Synthesis of Dimeric Steroid Trioxabispiroacetals Scaffolds by Gold(I)-Catalyzed Hydroalkoxylation-Hydration of Diynediols

Five novel dimers in which the steroid cores are bridged by a 6,5,6-trioxabispiroacetal moiety were synthesized by gold(I)-catalyzed hydroalkoxylation-hydration of steroid di-ynediols. The double spiroacetalization proceeded with excellent yield and
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  DOI: 10.1002/ejoc.201900860  Full Paper Steroid Dimers Synthesis of Dimeric Steroid Trioxabispiroacetals Scaffolds byGold(I)-Catalyzed Hydroalkoxylation–Hydration of Diynediols Ricardo M. Valdez-García, [a] Carlos Alarcón-Manjarrez, [a] Annia Galano, [b] Braulio Rodríguez-Molina, [c] Marcos Flores-Álamo, [a] and Martín A. Iglesias-Arteaga* [a] Abstract:  Five novel dimers in which the steroid cores arebridged by a 6,5,6-trioxabispiroacetal moiety were synthesizedby gold(I)-catalyzed hydroalkoxylation–hydration of steroid di-ynediols. The double spiroacetalization proceeded with excel-lent yield and produced almost exclusively the C2 symmetrical trans  diastereomer. A small amount of the  cis  unsymmetricaldiastereomer was isolated only in one case. Density FunctionalTheory calculations were used to further analyze and justify thepopulation of the diastereomers. Characterization of the ob- Introduction The design and synthesis of molecular scaffolds for supramolec-ular chemistry occupies a paramount place in modern chemis-try. Since it has been recognized that flexibility of the receptorhinders structural predictions, [1] the design of predictable artifi-cial receptors therefore should be based on rigid frameworks. Figure 1. Design of a C2 symmetric steroid trioxabispiroacetal scaffold.[a]  Facultad de Química, Universidad Nacional Autónoma de México,Ciudad Universitaria, 04510 Ciudad de México, MéxicoE-mail:  [b]  Departamento de Química, División de Ciencias Básicas e Ingeniería,Universidad Autónoma Metropolitana-Iztapalapa, Av. San Rafael Atlixco No.186, C.P.09340, Ciudad de México, México [c]  Instituto de Química, Universidad Nacional Autónoma de México,Ciudad Universitaria, 04510 Ciudad de México, MéxicoSupporting information and ORCID(s) from the author(s) for this article areavailable on the WWW under J. Org. Chem.  2019 , 4916–4927 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4916 tained dimers was based on combined 1D and 2D NMR tech-niques. X-ray diffraction of one of the obtained dimers corro-borated the anticipated V-shaped structure and provided addi-tional structural insights on the crystal network. Unexpectedly,the crystalline array showed interconnected voids, resulting inchannels that make this new class of steroid dimers suitablecandidates for the development of applications on solid statesupramolecular chemistry.Although the prediction of crystal structures in most cases isnot possible, [2] several reports initially guided by serendipityand later by a rational design have described that crystallinebile acid derivatives show interesting properties as porous ma-terials. [3] Due to the rigid nature of the steroid nucleus and thehigh level of functionality of bile acids (i.e cholic acid), thesereadily available compounds have played a leading role in thesynthesis of steroid-based receptors. [1,3] In addition, some othernaturally occurring steroids have been employed in the synthe-sis of crystalline molecular rotors, [4] in which the supramolec-ular interactions exert a crucial influence in the desired intra-molecular motion, allowing the regulation of dynamic of therotating fragment in the solid state. [4d] As a part of our ongoing program on the synthesis and studyof crystalline materials derived from monomeric [5] and di-  Full Paper meric, [4,6] steroids we decided to set up procedures for the syn-thesis of dimers in which the steroid cores are bridged by a6,5,6-trioxabispiroacetal moiety. Inspired by the 3D architectureof the 6,5,6 trioxadispiro core (Figure 1, left) we envisaged adimeric structure in which two 4-oxasteroid nuclei are bridgedby a central THF ring through spiroacetals carbons at positionsC-3 and C-3 ′ . The inspection of a PM3-optimized model of thedesigned 6,5,6 trioxadispiro steroid dimer revealed an attractiveV-shaped structure in which the alpha sides of both steroidcores point inward a conical cavity. The rigid nature of theframeworks fused to each side THP ring of the 6,5,6 trioxadi-spiro moiety is expected to restrict the conformational equilib-rium of the THP rings and should confer significant rigidity tothe resulting structure (Figure 1, right).Bispiroacetals are a subfamily of naturally occurring com-pounds bearing a trioxabispiroacetal unit that consists of a cen-tral tetrahydrofuran (THF) or tetrahydropyran (THP) ring, linkedto two outer THF or