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Article

Asymmetric Synthesis of (−)-6-Desmethyl-Fluvirucinine A1 via Conformationally-Controlled Diastereoselective Lactam-Ring Expansions

by
Hyunyoung Moon
1,2,†,
Hojong Yoon
2,†,
Changjin Lim
1,2,
Jaebong Jang
2,
Jong-Jae Yi
1,
Jae Kyun Lee
3,
Jeeyeon Lee
2,
Younghwa Na
1,
Woo Sung Son
1,
Seok-Ho Kim
1,* and
Young-Ger Suh
1,2,*
1
Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, 120 Haeryong-ro, Pocheon 11160, Gyeonggi-do, Korea
2
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
3
Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2018, 23(9), 2351; https://doi.org/10.3390/molecules23092351
Submission received: 1 September 2018 / Revised: 8 September 2018 / Accepted: 10 September 2018 / Published: 14 September 2018
(This article belongs to the Special Issue Stereogenic Centers)
Browse Figures
Versions Notes

Abstract

:
The versatile synthesis of (−)-6-desmethyl-fluvirucinine A1 was accomplished at a 24% overall yield through a thirteen-step process from a known vinylpiperidine. The key part involved the elaboration of the distal stereocenters and a macrolactam skeleton via conformationally-induced diastereocontrol and the iterative aza-Claisen rearrangements of lactam precursors.

Graphical Abstract

1. Introduction

Fluvirucins, a class of macrolactam alkaloids, including fluvirucin A1-2 and B1-5 (1–7) (Figure 1) were isolated in the 1990s [1,2,3,4,5,6]. These macrolactam antibiotics have drawn significant attention due to their considerable inhibitory activities against the influenza A virus in Madin—Darby canine kidney (MDCK) cells [3,4]. They commonly consist of 2,6-dialkyl-10-ethyl-3(or 9)-hydroxy-13-tridecanelactam as an aglycon called fluvirucinine, which possesses four stereogenic centers and is connected to a carbohydrate by a glycosidic linkage. The synthesis of fluvirucinines has continuously attracted the attention of organic chemists [7,8,9,10,11,12,13,14,15] due to the difficult stereocontrol during the creation of distant stereogenic centers. Recently, three new macrolactams, including 6-desmethyl-N-methylfluvirucin A1 (8), N-methylfluvirucin A1 (9), and fluvirucin B0 (10), were isolated from Nonomuraea terkmeniaca MA7364 [16] and Nonomuraea terkmeniaca MA7381 [17], respectively. In particular, 6-desmethyl-N-methylfluvirucin A1 (8) exhibited in vitro activity (EC90 15 ± 5 μg/mL) against Haemonchus contortus larvae. The absolute configurations of C2, C3, and C10 of 8 and 9 have not been determined yet, although the relative stereochemistry of C2 and C3 has been disclosed. The stereochemistries of C2, C3, and C10 of 8 and 9 have been considered the same as those reported for the fluvirucin A series [16].
Recently, we have been interested in 6-desmethyl-N-methylfluvirucin A1 (8) since it has biological activities even though 6-desmethyl-fluvirucinine A1 (11), which is an aglycon of 8, is devoid of the characteristic C6-alkyl substituent of the fluvirucin family [16]. In particular, our interests are focused on the effect of the stereochemistry of 6-desmethyl-fluvirucinine A1 on biological activities (Figure 2). Along this line, we have been working on the synthesis of 13 as an antipode of 6-desmethyl-fluvirucinine A1 (11) [16]. Herein, we describe synthesis and structural confirmation of (−)-6-desmethyl-fluvirucinine A1 (13).

2. Results and Discussion

2.1. Synthetic Strategy for (−)-6-Desmethyl-Fluvirucinine A1 (13)

Our synthetic strategy for 13 was based on the amide enolate-induced lactam ring expansion strategy [18,19,20], which was established by us for the synthesis of macrolactam alkaloids (Scheme 1) [14,15,21,22,23,24,25,26,27,28,29]. However, the diastereoselective aza-Claisen rearrangement (ACR) of 14, which does not possess the characteristic C6-methyl substituent, remains a formidable task because the C6-substituent seemed to influence the formation of a chair-like transition state in the key ACR [14,15].

2.2. The First ACR and Diastereoselective Amidoalkylation for Synthesis of Ester 15

Our synthesis was commenced with the preparation of azacycle 17, which is the first ACR precursor, through the acetylation of the known and optically active vinylpiperidine 18 [14], as shown in Scheme 2. The subjection of 17 to the first ACR (LiHMDS, toluene, reflux) [14,15,21,22,23,24] produced the ring-expanded lactam 19 with a 72% yield. Our initial attempt for the amidoallylation of 19, which was commonly utilized to prepare a second ACR precursor in our previous syntheses [15,23,30,31,32,33], was not successful. We encountered difficult diastereocontrol in the amidoallylation of 19, which was likely due to the absence of the 2-methyl substituent [15]. We anticipated that the ring-olefin in a medium sized-lactam system can induce an intrinsic ring strain that results in an improved diastereoselective amidoalkylation. In addition, we decided to execute an amidoalkylation with ketene acetal 21 as a bulky nucleophile [34]. After the Boc-protection of lactam 19, the resulting lactam 16 was subjected to a sequence [15,23,30,31,32,33,34] of DIBAL-H reduction followed by the trapping of the resulting alkoxide with TMSOTf and the addition of ketene acetal 21 to the unstable N,O-acetal TMS-ether 20 in the presence of BF3∙OEt2. Indeed, a highly diastereoselective amidoalkylation of 16 was observed, which afforded methyl ester 15 with a 75% yield for three steps and a small amount of diastereoisomer (10:1). The excellent diastereoselectivity was likely due to the sterically favored Si-face attack of the bulky ketene acetal 21 in the energetically favorable (Z)-N-acyl iminium intermediate 22 that was generated from N,O-acetal TMS ether 20 [34,35].

