Letter Cite This: Org. Lett. 2019, 21, 5757−5761
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Stereocontrolled Synthesis of the Daphenylline Pentacyclic ACDEF Ring System Sergi Jansana, Faïza Diaba,* and Josep Bonjoch* Laboratori de Química Orgànica, Facultat de Farmàcia, IBUB, Universitat de Barcelona, Av. Joan XXIII s/n, Barcelona 08028, Spain
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S Supporting Information *
ABSTRACT: An azapentacyclic compound with the daphenylline ACDEF ring framework was synthesized from a benzo[e]indole intermediate efficiently obtained by a 5-endo-trig radical cyclization of a bicyclic trichloroenamide. Stereocontrolled processes were used to generate the three stereogenic methine carbons in the pyrrolidine C ring including the all-carbon quaternary stereocenter at C5. Ring closure to build both seven- and five-membered rings was achieved by Friedel−Crafts reactions.
D
aphenylline is a structurally unique Daphniphyllum alkaloid with a rearranged 22-nor-calyciphylline skeleton embodying a benzene ring (Figure 1).1,2 Since its isolation a decade ago, five total syntheses of daphenylline have been reported.3−7 In the total syntheses of Li3,6 Zhai,5 and Qiu,7 the benzene ring is not formed until the last steps, taking advantage of advanced intermediates previously used for the synthesis of daphniphyllum alkaloids without a benzene ring. In Li’s total syntheses, the last ring closure of the synthetic sequence involves a radical cyclization leading to the seven-membered D ring3 or a ring-expansion/aromatization/aldol cascade toward the arene E ring,6 while Zhai’s approach culminates in an aldol reaction to provide the five-membered F ring (Figure 1a). A successful de novo synthesis, starting from a methoxyindanone, was devised by Fukuyama,4 in which a cycloaddition of a cyclic azomethine ylide allowed the simultaneous assembly of rings A and C in the last ring-forming step. Very recently, Qiu reported a new
Figure 2. Synthesis of daphenylline polycyclic fragments with an embedded benzene ring showing the sequence in which the rings were assembled: (a) precedents; (b) present work.
approach from (S)-carvone using a tandem Robinson annulation to build the aromatic moiety and a Nazarov-type cyclization in the last F ring-forming step.7 Other approaches in Received: June 26, 2019 Published: July 2, 2019
Figure 1. Structure and total syntheses of daphenylline. © 2019 American Chemical Society
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DOI: 10.1021/acs.orglett.9b02211 Org. Lett. 2019, 21, 5757−5761
Letter
Organic Letters Scheme 1. Synthesis of Tetracyclic ACDE Ring System
secondary enamine (not shown)14 and then, after treatment with trichloroacetyl chloride, trichloroacetamide 2 in 71% overall yield. The next crucial step involved a radical cyclization upon the tetrasubstituted double bond to generate the quaternary stereocenter. When trichloroacetamide 2 was submitted to radical reductive conditions with the slow addition of a solution of Bu3SnH and AIBN in refluxing benzene, tricyclic fused γ-lactam 3 was exclusively obtained in 70% yield on a tengram scale.15 Enamide 3 was allylated using LHMDS and allyl bromide at −78 °C to diastereoselectively give 4 in 94% yield. The selectivity of the allylation was controlled by the steric hindrance generated by the neighboring methyl group. Reduction of the acyliminium species obtained from 4 using cyanoborohydride in acidic medium selectively afforded cishydrobenzo[e]indole 5. It should be noted that the synthesis of lactam 5 not only gave the stereochemistry required for the synthetic approach (i.e., a five-membered ring with three contiguous stereogenic centers stereoselectively achieved) but also constituted the first reported synthesis of a trans-1,9bdisubstituted cis-fused benzo[e]indole ring.16 Having attained the ACE ring fragment, we proceeded toward the formation of the D ring. Thus, compound 5 was submitted to a sequential hydroboration/oxidation leading to alcohol 6, which was oxidized using stoichiometric NaClO2, catalytic TEMPO, and NaOCl,17 allowing us to efficiently obtain carboxylic acid 7 (85% yield from 5). The seven-membered ring closure was carried out under classical Friedel−Crafts cyclization conditions using thionyl chloride to convert 7 into the corresponding acyl chloride, which was treated in situ with AlCl3 in refluxing dichloromethane to give tetracyclic ketone 8 in excellent yield (95%). The remaining obstacle to construct the five-membered F ring was the diastereoselective introduction