Total syntheses of (+)-agelastatin A and (+)-agelastatin B through cationic cyclizations

Tetrahedron 73 (2017) 4538e4544

Contents lists available at ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Total syntheses of (þ)-agelastatin A and (þ)-agelastatin B through cationic cyclizations Yanmin Yao a, c, Xiaobin Wang a, Guangxin Liang a, b, * a

State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China c Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 February 2017 Received in revised form 5 June 2017 Accepted 5 June 2017 Available online 8 June 2017

We report concise asymmetric total syntheses of tetracyclic marine alkaloids (þ)-agelastatin A and (þ)-agelastatin B using a cationic cyclization-based approach, which features straightforward transformations with cost-effective chemicals and reagents. © 2017 Published by Elsevier Ltd.

Keywords: Pyrrole-imidazole marine alkaloids (þ)-Agelastatin A (þ)-Agelastatin B Total synthesis Cationic cyclization

1. Introduction Agelastatins belong to the pyrrole-imidazole family of marine alkaloids (Fig. 1).1 This group of architecturally unusual tetracyclic compounds features a densely functionalized cyclopentane ring bearing four contiguous stereogenic centers substituted with nitrogen functionalities. Of the many fascinating secondary metabolites uncovered in recent years, agelastatins stood out not only for their intriguing chemical structures but also for their exceptional biological activities. For instance, Agelastatin A (1, Fig. 1), originally isolated by Pietra and co-workers in 1993,2 exhibits nanomolar cytotoxicity against a wide range of human cancer cell lines.3 It also displays selective inhibition of GSK-3b (glycogen synthase kinase3b) at low concentrations, suggesting its potential role in preventing Alzheimer's disease.4 In addition, the alkaloid might function as a novel insulin mimetic,4a as well as potent insecticide against larvae of beet army worm and corn rootworm.5 The highly complex heterocyclic framework, biological and pharmacological functions, as well as limited natural supply of agelastatins have

DOI of original article: http://dx.doi.org/10.1016/j.tet.2017.05.079. * Corresponding author. State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China. E-mail address: [email protected] (G. Liang). http://dx.doi.org/10.1016/j.tet.2017.06.009 0040-4020/© 2017 Published by Elsevier Ltd.

prompted substantial interest from synthetic community, leading to various innovative solutions to their total syntheses.6

2. Results/Discussion Intrigued by the synthetic challenge posed by agelastatins, we initiated a program to study the total synthesis of this small group of marine alkaloids in mid-2009. To best of our knowledge, all reported synthetic strategies prior to our study had relied on elaboration of 5-membered carbocyclic intermediates to introduce the required substituents on the densely functionalized cyclopentane ring. We conceived a new strategy which harnesses the intrinsic chemical reactivity of an intermediate 9 to generate the central C ring at the late stage of the synthesis through a cationic cyclization (Scheme 1). Specifically, activation of the hemiaminal 9 with acid would produce a highly electrophilic N-acyl iminium ion 8, which would be quenched by the electron-rich double bond in the imidazolone heterocycle and afford another reactive acyliminium ion 7.7 Subsequent substitution reaction with water would convert this cationic intermediate to agelastatin A. We speculated that the key intermediate 9 utilized in this strategy could be readily prepared from lactone 11 through an aminolysis and oxidation sequence. Taken together, our strategy breaks down the complex fused tetracyclic target molecule into a much less complicated bicyclic

Y. Yao et al. / Tetrahedron 73 (2017) 4538e4544

4539

Fig. 1. Structures of agelastatin alkaloids.

Scheme 2. Total synthesis of (þ)-agelastatin A. Reagents and conditions: [a] LiAlH4, THF, then AcOH, 12, H2SO4, 52%; [b] SO3$Py, DMSO, NEt3, RT, then MeNO2, 85%; [c] H2, Pd/C, MeOH, RT, then methyl isocyanate, 100%; [d] (COCl)2, DMSO, 78  C, then NEt3, -78  C to RT, 82%; [e] NH3, MeOH, 40  C, 90%; [f] (COCl)2, DMSO, 78  C, then (iPr)2NEt, 78  C to RT, 85%; [g] 0.1N HCl(aq), reflux, 21% (20), 36% (21), 29% (22); [h] NBS, MeOH, RT, 79% (22 / ent-1).

Scheme 1. Retrosynthetic analysis of (e)-agelastatin A.

precursor 11 with only one stereogenic center, which could be derived from D-aspartic acid. To examine the feasibility of our strategy, we pursued a forward synthesis (Scheme 2) starting with the cost-effective HCl salt of Laspartic acid diethyl ester (13, Scheme 2). A facile one-pot reaction converted 13 to lactone 14 in 52% yield. We assume that reduction of the amino ester 13 with LiAlH4 produced amino dialcohol, which underwent a Paal-Knorr pyrrole synthesis8 upon the treatment of AcOH and 12.9 Subsequent addition of concentrated sulfuric acid catalyzed the transesterification to afford the lactone in reasonable yield. The Parikh-Doering oxidation10 of the alcohol 14 to aldehyde and subsequent Henry reaction11 in the same pot accomplished the carbon chain elongation with a nitro group in 15. Further functionalization of the nitro group through a hydrogenation and nucleophilic addition sequence easily generated 16. Treatment of 16 under a typical Swern oxidation12 condition successfully drove tandem oxidation, ring closure and elimination to furnish the imidazolone heterocycle in 17. As we anticipated, aminolysis on the lactone 17 and subsequent Swern oxidation of 18 provided the hemiaminal 19 as a pair of diastereomers. Under the optimal reflux condition in 0.1 N hydrochloric acid, the key intermediate 19 was transformed to the desired product 22 in 29% yield together with

two side products 20 and 21 in 21% and 36% yield, respectively. We speculate that the side product 20 was obtained from 23 due to elimination occurring before the C ring formation (Scheme 3). After the C ring formation, nucleophilic substitution on the cationic intermediate with water produced 22 as the desired product. Meanwhile, a competitive elimination reaction led to the undesired 21 as a side product. Notably, our attempt to convert 21 to 22 by testing a variety of acidic conditions turned out to be fruitless. Nevertheless, by following a well-established bromination procedure,13 we achieved a total synthesis of (þ)-agelastatin A in 8 steps from L-aspartic acid derivative 13. While encouraged by the accomplishment of an asymmetric total synthesis of (þ)-agelastatin A, we were concerned about the optical purity of the product since it might be eroded by potential epimerization through equilibrium described in Scheme 3. To accurately qualify the optical purity of ent-1 using chiral HPLC analysis, we carried out a racemic synthesis of (±)-22. Our synthesis of (±)-18, the precursor of (±)-22, was illustrated in Scheme 4. This synthetic sequence employed the classic hydrogenation strategy for unnatural amino acid preparation. The unsaturated substrate 27 for hydrogenation was synthesized from aldehyde 2514 and phosphonate 26.15 Pd/C catalyzed hydrogenation of 27 neatly produced the unnatural amino ester 28 in 95% yield. Treatment of 28 with Na in liquid NH3 fulfilled both debenzylation and reduction of the ester group to produce the amino alcohol 29 in good yield. The Paal-Knorr pyrrole synthesis using 12 followed by aminolysis smoothly generated (±)-18. Applying the reaction conditions for synthesis of 22 described earlier in this study, we were able to convert (±)-18 to the reference standard (±)-22.

