Enantiopure Aromatic Saddles Bearing the Fenestrindane Core - The

Dec 14, 2018 - (29) This reduction step served to revert a small amount of a 4-fold cyclized, benzhydrylic monohydroxylated side product back to the t...
0 downloads 0 Views 2MB Size
Download PDF
Article Cite This: J. Org. Chem. 2019, 84, 869−878

pubs.acs.org/joc

Enantiopure Aromatic Saddles Bearing the Fenestrindane Core Wai-Shing Wong,† Ho-Wing Tse,† Enoch Cheung,† Dietmar Kuck,*,‡ and Hak-Fun Chow*,† †

Department of Chemistry and Institute of Molecular Functional Materials, The Chinese University of Hong Kong, Shatin, Hong Kong ‡ Department of Chemistry and Center for Molecular Materials (CM2), Bielefeld University, 33615 Bielefeld, Germany

Downloaded via KAROLINSKA INST on January 18, 2019 at 11:46:57 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: The synthesis of enantiomerically pure, configurationally stable fenestrindane-based polyaromatic compounds with saddle-like structures is reported. Seven racemic fenestrane synthetic precursors were first screened by chiral HPLC for resolvability into enantiomers. Among the three resolvable precursors, a tribenzofenestrene derivative was resolved on a semipreparative scale, and the absolute configuration of the more slowly eluting enantiomer was established by X-ray crystallography. The enantiopure tribenzofenestrenes were then separately converted, in six steps, to the saddle-shaped fenestrindane derivatives in optically pure form. The two enantiomeric pairs of saddles were characterized by 1H and 13C NMR spectroscopy, mass spectrometry, and circular dichroism spectroscopy. All new compounds reported herein represent the first enantiopure non-natural carbocyclic fenestranes isolated to date.

■

INTRODUCTION Nonplanar (curved) polyarenes have emerged as attractive synthetic targets owing to their diverse molecular and crystal packing structures and their applications in materials science.1 In particular, conformationally flexible congeners have been shown to undergo dynamic processes such as bowl-to-bowl inversion2,3 and saddle-to-saddle inversion4 in the solution state. If the inversion occurs between two molecular configurations that are nonsuperimposable mirror images of each other, then the inversion process is equivalent to enantiomerization. In cases where the nonplanar polyarene possesses more than one stereogenic unit,5,6 inversion of only one of them brings about diastereomerization. If the inversion equilibrium is rapid under ambient conditions, physical isolation of individual enantiomers and/or diastereomers is kinetically precluded. These molecules are thereby regarded as practically achiral, even if their most stable geometry is chiral.7 To explore the specific properties of chiral nonplanar polyarenes, the inversion dynamics must be slow enough under ambient conditions. The individual enantiomers can thus be characterized before racemization. For instance, the bowlshaped sumanene derivatives 18 and 29 are both inherently chiral (Figure 1a). The bowl-to-bowl inversion barrier (ΔG⧧) of 1b was determined by 1H NMR spectroscopy to be 32.2 kcal/mol at 140 °C, while that of 2 was calculated by DFT to be 68.4 kcal/mol.10 These values pinpointed the stereochemical stability of 1 and 2, yet they have not been resolved © 2018 American Chemical Society

Figure 1. Chiral, configurationally stable polyarenes that are (a) bowlshaped (1 and 2) and (b) saddle-shaped (3 and 4).

into enantiopure forms. On the other hand, enantiomeric πbowls with borderline rigidity have been resolved by chiral HLPC11 and prepared by asymmetric synthesis.12 Saddleshaped polyarenes that are configurationally stable have also Received: October 23, 2018 Published: December 14, 2018 869

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry

Scheme 1. Previously Reported Synthesis of the Saddle-Shaped Polyarenes 7 and 8 from the Tetraarylfenestrindanes 5 and 6, Respectively, via Scholl-Type Cyclization

been reported. For example, 2,15-disubstituted 1,16dehydro[6]helicenes 3a−c were chromatographically separated into enantiopure forms,13 and the enantiopure, quadruply benzannulated ortho-tetraphenylene (R,R)-4 was synthesized from an enantiomerically pure starting material14 (Figure 1b). The enantiomers of less conjugated ortho-tetraphenylenes have also been obtained by enantioselective rhodium-catalyzed [2 + 2 + 2] cycloaddition15 and by diastereomer derivatization.16 We have been interested in the synthesis of nonplanar πconjugated derivatives bearing skeletal sp3 carbons placed outside of the conjugated framework.17−19 In particular, the tetrabenzo[5.5.5.5]fenestrane (fenestrindane) motif20 has been utilized to construct polyaromatic saddles. Recently, we reported that 1,4,9,12-tetraarylfenestrindanes (5 and 6) can undergo 4-fold Scholl-type heptagonal ring closure to furnish the 4-fold cove-bridged derivatives 7 and 8, respectively (Scheme 1).19b Noticeably, the X-ray crystal structure of 7 revealed a saddle-shaped molecular geometry with D2d symmetry, in agreement with the NMR data. The presence of dihedral planes in 7 renders the molecule achiral. Evidently, the 16-ring carbon skeleton in 7 and 8 is intrinsically achiral, but the latter congener is indeed chiral owing to the positioning of the four additional methoxy groups. Consequently, we pursued the preparation and characterization of enantiopure aromatic saddles containing a fenestrindane core, such as 8. Molecular Design. The chirality of 8 necessitates the ortho-phenylene linkage across each cove region of fenestrindane to be unsymmetrically substituted, such that the dihedral planes in the carbon framework are destroyed. Furthermore, we envisioned that fenestrindane derivative 9 could similarly be transformed into the fenestrindane-based saddle 10 upon 4-fold cyclodehydrogenation (Figure 2). As each ortho-phenylene unit in saddle 10 is desymmetrized by the presence of one ethoxy group and one methoxy group,

another chiral saddle can be formed. More importantly, the chiral saddles 8 and 10 can be presumed to be stable against enantio- and diastereomerization. Although fenestrindane derivatives are known to be conformationally flexible,21 such flexibility is manifested in the interconversion between conformers that are equivalent but not enantiomeric. In theory, enantiomerization of a chiral fenestrindane requires configuration inversion about all five sp3-hybridized carbon atoms; inversion at only one methine carbon of the all-cisfenestrane core results in the diastereomeric cis,cis,cis,trans structure and is enthalpically unfavorable.22,23 In the present paper, we disclose our results on the preparation and chiroptical properties of the enantiomerically pure tetraarylfenestrindanes 6 and 9, of their synthetic precursors, and of the 4-fold cove-bridged fenestrindane-based saddles 8 and 10. To the best of our knowledge, all synthetic chiral fenestranes have only been prepared as racemates.23b Also, several groups have accomplished the total synthesis toward the only known natural fenestrane, laurenene, albeit in racemic form.24 Therefore, the new compounds reported in this work represent the first enantiopure congeners in the realm of carbocyclic fenestrane chemistry.

■

RESULTS AND DISCUSSION Chiral Resolution of the Precursor Molecules by HPLC. One can straightforwardly aim at resolving the enantiomers of target saddles 8 and 10 synthesized in racemic form. However, this strategy is not preferable in the long run because the resolution of every new chiral saddle other than 8 and 10 has to be reoptimized. In the alternative strategy, the seven racemic precursors 11−17, which are mutual to both target saddles 8 and 10, were prepared according to the developed synthesis19b (Figure 3). The ideal scenario is the successful chiral resolution of rac-17. In that case, the enantiomers of 17 will serve as key intermediates toward 8, 10, and other intriguing derivatives in enantiopure form. Chiral HPLC was used to examine the resolvability of the seven precursor racemates 11−17 and also of rac-8 due to sample availability. On the basis of previous experience in chiral tribenzotriquinacene derivatives,25 the CHIRALPAK IB column composed of cellulose tris(3,5-dimethylphenylcarbamate) was used. Among the eight racemates tested, only three (11, 13, and 15) were resolvable into enantiopure forms using hexane/isopropyl alcohol (7/3 v/v) as the eluent at a flow rate of 6 mL/min.26 The chromatograms of these successful separations are shown in Figure 4. In principle, fenestrindane 15 is the best candidate for semipreparative resolution because

Figure 2. New chiral fenestrindane derivatives reported in this work. 870

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry

Figure 3. Racemic precursors 11−17 that were subjected to chiral HPLC. The resolvable racemates 11, 13, and 15 are highlighted.

