Total Syntheses of Arcyriaflavin A and Calothrixin B Using 2,2

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Total Syntheses of Arcyriaflavin A and Calothrixin B Using 2,2′Bisindole-3-acetic Acid Derivative as a Common Intermediate Sungjong Lee,† Kyung-Hee Kim,† and Cheol-Hong Cheon* Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea S Supporting Information *

ABSTRACT: A new protocol for the synthesis of 2,2′-bisindole-3acetic acid derivatives from aldimines derived from 2-aminocinnamic acid derivatives and indole-2-carboxaldehyde was developed via a cyanide-catalyzed imino-Stetter reaction. With this protocol, the divergent total syntheses of arcyriaflavin A, a representative indolocarbazole natural product, and calothrixin B, a representative indolo[3,2-j]phenanthridine natural product, were completed using a 2,2′-bisindole-3-acetic acid derivative as the common intermediate.

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common building block. The structural difference between these two types of natural products is that the first type has an additional carbazole moiety, whereas the second type has a phenanthridine scaffold. Since the phenanthridine ring could be formed from the carbazole ring in the proposed biosynthetic pathway of the second type of natural products,5,6 we hypothesized that these two types of natural products could be prepared from an indolocarbazole intermediate. Herein, we describe the divergent total syntheses of arcyriaflavin A (1) and calothrixin B (2) using a 2,2′-bisindole-3-acetic acid derivative as the common intermediate. The key intermediate could be prepared from aldimine, derived from a 2-aminocinnamic acid derivative and indole-2-carboxaldehyde, by a cyanide-catalyzed imino-Stetter reaction.7 Retrosynthetic analysis for the total syntheses of arcyriaflavin A (1) and calothrixin B (2) is depicted in Scheme 1. Considering their structural features, we envisioned that both arcyriaflavin A (1) and calothrixin B (2) could be prepared from 2,2′-bisindole3-acetic acid derivative 3 as the key intermediate.8 For example, arcyriaflavin A (1) was anticipated to be obtained by the formation of a D-ring from compound 4, which could be prepared through C-ring formation from the key intermediate 3. On the other hand, the proposed biosynthetic pathway of calothrixin B (2) suggested that the indolo[3,2-j]phenanthridine scaffold present in calothrixin B could be prepared from indolocarbazole 5;5,6 hence, calothrixin B (2) was expected to be prepared from 3 through the C′-ring formation, followed by formylation. The key to the success of this approach would be the preparation of 2,2′-bisindole-3-acetic acid derivative 3.9 Very recently, our group developed a synthetic protocol for 2substituted indole-3-acetic acid derivatives from aldimines, derived from 2-aminocinnamic acid derivatives and aldehydes, via a cyanide-catalyzed imino-Stetter reaction.7 Based on this

ndolocarbazole and indolo[3,2-j]phenanthridine alkaloids have drawn considerable attention from the synthetic and pharmaceutical communities because these natural products exhibit interesting biological activities.1,2 Moreover, they possess distinct structural features. For example, arcyriaflavin A, staurosporinone, and rebeccamycin possess an indolocarbazole scaffold, while calothrixins A and B have the indolo[3,2j]phenanthridine skeleton (Figure 1).

Figure 1. Structures of indolocarbazole and indolo[3,2-j]phenanthridine natural products.

Because of the distinctive skeletal features of these two types of natural products, most of the previous total syntheses have been developed through independent synthetic routes starting from materials bearing different scaffolds,3,4,6 and there have been no reports on the synthesis of these two types of natural products from a common intermediate. Although these natural products apparently possess very different structural features, we noticed a structural similarity between them; they both have pentafused heteroaromatic structures bearing the indole moiety as the © 2017 American Chemical Society

