Total Synthesis and Antimicrobial Activities of All Stereoisomers of

Moreover, their in vitro antimicrobial activities against some fungi and bacteria were .... Then, the macrolactonization of the free C3-hydroxy seco a...
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Cite This: J. Org. Chem. 2018, 83, 7886−7899

Total Synthesis and Antimicrobial Activities of All Stereoisomers of (16Z,20E)‑Eushearilide and (16E,20E)‑Eushearilide Takayuki Tonoi,* Takehiko Inohana, Teruyuki Sato, Tomoki Yoshida, and Isamu Shiina* Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

J. Org. Chem. 2018.83:7886-7899. Downloaded from pubs.acs.org by STEPHEN F AUSTIN STATE UNIV on 08/03/18. For personal use only.

S Supporting Information *

ABSTRACT: As promising antifungal agents, the eight stereoisomers of eushearilide, including the natural compound, were synthesized relying on an asymmetric Mukaiyama aldol reaction, Julia−Kocienski olefination, and Shiina macrolactonization. Moreover, their in vitro antimicrobial activities against some fungi and bacteria were evaluated by the disk-diffusion method, which revealed that not only natural eushearilide but also its stereoisomers exhibited significant antimicrobial activity against a variety of fungi and bacteria.

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INTRODUCTION Eushearilide1 isolated by Hosoe et al. from a culture of the fungus Eupenicillium shearii is an attractive natural macrolide because it possesses a broad antifungal activity against diverse fungi and yeasts including the human pathogens Aspergillus f umigatus, Trichophyton spp., and Candida spp. Moreover, eushearilide has unique structural characteristics including nonconjugated dienes (16E and 20E) and a phosphorylcholine moiety, which is in sharp contrast to typical polyene macrolides2 generally containing a conjugated polyene chain and a 1,3-polyol moiety, such as in the popular antifungal agents amphotericin B, nystatin, and pimaricin. On the other hand, the relative and absolute configuration at the C3 and C23 chiral centers of eushearilide was not known before our synthesis. Therefore, we initiated a project aimed at the total synthesis of eushearilide so as to clarify the absolute stereochemistry of the natural product and to promote studies of its structure−activity relationship (SAR).3,4 Thus, we have recently achieved enantioselective total synthesis of (3S,16E,20E,23S)-(+)-1, the naturally occurring eushearilide, as shown in Figure 1, which is found to exhibit significant antimicrobial activity against a variety of fungi and bacteria.5 On the basis of this result, we next focused our efforts on the preparation of eushearilide stereoisomers to further explore their biological activities. We also improved our synthetic route to ensure a sufficient supply of eushearilides for future SAR studies. First, the stereoselective synthesis of the C16−C17 alkene in 1 was performed by Julia−Kocienski olefination6 instead of a modified Wittig reaction7 that forms a phosphine oxide as a byproduct, which can pose a problem during © 2018 American Chemical Society

Figure 1. Structure of natural eushearilide, (3S,16E,20E,23S)-(+)-1.

purification and generally cause a decrease in the yield and purity of the desired product (Scheme 1). In view of minimizing the number of synthetic processes and improving the overall yield, we next reduced the number of protection and deprotection steps compared to our previous synthetic strategy. We prepared a seco acid with a free hydroxy group at C3 as a ring-closure precursor and attempted to cyclize the seco acid by 2-methyl-6-nitrobenzoic anhydride (MNBA)8-promoted lactonization promoted by nucleophilic catalysts under basic conditions,9,10 as outlined in Scheme 2. Thus, all eight stereoisomers of (16Z,20E)- and (16E,20E)eushearilides containing the C3 and C23 stereogenic centers and the C16−C17 double bond were synthesized. Herein, we report an improved total synthesis of the eushearilide stereoisomers and the results of detailed in vitro investigations of their antimicrobial activities. Received: March 28, 2018 Published: May 31, 2018 7886

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

Article

The Journal of Organic Chemistry Scheme 1. Formation of the (E)-Alkene Moiety by Julia−Kocienski Olefination

Scheme 2. Improved Method for the Synthesis of the 24-Membered Macrolactone Skeleton of Eushearilide

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RESULTS AND DISCUSSION First, the synthetic route to the desired seco acid is depicted in Scheme 3. When aldehyde 3, which was prepared by conventional oxidation of primary alkenyl alcohol 2,5 was subjected to Julia−Kocienski olefination6 with 5-methanesulfonyl-1-phenyl-1H-tetrazole 411 and potassium hexamethyldisilazide at −78 °C, the desired diene 5 was obtained in a high yield with a very high stereoselectivity (90%, E/Z = 93/7). The geometry of the C8−C9 alkene in 5 was determined to be E on the basis of the downfield shifts of the allylic carbons (δC 32.6 [C7] and δC 32.6 [C10]), while the Z-configured alkene of the C8−C9 double bond was determined from the upfield shifts of the allylic carbons (δC 27.3 [C7] and δC 27.2 [C10]).12 Consecutive deprotection of a primary TBS ether in 5 using ammonium fluoride followed by oxidation of the alcohol 6 gave the corresponding aldehyde 7 in a satisfactory yield. The aldol product 9 bearing a (3S)-3-hydroxy thioester moiety was diastereoselectively constructed by the asymmetric Mukaiyama aldol reaction13 of 1-ethylthio-1-(trimethylsiloxy)ethene 8 and the aldehyde 7 in the presence of an (R)-diamine-Sn(II) complex and nBu3SnF as a chiral promoter. Then the transesterification of thioester 9 with silver trifluoroacetate as a Lewis acid was conducted to afford the corresponding ethyl ester 10. A one-pot cleavage of the benzyloxymethyl (BOM) and the ethyl ester without p-methoxybenzyl (PMB) protection

of the secondary hydroxy group in 10 was executed to yield the desired free C3-hydroxy seco acid 11 in a high yield (96%, 2 steps). Then, the macrolactonization of the free C3-hydroxy seco acid 11 was attempted by exploiting a combination of MNBA and 4-(dimethylamino)pyridine (DMAP) or 4(dimethylamino)pyridine N-oxide (DMAPO) as a nucleophilic catalyst (Table 1). An overstoichiometric amount of DMAP (6.0 equiv) was used with MNBA (1.3 equiv) in CH2Cl2 at rt or 40 °C to give the desired monomeric lactone 12 in 84% or 80% yield, respectively (entries 1 and 2), and none of the undesired β-lactone was formed under these conditions. When a catalytic amount of DMAP (0.2 equiv) was used in the presence of excess triethylamine (3.0 equiv) as a desalting agent (entries 3 and 4), lactone 12 was obtained in a moderate to good yield (68% and 78%, respectively) accompanied by small amounts of the undesired lactone dimer. Additionally, when a catalytic amount of DMAPO and a three hold excess of triethylamine (3.0 equiv) were used at rt, the yield of the desired monomeric lactone 12 decreased to 60% (entry 5). Under the same reaction conditions, but at 40 °C, the yield significantly decreased to 38% accompanied by small amounts of byproducts such as the dimer (3%) and β-lactone (15%, entry 6).14 Furthermore, when dysprosium(III) triflate was used as a Lewis acid for this cyclization in the presence of MNBA with 7887

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

Article

The Journal of Organic Chemistry Scheme 3. Preparation of the Free C3-Hydroxy Seco Acid 11

Table 1. Macrolactonization by MNBA-Mediated Cyclization of Free C3-Hydroxy Seco Acid 11

entry 1 2 3 4 5 6 7

conditions MNBA MNBA MNBA MNBA MNBA MNBA MNBA

(1.3 (1.3 (1.3 (1.3 (1.3 (1.3 (1.3

equiv), equiv), equiv), equiv), equiv), equiv), equiv),

DMAP (6.0 equiv) DMAP (6.0 equiv) DMAP (0.2 equiv), Et3N (3.0 equiv) DMAP (0.2 equiv), Et3N (3.0 equiv) DMAPO (0.2 equiv), Et3N (3.0 equiv) DMAPO (0.2 equiv), Et3N (3.0 equiv) DMAP (6.0 equiv), Dy(OTf)3 (0.3 equiv)

temp/°C

monomer/%

dimer/%

β-lactone/%

rt 40 rt 40 rt 40 rt

84 80 68 77 60 38 59

trace trace 7 5 7 3 9

0 0 trace 4 3 15 6

Scheme 4. Completion of the Total Synthesis of (3S,16E,20E,23S)-1 by Introduction of the Phosphate Moiety of Phosphorylcholine

DMAP,10b the reaction proceeded to give 12 in a moderate yield (59%, entry 7). Thus, even when free C3-hydroxy seco acid was employed to reduce the number of protection and deprotection steps in the synthetic process, a combination of MNBA and stoichiometric quantities of DMAP for the macrolactonization was confirmed to be more effective than employing seco acid bearing PMB ether at C3. With the desired macrolactone 12 in hand, a phosphorylcholine moiety15 was directly introduced at the free C3-hydroxy

group in 12 to afford the desired (3S,16E,20E,23S)-1 (Scheme 4). The improved total synthesis provided 1 in 16 steps (longest linear sequence) and 13.4% yield from commercially available starting materials (previous route: 18 steps and 5.3% yield). Moreover, we achieved the asymmetric total synthesis of (3R,16Z,20E,23S)-1, via an exclusively Z-selective Wittig olefination16 in the presence of 18-crown-6 ether and 7888

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

Article

The Journal of Organic Chemistry Scheme 5. Preparation of (3R,16Z,20E,23S)-1

potassium tert-butoxide as a base starting from the known aldehyde5 as depicted in Scheme 5. Likewise, we prepared all of the remaining six stereoisomers to further explore their biological activities. R/S-Propylene oxide and a chiral Lewis acid for the asymmetric aldol reaction were used for the construction of C3 and C23 stereogenic centers, respectively, and two olefination methods (Wittig and Julia−Kocienski) were employed for the stereoselective construction of the C16−C17 alkene. Thus, the eight stereoisomers, (3R,16Z,20E,23S)-, (3S,16Z,20E,23R)-, (3S,16Z,20E,23S)-, (3R,16Z,20E,23R)-, (3S,16E,20E,23S)-, (3R,16E,20E,23R)-, (3S,16E,20E,23R)-, and (3R,16E,20E,23S)-1 were individually prepared.17 We then compared the 13C NMR spectra of these stereoisomers with those of the natural eushearilide (Figures 2 and 3). With regard to the four stereoisomers of (16Z,20E)-eushearilides, we found that the 13C NMR spectra of these stereoisomers were different from that of the natural product. Particularly, the chemical shifts of the Z-configured alkene (C16−C17) and its neighboring carbons certainly differ from those of the natural product (Figure 2). On the other hand, the 13C NMR spectra of the four stereoisomers of the (16E,20E)-eushearilides showed a good agreement with those of the natural product (Figure 3). However, the 13C NMR spectra of the two stereoisomers of the (16E,20E)-eushearilides, (3S,23R)- and its

enantiomer, were slightly different from those of the natural product. Therefore, we were able to eventually confirm that (3S,16E,20E,23S)-1, whose specific optical rotation ([α]D25 +11.3 [c 0.85, MeOH]) was almost identical with the literature value of the natural product ([α]25 D +12.8 [c 0.75, MeOH]), is the naturally occurring eushearilide. Finally, we investigated the in vitro antimicrobial activities of the obtained stereoisomers by the disk-diffusion method in reference to the Clinical and Laboratory Standards Institute (CLSI) guidelines,18 in which the zone of inhibition was measured in millimeters for each microorganism. The microorganisms tested were pathogenic filamentous fungi (Trichophyton mentagrophytes NBRC 5466; Aspergillus niger NBRC 105649) and pathogenic bacteria (Staphylococcus aureus NBRC 12732, IID 1677 (MRSA), and ATCC 43300 (MRSA); Enterococcus faecalis ATCC 29212 and ATCC 51575 (VRE)). Initially, the synthesized (3S,16E,20E,23S)-1 was investigated with various fungi and bacteria (Table 2). The inhibition diameters for Trichophyton mentagrophytes NBRC 5466 and Aspergillus niger NBRC 105649 were 17.3 and 4.3 mm, respectively. On the other hand, the antibacterial activity of (3S,16E,20E,23S)-1 against Enterococcus faecalis was relatively high (7.6 mm diameter in ATCC 29212 and 4.7 mm diameter in ATCC 51575) compared with that against Staphylococcus aureus (1.3 mm diameter in NBRC 12732, 1.4 mm diameter in 7889

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

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The Journal of Organic Chemistry

Figure 2. Comparison of 13C NMR spectra of the stereoisomers of (16Z,20E)-eushearilides. Δδ indicates the differences in the 13C chemical shifts between the natural and synthetic compounds; Δδ = δ (synthetic) − δ (natural).

