Total Syntheses of 3 - ACS Publications

and Takao Saito. ‡*. †. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba,. 1-1-1 Tennodai, Tsukuba, Ibarak...
0 downloads 0 Views 981KB Size
Download PDF
Note pubs.acs.org/joc

Cite This: J. Org. Chem. 2018, 83, 11450−11457

Total Syntheses of 3-epi-Litsenolide D2 and Lincomolide A Noriki Kutsumura,*,†,‡ Akito Kiriseko,‡ Kentaro Niwa,‡ and Takao Saito*,‡ †

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan ‡ Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

J. Org. Chem. 2018.83:11450-11457. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/21/18. For personal use only.

S Supporting Information *

ABSTRACT: The first total syntheses of 3-epi-litsenolide D2 and its enantiomer lincomolide A were achieved. The synthetic highlights of our approach include olefin cross metathesis and bromine addition to the generated double bond, followed by the regioselective HBr-elimination and intramolecular carbonylation using bis(triphenylphosphine)dicarbonylnickel. This investigation also revealed that the previously reported specific optical rotation of 3-epi-litsenolide D2 should be revised.

I

8β, produced the desired vinyl bromide 9β.7 Deacetylation of 9β produced 10β, which was subsequently subjected to intramolecular carbonylation 8 using 2.0 equiv of bis(triphenylphosphine)dicarbonylnickel under harsh conditions that afforded the proposed structure of 1 in an 82% yield. The spectroscopic data (1H and 13C NMR, IR, and HRMS) obtained for our synthetically prepared compound 1 were completely identical with the previously reported data; however, the specific rotation, ([α]25D +107.2 (c 0.12, dioxane), [α]25D +100.7 (c 1.00, CHCl3)) was completely different from the reported value ([α]26D −69.8 (c 1.29, dioxane)).1 Further literature survey revealed that the enantiomer of 1, lincomolide A (11), was isolated from the stem bark of Lindera communis belonging to the Lauraceae family in 2001 by Tsai and coworkers and that its specific rotation was reported to be [α]25D −110 (c 0.45, CHCl3) (Figure 2).9 Regardless, 11 was determined to possess the (3S,4S)-configuration by performing the nuclear Overhauser effect spectroscopy (NOESY) experiment and by comparing with the literature data.2 These results indicated that the reported values for the specific rotation of 1, 11, or both 1 and 11 were inaccurate. To gain more insight into this issue, we reviewed the 1H NMR spectral data, especially the vinyl proton at the C6 position, and specific rotation of the related analogues that have been reported. This investigation revealed several reports on α,β′-conjugated γ-lactone derivatives bearing 3-hydroxy and 4-methyl groups, a small fraction of which has been depicted in Figure 3.2,9−15 Given the relationship between the structure and the physical property, two notable features can be observed that are as follows: (1) the chemical shifts of the vinyl protons at the C6 position clearly revealed that the exoalkene moiety of the γ-lactone derivatives can exhibit either the Z- or E-form. Namely, the protons in the Z-form geometry

n 2001, Lee and coworkers isolated 3-epi-Litsenolide D2 (1) from the root and stem of Alseodaphne andersonii, a large tree belonging the Lauraceae family that is indigenous to the Yunnan Province in China.1 As the structure of 1, the authors proposed an α,β′-conjugated γ-lactone substituted with the 3hydroxy and 4-methyl groups (Figure 1). The cis stereo-

Figure 1. Structural determination of 3-epi-litsenolide D2 (1).

chemistry between C-3 and C-4 was determined by the nuclear Overhauser effect (NOE) experiment, and the absolute stereochemistry at C-4 was deduced by comparison of the specific optical rotation value2 with that of 4α-methyl-2butenolide (2), which was obtained from 1 in three steps.1 3-epi-Litsenolide D2 (1) was reported to inhibit the HIV-1 replication in a green fluorescent protein-based reporter cell line (HOG.R5) with an IC50 value of 9.9 μM.3 With an objective to perform further biological tests and develop an effective strategy for the related γ-lactone derivatives, we initiated the synthetic study of 1, as depicted in Scheme 1. Our synthetic strategy for 1 was initiated from the known chiral diol 3,4 which was derived from the commercially available ethyl sorbate by Sharpless asymmetric dihydroxylation using 1 mol % of (DHQD)2PHAL as a chiral ligand (Scheme 1).5 The transformation of diol 3 into triacetate 5 proceeded via an intermediate triol 4. Further, olefin cross metathesis (CM) of 5 with 1-tridecene in the presence of 2,6dichloro-1,4-benzoquinone (6)6 and Hoveyda−Grubbs second generation catalyst produced diacetate 7β in 69% yield (E/Z = 3.6/1.0). Bromine addition to the obtained 7β, followed by the regioselective trans-HBr elimination of the resulting dibromide © 2018 American Chemical Society

Received: July 17, 2018 Published: August 13, 2018 11450

DOI: 10.1021/acs.joc.8b01825 J. Org. Chem. 2018, 83, 11450−11457

Note

The Journal of Organic Chemistry Scheme 1. Synthesis of 3-epi-Litsenolide D2 (1)

were conducted using 1-tridecene to improve the yield and the E selectivity (Table 1). Thus, the reaction of triacetate 5 with 1-tridecene in the presence of the Hoveyda−Grubbs second generation catalyst generated 7β in a yield of 69% with an E/Z selectivity of 3.6/1.0 (Scheme 1 and Table 1, entry 1). The CM reaction of the acetonide-protected 12 with 1-tridecene (15 equiv) produced complex mixtures (entry 2); however, by reducing the amount of 1-tridecene to 5 equiv and by adding 2,6-dichloro-1,4-benzoquinone (6, 0.1 equiv), only the desired acetonide 13 was obtained as the E-product, albeit in low yield (entry 3). The usage of the TIPS- or TBS-protected allyl alcohols 14 or 17β improved the yields and E selectivity of 15 and 18β (entries 4 and 6). Further, the reaction of sterically hindered di-TBS-protected allyl alcohol 16 did not progress under any conditions (entry 5). Eventually, an optimal result was obtained by employing 17α16 as the substrate for the total synthesis of 11; the reaction of 17α with 5 equiv of 1-tridecene using the Hoveyda−Grubbs second generation catalyst successfully generated the desired E-alkene 18α in a yield of 83% with high selectivity (E/Z = 12/1.0) (entry 7). Further, the obtained 18α was treated with TBAF to generate diol 19 in high yield (Scheme 2). Next, the steps of synthesizing 11 are similar to those of synthesizing 1 and are listed as follows: the acetylation of 19; bromine addition of 7α; regioselective HBr elimination7 of 8α; deacetylation of 9α; and intramolecular carbonylation8 of 10α. The spectroscopic data