Received: March 8, 2017 Published: May 18, 2017 2785

DOI: 10.1021/acs.orglett.7b00687 Org. Lett. 2017, 19, 2785−2788

Letter

Organic Letters

amount of cyanide (entry 2). Although 8a was completely consumed with a stoichiometric amount of cyanide, the desired product 3a was still obtained in a low yield along with an unidentifiable complex mixture. Furthermore, 3a was unstable and decomposed during the storage even at a low temperature. We suspected that a free N−H group present in the indole moiety at the 2-position of 3a might be responsible for the instability of this indole product. Thus, we decided to utilize the aldimines, derived from an N-protected indole-2-carboxaldehyde, rather than 8a, obtained from an unprotected indole-2carboxaldehyde, in this transformation. When aldimine 8b derived from N-benzyl-protected indole-2-carboxaldehyde was subjected to the imino-Stetter reaction with 10 mol % of cyanide, to our delight, the desired 2,2′-bisindole product 3b was obtained in excellent yield within only 20 min (entry 3). Under these conditions, other aldimines obtained from indole-2-carboxaldehydes bearing a different N-protecting group were explored (entries 3−5). To our delight, several N-protecting groups were well-tolerated in the imino-Stetter reaction, and the desired 2,2′bisindole products 3 were obtained in excellent yields, regardless of the electronic nature of the protecting groups. Furthermore, aldimine 8e derived from cinnamamide could be applicable to this protocol; the desired 2,2′-bisindole-3-acetamide 3e was obtained in excellent yield within a very short reaction time, albeit with the use of a stoichiometric amount of cyanide10 (entry 6). In addition, this transformation could be performed using aldimine 8b, generated in situ from ethyl 2-aminocinnamate and N-benzylindole-2-carboxaldehyde without further purification, and the 2,2′-bisindole product 3b was obtained in a similar yield (entries 3 and 7). Finally, this transformation could be performed on a 20 mmol scale without any loss of catalytic efficiency (entry 8). With compound 3b in hand, we attempted to complete the total synthesis of arcyriaflavin A (1) (Scheme 2). Friedel−Crafts

Scheme 1. Retrosynthetic Analysis of the Total Syntheses of Arcyriaflavin A (1) and Calothrixin B (2)

method, we hypothesized that 2,2′-bisindole-3-acetic acid derivative 3 could be prepared via the cyanide-catalyzed iminoStetter reaction from aldimine 8, which is derived from a 2aminocinnamic acid derivative and indole-2-carboxaldehyde. On the basis of this hypothesis, we first investigated the preparation of 2,2′-bisindole-3-acetic acid derivatives 3 from aldimines 8, obtained from 2-aminocinnamic acid derivatives and indole-2-carboxaldehyde (Table 1). When aldimine 8a, obtained Table 1. Synthesis of 2,2′-Bisindole-3-acetic Acid Derivatives 3 from Aldimines 8a

Scheme 2. First Attempt for the Synthesis of Arcyriaflavin A (1) entry

aldimine 8

Y

R

indole 3

time (min)

yieldb (%)

1 2c 3 4 5 6c 7d 8d,e

8a 8a 8b 8c 8d 8e 8b 8b

OEt OEt OEt OEt OEt NHBn OEt OEt

H H Bn Me Ts Bn Bn Bn

3a 3a 3b 3c 3d 3e 3b 3b

>120 60 20 20 10 10 20 30

13 ∼20 98 99 95 95 95 97

a

Reaction conditions: 8 (1.0 mmol), NaCN (0.10 mmol), DMF (5.0 mL), under Ar, 60 °C. bIsolated yield by flash column chromatography. c100 mol % of NaCN was used. dAldimine 8b, prepared from ethyl 2-aminocinnamate and N-benzylindole-2-carboxaldehyde, was used as obtained without further purification. e20 mmol scale.

reaction of 3b with ethyl glyoxylate yielded 3′-α-hydroxy ester 9 as an inseparable mixture of two atropdiastereomers, which was directly oxidized to 3′-α-ketoester 10 with an excess amount of MnO2. When 10 was subjected to the 6-membered C-ring formation reaction with t-BuOK, the formation of the indolocarbazole product 11 was observed in the crude mixture. However, rather disappointingly, compound 11 could not be isolated because it underwent decomposition during the aqueous workup.

