Asymmetric Total Synthesis and Absolute Configuration Determination of

Jul 3, 2018 - The first asymmetric total synthesis of (−)-verrupyrroloindoline (20% overall yield in 6 steps) is described. The short approach was e...
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Asymmetric Total Synthesis and Absolute Configuration Determination of (−)-Verrupyrroloindoline Zhi-Ping Yang,† Qian He,† Jian-Liang Ye,*,† and Pei-Qiang Huang*,†,‡ †

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Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China ‡ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China S Supporting Information *

ABSTRACT: The first asymmetric total synthesis of (−)-verrupyrroloindoline (20% overall yield in 6 steps) is described. The short approach was enabled by Buchwald’s Cu(II)-catalyzed asymmetric conjugate reduction, DMDOtriggered one-pot four-step tandem reaction, and the first amide-selective Ir-catalyzed direct reduction of β-carboethoxy tertiary lactam. Along with the total synthesis, the absolute configuration of natural verrupyrroloindoline was determined as 7R,10R,11R.

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core containing a pharmacologically important pyrroloindoline unit and enaminoester moiety, which represents a rare natural alkaloid class. Although similar ring systems have been built chemically by Jackson/Shannon3 and Loh,4 respectively, alkaloids [crocagins A (2), B (3)] possessing similar skeletons were reported only one year later by Müller and co-workers.5 As part of a general program aimed at the development of step-economical synthetic methodologies,6 recently, we have achieved the highly efficient synthesis of indoline-based polycyclic natural products of the chaetominine class.7 Herein, we disclose the concise asymmetric total synthesis of verrupyrroloindoline (1), along with the determination of the absolute configuration of this natural product. As outlined in Scheme 1, our retrosynthetic analysis of (−)-verrupyrroloindoline (1) implicated the generation of the characteristic enaminoester moiety by selective reduction of βcarboethoxy lactam 4. The corresponding precursor 5 could be installed via intramolecular lactamization of pyrroloindoline 6, which was expected to be accessible from chiral tryptamine derivative 7 through a one-pot cascade indole epoxidationepoxide ring-opening cyclization strategy.7,8 The chiral side chain in indole derivative 7 was envisioned to be introduced via coupling of N-Boc tryptamine 9 with β-iodo enoate 10 followed by Buchwald’s Cu(II)-catalyzed asymmetric conjugate reduction.9 As shown in Scheme 2, our synthesis commenced with the coupling of commercially available N-Boc tryptamine 9 with βiodo enolate 10. Under Buchwald’s conditions (toluene, CuI 10 mol %, K3PO4, N1,N2-dimethylethane-1,2-diamine, 65 °C, 24 h),8 compound 8 was produced in 89% yield. It was

arine organisms, such as algae, sponges, and corals, are rich sources of pharmacologically important compounds with new molecular architectures.1 However, their scarcity, owing to both the low availability and low isolation yield and the unsustained collection of marine organisms, frequently hampers the latter chemical and preclinical studies. In this context, an efficient synthesis of a marine natural product is always in high demand to offer a reliable supply. In 2016, Yan, Gustafson and their co-workers reported the isolation of 19 metabolites with diverse structures, including 1.5 mg of the rare pyrroloindoline alkaloid verrupyrroloindoline (1) from soft coral Sinularia verruca van Ofwegen (wet weight 1.2 kg) collected in the South China Sea (Figure 1).2

Figure 1. Natural products possessing 2a,5a-diazacyclopenta[jk]fluorene core.

