Six-Step Total Synthesis of Azaspirene - The Journal of Organic

Jul 12, 2017 - The total synthesis of (±)-azaspirene (1) was achieved in a total of six steps from commercially available materials. Keys to the conc...
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Six-Step Total Synthesis of Azaspirene Taeho Kang,† Deokhee Jo,†,‡ and Sunkyu Han*,†,‡ †

Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea

‡

S Supporting Information *

ABSTRACT: The total synthesis of (±)-azaspirene (1) was achieved in a total of six steps from commercially available materials. Keys to the conciseness of our synthetic approach were the effective γ-lactam formation from linear precursor 36 and successful tandem epoxidations of γ-lactam 34 to afford α,β-epoxy-γ-hydroxy-γ-lactam intermediate 14. While our streamlined synthesis of azaspirene (1) sought inspiration from its biogenetic hypothesis, experimentally observed chemical reactivity of biosynthetically relevant precursors conversely provides insights to the biological origin of this natural product.

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INTRODUCTION Since the isolation of pseurotin A (3) by Tamm and co-workers in 1976,1 various spirocyclic fungal metabolites biosynthesized by the polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) machinery have been isolated (Figure 1).2 In 2002,

azaspirene (1) can inhibit the growth of human uterine carcinosarcoma (UCS) by acting as antiangiogenic reagents.5 Due to its promising biological activities as well as a complex molecular structure featuring a 1-oxa-7-azaspiro[4.4]non-2-ene4,6-dione skeleton with a hexadiene substituent (Figure 1), azaspirene (1) has drawn significant attention from the synthetic community, and inventive solutions to 1 have been reported. In 2002, Hayashi and co-workers reported the first enantioselective total synthesis of (−)-azaspirene (1, 15 steps) via a Lewis acid-mediated Mukaiyama aldol reaction and a sodium hydride-promoted intramolecular hydroamidation reaction.6 In 2004, Tadano and co-workers completed the synthesis of (−)-azaspirene (1, 33 steps) along with (−)-pseurotins A (3) and F2 starting from D-glucose.7 Most recently, Tanabe, Misaki, and co-workers completed the synthesis of (−)-azaspirene (1, 29 steps) by using a titanium-mediated Claisen condensation reaction.8 Inspired by the biosynthetic hypothesis of the spirocyclic PKS-NRPS-based fungal metabolites,9 we recently reported a total synthesis of berkeleyamide D (2, Scheme 1).10 We first assembled linear precursor 8 from phenylacetaldehyde (5), β-ketoester 6, and L-leucinol. Alcohol 8 was subjected to a Snider protocol which involved modified Pfitzner−Moffatt oxidation conditions followed by a base treatment to afford γ-lactam 9.11 We found that magnesium monoperoxyphthalate (MMPP) was the optimal oxidant for consecutive epoxidations of γ-lactam 9 to give epoxide intermediate 10. Silyl ether 10 was transformed to enol derivative 12 through a hydroxy to methoxy substitution followed by an oxidation of the secondary alcohol group in 11. Ketone 12 underwent a

Figure 1. Representative spirocyclic PKS-NRPS-based fungal metabolites.

Osada, Kakeya, and co-workers discovered azaspirene (1), a novel angiogenesis inhibitor isolated from the fungus Neosartorya sp., which showed an ability to inhibit endothelial migration induced by vascular endothelial growth factor (ED100 = 27.1 μM).3 In their subsequent studies, the Osada group confirmed the in vivo antiangiogenic activity by both a tumor neo-angiogenesis assay and a chicken chorioallantoic membrane (CAM) assay.4 They also showed that azaspirene (1) specifically blocks vascular endothelial growth factor (VEGF)-induced phosphorylation of Rik1-associated factor (Raf-1). More recently, Emoto and co-workers showed that structurally simplified analogues of © 2017 American Chemical Society

Received: May 18, 2017 Published: July 12, 2017 9335

DOI: 10.1021/acs.joc.7b01224 J. Org. Chem. 2017, 82, 9335−9341

Article

The Journal of Organic Chemistry Scheme 1. Our Previous Total Synthesis of (±)-Berkeleyamide D (2)a

Scheme 2. Initial Retrosynthetic Analysis of Azaspirene (1)

mediate 14. α,β-Epoxy-γ-hydroxy-γ-lactam 14 was designed to be derived from a linear precursor 15 by a sequence that involves four oxidations. Amide 15 was planned to be accessed by an initial aldol reaction of aldehyde 16 and β-ketoester 17 followed by a peptide coupling of the resulting aldol adduct with L-phenylalaninol (18). Our first-generation total synthesis of azaspirene (1) commenced with an aldol reaction between aldehyde 16 and commercially available β-ketoester 17 (Scheme 3).13 Compound 17 was first treated with 1.1 equiv of sodium hydride followed by the addition of another 1.1 equiv of n-butyllithium to give the dienolate intermediate. The resulting dienolate intermediate was allowed to react with commercially available α,β− γ,δ-unsaturated aldehyde 16 to give secondary alcohol 19 in 90% yield as a mixture of two inseparable diastereomers. Silyl protection of alcohol 19 and a subsequent peptide coupling with L-phenylalaninol (18) were achieved in 84% and 75% yield, respectively, to afford linear intermediate 15 as a mixture of four inseparable diastereomers.14 A modified Pfitzner−Moffatt oxidation of alcohol 15 afforded the aldehyde intermediate which underwent an intramolecular Knoevenagel condensation upon treatment with base to give lactam 21 in 86% yield over two steps.11 With lactam 21 in hand, we attempted our previously developed double epoxidations with MMPP.10 Lactam 21 underwent an electrophilic epoxidation at the most electron-rich enamide moiety followed by an epoxide opening to give γ-hydroxy-γlactam intermediate 22. Consistent with our observations made during the berkeleyamide D (2) synthesis,10 MMPP was an effective oxidant for both the electrophilic and the nucleophilic epoxidation. Moreover, MMPP induced a hydroxy-directed epoxidation of intermediate 22 to yield epoxide 23 in 54% yield. It is important to note that MMPP reacted selectively with the electron-rich enamide moiety in 21, and the conjugated diene moiety in either 21 or 22 did not show any noticeable reactivity. Treatment of 23 with triethylamine trihydrofluoride afforded the desilylated allylic alcohol 24. In sharp contrast to our previous observation made en route to berkeleyamide D (2), oxidation of the allylic alcohol moiety in 24 progressed smoothly even in the presence of the γ-hydroxy-γ-lactam moiety to give the ketone intermediate. Furthermore, the enol tautomer of the resulting ketone intermediate underwent a spontaneous intramolecular epoxide opening to afford (±)-azaspirene (1) in 42% yield over two steps. Spectroscopic and spectrometric data of our synthetic azaspirene (1) matched those of the natural 1.15 With an eight-step total synthesis of azaspirene (1) established, we sought to further streamline the synthetic

