyl compound in short time and excellent yield. The protocol developed for phenylacetylene was successfully extended to the synthesis of 4-(4’-subst.)phenethynyl derivatives.  We carried out the semihydrogenation of certain compounds synthesized by Sonogashira coupling. Microwave-assisted partial saturation of (4’-methoxyphenyl)ethynyl compounds was achieved in the 3-methyl ether series. We applied DMF/KOH as the hydrogen source and Pd(PPh3)2Cl2 as the catalyst. Under the applied conditions, cis-alkenes were formed from 2-phenethynyl derivatives while 4-phenethynyl derivatives led to trans-alkenes chemo- and stereoselectively. Semihydrogenation of compounds bearing phenolic OH did not result in 2- or 4-phenethenyl compounds; rather, formation of benzo[b]furans occurred. Additionally, we transformed 2- and 4-phenethynyl derivatives in ethyl acetate under 20 bar H2 with palladium-on-charcoal to 2- and 4-phenethyl derivatives, respectively, in excellent yields.  We performed not only C–C but C–N cross couplings as well starting from the ring A halogenated derivatives. We have developed an efficient protocol for the Buchwald–Hartwig amination of 2-bromo-3-O-methyl-13α-estrone with aniline. An optimization process was performed by the systematic changes of catalyst, base and ancillary ligand. We compared conventional heating and microwave-assisted heat transfer and found that microwave irradiation shortened reaction times significantly. The highest yields were achieved by using Pd(OAc)2 as catalyst, KOtBu as base and XPhos as ancillary ligand at 100 °C in a microwave reactor. With the best reaction conditions in hand, couplings at C-2 were extended to monosubstituted anilines bearing substituents at ortho, meta or para positions with varied electronic properties. All couplings proceeded with high yields. We noticed that the electronic nature of the substituents influenced the conversion slightly but their position did not have any effect.  4-Bromo-3-O-methyl- and 2- or 4-bromo-3-O-benzyl-13α-estrone were successfully aminated with aniline without the need for changing reaction conditions established for couplings at C-2.  Coupling with benzophenone imine instead of aniline was performed in order to gain 2- or 4-amino derivatives. 2- and 4-(N-diphenylmethylideneamino)-13α-estrones were efficiently transformed into the appropriate amino counterparts in a subsequent reaction step. Liberation of the NH2 function was achieved by Bronsted acid in the case of 3-methyl ethers and via hydrogenolysis from the 3-benzyl ether using palladium-on-charcoal catalyst.  In the final part of our work we have synthesized BODIPY-based fluorescent estrone conjugates via CuAAC. First, we synthesized estrone derivatives and BODIPY-dyes (BODIPY1-alkyne, BODIPY2-azide) containing alkyne or azide moiety. We performed the labelling of ring A (at C-2) and ring D (at C-15) of estrone. Novel BODIPY-azide was synthesized via condensation of trisubstituted pyrrole and ω-bromovaleric chloride formed in situ. Bromo-BODIPY was formed with BF3.OEt2 and base without the isolation of the intermediate. The new BODIPY-azide was formed in a bromine-to-azide exchange reaction.  We carried out Michael addition on Δ15,16 estrone in order to introduce the azide group or O-propargyl nucleophile to position 15. The nucleophiles attacked in a stereoselective manner from the β direction to C-15 leading to the formation of 15β-azide and 15β-O-propargyl derivatives. Additionally, we introduced the ethynyl group onto C-2 by coupling trimethylsilylacetylene (TMSA) via our microwave-assisted protocol established previously. Deprotection was carried out with tetrabutylammonium fluoride (TBAF) in situ during the “click” reaction. With the necessary alkynes and azides in hand, we conjugated the BODIPY dyes with the steroids. CuAAC reactions yielded the desired fluorescent estrone conjugates in short reaction time under conventional heating in good yields.  We have synthesized several novel potent antitumoral 13α-estrone derivatives. Certain new ring A substituted compounds efficiently inhibited the key enzymes of estrogen biosynthesis. We also synthesized novel fluorescent estrone-BODIPY conjugates, which might serve as labelled substrates in the development of fluorescent biochemical assays.

Ösztrán vázas vegyületek A- és D-gyűrűben történő módosítása