Figure 2. Comparison of the specific rotation of 1 with that of the enantiomer 11.

ranged from 6.54 to 6.56 ppm (see litsenolides C1 and D1, 4epi-litsenolide C1, and licunolide A), whereas the protons in Eform geometry ranged from 6.93 to 7.01 ppm (Figures 2 and 3); (2) only the structures bearing a hydroxy group with Rconfiguration at the C3 position exhibited dextrorotatory specific rotation ([α]24D +77.1, see ent-isodihydromahubenolide B vs. all the others with S-configuration of levorotatory in Figure 3 and those in previous reports15). Therefore, it seems reasonable to conclude that we accomplished the total synthesis of 3-epi-litsenolide D2 (1) and that the reported specific rotation1 of 1 was inaccurate. To prove our hypothesis, we further tackled the synthesis of 11 to obtain its spectroscopic data. First, in-depth intermolecular olefin CM reactions for carbon elongation

Figure 3. Relationship between the structure and physical property in α,β′-conjugated γ-lactone derivatives bearing 3-hydroxy and 4-methyl groups. 11451

DOI: 10.1021/acs.joc.8b01825 J. Org. Chem. 2018, 83, 11450−11457

Note

The Journal of Organic Chemistry Table 1. Preliminary Screening for Olefin Cross Metathesis Conditions

entry

substrate

equiv

cat. (mol %)

1 2 3 4 5 6 7

5 12 12 14 16 17β 17α

3 15 5 15 2 5 5

HG2a (10) G2c (10) G2c (10) G2c (5) HG2a or G2c G2c (5) HG2a (5)

conditions 70 °C, 70 °C, 70 °C, rt, 8 h 40 °C 40 °C, 40 °C,

25 h to rt, 23 hb 9 h to rt, 15 h 7 h to rt, 90 hb

12 h to rt, 15 hd 6 h to rt, 15 hd

results 7β (69%, E/Z = 3.6/1.0), 5 (29%) complex mixtures 13 (25%, E-form only), 12 (13%) 15 (68%, E/Z = 9.0/1.0) no reaction 18β (82%, E/Z = 8.7/1.0) 18α (83%, E/Z = 12/1.0)

a

Hoveyda−Grubbs second-generation catalyst. b2,6-Dichloro-1,4-benzoquinone (6, 0.1 equiv) was added. cGrubbs second-generation catalyst. Dichloromethane was used as a solvent.

d

Scheme 2. Synthesis of Lincomolide A (11)

their analytical data of the compounds 3,4 12,17 22,17,18 23,19 and 17α20 have been reported. The structures of 20−23 and the NMR spectral data are shown in the Supporting Information. (4R,5R,E)-Hex-2-ene-1,4,5-triyl triacetate (5). A mixture of 3 (387 mg, 2.22 mmol) and DIBAL-H (11 mL, 11.2 mmol, 1.02 M in hexane) in THF (22 mL) was stirred at −78 °C for 5 h. After the addition of 30% potassium sodium tartrate aq. (10 mL) at 0 °C, the mixture was extracted with THF (20 mL × 2, 10 mL × 2), washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was partly purified by silica gel short-column chromatography (CHCl3/MeOH = 6/1) to afford a crude triol 4. Then, a mixture of 4, Ac2O (3.2 mL, 33.9 mmol), and DMAP (26.2 mg, 0.214 mmol) in pyridine (11 mL) was stirred at room temperature for 3 h. After the addition of 1 M HCl aq. (20 mL) at 0 °C, the mixture was extracted with EtOAc (10 mL × 3), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 2/1) to afford 5 (424 mg, 1.64 mmol, 74% in 2 steps) as a colorless oil. [α]25D +11.8 (c 1.00, CHCl3); IR (neat) 2985, 2939, 1743, 1227 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.20 (d, J = 6.5 Hz, 3H), 2.05 (s, 3H), 2.08 (s, 3H), 2.09 (s, 3H), 4.57 (dd, J = 5.7, 1.3 Hz, 2H), 5.04 (dq, J = 6.5, 6.5 Hz, 1H), 5.34 (ddd, J = 6.5, 6.5, 1.0 Hz, 1H), 5.68 (ddt, J = 15.6, 6.5, 1.3 Hz, 1H), 5.87 (dtd, J = 15.6, 5.7, 1.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 16.0 (CH3), 20.8 (CH3), 20.9 (CH3), 21.0 (CH3), 63.6 (CH2), 70.2 (CH), 74.4 (CH), 127.9 (CH), 129.0 (CH), 169.8 (C), 170.1 (C), 170.4 (C); HRMS-ESI: m/z [M + Na]+ calcd for C12H18O6Na: 281.0996, found 281.0997. (2R,3R,E)-Hexadec-4-ene-2,3-diyl diacetate (7β). A mixture of 5 (18.5 mg, 0.0716 mmol), 1-tridecene (35 μL, 0.147 mmol), 2,6dichloro-1,4-benzoquinone (6) (1.5 mg, 0.00848 mmol), and Hoveyda−Grubbs second generation catalyst (2.30 mg, 0.00367 mmol) in 1,2-dichloroethane (0.72 mL) was stirred at 70 °C for 13 h

(1H and 13C NMR, IR, and HRMS) and the specific rotation ([α]25D −93.7 (c 1.00, CHCl3)) of 11 were quite similar to those that have been previously reported (see Figure 2).9 In conclusion, we achieved the first total syntheses of 3-epilitsenolide D2 (1) and its enantiomer, lincomolide A (11). The two asymmetric centers, i.e. (3R,4R) in 1 and (3S,4S) in 11, were constructed by Sharpless asymmetric dihydroxylation of the commercially available ethyl sorbate. By performing a series of key reactions, including E-selective olefin cross metathesis, bromine addition, regioselective HBr elimination, and intramolecular carbonylation, the desired chiral αalkylidene γ-lactone skeletons bearing 3-hydroxy and 4-methyl groups were obtained in good yields. We believe that our synthetic procedure could be useful to complete the synthetic and biological studies of other related α-alkylidene γ-lactone derivatives.

