Application of a Ruthenium-Catalyzed Allylation–Cycloisomerization Cascade to the Synthesis of (±)-Herbindole A

Abstract

A short and efficient total synthesis of the cytotoxic cyclopent[g]indole alkaloid (±)-herbindole A from dihydromesitylene has been achieved by incorporating a ruthenium-catalyzed allylation–cycloisomerization cascade reaction as the key step. The protocol has also been applied to the synthesis of the unnatural trans-epimer of the marine natural product.

Transition-metal-catalyzed cascade reactions starting with relatively simple subunits produce molecular complexity and are thus particularly suitable for the preparation of natural products and analogues as important lead structures in drug discovery. These reactions provide an atom-economical approach to the rapid synthesis of complex molecular scaffolds from readily available starting materials.[1] An exceptionally broad range of transition-metal-catalyzed transformations was reported for acyclic compounds containing ene and yne fragments.[2] Thereof, the 1-alkenyl propargyl alcohols are particularly easily accessible from α,β-unsaturated aldehydes or ketones. A broad range of transition-metal-catalyzed conversions of this motif have been reported.[2a]

As part of our continuing interest in the development of new transition-metal-catalyzed cascade reactions, we discovered that bifunctional ruthenium cyclopentadienone complexes such as catalyst A (Scheme [1]) catalyze allyl­ation–cycloisomerization sequences of 1-alkenyl propargyl alcohols and various nucleophiles to yield diverse carbo- and heterocyclic products.[3] Highly substituted indoles were obtained from pyrrole as the nucleophilic compound.[3d] Herein, we describe the application of this new ruthenium-catalyzed cascade reaction to the total synthesis of the polyalkylated cyclopent[g]indole alkaloid herbindole A (1) as the key step (Scheme [1]).

Herbindole A is one of three 6,7-benzannulated indole natural products that were isolated from the Western Australian sponge Axinella sp. in 1990.[4a] The herbindoles are pseudoenantiomeric to the closely related trikentrins, which were isolated in 1986.[4b] Herbindole A was reported to exhibit cytotoxic activity against KB cells (5 μg/mL) and to act as fish antifeedant.[4a] Since the first asymmetric total synthesis of the unnatural (+)-herbindole A, reported in 1992, three racemic and two asymmetric syntheses of the natural occurring (–)-herbindole A have been reported.[5]

Our retrosynthetic analysis of herbindole A (1) identified propargyl alcohol 2 as a suitable precursor for the ruthenium-catalyzed cascade reaction with pyrrole. The parent compound 3 could be obtained by regioselective aldolization of keto aldehyde 4. We planned to generate syn-dimethylated oxoheptanal 4 from dihydromesitylene 5 in a three-step sequence of partial dihydroxylation, hydrogenation, and oxidative diol fragmentation (Scheme [2]).

The asymmetric dihydroxylation of 5 was previously reported by Landais et al. by employing various chiral ligands.[6] They obtained the best results by using AD-mix α, leading to diol 6 in 52% yield, 60% de and 60% ee. Since we obtained a higher yield and a significantly higher diastereoselectivity from the non-asymmetric reaction with low catalyst load, we decided to develop a racemic synthesis of (±)-herbindole A (1) at this stage.

