Reactivity of 2-Nitropyrrole Systems: Development ... - ACS Publications

Oct 1, 2018 - Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Symonds. Street, Auckland 1010, New Zealand. •S Support...
0 downloads 0 Views 1MB Size
Download PDF
Article Cite This: J. Org. Chem. 2018, 83, 12460−12470

pubs.acs.org/joc

Reactivity of 2‑Nitropyrrole Systems: Development of Improved Synthetic Approaches to Nitropyrrole Natural Products Xiao-Bo Ding,† Margaret A. Brimble,*,†,‡ and Daniel P. Furkert*,†,‡ †

School of Chemical Sciences and ‡Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Symonds Street, Auckland 1010, New Zealand

J. Org. Chem. 2018.83:12460-12470. Downloaded from pubs.acs.org by REGIS UNIV on 10/19/18. For personal use only.

S Supporting Information *

ABSTRACT: Fundamental study of the reactivity of 2nitropyrrole systems has enabled the identification of effective methods for incorporation of this unusual motif into advanced natural product frameworks. The presence of electron-rich pyrrole N-protecting groups (BOM, Boz) was demonstrated to enable a variety of previously unsuccessful palladiummediated cross-couplings to be carried out in high yield. Based on this foundation, a series of regio- and stereoselective synthetic routes toward the nitropyrrolin and heronapyrrole families of natural products was developed by our group (G1−3). A full account of the strategic evolution of these approaches is reported here, highlighting the details of the setbacks encountered and eventual successes achieved en route, including the total synthesis of heronapyrrole B. The fundamental studies and completed total syntheses provide general access to the bioactive 2-nitropyrrole natural product manifold and also establish practical and efficient methods for preparation and elaboration of the medicinally relevant 2nitropyrrole motif.

■

INTRODUCTION The nitropyrrolins A−E 1−5 (Figure 1) and heronapyrroles A−D 6−9 are structurally related pyrroloterpene natural products sharing an unusual 2-nitro-4-alkylpyrrole core.1 Nitropyrrolins A−E 1−5 were isolated from the culture broth of the MAR4 strain CNQ-509, obtained from a marine sediment sample collected off La Jolla, California by Fenical et al. in 2010.1a The simultaneously reported heronapyrroles A− C 6−8 were produced by a Streptomyces sp. (CMB-M0423) isolated from a beach sand sample off Heron Island, Australia by Capon et al.1b Heronapyrrole D 9 was also produced by Streptomyces sp. (CMB-M0423) and later reported by Capon and Stark in 2014.2 Nitropyrrolins A 1, B 2, and D 4 exhibit cytotoxic activity toward human colon carcinoma cell line HCT-116 (1; IC50 31.1 μM, 2; IC50 31.0 μM, and 4; IC50 5.7 μM).1a Heronapyrroles A−D 6−9 were found to display promising activity against Gram-positive bacteria Staphylococcus aureus ATCC 9144 (IC50 0.6−1.1 μM) and Bacillus subtilis ATCC 6633 (IC50 1.1−6.5 μM) without exhibiting cytotoxicity toward mammalian cell lines.1b The novel molecular architecture, promising biological activities, and unconfirmed stereochemical assignments make these natural products attractive synthetic targets. In 2012, Stark et al. reported the first synthesis of the enantiomer of heronapyrrole C 8 and proposed the absolute stereochemisty of the natural product.3 Morimoto et al. later reported the syntheses of heronapyrroles A 6 and B 7 and nitropyrrolins A 1, B 2, and D 4.4 The Stark and Morimoto syntheses of this © 2018 American Chemical Society

family of natural products demonstrated that the desired nitration of alkylpyrrole 10 was a challenging task, featuring low yields and regioselectivity in favor of the undesired nitropyrrole 11 (Scheme 1). To fully control the regioselectivity, our synthetic program introduced the nitro group at the start of the synthesis and achieved a first generation synthesis of heronapyrrole C using a key Julia−Kocienski olefination of aldehyde 13 and sulfone 14 (Scheme 1, G1).5 This strategy provided completely regioselective access to the required nitropyrrole unit, but the yield and E/Z selectivity of the olefination (42%, E/Z ca. 1:1) were not satisfactory. We later reported an improved second generation synthesis (Scheme 1, G2) that hinged on a robust cross-coupling of iodide 15 and vinyl stannane 16 for construction of the 4-alkyl-2-nitropyrrole framework, enabling access to heronapyrroles C 8 and D 9.6 Encouraged by this improved synthesis of heronapyrroles C and D, in this work, we aimed to further apply our successful cross-coupling strategy to the synthesis of other members of the 2-nitropyrrole natural product manifold, in particular nitropyrrolin A 1 and heronapyrrole B 7, that feature a C7,8 anti diol motif. The Stille coupling strategy successfully provided access to the 4-alkyl-2-nitropyrrole framework, but further elaboration toward the final natural products proved surprisingly problematic. We report here the development of effective new cross-coupling protocols for 4-iodo-2-nitroReceived: July 5, 2018 Published: October 1, 2018 12460

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry

Figure 1. Natural products featuring the 2-nitropyrrole motif.

Scheme 1. Synthetic Strategies Investigated for Access to 2-Nitropyrrole Natural Products

by iodination afforded iodide 22 in excellent overall yield. The stereochemistry of iodide 22 was later confirmed by comparison of synthetic and isolated natural product spectral data. With iodide 22 in hand, the key alkylation of sulfone 21 was next investigated. Despite abundant literature precedent,9 however, and the examination of a wide range of additional conditions, it did not prove possible to achieve the desired alkylation to effect the union of 21 and 22. Decomposition of the starting material was observed in most cases, likely due to the sensitive nature of the 2-nitropyrrole motif in 22. To avoid exposure of labile 2-nitropyrrole fragments to harsh alkylation conditions, it was decided to install this fragment at a later stage. Accordingly, the revised plan aimed to synthesize heronapyrrole B 7 from diene 26 via regioselective C7,8 dihydroxylation followed by desulfonylation (Scheme 4). Diene 26 would be constructed by Stille coupling of iodide 23 and advanced stannane 27 which, in turn, would be available

pyrroles 17, that had previously been unsuccessfully investigated by other groups, and the subsequent successful total syntheses of natural products 1 and 7 (Scheme 1, G3).7

■

RESULTS AND DISCUSSION We initially envisaged that synthesis of both nitropyrrolin A 1 and heronapyrrole B 7 could be achieved from common intermediate sulfone 20 via an additional regioselective C15,16 dihydroxylation for heronapyrrole B (Scheme 2). Sulfone 20 in turn would be obtained by alkylation of sulfone 21 with epoxy iodide 22 that could be prepared via Stille coupling of iodide 23 and vinyl stannane 24. Synthetic studies based on this initial retrosynthetic analysis commenced with the Stille coupling of iodide 23 and vinyl stannane 24 to afford allylic alcohol 25 (Scheme 3).6 Sharpless asymmetric epoxidation of alcohol 25 using (−)-DIPT, selected by application of the Sharpless mnemonic,8 followed 12461

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry

performing the sulfone alkylation on substrates not containing a 2-nitropyrrole unit. Synthetic investigations applying this revised approach commenced with Sharpless asymmetric dihydroxylation of sulfone 21 (Scheme 5) using the ligand (DHQ)2PHAL as prescribed by the standard Sharpless mnemonic.10 Protection of the resulting diol with 2,2-dimethoxypropane (DMP) afforded acetonide 29, which underwent alkylation on treatment with KOtBu and bromide 28, circumventing the previously encountered problems with this step, to afford iodide 30 in 75% yield. Subsequent palladium-mediated stannylation of 30 with hexamethylditin afforded stannane 27 in 68% yield. Stille coupling of 27 and iodide 23 then gave diene 26 in 76% yield. Regioselective Sharpless asymmetric dihydroxylation of diene 26 followed by protection of the resulting diol, again with 2,2-dimethoxypropane, afforded sulfone 31. With sulfone 31 in hand, desulfonylation was next investigated; however, despite investigation of a wide range of conditions for palladium-catalyzed reductive desulfonylation,11 [e.g., PdCl2(dppp), Pd(OAc)2/dppp, Pd(PPh)4) with boron hydrides (e.g., KBH4, NaHB(OAc)3, NaBH4 or LiHBEt3) in various solvents], access to 32 was not able to be secured. Decomposition was observed in most cases. This approach had demonstrated the utility of our previously established sp3−sp2 Stille coupling strategy for construction of the 4-alkyl-2-nitropyrrole framework after reordering of the synthetic sequence to accommodate the sulfone and enable the necessary asymmetric regioselective dihydroxylations en route to diene 31. The difficulties encountered in the problematic desulfonylation, however, forced us to seek an alternative strategy to access the natural product framework. During our previous studies into the synthesis of heronapyrrole C 8, we initially attempted to construct the 4allyl-2-nitropyrrole framework via cross coupling of iodide 33a and a number of organometallic species (Table 1, entries 1−4). Various allylic organometallic reagents were investigated; however, none of them had afforded the corresponding nitropyrrole derivatives. Stark and coworkers also earlier reported investigations into the coupling reactivity of the 2nitropyrrole system using N-Boc protected 4-iodo-2-nitropyrrole 33a; however, efforts to achieve coupling reactions using aryl boronic acids or pinacolborane were abandoned after failing to deliver the expected products.12 Despite these setbacks and the unproductive literature precedent, we carried out further investigations into the sought-after cross-coupling step using the 2-nitropyrroles 33b and 33c. 2-Nitropyrroles 33b and 33c incorporating an electron donating protecting group (N-BOM, N-Boz) on the pyrrole nucleus were revealed to be highly competent cross-coupling partners, in marked contrast to the N-Boc series earlier probed by Stark. Suzuki−Miyaura coupling reactions using aryl boronic acids with different electronic properties afforded the expected biaryl products in good yields (Table 1, entries 5 and 6). Stille coupling using vinyl tributyltin, catalyzed by Pd(dppf)Cl2 in DMF, successfully afforded vinyl 2-nitropyrroles in 90 and 86% yield (Table 1, entries 7 and 8). Finally, Sonogashira coupling using 3-butyn-1-ol generated the desired alkyne in 92% yield (Table 1, entry 9). From the results in Table 1, taken together with the earlier work reported by ourselves and others, it appears clear that the electronic effect of the N-protecting group has a considerable influence on the coupling reactivity of the 2-nitropyrrole system; an electron donating protecting group is critical for productive cross-