■

EXPERIMENTAL SECTION

General Information. Infrared spectra were recorded with a Horiba FT-710 model spectrophotometer. 1H and 13C NMR spectral data were obtained with a Bruker Avance 600, a JEOL JNM-LA 500, a JEOL JNM-AL 300, or a JEOL JNM-ECS 400 instruments. Chemical shifts are quoted in ppm using tetramethylsilane (TMS, δ 0 ppm) as the reference for 1H NMR spectroscopy and CDCl3 (δ 77.0 ppm) for 13 C NMR spectroscopy. Mass spectra were measured with a Bruker Daltonics microTOF or a Hitachi double focusing M-80B spectrometer. Optical rotations were recorded on a JASCO DIP360 digital polarimeter. Column chromatography was carried out on silica gel (Kanto Chemical Co. or Merck Co. Ltd.). All reactions were performed under an argon atmosphere. The synthetic procedures and 11452

DOI: 10.1021/acs.joc.8b01825 J. Org. Chem. 2018, 83, 11450−11457

Note

The Journal of Organic Chemistry

(2R,3S,E)-4-Bromohexadec-4-ene-2,3-diol (10β). A mixture of 9β (8.00 mg, 0.0191 mmol) and K2CO3 (13.4 mg, 0.0970 mmol) in MeOH (0.19 mL) was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc = 5/2) to afford 10β (6.20 mg, 0.0185 mmol, 97%) as a colorless oil. [α]25D −4.0 (c 0.65, CHCl3); IR (neat) 3402, 2924, 2854, 2337, 1643, 1458, 1049 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H), 1.19−1.47 (m, 18H), 2.16 (m, 2H), 2.41 (br s, 1H), 2.52 (br m, 1H), 3.89 (dq, J = 7.9, 6.3 Hz, 1H), 4.13 (d, J = 7.9 Hz, 1H), 6.10 (t, J = 7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.1 (CH3), 18.1 (CH3), 22.7 (CH2), 29.13 (CH2), 29.14 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 30.0 (CH2), 31.9 (CH2), 70.5 (CH), 74.4 (CH), 124.3 (C), 137.4 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C16H3179BrO2Na: 357.1400, found 357.1396; [M + Na]+ calcd for C16H3181BrO2Na: 359.1381, found 359.1379. 3-epi-Litsenolide D2 (1). In a sealed tube, a mixture of 10β (30.5 mg, 0.0909 mmol), triethylamine (29 μL, 0.209 mmol), and Ni(PPh3)2(CO)2 (117 mg, 0.183 mmol) in THF (1.0 mL) was stirred at 70 °C for 4 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (CHCl3 to hexane/EtOAc = 2/1) to afford 3-epi-litsenolide D2 (1) (22.7 mg, 0.0744 mmol, 82%) as a colorless solid. [α]25D +100.7 (c 1.00, CHCl3), [α]25D +107.2 (c 0.12, dioxane); IR (neat) 3394, 2924, 2846, 1728, 1689, 1635, 1458, 1211, 1041, 987, 918, 733 cm−1; 1H NMR (600 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.21−1.37 (m, 16H), 1.46 (d, J = 6.6 Hz, 3H), 1.52 (m, 2H), 1.99 (br m, 1H), 2.40 (m, 2H), 4.54 (dq, J = 6.6, 5.7 Hz, 1H), 4.82 (dd, J = 6.7, 5.7 Hz, 1H), 6.94 (t, J = 7.7 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.0 (CH3), 14.1 (CH3), 22.7 (CH2), 28.4 (CH2), 29.3 (CH2), 29.4 (CH2), 29.4 (CH2), 29.5 (CH2), 29.60 (CH2), 29.62 (CH2), 29.9 (CH2), 31.9 (CH2), 67.7 (CH), 78.9 (CH), 130.5 (C), 147.9 (CH), 170.2 (C); HRMS-ESI: m/z [M + Na]+ calcd for C17H30O3Na: 305.2087, found 305.2087. (E)-3-((4R,5R)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (12).17 Acetonide-protected 12 was prepared from 3 by the reported procedure. [α]25D −16.0 (c 1.00, CHCl3); IR (neat) 3425, 2985, 2931, 1173 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.26 (d, J = 6.0 Hz, 3H), 1.41 (s, 3H), 1.43 (s, 3H), 3.80 (dq, J = 8.4, 6.0 Hz, 1H), 3.96 (dd, J = 8.4, 7.6 Hz, 1H), 4.19 (dd, J = 5.2, 1.6 Hz, 2H), 5.70 (ddt, J = 15.5, 7.6, 1.6 Hz, 1H), 5.99 (dt, J = 15.5, 5.2 Hz, 1H), The OH peak was not observed.; 13C NMR (150 MHz, CDCl3) δ 16.4 (CH3), 26.9 (CH3), 27.3 (CH3), 62.5 (CH2), 76.6 (CH), 83.2 (CH), 108.4 (C), 127.1 (CH), 134.3 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C9H16O3Na: 195.0992, found 195.0992. (4R,5R)-2,2,4-Trimethyl-5-((E)-tridec-1-en-1-yl)-1,3-dioxolane (13). Acetonide-protected 13 was prepared in a similar way to the synthesis of 7β. Colorless oil (10.3 mg, 0.0347 mmol, 25%), [α]25D −9.3 (c 1.00, CHCl3); IR (neat) 2978, 2924, 2854, 1458, 1173, 972 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.23 (d, J = 5.9 Hz, 3H), 1.24−1.43 (m, 24H), 2.05 (dtd, J = 6.8, 6.8, 1.3 Hz, 2H), 3.75 (dq, J = 8.2, 5.9 Hz, 1H), 3.87 (dd, J = 8.2, 8.0 Hz, 1H), 5.39 (ddt, J = 15.2, 8.0, 1.3 Hz, 1H), 5.80 (dt, J = 15.2, 6.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.1 (CH3), 16.4 (CH3), 22.7 (CH2), 27.0 (CH3), 27.3 (CH3), 28.9 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 29.56 (CH2), 29.62 (CH2), 29.64 (CH2), 31.9 (CH2), 32.3 (CH2), 76.6 (CH), 84.2 (CH), 108.0 (C), 126.3 (CH), 136.9 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C19H36O2Na: 319.2608, found 319.2608. (4R,5R,E)-5-((Triisopropylsilyl)oxy)hex-2-ene-1,4-diol (14). A mixture of 3 (342 mg, 1.96 mmol), imidazole (335 mg, 4.92 mmol), DMAP (23.9 mg, 0.196 mmol), and TIPSCl (0.62 mL, 2.93 mmol) in DMF (20 mL) was stirred at 80 °C for 8.5 h and additionally stirred at room temperature for 17.5 h. After the addition of H2O (30 mL) at 0 °C, the mixture was extracted with EtOAc (20 mL × 3), washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 6/1 to EtOAc) to afford the desired allyl alcohol 20 (ethyl (2E,4R,5R)-5-triisopropylsilyloxy-4-hydroxy-2-hex-

