Note Cite This: J. Org. Chem. 2018, 83, 10573−10579
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Synthesis of the Polyoxygenated Cyclohexanoid Core of Bioactive Glycosides Xylosmin and Flacourtosides E and F Nagi Reddy Modugu*,† and Goverdhan Mehta‡ †
Department of Organic Synthesis and Process Chemistry (CSIR), Indian Institute of Chemical Technology, Hyderabad 500007, India ‡ School of Chemistry, University of Hyderabad, Hyderabad 500046, India
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ABSTRACT: A flexible synthesis of the carbocyclic core present in glycosides xylosmin and flacourtosides E and F, natural products exhibiting antimalarial and antiarboviral activities, has been accomplished. Our approach emanates from the Diels−Alder adduct of cyclopentadiene and MOM-protected 2-hydroxymethyl-p-benzoquinone and takes advantage of the stereochemical propensity of the norbornyl-fused scaffolds to generate the dense oxy-functionalization pattern with stereocontrol, enroute to a racemic synthesis of the carbocyclic core present in the aforementioned bioactive materials. This effort augurs well for exploring chemical diversity space around their scaffold.
M
Southeast Asia in the periphery of the India ocean and with many folklore remedies for diverse disorders associated with it, displayed significant inhibitory activity in virus-cell-based assays against CHIKV and DENV arboviral diseases.1−3 These observations led to detailed chemical investigations, and in a collaborative effort, Litaudon et al.5a reported the isolation of six new phenolic glycosides named flacourtosides A−F (1−6) and a known phenolic glycoside xylosmin 7, along with several previously reported but unrelated compounds, from the plant material collected in Madagascar (Figure 1). Interestingly, purified flacourtosides A−F, unlike the whole extracts, did not exhibit significant activity against CHIKV virus assays, but flacourtoside E showed a reduced activity in the DENV RNA polymerase essay.5a Concurrently, another group6 has reported the isolation of related flacourtosides and xylosmin along with some other known natural products from Flacoutia indica in India and examined their β-hematin inhibitory activity and potential as antimalarial agents. Flacourtosides A−F (1−6) and xylosmin (7) are interesting hybrid constructs being glycosylated 2-hydroxymethyl hydroquinone derivatives with varying degrees of additional benzolation on the hexose moiety (Figure 1). Among these phenolic glycosides, flacourtosides E and F (5 and 6) and xylosmin (7) are structurally quite intriguing as their aromatic hydoxymethyl group is present as a carboxylic acid functionality further esterified with a complex polyoxygenated cyclohexanoid core 8 (in red font, Figure 1). The structure and relative stereochemistry of the functionalities on 8 were followed by the X-ray crystal structure determination of
alaria is a life threatening infectious disease caused by single-celled parasitic protozoans belonging to genus Plasmodium and transmitted through the bite of female Anopheles mosquitoes. It has continued to ravage human health with 216 million clinical cases and 4.5 million fatalities in 2016 in some of the poorest parts of the world.1 A range of preventive interventions and new therapies are beginning to show encouraging trends, but new challenges in the form of MDR malaria continue to emerge, underscoring the need for the continuous quest for new molecular leads.2 Concurrently, relatively new vector borne diseases, like dengue, chikungunya, and zika, caused by arbovirues, like CHIKV, DENV, and ZIKV, respectively, and perpetrated mainly by the bite of female Aedes aegypti mosquitoes, have assumed epidemic proportions in certain pockets of Africa and Southeast Asia, with nearly 500 million infections every year.3 Broad spectrum antivirals to treat these potentially fatal infections are generally lacking, and several vaccine candidates are still in the developmental phase. These arbovirus (CHIKV, DENV, and ZIKV)-mediated diseases and malaria continue to remain a major global health concern1−3 and underscore the need for continued efforts toward developing new therapeutic leads and molecular entities, both from natural sources and through synthesis, for effective clinical interventions. The remarkable efficacy and success of the natural product artemisinine, and of its synthetic analogs for treating malaria, serves as a motivating example,4 among many others, for further exploration of natural product-based leads from traditional medicine and empirical observations of indigenous people. In this context, our attention was drawn to the report5 that the plant extracts from the stem bark of the deciduous tree Flacoutia ramontchi, widely distributed from Africa to India and © 2018 American Chemical Society
Received: June 3, 2018 Published: August 6, 2018 10573
DOI: 10.1021/acs.joc.8b01389 J. Org. Chem. 2018, 83, 10573−10579
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Figure 1. Representative examples of bioactive flacourtosides and xylosmin.