Scheme 2. Initial Retrosynthetic Analysis

Scheme 3. Unsuccessful Attempted Alkylation of Sulfone 21

Scheme 4. Revised Retrosynthesis via Stille Coupling of Advanced Stannane 27

from allyl bromide 28 and sulfone 29. This approach would still guarantee the ability to control the regioselectivity of the necessary alkene epoxidation and dihydroxylations while 12462

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry Scheme 5. Revised Approach Halted by Problematic Desulfonylation of 31

basic conditions, final access to 39 was eventually effected by treatment with pyridine in methanol.21 Diastereoselective ketone reduction could then be carried out with good diastereoselectivity (d.r. ∼ 6:1) using (R)-2-methyl-CBSoxazaborolidine.22 The major product 44a was presumed to bear the required 7R stereogenic center based on examples of typical CBS reductions. This was later confirmed by comparison of spectral data for the synthetic and isolated natural products. Nitropyrrolin A 1 was readily prepared by high-yielding NBoz deprotection of 44a (Scheme 8). Alternatively, access to heronapyrrole B 7 was achieved through Sharpless asymmetric dihydroxylation of diol 44a using AD-mix-α, affording tetrol 45 in 40% yield, along with small amount of the 11,12-dihydroxy regioisomer. The stereochemistry of the newly introduced C15 stereogenic center was expected to be R by application of the standard mnemonic.10 Mild deprotection of the N-Boz pyrrole masking group then afforded heronapyrrole B 7 in 90% yield. The spectroscopic data and specific rotation of our synthetic heronapyrrole B were in good agreement with earlier synthetic data (this work [α]D +10.6; Morimoto [α]D +9.95; natural [α]D +33.3), although the magnitude of the rotation in the original isolation report was somewhat greater.1b,4a

coupling. This successful coupling strategy now provided us with a reliable platform to prepare novel 4-substituted-2nitropyrrole derivatives for further investigation of the 2nitropyrrole pharmacophore and total synthesis. Based on the robust success of the cross-coupling reactivity study, it then appeared feasible to assemble nitropyrrolin A 1 and heronapyrrole B 7 from the common intermediate hydroxyketone 39, in turn derived from propargylic alcohol 19 (Scheme 6). Advanced alcohol 19 would be assembled via Sonogashira coupling of N-Boz protected 4-iodo-2-nitropyrrole 33c and terminal alkyne 18.7,13 As expected based on our cross-coupling study, Sonogashira coupling of 4-iodo-2-nitropyrrole 33b and terminal alkyne 1813 successfully afforded propargylic alcohol 19 in 90% yield (Scheme 7). As the regioselective hydration of internal propargylic alcohols has been reported to be a challenging task,14 three strategies were devised for parallel investigation to effect the desired conversion of 19 into 39: (1) introduction of a neighboring acetate group (e.g., 40) to assist regioselective hydration,15 (2) ketone assisted indirect hydration via a ketal intermediate (e.g., 41),16 and (3) CO2-promoted direct or indirect hydration via a cyclic carbonate intermediate (e.g., 42).17 Accordingly, alcohol 19 was initially converted into the corresponding acetate 40 in 75% yield, with expectation that the neighboring acetate group would assist the desired regioselective alkyne hydration (Scheme 7).15 Unfortunately, attempted hydration of alkyne 40 using mercury sulfate (HgSO4)18 or other catalysts (NaAuCl419 and PdCl2(CH3CN)220) under various conditions only led to decomposition or recovery of starting material. Alternatively, treatment of propargylic alcohol 19 with trifluoroacetophenone in the presence of silver nitrate and DBU successfully afforded ketal 41 as a mixture of two diastereomers (d.r. 1:1) in 85% yield.16 However, the subsequent hydrolysis of ketal 41 turned out to be challenging; even strong acid such as aqueous HCl (1M) in THF was not able to hydrolyze the ketal at room temperature, and use of elevated temperatures only led to decomposition. Finally, as reported previously,7 CO2-promoted hydration of alkyne 19 was successfully achieved, giving carbonate 42 in high yield that was then converted to 43 by an unusual carbonate opening with p-toluenesulfonamide. Despite the limited stability of the 2-nitropyrrole to a range of acidic or

■

CONCLUSION In conclusion, the strategic evolution of synthetic approaches to the 2-nitropyrrole natural products nitropyrrolin A 1 and heronapyrrole B 7 is described. Initially, an unusual sp2−sp3 Stille coupling enabled successful synthesis of advanced epoxy iodide 22; however, subsequent alkylation proved challenging due to the sensitive nitropyrrole subunit. A revised strategy based on Stille coupling of iodide 23 and vinyl stannane 27 successfully established the framework of heronapyrrole B 7, leading to the final stages of the total synthesis; however, a challenging desulfonylation step defeated this approach. Crucially, fundamental study of the palladium-mediated cross-coupling of the 4-iodo-2-nitropyrrole system revealed a critical dependence on the use of an electron-donating Nsubstituent for success. Based on this work, construction of the required 2-nitro-4-alkylpyrrole framework was achieved using a highly efficient Sonogashira coupling. Regioselective hydration of a propargylic alcohol in the presence of the sensitive 2nitropyrrole subunit then enabled the total synthesis of nitropyrrolin A 1 and heronapyrrole B 7. 12463

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry Table 1. N-Substituent Dependent Cross-Coupling of 4-Iodo-2-nitropyrrole Systems

a Conditions: (A) Various catalytic systems; (B) Pd(dppf)Cl2, Cs2CO3, DMF, 90 °C; (C) Pd(dppf)Cl2, DMF, 80 °C; (D) Pd(PPh3)2Cl2, CuI, Et3N, DMF, rt. bIsolated yield.

■

The specific reactivity pattern of 2-nitro-4-iodopyrrole systems revealed in this work provide reliable and efficient methods to prepare 4-substituted-2-nitropyrrole derivatives to support investigation of the little-explored 2-nitropyrrole pharmacophore. The synthetic strategies reported here provide efficient preparative access to 2-nitropyrrole natural products and will facilitate material supply for ongoing biological evaluation of the natural products and derivative libraries.

EXPERIMENTAL SECTION

General. Unless otherwise noted, all reactions were performed under an oxygen-free atmosphere of nitrogen using standard techniques. Tetrahydrofuran (THF), dichloromethane (CH2Cl2), dimethylformamide (DMF), and acetonitrile (MeCN) were dried by passage through a column of activated alumina under N2 using an LC Technology solvent purification system. All other reagents were used as received unless otherwise noted. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials unless otherwise stated. Reactions were monitored by thin-layer 12464

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry Scheme 6. Retrosynthesis of 1 and 7 via Sonogashira Coupling and Alkyne Hydration

Scheme 8. Synthesis of Nitropyrrolin A (1) and Heronapyrrole B (7)

chromatography (TLC) carried out on silica gel plates using UV light as the visualizing agent and an ethanolic solution of vanillin and ammonium molybdate and heat as developing agents. Silica gel (60, 230−400 mesh) was used for flash column chromatography. NMR spectra were recorded at room temperature in CDCl3 or CD3OD solution on a spectrometer operating on a Bruker 400 MHz instrument. Chemical shifts are reported in parts per million on the δ scale, and coupling constants, J, are in Hertz. Multiplicities are reported as s (singlet), br s (broad singlet), d (doublet), dd (doublet of doublets), ddd (doublet of doublets of doublets), t (triplet), and m (multiplet). Where distinct from those due to the major diastereomer, resonances due to minor diastereomers are denoted by an asterisk. 1H and 13C NMR resonances were assigned using a combination of DEPT 135, COSY, HSQC, HMBC, and NOESY spectra. Resonances due to the presence of a diastereoisomer are denoted with an asterisk *. IR spectra were recorded using a thin film on a composite of zinc selenide and diamond crystal on an FT-IR system transform spectrometer. Melting points are uncorrected. HRMS was performed using a spectrometer operating at a nominal accelerating voltage of 70 eV or a TOF-Q mass spectrometer.

