Browsing by Author "Bull, James R"

Now showing 1 - 16 of 16
  • Thumbnail Image
    Item
    Open Access
    Approaches toward the enantioselective total synthesis of amarogentic
    (2001) Stevens, Anne Therese; Bull, James R; Chibale, Kelly
    Three different, but complementary strategies for the enantioselective synthesis of the secoiridoid core of amarogentin were evaluated. The first is based on the enantioselective desymmetrisation of meso-anhydrides using titanium TADDOLates. 1,2,4,6-Tetrahydrophthalic anhydride was desymmetrised and chemoselectively reduced to give (3aR, 7aS)-3a,4,7,7a-Tetrahydro-3H-isobenzofuran-1-one. Further development of this route was performed on a racemic model.
  • Thumbnail Image
    Item
    Open Access
    Chemistry and properties of perhydrobenzo[4.5.6]cholestanes
    (1997) Mohamed, Camielah; Bull, James R; Gammon, David
    The investigations undertaken include an intramolecular Michael-aldol approach and a cycloaddition approach to the synthesis ofperhydrobe,nzo[4.5.6]cholestanes. A reaction sequence has been developed to obtain the 3 P-acetoxy-4cx.,5cx. - dihydrobenzo [ 4.5 .6] cholestan-5' (6'H)-one 85 in an optimised yield from the 3Pacetoacetoxy-i:4-6-ketone 71. The key steps in the transformation involved base-treatment of the 3P-acetoacetoxy enoneto give (2R)-2-(3P-hydroxy-6-oxo-5P-cholestan-4p-yl)-3- oxobutanoic acid 1,3'-lactone 79, which was followed by_lactone cleavage, decarboxylation and intramolecular aldol closure of the derived lactone to give 3P,6-dihydroxy4cx.,4',5P,6P-tetrahydrobenzo[4.5.6]cholestan-5'(6'H)-one 81. Treatment of 3P-acetoxy-6- hydroxy-4cx.,4',5P,6P-tetrahydrobenzo [4.5.6] cholestan-5'(6'H)-one 82 with HMPA and phosphoryl chloride gave the 3p-acetoxy-4cx.,4', sp,6-tetrahydrobenzo [ 4.5.6] cholest-6-en5'(6'H)-one 83 and the 4cx.,5cx. -i:4 '-isomer 85. The formation of 3p-hydroxy-4cx.,5cx. - dihydrobenzo [4.5.6] cholestan-5'(6'H)-one 80 when treating the lactone 79 with potassium hydroxide indicated an alternative reaction pathway to the 4cx.,5cx. -isomer. However, conditions were not established for the isolation of the 4cx.,5cx. -i: 4 '-isomer 80 in an appreciable yield. Access to the 4cx.,5P-isomer was achieved by treating the 3P-acetoxy-6p-hydroxy derivative 82 with BF3.OEt2 which gave the 4cx.,5p-i:6 -isomer 83 and 3P-acetoxy-4cx.,4',5P, 6-dihydrobenzo [4.5.6] cholestan-5'(6'H)-one 86. Thionyl choride-pyridine treatment of the 3 P-acetoxy-6p-hydroxy derivative 82 gave an inconclusive result including the formation of the expected 4cx.,5(3-i:6 -isomer 83. The expected thermodynamic relationship between the 4cx.,5cx. -isomer 85 and the 4P,5cx. -isomer was confirmed by base equilibration of the 4cx.,5cx. -isomer into the 4p,5cx. -isomer. Detailed 400 MHz 1 H and 13C NMR data of key pentacyclic cholestanes enabled interpretations about their structural ~d conformational properties and related thermodynamic stabilities. 2 The Diels-Alder cycloaddition of 6-methylenecholest-4-en-3p-ol 96 with acrolein and methyl vinyl ketone gave 6' a-acetyl-4P,4' ,5' p,6' -tetrahydrobenzo[ 4.5 .6]cholestan-3 Pyl acetate 97 and 3P,6'-epoxymethano-4P,4' ,5' ,6'-tetrahydrobenzo[4.5.6]cholestan-6' 1 P-yl acetate 98 respectively. The structures of these cycloaddition products were determined with 400 MHz 1H and 13C NMR data which included NOE spectra. The 6' -H orientation in the cycloadduct 98 could however not be established unambiguously.