IID 1677, and 3.0 mm diameter in ATCC 43300). It should be noted that the synthetic compound (3S,16E,20E,23S)-1 clearly exhibits antibacterial activity against certain microorganisms including MRSA and VRE, which cause a serious hospitalacquired infection around the world, as well as antifungal activity as described in the published literature. Furthermore, the antifungal activities of the eushearilide stereoisomers were assayed against Trichophyton mentagrophytes NBRC 5466 relative to that of (3S,16E,20E,23S)-1, which was used as an index of antifungal activity (Table 3). In these experiments, (3S,16Z,20E,23R)-1 and (3R,16Z,20E,23R)-1, the originally proposed structures of eushearilide, were found to show the same level of antifungal activity as (3S,16E,20E,23S)1. However, their enantiomers as well as (3S,16E,20E,23R)-1 and its enantiomer exhibited no inhibition of T. mentagrophytes NBRC 5466. Therefore, the antifungal activity of eushearilide might be affected not by the geometrical configurations of the C16−C17 alkene but rather by the relative configuration at the C3 and C23 chiral centers.

In conclusion, by the comprehensive tuning of the reaction conditions and the efficient macrolactonization, an improved total synthesis of natural eushearilide and its seven stereoisomers was achieved, which enabled the significant improvement of the total yield (13.4% in 16 steps). Moreover, the preliminary SAR of eushearilides was carried out by employing these synthetic stereoisomers, and consequently eushearilide was found to exhibit not only antifungal activity but also antibacterial activity against a variety of microorganisms for the first time.

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EXPERIMENTAL SECTION

General Information. Optical rotations were determined using a Jasco P-1020 polarimeter. Infrared (IR) spectra were obtained using a Jasco FT/IR-4600 Fourier transform infrared spectrometer. Proton and carbon nuclear magnetic resonance (1H and 13C NMR) spectra were recorded with chloroform (in CDCl3) on the following instruments: JEOL JNM-AL500 (1H at 500 MHz and 13C at 125 MHz). Mass spectra were determined by a Bruker Daltonics micrOTOF focus (ESI-TOF) mass spectrometer. Thin layer 7890

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

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The Journal of Organic Chemistry

Figure 3. Comparison of 13C NMR spectra of the stereoisomers of (16E,20E)-eushearilides. Δδ indicates the differences in the 13C chemical shifts between the natural and synthetic compounds; Δδ = δ (synthetic) − δ (natural). chromatography was performed on Wakogel B5F. HPLC was performed with a Hitachi LaChrom Elite system composed of the Organizer, L-2400 UV Detector, and L-2130 Pump. All reactions were carried out under an argon atmosphere in dried glassware unless otherwise noted. CH2Cl2 was distilled from diphosphorus pentoxide and then calcium hydride and dried over 4 Å molecular sieves. Toluene was distilled from diphosphorus pentoxide and dried over 4 Å molecular sieves, and THF and diethyl ether were distilled from sodium/benzophenone immediately prior to use. All reagents were purchased from Tokyo Kasei Kogyo Co., Ltd., Kanto Chemical Co., Inc., or Aldrich Chemical Co., Inc. and used without further purification unless otherwise noted. MNBA was purchased from Tokyo Kasei Kogyo Co. Ltd. (TCI M1439). Experimental Procedures and Analytical Data. (4E,7S)-7((Benzyloxy)methoxy)oct-4-enal (3). To a cooled (0 °C) solution of primary alkenyl alcohol5 (77.1 mg, 0.292 mmol) in CH2Cl2 (2.3 mL) and DMSO (0.58 mL) were added Et3N (0.33 mL, 2.33 mmol) and

Table 2. Antimicrobial Activity of (3S,16E,20E,23S)Eushearilidea microorganism

strain no.

zone of inhibition (mm)b

Trichophyton mentagrophytes Aspergillus niger Staphylococcus aureus Staphylococcus aureus Staphylococcus aureus Enterococcus faecalis Enterococcus faecalis

NBRC 5466 NBRC 105649 NBRC 12732 IID 1677 ATCC 43300 ATCC 29212 ATCC 51575

17.3 4.3 1.3 1.4 3.0 7.6 4.7

a

The clear zone of inhibition (mm) around a paper disk impregnated with an antimicrobial agent at a concentration of 50 μg/disk. bFor compound (3S,16E,20E,23S)-1.

7891

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

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The Journal of Organic Chemistry

5-((14-((tert-Butyldimethylsilyl)oxy)tetradecyl)sulfonyl)-1-phenyl1H-tetrazole (4). To a cooled (0 °C) solution of the tetrazole S2 (251 mg, 0.497 mmol) and NaHCO3 (167 mg, 1.99 mmol) in CH2Cl2 (9.9 mL) was added mCPBA (334 mg, 1.49 mmol). After the mixture was warmed to room temperature, stirring was continued for 40 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and Na2S2O3; the organic layer was separated, and the aqueous layer extracted with CH2Cl2 three times. The combined organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/EtOAc = 5/1) to afford the desired PT sulfone 4 (239 mg, 90%): IR (neat) 2924, 2854, 1149 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.70−7.58 (m, 5H, aromatic H), 3.73 (t, J = 8.0 Hz, 2H, H-1), 3.59 (t, J = 6.9 Hz, 2H, H-14), 1.98−1.92 (m, 2H, H-2), 1.53−1.46 (m, 4H, 3-H, H-13), 1.35−1.25 (m, 18H, H-4 to H-12), 0.89 (s, 9H, TBS), 0.04 (s, 6H, TBS); 13C NMR (125 MHz, CDCl3) δ 153.5, 133.0, 131.4, 129.7, 125.0, 63.3, 56.0, 32.8, 29.6, 29.5, 29.5, 29.4, 29.2, 28.9, 28.1, 26.0, 25.8, 21.9, 18.3, −5.29; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C27H48N4O3SSiNa 559.3109, found 559.3102. (2S,4E,8E)-14-tert-Butyldimethylsilyloxy-2-benzyloxymethoxydocosa-4,8-diene (5). To a cooled (−78 °C) solution of sulfone 4 (88 mg, 0.164 mmol) in anhydrous DME (3.3 mL) was added KHMDS (1.0 M in THF, 0.23 mL, 0.226 mmol), and the mixture was stirred for 5 min. Then, aldehyde 3 (33 mg, 0.126 mmol) in anhydrous DME (3.3 mL) was added dropwise via a cold cannula to a solution for over 5 min at −78 °C. After the completion of the dripping, the mixture was stirred for 1 h. Then, the reaction mixture was quenched with H2O. The organic layer was separated, and the aqueous layer was extracted with diethyl ether three times. The combined organic layers were washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/EtOAc = 8/1) to afford the product as an E/Z isomeric mixture (65 mg, 90%, E/Z = 93/7). Furthermore, the mixture was purified by column chromatography on silica gel impregnated with silver nitrate (hexane/EtOAc = 40/1) to afford 5 (61 mg, 84%): [α]23 D −3.63 (c 1.00, CHCl3); IR (neat) 2923, 2854 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.33 (m, 5H, BOM), 5.51−5.38 (m, 4H, H-4, H-5, H-8, H-9), 4.79 (dd, J = 6.9, 14.6 Hz, 2H, BOM), 4.62 (dd, J = 12.0, 15.5 Hz, 2H, BOM), 3.79 (ddd, J = 6.3, 12.3, 12.5 Hz, 1H, H-2), 3.59 (t, J = 6.3 Hz, 2H, H-22), 2.22 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-3), 2.17 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-3), 2.05 (brs, 4H, H-6, H-7), 1.95 (dd, J = 6.9, 12.3 Hz, 2H, H-10), 1.51 (tt, J = 6.9, 6.9 Hz, 2H, H-21), 1.31−1.25 (m, 20H, H-11 to H-20), 1.17 (d, J = 6.3 Hz, 3H, H-1), 0.89 (s, 9H, TBS), 0.06 (s, 6H, TBS); 13 C NMR (125 MHz, CDCl3) δ 138.0, 132.7, 130.8, 129.5, 128.4, 127.8, 127.6, 126.2, 92.8, 73.0, 69.3, 63.4, 40.1, 32.9, 32.8, 32.6, 32.6, 29.7, 29.6, 29.6, 29.5, 29.2, 25.8, 26.0, 19.9, 18.4, −5.23; HRMS (ESI/ TOF) m/z [M + Na]+ calcd for C36H64O3SiNa 595.4517, found 595.4494. (21S,14E,18E)-21-Benzyloxymethoxydocosa-14,18-dien-1-ol (6). To a cooled (0 °C) solution of 5 (750 mg, 1.31 mmol) in THF (13 mL) was added TBAF (1.0 M in THF, 3.9 mL, 3.9 mmol), and the resulting solution was stirred at rt for 3 h. After cooling the mixture to 0 °C, saturated aqueous NaHCO3 was added. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/EtOAc = 10/1) to afford 6 (596 mg, 99%): [α]20 D −3.28 (c 1.01, CHCl3); IR (neat) 3402, 2923, 2854 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.27 (m, 5H, BOM), 5.51−5.34 (m, 4H, H-14, H-15, H-18, H-19), 4.79 (dd, J = 7.5, 14.3 Hz, 2H, BOM), 4.61 (dd, J = 11.5, 15.5 Hz, 2H, BOM), 3.79 (ddd, J = 6.3, 12.3, 12.6 Hz, 1H, H-21), 3.64 (t, J = 6.9 Hz, 2H, H-1), 2.28 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-20), 2.16 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-20), 2.04 (brs, 4H, H-16, H-17), 1.95 (dd, J = 6.9, 12.3 Hz, 2H, H-13), 1.56 (tt, J = 6.9, 6.9 Hz, 2H, H-2), 1.31−1.25 (m, 20H, H3 to H-12), 1.17 (d, J = 6.3 Hz, 3H, H-22); 13C NMR (125 MHz, CDCl3) δ 138.0, 132.7, 130.8, 129.5, 128.4, 127.9, 127.6, 126.2, 92.8, 73.0, 69.3, 63.1, 53.9, 40.1, 32.8, 32.6, 32.6, 29.6, 29.6, 29.5, 29.4, 29.4,

Table 3. Antifungal Activity of Each Stereoisomer of Eushearilidea compound

zone of inhibition (mm)b

(3S,16E,20E,23S)-1 (3R,16E,20E,23R)-1 (3S,16E,20E,23R)-1 (3R,16E,20E,23S)-1 (3S,16Z,20E,23R)-1 (3R,16Z,20E,23S)-1 (3R,16Z,20E,23R)-1 (3S,16Z,20E,23S)-1

