Total Synthesis of (+)-Gliocladin C Based on One-Pot Construction of

Letter Cite This: Org. Lett. 2017, 19, 6582−6585

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Total Synthesis of (+)-Gliocladin C Based on One-Pot Construction of a 3a-(3-Indolyl)pyrroloindoline Skeleton by Sulfonium-Mediated Cross-Coupling of Tryptophan and Indole Masanori Tayu, Yi Hui, Shiori Takeda, Kazuhiro Higuchi,* Nozomi Saito,* and Tomomi Kawasaki* Meiji Pharmaceutical University, Kiyose, Tokyo 204-8588, Japan S Supporting Information *

ABSTRACT: Total synthesis of (+)-gliocladin C has been achieved on the basis of one-pot construction of the 3a-(3indolyl)pyrroloindoline core structure by the cross-coupling of a tryptophan derivative and an indole promoted by a sulfonium species generated from dialkylsulfoxide and triflic anhydride.

T

he 3a-(3-indolyl)pyrroloindoline core 1 is a frequently found key structure in a large family of pyrroloindoline alkaloids, which are known to show unique biological activities such as anti-bacterial activities, anti-nematicidal activities, and anti-cancer activities (Figure 1, 1).1 Among the 3a-(3-

Figure 1. 3a-(3-Indolyl)pyrroloindoline core 1 and (+)-gliocladin C (2).

Figure 2. Outline of two synthetic methods to construct the 3a-(3indolyl)pyrroloindoline framework.

indolyl)pyrroloindoline alkaloids, (+)-gliocladin C (2) was isolated from a strain of Gliocladium roseum in 2004 and was revealed to exert cytotoxicity against P388 lymphocytic leukemia cells.2a It has also attracted the attention of many synthetic organic chemists because of its rather unique structure including a trioxopiprazine unit. Since Overman’s group demonstrated the first total synthesis of 2 in 2007,3a the results of several synthetic studies of 2 have been reported.3−5 The crucial points for the construction of the 3a-(3indolyl)pyrroloindoline framework of 2 are (1) how to install a 3-indolyl group into the C3a position of 1 and (2) how to form a pyrroloindoline core structure. In previously reported total syntheses, there were two main types of methods (Figure 2). The first one was a method via intramolecular reductive amination of aminoethyloxindole bearing a 3-indolyl group, and Overman,3a,b Gong,3e and Martin’s groups5 employed this route in their synthesis (eq 1). On the other hand, Stephenson3c and Moavassaghi’s groups3d conducted construction of a pyrroloindoline skeleton first by bromoniumspecies-mediated cyclization of a tryptamine derivative (eq 2), and then they introduced a 3-indolyl group into the C3a © 2017 American Chemical Society

position by a substitution reaction to give the 3a-(3indolyl)pyrroloindoline derivative. Recently, we developed a method for one-pot construction of a 3a-(3-indolyl)pyrroloindoline skeleton 6 by sulfoniumspecies-promoted cross-coupling of tryptamine derivatives 3 and indoles 5 (Scheme 1).6 Thus, tryptamine derivative 3 reacted with the sulfonium salt 4 generated from DMSO and Tf2O to give the iminium species 7, from which intramolecular cyclization proceeded to afford pyrroloindoline intermediate 8. Finally, substitution reaction with indole 5 on the C3a position of 8 occurred, and 3a-(3-indolyl)pyrroloindoline derivative 6 was produced. With this as a background, we planned a total synthesis of (+)-gliocladin C (2) based on our 3a-(3-indolyl)pyrroloindoline one-pot construction strategy. Retrosynthetic analysis of 2 is shown in Scheme 2. A trioxopiperazine moiety would be Received: October 23, 2017 Published: December 5, 2017 6582

DOI: 10.1021/acs.orglett.7b03293 Org. Lett. 2017, 19, 6582−6585

Letter

Organic Letters Scheme 1. Sulfonium Species-Mediated Cross-Coupling Reaction of Tryptamine Derivatives and Indole