from indole-2-carboxaldehyde, was subjected to the reaction conditions7 previously used for the synthesis of 2-substituted indole-3-acetic acid derivatives in the presence of 10 mol % of cyanide, unfortunately, the desired 2,2′-bisindole-3-acetic acid derivative 3a was obtained in only 13% yield, and most of the starting material remained unreacted in the reaction mixture (entry 1). To increase the yield of 3a in this transformation, the same transformation was performed with a stoichiometric 2786

DOI: 10.1021/acs.orglett.7b00687 Org. Lett. 2017, 19, 2785−2788

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Organic Letters

corresponding carboxylic acid 17 in quantitative yield (Scheme 4).

We speculated that the instability of compound 11 during the aqueous workup might be due to the presence of a free N−H group. Thus, we attempted to prepare N,N′-diprotected 2,2′bisindole-3-acetic acid derivative as the starting material for the total synthesis of arcyriaflavin A (1) (Scheme 3). N,N′-

Scheme 4. Total Synthesis of Calothrixin B (2)

Scheme 3. Total Synthesis of Arcyriaflavin A (1)

Subsequent treatment of 17 with pyrophosphoric acid (PPA) provided 5-hydroxyindolecarbazole compound 18.13 Unfortunately, 18 was unstable and decomposed into unidentifiable mixtures during the aqueous workup. Hence, without aqueous workup, indolocarbazole 18 was directly subjected to the Vilsmeier−Haack reaction by adding DMF and POCl3 to the reaction mixture. However, the yield of the formylated compound 19 was too low for the application of this synthetic route to the total synthesis of calothrixin B (2) (eq 1).

dibenzylated 2,2′-bisindole product 12 was prepared in 96% yield by the treatment of compound 3b with benzyl bromide in the presence of K2CO3. Friedel−Crafts reaction of 12 with ethyl glyoxylate, followed by oxidation with MnO2, provided N,N′dibenzylated 2,2′-bisindole product 13 in 78% yield over two steps.11 Treatment of compound 13 with t-BuOK completed the 6membered C-ring formation, affording indolocarbazole compound 14. Without isolation, compound 14 was directly subjected to hydrolysis under basic conditions to produce dicarboxylic acid, which in turn was converted into the corresponding anhydride 15 through thermal dehydration. Without further purification, anhydride 15 was treated with ammonium acetate at 140 °C to furnish N,N′-dibenzyl-protected arcyriaflavin A (16). Notably, the formation of both the C and D rings present in the natural product could be achieved from compound 13 in the same pot without the isolation of any intermediates, and the final imide product 16 was obtained in 83% yield over three steps. Final deprotection of the benzyl groups with AlCl3 in the presence of anisole12 provided the desired arcyriaflavin A (1) in 95% yield. Overall, we completed the total synthesis of arcyriaflavin A (1) from readily available starting materials, in 57% overall yield over five steps. After the successful application of 2,2′-bisindole-3-acetic acid derivative 3b to the total synthesis of arcyriaflavin A (1), one of the indolocarbazole natural products, we further attempted to complete the total synthesis of calothrixin B (2), an indolo[3,2j]phenanthridine natural products, from the same intermediate 3b. In this approach, we planned to prepare the key intermediate 5 from 2,2′-bisindole-3-acetic acid derivative 3 through the formation of the C′-ring by benzannulation followed by introduction of a formyl group. With this synthetic plan in mind, the ester moiety in 3b was hydrolyzed using an aqueous LiOH solution to afford the