17.3 3.7 0c 0c 12.0 0c 6.3 0c

a

The clear zone of inhibition (mm) around a paper disk impregnated with an antimicrobial agent at a concentration of 50 μg/disk. bFor the microoganism Trichophyton mentagrophytes NBRC 5466. cThere was no zone of inhibition. SO3·Py (185 mg, 1.67 mmol). After the solution was stirred at rt for 1 h, the reaction mixture was quenched with saturated aqueous ammonium chloride at 0 °C. The organic layer was separated, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/diethyl ether = 5/1) to afford 3 (68 mg, 89%): [α]25 D −5.01 (c 1.01, CHCl3); IR (neat) 2931, 2858, 1728 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.74 (t, J = 1.4 Hz, 1H, H-1), 7.35−7.26 (m, 5H, BOM), 5.53−5.46 (m, 2H, H-4, H-5), 4.78 (m, 2H, BOM), 4.61 (m, 2H, BOM), 3.80 (sx, J = 6.3 Hz, 1H, H-7), 2.47 (dt, J = 1.3, 7.2 Hz, 2H, H-2), 2.34 (dt, J = 3.9, 9.7 Hz, 2H, H-3), 2.27 (ddd, J = 3.1, 6.1, 12.9 Hz, 1H, H-6), 2.17 (ddd, J = 3.4. 5.9, 12.6 Hz, 1H, H-6), 1.17 (d, J = 6.3 Hz, 3H, H-8); 13C NMR (125 MHz, CDCl3) δ 202.0, 137.9, 130.5, 128.3, 127.7, 127.6, 127.6, 92.8, 72.7, 69.2, 43.3, 39.8, 25.1, 19.9; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C16H22O3Na 285.1461, found 285.1464. (14-tert-Butyldimethylsilyloxy)tetradecan-1-ol (S1).19 To a cooled (0 °C) solution of tetradecane-1,14-diol (817 mg, 3.55 mmol) in CH3CN (4.0 mL) and hexane (31.5 mL) were added Et3N (0.6 mL, 4.26 mmol) and TBSCl (561 mg, 3.72 mmol). The solution was stirred at 55 °C for 24 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with EtOAc three times. The combined organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/EtOAc = 10/1) to afford the monosilylated diol S1 (1.08 g, 83%): IR (neat) 3394, 2927, 2865 cm−1; 1H NMR (500 MHz, CDCl3) δ 3.60 (m, 4H, H-1, H-14), 2.28 (m, 4H, H-2, H-13), 1.65− 1.23 (m, 20H, H-3 to H-12), 0.89 (s, 9H, TBS), 0.063 (s, 6H, TBS); 13 C NMR (125 MHz, CDCl3) δ 63.4, 63.1, 32.9, 32.8, 29.6, 29.6, 29.6, 29.4, 29.4, 26.0, 25.8, 25.7, 25.6, 18.5, −5.25; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C20H44O2SiNa 367.3003, found 367.3001. 5-((14-((tert-Butyldimethylsilyl)oxy)tetradecyl)thio)-1-phenyl-1Htetrazole (S2). To a cooled (0 °C) solution of the monosilylated diol S1 (1.18 g, 3.42 mmol) in THF (34 mL) were added 1-phenyl-1Htetrazole-5-thiol (732 mg, 4.11 mmol), triphenylphosphine (1.07 g, 4.11 mmol), and diisopropyl azodicarboxylate (DIAD) (1.9 M in toluene, 2.2 mL, 4.11 mmol). After the solution was stirred at 0 °C for 3.5 h, the reaction mixture was evaporated. The crude product was purified by column chromatography on silica gel (hexane/EtOAc = 5/ 1) to afford the tetrazole S2 (1.58 g, 92%): IR (neat) 2924, 2854 cm−1; 1 H NMR (500 MHz, CDCl3) δ 7.59−7.51 (m, 5H, aromatic H), 3.59 (t, J = 6.9 Hz, 2H, H-14), 3.39 (t, J = 7.4 Hz, 2H, H-1), 1.81 (qn, J = 7.5 Hz, 2H, H-2), 1.50 (qn, J = 6.5 Hz, 2H, H-13), 1.43 (qn, J = 7.5 Hz, 2H, H-3), 1.31−1.24 (m, 18H, H-4 to H-12), 0.88 (s, 9H, TBS), 0.04 (s, 6H, TBS); 13C NMR (125 MHz, CDCl3) δ 154.5, 133.7, 130.0, 129.7, 123.8, 63.3, 33.3, 32.9, 29.6, 29.6, 29.5, 29.4, 28.6, 29.0, 29.0, 26.0, 25.8, 18.4, −5.28; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C27H48N4OSSiNa 527.3210, found 527.3227. 7892

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

Article

The Journal of Organic Chemistry 29.2, 29.1, 25.7, 20.8, 14.1, 19.9; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C30H50O3Na 481.3652, found 481.3659. (21S,14E,18E)-21-Benzyloxymethoxydocosa-14,18-dienal (7). To a cooled (0 °C) solution of 6 (600 mg, 1.31 mmol) in CH2Cl2 (10.5 mL) and DMSO (2.6 mL) were added Et3N (1.5 mL, 10.5 mmol) and SO3·Py (833 mg, 5.23 mmol). After the solution was stirred at rt for 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride at 0 °C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/EtOAc = 30/1) to afford 7 (508 mg, 85%): [α]21 D −3.91 (c 1.00, CHCl3); IR (neat) 2924, 2854, 1727 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.65 (t, J = 1.7 Hz, 1H, H1), 7.27−7.18 (m, 5H, BOM), 5.43−5.30 (m, 4H, H-14, H-15, H-18, H-19), 4.70 (dd, J = 6.9, 14.3 Hz, 2H, BOM), 4.53 (dd, J = 12.0, 15.5 Hz, 2H, BOM), 3.71 (ddd, J = 6.3, 12.3, 12.5 Hz, 1H, H-21), 2.31 (ddd, J = 2.3, 7.2, 7.3 Hz, 2H, H-3), 2.19 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-20), 2.07 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-20), 1.97 (brs, 4H, H-16, H-17), 1.88 (dd, J = 6.9, 12.9 Hz, 2H, H-13), 1.53 (tt, J = 7.5 Hz, 2H, H-2), 1.25−1.18 (m, 18H, H-4 to H-12), 1.09 (d, J = 6.3 Hz, 3H, H-22); 13C NMR (125 MHz, CDCl3) δ 202.7, 138.0, 132.6, 130.7, 129.4, 128.3, 127.8, 127.5, 126.2, 92.7, 72.9, 69.2, 43.8, 40.0, 32.7, 32.5, 32.5, 29.6, 29.5, 29.5, 29.4, 29.3, 29.1, 22.0, 19.8; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C30H48O3Na 479.3496, found 479.3514. (3S,16E,20E,23S)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienthioate (9). To a solution of Sn(OTf)2 (695 mg, 1.67 mmol) in CH2Cl2 (14.3 mL) were added a solution of (R)-1-methyl-2(1-naphthylaminomethyl)pyrrolidine (436 mg, 1.81 mmol) in CH2Cl2 (2.0 mL) and nBu3SnF (516 mg, 1.67 mmol), respectively. The mixture was cooled to −78 °C. To the reaction mixture were added solutions of KSA 8 (294 mg, 1.67 mmol) in CH2Cl2 (3.0 mL) and the aldehyde 7 (508 mg, 1.11 mmol) in CH2Cl2 (3.0 mL) at −78 °C, successively. The mixture was stirred for 12 h at that temperature and then quenched with saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/EtOAc = 10/1) to afford the aldol product 9 (520 mg, 83%, dr = 96/4): [α]21 D +4.87 (c 1.00, CHCl3); IR (neat) 2924, 2854, 1727 cm−1; HPLC analysis DAICEL CHIRALPAC IB-3, UV 254 nm, temperature 25 °C, hexane/iPrOH = 99/1, flow rate 0.5 mL/min, tR = 19.9 min, 21.4 min; 1 H NMR (500 MHz, CDCl3) δ 7.36−7.27 (m, 5H, BOM), 5.51−5.34 (m, 4H, H-16, H-17, H-20, H-21), 4.80 (dd, J = 7.5, 14.3 Hz, 2H, BOM), 4.61 (ddd, J = 11.5, 15.5 Hz, 2H, BOM), 4.05 (brs, 1H, OH), 3.80 (ddd, J = 6.3, 10.3, 12.6 Hz, 1H, H-3), 2.90 (q, J = 7.5 Hz, 2H, Et), 2.74 (dd, J = 2.9, 15.5 Hz, 1H, H-23), 2.65 (m, 2H, H-2), 2.28 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-22), 2.17 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-22), 2.04 (brs, 4H, H-18, H-19), 1.95 (qn, J = 7.5 Hz, 2H, H15), 1.55−1.25 (m, 25H, H-4 to H-14, Et), 1.17 (d, J = 6.3 Hz, 3H, H24); 13C NMR (125 MHz, CDCl3) δ 199.7, 138.0, 132.7, 130.8, 129.4, 128.4, 127.8, 127.6, 126.2, 92.8, 73.0, 69.2, 68.7, 50.6, 40.0, 36.5, 32.8, 32.6, 32.5, 29.6, 29.6, 29.6, 29.5, 29.5, 29.5, 29.5, 29.1, 25.4, 23.3, 19.9, 14.6; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C34H56O4SNa 583.3792, found 583.3778. (3S,16E,20E,23S)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienoate (10). To a cooled (0 °C) solution of 9 (260 mg, 0.48 mmol) in ethanol (9.5 mL) were added iPr2NEt (0.33 mL, 1.91 mmol) and AgOCOCF3 (211 mg, 0.95 mmol). After the solution was stirred at rt for 3 h, the reaction mixture was quenched with H2O. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/EtOAc = 5/ 1) to afford 10 (225 mg, 98%): [α]20 D +4.27 (c 1.02, CHCl3); IR (neat) 3464, 2924, 2854, 1728 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35− 7.27 (m, 5H, BOM), 5.52−5.34 (m, 4H, H-16, H-17-H, H-20, H-21), 4.80 (dd, J = 7.5, 14.3 Hz, 2H, BOM), 4.61 (ddd, J = 12.0, 15.5 Hz, 2H, BOM), 4.17 (q, J = 6.9 Hz, 2H, Et), 4.00 (brs, 1H, OH), 3.80

(ddd, J = 6.3, 10.3, 12.6 Hz, 1H, H-3), 2.94 (d, J = 4.0 Hz, 1H, H-23), 2.51−2.48 (m, 2H, H-2), 2.28 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-22), 2.15 (ddd, J = 6.3, 6.9, 10.0 Hz, 1H, H-22), 2.04 (brs, 4H, H-18, H19), 1.95 (m, 2H, H-15), 1.63−1.25 (m, 25H, H-4 to H-14, Et), 1.17 (d, J = 6.3 Hz, 3H, H-24); 13C NMR (125 MHz, CDCl3) δ 173.1, 138.0, 132.7, 130.8, 129.5, 128.4, 127.8, 127.6, 126.2, 92.8, 73.0, 69.3, 68.0, 60.6, 41.3, 40.0, 36.5, 32.8, 32.6, 32.6, 29.6, 29.6, 29.6, 29.5, 29.2, 25.5, 19.9, 14.2; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C34H56O5Na 567.4020, found 567.4000. (3S,16E,20E,23S)-3,23-Dihydroxytetracosa-16,20-dienoic Acid (11). A solution of 10 (496 mg, 0.910 mmol) in 2.0 M HCl (EtOH/HCl = 5/1, 18.2 mL) was stirred at rt for 24 h. After the starting material was consumed, 4.0 M aqueous LiOH was added at 0 °C. Distilled water (2.6 mL) was poured into the reaction mixture, followed by the addition of 4.0 M aqueous LiOH (0.46 mL, 1.82 mmol). The mixture was stirred at rt for 24 h, and 1.0 M HCl was added until the solution became acidic. The organic layer was separated, and the aqueous layer was extracted with EtOAc five times. The combined organic layer was washed with H2O and brine and dried over Na2SO4. After evaporation of the solvent, to the organic phase was added a 10% aqueous NaOH solution, and the organic phase was washed with EtOAc five times. The aqueous phase was separated, 1.0 M HCl was added, and the phase was washed with EtOAc five times. The combined organic layers were washed with H2O and brine and dried over Na2SO4. After evaporation of the solvent, AcOH was removed under reduced pressure to afford 11 (345 mg, 96%, 2 steps) as a white solid: mp 66.8−69.2 °C; [α]20 D +11.6 (c 1.08, CHCl3); IR (neat) 3355, 2916, 2846, 1682 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.55−5.34 (m, 4H, H-16, H-17, H-20, H-21), 4.04−4.00 (m, 1H, H-3), 3.78 (sx, J = 5.9 Hz, 1H, H-23), 2.57 (dd, J = 2.9, 16.6 Hz, 1H, H-2), 2.47 (dd, J = 9.2, 16.6 Hz, 1H, H-2), 2.23−2.18 (m, 1H, H22), 2.11−2.05 (m, 5H, H-18, H-19, H-22), 1.96 (q, J = 6.7 Hz, 2H, H-15), 1.56−1.44 (m, 4H, H-4, H-5), 1.31−1.25 (m, 18H, H-6 to H14), 1.18 (d, J = 6.3 Hz, 3H, H-24); 13C NMR (125 MHz, CDCl3) δ 176.6, 134.3, 131.1, 129.4, 126.1, 67.9, 67.1, 42.4, 40.8, 36.5, 32.7, 32.5, 32.5, 29.5, 29.5, 29.5, 29.4, 29.1, 25.4, 22.5; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H44O4Na 419.3132, found 419.3136. (3S,16E,20E,23S)-3-Hydroxy-23-methyltricosa-16,20-dienolide (12). To a solution of MNBA (22 mg, 63.3 μmol) and DMAP (35.7 mg, 0.292 mmol) in CH2Cl2 (19.5 mL) at rt was slowly added a solution of the seco acid 11 (19.3 mg, 48.7 μmol) in CH2Cl2 (4.5 mL) with a mechanically driven syringe over a 12 h period. After the mixture cooled to 0 °C, saturated aqueous NaHCO3 was added. The organic layer was separated; the aqueous layer was extracted with CH2Cl2, and the organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/EtOAc = 3/1) to afford 12 (15.5 mg, 84%): [α]22 D −13.5 (c 0.87, CHCl3); IR (neat) 3410, 2924, 2854, 1728 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.51−5.34 (m, 4H, H-16, H-17, H-20, H-21), 5.00 (dt, J = 1.5, 6.0 Hz, 1H, H-3), 3.94 (m, 1H, H-23), 2.54−2.39 (m, 2H, H-2), 2.31−2.17 (m, 2H, H-22), 2.05 (brs, 4H, H-18, H-19), 2.00 (d, J = 5.5 Hz, 2H, H-15), 1.58−1.27 (m, 22 H, H-4 to H-14), 1.24 (d, J = 6.0 Hz, 3H, H24); 13C NMR (125 MHz, CDCl3) δ 172.2, 133.7, 130.8, 129.8, 125.0, 70.8, 68.2, 41.4, 39.0, 36.1, 32.9, 32.5, 31.9, 28.7, 28.6, 28.4, 28.2, 28.2, 28.2, 28.1, 28.0, 27.5, 24.7, 19.6; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H42O3Na 401.3026, found 401.3008. (4S)-4-((13E,17E,20S)-20-Hydroxyhenicosa-13,17-dien-1-yl)oxetan-2-one (β-Lactone). To a solution of MNBA (20.0 mg, 58.0 μmol), DMAPO (1.2 mg, 8.9 μmol), and E3N (19 μL, 0.134 mmol) in CH2Cl2 (17.5 mL) at 40 °C was slowly added a solution of the seco acid 11 (17.7 mg, 44. μmol) in CH2Cl2 (4.5 mL) with a mechanically driven syringe over a 12 h period. After the mixture cooled to 0 °C, saturated aqueous NaHCO3 was added. The organic layer was separated; the aqueous layer was extracted with CH2Cl2, and the organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/EtOAc = 3/1) to afford the desired product 12 (6.4 mg, 38%) and β-lactone as a major byproduct (2.5 mg, 15%): [α]25 D +7.05 (c 0.37, CHCl3); IR (neat) 3371, 2916, 7893

