SYNTHESIS OF SILA-ANALOGS AND SILICON-CONTAINING DERIVATIVES OF DRUGS AND DEVELOPMENT AND APPLICATION OF THE Si-2,4,6-TRIMETHOXYPHENYL MOIETY AS A NOVEL PROTECTING GROUP IN ORGANOSILICON CHEMISTRY DISSERTATION ZUR ERLANGUNG DES NATURWISSENSCHAFTLICHEN DOKTORGRADES DER BAYERISCHEN JULIUS-MAXIMILIANS-UNIVERSITÄT WÜRZBURG VORGELEGT VON DIPLOM-CHEMIKER JÜRGEN OLIVER DAIß AUS HEILBRONN WÜRZBURG 2004 SYNTHESIS OF SILA-ANALOGS AND SILICON-CONTAINING DERIVATIVES OF DRUGS AND DEVELOPMENT AND APPLICATION OF THE Si-2,4,6-TRIMETHOXYPHENYL MOIETY AS A NOVEL PROTECTING GROUP IN ORGANOSILICON CHEMISTRY DISSERTATION ZUR ERLANGUNG DES NATURWISSENSCHAFTLICHEN DOKTORGRADES DER BAYERISCHEN JULIUS-MAXIMILIANS-UNIVERSITÄT WÜRZBURG VORGELEGT VON DIPLOM-CHEMIKER JÜRGEN OLIVER DAIß AUS HEILBRONN WÜRZBURG 2004 Eingereicht am: ................................................. bei der Fakultät für Chemie und Pharmazie 1. Gutachter:...................................................... 2. Gutachter:...................................................... der Dissertation 1. Prüfer:............................................................ 2. Prüfer:............................................................ 3. Prüfer:............................................................ des Öffentlichen Promotionskolloquiums Tag des Öffentlichen Promotionskolloquiums: ....................... Doktorurkunde ausgehändigt am: ..................... TABLE OF CONTENTS I Table of Contents 1 Introduction ..............................................................................................1 2 Aim ............................................................................................................3 2.1 Sila-venlafaxine ................................................................................................3 2.1.1 Derivatives of sila-venlafaxine ....................................................................4 2.1.2 Prodrugs of sila-venlafaxine .......................................................................5 2.2 Disila-bexarotene .............................................................................................5 2.3 Disila-AG-045572 (disila-CMPD1)....................................................................7 2.4 (Chloromethyl)silanes.......................................................................................7 2.4.1 Tris(chloromethyl)silanes............................................................................7 2.4.2 Dichlorobis(chloromethyl)silane..................................................................8 2.5 Silicon-based allosteric modulators of muscarinic M2 receptors.......................8 2.6 Sila-gabapentin ..............................................................................................10 3 Synthesis of sila-venlafaxine and derivatives.....................................11 3.1 Synthesis of racemic and non-racemic sila-venlafaxine .................................11 3.1.1 Method A: synthesis of rac-sila-venlafaxine (rac-12b) via a hydridosilane ............................................................................................11 3.1.2 Method B: synthesis of rac-sila-venlafaxine (rac-12b) using the Si-2,4,6-trimethoxyphenyl group as a protecting group ............................12 3.1.3 Resolution of rac-sila-venlafaxine (rac-12b) .............................................13 3.2 Synthesis of the rac-sila-venlafaxine derivative rac-1-[2-(dimethylamino)- 1-(4-methoxyphenyl)ethyl]-1-silacyclopentan-1-ol (rac-13).............................14 3.3 Attempted synthesis of the rac-sila-venlafaxine derivative rac-1-[2-(dimethyl- amino)-1-(4-methoxyphenyl)ethyl]-1-silacyclobutan-1-ol (rac-14) ..................15 3.4 Synthesis of rac-desmethoxy-sila-venlafaxine (rac-1-[2-(dimethylamino)- 1-phenylethyl]-1-silacyclohexan-1-ol, rac-15).................................................17 3.5 Synthesis of sila-venlafaxine prodrugs ...........................................................18 4 Synthesis of disila-bexarotene .............................................................20 II TABLE OF CONTENTS 5 Synthesis of disila-AG045572 ...............................................................21 6 Synthesis of (chloromethyl)silanes......................................................25 6.1 Synthesis of chlorotris(chloromethyl)silane (23) and tris(chloromethyl)methoxysilane (24)..............................................................25 6.2 Synthesis of dichlorobis(2,4,6-trimethoxyphenyl)silane (104) and attempted synthesis of dichlorobis(chloromethyl)silane (25) via 104 ..............................25 7 Synthesis of W84-type silicon-based allosteric modulators of muscarinic M2 receptors........................................................................27 7.1 Synthesis of