Note Cite This: J. Org. Chem. 2017, 82, 11262-11268
pubs.acs.org/joc
Total Synthesis of Kanamienamide D. Prabhakar Reddy, Ning Zhang, Zhimei Yu, Zhen Wang, and Yun He* Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P.R. China S Supporting Information *
ABSTRACT: Kanamienamide is a novel enol ether containing enamide with a single digit micromolar inhibitory activity against cancer cell lines. An efficient and convergent total synthesis of kanamienamide has been developed for the first time, which features a Cu-mediated amide coupling with vinyl iodide at the late stage. Other key transformations include Evans asymmetric alkylation, CBS asymmetric reduction, ring-closing metathesis reaction, and Stork−Zhao−Wittig olefination. This strategy is amenable for facile analogue preparation and SAR studies.
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oxidation followed by Stark−Zhao−Wittig olefination from diene 4, which could be prepared from the HATU-mediated coupling of acid 5 and amino ester 6. Acid 5 could be accessed from the well-known iodo compound 7 via the Evans asymmetric alkylation and amine 6 from commercially available δ-valero lactone 8 via the formation of the Weinreb amide, protection of resulted alcohol, and vinylation of Weinreb amide, CBS asymmetric reduction and ester formation with NBoc-N-methyl-L-leucine 9. The synthesis of acid fragment 5 was started from the wellknown intermediate 7, which could be easily prepared from (S)-Roche ester7 or (R)-4-benzyl-3-propionyloxazolidin-2-one8 each in three steps. Generation of the 1,3-anti relationship of two stereogenic methyl groups required an asymmetric method, which could be accomplished by those developed by Evans9 and Sonnet10 using prolinol as a chiral auxiliary. In fact, treatment of iodide 7 with the in situ generated dianion of Npropyl-L-prolinol 10 gave the known dimethyl amide 11 in an 81% yield with a 92:8 diastereoselectivity as determined by 1H NMR.11 Amide 11 was exposed to 1 N hydrochloric acid to provide the known corresponding acid, which was allowed to react with lithium aluminum hydride, giving rise to alcohol 12 in an excellent yield. Oxidation of 12 to the corresponding aldehyde with the Dess−Martin periodinane,12 followed by Wittig olefination with the in situ generated phosphorane 13, afforded terminal olefin 14. Deprotection of the benzyl ether with Li-Napthalenide13 resulted in alcohol 15 in an 83% yield, which was oxidized further with the Jones’ reagent (CrO3, H2O, H2SO4, acetone)14 to furnish the desired acid 5 in a 78% yield (Scheme 2). The synthesis of amino ester 6 commenced from the known intermediate 16,15 which could be prepared from δ-valero lactone 8 in two steps in a 75% overall yield. Treatment of
arine cyanobacteria is one of the main sources of secondary metabolites with the potential for biotechnological applications, specifically in the pharmacological field.1 A wide range of structurally diverse natural products of marine cyanobacteria induce cytotoxicity, anti-inflammatory, and antibacterial activities.2 The potential of such natural products as anticancer agents has been extensively explored, and several compounds have been under clinical evaluations.3 Kanamienamide (1) was isolated from marine cyanobacterium Moorea bouillonii collected at the shore of Kanami on the Tokunosima Island by Suenaga et al. in 2016 (Figure 1).4 It was the first
Figure 1. Structure of kanamienamide (1).