Dihydroxylation of dihydromesitylene 5 with low catalyst load furnished racemic diol 6 in good yield with high diastereoselectivity (Scheme [3]). Diol 6 was diastereoselectively hydrogenated to obtain saturated diol 7 in high yield. The stereoselectivity dropped significantly when the reaction was not directly stopped after completion. Ketoaldehyde 4 was quantitatively formed from 7 by oxidative diol fragmentation without loss of stereoselectivity. The synthesis of 4 was performed on a gram scale, and syn-building block 4 was obtained from dihydromesitylene (5) in three steps and 57% overall yield. The following 5-enol exo aldolization of ketoaldehyde 4 led to cyclopentane 8, applying the protocol of Baati et al.[7] In agreement with their investigations regarding the cyclization of 6-oxoheptanal, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) proved to be the best catalyst to promote this reaction with the desired regioselectivity. Other bases such as proline, pyrrolidine, 1,8-diaza­bicyclo[5.4.0]undec-7-ene (DBU) or acidic catalysts led to low yields, regioisomeric products or complex mixtures. Aldol product 8 was obtained in the form of four inseparable diastereomers in a 10:4:2:1 ratio. Acidic dehydration of the crude aldol product 8 generated the desired cyclopentene 3 in good yield and moderate diastereoselectivity of 4:1 favoring the cis-isomer 3a. The loss of stereoselectivity presumably occurs at the stage of the aldehyde 4, which is already enolized under the weakly basic conditions of the aldolization step. Unfortunately, all further attempts to optimize the stereochemical outcome of this cyclization by varying the amount or nature of the base, the solvent or the temperature failed. In contrast, combination of the aldolization step with a subsequent elimination of a trifluoroacetate generated in situ in a one-pot process furnished cyclopentene 3 in a 2:1 ratio favoring the sterically less demanding trans-isomer 3b. Reversal of the dr compared to 4 could be rationalized by thermodynamic enolization of enone 3 when strong bases are applied, but isomerization of pure 3a in the presence of DBU (20 mol-%) in tetrahydrofuran (THF) at room temperature was not observed. However, ethynylation of cis-diastereomer 3a generated the cyclization precursor 2 in a separable 2:1 ratio and 73% yield. Since both diastereomers of 2 are suitable precursors for the final ruthenium-catalyzed allylation–cycloisomerization cascade, the mixture was further converted to furnish (±)-herbindole A (1) in 76% yield.[8] In total, (±)-herbindole A (1) was generated from dihydromesitylene in seven steps with an overall yield of 22% (Scheme [3]).

The trans-diastereomer of enone 3, which was generated from ketoaldehyde 4 in 40% yield, is a suitable precursor for (±)-epi-herbindole A (10; Scheme [4]). Ethynylation of 3b generated the propargyl alcohols 9 in 71% yield with a dr of 2:1. Final ruthenium-catalyzed conversion of the diastereomeric mixture 9 with pyrrole led to (±)-epi-herbindole A (10) in 71% yield and an overall yield of 11% from dihydromesitylene.

In conclusion, we have demonstrated short and efficient total syntheses of (±)-herbindole A and (±)-epi-herbindole A, which were achieved by using a ruthenium-catalyzed allylation–cycloisomerization cascade reaction. It is the first application of this methodology in total synthesis. Compared with previously published routes to herbindole A,[5] our synthetic strategy leads to the second highest overall yield reported, makes use of very simple starting materials, does not require any protecting groups, and involves the least number of steps. We are convinced that transition-metal-catalyzed cascade transformations will be of significant utility for natural product synthesis and drug discovery.

Acknowledgment

Financial support by the Deutsche Forschungsgemeinschaft (DFG, HA 3554/7-1) is gratefully acknowledged.

• References

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• 8 Procedure for the Ruthenium-Catalyzed Key Step: 2-(cis-3,5-Dimethylcyclopent-1-en-1-yl)but-3-yn-2-ol (2; 150 mg, 0.91 mmol) and catalyst A (9 mg, 0.018 mmol) were dissolved in toluene (2 mL) and pyrrole (65 mg, 0.97 mmol) and a solution of TFA in toluene (0.04 M, 0.45 mL) were subsequently added. The mixture was heated for 5 min at 200 °C using microwave irradiation. Evaporation of the solvent and flash chromatography on silica (pentane/Et₂O) furnished the purified product 1 (148 mg, 76%) as a slightly yellow powder. ¹H NMR (600 MHz, CDCl₃): δ = 1.34 (d, J = 7.1 Hz, 3 H), 1.44 (d, J = 7.2 Hz, 3 H), 1.54 (dt, J = 13.0, 2.1 Hz, 1 H), 2.32 (s, 3 H), 2.47 (s, 3 H), 2.69 (dt, J = 13.0, 9.1 Hz, 1 H), 3.38–3.43 (m, 1 H), 3.43–3.49 (m, 1 H), 6.54 (dd, J = 3.2, 2.1 Hz, 1 H), 7.12 (dd, J = 3.2, 2.3 Hz, 1 H), 7.92 (br. s, NH). ¹³C NMR (150 MHz, CDCl₃): δ = 15.5 (CH₃), 15.8 (CH₃), 23.0 (CH₃), 24.0 (CH₃), 37.3 (CH), 39.3 (CH), 42.0 (CH₂), 101.8 (CH), 123.0 (CH), 123.4 (C), 126.6 (C), 126.8 (C), 127.9 (C), 130.7 (C), 142.2 ppm (C). IR: 3410 (w), 2955 (m), 2925 (m), 2865 (m), 1692 (w), 1655 (m), 1598 (w), 1447 (m), 1372 (w), 1316 (w), 1278 (m), 1073 (w), 723 (m), 701 (s), 638 (m) cm^–1. MS (EI): m/z (%) = 214 (38) [M⁺ + 1], 213 (45) [M⁺], 199 (75), 198 (100), 183 (30), 182 (32), 105 (29). HRMS: m/z [M⁺] calcd for C₁₅H₁₉N: 213.1517; found: 213.1517.