Scheme 1. Retrosynthetic Plan toward the Xylosmin Carbocyclic Core
xylosmin 7.5b Given ample precedence of many polyoxygenated cyclohexanoids exhibiting diverse bioactivities, it is not unreasonable to assume that this carbocyclic core 8 could be a significant contributor to their bioactivity profile, either as a standalone entity or as a dominant substructure. Thus, the synthesis of the carbocyclic segment 8 of xylosmin 7 and the related phenolic glycosides is of interest to map diversity around this scaffold in order to gauge its bioactivity potential and to further embed this moiety into other frameworks using its carboxylic acid handle to create new hybrid systems.7 A very recent chemoenzymatic synthesis of 8 in eight steps from sodium benzoate by the group of Hudlicky8 is the first such effort and sets the stage for more to follow. Enantioselective synthesis of 8 by Hudlicky et al. has also led these authors to make a tentative suggestion about the absolute stereochemistry of the natural product.8 The synthesis of 8 is an important and potentially useful undertaking and a nontrivial one, considering that its three contiguous hydroxyl groups are poised on the same face of a fully functionalized cyclohexanoid core with the middle hydroxyl group on a quaternary center bearing a carboxylic acid moiety. In view of our group’s continuing interest in polyoxygenated cyclohexanoid and related natural products,9 we were drawn to the polyfunctional cyclohexanoid core 8 present in xylosmin and selected flacourtosides, and we
wish to report its synthesis through steps that are convenient to execute ,and it has potential for diversity creation. An approach to the polyoxygenated carbocyclic core 8, delineated here, was founded on a flexible synthetic strategy toward oxygenated cyclohexanoid natural products that originated from the readily accessible Diels−Alder (D−A) adduct of cyclopentadiene and an appropriately substituted pbenzoquinone.9 The derived endo-tricyclic D−A cycloadducts, bearing a tricyclo[6.2.1.02,7]undecane framework, are known for their predictable stereo- and regio-selective preferences, which are characteristic of fused norbornyl systems. Disengagement of the cyclopentane moiety through a retro-D−A reaction, after the buildup of the functional network, then unravels the cyclohexanoid core for further functional group adjustments. This strategy9 appeared amenable toward the construction of the carbocyclic core 8. A retrosynthetic perspective aimed toward 8 from the D−A cycloadduct of cyclopentadiene and MOM-protected 2hydroxymethyl-p-benzoquinone 910 via the tricyclic cis-diol 10 and involving the stereochemically defined PNB-protected cyclohexanoid-triol 11 as an advanced intermediate is shown in Scheme 1. Execution of this plan commenced with the D−A reaction between the 2-hydroxymethylquinone 9 and cyclopentadiene to furnish an endo-tricyclic adduct 12. Luche 10574
DOI: 10.1021/acs.joc.8b01389 J. Org. Chem. 2018, 83, 10573−10579
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The Journal of Organic Chemistry Scheme 2. Synthesis of the Advanced Intermediate 17
Scheme 3. Synthesis of the Xylosmin Carbocyclic Core 8
reduction11 on 12 resulted in a hydride addition from the topologically favored convex face and led stereoselectively to the endo,endo-diol 10 as the only diastereomer. The two endodisposed 1,4-hydroxyl groups in 10 along with the norbornene double bond in 10 needed to be concurrently protected to facilitate regio- and stereoselectively oxyfunctionalization of the cyclohexene double bond. This protective group maneuvers were sought to be accomplished through an intramolecular bromo-etherification protocol.12 Reaction of 10 with an excess of N-bromosuccinamide led to the tetracyclic-bromide 13 in an one-pot operation, through
which the three aforementioned functionalities were internally protected. The unprotected hydroxyl group in the resulting 13 was converted into a p-nitrobenzoate (PNB) derivative, and now the cyclohexene double bond in the resulting 14 was freely accessible for executing the proposed oxyfunctionalization protocol. OsO4-mediated catalytic dihydroxylation13 in 14 was predestined to be exo-selective and smoothly led to tetracyclic cis-diol 15, which was converted into an acetonide 16. Now, the internally protected functionalities in 16 were liberated on exposure to Zn in MeOH−AcOH milieu14 to yield a PAB (p-aminobenzoate)-protected pentaoxygenated 10575