of a functionalized twocarbon side chain at C10 from benzylic ketone 8. The initial attempts are illustrated in Scheme 2. Homologation reactions of ketone 8 using diethyl phophonoacetate to obtain the corresponding α,β-unsaturated ester were unsuccessful under Horner-Wadsworth-Emmons reaction conditions using NaH as the base, previously efficiently employed in 2-benzosuberone,18 or other bases (LDA, Cs2CO3, LiOH). Steric hindrance due to the spatial proximity of the C21 methyl group or less carbonyl character because of an easy enolate formation could explain this low reactivity. The next step was to attempt an allylation process, either from benzylic alcohol 9 or the corresponding xanthate 9a and bromide 9b. Reduction of ketone 8 with NaBH 4
Scheme 2. Unsuccessful Initial Attempts To Introduce a SideChain at C-10
this field leading to tri- and tetracyclic fragments of daphenylline in which the aromatic E ring is embedded are summarized in Figure 2.8−12 Three of them use a benzene compound as starting material leading to nitrogen-containing tetracyclic compounds,9−11 whereas Liang’s approach12 starts from (S)-carvone (ring A) and She’s synthesis of the tricarbocyclic DEF structure begins with a cyclopentene compound.8 Herein, the synthesis of the ACDEF pentacyclic ring system of daphenylline is reported. Using a 2-tetralone as a platform in which rings AE were embedded, our approach would involve the use of a radical cyclization to elaborate the fully substituted stereogenic center during the C ring closure.13 Two successive Friedel−Crafts acylation reactions would then serve to build the seven- and five-membered rings (Figure 2). This analysis prompted us to begin our approach from the commercially available dihydronaphtalenone 1 (Scheme 1), which reacted with benzylamine to give the corresponding 5758
DOI: 10.1021/acs.orglett.9b02211 Org. Lett. 2019, 21, 5757−5761
Letter
Organic Letters Scheme 3. Synthesis of Pentacyclic ACDEF Ring System
terminal double bond, followed by cyclization of the allylic cation to form the six-membered ring prior to the protonolysis of the C−Hg bond.21 After these unsuccessful attempts to form the C10−C17 bond, we decided to prepare a ring closure precursor by means of a detour, in which the side chain would be introduced at C10 from an α-ketone alkylation, implying a previous 1,2-carbonyl transposition22 from ketone 8 (Scheme 3). Since our unsuccessful studies (Scheme 2) had provided alkene 10 in good yield from alcohol 9, we took advantage of the reduction− elimination sequence of 8 to 10 for the ketone transposition (8 →13). Treatment of alkene 10 with m-CPBA furnished the corresponding epoxide (not shown), which upon rearrangement with zinc iodide gave ketone 13. The regioselectivity of the process agrees with the behavior observed in aromatic ring-fused cycloalkene oxides,23 in which the exclusive migration of an αhydrogen gives the corresponding ketone. The four-step procedure, which did not require any purification, allowed the isolation of 13 in 54% overall yield (an average of 85% for each step). Next, the alkylation of 13 using LHMDS and tert-butyl iodoacetate gave 14 with a minimal erosion of its diastereoselective purity (less than 5%). The configuration at C10 was established by NOESY spectroscopic analysis, which revealed that the newly generated center possesses a β-hydrogen atom. NOESY cross-peaks of H-10/H-6 and H3-21 indicate their cisrelationship in the cycloheptane ring. The stereochemical result of the alkylation agrees with the results consistently obtained from tetracyclic compounds, in which the attack of either nucleophiles or electrophiles takes place from the bottom face of the seven-membered ring. Removal of the ketone carbonyl group in 14 was achieved by formation of the corresponding tosylhydrazone, followed by treatment with NaBH4.24 In the course of the process, a partial epimerization at C10 was observed, compound 15 being formed as a 5:1 mixture of epimers, both isolated in a pure form. Having succeeded in the stereocontrolled installation of the side chain, we carried out the Friedel−Crafts reaction upon the acid resulting from a cleavage of the tert-butyl ester in 15 leading to ketone 16. Thus, the construction of the pentacyclic ACDEF ring system of daphenylline was achieved in high yield, the stereostructure of 16 being supported by its X-ray data (Figure 3). Hydrogenation of ketone 16 followed by reduction of the resulting lactam 17 with LiAlH4 afforded amine 18 (Scheme 3), thus completing a
Figure 3. X-ray of pentacyclic compound 16.