Reagents and conditions: (a) NaH, n-BuLi, THF, −78 → +23 °C, 82%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 82%; (c) L-leucinol, DMAP, PhCH3, reflux, 78%; (d) EDC·HCl, Cl2CHCOOH, DMSO, PhCH3, 23 °C; (e) NaOH, EtOAc, H2O, 23 °C, 82% (two steps); (f) MMPP·6H2O, THF, MeOH, 0 °C; (g) CSA, HC(OMe)3, MeOH, 23 °C, 34% (two steps); (h) DMP, CH2Cl2, 23 °C; (i) Et3N, CH2Cl2, 23 °C; (j) TsOH· H2O, THF, H2O, 23 °C, 59% (three steps). TBSOTf = tert-butyldimethylsilyl trifluoromethanesulfonate, DMAP = 4-dimethylaminopyridine, EDC = 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, MMPP = magnesium monoperoxyphthalate, CSA = camphorsulfonic acid, DMP = Dess−Martin periodinane, TsOH = p-toluenesulfonic acid. a

facile intramolecular epoxide opening in the presence of base to afford spirocycle 13 consistent with Kuramochi’s reports.12 Spirocycle 13, upon hydrolysis under acidic conditions, yielded (±)-berkeleyamide D (2) in 10 steps from commercially available materials. We envisioned that azaspirene (1), which contains a conjugated diene moiety prone to oxidation, can serve as an excellent platform to test the versatility of our synthetic strategies derived from the total synthesis of berkeleyamide D (2). Herein, we describe our first-generation eight-step total synthesis of (±)-azaspirene (1) which was enabled by a direct application of our previously devised synthetic sequence for berkeleyamide D (2). We then manifest the evolution of our initial synthetic approach by devising a more streamlined second-generation six-step total synthesis of (±)-azaspirene (1). The differential cyclization mode exerted by the methyl substituent present in the key linear precursor enabled the dramatic improvement.

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RESULTS AND DISCUSSION We devised the first-generation synthetic strategy of azaspirene (1, Scheme 2) by adopting lessons learned from our previous total synthesis of berkeleyamide D (2, Scheme 1). The spirocyclic core of azaspirene (1) was planned to be constructed via an intramolecular epoxide opening by the enol moiety of inter9336

DOI: 10.1021/acs.joc.7b01224 J. Org. Chem. 2017, 82, 9335−9341

Article

The Journal of Organic Chemistry Scheme 3. First-Generation Total Synthesis of (±)-Azaspirene (1)a

Scheme 4. Observed and Expected Cyclizations of 26 and 31

Our second-generation total synthesis of azaspirene (1) commenced by treating allylic alcohol 19 with Dess−Martin periodinane (DMP) to provide 35 (keto/enol = 1/4) in 70% yield (Scheme 5). Peptide coupling of 35 and L-phenylalaninol Scheme 5. Second-Generation Total Synthesis of (±)-Azaspirene (1)a

Reagents and conditions: (a) NaH, n-BuLi, THF, −78 → +23 °C, 90%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 84%; (c) L-phenylalaninol, DMAP, PhCH3, reflux, 75%; (d) EDC·HCl, Cl2CHCOOH, DMSO, PhCH3, 23 °C; (e) NaOH, EtOAc, H2O, 23 °C, 86% (two steps); (f) MMPP·6H2O, THF, MeOH, 0 → 23 °C, 54%; (g) Et3N· 3HF, MeOH, 23 °C; (h) DMP, CH2Cl2, 23 °C, 42% (two steps). TBSOTf = tert-butyldimethylsilyl trifluoromethanesulfonate, DMAP = 4-dimethylaminopyridine, EDC = 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, MMPP = magnesium monoperoxyphthalate, DMP = Dess−Martin periodinane. a

sequence. During our synthetic studies toward berkeleyamide D (2),10 we observed that linear aldehyde 26 accessed from alcohol 25 underwent an intramolecular Knoevenagel condensation for an exclusive formation of seven-membered lactam 30 upon treatment with base (Scheme 4A). This is most likely due to a more efficient β-hydroxy elimination of seven-membered intermediate 29 than that of five-membered intermediate 27. Therefore, we envisioned that the substitution of the α-proton with a methyl group would remove any potential β-hydroxy elimination and alter the cyclization mode (Scheme 4B). ε-Lactam 32 formed via an intramolecular aldol reaction does not possess the α-proton that can induce a β-hydroxy elimination. On the other hand, γ-lactam 33 can undergo a β-hydroxy elimination to yield enamide 34. Hence, we anticipated that tetracarbonyl intermediate 31 would afford γ-lactam 34 under basic conditions. Tandem epoxidations of 34 would then yield the target natural product 1.