DOI: 10.1021/acs.joc.8b01389 J. Org. Chem. 2018, 83, 10573−10579
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of the spots on TLC plates was achieved by exposure to iodine vapor, under UV light, or by spraying with either ethanolic vanillin or 30% H2SO4−methanol solution and heating the plates at ∼120 °C. Commercial silica gel (100−200 mesh particle size) was used for column chromatography. 1H NMR and 13C NMR spectra were recorded in CDCl3, DMSO-d6, and D2O as the solvents on a 400 or 500 MHz spectrometer at ambient temperature. The chemical shifts are expressed in a parts per million (δ) scale using tetramethylsilane (Me4Si) as the internal standard. The standard abbreviations s, d, t, q, and m refer to singlet, doublet, triplet, quartet, and multiplet, respectively. Coupling constants (J), whenever discernible, have been reported in Hz. IR spectra were recorded on a Bruker infrared spectrophotometer and are reported as cm−1. High-resolution mass spectra (HRMS) were recorded on a Q-TOF Micro mass spectrometer. rel-(1S,4R,4aS,8aR)-6-((Methoxymethoxy)methyl)-1,4,4a,8a-tetrahydro-1,4-methano-naphthalene-5,8-dione (12). To a stirred solution of p-benzoquinone 9 (2.0 g, 10.9 mmol) in 20 mL of MeOH at 0 °C was added cyclopentadiene (0.9 g, 13.2 mmol), and the reaction mixture was stirred for 2 h at 0 °C. After completion of the reaction, methanol was removed under reduced pressure, and the crude residue was purified by filtration through a silica gel column (eluent: 10% EtOAc in hexane) to furnish the tricyclic adduct 12 (2.6 g, 95%) as a yellow liquid. IR (neat): 3033, 2923, 1722, 1641, 1169, 1072 cm−1. 1H NMR (400 MHz, CDCl3, δ): 6.71 (t, J = 1.5 Hz, 1H), 6.09−6.03 (m, 2H), 4.67 (s, 2H), 4.35−4.29 (m, 2H), 3.54 (s, 2H), 3.36 (s, 3H), 3.25−3.24 (m, 2H), 1.54 (d, J = 8.8 Hz, 1H), 1.44 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 199.4, 199.2, 153.6, 138.8, 135.5, 134.9, 95.6, 72.6, 55.3, 49.1, 49.0, 48.9, 48.7, 48.6. HRMS (ES) (m/ z): (M + Na)+ calcd for C14H16NaO4, 271.0946; found, 271.0946. rel-(1S,4R,4aS,5S,8R,8aR)-6-((Methoxymethoxy)methyl)1,4,4a,5,8,8a-hexahydro-1,4-methanonaphthalene-5,8-diol (10). To a stirred solution of the ene-dione 12 (1.5 g, 6.0 mmol) in MeOH (10 mL), cooled to −10 °C, was added CeCl3·7H2O (4.9 g, 13.3 mmol), followed by a portion-wise addition of NaBH4 (0.4 g, 12.1 mmol). After 20 min, the reaction was quenched with saturated aqueous NH4Cl solution. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography (eluent: 35% EtOAc in hexane) to afford the endo,endodiol 10 (1.3 g, 85%) as a white solid. mp 95−96 °C. IR (neat) 3382, 2937, 2864, 1453, 1166, 1062 cm−1. 1H NMR (400 MHz, CDCl3, δ): 5.99 (dd, J = 8.5, 2.8 Hz, 2H), 5.76 (dd, J = 2.7, 1.2 Hz, 1H), 4.64 (s, 2H), 4.40 (d, J = 5.4 Hz, 2H), 4.12 (d, J = 12.0 Hz, 1H), 4.04 (d, J = 12.1 Hz, 1H), 3.38 (s, 3H), 2.96 (d, J = 13.4 Hz, 2H), 2.72−2.67 (m, 2H), 1.43−140 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): 139.6, 135.3, 134.0, 124.9, 90.5, 72.6, 65.6, 64.7, 54.6, 50.6, 45.6, 42.2, 37.0, 34.7. HRMS (ES) (m/z): (M + Na)+ calcd for C14H 20NaO4, 275.1259; found, 275.1262. rel-(2S,2aS,2a1R,4aR,5S,7aR)-8-Bromo-6-((methoxymethoxy)methyl)-2,2a,2a1,3,4,4a,5,7a-octahydro-2,4-methanoindeno[7,1bc]furan-5-ol (13). N-Bromosuccinimide (700 mg, 3.9 mmol) was added to a stirred solution of the diol 10 (1.0 g, 3.9 mmol) in dry DCM (10 mL) at 0 °C, and the reaction mixture was stirred for 3 h at 0 °C. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and DCM (10 mL). The organic layer was washed successively with 20% aqueous Na2S2O3, saturated aqueous NaHCO3, and brine, and then it was dried over Na2SO4. Concentration of the solvent afforded a residue, which was purified by column chromatography (eluent: 20% EtOAc in hexane) to obtain tetracyclic bromide 13 (1.0 g, 80%) as a white solid. mp 132−134 °C. IR (neat) 3272, 2923, 2853, 1443, 1162, 1086, 567 cm−1. 1H NMR (400 MHz, CDCl3, δ): 5.92 (d, J = 3.9 Hz, 1H), 4.67 (s, 3H), 4.58 (d, J = 4.7 Hz, 1H), 4.37 (t, J = 5.5 Hz, 1H), 4.28 (d, J = 12.0 Hz, 1H), 4.15 (s, 1H), 4.11 (d, J = 2.2 Hz, 1H), 3.41 (s, 3H), 3.06 (s, 1H), 2.93−2.91 (m, 1H), 2.76 (s, 1H), 2.60−2.55 (m, 2H), 2.16 (d, J = 11.0 Hz, 1H), 1.57 (dd, J = 11.0, 1.4 Hz, 1H). 13C NMR (100 MHz,