Figure 4. Chromatograms for the chiral resolution of racemates 11, 13, and 15 by HPLC (stationary phase, CHIRALPAK IB; mobile phase, hexane/isopropyl alcohol (7/3 v/v); flow rate, 6 mL/min). See text for the assignment of the absolute configuration.

it occurs at the latest stage in the synthetic route toward 8 and 10. Unfortunately, the limited solubility of compound 15 in organic solvents hampered large-scale enantiomer separation. In practice, the racemic tribenzofenestrene 13 was selected for semipreparative resolution by HPLC. After numerous trials, the mobile phase composition was optimized to be hexane/ ethyl acetate (4/1 v/v) for the resolution of rac-13 at sample concentrations up to 100 mg/mL. Establishment of Absolute Configurations. Single crystals were obtained from a chloroform solution of (+)-11 (the more slowly eluting enantiomer) and from an ethyl acetate solution of (+)-13 (the faster eluting enantiomer) by slow evaporation. The X-ray crystal structure of (+)-11 was acquired using the Mo Kα line (0.71 Å), whereas that of (+)-13 was determined using the Cu Kα line (1.54 Å).27 Enabled by the anomalous dispersion effect,28 the absolute configurations of (+)-(4bR,8bR,12bS,13S,15S,15aS)-11 and (+)-(4bR,8bR,12bS,14aS)-13 were unequivocally determined (Figure 5). For readability, these two enantiomers are denoted hereafter as (4bR)-11 and (4bR)-13. The benzhydrylic carbon C4b is arbitrarily chosen because its configuration is invariant along the synthetic route. Likewise, the remaining enantiopure compounds are designated only by this benzhydrylic carbon, which may be numbered differently on the basis of IUPAC rules. Synthesis of the Enantiopure Tetrakis(triflate)s 17. The enantiomerically pure dibromofenestranones 11 obtained by semipreparative HPLC were independently subjected to synthetic steps identical to those performed on rac-11. Shown in Scheme 2 is the synthetic route starting with (4bR)-11; the

Figure 5. X-ray crystal structures and structural formulas of (4bR)-11 and (4bR)-13. Only the hydrogen atoms that are bonded to chiral centers are shown in the X-ray structures; all others are omitted for clarity.

same steps involving the compounds of opposite chirality were also carried out but are not displayed. Hence, (4bR)-11 and (4bS)-11 were subjected to the ring contraction−decarboxylation sequence to afford the corresponding tribenzofenestrenes (4bR)-13 and (4bS)-13, respectively. The chiroptical properties of these individually synthesized samples matched well with those of the samples obtained from the HPLC resolution of rac-13. Afterward, both (4bR)-13 and (4bS)-13 871

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry Scheme 2. Synthesis toward the Enantiopure Tetrakis(triflate) (4bR)-17a

Reagents and conditions: (a) KOH (18 equiv), THF, 70 °C, 3 h, 73−79%; (b) Cu (30 equiv), quinoline, 240 °C, 3 h, 31−39%; (c) tetrachlorothiophene-1,1-dioxide (1.2 equiv), xylenes, 140 °C, 2.5 d, 78−85%; (d) Na (40 equiv), tBuOH, THF, 70 °C, 16 h, 86−91%; (e) BBr3 (8 equiv), CH2Cl2, 0−20 °C, 14 h, 91−93%; (f) Tf2O (10 equiv), pyridine (10 equiv), CH2Cl2, 0−20 °C, 14 h, 74−80%. Note that the synthesis involving the opposite enantiomers, i.e., from (4bS)-11 to (4bS)-17, is identical and thus not shown. a

Scheme 3. Suzuki−Miyaura Coupling of the Enantiopure Tetrakis(triflate)s (4bR)-17 and (4bS)-17 and Subsequent 4-Fold Scholl-Type Cyclization Giving the Respective Saddles (4b2R)-8 and (4b2R)-10 as Well as (4b2S)-8 and (4b2S)-10a

Reagents and conditions: (a) 2,3,4-trimethoxyphenylboronic acid, K3PO4·1.5H2O, Pd(OAc)2, SPhos, toluene, 110 °C, 3 d, 75−81%; (b) (i) DDQ, TfOH, CH2Cl2, 0 °C, 1 h. (ii) Et3SiH, TFA, CH2Cl2, 0−20 °C, 1 h, 51−52%. (c) 3-Ethoxy-4-methoxyphenylboronic acid, Cs2CO3, Pd2(dba)3, SPhos, toluene/H2O, 110 °C, 3 d, 65−74%. (d) (i) DDQ, TfOH, CH2Cl2, 0 °C, 1 h. (ii) Et3SiH, TFA, CH2Cl2, 0−20 °C, 1 h, 57−60%.

a

reported. In addition, the enantiomeric relationships of all compounds were substantiated by electronic circular dichroism (ECD) spectroscopy and specific rotation measurements. For each enantiomeric pair, the ECD profiles recorded in chloroform were mutual mirror images reflected about the xaxis (see the Supporting Information). Synthesis of the Enantiopure Saddles. With the enantiopure tetrakis(triflate)s (4bR)-17 and (4bS)-17 in hand, the enantiomeric fenestrindane-based saddles could be prepared in two steps (Scheme 3). First, Suzuki−Miyaura

obtained from repeated resolutions were converted to the respective tetrakis(triflate)s (4bR)-17 and (4bS)-17 in four steps. The reaction yields of the enantiopure products 12−17 paralleled those of their racemic counterparts. Characterization of the Enantiopure Precursors 11− 17. The constitutions of all pure enantiomers mentioned were confirmed by NMR spectroscopy and mass spectrometry. The 1 H and 13C NMR spectra of each pair of enantiomers in the series 11−17 (see the Supporting Information) were almost identical to those of their racemic counterparts previously 872

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry

the 1H NMR spectrum of the 4-fold cyclized molecule (4b2R)10 (Figure 6b), the four sets of aromatic protons were reflected by only three singlets at δ 7.75, 7.72, and 7.48 ppm integrating in the ratio 4:4:8. Notably, the benzhydrylic protons of the saddle (4b2R)-10 resonated at δ 4.65 ppm, that is, considerably upfield as compared to the corresponding resonance at δ 5.39 ppm in the precursor molecule (4bR)-9. This upfield shift is diagnostic of successful cycloheptatriene ring formation in similar analogues.18,19b Chiroptical Properties. The optical activities of the enantiomeric tetraarylfenestrindanes 6 and 9 and of the saddles 8 and 10 were determined. The specific rotations of (4bR)-6 and (4bS)-6 were −98 and +86, which dwindled in magnitude to −10 and +13 upon 4-fold cyclization into (4b2R)-8 and (4b2S)-8, respectively. For the tetrakis(3-ethoxy4-methoxyphenyl)fenestrindanes (4bR)-9 and (4bS)-9, the corresponding changes in specific rotation were −178 → +30 and +179 → −28, where sign reversals were observed. Shown in Figure 7 are the ECD spectra of the four enantiomeric pairs 6 and 9 as well as 8 and 10. Within the wavelength range, one could find exciton coupling only in the tetrakis(2,3,4trimethoxyphenyl)fenestrindanes 6, as evidenced by the negative and positive Cotton effects of (4b2R)-6 and (4b2S)6, respectively. Because of the ortho-methoxy groups in the para-terphenyl chromophores in 6, rotation around the aryl− aryl bonds is believed to be restricted.30 The axial chirality of these chromophores may account for the exciton coupling in 6. On the other hand, the 3-ethoxy-4-methoxy groups in 9 allowed unhindered aryl−aryl rotation. For the enantiopure saddles 8 and 10, an extended conjugation may underlie the absence of Cotton effects in the ECD spectra. Interestingly, despite structural resemblance to the achiral octamethoxy saddle 7, the saddles (4b2R)-10 and (4b2S)-10 exhibited pronounced chiroptical properties resulting just from the small difference between the ethoxy and methoxy groups on the molecular periphery.

coupling of (4bR)-17 and (4bS)-17 with 2,3,4-trimethoxyphenylboronic acid afforded the tetrakis(2,3,4-trimethoxyphenyl)fenestrindanes (4bR)-6 and (4bS)-6, while switching the coupling partner to 3-ethoxy-4-methoxyphenylboronic acid afforded the tetrakis(3-ethoxy-4-methoxyphenyl)fenestrindanes (4bR)-9 and (4bS)-9, respectively. Second, each of the enantiopure tetraarylfenestrindanes was treated with 2,3-dichloro-5,6-dicyano-para-benzoquinone (DDQ) and triflic acid to effect the 4-fold cyclodehydrogenation. After complete consumption of the reactant, the reaction was quenched with aqueous sodium bicarbonate. The organic material was then treated with triethylsilane and trifluoroacetic acid.29 This reduction step served to revert a small amount of a 4-fold cyclized, benzhydrylic monohydroxylated side product back to the target saddle. Upon purification, the four enantiopure fenestrindane-based saddles (4b2R)-8, (4b2S)-8, (4b2R)-10, and (4b2S)-10 were isolated in 51−60% yield. Structural Characterization. The NMR data of the enantiopure compounds (4bR)-6 and (4bS)-6 and of (4b2R)-8 and (4b2S)-8 were consistent with those of their corresponding racemates.19b Besides, these enantiopure 4-fold arylated and 4fold benzo-bridged fenestrindanes generally have lower melting points than their racemic counterparts (Table 1). This Table 1. Melting Point Ranges of Enantiopure and Racemic Samples of 6 and 8 sample

melting point range (°C)

(4bR)-6 (4bS)-6 rac-6a (4b2R)-8 (4b2S)-8 rac-8a

187−193 185−189 196−198 289−293 291−295 301−304

a

Adopted from ref 19b.

