Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Brønsted Acid Catalyzed [6 + 2]-Cycloaddition of 2‑Vinylindoles with in Situ Generated 2‑Methide‑2H‑pyrroles: Direct, Catalytic, and Enantioselective Synthesis of 2,3-Dihydro‑1H‑pyrrolizines Isa Kallweit and Christoph Schneider* Org. Lett. Downloaded from pubs.acs.org by UNIV OF CALIFORNIA SANTA BARBARA on 01/08/19. For personal use only.
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany S Supporting Information *
ABSTRACT: We describe herein an organocatalytic, diastereo- and enantioselective [6 + 2]-cycloaddition toward the synthesis of densely substituted 2,3-dihydro-1H-pyrrolizines bearing three contiguous stereogenic centers which are obtained with good yields, as single diastereomers, and with excellent enantioselectivity. A crucial feature of this one-step process leading to a prominent structural motif in many biologically active natural products is a BINOL-derived phosphoric acid catalyzed reaction of 1H-pyrrole-2-yl carbinols with 2-vinylindoles via the corresponding hydrogen-bonded chiral 2-methide-2H-pyrroles.
T
pyrrolizine lactones with outstanding levels of diastereo- and enantiocontrol.8 We envisioned a new catalytic, enantioselective strategy toward this structural motif which was inspired by a route to fused indole systems (Scheme 1A). 1H-Indol-2-yl carbinols have been shown to be smoothly dehydrated into chiral, hydrogen-bonded 2-methide-1H-indoles with chiral Brønsted acids and were then trapped by various nucleophiles with excellent enantioselectivity to produce open-chain as well as annulated indole-based heterocycles.9 The versatility of this
he pyrrolizine structural motif is endowed with a variety of natural products displaying appealing biological activities.1−7 Phythochemical pyrrolizines such as dehydromonocrotaline (1) originate from pyrrolizidine alkaloid metabolism and are known to be potent hepatotoxines, genotoxines, and carcinogenes (Figure 1).2 Other pharmacological examples are the commercially successful analgesic ketrolac (2),3 or licofelone (3), which showed promising features in treatment of osteoarthritis.4
Scheme 1. Conceptualization of This Work
Figure 1. Representative biologically active compounds incorporating a 2,3-dihydro-1H-pyrrolizine skeleton.
However, despite the interesting biological and medicinal properties, little effort has been devoted toward their asymmetric synthesis.5−8 Using a chiral auxiliary the Zecchi group reported the diastereoselective synthesis of pyrrolizidines and indolizidines via an intramolecular cycloaddition of nitrones.6 In an organocatalytic approach Cho et al. employed a domino Michael-aldol cyclization of 2-pyrrolyl carbaldehydes and enals to access highly functionalized 2,3-dihydro-1Hpyrrolizines.7 Finally, the Smith group developed an isothiourea-catalyzed Michael-lactonization process to furnish tricyclic © XXXX American Chemical Society
Received: November 30, 2018
A
DOI: 10.1021/acs.orglett.8b03833 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization Studiesa
concept in the synthesis of various enantiomerically highly enriched indole derivatives has been amply demonstrated in recent years by the groups of Han, Shi, and ourselves.10−12 In analogy we expected 1H-pyrrole-2-yl carbinols to be readily converted into the corresponding hydrogen-bonded pyrrolyl methides by means of chiral Brønsted acid catalysis (Scheme 1B). These highly reactive intermediates should then engage the electron-rich 2-vinylindoles in a [6 + 2]cycloaddition to yield 2,3-dihydro-1H-pyrrolizines in a onepot process. 