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

Article

The Journal of Organic Chemistry 2846, 1813 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.55−5.35 (m, 4H, H-17, H-18, H-21, H-22), 4.50 (m, 1H, H-3), 3.77 (m, 1H, H-24), 3.50 (dd, J = 5.7, 16.0 Hz, 1H, H-3), 3.07 (dd, J = 4.3, 16.3 Hz, 1H, H3), 2.22−2.18 (m, 2H, H-23), 2.11−2.05 (m, 5H, H-23, H-19, H-20), 1.96 (q, J = 6.7 Hz, 2H, H-16), 1.89−1.84 (m, 1H, H-5), 1.77−1.71 (m, 1H, H-5), 1.62−1.55 (m, 2H, H-6), 1.34−1.25 (m, 18H, H-7 to H-15), 1.18 (d, J = 6.3 Hz, 3H, H-25); 13C NMR (125 MHz, CDCl3) δ 168.4, 134.2, 131.1, 129.4, 126.2, 71.3, 67.0, 42.9, 42.5, 34.7, 32.7, 32.6, 32.5, 29.6, 29.6, 29.6, 29.6, 29.5, 29.5, 29.4, 29.2, 29.1, 24.9, 22.6; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H42O3Na 401.3026, found 401.3022. (3S,16E,20E,23S)-Eushearilide (1). To a cooled (0 °C) solution of alcohol 12 (108.7 mg, 0.287 mmol) in toluene (5.7 mL) were added Et3N (0.160 mL, 1.15 mmol) and 2-chloro-2-oxo-1,3,2-dioxaphospholane (79.2 μL, 0.861 mmol). The resulting mixture was stirred at that temperature for 15 min. Then, the cooling bath was removed, and the stirring was continued at rt for another 4 h. This process was repeated twice until the reaction was completed. The crude product obtained after separation of amine salt by filtration was used in the next step without further purification. To a cooled (−15 °C) solution of the crude product in CH3CN (5.7 mL) was added an excess amount of Me3N (4.3 mL, 2.0 M in THF). The solution was stirred at 70 °C for 14 h in a stirred stainless steel autoclave. After the mixture cooled to rt, the solvent was removed, and the crude product was purified by column chromatography on silica gel (Chromatorex NH-DM1020; chloroform/MeOH = 6/1) to afford 1 (87.1 mg, 56%): [α]20 D +11.3 (c 0.85, CH3OH); IR (neat) 3432, 2954, 2537, 2090, 1728 cm−1; 1H NMR (500 MHz, CD3OD) δ 5.52−5.37 (m, 4H, H-16, H-17, H-20, H-21), 4.87 (m, 1H, H-23), 4.57−4.51 (m, 1H, H-3), 4.26 (d, J = 2.9 Hz, 2H, H-25), 3.63 (dd, J = 2.9, 4.0 Hz, 2H, H-26), 3.22 (s, 9H, H27), 2.82 (dd, J = 4.3, 14.6 Hz, 1H, H-2), 2.54 (dd, J = 8.6, 14.3 Hz, 1H, H-2), 2.25 (ddd, J = 7.0, 14.0, 20.0 Hz, 2H, H-22), 2.07 (brs, 4H, 18-H, 19-H), 2.00 (dd, J = 5.7, 9.7 Hz, 2H, H-15), 1.65 (ddt, J = 7.0, 14.0 Hz, 2H, H-4), 1.47−1.30 (m, 20H, H-5 to H-14), 1.20 (d, J = 6.3 Hz, 3H, H-24); 13C NMR (125 MHz, CD3OD) δ 171.8 (C-1), 134.7 (C-20), 131.8 (C-16), 131.2 (C-17), 126.5 (C-21), 74.1 (d, J = 5.8 Hz, C-3), 72.3 (C-23), 67.5 (d, J = 3.6 Hz, C-26), 60.3 (d, J = 4.3 Hz, C25), 54.7 (d, J = 4.3 Hz, C-27), 41.9 (C-2), 40.0 (C-22), 36.1 (d, J = 5.7 Hz, C-4), 33.9 (C-19), 33.6 (C-18), 32.8 (C-15), 30.1 (C-6), 29.5 (C-14), 29.8, 29.7, 29.7, 29.6, 29.4, 29.2 (C-7 to C-12), 28.4 (C-13), 25.4 (C-5), 19.7 (C-24); HRMS (ESI/TOF) m/z [M + Na]+ calcd for C29H54NO6PNa 566.3581, found 566.3592. (2S,4E,8Z)-14-tert-Butyldimethylsilyloxy-2-benzyloxymethoxydocosa-4,8-diene (13). To a cooled (0 °C) solution of phosphonium salt (21 mg, 61.9 μmol) and 18-crown-6 (29.4 mg, 0.111 mmol) in THF (0.62 mL) was added KOtBu (1.0 M in THF, 0.07 mL, 68.1 μmol), and the mixture was stirred for 5 min. Then, the solution of the ylide formed was added dropwise via a cold cannula to a solution of the aldehyde (39.4 mg, 68.1 μmol) in THF (0.62 mL) for over 5 min at that temperature. After the completion of the dripping, the mixture was stirred for 1 h. Then, the reaction mixture was quenched with saturated aqueous ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 10/1) to afford the product (26.7 mg, 76%, Z/E > 99/1): −1 1 [α]25 D −2.45 (c 0.99, CHCl3); IR (neat) 2924, 2854 cm ; H NMR (500 MHz, CDCl3) δ 7.36−7.27 (m, 5H, BOM), 5.54−5.32 (m, 4H, 4-H, 5-H, 8-H, 9-H), 4.80 (q, J = 7.4 Hz, 2H, BOM), 4.63 (dd, J = 11.7, 15.2 Hz, 2H, BOM), 3.81 (sx, J = 6.5 Hz, 1H, 2-H), 3.60 (t, J = 6.6 Hz, 2H, 22-H), 2.30−2.28 (m, 1H, 3-H), 2.20−2.15 (m, 1H, 3-H), 2.10−2.05 (m, 4H, 7-H, 10-H), 2.03−1.99 (m, 2H, 6-H), 1.53−1.49 (m, 2H, 21-H), 1.31−1.26 (m, 20H, 11-H to 20-H), 1.19 (d, J = 6.3 Hz, 3H, 1-H), 0.90 (s, 9H, TBS), 0.056 (s, 6H, TBS); 13C NMR (125 MHz, CDCl3) δ 138.0, 132.7, 130.3, 128.9, 128.4, 127.8, 127.6, 126.3, 92.7, 72.9, 69.3, 63.3, 40.1, 32.9, 32.8, 29.7, 29.7, 29.6, 29.6, 29.6, 29.5, 29.5, 29.4, 29.3, 25.8, 27.3, 27.2, 26.0, 19.9, 18.4, −5.28; HRMS (ESI/ TOF) m/z [M + Na]+ calcd for C36H64O3SiNa 595.4517, found 595.4527.

(21S,14Z,18E)-21-Benzyloxymethoxydocosa-14,18-dien-1-ol (14). To a cooled (0 °C) solution of the silyl ether (757 mg, 1.32 mmol) in THF (13.2 mL) was added TBAF (1.0 M in THF, 4.0 mL, 3.96 mmol), and the mixture was stirred at room temperature for 3 h. After the completion of the reaction, the reaction was quenched with saturated aqueous sodium hydrogencarbonate at 0 °C. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/ ethyl acetate = 5/1) to afford the alcohol (596 mg, 98%): [α]26 D −3.93 (c 0.71, CHCl3); IR (neat) 3410, 2924, 2854 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 5H, BOM), 5.53−5.31 (m, 4H, 14H,15-H, 18-H, 19-H), 4.80 (q, J = 7.3 Hz, 2H, BOM), 4.62 (dd, J = 11.7, 15.2 Hz, 2H, BOM), 3.80 (sx, J = 6.3 Hz, 1H, 21-H), 3.63 (t, J = 6.6 Hz, 2H, 1-H), 2.31−2.25 (m, 1H, 20-H), 2.19−2.14 (m, 1H, 20H), 2.10−2.05 (m, 4H, 16-H,17-H), 2.02−1.98 (m, 2H, 13-H), 1.56 (qn, J = 6.0 Hz, 2H, 2-H), 1.33−1.26 (m, 20H, 3-H to 12-H), 1.18 (d, J = 6.3 Hz, 3H, 22-H); 13C NMR (125 MHz, CDCl3) δ 138.0, 132.7, 130.3, 128.9, 128.4, 127.8, 127.6, 126.3, 92.7, 72.9, 69.3, 63.0, 40.0, 32.8, 29.7, 29.7, 29.6, 29.6, 29.6, 29.6, 29.6, 29.5, 29.4, 29.3, 25.7, 27.2, 27.2, 19.9; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C30H50O3Na 481.3652, found 481.3644. (21S,14Z,18E)-21-Benzyloxymethoxydocosa-14,18-dienal (15). To a cooled (0 °C) solution of the alcohol (566 mg, 1.23 mmol) in dichloromethane (9.9 mL) and DMSO (2.5 mL) were added Et3N (1.38 mL, 9.88 mmol) and SO3·Py (786 mg, 4.94 mmol). After the solution was stirred at room temperature for 3 h, the reaction mixture was quenched with saturated aqueous ammonium chloride at 0 °C. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/diethyl ether = 10/1) to afford the aldehyde (483 mg, 86%): −1 1 [α]25 D −3.36 (c 0.96, CHCl3); IR (neat) 2924, 2854, 1728 cm ; H NMR (500 MHz, CDCl3) δ 9.76 (t, J = 1.7 Hz, 1H, 1-H), 7.35−7.27 (m, 5H, BOM), 5.53−5.31 (m, 4H, 14-H, 15-H, 18-H, 19-H), 4.80 (q, J = 7.3 Hz, 2H, BOM), 4.62 (dd, J = 11.7, 15.2 Hz, 2H, BOM), 3.80 (sx, J = 6.5 Hz, 1H, 21-H), 2.41 (td, J = 1.9, 7.3 Hz, 2H, 3-H), 2.31− 2.26 (m, 1H, 20-H), 2.19−2.14 (m, 1H, 20-H), 2.10−2.05 (m, 4H, 16H, 17-H), 2.02−1.98 (m, 2H, 13-H), 1.62 (qn, J = 7.0 Hz, 2H, 2-H), 1.30−1.27 (m, 18H, 4-H to 12-H), 1.18 (d, J = 6.3 Hz, 3H, 22-H); 13C NMR (125 MHz, CDCl3) δ 202.9, 138.0, 132.7, 130.3, 128.9, 128.4, 127.8, 127.6, 126.3, 92.7, 72.9, 69.2, 43.9, 40.0, 32.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.3, 29.1, 27.2, 27.2, 22.0, 19.9; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C30H48O3Na 479.3496, found 479.3484. (3R,16Z,20E,23S)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienthioate (16). To a solution of Sn(OTf)2 (218 mg, 0.522 mmol) in dichloromethane (4.0 mL) were added solutions of (S)-1methyl-2-(1-naphthylaminomethyl)pyrrolidine (137 mg, 0.567 mmol) in dichloromethane (1.0 mL) and nBu3SnF (161 mg, 0.522 mmol), respectively. The mixture was cooled to −78 °C. To the reaction mixture were added solutions of KSA (92 mg, 0.522 mmol) in dichloromethane (1.0 mL) and the aldehyde (159 mg, 0.348 mmol) in dichloromethane (1.0 mL) at −78 °C, successively. The mixture was stirred for 1 h at that temperature and then quenched with saturated aqueous sodium hydrogencarbonate. After filtration through a pad of Celite, the organic layer was separated and the aqueous layer was extracted with dichloromethane three times. The combined organic layer was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 5/1) to afford the aldol product (142 mg, 73%, dr = 94/6): [α]27 D −10.8 (c 1.01, CHCl3); IR (neat) 3433, 2924, 2854, 1682 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 5H, BOM), 5.53−5.31 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.79 (q, J = 7.3 Hz, 2H, BOM), 4.62 (dd, J = 12.0, 14.9 Hz, 2H, BOM), 4.06−4.02 (m, 1H, 3-H), 3.80 (sx, J = 6.1 Hz, 1H, 23-H), 2.90 (q, J = 7.4 Hz, 2H, Et), 2.74 (dd, J = 3.4, 15.5 Hz, 1H, 2-H), 2.65 (dd, J = 8.5, 15.5 Hz, 1H, 2-H), 2.31−2.25 (m, 1H, 22-H), 2.19−2.14 (m, 1H, 22-H), 2.10−2.05 (m, 4H, 18-H, 19-H), 2.02−1.98 7894