2.3. The Second ACR and Completion of the Synthesis

For the preparation of the second ACR precursor, olefin hydrogenation of 15 produced ester 23 as show in Scheme 3. DIBAL-H reduction of 23 and treatment of the resulting aldehyde with TBSCl in the presence of DBU in dichloromethane [36,37] selectively produced (E)-enol ether 24 with a 67% yield for three steps. Boc deprotection of 24 and propionylation of the resulting amine 25 afforded the second ACR precursor 14 with a 80% yield for three steps. Finally, subjection of 14 to the standard ACR conditions (iPrMgCl in benzene, 60 °C) [25,26,27,28,29] produced the desired ring-expansion product 26 with a 99% yield in favor of the anti-stereoisomer (19:1). The ACR with other bases, including LiHMDS, resulted in a low diastereoselectivity (≈1.1–1.2:1) for the anti-product. It is noteworthy that the anti-stereoisomer 26 in the absence of the 6-methyl substituent, which was considered important for the diastereoselective ACR, was selectively produced [15,23]. The stereochemistry of 26 was confirmed by X-ray crystallographic analysis (Figure 3) [38].
For the completion of the synthesis, macrolactam 26 was hydrogenated and then desilylated to produce 14 with a 99% yield for two steps (Scheme 4).

3. Materials and Methods

3.1. General Information

Unless stated otherwise, all reactions were performed under an argon atmosphere with dry solvents under anhydrous conditions. Tetrahydrofuran (THF) and Et2O were distilled immediately before use in sodium benzophenone ketyl. Dichloromethane, chloroform, triethylamine, acetonitrile, and pyridine were freshly distilled from calcium hydride. All starting materials and reagents were obtained from commercial suppliers and were used without further purification, unless otherwise noted. Solvents for routine isolation of products and chromatography were reagent grade and glass distilled. Silica gel 60 (230–400 mesh, Merck, Kenilworth, NJ, USA) was used for flash column chromatography. Reaction progress was monitored by thin-layer chromatography (TLC), which was performed using 0.25 mm silica gel plates (Merck, Kenilworth, NJ, USA). Optical rotations were measured with a P-2000 digital polarimeter (JASCO, Easton, MD, USA) at ambient temperature using a 100 mm cell of 2 mL capacity. 1H- and 13C-NMR spectra were recorded on a JNM-LA 300 (JEOL, Tokyo, Japan), AVANCE-500 (Brucker, Billerica, MA, USA), AVANCE-400 (Brucker, Billerica, MA, USA), and JNM-ECA-600 (JEOL, Tokyo, Japan). 1H-NMR data were reported as follows: chemical shift (parts per million, δ), multiplicity (br, broad signal; s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet and/or multiple resonances), coupling constant in hertz (Hz), and number of protons. Infrared spectra were recorded on a JASCO FT-IR-4200 spectrometer and are reported in the frequency of absorption (cm−1). High resolution mass spectra (HR-MS) were obtained with a JMS-700 (JEOL, Tokyo, Japan) instrument and Q TOF 6530 (Agilent, Santa Clara, CA, USA).

