Letter pubs.acs.org/OrgLett
Helically Chiral 1‑Sulfur-Functionalized [6]Helicene: Synthesis, Optical Resolution, and Functionalization Tetsuya Tsujihara,*,† Da-Yang Zhou,‡ Takeyuki Suzuki,‡ Satoru Tamura,† and Tomikazu Kawano*,† †
Department of Medicinal and Organic Chemistry, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan Comprehensive Analysis Center, Institute of Scientific and Industrial Research, Osaka University, Mihogaoka, Ibaraki 567-0047, Japan
‡
S Supporting Information *
ABSTRACT: The synthesis and optical resolution of helically chiral 5,6,9,10-tetrahydro-1-[6]helicenethiol and its subsequent transformations to enantiopure 1-sulfur-functionalized [6]helicenes are reported. A novel enantiopure [7]thiahelicene having a thiophene ring at the terminal position of the [6]helicene skeleton was synthesized.
H
enantiopure [7]thiahelicene12 (P)-4, having a thiophene ring at the terminal position of the [6]helicene skeleton, was also achieved.
elicenes and helicene-like molecules are attractive nonplanar screw-shaped compounds formed from ortho-fused benzene or other aromatic rings.1 Optical resolutions of various helicenes have been reported,2 and the resulting optically active helicene derivatives have been applied to liquid crystals,3 molecular switches,4 chiral recognition of biomolecules,5 organocatalysts,6 and chiral ligands.7 Recently, chiral 1- and/or 2-functionalized helicenes have been found to be ideal synthetic targets for asymmetric catalysis because the functional groups are located near the helical axis, which enabled stereocontrol by helicity in catalytic asymmetric transformations.6−8 For example, Suemune, Usui, and coworkers reported the development of [5]helicenylphosphine ligands, which have a diphenylphosphino group at the 1position of the [5]helicene skeleton, and their applications to highly enantioselective Pd-catalyzed reactions.8e We have previously reported the multigram scale synthesis of helically chiral 1-oxygen-functionalized [6]helicene derivatives and developed an efficient optical resolution method for 1[6]helicenols.9 The resulting enantiopure 1-[6]helicenols were used as chiral building blocks for helicene-based phosphinite ligands, which provided up to 90% ee on the Pd-catalyzed asymmetric allylic alkylation. Although there have been several reports on the synthesis and optical resolution of helicenes bearing a hydroxy group,2,9,10 to our knowledge, no report on that of 1-sulfurfunctionalized helicene derivative exists.11 Considering the potential applications of 1-sulfur-functionalized helicenes in material science as well as organic and organometallic chemistry, it would be valuable to develop efficient synthetic routes and optical resolution methods for helically chiral 1sulfur-functionalized helicenes. Herein, we report the synthesis and optical resolution of 5,6,9,10-tetrahydro-1-[6]helicenethiol rac-2, and its subsequent transformations to produce enantiopure 1-acetylthio[6]helicene (P)-3 as a chiral building block (Scheme 1). Moreover, the synthesis of novel © 2017 American Chemical Society
Scheme 1. Synthetic Approach to (P)-3 and (P)-4
For the introduction of a sulfur functionality into the 1position of the [6]helicene skeleton, we envisaged the Miyazaki−Newman−Kwart (MNK) rearrangement13,14 of Othiocarbamate rac-5 derived from 5,6,9,10-tetrahydro-1-[6]helicenol rac-19 as the key step. rac-5 was readily obtained in 93% isolated yield from the reaction of rac-1 with dimethylthiocarbamoyl chloride in the presence of sodium hydride (Scheme 2). With prepared rac-5 in hand, we initially performed the MNK rearrangement of rac-5 in N-methylpyrrolidone (NMP) under reflux conditions for 7 h. However, only a trace amount of the desired rearranged product was formed. Therefore, we next examined the microwave-assisted MNK rearrangement13b of rac-5 (Table 1). The reaction of rac-5 in NMP at 260 °C for 3 h afforded the desired S-thiocarbamate rac-6 in 17% yield, Received: May 15, 2017 Published: June 7, 2017 3311
DOI: 10.1021/acs.orglett.7b01470 Org. Lett. 2017, 19, 3311−3314
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Organic Letters Scheme 2. Preparation of rac-5
Table 1. Microwave-Assisted Miyazaki−Newman−Kwart Rearrangement of rac-5a
Figure 1. POV-ray drawing of rac-6 with probability ellipsoids drawn at the 50% level. Hydrogen atoms are omitted for clarity.