silicon-based allosteric modulators containing a quaternary ammonium nitrogen atom...............................................................................27 7.2 Synthesis of a silicon-based allosteric modulator containing a tertiary nitrogen atom .................................................................................................32 8 Synthesis of β-carbonylsilanes: partial synthesis of sila-gabapentin.......................................................................................33 9 Biological studies ..................................................................................35 9.1 Sila-venlafaxine and derivatives .....................................................................35 9.2 Silicon-based allosteric modulators of muscarinic receptors ..........................36 10 The performance of the Si-2,4,6-trimethoxyphenyl moiety as a novel protecting group in organosilicon chemistry ...........................38 10.1 Discussion......................................................................................................38 10.2 Conclusions....................................................................................................40 11 Results of the single-crystal X-ray diffraction studies .......................42 11.1 rac-Sila-venlafaxine hydrochloride (rac-12b⋅HCl)...........................................42 11.2 (R)-Sila-venlafaxine hydrobromide ((R)-12b⋅HBr) ..........................................44 TABLE OF CONTENTS III 11.3 rac-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclopentan-1-ol (rac-13)...........................................................................................................45 11.4 rac-Desmethoxy-sila-venlafaxine (rac-1-[2-(dimethylamino)-1-phenylethyl]- 1-silacyclohexan-1-ol, rac-15) ........................................................................46 11.5 rac-Desmethoxy-sila-venlafaxine hydrochloride (rac-[2-(1-hydroxy-1-sila- 1-cyclohexyl)-2-phenylethyl]dimethylammonium chloride, rac-15⋅HCl) ..........47 11.6 Bexarotene (21a)............................................................................................48 11.7 Disila-bexarotene (21b)..................................................................................49 11.8 Disila-AG-045572 (22b)..................................................................................50 11.9 1-Methoxy-1-(2,4,6-trimethoxyphenyl)-1-silacyclohexane (61).......................51 11.10 1-[1-(4-Methoxyphenyl)vinyl]-1-(2,4,6-trimethoxyphenyl)-1-silacyclohexane (62).................................................................................................................52 11.11 1-Methoxy-1-(2,4,6-trimethoxyphenyl)-1-silacyclobutane (74)........................53 11.12 1-[1-(4-Methoxyphenyl)vinyl]-1-(2,4,6-trimethoxyphenyl)-1-silacyclobutane (75).................................................................................................................54 11.13 Methyl 4-[1-(3,5,5,8,8-pentamethyl-5,8-disila-5,6,7,8-tetrahydro-2- naphthyl)vinyl]benzoate (89) ..........................................................................54 11.14 5-[(3,5,5,8,8-Pentamethyl-5,8-disila-5,6,7,8-tetrahydro-2-naphthyl)methyl]- 2-furoic acid (99) ............................................................................................55 11.15 Tris(chloromethyl)(2,4,6-trimethoxyphenyl)silane (103) .................................56 11.16 Dichlorobis(2,4,6-trimethoxyphenyl)silane (104) ............................................56 11.17 1,1´-Oxybis{[(1-sila-1-cyclohexyl)methyl]ammonium} dichloride dihydrate (145⋅2H2O) .....................................................................................................57 11.18 1,1'-(Oxybis-1-silacyclobutane-1,1-diyl)bis(2,4,6-trimethoxybenzene) (146) ..58 12 Summary.................................................................................................60 12.1 Sila-venlafaxine and derivatives .....................................................................60 12.2 Disila-bexarotene ...........................................................................................63 12.3 Disila-AG045572 ............................................................................................63 12.4 (Chloromethyl)silanes.....................................................................................65 12.5 Silicon-based allosteric modulators of muscarinic M2 receptors.....................65 12.6 β-Carbonylsilanes...........................................................................................68 13 Zusammenfassung ................................................................................69 IV TABLE OF CONTENTS 13.1 Sila-venlafaxin und Derivative ........................................................................69