  • Thumbnail Image
    Item
    Open Access
  • Thumbnail Image
    Item
    Open Access
    Cycloaddition studies in steroidal 14,16-dienes
    (1991) Loedolff, Michiel C; Bull, James R
    Studies have been conducted in synthesising ring D-substituted steroidal 14,16-dienes. The aim was to explore the scope for carrying out cycloaddition reactions, and exploiting the built-in bridge substituents of derived 14,17-cycloadducts, for eventual conversion into bridge-functionalised 19-norsteroids.
  • Thumbnail Image
    Item
    Open Access
    Cycloaddition-fragmentation mediated pathways to ring D modified 19-norsteroids
    (1997) Sickle, Eugene Stanford; Bull, James R
    An efficient strategy for the synthesis of 14β-3'-oxobutyl 19-norsteroids has been developed and the intramolecular reactivity of the derived compounds has been investigated. The approach is based on cycloaddition of methyl vinyl ketone to 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate which proceeded with a high degree of regio- and stereoselectivity to give 16α-acetyl-3-methoxy-14, 17α-ethenoestra-1 ,3,5(1 O)-trien-17β-yl acetate. The cycloadduct underwent base mediated fragmentation, affording an efficient and stereocontrolled synthesis of 3-methoxy-14β-3'-oxobutylestra-1,3,5(10),15-tetraen-17-one which in turn gave 3-methoxy-5',6'-dihydro-15αH-benzo[14,15]-14β-estra-1,3,5(1O)-trien-4'(3'H), 17-dione via an intramolecular Michael reaction. Regioselective deoxygenation of the dione at C-4', followed by standard functional group modifications provided the parent 14β-perhydrobenzo[14,15]-estradiol analogues. An alternative, more expedient, route to this novel steroidal ring system was developed which relied on an anionic oxy-Cope rearrangement as the key step. Thus methylenation of the cycloadducts derived from reaction of the dienyl acetate and selected dienophiles (acrolein and methyl vinyl ketone) gave after hydrolysis of the bridgehead ester, substrates which underwent [3,3]sigmatropic rearrangement to generate a series of 14β-perhydrobenzo[14,15]-17-ketones.
  • Thumbnail Image
    Item
    Open Access
    Design and synthesis of ring D modified steroidal hormones
    (1992) Grundler, Claudia; Bull, James R
    Cycloadditions of steroidal 14,16-dienes with ketene equivalents were investigated, as routes to estradiol and estriol analogues. The cycloadduct of 3-methoxyestra-1,3,5(10), 14,16-pentaen-17-yl acetate and 2-chloroacrylonitrile underwent an unprecedented tandem rearrangement, on attempted alkaline hydrolysis to the corresponding ketone. This product, obtained in ca. 90% yield, was formulated as (16¹R)-3-methoxy-17-oxo-15β,16¹-cyclo-14,16β-ethano-14β-estra-1,3,5(10)-triene-16¹-carbonitrile. The chemistry of the 16¹-carbonitrile was extensively studied and, in addition, the derived estradiol analogues were prepared and evaluated for receptorbinding affinity. The 16¹-carbonitrile, and its derivatives, could be transformed into 14,15-dihydrocyclobutano or 14β,16β-bridged compounds by cleavage of a cyclopropyl bond. Indeed, a 14,15-dihydrocyclobutano estradiol analogue was synthesised and submitted for biological evaluation. The cycloadduct of 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate and 2-acetoxyacrylonitrile afforded the corresponding 17-hydroxy 16-oxo compound on alkaline hydrolysis. The 17-hydroxy 16-oxo compound was efficiently converted to the 14α,17α-ethano 15,16-etheno compound by the Shapiro reaction. Reduction of the 17- hydroxy 16-oxo compound led to the formation of the corresponding 16,17-diols, which gave the derived 14β-compounds on glycol cleavage. Furthermore, under acidic conditions the 16,17-diols were found to undergo high yield 16(17 --> l7¹)abeo rearrangements, to afford 14,16-etheno compounds.
