Letter pubs.acs.org/OrgLett
Total Synthesis and Absolute Configuration of Raputindole A Mario Kock, Peter G. Jones, and Thomas Lindel* TU Braunschweig, Institute of Organic Chemistry, Hagenring 30, 38106 Braunschweig, Germany S Supporting Information *
ABSTRACT: The first total synthesis of the bisindole alkaloid raputindole A from the rutaceous plant Raputia simulans is reported. The key step is a Au(I)-catalyzed cyclization that assembles the cyclopenta[f ]indole tricycle from a 6-alkynylated indoline precursor. The isobutenyl side chain was installed by Suzuki−Miyaura cross-coupling, followed by a regioselective reduction employing LiDBB. Starting from 6-iodoindole, the sequence needs nine steps and provided (±)-raputindole A in 6.6% overall yield. The absolute configuration of the natural product (+)-raputindole A was determined by quantum chemical calculation of the ECD spectrum.
A
and allenyl acetates via one 3,3-shift or two consecutive 1,2shifts of the acetoxy group.8 In the area of natural product synthesis, Lee et al. published the formal synthesis of the cyclopenta[g]indole derivative herbindole B via Au(I)-catalyzed cyclization of an N-tosylindoline-derived propargylacetate.9 Scarpi, Occhiato, and co-workers achieved the Au(I)-catalyzed pentannulation at an enamine moiety, obtaining cyclopenta[b]indolones that were converted to the bruceollines H and I.10 Our total synthesis of (±)-raputindole A (rac-1) was to start from N-TIPS-6-iodoindoline (5, Scheme 1).6 Four C−C
mong alkaloids derived from prenylated indole-based precursors, the raputindoles (1−4, Figure 1) from the
Scheme 1. Synthesis of the Tricyclic Core of Raputindole A and Introduction of the Isobutenyl Side Chain
Figure 1. Bisindole alkaloids raputindole A−D (1−4) from the Amazonian tree Raputia simulans.
rutaceous tree Raputia simulans Kallunki are unique because they are dimeric and feature a rare cyclopenta[f ]indole tricyclic partial structure.1 In addition to compounds 1−4, nodulisporic acids,2 the shearinines3 and janthitrems4 also contain a cyclopenta[f ]indole partial structure. Cyclopenta[f ]indole systems have been accessed from indene-based starting materials.5 We felt that a different strategy exploiting indole derivatives should be developed. Recently, we reported the synthesis of cyclopenta[f ]indolin7-ones from propargyl acetates employing Au(I) catalysis, which proved to be more efficient than the Lewis acid induced cyclization of 6-hydroxyallylated indoles.6 Cyclopentannulation starting from propargyl acetates had first been described by Nolan and co-workers in 2006, who obtained indene derivatives and also found acetoxyallenes behaving in a similar manner.7 Cavallo, Nolan, and co-workers showed that Au(I) catalyzes the interconversion of propargyl © 2017 American Chemical Society
couplings were planned, beginning with the alkynylation at C6, followed by Au(I)-catalyzed cyclopentannulation, introduction of the isobutenyl side chain, and incorporation of the second indole unit. Sonogashira coupling of commercially available enynol 6 with N-TIPS-6-iodoindoline (5) and subsequent acetylation of the alcohol gave cyclization precursor Received: September 27, 2017 Published: November 17, 2017 6296
DOI: 10.1021/acs.orglett.7b03014 Org. Lett. 2017, 19, 6296−6299
Letter
Organic Letters
analyses, indicating that the configuration of the secondary stereogenic center had remained unchanged. The overall replacement of the acetoxy by the aryl group at the quaternary center had proceeded largely with inversion of configuration. In both experiments, the de values of the products were lower than that of the noncyclized precursors. The mirror-like product ratios suggest that the stereochemical outcome of the Au(I)-catalyzed cyclization depended only on the configuration of the quaternary center. The formation of diastereomers 10a and 10b is in agreement with competing reaction pathways, of which one involves a stereospecific 3,3-acetoxy shift, whereas the other proceeds in a nonstereospecific manner via two consecutive 1,2-acetoxy shifts (Scheme 3).8 In the latter case, an allyl cation (11) should be