4540

Y. Yao et al. / Tetrahedron 73 (2017) 4538e4544

Scheme 3. Possible epimerization of the stereogenic center in 23.

Scheme 5. Total synthesis of (þ)-agelastatin B. Reagents and conditions: [a] NBS, MeOH, RT; [b] (COCl)2, DMSO, 78  C, then NEt3, 78  C to RT, 37% (32a), 45% (32b); [c] NH3, MeOH, 40  C, 90% (32b / 33); [d] (COCl)2, DMSO, 78  C, then (iPr)2NEt, 78  C to RT, 85%; [e] 0.1N HCl(aq), reflux, 29%; [f] NBS, MeOH, RT, 90%.

Scheme 4. A racemic synthesis of (±)-18. Reagents and conditions: [a] DBU, CH2Cl2, RT, 67%; [b] H2, Pd/C, MeOH, RT, 95%; [c] Na, NH3, THF, 78  C, 87%; [d] 12, AcOH:EtOH ¼ 3:1, 55  C, 61%; [e] NH3, MeOH, 40  C, 77%.

Gratifyingly, the chiral HPLC analysis showed greater than 99% enantiomeric excess of 22 prepared using our approach, indicating that the equilibrium we illustrated in Scheme 3 rarely took place under our reaction conditions. It merits a note that while we were optimizing our cyclization conditions to improve the chemical yield of 22, Movassaghi and coworkers reported the synthesis of agelastatins with the same synthetic strategy.7a In their study, they used 31 (Scheme 5) for the key cyclization and achieved 47% yield for the synthesis of (e)-agelastatin A. We applied their reaction conditions, but did not obtain improved yield of 22. Inspired by their speculation that the bromo group on pyrrole facilitated the desired cyclization, we attempted to use a similar substrate to improve the yield of the key cyclization step. Unfortunately, we were not able to make this substrate with the same bromo-substitution pattern on pyrrole. Bromination of 16 afforded a pair of regioisomers, which transformed to 32a and 32b upon Swern oxidation. Interestingly, 32a completely decomposed when treated with aminolysis conditions, whereas 32b was converted to 33 in excellent yield under the same conditions. By employing a typical procedure reported previously, we were able to transform 33 to (þ)-agelastatin B16 in a similar fashion. Notably, the new substrate 33 behaved the same as 18 in the key cyclization reaction and did not give improved chemical yield for the desired product.

3. Conclusion In summary, we have developed a cationic cyclization-based approach for the asymmetric synthesis of agelastatins. Both (þ)-agelastatin A and (þ)-agelastatin B were prepared through concise synthetic sequence involving straightforward

transformations. Cost-effective chemicals and reagents were utilized in each step of our route. Additionally, a different synthetic approach was developed for synthesizing a racemic key intermediate 18 required in the synthetic sequence. Using chiral HPLC analysis with (±)-22 as a reference standard, we demonstrated our synthetic route reliably achieved chirality transfer with no erosion of the optical purity of the target compound.

4. Experimental section 4.1. General All sensitive reactions were performed under an atmosphere of Ar. Reagents obtained from Acros, Aldrich, J&K, and Aladdin were used without further purification. THF and Et2O were dried by distillation over Na/diphenyl ketone. CH2Cl2, and CH3NO2 were dried by distillation over CaH2. TLC inspections were on silica gel GF254 plates. Column chromatography was generally performed on silica gel (200e300 mesh). 1 H NMR and 13C NMR spectra were recorded on a Bruker AVANCE AV400 (400 MHz and 100 MHz). Signal positions were recorded in ppm with the abbreviations s, d, t, q, br, m and app denoting singlet, doublet, triplet, quartet, broad, multiplet and apparent respectively. All NMR chemical shifts were referenced to residual solvent peaks or to Si(CH3)4 as an internal standard, spectra recorded in CDCl3 were referenced to residual CHCl3 at 7.26 ppm for 1H or 77.0 ppm for 13C, spectra recorded in CD3OD were referenced to residual CD2HOD at 3.31 ppm for 1H or 49.15 ppm for 13C, spectra recorded in D2O were referenced to residual H2O at 4.79 ppm for 1H. All coupling constants, J, are quoted in Hz. IR spectra were recorded on a Bruker Tensor 27 FTIR spectrometer and reported in wave numbers (cm1). High resolution mass spectra (HRMS) were obtained on an IonSpec QFT mass spectrometer with ESI resource. Optical rotations are recorded on a Perkin-Elmer 341 polarimeter (using the sodium D line; 589 nm) at 25  C.