  • Thumbnail Image
    Item
    Open Access
    Intramolecular Diels-Alder reactions of conformationally restricted systems
    (2000) Gordon, Richard Spencer; Bull, James R; Hunter, Roger
    In the first phase of this investigation, the synthesis of triene systems, linked via a diester tether was investigated with the aim of studying the respective thermal Intramolecular Diels-Alder (IMDA) properties. It was envisaged that the diene and dienophile would be linked via a conformationally restricted spacer, trans-cyc1ohexane-l,2-dicarboxylic acid anhydride.
  • Thumbnail Image
    Item
    Open Access
    Novel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroids
    (1995) Mountford, Pia Gail; Bull, James R
    An efficient synthetic strategy for the stereoselective introduction of a 14β-allyl group to estrone 3-methyl ether has been developed. The approach involves regio- and stereoselective Diets-Alder cycloaddition of acrolein to 3-methoxyestra-1,3,5(10),14,16- pentaen-17-yl acetate. Hydride reduction of the formyl group of the cycloadduct, followed by tosylation of the resultant primary hydroxy group, gave rise to a 17β-alkoxy 16¹-tosylate. Base-mediated Wharton fragmentation of the 1,3-removed diol derivative produced the 14β-allyl Δ¹⁵-17-ketone. Chemoselective conjugate reduction of the ring enone gave rise to 14-allyl-3-methoxy-14β-estra-1,3,5(10)-trien-17-one in 51% overall yield for five steps. Regioselective oxidation of the 14β-allyl group furnished precursors for intramolecular coupling reactions with the 17-oxo group, providing access to a series of 14β,17β-propanoestradiol and 'estriol' analogues. Wacker oxidation of the 14-allyl-3-methoxy-14β-estra-1,3,5(10),15-tetraen-17- one gave rise to both the 14β-acetonyl and 14β-formylethyl derivatives. The acetonyl enone underwent cerium(III)-mediated aldol condensation with the 17-oxo group to yield the 14β,17β-propano Δ¹⁵-estradiol analogue. This series of β-face propano bridged estradiols displayed no competitive binding affinity for the estradiol receptor. The enolisable 14β-acetonyl group was also shown to undergo smooth Michael addition to C(15). The product, 3-methoxy-3'H,l5αH-cyclopenta[14,15]-14β-estra-1,3,5(10)-triene- 4'(5'H),17-dione, was regioselectively deoxygenated and reduced to yield the 3,17- estradiol analogues. The 3,17β-estradiol displayed promising binding affinity for the estradiol receptor site, whereas the 17α-epimer was biologically inactive. The 14β-formylethyl enone underwent vinylogous reductive cyclisation with C(lS), to yield the 3'-hydroxy cyclopenta[14,15] 17-ketone. No regioselective coupling with the 17-oxo group was observed. Various attempts to homologate ring D of the 14β-allyl 17-ketone or its Δ¹⁵-analogue are described, none of which were successful. However, the silyl enol ether derivative of estrone 3-methyl ether underwent facile cyclopropanation of the Δ¹⁶-bond. Iron(III) chloride-mediated cleavage of the zero bridge of the resultant bicyclo[3.1.0] hexanoid intermediate gave rise to the D-homo Δ¹⁶-17a-ketone. Conversion of the en one into the derived 14,16-dienyl 17a-ketone furnished an intermediate for conjugate addition studies.