THP rings through two spiroacetal atoms.In general, the different trioxabispiroacetal units are product of the formal cyclization of dihydroxylated  γ - (y = 1) or  δ - (y = 2)diketones of the general structure  1 . This gives rise to a widediversity derived from the six possible units  (2a–f)  (Scheme 1). Scheme 1. The six possible trioxabispiroacetal units ( 2a–f  ). Biologically active naturally occurring bispiroacetals of com-plex structures include toxins like pinnatoxins (3 and 4), [7] andspirolides  (5) [8] as well as the polyether ionophore salinomycin (6) [9] (Figure 2), amongst many others, [10] but to the best of ourknowledge, no steroid bearing the trioxabispiroacetal unit hasbeen isolated or synthesized. Figure 2. Some naturally occurring biologically active spiroacetals. Eur. J. Org. Chem.  2019 , 4916–4927  © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4917 The challenging structures of naturally occurring bispiroacet-als and their interesting biological properties have triggeredintensive work aiming to provide access to the different trioxa-bispiroacetal units. The available toolbox for the synthesis of such compounds includes multiple alternatives. [10] Some of them involve masked (or protected) dihydroxylated  γ - or  δ -di-ketones or their synthetic equivalents. [11] In an attractive ap-proach Lee and co-workers described the synthesis of a varietyof bispiroacetals employing the gold(I) catalyzed hydroalkoxylation-hydration of diynediols (Scheme 2). [12] Scheme 2. Gold(I) catalyzed hydroalkoxylation-hydration of diynediols. Herein we describe the synthesis of five dimeric trioxabi-spiroacetals by gold(I) catalyzed hydroalkoxylation-hydration of dimeric steroid diynediols. The characterization of the obtainedcompounds was based on a combination of 1D and 2D NMRtechniques. Single crystal X-ray diffraction of the obtained com-pounds corroborated the anticipated V-shaped structure andrevealed an interesting supramolecular array with significantvoids within the crystal network. In addition, Density FunctionalTheory (DFT) based Natural Bond Orbital (NBO) calculations ex-plained the obtained diastereomeric ratio based on structuraland energetic features of the obtained dimers.  Full Paper Results and Discussion The alkynones  11a–c , which are available in our laboratory fromprevious works [4d,5b,6a] and have steroid cores with different hy-drophilicity were selected as starting materials. Luche reductionof   11a–c  afforded the corresponding alkynols  12a–c . Palladiumcatalyzed dimerization of   12a–c  led to the correspondingsteroid diynediols  13a–c  (Scheme 3). Scheme 3. Synthesis of the diynediols  13a–c . Treatment of the dimeric diynediol  13a  with (acetonitrile)-[(2-biphenyl)di- tert  -butylphosphane]gold(I) hexafluoroantimon-ate (JohnPhos-Au(MeCN)SbF 6 ) in a wet 4:1 CH 2 Cl 2 /CH 3 OH solu-tion, followed by chromatographic separation afforded 52 %the C-2 symmetric dimer  3 S ,3 ′ S-14 , and 25 % its monoacetyl-ated partner  3 S ,3 ′ S -14a  product of the Lewis acid catalyzedhydrolysis of one of the acetates (Scheme 4).Contrary to the generally low diastereoselectivity previouslydescribed by Lee and co-workers in the synthesis of the “naked”6,5,6 and 5,5,6 trioxadispiro ketals (vide infra Scheme 2), [12] the77 % combined yield indicates a highly diastereoselective proc-ess that exclusively produces the  3 S ,3 ′ S  assemblage. Figure 3.  1 H NMR spectrum of the obtained dimer  (3 S ,3 ′ S- 14) . Eur. J. Org. Chem.  2019 , 4916–4927  © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4918 Scheme 4. Gold catalyzed double spiroacetalization of diynediol  13a . A single set of   1 H and  13 C NMR signals points toward a C2symmetrical structure for the obtained compound, and elimi-nates the unsymmetrical partner ( 3 S ,3 ′ R -14 ) (Scheme 4, Fig-ure 3 and Figure 4). The downfield  13 C signals correspondingto C-3/C-3 ′  (spiroacetals) at 106.5 ppm and C-5/C-5 ′  (C–O) at76.2 ppm as well as the  1 H signal of H-5/5 ′  at 3.44 ppm (dd,J = 11.5, 4.4 Hz, 2H) suggests the presence of the trioxabi-spiroacetal moiety. Additional signals associated to the acetyl-ated alcohols attached to C-17/17 ′  [4.57, dd, J = 9.1, 7.7 Hz, 2H,H-17/17 ′  and 82.8, C-17/17 ′ ] as well as the methyl groups [H-18/18 ′  0.78 ppm, s 6H, C-18/18 ′ , 12.1 ppm and 0.88 ppm H-19/  Full Paper Figure 4.  13 C NMR spectrum of the obtained dimer  (3 S ,3 ′ S- 14) . 