The optical resolution of 1-sulfur-functionalized [6]helicene was carried out by using a chiral resolving agent as shown in Scheme 3. Thus, the dimethylcarbamoyl group of rac-6 was entry
solvent
temp (°C)
yieldb (%)
1 2c 3d 4 5 6 7 8 9 10 11 12e 13f,g
NMP NMP NMP NMP NMP N,N-diethylaniline DCB DMA sulfolane DMF 1-n-octyl-2-pyrrolidone 1-n-octyl-2-pyrrolidone 1-n-octyl-2-pyrrolidone
260 260 260 280 300 300 300 300 300 300 300 300 300
17 (82) 36 (59) 56 (28) 46 (47) 74 (10) 63 (29) 65 (26) 68 (6) 16 (0) 0 (23) 82 (7) 85 (3) 91h
Scheme 3. Optical Resolution and Transformation of rac-2
a
All reactions were performed at the indicated temperature in sealed reaction vials filled with argon gas. bNMR yield based on hydroquinone dimethyl ether as an internal standard. The values in parentheses are the amounts of unreacted 5. cFor 6 h. dFor 12 h. eFor 4 h. f1.31 g (3.00 mmol) of rac-5 was used in 1-n-octyl-2-pyrrolidone (0.50 M). gFor 3.5 h. hIsolated yield.
and 82% of rac-5 remained unreacted (entry 1). The prolonged reaction times (6 and 12 h) improved the yield of rac-6, but the reactions were not completed at 260 °C (entries 2 and 3). Higher reaction temperatures (280 and 300 °C) facilitated the MNK rearrangement of rac-5, and the yield of rac-6 increased to 74% (entries 4 and 5). In these reactions, some amounts of byproducts arising from the decomposition of rac-5 and/or rac6 were also observed. To improve the yield of rac-6, effects of solvent were investigated (entries 5−11). Upon conducting the reaction in N,N-diethylaniline, 1,2-dichlorobenzene (DCB), and N,N-dimethylacetamide (DMA), which are frequently employed in microwave-assisted MNK rearrangements,13b the yield of rac-6 did not improve (entries 6−8). Sulfolane and N,N-dimethylformamide (DMF) were also ineffective (entries 9 and 10). To our delight, the MNK rearrangement of rac-5 proceeded smoothly in 1-n-octyl-2-pyrrolidone to furnish rac-6 in 82% yield (entry 11). Furthermore, 85% yield of rac-6 was obtained after 4 h (entry 12). Based on the optimized conditions, we next performed a gram-scale microwave-assisted MNK rearrangement of rac-5 (entry 13). Thus, with 1.31 g of rac-5, rac-6 was successfully obtained in 91% isolated yield (1.19 g, 2.74 mmol). Since the 1-position of [6]helicene is sterically most crowded, it is noteworthy that the synthetic strategy based on the MNK rearrangement for introducing sulfur functionality was effective. The structure of rac-6 was confirmed by NMR, HRMS, IR, and X-ray analysis (Figure 1).
removed by treatment with potassium hydroxide to give 5,6,9,10-tetrahydro-1-[6]helicenethiol rac-2 in 94% isolated yield.15 Treatment of rac-2 with acyl chloride (S,S)-716,17 afforded a mixture of diastereomers. These diastereomers were readily separated by flash column chromatography over silica gel and purified by reprecipitation to give (P,S,S)-8a and (M,S,S)-9a in 35% and 32% isolated yield, respectively (the 3312
DOI: 10.1021/acs.orglett.7b01470 Org. Lett. 2017, 19, 3311−3314
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Organic Letters purity of each diastereomer ratio (dr) was >99.5%).18 Subsequent dehydrogenation of the tetrahydro[6]helicene skeleton of 8a and 9a was carried out successfully by using triphenylmethylium tetrafluoroborate (Ph3CBF4) and 2,4,6collidine to afford (P,S,S)-8b and (M,S,S)-9b in 87% and 93% isolated yield, respectively. The relative and absolute configurations of (P,S,S)-8b and (M,S,S)-9b were unequivocally determined by X-ray analysis (Scheme 3). Removal of the chiral auxiliary and subsequent transformation of (P,S,S)-8a and (P,S,S)-8b are shown in Scheme 4. Treatment of (P,S,S)-8a with sodium methoxide (NaOMe) Scheme 4. Synthesis of (P)-3a and (P)-3b
followed by acetylation gave enantiopure 1-acetylthio-5,6,9,10tetrahydro[6]helicene (P)-3a in 87% isolated yield. Using the same procedure, enantiopure 1-acetylthio[6]helicene (P)-3b was obtained in 89% isolated yield from (P,S,S)-8b. Similarly, the corresponding enantiomers (M)-3a and (M)-3b were obtained from (M,S,S)-9a and (M,S,S)-9b, respectively. Thus, our optical resolution strategy via common synthetic intermediate 8a provided two types of 1-acetylthio[6]helicenes (3a and 3b) in enantiopure forms, efficiently.19 The obtained [6]helicene derivatives 3 might be useful chiral building blocks for asymmetric reactions.20 Next, we turned our attention to the synthesis of a novel optically active heterohelicene. Thus, the utilization of (P,S,S)8b as a chiral building block afforded enantiopure [7]thiahelicene (P)-4 as shown in Scheme 5. Removal of the
Figure 2. UV−vis absorption and CD spectra in CHCl3 (1.0 × 10−5 M): (a) (+)-(P)-3a and (−)-(M)-3a; (b) (+)-(P)-3b and (−)-(M)-3b; (c) (+)-(P)-4 and (−)-(M)-4.