3-Alkyl-2-vinylindoles have been introduced as powerful two-carbon dienophiles by the Shi group.13 2-Methide-2H-pyrroles or azafulvenes are known in the literature as important intermediates especially in the biosynthesis of porphyrines14 and that of other natural products like myrmicarin alkaloid dimers,15 and (+)-roseophilin.16 Their application in synthetic organic chemistry, however, has been rather limited and include merely two cases: a dual Brønsted acid- and Au(I)-catalyzed addition−cyclization reaction of Nmethylated 1H-pyrrol-2-yl carbinols to produce annulated bisindoles17a and a biomimetic synthesis of the sciodole alkaloid framework through a base-mediated elimination and subsequent amination.17b The reason for this surprisingly little use of such an important and highly useful substrate class most likely stems from the instability of pyrrol-2-yl-carbinols and the exceptional reactivity of the pyrrole nucleus toward electrophilic attack resulting in facile oligomerization reactions. Not surprisingly therefore, no enantioselective processes have been reported that exploit the highly reactive nature of 2-methide2H-pyrroles. In order to tackle these problems we reasoned that a suitable electron-withdrawing group positioned at C5 of the pyrrole nucleus would block this position effectively and additionally prevent oligomerization by electronic deactivation. We expected that the pyrrole reactivity could thus be attenuated and the synthetic potential of 2-methide-2H-pyrroles fully harnessed. We started our studies with reactions of 5-carboxylated 1Hpyrrol-2-yl carbinol 4a which was readily available by Grignard addition from the corresponding pyrrolyl carbaldehyde.17 Treatment of carbinol 4a with 2-vinylindole 5a in the presence of (R)-BINOL-derived phosphoric acid 7a in dichloromethane at rt led to the formation of the all-trans cycloaddition product 6a in moderate yield and enantioselectivity (Table 1, entry 1). Subsequently, various other phosphoric acids 7b−7g with different 3,3′-aryl substituents within the BINOL backbone18 were screened in this reaction and a high dependence on the steric bulk was observed. Phosphoric acids with too bulky substituents (e.g., 7b and 7c) resulted in low conversion and/ or no enantioselectivity, whereas gradually reducing the steric demand of the aryl residues steadily improved the selectivity. The highest enantioselectivity was eventually obtained with phosphoric acid 7g lacking a 4-substituent within the 3,3′-aryl groups (Ar = 2,6-Et2C6H3) which delivered the cycloaddition product 6a with 58% yield and 77:23 e.r. (entry 7). Changing the solvent to toluene further enhanced the selectivity to 85:15 e.r. (entry 8). Addition of 4 Å molecular sieves resulted in a considerable improvement of the enantiomeric ratio to 95:5, although it still gave rise to the product in only moderate 64% yield (entry 9). Gratifyingly, increasing the reaction temperature to 60 °C and using a slight excess of alcohol 4a sharply accelerated the reaction rate and raised the yield to 90% without a significant loss in enantioselectivity. In addition, a
entry
cat.
solvent
additive
time [h]
yield [%]b
e.r.c
1 2 3 4 5 6 7 8 9 10d
7a 7b 7c 7d 7e 7f 7g 7g 7g 7g
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene toluene toluene
− − − − − − − − 4 Å MS 4 Å MS
19 24
44 51 no reaction 69 62 62 58 57 64 90
63:37 43:57
19 48 24 24 48 48 24
65:35 70:30 45:55 77:23 85:15 95:5 94:6
a
Reaction conditions: 0.10 mmol of 1H-pyrrol-2-yl carbinol 4a, 0.15 mmol of 2-vinylindole 5a, catalyst 7 (10 mol %), 4 Å molecular sieves (powdered, 30 mg), solvent (1 mL), rt, diastereomeric ratio was determined by 1H NMR and was >20:1 in all cases. bYield of isolated product after purification by flash column chromatography. c Enantiomeric ratio determined by HPLC on a chiral stationary phase (see the Supporting Information) d0.12 mmol of 1H-pyrrol-2-yl carbinol 4a, 0.10 mmol of 2-vinyl indole 5a, reaction temperature: 60 °C.