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

Article

The Journal of Organic Chemistry

(500 MHz, CDCl3) δ 5.53−5.32 (m, 4H, 16-H, 17-H, 20-H, 21-H), 5.00 (td, J = 6.1, 12.2 Hz, 1H, 23-H), 3.98 (m, 1H, 3-H), 2.49 (dd, J = 3.4, 16.0 Hz, 1H, 2-H), 2.39 (dd, J = 8.0, 16.0 Hz, 1H, 2-H), 2.32− 2.19 (m, 2H, 22-H), 2.09−2.00 (m, 6H, 15-H, 18-H, 19-H), 1.55−1.28 (m, 22H, 4-H to 14H), 1.23 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 172.4, 133.6, 130.4, 128.9, 125.0, 70.7, 68.2, 41.3, 39.0, 36.0, 32.8, 29.1, 29.2, 28.5, 28.4, 28.3, 28.1, 28.1, 28.0, 27.8, 27.1, 26.8, 24.4, 19.5; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H42O3Na 401.3026, found 401.3024. (3R,16Z,20E,23S)-Eushearilide. According to the same process as 1, (3R,16Z,20E,23S)-eushearilide was obtained (12.2 mg, 40%) from the corresponding alcohol: [α]27 D −10.5 (c 0.81, CH3OH); IR (neat) 3448, 2924, 2862, 1728 cm−1; 1H NMR (500 MHz, CD3OD) δ 5.54−5.32 (m, 4H, H-16, H-17, H-20, H-21), 4.88 (m, 1H, H-23), 4.54 (m, 1H, H-3), 4.26 (brs, 2H, H-25), 3.63 (m, 2H, H-26), 3.22 (s, 9H, H-27), 2.83 (dd, J = 3.4, 14.9 Hz, 1H, H-2), 2.51 (dd, J = 8.6, 14.9 Hz, 1H, H2), 2.28−2.19 (m, 2H, H-22), 2.11−2.03 (m, 6H, H-15, H-18, H-19), 1.65 (m, 2H, H-4), 1.43−1.31 (m, 20H, H-5 to H-13), 1.20 (d, J = 6.3 Hz, 3H, H-24); 13C NMR (125 MHz, CD3OD) δ 172.0, 134.7, 131.3, 130.2, 126.5, 74.1, 72.1, 67.6, 60.3, 54.7, 41.6, 40.2, 36.1, 33.9, 29.8, 29.7, 30.0, 27.5, 29.9, 29.7, 29.7, 29.6, 29.4, 29.2, 28.4, 25.4, 19.8; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C29H54NO6PNa 566.3581, found 566.3560. (3S,16Z,20E,23R)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienthioate (ent-16). [α]21 D +11.48 (c 1.00, CHCl3). (3S,16Z,20E,23R)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienoate (ent-17). [α]23 D +10.07 (c 1.00, CHCl3). (3S,16Z,20E,23R)-3,23-Dihydroxytetracosa-16,20-dienoic Acid (ent-18). [α]25 D +5.78 (c 0.40, CHCl3). (3S,16Z,20E,23R)-12. [α]20 D +26.7 (c 0.58, CHCl3). (3S,16Z,20E,23R)-Eushearilide. According to the same process as 1, (3S,16Z,20E,23R)-eushearilide was obtained (15.2 mg, 42%) from the corresponding alcohol: [α]20 D +10.5 (c 0.22, MeOH); IR (neat) 3433, 2924, 1720 cm−1; 1H NMR (500 MHz, CD3OD) δ 5.53−5.34 (m, 4H, H-16, H-17, H-20, H-21), 4.89 (m, 1H, H-23), 4.26 (m, 2H, H-25), 4.09 (m, 1H, H-3), 3.63 (m, 2H, H-26), 3.22 (s, 9H, H-27), 2.82 (dd, J = 4.6, 14.9 Hz, 1H, H-2), 2.51 (dd, J = 8.6, 14.0 Hz, 1H, H-2), 2.26 (m, 2H, H-22), 2.11−2.00 (m, 6H, H-15, H-18, H-19), 1.63 (m, 2H, H-4), 1.43−1.28 (m, 20H, H-5 to H-14), 1.20 (d, J = 6.3 Hz, 3H, H24); 13C NMR (125 MHz, CD3OD) δ 172.0, 134.7, 131.2, 130.2, 126.5, 76.7, 74.1, 71.4, 60.3, 54.7, 41.6, 40.2, 36.0, 33.9, 30.8, 30.0, 29.6, 29.8, 29.8, 29.7, 29.7, 29.4, 29.2, 28.4, 27.5, 25.4, 19.8; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C29H54NO6PNa 566.3581, found 566.3604. (3S,16Z,20E,23S)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienthioate (16′). To a solution of Sn(OTf)2 (423 mg, 1.01 mmol) in dichloromethane (9.1 mL) were added solutions of (R)-1-methyl-2-(1-naphthylaminomethyl)pyrrolidine (265 mg, 1.10 mmol) in dichloromethane (1.5 mL) and nBu3SnF (314 mg, 1.01 mmol), respectively. The mixture was cooled to −78 °C. To the reaction mixture were added solutions of KSA (179 mg, 1.01 mmol) in dichloromethane (1.5 mL) and the aldehyde (309 mg, 0.677 mmol) in dichloromethane (1.5 mL) at −78 °C, successively. The mixture was stirred for 2 h at that temperature and then quenched with saturated aqueous sodium hydrogencarbonate. After filtration through a pad of Celite, the organic layer was separated and the aqueous layer was extracted with dichloromethane three times. The combined organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate = 10/1) to afford the aldol product (307 mg, 81%, dr = 95/5): [α]25 D +5.17 (c 0.99, CHCl3); IR (neat) 3417, 2924, 2854, 1682 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 5H, BOM), 5.53−5.31 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.79 (q, J = 7.3 Hz, 2H, BOM), 4.62 (dd, J = 11.7, 15.2 Hz, 2H, BOM), 4.07−4.02 (m, 1H, 3-H), 3.80 (sx, J = 6.3 Hz, 1H, 23H), 2.90 (q, J = 7.4 Hz, 2H, Et), 2.74 (dd, J = 3.2, 15.8 Hz, 1H, 2-H), 2.65 (dd, J = 8.6, 15.5 Hz 1H, 2-H), 2.30−2.25 (m, 1H, 22-H), 2.19− 2.14 (m, 1H, 22-H), 2.09−2.04 (m, 4H, 18-H, 19-H), 2.02−1.98 (m, 2H, 15-H), 1.53−1.41 (m, 2H, 4-H), 1.31−1.26 (m, 23H, 5-H to 14H, Et), 1.18 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3)

(m, 2H, 15-H), 1.53−1.39 (m, 2H, 4-H), 1.33−1.24 (m, 23H, 5-H to 14-H, Et), 1.18 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 199.6, 138.0, 132.7, 130.3, 128.9, 128.4, 127.8, 127.6, 126.3, 92.8, 73.0, 69.3, 68.7, 50.7, 40.0, 36.6, 32.8, 29.7, 29.6, 29.6, 29.5, 29.5, 29.5, 29.3, 25.4, 27.2, 27.2, 23.3, 19.9, 14.6; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C34H56O4SNa 583.3792, found 583.3804. (3R,16Z,20E,23S)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienoate (17). To a cooled (0 °C) solution of the aldol (142 mg, 0.253 mmol) in ethanol (2.5 mL) were added iPr2NEt (0.18 mL, 1.01 mmol) and AgOCOCF3 (112 mg, 0.506 mmol). After the solution was stirred at room temperature for 5 h, the reaction mixture was filtered through Celite. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 4/1) to afford the desired product (131 mg, 95%): [α]26 D −10.9 (c 0.99, CHCl3); IR (neat) 3448, 2924, 2854, 1728 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 5H, BOM), 5.53−5.31 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.79 (q, J = 7.4 Hz, 2H, BOM), 4.62 (dd, J = 11.5, 15.5 Hz, 2H, BOM), 4.17 (q, J = 7.3 Hz, 2H, Et), 4.02−3.97 (m, 1H, 3-H), 3.80 (sx, J = 6.1, 1H, 23-H), 2.95 (d, J = 3.4 Hz, 1H, OH), 2.49 (dd, J = 2.9, 16.6 Hz, 1H, 2-H), 2.39 (dd, J = 8.9, 16.3 Hz, 1H, 2-H), 2.30−2.25 (m, 1H, 22-H), 2.19−2.14 (m, 1H, 22-H), 2.10−1.98 (m, 6H, 15-H, 18-H, 19-H), 1.55−1.41 (m, 2H, 4-H), 1.32−1.26 (m, 23H, 5-H to 14-H, Et), 1.18 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 173.1, 138.0, 132.6, 130.3, 128.9, 128.4, 127.8, 127.6, 126.3, 92.7, 72.9, 69.2, 68.0, 60.6, 41.3, 40.0, 36.5, 32.8, 29.7, 29.6, 29.6, 29.5, 29.5, 29.5, 29.3, 27.2, 27.1, 25.4, 19.9, 14.1; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C34H56O5Na 567.4020, found 567.4040. (3R,16Z,20E,23S)-3,23-Dihydroxytetracosa-16,20-dienoic Acid (18). A solution of the ester (131 mg, 0.240 mmol) in 2.0 M HCl (EtOH/HCl = 5/1, 4.8 mL) was stirred at room temperature for 16 h. After the starting material was consumed, 4.0 M aqueous LiOH was added at 0 °C. Distilled water (1.5 mL) was poured into the reaction mixture, followed by the addition of 4.0 M aqueous LiOH (0.12 mL, 0.481 mmol). The mixture was stirred at room temperature for 66 h, and 1.0 M aqueous HCl was added until the solution became acidic. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate five times. The combined organic layer was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, to the organic phase was added a 10% aqueous NaOH solution, and the phase was washed with ethyl acetate five times. The aqueous phase was separated, and a 1.0 M aqueous HCl solution was added; the phase was washed with ethyl acetate five times. The combined organic layers were washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, AcOH was removed under reduced pressure to afford the desired product (87.9 mg, 92%) as a white solid: mp 46.0−48.0 °C; [α]26 D −5.77 (c 1.20, CHCl3); IR (neat) 3379, 2916, 2854, 1689 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.57−5.30 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.04−4.00 (m, 1H, 3-H), 3.79 (sx, J = 6.1 Hz, 1H, 23-H), 2.57 (dd, J = 2.9, 16.6 Hz, 1H, 2-H), 2.47 (dd, J = 8.9, 16.3 Hz, 1H, 2-H), 2.23−2.18 (m, 1H, 22H), 2.12−1.99 (m, 5H, 22-H, 18-H, 19-H), 2.01 (q, J = 6.9 Hz, 2H, 15-H), 1.56−1.42 (m, 4H, 4-H, 5-H), 1.34−1.26 (m, 18H, 6-H to 14H), 1.19 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 177.0, 134.1, 130.5, 128.8, 126.1, 68.0, 67.3, 42.4, 41.0, 36.4, 32.7, 29.6, 29.6, 29.6, 29.6, 29.5, 29.5, 29.4, 29.2, 27.2, 27.0, 25.4, 22.4; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H44O4Na 419.3132, found 419.3139. (3R,16Z,20E,23S)-12. To a solution of MNBA (31 mg, 90.5 μmol) and DMAP (51 mg, 0.418 mmol) in dichloromethane (30 mL) at 40 °C was slowly added a solution of the seco -acid (27.6 mg, 69.6 μmol) in dichloromethane (5.0 mL) with a mechanically driven syringe over a 12 h period. After the mixture cooled to 0 °C, saturated aqueous sodium hydrogencarbonate was added. The organic layer was separated; the aqueous layer was extracted with dichloromethane, and the organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 3/ 1) to afford the desired macrolactone (22 mg, 84%): [α]21 D −27.0 (c 0.65, CHCl3); IR (neat) 34402, 2924, 2854, 1728 cm−1; 1H NMR 7895

