Letter Cite This: Org. Lett. 2018, 20, 6166−6169
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Total Synthesis of Anti-tuberculosis Natural Products Ilamycins E1 and F Yingying Cheng,† Shoubin Tang,† Yian Guo,* and Tao Ye* State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen 518055, China
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ABSTRACT: The first total synthesis of the potent antituberculosis cyclopeptide natural products ilamycins E1 and F was achieved. This highly convergent strategy consists of the synthesis of the two units 10 and 11 and linking them together to form the macrocyclic lactam 31. The upper unit 10 was prepared from tryptophan in five steps, and the lower unit 11 was prepared from glutamic acid in thirteen steps. Conversion of ilamycin F, the most abundant of the cyclopeptides, into the more active congener, ilamycin E1, was also accomplished. This would provide sufficient material of ilamycin E1 for more extensive biological studies.
T
uberculosis (TB) is the leading cause of infectious disease mortality in the world by a bacterial pathogen. In 2016, 10.4 million people developed active TB worldwide, of whom 1.7 million died, including 0.4 million among people with HIV.1 The approved anti-tuberculosis regimens consist of three or four drugs comprising isoniazid, rifampin, pyrazinamide, and/or ethambutol. However, these regimens have severe and sometimes irreversible side effects and are associated with poor patient adherence, high mortality, and further acquisition of drug resistance.2 The ever-increasing occurrence of potentially incurable multiple-drug-resistant (MDR) TB strains and the lack of efficacy of current treatments in immune-depressed patients combine to make the discovery of anti-TB agents with novel structures an urgent priority. Ilamycin E1 (7) is a cyclopeptide isolated from the fermentation of marine Streptomyces atratus SCSIO ZH16 obtained from a deep South China Sea sediment sample (Figure 1).3 It is a member of a family of cyclopeptide natural products that differ either in the structure of their respective 2-amino-4methylpentanedioic acid residue or in the N-substitution moiety of the tryptophan residue. The structure and stereochemistry of ilamycins have been determined by extensive spectroscopic and X-ray crystallographic analyses. Only two of the seven L-amino acid residues are incorporated in their unmodified naturally occurring form; one is N-methylated, and four of the component residues are novel. Within this set, ilamycins E1 (7) and E2 (8) emerged as promising lead compounds, which revealed very potent anti-tuberculosis activity with a minimum inhibitory concentration value of ≈9.8 nM to Mycobacterium tuberculosis H37Rv.3 As part of our research program on the synthesis of bioactive macrocyclic natural products,4 we have been involved in the synthetic studies toward lydiamycin A,5 an antituberculosis marine cyclodepsipeptide. Herein, we disclose the first total synthesis of ilamycins E1 (7) and F (2) and thus © 2018 American Chemical Society
Figure 1. Structures of ilamycins.
confirm both the absolute and relative stereochemistries of the natural products. As delineated in our retrosynthetic blueprint, the acid-labile 3amino-6-hydroxy-2-piperidone (Ahp) unit was envisioned to be introduced at the late stage of the synthesis. Thus, ilamycin E1 (7) could arise from macrolactamization of linear precursor 9, which, in turn, would be convergently accessible from the less complex fragments tripeptide 10 and tetrapeptide 11. Further Received: August 18, 2018 Published: September 25, 2018 6166
DOI: 10.1021/acs.orglett.8b02643 Org. Lett. 2018, 20, 6166−6169
Letter
Organic Letters
methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (HATU)12 and provided dipeptide 24 in 94% yield in two steps. A subsequent hydrogenolysis of the Cterminal benzyl ester in the presence of Pd/C and hydrogen chloride in dioxane provided the corresponding acid 13, which was immediately condensed with free amine 12 in the presence of HOAt, EDCI, and DIPEA to afford the desired tetrapeptide 11 in 57% yield (Scheme 3).