• References

• 1a Wang Y, Zhang L, Lu P, Gao H, Zhang J, Xu P.-F, Wei H In Catalytic Cascade Reactions . Xu P.-F, Wang W. John Wiley & Sons; Hoboken: 2014: 145-331
  Search in Google Scholar
• 1b Negishi E.-I, Wang G, Zhu G, von Zezschwitz P, De Meijere A, Patil NT, Yamamoto Y, Balme G, Bouyssi D, Monteiro N, Müller TJ. J, Pérez-Castells J, Aubert C, Fensterbank L, Gandon V, Malacria M, Bruneau C, Dérien S, Dixneuf PH In Metal Catalyzed Cascade Reactions . Müller TJ. J. Springer; Berlin: 2006: 1-340
  CrossrefSearch in Google Scholar
• 1c Tietze LF, Brasche B, Gericke K In Domino Reactions in Organic Synthesis . Wiley-VCH; Weinheim: 2006: 359-493
  CrossrefSearch in Google Scholar
• 1d Kumar K In Concepts and Case Studies in Chemical Biology . Waldmann H, Janning P. Wiley-VCH; Weinheim: 2014: 391-414
  Search in Google Scholar
• 1e Nicolaou KC, Edmonds DJ, Bulger PB. Angew. Chem. Int. Ed. 2006; 43: 7134 ; Angew. Chem. 2006, 118, 7292
  Search in Google Scholar
• 1f Jones AC, May JA, Sarpong R, Stoltz BM. Angew. Chem. Int. Ed. 2014; 53: 2556 ; Angew. Chem. 2014, 126, 2590
  CrossrefPubMedSearch in Google Scholar
• 2a Haak E.; Eur. J. Org. Chem.; 2016, in press; DOI: 10.1002/ejoc.201601076.
• 2b Kumari AL. S, Reddy AS, Swamy KC. K. Org. Biomol. Chem. 2016; 14: 6651
  CrossrefPubMedSearch in Google Scholar
• 2c Watson ID. G, Toste FD. Chem. Sci. 2012; 3: 2899
  Search in Google Scholar
• 2d Pérez-Galán P, López-Carrillo V, Echavarren AM. Contrib. Sci. 2010; 6: 143
  Search in Google Scholar
• 2e Jiménez-Núñez E, Echavarren AM. Chem. Rev. 2008; 108: 3326
  Search in Google Scholar
• 2f Michelet V, Toullec PY, Genêt J.-P. Angew. Chem. Int. Ed. 2008; 47: 4268 ; Angew. Chem. 2008, 120, 4338
  Search in Google Scholar
• 2g Zhang L, Sun J, Kozmin SA. Adv. Synth. Catal. 2006; 348: 2271
  Search in Google Scholar
• 2h Bruneau C, Dérien S, Dixneuf PH. Top. Organomet. Chem. 2006; 19: 295
  Search in Google Scholar
• 3a Thies N, Haak E. Angew. Chem. Int. Ed. 2015; 54: 4097 ; Angew. Chem. 2015, 127, 4170
  CrossrefPubMedSearch in Google Scholar
• 3b Thies N, Gerlach M, Haak E. Eur. J. Org. Chem. 2013; 7354
• 3c Jonek A, Berger S, Haak E. Chem. Eur. J. 2012; 18: 15504
  CrossrefPubMedSearch in Google Scholar
• 3d Thies N, Hrib CG, Haak E. Chem. Eur. J. 2012; 18: 6302
  CrossrefSearch in Google Scholar
• 4a Herb R, Carroll AR, Yoshida WY, Scheuer PJ. Tetrahedron 1990; 46: 3089
  CrossrefSearch in Google Scholar
• 4b Capon RJ, MacLeod JK, Scammells PJ. Tetrahedron 1986; 42: 6545