tricycle 17 (Scheme 2). Unexpectedly, the nitro group of the PNB protecting group also underwent concurrent reduction to the amino group during the zinc reduction step. An X-ray crystal structure of the PAB-protected advanced intermediate 17 secured its formulation. The free secondary hydroxyl group in 17 was readily oxidized with PCC, though the reaction was slow due to its hindered environment, to furnish cyclohexanone derivative 18 with the carbonyl group installed at the desired location. A stage was now reached wherein the cyclopentadiene appendage in 18 had to be removed. The retro-D−A reaction in 18 was smoothly executed, although in modest yield, to furnish the protected but fully functional cyclohexenone 19. A key maneuver was now warranted to put in place the requisite C-2 hydroxy group stereochemistry, and this necessitated a Mitsunobu-type inversion at C-2 in 20. In order to implement it, the PAB-protection in 19 was selectively removed under mild conditions, and the resulting free C-2 hydroxyl compound 20 was subjected to the carefully crafted Mitsunobu regime15 to furnish C-2 hydroxy-inverted and PNB-protected cyclohexenoid 21 with secured stereochemistry that fully maps into the target structure. The stage was now set for the key step en route to 11 with the installation of the sensitive C-1 carboxylic acid functionality utilizing the pre-existing protected C-1 hydroxymethyl group handle. MOM deprotection in 21 was selectively carried out with Meerwein’s reagent16 to furnish primary alcohol 11 (Scheme 3). A direct oxidation of 11 to carboxylic acid 22 proved capricious, and therefore a two step protocol was resorted to. The primary hydroxyl bearing 11 was first oxidized to aldehyde in a triphosgene−DMSO milieu17 to the corresponding aldehyde and further, via Pinnick oxidation,18 to the carboxylic acid 22. The end game toward the target 8 required sequential deprotection of PNB and acetonide moieties in 22 under mild conditions, given the sensitive array of hydroxyl functionalities, and this was accomplished quite uneventfully at room temperature, as shown in Scheme 3, to deliver the target carbocyclic core 8 present in xylosmin. This smooth deprotection was a gratifying outcome as Hudlicky et al. had noted decomposition during the deprotection end game with their fully embellished substrates during the synthesis of 8. The spectra (1H NMR and 13 CNMR) of 8 were clean and identical to those reported.8 In summary, a synthesis of the polyoxygenated carbocyclic core present in bioactive xylosmin and related flacourtosides was achieved from the D−A adduct of cyclopentadiene and MOM-protected 2-hydroxymethyl-p-benzoquinone employing regio- and stereo-controlled steps involving internal protection through bromoetherfication and retro-D−A reactions as the key maneuvers. The approach can be adapted toward accessing an enantioselective variant9d,f,g and diversity creation.
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EXPERIMENTAL SECTION
General Information. All moisture and air sensitive reactions were performed using a standard syringe−septum technique in an atmosphere of nitrogen with dry, freshly distilled solvents. Low temperatures were maintained using liquid nitrogen in combination with an appropriate solvent. Hexane refers to the petroleum ether fraction boiling between 60 and 80 °C. Dry THF and ether were prepared by distilling them from sodium benzophenone ketyl. DCM and TEA were freshly distilled over calcium hydride before use. Methanol was distilled from its alkoxide (formed by the reaction with activated magnesium) and stored over 4 Å molecular sieves. Reactions were monitored by thin layer chromatography (TLC). Visualization 10576
DOI: 10.1021/acs.joc.8b01389 J. Org. Chem. 2018, 83, 10573−10579