Y. Yao et al. / Tetrahedron 73 (2017) 4538e4544

4.2. (S)-4-(2-hydroxyethyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4] oxazin-1-one (14)17 To a slurry of LAH (3.0 g, 78.4 mmol) in dry THF (30 mL) was added a solution of L-aspartic acid diethyl ester hydrochloride 13 (7.5 g, 62.7 mmol) in dry THF (50 mL) dropwise at 0  C under a nitrogen atmosphere. Then the solution was heated to reflux and stirred for 1 h. The reaction was cooled to 0  C with ice-water and MeOH (25 mL) was added carefully. After being stirred for 10 min, AcOH (6 mL) and 12 (14.9 g, 94.05 mmol) were added. The reaction was allowed to warm to room temperature and stirred for 12 h. Then conc. H2SO4 (17 mL) was added slowly, and the reaction was heated to reflux for 12 h. The reaction was cooled to 0  C and diluted with saturated NaCl solution (200 mL) and EtOAc (200 mL) and then separated. The aqueous layer was extracted with EtOAc (3  100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (100 mL), dried over anhydrous MgSO4 and evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (1:2 petroleum ether:AcOEt) to give 14 (5.9 g, 32.6 mmol, 52%) as a white solid. Data for 14: Rf 0.22 (1:3 petroleum ether:EtOAc); 1 mp: 68e69  C; [a]25 D -39.6 (c 1.6, MeOH); H NMR (400 MHz, CDCl3) d 7.10 (d, J ¼ 3.8, 1 H), 7.00 (s, 1 H), 6.35e6.25 (m, 1 H), 4.70 (dd, J ¼ 11.6, 3.1, 1 H), 4.57e4.42 (m, 1 H), 3.89e3.78 (m, 1 H), 3.61 (ddd, J ¼ 10.9, 8.5, 4.4, 1 H), 2.08 (ddd, J ¼ 11.0, 8.9, 5.0, 2 H), 1.70 (s, 1 H); 13 C NMR (100 MHz, CDCl3) d 159.0, 124.9, 118.4, 118.0, 110.7, 70.0, 58.3, 50.4, 34.5; IR (thin film): nmax 3450, 2941, 2877, 1686, 1535, 1471, 1405, 1335, 1211, 1109, 1070, 760; HRMS (ESI): Calcd for C9H11NO3Na [MþNa]þ 204.0631, found: 204.0629. 4.3. (4S)-4-(2-hydroxy-3-nitropropyl)-3,4-dihydro-1H-pyrrolo[2,1c][1,4]oxazin-1-one (15) DMSO (41.1 mL, 579.0 mmol) activated with SO3Py (11.1 g, 69.5 mmol) for 10 min was added dropwise into a solution of 14 (7.0 g, 38.6 mmol) and Et3N (107.6 mL, 772.0 mmol) in CH2Cl2 (210 mL). The reaction mixture was stirred at room temperature for 5 h. Then MeNO2 (20.8 mL, 386.0 mmol) was added and the reaction was stirred at room temperature for 15 h. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (1:2 petroleum ether:AcOEt) to give 15 (7.8 g, 32.8 mmol, 85%) as a white solid. Data for 15: Rf 0.23 (1:1 petroleum ether:EtOAc); 1H NMR (400 MHz, CD3OD) d 7.21 (d, J ¼ 9.0, 1 H), 7.09e7.02 (m, 1 H), 6.34 (dd, J ¼ 6.4, 2.6, 1 H), 4.75 (dd, J ¼ 11.7, 3.2, 0.5 H), 4.72e4.65 (m, 1 H), 4.65e4.58 (m, 1.5 H), 4.58e4.52 (m, 1 H), 4.50e4.38 (m, 1.5 H), 4.20e4.11 (m, 0.5 H), 2.14e2.02 (m, 1 H), 1.94 (tdd, J ¼ 14.4, 10.3, 4.6, 1 H); 13C NMR (100 MHz, CD3OD) d 161.3, 127.3, 126.2, 119.7, 119.2, 118.9, 112.0, 111.7, 82.1, 81.8, 72.3, 70.2, 66.64, 66.55, 51.8, 51.7, 37.1, 36.8; IR (thin film): nmax 3452, 2505, 1676, 1545, 1410, 1383, 1335, 1095, 754; HRMS (ESI): Calcd for C10H12N2O5Na [MþNa]þ 263.0638, found: 263.0631. 4.4. 1-(2-Hydroxy-3-((S)-1-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4] oxazin-4-yl)propyl)-3-methylurea (16) To a solution of 15 (7.5 g, 31.5 mmol) in MeOH (100 mL) was added Pd/C (10% Pd content, 375 mg), and the reaction vessel was evacuated and back-filled with hydrogen (1 atm.). The reaction mixture was stirred under hydrogen at room temperature for 4 h. Then methyl isocyanate (5M in toluene, 7 mL, 34.7 mmol) was added. Then the mixture was filtered over a plug of silica gel topped with Celite (MeOH eluent) to afford 16 (8.4 g, 31.5 mmol, 100%) as a white solid. Data for 16: Rf 0.29 (9:1CH3Cl:MeOH); 1H NMR (400 MHz, CD3OD) d 7.23e7.16 (m, 1 H), 7.03 (d, J ¼ 4.0, 1 H), 6.31