a Reagents and conditions: (a) DMP, CH2Cl2, 23 °C, 70%; (b) L-phenylalaninol, DMAP, PhCH3, reflux, 50%; (c) EDC·HCl, Cl2CHCOOH, DMSO, PhCH3, 23 °C; (d) NaOH, EtOAc, H2O, 23 °C; (e) MMPP·6H2O, THF, MeOH, 0 → 23 °C, 32% (three steps). DMP = Dess−Martin periodinane, DMAP = 4-dimethylaminopyridine, EDC = 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, MMPP = magnesium monoperoxyphthalate.

(18) was achieved by heating them in the presence of a catalytic amount of DMAP to afford amide 36 (keto/enol = 1/2) in 50% yield.14 Alcohol 36 was oxidized to an aldehyde utilizing 9337

DOI: 10.1021/acs.joc.7b01224 J. Org. Chem. 2017, 82, 9335−9341

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The Journal of Organic Chemistry a modified Pfitzner−Moffatt oxidation.11 As anticipated (Scheme 4), when the resulting linear aldehyde intermediate was treated with aqueous sodium hydroxide solution, γ-lactam 34 was formed exclusively. Tandem epoxidations of lactam 34 with MMPP afforded epoxide intermediate 14 which underwent an in situ spirocyclization to yield (±)-azaspirene (1) in 32% yield over three steps. Notably, the MMPP-mediated double epoxidations of 34 proceeded with comparable efficiency to our first-generation total synthesis of 1 (Scheme 3) despite the presence of the α,β−γ,δ-unsaturated ketone moiety probable to oxidation. While our total synthesis of azaspirene (1) was inspired by its biosynthetic hypothesis, the chemical reactivity of biosynthetically relevant synthetic precursors conversely provided insights to the biosynthesis of this natural product. In 2014, Tang and co-workers reported elegant biosynthetic studies of azaspirene (1, Scheme 6A).9d Although the focus of Tang’s report was on

We showed that the condensative cyclization of aldehyde 31 results in enamide derivative 34 (Scheme 6B). The preferential formation of dienol tautomer 34 over enone tautomer 40 was consistent with observations from Snider’s report11 and our previous studies en route to berkeleyamide D.10 We therefore propose that the flavin-dependent monooxygenase in PsoF would biotransform enamide 34 to intermediate 43 via an electrophilic epoxidation. Subsequent epoxide opening by the enol moiety in 43 would yield α,β-unsaturated-γ-hydroxy-γlactam 44.11 For the final biosynthetic step, we envision a PsoG-mediated nucleophilic epoxidation of 44 to give epoxide 14 followed by a spirocyclization to yield azaspirene (1).

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CONCLUSION To conclude, we have completed a six-step total synthesis of (±)-azaspirene (1) in 10.0% overall yield from commercially available aldehyde 16 and β-ketoester 17. Keys to the brevity of our synthesis were (1) the effective γ-lactam formation from linear precursor 36, (2) the successful consecutive epoxidations of γ-lactam 34 to afford α,β-epoxy-γ-hydroxy-γ-lactam 14, and (3) the in situ spirocyclization of epoxide 14 to yield the final target 1. The methyl substituent in 36 was critical in preventing the formation of the ε-lactam derivative, an undesired product observed during our previous studies toward berkeleyamide D (2). Our concise second-generation synthetic route to (±)-azaspirene (1) provides a platform for the enantioselective total synthesis of this family of natural products. The discovery of highly enantioselective epoxidation conditions of enamide intermediate 34 would forge azaspirene (1) with high enantiomeric excess. Studies toward this goal are currently undergoing and will be the subject of our future report.

Scheme 6. Revision of the Biosynthetic Hypothesis of Azaspirene (1)

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EXPERIMENTAL SECTION

General Experimental Methods. All reactions were performed in oven-dried or flame-dried round-bottomed flasks. Unless otherwise noted, the flasks were fitted with rubber septa and reactions were conducted under a positive pressure of argon. Stainless steel syringes or cannulae were used to transfer air- and moisture-sensitive liquids. Flash column chromatography was performed as described by Still et al. using silica gel (60 Å pore size, 40−63 μm, 4−6% H2O content).16 Analytical thin-layer chromatography (TLC) was performed using glass plates precoated with 0.25 mm silica gel impregnated with a fluorescent indicator (254 nm). Thin-layer chromatography plates were visualized by exposure to ultraviolet light and/or by exposure to an aqueous solution of ceric ammonium molybdate (CAM). Unless otherwise stated, all commercial reagents and solvents were used without additional purification with the following exceptions: dichloromethane and tetrahydrofuran were purchased from commercial vendors, respectively, and were purified by the method of Grubbs et al. under positive argon pressure.17 Proton and carbon nuclear magnetic resonance spectra were recorded with an Agilent Technologies DD2 (600 MHz) spectrometer. Proton nuclear magnetic resonance spectra are referenced from the residual protium in the NMR solvent (CDCl3: δ 7.24 (CHCl3) or DMSO-d6: δ 2.50 (DMSO-d5)). Data are reported in the following manners: chemical shift in ppm [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, app = apparent, br = broad), coupling constant(s) in hertz, integration]. Carbon-13 nuclear magnetic resonance spectra are referenced from the carbon resonances of the solvent (CDCl3: δ 77.23 or DMSO-d6: δ 39.51). Data are reported in the following manners: chemical shift in ppm. Highresolution mass spectra were obtained from KAIST Research Analysis Center (Daejeon) by using the ESI method. Procedures for the First-Generation Total Synthesis of Azaspirene (1). (6E,8E)-tert-Butyl 5-Hydroxy-4-methyl-3-oxoundeca-6,8-dienoate (19). To a suspension of sodium hydride (NaH, 60%