and additionally stirred at room temperature for 12 h. To the reaction mixture were added 1-tridecene (17 μL, 0.0735 mmol) and Hoveyda−Grubbs second generation catalyst (2.30 mg, 0.00367 mmol) at room temperature. The mixture was stirred at 70 °C for 12 h and additionally stirred at room temperature for 11 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/EtOAc = 10/1 to 1/1) to afford 7β (16.8 mg, 0.0493 mmol, 69%, E/Z = 3.6/1.0) as a colorless oil and 5 (5.3 mg, 0.0205 mmol, 29%). The E-form of 7β was separated from the Z-form of 7β by preparative TLC (Silica gel 60 F254, 0.5 mm, Merck, hexane/EtOAc = 17/1 × 3 times). [α]25D −11.2 (c 1.00, CHCl3); IR (neat) 2924, 2854, 1743, 1227, 972 cm−1; 1 H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H), 1.22−1.42 (m, 20H), 2.04 (s, 3H), 2.06 (s, 3H), 5.00 (dq, J = 7.5, 6.5 Hz, 1H), 5.27 (dd, J = 7.6, 7.5 Hz, 1H), 5.34 (ddt, J = 15.0, 7.6, 1.4 Hz, 1H), 5.80 (dt, J = 15.0, 6.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.1 (CH3), 16.3 (CH3), 21.1 (CH3), 21.1 (CH3), 22.7 (CH2), 28.8 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 29.58 (CH2), 29.62 (CH2), 29.64 (CH2), 31.9 (CH2), 32.3 (CH2), 70.8 (CH), 75.9 (CH), 124.0 (CH), 137.3 (CH), 170.0 (C), 170.3 (C); HRMS-ESI: m/z [M + Na]+ calcd for C20H36O4Na: 363.2506, found 363.2504. (2R,3S)-4,5-Dibromohexadecane-2,3-diyl diacetate (8β). A mixture of 7β (340 mg, 0.999 mmol), pyridine (0.24 mL, 2.97 mmol), and pyridinium bromide perbromide (>85%) (961 mg, 3.01 mmol) in CH3CN (10 mL) was stirred at room temperature for 18 h. After the addition of sat. Na2SO3 aq. (10 mL) at 0 °C, the mixture was extracted with EtOAc (10 mL × 3), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 10/1) to afford 8β (346 mg, 0.692 mmol, 69%, as a ca. 2/1 diastereomers) as a yellow oil. IR (neat) 2927, 2854, 1749, 1458, 1373, 1211 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H), 1.21−1.43 (m, 18H), 1.66−1.99 (m, 2H), 2.03 (s, 3H), 2.12 (s, 3H), 4.08 (m, 1H), 4.19 (dd, J = 9.5, 2.6 Hz, 1H), 5.22 (m, 1H), 5.59 (m, 1H); diastereomer, 0.88 (t, J = 7.0 Hz, 3H), 1.21−1.43 (m, 22H), 1.66−1.99 (m, 1H), 2.10 (s, 3H), 2.18 (s, 3H), 4.12 (td, J = 10.0, 3.2 Hz, 1H), 4.43 (dd, J = 9.4, 3.2 Hz, 1H), 5.29 (dd, J = 9.4, 2.1 Hz, 1H), 5.51 (qd, J = 7.0, 2.1 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.1 (CH3), 16.3 (CH3), 20.7 (CH3), 21.06 (CH3), 22.7 (CH2), 27.4 (CH2), 28.9 (CH2), 29.3 (CH2), 29.41 (CH2), 29.53 (CH2), 29.61 (CH2), 29.61 (CH2), 31.9 (CH2), 36.6 (CH2), 54.3 (CH), 56.2 (CH), 71.9 (CH), 74.2 (CH), 169.5 (C), 170.2 (C); diastereomer, 14.1 (CH3), 16.7 (CH3), 20.6 (CH3), 21.12 (CH3), 21.7 (CH2), 26.4 (CH2), 27.6 (CH2), 28.8 (CH2), 29.43 (CH2), 29.55 (CH2), 29.61 (CH2), 29.61 (CH2), 33.8 (CH2), 34.6 (CH2), 54.5 (CH), 57.2 (CH), 69.3 (CH), 74.3 (CH), 169.7 (C), 170.0 (C); HRMS-ESI: m/ z [M + Na]+ calcd for C20H3679Br79BrO4Na: 521.0873, found 521.0874; [M + Na]+ calcd for C20H3679Br 81BrO4Na: 523.0853, found 523.0853; [M + Na]+ calcd for C20H3681Br 81BrO4Na: 525.0837, found 525.0832. (2R,3S,E)-4-Bromohexadec-4-ene-2,3-diyl diacetate (9β). A mixture of 8β (1.35 g, 2.70 mmol) and DBU (0.44 mL, 2.94 mmol) in DMF (27 mL) was stirred at 60 °C for 1 h. After the addition of sat. NH4Cl aq. (20 mL) at 0 °C, the mixture was extracted with hexane/ EtOAc (2/1, 20 mL × 3), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 10/1) to afford 9β (1.12 g, 2.68 mmol, 99%) as a colorless oil. [α]25D +5.1 (c 1.00, CHCl3); IR (neat) 2924, 2854, 1743, 1643, 1234 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.23−1.48 (m, 18H), 2.04 (s, 3H), 2.08 (s, 3H), 2.26 (m, 2H), 5.28 (dq, J = 8.7, 6.4 Hz, 1H), 5.59 (d, J = 8.7 Hz, 1H), 6.16 (t, J = 7.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.1 (CH3), 16.0 (CH3), 20.8 (CH3), 21.1 (CH3), 22.7 (CH2), 29.0 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 30.1 (CH2), 31.9 (CH2), 70.6 (CH), 72.8 (CH), 118.5 (C), 140.2 (CH), 169.7 (C), 170.1 (C); HRMS-ESI: m/z [M + Na]+ calcd for C20H3579BrO4Na: 441.1611, found 441.1609; [M + Na]+ calcd for C20H3581BrO4Na: 443.1593, found 443.1589. 11453