single recrystallization from a mixture of CH2Cl2 and hexanes gave pyrrolizine 6a with e.r. 99:1. The substrate scope of the reaction was investigated with regard to the 2-methide-2H-pyrrole intermediate by reacting differently substituted 1H-pyrrol-2-yl carbinols 1 with 2vinylindole 5a (Scheme 2). We first focused our variations on the pyrrole core: with pyrrol-2-yl carbinols bearing various alkyl groups, a phenyl group and a hydrogen atom at the 4position of the pyrrole nucleus, respectively, the reaction proceeded smoothly under the optimized reaction conditions and furnished cycloaddition products 6a−d as single diastereomers, in moderate-to-good yields and uniformly high enantioselectivities of up to 97:3 e.r. The structural diversity was expanded with hexahydro-1H-pyrrolo[2,1-a] isoindole 6e which was obtained in good yield and selectivity from the corresponding tetrahydro-2H-isoindole derivative 4e. Different aryl residues at the carbinol center were investigated next. Irrespective of the electronic and steric properties of the aryl groups pyrrolizines 6f−o were isolated with complete diastereoselectivity, good yields, and excellent enantiomeric ratios of up to 97:3. However, aryl residues with an orthosubstituent such as 4o not only lowered the reaction rate but also gave rise to product 6o with only moderate enantioselectivity (77:23 e.r.). We next aimed to expand the scope of this process by subjecting different 3-methyl-2-vinyl-1H-indoles 5a−h bearing various aryl and alkyl substituents at the terminal position of the vinyl moiety to the reaction (Scheme 3). Generally, both electron-donating and electron-withdrawing groups at the B
DOI: 10.1021/acs.orglett.8b03833 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scope of the Synthesis of 2,3-Dihydro1H-pyrrolizines 6a
Scheme 3. Substrate Scope of the Synthesis of 2,3-Dihydro1H-pyrrolizines 8a
a
Reaction conditions: 0.12 mmol of 1H-pyrrol-2-yl carbinol 4b, 0.10 mmol of 2-vinylindole 5, catalyst 7g (10 mol %), 30 mg of 4 Å MS, toluene (1 mL), 60 °C, 2 d, diastereomeric ratio was determined via NMR and is >20:1 in all cases; enantiomeric ratio determined by HPLC on a chiral stationary phase (see the Supporting Information). b Reaction temperature: 80 °C. cReaction temperature: rt.
a Reaction conditions: 0.12 mmol of 1H-pyrrol-2-yl carbinol 4, 0.10 mmol of 2-vinylindole 5a, catalyst 7g (10 mol %), 30 mg of 4 Å MS, toluene (1 mL), 60 °C, 2 d, diastereomeric ratio was determined by 1 H NMR and was >20:1 in all cases. Enantiomeric ratio determined by HPLC on a chiral stationary phase (see the Supporting Information). bReaction time: 4 d.
terminal aryl group were readily tolerated providing the cycloaddition products as single diastereomers in moderate to good yields and with enantioselectivities of 89:11 e.r. or higher. However, when substituents in the meta or ortho position were introduced, the reaction rate decreased substantially and a reaction temperature of 80 °C was required to complete conversion. Although 2-vinylindole 5h carrying a terminal methyl group showed signs of decomposition under the acidic reaction conditions, we were also able to isolate the corresponding pyrrolizine 8h with moderate yield and enantioselectivity when the reaction was performed at rt. The absolute configuration of the products was determined by X-ray crystal structure analysis of indolyl hydroperoxide 9 (CCDC 1874878), an oxidation product of dihydropyrrolizine 6h, followed by assignment for all other dihydropyrrolizines by analogy (Figure 2). Hydroperoxide 9 crystallized from a solution of 6h upon exposure to light and contact with air. A deliberate synthesis of this compound, however, could be achieved by reaction of 6h with photosensitized singlet oxygen (see the Supporting Information). In order to demonstrate the applicability of this process we conducted the synthesis of 2,3-dihydro-1H-pyrrolizine 6h on gram scale (Scheme 4, top). With only 5 mol % of Brønsted acid catalyst 7g the cycloaddition proceeded to completion within 48 h at 60 °C furnishing product 6h in 89% yield and with 96:4 e.r. which was further enhanced to >99.5:0.5 e.r. by a single recrystallization. To obtain some mechanistic insight we carried out a control experiment using N-methylated 2-vinyl-1H-indole 10 (Scheme
Figure 2. X-ray crystal structure of 9. Thermal ellipsoids are set at 50% probability.