7 in excellent yield over two steps (Scheme 1). Handling of the resulting allyl acetate 7 had to strictly avoid heating over 30 °C in order to prevent Claisen rearrangement to the conjugated enyne. Cyclization of propargyl acetate 7 under optimized conditions,11 including sonication to activate the Au(I)-catalyst and filtration through Celite to remove excess silver salts, followed by methanolysis afforded cyclopenta[f ]indoline 8 in very good yield (85%, Scheme 1) and complete regioselectivity. This regioselectivity is retained even without the bulky N-TIPS group. However, electron-deficient N-tosylindoline only gave a tosylindolinyl cyclopentenone in poor yield (see the Supporting Information). The cyclization is initiated by Au(I) activation of alkyne 7, followed by either a 3,3-migration or two consecutive 1,2migrations of the acetoxy group to give an allene intermediate, as investigated by Cavallo, Nolan, and co-workers for the case of 2-methylbut-3-yn-2-yl acetate.8 Nucleophilic attack of the indoline 5-position at the Au(I)-activated allene would lead to cyclization, followed by rearomatization and protodeauration affording product 8. Scheme 2 shows an experiment that supports the existence of both pathways in our case. Diastereomeric propargyl acetates
Scheme 3. Proposed First Steps of the Mechanism of the Au(I)-Catalyzed Cyclization, Outlined for Diastereomer 9b
Scheme 2. Au(I)-Catalyzed Cyclization of Diastereomeric Propargyl Esters 9a and 9b Affording Cyclopenta[f ]indolines 10a and 10b and X-ray Structure of Diastereomer 10aa
a
formed after the first 1,2-acetoxy shift that leaves room for the formation of the two diastereomeric intermediates 12 and 13, which could undergo Nazarov-type cyclizations to the tricyclic vinyl acetates preceding 10a and 10b, respectively. Toward raputindole A (1), the isobutenyl side chain had to be introduced (Scheme 4). Attempts to utilize the carbonyl function of ketone 8 by reaction with organometallic species, Wittig-type reactions, reduction followed by Mitsunobu reaction, Corey−Chaykovsky reaction, or conversion to the benzyl bromide12 failed due to poor reactivity or product lability. However, vinyl triflate 14 was accessible by αdeprotonation with LHMDS and trapping of the enolate with PhNTf2. In the event, it turned out that the subsequent cross coupling required the removal of the bulky TIPS protecting group. Desilylation with aqueous HCl during workup gave the unprotected indoline vinyl triflate 15 in very good yield. Suzuki−Miyaura coupling of 15 with isobutenyl tetrafluoroborate (16)13 at 70 °C afforded the desired indoline-based triene 17 in good yield and short reaction time. The internal indene double bond of 17 had to be reduced selectively in the presence of the isobutenyl and vinyl side chains. Under conditions of heterogeneous catalytic hydrogenation the order of reactivity proved to be opposite. There are reports that Birch reaction with lithium metal had been selective toward benzylic double bonds.14 Indeed, treatment of triene 17 with lithium 4,4′-di-tert-butyldiphenylide (LiDBB) and 2,6-di-tert-butylphenol as a sterically demanding proton source15 in THF at −78 °C gave the desired product 19 in 73% yield (dr = 1:1, Scheme 4). The diastereomers were not separable by column chromatography at this stage. In addition,
Hydrogens omitted for clarity.
9a and 9b were obtained via nucleophilic addition of lithiated N-TIPS-6-ethynylindoline to (S)-3-(benzyloxy)butan-2-one, followed by acetylation and separation by chromatography (9a:9b 10:1 and 1:23, respectively; see the Supporting Information). Au(I)-catalyzed cyclization of each of the diastereomers 9a and 9b, followed by methanolysis, afforded diastereomeric cyclopenta[f ]indolinones 10a and 10b in ratios of 5:2 and 2:5, respectively. The relative (and absolute) configurations of 10a and 10b were determined by X-ray 6297
DOI: 10.1021/acs.orglett.7b03014 Org. Lett. 2017, 19, 6296−6299
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Organic Letters
measured (MeOH) and gave expected mirror image spectra (see the Supporting Information). We performed a quantum-chemical calculation of the ECD spectrum of (+)-raputindole A (1). MMFF calculations showed that 19 conformers possessed a relative energy within a 3 kcal/ mol range with respect to the most stable one. The conformers were then optimized by DFT calculations at the CAM-B3LYP/ LanL2DZ level in methanol (PCM) using Gaussian 09.16 The resulting eight remaining conformers (3 kcal/mol range, not identical) were submitted to TDDFT calculations at the CAMB3LYP/LanL2DZ level followed by plotting of their UV and ECD spectra utilizing SpecDis v1.70.1.17 The eight ECD spectra were Boltzmann-weighted, summed, and UV-corrected to give the spectrum depicted in Figure 2. The calculated spectrum is in good agreement with the experimental one. We conclude that the absolute configuration of (+)-raputindole A (1) is (5R,7R).