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

Article

The Journal of Organic Chemistry δ 199.7, 138.0, 132.7, 130.3, 128.9, 128.4, 127.8, 127.6, 126.3, 92.7, 72.9, 69.3, 68.7, 50.6, 40.0, 36.5, 32.8, 29.7, 29.6, 29.6, 29.5, 29.5, 29.5, 29.3, 25.4, 27.2, 27.2, 23.4, 19.9, 14.6; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C34H56O4SNa 583.3792, found 583.3775. (3S,16Z,20E,23S)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienoate (17′). Author: To a cooled (0 °C) solution of 16′ (307 mg, 0.547 mmol) in ethanol (5.5 mL) was added iPr2NEt (0.382 mL, 2.19 mmol) and AgOCOCF3 (242 mg, 1.09 mmol). After the solution was stirred at room temperature for 6 h, the reaction mixture was filtered through Celite. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate = 4/1) to afford the desired product (284 mg, 95%): [α]25 D +3.35 (c 1.01, CHCl3); IR (neat) 3448, 2924, 2854, 1728 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 5H, BOM), 5.53−5.31 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.79 (q, J = 7.3 Hz, 2H, BOM), 4.62 (dd, J = 11.5, 15.5 Hz, 2H, BOM), 4.17 (q, J = 7.1 Hz, 3H, Et), 4.02−3.97 (m, 1H, 3-H), 3.80 (sx, J = 6.3, 1H, 23-H), 2.49 (dd, J = 2.9, 16.6 Hz, 1H, 2-H), 2.39 (dd, J = 9.2, 16.0 Hz, 1H, 2H), 2.30−2.25 (m, 1H, 22-H), 2.19−2.14 (m, 1H, 22-H), 2.11−1.98 (m, 6H, 15-H, 18-H, 19-H), 1.55−1.38 (m, 2H, 4-H), 1.32−1.26 (m, 23H, 5-H to 14-H, Et), 1.18 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 173.1, 138.0, 132.7, 130.3, 128.9, 128.4, 127.8, 127.6, 126.3, 92.7, 72.9, 69.2, 68.0, 60.6, 41.3, 40.0, 36.5, 32.8, 29.7, 29.6, 29.5, 29.5, 29.3, 27.3, 27.2, 25.4, 19.9, 14.1; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C34H56O5Na 567.4020, found 567.4037. (3S,16Z,20E,23S)-3,23-Dihydroxytetracosa-16,20-dienoic Acid (18′). A solution of the ester (33.7 mg, 0.062 mmol) in 2.0 M HCl (EtOH/HCl = 5/1 v/v) was stirred at room temperature for 16 h. After the starting material was consumed, 4.0 M aqueous LiOH was added at 0 °C. Distilled water (0.45 mL) was poured into the reaction mixture, followed by the addition of 4.0 M aqueous LiOH (0.03 mL, 0.124 mmol). The mixture was stirred at room temperature for 43 h, and 1.0 M aqueous HCl was added until the solution became acidic. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate five times. The combined organic layer was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, a 10% aqueous NaOH solution was added to the organic phase. The organic phase was washed with ethyl acetate five times; a 1.0 M aqueous HCl solution was added to the aqueous phase, and the water phase was washed with ethyl acetate five times. The combined organic layers were washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the desired product was obtained as a white solid (24.6 mg, quant): mp 44.5−45.2 °C; [α]22 D +8.35 (c 1.00, CHCl3); IR (neat) 3355, 2916, 2846, 1689 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.57−5.30 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.04−4.00 (m, 1H, 3-H), 3.79 (sx, J = 6.1 Hz, 1H, 23-H), 2.57 (dd, J = 2.9, 16.6 Hz, 1H, 2-H), 2.47 (dd, J = 8.9, 16.3 Hz, 1H, 2H), 2.23−2.18 (m, 1H, 22-H), 2.12−1.99 (m, 5H, 22-H, 18-H, 19-H), 2.01 (q, J = 6.9 Hz, 2H, 15-H), 1.56−1.42 (m, 4H, 4-H, 5-H), 1.34− 1.26 (m, 18H, 6-H to 14-H), 1.19 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 177.1, 134.1, 130.5, 128.9, 126.1, 68.0, 67.3, 42.4, 41.0, 36.4, 32.7, 29.6, 29.6, 29.6, 29.6, 29.5, 29.5, 29.4, 29.2, 27.2, 27.0, 25.4, 22.4; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H44O4Na 419.3132, found 419.3124. (3S,16Z,20E,23S)-12. To a solution of MNBA (23.0 mg, 0.067 mmol) and DMAP (37.7 mg, 0.309 mmol) in dichloromethane (20.6 mL) at rt was slowly added a solution of the seco acid (20.4 mg, 0.051 mol) in dichloromethane (5.1 mL) with a mechanically driven syringe over a 12 h period. After the mixture cooled to 0 °C, saturated aqueous sodium hydrogencarbonate was added. The organic layer was separated; the aqueous layer was extracted with dichloromethane, and the organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 3/ 1) to afford the desired macrolactone (14.0 mg, 72%): [α]27 D −14.10 (c 1.10, CHCl3); IR (neat) 34402, 2924, 2854, 1728 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.53−5.32 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.99 (td, J = 5.9, 12.0 Hz, 1H, 23-H), 3.94 (m, 1H, 3-H), 2.51 (dd, J = 4.0, 16.0 Hz, 1H, 2-H), 2.41 (dd, J = 7.4, 15.5 Hz, 1H, 2-H), 2.31− 2.19 (m, 2H, 22-H), 2.11−1.98 (m, 6H, 15-H, 18-H, 19-H), 1.53−1.27

(m, 22H, 4-H to 14H), 1.23 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 172.3, 133.6, 130.4, 128.9, 125.1, 70.7, 68.0, 41.5, 39.1, 35.9, 32.8, 29.2, 29.1, 28.5, 28.4, 28.3, 28.1, 28.1, 28.0, 27.8, 27.1, 27.0 (C15), 24.5, 19.7; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H42O3Na 401.3026, found 401.3024. (3S,16Z,20E,23S)-Eushearilide. According to the same process as 1, (3S,16Z,20E,23S)-eushearilide was obtained (17.4 mg, 45%) from the corresponding alcohol: [α]30 D +5.91 (c 0.80, CH3OH); IR (neat) 3433, 2924, 2862, 1720 cm−1; 1H NMR (500 MHz, CD3OD) δ 5.54−5.32 (m, 4H, H-16, H-17, H-20, H-21), 4.87 (m, 1H, H-23), 4.53 (m, 1H, H-3), 4.26 (brs, 2H, H-25), 3.62 (m, 2H, H-26), 3.21 (s, 9H, H-27), 2.82 (dd, J = 4.5, 14.5 Hz, 1H, H-2), 2.53 (dd, J = 8.0, 14.5 Hz, 1H, H2), 2.32−2.19 (m, 2H, H-22), 2.13−2.01 (m, 6H, H-15, H-18, H-19), 1.64 (m, 2H, H-4), 1.43−1.30 (m, 20H, H-5 to H-14), 1.20 (d, J = 6.3 Hz, 3H, H-24); 13C NMR (125 MHz, CD3OD) δ 171.8, 134.8, 131.3, 130.3, 126.4, 74.1, 72.2, 67.5, 60.3, 54.7, 42.0, 40.1, 36.0, 33.8, 29.8, 29.8, 30.0, 27.5, 29.9, 29.8, 29.7, 29.7, 29.4, 29.2, 28.4, 25.4, 19.7; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C29H54NO6PNa 566.3581, found 566.3590. (3R,16Z,20E,23R)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienthioate (ent-16′). [α]20 D −4.76 (c 1.01, CHCl3). (3R,16Z,20E,23R)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetraco20 sa-16,20-dienoate (ent-17′). [α]D −4.17 (c 1.13, CHCl3). (3R,16Z,20E,23R)-3,23-Dihydroxytetracosa-16,20-dienoic acid (ent-18′). [α]26 D −9.59 (c 0.89, CHCl3). (3R,16Z,20E,23R)-12. [α]20 D −13.3 (c 1.06, CHCl3). (3R,16Z,20E,23R)-Eushearilide. According to the same process as 1, (3R,16Z,20E,23R)-eushearilide was obtained (37.0 mg, 68%) from the corresponding alcohol: [α]20 D −7.2 (c 0.94, CH3OH); IR (neat) 3402, 2924, 1720 cm−1; 1H NMR (500 MHz, CD3OD) δ 5.50−5.32 (m, 4H, H-16, H-17, H-20, H-21), 4.89 (m. 1H, H-23), 4.54 (m, 1H, H-3), 4.26 (brs, 2H, H-25), 3.63 (m, 2H, H-26), 3.22 (s, 9H, H-27), 2.82 (dd, J = 4.0, 14.3 Hz, 1H, H-2), 2.53 (dd, J = 8.6, 14.3 Hz, 1H, H-2), 2.25 (dd, J = 6.9, 13.2 Hz, 1H, H-22), 2.23 (dd, J = 6.9, 13.2 Hz, 1H, H-22), 2.12−2.02 (m, 6H, H-15, H-18, H-19), 1.65 (m, 2H, H-4), 1.49−1.28 (m, 20H, H-5 to H-14), 1.20 (d, J = 6.3 Hz, 3H, H-24); 13C NMR (125 MHz, CD3OD) δ 171.7, 134.8, 131.2, 130.2, 126.4, 74.1, 72.2, 67.4, 60.3, 54.6, 42.0, 40.1, 36.0, 33.8, 30.0, 29.9, 29.8, 29.7, 29.6, 29.4, 29.2, 29.8, 29.7, 28.3, 27.5, 25.3, 19.6; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C29H54NO6PNa 566.3581, found 566.3592. (4E,7R)-7-((Benzyloxy)methoxy)oct-4-enal (ent-3). [α]26 D +5.27 (c 0.97, CHCl3). (2R,4E,8E)-14-tert-Butyldimethylsilyloxy-2-benzyloxymethoxydocosa-4,8-diene (ent-5). [α]20 D +4.39 (c 1.04, CHCl3). (21R,14E,18E)-21-Benzyloxymethoxydocosa-14,18-dien-1-ol (ent-6). [α]20 D + 4.29 (c 1.05, CHCl3). (21R,14E,18E)-21-Benzyloxymethoxydocosa-14,18-dienal (ent-7). [α]20 D +4.78 (c 1.02, CHCl3). (3R,16E,20E,23R)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienthioate (ent-9). [α]20 D −4.89 (c 1.01, CHCl3). (3R,16E,20E,23R)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienoate (ent-10). [α]20 D −5.16 (c 1.00, CHCl3). (3R,16E,20E,23R)-3,23-Dihydroxytetracosa-16,20-dienoic Acid (ent-11). [α]25 D −11.02 (c 1.00, CHCl3). (3R,16E,20E,23R)-12. [α]20 D +14.2 (c 1.03, CHCl3). (3R,16E,20E,23R)-Eushearilide. According to the same process as 1, (3R,16E,20E,23R)-eushearilide was obtained (9.7 mg, 45%) from the corresponding alcohol: [α]20 D −10.9 (c 0.71, CH3OH); IR (neat) 3432, 2954, 2537, 2090, 1728 cm−1; 1H NMR (500 MHz, CD3OD) δ 5.52− 5.36 (m, 4H, H-16, H-17, H-20, H-21), 4.87 (m, 1H, H-23), 4.54 (m, 1H, H-3), 4.27 (brs, 2H, H-25), 3.63 (m, 2H, H-26), 3.22 (s, 9H, H27), 2.82 (dd, J = 4.0, 14.0 Hz, 1H, H-2), 2.54 (dd, J = 8.6, 14.0 Hz, 1H, H-2), 2.31−2.19 (m, 2H, H-22), 2.07 (brs, 4H, H-18, H-19), 2.00 (d, J = 4.6 Hz, 2H, H-15), 1.65 (m, 2H, H-4), 1.40−1.30 (m, 20H, H-5 to H-14), 1.19 (d, J = 6.3 Hz, 3H, H-24); 13C NMR (125 MHz, CD3OD) δ 171.7, 134.7, 131.8, 131.2, 126.5, 74.1, 72.3, 67.5, 60.4, 54.7, 41.9, 40.0, 36.1, 33.9, 33.6, 32.7, 30.1, 29.5, 29.8, 29.7, 29.7, 29.6, 29.4, 29.2, 28.5, 25.4, 19.7; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C29H54NO6PNa 566.3581, found 566.3592. (3S,16E,20E,23R)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienthioate (ent-9′). [α]28 D +20.0 (c 0.99, CHCl3). 7896