natural enamide that possesses an N-Me-enamide adjacent to an enol ether.5 The structure of kanamienamide was elucidated by detailed spectroscopic studies. Preliminary biological evaluations of kanamienamide revealed potent growth-inhibitory activity toward HeLa cells with an IC50 value of 2.5 μM, and it induced an apoptosis-like cell death. Its unique structural motif, promising biological activity and our interest toward the total synthesis of biologically active natural products,6 impelled us to develop an efficient strategy for the total synthesis of kanamienamide (1) and its SAR studies. As outlined in Scheme 1, our synthetic strategy for kanamienamide (1) involves a late stage Cu-catalyzed crosscoupling of vinyl iodide 3 with enol ether N-methylamide 2. The 11-membered Z-vinyliodo macrolactone 3 could be synthesized via ring-closing metathesis and hydrogenation, © 2017 American Chemical Society
Received: August 7, 2017 Published: September 25, 2017 11262
DOI: 10.1021/acs.joc.7b01984 J. Org. Chem. 2017, 82, 11262−11268
Note
The Journal of Organic Chemistry Scheme 1. Retrosynthetic Analysis of Kanamienamide (1)
The synthesis of enol ether amide 2 began with the known enol ether 21,18 which could be synthesized by the reported procedure from commercially available methyl 3-oxo-pentanoate 20. Hydrolysis of ester 20 gave the corresponding acid 22, which was coupled with methyl amine to produce the enol ether amide 2 in a good overall yield (Scheme 4).19
Scheme 2. Synthesis of Acid Fragment 5
Scheme 4. Synthesis of Enol Ether Amide 2
With the key fragments 2, 5, and 6 in hand, we began the assembly by first coupling acid 5 and amine 6 under the HATU condition, yielding diene 4 in an 80% yield. The ring-closing metathesis reaction20,21 of diene 4 using the Grubbs’ second generation catalyst (20 mol %) in refluxing dichloromethane furnished the 11-membered macrolactone smoothly (E/Z > 95:5 by 1H NMR). The crude product was subjected to hydrogenation with the Pd−C catalyst in ethyl acetate, furnishing the saturated macrolactone 23 in a 67% yield over two steps. The Dess−Martin periodinane oxidation of 23 afforded the corresponding aldehyde, which was subsequently converted to the terminal Z-vinyl iodide 3 in a 69% yield with good stereoselectivity by the Stork−Zhao−Wittig olefination protocol22 using (iodomethyl)triphenylphosphonium iodide23 (Scheme 5). The critical step in our kanamienamide (1) synthesis was the cross-coupling between the Z-vinyl iodo macrolactone 3 and sensitive enol ether amide 2, and a series of explorations were carried out. Our attempt was to utilize the method developed by Shen et al. (copper(I) carboxylate catalysis); however, it failed to provide the required product and resulted in only decomposition of both starting materials.24 The Ag2CO3promoted Pd-catalyzed alkenylation of amide 225 did not take place, ending up with the recovery of both 2 and 3. Eventually, the cross-coupling reaction was obtained under modified
Weinreb amide 16 with vinylmagnisium bromide at 0 °C gave the vinyl ketone 17 in a 93% yield. The asymmetric reduction of 17 with the (R)-CBS catalyst16 provided the chiral alcohol 1817 in an 89% yield with 91% ee (determined by HPLC). Esterification of 18 and N-Boc-Nmethyl-L-leucine 9 using EDCI followed by Boc deprotection with TFA afforded the amine fragment 6 in an excellent yield (Scheme 3). Scheme 3. Synthesis of Amino Ester 6
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DOI: 10.1021/acs.joc.7b01984 J. Org. Chem. 2017, 82, 11262−11268
Note
The Journal of Organic Chemistry Scheme 5. Total Synthesis of Kanamienamide (1)
with ceric ammonium molybdate. 1H NMR spectra were obtained on an Agilent 400MR or 600MR DD2 spectrometer at ambient temperature. Data were reported as follows: chemical shifts on the δ scale using a residual proton solvent as the internal standard [δ 7.26 (CDCl3) and δ 7.16 (C6D6)], multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, and coupling constants (J) in hertz (Hz). 13C NMR spectra were obtained with proton decoupling on an Agilent 400MR or 600MR DD2 (100 or 150 MHz) spectrometer and were reported in ppm with a residual solvent for the internal standard [δ 77.16 ± 0.06 (CDCl3) and δ 128.06 ± 0.02 (C6D6)]. High-resolution mass spectra were obtained on a Bruker Solarix 7.0T FT-ICR MS spectrometer. Abbreviations: TMS = trimethylsilyl, Bn = benzyl, Boc = tert-butoxycarbonyl, DIPEA = N,N-diisopropylethylamine, DMAP = 4-dimethylaminopyridine, DMF = N,N-dimethylformamide, DMP = Dess−Martin periodinane, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5b]pyridinium 3-oxid hexafluorophosphate, LDA = lithium diisopropylamide, EDCI = 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, PE = petroleum ether, EtOAc = ethyl acetate.
conditions (1.0 equiv of CuI, 2.0 equiv of N,N-dimethylethylenediamine, Cs2CO3, toluene, 90 °C) with copper catalysis,26,27 furnishing kanamienamide (1) in a 42% yield (Table 1). The analytical data of the synthetic kanamienamide (1) were in full agreement with the values reported for the natural product.28 Table 1. Optimization for Cross-Coupling Reaction entry 124 225 326 427
reagents and conditions
results
2 (3.0 equiv), 3 (1.0 equiv), CuTc (10 mol %), decomposition of Cs2CO3 (2.0 equiv), NMP, 12 h, 90 °C 2 and 3 2 (3.0 equiv), 3 (1.0 equiv), Pd2(dba)3 (5 mol %), no reaction, 2 Xanthphos (15 mol %), Ag2CO3 (1.4 equiv), MS and 3 recovery 4 Å, THF, 65 °C, 24 h 2 (3.0 equiv), 3 (1.0 equiv), CuI (5 mol %),