The relative configuration of 7S*,10S*,11S* was assigned based on the observed NOESY correlations. Although the specific optical rotation has been measured {[α]D25 −22 (c 0.06, CHCl3)}, its absolute configuration has not been determined due to the scarcity of the compound. Verrupyrroloindoline (1) features a 2a,5a-diazacyclopenta[jk]fluorene © XXXX American Chemical Society

Received: May 18, 2018

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DOI: 10.1021/acs.orglett.8b01579 Org. Lett. XXXX, XXX, XXX−XXX

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has not been determined owing to unassigned 1H NMR resonances due to restricted C−N amide bond rotation. Next, because deprotection of N-Boc with TFA failed, an alternative approach consisting of successive N-Boc cleavage,10 formation of pyrimidine ring, and TMS protection of hydroxyl11 was envisioned. Ye and Xu’s protocol (TMSOTf/ DIPEA) employing a large excess of DIPEA (145 equiv)10b was first examined; however, that turned out to be unfruitful. Upon reducing the amount of DIPEA to 3.0 equiv, four isomers 12−15 in a ratio of 45:20:7:28 were formed in an 80% combined yield (Scheme 3). To facilitate the cyclization

Scheme 1. Retrosynthetic Analysis of Verrupyrroloindoline (1)

Scheme 3. Formation of Tetrahydropyrimidin-4(1H)-one Ring

Scheme 2. Installation of Chiral Side Chain and Construction of the Pyrroloindoline

process, an alternative stronger base partner was attempted. Gratifyingly, treatment of the diastereomeric mixture 6 and 11 with TMSOTf/2,6-lutidine led to two separable diastereomers 12 and 14 (dr = 2.4:1) in 60% yield. The enantiomeric excess of 12 was determined as 89% ee by chiral HPLC analysis. The structure and stereochemistry including the absolute configuration of the major isomer 12 were determined by X-ray diffraction (CCDC: 1843837) [Flack parameter x (μ) = 0.04 (7)] to be 7R,10S,11R.12 The results indicated that the Buchwald’s catalytic asymmetric copper hydride reduction of 8 in the presence of (S)-BINAP resulted in an R-configuration [(R)-7]. To our delight, the result also revealed the cisrelationship between 14-Me, H10, 7-OTMS, needed for the synthesis of verrupyrroloindoline (1). The relative configuration of 14, i.e., 14-Me, H10/7-OTMS located in opposite faces, was confirmed by the observed correlations between H10/H11 in the NOESY spectrum (see structure 14 in Scheme 3). The (7S,10R,11R)-absolute configuration of minor isomer 14 was deduced. In order to improve the efficiency, we envisaged a one-pot four-step sequence: oxidative cyclization, N-Boc cleavage, cyclization again, and TMS protection (Scheme 4). Thus, compound 7 was treated with DMDO at −78 °C for 30 min followed by concentration in vacuo, and the resulting mixture

observed that by elevating the reaction temperature to 80 °C and running for 16 h, the yield of 8 was improved to 98%. Following Buchwald’s catalytic asymmetric copper hydride reduction procedure [Cu(OAc)2·H2O 5 mol %, (S)-BINAP 5 mol %, PMHS (polymethylhydrosiloxane), t-BuOH, THF, rt, overnight],9 the conjugate reduction of 8 smoothly afforded 7 in 90% yield and in 90% ee. The absolute configuration of 7 was determined at a later stage. With compound 7 in hand, a dimethyldioxirane (DMDO)-initiated oxidative cyclization strategy7 was used to construct the pyrrolo-[2,3-b]indole ring system. Treatment of 7 with DMDO in acetone (CH2Cl2, −78 °C, 30 min) produced two inseparable diastereomers 6 and 11 in a 90% combined yield. In this event, the ratio of 6 and 11 B

