Electrophilic destannylation: stereospecific introduction of electrophiles at the 21 position of (17.alpha.)-19-norpregna-1,3,5(10),20-tetraene-3,17.beta.-diols
Abstract:As part of our program to develop radiopharmaceuticals for the detection and diagnosis of estrogen-responsive breast cancer, we have focused on the use of organometallic substituents to facilitate the introduction of the radionuclide. As a result we initiated the application of organotin chemistry to the field of radiopharmaceutical chemistry in our preparation of the labeled antiestrogen [125I]iodotamoxifen.1-3 In that synthesis we could selectively lithiate and subsequently stannylate ortho to the (dimethyla… Show more
“…As part of our program to prepare novel high-affinity ligands for the estrogen receptor, we have undertaken the systematic development of novel probes for the hormone binding domain (HBD). In our previous studies we have reported the preparation of derivatives of estradiol bearing substituents at either the 11β-position (compounds 1a − f ) − or the 17α-position (compounds 2a − d, 3a − d ) − (Figure ). In each case, structure−activity relationships were developed which identified the effect of the substituent's properties on the ligand's affinity.…”
We have synthesized six new estrogens substituted at the 11beta-position with a methoxy or vinyl group and at the 17alpha-position with an (E)- or (Z)-chloro/iodovinyl moiety. The products were obtained in good overall yields from the corresponding tri-n-butylstannylvinyl intermediates using the electrophilic halodestannylation methodology. The six new ligands were compared to the 11beta-unsubstituted chloro/iodovinyl derivatives and the 11beta-methoxy (E)- and (Z)-iodovinyl estrogens to evaluate the effects of 11beta-substitution and 20E/Z-stereochemistry. While all the compounds exhibited high affinity for the estrogen receptor, the 20Z-isomers demonstrated higher affinity than the corresponding 20E-isomers. In addition, the presence of the lipophilic 11beta-substituent was favored over either no substituent or a polar (methoxy) group. Within each isomeric series, the presence of the 21-halo substituent had different effects. For the 20E-series, the 21-chloro products had a higher affinity than the 21-iodo analogue, whereas for the 20Z-series the effect was reversed. These results provide additional insights into the interaction of substituted estradiols with the hormone binding domain of the estrogen receptor.
“…As part of our program to prepare novel high-affinity ligands for the estrogen receptor, we have undertaken the systematic development of novel probes for the hormone binding domain (HBD). In our previous studies we have reported the preparation of derivatives of estradiol bearing substituents at either the 11β-position (compounds 1a − f ) − or the 17α-position (compounds 2a − d, 3a − d ) − (Figure ). In each case, structure−activity relationships were developed which identified the effect of the substituent's properties on the ligand's affinity.…”
We have synthesized six new estrogens substituted at the 11beta-position with a methoxy or vinyl group and at the 17alpha-position with an (E)- or (Z)-chloro/iodovinyl moiety. The products were obtained in good overall yields from the corresponding tri-n-butylstannylvinyl intermediates using the electrophilic halodestannylation methodology. The six new ligands were compared to the 11beta-unsubstituted chloro/iodovinyl derivatives and the 11beta-methoxy (E)- and (Z)-iodovinyl estrogens to evaluate the effects of 11beta-substitution and 20E/Z-stereochemistry. While all the compounds exhibited high affinity for the estrogen receptor, the 20Z-isomers demonstrated higher affinity than the corresponding 20E-isomers. In addition, the presence of the lipophilic 11beta-substituent was favored over either no substituent or a polar (methoxy) group. Within each isomeric series, the presence of the 21-halo substituent had different effects. For the 20E-series, the 21-chloro products had a higher affinity than the 21-iodo analogue, whereas for the 20Z-series the effect was reversed. These results provide additional insights into the interaction of substituted estradiols with the hormone binding domain of the estrogen receptor.