19 ′ , s 6H; C-19/19 ′  11.7 ppm] corroborate the integrity of theandrostane core.The severe overlapping of the  1 H signals of the steroid coreshindered the determination of the configuration of the spirocenters C-3 and C-3 ′  employing NOE experiments. However, theobtained compound produced monocrystals suitable for X-rayDiffraction studies that revealed its structure as the C2 symmet-rical  trans  trioxabispiroacetal ( 3 S ,3 ′ S -14 ) in which both O–C-3and O–C-3 ′  bonds of the central THF ring are in axial orientationwith respect to the THP rings of the outer steroid cores (Fig-ure 5).The asymmetric unit of   3 S ,3 ′ S -14  consists of two crystallo-graphically independent dimeric molecules (Z ′ =2). This rela-tively uncommon feature is not surprising in steroids, giventheir chirality and, in this case the irregular shape of the synthe-sized dimer. [13] In each molecule the spiro centers at C-3 andC-3 ′  in the two side 4-oxa-5 α -androstan-17  -ol acetate frag-ments are also part of the central THF ring. Each  trans- fusedtetracyclic 4-oxa-5 α -androstan-17  -ol acetate core defines aplane and the angle between these planes is 74.7° for molecule1 and 70.5° for molecule 2; resulting in the predicted V-shapeddimeric structures (Figure 1 and Figure 5).The different angles between each pair of planes in mol-ecules 1 (74.7°) and 2 (70.5°) suggest that, in spite of the rigidity Eur. J. Org. Chem.  2019 , 4916–4927  © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4919 Figure 5. ORTEP drawing of the asymmetric unit of compound  3S,3 ′ S-14  withthe thermal ellipsoids drawn at 50 % probability. Dotted lines representplanes defined by the ABCD rings and the angles between these planes. of the framework, the inner cavity can be slightly expandedwithout a significant deviation of the 3D architecture (Figure 5),leaving open the possibility of inclusion of medium size mol-ecules. To quantify the torsion of the trioxadispiro fragment, the  Full Paper puckering parameters [14] were defined for the crystallographi-cally different heterocycles. In molecule 1, the THF ring assumesa twisted conformation on C-4A–C-4B [15] while the six-mem-bered THP ring on O-3, adopts a slightly distorted chair confor-mation. [16,17] Similarly, the THP ring on O-1 adopts a slightlydistorted chair conformation. [18] In the case of molecule 2, thecentral THF ring adopts a twisted conformation, [19] while theTHP ring on O-3 adopts a slight distorted chair conformation. [20] Finally, the THP ring on O-1 is in a slightly distorted chair con-formation. [21] The average magnitude of the C–C distance of the steroid framework is 1.534 Å, while the C–O distances are1.439 Å for the five-membered THF ring, and 1.421 Å for six-membered THP ring. Table 1 shows the C–O bond lengths cor-responding to the trioxaspiro moiety of compound  3 S ,3 ′ S -14 . Table 1. C–O bond lengths [Å] of the trioxaspiro moiety of   3S,3 ′ S-14 . [a] Bond Molecule 1 Molecule 2C-5 ′ –O1 1.431(4) 1.430(4)O1–C-3 ′  1.421(4) 1.433(4)C-3 ′ –O2 1.443(4) 1.447(4)O2–C-3 1.429(4) 1.440(4)C-3–O3 1.415(4) 1.415(4)O3–C-5 1.433(4) 1.442(4)[a] Root mean square. Considering that no strong hydrogen-bond donors arepresent in the dimeric structure, only weak intermolecular inter-actions of the C–H ··· O type should be expected. Hence, a C-21–H-21 ··· O-4 interaction was identified between neighbors of molecule 1 (Figure 6), with a hydrogen–acceptor distance of 2.342 Å. [22] For molecule 2, the distance of this interaction is2.445 Å. Both short contacts form a  C  1 1  (26)  motif  [23] along the Figure 6. Crystal network of   3 S ,3 ′ S -14 , down the  a-axis , showing the short contacts between the symmetry equivalent for  molecule 1  (green) and  molecule 2 (blue) emphasizing the  C  1 1 (26)  and  R 2 1 (5)  motifs. Eur. J. Org. Chem.  2019 , 4916–4927  © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4920 crystalline c-axis. Other weak intermolecular interactions be-tween both molecules were observed through C-12D–H-12H ··· O4B (2.524 Å) and C-11D–H-11G ··· O-4B (2.678 Å), forminga R 21 (5)  motif. These interactions expand through the a-axisleading to an infinite array of sheets (Figure 6, for detailed label-ing of interactions see Figure S7 in Supporting information).Interestingly, while the above-mentioned weak hydrogenbonds are established between the inner cavities (belly) of thedimers, a large empty space of ca. 541 Å 3 is generated in theopposite (back) faces of the dimeric molecules (Figure 7, seealso Figure S3 and Figure S4 in Supporting information). [24] Thisvoid represent up to 23 % of the volume within the unit celland is interconnected through the sheets, generating a channelthat propagates through the crystallographic a-axis. This featuremay enable interesting applications for this new class of steroiddimers as porous materials. Figure 7. (a) View down the  a -axis of the large interconnected voids gener-ated in between the dimer molecules upon crystallization. (b) View down the b -axis. (c) View down the  c  -axis highlighting the one-dimensional channelacross the steroidal sheets.
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