Allylic Alcohol 25. To a degassed solution of iodide 23 (70 mg, 0.21 mmol) and vinyl tributyltin 24 (76 mg, 0.24 mmol) in DMF (1 mL) was added Pd2(dba)3 (10 mg, 5 mol %). The mixture was heated to 80 °C and stirred for 2 h. Then, the resulting mixture was diluted with diethyl ether (15 mL), washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 10:1) to afford allylic alcohol 25 (50 mg, 85%) as a light yellow oil; IR νmax (neat)/cm−1: 1H NMR (300 MHz, CDCl3): δ 7.05−7.01 (d, J = 2.3 Hz, 1 H), 6.92 (d, J = 2.3 Hz, 1H), 5.58−5.51 (m, 1H), 4.06 (s, 2H), 3.19 (d, J = 7.4 Hz, 2H), 1.73 (s, 3H), 1.56 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 147.1, 137.1, 123.9, 121.8, 117.3 (2C), 86.7, 68.2, 27.5 (3C), 24.7, 13.7, CNO2 was not observed; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H20N2NaO5 319.1264; Found: 319.1267. Epoxy Iodide 22. To a suspension of powdered, activated molecular sieves (4 Å) in CH2Cl2 (10 mL) was added Ti(OiPr)4 (457 mg, 1.61 mmol), L-(+)-diethyl tartrate (351 mg, 1.70 mmol), and tert-butyl hydroperoxide (1.08 mL, 5.0 M solution in decane, 5.40 mmol) at −20 °C. After 25 min, allylic alcohol 25 (800 mg, 2.70 mmol) in CH2Cl2 (5 mL) was added dropwise over 30 min. The mixture was stirred at −20 °C for 1 h and then slowly warmed to 0 °C over 1 h. The reaction was quenched with H2O (1.0 mL) and allowed to warm to rt. After 30 min of vigorous stirring, the solution was

Scheme 7. Attempted Approaches for Elaboration of Propargylic Alcohol 19 Towards the Natural Product Framework and the Succesful Route7 Using p-Toluenesulfonamide as Nucleophile

12465

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc 3:1) to afford the epoxy alcohol (775 mg, 92%) as a yellow oil: [α]D20 = +18.8 (c 2.21, CHCl3); IR νmax (neat)/cm−1: 3420, 2982, 1761, 1521, 1472, 1387, 1372, 1328, 1284, 1253, 1149, 1086, 1036, 840, 809, 769; 1H NMR (CDCl3, 400 MHz): δ 7.15−7.14 (m, 1H), 7.00 (d, J = 2.2 Hz, 1H), 3.72−3.60 (m, 2H), 3.23 (t, J = 6.4 Hz, 1H), 2.71 (d, J = 6.3 Hz, 2H), 1.57 (s, 9H), 1.37 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 146.8, 124.4, 120.5, 117.1, 87.0, 65.0, 61.3, 58.9, 27.5 (3C), 25.8, 14.3, CNO2 was not observed; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H20N2NaO6 335.1214; Found 335.1210. To a stirred solution of the above epoxy alcohol (360 mg, 1.15 mmol) in CH2Cl2 (8 mL) was added imidazole (230 mg, 3.38 mmol) at 0 °C. When the imidazole was totally dissolved, PPh3 (600 mg, 2.29 mmol) was added in one portion followed by addition of I2 beads (590 mg, 2.32 mmol) portion-wise. The solution was stirred vigorously at 0 °C for 1 h and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and washed with saturated aqueous Na2S2O3. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 10:1) to afford epoxy iodide 22 (417 mg, 86%) as a yellow oil: [α]D20 = −11.8 (c 1.56, CHCl3); IR νmax (neat)/cm−1: 2981, 1760, 1520, 1472, 1371, 1327, 1283, 1252, 1148, 1087, 840, 809, 768; 1H NMR (CDCl3, 400 MHz): δ 7.19− 7.18 (m, 1H), 7.01 (d, J = 2.2 Hz, 1H), 3.26 (d, J = 9.9 Hz, 1H), 3.10 (d, J = 9.9 Hz, 1H), 3.05 (t, J = 6.3 Hz, 1H), 2.68 (d, J = 6.3 Hz, 2H), 1.56 (s, 9H), 1.54 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 146.7, 138.4 (weak, CNO2), 124.4, 119.8, 117.0, 87.0, 65.1, 60.5, 27.5 (3C), 26.6, 16.1, 12.8; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H19IN2NaO5 445.0231; Found 445.0219. Sulfone 21. To a stirred solution of geraniol (3.08 g, 20.0 mmol) and Ph3P (7.86 g, 30.0 mmol) in THF (100 mL) was added NBS (5.34 g, 30.0 mmol) in small portions at −20 °C over 20 min. The mixture was warmed to 0 °C over 30 min, then PhSO2Na (6.56 g, 40.0 mmol) and Bu4NI (0.73 g, 2.0 mmol) were added portion-wise over 10 min. The mixture was stirred overnight and then concentrated in vacuo. The residue was diluted with EtOAc (60 mL) and washed with saturated aqueous Na2S2O3 (50 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic extracts were successively washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 5:1) to afford sulfone 21 (5.00 g, 90%) as a colorless oil: 1H NMR (CDCl3, 300 MHz): δ 7.88−7.84 (m, 2H), 7.66−7.60 (m, 1H), 7.55−7.49 (m, 2H), 5.18 (t, J = 7.9 Hz, 1H), 5.05−4.99 (m, 1H), 3.80 (d, J = 7.9 Hz, 2H), 2.00−1.98 (m, 4H), 1.68 (s, 3H), 1.58 (s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 146.3, 138.7, 138.5, 132.1, 128.9 (2C), 128.6 (2C), 123.4, 110.3, 56.1, 39.6, 26.2, 25.7, 17.6, 16.1; Spectroscopic data were in good agreement with those previously reported.23 Acetonide 29. To a suspension of K3Fe(CN)6 (3.73 g, 11.3 mmol), K2CO3 (1.56 g, 11.3 mmol) and (DHQ)PHAL (29.4 mg, 0.38 mmol) in t-BuOH (20 mL) and H2O (20 mL) was added OsO4 (0.20 mL, 40 mg/mL in tert-butanol, 0.015 mmol) at 0 °C. After 10 min, methanesulfonamide (359 mg, 3.78 mmol) was added, followed by sulfone 21 (1.05 g, 3.78 mmol). The reaction mixture was stirred for 24 h at 0 °C and then quenched with saturated aqueous sodium sulfite (5 mL), warmed to room temperature, and stirred for another 1 h. The mixture was extracted with ethyl acetate (3 × 30 mL), and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 1:2) to afford the expected diol (1.08 g, 92%) as a colorless oil: [α]D20 = +5.6 (c 1.86, CHCl3); IR νmax (neat)/cm−1: 3480, 2977, 2518, 1447, 1304, 1146, 1083, 732, 687; 1H NMR (CDCl3, 400 MHz): δ 7.87−7.81 (m, 2H), 7.64−7.59 (m, 1H), 7.55−7.48 (m, 2H), 5.25−5.16 (m, 1H), 3.81 (d, J = 9.6 Hz, 2H), 3.26 (dd, J = 10.7, 1.5 Hz, 1H), 2.46 (brs, 1 H, OH), 2.45 (brs, 1 H, OH), 2.29−2.19 (m, 1H), 2.11−2.01 (m, 1H), 1.53−1.42 (m, 1H), 1.44−1.38 (m, 1H), 1.35 (s, 3H), 1.16 (s, 3H), 1.11 (s, 3H); 13 C NMR (CDCl3, 100 MHz): δ 146.5, 138.8, 133.7, 129.1 (2C),