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The Journal of Organic Chemistry CDCl3, δ): 139.3, 124.6, 95.5, 90.1, 81.9, 72.6, 64.6, 57.6, 53.8, 49.5, 48.1, 48.0, 40.3, 35.0. HRMS (ES) (m/z): (M + Na)+ calcd for C14H19BrNaO4, 353.0364; found, 353.0368. rel-(2S,2aS,2a1R,4aR,5S,7aR)-8-Bromo-6-((methoxymethoxy)methyl)-2,2a,2a1,3,4,4a,5,7a-octahydro-2,4-methanoindeno[7,1bc]furan-5-yl 4-nitrobenzoate (14). p-Nitrobenzoyl chloride (1.3 g, 7.2 mmol) was added at 0 °C to a stirred solution of 13 (1.2 g, 3.6 mmol) in DCM (10 mL), containing triethylamine (1.2 g, 11.6 mmol) and DMAP (44 mg, 0.4 mmol). The resulting reaction mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 solution (10 mL) at 0 °C, and the mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, and then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was passed through a silica gel column (eluent: 8% EtOAc in hexane) to deliver the PNB derivative 14 (1.5 g, 88%) as a white solid. mp 175− 177 °C. IR (neat) 3065, 2945, 2869, 1736, 1600, 1453, 1167, 1049, 549 cm−1. 1H NMR (400 MHz, CDCl3, δ): 8.32 (d, J = 8.3 Hz, 2H), 8.21 (d, J = 8.6 Hz, 2H), 6.03 (d, J = 9.4 Hz, 1H), 4.63−4.48 (m, 4H), 4.18−4.11 (m, 3H), 4.03 (d, J = 12.5 Hz, 1H), 3.27 (s, 3H), 2.96 (t, J = 4.9 Hz, 1H), 2.89−2.86 (m, 1H), 2.74−2.70 (m, 1H), 2.31 (s, 1H), 2.11 (d, J = 11.1 Hz, 1H), 1.59 (d, J = 11.1 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 164.4, 150.8, 134.9, 134.6, 130.8, 129.1, 123.9, 96.0, 90.5, 72.0, 69.6, 67.5, 60.4, 55.5, 54.0, 50.8, 46.8, 39.1, 36.8, 34.0. HRMS (ES) (m/z): (M + Na) + calcd for C21H22BrNNaO7, 502.0477; found, 502.0479. rel-(2S,2aS,2a1R,4aR,5S,6S,7S,7aR)-8-Bromo-6,7-dihydroxy-6((methoxymethoxy)-methyl)-decahydro-2,4-methanoindeno[7,1bc]furan-5-yl 4-nitrobenzoate (15). To a solution of PNB derivative 14 (700 mg, 1.5 mmol) in THF (8 mL) were added successively at room temperature N-methylmorpholine-N-oxide (204 mg, 1.7 mmol), t-butanol (3 mL), water (0.5 mL), and OsO4 (1.5 mL, 0.065 mmol, 0.05 M in tert-butyl alcohol) at room temperature. The reaction mixture was stirred for 24 h, quenched with solid Na2SO3 (200 mg), further stirred at room temperature for 20 min, and then florisil (200 mg) was added. The contents were stirred for 15 min and then filtered through a Celite pad. Concentration and column chromatography over silica gel (eluent: 60% EtOAc in hexane) gave cis-diol 15 as a white solid (635 mg, 85%). mp 186−188 °C. IR (neat) 3406, 2926, 2855, 1736, 1437, 1219, 1075 cm−1. 1H NMR (400 MHz, DMSO-d6, δ): 8.40 (d, J = 8.9 Hz, 2H), 8.23 (d, J = 8.9 Hz, 2H), 5.76 (s, 4H), 5.59 (d, J = 9.1 Hz, 1H), 5.17 (d, J = 7.0 Hz, 1H), 5.13 (s, 1H), 4.44 (d, J = 6.4 Hz, 1H), 4.40 (d, J = 6.4 Hz, 1H), 4.34 (d, J = 4.4 Hz, 1H), 3.84 (dd, J = 7.0, 2.2 Hz, 1H), 3.58 (s, 1H), 2.96 (s, 3H), 2.80−2.74 (m, 2H), 2.21 (s, 1H), 1.92 (d, J = 10.7 Hz, 1H), 1.72 (d, J = 10.5 Hz, 1H). 13C NMR (100 MHz, DMSO-d6, δ): 164.1, 151.1, 134.8, 131.1, 124.7, 96.8, 87.8, 85.9, 74.1, 73.3, 71.7, 71.0, 57.5, 55.4, 54.8, 48.3, 46.0, 37.9, 35.8. HRMS (ES) (m/z): (M + Na)+ calcd for C21H24BrNNaO9, 536.0532; found, 536.0532. rel-(2S,2aS,2a1R,4aR,5S,5aR,8aS,8bR)-9-Bromo-5a((methoxymethoxy)methyl)-7,7-dimethyldecahydro-2,4methanofuro[2′,3′,4’:7,1]indeno[5,6-d][1,3]dioxol-5-yl-4-nitro-benzoate (16). To a stirred solution of cis-diol 15 (600 mg, 1.2 mmol) and 2,2-dimethoxypropane (122 mg, 1.2 mmol) in DCM (10 mL) was added PPTS (30 mg, 0.2 mmol), and the reaction mixture was stirred for 6 h at room temperature. The reaction was quenched by the addition of water (10 mL) and diluted with DCM (15 mL). The organic phase was separated, and the aqueous layer was extracted with DCM (3 × 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified through silica gel column chromatography (eluent: 10% EtOAc in hexane) to give acetonide 16 (543 mg, 84%) as a white solid. mp 195−197 °C. IR (neat) 3032, 2934, 2884, 1743, 1161, 1032 cm−1. 1H NMR (500 MHz, CDCl3, δ): 8.27 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 5.80 (d, J = 10.3 Hz, 1H), 4.59−4.55 (m, 2H), 4.50−4.48 (m, 2H), 4.22−4.20 (m, 1H), 3.86 (d, J = 11.3 Hz, 1H), 3.77 (d, J = 11.3 Hz, 1H), 3.25 (s, 3H), 2.95−2.91 (m, 2H), 2.63− 2.61 (m, 1H), 2.25 (s, 1H), 2.14 (d, J = 10.2 Hz, 1H), 1.61 (d, J = 11.2 Hz, 2H), 1.44 (s, 3H), 1.38 (s, 3H). 13C NMR (125 MHz, CDCl3, δ): 163.6, 150.8, 134.7, 130.8, 123.9, 108.8, 96.9, 87.5, 81.7,
