Accepted Manuscript. A biomimetic synthesis of the skeleton of trigonoliimine C. Sheng Liu, Xiao-Jiang Hao

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1 Accepted Manuscript A biomimetic synthesis of the skeleton of trigonoliimine C Sheng Liu, Xiao-Jiang Hao PII: S (11) DOI: /j.tetlet Reference: TETL To appear in: Received Date: 14 June 2011 Revised Date: 15 July 2011 Accepted Date: 16 August 2011 Please cite this article as: Liu, S., Hao, X-J., A biomimetic synthesis of the skeleton of trigonoliimine C, Tetrahedron Letters (2011), doi: /j.tetlet This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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3 1 A biomimetic synthesis of the skeleton of trigonoliimine C Sheng Liu, Xiao-Jiang Hao The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang , PRC State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai , PRC ARTI C LE IN FO ABS TRACT Article history: Received Received in revised form Accepted Available online On basis of biomimetic concepts, the skeleton of trigonoliimine C was readily achieved in 5 steps from N-phthaloyl tryptamine. This result suggested an useful synthetic strategy for trigonoliimine alkaloids with this unique ring system Elsevier Ltd. All rights reserved. Keywords: Indole alkaloids Trigonoliimine C Biomimetic synthesis Trigonoliimines A-C (1-3, Fig. 1), three unprecedented indole alkaloids with a novel polycyclic system, were isolated from the extract of the leaves of Trigonostemon. lii Y. T. Chang collected in Yunnan Province of China by our group. 1 Notably, trigonoliimine A showed modest anti-hiv-1 activity (EC 50 = 0.95 g/ml, TI = 7.9). hydroxyindoline was considered as a key fragment and supposed to be a crucial intermediate for many natural indoles. 3 We envision that the bistryptamine derivative 4 may be oxidized to give 5, which in turn undergoes the alternative path and leads to the frameworks of trigonoliimines A-C as indicated in Scheme 1. In our hypothesis, a combination of pinacol-like rearrangement and cyclization can convert intermediate 5 into trigonoliimine C Figure 1. Trigonoliimines A-C (1-3) Their remarkably unique structural features and interesting bioactive properties prompt us to initial the biomimetic synthesis of trigonoliimines A-C, 2 as well as the modification of its structure for finetuning of the biological activity of these highmodified bisindole alkaloids derivatives. Although 1 and 2 shared an identical framework which was quite distinct from 3 in its polycyclic system, on the basis of a common indole fragment found in these alkaloids, we expected that trigonoliimines A-C may be derived from an unified precursor 5 (Scheme 1) by their biosynthetic pathway, since the Scheme 1. biogenesis Corresponding author. Tel.: ; fax: ; haoxj@mail.kib.ac.cn of trigonoliimines A-C

4 2 Scheme 2. Reagents and conditions: (a) i: TFA, 2 h. ii: DDQ, 1,4-dioxane; (b) Oxone, Acetone, NaHCO 3 ; (c) Formic acid-saturated Toluene, 110 o C; (d) Sr(OTf) 3, PhMe, 110 o C, 2 h; (e) 80 % hydrazine hydrate, DCM/MeOH, 24 h, rt; (f) HCOOEt, DMF, 65 o C, 18 h; (Path A). In the other parallel direction, an intramocular nucleophilic substitution followed by a ring-opening rearrangement would lead to the formation of the typical framework of trigonoliimines A and B (Path B). Although this rearrangement type is less common, a similar transformation style had been reported in the total synthesis of calothrixin B. 4 With above biosynthetic view in mind, we began our synthesis studies towards the skeleton of trigonoliimine C. To control the synthesis to undergo the desired reaction cascade of Path A, our process started with N-phthaloyl tryptamine 8 (Scheme 2), which was dimerized conveniently by dissolving the substrate in TFA and followed by oxidation with DDQ to afford 2, 2'-biindolyl 9. 5 Then we explored the direct conversion of this protected bistryptamine to the corresponding mono-hydroxybisindole. After several attempts, we found that 9 was oxidized rapidly with in situ generated dimethyldioxirane 6 to afford the desired 11 in 70 % yield accompanied with 10 % of 3, 3 -dihydroxybisindole 10. With the critical intermediate 11 in hand, we focused on the development of optimal conditions for its isomerization to the desired indoxyl 12. Our substrate was subjected to the reaction condition of HCOOH/ toluene. 7 This transformation was rather inefficient and only gave 12 in 10 % yield after refluxing for 36 h. This might be caused by the poor solubility and distribution of 11 in toluene. However, we were able to circumvent this problem by replacing the two-phase mixtures of solvent and catalyst with HCOOH-saturated toluene for this key rearrangement. In this case, the optimal conversion afforded 12 in 50% yield. 8 Other than the above condition, we performed a solvent (DMF, MeCN) and acid (TFA, CSA, Sr(OTf) 3 ) screening. Unfortunately, all efforts had not been succeeded. Notably, treatment of 11 with Sr(OTf) 3 in toluene at 110 o C led to exclusive isolation of 13 in 70% yield, the migration of an 2 - indoly group may be very significant for synthesis of dimeric indole alkaloids. The di Phth group of 12 was cleaved using excess hydrazine to afford a corresponding hydrazine adduct 14. Heating this free amine with ethyl formate in DMF, gratifyingly, we succeed in constructing the seven-membered ring without detecting any five-membered cyclization. Hence, the reaction gave the desired product 15 in 40% yield. 9 Di-formyl protection also occurred concomitantly in this reaction to yield product 16. Unexpectedly, the 1 H NMR and 13 C NMR spectra of compound 15 in DMSO-d6 was found to be quite complex compared to the spectra recorded for the natural product. 1 Detailed investigation indicated that these tanglesome signals exhibited a tautomerism between 15 and 17 (Table 1). Tautomer 17 was formed in a five-member ring-closing reaction by attack of the nitrogen atom of the side chain in 15 at the iminic carbon center. This tautomerism was an acid/base-catalyzed process and totally inhibited in acidic DMSO-d 6. It seemed reasonable since our synthetic target lacked of a p-methoxyl electron-donating group which might stabilize the imine structure in the natural alkaloid. Table 1. Tautomerism of 15 in acid/base solvents Entry NMR Solvents Ratio a (15 : 17 1 Pyridine-d 5 66 : 34 2 Dimethyl Sulfoxide-d 6 75 : 25 3 Dimethyl Sulfoxide-d 6+ TFA-d 1 100: 0 a Ratios determined by 1 H NMR. In conclusion, we have investigated the proposed biomimetic oxidative rearrangement of bistryptamine framework into the core ring system of trigonoliimine C. The preliminary results reported here partially testified our biosynthetic hypothesis about trigonoliimine C, which inspired our efforts toward the total synthesis of trigonoliimine alkaloids. Further studies are ongoing and will be reported in due course. Acknowledgments The work was financially supported by the State Key Laboratory of Drug Research (SIMM1106KF-03). References and notes 1. Tan, C.-J.; Di, Y.-T. ; Wang, Y.-H.; Zhang, Y.; Si, Y.-K.; Zhang, Q.; Gao, S.; Hu, X. -J.; Fang, X.; Li, S. -F.; Hao. X. -J. Org. Lett. 2010, 12, On the occasion of our submission, Tambar and Movassaghi's total synthesis of trigonoliimine C was published online: a) Qi, X.; Bao, H.;Tambar, U. K. J. Am. Chem. Soc., 2011, ASAP; b) Han. S; Movassaghi M. J. Am. Chem. Soc., 2011, ASAP. 3. Schmidt, M. A.; Movassaghi, M. Synlett. 2008, Sperry, J; McErlean, C. S. P.; Slawin, A. M. Z.; Moody, C. J. Tetrahedron Lett. 2007, 48, a) Bergman, J.; Koch, E.; Pelcman, B. Tetrahedron Lett. 1995, 36, ; b) Gilbert, E. J.; Ziller, J. W.; Van Vranken, D. L. Tetrahedron 1997, 53, Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Org. Lett. 2008, 10, Liu, Y.; McWhorter Jr, W. W. J. Org. Chem. 2003, 68,