  • Thumbnail Image
    Item
    Open Access
    Stereoselective reactions of 16-Methylene 19-Norsteroids
    (1991) Kaiser, Delene Anne; Bull, James R
    The influence of the 17-substituent upon epoxidation of 3-methoxy-16-methylene-estra- 1,3,5(10)-trien-17-one and the derived 17β-hydroxy and 17β-acetoxy compounds was investigated. Alkaline hydrogen peroxide epoxidation of 3-methoxy-16-methyleneestra- 1,3,5(10)-trien-17-one occurred in good yields, but poor stereoselectivity was obtained due to mechanistic considerations. Poor stereoselectivity was also obtained for the peracid epoxidation of 3-methoxy-16-methylene-estra-1,3,5(10)-trien-17β-ol, due to the pseudo-equatorial position of the 17β-hydroxyl group. However, excellent stereoselectivity was obtained using Sharpless conditions (vanadium catalyst), which gave only the epoxide syn to the hydroxyl group, in good yields. Surprisingly, peracid epoxidation of 3-methoxy-16-methylene-estra-1,3,5(10)-trien-17β-yl acetate favoured equatorial attack resulting in a 2:1 ratio of the (16R)- and (16S)-epoxide isomers, instead of the expected axial approach by the peracid.
  • Thumbnail Image
    Item
    Open Access
    Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes
    (1992) Borry, Joost; Bull, James R
    An intramolecular Michael-aldol reaction sequence has been developed for the stereocontrolled synthesis of pentacyclic steroids! with the new six-membered ring attached to the C(4) and C(6) positions. Cholesterol was converted into 3β-hydroxycholest-4-en-6-one by standard methods, and the corresponding 3α-isomer was obtained through Mitsunobu inversion. Acetoacetylation of the 3-alcohols afforded the corresponding 3β- and 3α-acetoacetoxycholest-4-en-6-ones, which served as substrates for an investigation of intramolecular condensation routes to the target ring systems. Base treatment of the 3β-ester resulted in an efficient and stereocontrolled intramolecular Michael addition to give (2R)-2-(3β-hydroxy- 6-oxo-5β-cholestan-4β-yl)-3-oxobutanoic acid 1,3'-lactone, and reaction conditions were developed to achieve sequential lactone cleavage, decarboxylation, and aldol closure, leading to 3β,6-dihydroxy- 4α,4',5β,6β-tetrahydrobenzo[4.5.6]cholestan-5'(6'H)-one. Although this product resisted base-mediated B-elimination, acid treatment resulted in dehydration to give the corresponding Δ⁶-compound. which underwent double bond isomerisation and 5-epimerisation. to give 3β-hydroxy- 4α,5α-dihydrobenzo[4.5.6]cholestan-5'(6'H)-one. A similar series of reactions was performed on the 3α-acetoacetate, leading finally to formation of 3α-hydroxy-4β,5α-dihydrobenzo[4.5.6]cholestan-5'(6'H)-one. Modification of foregoing reaction conditions, resulted in the design of a tandem Michael-aldol sequence, in which the 3-acetoacetates could be converted directly into the corresponding pentacyclic enones. These products were interrelated via base-mediated equ1llbration of their respective 3,6-diketones, leading to the thermodynamically favoured 4β,5α-isomer. Preliminary investigations into the stereoselective reduction of the olefinic bond in the 4α.5α-isomer, resulted in the formation of a new class of. hexahydrobenzo[4.5.6]cholestane derivatives. The structural and conformational properties of the condensation products were studied with the aid of ¹H NMR, ¹³C NMR, and IR spectroscopy.