3.2. Experimental Part

1-((2R,3S)-3-Ethyl-2-vinylpiperidin-1-yl)ethan-1-one (17). To a cooled (0 °C) solution of piperidine 18 (1.0 g, 5.0 mmol) in CH2Cl2 (15 mL) were added DMAP (catalytic amount), Et3N (2.0 mL, 15.0 mmol), and acetyl chloride (0.5 mL, 7.5 mmol). The mixture was stirred for 2 h at room temperature, quenched with water, and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified uisng flash column chromatography (EtOAc/Hexane = 1:2) to provide 770 mg (85%) of 17. [α] D 20 = −33.66 (c 1.08, CHCl3); 1H-NMR (CDCl3, 500 MHz, mixture of rotamers) δ 5.82–5.73 (m, 1H), 5.23–5.19 (m, 1.5H), 5.07–5.01 (m, 1H), 4.46 (d, J = 11.3 Hz, 0.5H), 4.18 (s, 0.5H), 3.54 (d, J = 13.1 Hz, 0.5H), 3.17 (t, J = 11.8 Hz, 0.5H), 2.64 (t, J = 12.8 Hz, 0.5H), 2.11 (s, 1.5H), 2.05 (s, 1.5H), 1.64 (m, 3H), 1.50–1.43 (m, 3H), 1.40–1.28 (m, 1H), 0.92 (t, J = 6.6 Hz, 3H); 13C-NMR (CDCl3, 100 MHz, mixture of rotamers) δ 170.7, 137.0, 136.7, 116.1, 115.9, 115.8, 59.6, 53.6, 53.5, 42.4, 42.3, 39.7, 38.7, 37.0, 24.1, 23.4, 23.3, 23.1, 21.3, 20.8, 19.6, 12.2; IR (thin film, neat) νmax 3477, 2937, 1651, 1423, 1267 cm−1; HR-MS (ESI+) calcd. for C11H19NNaO [M + Na]+ 204.1359; found 204.1360.
(S,E)-7-Ethyl-3,4,7,8,9,10-hexahydroazecin-2(1H)-one (19). To a refluxing solution of amide 17 (750 mg, 4.1 mmol) in toluene (40 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in toluene, 12.4 mL, 12.4 mmol). The mixture was stirred for 1 h at the same temperature, cooled to room temperature, quenched with water, and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified using flash column chromatography (EtOAc/Hexane = 1:1) to provide 540 mg (72%) of 19. [α] D 20 = +15.07 (c 0.55, CHCl3); 1H-NMR (CDCl3, 600 MHz) δ 5.76 (br s, 1H), 5.27 (ddd, J = 15.1, 10.1, 5.0 Hz, 1H), 5.00 (dd, J = 15.6, 9.6 Hz, 1H), 3.39 (dd, J = 13.8, 7.5 Hz, 1H), 2.76 (dd, J = 12.8, 8.2 Hz, 1H), 2.22–2.11 (m, 3H), 1.95 (td, J = 11.3, 5.5 Hz, 1H), 1.74–1.70 (quint, J = 6.6 Hz, 2H), 1.59–1.57 (m, 1H), 1.25–1.14 (m, 3H), 1.13–1.06 (m, 1H), 0.69 (t, J = 7.4 Hz, 3H); 13C-NMR (CDCl3, 150 MHz) δ 173.0, 138.7, 126.6, 45.8, 40.5, 38.5, 35.7, 29.5, 28.2, 26.7, 11.8; IR (thin film, neat) νmax 3309, 2926, 1645, 1554 cm−1; HR-MS (ESI+) calcd. for C11H20NO [M + H]+ 182.1539; found 182.1532.
tert-Butyl (S,E)-5-ethyl-10-oxo-3,4,5,8,9,10-hexahydroazecine-1(2H)-carboxylate (16). To a cooled (−78 °C) solution of lactam 19 (530 mg, 2.9 mmol) in THF (9 mL) was slowly added nBuLi (2.5 M in hexane, 1.8 mL, 4.5 mmol). The mixture was stirred for 10 min at the same temperature and a solution of Boc2O (2.8 mL, 6.1 mmol) in THF (3 mL) was added. The reaction mixture was stirred for 1 h 50 min at the same temperature, quenched with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified using flash column chromatography (EtOAc/Hexane = 1:20) to provide 814 mg (99%) of 16. [α] D 20 = −16.08 (c 0.98, CHCl3); 1H-NMR (CDCl3, 300 MHz) δ 5.36–5.26 (m, 1H), 5.01(br s, 1H), 3.70–3.56 (m, 2H), 3.21 (br s, 1H), 2.80 (br s, 1H), 2.80–2.31 (m, 2H), 1.71–1.67 (m, 2H), 1.56 (s, 1H), 1.53 (s, 10H), 1.34–1.22 (m, 3H), 0.80 (t, J = 8.9 Hz, 3H); 13C-NMR (CDCl3, 125 MHz, mixture of rotamers) δ 177.5, 153.5, 146.7, 138.9, 126.0, 85.1, 82.5, 47.1, 46.3, 39.3, 33.4, 33.1, 30.9, 29.2, 28.9, 28.1, 27.8, 27.6, 27.4, 24.8, 24.7 12.1; IR (thin film, neat) νmax 2961, 1726, 1691, 1369, 1148 cm−1; HR-MS (ESI+) calcd. for C16H27NNaO3 [M + Na]+ 304.1883; found 304.1867.
tert-Butyl (5S,10S,E)-5-ethyl-10-(2-methoxy-2-oxoethyl)-3,4,5,8,9,10-hexahydroazecine-1(2H)-carboxylate (15). To a cooled (−78 °C) solution of lactam 16 (860 mg, 3.1 mmol) in CH2Cl2 (9 mL) was slowly added diisobutylaluminium hydride (DIBAL-H) (1.0 M in toluene, 5.5 mL, 5.5 mmol). After stirring for 10 min at the same temperature, pyridine (1.2 mL, 15.3 mmol) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.4 mL, 7.7 mmol) were added. The reaction mixture was stirred for 10 min at the same temperature, quenched with saturated Rochelle’s solution, and extracted with Et2O. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified using flash column chromatography (EtOAc/Hexane = 1:20, silica gel deactivated with Et3N) to afford unstable N,O-acetal TMS ether 20. To a cooled (−78 °C) solution of 20 in CH2Cl2 (9 mL) were added 1-(tert-butyldimethylsilyloxyl)-1-methoxyethane (1.1 mL, 4.9 mmol) 21 and BF3∙OEt2 (0.3 mL. 2.7 mmol). After stirring for 30 min at the same temperature, the reaction mixture was allowed to warm to 0 °C. The reaction mixture was quenched with Et3N and concentrated in vacuo. The residue was purified using flash column chromatography (EtOAc/Hexane = 1:10) to provide 783 mg of 15 as a diastereomeric mixture (75% for 2 steps, 68% for desired diastereomer). [α] D 20 = +37.66 (c 2.36, CHCl3); 1H-NMR (CDCl3, 500 MHz, mixture of rotamers) δ 5.51–5.42 (m, 1H), 5.20–5.13 (m, 1H), 3.71 (m, 0.5H), 3.61 (s, 3H), 3.20 (br s, 0.5H), 3.11–3.10 (m, 1H), 2.82 (dd, J = 15.0, 8.8 Hz, 0.5H), 2.53–2.47 (m, 1H), 2.43–2.37 (m, 0.5H), 2.31–2.26 (m, 1.5H), 2.19 (br s, 0.5H), 2.08 (br s, 0.5H), 1.98–1.89 (m, 1.5H), 1.83–1.76 (m, 1H), 1.67–1.62 (m, 1H), 1.45–1.39 (m, 10.5H), 1.36–1.29 (m, 1.5H), 1.27–1.15 (m, 2H), 0.93 (t, J = 12.2 Hz, 1H), 0.82 (t, J = 7.4 Hz, 3H); 13C-NMR (CDCl3, 150 MHz, mixture of rotamers) δ 173.0, 172.4, 155.3, 155.0, 135.2, 134.6, 131.5, 130.9, 79.6, 78.9, 64.4, 56.0, 51.6, 51.4, 48.3, 48.1, 40.3, 38.5, 35.9, 35.8, 34.4, 34.1, 33.5, 31.6, 30.6, 29.2, 28.6, 28.5, 28.4, 25.6, 22.6, 14.0, 12.2; IR (thin film, neat) νmax 2961, 2930, 1740, 1692, 1365, 1172 cm−1; LR-MS (FAB+) m/z 340 [M + H]+; HR-MS (FAB+) calcd. for C19H34NO4 [M + H]+ 340.2488; found 340.2484.
tert-Butyl (2S,7R)-7-ethyl-2-(2-methoxy-2-oxoethyl)azecane-1-carboxylate (23). To a solution of ester 15 (705 mg, 2.1 mmol) in MeOH (10 mL) was added 10% Pd/C (71 mg) and the mixturre was stirred under H2 (balloon pressure) for 19 h. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was purified using flash column chromatography (EtOAc/Hexane = 1:10) to provide 688 mg (97%) of 23. [α] D 20 = +23.72 (c 2.29, CHCl3); 1H-NMR (CDCl3, 500 MHz) δ 3.75 (br s, 1H), 3.61 (s, 3H), 3.49 (br s, 1H), 2.99–2.65 (m, 2H), 2.44–2.40 (m, 1H), 2.06–1.91 (m, 1H), 1.67 (br s, 2H), 1.41 (br s, 15H), 1.30 (s, 2H), 1.25–1.20 (m, 2H), 1.09 (br s, 2H), 0.81 (t, J = 7.2 Hz, 3H); 13C-NMR (CDCl3, 125 MHz) δ 172.5, 155.9, 79.7, 79.2, 56.1, 51.6, 39.1, 38.3, 37.0, 32.8, 30.8, 30.1, 28.5, 27.8, 26.7, 22.7, 11.9; IR (thin film, neat) νmax 2959, 2925, 1741, 1696, 1365, 1171 cm−1; LR-MS (FAB+) m/z 342 [M + H]+; HR-MS (FAB+) calcd. for C19H36NO4 [M + H]+ 342.2644; found 342.2644.
tert-Butyl (2S,7R)-2-((E)-2-((tert-butyldimethylsilyl)oxy)vinyl)-7-ethylazecane-1-carboxylate (24). To a cooled (−78 °C) solution of ester 23 (645 mg, 1.9 mmol) in CH2Cl2 (8 mL) was slowly added DIBAL-H (1.0 M in toluene, 2.4 mL, 2.4 mmol). The reaction mixture was stirred for 30 min at the same temperature, quenched with saturated Rochelle’s solution, and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude aldehyde was directly used for the next reaction without further purification. To a stirred solution of aldehyde in CH2Cl2 (9 mL) were added tert-butyldimethylsilyl chloride (TBSCl) (570 mg, 3.8 mmol) and DBU (0.9 mL, 6.0 mmol). The reaction mixture was refluxed for 1 h and concentrated in vacuo. The residue was purified using flash column chromatography (EtOAc/Hexane = 1:30, silica gel deactivated with Et3N) to provide 563 mg (70% for 2 steps) of 24. [α] D 20 = +26.68 (c 1.25, CHCl3); 1H-NMR (CDCl3, 500 MHz) δ 6.31 (dd, J = 15.8, 9.4 Hz, 1H), 5.10 (m, 1H), 3.64 (m, 1H), 2.85–2.78 (m, 1H), 2.04 (m, 1H), 1.74 (br s, 1H), 1.66–1.63 (m, 1H), 1.54 (s, 1H), 1.44 (s, 11H), 1.35 (m, 3H), 1.25–1.18 (m, 4H), 1.14 (br s, 2H), 0.89 (s, 9H), 0.86–0.84 (m, 4H), 0.11 (s, 6H); 13C-NMR (CDCl3, 125 MHz) δ 156.3, 141.3, 138.6, 111.9, 79.2, 78.8, 57.2, 36.4, 32.6, 30.0, 28.5, 26.2, 25.7, 25.6, 22.8, 18.4, 18.1, 11.9, −3.0, −4.8; IR (thin film, neat) νmax 2958, 2929, 1695, 1655, 1170, 839 cm−1; LR-MS (FAB+) m/z 426 [M + H]+; HR-MS (FAB+) calcd. for C24H48NO3Si [M + H]+ 426.3403; found 426.3394.