the importance of the methylation of the polyketide chain for the facile acyl transfer between PKS and NRPS units, the paper also proposed structures of advanced biosynthetic precursors based on mass spectrometry and UV spectroscopy. They proposed a PsoA-mediated amide bond formation between thioester 37 and amine 38 and a PsoA-mediated reduction of the resulting thioester 39 to aldehyde 31. They invoked an intramolecular condensative cyclization of aldehyde 31 and a subsequent PsoF-mediated epoxidation of the resulting enone 40 to afford epoxide 41. Compound 41 was anticipated to undergo an intramolecular epoxide opening to give spirocycle 42. The Tang group proposed a PsoG-mediated C−H activation of the C8 position of 42 for the last biosynthetic step. 9338

DOI: 10.1021/acs.joc.7b01224 J. Org. Chem. 2017, 82, 9335−9341

Article

The Journal of Organic Chemistry dispersion in mineral oil, 429 mg, 10.7 mmol, 1.10 equiv) in THF (25 mL) at 0 °C was added tert-butyl 3-oxopentanoate (17, 1.73 mL, 9.75 mmol, 1 equiv) dropwise under argon. After the reaction mixture was stirred at 0 °C for 30 min, a solution of n-BuLi (1.80 M in n-hexane, 5.94 mL, 10.7 mmol, 1.10 equiv) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 30 min. The resulting solution was cooled to −78 °C. Subsequently, (2E,4E)hepta-2,4-dienal (16, 90%, 1.39 mL, 9.75 mmol, 1.00 equiv) in THF (25 mL) was transferred by cannula to the reaction mixture. The reaction mixture was allowed to warm to 23 °C. After 3 h, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, the resulting mixture was diluted with ethyl acetate (100 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 100 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 4 cm, ht 15 cm; eluent: ethyl acetate/hexanes = 1:15−1:7) to afford (±)-19 (2:1 mixture of diastereomers, 2.50 g, 90%) as a yellow oil. 1H NMR and 13C NMR of 19 were taken with the sample containing 2:1 mixture of inseparable diastereomers: 1H NMR (599.2 MHz, CDCl3, major diastereomer) δ 6.22−6.14 (m, 1H), 6.00−5.94 (m, 1H), 5.76−5.68 (m, 1H), 5.49−5.45 (m, 1H), 4.15 (m, 1H), 3.48−3.37 (m, 2H), 2.83−2.73 (m, 1H), 2.42 (d, J = 3.7 Hz, 1H), 2.10−2.02 (m, 2H), 1.42 (s, 9H), 1.02 (d, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); 1H NMR (599.2 MHz, CDCl3, minor diastereomer) δ 6.22−6.14 (m, 1H), 6.00−5.94 (m, 1H), 5.76−5.68 (m, 1H), 5.49−5.45 (m, 1H), 4.43 (m, 1H), 3.48−3.37 (m, 2H), 2.83−2.73 (m, 1H), 2.56 (d, J = 3.7 Hz, 1H), 2.10−2.02 (m, 2H), 1.42 (s, 9H), 1.09 (d, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (150.7 MHz, CDCl3, major diastereomer) δ 207.5, 166.7, 138.1, 133.3, 130.5, 128.3, 82.1, 75.4, 51.9, 51.3, 28.2, 25.8, 13.8, 13.5; 13C NMR (150.7 MHz, CDCl3, minor diastereomer) δ 207.2, 166.7, 137.6, 132.5, 129.6, 128.5, 82.2, 72.7, 51.5, 50.3, 28.5, 28.2, 13.5, 10.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H26O4Na 305.1723, found 305.1725; TLC (ethyl acetate/ hexanes = 1:3) Rf 0.53 (CAM, UV). (6E,8E)-tert-Butyl 5-((tert-Butyldimethylsilyl)oxy)-4-methyl-3-oxoundeca-6,8-dienoate (20). To a stirred solution of (±)-19 (3.27 g, 11.6 mmol, 1 equiv) and 2,6-lutidine (2.01 mL, 17.4 mmol, 1.50 equiv) in CH2Cl2 (40 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 2.79 mL, 12.2 mmol, 1.05 equiv) dropwise at −78 °C. After 45 min, saturated aqueous sodium bicarbonate solution (40 mL) was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 40 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 5 cm, ht 15 cm; eluent: ethyl acetate/hexanes = 1:25) to afford (±)-20 (1:1 mixture of diastereomers, 3.86 g, 84%) as a colorless oil. 1H NMR and 13C NMR of 20 were taken with the sample containing 1:1 mixture of inseparable diastereomers: 1H NMR (599.2 MHz, CDCl3) δ 6.09−6.01 (m, 2H), 6.00−5.92 (m, 2H), 5.74−5.64 (m, 2H), 5.44−5.36 (m, 2H), 4.24 (app-t, J = 6.4 Hz, 1H), 4.13 (app-t, J = 8.3 Hz, 1H), 3.52−3.44 (m, 2H), 3.41−3.34 (m, 2H), 2.88−2.80 (m, 1H), 2.79−2.71 (m, 1H), 2.12−2.03 (m, 4H), 1.44 (s, 9H), 1.43 (s, 9H), 1.05 (d, J = 6.9 Hz, 3H), 0.99 (app-q, J = 7.6 Hz, 6H), 0.94 (d, J = 6.9 Hz, 3H), 0.87 (s, 9H), 0.82 (s, 9H), 0.03 (s, 3H), −0.01 (s, 3H), −0.03 (s, 3H), −0.04 (s, 3H); 13C NMR (150.7 MHz, CDCl3) δ 207.1, 205.8, 166.9, 166.8, 137.6, 137.3, 132.9, 132.2, 131.4, 130.5, 128.5, 128.4, 81.9, 81.8, 77.5, 75.6, 53.3, 52.8, 52.7, 51.7, 28.6, 28.3, 28.2, 26.1, 26.1, 25.9, 25.8, 18.4, 18.3, 13.6, 13.6, 12.5, −3.9, −4.0, −4.8, −4.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H40O4SiNa 419.2588, found 419.2591; TLC (ethyl acetate/hexanes = 1:10) Rf 0.43 (CAM, UV). (6E,8E)-5-((tert-Butyldimethylsilyl)oxy)-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-4-methyl-3-oxoundeca-6,8-dienamide (15). To a stirred solution of (±)-20 (3.84 g, 9.68 mmol, 1 equiv) and L-phenylalaninol (18, 1.46 g, 9.68 mmol, 1.00 equiv) in toluene (150 mL) was added 4-dimethylaminopyridine (DMAP, 591 mg, 4.84 mmol, 0.50 equiv) at 23 °C, and the reaction flask was equipped

