Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Asymmetric Synthesis of the DEFG Rings of Solanoeclepin A Mao Sun,†,‡ Wei-Dong Z. Li,*,† and Fayang G. Qiu*,‡ †
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, 55 Daxuecheng South Road, Shapingba, 401331 Chongqing, China ‡ Guangzhou Institute of Biomedicine and Health, The University of the Chinese Academy of Sciences, 190 Kaiyuan Avenue, The Science Park of Guangzhou, Guangzhou, Guangdong 510530, China
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S Supporting Information *
ABSTRACT: Starting from (R)-seudenol, an asymmetric synthesis of the DEFG rings of solanoeclepin A has been developed. The key transformations include the substratecontrolled asymmetric Staudinger ketene cycloaddition and the intramolecular aldol reaction leading to the tricyclo[5.2.1.01,6]decane core of solanoeclepin A in 10 steps in the longest reaction sequence.
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olanoeclepin A (Figure 1), first isolated from potato roots by Mulder et al. in 1986, is an environmentally friendly
implementation of Staudinger ketene cycloaddition and an intramolecular aldol reaction. On the basis of the previous synthetic studies and the architectural features of 1, we envisioned that a substrateinduced asymmetric Staudinger ketene cycloaddition to synthesize the DE ring and a subsequent intramolecular aldol condensation to complete the construction of the tricylo[5.2.1.01,6]decane skeleton may be feasible. The retrosynthetic analysis (Scheme 2) shows that the GF rings may be efficiently constructed via a chemoselective asymmetric cyclopropanation of RS3 and an intramolecular aldol reaction of RS2. The most challenging part of this synthetic plan is the construction of the all-carbon quaternary stereochemical center at the nonfused cyclobutane moiety of RS3. Therefore, the Tsuji−Trost allylation reaction may be effective to solve this problem, while the stereochemical configuration may be controlled through the chiral center of the bridgehead carbons of RS4, which may be generated from the asymmetric Staudinger ketene cycloaddition of RS5. The latter may be synthesized from the asymmetric hydrogenation of commercially available seudenone8 followed by benzylation. As shown in Scheme 3, O-benzylation of (R)-seudenol (96% ee)8 with benzyl bromide provided intermediate 3 in 98% yield. The [2 + 2] cycloaddition between intermediate 3 and dichloroketene generated in situ from trichloroacetyl chloride using zinc−copper alloy in the presence of phosphorus oxychloride gave the desired product 4 in 80% yield with excellent regio- and diastereoselectivity.9 It should be noted that protection of the hydroxyl group with an electronwithdrawing group such as acetyl or benzoyl resulted in no reaction. Subsequently, dechlorination of 4 with Zn/NH4Cl/ MeOH, 45%,10 followed by treatment with LiHMDS at −78 °C, generated a kinetic lithium enolate that was allowed to react with Mander’s reagent (NCCO2Et) in the presence of
Figure 1. Structure of solanoeclepin A.