DOI: 10.1021/acs.joc.8b01825 J. Org. Chem. 2018, 83, 11450−11457

Note

The Journal of Organic Chemistry

obtained bis(TBS)-protected compound 21 (182 mg, 0.451 mmol) and DIBAL-H (1.3 mL, 1.33 mmol, 1.02 M in hexane) in THF (4.5 mL) was stirred at −78 °C for 3 h. After the addition of 30% potassium sodium tartrate aq. (10 mL) at 0 °C, the mixture was extracted with EtOAc (5 mL × 3), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 4/1) to afford 16 (160 mg, 0.444 mmol, 98%) as a colorless oil. [α]25D +43.5 (c 1.00, CHCl3); IR (neat) 3340, 2854, 1257, 1103 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 3H), 0.05 (s 3H), 0.06 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 0.90 (s, 9H), 1.00 (d, J = 6.2 Hz, 3H), 1.33 (br m, 1H), 3.77 (qd, J = 6.2, 5.0 Hz, 1H), 4.11 (ddd, J = 5.0, 3.5, 1.2 Hz, 1H), 4.17 (m, 2H), 5.79 (dd, J = 15.5, 3.5 Hz, 1H), 5.87 (dtd, J = 15.5, 5.2, 1.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ −4.9 (CH3), −4.72 (CH3), −4.66 (CH3), −4.6 (CH3), 17.2 (CH3), 18.06 (C), 18.14 (C), 25.9 (CH3), 25.9 (CH3), 25.9 (CH3), 25.9 (CH3), 25.9 (CH3), 25.9 (CH3), 63.5 (CH2), 71.3 (CH), 75.1 (CH), 129.9 (CH), 130.7 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C18H40O3Si2Na: 383.2408, found 383.2406. (4R,5R,E)-5-((tert-Butyldimethylsilyl)oxy)hex-2-ene-1,4-diol (17β). A mixture of 3 (246 mg, 1.41 mmol), imidazole (384 mg, 5.64 mmol), and TBSCl (235 mg, 1.56 mmol) was stirred at 80 °C for 5.5 h. After the addition of H2O (15 mL) at 0 °C, the mixture was extracted with EtOAc (10 mL × 3), washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 8/1 to 2/1) to afford the desired allyl alcohol 22 (ethyl (2E,4R,5R)-5((tert-butyldimethylsilyl)oxy)-4-hydroxy-2-hexenoate)17,18 (209 mg, 0.723 mmol, 51%) as a colorless oil, the undesired homoallyl alcohol (ethyl (2E,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-hydroxy-2-hexenoate) (88.1 mg, 0.305 mmol, 22%) as a colorless oil, the undesired bis(TBS)-protected compound 21 (ethyl (2E,4R,5R)-4,5-bis((tertbutyldimethylsilyl)oxy)2-hexenoate) (43.9 mg, 0.109 mmol, 8%) as a colorless oil, and 3 (41.9 mg, 0.241 mmol, 17%). The desired allyl alcohol 22, [α]25D −6.1 (c 1.00, CHCl3); IR (neat) 3479, 2954, 2931, 1720, 1257, 1095 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.22 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 2.58 (d, J = 5.8 Hz, 1H), 3.77 (qd, J = 6.2, 5.0 Hz, 1H), 4.02 (dddd, J = 5.8, 5.0, 4.7, 1.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 6.12 (dd, J = 15.7, 1.7 Hz, 1H), 6.90 (dd, J = 15.7, 4.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ −4.9 (CH3), −4.4 (CH3), 14.2 (CH3), 18.0 (C), 20.1 (CH3), 25.7 (CH3), 25.7 (CH3), 25.7 (CH3), 60.3 (CH2), 71.1 (CH), 75.3 (CH), 122.0 (CH), 147.2 (CH), 166.3 (C); HRMSESI: m/z [M + Na]+ calcd for C14H28O4SiNa: 311.1649, found 311.1648. Next, a mixture of obtained allyl alcohol 22 (819 mg, 2.84 mmol) and DIBAL-H (8.5 mL, 8.84 mmol, 1.04 M in hexane) in THF (28 mL) was stirred at −78 °C for 4 h. After the addition of 30% potassium sodium tartrate aq. (50 mL) at 0 °C, the mixture was extracted with EtOAc (50 mL × 3), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 1/2) to afford 17β (654 mg, 2.65 mmol, 94%) as a colorless oil. [α]25D −17.6 (c 1.00, CHCl3); IR (neat) 3348, 2954, 2931, 2854, 1257, 1095 cm−1; 1 H NMR (300 MHz, CDCl3) δ 0.09 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.16 (d, J = 6.1 Hz, 3H), 1.39 (t, J = 5.8 Hz, 1H), 2.62 (d, J = 4.2 Hz, 1H), 3.67 (qd, J = 6.1, 6.1 Hz, 1H), 3.85 (dddd, J = 6.5, 6.1, 4.2, 1.1 Hz, 1H), 4.17 (dd, J = 5.8, 5.2 Hz, 2H), 5.69 (ddt, J = 15.5, 6.5, 1.5 Hz, 1H), 5.95 (dtd, J = 15.5, 5.2, 1.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ −4.9 (CH3), −4.3 (CH3), 18.0 (C), 19.9 (CH3), 25.8 (CH3), 25.8 (CH3), 25.8 (CH3), 62.9 (CH2), 71.8 (CH), 76.4 (CH), 130.3 (CH), 132.0 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C12H26O3SiNa: 269.1543, found 269.1546. (2R,3R,E)-2-((tert-Butyldimethylsilyl)oxy)hexadec-4-en-3-ol (18β). TBS-protected 18β was prepared in a similar way to the synthesis of 7β. Colorless oil (4.76 g, 12.8 mmol, 82%), [α]25D −19.4 (c 1.00, CHCl3); IR (neat) 3458, 2925, 2854, 1254, 1137, 965 cm−1; 1 H NMR (300 MHz, CDCl3) δ 0.09 (s, 6H), 0.88 (t, J = 6.9 Hz, 3H), 0.90 (s, 9H), 1.13 (d, J = 6.0 Hz, 3H), 1.19−1.42 (m, 18H), 2.03 (m, 2H), 2.58 (br d, J = 2.1 Hz, 1H), 3.63 (dq, J = 7.0, 6.0 Hz, 1H), 3.73 (m, 1H), 5.38 (dd, J = 15.5, 7.0 Hz, 1H), 5.73 (dt, J = 15.5, 6.6 Hz,