“…12 Hydrostannylation is a useful reaction for the preparation of carbon-functional organostannes and is the simplest and most direct route to transform alkynes into vinylstannes. 13 For the introduction of the iodine onto the vinyl substituent of the 17a-iodovinylestradiol we used the destannylation method. To obtain either the 20E or 20Z stannyl intermediates we previously4®-15 established a method using tri-n-butyltin hydride, with or without catalyst and with different reaction conditions (reaction time, temperature, and solvent polarity) to favor formation of either isomer.…”
We have prepared a series of 2- and 4-fluoro derivatives of the isomeric (17 alpha,20E)- and (17 alpha, 20Z)iodovinylestradiols (IVE2) and also the analogs substituted with either a 7 alpha-methyl (7 alpha-Me-IVE2) or 11 beta-methoxy group (11 beta-OMe-IVE2) and evaluated their in vitro and in vivo properties. Electrophilic substitution of the estrone derivatives with N-fluoropyridinium salt gave the 2- and 4-fluoro analogs which were subsequently converted to the 17 alpha-ethynyl derivatives. The tributylstannyl intermediates were obtained from the corresponding 17 alpha-ethynyl analogs using azobisisobutyronitrile or triethylborane as catalyst. All 12 products were also prepared as their no-carrier-added [125I]iodovinyl analogs via destannylation of the tributylstannyl precursors. Binding affinity for the estrogen receptor (ER) was in general higher for the 4-F derivatives as compared to the 2-F derivatives, while the 20Z isomers of the same compounds showed somewhat higher ER binding affinity as compared to the 20E isomers. The combination of an A-ring fluoro and 7 alpha- or 11 beta-substituent decreased ER binding affinity. Substitution of a fluoro atom at C-4 on either the 17 alpha-ethynylestradiol or isomeric 17 alpha-IVE2 enhanced the affinity of the parent molecule for the ER. A-ring fluorination of all other analogues tested had no effect or depressed ER binding affinity. Varying incubation conditions showed substantial differences in ER binding kinetics between the 20E and 20Z isomers. Tissue distribution in immature female rats showed that the highest uterus uptake and uterus to blood/nontarget ratios in the IVE2 series were obtained with the 4-F-(17 alpha,20Z)IVE2 isomer. The combination of A-ring fluoro and 7 alpha- or 11 beta-substitution decreased uterus uptake but had little or no effect on uterus to blood/nontarget ratios. The highest uterus to blood ratios were observed for the 4-F-(17 alpha,20E)11 beta-OMe-IVE2 (75 at 6 h and 125 at 12 h pi) reflecting rapid blood clearance and in vivo stability, as confirmed by the low levels of thyroid radioactivity. The lack of correlation between ER binding affinities and uterus uptake, and/or uptake ratios, suggests that other factors, including nonspecific binding and metabolic processes, also are involved in the tissue localization process. Our data suggest that 4-F substitution onto (17 alpha,20Z)IVE2 and (17 alpha,20E)11 beta-OMe-IVE2 enhances the potential of these compounds to function as SPECT imaging agents of ER-rich tissues.
“…Protection as a p -methoxybenzylidene acetal (Scheme ), followed by Wacker oxidation 66 led to methyl ketone (−)- 62 in modest yield. Conversion to the kinetic enol triflate 67 and treatment with in situ-generated Bu 2 CuLi·LiCN, furnished vinyl stannane (−)- 64 which was then transformed to vinyl iodide (−)- 60 (I 2 , CCl 4 ). , Although the overall yield for this five-step process was not suitable for large-scale material advancement, we proceeded with initial attempts to effect the coupling reaction. 18 …”
mentioning
confidence: 99%
“…Initially, we planned to generate vinyl lithium 66 from vinyl stannane (−)- 64 via transmetalation . However, when a mixture of (−)- 64 and n -butyllithium was stirred at −78 °C, no reaction occurred (Scheme ).…”
An asymmetric synthesis of the stereochemically fully endowed C(9−25) spiroketal fragment (+)-BC of the calyculins (1−8) is described. Highlights of the synthesis include: a highly diastereoselective IBr-induced iodocarbonate cyclization to introduce the C(21) stereocenter in epoxide (+)-18, fragment unions
exploiting the reaction of acyl anion equivalents with epoxides to construct masked advanced aldols (−)-35
and (+)-71 as single diastereomers, chelation-controlled addition of the C(14−15) vinyl group to aldehyde
(+)-38 to set the stereogenicity at C(16), selective reduction of the C(13) ketone via 1,3-induction, and
development of an orthogonal protection scheme permitting both convenient installation of the C(17) phosphate
group and flexibility in subsequent fragment couplings.
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