with a reflux condenser. The resulting reaction mixture was heated to 130 °C. After 6 h, the reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 5 cm, ht 13 cm; eluent: ethyl acetate/hexanes = 1:3−1:1) to afford 15 (mixture of four diastereomers, 3.44 g, 75%) as a yellow oil. 1H NMR and 13C NMR of 15 were taken with the sample containing four inseparable diastereomers: 1H NMR (599.2 MHz, CDCl3) δ 7.46 (app-t, J = 7.7 Hz, 1H), 7.30−7.16 (m, 5H), 6.11−6.01 (m, 1H), 6.00−5.92 (m, 1H), 5.77−5.66 (m, 1H), 5.42−5.30 (m, 1H), 4.27−4.09 (m, 2H), 3.71−3.61 (m, 1H), 3.59−3.50 (m, 1H), 3.50−3.35 (m, 2H), 2.93−2.60 (m, 4H), 2.13−2.03 (m, 2H), 1.05−0.87 (m, 6H), 0.87−0.77 (m, 9H), 0.05−-0.09 (m, 6H); 13C NMR (150.7 MHz, CDCl3) δ 210.8, 210.7, 209.5, 209.4, 166.8, 166.8, 166.7, 166.6, 138.0, 138.0, 138.0, 138.0, 137.8, 137.8, 137.8, 137.8, 133.3, 133.2, 132.4, 132.4, 131.0, 130.9, 130.2, 130.2, 129.4, 129.4, 129.4, 129.4, 128.9, 128.8, 128.8, 128.7, 128.3, 128.3, 128.2, 128.2, 126.8, 126.8, 126.8, 126.8, 77.3, 77.3, 75.4, 75.3, 64.6, 64.6, 64.5, 64.5, 54.4, 54.4, 53.7, 53.7, 53.6, 53.6, 53.5, 53.5, 49.7, 49.6, 49.5, 49.4, 37.3, 37.3, 37.3, 37.3, 26.0, 26.0, 26.0, 26.0, 25.8, 25.8, 25.8, 25.8, 18.3, 18.3, 18.2, 18.2, 13.5, 13.5, 13.5, 13.5, 13.3, 13.3, 12.3, 12.2, −3.8, −3.8, −4.0, −4.0, −4.8, −4.8, −4.8, −4.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H43NO4SiNa 496.2854, found 496.2855; TLC (ethyl acetate/hexanes = 1:1) Rf 0.58 (CAM, UV). (Z)-5-Benzyl-3-((4E,6E)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxy2-methylnona-4,6-dien-1-ylidene)-1H-pyrrol-2(3H)-one (21). To a stirred solution of 15 (965 mg, 2.04 mmol, 1 equiv) in DMSO (15 mL) and toluene (15 mL) were added 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC·HCl, 1.96 g, 10.2 mmol, 5.00 equiv) and dichloroacetic acid (340 μL, 4.08 mmol, 2.00 equiv) at 23 °C. After 14 h, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, the resulting mixture was diluted with ethyl acetate (40 mL) and water (10 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 40 mL), and the organic layers were combined. Aqueous sodium hydroxide solution (0.5 M, 120 mL) was added to the combined organic layers and stirred vigorously at 23 °C. After 2 h, the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 100 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 4 cm, ht 10 cm; eluent: ethyl acetate/hexanes = 1:5) to afford (±)-21 (1:1 mixture of diastereomers, 796 mg, 86% over two steps) as a yellow-green oil. We observed severe streaking during the flash column chromatography. 1H NMR and 13C NMR of 21 were taken with the sample containing 1:1 mixture of inseparable diastereomers: 1 H NMR (599.3 MHz, CDCl3) δ 9.44 (br-s, 1H), 9.38 (br-s, 1H), 7.35−7.21 (m, 10H), 6.24−6.11 (m, 2H), 6.11−5.95 (m, 2H), 5.82−5.66 (m, 2H), 5.58−5.46 (m, 4H), 4.36−4.27 (m, 2H), 3.69 (app-d, J = 7.0 Hz, 4H), 2.76−2.66 (m, 2H), 2.20−2.07 (m, 4H), 1.29 (d, J = 6.9 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H), 0.95 (s, 9H), 0.82 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H), 0.01 (s, 3H), −0.01 (s, 3H); 13C NMR (150.7 MHz, CDCl3) δ 176.5, 176.0, 171.9, 171.7, 137.4, 137.3, 136.9, 136.5, 133.0, 132.8, 132.5, 131.9, 131.8, 131.5, 129.0, 129.0, 128.7, 128.7, 128.6, 128.6, 126.8, 126.8, 108.3, 107.6, 98.8, 98.4, 75.8, 75.5, 45.5, 45.1, 34.9, 34.9, 26.0, 25.8, 25.8, 25.7, 18.3, 18.0, 14.2, 13.7, 13.5, 13.5, −4.0, −4.1, −4.7, −5.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H39NO3SiNa 476.2591, found 476.2597; TLC (ethyl acetate/ hexanes = 1:3) Rf 0.69 (CAM, UV). 4-Benzyl-1-((4E,6E)-3-((tert-butyldimethylsilyl)oxy)-2-methylnona-4,6-dienoyl)-4-hydroxy-6-oxa-3-azabicyclo[3.1.0]hexan-2-one (23). To a stirred solution of (±)-21 (209 mg, 0.461 mmol, 1 equiv) in a 1:1 mixture of THF/methanol (20 mL) was added magnesium monoperoxyphthalate hexahydrate (MMPP·6H2O, 80%, 313 mg, 0.507 mmol, 1.10 equiv) at 0 °C. The reaction mixture was allowed to warm to 23 °C. After 1 h, saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, the resulting mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate 9339