4541

(ddd, J ¼ 6.8, 4.0, 2.6, 1 H), 4.69 (ddd, J ¼ 12.7, 7.9, 2.6, 1 H), 4.62e4.48 (m, 2 H), 3.79 (q, J ¼ 5.4, 0.5 H), 3.56e3.49 (m, 0.5 H), 3.34e3.29 (m, 0.5 H), 3.15 (ddd, J ¼ 8.3, 5.5, 1.8, 1.5 H), 2.71 (s, 1.5 H), 2.68 (s, 1.5 H), 2.05e1.93 (m, 1 H), 1.92e1.74 (m, 1 H); 13C NMR (100 MHz, CD3OD) d 162.1, 161.4, 127.3, 126.1, 119.6, 119.2, 118.8, 118.7, 111.9, 111.5, 72.5, 70.6, 68.9, 68.8, 52.2, 52.0, 47.4, 47.2, 37.8, 37.5, 27.1; IR (thin film): nmax 3375, 2935, 1701, 1653, 1576, 1406, 1329, 1086, 1049, 750; HRMS (ESI): Calcd for C12H17N3O4Na [MþNa]þ 290.1111, found: 290.1114. 4.5. (S)-4-((3-methyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl) methyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (17)18 To a solution of oxalyl chloride (1.9 mL, 22.5 mmol) in CH2Cl2 (80 mL) at 78  C was slowly added DMSO (3.2 mL, 45.0 mmol). After 15 min, a solution of 16 (4.0 g, 15.0 mmol) in CH2Cl2 (50 mL) was added to the reaction mixture. After being stirred for 30 min at 78  C the mixture was quenched with Et3N (10.5 mL, 75.0 mmol) and stirred at 78  C for 30 min and then warmed up to 25  C, and 3N HCl aqueous solution (25 mL) was added and stirred for 30 min. The mixture was neutralized with 0.5N NaHCO3 solution to pH 8. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 CHCl3:MeOH) to give 17 (3.0 g, 18.5 mmol, 82%) as a white solid. Data for 17: Rf 0.37 (9:1CH3Cl:MeOH); [a]25 D -100.3 (c 0.6, MeOH); 1H NMR (400 MHz, CD3OD) d 7.07 (dd, J ¼ 4.0, 1.3, 1 H), 6.96e6.92 (m, 1 H), 6.30 (dd, J ¼ 3.9, 2.6, 1 H), 6.18 (s, 1H), 4.70 (dd, J ¼ 11.9, 3.2, 1 H), 4.63e4.52 (m, 2 H), 3.05 (s, 3 H), 3.02 (dd, J ¼ 7.1, 4.5, 2 H); 13C NMR (100 MHz, CD3OD) d 160.9, 155.9, 126.9, 121.1, 119.2, 118.9, 111.7, 108.0, 70.7, 54.2, 28.8, 27.3; IR (thin film): nmax 3442, 2945, 1714, 1655, 1535, 1456, 1400, 1306, 1198, 1082, 1047; HRMS (ESI): Calcd for C12H13N3O3Na [MþNa]þ 270.0849, found: 270.0843. 4.6. (S)-1-(1-hydroxy-3-(3-methyl-2-oxo-2,3-dihydro-1Himidazol-4-yl)propan-2-yl)-1H-pyrrole-2-carboxamide (18) 17 (2.0 g, 10.1 mmol) dissolved in MeOH (50 mL) was added into a sealed tube, and the solution was cooled to 0  C under ice bath. Then NH3 was bubbled into the solution until saturated. Then the solution was warmed to 40  C and stirred for 2 d. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (using a gradient 9:1 to 3:1 EtOAc:MeOH) to give 18 (1.8 g, 8.3 mmol, 82%) as a yellow solid. 1 Data for 18: Rf 0.28 (4:1 EtOAc:MeOH); [a]25 D -6.3 (c 2.7, MeOH); H NMR (400 MHz, CD3OD) d 7.18e7.10 (m, 1 H), 6.77 (dd, J ¼ 3.9, 1.5, 1 H), 6.18e6.11 (m, 1 H), 5.94 (s, 1 H), 5.71 (dd, J ¼ 9.0, 5.5, 1 H), 3.86 (dd, J ¼ 5.7, 1.7, 2 H), 3.13 (s, 3 H), 3.05 (dd, J ¼ 15.7, 5.3, 1 H), 2.93 (dd, J ¼ 15.7, 9.1, 1 H); 13C NMR (100 MHz, CD3OD): d 166.8, 155.5, 126.6, 125.3, 122.4, 115.2, 109.4, 106.9, 65.4, 57.4, 28.6, 27.5; IR (thin film): nmax 3446, 2914, 1657, 1595, 1456, 1425, 1390, 1275, 1090; HRMS (ESI): Calcd for C12H16N4O3Na [MþNa]þ 287.1115, found: 287.1108. 4.7. (4S)-3-hydroxy-4-((3-methyl-2-oxo-2,3-dihydro-1H-imidazol4-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (19) To a solution of oxalyl chloride (0.3 mL, 3.8 mmol) in CH2Cl2 (30 mL) at 78  C was slowly added DMSO (0.5 mL, 8.0 mmol). After 15 min, a solution of 18 (1.8 g, 2.5 mmol) in CH2Cl2 (30 mL) was added to the reaction mixture. After being stirred for 30 min at 78  C the mixture was quenched with DIPEA (2.0 mL, 12.5 mmol), stirred at 78  C for 30 min and then warmed up to 25  C, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (using

4542

Y. Yao et al. / Tetrahedron 73 (2017) 4538e4544

a gradient 9:1 to 3:1 EtOAc:MeOH) to give 19a (0.9 g, 1.1 mmol, 45%) and 19b (0.6 g, 1.0 mmol, 40%) as white solids. Data for 19a: Rf 0.27 1 (4:1 EtOAc:MeOH); [a]25 D þ13.7 (c 0.6, MeOH); H NMR (400 MHz, CD3OD) d 7.07 (s, 1 H), 6.92 (d, J ¼ 3.8, 1 H), 6.29 (s, 1 H), 6.26 (t, J ¼ 3.1, 1 H), 5.10 (d, J ¼ 2.8, 1 H), 4.48e4.38 (m, 1 H), 3.28 (dd, J ¼ 15.3, 6.6, 1 H), 3.20 (s, 3 H), 3.13 (dd, J ¼ 15.3, 8.0, 1 H); 13C NMR (100 MHz, CD3OD) d 162.5, 155.9, 124.6, 121.2, 115.2, 110.7, 107.7, 76.3, 58.3, 27.5, 24.8; IR (thin film): nmax 3435, 3200, 3156, 3036, 2959, 2918, 1665, 1549, 1458, 1418, 1294, 1074, 930, 800; HRMS (ESI): Calcd for C12H14N4O3Na [MþNa]þ 285.0958, found: 285.0951. Data for 19b: Rf 0.24 (4:1 EtOAc:MeOH); [a]25 D -139.4 (c 1.0, MeOH) 1H NMR (400 MHz, CD3OD) d 6.91 (d, J ¼ 3.8, 1 H), 6.77 (s, 1 H), 6.23e6.18 (m, 1 H), 6.16 (s, 1 H), 5.1 (s, 1 H), 4.43e4.36 (m, 1 H), 3.00e2.92 (m, 4 H), 2.74 (dd, J ¼ 15.4, 8.8, 1 H); 13C NMR (100 MHz, CD3OD) d 162.0, 155.7, 126.6, 122.9, 121.2, 115.2, 110.7, 107.9, 77.6, 61.3, 30.1, 27.1; IR (thin film): nmax 3291, 2957, 2928, 1663, 1553, 1472, 1321, 1209, 1070, 752; HRMS (ESI): Calcd for C12H14N4O3Na [MþNa]þ 285.0958, found: 285.0951. 4.8. 4-((3-Methyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl)methyl) pyrrolo[1,2-a]pyrazin-1(2H)-one (20), (5aS,9aS)-8-methyl5,5a,6,8,9,9a-hexahydroimidazo[40 ,50 :4,5]cyclopenta[1,2-e]pyrrolo [1,2-a]pyrazine-4,7-dione (21) and (5aR,5bR,8aR,9aS)-8a-hydroxy8-methyl-5,5a,5b,6,8,8a,9,9a-octahydroimidazo[40 ,50 :4,5]cyclopenta [1,2-e]pyrrolo[1,2-a]pyrazine-4,7-dione (22) 19 (100 mg, 0.38 mmol) was dissolved in 0.1N HCl aqueous solution (5 mL) at 0  C, and the reaction mixture was quickly warmed up to reflux and stirred for 4 h. Then the reaction was neutralized with 0.5N aqueous NaHCO3 solution to pH 8. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting (6:1 CH2Cl2:MeOH) to give 20 (19 mg, 0.08 mmol, 21%), 21 (33 mg, 0.14 mmol, 36%) and 22 (29 mg, 0.11 mmol, 29%). Data for 20: Rf 0.40; 1H NMR (400 MHz, CD3OD) d 7.38 (dd, J ¼ 2.5, 1.4, 1 H), 7.05 (dd, J ¼ 4.0, 1.2, 1 H), 6.58 (dd, J ¼ 3.9, 2.7, 1 H), 6.25 (s, 1 H), 6.16 (s, 1 H), 3.86 (s, 2 H), 3.12 (s, 3 H); IR (thin film): nmax 3233, 3055, 2922, 2851, 1713, 1661, 1555, 1462, 1408, 1321, 1146, 984, 750; HRMS (ESI): Calcd for C12H12N4O2Na [MþNa]þ 267.0852, found: 267.0859; Data for 21: Rf 0.47 (4:1 EtOAc:MeOH); [a]25 D -0.9 (c 0.7, MeOH); 1 H NMR (400 MHz, CD3OD) d 7.07 (d, J ¼ 4.1, 1 H), 6.68 (d, J ¼ 4.1, 1 H), 6.52 (s, 1 H), 4.96 (d, J ¼ 7.1, 1 H), 4.06 (dt, J ¼ 7.1, 4.5, 1 H), 3.15 (d, J ¼ 4.4, 2 H), 2.76 (s, 3 H). 13C NMR (100 MHz, CD3OD) d 164.5, 158.7, 128.5, 122.6, 114.5, 112.7, 111.8, 111.4, 56.1, 47.9, 28.4, 24.4; IR (thin film): nmax 3235, 3057, 2920, 1653, 1558, 1541, 1506, 1456, 1417, 1395, 1361, 1260, 1130, 1082, 1053, 768; HRMS (ESI): Calcd for C12H12N4O2Na [MþNa]þ 267.0852, found: 267.0852. Data for 22: Rf 0.33 (4:1 EtOAc:MeOH); [a]25 D þ58.3 (c 0.8, MeOH); 1H NMR (400 MHz, CD3OD) d 6.95e6.90 (m, 1 H), 6.79 (dd, J ¼ 3.9, 1.4, 1 H), 6.16e6.09 (m, 1 H), 4.60e4.51 (m, 1 H), 3.91 (d, J ¼ 4.9, 1 H), 3.71 (s, 1 H), 2.70 (s, 3 H), 2.55e2.49 (m, 1 H), 2.19 (dd, J ¼ 13.3, 10.3, 1 H); 13C NMR (100 MHz, CD3OD) d 162.1, 161.4, 125.7, 122.9, 115.5, 111.1, 95.8, 68.0, 62.9, 55.7, 41.7, 24.2; IR (thin film): nmax 3422, 3277, 3235, 3100, 2928, 1661, 1594, 1449, 1416, 1356, 1304, 1209, 1134, 1070, 750; HRMS (ESI): Calcd for C12H14N4O3Na [MþNa]þ 285.0958, found: 285.0958. Compound 22 was found to be 99% ee by chiral HPLC analysis [Phenomenex Lux 3u Cellulose-1; 0.60 mL/min; 30% isopropanol in hexanes; tR(major) ¼ 20.5 min, tR(minor) ¼ 24.5 min].