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

Article

The Journal of Organic Chemistry

25.4, 19.9, 14.1; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C34H56O5Na 567.4020, found 567.4012. (3R,16E,20E,23S)-3,23-Dihydroxytetracosa-16,20-dienoic Acid (11′). A solution of the hydroxyester (140 mg, 0.257 mmol) in 2.0 M HCl (EtOH/HCl = 5/1, 5.1 mL) was stirred at room temperature for 37 h. After the starting material was consumed, 4.0 M aqueous LiOH was added at 0 °C. Distilled water (1.8 mL) was poured into the reaction mixture, followed by the addition of 4.0 M aqueous LiOH (0.13 mL, 0.514 mmol). The mixture was stirred at room temperature for 26 h, and 1.0 M aqueous HCl was added until the solution became acidic. The organic layer was separated,and the aqueous layer was extracted with ethyl acetate five times. The combined organic layer was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, to the organic phase was added a 10% aqueous NaOH solution, and the phase was washed with ethyl acetate five times. The aqueous phase was separated; a 1.0 M aqueous HCl solution was added, and the phase was washed with ethyl acetate five times. The combined organic layers were washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, AcOH was removed under reduced pressure to afford the desired product (96.4 mg, 95%) as a white solid: mp 69.0−75.0 °C; [α]26 D −4.59 (c 1.20, CHCl3); IR (neat) 3386, 2916, 2846, 1689 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.55−5.35 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.03 (brs, 1H, 3-H), 3.78 (sx, J = 6.2 Hz, 1H, 23-H), 2.57 (dd, J = 1.7, 16.0 Hz, 1H, 2-H), 2.47 (dd, J = 9.2, 16.6 Hz, 1H, 2-H), 2.23−2.18 (m, 1H, 22-H), 2.11−2.06 (m, 5H, 22-H, 18-H, 19-H), 1.96 (q, J = 6.7 Hz, 2H, 15-H), 1.56−1.44 (m, 4H, 4-H, 5-H), 1.34−1.26 (m, 18H, 6-H to 14H), 1.19 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 177.1, 134.2, 131.1, 129.4, 126.0, 68.0, 67.3, 42.4, 41.0, 36.4, 32.7, 32.5, 32.5, 29.6, 29.5, 29.5, 29.4, 29.1, 25.4, 22.4; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H44O4Na 419.3132, found 419.3135. (3R,16E,20E,23S)-12. To a solution of MNBA (31.3 mg, 90.8 μmol) and DMAP (51.2 mg, 0.419 mmol) in dichloromethane (30 mL) at 40 °C was slowly added a solution of the seco acid (27.7 mg, 69.8 μmol) in dichloromethane (5.0 mL) with a mechanically driven syringe over a 12 h period. After the mixture was cooled to 0 °C, saturated aqueous sodium hydrogencarbonate was added. The organic layer was separated; the aqueous layer was extracted with dichloromethane, and the organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 3/ 1) to afford the product (21.4 mg, 81%): [α]28 D −18.3 (c 1.10, CHCl3); IR (neat) 3417, 2924, 2854, 1728 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.52−5.34 (m, 4H, 16-H, 17-H, 20-H, 21-H), 5.00 (td, J = 12.3, 6.1 Hz, 1H, 23-H), 3.96 (m, 1H, 3-H), 2.48 (dd, J = 3.4, 16.0 Hz, 1H, 2H), 2.38 (dd, J = 8.3, 15.8 Hz, 1H, 2-H), 2.32−2.18 (m, 2H, 22-H), 2.04 (br s, 4H, 18-H, 19-H), 1.99 (dd, J = 5.7, 10.9 Hz, 2H, 15-H), 1.55−1.27 (m, 22 H, 4-H to 14-H), 1.24 (d, J = 6.0 Hz, 3H, 24-H); 13 C NMR (500 MHz, CDCl3) δ 172.4, 133.6, 130.8, 129.8, 125.2, 70.7, 68.1, 41.6, 39.1, 36.1, 32.9, 32.6, 32.0, 28.6, 28.5, 28.4, 28.2, 28.2, 28.2, 28.1, 28.0, 27.5, 24.9, 19.7; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C24H42O3Na 401.3026, found 401.3018. (3R,16E,20E,23S)-Eushearilide. According to the same process as 1, (3R,16E,20E,23S)-eushearilide was obtained (11.0 mg, 36%) from the corresponding alcohol: [α]26 D −11.2 (c 0.73, CH3OH); IR (neat) 3433, 2924, 2854, 1720 cm−1; 1H NMR (500 MHz, CD3OD) δ 5.51−5.36 (m, 4H, H-16, H-17, H-20, H-21), 4.88 (m, 1H, H-23), 4.55 (m, 1H, H-3), 4.26 (brs, 2H, H-25), 3.63 (m, 2H, H-26), 3.22 (s, 9H, H-27), 2.82 (dd, J = 4.5, 15.5 Hz, 1H, H-2), 2.52 (dd, J = 8.5, 14.5 Hz, 1H, H2), 2.28−2.19 (m, 2H, H-22), 2.06 (brs, 4H, H-18, H-19), 2.00 (d, J = 5.5 Hz, 2H, H-15), 1.65 (m, 2H, H-4), 1.42−1.30 (m, 20H, H-5 to H14), 1.20 (d, J = 6.3 Hz, 3H, H-24); 13C NMR (125 MHz, CD3OD) δ 172.0, 134.6, 131.8, 131.2, 126.6, 74.1, 72.0, 67.6, 60.3, 54.7, 41.5, 40.1, 36.2, 34.0, 33.7, 32.7, 30.1, 29.5, 29.8, 29.8, 29.7, 29.6, 29.3, 29.2, 28.4, 25.4, 19.8; HRMS (ESI/TOF) m/z [M + Na] + calcd for C29H54NO6PNa 566.3581, found 566.3588. In Vitro Antimicrobial Assay. The antimicrobial assay against various fungi and bacteria was performed using the disk-diffusion method according to the Clinical and Laboratory Standards (CLSI)

(3S,16E,20E,23R)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienoate (ent-10′). [α]27 D +10.4 (c 1.02, CHCl3). (3S,16E,20E,23R)-3,23-Dihydroxytetracosa-16,20-dienoic Acid (ent-11′). [α]26 D +5.01 (c 1.00, CHCl3). (3S,16E,20E,23R)-12. [α]20 D +21.6 (c 1.08, CHCl3). (3S,16E,20E,23R)-Eushearilide. According to the same process as 1, (3S,16E,20E,23R)-eushearilide was obtained (10.6 mg, 38%) from the corresponding alcohol: [α]27 D +9.42 (c 0.71, CH3OH); IR (neat) 3410, 2924, 2854, 1720 cm−1; 1H NMR (500 MHz, CD3OD) δ 5.51−5.36 (m, 4H, H-16, H-17, H-20, H-21), 4.89 (m, 1H, H-23), 4.53 (m, 1H, H-3), 4.25 (brs, 2H, H-25), 3.62 (m, 2H, H-26), 3.21 (s, 9H, H-27), 2.81 (dd, J = 4.9, 15.2 Hz, 1H, H-2), 2.51 (dd, J = 8.6, 14.3 Hz, 1H, H2), 2.28−2.19 (m, 2H, H-22), 2.06 (brs, 4H, H-18, H-19), 1.99 (m, 2H, H-15), 1.65 (dd, J = 6.3 Hz, 2H, H-4), 1.41−1.29 (m, 20H, H-5 to H-14), 1.20 (d, J = 5.7 Hz, 3H, H-24); 13C NMR (125 MHz, CD3OD) δ 172.0, 134.6, 131.8, 131.2, 126.6, 74.1, 72.0, 67.5, 60.3, 54.7, 41.5, 40.1, 36.1, 34.0, 33.7, 32.7, 30.1, 29.5, 29.8, 29.8, 29.7, 29.6, 29.3, 29.2, 28.4, 25.4, 19.8; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C29H54NO6PNa 566.3581, found 566.3558. (3R,16E,20E,23S)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienthioate (9′). To a solution of Sn(OTf)2 (205 mg, 0.493 mmol) in dichloromethane (4.0 mL) were added solutions of (S)-1-methyl-2-(1-naphthylaminomethyl)pyrrolidine (129 mg, 0.535 mmol) in dichloromethane (1.0 mL) and nBu3SnF (152 mg, 0.493 mmol), respectively. The mixture was cooled to −78 °C. To the reaction mixture were added solutions of KSA (87 mg, 0.493 mmol) in dichloromethane (1.0 mL) and the aldehyde (150 mg, 0.328 mmol) in dichloromethane (1.0 mL) at −78 °C, successively. The mixture was stirred for 12 h at that temperature and then quenched with saturated aqueous sodium hydrogencarbonate. After filtration through a pad of Celite, the organic layer was separated and the aqueous layer was extracted with dichloromethane three times. The combined organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 5/1) to afford the aldol product (154 mg, 83%, dr = 94.5/5.5): [α]25 D −16.4 (c 0.99, CHCl3); IR (neat) 3433, 2939, 2854, 1635 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 5H, BOM), 5.52−5.34 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.79 (q, J = 7.3 Hz, 2H, BOM), 4.62 (dd, J = 11.5, 15.5 Hz, 2H, BOM), 4.06−4.02 (m, 1H, 3-H), 3.80 (sx, J = 6.3 Hz, 1H, 23H), 2.90 (q, J = 7.4 Hz, 2H, Et), 2.73 (dd, J = 3.2, 15.8 Hz, 1H, 2-H), 2.65 (dd, J = 8.6, 16.0 Hz 1H, 2-H), 2.30−2.25 (m, 1H, 22-H), 2.18− 2.13 (m, 1H, 22-H), 2.04 (brs, 4H, 18-H, 19-H), 1.97−1.94 (m, 2H, 15-H), 1.53−1.41 (m, 2H, 4-H), 1.33−1.24 (m, 23H, 5-H to 14-H, Et), 1.17 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 199.7, 138.0, 132.7, 130.8, 129.4, 128.4, 127.8, 127.6, 126.2, 92.8, 73.0, 69.2, 68.7, 50.6, 32.8, 32.6, 32.5, 29.6, 29.6, 29.6, 29.5, 29.5, 29.5, 29.5, 29.1, 25.4, 23.3, 19.9, 14.6; HRMS (ESI/TOF) m/z [M + Na]+ calcd for C34H56O4SNa 583.3792, found 583.3804. (3R,16E,20E,23S)-Ethyl 23-Benzyloxymethoxy-3-hydroxytetracosa-16,20-dienoate (10′). To a cooled (0 °C) solution of the thioester (153 mg, 0.273 mmol) in EtOH (2.7 mL) were added iPr2NEt (0.19 mL, 1.09 mmol) and AgOCOCF3 (121 mg, 546 mmol). After the solution was stirred at room temperature for 4 h, the reaction mixture was filtered through Celite. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 4/1) to afford the product (141 mg, 95%): −1 [α]25 D −8.97 (c 1.02, CHCl3); IR (neat) 3440, 2924, 2862, 1728 cm ; 1 H NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 5H, BOM), 5.52−5.34 (m, 4H, 16-H, 17-H, 20-H, 21-H), 4.79 (q, J = 7.1 Hz, 2H, BOM), 4.62 (dd, J = 11.5, 15.5 Hz, 2H, BOM), 4.17 (q, J = 7.3 Hz, 2H, Et), 4.01−3.98 (m, 1H, 3-H), 3.79 (sx, J = 6.3, 1H, 23-H), 2.94 (d, J = 4.0 Hz, 1H, OH), 2.49 (dd, J = 2.9, 16.6 Hz, 1H, 2-H), 2.39 (dd, J = 9.2, 16.6 Hz, 1H, 2-H), 2.30−2.25 (m, 1H, 22-H), 2.18−2.13 (m, 1H, 22H), 2.04 (brs, 4H, 18-H, 19-H), 1.99−1.94 (m, 2H, 15-H), 1.55−1.38 (m, 2H, 4-H), 1.32−1.25 (m, 23H, 5-H to 14-H, Et), 1.17 (d, J = 6.3 Hz, 3H, 24-H); 13C NMR (125 MHz, CDCl3) δ 173.1, 138.0, 132.7, 130.8, 129.5, 128.4, 127.8, 127.6, 126.2, 92.8, 73.0, 69.2, 68.0, 60.6, 41.3, 40.0, 36.4, 32.8, 32.6, 32.5, 29.6, 29.6, 29.6, 29.6, 29.5, 29.5, 29.2, 7897