■

probably results from the difference in solid-state packing between enantiopure and racemic samples. However, attempts to obtain single crystals for 6 and 8 in either enantiopure or racemic form for elucidating their crystal packing structures remained futile. For the new structures 9 and 10, representative 1H NMR spectral features are as follows. The spectrum of (4bR)-9 (Figure 6a) shows the AA′BB′ system of the benzo units as two multiplets centered at δ 6.73 and 6.04 ppm. The four equivalent ethoxy groups gave rise to a multiplet centered at δ 4.12 ppm (CH2) and a triplet at δ 1.47 ppm (CH3). The second-order spectrum of the former signal was due to the diastereotopicity of the methylene protons. In

CONCLUSIONS In summary, we have reported the chiral resolution and absolute configuration assignments of the fenestrindane precursors 11−17, which allowed the synthesis of stereochemically stable, chiral aromatic saddles 8 and 10 in enantiopure form. All of these new compounds represent the first enantiopure non-natural carbocyclic fenestranes isolated to date. The structural and chiroptical properties of 8 and 10 have been elucidated. It is envisaged that the electron-rich aromatic rings of the enantiomers 8 and 10 can be further functionalized to generate other chiral saddle-shaped polyarene

Figure 6. Stacked 1H NMR spectra of (a) (4bR)-9 and (b) (4b2R)-10 (400 MHz, CDCl3, 22 °C). 873

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry

Figure 7. ECD spectra of the enantiopure tetraarylfenestrindanes 6 and 9 and of the fenestrindane-based saddles 8 and 10 (CHCl3, 1 mg/mL). and 100 mg/mL, respectively, using hexane/ethyl acetate (4/1 v/v) as the mobile phase at a respective flow rate of 5 and 6 mL/min. (+)-(4bR,8bR,12bS,13S,15S,15aS)-13,15-Dibromo-1,4,9,12-tetramethoxy-cis,cis,cis,cis-4b,8b,12b,13,15,15a-hexahydro-14Hdibenzo[2,3:4,5]pentaleno[1,6-jk]fluoren-14-one [(4bR)-11]. M.p.: 219−222 °C (dec.); [α]D25 +244 (c 0.04, CHCl3); Rf: 0.67 (hexane/ EtOAc = 2/1); 1H NMR (400 MHz, CDCl3): δ = 7.44−7.42 (m, 2H, ArH), 7.15−7.13 (m, 2H, ArH), 6.72 (AB, ΔδAB = 0.03, J = 8.8 Hz, 4H, ArH), 5.85 (d, J = 6.4 Hz, 2H, CHBr), 4.97 (s, 2H, CH), 4.20 (d, J = 6.3 Hz, 2H, CH), 3.79 (s, 6H, OCH3), 3.78 (s, 6H, OCH3); 13C NMR (101 MHz, CDCl3): δ = 196.9, 151.1, 151.0, 142.2, 131.9, 130.9, 127.2, 126.3, 111.3, 110.0, 68.3, 58.1, 55.8, 55.7, 55.1, 50.6; HRMS (EI) m/z: M+• Calcd for C30H2679Br2O5 624.0142; Found 624.0127. (−)-(4bS,8bS,12bR,13R,15R,15aR)-13,15-Dibromo-1,4,9,12-tetramethoxy-cis,cis,cis,cis-4b,8b,12b,13,15,15a-hexahydro-14Hdibenzo[2,3:4,5]pentaleno[1,6-jk]fluoren-14-one [(4bS)-11]. M.p.: 218−221 °C (dec.); [α]D25 −231 (c 0.04, CHCl3); Rf: 0.67 (hexane/ EtOAc = 2/1); 1H NMR (400 MHz, CDCl3): δ = 7.44−7.40 (m, 2H, ArH), 7.16−7.11 (m, 2H, ArH), 6.72 (AB, ΔδAB = 0.03, J = 8.8 Hz, 4H, ArH), 5.85 (d, J = 6.4 Hz, 2H, CHBr), 4.97 (s, 2H, CH), 4.20 (d, J = 6.4 Hz, 2H, CH), 3.79 (s, 6H, OCH3), 3.77 (s, 6H, OCH3); 13C NMR (101 MHz, CDCl3): δ = 196.9, 151.1, 151.0, 142.2, 131.9, 130.9, 127.2, 126.3, 111.3, 111.0, 68.3, 58.1, 55.8, 55.7, 55.1, 50.6; HRMS (EI) m/z: M+• Calcd for C30H2679Br2O5 624.0142; Found 624.0160. To a stirred solution of enantiopure dibromofenestranone (4bR)11 or (4bS)-11 (1.50 g, 2.39 mmol) in THF (80 mL) was added KOH pellets (2.42 g, 43.1 mmol). The mixture was stirred vigorously at 70 °C under nitrogen for 3 h. The cooled mixture was concentrated to ca. 20 mL, acidified with 1.2 M aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic solution was washed with water, dried with sodium sulfate, filtered, and then concentrated in vacuo to afford the enantiopure fenestrenecarboxylic acid (4bR)-12 or (4bS)-12 (73−79%) as a brown solid, which was used directly in the next step. Flash column chromatography (CHCl3/EtOAc = 10/1 gradient to 4/1) produced analytically pure (4bR)-12 and (4bS)-12 as colorless solids. (+)-(4bR,4b1R,8bR,12bS,14aS)-1,4,9,12-Tetramethoxy-cis,cis,cis,cis-4b,8b,12b,14a-tetrahydrodibenzo[a,f ]benzo[2,3]pentaleno[1,6cd]pentalene-13-carboxylic acid [(4bR)-12]. M.p.: 273−276 °C (dec.); [α]D25 +127 (c 0.02, CHCl3); Rf: 0.24 (CHCl3/EtOAc = 4/1); 1 H NMR (400 MHz, CDCl3, CO2H signal not observed): δ = 7.75− 7.72 (m, 2H, ArH), 7.19−7.17 (m, 3H, ArH and CH), 6.73 (AB, ΔδAB = 0.05, J = 8.5 Hz, 2H, ArH), 6.69 (AB, ΔδAB = 0.07, J = 8.4 Hz, 2H, ArH), 5.00 (s, 1H, CH), 4.99 (s, 1H, CH), 4.65 (m, 1H, CH),

derivatives. Most notably, tetrakis(triflate)s (4bR)-17 and (4bS)-17 are key compounds toward molecules that bear multiple saddle points and that should be accessible in a stereocontrolled manner via chirality-assisted synthesis,31 and toward 4-fold functionalized fenestrindanes via other types of coupling such as the Mizoroki−Heck reaction. This may facilitate expansion of the relatively underexplored fenestrindane chemistry. Hence, this work forms a basis for potential fenestrindane-based chiral molecular assembly and chiral recognition.

■

EXPERIMENTAL SECTION

General. All chemicals and solvents were purchased and directly used. Tetrahydrofuran and dichloromethane were distilled from sodium-benzophenone ketyl and calcium hydride, respectively. All reactions were carried out under air and monitored by TLC (silica gel 60 F254), unless otherwise specified. Flash column chromatography was performed on Davisil bare silica (60 Å, 40−63 μm), unless otherwise specified. Melting points were measured using the Stuart melting point apparatus SMP40 and are uncorrected. Specific rotations were measured on a Rudolph Autopol II automatic polarimeter at 25 °C using the sodium D line (589 nm); the concentrations in chloroform are reported in g/(100 mL). The NMR spectra were acquired on a Bruker Avance III 400, 500, or 700 spectrometer in CDCl3 at 22 °C, unless otherwise specified. The spectra were internally calibrated by the residual solvent signal (1H) or solvent signal (13C), and chemical shift values are reported in parts per million. Mass spectra were obtained on a Fisons VG Autospec X double-focusing MS (EI, 70 eV), a Thermo Q Exactive Focus Orbitrap MS (ESI or APCI), or a Bruker SolariX 9.4 T FT-ICR MS (ESI). Chiral Resolution by HPLC. The solvents used were suction filtered through nylon membrane filters (0.2 μm). The chromatographic system consisted of a Waters 515 HPLC pump, a Waters 2707 autosampler, a Daicel CHIRALPAK IB semipreparative column (20 mm × 250 mm), a Waters 2489 UV/visible detector (254 nm), and a Waters fraction collector III. The racemates 11−17 were synthesized and purified according to established procedures.19b They were dissolved in chloroform, injected (2.0 mL), and eluted with hexane/ isopropyl alcohol (7/3 v/v) at a flow rate of 5 mL/min. For accumulation of enantiopure materials, chromatographic separations were repeated on a larger scale. The maximum sample concentrations of racemates 11 and 13 for effective resolution were found to be 50 874