Scheme 4. Regioselective Reduction of Cyclopenta[f ]indoline 17 and Access to (±)-Raputindole A (rac-1)
Figure 2. Experimental (black) and calculated (red, 5R,7Rconfiguration, graph scaled) ECD spectra of (+)-raputindole A (1) in methanol.
side products were observed in the 10% range that resulted from protonation of the intermediate benzyl radical anion 18 at the allylic position and from a subsequent reduction of the incipient exocyclic benzylic double bond (see the Supporting Information). The total synthesis of (±)-raputindole A (rac-1) was completed by a phosphine-free Heck reaction of alkene 19 with unprotected 6-iodoindole. Spontaneous oxidation of the indoline to the indole took place during column chromatography on silica gel to give (±)-raputindole A (rac-1) and its diastereomer rac-20 in 56% overall yield. Final purification required reversed-phase column chromatography on LiChroprep RP-18. Pure rac-1 was isolated. However, rac-20 was difficult to purify due to contamination (about 10%) with the regioisomeric Heck product. Overall, (±)-raputindole A (rac-1) was obtained in 6.6% yield over nine linear steps from N-TIPS6-iodoindoline (5). To obtain enantiomerically pure natural product we separated both enantiomers of (±)-raputindole A (rac-1) via semipreparative chiral HPLC (ChiralpakIA 250 × 10 mm, 5 μm particle size, 5 mL/min n-hexane/THF (88:12), isocratic, UVdetection at 291 nm). The optical rotatory power of synthetic (+)-raputindole A ([a]21.9 D (MeOH, c = 0.105) +90.5) was in good agreement with the literature value ([α]D (MeOH, c = 0.105) +82.8). ECD spectra of both enantiomers were
In summary, the bisindole alkaloid raputindole A (1) was synthesized in the racemic form for the first time. The cyclopenta[f ]indole tricycle was assembled by Au(I)-catalyzed cyclization from a 6-alkynylated indoline precursor, which probably proceeds via competing stereospecific 3,3-acetoxy and nonstereospecific consecutive 1,2-acetoxy shifts. Regioselective reduction employing LiDBB gave access to the indane moiety. The sequence requires nine steps and provided (±)-raputindole A in 6.6% overall yield. The absolute configuration of the natural product (+)-raputindole A was determined as (5R,7R).
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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.7b03014. Relevant experimental procedures, characterization data, and NMR spectra (PDF) Accession Codes
CCDC 1576393−1576394 contain the supplementary crystallographic data for this paper. These data can be obtained free of 6298
DOI: 10.1021/acs.orglett.7b03014 Org. Lett. 2017, 19, 6296−6299
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Organic Letters
(14) Mans, D. J.; Cox, G. A.; RajanBabu, T. V. J. Am. Chem. Soc. 2011, 133, 5776−5779. (15) Donohoe, T. J.; Headley, C. E.; Cousins, R. P. C.; Cowley, A. Org. Lett. 2003, 5, 999−1002. (16) Gaussian 09, revision A.02: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; M. Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford, CT, 2009. (17) (a) Bruhn, T.; Schaumlöffel, A.; Hemberger, Y.; Pecitelli, G. SpecDis, version 1.70.1, Berlin, Germany, 2017, https:/specdissoftware.jimdo.com, accessed November 16, 2017. (b) Bruhn, T.; Schaumlöffel, A.; Hemberger, Y.; Bringmann, G. Chirality 2013, 25, 243−249.
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 Author
*E-mail:
[email protected]. ORCID
Thomas Lindel: 0000-0002-7551-5266 Notes
The authors declare no competing financial interest.
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