temperature and stirred for 6 h. Then the solution was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (7:1 CH2Cl2:MeOH) to afford (þ)-agelastatin A (ent-1) (9 mg, 0.030 mmol, 79%). Data for (þ)-agelastatin A: Rf 0.27 (5:1 EtOAc:MeOH); [a]25 D þ54.0 (c 0.6, MeOH);S1 1H NMR (400 MHz, CD3OD) d 6.81 (d, J ¼ 4.0, 1 H), 6.23 (d, J ¼ 4.0, 1 H), 4.50 (dt, J ¼ 11.9, 6.0, 1 H), 3.98 (d, J ¼ 5.4, 1 H), 3.78 (s, 1 H), 2.71 (s, 3 H), 2.55 (dd, J ¼ 13.1, 6.4, 1 H), 2.00 (t, J ¼ 12.6, 1 H); 13 C NMR (100 MHz, CD3OD) d 161.4, 161.1, 124.2, 116.0, 113.8, 107.2, 95.7, 67.4, 62.2, 54.4, 40.0, 24.2; IR (thin film): nmax 3281, 2957, 2982, 2859, 1651, 1553, 1456, 1423, 1383, 1271, 1138, 1094; HRMS þ (ESI): Calcd for C12H79 363.0063, found 13 BrN4O3Na [MþNa] 363.0058. 4.10. Methyl (Z)-3-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1Himidazol-4-yl)-2-(((benzyloxy)carbonyl)amino)acrylate (27) To a solution of phosphonate 26 (4.88 g, 15.28 mmol) in CH2Cl2 (30 mL) was added DBU (1.91 mL, 16.81 mmol) at 0  C and stirred for 20 min. Then a solution of 25 (3.30 g, 15.28 mmol) in CH2Cl2 (30 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was diluted with H2O (40 mL) and 1 N HCl (40 mL). After being stirred for 20 min, the reaction mixture was diluted with EtOAc (60 mL) and separated. The aqueous layer was extracted with EtOAc (3  30 mL). The combined organic layers were washed with saturated aqueous NaHSO3 (50 mL), brine (20 mL), dried over MgSO4, and concentrated to give 27 (3.60 g, 67%) as a solid. Data for 27: Rf 0.50 (95:5 CHCl3:MeOH); mp: 144e146  C; 1H NMR (400 MHz, CDCl3) d 7.40e7.16 (m, 10H), 7.09 (s, 1H), 6.53 (s, 1H), 6.10 (s, 1H), 5.07 (s, 2H), 4.73 (s, 2H), 3.77 (s, 3H), 3.32 (s, 3H); 13C NMR (100 MHz, CDCl3) d 165.1, 152.6, 136.2, 135.9, 128.8, 128.6, 128.4, 128.3, 128.0, 127.8, 119.1, 118.1, 116.1, 67.5, 52.6, 47.5, 27.7; IR (thin film): ymax 3427, 2952, 1726, 1671, 1636, 1574, 1501, 1457, 1437, 1306, 1258, 1168, 1051; HRMS (ESI): Calcd for C23H24N3O5 [MþH]þ 422.1710, found: 422.1701. 4.11. Methyl 2-amino-3-(1-benzyl-3-methyl-2-oxo-2,3-dihydro1H-imidazol-4-yl)propanoate (28) To a solution of 27 (2.83 g, 6.95 mmol) in methanol (50 mL) was added Pd/C (10% Pd content, 0.283 g). The reaction vessel was evacuated and back-filled with hydrogen (1 atm.). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 1 d. Then the mixture was filtered over a plug of silica gel topped with Celite (MeOH eluent), and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (95:2 to 95:5 CHCl3: MeOH) to give 28 (1.91 g, 95%) as a yellow oil. Data for 28: Rf 0.26 (9:1 CHCl3:MeOH); 1H NMR (400 MHz, CDCl3) d 7.45e7.09 (m, 5H), 5.95 (s, 1H), 4.76 (q, J ¼ 15.1 Hz, 2H), 3.65 (s, 3H), 3.60 (t, J ¼ 6.5 Hz, 1H), 3.25 (s, 3H), 2.81 (dd, J ¼ 15.3, 5.5 Hz, 1H), 2.62 (dd, J ¼ 15.2, 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 174.8, 153.6, 137.1, 128.7, 127.9, 127.7, 119.0, 107.6, 53.4, 52.1, 47.0, 30.4, 27.7; IR (thin film): ymax 3372, 3303, 3028, 2952, 1740, 1677, 1492, 1464, 1395, 1360, 1271, 1202, 1161, 1030, 837; HRMS (ESI): Calcd for C15H20N3O3 [MþH]þ 290.1499, found: 290.1496. 4.12. 5-(2-Amino-3-hydroxypropyl)-1-methyl-1,3-dihydro-2Himidazol-2-one (29)