  • Thumbnail Image
    Item
    Open Access
    Studies in ring D fragmentation of estrone
    (1998) Ray, Peter Christopher; Bull, James R
    Studies have been conducted in synthesising 14-allyl 19-norsteroids. The eventual aim is to convert the 14-allyl derivatives into bridge-functionalised 19-norsteroids. Two approaches were investigated, with the immediate aim of generating fragmentation intermediates suitable for 14-allylation. The approaches were based on cleavage of the 16,17-bond via oxidative cleavage or fragmentation methodology. The oxidative cleavage routes involved the preparation of 3-methoxy-17 –methylestra-1,3,5(10), 16-tetraen-15-one, which was shown not to undergo regioselective 14-methylation. In an alternative approach 3-methoxy-17a-methylestra-1,3,5(10),14tetraene- 16β, 17β-diol was synthesised. However, the lability of the primary cleaved product prompted synthesis of 3-methoxy-16,17-seco-17a-homoestra-1,3,5(10)-triene16,17a- dione. Chemodifferentiation of the carbonyl groups of the seco derivative provided access to 16-acetoxy-3-methoxy-16, 17-seco-17a-homoestra-1,3,5(10)-trien-17a-one, in an overall yield of 60% from estrone 3-methyl ether. The fragmentation approaches involved conjugate stannylation and silylation of 3-methoxyestra-1,3,5,(10), 15-tetraen-17 -one to give the 15β-trimethylstannyl and 15β-trimethylsilyl 17 -ketones respectively. The stannyl ketone was converted to the 3-methoxy-17a-methyl-15β-trimethylstannylestra-1,3,5,(10)-trien-l7β-ol. Generation of the derived alkoxy radical resulted in formation of 3-methoxy-16, 17-seco-17a-homoestra1,3,5( 10),15-tetraen-17a-one, in low yield, The silyl ketone was converted to the 17acetoxyimino- 3 -methoxy-15β-trimethylsilylestra-l,3,5( 10)-trien, Fragmentation with the borontrifluoride diethyl ether complex resulted in formation of the undesired 3-methoxy13,17-secoestra-l ,3,5(1 0),l4-tetraen-17-nitrile. Since the 15β-trimethylsilyl group did not direct the fragmentation, the 17-acetoxyimino-3-methoxy-16β-trimethylsilylmethylestra-1,3,5(10)-triene was synthesised in the hope that it would be more amenable to silicon directed fragmentation, However, fragmentation with the boron trifluoride diethyl ether complex resulted In formation of the undesired 17-acetoxy-3-methoxy 16β-trimethylsilylmethyl-17a-aza-17a-homoestra-1,3,5(10), 17-tetraene.
  • Thumbnail Image
    Item
    Open Access
    Synthesis and cycloaddition chemistry 1,3-Bis(phenylsulfonyl)propadiene
    (1998) Desmond-Smith, Nicholas Stuart; Bull, James R; Hunter, Roger
    An efficient synthesis of the highly activated I J-bis(phenylsulfonyl)propadiene is described. Starting from benzenesulfonyl chloride and propargyl bromide the key step of the synthesis is the addition of benzene sulfonyl iodide to phenylsulfonylpropyne. This is demonstrated to occur under thermal conditions in the presence of a radical initiator to obtain (E)-2-iodo-1 ,3-bis(phenylsulfonyl)prop-I-ene. Triethylamine induced dehydroiodination of the above addition product afforded high quality 1,3bis( phenylsulfonyl)propadiene after an aqueous reverse quench procedure without further purification. I ,3-Bis(phenylsulfonyl)propadiene was sho'TI to be stable under refluxing conditions towards diethyl ether, chloroform, ethyl acetate and benzene. Reaction with methanol occurred to yield (E)-2-methoxy-1 ,3-bis(phenylsulfonyl)prop-I-ene and with tetrahydrofuran to yield 2-(2-tetrahydrofuranyl)-(E)-1 ,3-bis(phenylsulfonyl)propene, in a novel insertion reaction. The homocyclisation of 1,3-bis(phenylsulfonyl)propadiene under thermal conditions was demonstrated to yield the highly substituted 2,7bis( phenylsulfonylmethylene)-3,4,5,6-tetraphenylsulfonyI-spiro[3.3.0]heptane. Reaction with cyclopentadiene, furan, butadiene and Danishefsky's diene has been conducted in a regio- and peri-selectivity study to yield the [4+2] cycloadducts. Treatment of the furan cycloadducts with potassium t-butoxide opened up the oxygen bridge of three of the furan cycloadducts and resulted in aromatisation to the 3-phenylsulfonyl-2phenylsulfonylmethylphenol. The remaining cycloadduct was converted to the phenol derivative by treatment with sodium hydride. Potassium methoxide treatment of the furan cycloadducts resulted in the isolation of a methoxide addition product together with the aromatised adduct. Procedures for the synthesis ofphenylsulfinylpropadiene and phenylsulfonylpropadiene are described.