Scheme 5. Synthesis of (P)-4
In summary, we have synthesized 1-sulfur-functionalized [6]helicenes via a microwave-assisted Miyazaki−Newman− Kwart rearrangement and developed a method for the optical resolution of helically chiral 5,6,9,10-tetrahydro-1-[6]helicenethiol rac-2. The resolution method provided two types of enantiopure 1-sulfur-functionalized [6]helicenes, (P)3a and (P)-3b, from common synthetic intermediate (P,S,S)8a. From the viewpoints of resolution efficiency and step economy, this approach might be valuable. Furthermore, novel enantiopure [7]thiahelicene 4 was also synthesized via our developed synthetic protocol. We believe that this work is a promising step toward new investigations of sulfur-functionalized helicenes. Further studies on the application of 3 and 4 to asymmetric catalysts and chiral materials are currently in progress.
chiral auxiliary of (P,S,S)-8b by NaOMe, subsequent alkylation with 1,1-diethoxy-2-iodoethane, and formation of the thiophene ring mediated by boron trifluoride diethyl etherate (BF3· Et2O)21 gave enantiopure [7]thiahelicene (P)-4 in 66% isolated yield over three steps. Enantiomer (M)-4 was prepared similarly from (M,S,S)-9b; the structures of (P)-4 and (M)-4 were identified by NMR and HRMS. Finally, the optical properties of 3a, 3b, and 4 were investigated by UV−vis absorption and circular dichroism (CD) in CHCl3 as shown in Figure 2. The CD spectra of each enantiomer of 3a, 3b, and 4 exhibit mirror-image relationships in the absorption bands of the UV−vis spectra. The (+)-helicenes possess a positive sign for the longest wavelength CD band and vice versa, as found for previously reported (+)-(P)-[6]helicene.22 For [7]thiahelicene 4, the longest wavelength CD band shows a red shift of about 44 and 7 nm compared to that in 3a and 3b, respectively.
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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.orglett.7b01470. Experimental procedures, characterization data, 1H NMR and 13C NMR spectra for all new compounds, and HPLC charts of 3a, 3b, 4, (P,S,S)-8a, and (M,S,S)-9a (PDF) Crystallographic data for 1 (CIF) 3313
DOI: 10.1021/acs.orglett.7b01470 Org. Lett. 2017, 19, 3311−3314
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Organic Letters
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(b) Ben Braiek, M.; Aloui, F.; Ben Hassine, B. Tetrahedron Lett. 2013, 54, 424−426. (c) Usui, K.; Yamamoto, K.; Shimizu, T.; Okazumi, M.; Mei, B.; Demizu, Y.; Kurihara, M.; Suemune, H. J. Org. Chem. 2015, 80, 6502−6508. (11) Selected examples of helicenethiols or their derivatives having sulfur functionalities at a position other than the 1-position: (a) Teplý, F.; Stará, I. G.; Starý, I.; Kollárovič, A.; Šaman, D.; Vyskočil, Š.; Fiedler, P. J. Org. Chem. 2003, 68, 5193−5197. (b) Areephong, J.; Ruangsupapichart, N.; Thongpanchang, T. Tetrahedron Lett. 2004, 45, 3067−3070. (c) Goretta, S.; Tasciotti, C.; Mathieu, S.; Smet, M.; Maes, W.; Chabre, Y. M.; Dehaen, W.; Giasson, R.; Raimundo, J.-M.; Henry, C. R.; Barth, C.; Gingras, M. Org. Lett. 2009, 11, 3846−3849. (d) Biet, T.; Fihey, A.; Cauchy, T.; Vanthuyne, N.; Roussel, C.; Crassous, J.; Avarvari, N. Chem. - Eur. J. 2013, 19, 13160−13167. (e) Salim, M.; Kimura, T.; Karikomi, M. Heterocycles 2013, 87, 547− 550. (f) Ž ádný, J.; Velíšek, P.; Jakubec, M.; Sýkora, J.; Církva, V.; Storch, J. Tetrahedron 2013, 69, 6213−6218. (g) Kushida, Y.; Shigeno, M.; Yamaguchi, M. Chem. - Eur. J. 2015, 21, 13788−13792 and references cited therein. (12) Selected examples of optically active thiahelicenes and their related compounds: (a) Rajca, A.; Miyasaka, M.; Pink, M.; Wang, H.; Rajca, S. J. Am. Chem. Soc. 