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry

1H, CH); 13C NMR (101 MHz, CDCl3, four aromatic signals merged into two): δ = 150.9, 150.7, 150.53, 150.48, 144.2, 144.0, 134.0, 133.8, 133.0, 132.2, 131.9, 131.3, 127.5, 127.4, 126.5, 125.5, 123.7, 110.9, 110.3, 108.9, 70.4, 62.8, 61.7, 61.6, 61.4, 55.9, 55.8, 55.6, 55.3, 51.5, 49.0; HRMS (APCI) m/z: [M + H]+ Calcd for C33H2735Cl4O4 627.0658; Found 627.0661. (−)-(4aS,4bR,4b1 R,8bS,12bS,16bR,16cR)-1,2,3,4-Tetrachloro5,8,13,16-tetramethoxy-cis,cis,cis,cis,cis-4a,4b,8b,12b,16b,16chexahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene [(8bS)-14]. M.p.: 153−156 °C; [α]D25 −69 (c 0.02, CHCl3); Rf: 0.74 (hexane/CHCl3 = 1/1); 1H NMR (400 MHz, CDCl3): δ = 7.82−7.81 (m, 1H, ArH), 7.74−7.73 (m, 1H, ArH), 7.22−7.16 (m, 2H, ArH), 6.74 (AB, ΔδAB = 0.08, J = 8.9 Hz, 2H, ArH, CH), 6.67 (AB, ΔδAB = 0.11, J = 8.9 Hz, 2H, ArH), 5.05 (s, 1H, CH), 4.99 (s, 1H, CH), 4.60 (s, 1H), 4.17 (d, J = 8.2 Hz, 1H, CH), 4.11 (d, J = 9.0 Hz, 1H, CH), 3.93 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.28 (t, J = 8.6 H, 1H, CH); 13C NMR (101 MHz, CDCl3, four aromatic signals merged into two): δ = 150.9, 150.6, 150.52, 150.47, 144.2, 144.0, 134.0, 133.8, 133.0, 132.2, 131.9, 131.2, 127.5, 127.4, 126.5, 125.5, 123.7, 110.9, 110.3, 108.9, 70.4, 62.8, 61.7, 61.6, 61.4, 55.9, 55.8, 55.6, 55.3, 51.5, 48.9; HRMS (APCI) m/z: [M + H]+ Calcd for C33H2735Cl4O4 627.0658; Found 627.0662. To a stirred solution of enantiopure (8bR)-14 or (8bS)-14 (1.60 g, 2.55 mmol) and tert-butyl alcohol (11 mL) in THF (60 mL) was added sodium metal (2.34 g, 102 mmol). The resulting mixture was heated to reflux under nitrogen for 16 h. Residual sodium was carefully destroyed with ethanol at 0 °C under nitrogen and then with water. The concentrated mixture (ca. 20 mL) was acidified with 1.2 M aqueous hydrochloric acid and then extracted with dichloromethane (50 mL × 3). The combined organic solution was washed with water, dried with sodium sulfate, filtered, and then evaporated in vacuo to furnish the enantiopure tetramethoxyfenestrindane (4bR)-15 or (4bS)-15 (4.30 g, 86−91%) as a colorless solid. (+)-(4bR,8bR,12bR,16bR)-1,4,9,12-Tetramethoxy-cis,cis,cis,cis4b,8b,12b,16b-tetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene [(4bR)-15]. M.p.: 268−271 °C (dec.); [α]D25 +150 (c 0.02, CHCl3); Rf: 0.57 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3): δ = 7.75−7.73 (m, 4H, ArH), 7.18−7.16 (m, 4H, ArH), 6.69 (s, 4H, ArH), 5.03 (s, 4H, CH), 3.85 (s, 12H, OCH3); 13 C NMR (101 MHz, CDCl3): δ = 150.9, 144.4, 133.9, 127.1, 126.9, 110.0, 71.9, 60.8, 55.6; HRMS (EI) m/z: M+• Calcd for C33H28O4 488.1982; Found 488.1983. (−)-(4bS,8bS,12bS,16bS)-1,4,9,12-Tetramethoxy-cis,cis,cis,cis4b,8b,12b,16b-tetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene [(4bS)-15]. M.p.: 268−271 °C (dec.); [α]D25 −149 (c 0.02, CHCl3); Rf: 0.57 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3): δ = 7.75−7.71 (m, 4H, ArH), 7.19−7.15 (m, 4H, ArH), 6.69 (s, 4H, ArH), 5.02 (s, 4H, CH), 3.85 (s, 12H, OCH3); 13 C NMR (101 MHz, CDCl3): δ = 150.9, 144.4, 133.9, 127.1, 126.9, 110.0, 71.9, 60.8, 55.6; HRMS (EI) m/z: M+• Calcd for C33H28O4 488.1982; Found 488.1983. To a stirred solution of (4bR)-15 or (4bS)-15 (290 mg, 0.59 mmol) in dichloromethane (6 mL) at 0 °C was slowly added boron tribromide (0.45 mL, 4.78 mmol) via a dropping funnel equipped with a calcium chloride drying tube. The resulting mixture was stirred at 20 °C for 14 h. The excess boron tribromide was destroyed with water at 0 °C, followed by the addition of sodium carbonate (0.63 g, 5.9 mmol). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic solution was washed with water, dried with sodium sulfate, and filtered. The evaporated residue was purified by flash column chromatography (hexane/EtOAc = 2/1 gradient to 1/1) to furnish the enantiopure tetrahydroxyfenestrindane (4bR)-16 or (4bS)-16 (91−93%) as a pale brown solid. (+)-(4bR,8bR,12bR,16bR)-cis,cis,cis,cis-4b,8b,12b,16bTetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene-1,4,9,12-tetraol [(4bR)-16]. M.p.: 189−194 °C; [α]D25 +179 (c 0.1, CHCl3); Rf: 0.70 (hexane/EtOAc = 1/2); 1H NMR (400 MHz, CD3OD): δ = 7.86−7.84 (m, 4H, ArH), 7.13−7.11 (m, 4H, ArH), 6.56 (s, 4H, ArH), 4.90 (s, 4H, CH); 13C NMR (101 MHz, CD3OD): δ = 148.2, 145.7, 133.2, 127.9, 127.7, 115.8, 73.2, 61.7;