77.5, 75.8, 74.4, 66.7, 60.4, 55.5, 55.4, 48.2, 44.7, 39.7, 36.2, 28.3, 27.1. HRMS (ES) (m/z): (M + Na)+ calcd for C24H28BrNNaO9, 576.0845; found, 576.0850. rel-(3aR,4S,4aS,5R,8S,8aR,9R,9aS)-9-Hydroxy-3a((methoxymethoxy)methyl)-2,2-dimethyl-3a,4,4a,5,8,8a,9,9a-octahydro-5,8-methanonaphtho[2,3-d][1,3]dioxol-4-yl-4-amino- benzoate (17). Freshly activated Zn powder (1.2 g, 18.1 mmol) and acetic acid (2 mL) were successively added to a stirred solution of acetonide 16 (400 mg, 0.7 mmol) in methanol (15 mL) at room temperature. The mixture was gradually heated to 70 °C and stirred for 4 h at same temperature. After being cooled, the reaction mixture was diluted with ether (20 mL) and filtered through a Celite pad. The filtrate was washed with saturated aqueous NaHCO3 and brine and then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified by filtration through a silica gel column (eluent: 20% EtOAc in hexane) to give hydroxyl-acetonide 17 (257 mg, 80%) as a white solid. mp 140−142 °C. IR (neat) 3366, 2954, 2853, 1733, 1438, 1168, 1057 cm−1. 1H NMR (400 MHz, CDCl3, δ): 7.58 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 8.7 Hz, 2H), 6.09− 6.07 (m, 1H), 5.67−5.65 (m, 2H), 4.42 (d, J = 6.5 Hz, 1H), 4.28 (d, J = 6.5 Hz, 1H), 4.18−4.14 (m, 1H), 3.94 (d, J = 3.4 Hz, 1H), 3.61 (d, J = 10.7 Hz, 1H), 3.53 (d, J = 10.7 Hz, 1H), 3.06 (s, 3H), 2.93−2.80 (m, 4H), 2.52 (d, J = 10.9 Hz, 1H), 1.43 (s, 3H), 1.40 (s, 3H), 1.34 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 164.6, 151.3, 135.6, 135.5, 131.4, 119.1, 114.2, 109.4, 96.8, 83.8, 79.9, 71.9, 69.4, 69.2, 55.2, 53.1, 45.5, 45.4, 39.7, 39.0, 27.7, 27.2. HRMS (ES) (m/z): (M + Na)+ calcd for C24H31NNaO7, 468.1998; found, 468.2018. rel-(3aR,4S,4aS,5R,8S,8aR,9aR)-3a-((Methoxymethoxy)methyl)2,2-dimethyl-9-oxo-3a,4,4a,5,8,8a,9,9a-octahydro-5,8 methanonaphtho[2,3-d][1,3]dioxol-4-yl-4-amino-benzoate (18). PCC (1.4 g, 6.7 mmol) was added to a solution of the alcohol 17 (500 mg, 1.1 mmol) in DCM (15 mL), and the reaction mixture was stirred for 3 days at room temperature. After completion of the reaction, the reaction mixture was directly loaded on a silica gel column and eluted with 8% EtOAc in hexane to afford ketone 18 (323 mg, 65%) as a white solid. mp 161−163 °C. IR (neat) 3510, 3389, 2960, 1737, 1687, 1455, 1128, 1068 cm−1. 1H NMR (400 MHz, CDCl3, δ): 7.73 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 6.15− 6.13 (m, 1H), 5.86 (d, J = 3.2 Hz, 1H), 5.55−5.53 (m, 1H), 4.55 (d, J = 6.6 Hz, 1H), 4.42 (d, J = 6.6 Hz, 1H), 3.78−3.75 (m, 1H), 3.64 (d, J = 10.9 Hz, 1H), 3.62 (dd, J = 10.9, 2.4 Hz, 1H), 3.44−3.41 (m, 1H), 3.21 (s, 3H), 3.06−3.00 (m, 2H), 2.54−2.51 (m, 2H), 1.67 (s, 3H), 1.53 (s, 3H), 1.35 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 207.9, 161.7, 153.2, 135.5, 134.2, 132.0, 131.3, 119.4, 117.4, 114.0, 96.8, 89.0, 82.0, 69.7, 68.7, 55.4, 51.2, 46.0, 45.5, 43.1, 42.4, 27.9, 27.8. HRMS (ES) (m/z): (M + Na)+ calcd for C24H29NNaO7, 466.1842; found, 466.1847. rel-(3aR,4S,7aR)-3a-((Methoxymethoxy)methyl)-2,2-dimethyl-7oxo-3a,4,7,7a-tetrahydro-benzo[d][1,3]dioxol-4-yl 4-aminobenzoate (19). A solution of the tricyclic ketone 18 (300 mg, 0.6 mmol) in diphenyl ether (3 mL) was heated at 230 °C for 40 min with stirring. The reaction mixture, after being cooled to RT, was directly loaded on a silica gel column. After removal of less polar diphenyl ether, elution with 15% EtOAc in hexane yielded the retroD−A product 19 (153 mg, 60%) as a colorless viscous oil. IR (neat) 3424, 3066, 2943, 1735, 1683, 1463, 1185, 1018 cm−1. 1H NMR (500 MHz, CDCl3, δ): 7.58 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 8.7 Hz, 2H), 6.08 (dd, J = 5.4, 3.1 Hz, 1H), 5.65 (t, J = 4.5 Hz, 2H), 4.42 (d, J = 6.6 Hz, 1H), 4.28 (d, J = 6.6 Hz, 1H), 4.18−4.16 (m, 1H), 4.07−4.04 (m, 1H), 3.94 (d, J = 3.4 Hz, 1H), 3.61 (d, J = 10.7 Hz, 1H), 3.54 (d, J = 10.7 Hz, 1H), 3.06 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H). 13C NMR (125 MHz, CDCl3, δ): 192.6, 163.4, 151.0, 138.9, 134.2, 131.0, 128.9, 123.8, 117.2, 96.8, 88.2, 72.2, 66.5, 65.6, 56.4, 27.9, 26.1. HRMS (ES) (m/z): (M + Na)+ calcd for C19H23NNaO7, 400.1372; found, 400.1372. rel-(3aR,7S,7aR)-7-hydroxy-7a-((Methoxymethoxy)methyl)-2,2dimethyl-7,7a-dihydro-benzo[d][1,3]dioxol-4(3aH)-one (20). To a stirred solution of enone 19 (150 mg, 0.4 mmol) in dry MeOH (2 mL), finely ground K2CO3 (274 mg, 2.0 mmol) was added at room temperature. The reaction mixture was stirred for 1 h at room temperature. After completion of the reaction, it was diluted with 10577
DOI: 10.1021/acs.joc.8b01389 J. Org. Chem. 2018, 83, 10573−10579