4.9. Synthesis of (þ)-agelastatin A (ent-1) To a solution of 22 (10 mg, 0.038 mmol) in a mixture of MeOH (1.5 mL) and THF (3.0 mL) cooled to 0  C was added NBS (6 mg, 0.034 mmol), and the reaction was allowed to warm to room

To liquid ammonia (3 mL) in a 25 mL two-necked flask cooled to 78  C was added Na (39.74 mg, 1.73 mmol) and stirred for 5 min. A solution of t-BuOH (0.081 mL) in THF (1 mL) was added to the blue ammonia solution, followed by a solution of amide 28

Y. Yao et al. / Tetrahedron 73 (2017) 4538e4544

(50 mg, 0.173 mmol) in THF (3 mL). The reaction mixture was stirred at 78  C for 30 min until the blue color disappeared. The reaction mixture then was quenched with solid NH4Cl (92.5 mg), and ammonia was allowed to evaporate by replacing the cooling bath with a water bath. The residue was dissolved in methanol (2 mL) and filtered. The filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (MeOH: CH2Cl2 ¼ 1: 1) to give 29 (25.7 mg, 87%) as a colorless oil. Data for 29: Rf 0.20 (MeOH); 1H NMR (400 MHz, D2O) d 6.27 (s, 1H), 3.66 (dd, J ¼ 12.1, 4.0 Hz, 1H), 3.50 (dd, J ¼ 12.1, 6.1 Hz, 1H), 3.29 (dtd, J ¼ 10.1, 6.1, 4.1 Hz, 1H), 3.06 (s, 3H), 2.71 (dd, J ¼ 15.8, 6.2 Hz, 1H), 2.57 (dd, J ¼ 15.7, 8.5 Hz, 1H); 13 C NMR (100 MHz, D2O) d 154.3, 119.6, 107.2, 61.4, 50.8, 27.1, 25.0; HRMS (ESI): Calcd for C7H14N3O2 [MþH]þ 172.1081, found: 172.1087. 4.13. Ethyl 1-(1-hydroxy-3-(3-methyl-2-oxo-2,3-dihydro-1Himidazol-4-yl)propan-2-yl)-1H-pyrrole-2-carboxylate (30) To a stirred solution of 12 (0.37 g, 0.234 mmol) in glacial acetic acid (6 mL) under N2 atmosphere at 55  C was added a solution of 29 (0.2 g, 0.117 mmol) in MeOH (2 mL) over 5 min. After being stirred for 1.5 h, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (3  30 mL). The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Toluene was added to the crude concentrate to assist (azeotropically) in the removal of acetic acid. The solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (95:2 to 95:5 CHCl3:MeOH) to give 30 (210 mg, 61%). Data for 30: Rf 0.42 (9:1 CHCl3:MeOH); 1H NMR (400 MHz, CDCl3) d 9.51 (s, 1H), 7.06e7.05 (m, 1H), 6.97 (dd, J ¼ 3.9, 1.7 Hz, 1H), 6.19 (dd, J ¼ 3.8, 2.8 Hz, 1H), 5.86 (s, 1H), 5.68 (s, 1H), 4.25 (q, J ¼ 7.1 Hz, 2H), 3.90 (d, J ¼ 5.2 Hz, 2H), 3.17 (s, 3H), 3.01 (dd, J ¼ 15.5, 6.3 Hz, 1H), 2.90 (dd, J ¼ 15.5, 8.2 Hz, 1H), 1.34 (t, J ¼ 7.1 Hz, 3H). 4.14. 1-(1-Hydroxy-3-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol4-yl)propan-2-yl)-1H-pyrrole-2-carboxamide ((±)-18) 30 (0.5 g, 1.70 mmol) dissolved in MeOH (10 mL) was added to a sealed tube, and the solution was cooled to 0  C under ice bath. Then NH3 was bubbled into the solution. When the solution was saturated by NH3, the solution was warmed to 40  C and stirred for 2 d. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (using a gradient 9:1 to 3:1 EtOAc/MeOH) to give (±)-18 (0.35 g, 77%) as a yellow solid. Data for (±)-18: Rf 0.28 (4:1 EtOAc:MeOH); 1H NMR (400 MHz, CD3OD): d 7.14e7.11 (m), 6.76 (dd, J ¼ 3.9, 1.5), 6.14e6.10 (m), 5.92 (s), 5.70 (dq, J ¼ 11.0, 5.5), 3.88e3.82 (m), 3.12 (s), 3.04 (dd, J ¼ 15.7, 5.3), 2.91 (dd, J ¼ 15.7, 9.1); 13C NMR (100 MHz, CD3OD): d 166.8, 155.5, 126.6, 125.3, 122.4, 115.2, 109.4, 106.9, 65.4, 57.4, 28.6, 27.5; IR (thin film): nmax 3446, 2914, 1657, 1595, 1456, 1425, 1390, 1275, 1090; HRMS (ESI): calcd for C12H16N4O3 [MþNa]þ 287.1115, found: 287.1108. 4.15. (S)-6-Bromo-4-((3-methyl-2-oxo-2,3-dihydro-1H-imidazol4-yl)methyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (32a) and (S)-7-bromo-4-((3-methyl-2-oxo-2,3-dihydro-1H-imidazol-4yl)methyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (32b)19 To a solution of 16 (1.5 g, 5.6 mmol) in MeOH (20 mL) cooled to 0  C was added NBS (997 mg, 5.6 mmol), and the cooling bath was removed. After stirring at room temperature for 4 h, the solution was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (9:1