128.4 (2C), 110.6, 77.8, 73.2, 56.1, 36.7, 29.3, 26.4, 23.2, 16.2; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H24NaO4S 335.1288; Found 335.1290. The above diol (312 mg, 1.00 mmol) was stirred together with camphorsulfonic acid (12 mg, 0.05 mmol) and 2,2-dimethoxypropane (520 mg, 5.00 mmol) in CH2Cl2 (5 mL) at room temperature for 3 h. The resulting mixture was then diluted with saturated aqueous NaHCO3 (15 mL) and extracted with dichloromethane (3 × 15 mL). The combined organics were washed with brine, dried over Na2SO4 ,and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 5:1) to afford acetonide 29 (334 mg, 95%) as a colorless oil: [α]D20 = +9.7 (c 1.21, CHCl3); IR νmax (neat)/cm−1: 2976, 2934, 1447, 1447, 1302, 1146, 1083, 738, 688; 1H NMR (CDCl3, 400 MHz): δ 7.89−7.85 (m, 2H), 7.66−7.61 (m, 1H), 7.56−7.50 (m, 2H), 5.22−4.28 (m, 1H), 3.81 (d, J = 8.1 Hz, 2H), 3.61 (dd, J = 9.7, 3.5 Hz, 1H), 2.29−2.19 (m, 1H), 2.09−2.00 (m, 1H), 1.58−1.49 (m, 1H), 1.44−1.38 (m, 4H), 1.36 (d, J = 1.0 Hz, 3H), 1.32 (s, 3H), 1.23 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 145.9, 138.8, 133.6, 129.0 (2C), 128.5 (2C), 110.6, 106.7, 82.7, 80.1, 56.1, 36.9, 28.6, 27.5, 26.9, 26.1, 22.9, 16.3; HRMS (ESITOF) m/z: [M + Na]+ Calcd for C19H28NaO4S 375.1601; Found 375.1590. Bromide 28. To a solution of (Z)-3-iodo-2-methylprop-2-en-1-ol (198 mg, 1.00 mmol) and Ph3P (340 mg, 1.30 mmol) in CH2Cl2 (5 mL) was added NBS (267 mg, 1.50 mmol) at −20 °C. After 1 h, the reaction mixture was diluted with pentane (20 mL), filtered through a silica plug and concentrated in vacuo to afford bromide 28 (200 mg, 77%), which was immediately used in the next step due to its instability: 1H NMR (CDCl3, 400 MHz): δ 6.20 (s, 1H), 4.08 (s, 2H), 2.06 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 143.3, 79.9, 37.4, 22.1. Spectroscopic data were in good agreement with those previously reported.24 Iodide 30. A solution of sulfone 29 (352 mg, 1.0 mmol) and bromide 28 (312 mg, 1.20 mmol) in THF (5 mL) was cooled to −45 °C. A solution of t-BuOK (134 mg, 1.2 mmol) in THF (2.0 mL) was added dropwise over 15 min. The resulting mixture was stirred at −45 °C for 1 h, quenched with saturated aqueous NH4Cl (1.0 mL), and warmed to room temperature. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 5:1) to afford iodide 30 (399 mg, 75%) as a colorless oil: IR νmax (neat)/cm−1: 3488, 2974, 1447, 1303, 1266, 1143, 1082, 734, 688; 1H NMR (CDCl3, 400 MHz): δ 7.92−7.84 (m, 2H), 7.69−7.61 (m, 1H), 7.60−7.53 (m, 2H), 5.99−5.96 (m, 1H), 5.14−5.06 (m, 1H), 4.15−4.06 (m, 1H), 3.66−5.59 (m, 1H), 2.92− 2.77 (m, 1H), 2.76−2.67 (m, 1H,), 2.06−1.94 (m, 1H), 1.82 (s, 1.5 H), 1.83* (s, 1.5 H), 1.58−1.45 (m, 1H), 1.47−1.43 (m, 1H), 1.41 (s, 3H), 1.40−1.35 (m, 1H), 1.33 (s, 3H), 1.31 (d, J = 1.2 Hz, 1.5H), 1.26* (d, J = 1.2 Hz, 1.5 H), 1.24 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 145.6, 145.5*, 142.9, 142.8*, 137.8, 133.6, 129.3 (2C), 128.9 (2C), 116.1, 116.0*, 106.7, 82.9, 82.8*, 80.1, 77.9, 77.8*, 62.6, 36.7, 36.8*, 36.6, 28.6, 27.6, 27.5*, 26.9, 26.2, 26.1*, 24.5, 24.4*, 23.0, 16.8, 16.7*; *donates minor isomer. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H33NaIO4S 555.1037; Found 555.1040. Stannane 27. A mixture of iodide 30 (53 mg, 0.10 mmol), DIPEA (4 mg, 0.03 mmol), (Me3Sn)2 (50 mg, 0.15 mmol), and (Ph3P)4Pd (11.5 mg, 0.01 mmol) in degassed toluene (1 mL) was stirred at 70 °C for 30 min. The resulting mixture was concentrated in vacuo. The residue was subjected to flash chromatography (hexanes/EtOAc 10:1) to afford stannane 27 (39 mg, 68%) as a colorless oil: IR νmax (neat)/cm−1: 3488, 2974, 1447, 1303, 1266, 1143, 1082, 734, 688; 1H NMR (CDCl3, 400 MHz): δ 7.86−7.82 (m, 2H), 7.66−7.61 (m, 1H), 7.55−7.49 (m, 2H), 5.56 (s, 1H), 4.92−4.85 (m, 1H), 4.05−3.93 (m, 1H), 3.65−3.55 (m, 1H), 3.00−2.90 (m, 1H), 2.40−2.28 (m, 1H,), 2.25−2.14 (m, 1H), 2.05−1.92 (m, 1H), 1.75 (s, 3H), 1.55−1.44 (m, 1H), 1.40 (s, 3H), 1.40−1.33 (m, 1H), 1.33 (s, 3H), 1.30 (d, J = 1.2 Hz, 1.5H), 1.28* (d, J = 1.2 Hz, 1.5H), 1.24 (s, 1.5H), 1.22* (s, 1.5H), 1.08 (s, 1.5H), 1.07* (s, 1.5H), 0.12 (s, 9H); 13C NMR 12466

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry (CDCl3, 100 MHz): δ 149.3, 149.2*, 145.2, 145.0*, 137.8, 137.7*, 133.5, 129.4*, 129.37, 129.3 (2C), 128.8 (2C), 116.91*, 116.87, 106.7, 82.7*, 82.1, 80.1, 63.53, 63.50*, 37.8, 37.6*, 36.8*, 36.7, 28.6, 27.7, 27.4*, 27.0*, 26.9, 26.2, 26.1*, 25.7, 25.6*, 22.98*, 22.95, 16.7, 16.5*; − 8.5 (3C); *donates minor isomer. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H42NaO4SSn 593.1722; Found 593.1726. Diene 26. To a degassed solution of iodide 23 (70 mg, 0.20 mmol) and stannane 27 (136 mg, 0.24 mmol) in DMF (1 mL) was added Pd2(dba)3 (10 mg, 5 mol %), and the mixture was stirred at 80 °C for 2 h. The mixture was diluted with diethyl ether (15 mL), washed with H2O/brine (1:1), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 6:1) to afford diene 26 (96 mg, 76%) as a light yellow oil: IR νmax (neat)/cm−1: 2925, 1652, 1620, 1603, 1449, 1339, 1188, 1098, 980, 766, 697; 1H NMR (CDCl3, 400 MHz): δ 7.86− 7.82 (m, 2H), 7.66−7.60 (m, 1H), 7.55−7.49 (m, 2H), 7.04−6.96 (m, 1H), 6.91−6.85 (m, 1H), 5.39−5.31 (m, 1H), 5.05−4.97 (m, 1H), 3.95−3.80 (m, 1H), 3.65−3.55 (m, 1H), 3.24−3.04 (m, 2H), 2.94−2.81 (m, 1H), 2.59−2.49 (m, 1H), 2.24−2.09 (m, 1H), 1.99− 1.87 (m, 1H), 1.68 (s, 3H), 1.57 (s, 9H), 1.47−1.37 (m, 4H), 1.35− 1.28 (m, 4H), 1.22 (s, 3H), 1.20 (d, J = 1.4 Hz, 1.5H), 1.13* (d, J = 1.4 Hz, 1.5H), 1.06 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 147.0, 145.3, 145.1*, 138.9 (weak, CNO2), 137.9, 137.8*, 113.6, 113.5*, 133.0, 129.2 (2C), 129.1*, 129.08*, 129.05, 128.9 (2C), 128.8*, 124.8, 124.0*, 123.9, 117.2*, 117.1, 117.09*, 117.07, 106.7, 86.7, 82.8*, 82.7, 80.0, 63.4, 36.9, 36.8*, 29.8, 29.5*, 28.6, 27.7, 27.6*, 27.5 (3C), 26.9, 26.1, 25.0, 23.62*, 23.60, 22.9, 22.8*, 16.4, 16.1*; *donates minor isomer. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C33H46N2NaO8S 653.2867; Found 653.2859. Sulfone 31. To a suspension of K3Fe(CN)6 (373 mg, 1.10 mmol), K2CO3 (156 mg, 1.10 mmol), and (DHQ)PHAL (2.9 mg, 0.038 mmol) in t-BuOH (2 mL) and H2O (2 mL) was added OsO4 (20 μL, 40 mg/mL in t-BuOH, 0.015 mmol) at 0 °C. After 10 min, methanesulfonamide (19 mg, 0.20 mmol) was added, followed by diene 26 (96 mg, 0.15 mmol). The reaction mixture was stirred for 24 h at 0 °C, then quenched with saturated aqueous sodium sulfite (1 mL), warmed to room temperature and stirred for 1 h. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (hexanes/EtOAc 1:2) to afford the diol (90 mg, 90%) as a colorless oil: IR νmax (neat)/cm−1: 3493, 2926, 1718, 1447, 1370, 1297, 1143, 1082, 734, 688; 1H NMR (CDCl3, 400 MHz): δ 7.86−7.80 (m, 2H), 7.66−7.60 (m, 1H), 7.55−7.49 (m, 2H), 7.19−7.10 (d, J = 2.2, 1H), 7.03−7.00 (m, 1H), 5.14 (d, J = 9.8 Hz. 1H), 4.30−4.14 (m, 1H), 3.64−3.49 (m, 2H), 2.76−2.59 (m, 2H), 2.51−2.34 (m, 2H), 2.23−2.11 (m, 1H), 2.05− 1.92 (m, 1H), 1.76−1.63 (m, 1H), 1.56 (s, 9H), 1.46−1.36 (m, 4H), 1.30 (s, 3H), 1.26−1.20 (m, 6H), 1.14 (s, 3H), 1.07(s, 1.5H), 1.05* (s, 1.5H). 13C NMR (CDCl3, 100 MHz): δ 146.9, 144.8, 144.2*, 138.3 (weak, CNO2), 137.3, 137.2*, 133.7, 133.6*, 129.35*, 129.29 (2C), 128.85 (2C), 128.81*, 125.1*, 125.0, 122.1, 122.0*, 119.4*, 118.8, 117.7, 106.8, 106.7*, 86.8, 83.2, 82.8*, 80.08, 80.05*, 78.5, 77.7*, 73.7, 73.5*, 60.9, 60.6*, 37.1, 36.8*, 35.1, 34.3*, 29.7*, 28.6, 28.5, 28.4, 27.3*, 27.5(3C), 26.9, 26.1, 26.0*, 23.7, 23.5*, 23.0, 22.9*, 16.4, 16.3*; *donates minor isomer. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C33H48N2NaO10S 687.2922; Found 687.2905. The above diol (90 mg, 0.14 mmol) was stirred together with camphorsulfonic acid (2.3 mg, 0.01 mmol) and 2,2-dimethoxypropane (52 mg, 0.50 mmol) in CH2Cl2 (1 mL) at room temperature for 3 h. The resulting mixture was diluted with saturated aqueous NaHCO3 (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 3:1) to afford sulfone 31 (94 mg, 95%) as a light yellow oil: IR νmax (neat)/cm−1: 2926, 1718, 1447, 1370, 1297, 1143, 1082, 734, 688; 1H NMR (CDCl3, 400 MHz): δ 7.86−7.80 (m, 2H), 7.66−7.60 (m, 1H), 7.55−7.49 (m, 2H), 7.20− 7.13 (m, 1H), 7.05−7.00 (m, 1H), 5.11 (d, J = 9.8 Hz, 1H), 4.17 (t, J = 10.3 Hz, 0.5 H), 3.95* (t, J = 9.3 Hz, 0.5 H), 3.91 (dd, J = 10.3, 3.1,