4.49 (m, 1H, CH), 3.89 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.77 (s, 3H, OCH3); 13C NMR (176 MHz, two methoxy signals overlap): δ = 168.5, 151.5, 151.0, 150.3, 149.3, 146.6, 143.7, 143.5, 136.6, 134.0, 133.1, 132.0, 131.7, 127.4, 127.3, 127.0, 126.8, 110.5, 110.3, 110.1, 109.5, 72.5, 60.9, 60.6, 59.9, 59.4, 55.8, 55.7, 55.6; HRMS (ESI) m/z: [M − H]− Calcd for C30H25O6 481.1657; Found 481.1662. (−)-(4bS,4b1S,8bS,12bR,14aR)-1,4,9,12-Tetramethoxy-cis,cis,cis,cis-4b,8b,12b,14a-tetrahydrodibenzo[a,f ]benzo[2,3]pentaleno[1,6cd]pentalene-13-carboxylic acid [(4bS)-12]. M.p.: 273−275 °C (dec.); [α]D25 −102 (c 0.02, CHCl3); Rf: 0.24 (CHCl3/EtOAc = 4/ 1); 1H NMR (400 MHz, CDCl3, CO2H signal not observed): δ = 7.75−7.72 (m, 2H, ArH), 7.19−7.17 (m, 3H, ArH and CH), 6.73 (AB, ΔδAB = 0.05, J = 8.6 Hz, 2H, ArH), 6.69 (AB, ΔδAB = 0.06, J = 8.6 Hz, 2H, ArH), 5.00 (s, 1H, CH), 4.99 (s, 1H, CH), 4.65 (m, 1H, CH), 4.49 (m, 1H, CH), 3.89 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.77 (s, 3H, OCH3); 13C NMR (101 MHz, CDCl3, two methoxy signals overlap): δ = 167.0, 151.7, 151.0, 150.4, 149.0, 147.7, 143.7, 143.5, 136.5, 134.2, 133.1, 131.7, 131.6, 127.5, 127.3, 127.0, 126.8, 110.7, 110.4, 110.2, 109.6, 72.7, 60.8, 60.4, 60.1, 59.0, 55.9, 55.7, 55.6; HRMS (ESI) m/z: [M − H]− Calcd for C30H25O6 481.1657; Found 481.1659. A suspension of enantiopure fenestrenecarboxylic acid (4bR)-12 or (4bS)-12 (0.80 g, 1.66 mmol) and copper powder (3.16 g, 49.7 mmol) in quinoline (24 mL) was heated to reflux under argon for 3 h. The cooled mixture was diluted with ethyl acetate (50 mL) and decanted to leave behind most residual copper. The organic solution was washed with 1.2 M aqueous hydrochloric acid (60 mL × 3) and with water, dried with sodium sulfate, and filtered. The evaporated residue was purified by flash column chromatography (hexane/EtOAc = 5/1) to afford the enantiopure tribenzofenestrene (4bR)-13 or (4bS)-13 (31−39%) as a colorless solid. (+)-(4bR,8bR,12bS,14aS)-1,4,9,12-Tetramethoxy-cis,cis,cis,cis4b,8b,12b,14a-tetrahydrodibenzo[a,f ]benzo[2,3]pentaleno[1,6cd]pentalene [(4bR)-13]. M.p.: 208−211 °C; [α]D25 +187 (c 0.02, CHCl3); Rf: 0.62 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3): δ = 7.83−7.79 (m, 2H, ArH), 7.19−7.15 (m, 2H, ArH), 6.68 (AB, ΔδAB = 0.05, J = 8.7 Hz, 4H, ArH), 6.05 (s, 2H, CH), 5.00 (s, 2H, CH), 4.41 (s, 2H, CH), 3.89 (s, 6H, OCH3), 3.78 (s, 6H, OCH3); 13C NMR (101 MHz, CDCl3): δ = 151.1, 150.3, 144.5, 134.4, 133.1, 131.6, 127.2, 126.9, 109.7, 109.5, 69.5, 63.4, 62.1, 55.8, 55.6; HRMS (ESI) m/z: [M + Na]+ Calcd for C29H26O4Na 461.1723; Found 461.1733. (−)-(4bS,8bS,12bR,14aR)-1,4,9,12-Tetramethoxy-cis,cis,cis,cis4b,8b,12b,14a-tetrahydrodibenzo[a,f ]benzo[2,3]pentaleno[1,6cd]pentalene [(4bS)-13]. M.p.: 208−212 °C; [α]D25 −179 (c 0.02, CHCl3); Rf: 0.62 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3): δ = 7.83−7.79 (m, 2H, ArH), 7.19−7.15 (m, 2H, ArH), 6.68 (AB, ΔδAB = 0.05, J = 8.7 Hz, 4H, ArH), 6.05 (s, 2H, CH), 5.00 (s, 2H, CH), 4.42 (s, 2H, CH), 3.89 (s, 6H, OCH3), 3.78 (s, 6H, OCH3); 13C NMR (101 MHz, CDCl3): δ = 151.1, 150.3, 144.5, 134.4, 133.1, 131.6, 127.2, 126.9, 109.7, 109.5, 69.5, 63.4, 62.1, 55.8, 55.6; HRMS (ESI) m/z: [M + Na]+ Calcd for C29H26O4Na 461.1723; Found 461.1732. A solution of enantiopure tribenzofenestrene (4bR)-13 or (4bS)13 (1.40 g, 3.19 mmol) and tetrachlorothiophene-1,1-dioxide32 (0.973 g, 3.83 mmol) in xylenes (8 mL) was heated to reflux for 2.5 d. The evaporated residue was purified by flash column chromatography (hexane/CHCl3 = 2/1) to furnish the dihydrofenestrindane (8bR)-14 or (8bS)-14 (78−85%) as a colorless solid. (+)-(4aR,4bS,4b 1S,8bR,12bR,16bS,16cS)-1,2,3,4-Tetrachloro5,8,13,16-tetramethoxy-cis,cis,cis,cis,cis-4a,4b,8b,12b,16b,16chexahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene [(8bR)-14]. M.p.: 151−154 °C; [α]D25 +69 (c 0.02, CHCl3); Rf: 0.74 (hexane/CHCl3 = 1/1); 1H NMR (400 MHz, CDCl3): δ = 7.83−7.81 (m, 1H, ArH), 7.74−7.73 (m, 1H, ArH), 7.23−7.17 (m, 2H, ArH), 6.74 (AB, ΔδAB = 0.08, J = 8.9 Hz, 2H, ArH), 6.67 (AB, ΔδAB = 0.11, J = 8.9 Hz, 2H, ArH), 5.05 (s, 1H, CH), 4.99 (s, 1H, CH), 4.60 (s, 1H, CH), 4.17 (d, J = 8.2 Hz, 1H, CH), 4.11 (d, J = 9.1 Hz, 1H, CH), 3.93 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.29 (t, J = 8.6 Hz, 875

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry

(400 MHz, CDCl3, 45 °C): δ = 7.18 (s, 4H, ArH), 7.10 (d, J = 8.5 Hz, 4H, ArH), 6.79 (d, J = 8.6 Hz, 4H, ArH), 6.73−6.71 (m, 4H, ArH), 6.10 (brs, 4H, ArH), 5.15 (s, 4H, CH), 3.94 (s, 12H, OCH3), 3.92 (s, 12H, OCH3), 3.41 (s, 12H, OCH3); 13C NMR (101 MHz, CDCl3, 45 °C): δ = 153.6, 151.9, 144.7, 143.7, 143.2, 135.2, 129.8, 129.3, 126.5, 125.9, 125.8, 108.0, 72.5, 61.3, 60.7, 58.9, 56.5; HRMS (ESI) m/z: [M + Na]+ Calcd for C65H60O12Na 1055.3977; Found 1055.3978. A Schlenk tube containing enantiopure tetrakis(triflate) (4bR)-17 or (4bS)-17 (50 mg, 52 μmol), (3-ethoxy-4-methoxyphenyl)boronic acid (102 mg, 0.52 mmol), cesium carbonate (203 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] (19 mg, 21 μmol), and SPhos (17 mg, 42 μmol) in toluene/water (5/1 v/v, 12 mL) was subjected to three freeze−pump−thaw cycles. The tube was then backfilled with nitrogen and then closed. The mixture was stirred at 110 °C for 3 d, cooled to 20 °C, and then filtered through a pad of Celite. The evaporated residue was purified by flash column chromatography (hexane/EtOAc = 2/1 gradient to 1/1) to afford the enantiopure tetrakis(3-ethoxy-4-methoxyphenyl)fenestrindane (4bR)-9 or (4bS)-9 (39 mg, 65−74%) as a colorless solid. (−)-(4bR,8bR,12bR,16bR)-1,4,9,12-Tetrakis(3-ethoxy-4-methoxyphenyl)-cis,cis,cis,cis-4b,8b,12b,16b-tetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene [(4bR)-9]. M.p.: 152− 157 °C; [α]D25 −178 (c 0.1, CHCl3); Rf: 0.60 (hexane/EtOAc = 1/ 1); 1H NMR (400 MHz, CDCl3): δ = 7.22 (s, 4H, ArH), 7.05 (dd, J = 8.2 and 1.9 Hz, 4H, ArH), 7.02 (d, J = 1.9 Hz, 4H, ArH), 6.96 (d, J = 8.3 Hz, 4H, ArH), 6.74−6.72 (m, 4H, ArH), 6.05−6.03 (m, 4H, ArH), 5.39 (s, 4H, CH), 4.19−4.06 (m, 8H, CH2), 3.94 (s, 12H, OCH3), 1.47 (t, J = 7.0 Hz, 12H, CH3); 13C NMR (126 MHz, CDCl3): δ = 148.9, 148.6, 144.1, 142.4, 139.1, 135.1, 129.8, 127.1, 125.9, 121.5, 114.4, 111.8, 70.9, 64.6, 59.8, 56.3, 15.0; HRMS (ESI) m/z: [M + Na]+ Calcd for C65H60O8Na 991.4180; Found 991.4180. (+)-(4bS,8bS,12bS,16bS)-1,4,9,12-Tetrakis(3-ethoxy-4-methoxyphenyl)-cis,cis,cis,cis-4b,8b,12b,16b-tetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene [(4bS)-9]. M.p.: 154− 158 °C; [α]D25 +179 (c 0.1, CHCl3); Rf: 0.60 (hexane/EtOAc = 1/1); 1 H NMR (400 MHz, CDCl3): δ = 7.23 (s, 4H, ArH), 7.06 (dd, J = 8.2 and 1.8 Hz, 4H, ArH), 7.03 (d, J = 1.7 Hz, 4H, ArH), 6.97 (d, J = 8.2 Hz, 4H, ArH), 6.75−6.73 (m, 4H, ArH), 6.06−6.04 (m, 4H, ArH), 5.40 (s, 4H, CH), 4.20−4.07 (m, 8H, CH2), 3.95 (s, 12H, OCH3), 1.48 (t, J = 7.0 Hz, 12H, CH3); 13C NMR (101 MHz, CDCl3): δ = 148.9, 148.6, 144.0, 142.4, 139.0, 135.1, 129.8, 127.0, 125.9, 121.5, 114.4, 111.8, 70.9, 64.6, 59.7, 56.2, 14.9; HRMS (ESI) m/z: [M + Na]+ Calcd for C65H60O8Na 991.4180; Found 991.4182. General Procedure for the Scholl-Type Cyclization of Enantiopure Tetraarylfenestrindanes 6 and 9. To a stirred solution of the enantiopure tetraarylfenestrindane (30 mg) in dichloromethane (5 mL) was added triflic acid (100 equiv) and then 2,3-dichloro-5,6-dicyano-para-benzoquinone (DDQ) (4.2 equiv) at 0 °C. After the solution was stirred at 0 °C under nitrogen for 1 h, it was diluted with dichloromethane (50 mL) and quenched with saturated aqueous sodium bicarbonate. The organic solution was washed with water, dried with sodium sulfate, and then evaporated. The residue was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (0.1 equiv) and triethylsilane (1.5 equiv) were added to the solution. After the solution was stirred for 1 h, it was diluted with dichloromethane (50 mL) and quenched with saturated aqueous sodium bicarbonate. The organic solution was washed with water, dried with sodium sulfate, filtered, and then evaporated. The residue was purified by flash column chromatography (hexane/EtOAc = 2/1 gradient to 1/1). (−)-(4b2R,6a2R,12a2R,18a2R)-Dodecamethoxy-Substituted Saddle [(4b2R)-8]. A pale yellow solid (51%). M.p: 289−293 °C; [α]D25 −10 (c 0.1, CHCl3); Rf = 0.60 (hexane/EtOAc = 1/1); 1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 4H, ArH), 7.81 (s, 4H, ArH), 7.31 (s, 4H, ArH), 4.55 (s, 4H, CH), 4.02 (s, 12H, OCH3), 4.00 (s, 12H, OCH3), 3.58 (s, 12H, OCH3); 13C NMR (101 MHz, CDCl3): δ = 154.2, 152.0, 144.0, 142.6, 142.4, 135.2, 134.1, 130.1, 129.5, 126.8, 125.8, 110.7, 65.5, 63.5, 61.3, 61.0, 56.1; HRMS (APCI) m/z: [M + H]+ Calcd for C65H53O12 1025.3532; Found 1025.3510.