4543

CH2Cl2:MeOH) to give a mixture of two bromides (1.8 g, 5.2 mmol, 93%). To a solution of oxalyl chloride (0.7 mL, 7.8 mmol) in CH2Cl2 (30 mL) at 78  C was slowly added DMSO (1.1 mL, 15.6 mmol). After 15 min, a solution of the bromide mixture (1.8 g, 5.2 mmol) in CH2Cl2 (30 mL) was added to the reaction mixture. After being stirred for 30 min at 78  C the mixture was quenched with DIPEA (4.5 mL, 26.0 mmol), stirred at 78  C for 30 min and then warmed up to 25  C, and 1N HCl aqueous solution was added and stirred for 30 min. The mixture was neutralized with 0.5 N NaHCO3 solution to pH 8. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 CH2Cl2:MeOH) to give 32a (518 mg, 2.1 mmol, 37%) and 32b (630 mg, 2.5 mmol, 45%) as a white solid. Data for 32a: Rf 0.52 (9:1 1 CHCl3:MeOH); [a]25 D -65.4 (c 1.0, MeOH) H NMR (400 MHz, CD3OD) d 7.09 (d, J ¼ 4.2, 1 H), 6.40 (d, J ¼ 4.2, 1 H), 6.08 (s, 1 H), 4.68 (s, 2 H), 4.64 (d, J ¼ 7.6, 1 H), 3.21 (s, 3 H), 3.04 (dd, J ¼ 15.4, 6.7, 1 H), 2.95 (dd, J ¼ 15.4, 7.5, 1 H); 13C NMR (100 MHz, CD3OD) d159.8, 156.0, 120.6, 120.4, 119.7, 114.5, 109.5, 108.5, 70.39, 52.9, 28.4, 27.6; IR (thin film): nmax 3134, 3030, 2947, 1709, 1670, 1533, 1452, 1402, 1323, þ 1229, 1091, 789; HRMS (ESI): Calcd for C12H79 12BrN3O3Na [MþNa] 347.9954, found:347.9960. Data for 32b: Rf 0.40 (9:1 CHCl3:MeOH); [a]25 D -20.4 (c 0.9, MeOH) 1H NMR (400 MHz, CD3OD) d 6.97 (d, J ¼ 1.5, 1 H), 6.95 (d, J ¼ 1.5, 1 H), 6.09 (s, 1 H), 4.63 (dd, J ¼ 11.9, 3.2, 1 H), 4.56e4.51 (m, 1 H), 4.48 (s, 1 H), 3.06 (s, 3 H), 2.95 (d, J ¼ 7.2, 2 H); 13C NMR (100 MHz, CD3OD) d 159.4, 155.9, 126.3, 120.7, 120.3, 119.7, 108.2, 99.2, 70.5, 54.0, 28.7, 27.4; IR (thin film): nmax 3289, 3126, 2955, 2930, 1674, 1533, 1474, 1391, 1337, 1217, 1105, 1024; HRMS (ESI): þ Calcd for C12H79 12BrN3O3Na [MþNa] 347.9954, found:347.9946. 4.16. (S)-4-Bromo-1-(1-hydroxy-3-(3-methyl-2-oxo-2,3-dihydro1H-imidazol-4-yl)propan-2-yl)-1H-pyrrole-2-carboxamide (33) 32b (500 mg, 1.5 mmol) dissolved in MeOH (15 mL) was added to a sealed tube, and the solution was cooled to 0  C under ice bath. Then NH3 was bubbled into the solution until saturated. Then the reaction was warmed to 40  C and stirred for 2 d. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (4:1 EtOAc:MeOH) to give 33 (452 mg, 1.4 mmol, 90%) as a white solid. Data for 33: Rf 0.26 1 (4:1 EtOAc:MeOH); [a]25 D -30.6 (c 0.8, MeOH) H NMR (400 MHz, CD3OD) d 7.24 (s, 1 H), 6.76 (s, 1 H), 5.98 (s, 1 H), 5.74 (s, 1 H), 3.84 (d, J ¼ 5.1, 2 H), 3.18 (s, 3 H), 3.02 (dd, J ¼ 15.6, 5.1, 1 H), 2.91 (dd, J ¼ 15.6, 9.3, 1 H); 13C NMR (100 MHz, CD3OD) d 165.5, 155.8, 127.7, 125.0, 122.1, 116.4, 106.9, 96.8, 65.1, 57.8, 28.6, 27.5; IR (thin film): nmax 3342, 3180, 2995, 2876, 1684, 1653, 1558, 1456, 1420, 1292, 1101, 1047, 926, 789; HRMS (ESI): Calcd for C12H79 15 BrN4O3Na [MþNa]þ 365.0220, found:365.0211. 4.17. (5aR,5bR,8aR,9aS)-2-bromo-8a-hydroxy-8-methyl5,5a,5b,6,8,8a,9,9a-octahydroimidazo[40 ,50 :4,5]cyclopenta[1,2-e] pyrrolo[1,2-a]pyrazine-4,7-dione (34) To a solution of oxalyl chloride (0.3 mL, 1.8 mmol) in CH2Cl2 (15 mL) at 78  C was slowly added DMSO (0.26 mL, 3.6 mmol). After 15 min, a solution of 33 (400 mg, 1.2 mmol) in CH2Cl2 (10 mL) and DMSO (5 mL) was added to the reaction mixture. After stirring for 30 min at 78  C, the mixture was quenched with DIPEA (0.9 mL, 5.0 mmol), stirred at 78  C for 30 min. Then warmed up to room temperature and stirred for 30 min, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (using a gradient 9:1 to 3:1 EtOAc:MeOH) to give a pair of diastereomers as a white solid. The diastereomers (100 mg, 0.29 mmol) were dissolved in 0.1N HCl aqueous solution (5 mL) at room temperature, and the reaction

4544

Y. Yao et al. / Tetrahedron 73 (2017) 4538e4544

mixture was quickly warmed up to reflux and stirred for 4 h. The mixture was neutralized with 0.5 N aqueous NaHCO3 solution to pH 8, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (6:1 CH2Cl2:MeOH) to give two by-products and 34 (29 mg, 0.09 mmol, 29%). Data for 34: Rf 0.33 (4:1 EtOAc:MeOH); [a]25 D þ30.0 (c 0.3, MeOH); 1H NMR (400 MHz, CD3OD) d 7.00 (d, J ¼ 1.6, 1 H), 6.74 (d, J ¼ 1.5, 1 H), 4.59e4.48 (m, 1 H), 3.91 (d, J ¼ 5.2, 1 H), 3.70 (s, 1 H), 2.69 (s, 3 H), 2.54 (dd, J ¼ 13.4, 6.2, 1 H), 2.19 (dd, J ¼ 13.3, 10.2, 1 H); 13 C NMR (100 MHz, CD3OD) d 161.3, 160.7, 125.1, 124.0, 116.6, 98.7, 95.7, 68.0, 62.7, 55.8, 41.6, 24.2; IR (thin film): nmax 3215, 3119, 3069, 2926, 2359, 1726, 1653, 1549, 1485, 1404, 1271, 1128, 756; HRMS e (ESI): Calcd for C12H79 13 BrN4O3 [MeH] 339.0098, found: 339.0102.