and highly active hatching stimulant of potato cyst nematode (PCN; Globodera rostochiensis and G. pallida) which causes severe damage to potato crops.1 Its complex chemical structure, elucidated via X-ray crystallographic analysis by Schenk,2 possesses five different ring sizes ranging from three to seven and includes a distinctive bicyclo[2.1.1]hexanone unit and an oxabicyclo[2.2.1]heptane moiety. The potential application value in agriculture and the fascinating architecture of solanoeclepin A has attracted considerable attention of synthetic chemists. In 2011, Tanino and Miyashita first completed the asymmetric total synthesis,3 and other groups including Adachi and Nishikawa,4 Hiemstra,5 Isobe,6 and Li7 reported their valuable synthetic studies of this molecule. The major challenge in the synthesis of solanoeclepin A is the construction of the highly strained DEFG ring system (right part) of 1, which contains three-, four-, five-, and sixmembered rings and bears six contiguous stereochemical centers, three of which are consecutive all-carbon quaternary stereochemical centers. Although novel strategies and methodologies have been employed in the synthesis of the tricylo[5.2.1.01,6]decene moiety by Isobe,6 Hiemstra,5 Adachi and Nishikawa,4a and Tanino and Miyashita3 (Scheme 1), in this communication, we demonstrate a concise asymmetric synthesis of this highly strained ring system by the © XXXX American Chemical Society
Received: November 22, 2018
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DOI: 10.1021/acs.orglett.8b03742 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Schematic Summary of the Previous Studies toward the DEF Ring System of 1
Scheme 3. Synthesis of Intermediate 8
congested quaternary stereochemical center, and intermediate 7 was prepared with complete diastereocontrol and in excellent yield (90%). Subsequent dimethyltitanocene-mediated carbonyl olefination afforded intermediate 8 in 76% yield.13 To test the key aldol condensation, the following experiments were performed. Reduction of 8 with an excessive amount of DIBAL-H at −78 °C led to intermediate 9, and the resulting hydroxyl group was protected with TBSCl in 94% yield (Scheme 4). Ozonolysis of the two terminal double Scheme 4. Test Reaction of the Key Intramolecular Aldol Condensation
Scheme 2. Retrosynthetic Analysis of DEFG Ring System of Solanoeclepin A
bonds of 9 was accomplished at −78 °C, and 10 was obtained in 90% yield.14 With cyclization precursor 10 in hand, several bases (t-BuOK,15d NaOMe,15b DBU) were attempted to effect the aldol condensation. However, only the elimination of benzyloxy group occurred. It was found that, to our delight, addition of 2.5 equiv of LiHMDS15a,c to the solution of 10 (0.01 M) in THF at −78 °C before slow warming to room temperature afforded the cyclization product 11 in 80% yield. To confirm the absolute stereochemistry of 11, acylation of the hydroxyl of 11 with DNBCl afforded compound 12, the structure of which was confirmed via X-ray crystallographic analysis.
HMPA to install the ethoxycarbonyl group at the methylene of the substituted cyclobutanone.11 To prepare the key intermediate 7, a variety of methods to allylate the β-keto ester 6 were attempted such as NaH, DBU, LiHMDS, or Cs2CO3 with allyl bromide, and all resulted in either Oallylation or decomposition of 6. Fortunately, the Tsuji−Trost allylation reaction12 was found to be effective to construct the B
DOI: 10.1021/acs.orglett.8b03742 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
overall yield for three steps. Subsequently, product 21 was obtained through LiHMDS-mediated intramolecular aldol reaction of 20 followed by protection of the newly generated hydroxyl group with DNBCl in 78% yield. The use of protecting group was to prevent the possible retro-aldol reaction during storage. In conclusion, we have accomplished the asymmetric synthesis of the highly strained tricyclo[5.2.1.01,6]decane 11 in 10 steps in the longest reaction sequence and the entire right-hand part of solanoeclepin A via two pivotal methods: (a) substrate-induced asymmetric Staudinger ketene cycloaddition to construct the DE ring and (b) the intramolecular aldol reaction to complete the highly strained tricyclo[5.2.1.01,6]decane skeleton.