HRMS (ESI) m/z: [M + Na]+ Calcd for C29H20O4Na 455.1254; Found 455.1254. (−)-(4bS,8bS,12bS,16bS)-cis,cis,cis,cis-4b,8b,12b,16bTetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene-1,4,9,12-tetraol [(4bS)-16]. M.p.: 188−193 °C; [α]D25 −185 (c 0.1, CHCl3); Rf 0.70 (hexane/EtOAc = 1/2); 1H NMR (400 MHz, CD3OD): δ = 7.88−7.85 (m, 4H, ArH), 7.14−7.12 (m, 4H, ArH), 6.58 (s, 4H, ArH), 4.93 (s, 4H, CH); 13C NMR (101 MHz, CD3OD): δ = 148.2, 145.6, 133.2, 127.8, 127.7, 115.8, 73.2, 61.6; HRMS (ESI) m/z: [M + Na]+ Calcd for C29H20O4Na 455.1254; Found 455.1255. Trifluoromethanesulfonic anhydride (0.78 mL, 4.6 mmol) was added to a stirred suspension of (4bR)-16 or (4bS)-16 (200 mg, 0.46 mmol) and pyridine (0.37 mL, 4.6 mmol) in dichloromethane (16 mL) at 0 °C under nitrogen. The mixture was stirred at 20 °C for 14 h, diluted with dichloromethane, washed with water twice, dried with sodium sulfate, and filtered. The filtrate was concentrated in vacuo to furnish the enantiopure tetrakis(trifloxy)fenestrindane (4bR)-17 or (4bS)-17 (74−80%) as a pale orange foamy solid which was used directly in the next step. Flash column chromatography (hexane/ EtOAc = 10/1) on neutral alumina yielded the analytically pure enantiomers (4bR)-17 and (4bS)-17 as a colorless solid. (+)-(4bR,8bR,12bR,16bR)-cis,cis,cis,cis-4b,8b,12b,16bTetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene-1,4,9,12-tetrayl tetrakis(trifluoromethanesulfonate) [(4bR)-17]. M.p.: 153−157 °C; [α]D25 +185 (c 0.1, CHCl3); Rf: 0.60 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3): δ = 7.67−7.65 (m, 4H, ArH), 7.38−7.36 (m and s, 8H, ArH), 5.16 (s, 4H, CH); 13C NMR (126 MHz, CDCl3): δ = 145.7, 140.8, 139.4, 129.3, 126.7, 122.9, 118.8 (q, JC−F = 323 Hz, CF3), 74.0, 58.9; HRMS (ESI) m/z: [M + Na]+ Calcd for C33H16F12O12S4Na 982.9225; Found 982.9224. (−)-(4bS,8bS,12bS,16bS)-cis,cis,cis,cis-4b,8b,12b,16bTetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene-1,4,9,12-tetrayl tetrakis(trifluoromethanesulfonate) [(4bS)-17]. M.p.: 154−158 °C; [α]D25 −176 (c 0.1, CHCl3); Rf: 0.60 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3): δ = 7.67−7.65 (m, 4H, ArH), 7.38−7.36 (m and s, 8H, ArH), 5.16 (s, 4H, CH); 13C NMR (126 MHz, CDCl3): δ = 145.6, 140.8, 139.4, 129.3, 126.7, 122.9, 118.8 (q, JC−F = 323 Hz, CF3), 74.0, 58.9; HRMS (ESI) m/z: [M + Na]+ Calcd for C33H16F12O12S4Na 982.9225; Found 982.9226. A Schlenk tube containing enantiopure tetrakis(triflate) (4bR)-17 or (4bS)-17 (100 mg, 0.104 mmol), 2,3,4-trimethoxyphenylboronic acid (441 mg, 2.08 mmol), potassium phosphate sesquihydrate (498 mg, 2.08 mmol), palladium(II) acetate (7.0 mg, 31 μmol), and 2dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) (26 mg, 62 μmol) in toluene (12 mL) was subjected to three freeze−pump−thaw cycles. The tube was then backfilled with nitrogen and then closed. The mixture was stirred at 110 °C for 3 d, cooled to 20 °C, and then filtered through a pad of Celite. The evaporated residue was purified by flash column chromatography (hexane/EtOAc = 2/1 gradient to 1/1) to afford the enantiopure tetrakis(2,3,4-trimethoxyphenyl)fenestrindane (4bR)-6 or (4bS)-6 (89 mg, 75−81%) as a colorless solid. (−)-(4bR,8bR,12bR,16bR)-1,4,9,12-Tetrakis(2,3,4-trimethoxyphenyl)-cis,cis,cis,cis-4b,8b,12b,16b-tetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene [(4bR)-6]. M.p.: 187− 193 °C; [α]D25 −98 (c 0.1, CHCl3); Rf: 0.65 (hexane/EtOAc = 1/1); 1 H NMR (500 MHz, CDCl3, 45 °C): δ = 7.17 (s, 4H, ArH), 7.10 (d, J = 8.5 Hz, 4H, ArH), 6.79 (d, J = 8.6 Hz, 4H, ArH), 6.73−6.71 (m, 4H, ArH), 6.09 (brs, 4H, ArH), 5.14 (s, 4H, CH), 3.94 (s, 12H, OCH3), 3.91 (s, 12H, OCH3), 3.41 (s, 12H, OCH3); 13C NMR (101 MHz, CDCl3, 45 °C): δ = 153.7, 151.9, 144.6, 143.7, 143.2, 135.2, 129.8, 129.3, 126.5, 125.9, 125.8, 108.0, 72.5, 61.3, 60.7, 58.9, 56.5; HRMS (ESI) m/z: [M + Na]+ Calcd for C65H60O12Na 1055.3977; Found 1055.3980. (+)-(4bS,8bS,12bS,16bS)-1,4,9,12-Tetrakis(2,3,4-trimethoxyphenyl)-cis,cis,cis,cis-4b,8b,12b,16b-tetrahydrodibenzo[a,f ]dibenzo[2,3:4,5]pentaleno[1,6-cd]pentalene [(4bS)-6]. M.p.: 185−189 °C; [α]D25 +86 (c 0.1, CHCl3); Rf: 0.65 (hexane/EtOAc = 1/1); 1H NMR 876