0.5 H), 3.82* (dd, J = 10.3, 2.6, 0.5 H), 3.63−3.56 (m, 1H), 2.78− 2.48 (m, 2H), 2.26−2.10 (m, 2H), 2.0−1.87 (m, 2H), 1.57 (s, 9H), 1.51−1.43 (m, 2H), 1.41* (s, 1.5H), 1.40 (s, 1.5H), 1.32 (s, 3H), 1.30* (s, 3H), 1.28 (s, 3H), 1.27* (s, 3H), 1.23 (s, 1.5H), 1.22* (s, 1.5H), 1.17 (s, 1.5H), 1.16* (s, 1.5H), 1.09 (s, 1.5H), 1.08* (s, 1.5H); 13C NMR (CDCl3, 100 MHz): δ 146.9, 144.5, 142.5*, 138.2 (weak, CNO2), 137.9, 137.8*, 133.5, 133.4*, 129.3*, 129.2 (2C), 128.7 (2C), 124.6, 121.4, 121.3*, 119.8*, 119.7, 117.5, 108.2*, 107.8, 106.7, 106.6*, 86.8, 84.7, 83.7*, 83.0, 82.8*, 80.9, 80.5*, 80.0, 601.1, 60.9*, 36.9, 36.8*, 33.0, 31.9*, 28.5, 28.0, 27.8*, 27.6, 27.4 (3C), 27.3*, 26.9, 26.8, 26.7*, 26.1, 26.07*, 26.0, 25.7*, 23.7*, 23.3, 22.9, 16.48, 16.2*; *donates minor isomer. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C36H52N2NaO10S 727.3235; Found 727.3238. N-BOM-4-(2-Methoxyphenyl)-2-nitropyrrole 34. To a degassed solution of iodide 33b (36 mg, 0.10 mmol) in DMF (1 mL) was added Pd(dppf)Cl2 (2.5 mg, 5 mol %), (2-methoxyphenyl)boronic acid (23 mg, 0.15 mmol), and Cs2CO3 (65 mg, 0.20 mmol). The mixture was stirred at 90 °C overnight, diluted with H2O (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/ EtOAc 9:1) to afford 34 (27 mg, 82%) as a yellow oil: IR νmax (neat)/ cm−1: 2935, 1465, 1358, 1304, 1203, 925, 736, 697; 1H NMR (CDCl3, 400 MHz): δ 7.63 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.51−7.45 (m, 1H), 7.26−7.36 (m, 6H), 6.98−7.04 (m, 2H), 5.82 (s, 2H), 4.61 (s, 2H), 3.92 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 156.4, 137.2, 136.5, 128.7 (2C), 128.6, 128.5, 128.2, 127.9 (2C), 127.8, 121.1, 121.0, 114.4, 111.3, 77.8, 71.0, 55.4, CNO2 was not observed; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H18N2NaO4 361.1159; Found 361.1163. N-BOM-4-(p-Tolyl)-2-nitropyrrole 35. To a solution of iodide 33b (36 mg, 0.10 mmol) in degassed DMF (1 mL) was added Pd(dppf)Cl2 (2.5 mg, 5 mol %), (4-methylphenyl)boronic acid (20 mg, 0.15 mmol), and CsCO3 (65 mg, 0.20 mmol). The mixture was stirred at 90 °C overnight, diluted with H2O (10 mL), and extracted with ethyl acetate (3× 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/ EtOAc 10:1) to afford 35 (25 mg, 78%): IR νmax (neat)/cm−1: 3104, 2918, 1446, 1372, 1353, 1292, 1202, 1073, 1043, 812, 695, 734; 1H NMR (CDCl3, 400 MHz): δ 7.39 (d, J = 1.9 Hz, 1H), 7.27−7.3 (m, 7H), 7.20−7.24 (m, 3H), 5.82 (s, 2H), 4.62 (s, 2H), 2.38 (s, 3H); 13 C NMR (CDCl3, 100 MHz): δ 137.3, 136.4, 129.7 (2C), 129.6, 128.6 (2C), 128.3, 127.8 (2C), 125.3 (2C), 125.1, 124.8, 112.4, 78.0, 71.3, 21.2, CNO2 was not observed; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H18N2NaO3 345.1215; Found 345.1218. N-BOM-4-(Vinyl)-2-nitropyrrole 36. A mixture of iodide 33b (395 mg, 1.10 mmol), vinyltributyltin (385 mg, 1.20 mmol), and Pd(dppf)Cl2 (8.0 mg, 0.01 mmol) in degassed DMF (2 mL) was stirred at 90 °C overnight. The mixture was directly subjected to flash chromatography (hexanes/EtOAc 10:1) to afford 36 (250 mg, 90%) as a yellow oil: IR vmax (neat)/cm−1: 3121, 3031, 2898, 1459, 1342, 1289, 1087, 1075, 904, 836, 734, 696. 1H NMR (CDCl3, 400 MHz): δ 7.33−7.25 (m, 6H), 6.99 (d, J = 2.2 Hz, 1H); 6.50−6.43 (dd, J = 17.5, 10.9 Hz, 1H), 5.74 (s, 2H), 5.55−5.51 (dd, J = 17.4, 1.0 Hz, 1H), 5.19−5.16 (dd, J = 10.9, 1.0 Hz, 1H), 4.56 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ 137.5 (weak, CNO2), 136.3, 128.6 (2C), 128.2, 127.8 (2C), 127.5, 126.4, 123.0, 114.0, 111.9, 77.8, 71.2; HRMS (ESITOF) m/z: [M + Na]+ Calcd for C14H14N2NaO3 281.0897; Found 281.0901. N-Boz-4-(Vinyl)-2-nitropyrrole 37. A mixture of iodide 33c (930 mg, 2.50 mmol), vinyltributyltin (950 mg, 3.00 mmol), and Pd(dppf)Cl2 (8 mg, 0.01 mmol) in degassed DMF (2.5 mL) was stirred at 90 °C for 3 h. The mixture was directly subjected to flash chromatography (hexanes/EtOAc 10:1) to afford 37 (571 mg, 84%) as a yellow solid: mp 101.3−103.9 °C; IR vmax (neat)/cm−1: 3125, 1724, 1468, 1352, 1258, 1084, 1066, 709; 1H NMR (CDCl3, 400 MHz): δ 8.02−8.04 (m, 2H), 7.56−7.61 (m, 1H), 7.41−7.47 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 6.42−6.49 (m, 1H), 6.46 (s, 2H), 5.55 (d, J = 17.4 Hz, 1H), 5.19 (dd, J = 11.0, 12467

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry 1.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 165.7, 133.9, 130.1 (2C), 128.6 (2C), 128.1, 127.2, 123.2, 121.7, 114.5, 112.2, 69.9, CNO2 was not observed; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H12N2NaO4 295.0690; Found 295.0693. N-BOM-4-(4′-Alkynyl)-2-nitropyrrole 38. To a solution of iodide 33b (90 mg, 0.25 mmol) in degassed DMF (0.5 mL) and Et3N (0.5 mL) was added Pd(PPh3)2Cl2 (9 mg, 5 mol %) and CuI (1 mg, 2.5 mol %). After 15 min, 4-pentyne-1-ol (32 mg, 0.38 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with Et2O (20 mL), filtered through a Celite plug, washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 7:1) to afford compound 38 (56 mg, 72%) as a yellow oil: IR νmax (neat)/cm−1: 3303, 2920, 1432, 1322, 1276, 1033, 843, 665; 1H NMR (CDCl3, 400 MHz): δ 7.38−7.27 (m, 5H), 7.21 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 5.73 (s, 2H), 4.56 (s, 2H), 3.79 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 6.0 Hz, 2H), 1.87−1.80 (m, 2H); 13C NMR (CDCl3, 100 MHz): δ 136.1, 130.6 (2C), 128.7, 128.3, 127.8 (2C), 117.5, 106.2, 90.2, 78.0, 72.7, 71.3, 61.7, 31.3, 15.9, CNO2 was not observed; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H18N2NaO4 337.1159; Found: 337.1167. Alkyne 19. Iodide 33c (148 mg, 0.40 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol), and CuI (7.6 mg, 0.04 mmol) were added successively to degassed triethylamine/DMF (2:1, 3 mL) and stirred for 10 min at room temperature. Alkyne 18 (105 mg, 0.48 mmol) in trimethylamine (0.5 mL) was slowly added over 30 min, and the mixture was stirred for a further 2 h. The reaction mixture was added slowly to a 1:1 mixture of cooled aqueous HCl (1M) and brine (30 mL) and extracted with diethyl ether (3 × 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 3:1 to 2:1) afforded alkyne 19 (168 mg, 90%) as a yellow oil. [α]D18 = −15.7 (c 2.30, CHCl3); IR νmax (neat)/cm−1: 3525, 2915, 1730, 1474, 1380, 1313, 1261, 1083, 1065, 1025, 839, 708; 1H NMR (CDCl3, 400 MHz) δ 8.05−8.00 (m, 2H), 7.63−7.57 (m, 1H), 7.48−7.41 (m, 2H), 7.33 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.46 (s, 2H), 5.24− 5.17 (m, 1H), 5.11−5.05 (m, 1H), 2.39−2.27 (m, 1H), 2.26−2.15 (m, 1H), 2.11−2.03 (m, 2H), 2.03−1.96 (m, 2H), 1.79−1.73 (m, 2H), 1.68 (d, J = 0.8 Hz, 3H), 1.66 (s, 3H), 1.59 (s, 3H), 1.54 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.6, 136.3, 134.0, 132.8, 131.5, 130.1, 128.6 (2C), 128.4 (2C), 124.1, 123.5, 117.6, 105.6, 93.9, 75.0, 69.8, 68.9, 43.3, 39.7, 29.8, 26.6, 25.7, 23.7, 17.7, 16.1, (NO2C not observed); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H32N2NaO5 487.2203; Found 487.2220. Acetate 40. A mixture of propargylic alcohol 19 (46 mg, 0.10 mmol), DMAP (3.6 mg, 0.03 mmol), Et3N (30.3 mg, 0.30 mmol), and Ac2O (51 mg, 0.50 mmol) in CH2Cl2 (1 mL) was stirred overnight at room temperature. The mixture was concentrate in vacuo, and the residue was purified by flash chromatography (hexanes/ EtOAc 8:1) to afford acetate 40 (38 mg, 75%) as a yellow oil: [α]D18 = −7.4 (c 2.00, CHCl3); IR νmax (neat)/cm−1: 2918, 1731, 1475, 1382, 1246, 2083, 1065, 1025, 837, 708; 1H NMR (CDCl3, 400 MHz) δ 8.05−8.00 (m, 2H), 7.63−7.57 (m, 1H), 7.48−7.41 (m, 2H), 7.35 (d, J = 2.06, 1H), 7.28 (d, J = 2.06, 1H), 6.45 (s, 2H), 5.19−5.12 (m, 1H), 5.12−5.05 (m, 1H), 2.26−2.12 (m, 2H), 2.11−1.95 (m, 8H), 1.91−1.82 (m, 1H), 1.71 (s, 3H), 1.68 (s, 3H), 1.62 (s, 3H), 1.59 (d, J = 1.79, 3H); 13C NMR (CDCl3, 400 MHz) δ 169.3, 165.6, 136.4, 135.9, 134.0, 133.0, 131.4, 130.1 (2C), 128.6 (2C), 128.4, 124.2, 123.0, 117.8, 105.4, 90.5, 75.3, 69.8, 41.4, 39.6, 26.7, 26.4, 25.7, 22.9, 21.9, 17.7, 16.0, CNO2 not observed; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C29H34N2NaO6 529.2309; Found 529.2300. Cyclic Ketal 41. To a solution of propargylic alcohol 19 (46 mg, 0.10 mmol) and trifluoromethyl acetophenone (22.8 mg, 0.12 mmol) in toluene (1.0 mL) was added AgNO3 (1.7 mg, 0.01 mmol) and DBU (1.5 mg, 0.01 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was purified by flash chromatography (hexanes/EtOAc, 10:1) to afford cyclic ketal 41 as a 1:1 mixture of two diastereomers (54 mg, 85%) as a yellow oil: IR νmax (neat)/cm−1: 2917, 1728, 1470, 1379, 1314, 1260, 1185, 1083, 1065, 1025, 955, 720, 707, 696; 1H