  • Thumbnail Image
    Item
    Open Access
    Synthesis and selective reactivity of 14β-formyl 19-norsteroids
    (1995) Hoadley, Clarissa; Bull, James R
    A synthetic route to 3-methoxy-16-methyl-14,17α-ethanoestra-1,3,5(10)-triene-15,16,l 7β3-triol 17β3-acetate was devised, based upon cycloaddition of a dienophilic 'propyne equivalent' to 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate. The dienophile chosen for this purpose, methyl propiolate, reacted with the diene regio- and stereoselectively to give methyl 17β3-acetoxy-3-methoxy-14, 17α-ethenoestra-1,3,5(10), 15-tetraene-16- carboxylate. The resulting cycloadduct was chemoselectively hydrogenated to give methyl 17β3-acetoxy-3-methoxy-14,17α-ethanoestra-1,3,5(10),15-tetraene-16-carboxylate. Attempted 1,2-reduction of this compound was unsuccessful and an indirect synthetic sequence to key intermediates for oxidative cleavage to 14(3-formyl 19-norsteroids was undertaken. cis-Dihydroxylation of the dihydrocycloadduct gave an isomeric mixture of the 15a,16a- and 15β3,16β3-diols, which were protected via acetonide formation. Sequential reduction of the ester functionality, chemoselective mesylation of the 161-hydroxy group of the resultant 161-hydroxymethyl 17-alcohols, and reduction of the 161-mesylate, gave the isomeric 16-methyl 15,16-acetonides. 17-Acetylation followed by diol deprotection gave the desired 3-methoxy-16-methyl-14,17a-ethanoestra-1,3,5(10)-triene-15,16,17(3-triol 17(3- acetates. A more direct and efficient route entailed conjugate addition of thiophenol to the dihydrocycloadduct to give methyl 17β3-acetoxy-3-methoxy-15a-phenylthio-14, 17α-ethanoestra- l,3,5(10)-triene-16f3-carboxylate. Reductive deoxygenation of the functionality on C(16) gave the 16β3-methyl 15a-phenylthio intermediate, the corresponding sulfoxide of which underwent smooth thermal elimination to yield the key intermediate, 3-methoxy-16- methyl-14,17α-ethanoestra-l,3,5(10),15-tetraen-17f3-ol. This hydroxy olefin, and the corresponding 17-acetate, underwent cis-dihydroxylation to give the desired 16-methyl 15,16-diols in superior overall yields. These intermediates underwent oxidative cleavage to give 17α-acetoxy-3-methoxy-20-oxo-19-nor-14β3-pregna-l,3,5(10)-triene-14-carbaldehyde. This strategy and related adaptations led to the synthesis of a variety of 17-substituted 14(3- formyl 19-norsteroids, including the 14β3-formyl analogue of estrone. Chemoselective reaction of this compound led to the synthesis of 14f3-hydroxymethyl- and 14β3-vinyl analogues of estradiol. Intramolecular aldol condensation of 17a-acetoxy-3-methoxy-20- oxo-19-nor-14β3-pregna-1,3,5(1 O)-triene-14-carbaldehyde gave 17 a-hydroxy-3-methoxy- 14,l 7β3-prop-172-eno-14β3-estra-1,3,5(10)-triene-171-one, which was converted into a novel bridged honnone analogue, (171S)-14β3,17β3-prop-172-eno-14β3-estra-1,3,5(1 O)-triene- 3, l 7a,171-triol. Further, it was shown that the 14β3,l 7β3-prop-172-eno 17a,l 71-diol underwent 16(16-+ l71)abeo rearrangement to 3-methoxy-14,17a-ethano-17a-homoestral, 3,5(10),15-tetraen-17a-one, which, on reduction, gave the corresponding 17ahomoestradiol analogues. Hormone analogues that were synthesised during this investigation were subjected to biological evaluation, and the results and structure activity implications reported.