strategic disconnection of the tetrapeptide 11 would result in two dipeptides 12 and 13 with similar complexity (Scheme 1). Scheme 1. Retrosynthetic Analysis
Scheme 3. Synthesis of Tetrapeptide 11
Synthesis of intermediate 12 (Scheme 2) commenced with an alkylation of the Schöllkopf chiral auxiliary 14,6 which was Scheme 2. Synthesis of Dipeptide 12 Preparation of tripeptide 11 from N-Teoc-protected tryptophan methyl ester (25) is presented in Scheme 4. Thus, Scheme 4. Synthesis of Tripeptide 10
further elaborated to N-Boc-(2S,4E)-2-amino-4-hexenoic acid 15 in a fashion analogous to that reported by Guillerm.7 The resulting acid was then converted into the corresponding 2(trimethylsilyl)ethyl ester 16 in 68% yield under Mitsunobu conditions.8 Subsequently, the Boc group was cleaved from 16 using hydrogen chloride in dioxane, and the thus-obtained primary amine was coupled with N-Fmoc-L-leucine 17 using EDCI (1-hydroxy-7-azabenzotriazole)(HOAt)9 and DIPEA to afford dipeptide 18 in 91% yield. Treatment of 18 with Et2NH effected the removal of the Fmoc protecting group to give the corresponding free amine 12, which was immediately used in the subsequent peptide coupling reaction. In parallel, the synthesis of dipeptide 13 requires the preparation of the known N-methyl-N-Boc amino acid 20, which was prepared from L-glutamic acid.10 Esterification of acid 20 with benzyl bromide under basic conditions afforded the corresponding benzyl ester 21 in 75% yield. Selective removal of the Boc carbamate from 21 in the presence of the silyl ether was accomplished using a mixture of trimethyl trifluoromethanesulfonate (TMSOTf) and triethyl amine to give rise to free amine 22.11 Coupling of 22 with N-Fmoc-L-alanine (23) was achieved through carboxyl activation with (1-[bis(dimethylamino)-
following Baran’s protocol,13 25 was subjected to a PdIIcatalyzed N-tert-prenylation process in the presence of stoichiometric amounts of AgI and CuII salts, which afforded the exclusively N-1-substituted product 26 on gram scale. Saponification of the methyl ester of 26 with LiOH in aqueous THF/MeOH, followed by coupling with the known N-methylL-leucine methyl ester 27 under HATU/HOAt conditions, furnished dipeptide 28 in 85% yield. This dipeptide was further elongated after hydrolysis of the methyl ester and condensation with 3-nitro-L-tyrosine 29 using the EDCI/HOAt conditions to give rise to the tripeptide 10 in 92% yield. With the two key required fragments in hand, the stage was now set for their assembly and elaboration into ilamycins E1 and F. Thus, the methyl ester moiety of 10 was hydrolyzed under mild conditions to liberate the carboxylic acid. The Fmoc group 6167
DOI: 10.1021/acs.orglett.8b02643 Org. Lett. 2018, 20, 6166−6169
Letter
Organic Letters
for the natural product. The identity of our synthetic sample (7) was then confirmed by HPLC co-injection with an authentic sample of the natural product. Having secured access to the macrocyclic core (31), we next explored elaboration of 31 en route to ilamycin F (2). Unfortunately, the conversion of the primary hydroxy group in 31 into the corresponding carboxylic acid by one-pot oxidation conditions proved problematic, which presumably resulted from the high electron density of the substrate. Gratifyingly, the aldehyde, obtained from Dess− Martin oxidation of the primary alcohol in 31, could be further oxidized to the carboxylic acid using Pinnick oxidation conditions21 to furnish ilamycin F (2) in 81% yield over two steps (Scheme 6).