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry (+)-(4b2S,6a2S,12a2S,18a2S)-Dodecamethoxy-Substituted Saddle [(4b2S)-8]. A pale yellow solid (52%). M.p: 291−295 °C; [α]D25 +13 (c 0.1, CHCl3); Rf = 0.60 (hexane/EtOAc = 1/1); 1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 4H, ArH), 7.81 (s, 4H, ArH), 7.31 (s, 4H, ArH), 4.55 (s, 4H, CH), 4.01 (s, 12H, OCH3), 4.00 (s, 12H, OCH3), 3.58 (s, 12H, OCH3); 13C NMR (126 MHz, CDCl3): δ = 154.2, 152.0, 144.0, 142.6, 142.4, 135.1, 134.0, 130.1, 129.5, 126.8, 125.8, 110.6, 65.5, 63.5, 61.3, 61.1, 56.1; HRMS (APCI) m/z: [M + H]+ Calcd for C65H53O12 1025.3532; Found 1025.3516. (+)-(4b2R,6a2R,12a2R,18a2R)-Tetraethoxytetramethoxy-Substituted Saddle [(4b2R)-10]. A pale yellow solid (60%). M.p: 244−248 °C; [α]D25 +30 (c 0.1, CHCl3); Rf = 0.60 (hexane/EtOAc = 1/1); 1H NMR (400 MHz, CDCl3): δ = 7.75 (s, 4H, ArH), 7.72 (s, 4H, ArH), 7.48 (s, 8H, ArH), 4.65 (s, 4H, CH), 4.35−4.20 (m, 8H, CH2), 4.03 (s, 12H, OCH3), 1.55 (t, J = 7.0 Hz, 12H, CH3); 13C NMR (101 MHz, CDCl3, six aromatic signals merged into three): δ = 148.8, 147.8, 142.5, 134.5, 130.60, 130.56, 126.8, 115.0, 113.9, 66.6, 64.7, 63.6, 56.3, 15.0; HRMS (APCI) m/z: [M + H]+ Calcd for C65H53O8 961.3735; Found 961.3733. (−)-(4b2S,6a2S,12a2S,18a2S)-Tetraethoxytetramethoxy-Substituted Saddle [(4b2S)-10]. A pale yellow solid (57%). M.p: 243−247 °C; [α]D25 −28 (c 0.1, CHCl3); Rf = 0.60 (hexane/EtOAc = 1/1); 1H NMR (400 MHz, CDCl3): δ = 7.75 (s, 4H, ArH), 7.72 (s, 4H, ArH), 7.481 (s, 4H, ArH), 7.479 (s, 4H, ArH), 4.65 (s, 4H, CH), 4.35−4.20 (m, 8H, CH2), 4.03 (s, 12H, OCH3), 1.55 (t, J = 7.0 Hz, 12H, CH3); 13 C NMR (101 MHz, CDCl3, six aromatic signals merged into three): δ = 148.8, 147.8, 142.5, 134.5, 130.60, 130.56, 126.8, 115.0, 113.9, 66.6, 64.7, 63.6, 56.3, 15.0; HRMS (APCI) m/z: [M + H]+ Calcd for C65H53O8 961.3735; Found 961.3736.

■

Room Temperature. J. Am. Chem. Soc. 1992, 114, 1920−1921. (b) Seiders, T. J.; Baldridge, K. K.; Grube, G. H.; Siegel, J. S. Structure/Energy Correlation of Bowl Depth and Inversion Barrier in Corannulene Derivatives: Combined Experimental and Quantum Mechanical Analysis. J. Am. Chem. Soc. 2001, 123, 517−525. (c) Hayama, T.; Baldridge, K. K.; Wu, Y.-T.; Linden, A.; Siegel, J. S. Steric Isotope Effects Gauged by the Bowl-Inversion Barrier in Selectively Deuterated Pentaarylcorannulenes. J. Am. Chem. Soc. 2008, 130, 1583−1591. (3) Bowl inversion of sumanenes: (a) Amaya, T.; Sakane, H.; Muneishi, T.; Hirao, T. Bowl-to-Bowl Inversion of Sumanene Derivatives. Chem. Commun. 2008, 765−767. (b) Higashibayashi, S.; Onogi, S.; Srivastava, H. K.; Sastry, G. N.; Wu, Y.-T.; Sakurai, H. Stereoelectronic Effect of Curved Aromatic Structures: Favoring the Unexpected endo Conformation of Benzylic-Substituted Sumanene. Angew. Chem., Int. Ed. 2013, 52, 7314−7316. (c) Shrestha, B. B.; Karanjit, S.; Higashibayashi, S.; Sakurai, H. Correlation between Bowl-Inversion Energy and Bowl Depth in Substituted Sumanenes. Pure Appl. Chem. 2014, 86, 747−753. (4) (a) Yamamoto, K.; Sonobe, H.; Matsubara, H.; Sato, M.; Okamoto, S.; Kitaura, K. Convenient New Synthesis of [7]Circulene. Angew. Chem., Int. Ed. Engl. 1996, 35, 69−70. (b) Pieters, G.; Gaucher, A.; Marrot, J.; Maurel, F.; Naubron, J.-V.; Jean, M.; Vanthuyne, N.; Crassous, J.; Prim, D. New Chiral CyclooctatrieneBased Polycyclic Architectures. Org. Lett. 2011, 13, 4450−4453. (c) Sakamoto, Y.; Suzuki, T. Tetrabenzo[8]circulene: Aromatic Saddles from Negatively Curved Graphene. J. Am. Chem. Soc. 2013, 135, 14074−14077. (d) Hatanaka, M. Puckering Energetics and Optical Activities of [7]Circulene Conformers. J. Phys. Chem. A 2016, 120, 1074−1083. (e) Gu, X.; Li, H.; Shan, B.; Liu, Z.; Miao, Q. Synthesis, Structure, and Properties of Tetrabenzo[7]circulene. Org. Lett. 2017, 19, 2246−2249. (f) Pun, S. H.; Chan, C. K.; Luo, J.; Liu, Z.; Miao, Q. A Dipleiadiene-Embedded Aromatic Saddle Consisting of 86 Carbon Atoms. Angew. Chem., Int. Ed. 2018, 57, 1581−1586. (g) Ikemoto, K.; Lin, J.; Kobayashi, R.; Sato, S.; Isobe, H. Fluctuating Carbonaceous Networks with a Persistent Molecular Shape: A SaddleShaped Geodesic Framework of 1,3,5-Trisubstituted Benzene (Phenine). Angew. Chem., Int. Ed. 2018, 57, 8555−8559. (5) Structures with more than one bowl: (a) Eisenberg, D.; Filatov, A. S.; Jackson, E. A.; Rabinovitz, M.; Petrukhina, M. A.; Scott, L. T.; Shenhar, R. Bicorannulenyl: Stereochemistry of a C40H18 Biaryl Composed of Two Chiral Bowls. J. Org. Chem. 2008, 73, 6073−6078. (b) Yanney, M.; Fronczek, F. R.; Henry, W. P.; Beard, D. J.; Sygula, A. Cyclotrimerization of Corannulyne: Steric Hindrance Tunes the Inversion Barriers of Corannulene Bowls. Eur. J. Org. Chem. 2011, 2011, 6636−6639. (c) Amaya, T.; Kobayashi, K.; Hirao, T. Synthesis and Characterization of Bisumanenyl. Asian J. Org. Chem. 2013, 2, 642−645. (6) Bowl−helicene hybrids: (a) Fujikawa, T.; Preda, D. V.; Segawa, Y.; Itami, K.; Scott, L. T. Corannulene−Helicene Hybrids: Chiral πSystems Comprising Both Bowl and Helical Motifs. Org. Lett. 2016, 18, 3992−3995. (b) Tokimaru, Y.; Ito, S.; Nozaki, K. Synthesis of Pyrrole-Fused Corannulenes: 1,3-Dipolar Cycloaddition of Azomethine Ylides to Corannulene. Angew. Chem., Int. Ed. 2017, 56, 15560− 15564. (7) Rickhaus, M.; Mayor, M.; Juríček, M. Chirality in Curved Polyaromatic Systems. Chem. Soc. Rev. 2017, 46, 1643−1660. (8) Amaya, T.; Nakata, T.; Hirao, T. Synthesis of Highly Strained πBowls from Sumanene. J. Am. Chem. Soc. 2009, 131, 10810−10811. (9) Abdourazak, A. H.; Marcinow, Z.; Sygula, A.; Sygula, R.; Rabideau, P. W. Buckybowls 2. Toward the Total Synthesis of Buckminsterfullerene (C 60 ): Benz[5,6]-as-indaceno[3,2,1,8,7mnopqr]indeno[4,3,2,1-cdef ]chrysene. J. Am. Chem. Soc. 1995, 117, 6410−6411. (10) Sygula, A.; Rabideau, P. W. Bowl-to-Bowl Inversion in Polynuclear Aromatic Hydrocarbons with Curved Surfaces: an ab initio Study. J. Chem. Soc., Chem. Commun. 1994, 1497−1499.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02719. IUPAC numbering scheme, X-ray crystallographic parameters with ORTEP plots, ECD spectra, melting point comparison with racemates, 1H and 13C NMR spectra, and mass spectra (PDF) Crystallographic information file for (4bR)-11 (CIF) Crystallographic information file for (4bR)-13 (CIF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hak-Fun Chow: 0000-0002-7621-0851 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the RGC-CRF (C4030-14G) and UGC-AoE (AoE/ P-03/08) of HKSAR and the Faculty of Science, CUHK (direct grant: 4053267), for the financial support.