2. 3.

4.

5. 6.

4.18. Synthesis of (þ)-agelastatin B (ent-2) To a solution of 34 (10 mg, 0.029 mmol) in a mixture of MeOH (1.5 mL) and THF (3.0 mL) cooled to 0  C was added NBS (6 mg, 0.034 mmol), and the reaction was allowed to warm to room temperature and stirred for 6 h. Then the solution was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (7:1 CH2Cl2:MeOH) to afford (þ)-agelastatin B (ent-2)(11 mg, 0.26 mmol, 90%). Data for (þ)-agelastatin B: Rf 0.27 (1:5 MeOH:EtOAc); [a]25 D þ53.1 (c 0.7, MeOH);S2 1H NMR (400 MHz, CD3OD) d 6.94 (s, 1 H), 4.57 (dt, J ¼ 12.1, 6.1, 1 H), 4.09 (d, J ¼ 5.5, 1 H), 3.85 (s, 1 H), 2.78 (s, 3 H), 2.65 (dd, J ¼ 13.1, 6.5, 1 H), 2.09 (t, J ¼ 12.6, 1 H); 13C NMR (100 MHz, CD3OD) d 161.3, 160.0, 124.8, 116.9, 108.7, 101.7, 95.6, 67.4, 62.1, 55.4, 39.9, 24.2; IR (thin film): nmax 3227, 2926, 1653, 1553, 1489, 1404, e 1086, 752; HRMS (ESI): Calcd for C12H79 11Br2N4O3 [MeH] 416.9203, found: 416.9198. Acknowledgments We thank the National Key Research and Development Program of China (2017YFD0201404) and the National Natural Science Foundation of China (21421062, 21372127) for financial support.

7.

8.

9.

10. 11. 12. 13. 14. 15. 16.

17.

Appendix A. Supplementary data 18.

Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.06.009. References 1. For recent reviews on pyrrole-imidazole alkaloids, see: a) Weinreb SM. Nat

19.

Prod Rep. 2007;24:931e948; b) Al-Mourabit A, Zancanella MA, Tilvi S, Romo D. Nat Prod Rep. 2011;28: 1229e1260; c) Wang X, Ma Z, Wang X, De S, Ma Y, Chen C. Chem Commun. 2014;50: 8628e8639. D'Ambrosio M, Guerriero A, Debitus C, et al. J Chem Soc Chem Commun. 1993: 1305e1306. a) Mason CK, McFarlane S, Johnston PG, et al. Mol Cancer Ther. 2008;7: 548e558; b) Kapoor S. J Cancer Res Clin Oncol. 2008;134:927e928. a) Meijer L, Thunnissen AMWH, White AW, et al. Chem Biol. 2000;7:51e63; b) Hale KJ, Domostoj MM, El-Tanani M, Campbell FC, Mason CK. In: Harmata M, ed. Strategies and Tactics in Organic Synthesis. vol. 6. London: Elsevier Academic Press; 2005:352e394. Ch. 11. Hong TW, Jímenez DR, Molinski TF. J Nat Prod. 1998;61:158e161. For total synthesis of agelastatin A, see: a) Dong G. Pure Appl Chem. 2010;82: 2231e2246. and references there in; b) Menjo Y, Hamajima A, Sasaki N, Hamada Y. Org Lett. 2011;13:5744e5747; c) Kano T, Sakamoto R, Akakura M, Maruoka K. J Am Chem Soc. 2012;134: 7516e7520; d) Reyes JCP, Romo D. Angew Chem Int Ed. 2012;51:6870e6873; e) Duspara PA, Batey RA. Angew Chem Int Ed. 2013;52:10862e10866; f) Han S, Siegel DS, Morrison KC, Hergenrother PJ, Movassaghi M. J Org Chem. 2013;78:11970e11984. For a closely similar strategy reported, see: a) Movassaghi M, Siegel DS, Han S. Chem Sci. 2010;1:561e566. for discussion of such 5-(enol-endo)-exo-trig type of cyclization, see:; b) Baldwin JE, Lusch MJ. Tetrahedron. 1982;38:2939e2947; c) Gramain JC, Remuson R. Heterocycles. 1989;29:1263e1273; d) Heaney H, Taha MO. Tetrahedron Lett. 1998;39:3341e3344. a) Paal G. Chem Ber. 1884;17:2756; b) Knorr L. Chem Ber. 1884;17:2863; c) Trost BM, Doherty GA. J Am Chem Soc. 2000;122:3801e3810. a) Macritchie JA, Silcock A, Willis CL. Tetrahedron Asymmetry. 1997;8: 3895e3902; b) Hughes CC, Kauffman CA, Jensen PR, Fenical W. J Org Chem. 2010;75: 3240e3250. Parikh JR, Doering W v E. J Am Chem Soc. 1967;89:5505e5507. Luzzio FA. Tetrahedron. 2001;57:915e945. Mancuso AJ, Huang S, Swern D. J Org Chem. 1978;43:2480e2482. a) Feldman KS, Saunders JC. J Am Chem Soc. 2002;124:9060e9061; b) Feldman KS, Saunders JC, Wrobleski ML. J Org Chem. 2002;67:7096e7109. A similar para-bromobenzyl protected compound has been reported, see: Smith CD, Batey RA Tetrahedron. 2007;64:652e663. Mazurkiewicz R, Ku znik A. Tetrahedron Lett. 2006;47:3439e3442. For isolation of agelastatin B, see: a) D'Ambrosio M, Guerriero A, Chiasera G, Pietra F. Helv Chim Acta. 1994;77:1895e1902. For total synthesis of agelastatin B, see:; b) references 6f, 7a and 13. For two alternative step-wise preparations of 14, please see the Supplementary Material. For alternative synthetic approach of 17, please see the Supplementary Material. For alternative attempts of preparing brominated substrates, please see the Supplementary Material.