DOI: 10.1021/acs.orglett.8b01579 Org. Lett. XXXX, XXX, XXX−XXX

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Finally, cleavage of the TMS group of 17 with TBAF in THF led to the desired verrupyrroloindoline (1) in 85% yield (Scheme 5). The spectral data and sense of optical rotation of our synthetic product matched those reported for the natural verrupyrroloindoline (1).2 However, the specific optical rotation value of 1 exhibited a much higher value compared with that reported for the natural product {[α]D25 −631 (c 1.0, CHCl3) versus [α]D25 −22 (c 0.06, CHCl3)2}. The difference could be attributed to the impurity presented in the isolated natural sample as indicated by the reported 1H and 13C NMR spectra, to the low quantity available for an accurate measure of specific rotation (0.6 mg), or a partial racemization. Actually, verrupyrroloindoline might be an acid-labile natural product. Indeed, we have observed that quenching the final deprotection reaction with aqueous NH4Cl resulted in some unidentified products. In any event, the X-ray diffraction results of 12 allowed us to unequivocally establish the absolute configuration of verrupyrroloindoline (1) as 7R,10R,11R. In summary, we disclose the first asymmetric total synthesis of verrupyrroloindoline (1) in 6 steps with an overall yield of 20% from commercially available N-Boc tryptamine 9 and βiodo enolate 10. Our short approach features the following: (1) Buchwald’s Cu(II)-catalyzed asymmetric conjugate reduction was utilized to build the first chiral carbon; (2) the characteristic 2a,5a-diazacyclopenta[jk]fluorene core was expediently constructed through a DMDO-initiated one-pot four-step tandem reaction; and (3) chemoselective Ir-catalyzed direct reduction of β-carboethoxy tertiary lactam was first achieved to afford an enamino ester. Through this enantioselective total synthesis, the absolute configuration of natural (−)-verrupyrroloindoline (1) was unequivocally determined as 7R,10R,11R.

was exposed to TMSOTf/2,6-lutidine at 0 °C for 1 h. To our delight, 12 and 14 were isolated in 58% yield with a slight increase in dr (3:1). Next, the carboethoxy group at C12 of 12 was installed via deprotonation of LDA and capturing the resulting enolate with ethyl chloroformate, which afforded 16 as a single diastereomer in 80% yield. The 11,12-trans stereochemistry was assigned on the basis of the observed H10/H12, H12/H14, H14/H10 correlations in the NOESY spectrum (see the arrows on structure 16). With 16 in hand, we next focused our attention on the transformation of the β-carboethoxy tertiary lactam functionality (a 1,3-dicarbonyl compound) into an enamino ester subunit, which implicates the selective reduction of the less reactive lactam group in the presence of the ester group. A survey of the literature showed that although this is an important transformation in organic synthesis, only a four-step method, consisting of conversion of lactams to the thioamides with Lawesson’s reagent, S-methylation with CH3I, deprotonation, and desulfurization with Raney Ni, is available.13 In addition, during the past decade the catalytic protocols of direct transformation of tertiary amides were well developed.14 Notably, the direct reduction of aliphatic tertiary amides to enamines has been realized by the [IrCl(CO)(PPh3)2] (Vaska’s complex)/TMDS14a,d−f,i or [Mo(CO)6]/TMDS14c,n,o system. Inspired by these achievements, we attempted to carry out Ir-catalyzed reduction of β-carboethoxy lactams 16 to afford enamino esters. Thus, 16 was subjected to the Ircatalyzed reduction conditions [IrCl(CO)(PPh3)2 (1 mol %), TMDS (2.0 equiv), toluene, rt].14a,d−f,i Unexpectedly, most of the starting material was recovered, along with a trace amount of reduction product 17. Increasing the amount of catalyst to 20 mol % did significantly improve the yield to 45% but at a moderate conversion (60%). To our pleasure, further increasing the equivalents of TMDS to 4.0 gave 17 in a good yield (75%, Scheme 5).

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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.8b01579. Experimental procedure, products characterization data, and 1H/13C NMR spectra of new compounds, NOESY spectra of compounds 14 and 16, chiral HPLC diagrams of compounds 7 and 12, and X-ray data for 12 (PDF) Accession Codes

CCDC 1843837 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].

Scheme 5. Total Synthesis of (−)-Verrupyrroloindoline (1)

ORCID

Jian-Liang Ye: 0000-0003-1488-7311 Pei-Qiang Huang: 0000-0003-3230-0457 Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.8b01579 Org. Lett. XXXX, XXX, XXX−XXX