  • Thumbnail Image
    Item
    Open Access
    Synthesis and structure activity relationships of ring D modified steroidal hormones
    (1995) Jardine, Mogamad Anwar; Bull, James R
    The synthesis of steroidal 14α,16-methano, 14α,17-methano-, 14α,17-ethano- and 14α,17-propano estradiol analogues as well as 14α-alkyl and 14α-functionalised-alkyl estradiol analogues was investigated. Furthermore, the synthesis of 17β-hydroxy-17α, 14-(epoxymethano)androst-4-en-3-one was undertaken and acid-mediated rearrangement of the 14,17-etheno bridged testosterone analogue gave the 14,16-ethano analogue of androst-4-en-3,17-dione. Established ring D cycloaddition and oxidative cleavage methodology gave ring D 14α-formyl and 14α, 17α-diformyl compounds as key intermediates in the overall synthetic plan. Chemoselective- and stereoselective nucleophilic addition at C-14¹ of the 14α-formyl-3-methoxyestra-1,3,5(10)-trien-17-one provided access to 14α-alkyl- and 14α-alkyl-functionalised 19-norsteroids for elaboration toward 14α,17-propano- and 14α-alkylamide estradiol analogues. Synthesis of the 14α,17-methano bridged steroid was attainable indirectly through intramolecular pinacol coupling between the 17-oxo- and 14-formyl group of 14αformyl- 3-methoxyestra-1,3,5(10)-trien-17-one. The 14α, 16-methano bridged steroid was synthesised via base-mediated intramolecular cyclisation of 14-(toluene-p-sulfonyloxy)methyl-3-methoxyestra-1,3,5( 1 0)-trien-17-one. Novel compounds were characterised with the aid of high field NMR techniques. A X-ray crystal structure determination of the strained ring D 14α, 17-methano bridged estriol analogue corroborated its structure. The minimum energy conformation of novel estradiol analogues were superimposed on estradiol, and their least square fit values determined and discussed in relation to biological activity. These analogues will contribute toward defining the structural parameters responsible for certain pattern of hormonal activity, and hence, the ultimate goal of predictive drug design.
  • Thumbnail Image
    Item
    Open Access
    Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids
    (1996) Loedolff, Michiel Christiaan; Bull, James R
    Studies have been conducted in synthesising ring D alkyl 19- norsteroids. The aim was to investigate methods for the stereoselective introduction of alkyl groups at C(14) and C(15), for eventual conversion of the intermediates into 14- and 15-alkyl analogues of estradiol hormones. In the first phase of this investigation, 17β-tert-butyldimethylsilyloxyestra-1,3,5(10),14-tetraen-l6-one was synthesised as starting material for alkylation experiments. Estrone 3-methyl ether was converted into the derived 17β-hydroxy 16-ketone by standard methods. This conversion involved the introduction of a 16α-hydroxyl group by bromination-hydrolysis, followed by base-mediated rearrangement of the hydroxy ketone to the thermodynamically preferred 16-ketone. Protection of the 17β-hydroxyl group as a TBS ether, followed by palladium acetate-mediated dehydrosilylation of the derived ∆¹⁵-16-trimethylsilyloxy enol ether gave the ∆¹⁴-16-ketone.The 17β-silyloxy ∆¹⁴-16-ketone resisted conjugate addition reactions, leading only to products of 1,2-alkylation. Stereoselective introduction of a 16-allyl group gave the corresponding ∆¹⁴-16-allyl 16-alcohols, but these compounds showed no sigmatropic reactivity and failed