An efficient asymmetric synthesis of an estrogen receptor modulator by sulfoxide-directed borane reduction

Abstract

An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an ␣,␤-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols. E strogen receptors (ERs) are members of the steroid hormone nuclear receptor superfamily. They are ligand-dependent transcription factors that bind to specific DNA sequences and regulate gene expression. There are two known members of the estrogen receptor family, ER␣ and ER␤, encoded by distinct genes. ER modulators are potentially useful agents for treatment or prevention of a variety of conditions related to estrogen functions, including bone loss, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of low-density lipoprotein cholesterol, cardiovascular disease, obesity, incontinence, and cancer (refs. 1-4 and references cited in ref. 4). SERMs are ER ligands that act like estrogens in some tissues, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic activity, depending on the context in which their activity is examined. Fig. 1) is a potent ER␣ SERM being evaluated as part of the selective ER antagonist program at Merck (1-4). Although there are several methods for the synthesis of the core cis-2,3-disubstituted-dihydrobenzoxathiin, the asymmetric synthesis of these compounds has not been reported (1-7). Herein, we report an enantioselective synthesis of 1. Experimental ProceduresGeneral. Chemicals were used as received from commercial sources unless otherwise noted. NMR data were collected on Bruker Avance NMR spectrometers. Chemical shifts are reported in ppm downfield from tetramethylsilane. HPLC purity data are reported as area percentage of the desired peak from the total peaks. HPLC conditions are listed in supporting information, which is published on the PNAS web site. High-resolution mass spectrometer (HRMS) data were collected on a Micromass API US Ultima quadrupole time-of-flight (QTOF) mass spectrometer. Vinyl Sulfide 6.A 100-liter round-bottom flask was charged with ketone 7 (8.01 kg, 12.2 mol) and 48 liters of acetonitrile followed by phenylphosphonic dichloride (2.50 kg, 12.9 mol). The flask was fitted with a reflux condenser with off-gases vented through a caustic scrubber, and the reaction mixture was heated to reflux (75°C). After about 2 h, HPLC assay showed Ͼ99% conversion. The reaction mixture was concentrated under reduced pressure at 20-50°C to 28 liters. Diisopropylethylamine (786 g, 6.08 mol) was added, followed by 28 liters of denatured ethanol (denatured with 0.5% toluene). The solution was ...

Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands

“…The final step that involved cleavage of benzyl protecting group from the phenol turned out to be more challenging than we anticipated. 17 Our first attempts used hydrogenolysis with Pd/C, but this led to both debenzylation and an unexpected, undesired further reduction of the very hindered olefin in the oxabicyclic ring. An alternative debenzylation condition using FeCl 3 18 led to opening of the oxabicyclic ring.…”

“…An alternative debenzylation condition using FeCl 3 18 led to opening of the oxabicyclic ring. However, a TMSI-mediated debenzylation, 17 conducted in the presence of thiourea, allowed us avoid any side reactions and obtain the desired free phenol derivative (Scheme 3). …”

Synthesis of planar chiral ferrocenyl sulfides and evaluation as catalysts for the asymmetric epoxidation of aldehydes

“…A literature precedent, 36 in the context of a drug process development, has shown that a sulfoxide moiety can assist the reduction of an alkene otherwise sluggish towards borane reaction. We were glad to observe that addition of borane-dimethyl sulfide to hydroxyl sulfinyl ferrocene 4f provided compound 5f, with both desired reductions (Scheme 8).…”

Applications of Catalytic Asymmetric Sulfide Oxidations to the Syntheses of Biologically Active Sulfoxides

“…In this case, however, stoichiometric quantities of the titanium reagent were required to achieve such high enantioselectivity. [58] In the field of biocatalysis very few sulfoxidation processes have been significantly scaled-up for the synthesis of biologically active compounds. Although several clear advantages have been already pointed out (vide supra), some key bottlenecks, such as inhibition of the enzyme activity by (high concentration of) both substrate and product, the low availability of catalyst and the downstream product recovery, due (in part) to the high dilution conditions have so far hampered the application of this methodology.…”