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(14) (a) Motoyama, Y.; Aoki, M.; Takaoka, N.; Aoto, R.; Nagashima, H. Chem. Commun. 2009, 1574−1576. (b) Volkov, A.; Tinnis, F.; Adolfsson, H. Org. Lett. 2014, 16, 680−683. (c) Volkov, A.; Tinnis, F.; Slagbrand, T.; Pershagen, I.; Adolfsson, H. Chem. Commun. 2014, 50, 14508−14511. (d) Gregory, A. W.; Chambers, A.; Hawkins, A.; Jakubec, P.; Dixon, D. J. Chem. - Eur. J. 2015, 21, 111− 114. (e) Nakajima, M.; Sato, T.; Chida, N. Org. Lett. 2015, 17, 1696− 1699. (f) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.; Sato, T.; Chida, N. J. Am. Chem. Soc. 2016, 138, 5246−5249. (g) Tinnis, F.; Volkov, A.; Slagbrand, T.; Adolfsson, H. Angew. Chem., Int. Ed. 2016, 55, 4562−4566. (h) Volkov, A.; Tinnis, F.; Slagbrand, T.; Trillo, P.; Adolfsson, H. Chem. Soc. Rev. 2016, 45, 6685−6697. (i) Huang, P.-Q.; Ou, W.; Han, F. Chem. Commun. 2016, 52, 11967−11970. (j) Fuentes de Arriba, A. L.; Lenci, E.; Sonawane, M.; Formery, O.; Dixon, D. J. Angew. Chem., Int. Ed. 2017, 56, 3655−3659. (k) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.; Sato, T.; Chida, N. Bull. Chem. Soc. Jpn. 2017, 90, 893−904. (l) Shi, H.; Michaelides, I. N.; Darses, B.; Jakubec, P.; Nguyen, Q. N. N.; Paton, R. S.; Dixon, D. J. J. Am. Chem. Soc. 2017, 139, 17755−17758. (m) Yoritate, M.; Takahashi, Y.; Tajima, H.; Ogihara, C.; Yokoyama, T.; Soda, Y.; Oishi, T.; Sato, T.; Chida, N. J. Am. Chem. Soc. 2017, 139, 18386− 18391. (n) Slagbrand, T.; Volkov, A.; Trillo, P.; Tinnis, F.; Adolfsson, H. ACS Catal. 2017, 7, 1771−1775. (o) Slagbrand, T.; Kervefors, G.; Tinnis, F.; Adolfsson, H. Adv. Synth. Catal. 2017, 359, 1990−1995. (p) Johnson, T. C.; Elbert, B. L.; Farley, A. J. M.; Gorman, T. W.; Genicot, C.; Lallemand, B.; Pasau, P.; Flasz, J.; Castro, J. L.; MacCoss, M.; Dixon, D. J.; Paton, R. S.; Schofield, C. J.; Smith, M. D.; Willis, M. C. Chem. Sci. 2018, 9, 629−633. (q) Sato, T.; Yoritate, M.; Tajima, H.; Chida, N. Org. Biomol. Chem. 2018, 16, 3864−3875.

ACKNOWLEDGMENTS Financial support of this work is provided by the National Key R&D Program of China (Grant No. 2017YFA0207302), the National Natural Science Foundation of China (21332007 and 21472153), the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of Ministry of Education, the Fundamental Research Funds for the Central Universities (20720150044), and the Natural Science Foundation of Fujian Province of China (2017J01021).