■

REFERENCES

(1) (a) Narita, A.; Wang, X.-Y.; Feng, X.; Müllen, K. New Advances in Nanographene Chemistry. Chem. Soc. Rev. 2015, 44, 6616−6643. (b) Segawa, Y.; Ito, H.; Itami, K. Structurally Uniform and Atomically Precise Carbon Nanostructures. Nat. Rev. Mater. 2016, 1 (1), 15002. (c) Márquez, I. R.; Castro-Fernández, S.; Millána, A.; Campaña, A. G. Synthesis of Distorted Nanographenes Containing Seven- and EightMembered Carbocycles. Chem. Commun. 2018, 54, 6705−6718. (2) Bowl inversion of corannulenes: (a) Scott, L. T.; Hashemi, M. M.; Bratcher, M. S. Corannulene Bowl-to-Bowl Inversion Is Rapid at 877

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878

Article

The Journal of Organic Chemistry

110, 4858−4860. (d) Paquette, L. A.; Okazaki, M. E.; Caille, J.-C. A Formal Total Synthesis of (±)-Laurenene. J. Org. Chem. 1988, 53, 477−481. (25) Xu, W.-R.; Chow, H.-F.; Cao, X.-P.; Kuck, D. Regiocontrolled Synthesis and Optical Resolution of Mono-, Di-, and Trisubstituted Tribenzotriquinacene Derivatives: Key Building Blocks for Further Assembly into Molecular Squares and Cubes. J. Org. Chem. 2014, 79, 9335−9346. (26) We thank a reviewer for pointing out his/her experience that CHIRALPAK ID−IH are better suitable than CHIRALPAK IA−IC for the resolution of polycyclic compounds, such as the target saddle 8. Nonetheless, due to limited resources and the long-term advantage of obtaining precursor 17 in enantiopure form, further resolution experiments on rac-8 were not conducted. (27) CCDC 1863701 and 1864762 contain the supplementary crystallographic data of (4bR)-11 and (4bR)-13, respectively. These data are obtainable free of charge from The Cambridge Crystallographic Data Centre. (28) Flack, H. D. On Enantiomorph-Polarity Estimation. Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, 39, 876−881. (29) Carey, F. A.; Tremper, H. S. Carbonium Ion−Silane Hydride Transfer Reactions. I. Scope and Stereochemistry. J. Am. Chem. Soc. 1968, 90, 2578−2583. (30) The hindered rotation of the 2,3,4-trimethoxyphenyl groups in (4bR)-6 and (4bS)-6 was evident because of the signal broadening in the 1H and 13C NMR spectra recorded at room temperature. The resonances became sharper when the spectra were recorded at 45 °C. (31) (a) Liu, X.; Weinert, Z. J.; Sharaf, M.; Liao, C.; Li, J.; Schneebeli, S. T. Regulating Molecular Recognition with C-Shaped Strips Attained by Chirality-Assisted Synthesis. Angew. Chem., Int. Ed. 2015, 54, 12772−12776. (b) Mastalerz, M. Single-handed Towards Nanosized Organic Molecules. Angew. Chem., Int. Ed. 2016, 55, 45− 47. (c) Beaudoin, D.; Rominger, F.; Mastalerz, M. Chirality-Assisted Synthesis of a Very Large Octameric Hydrogen-Bonded Capsule. Angew. Chem., Int. Ed. 2016, 55, 15599−15603. (32) Raasch, M. S. Annulations with Tetrachlorothiophene 1,1Dioxide. J. Org. Chem. 1980, 45, 856−867.

(11) Tsuruoka, R.; Higashibayashi, S.; Ishikawa, T.; Toyota, S.; Sakurai, H. Optical Resolution of Chiral Buckybowls by Chiral HPLC. Chem. Lett. 2010, 39, 646−647. (12) (a) Higashibayashi, S.; Sakurai, H. Asymmetric Synthesis of a Chiral Buckybowl, Trimethylsumanene. J. Am. Chem. Soc. 2008, 130, 8592−8593. (b) Tan, Q.; Higashibayashi, S.; Karanjit, S.; Sakurai, H. Enantioselective Synthesis of a Chiral Nitrogen-Doped Buckybowl. Nat. Commun. 2012, 3, 891. (13) Yamamoto, K.; Harada, T.; Okamoto, Y.; Chikamatsu, H.; Nakazaki, M.; Kai, Y.; Nakao, T.; Tanaka, M.; Harada, S.; Kasai, N. Synthesis and Molecular Structure of [7]Circulene. J. Am. Chem. Soc. 1988, 110, 3578−3584. (14) Rajca, A.; Safronov, A.; Rajca, S.; Wongsriratanakul, J. D2Symmetric Dimer of 1,1′-Binaphthyl and Its Chiral π-Conjugated Carbodianion. J. Am. Chem. Soc. 2000, 122, 3351−3357. (15) Shibata, T.; Chiba, T.; Hirashima, H.; Ueno, Y.; Endo, K. Catalytic Enantioselective Synthesis of Chiral Tetraphenylenes: Consecutive Inter- and Intramolecular Cycloadditions of Two Triynes. Angew. Chem., Int. Ed. 2009, 48, 8066−8069. (16) Wu, A.-H; Hau, C.-K.; Wong, H. N. C. Synthesis of Enantiopure (S,R,S)- and (R,S,R)-1,4,5,8,9,16-Hexahydroxytetraphenylenes. Adv. Synth. Catal. 2007, 349, 601−608. (17) Mughal, E. U.; Kuck, D. Merging Tribenzotriquinacene with Hexa-peri-hexabenzocoronene: a Cycloheptatriene Unit Generated by Scholl Reaction. Chem. Commun. 2012, 48, 8880−8882. (18) (a) Ip, H.-W.; Ng, C.-F.; Chow, H.-F.; Kuck, D. Three-Fold Scholl-Type Cycloheptatriene Ring Formation around a Tribenzotriquinacene Core: Toward Warped Graphenes. J. Am. Chem. Soc. 2016, 138, 13778−13781. (b) Ip, H.-W.; Chow, H.-F.; Kuck, D. Electronic and Steric Effects on the Three-Fold Scholl-Type Cycloheptatriene Ring Formation around a Tribenzotriquinacene Core. Org. Chem. Front. 2017, 4, 817−822. (19) (a) An, P.; Chow, H.-F.; Kuck, D. A Polycyclic Aromatic Hydrocarbon Bearing an All-cis Tetrabenzo[5.5.5.5]fenestrane (Fenestrindane) Core Merged with Two Hexa-peri-hexabenzocoronene Units. Synlett 2016, 27, 1255−1261. (b) Wong, W.-S.; Ng, C.-F.; Kuck, D.; Chow, H.-F. From Fenestrindane towards Saddle-Shaped Nanographenes Bearing a Tetracoordinate Carbon Atom. Angew. Chem., Int. Ed. 2017, 56, 12356−12360. (20) (a) Kuck, D.; Bögge, H. Benzoannelated Centropolyquinanes. 2. all-cis-Tetrabenzotetracyclo[5.5.1.04,13.010,13]tridecane, “Fenestrindan”. J. Am. Chem. Soc. 1986, 108, 8107−8109. (b) Bredenkötter, B.; Linke, J.; Kuck, D. Stereocontrolled Access to Benzo-Annelated all-cisand cis,cis,cis,trans-[5.5.5.6]Fenestranones and all-cis-[5.5.5.5]Fenestranes. Eur. J. Org. Chem. 2017, 2017, 4414−4428. (21) (a) Kuck, D.; Schuster, A.; Krause, R. A. Benzoannelated Centropolyquinanes. Part IX. Synthesis and Conformational Behavior of Fenestrindans (Tetrabenzo[5.5.5.5]fenestranes) with Four Bridgehead Substituents. J. Org. Chem. 1991, 56, 3472−3475. (b) Kuck, D. Three-Dimensional Hydrocarbon Cores Based on Multiply Fused Cyclopentane and Indane Units: Centropolyindanes. Chem. Rev. 2006, 106, 4885−4925. (22) Luef, W.; Keese, R. Angular Distortions at Tetracoordinate Carbon Planoid Distortions in α,α′-Bridged Spiro[4.4]nonanes and [5.5.5.5]Fenestranes. Helv. Chim. Acta 1987, 70, 543−553. (23) (a) Keese, R. Carbon Flatland: Planar Tetracoordinate Carbon and Fenestranes. Chem. Rev. 2006, 106, 4787−4808. (b) Boudhar, A.; Charpenay, M.; Blond, G.; Suffert, J. Fenestranes in Synthesis: Unique and Highly Inspiring Scaffolds. Angew. Chem., Int. Ed. 2013, 52, 12786−12798. (24) (a) Crimmins, M. T.; Gould, L. D. Intramolecular Photocycloaddition. Cyclobutane Fragmentation: Total Synthesis of (±)-Laurenene. J. Am. Chem. Soc. 1987, 109, 6199−6200. (b) Tsunoda, T.; Amaike, M.; Tambunan, U. S. F.; Fujise, Y.; Itô, S.; Kodama, M. Total Synthesis of (±)-Lauren-1-ene, the Unique Fenestrane Diterpene. Tetrahedron Lett. 1987, 28, 2537−2540. (c) Wender, P. A.; von Geldern, T. W.; Levine, B. H. Synthetic Studies on Arene−Olefin Cycloadditions. 10. A Concise, Stereocontrolled Total Synthesis of (±)-Laurenene. J. Am. Chem. Soc. 1988, 878

DOI: 10.1021/acs.joc.8b02719 J. Org. Chem. 2019, 84, 869−878