to undergo anionic oxy-Cope rearrangement. Hydride reduction of the 16-oxo group gave the corresponding At4-16-alcohols. The stereoselectivity was dependant on the choice of reagent. The ∆¹⁴-l6α-alcohol underwent ·stereodirected cyclopropanation to give 17β-tert-butyldimethylsilyloxy-14,15α-methyleneestra-1,3,5(10)-trien-16α-ol. Oxidation of this compound gave the corresponding 14α,15α methylene16-ketone, dissolving metal reduction of which furnished the 16β-alcohol. Routine deprotection of the epimeric pair of methylene 16-alcohols gave the derived estriol analogues, which were subjected to biological evaluation. Treatment of the 14α,15α methylene16-ketone with lithium in liquid ammonia gave 17β-tert-butyldimethylsilyloxy-14-methylestra-l,3,5(10)-trien-16-one. Stereoselective reduction of the 16-oxo group gave the epimeric 14α-methyl 16-alcohols. Deprotection of these compounds at C(3) gave a second pair of estriol analogues, which were also assayed for receptor binding affinity.
  • Thumbnail Image
    Item
    Open Access
    Synthesis and structure-activity studies of skeletally modified estradiol analogues
    (1997) De Koning, Pieter David; Bull, James R
    In the first phase of this investigation, synthetic approaches to skeletally modified variants of 14,17α-ethanoestra-l,3,5(10)-triene-3,17β-diol were examined, with the purpose of determining the influence of configurational inversion at C-8, C-9 or C-13 upon the high oral estrogenicity associated with introduction of a 14, 17-ethano bridge into the estradiol skeleton. 3-Methoxyestra-1,3,5(10)-trien-17-one was converted conventionally into the 13α-isomer, which underwent sequential silyl enol ether formation and dehydrosilylation into 3-methoxy-13α-estra-1,3,5(10), 15-tetraen-17-one, which failed to undergo conversion into the corresponding 3-methoxy-13α-estra-1,3 ,5( 10), 14, 16-pentaen-17-yl acetate required for cycloaddition studies. Hydrogenation of 3-methoxyestra-1,3,5( 10),8, 14-pentaen-17β-yl acetate afforded 3-methoxy-8α-estra-1,3 ,5(10)-trien-17β-yl acetate, which was converted into 3-methoxy-8α-estra-1,3 ,5(10), 14, 16-pentaen-17-yl acetate. Cycloaddition with phenyl vinyl sulfone gave a mixture of products, which was converted into the desired 14,17α-ethano-8α-estra- 1,3,5(10)-triene-3, 17β-diol, by a hydrogenation, desulfonylation, deprotection reaction sequence. The unexpectedly complex result for the cycloaddition reaction was interpreted with the assistance of other cycloaddition reactions of the Δ¹⁴,¹⁶-dienyl acetate. 17,17-Ethylenedioxy-3-methoxy-9β-estra-l ,3,5(10)-trien-11-one was readily prepared from estrone using conventional methodology. Deoxygenation followed by standard functional group manipulation afforded 3-methoxy-9β-estra-1 ,3 ,5(10)-trien-17-one. As a result of the poor overall yield, the optimisation of a number of steps in this reaction sequence was investigated. Despite some improvement in the yields, subsequent conversion into the target, 14, 17a-ethano-9β-estra-1,3 ,5(10)-triene-3, 17β-diol was not synthetically useful. However, dehydrogenation of 14, 17α-ethanoestra-1,3,5(10)-triene-3, 17β-diol followed by standard functional group modification gave 14, 17 a-ethanoestra-1,3 ,5(10),9(11)-tetraene- 3, 17β-diyl diacetate, hydrogenation of which afforded 14, 17α-ethano-9β-estra-1 ,3,5(10)triene-3, 17β-diol, after conventional deprotection, in moderate yield.