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REFERENCES

(1) Li, J. W. H.; Vederas, J. C. Science 2009, 325, 161−165. (2) Yuan, W.; Cheng, S.; Fu, W.; Zhao, M.; Li, X.; Cai, Y.; Dong, J.; Huang, K.; Gustafson, K. R.; Yan, P. J. Nat. Prod. 2016, 79, 1124− 1131. (3) (a) Jackson, A. H.; Shannon, P. V. R.; Wilkins, D. J. J. Chem. Soc., Chem. Commun. 1987, 653−654. (b) Wilkins, D. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1994, 1, 299−307. (4) Xiao, J.; Loh, T.-P. Tetrahedron Lett. 2008, 49, 7184−7186. (5) (a) Bihelovic, F.; Stichnoth, D.; Surup, F.; Mueller, R.; Trauner, D. Angew. Chem., Int. Ed. 2017, 56, 12848−12851. (b) Viehrig, K.; Surup, F.; Volz, C.; Herrmann, J.; Fayad, A. A.; Adam, S.; Koehnke, J.; Trauner, D.; Müller, R. Angew. Chem., Int. Ed. 2017, 56, 7407−7410. (6) (a) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Angew. Chem., Int. Ed. 2010, 49, 3037−3040. (b) Xiao, K.-J.; Wang, A.-E; Huang, P.-Q. Angew. Chem., Int. Ed. 2012, 51, 8314−8317. (c) Lang, Q.-W.; Hu, X.-N.; Huang, P.-Q. Sci. China: Chem. 2016, 59, 1638−1644. (d) Huang, P.-Q.; Huang, Y.-H.; Geng, H.; Ye, J.-L. Sci. Rep. 2016, 6, 28801. (e) Huang, P.-Q.; Chen, H. Chem. Commun. 2017, 53, 12584−12587. (f) Huang, P.-Q.; Huang, Y.-H. Chin. J. Chem. 2017, 35, 613−620. (g) Huang, P.-Q.; Huang, Y.-H.; Wang, S.R. Org. Chem. Front. 2017, 4, 431−444. (h) Huang, P.-Q.; Ou, W. Eur. J. Org. Chem. 2017, 2017, 582−592. (i) Zheng, J.-F.; Hu, X.-N.; Xu, Z.; Cai, D.-C.; Shen, T.-L.; Huang, P.-Q. J. Org. Chem. 2017, 82, 9693−9703. (j) Huang, P.-Q.; Geng, H. Green Chem. 2018, 20, 593− 599. (k) Wang, A.-E; Yu, C.-C.; Chen, T.-T.; Liu, Y.-P.; Huang, P.-Q. Org. Lett. 2018, 20, 999−1002. (l) Hu, X.-N.; Shen, T.-L.; Cai, D.-C.; Zheng, J.-F.; Huang, P.-Q. Org. Chem. Front. 2018, 5, 2051−2056. (7) (a) Luo, S.-P.; Peng, Q.-L.; Xu, C.-P.; Wang, A.-E; Huang, P.-Q. Chin. J. Chem. 2014, 32, 757−770. (b) Peng, Q.-L.; Luo, S.-P.; Xia, X.E.; Liu, L.-X.; Huang, P.-Q. Chem. Commun. 2014, 50, 1986−1988. (c) Xu, C.-P.; Luo, S.-P.; Wang, A.-E; Huang, P.-Q. Org. Biomol. Chem. 2014, 12, 2859−2863. (d) Mao, Z.-Y.; Geng, H.; Zhang, T.-T.; Ruan, Y.-P.; Ye, J.-L.; Huang, P.-Q. Org. Chem. Front. 2016, 3, 24−37. (8) (a) Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 2995−2998. (b) Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 2993−2995. (c) Kamenecka, T. M.; Danishefsky, S. J. Chem. - Eur. J. 2001, 7, 41−63. (d) Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 7119−7137. (9) Rainka, M. P.; Aye, Y.; Buchwald, S. L. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5821−5823. (10) (a) Xie, W.; Jiang, G.; Liu, H.; Hu, J.; Pan, X.; Zhang, H.; Wan, X.; Lai, Y.; Ma, D. Angew. Chem., Int. Ed. 2013, 52, 12924−12927. (b) Wang, M.; Feng, X.; Cai, L.; Xu, Z.; Ye, T. Chem. Commun. 2012, 48, 4344−4346. (11) Umehara, A.; Ueda, H.; Tokuyama, H. Org. Lett. 2014, 16, 2526−2529. (12) For determining absolute structure based on Flack parameter, see: Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143−1148. (13) (a) Duhamel, P.; Kotera, M. J. Org. Chem. 1982, 47, 1688− 1691. (b) Duhamel, P.; Kotera, M.; Monteil, T.; Marabout, B.; Davoust, D. J. Org. Chem. 1989, 54, 4419−4425. (c) Zhang, H.; Ma, X.; Kang, H.; Hong, L.; Wang, R. Chem. - Asian J. 2013, 8, 542−545. D

DOI: 10.1021/acs.orglett.8b01579 Org. Lett. XXXX, XXX, XXX−XXX