Note
The Journal of Organic Chemistry water (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified through silica gel column chromatography (eluent: 25% EtOAc in hexane) to give hydroxy enone 20 (82 mg, 80%) as a colorless oil. IR (neat) 3347, 2945, 1682, 1453, 1167, 1049 cm−1. 1H NMR (400 MHz, CDCl3, δ): 6.71 (dd, J = 10.1, 2.4 Hz, 1H), 5.97−6.01 (m, 1H), 5.28 (s, 1H), 4.81 (s, 2H), 4.70 (d, J = 6.6 Hz, 1H), 3.87 (d, J = 10.7 Hz, 1H), 3.60 (d, J = 10.7 Hz, 1H), 3.43 (s, 3H), 1.54 (s, 3H), 1.45 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 193.5, 144.3, 126.4, 119.3, 97.2, 67.9, 65.6, 63.6, 56.7, 55.8, 28.4, 26.7. HRMS (ES) (m/z): (M + Na)+ calcd for C12H18NaO6, 281.1001; found, 281.1002. rel-(3aR,4R,7aR)-3a-((Methoxymethoxy)methyl)-2,2-dimethyl-7oxo-3a,4,7,7a-tetrahydro-benzo[d][1,3]dioxol-4-yl 4-Nitrobenzoate (21). To a stirred solution of triphenylphosphine (122 mg, 0.4 mmol), hydroxy enone 20 (80 mg, 0.3 mmol), and 4-nitrobenzoic acid (78 mg, 0.4 mmol) in dry THF (10 mL) was added a THF solution of diisopropyl azodicarboxylate (94 mg, 0.4 mmol) dropwise at −40 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 8 h. After completion of the reaction, the mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated NaHCO3 (3 mL) and brine (2 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using 8% EtOAc in hexane to afford the PNB derivative 21 (98 mg, 78%) as a clear oil. IR (neat) 2976, 2885, 1733, 1683, 1456, 1170, 1045 cm−1. 1H NMR (400 MHz, CDCl3, δ): 8.30 (d, J = 8.9 Hz, 2H), 8.21 (d, J = 8.9 Hz, 2H), 6.55 (dd, J = 10.1, 2.4 Hz, 1H), 6.09−6.07 (m, 1H), 5.67 (s, 1H), 4.42 (s, 2H), 4.28 (d, J = 6.6 Hz, 1H), 3.63 (d, J = 10.7 Hz, 1H), 3.56 (d, J = 10.7 Hz, 1H), 3.06 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 197.4, 164.4, 150.8, 134.9, 134.6, 130.8, 129.1, 123.9, 119.2, 96.0, 90.5, 72.0, 69.6, 67.5, 55.5, 26.9, 25.1. HRMS (ES) (m/z): (M + Na)+ calcd for C19H21NNaO9, 430.1114; found, 430.1115. rel-(3aR,4R,7aR)-3a-(Hydroxymethyl)-2,2-dimethyl-7-oxo3a,4,7,7a-tetrahydrobenzo[d][1,3]-dioxol-4-yl 4-Nitrobenzoate (11). To a cooled (0 °C) solution of PNB derivative 21 (50 mg, 0.1 mmol) in 2 mL of dry DCM was added a solution of triphenylcarbenium−tetrafluoroborate (122 mg, 0.4 mmol) in 1 mL of dry DCM. The resulting dark yellow solution was stirred at ice bath temperature for 3 h, directly loaded on a silica gel column, and eluted with 15% EtOAc in hexane to afford primary alcohol 11 (38 mg, 85%) as a colorless oil. IR (neat) 3402, 2973, 1733, 1681, 1458, 1118, 1045 cm−1. 1H NMR (400 MHz, CDCl3, δ): 8.27 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 6.59 (t, J = 8.1 Hz, 1H), 6.12 (d, J = 8.2 Hz, 1H), 5.20 (s, 1H), 4.41 (d, J = 6.5 Hz, 1H), 3.86 (d, J = 10.7 Hz, 1H), 3.77 (d, J = 10.7 Hz, 1H), 1.44 (s, 3H), 1.38 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 198.3, 163.5, 150.9, 138.6, 134.7, 130.8, 125.8, 123.9, 117.0, 87.5, 74.0, 66.5, 55.5, 28.3, 27.1. HRMS (ES) (m/z): (M + Na)+ calcd for C17H17NNaO8, 386.0852; found, 386.0859. rel-(3aR,4R,7aR)-2,2-Dimethyl-4-((4-nitrobenzoyl)oxy)-7-oxo3a,4,7,7a-tetrahydrobenzo-[d][1,3]dioxole-3a-carboxylic Acid (22). To a stirred solution of bis(trichloromethyl)carbonate (triphosgene) (163 mg, 0.5 mmol) in 2 mL of dry DCM at −40 °C was added dry DMSO (18.9 mg, 0.3 mmol), and the reaction mixture was stirred at the same temperature for 15 min. A solution of alcohol 11 (80 mg, 0.2 mmol) in 1 mL of dry DCM was slowly added at the same temperature. After being stirred for 15 min, triethyl amine (0.7 mL) was added dropwise, maintaining the temperature below −40 °C. The resulting suspension was allowed to come to 25 °C over a period of 3 h, and the reaction was monitored by TLC. The reaction mixture was diluted with DCM (15 mL), washed with water (2 × 5 mL) and brine, and dried over Na2SO4. After concentration, the crude aldehyde product was used for the next step without purification. To a stirred solution of the resultant aldehyde (50 mg, 0.1 mmol) in t-BuOH (3.0 mL) and H2O (1.0 mL) was added 2-methyl-2butene (48 mg, 0.7 mmol), followed by NaH2PO4 (166 mg, 1.4 mmol), and the mixture was cooled to 0 °C. To this mixture was added NaClO2 (75 mg, 0.8 mmol) as a 1.40 M solution of 3:1 tBuOH/H2O (0.4 mL), and the mixture was stirred for 15 h at 0 °C.