1-((2S,7R)-2-((E)-2-((tert-Butyldimethylsilyl)oxy)vinyl)-7-ethylazecan-1-yl)propan-1-one (14). To a cooled (0 °C) solution of silyl enol ether 24 (69.4 mg, 0.16 mmol) in CH2Cl2 (2 mL) were added 2,6-lutidine (0.1 mL, 0.64 mmol) and TMSOTf (0.1 mL, 0.48 mmol). The mixture was stirred for 30 min at the same temperature, quenched with MeOH, and concentrated in vacuo. The crude amine 25 was directly used for the next reaction without further purification. To a stirred solution of amine 25 in CH2Cl2 (2 mL) were added DMAP (catalytic amount), Et3N (0.1 mL, 0.48 mmol), and propionic anhydride (0.04 mL, 0.32 mmol). The reaction mixture was stirred for 1 h and concentrated in vacuo. The residue was purified using flash column chromatography (EtOAc/Hexane = 1:10, silica gel deactivated with Et3N) to provide 49.8 mg (80% for 2 steps) of 14. [α] D 20 = +12.16 (c 2.00, CHCl3); 1H-NMR (CDCl3, 500 MHz) δ 6.31 (d, J = 15.5 Hz, 1H), 6.22 (d, J = 15.5 Hz, 1H), 5.23 (br s, 1H), 4.93 (dd, J = 12.1, 6.6 Hz, 1H), 4.13 (t, J = 8.6 Hz, 1H), 3.49–3.37 (m, 2H), 3.08–2.92 (m, 2H), 2.38–2.27 (m, 2H), 2.24 (qd, J = 7.5, 2.4 Hz, 3H), 2.03 (m, 1H), 1.89–1.86 (m, 1H), 1.75 (br s, 1H), 1.65–1.55 (m, 2H), 1.49–1.47 (m, 1H), 1.39 (m, 1H), 1.26–1.13(m, 2H), 1.11–1.06 (m, 2H), 0.85 (s, 9H), 0.82 (t, J = 7.4 Hz, 3H), 0.07 (s, 6H); 13C-NMR (CDCl3, 125 MHz, mixture of rotamers) δ 175.0, 174.8, 174.5, 142.6, 142.0, 141.7, 111.8, 111.7, 111.6, 56.6, 56.1, 41.8, 39.4, 37.4, 36.7, 32.7, 31.6, 31.0, 31.0, 30.8, 30.7, 30.5, 29.8, 29.7, 29.7, 29.5, 29.4, 29.4, 29.3, 29.2, 28.2, 28.0, 27.8, 27.5, 27.4, 25.7, 25.6, 25.5, 25.5, 25.2, 25.0, 24.8, 24.5, 24.2, 23.8, 23.3, 18.3, 11.9, 9.4, −5.3; IR (thin film, neat) νmax 2956, 2930, 1653, 839 cm−1; LR-MS (FAB+) m/z 382 [M + H]+; HR-MS (FAB+) calcd. for C22H44NO2Si [M + H]+ 382.3141; found 382.3139.
(3S,4R,11R,E)-4-((tert-Butyldimethylsilyl)oxy)-11-ethyl-3-methylazacyclotetradec-5-en-2-one (26). To a heated (60 °C) solution of amide 14 (46.6 mg, 0.13 mmol) in benzene (3 mL) was slowly added iPrMgCl (1.0 M in hexane, 0.5 mL, 0.5 mmol). The reaction mixture was stirred for 40 min at the same temperature, cooled to room temperature, quenched with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified using flash column chromatography (EtOAc/Hexane = 1:10) to provide 46.1 mg of 26 as a diastereomeric mixture (99%, 95% for desired diastereomer). [α] D 20 = −62.95 (c 0.62, CHCl3); 1H-NMR (CDCl3, 500 MHz) δ 6.25 (s, 1H), 5.59–5.54 (m, 1H), 5.37 (dd, J = 15.5, 5.8 Hz, 1H), 4.18 (t, J = 6.5 Hz, 1H), 3.89–3.83 (m, 1H), 2.51 (m, 1H), 2.27 (quint, J = 7.1 Hz, 1H), 2.01 (m, 2H), 1.56 (s, 1H), 1.48–1.38 (m, 2H), 1.36–1.20 (m, 8H), 1.17 (d, J = 7.0 Hz, 3H), 1.07–0.99 (m, 2H), 0.89 (s, 9H), 0.83 (t, J = 7.3 Hz, 3H), 0.06 (s, 3H), 0.02 (s,3H); 13C-NMR (CDCl3, 125 MHz) δ 173.9, 131.8, 130.7, 75.0, 48.4, 39.4, 37.7, 31.0, 30.9, 27.2, 27.1, 26.4, 25.9, 23.8, 23.6, 18.1, 15.1, 12.0, −4.3, −4.9; IR (thin film, neat) νmax 3279, 2928, 1638, 775 cm−1; LR-MS (FAB+) m/z 382 [M + H]+; HR-MS (FAB+) calcd. for C22H44NO2Si [M + H]+ 382.3141; found 382.3140.
Crystal Data for26. C22H43NO2Si (M = 381.67 g/mol), orthorhombic, space group P21212 (no. 18), a = 9.4913(8) Å, b = 31.653(3) Å, c = 8.524(1) Å, V = 2560.9(5) Å3, Z = 4, T = 300 K, µ(MoKa) = 1.052 mm−1, Dcalc = 0.990 g/cm3, 25442 reflections measured, 5869 unique (Rint = 0.1257) which were used in all calculations. The final R1 was 0.1071 (I > 2σ(I)) and wR2 was 0.2824 (all data).
(−)-6-Desmethyl-fluvirucinine A1 (13). To a solution of lactam 26 (39.8 mg, 0.10 mmol) in a mixture of EtOAc and MeOH (1:1, 2 mL) was added 10% Pd/C (4.0 mg) and the mixture was stirred under H2 (balloon pressure) for 12 h. The reaction mixture was filtered through Celite® and concentrated in vacuo. The crude lactam 27 was directly used for the next reaction without further purification. To a stirred solution of lactam 27 in THF (1 mL) was added tetrabutylammonium fluoride (TBAF) (1.0 M in THF, 0.2 mL, 0.20 mmol) at room temperature. The mixture was stirred for 1 h at the same temperature, quenched with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hexane/MeOH = 25:25:1) to provide 27.8 mg (99% for 2 steps) of 13. [α] D 20 = −76.61 (c 0.18, MeOH); 1H-NMR (MeOD, 500 MHz) δ 4.58 (s, 1H), 3.68–3.62 (m, 2H), 2.69 (ddd, J = 13.6, 7.7, 1.7 Hz, 1H), 2.37–2.31(m, 1H), 1.62–1.52 (m, 2H), 1.50–1.45 (m, 4H), 1.43–1.41 (m, 4H), 1.39–1.32 (m, 3H), 1.30–1.26 (m, 2H), 1.24–1.10 (m, 4H), 1.17 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H); 13C-NMR (MeOD, 150 MHz) δ 178.7, 74.6, 48.8, 40.3, 38.5, 35.3, 32.6, 29.8, 28.9, 28.7, 27.8, 27.5, 24.2, 22.7, 16.8, 12.7; IR (thin film, neat) νmax 3388, 3305, 1637, 790 cm−1; HR-MS (ESI+) calcd. for C16H31NO2 [M + H]+ 270.2428; found 270.2426.