With a reliable method to construct the tricyclic skeleton 11 in hand, we began to synthesize the DEFG rings of solanoeclepin A (Scheme 5). Reduction of the ethyl ester of Scheme 5. Construction of the DEFG Rings of Solanoeclepin A
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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.8b03742. Detailed experimental procedures; NMR data (PDF) Accession Codes
CCDC 1873769 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.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Fayang G. Qiu: 0000-0002-0850-468X Notes
intermediate 8 with excessive DIBAL-H, Dess−Martin oxidation of the newly generated hydroxyl, and chain extension using the Horner−Wadsworth−Emmons reaction with triethyl phosphonoacetate gave the (E)-unsaturated ester 14 in 88% yield over three steps from 8. The first few attempts to construct the cyclopropane with trimethylsulfoxonium iodide were unsuccessful. Thus, ozonolysis of 14,14 with careful TLC monitoring, afforded aldehyde 15 in 90% yield at −78 °C. Subsequently, protection of the aldehyde with ethylene glycol in the presence of a catalytic amount of TsOH·H2O, reduction of the ethyl ester with DIBAL-H afforded 17 in 84% yield over two steps. At this point, a substrate-controlled Simmons− Smith cyclopropanation was investigated. Under these conditions, the cyclopropane was isolated in low yield as an inseparable 2:1 mixture of two diastereomers favoring the desired product (determined by proton NMR). Much to our delight, when the resulting allylic alcohol was treated with diiodomethane and diethylzinc in the presence of the 1,3,2dioxaborolane ligand16 (ligand A), cyclopropane 18 was obtained in 90% yield as a single isomer. Apparently, the high chemo- and stereoselectivity is a result of reagent control. To complete the construction of the right-hand part of solanoeclepin A, alcohol 18 was protected with TBDPSCl, and the diethylacetal hydrolysis followed by ozonolysis of the terminal double bond afforded cyclobutanone 20 in 70%
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to Launch Pharma of Guangzhou for a fellowship to M.S. and the National Natural Science Foundation of China for financial support of this work (Grant Nos. 21372221, 21672030, and 21572228).
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REFERENCES
(1) (a) Mulder, J. G.; Diepenhorst, P.; Brüggemann-Rotgans, I. E. M. PCT Int. Appl. WO 93/02,083, 1993. (b) Mulder, J. G.; Diepenhorst, P.; Brüggemann-Rotgans, I. E. M. Chem. Abstr. 1993, 118, 185844z. (2) Schenk, H.; Driessen, R. A. J.; de Gelder, R.; Goubitz, K.; Nieboer, H.; Brüggemann-Rotgans, I. E. M.; Diepenhorst, P. Croat. Chem. Acta 1999, 72, 593−606. (3) Tanino, K.; Takahashi, M.; Tomata, Y.; Tokura, H.; Uehara, T.; Miyashita, M. Nat. Chem. 2011, 3, 484−488. (4) (a) Komada, T.; Adachi, M.; Nishikawa, T. Chem. Lett. 2012, 41, 287−289. (b) Adachi, M.; Torii, M.; Nishikawa, T. Synlett 2015, 26, 965−969. (5) (a) Blaauw, R. H.; Brière, J.-F.; de Jong, R.; Benningshof, J. C. J.; van Ginkel, A. E.; Rutjes, F. P. J. T.; Fraanje, J.; Goubitz, K.; Schenk, H.; Hiemstra, H. Chem. Commun. 2000, 1463. (b) Benningshof, J. C. J.; Blaauw, R. H.; van Ginkel, A. E. J. H.; Rutjes, F. P. J. T.; Fraanje, J.; C