2004, 126, 15211−15222. (b) Miyasaka, M.; Pink, M.; Rajca, S.; Rajca, A. Angew. Chem., Int. Ed. 2009, 48, 5954−5957. (c) Rajca, A.; Pink, M.; Xiao, S.; Miyasaka, M.; Rajca, S.; Das, K.; Plessel, K. J. Org. Chem. 2009, 74, 7504−7513. (d) Zak, J. K.; Miyasaka, M.; Rajca, S.; Lapkowski, M.; Rajca, A. J. Am. Chem. Soc. 2010, 132, 3246−3247. (e) Miyasaka, M.; Pink, M.; Olankitwanit, A.; Rajca, S.; Rajca, A. Org. Lett. 2012, 14, 3076−3079. (f) Fujikawa, T.; Segawa, Y.; Itami, K. J. Am. Chem. Soc. 2016, 138, 3587−3595. (g) Yamamoto, Y.; Sakai, H.; Yuasa, J.; Araki, Y.; Wada, T.; Sakanoue, T.; Takenobu, T.; Kawai, T.; Hasobe, T. Chem. - Eur. J. 2016, 22, 4263−4273. (h) Biet, T.; Martin, K.; Hankache, J.; Hellou, N.; Hauser, A.; Bürgi, T.; Vanthuyne, N.; Aharon, T.; Caricato, M.; Crassous, J.; Avarvari, N. Chem. - Eur. J. 2017, 23, 437−446. (13) (a) Zonta, C.; De Lucchi, O.; Volpicelli, R.; Cotarca, L. Top. Curr. Chem. 2007, 275, 131−161. (b) Moseley, J. D.; Lenden, P. Tetrahedron 2007, 63, 4120−4125. (c) Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J. S. Synthesis 2008, 661−689. (14) MNK rearangement of O-thiocarbamate derived from 3-[6] helicenol was reported. See ref 11a. (15) rac-2 is stable enough to be isolated by precipitation as described in the experimental procedure (Supporting Information). However, rac-2 is not so stable in solution due to the formation of diastereomeric disulfides and other unidentified compounds under air. The isolation and structural determination of these compounds are in progress. (16) Vincent, A.; Deschamps, D.; Martzel, T.; Lohier, J.-F.; Richards, C. J.; Gaumont, A.-C.; Perrio, S. J. Org. Chem. 2016, 81, 3961−3966. (17) In addition to (S,S)-7, (1S)-camphanic chloride, (−)-menthyl chloroformate, N-(p-toluenesulfonyl)-L-phenylalanyl chloride, and acyl chloride of N-phthaloyl-L-leucine were examined as chiral resolving agents. See the Supporting Information for details (Table S1). (18) The diastereomer ratio was determined by HPLC. See the Supporting Information (Figure S1). (19) The synthesis of the enantiopure parent 1-[6]helicenethiol from (P,S,S)-8b, (M,S,S)-9b, and 3b should be possible. However, the lifetime of free thiol is not enough to measure the physical data on a reliable level. See also ref 15. (20) Selected examples of chiral thioesters as auxiliary: (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron 1994, 50, 9471−9486. (b) Fanjul, S.; Hulme, A. N. J. Org. Chem. 2008, 73, 9788−9791. (21) Vazquez, A. J.; Nudelman, N. S. J. Phys. Org. Chem. 2012, 25, 925−932. (22) Abbate, S.; Longhi, G.; Lebon, F.; Castiglioni, E.; Superchi, S.; Pisani, L.; Fontana, F.; Torricelli, F.; Caronna, T.; Villani, C.; Sabia, R.; Tommasini, M.; Lucotti, A.; Mendola, D.; Mele, A.; Lightner, D. A. J. Phys. Chem. C 2014, 118, 1682−1695.
Crystallographic data for 6 (CIF) Crystallographic data for (P,S,S)-8b (CIF) Crystallographic data for (M,S,S)-9b (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Tetsuya Tsujihara: 0000-0001-8497-693X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was performed under the Cooperative Research Program of “Network Joint Research Center for Materials and Devices” and financially supported by JSPS KAKENHI Grant No. JP15K18835. We thank Biotage Japan, Ltd., for assistance with data collection. We also thank Dr. Chikara Dohno and Prof. Kazuhiko Nakatani at Osaka University for the CD spectral analysis. We are also grateful to the technical staff of the Comprehensive Analysis Center of Institute of Scientific and Industrial Research (Osaka University) for their assistance.
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