Scheme 3. Sulfonium-Species-Mediated 3a-(3-Indolyl)pyrroloindoline Construction

Scheme 2. Retrosynthetic Analysis of (+)-Gliocladin C (2)

Table 1. Investigation of Substituent Effects on Diastereoselectivitya

entry

18 (R1)

13 (R2, R3, R4)

yield (%, 16:17)b

1 2 3 4 5 6 7 8 9

18a (nBu) 18b (iPr) 18c (iBu) 18d (tBu) 18b (iPr) 18b (iPr) 18b (iPr) 18b (iPr) 18b (iPr)

13a (Me, CO2Me, CO2Me) 13a (Me, CO2Me, CO2Me) 13a (Me, CO2Me, CO2Me) 13a (Me, CO2Me, CO2Me) 13b (allyl, CO2Me, CO2Me) 13c (Bn, CO2Me, CO2Me) 13d (Bn, Boc, CO2Me) 13e (Bn, CO2Me, CO2Bn) 13f (Bn, CO2Me, CO2tBu)

16a + 17a: 87 (3.5:1) 16a + 17a: 86 (4.1:1) 16a + 17a: 90 (3.2:1) not detectedc 16b + 17b: 71 (5.1:1) 16c + 17c: 93 (6.7:1) 16d + 17d: 17 (1.6:1) 16e + 17e: 74 (5.3:1) 16f + 17f: 69 (2.6:1)

a

Conditions: R12SO (1 equiv), Tf2O (1 equiv), DTBP (2 equiv), CH2Cl2 ([13] = 0.2 M). bThe ratio of 16 to 17 was determined by HPLC analysis. cStarting material L-13a was recovered in quantitative yield.

synthesized by condensation of imine 9 and glyoxylate 10 by using Stephenson’s method.3c Imine 9 was expected to be obtained by the oxidation of amine 11, which could be synthesized from ester 12 via deprotection followed by amination. Finally, 3a-(3-indolyl)pyrroloindoline 12 should be obtained by the sulfonium-species-mediated cross-coupling of D-tryptophan derivative D-13 and indole (14). To examine the feasibility of this plan, the reaction of cheap and readily available L-tryptophan derivative L-13a and Nmethylindole (15) was investigated (Scheme 3). To a solution of L-13a and DMSO in CH2Cl2 were added Tf2O and 2,6-ditert-butylpyridine (DTBP) at −78 °C. After checking the disappearance of L-13a by TLC analysis, N-methylindole (15) was added to the reaction mixture. As a result, the desired 3a(3-indolyl)pyrroloindoline derivatives 16a and 17a were obtained in a total yield of 69% in a ratio of 2.7 to 1 (Scheme 3).7,8 Next, we investigated the effects of substituents of reagents and substrates on the diastereoselectivity (Table 1). First, the effects of sulfoxide reagents were examined (entries 1−4). Several dialkylsulfoxides 18 were tested using 13a as a substrate, and it was found that bulky di(isopropyl)sulfoxide (18b) gave the best diastereoselectivity. It was also found that introduction of a bulkier protecting group to the nitrogen atom

on the indole ring in 13 improved the diastereoselectivity (entries 5 and 6), and the reaction of Na-benzyltryptophan derivative 13c using sulfoxide 18b provided the pyrroloindoline derivatives 16c and 17c in a ratio of 6.7 to 1 (entry 6). On the other hand, changing the substituents on the side chain of tryptophan (13d−13f) was not so effective for improvement of the diastereoselectivity (entries 7−9). With optimized conditions in hand (Table 1, entry 6), Dtryptophan derivative D-13c was reacted with indole (14) by using the sulfonium species generated from iPr2SO (18b) and Tf2O (Scheme 4). As a result, desired 3a-(3-indolyl)pyrroloindoline 19 and its diastereomer 20 were obtained in yields of 70% and 7%, respectively. We next investigated transformation of the ester moiety of 19 to N-methylamide 21 (Scheme 5). However, the reaction of 19 and methylamine was not fruitful, and 21 was not obtained under any reaction conditions. Since both the 3-indolyl group and the methoxycarbonyl group on the pyrrolidine ring were thought to prevent the nucleophilic attack of methylamine to the ester carbonyl group at the C2 position, epimerization of 19 was investigated in order to reduce such steric hindrance. When 19 was treated with s-BuLi, epimerization of 19 occurred to 6583