5 8. Conversion of 3-hydroxy-2, 2 -biindole 11 to 12: A solution of 11 (400 mg, 0.67 mmol) in 80 ml HCOOH-saturated toluene (this solvent was obtained by using 80 ml toluene extracted over 20 ml 88% aqueous HCOOH) was refluxed at 110 o C for 12 h. The reaction mixture was directly purified by column chromatography (Petroleum ether /AcOEt-2:1 to 1:1) and gave 12 (200 mg, 50%) as a yellow solid. IR (KBr) 3455, 1770, 1704, 1398, 719; 1 H NMR (400 MHz, CDCl 3): 9.09 (s, 1H), 7.91 (m, 2H), 7.76 (m, 2H), 7.64 (m, 2H), (m, 5H), 7.25 (t, J =8.0 Hz, 2H) 7.08 (t, J =7.6 Hz, 1H),7.00 (t, J =7.6 Hz, 1H), 6.83 (s, 1H), 6.80 (t, J =7.2 Hz, 1H), (m, 3H), 3.80 (m, 1 H), 3.16 (t, J =8.4 Hz, 2H), 2.70 (m, 1 H), 2.45 (m, 1 H); 13 C NMR (100 MHz, CDCl 3): 200.7, 168.6, 168.1, 160.9, 138.3, 135.3, 134.0, 133.8, 132.2, 131.5, 130.3, 128.4, 125.2, 123.3, 123.0, 122.9, 119.6, 119.0, 118.2, 117.9, 112.9, 111.0, 108.9, 67.6, 38.8, 36.8, 33.5, 24.1; LRMS (ESI): calcd for C 36H 26N 4O 5 [M+Na] +, 617; Found: [M+Na] +, 617. HRMS (Monoisotopic): calcd. for C 36H 26N 4O ; Found: Compound 15: IR (KBr) 3454, 2923, 1644, 1464, 747; 1 H NMR for major tautomer (400 MHz, DMSO-d 6) 10.6 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.41 (t, J =7.2 Hz, 2H), 7.35 (d, J =8.0 Hz, 1H), 7.22 (t, J =7.6 Hz, 1H), 7.12 (t, J =8.0 Hz, 1H), 7.08 (t, J =7.6 Hz, 1H), 7.00 (t, J =7.6 Hz, 1H), 6.98 (t, J =7.6 Hz, 1H), 6.76 (d, J =8.0 Hz, 1H), 6.70 (s, 1H), 6.64 (t, J =7.6 Hz, 1H), 4.27 (t, J =8.0 Hz, 1H), 4.06 (d, J =12.0 Hz, 1H), (m, 3H), 2.82 (m, 1 H), 2.52 (m, 1H), 2.29 (m, 1H); 13 C NMR for major tautomer (100 MHz, DMSO-d 6) 171.1, 161.0, 155.0, 134.8, 133.2, 131.7, 127.9, 122.2, 121.4, 118.5, 117.7, 117.7, 117.8, 110.9, 110.2, 108.7, 65.7, 46.9, 39.1, 33.5, HRMS (Monoisotopic), calcd. for C 21H 20N 4O ; Found: Click here to remove instruction text... 3