Because the remaining PPA used in the benzannulation was difficult to remove from the reaction mixture before the subsequent formylation reaction, we speculated that the remaining PPA might interfere with the Vilsmeier−Haack reaction, leading to a low yield of 19. Thus, we attempted to use a more easily removable dehydration reagent for the benzannulation reaction. Particularly, both benzannulation and Vilsmeier−Haack reactions require a dehydration reagent; thus, we planned to carry out both the transformations with a single dehydration reagent by the subsequent addition of DMF for the formylation after the benzannulation in the same pot. Since POCl3 is one of the most commonly used dehydration reagents in the Vilsmeier−Haack reaction, these transformations were carried out using POCl3. When POCl3 was used as the dehydration agent for the benzannulation, complete formation of indolocarbazole 18 was observed in the reaction mixture. After concentration of the reaction mixture, the crude mixture of 18 was dissolved in DMF, and the formylation reaction was successfully performed in the same pot by simply adding POCl3 to the reaction mixture, thus obtaining the formylated indolocarbazole 19 in 88% yield over two steps. Finally, we focused on the construction of the phenanthridine moiety from the carbazole moiety via an oxidation/hydrolysis/ quinoline formation sequence.5,6 When compound 19 was 2787

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Org. Chem. 2003, 68, 8008. (c) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3721. (d) Faul, M. M.; Engler, T. A.; Sullivan, K. A.; Grutsch, J. L.; Clayton, M. T.; Martinelli, M. J.; Pawlak, J. M.; LeTourneau, M.; Coffey, D. S.; Pedersen, S. W.; Kolis, S. P.; Furness, K.; Malhotra, S.; Al-awar, R. S.; Ray, J. E. J. Org. Chem. 2004, 69, 2967. (e) Pelly, S. C.; Parkinson, C. J.; van Otterlo, W. A. L.; de Koning, C. B. J. Org. Chem. 2005, 70, 10474. (f) Howard-Jones, A. R.; Walsh, C. T. J. Am. Chem. Soc. 2006, 128, 12289. (g) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J. Org. Chem. 2007, 72, 2008. (h) Delarue-Cochin, S.; McCortTranchepain, I. Org. Biomol. Chem. 2009, 7, 706. (i) Rajeshwaran, G. G.; Mohanakrishnan, A. K. Org. Lett. 2011, 13, 1418. (4) For selected examples of the total synthesis of calothrixin B (2), see: (a) Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000, 2, 3735. (b) Sissouma, D.; Maingot, L.; Collet, S.; Guingant, A. J. Org. Chem. 2006, 71, 8384. (c) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2006, 8, 561. (d) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011, 13, 3356. (e) Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2014, 79, 736. (f) Dethe, D. H.; Murhade, G. M. Eur. J. Org. Chem. 2014, 2014, 6953. (g) Ramalingam, B. M.; Saravanan, V.; Mohanakrishnan, A. K. Org. Lett. 2013, 15, 3726. (h) Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2013, 78, 2802. (i) Abe, T.; Ikeda, T.; Choshi, T.; Hibino, S.; Hatae, N.; Toyata, E.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem. 2012, 2012, 5018. (5) For a proposed biosynthetic pathway for calothrixin B (2), see: (a) Yamabuki, A.; Fujinawa, H.; Choshi, T.; Tohyama, S.; Matsumoto, K.; Ohmura, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2006, 47, 5859. (b) McErlean, C. S. P.; Sperry, J.; Blake, A. J.; Moody, C. J. Tetrahedron 2007, 63, 10963. (6) For selected examples of the total synthesis of calothrixin B (2) via a biomimetic route, see: (a) Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N. M.; Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron 1999, 55, 13513. (b) Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.; Ikegata, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2005, 46, 5263. (c) Ramalingam, B. M.; Saravanan, V.; Mohanakrishnan, A. K. Org. Lett. 2013, 15, 3726. (d) Saravanan, V.; Ramalingam, B. M.; Mohanakrishnan, A. K. Eur. J. Org. Chem. 2014, 2014, 1266. (7) (a) Lee, S.; Seo, H.-A.; Cheon, C.-H. Adv. Synth. Catal. 2016, 358, 1566. (b) Seo, H.-A.; Cheon, C.-H. J. Org. Chem. 2016, 81, 7917. (8) For our contribution to the skeleton-divergent total synthesis of alkaloids, see: Kwon, S. H.; Seo, H.-A.; Cheon, C.-H. Org. Lett. 2016, 18, 5280. (9) The previous methods for the preparation of this intermediate relied on the introduction of an acetic acid moiety at the 3-position of the 2,2′-bisindole compounds; see: (a) Bergman, J.; Koch, E.; Pelcman, B. Tetrahedron 1995, 51, 5631. (b) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1. (10) Our studies on the imino-Stetter reaction with a cyanide suggested that a substrate bearing an acidic proton generally required a stoichiometric amount of cyanide. For details, see ref 7. (11) The order of events played a crucial role in the success of the synthesis. Unfortunately, introduction of a 3′-α-keto ester moiety into compound 3b, followed by benzyl protection, did not furnish compound 13. Instead, several side products were observed in the reaction mixture. (12) For an example of the deprotection of the N-benzyl moiety of indole with AlCl3 in the presence of anisole, see: Silva, L. F.; Craveiro, M. Org. Lett. 2008, 10, 5417. (13) For an example of benzannulation with PPA, see: Maingot, L.; Thuaud, F.; Sissouma, D.; Collet, S.; Guingant, A.; Evain, M. Synlett 2008, 2008, 263.