4, bottom). When we submitted it to a reaction with 1Hpyrrol-2-yl carbinol 4b under otherwise identical reaction condition no conversion was observed indicating the crucial role of a free N−H moiety for double hydrogen bonding as outlined above. We assume a transition state assembly such as in Scheme 5 to account for the observed diastereo- and enantioselectivity. The lower 3-aryl group within the BINOL backbone effectively shields the bottom side of the 2-methide pyrrole and directs the incoming dienophile to the top face.19 In summary, we have established the first catalytic, asymmetric application of 2-methide-2H-pyrroles in organic synthesis, namely a [6 + 2]-cycloaddition with electron-rich dienophiles. This one-step procedure is catalyzed by a chiral BINOL-derived phosphoric acid and enables a straightforward synthetic access toward highly substituted 2,3-dihydro-1Hpyrrolizines. The products 6 and 8 are obtained in typically good yields and excellent levels of diastereo- and enantiocontrol. Further studies along these lines are currently ongoing in our laboratories and will be reported in due course. C
DOI: 10.1021/acs.orglett.8b03833 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
crystal structure analysis as well as Wencke Leinung (University of Leipzig) for her valuable practical support.
Scheme 4. Synthesis of 2,3-Dihydro-1H-pyrrolizine 6h on Gram Scale and Control Experiment with N-Methylated Vinylindole 10
■
(1) (a) Mattocks, A. R. Nature 1968, 217, 723. (b) Smith, L. W.; Culvenor, C. C. J. J. Nat. Prod. 1981, 44, 129. (c) Segall, H. J.; Wilson, D. W.; Dallas, J. L.; Haddon, W. F. Science 1985, 229, 472. (2) (a) Kuhara, K.; Takanashi, J.; Hirono, I.; Furuya, T.; Asada, Y. Cancer Lett. 1980, 10, 117. (b) Yee, S. B.; Kinser, S.; Hill, D. A.; Barton, C. C.; Hotchkiss, J. A.; Harkema, J. R.; Ganey, P. E.; Roth, R. A. Toxicol. Appl. Pharmacol. 2000, 166, 173. (c) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773. (3) (a) Rooks, W. A., II; Tomolonis, A. J.; Maloney, P. J.; Wallach, M. B.; Schuler, M. E. Agents Actions 1982, 12, 684. (b) Franco, F.; Greenhouse, R. J. J. Org. Chem. 1982, 47, 1682. (c) Muchowski, J. M.; Unger, S. H.; Ackrell, J.; Cheung, P.; Cooper, G. F.; Cook, J.; Gallegra, P.; Halpern, O.; Koehler, R.; Kluge, A. F.; Van Horn, A. R.; Antonio, Y.; Carpió, H.; Franco, F.; Galeazzi, E.; Garcia, I.; Greenhouse, R.; Guzmán, A.; Iriarte, J.; Leon, A.; Peña, A.; Peréz, V.; Valdéz, D.; Ackerman, N.; Bailaron, S. A.; Krishna Murthy, D. V.; Rovito, J. R.; Tomolonis, A. J.; Young, J. M.; Rooks, W. H., II J. Med. Chem. 1985, 28, 1037. (4) (a) Laufer, S. A.; Augustin, J.; Dannhardt, G.; Kiefer, W. J. Med. Chem. 1994, 37, 1894. (b) Laufer, S. A.; Tries, S.; Augustin, J.; Elsaesser, R.; Albrecht, W.; Guserle, R.; Algate, D. R.; Atterson, P. R.; Munt, P. L. Arzneim.