enoate) (255 mg, 0.773 mmol, 39%) as a colorless oil, the undesired homoallyl alcohol (ethyl (2E,4R,5R)-4-triisopropylsilyloxy-5-hydroxy2-hexenoate) (66.7 mg, 0.202 mmol, 10%) as a colorless oil, and 3 (135 mg, 0.772 mmol, 39%). The desired allyl alcohol 20, [α]25D +1.5 (c 1.00, CHCl3); IR (neat) 3464, 2947, 2870, 1712, 1465, 1257, 1103 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.05−1.09 (m, 21H), 1.25 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H), 2.67 (d, J = 5.1 Hz, 1H), 3.93 (dq, J = 6.2, 6.2 Hz, 1H), 4.06 (dddd, J = 6.2, 5.1, 4.7, 1.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 6.14 (dd, J = 15.6, 1.8 Hz, 1H), 6.95 (dd, J = 15.6, 4.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.5 (CH), 12.5 (CH), 12.5 (CH), 14.2 (CH3), 18.0 (CH3), 18.0 (CH3), 18.0 (CH3), 18.1 (CH3), 18.1 (CH3), 18.1 (CH3), 20.2 (CH3), 60.4 (CH2), 71.5 (CH), 75.6 (CH), 122.1 (CH), 147.0 (CH), 166.3 (C); HRMS-ESI: m/z [M + Na]+ calcd for C17H34O4SiNa: 353.2119, found 353.2123. Next, a mixture of obtained allyl alcohol 20 (215 mg, 0.650 mmol) and DIBAL-H (1.9 mL, 1.94 mmol, 1.02 M in hexane) in THF (6.5 mL) was stirred at −78 °C for 3.5 h. After the addition of 30% potassium sodium tartrate aq. (30 mL) at 0 °C, the mixture was extracted with EtOAc (10 mL × 3), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 1/1) to afford 14 (182 mg, 0.632 mmol, 97%) as a colorless oil. [α]25D −10.9 (c 1.00, CHCl3); IR (neat) 3363, 2947, 2862, 1466, 1250, 1103 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.05−1.10 (m, 21H), 1.20 (d, J = 5.9 Hz, 3H), 1.50 (br m, 1H), 2.75 (br d, J = 3.4 Hz, 1H), 3.84 (dq, J = 5.9, 5.9 Hz, 1H), 3.87 (m, 1H), 4.17 (dd, J = 5.4, 1.4 Hz, 2H), 5.73 (ddt, J = 15.6, 6.0, 1.4 Hz, 1H), 5.96 (dtd, J = 15.6, 5.4, 1.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.6 (CH), 12.6 (CH), 12.6 (CH), 18.05 (CH3), 18.05 (CH3), 18.05 (CH3), 18.10 (CH3), 18.10 (CH3), 18.10 (CH3), 20.0 (CH3), 63.1 (CH2), 72.1 (CH), 76.8 (CH), 130.5 (CH), 131.9 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C15H32O3SiNa: 311.2013, found 311.2017. (2R,3R,E)-2-((Triisopropylsilyl)oxy)hexadec-4-en-3-ol (15). TIPSprotected 15 was prepared in a similar way to the synthesis of 7β. Colorless oil (121 mg, 0.293 mmol, 68%), [α]25D −16.2 (c 1.00, CHCl3); IR (neat) 3456, 2931, 2862, 1466, 1250, 1134 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.04−1.11 (m, 21H), 1.17 (d, J = 5.8 Hz, 3H), 1.22−1.41 (m, 18H), 2.04 (dt, J = 6.9, 6.9 Hz, 2H), 2.69 (br d, J = 3.2 Hz, 1H), 3.74−3.84 (m, 2H), 5.42 (dd, J = 15.4, 6.7 Hz, 1H), 5.74 (dt, J = 15.4, 6.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.6 (CH), 12.6 (CH), 12.6 (CH), 14.1 (CH3), 18.07 (CH3), 18.07 (CH3), 18.07 (CH3), 18.14 (CH3), 18.14 (CH3), 18.14 (CH3), 20.0 (CH3), 22.7 (CH2), 29.1 (CH2), 29.2 (CH), 29.3 (CH2), 29.5 (CH2), 29.60 (CH2), 29.64 (CH2), 29.7 (CH2), 31.9 (CH2), 32.4 (CH2), 72.4 (CH), 77.7 (CH), 129.1 (CH), 134.4 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C25H52O2SiNa: 435.3629, found 435.3629. (4R,5R,E)-4,5-Bis((tert-butyldimethylsilyl)oxy)hex-2-en-1-ol (16). A mixture of 3 (119 mg, 0.685 mmol), TBSCl (372 mg, 2.47 mmol), imidazole (237 mg, 3.49 mmol), and DMAP (8.70 mg, 0.0712 mmol) in DMF (7.0 mL) was stirred at room temperature for 14.5 h and additionally stirred at 80 °C for 12.5 h. After the addition of H2O (10 mL) at 0 °C, the mixture was extracted with hexane/ EtOAc (2/1, 10 mL × 3), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 20/1 to 4/1) to afford the desired bis(TBS)-protected compound 21 (ethyl (2E,4R,5R)-4,5-bis((tertbutyldimethylsilyl)oxy)2-hexenoate) (221 mg, 0.550 mmol, 80%) as a colorless oil. [α]25D +59.8 (c 1.00, CHCl3); IR (neat) 2954, 2854, 1728, 1257, 1111 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 3H), 0.06 (s, 3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 0.92 (s, 9H), 1.00 (d, J = 6.3 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 3.83 (qd, J = 6.3, 5.2 Hz, 1H), 4.20 (qd, J = 7.1, 2.5 Hz, 2H), 4.27 (ddd, J = 5.2, 3.5, 1.9 Hz, 1H), 6.04 (dd, J = 15.8, 1.9 Hz, 1H), 7.09 (dd, J = 15.8, 3.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ − 5.0 (CH3), −4.9 (CH3), −4.8 (CH3), −4.6 (CH3), 14.2 (CH3), 17.3 (CH3), 18.0 (C), 18.1 (C), 25.8 (CH3), 25.8 (CH3), 25.8 (CH3), 25.8 (CH3), 25.8 (CH3), 25.8 (CH3), 60.2 (CH2), 71.0 (CH), 74.8 (CH), 121.4 (CH), 147.7 (CH), 166.6 (C); HRMS-ESI: m/z [M + Na]+ calcd for C20H42O4Si2Na: 425.2514, found 425.2514. Next, a mixture of 11454