treated with CAN, the desired product 21 was not formed; instead, a complex mixture was obtained. Since a literature survey suggested that the free O−H and N−H groups present in compound 19 should be protected for this transformation,5b they were protected with methoxymethyl (MOM) groups. When the MOM-protected compound 20 was treated with CAN, the phenanthridine moiety was generated to afford N-benzylprotected calothrixin B 21 in 71% yield. Subsequent deprotection of the benzyl group with AlCl3 in the presence of anisole12 provided the desired 2 in 76% yield. Overall, the total synthesis of calithroxin B (2) was completed from readily available starting materials in 34% overall yield over six steps. In summary, we have developed a new protocol for the synthesis of 2,2′-bisindole-3-acetic acid derivatives using aldimines derived from 2-aminocinnamic acid derivatives and N-protected indole-2-carboxaldehyde via a cyanide-catalyzed imino-Stetter reaction. Several 2,2′-bisindole-3-acetic acid derivatives bearing different N-protecting groups were obtained in excellent yields within very short reaction times. Furthermore, we completed the first divergent total syntheses of arcyriaflavin A (1) and calothrixin B (2) using a 2,2′-bisindole-3-acetic acid derivative as the key intermediate. Further development of the total synthesis of other benzofused heteroaromatic compounds is currently underway in our laboratory, and the results will be reported in due course.

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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.7b00687. Experimental procedures and spectral data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Cheol-Hong Cheon: 0000-0002-6738-6193 Author Contributions †

S.L. and K.-H.K. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean Government (NRF-20100020209 and NRF-2015R1D1A1A01057200). C.H.C. also acknowledges financial support from an NRF grant funded by the Korean Government (NRF-2014-011165, Center for New Directions in Organic Synthesis).

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REFERENCES

(1) For reviews on indolocarbazole alkaloids, see: (a) Sánchez, C.; Méndez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23, 1007. (b) Nakano, H.; Omura, S. J. Antibiot. 2009, 62, 17. (2) For reviews on indolo[3,2-j]phenanthridine alkaloids, see: (a) Xu, S.; Nijampatnam, B.; Dutta, S.; Velu, S. E. Mar. Drugs 2016, 14, 17. (b) Parvatkar, P. T. Curr. Org. Chem. 2017, 20, 839. (3) For selected examples of the total synthesis of arcyriaflavin A (1), see: (a) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J.; Pflum, D. A.; Petsch, D. T. J. Am. Chem. Soc. 1997, 119, 9641. (b) Sanchez-Martinez, C.; Faul, M. M.; Shih, C.; Sullivan, K. A.; Grutsch, J. L.; Cooper, J. T.; Kolis, S. P. J. 2788

DOI: 10.1021/acs.orglett.7b00687 Org. Lett. 2017, 19, 2785−2788