in tetrapeptide 11 was removed by diethylamine, allowing its amino terminus to be coupled with the carboxylic acid derived from 10, utilizing (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate) (PyAOP),14 in the presence of DIPEA, furnishing the corresponding heptapeptide with no apparent loss of stereochemical integrity (Scheme 5). The Scheme 5. Synthesis of Ilamycins E1
Scheme 6. Interconversion of Alcohol 31 and Ilamycin F
It is worth noting that ilamycin F (2) was the abundant member of the family, which can be obtained in multigram quantities through genetically engineered bacterial fermentation (Jianhua Ju, personal communication, 2018). However, ilamycin E1/E2, being about 100-fold more potent than ilamycin F (2), could not be produced easily in large scale. An intriguing strategic premise was the possibility that the conversion of ilamycin F to ilamycin E1 could be accomplished. We therefore sought to implement reliable reduction chemistry for the conversion of ilamycin F (2) to the alcohol 31, which is the key precursor for ilamycin E1 (7). Thus, by treatment of acid 2 with ethyl chloroformate and triethylamine in THF, the phenol group was transformed into an ethyl carbonate, and the ethyl chloroformate derived mixed anhydride was reduced with sodium borohydride. This was then subjected to hydrolysis of the ethyl carbonate moiety under basic conditions to give rise to the corresponding alcohol 31 in 77% yield over two steps (Scheme 6). In summary, we disclosed the first total synthesis of the potent anti-tuberculosis natural products ilamycins E1 and F. The route was convergent and offers a general approach to access the remaining members of this class of natural products as well as other potentially bioactive analogues.
resulting condensate 30 was immediately engaged in a global deprotection with TBAF in THF at ambient temperature to give rise to the corresponding linear precursor, which set the stage for examination of the key macrocyclization reaction. Through an extensive screening of peptide coupling reagents including HATU, PyAOP, DEPBT (3-(diethoxyphosphoryloxy)-1,2,3benzotrizin-4(3H)-one),15 BEP (2-bromo-1-ethylpyridinium tetrafluoroborate), 16 BOPCl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), DPPA (diphenylphosphoryl azide), and FDPP (pentafluorophenyl diphenylphosphinate),17,18 we found that the use of FDPP/DIPEA in dichloromethane was optimal, and the macrolactamization afforded the corresponding cyclopeptide (31) along with its diphenylphosphinated esters. The latter were not thoroughly characterized. Instead, they were directly converted into 31 by treatment with potassium carbonate in methanol. The overall yield of 31 from linear precursor 30 was 43%. With the preparation of the fully functionalized macrocyclic core (31), an important stage in the synthesis was reached. The remaining tasks primarily involved construction of the 3-amino-6-hydroxy-2-piperidone (Ahp) moiety. Thus, chemoselective oxidation of the primary alcohol of 31 in the presence of phenol and electron-rich indole moieties proceeded smoothly under Dess−Martin conditions.19 The crude aldehyde was subsequently treated with potassium carbonate in methanol20 to give rise to ilamycin E1 (7) as a single isomer. The spectral data for the synthetic material (1H NMR, 13C NMR, and HRMS) were identical to those published
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02643. Experimental details and data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
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[email protected]. 6168
DOI: 10.1021/acs.orglett.8b02643 Org. Lett. 2018, 20, 6166−6169
Letter
Organic Letters ORCID
Passarella, D.; Piacenti, P.; Silvani, A. Eur. J. Org. Chem. 2001, 2001, 1377. (21) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
Yian Guo: 0000-0002-0341-6816 Tao Ye: 0000-0002-2780-9761 Author Contributions †
Y.C. and S.T. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from the Shenzhen Peacock Plan (KQTD2015071714043444), the NSFC (21772009), the SZSTIC (JCYJ20160527100424909, JCYJ20170818090017617, JCYJ20170818090238288), and the GDNSF (2014B030301003). We thank Dr. Jianhua Ju of the South China Sea Institute of Oceanology for providing authentic samples of ilamycins E1 and F.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b02643 Org. Lett. 2018, 20, 6166−6169