Letter

Organic Letters

(+)-gliocladin C (2) was synthesized by deprotection of the Nbenzyl group under Birch reduction conditions. In summary, we have achieved total synthesis of (+)-gliocladin C (2). The key reactions of the total synthesis were cascade cyclization of a tryptophan derivative and installation of a 3-indolyl group into the C3a position of pyrroloindoline promoted by a sulfonium species generated from dialkylsulfoxide and triflic anhydride. The 3a-(3-indolyl)pyrroloindoline core structure of 2 could be efficiently constructed in one pot.

Scheme 4. Construction of 3a-(3-Indolyl)pyrroloindoline from D-Tryptophan Derivative

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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.7b03293. Experimental details and characterization data (PDF)

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Scheme 5. Functional Group Transformation from 19 via Epimerization

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Nozomi Saito: 0000-0003-3472-0391 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from JSPS KAKENHI Grant Number 17K15427. We also thank N. Eguchi, T. Koseki, and S. Yamada at the Analytical Center of our university for performing microanalysis, NMR, and mass spectrometry measurements.

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give the corresponding epimer 22 in quantitative yield.9 As expected, the reaction of 22 and N-methylamine proceeded smoothly to give 23 in 71% yield. The methoxycarbonyl group on the pyrrolidine ring of 23 was removed with iodotrimethylsilane to give 24, which was oxidized by treatment of NCS followed by addition of DBU (Scheme 6).10 Resulting imine 25 was condensed with chloroglyoxylate,3c to produce trioxopiperazine 26. Finally,

REFERENCES

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Scheme 6. Synthesis of (+)-Gliocladin C (2) from 23

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Organic Letters M.; Hao, X.-Y.; Liu, S.; Hao, X.-J. Tetrahedron Lett. 2013, 54, 692. (c) Jing, C.; Xing, D.; Wang, C.; Hu, W. Tetrahedron 2015, 71, 3597. (d) Hajra, S.; Maity, S.; Maity, R. Org. Lett. 2015, 17, 3430. (e) Zhu, G.; Bao, G.; Li, Y.; Sun, W.; Li, J.; Hong, L.; Wang, R. Angew. Chem., Int. Ed. 2017, 56, 5332. (f) Lei, H.; Wang, L.; Xu, Z.; Ye, T. Org. Lett. 2017, 19, 5134. (5) For examples of total synthesis of racemic gliocladin C, see: Hodges, T. R.; Benjamin, N. M.; Martin, S. F. Org. Lett. 2017, 19, 2254. (6) (a) Tayu, M.; Higuchi, K.; Ishizaki, T.; Kawasaki, T. Org. Lett. 2014, 16, 3613. (b) Tayu, M.; Ishizaki, T.; Higuchi, K.; Kawasaki, T. Org. Biomol. Chem. 2015, 13, 3863. (c) Tayu, M.; Suzuki, Y.; Higuchi, K.; Kawasaki, T. Synlett 2016, 27, 941. (7) Stereochemistry of all 3a-(3-indolyl)pyrroloindoline derivatives was determined by analysis of 1H NMR spectral data; see: Supporting Information. (8) Similar selectivity was observed in pyrroloindoline formation by cyclization of a tryptophan derivative; see: (a) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151. (b) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953. (c) López, C. S.; Pérez-Balado, C.; Rodríguez-Graña, P.; de Lera, Á . R. Org. Lett. 2008, 10, 77. (9) The epimerization of 19 did not proceed using other bases such as DBU, tBuOK, NaOMe, and NaH. (10) Iizuka, T.; Takiguchi, S.; Kumakura, Y.; Tsukioka, N.; Higuchi, K.; Kawasaki, T. Tetrahedron Lett. 2010, 51, 6003.

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Total Synthesis of (+)-Gliocladin C Based on One-Pot Construction of

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