-Forsch. 1995, 45, 27. (c) Ulbrich, H.; Fiebich, B.; Dannhardt, G. Eur. J. Med. Chem. 2002, 37, 953. (d) Liedtke, A. J.; Keck, P. R. W. E. F.; Lehmann, F.; Koeberle, A.; Werz, O.; Laufer, S. A. J. Med. Chem. 2009, 52, 4968. (5) For reviews, see: (a) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773. (b) Robertson, J.; Stevens, K. Nat. Prod. Rep. 2014, 31, 1721. For examples of racemic syntheses, see: (c) Yan, Z.-Y.; Xiao, Y.; Zhang, L. Angew. Chem., Int. Ed. 2012, 51, 8624. (d) Gu, Y.; Hu, P.; Ni, C.; Tong, X. J. Am. Chem. Soc. 2015, 137, 6400. (e) Sugimoto, K.; Yamamoto, N.; Tominaga, D.; Matsuya, Y. Org. Lett. 2015, 17, 1320. (f) Shimbayashi, T.; Nakamoto, D.; Okamoto, K.; Ohe, K. Org. Lett. 2018, 20, 3044. (6) (a) Arnone, A.; Broggini, G.; Passarella, D.; Terraneo, A.; Zecchi, G. J. Org. Chem. 1998, 63, 9279. (b) Beccalli, E. M.; Broggini, G.; Farina, A.; Malpezzi, L.; Terraneo, A.; Zecchi, G. Eur. J. Org. Chem. 2002, 2002, 2080. (c) Borsini, E.; Broggini, G.; Contini, A.; Zecchi, G. Eur. J. Org. Chem. 2008, 2008, 2808. (7) (a) Bae, J.-Y.; Lee, H.-J.; Youn, S.-H.; Kwon, S.-H.; Cho, C.-W. Org. Lett. 2010, 12, 4352. (b) Lee, H.-J.; Cho, C.-W. J. Org. Chem. 2013, 78, 3306. (c) Lee, H.-J.; Cho, C.-W. Eur. J. Org. Chem. 2014, 2014, 387. (8) Stark, D. G.; Williamson, P.; Gayner, E. R.; Musolino, S. F.; Kerr, R. W. F.; Taylor, J. E.; Slawin, A. M. Z.; O’Riordan, T. J. C.; Macgregor, S. A.; Smith, A. D. Org. Biomol. Chem. 2016, 14, 8957. (9) Excellent review: Mei, G.-J.; Shi, F. J. Org. Chem. 2017, 82, 7695. (10) (a) Qi, S.; Liu, C. Y.; Ding, J. Y.; Han, F.-S. Chem. Commun. 2014, 50, 8605. (b) Liu, C.-Y.; Han, F.-S. Chem. Commun. 2015, 51, 11844. (11) (a) Zhao, J.-J.; Sun, S.-B.; He, S.-H.; Wu, Q.; Shi, F. Angew. Chem., Int. Ed. 2015, 54, 5460. (b) Gong, Y.-X.; Wu, Q.; Zhang, H.H.; Zhu, Q.-N.; Shi, F. Org. Biomol. Chem. 2015, 13, 7993. (c) Zhu, Z.-Q.; Shen, Y.; Sun, X.-X.; Tao, J.-Y.; Liu, J.-X.; Shi, F. Adv. Synth. Catal. 2016, 358, 3797. (d) Li, C.; Zhang, H.-H.; Fan, T.; Shen, Y.; Wu, Q.; Shi, F. Org. Biomol. Chem. 2016, 14, 6932. (e) Zhang, H.-H.; Wang, C.-S.; Li, C.; Mei, G.-J.; Li, Y.; Shi, F. Angew. Chem., Int. Ed. 2017, 56, 116. (f) Zhu, Z.-Q.; Shen, Y.; Liu, J.-X.; Tao, J.-Y.; Shi, F. Org. Lett. 2017, 19, 1542. (g) He, Y.-Y.; Sun, X.-X.; Li, G.-H.; Mei, G.J.; Shi, F. J. Org. Chem. 2017, 82, 2462. (h) Sun, X.-X.; Li, C.; He, Y.Y.; Zhu, Z.-Q.; Mei, G.-J.; Shi, F. Adv. Synth. Catal. 2017, 359, 2660. (i) Wu, J.-L.; Wang, C.-S.; Wang, J.-R.; Mei, G.-J.; Shi, F. Org. Biomol. Chem. 2018, 16, 5457. (12) (a) Bera, K.; Schneider, C. Chem. - Eur. J. 2016, 22, 7074. (b) Bera, K.; Schneider, C. Org. Lett. 2016, 18, 5660. (13) Excellent review: Mei, G.-J.; Shi, F. Synlett 2016, 27, 2515.