DOI: 10.1021/acs.orglett.8b03742 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Goubitz, K.; Schenk, H.; Hiemstra, H. Chem. Commun. 2000, 1465. (c) Blaauw, R. H.; Brière, J.-F.; de Jong, R.; Benningshof, J. C. J.; van Ginkel, A. E.; Fraanje, J.; Goubitz, K.; Schenk, H.; Rutjes, F. P. J. T.; Hiemstra, H. J. Org. Chem. 2001, 66, 233. (d) Brière, J.-F.; Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2001, 2001, 2371. (e) Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen, J. H.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 2001, 1, 2250. (f) Benningshof, J. C. J.; Blaauw, R. H.; van Ginkel, A. E.; van Maarseveen, J. H.; Rutjes, F. P. J. T.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 2002, 1, 1693. (g) Benningshof, J. C. J.; IJsselstijn, M.; Wallner, S. R.; Koster, A. L.; Blaauw, R. H.; van Ginkel, A. E.; Brière, J.-F.; van Maarseveen, J. H.; Rutjes, F. P. J. T.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 2002, 1, 1701. (h) Buu Hue, B. T.; Dijkink, J.; Kuiper, S.; Larson, K. K.; Guziec, F. S., Jr.; Goubitz, K.; Fraanje, J.; Schenk, H.; van Maarseveen, J. H.; Hiemstra, H. Org. Biomol. Chem. 2003, 1, 4364. (i) Buu Hue, B. T.; Dijkink, J.; Kuiper, S.; van Schaik, S.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2006, 2006, 127. (j) Lutteke, G.; Kleinnijenhuis, R. A.; Jacobs, I.; Wrigstedt, P. J.; Correia, A. C. A.; Nieuwenhuizen, R.; Buu Hue, B. T. B.; Goubitz, K.; Peschar, R.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2011, 2011, 3146. (k) Kleinnijenhuis, R. A.; Timmer, B. J. J.; Lutteke, G.; Smits, J. M. M.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. Chem. - Eur. J. 2016, 22, 1266−1269. (6) (a) Tojo, S.; Isobe, M. Synthesis 2005, 1237. (b) Adachi, M.; Yamauchi, E.; Komada, T.; Isobe, M. Synlett 2009, 2009, 1157. (c) Tsao, K.-W.; Cheng, C.-Y.; Isobe, M. Org. Lett. 2012, 14, 5274. (d) Chuang, H.-Y.; Isobe, M. Org. Lett. 2014, 16, 4166. (e) Lin, Y. T.; Lin, F. Y.; Isobe, M. Org. Lett. 2014, 16, 5948. (f) Chuang, H. Y.; Isobe, M. Tetrahedron 2017, 73, 2705−2714. (g) Chuang, H. Y.; Isobe, M. J. Org. Chem. 2017, 82, 2045−2058. (7) Liu, G.; Han, J. C.; Li, C. C. Tetrahedron 2017, 73, 3629−3635. (8) Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.; Saito, T.; Kayaki, Y.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 14960− 14963. (9) (a) Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879. (b) Brocksom, T. J.; Coelho, F.; Deprés, J. P.; Greene, A.; Freire de Lima, M. E.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.; Wang, Y. Y. J. Am. Chem. Soc. 2002, 124, 15313−15325. (10) Darses, B.; Greene, A. E.; Poisson, J. F. J. Org. Chem. 2012, 77, 1710−1721. (11) Luo, S. J.; Zificsak, C. A.; Hsung, R. P. Org. Lett. 2003, 5, 4709−4712. (12) (a) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J. Org. Chem. 1985, 50, 1523−1529. (b) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393−5407. (c) Trost, B. M. Tetrahedron 2015, 71, 5708−5733. (d) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395−422. (13) (a) Brown, B.; Hegedus, L. S. J. Org. Chem. 1998, 63, 8012− 8018. (b) Payack, J. F.; Hughes, D. L.; Cai, D. W.; Cottrell, I. F.; Verhoeven, T. R. Org. Synth. Coll. 2003, 10, 355. (14) Van Ornum, S. G.; Champeau, R. M.; Pariza, R. Chem. Rev. 2006, 106, 2990−3001. (15) (a) Wu, H. Y.; Walker, K. A. M.; Nelson, J. T. J. Org. Chem. 1990, 55, 5074−5078. (b) Colvin, E. W.; Cameron, S. J. Chem. Soc., Perkin Trans. 1 1989, 1, 365−370. (c) Smith, A. B.; Leenay, T. L. J. Am. Chem. Soc. 1989, 111, 5761−5768. (d) Yadav, J. S.; Goreti, R.; Pabbaraja, S.; Sridhar, B. Org. Lett. 2013, 15, 3782−3785. (16) (a) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120, 11943−11952. (b) Tanino, K.; Takahashi, M.; Tomata, Y.; Tokura, H.; Uehara, T.; Miyashita, M. Nat. Chem. 2011, 3, 484−488. (c) Kleinnijenhuis, R. A.; Timmer, B. J. J.; Lutteke, G.; Smits, J. M. M.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. Chem. - Eur. J. 2016, 22, 1266−1269.
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DOI: 10.1021/acs.orglett.8b03742 Org. Lett. XXXX, XXX, XXX−XXX