DOI: 10.1021/acs.joc.7b01224 J. Org. Chem. 2017, 82, 9335−9341

Article

The Journal of Organic Chemistry (2 × 20 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 3 cm, ht 12 cm; eluent: ethyl acetate/hexanes = 1:2) to afford (±)-23 (mixture of four diastereomers, 121 mg, 54%) as a pale yellow oil. 1H NMR and 13C NMR of 23 were taken with the sample containing four inseparable diastereomers: 1 H NMR (599.2 MHz, CDCl3) δ 7.35−7.18 (m, 5H), 6.16−6.03 (m, 1H), 6.02−5.84 (m, 2H), 5.77−5.68 (m, 1H), 5.49−5.27 (m, 1H), 4.38−4.18 (m, 1H), 4.11−3.96 (m, 1H), 3.21−2.91 (m, 2H), 2.88−2.74 (m, 1H), 2.14−2.04 (m, 2H), 1.27−0.93 (m, 6H), 0.92−0.80 (m, 9H), 0.14−-0.08 (m, 6H); 13C NMR (150.7 MHz, CDCl3) δ 201.9, 201.4, 201.2, 201.1, 166.8, 166.7, 166.3, 166.3, 138.1, 137.7, 137.6, 137.4, 133.2, 133.2, 133.1, 133.0, 133.0, 132.3, 131.9, 131.8, 131.3, 131.0, 130.9, 130.9, 130.9, 130.8, 130.8, 130.6, 129.4, 129.3, 129.3, 129.2, 128.9, 128.9, 128.9, 128.8, 128.5, 128.4, 128.4, 127.8, 84.5, 84.4, 84.4, 84.3, 76.0, 75.8, 75.0, 73.4, 64.0, 63.8, 63.6, 63.4, 62.9, 62.8, 62.8, 62.5, 50.4, 49.5, 48.0, 47.1, 43.6, 43.6, 43.6, 43.5, 26.2, 26.1, 26.1, 26.0, 25.9, 25.9, 25.9, 25.8, 18.4, 18.4, 18.3, 18.3, 13.6, 13.6, 13.5, 13.2, 12.8, 12.8, 12.6, 12.0, −3.9, −3.9, −3.9, −4.0, −4.5, −4.6, −4.7, −4.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H39NO5SiNa 508.2490, found 508.2493; TLC (ethyl acetate/ hexanes = 1:3) Rf 0.30 (CAM, UV). (±)-Azaspirene (1). To a stirred solution of (±)-23 (51.8 mg, 0.107 mmol, 1 equiv) in methanol (4.5 mL) was added triethylamine trihydrofluoride (1.5 mL) at 23 °C. After 24 h, saturated aqueous sodium bicarbonate solution (12 mL) was added to the reaction mixture, the resulting mixture was diluted with ethyl acetate (12 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 12 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude residue of (±)-24 was used in the next step without further purification. To a stirred solution of (±)-24 in dichloromethane (5 mL) was added Dess−Martin periodinane (DMP, 50.0 mg, 0.118 mmol, 1.10 equiv) at 23 °C. After 1.5 h, a mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution (1:1, 6 mL) was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 6 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 2.5 cm, ht 10 cm; eluent: ethyl acetate/hexanes = 1:3) to afford (±)-azaspirene (1, 16.5 mg, 42% over two steps) as a white solid: 1H NMR (599.2 MHz, CDCl3) δ 7.36−7.22 (m, 6H), 6.52 (br-s, 1H), 6.31−6.23 (m, 3H), 5.99 (br-s, 1H), 4.47 (d, J = 10.0 Hz, 1H), 3.24 (d, J = 11.3 Hz, 1H), 2.96−2.90 (m, 2H), 2.26−2.19 (m, 2H), 1.74 (s, 3H), 1.05 (t, J = 7.3 Hz, 3H); 13C NMR (150.7 MHz, CDCl3) δ 198.7, 183.5, 165.3, 148.5, 142.3, 134.5, 130.7, 129.0, 128.6, 127.8, 114.8, 110.8, 93.5, 84.8, 74.8, 43.0, 26.5, 13.0, 5.9; 1H NMR (599.2 MHz, (CD3)2SO) δ 9.51 (s, 1H), 7.38−7.26 (m, 5H), 7.15 (dd, J = 15.4, 10.6 Hz, 1H), 6.60 (d, J = 15.4 Hz, 1H), 6.45−6.31 (m, 2H), 6.18 (d, J = 4.4 Hz, 1H), 5.87 (s, 1H), 4.10 (d, J = 4.4 Hz, 1H), 3.01 (d, J = 13.9 Hz, 1H), 2.94 (d, J = 13.9 Hz, 1H), 2.21−2.15 (m, 2H), 1.68 (s, 3H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (150.7 MHz, (CD3)2SO) δ 198.9, 181.5, 164.8, 147.5, 140.7, 135.8, 130.8, 128.4, 128.1, 126.9, 115.1, 110.3, 93.6, 85.4, 71.1, 40.5, 25.6, 12.6, 5.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C21H23NO5Na 392.1468, found 392.1463; TLC (ethyl acetate/hexanes = 1:1) Rf 0.52 (CAM, UV); mp 164−165 °C. Procedures for the Second-Generation Total Synthesis of Azaspirene (1). (6E,8E)-tert-Butyl 4-Methyl-3,5-dioxoundeca-6,8dienoate (35). To a stirred solution of (±)-19 (2.50 g, 8.85 mmol, 1 equiv) in dichloromethane (110 mL) was added Dess−Martin periodinane (DMP, 5.64 g, 13.3 mmol, 1.50 equiv) at 23 °C. After 2 h, a mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution (1:1, 150 mL) was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 100 mL), and the combined organic layers were washed with brine (250 mL), dried