Scheme 5. Plausible Transition State Assembly
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03833. Experimental procedures and analytical data (1H and 13 C NMR spectra and HPLC traces) for all new compounds and X-ray data for 9 (PDF) Accession Codes
CCDC 1874878 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Christoph Schneider: 0000-0001-7392-9556 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We thank the Deutsche Forschungsgemeinschaft (SCHN 441/ 11-2) for their generous financial support of this work and Evonik and BASF for the donation of chemicals. We thank Toni Grell (University of Leipzig) for obtaining the X-ray D
DOI: 10.1021/acs.orglett.8b03833 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (14) (a) Shemin, D.; Russell, C. S. J. Am. Chem. Soc. 1953, 75, 4873. (b) Rothemund, P. J. Am. Chem. Soc. 1935, 57, 2010. (c) Rothemund, P. J. Am. Chem. Soc. 1936, 58, 625. (d) Sessler, J. L.; Mozaffari, A.; Johnson, M. R. Org. Synth. 1992, 70, 68. (15) (a) Ondrus, A. E.; Movassaghi, M. Org. Lett. 2009, 11, 2960. (b) Ondrus, A. E.; Movassaghi, M. Chem. Commun. 2009, 0, 4151. (16) Frederich, J. H.; Harran, P. G. J. Am. Chem. Soc. 2013, 135, 3788. (17) (a) Inamdar, S. M.; Gonnade, R. G.; Patil, N. T. Org. Biomol. Chem. 2017, 15, 863. (b) Homer, J. A.; Sperry, J. Org. Biomol. Chem. 2018, 16, 6882. For other relevant information on the use and properties of 2-methide-2H-pyrrole intermediates, see: (c) Abell, A. D.; Nabbs, B. K.; Battersby, A. R. J. Am. Chem. Soc. 1998, 120, 1741. (d) Dinsmore, A.; Mandy, K.; Michael, J. P. Org. Biomol. Chem. 2006, 4, 1032. (18) Recent representative reviews: (a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. (b) Held, F. E.; Grau, D.; Tsogoeva, S. B. Molecules 2015, 20, 16103. (19) This transition state assembly is merely a stereochemical representation and not meant to classify this reaction as a concerted process. We are fully aware that concerted [6 + 2]-cycloadditions of fulvenes are symmetry-forbidden processes and most likely proceed via zwitterionic intermediates; for example, see: (a) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 781. (b) Wu, T. S.; Houk, K. N. J. Am. Chem. Soc. 1985, 107, 5308. (c) Hayashi, Y.; Gotoh, H.; Honma, M.; Sankar, K.; Kumar, I.; Ishikawa, H.; Konno, K.; Yui, H.; Tsuzuki, S.; Uchimaru, T. J. Am. Chem. Soc. 2011, 133, 20175.
E
DOI: 10.1021/acs.orglett.8b03833 Org. Lett. XXXX, XXX, XXX−XXX