diastereoselectively gave alcohol 9 (94% yield), which resulted from the hydride attack from the less hindered bottom face, avoiding the interaction with the methyl group on the top face. Its stereostructure was supported by X-ray data (see SI). Reaction of 9 with allyltrimethylsilane, using FeCl3.6H2O as a Lewis acid, returned the starting material. When TiCl4 was used, no productive compound was isolated, whereas working with InCl3 resulted in an elimination process, alkene 10 (see Scheme 3) being isolated in 77% yield. The use of Keck’s allylation conditions with allyltributylstannane, either from xanthate 9a or bromide 9b, was also unsuccessful, alkene 10 again being isolated through a thermal elimination.19 At this point, we considered the possibility of assembling the seven-membered ring using a precursor for the cyclization step with both C16 and C17 already incorporated (Scheme 2b). Thus, allylic alcohol 11 was prepared from aldehyde 6a to attempt a Hg(OTf)2-catalyzed arylene cyclization, similar to that reported by Nishizawa.20 In these reaction conditions, the 1:1 epimeric mixture of allylic alcohols 11 led to the formation of a six-membered rather than a seven-membered ring. A 2:1 epimeric mixture of tetracyclic compounds 12a was isolated and structurally elucidated after analyzing NMR data as well as those of the epimeric mixture 12b obtained by hydrogenation of the alkene moiety in 12a. This unprecedented tetracyclic heterocycle may have been generated by the formation of an initial diene from the allylic alcohol 11 and mercuriation of the 5759
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Organic Letters
(8) Li, H.; Qiu, Y.; Zhao, C.; Yuan, Z.; Xie, X.; She, X. Diels-Alder/ Oxidative Aromatization Approach Towards the all-Carbon DEF Tricyclic Skeleton of Daphenylline. Chem. - Asian J. 2014, 9, 1274− 1277. (9) Fang, B.; Zheng, H.; Zhao, C.; Jing, P.; Li, H.; Xie, X.; She, X. Synthesis of the Tetracyclic Core (ABCE Rings) of Daphenylline. J. Org. Chem. 2012, 77, 8367−8373. (10) Li, H.; Zheng, J.; Xu, S.; Ma, D.; Zhao, C.; Fang, B.; Xie, X.; She, X. Rapid Construction of the [6−6−6−5] Tetracyclic Skeleton of the Daphniphyllum Alkaloid Daphenylline. Chem. - Asian J. 2012, 7, 2519− 2522. (11) Wang, W.; Li, G.-P.; Wang, S.-F.; Shi, Z.-F.; Cao, X.-P. Direct and Short Construction of the ACDE Ring System of Daphenylline. Chem. Asian J. 2015, 10, 377−382. (12) Deng, M.; Yao, Y.; Li, X.; Li, N.; Zhang, X.; Liang, G. Rapid Construction of the ABCE Tetracyclic Amine Skeleton in Daphenylline Enabled by an Amine-Borane Complexation Strategy. Org. Lett. 2019, 21, 3290−3294. (13) Coussanes, G.; Bonjoch, J. Syntesis of the Tetracyclic ABCD Ring Domain of Calyciphylline-A Type Alkaloids via Reductive Radical Cyclizations. Org. Lett. 2017, 19, 878−881. (14) A characteristic narrow triplet at δH 1.91 (J = 1.4 Hz) appears for the methyl group. See also Volpe, T.; Revial, G.; Pfau, M.; d’Angelo, J. Enantioselective Synthesis of Ring-C Aromatic Stereoids by Asymmetric Michael-type Alkylation of Chiral Amines. Tetrahedron Lett. 1987, 28, 2367−2370. (15) For a proposed mechanism for the formation of enamides in related processes, see: (a) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. B- and γ-Lactams by Nickel Powder Mediated 4-eco or 5endo Radical Cyclisations. A Concise Construction of the Mesembrine Skeleton. Tetrahedron 1998, 54, 1029−1040. (b) Clark, A. J.; Curran, D. P.; Fox, D. J.; Ghelfi, F.; Guy, C. S.; Hay, B.; James, N.; Phillips, J. M.; Roncaglia, F.; Sellars, P. B.; Wilson, P.; Zhang, H. Axially Chiral Enamides: Substituent Effects, Rotation Barriers, and Implications for their Cyclization Reactions. J. Org. Chem. 2016, 81, 5547−5565. (16) For a synthesis of cis-1,9b-disubstituted cis-hydrobenzo[b] indoles, see: Urruzuno, I.; Mugica, O.; Oiarbide, M.; Palomo, C. Bifunctional Bronsted Base Catalyst Enabled Regio-, Diastereo-, and Enantioselective Cα-Alkylation of β-Tetralones and Related AromaticRing-Fused Cycloalkanones. Angew. Chem., Int. Ed. 2017, 56, 2059− 2063. (17) Zaho, M. M.; Li, J.; Mano, E.; Song, Z. J.; Tschaen, D. M. Oxidation of primary alcohols to carboxylic acid with sodium chlorite catalyzed by TEMPO and bleach: 4-methoxyphenylacetic acid. Org. Synth. 