4. Conclusions

The versatile synthesis of (−)-6-desmethyl-fluvirucinine A1 (13) was accomplished through 13 steps with a 24% overall yield from the known vinylpiperidine 18. The key part of the synthesis included the highly diastereoselective ACR of the 10-membered lactam intermediate for the elaboration of the 14-membered lactam framework via the conformationally-induced diastereocontrol of the distal stereocenters. The stereochemical effect of 6-desmethyl-fluvirucinine A1 on the biological activities and the synthesis of the carbohydrate moiety will be reported in future research.

Supplementary Materials

The supplementary materials are available online.

Author Contributions

Y.-G.S., S.-H.K., H.M., H.Y., and J.J. conceived and designed the experiments; H.M., H.Y., J.J., and C.L. performed the experiments; J.-J.Y., J.K.L., J.L., Y.N., and W.S.S. analyzed the data; Y.-G.S., S.-H.K., H.M., H.Y., and C.L. wrote the paper; all authors read and approved the final manuscript.

Funding

This work was supported by the GRRC program of Gyeonggi province (GRRC-CHA2018-B02).

Conflicts of Interest

The authors declare no conflict of interest.

References and Notes

  1. Naruse, N.; Tenmyo, O.; Kawano, K.; Tomita, K.; Ohgusa, N.; Miyaki, T.; Konishi, M.; Oki, T. Fluvirucins A1, A2, B1, B2, B3, B4 and B5, new antibiotics active against influenza A virus. I. Production, isolation, chemical properties and biological activities. J. Antibiot. 1991, 44, 733–740. [Google Scholar] [CrossRef] [PubMed]
  2. Naruse, N.; Tsuno, T.; Sawada, Y.; Konishi, M.; Oki, T. Fluvirucins A1, A2, B1, B2, B3, B4 and B5, new antibiotics active against influenza A virus. II. Structure determination. J. Antibiot. 1991, 44, 741–755. [Google Scholar] [CrossRef] [PubMed]
  3. Naruse, N.; Konishi, M.; Oki, T.; Inouye, Y.; Kakisawa, H. Fluvirucins A1, A2, B1, B2, B3, B4 and B5, new antibiotics active against influenza A virus. III. The stereochemistry and absolute configuration of fluvirucin A1. J. Antibiot. 1991, 44, 756–761. [Google Scholar] [CrossRef] [PubMed]
  4. Tomita, K.; Oda, N.; Hoshino, Y.; Ohkusa, N.; Chikazawa, H. Fluvirucins A1, A2, B1, B2, B3, B4 and B5, new antibiotics active against influenza A virus. IV. Taxonomy on the producing organisms. J. Antibiot. 1991, 44, 940–948. [Google Scholar] [CrossRef] [PubMed]
  5. Hegde, V.R.; Patel, M.G.; Gullo, V.P.; Ganguly, A.K.; Sarre, O.; Puar, M.S.; McPhail, A.T. Macrolactams: A new class of antifungal agents. J. Am. Chem. Soc. 1990, 112, 6403–6405. [Google Scholar] [CrossRef]
  6. Hegde, V.; Patel, M.; Horan, A.; Gullo, V.; Marquez, J.; Gunnarsson, I.; Gentile, F.; Loebenberg, D.; King, A.; Puar, M.; et al. Macrolactams: A novel class of antifungal antibiotics produced by Actinomadura spp. SCC 1776 and SCC 1777. J. Antibiot. 1992, 45, 624–632. [Google Scholar] [CrossRef] [PubMed]
  7. Houri, A.F.; Xu, Z.M.; Cogan, D.A.; Hoveyda, A.H. Cascade catalysis in synthesis. an enantioselective route to Sch-38516 (and fluvirucin B1) aglycon macrolactam. J. Am. Chem. Soc. 1995, 117, 2943–2944. [Google Scholar] [CrossRef]
  8. Xu, Z.M.; Johannes, C.W.; Salman, S.S.; Hoveyda, A.H. Enantioselective total synthesis of antifungal agent Sch 38516. J. Am. Chem. Soc. 1996, 118, 10926–10927. [Google Scholar] [CrossRef]
  9. Xu, Z.M.; Johannes, C.W.; Houri, A.F.; La, D.S.; Cogan, D.A.; Hofilena, G.E.; Hoveyda, A.H. Applications of Zr-catalyzed carbomagnesation and Mo-catalyzed macrocyclic ring closing metathesis in asymmetric synthesis. Enantioselective total synthesis of Sch 38516 (Fluvirucin B1). J. Am. Chem. Soc. 1997, 119, 10302–10316. [Google Scholar] [CrossRef]
  10. Trost, B.M.; Ceschi, M.A.; Konig, B. Palladium-catalyzed additions of alkenyl epoxides to pronucleophiles: A synthesis of the macrolactam aglycone of fluviricin B1. Angew. Chem. Int. Ed. 1997, 36, 1486–1489. [Google Scholar] [CrossRef]
  11. Martin, M.; Mas, G.; Urpi, F.; Vilarrasa, J. High-yielding enantioselective synthesis of the macrolactam aglycon of Sch 38516 from two units of (2R)-2-ethyl-4-penten-1-ol. Angew. Chem. Int. Ed. 1999, 38, 3086–3089. [Google Scholar] [CrossRef]
  12. Liang, B.; Negishi, E. Highly efficient asymmetric synthesis of fluvirucinine A1, via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)-lipase-catalyzed acetylation tandem process. Org. Lett. 2008, 10, 193–195. [Google Scholar] [CrossRef] [PubMed]
  13. Llacer, E.; Urpi, F.; Vilarrasa, J. Efficient approach to fluvirucins B2, B5, Sch 38518, and Sch 39185. First synthesis of their aglycon, via CM and RCM reactions. Org. Lett. 2009, 11, 3198–3201. [Google Scholar] [CrossRef] [PubMed]
  14. Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.; Koo, B.-A.; Kim, H.-S. Asymmetric total synthesis of fluvirucinine A1. Angew. Chem. Int. Ed. 1999, 38, 3545–3547. [Google Scholar] [CrossRef]
  15. Lee, Y.-S.; Jung, J.-W.; Kim, S.-H.; Jung, J.-K.; Paek, S.-M.; Kim, N.-J.; Chang, D.-J.; Lee, J.; Suh, Y.-G. First total synthesis and structural confirmation of fluvirucinine A2 via an iterative ring expansion strategy. Org. Lett. 2010, 12, 2040–2043. [Google Scholar] [CrossRef] [PubMed]
  16. Ayers, S.; Zink, D.L.; Mohn, K.; Powell, J.S.; Brown, C.M.; Murphy, T.; Grund, A.; Genilloud, O.; Salazar, O.; Thompson, D.; et al. Anthelmintic macrolactams from Nonomuraea turkmeniaca MA7364. J. Nat. Prod. 2007, 70, 1371–1373. [Google Scholar] [CrossRef] [PubMed]
  17. Ayers, S.; Zink, D.L.; Powell, J.S.; Brown, C.M.; Grund, A.; Genilloud, O.; Salazar, O.; Thompson, D.; Singh, S.B. Anthelmintic macrolactams from Nonomuraea turkmeniaca MA7381. J. Antibiot. 2008, 61, 59–62. [Google Scholar] [CrossRef] [PubMed]
  18. Majumdar, K.C.; Bhattacharyya, T.; Chattopadhyay, B.; Sinha, B. Recent advances in the aza-Claisen rearrangement. Synthesis 2009, 13, 2117–2142. [Google Scholar] [CrossRef]
  19. Jung, J.-W.; Kim, S.-H.; Suh, Y.-G. Advances in aza-Claisen-rearrangement-induced ring-expansion strategies. Asian J. Org. Chem. 2017, 6, 1117–1129. [Google Scholar] [CrossRef]
  20. Castro, A.M.M. Claisen rearrangement over the past nine decades. Chem. Rev. 2004, 104, 2939–3002. [Google Scholar] [CrossRef] [PubMed]