DOI: 10.1021/acs.joc.8b01825 J. Org. Chem. 2018, 83, 11450−11457

Note

The Journal of Organic Chemistry

(50 mL × 3), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 10/1) to afford 7α (1.59 g, 4.68 mmol, 99%) as a colorless oil. [α]25D +7.9 (c 1.00, CHCl3); IR (neat) 2924, 2854, 1743, 1230, 976 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H), 1.21−1.41 (m, 20H), 2.04 (s, 3H), 2.06 (s, 3H), 5.00 (dq, J = 7.5, 6.5 Hz, 1H), 5.26 (dd, J = 7.5, 6.5 Hz, 1H), 5.34 (dd, J = 15.0, 6.5 Hz, 1H), 5.80 (dt, J = 15.0, 6.8 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 14.1 (CH3), 16.3 (CH3), 21.1 (CH3), 21.1 (CH3), 22.7 (CH2), 28.8 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 29.58 (CH2), 29.62 (CH2), 29.7 (CH2), 31.9 (CH2), 32.3 (CH2), 70.8 (CH), 75.9 (CH), 124.0 (CH), 137.4 (CH), 170.0 (C), 170.3 (C); HRMS-ESI: m/z [M + Na]+ calcd for C20H36O4Na: 363.2506, found 363.2510. (2S,3R)-4,5-Dibromohexadecane-2,3-diyl diacetate (8α). Dibromide 8α was prepared in a similar way to the synthesis of 8β. Yellow oil (577 mg, 1.15 mmol, 64%, as a ca. 4/1 diastereomers), IR (neat) 2924, 2854, 1747, 1458, 1373, 1215 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.21− 1.38 (m, 18H), 1.75−1.96 (m, 2H), 2.10 (s, 3H), 2.18 (s, 3H), 4.12 (td, J = 10.0, 3.5 Hz, 1H), 4.43 (dd, J = 9.6, 3.5 Hz, 1H), 5.29 (dd, J = 9.6, 2.4 Hz, 1H), 5.50 (qd, J = 6.4, 2.4 Hz, 1H); diastereomer, 0.88 (t, J = 7.1 Hz, 3H), 1.20−1.38 (m, 21H), 1.75−1.96 (m, 2H), 2.03 (s, 3H), 2.12 (s, 3H), 4.08 (m, 1H), 4.19 (dd, J = 9.4, 2.5 Hz, 1H), 5.23 (m, 1H), 5.59 (dd, J = 7.4, 2.5 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.1 (CH3), 16.7 (CH3), 20.6 (CH3), 21.11 (CH3), 22.7 (CH2), 27.4 (CH2), 28.8 (CH2), 29.3 (CH2), 29.42 (CH2), 29.54 (CH2), 29.60 (CH2), 29.61 (CH2), 31.9 (CH2), 34.6 (CH2), 54.5 (CH), 57.1 (CH), 69.3 (CH), 74.3 (CH), 169.7 (C), 169.9 (C); diastereomer, 16.2 (CH3), 20.7 (CH3), 21.05 (CH3), 21.05 (CH3), 22.7 (CH2), 26.4 (CH2), 28.9 (CH2), 29.3 (CH2), 29.40 (CH2), 29.52 (CH2), 29.60 (CH2), 29.61 (CH2), 31.9 (CH2), 36.6 (CH2), 54.3 (CH), 56.2 (CH), 71.9 (CH), 74.1 (CH), 169.5 (C), 170.2 (C); HRMS-ESI: m/z [M + Na]+ calcd for C20H3679Br79BrO4Na: 521.0873, found 521.0877; [M + Na]+ calcd for C20H3679Br 81 BrO4Na: 523.0853, found 523.0857; [M + Na]+ calcd for C20H3681Br 81BrO4Na: 525.0837, found 525.0838. (2S,3R,E)-4-Bromohexadec-4-ene-2,3-diyl diacetate (9α). Vinyl bromide 9α was prepared in a similar way to the synthesis of 9β. Colorless oil (442 mg, 1.05 mmol, 97%), [α]25D −9.4 (c 1.00, CHCl3); IR (neat) 2927, 2854, 1747, 1643, 1234 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.20 (d, J = 6.5 Hz, 3H), 1.23−1.50 (m, 18H), 2.04 (s, 3H), 2.08 (s, 3H), 2.27 (m, 2H), 5.28 (dq, J = 8.7, 6.5 Hz, 1H), 5.59 (d, J = 8.7 Hz, 1H), 6.16 (t, J = 7.7 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.1 (CH3), 16.1 (CH3), 20.8 (CH3), 21.1 (CH3), 22.7 (CH2), 29.0 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 30.1 (CH2), 31.9 (CH2), 70.6 (CH), 72.8 (CH), 118.5 (C), 140.3 (CH), 169.8 (C), 170.2 (C); HRMS-ESI: m/z [M + Na]+ calcd for C20H3579BrO4Na: 441.1611, found 441.1606; [M + Na]+ calcd for C20H3581BrO4Na: 443.1593, found 443.1586. (2S,3R,E)-4-Bromohexadec-4-ene-2,3-diol (10α). Vinyl bromide 10α was prepared in a similar way to the synthesis of 10β. Colorless oil (261 mg, 0.778 mmol, 86%), [α]25D +3.1 (c 0.65, CHCl3); IR (neat) 3394, 2924, 2854, 1643, 1462, 1053 cm−1; 1H NMR (600 MHz, CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H), 1.20−1.44 (m, 18H), 2.16 (m, 2H), 2.39 (br s, 1H), 2.53 (br m, 1H), 3.89 (dq, J = 7.7, 6.3 Hz, 1H), 4.13 (dd, J = 7.7, 6.6 Hz, 1H), 6.10 (t, J = 7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.1 (CH3), 18.1 (CH3), 22.7 (CH2), 29.1 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 30.0 (CH2), 31.9 (CH2), 70.5 (CH), 74.4 (CH), 124.4 (C), 137.4 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C16H3179BrO2Na: 357.1400, found 357.1399; [M + Na]+ calcd for C16H3181BrO2Na: 359.1381, found 359.1386. Lincomolide A (11). In a sealed tube, a mixture of 10α (44.9 mg, 0.134 mmol), Et3N (55 μL, 0.397 mmol), DMAP (1.20 mg, 0.0107 mmol), and Ni(PPh3)2(CO)2 (260 mg, 0.407 mmol) in THF (1.3 mL) was stirred at 70 °C for 7.5 h. The mixture was concentrated under reduced pressure and purified by silica gel column