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

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The Journal of Organic Chemistry guidelines.18 Details of the assay method are described in the Supporting Information.

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Kubota, M.; Oshiumi, H.; Hashizume, M. An Effective Use of Benzoic Anhydride and Its Derivatives for the Synthesis of Carboxylic Esters and Lactones: A Powerful and Convenient Mixed Anhydride Method Promoted by Basic Catalysts. J. Org. Chem. 2004, 69, 1822−1830. (9) For reviews, see: (a) Shiina, I. An Adventurous Synthetic Journey with MNBA from Its Reaction Chemistry to the Total Synthesis of Natural Products. Bull. Chem. Soc. Jpn. 2014, 87, 196−233. (b) Shiina, I. Total Synthesis of Natural 8- and 9-Membered Lactones: Recent Advancements in Medium-Sized Ring Formation. Chem. Rev. 2007, 107, 239−273. (10) For recent examples of the MNBA-mediated condensation used in total synthesis by other research groups, see: (a) Schweitzer, D.; Kane, J. J.; Strand, D.; McHenry, P.; Tenniswood, M.; Helquist, P. Total Synthesis of Iejimalide B. An Application of the Shiina Macrolactonization. Org. Lett. 2007, 9, 4619−4622. (b) Goodreid, J. D.; dos Santos, E. d. S.; Batey, R. A. A Lanthanide(III) Triflate Mediated Macrolactonization/Solid-Phase Synthesis Approach for Depsipeptide Synthesis. Org. Lett. 2015, 17, 2182−2185. (c) Manaviazar, S.; Nockemann, P.; Hale, K. J. Total Synthesis of the GRP78Downregulatory Macrolide (+)-Prunustatin A, the Immunosuppressant (+)-SW-163A, and a JBIR04 Diastereoisomer That Confirms JBIR-04 Has Nonidentical Stereochemistry to (+)-Prunustatin A. Org. Lett. 2016, 18, 2902−2905. (d) Nicolaou, K. C.; Pulukuri, K. K.; Rigol, S.; Heretsch, P.; Yu, R.; Grove, C. I.; Hale, C. R. H.; ElMarrouni, A.; Fetz, V.; Brönstrup, M.; Aujay, M.; Sandoval, J.; Gavrilyuk, J. Synthesis and Biological Investigation of Δ12-Prostaglandin J3 (Δ12-PGJ3) Analogues and Related Compounds. J. Am. Chem. Soc. 2016, 138, 6550−6560. (e) Yahata, K.; Ye, N.; Iso, K.; Naini, S. R.; Yamashita, S.; Ai, Y.; Kishi, Y. Unified Synthesis of Right Halves of Halichondrins A− C. J. Org. Chem. 2017, 82, 8792−8807. (11) For the preparation of PT sulfone 4, a synthetic scheme is provided in the Supporting Information. (12) (a) de Haan, J. W.; van de Ven, L. J. M. Configurations and Conformations in Acyclic, Unsaturated Hydrocarbons. A 13C NMR Study. Org. Magn. Reson. 1973, 5, 147−153. (b) Lee, Y.; Jang, K. H.; Jeon, J.; Yang, W.-Y.; Sim, C. J.; Oh, K.-B.; Shin, J. Cyclic Bis-1,3dialkylpyridiniums from the Sponge Haliclona sp. Mar. Drugs 2012, 10, 2126−2137. (c) Damodaran, V.; Ryan, J. L.; Keyzers, R. A. Cyclic 3-Alkyl Pyridinium Alkaloid Monomers from a New Zealand Haliclona sp. Marine Sponge. J. Nat. Prod. 2013, 76, 1997−2001. (d) Czajkowska-Szczykowska, D.; Jastrzebska, I.; Santillan, R.; Morzycki, J. W. The Synthesis of Disteroidal Macrocyclic Molecular Rotors by an RCM Approach. Tetrahedron 2014, 70, 9427−9435. (13) (a) Mukaiyama, T.; Kobayashi, S.; Uchiro, H.; Shiina, I. Catalytic Asymmetric Aldol Reaction of Silyl Enol Ethers with Aldehydes by the Use of Chiral Diamine Coordinated Tin(II) Triflate. Chem. Lett. 1990, 19, 129−132. (b) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, I.; Mukaiyama, T. Asymmetric Aldol Reaction between Achiral Silyl Enol Ethers and Achiral Aldehydes by Use of a Chiral Promoter System. J. Am. Chem. Soc. 1991, 113, 4247−4252. (c) Shiina, I. Asymmetric Mukaiyama Aldol Reactions Using Chiral Diamine−Coordinated Sn(II) Triflate: Development and Application to Natural Product Synthesis. Chem. Rec 2014, 14, 144−183. (14) The experimental details including full characterization data of the β-lactone obtained are described in the Experimental Section. In addition, no formation of β-lactone was observed in the following syntheses: (a) Doi, T.; Iijima, Y.; Shin-ya, K.; Ganesan, A.; Takahashi, T. A Total Synthesis of Spiruchostatin A. Tetrahedron Lett. 2006, 47, 1177−1180. (b) Benelkebir, H.; Donlevy, A. M.; Packham, G.; Ganesan, A. Total Synthesis and Stereochemical Assignment of Burkholdac B, a Depsipeptide HDAC Inhibitor. Org. Lett. 2011, 13, 6334−6337. (15) Qin, D.; Byun, H.-S.; Bittman, R. Synthesis of Plasmalogen via 2,3-Bis-O-(4′-methoxybenzyl)-sn-glycerol. J. Am. Chem. Soc. 1999, 121, 662−668. (16) Tago, K.; Arai, M.; Kogen, H. A Practical Total Synthesis of Plaunotol via Highly Z-Selective Wittig Olefination of α-Acetal Ketones. J. Chem. Soc., Perkin Trans. 2000, 1, 2073−2078.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00774. Syntheses of compounds, in vitro evaluation of the antimicrobial activity of eushearilide, and copies of 1H and 13C NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Isamu Shiina: 0000-0002-8749-2540 Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Hosoe, T.; Fukushima, K.; Takizawa, K.; Itabashi, T.; Kawahara, N.; Vidotto, V.; Kawai, K. A New Antifungal Macrolide, Eushearilide, Isolated from Eupenicillium shearii. J. Antibiot. 2006, 59, 597−600. (2) For a review on polyene macrolide antibiotics, see: Rychnovsky, S. D. Oxo Polyene Macrolide Antibiotics. Chem. Rev. 1995, 95, 2021− 2040. (3) Tonoi, T.; Kawahara, R.; Yoshinaga, Y.; Inohana, T.; Fujimori, K.; Shiina, I. Total Synthesis of (3R,16E,20E,23R)-(−)-Eushearilide and Structural Determination of Naturally Occurring Eushearilide. Tetrahedron Lett. 2015, 56, 1356−1359. (4) During our continuing studies on the synthesis of eushearilide, Higashiyama et al. reported the total synthesis of the proposed structures of eushearilides, (3R,16Z,20E,23S)- and (3R,16Z,20E,23R)eushearilide: Yamauchi, T.; Takidaira, J.; Okamoto, K.; Sugiura, T.; Horikoshi, H.; Kudo, S.; Sasaki, S.; Mizushima, N.; Higashiyama, K. Total Synthesis of the Proposed Structures of Eushearilide. Heterocycles 2014, 88, 1175−1189. (5) Tonoi, T.; Kawahara, R.; Inohana, T.; Shiina, I. Enantioselective Total Synthesis of Naturally Occurring Eushearilide and Evaluation of Its Antifungal Activity. J. Antibiot. 2016, 69, 697−701. (6) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. A Stereoselective Synthesis of trans-1,2-Disubstituted Alkenes Based on the Condensation of Aldehydes with Metallated 1-Phenyl-1H-tetrazol5-yl Sulfones. Synlett 1998, 1998, 26−28. For reviews, see: (b) Aïssa, C. Mechanistic Manifold and New Developments of the Julia− Kocienski Reaction. Eur. J. Org. Chem. 2009, 2009, 1831−1844. (c) Blakemore, P. R. The Modified Julia Olefination: Alkene Synthesis via the Condensation of Metallated Heteroarylalkylsulfones with Carbonyl Compounds. J. Chem. Soc., Perkin Trans. 2002, 1, 2563− 2585. (7) (a) Schlosser, M.; Christmann, K. F. Olefinierungen mit Phosphor-Yliden, I: Mechanismus und Stereochemie der Wittigreaktion. Liebigs Ann. Chem. 1967, 708, 1−35. (b) Schlosser, M.; Tuong, H. B.; Schaub, B. The Betaine-ylid Route to Trans-Alkenols. Tetrahedron Lett. 1985, 26, 311−314. (c) Wang, Q.; Deredas, D.; Huynh, C.; Schlosser, M. Sequestered Alkyllithiums: Why Phenyllithium Alone is Suitable for Betaine-Ylide Generation. Chem. - Eur. J. 2003, 9, 570−574. (8) (a) Shiina, I.; Ibuka, I.; Kubota, M. A New Condensation Reaction for the Synthesis of Carboxylic Esters from Nearly Equimolar Amounts of Carboxylic Acids and Alcohols Using 2-Methyl-6nitrobenzoic Anhydride. Chem. Lett. 2002, 31, 286−287. (b) Shiina, I.; Kubota, M.; Ibuka, R. A Novel and Efficient Macrolactonization of ω-Hydroxycarboxylic Acids Using 2-Methyl-6-Nitrobenzoic Anhydride (MNBA). Tetrahedron Lett. 2002, 43, 7535−7539. (c) Shiina, I.; 7898

DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899

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The Journal of Organic Chemistry (17) For the preparation of all stereoisomers of 12, precursors of 1 and synthetic schemes of their intermediates are provided in the Supporting Information. (18) (a) National Committee for Clinical Laboratory Standards: Standard methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standards, NCCLS: Villanova, 1983. (b) National Committee for Clinical Laboratory Standards: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 2nd ed.; Tentative standard, NCCLS: Villanova, 1988. (19) Wilke, B. I.; Dornan, M. H.; Yeung, J.; Boddy, C. N.; Pinto, A. Hexanes/Acetonitrile: A Binary Solvent System for the Efficient Monosilylation of Symmetric Primary and Secondary Diols. Tetrahedron Lett. 2014, 55, 2600−2602.

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DOI: 10.1021/acs.joc.8b00774 J. Org. Chem. 2018, 83, 7886−7899