  21. Suh, Y.-G.; Lee, J.-Y.; Kim, S.-A.; Jung, J.-K. A new ring expansion reaction of 1-acyl-2-vinylpiperidine and 1-acyl-2-vinylpiperazine via aza-Claisen rearrangement of amide enolate. Synth. Commun. 1996, 26, 1675–1680. [Google Scholar] [CrossRef]
  22. Jung, J.-K.; Choi, N.-S.; Suh, Y.-G. Functional divergency oriented synthesis of azoninones as the key intermediates for bioactive indolizidine alkaloids analogs. Arch. Pharm. Res. 2004, 27, 985–989. [Google Scholar] [CrossRef] [PubMed]
  23. Suh, Y.-G.; Lee, Y.-S.; Kim, S.-H.; Jung, J.-K.; Yun, H.; Jang, J.; Kim, N.-J.; Jung, J.-W. A stereo-controlled access to functionalized macrolactams via an aza-Claisen rearrangement. Org. Biomol. Chem. 2012, 10, 561–568. [Google Scholar] [CrossRef] [PubMed]
  24. Yun, H.; Kim, J.; Sim, J.; Lee, S.; Han, Y.T.; Chang, D.-J.; Kim, D.-D.; Suh, Y.-G. Asymmetric syntheses of 1-deoxy-6,8a-di-epi-castanospermine and 1-deoxy-6-epi-castanospermine. J. Org. Chem. 2012, 77, 5389–5393. [Google Scholar] [CrossRef] [PubMed]
  25. Paek, S.-M.; Kim, N.-J.; Shin, D.; Jung, J.-K.; Jung, J.-W.; Chang, D.-J.; Moon, H.; Suh, Y.-G. A concise total synthesis of (+)-tetrabenazine and (+)-α-dihydrotetrabenazine. Chem. Eur. J. 2010, 16, 4623–4628. [Google Scholar] [CrossRef] [PubMed]
  26. Jang, J.; Jung, J.-W.; Ahn, J.; Sim, J.; Chang, D.-J.; Kim, D.-D.; Suh, Y.-G. Asymmetric formal synthesis of schulzeines A and C. Org. Biomol. Chem. 2012, 10, 5202–5204. [Google Scholar] [CrossRef] [PubMed]
  27. Sim, J.; Yun, H.; Jung, J.-W.; Lee, S.; Kim, N.-J.; Suh, Y.-G. Achiral auxiliary-assisted chiral transfer via microwave-accelerated aza-Claisen rearrangement: A short synthesis of (+)-1-hydroxyquinolizidinone. Tetrahedron Lett. 2012, 53, 4813–4815. [Google Scholar] [CrossRef]
  28. Moon, H.; An, H.; Sim, J.; Kim, K.; Paek, S.-M.; Suh, Y.-G. Efficient strategy for the stereoselective synthesis of 2,3-disubstituted benzo[α]quinolizidine alkaloids: Concise synthesis of (−)-protoemetinol. Tetrahedron Lett. 2015, 56, 608–611. [Google Scholar] [CrossRef]
  29. Suh, Y.-G.; Lim, C.; Sim, J.; Lee, J.K.; Surh, Y.-J.; Paek, S.-M. Construction of the azacyclic core of tabernaemontanine-related alkaloids via tandem Reformatsky aza-Claisen rearrangement. J. Org. Chem. 2017, 82, 1464–1470. [Google Scholar] [CrossRef] [PubMed]
  30. Suh, Y.-G.; Shin, D.-Y.; Jung, J.-K.; Kim, S.-H. The versatile conversion of acyclic amides to α-alkylated amines. Chem. Commun. 2002, 1064–1065. [Google Scholar] [CrossRef]
  31. Suh, Y.-G.; Kim, S.-H.; Jung, J.-K.; Shin, D.-Y. The versatile conversion of lactams to the α-alkylated azacycles via cyclic N,O-acetal TMS ether. Tetrahedron Lett. 2002, 43, 3165–3167. [Google Scholar] [CrossRef]
  32. Jung, J.-W.; Shin, D.-Y.; Seo, S.-Y.; Kim, S.-H.; Paek, S.-M.; Jung, J.-K.; Suh, Y.-G. A new entry to functionalized cycloalkylamines: Diastereoselective intramolecular amidoalkylation of N,O-acetal TMS ether possessing allylsilane. Tetrahedron Lett. 2005, 46, 573–575. [Google Scholar] [CrossRef]
  33. Suh, Y.-G.; Jang, J.; Yun, H.; Han, S.M.; Shin, D.; Jung, J.-K.; Jung, J.-W. Expedient synthesis of chiral homoallylamines via N,O-acetal TMS ethers and its application. Org. Lett. 2011, 13, 5920–5923. [Google Scholar] [CrossRef] [PubMed]
  34. Shin, D.-Y.; Jung, J.-K.; Seo, S.-Y.; Lee, Y.-S.; Paek, S.-M.; Chung, Y.K.; Shin, D.M.; Suh, Y.-G. Stereoselective formation of N-acyliminium ion via chiral N,O-acetal TMS ether and its application to the synthesis of β-amino acids. Org. Lett. 2003, 5, 3635–3638. [Google Scholar] [CrossRef] [PubMed]
  35. Geometry optimization of (Z)-N-acyl iminium intermediate 22 was performed using ChemBio3D (Ver 14.0), Avogadro, and MOPAC. Details of the geometry opimization are provided in the Supplementary Materials.
  36. Taniguchi, Y.; Inanaga, J.; Yamaguchi, M. Use of 1,8-diazabicyclo[5.4.0]undec-7-ene in preparation of trimethylsilyl enol ethers and trimethylsilylacetylenes. Bull. Chem. Soc. Jpn. 1981, 54, 3229–3230. [Google Scholar] [CrossRef]
  37. Fleming, I.; Barbero, A.; Walter, D. Stereochemical control in organic synthesis using silicon-containing compounds. Chem. Rev. 1997, 97, 2063–2192. [Google Scholar] [CrossRef] [PubMed]
  38. Cambridge Crystallographic Data Centre; CCDC 1864701 (Online); 12 Union Road, Cambridge CB2 1EZ, UK. Available online: http://www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 10 September 2018).
Sample Availability: Samples of compounds are available from the authors.
Molecules 23 02351 g001 550
Figure 1. Structures of fluvirucins.
Figure 1. Structures of fluvirucins.
Molecules 23 02351 g001
Molecules 23 02351 g002 550
Figure 2. 6-Desmethyl-fluvirucinine A1 (11) and the carbohydrate part (12) of 6-desmethyl-N-methylfluvirucin A1 (8).
Figure 2. 6-Desmethyl-fluvirucinine A1 (11) and the carbohydrate part (12) of 6-desmethyl-N-methylfluvirucin A1 (8).
Molecules 23 02351 g002
Molecules 23 02351 sch001 550
Scheme 1. Retrosynthetic analysis for synthesis of 13 as an antipode of 11.
Scheme 1. Retrosynthetic analysis for synthesis of 13 as an antipode of 11.
Molecules 23 02351 sch001
Molecules 23 02351 sch002 550
Scheme 2. Preparation and diastereoselective amidoalkylation of 16.
Scheme 2. Preparation and diastereoselective amidoalkylation of 16.
Molecules 23 02351 sch002
Molecules 23 02351 sch003 550
Scheme 3. Synthesis of macrolactam 26.
Scheme 3. Synthesis of macrolactam 26.
Molecules 23 02351 sch003
Molecules 23 02351 g003 550
Figure 3. X-ray crystallographic structure of 32. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii; black = carbon, red = oxygen, blue = nitrogen, and yellow = silicon.
Figure 3. X-ray crystallographic structure of 32. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii; black = carbon, red = oxygen, blue = nitrogen, and yellow = silicon.
Molecules 23 02351 g003
Molecules 23 02351 sch004 550
Scheme 4. Completion of the (−)-6-demethyl-fluvirucinine A1 (13) synthesis.
Scheme 4. Completion of the (−)-6-demethyl-fluvirucinine A1 (13) synthesis.
Molecules 23 02351 sch004