NMR (CDCl3, 400 MHz): δ 8.11−8.01 (m, 2H), 7.74−7.63 (m, 2H), 7.61−7.54 (m, 1H), 7.50−7.37 (m, 7H), 6.54 (s, 2H), 5.20−4.83 (m, 3H), 2.41−1.63 (m, 8H), 1.68* (s, 2H), 1.62 (s, 4H), 1.60 (s, 2H), 1.53*(s, 1H), 1.32* (s, 1H), 1.21(s, 2H); 13C NMR (CDCl3, 400 MHz) δ 165.7.3, 156.1*, 155.9, 136.9, 136.1, 135.9*, 134.5, 134.0*, 133.8, 131.4, 131.3*, 130.1, 130.0 (4C), 128.7, 128.6 (4C), 128.2 (2C), 126.9, 126.6*, 124.2, 124.1*, 123.1, 122.6*, 118.89, 118.87*, 114.4, 88.7*, 88.4, 87.6*, 86.8, 70.1, 41.9*, 40.2, 39.6, 39.5*, 27.2, 26.7, 26.5*, 25.7, 25.6*, 22.6*, 22.2, 17.7, 17.6*, 15.9, 15.7*; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C35H37F3N2NaO6 661.2496; Found 661.2500. Cyclic Carbonate 42. To a solution of 2-nitropyrrole 19 (600 mg, 1.3 mmol) in dichloromethane (0.5 mL) in a 45 mL sealed tube was added PPh3 (85 mg, 0.32 mmol) and AgCO3 (36 mg, 0.13 mmol). The mixture was stirred for 5 min before dry ice (600 mg) was quickly sealed inside to create a CO2 atmosphere. The mixture was stirred at room temperature overnight and then directly subjected to flash chromatography (hexanes/EtOAc 5:1 to 3:1) to afford cyclic carbonate 42 (594 mg, 90%) as a yellow liquid. [α]D18 = +0.7 (c 1.60, CHCl3); IR νmax (neat)/cm−1: 1829, 1728, 1474, 1384, 1305, 1263, 1085, 709; 1H NMR (CDCl3, 400 MHz) δ 8.08−7.98 (m, 2H), 7.63−7.53 (m, 1H), 7.50−7.37 (m, 4H), 6.48 (s, 2H), 5.35 (s, 1H), 5.11−5.00 (m, 2H), 2.39−2.27 (m, 2H), 2.26−1.89 (m, 5H), 1.83− 1.73 (m, 1H), 1.66 (s, 3H), 1.63 (s, 3H), 1.57 (s, 3H), 1.56 (s, 3H); 13 C NMR (CDCl3, 100 MHz) δ 165.7, 151.0, 150.4, 137.2, 134.0, 131.6, 130.1, 129.1, 128.7 (2C), 128.6 (2C), 124.1, 121.6, 116.6, 114.5, 93.2, 87.7, 70.2, 40.5, 39.6, 26.6 (2C), 25.7, 22.0, 17.7, 16.1, (NO2C not observed); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H32N2NaO7 531.2102; Found 531.2097. Toluenesulfonyl Carbamate 43. A mixture of cyclic carbonate 42 (112 mg, 0.2 mmol), p-toluenesulfonylamide (137 mg, 0.8 mmol), and K2CO3 (55 mg, 0.4 mmol) in DMF (1 mL) was stirred at 80 °C for 3 h. The resulting mixture was diluted with brine (25 mL) and extracted with diethyl ether (3 × 25 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 1:1) afforded toluenesulfonyl carbamate 43 (111 mg, 90%) as a light yellow oil. [α]D20 = −12.6 (c 5.10, CHCl3); IR νmax (neat)/cm−1: 1924, 1727, 1468, 1451, 1376, 1262, 1156, 1085, 1066, 735, 710, 662; 1H NMR (CDCl3, 400 MHz) δ 8.01 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.62−7.54 (m, 1H), 7.46−7.39 (m, 2H), 7.37−7.30 (m, 2H), 7.10 (s, 1H), 7.02 (s, 1H), 6.42 (s, 2H), 5.13−4.90 (m, 2H), 3.41 (s, 2H), 2.41 (s, 3H), 2.09−1.78 (m, 8H), 1.67 (s, 3H), 1.58 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 204.2, 181.4, 165.7, 149.4, 145.4, 136.8, 136.6, 135.4, 133.8, 131.6, 130.0, 129.7 (2C), 128.6 (2C), 128.5 (2C), 128.3 (2C), 124.0, 122.0, 116.4, 116.1, 39.6, 36.4, 34.7, 33.5, 26.5, 25.7, 21.6 (2C), 20.2, 17.7, 15.9, NO2C not observed; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C35H41N3NaO9S 702.2456; Found 702.2452. Hydroxyketone 39. A solution of toluene sulfonyl carbomate 43 (111 mg, 0.16 mmol) in pyridine/methanol (2:1, 3 mL) was stirred at 70 °C overnight. The resulting mixture was concentrated in vacuo and purified by flash chromatography (hexanes/EtOAc 2:1) to afford hydroxyketone 39 (47 mg, 60%) as a light yellow oil. [α]D20 = +9.0 (c 2.60, CHCl3); IR νmax (neat)/cm−1: 3496, 2851, 1722, 1452, 1375, 1308, 1065, 1025, 710; 1H NMR (CDCl3, 400 MHz) δ 8.03 (br d, J = 8.0 Hz, 2H), 7.59 (br t, J = 7.1 Hz, 1H), 7.44 (br t, J = 8.0 Hz, 2H), 7.20 (br s, 1H), 7.18 (br s, 1H), 6.46 (s, 2H), 5.12−5.01 (m, 2H), 3.71 (s, 2H), 2.16−1.98 (m, 3H), 1.98−1.90 (m, 2H), 1.86−1.75 (m, 3H), 1.67 (s, 3H), 1.59 (s, 3H), 1.55 (s, 3H), 1.40 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 210.7, 165.7, 136.8, 136.5, 133.9, 131.5, 130.0, 129.7, 128.6 (2C), 128.5 (2C), 124.1, 122.9, 116.2, 115.9, 97.1, 69.9, 39.6. 39.5, 33.7, 26.5, 25.7, 25.6, 22.2, 17.7, 16.0; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H34N2NaO6 505.2309; Found 505.2293. Diols 44a and 44b. A solution of (R)-CBS (1 M solution in toluene, 0.3 mL, 0.3 mmol) in THF (5 mL) was treated with the dropwise addition of BH3·DMS (22 mg, 0.3 mmol) in THF (0.3 mL). The resulting mixture was stirred at room temperature for 20 min and then cooled to −40 °C. A solution of hydroxyketone 39 (57 mg, 0.12 12468