2005, 81, 195−203. (18) (a) Lee, M.; Haseltine, J. N.; Smith, A. B., III; Hochstrasser, R. M. Isomerization Processes of Electronically Excited Stilbene and Diphenylbutadiene in Liquids: Are They One-dimensional? J. Am. Chem. Soc. 1989, 111, 5044−5051. (b) Amano, Y.; Noguchi, M.; Nakagomi, M.; Muratake, H.; Fukasawa, H.; Shudo, K. Design, Synthesis and Evaluation of Retinoids with Novel Bulky Hydrophobic Partial Structures. Bioorg. Med. Chem. 2013, 21, 4342−4350. (19) Fernandez, F.; Garcia-Mera, X.; Rodriguez-Borges, J. E.; Blanco, J. M. Tetrahedron Lett. 2001, 42, 5239−5240. (b) Xie, J.; Wolfe, A. L.; Boger, D. L. Total Synthesis of Kopsinine. Org. Lett. 2013, 15, 868− 870. (20) Namba, K.; Yamamoto, H.; Sasaki, I.; Mori, K.; Imagawa, H.; Nishizawa, M. Hg(OTf)2-Catalyzed Arylene Cyclization. Org. Lett. 2008, 10, 1767−1770. (21) For a related process, see: Namba, K.; Nakagawa, Y.; Yamamoto, H.; Imagawa, H.; Nishizawa, M. Hg(OTf)2-Catalyzed Cyclization of NTosylanilinoallylic alcohols to 2-Vinylindolines. Synlett 2008, 2008, 1719−1723. (22) Jensen, B. L.; Slobodzian, S. V. A Concise Synthesis of 1Substituted-2-tetralones by Selective Diol Dehydration Leading to Ketone Transposition. Tetrahedron Lett. 2000, 41, 6029−6033. (23) Ranu, B. C.; Jana, U. Indium(III) Chloride-Promoted Rearrangement of Epoxides: A Selective Synthesis of Substituted Benzylic Aldehydes and Ketones. J. Org. Chem. 1998, 63, 8212−8216.
series of valuable compounds for a new approach to the targeted alkaloid. In summary, the azapentacyclic octahydro-7,8(epiminomethano)naphto[2,1,8-cde]azulene system (Figure 3), which constitutes the ACDEF fragment of daphenylline, has been synthesized for the first time, providing an interesting precursor to this alkaloid. Efforts to elaborate the remaining bridged piperidine B ring, from a pentacyclic structure (e.g., 18) en route to daphenylline, are ongoing in our laboratory.25
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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.9b02211. Experimental procedures, spectroscopic and analytical data, NMR spectra copies of new compounds (PDF) Accession Codes
CCDC 1915690 (compound 16) and 1915680 (compound 9, in SI) contain 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 data_request@ccdc. cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Josep Bonjoch: 0000-0002-5551-6720 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support for this research was provided by Project CTQ2016-75350-P from the Ministry of Economy, Industry, and Competitiveness of Spain/FEDER funds.
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REFERENCES
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Organic Letters (24) (a) Caglioti, L. Reduction of Ketones by Use of the Tosylhydrazone Derivatives. Org. Synth. 1972, 52, 122−123. (b) Westphal, J.; Schumacher, C. E.; Schmalz, H.-G. The Wender Cedrene Synthesis Revisited: A Catalytic Enantioselective Entry to the Chiral Key Intermediate. Synthesis 2016, 49, 218−224. (25) Because of the paucity of material, only an unsuccessful preliminary study of the elaboration of bridged piperidine ring B was performed. A brief description of the results is included in the SI.
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