The reaction was subsequently quenched via the addition of saturated aqueous NH4Cl (1.0 mL). The resulting mixture was partitioned between EtOAc and H2O, and the aqueous layer was further extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified through silica gel column chromatography (eluent: 70% EtOAc in hexane) to give acid 22 (39 mg, 75%) as a clear viscous oil. IR (neat) 3372, 2927, 1744, 1716, 1455, 1232, 1075 cm−1. 1H NMR (400 MHz, CDCl3, δ): 8.28 (d, J = 8.9 Hz, 2H), 8.16 (d, J = 8.8 Hz, 2H), 6.81 (dd, J = 10.1, 2.1 Hz, 1H), 6.17 (dd, J = 10.2, 2.4 Hz, 1H), 5.06 (t, J = 2.4 Hz, 1H), 4.75 (s, 1H), 1.46 (s, 3H), 1.40 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 196.1, 172.1, 163.2, 150.4, 135.7, 133.5, 130.2, 125.1, 122.2, 116.4, 96.5, 92.5, 66.3, 27.5, 26.3. HRMS (ES) (m/z): (M + Na)+ calcd for C17H15NNaO9, 400.0645; found, 400.0653. rel-(1R,2R,6R)-1,2,6-Trihydroxy-5-oxocyclohex-3-enecarboxylic Acid (8). To a stirred solution of acid 22 (100 mg, 0.3 mmol) in dry MeOH (2 mL), solid K2CO3 (183 mg, 1.3 mmol) was added at room temperature, and the reaction mixture was stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction was quenched by addition of 5 mL of water and extracted with EtOAc (3 × 5 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude hydroxy acetonide was used for the next step without purification. A solution of the resulting hydroxy acetonide (60 mg, 0.3 mmol) in trifluoroacetic acid (1.8 mL) and water (0.2 mL) was stirred at room temperature for 30 min. The mixture was concentrated in vacuo to afford a residue, which was purified by silica gel column chromatography (eluent: 100% EtOAc) to give triol 8 (27 mg, 55%) as a white solid. mp 135−137 °C. IR (neat) 3449, 2927, 1729, 1697, 1260, 1050 cm−1. 1H NMR (400 MHz, D2O, δ): 6.94 (dd, J = 10.3, 1.9 Hz, 1H), 6.14 (dd, J = 10.6, 2.7 Hz, 1H), 5.05 (t, J = 2.3 Hz, 1H), 4.79 (s, 1H). 13C NMR (100 MHz, CD3OD, δ): 201.3, 176.3, 152.9, 127.2, 86.9, 77.3, 71.6. HRMS (ES)− (m/z): (M − H)+ calcd for C7H7O6, 187.0243; found, 187.0283 (reported 187.0316).8
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01389. X-ray crystallographic data for compound 17 (CIF) Scanned copies of 1H NMR and13C NMR spectra of all new compounds and X-ray crystallographic data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Nagi Reddy Modugu: 0000-0001-9019-3325 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Nagi Reddy Modugu thanks the Department of Science and Technology, Government of India for the award of the INSPIRE-Faculty fellowship [IFA13-CH-108] and Dr. S. Chandrasekhar, Director IICT, for extending all of the facilities and research facilitation (IICT/Pubs./2018/189). G.M. acknowledges the research support from Dr. Reddy’s Laboratories (DRL) and an award of Dr. Kallam Anji Reddy, Chair at the University of Hyderabad.
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REFERENCES
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DOI: 10.1021/acs.joc.8b01389 J. Org. Chem. 2018, 83, 10573−10579
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The Journal of Organic Chemistry
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DOI: 10.1021/acs.joc.8b01389 J. Org. Chem. 2018, 83, 10573−10579