over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 5 cm, ht 15 cm; eluent: ethyl acetate/hexanes = 1:15) to afford 35 (1.74 g, 70%) as a yellow oil. Compound 35 was obtained as a mixture of keto/enol tautomers (keto/enol = 1/4): 1H NMR (599.2 MHz, CDCl3, major enol tautomer) δ 7.25−7.17 (m, 1H), 6.26−6.08 (m, 3H), 3.41 (d, J = 1.3 Hz, 2H), 2.19−2.12 (m, 2H), 1.85 (d, J = 1.3 Hz, 3H), 1.42 (d, J = 1.3 Hz, 9H), 1.00 (app-td, J = 7.4, 1.2 Hz, 3H); 1H NMR (599.2 MHz, CDCl3, minor keto tautomer) δ 7.25−7.17 (m, 1H), 6.26−6.08 (m, 3H), 4.01−3.96 (m, 1H), 3.36 (dd, J = 9.4, 1.3 Hz, 2H), 2.19−2.12 (m, 2H), 1.39 (d, J = 1.3 Hz, 9H), 1.30 (dd, J = 6.9, 1.3 Hz, 3H), 1.00 (app-td, J = 7.4, 1.2 Hz, 3H); 13C NMR (150.7 MHz, CDCl3, major enol tautomer) δ 194.0, 175.3, 167.1, 145.5, 141.7, 128.8, 121.0, 105.2, 82.0, 46.7, 28.1, 26.3, 13.1, 12.2; 13C NMR (150.7 MHz, CDCl3, minor keto tautomer) δ 200.2, 196.4, 166.4, 149.2, 145.6, 127.9, 125.6, 82.3, 58.8, 49.0, 28.1, 26.4, 13.0, 12.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H24O4Na 303.1567, found 303.1574; TLC (ethyl acetate/hexanes = 1:5) Rf 0.54 (CAM, UV). (6E,8E)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-4-methyl-3,5-dioxoundeca-6,8-dienamide (36). To a stirred solution of 35 (265 mg, 0.945 mmol, 1 equiv) and L-phenylalaninol (18, 143 mg, 0.945 mmol, 1.00 equiv) in toluene (100 mL) was added 4-dimethylaminopyridine (DMAP, 57.8 mg, 0.473 mmol, 0.50 equiv) at 23 °C, and the reaction flask was equipped with a reflux condenser. The resulting reaction mixture was heated to 115 °C. After 3 h, the reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 2.5 cm, ht 12 cm; eluent: dichloromethane/ methanol = 40:1−35:1) to afford 36 (170 mg, 50%) as a pale yellow oil. Compound 36 was obtained as a mixture of keto/enol tautomers (keto/enol = 1/2): 1H NMR (599.2 MHz, CDCl3, major enol tautomer) δ 7.33−7.15 (m, 6H), 6.84 (d, J = 7.0 Hz, 1H), 6.35−6.07 (m, 3H), 4.22−4.12 (m, 1H), 3.75−3.66 (m, 1H), 3.61−3.51 (m, 1H), 3.43−3.29 (m, 2H), 2.92−2.78 (m, 2H), 2.58 (br-s, 1H), 2.25−2.17 (m, 2H), 1.85 (s, 3H), 1.08−1.02 (m, 3H); 1H NMR (599.2 MHz, CDCl3, the first minor keto tautomer) δ 7.33−7.15 (m, 6H), 6.79 (d, J = 7.0 Hz, 1H), 6.35−6.07 (m, 3H), 4.22−4.12 (m, 1H), 4.01−3.93 (m, 1H), 3.75−3.66 (m, 1H), 3.61−3.51 (m, 1H), 3.43− 3.29 (m, 2H), 2.92−2.78 (m, 2H), 2.58 (br-s, 1H), 2.25−2.17 (m, 2H), 1.30 (app-t, J = 6.6 Hz, 3H), 1.08−1.02 (m, 3H); 1H NMR (599.2 MHz, CDCl3, the second minor keto tautomer) δ 7.33−7.15 (m, 6H), 6.70 (d, J = 8.4 Hz, 1H), 6.35−6.07 (m, 3H), 4.22−4.12 (m, 1H), 4.01−3.93 (m, 1H), 3.75−3.66 (m, 1H), 3.61−3.51 (m, 1H), 3.43−3.29 (m, 2H), 2.92−2.78 (m, 2H), 2.58 (br-s, 1H), 2.25−2.17 (m, 2H), 1.30 (app-t, J = 6.6 Hz, 3H), 1.08−1.02 (m, 3H); 13C NMR (150.7 MHz, CDCl3, major enol tautomer) δ 194.9, 176.2, 167.1, 146.4, 142.5, 137.7, 129.4, 128.7, 128.7, 126.7, 120.8, 105.6, 64.3, 53.5, 45.7, 37.2, 26.4, 13.1, 12.2; 13C NMR (150.7 MHz, CDCl3, minor keto tautomers) δ 203.0, 202.9, 197.6, 197.3, 166.1, 166.0, 149.9, 149.8, 146.2, 146.2, 137.8, 137.8, 129.4, 129.4, 128.8, 128.8, 128.7, 128.7, 127.8, 127.8, 125.5, 125.5, 63.8, 63.8, 58.6, 58.3, 53.4, 53.4, 49.3, 49.0, 37.1, 37.1, 26.5, 26.5, 13.0, 13.0, 12.9, 12.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C21H27NO4Na 380.1832, found 380.1832; TLC (ethyl acetate) Rf 0.55 (CAM, UV). (±)-Azaspirene (1). To a stirred solution of 36 (33.5 mg, 0.094 mmol, 1 equiv) in DMSO (1 mL) and toluene (1 mL) were added 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDC·HCl, 90.1 mg, 0.470 mmol, 5.00 equiv) and dichloroacetic acid (15.5 μL, 0.188 mmol, 2.00 equiv) at 23 °C. After 19 h, saturated aqueous ammonium chloride solution (5 mL) was added to the reaction mixture, the resulting mixture was diluted with ethyl acetate (5 mL) and water (5 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 5 mL), and the organic layers were combined. Aqueous sodium hydroxide solution (0.5 M, 15 mL) was added to the combined organic layers and stirred vigorously at 23 °C. After 1.5 h, the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 15 mL), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and 9340