  CrossrefSearch in Google Scholar
• 5a Chandrasoma N, Pathmanathan S, Buszek KR. Tetrahedron Lett. 2015; 56: 3507
  CrossrefSearch in Google Scholar
• 5b Saito N, Ichimaru T, Sato Y. Org. Lett. 2012; 14: 1914
  CrossrefPubMedSearch in Google Scholar
• 5c Buszek KR, Brown N, Luo D. Org. Lett. 2009; 11: 201
  CrossrefPubMedSearch in Google Scholar
• 5d Jackson SK, Kerr MA. J. Org. Chem. 2007; 72: 1405
  CrossrefPubMedSearch in Google Scholar
• 5e Muratake H, Mikawa A, Saino T, Natsume M. Chem. Pharm. Bull. 1994; 42: 854
  CrossrefSearch in Google Scholar
• 5f Muratake H, Mikawa A, Natsume M. Tetrahedron Lett. 1992; 33: 4595
  CrossrefSearch in Google Scholar
• 6a Landais Y, Zekri E. Eur. J. Org. Chem. 2002; 4037
• 6b Landais Y, Zekri E. Tetrahedron Lett. 2001; 42: 6547
  CrossrefSearch in Google Scholar
• 7a Ghobril C, Sabot C, Mioskowski C, Baati R. Eur. J. Org. Chem. 2008; 4104
• 7b Hammar P, Ghobril C, Antheaume C, Wagner A, Baati R, Himo F. J. Org. Chem. 2010; 75: 4728
  CrossrefPubMedSearch in Google Scholar
• 8 Procedure for the Ruthenium-Catalyzed Key Step: 2-(cis-3,5-Dimethylcyclopent-1-en-1-yl)but-3-yn-2-ol (2; 150 mg, 0.91 mmol) and catalyst A (9 mg, 0.018 mmol) were dissolved in toluene (2 mL) and pyrrole (65 mg, 0.97 mmol) and a solution of TFA in toluene (0.04 M, 0.45 mL) were subsequently added. The mixture was heated for 5 min at 200 °C using microwave irradiation. Evaporation of the solvent and flash chromatography on silica (pentane/Et₂O) furnished the purified product 1 (148 mg, 76%) as a slightly yellow powder. ¹H NMR (600 MHz, CDCl₃): δ = 1.34 (d, J = 7.1 Hz, 3 H), 1.44 (d, J = 7.2 Hz, 3 H), 1.54 (dt, J = 13.0, 2.1 Hz, 1 H), 2.32 (s, 3 H), 2.47 (s, 3 H), 2.69 (dt, J = 13.0, 9.1 Hz, 1 H), 3.38–3.43 (m, 1 H), 3.43–3.49 (m, 1 H), 6.54 (dd, J = 3.2, 2.1 Hz, 1 H), 7.12 (dd, J = 3.2, 2.3 Hz, 1 H), 7.92 (br. s, NH). ¹³C NMR (150 MHz, CDCl₃): δ = 15.5 (CH₃), 15.8 (CH₃), 23.0 (CH₃), 24.0 (CH₃), 37.3 (CH), 39.3 (CH), 42.0 (CH₂), 101.8 (CH), 123.0 (CH), 123.4 (C), 126.6 (C), 126.8 (C), 127.9 (C), 130.7 (C), 142.2 ppm (C). IR: 3410 (w), 2955 (m), 2925 (m), 2865 (m), 1692 (w), 1655 (m), 1598 (w), 1447 (m), 1372 (w), 1316 (w), 1278 (m), 1073 (w), 723 (m), 701 (s), 638 (m) cm^–1. MS (EI): m/z (%) = 214 (38) [M⁺ + 1], 213 (45) [M⁺], 199 (75), 198 (100), 183 (30), 182 (32), 105 (29). HRMS: m/z [M⁺] calcd for C₁₅H₁₉N: 213.1517; found: 213.1517.

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