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry

1.12 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 165.8, 136.7, 133.8, 132.2, 130.0, 129.6, 128.7 (2C), 128.5 (2C), 124.1, 122.3, 116.2, 78.4, 78.0, 75.1, 74.0, 69.9, 38.8, 33.3, 28.5, 25.7, 24.6, 23.1, 22.0, 20.8, 17.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H38N2NaO8 541.2521; Found 541.2520. Heronapyrrole B 7. To a solution of tetrol 45 (41 mg, 0.08 mmol) in methanol (0.5 mL) was added aqueous K2CO3 (1M, 0.1 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min, diluted with H2O (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 1:1) afforded heronapyrrole B (7) (27 mg, 90%) as a light yellow oil: [α]D20 = +10.6 (c 0.50, MeOH); [Morimoto [α]D +9.95 (c 0.42, MeOH);4a natural [α]D +33.3 (c 0.05, MeOH)1b 1H NMR (600 MHz, CD3OD) δ 7.02 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 1.8 Hz, 1H), 5.21 (t, J = 6.7 Hz, 1H), 3.46 (dd, J = 10.6, 1.7 Hz, 1H), 3.23 (dd, J = 10.5, 1.5 Hz, 1H), 2.85 (dd, J = 14.7, 1.3 Hz, 1H), 2.43 (dd, J = 14.7, 10.6 Hz, 1H), 2.28−2.20 (m, 1H), 2.21− 2.04 (m, 2H), 2.01 (ddd, J = 13.5, 8.8, 7.4 Hz, 1H), 1.74−1.67 (m, 1H), 1.65 (s, 3H), 1.66−1.49 (m, 2H), 1.40−1.25 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H); 13C NMR (150 MHz, CD3OD): δ 138.6, 136.0, 126.3, 126.1, 124.6, 112.3, 79.3, 79.0, 75.3, 73.8, 39.9, 37.9, 30.8, 29.5, 25.6, 24.9, 22.8, 21.5, 16.1. The spectroscopic data were in agreement with those reported in the literature.1b,4a

mmol) in THF (0.5 mL) was added dropwise, and the reaction mixture was stirred at −40 °C for 3 h. The reaction was quenched with MeOH (0.1 mL) and concentrated in vacuo. Purification of the crude residue by flash column chromatography (hexanes/EtOAc 2:1 to 1:1) afforded diols 44a (35 mg, 60%) and 44b (6 mg, 11%) as yellow oils. 44a: [α]D20 = +8.7 (c 0.90, CHCl3); IR νmax (neat)/cm−1: 351, 2923, 1726, 1465, 1451, 1375, 1310, 1260, 1084, 711; 1H NMR (CDCl3, 400 MHz) δ 8.06−8.00 (m, 2H), 7.61−7.56 (m, 1H), 7.47− 7.40 (m, 2H), 7.21 (d, J = 2.58, 1H), 7.14 (d, J = 2.58, 1H), 6.45 (s, 2H), 5.20−5.12 (m, 1H), 5.11−5.04 (m, 1H), 3.55 (dd, J = 10.8, 2.2 Hz, 1H), 2.77 (dd, J = 14.7, 2.1 Hz, 1H), 2.49 (dd, J = 14.7, 10.7 Hz, 1H), 2.24−2.00 (m, 6H), 1.76−1.68 (m, 1H), 1.68 (d, J = 1.0 Hz, 3H), 1.64 (s, 3H), 1.60 (s, 3H), 1.41−1.51 (m, 1H), 1.24 (s, 3H); 13 C NMR (CDCl3, 100 MHz) δ 165.7, 136.0, 133.8, 131.5, 130.0, 129.5, 128.7 (2C), 128.6 (2C), 124.1 (2C), 122.1, 116.1, 78.1, 74.5, 69.9, 39.7, 36.2, 28.5, 26.6, 25.7, 23.4, 22.0, 17.7, 16.1 (NO2C not observed); HRMS (ESI-TOF) m/z: [M + Na] + Calcd for C27H36N2NaO6 507.2466; Found 507.2466. 44b: [α]D20 = +4.7 (c 1.20, CHCl3); IR νmax (neat)/cm−1:351, 2923, 1725, 1465, 1451, 1373, 1311, 1260, 1084, 711; 1H NMR (CDCl3, 400 MHz) δ 8.06− 8.00 (m, 2H), 7.61−7.56 (m, 1H), 7.47−7.40 (m, 2H), 7.21 (d, J = 2.6 Hz, 1H), 7.14 (d, J = 2.58, 1H), 6.44 (s, 2H), 5.20−5.12 (m, 1H), 5.11−5.04 (m, 1H), 3.58 (dd, J = 10.7, 2.2 Hz, 1H), 2.62 (dd, J = 14.7, 2.1 Hz, 1H), 2.47 (dd, J = 14.7, 10.7 Hz, 1H), 2.20−2.00 (m, 6H), 1.69 (d, J = 1.0 Hz, 3H), 1.64−1.52 (m, 2H), 1.63 (s, 3H), 1.60 (s, 3H), 1.19 (s, 3H);13C NMR (CDCl3, 100 MHz) δ 165.8, 136.1, 133.9, 131.6, 130.0, 129.5, 128.7 (2C), 128.6 (2C), 124.1, 123.9, 122.0, 116.2, 76.9, 74.7, 69.9, 39.7, 38.8, 28.7, 26.6, 25.7, 22.1, 21.2, 17.7, 16.1 (NO2C not observed); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H36N2NaO6 507.2466; Found 507.2466. Nitropyrrolin A 1. To a solution of diol 44a (37 mg, 0.076 mmol) in methanol (0.5 mL) was added aqueous K2CO3 (1M, 0.1 mL) dropwise at 0 °C. The mixtue was stirred at 0 °C for 30 min, then diluted with H2O (10 mL) and extracted with diethyl ether (3 × 15 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 1:1) afforded nitropyrrolin A (1) (24 mg, 92%) as a light yellow oil. [α]D20 = +20.7 (c 0.15, CH2Cl2), [natural, [α]D24 = +8 (c 0.05, CH2Cl2);1a Morimoto, [α]D24 = +26.6 (c 0.05, CH2Cl2)4b]; 1H NMR (CDCl3, 400 MHz) δ 9.40 (br s, 1H), 7.05 (d, J = 1.7, 1H), 6.89 (d, J = 1.7 Hz, 1H), 5.18 (m, 1H), 5.09 (m, 1H), 3.57 (dd, J = 10.5, 2.0 Hz, 1H), 2.73 (dd, J = 14.8, 2.0 Hz, 1H), 2.53 (dd, J = 14.8, 10.5 Hz, 1H), 2.23−2.00 (m, 8H), 1.69 (d, J = 1.0 Hz, 3H), 1.72 (ddd, J = 14.0, 10.3, 6.0 Hz, 1H), 1.66 (s, 3H), 1.61 (s, 3H), 1.49 (ddd, J = 14.0,10.3, 6.0 Hz, 1H), 1.27 (s, 3H); 13 C NMR (CDCl3, 100 MHz) δ 137.5, 136.0, 131.6, 124.4, 124.2, 124.1, 122.0, 111.2, 78.3, 74.6, 39.7, 36.2, 28.8, 26.6, 25.7, 23.4, 22.0, 17.7, 16.1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H31N2O4 351.2284; Found 351.2280. The spectroscopic data were in agreement with those reported in the literature.1a,4b Tetraol 45. To a suspension of K3Fe(CN)6 (329 mg, 1.00 mmol), K2CO3 (138 mg, 1.00 mmol), and (DHQ)PHAL (3.0 mg, 0.04 mmol) in tert-butanol (2 mL) and H2O (2 mL) was added OsO4 (20 μL, 40 mg/mL in tert-butanol, 0.015 mmol) at 0 °C. After 10 min, methanesulfonamide (19 mg, 0.20 mmol) was added followed by diol 44a (96 mg, 0.20 mmol). After 24 h at 0 °C, the reaction mixture was quenched with saturated sodium sulfite (1 mL), warmed to room temperature, and stirred for another 1 h. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (hexanes/EtOAc 1:2) to afford tetraol 45 (41 mg, 40%) as a light yellow oil: [α]D20 = +6.1 (c 1.90, CHCl3); IR νmax (neat)/cm−1: 3510, 2923, 1726, 1465, 1451, 1375, 1310, 1260, 1084, 711; 1H NMR (CDCl3, 400 MHz): δ 8.06−8.00 (m, 2H), 7.61−7.56 (m, 1H), 7.47−7.40 (m, 2H), 7.21 (d, J = 2.5, 1H), 7.16 (d, J = 2.5 Hz, 1H), 6.42 (s, 2H), 5.14−5.07 (m, 1H), 3.56 (dd, J = 10.8, 2.2 Hz, 1H), 3.42 (dd, J = 10.1, 1.7 Hz, 1H), 2.65 (dd, J = 14.7, 2.1 Hz, 1H), 2.45 (dd, J = 14.7, 10.7 Hz, 1H), 2.13−2.04 (m, 2H), 1.96−1.81 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.58−1.44 (m, 4H), 1.19 (s, 3H),

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01692. Spectral data for all new compounds (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Margaret A. Brimble: 0000-0002-7086-4096 Daniel P. Furkert: 0000-0001-6286-9105 Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS The authors thank the NZ Ministry for Science and Innovation for financial support (IIOF Grant). REFERENCES