DOI: 10.1021/acs.joc.7b01224 J. Org. Chem. 2017, 82, 9335−9341

Article

The Journal of Organic Chemistry

T.; Noguchi, H.; Hotta, K.; Tang, Y.; Watanabe, K. Angew. Chem., Int. Ed. 2014, 53, 8475. (d) Zou, Y.; Xu, W.; Tsunematsu, Y.; Tang, M.; Watanabe, K.; Tang, Y. Org. Lett. 2014, 16, 6390. (10) Jo, D.; Han, S. Org. Chem. Front. 2017, 4, 506. (11) Snider, B. B.; Neubert, B. J. J. Org. Chem. 2004, 69, 8952. (12) (a) Komori, K.; Taniguchi, T.; Mizutani, S.; Monde, K.; Kuramochi, K.; Tsubaki, K. Org. Lett. 2014, 16, 1386. (b) Mizutani, S.; Komori, K.; Kai, C.; Kuramochi, K.; Tsubaki, K. Tetrahedron 2016, 72, 6640. (13) Huckin, S. N.; Weiler, L. Tetrahedron Lett. 1971, 12, 4835. (14) Witzeman, J. S.; Nottingham, W. D. J. Org. Chem. 1991, 56, 1713. (15) See the Supporting Information for details. (16) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923. (17) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518.

concentrated under reduced pressure. The resulting crude residue of 34 was used in the next step without further purification. To a stirred solution of 34 in a 1:1 mixture of THF/methanol (4 mL) was added magnesium monoperoxyphthalate hexahydrate (MMPP·6H2O, 80%, 63.9 mg, 0.103 mmol, 1.10 equiv) at 0 °C. The reaction mixture was allowed to warm to 23 °C. After 1 h, saturated aqueous sodium bicarbonate solution (4 mL) was added to the reaction mixture, the resulting mixture was diluted with ethyl acetate (5 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 5 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diameter 1.5 cm, ht 12 cm; eluent: ethyl acetate/hexanes = 1:3) to afford (±)-azaspirene (1, 10.9 mg, 32% over three steps) as a white solid: 1H NMR (599.2 MHz, CDCl3) δ 7.36−7.22 (m, 6H), 6.51 (br-s, 1H), 6.31−6.23 (m, 3H), 5.98 (br-s, 1H), 4.47 (s, 1H), 3.25 (d, J = 13.9 Hz, 1H), 2.94 (app-d, J = 13.8 Hz, 2H), 2.26−2.19 (m, 2H), 1.74 (s, 3H), 1.05 (t, J = 7.5 Hz, 3H).

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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.joc.7b01224. Comparison of spectroscopic data of our synthetic azaspirene (1) to the natural azaspirene (1); 1H and 13 C NMR spectra of all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sunkyu Han: 0000-0002-9264-6794 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Thomas Taehyung Kim for helping us revise the manuscript. We are grateful for financial support provided by the National Research Foundation of Korea (2015R1C1A1A020363) and the Institute for Basic Science (IBS-R010-D1).

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REFERENCES

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DOI: 10.1021/acs.joc.7b01224 J. Org. Chem. 2017, 82, 9335−9341