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MDPI and ACS Style

Moon, H.; Yoon, H.; Lim, C.; Jang, J.; Yi, J.-J.; Lee, J.K.; Lee, J.; Na, Y.; Son, W.S.; Kim, S.-H.; et al. Asymmetric Synthesis of (−)-6-Desmethyl-Fluvirucinine A1 via Conformationally-Controlled Diastereoselective Lactam-Ring Expansions. Molecules 2018, 23, 2351. https://doi.org/10.3390/molecules23092351

AMA Style

Moon H, Yoon H, Lim C, Jang J, Yi J-J, Lee JK, Lee J, Na Y, Son WS, Kim S-H, et al. Asymmetric Synthesis of (−)-6-Desmethyl-Fluvirucinine A1 via Conformationally-Controlled Diastereoselective Lactam-Ring Expansions. Molecules. 2018; 23(9):2351. https://doi.org/10.3390/molecules23092351

Chicago/Turabian Style

Moon, Hyunyoung, Hojong Yoon, Changjin Lim, Jaebong Jang, Jong-Jae Yi, Jae Kyun Lee, Jeeyeon Lee, Younghwa Na, Woo Sung Son, Seok-Ho Kim, and et al. 2018. "Asymmetric Synthesis of (−)-6-Desmethyl-Fluvirucinine A1 via Conformationally-Controlled Diastereoselective Lactam-Ring Expansions" Molecules 23, no. 9: 2351. https://doi.org/10.3390/molecules23092351

APA Style

Moon, H., Yoon, H., Lim, C., Jang, J., Yi, J. -J., Lee, J. K., Lee, J., Na, Y., Son, W. S., Kim, S. -H., & Suh, Y. -G. (2018). Asymmetric Synthesis of (−)-6-Desmethyl-Fluvirucinine A1 via Conformationally-Controlled Diastereoselective Lactam-Ring Expansions. Molecules, 23(9), 2351. https://doi.org/10.3390/molecules23092351

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