(1) (a) Kwon, H. C. A.; Espindola, P. D.; Park, J.-S.; Prieto-Davó, A.; Rose, M.; Jensen, P. R.; Fenical, W. Nitropyrrolins A−E, Cytotoxic Farnesyl-α-nitropyrroles from a Marine-Derived Bacterium within the Actinomycete Family Streptomycetaceae. J. Nat. Prod. 2010, 73, 2047− 2052. (b) Raju, R. A.; Piggott, M.; Barrientos Diaz, L. X.; Khalil, Z.; Capon, R. J. Heronapyrroles A−C: Farnesylated 2-Nitropyrroles from an Australian Marine-Derived Streptomyces sp. Org. Lett. 2010, 12, 5158−5161. (c) Ding, X.-B.; Brimble, M. A.; Furkert, D. P. Nitropyrrole natural products: isolation, biosynthesis and total synthesis. Org. Biomol. Chem. 2016, 14, 5390−5401. (2) Schmidt, J.; Khalil, Z.; Capon, R. J.; Stark, C. B. Heronapyrrole D: A case of co-inspiration of natural product biosynthesis, total synthesis and biodiscovery. Beilstein J. Org. Chem. 2014, 10, 1228− 1232. (3) Schmidt, J.; Stark, C. B. Biomimetic Synthesis and Proposal of Relative and Absolute Stereochemistry of Heronapyrrole C. Org. Lett. 2012, 14, 4042−4045. (4) (a) Matsuo, T.; Hashimoto, S.; Nishikawa, K.; Kodama, T.; Kikuchi, S.; Tachi, Y.; Morimoto, Y. Total synthesis and complete 12469

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470

Article

The Journal of Organic Chemistry stereochemical assignment of heronapyrroles A and B. Tetrahedron Lett. 2015, 56, 5345−5348. (b) Mitani, H.; Matsuo, T.; Kodama, T.; Nishikawa, K.; Tachi, Y.; Morimoto, Y. Total synthesis of nitropyrrolins A, B, and D. Tetrahedron 2016, 72, 7179−7184. (5) Ding, X. B.; Furkert, D. P.; Capon, R. J.; Brimble, M. A. Total Synthesis of Heronapyrrole C. Org. Lett. 2014, 16, 378−381. (6) Ding, X. B.; Furkert, D. P.; Brimble, M. A. 2-Nitropyrrole crosscoupling enables a second generation synthesis of the heronapyrrole antibiotic natural product family. Chem. Commun. 2016, 52, 12638− 12641. (7) Ding, X. B.; Furkert, D. P.; Brimble, M. A. General Synthesis of the Nitropyrrolin Family of Natural Products via Regioselective CO2Mediated Alkyne Hydration. Org. Lett. 2017, 19, 5418−5421. (8) Katsuki, T.; Sharpless, K. B. The First Practical Method for Asymmetric Epoxidation. J. Am. Chem. Soc. 1980, 102, 5974−5976. (9) (a) Rainier, J. D.; Smith, A. B. Polyene cyclizations to indole diterpenes. The first synthesis of (+)-emindole SA using a biomimetic approach. Tetrahedron Lett. 2000, 41, 9419−9423. (b) Xiao, X. Y.; Park, S. K.; Prestwich, G. D. Phenyl sulfone-directed diastereoselective cyclization of an epoxy allylsilane system. J. Org. Chem. 1988, 53, 4869−4872. (c) Ohtawa, M.; Matsunaga, M.; Fukunaga, K.; Shimizu, R.; Shimizu, E.; Arima, S.; Ohmori, J.; Kita, K.; Shiomi, K.; Omura, S. Design, synthesis, and biological evaluation of air-stable nafuredin-γ analogs as complex I inhibitors. Bioorg. Med. Chem. 2015, 23, 932−943. (10) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Catalytic Asymmetric Dihydroxylation. Chem. Rev. 1994, 94, 2483−2547. (11) (a) Trost, B. M.; Dong, G.; Vance, J. A. Cyclic 1,2-Diketones as Core Building Blocks: A Strategy for the Total Synthesis of (−)-Terpestacin. Chem. - Eur. J. 2010, 16, 6265−6277. (b) Mohri, M.; Kinoshita, H.; Inomata, K.; Kotake, H. Palladium-Catalyzed Regio- and stereoselective Defulfonylation of Allylic Sulfones with LiHBEt3. Application to the Synthesis of Squalene. Chem. Lett. 1985, 14, 451−454. (c) Tong, R.; Boone, M. A.; McDonald, F. E. Stereoand Regioselective Synthesis of Squalene Tetraepoxide. J. Org. Chem. 2009, 74, 8407−8409. (d) Ito, F.; Ohbatake, Y.; Aoyama, S.; Ikeda, T.; Arima, S.; Yamada, Y.; Ikeda, H.; Nagamitsu, T. Total Synthesis of (+)-Clavulatriene A. Synthesis 2015, 47, 1348−1355. (12) Schmidt, J.; Stark, C. B. Synthetic Endeavors toward 2-Nitro-4Alkylpyrroles in the Context of the Total Synthesis of Heronapyrrole C and Preparation of a Carboxylate Natural Product Analogue. J. Org. Chem. 2014, 79, 1920−1928. (13) Carreras, J.; Livendahl, M.; McGonigal, P. R.; Echavarren, A. M. Gold(I) as an Artificial Cyclase: Short Stereodivergent Syntheses of (−)-Epiglobulol and (−)-4β,7α-and (−)-4α,7α-Aromadendranediols. Angew. Chem., Int. Ed. 2014, 53, 4896−4899. (14) Hintermann, L.; Labonne, A. Catalytic Hydration of Alkynes and Its Application in Synthesis. Synthesis 2007, 2007, 1121−1150. (15) Ghosh, N.; Nayak, S.; Sahoo, A. K. Gold-Catalyzed Regioselective Hydration of Propargyl Acetates Assisted by a Neighboring Carbonyl Group: Access to α-Acyloxy Methyl Ketones and Synthesis of (±)-Actinopolymorphol B. J. Org. Chem. 2011, 76, 500−511. (16) Wang, J.; Li, F.; Xie, H.; Xu, M.; Zhao, X.; Liu, L.; Zhao, W.-X. Silver salts and DBU cooperatively catalyzed domino reaction of propargylic alcohols with trifluoromethyl ketones: direct method to trifluoromethyl-substituted 5-alkylidene-1,3-dioxolane derivatives. Appl. Organomet. Chem. 2017, 31, e3545. (17) (a) He, H.; Qi, C.; Hu, X.; Guan, Y.; Jiang, H. Efficient synthesis of tertiary α-hydroxy ketones through CO2-promoted regioselective hydration of propargylic alcohols. Green Chem. 2014, 16, 3729−3733. (b) Ouyang, L.; Tang, X.; He, H.; Qi, C.; Xiong, W.; Ren, Y.; Jiang, H. Copper-Promoted Coupling of Carbon Dioxide and Propargylic Alcohols: Expansion of Substrate Scope and Trapping of Vinyl Copper Intermediate. Adv. Synth. Catal. 2015, 357, 2556−2565. (c) Qi, C.; Jiang, H.; Huang, L.; Yuan, G.; Ren, Y. Carbon Dioxide Triggered and Copper-Catalyzed Domino Reaction: Efficient Construction of Highly Substituted 3(2H)-Furanones from Nitriles and Propargylic Alcohols. Org. Lett. 2011, 13, 5520−5523. (d) Song,

Q. W.; He, L. N. Robust Silver(I) Catalyst for the Carboxylative Cyclization of Propargylic Alcohols with Carbon Dioxide under Ambient Conditions. Adv. Synth. Catal. 2016, 358, 1251−1258. (e) Zhou, Z. H.; Song, Q. W.; Xie, J. N.; Ma, R.; He, L. N. Silver(I)Catalyzed Three-Component Reaction of Propargylic Alcohols, Carbon Dioxide and Monohydric Alcohols: Thermodynamically Feasible Access to β-Oxopropyl Carbonates. Chem. - Asian J. 2016, 11, 2065−2071. (18) Mello, R.; Alcalde-Aragonés, A.; González-Núñez, M. E. Silicasupported HgSO4/H2SO4: a convenient reagent for the hydration of alkynes under mild conditions. Tetrahedron Lett. 2010, 51, 4281− 4283. (19) (a) Fukuda, Y.; Utimoto, K. Effective transformation of unactivated alkynes into ketones or acetals with a gold(III) catalyst. J. Org. Chem. 1991, 56, 3729−3731. (b) Xu, B.; Wang, W.; Liu, L.-P.; Han, J.; Jin, Z.; Hammond, G. B. Synthetic evolutions in the nucleophilic addition to alkynes. J. Organomet. Chem. 2011, 696, 269−276. (c) Imi, K.; Imai, K.; Utimoto, K. Regioselective hydration of alkynones by palladium catalysis. Tetrahedron Lett. 1987, 28, 3127−3130. (20) Kato, K.; Yamamoto, Y.; Akita, H. Unusual formation of cyclicorthoesters by Pd(II)-mediated cyclization−carbonylation of propargylic acetates. Tetrahedron Lett. 2002, 43, 6587−6590. (21) Manabe, S.; Yamaguchi, M.; Ito, Y. Sulfonylcarbamate as a versatile and unique hydroxy-protecting group: a protecting group stable under severe conditions and labile under mild conditions. Chem. Commun. 2013, 49, 8332−8334. (22) Corey, E. J.; Helal, C. J. Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. Angew. Chem., Int. Ed. 1998, 37, 1986−2012. (23) Murakami, T.; Furusawa, K. One-Pot Synthesis of Aryl Sulfones from Alcohols. Synthesis 2002, 2002, 479−482. (24) Larock, R. C.; Han, X. Palladium-Catalyzed Cross-Coupling of 2,5-Cyclohexadienyl-Substituted Aryl or Vinylic Iodides and Carbon or Heteroatom Nucleophiles. J. Org. Chem. 1999, 64, 1875−1887.

12470

DOI: 10.1021/acs.joc.8b01692 J. Org. Chem. 2018, 83, 12460−12470