1H); 13C NMR (150 MHz, CDCl3) δ −4.8 (CH3), −4.2 (CH3), 14.1 (CH3), 18.0 (C), 20.0 (CH3), 22.7 (CH2), 25.8 (CH3), 25.8 (CH3), 25.8 (CH3), 29.1 (CH2), 29.2 (CH2), 29.3 (CH2), 29.5 (CH2), 29.59 (CH2), 29.63 (CH2), 29.7 (CH2), 31.9 (CH2), 32.4 (CH2), 72.2 (CH), 77.4 (CH), 129.1 (CH), 134.3 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C22H46O2SiNa: 393.3159, found 393.3158. (4S,5S,E)-5-((tert-Butyldimethylsilyl)oxy)hex-2-ene-1,4-diol (17α).20 TBS-protected diol 17α was prepared from the enantiomer of 3 (ethyl (2E,4S,5S)-4,5-dihydroxy-2-hexenoate) in a similar way to the synthesis of 17β. The intermediate allyl alcohol 23 (ethyl (2E,4S,5S)-5-((tert-butyldimethylsilyl)oxy)-4-hydroxy-2-hexenoate),19 Colorless oil (2.84 g, 9.85 mmol, 37%), [α]25D +4.6 (c 1.00, CHCl3); IR (neat) 3479, 2954, 2931, 1720, 1257, 1095 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.22 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 2.60 (d, J = 5.8 Hz, 1H), 3.77 (qd, J = 6.2, 5.0 Hz, 1H), 4.02 (dddd, J = 5.8, 5.0, 4.6, 1.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 6.12 (dd, J = 15.6, 1.7 Hz, 1H), 6.90 (dd, J = 15.6, 4.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ −4.9 (CH3), −4.4 (CH3), 14.2 (CH3), 18.0 (C), 20.1 (CH3), 25.7 (CH3), 25.7 (CH3), 25.7 (CH3), 60.4 (CH2), 71.1 (CH), 75.2 (CH), 122.0 (CH), 147.3 (CH), 166.3 (C); HRMS-ESI: m/z [M + Na]+ calcd for C14H28O4SiNa: 311.1649, found 311.1644. TBS-protected diol 17α,20 colorless oil (2.29 g, 9.29 mmol, 96%), [α]25D +14.0 (c 1.00, CHCl3); IR (neat) 3371, 2962, 2931, 2854, 1257, 1095 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.09 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.15 (d, J = 6.2 Hz, 3H), 1.76 (t, J = 5.8 Hz, 1H), 2.68 (d, J = 4.2 Hz, 1H), 3.67 (qd, J = 6.2, 6.2 Hz, 1H), 3.84 (dddd, J = 6.3, 6.2, 4.2, 1.1 Hz, 1H), 4.16 (dd, J = 5.8, 5.3 Hz, 2H), 5.69 (ddt, J = 15.5, 6.3, 1.5 Hz, 1H), 5.94 (dtd, J = 15.5, 5.3, 1.1 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ −4.8 (CH3), −4.3 (CH3), 18.0 (C), 19.9 (CH3), 25.8 (CH3), 25.8 (CH3), 25.8 (CH3), 62.9 (CH2), 71.9 (CH), 76.4 (CH), 130.3 (CH), 132.1 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C12H26O3SiNa: 269.1543, found 269.1541. (2S,3S,E)-2-((tert-Butyldimethylsilyl)oxy)hexadec-4-en-3-ol (18α). TBS-protected 18α was prepared in a similar way to the synthesis of 7β. Colorless oil (2.79 g, 7.52 mmol, 83%), [α]25D +16.7 (c 0.50, CHCl3); IR (neat) 3475, 2927, 2854, 1254, 1134, 968 cm−1; 1 H NMR (300 MHz, CDCl3) δ 0.09 (s, 6H), 0.88 (t, J = 7.0 Hz, 3H), 0.91 (s, 9H), 1.12 (d, J = 6.1 Hz, 3H), 1.19−1.43 (m, 18H), 2.03 (m, 2H), 2.58 (d, J = 3.7 Hz, 1H), 3.63 (dq, J = 7.1, 6.1 Hz, 1H), 3.73 (m, 1H), 5.38 (dd, J = 15.4, 7.1 Hz, 1H), 5.73 (dt, J = 15.4, 6.7 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ −4.8 (CH3), −4.2 (CH3), 14.1 (CH3), 18.0 (C), 20.0 (CH3), 22.7 (CH2), 25.8 (CH3), 25.8 (CH3), 25.8 (CH3), 29.1 (CH2), 29.2 (CH2), 29.4 (CH2), 29.5 (CH2), 29.60 (CH2), 29.64 (CH2), 29.7 (CH2), 31.9 (CH2), 32.4 (CH2), 72.2 (CH), 77.4 (CH), 129.1 (CH), 134.4 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C22H46O2SiNa: 393.3159, found 393.3160. (2S,3S,E)-Hexadec-4-ene-2,3-diol (19). A mixture of 18α (2.74 g, 7.72 mmol) and TBAF (8.5 mL, 8.50 mmol, 1.0 M in THF) in THF (39 mL) was stirred at room temperature for 15.5 h. After the addition of sat. NH4Cl aq. (50 mL), the mixture was extracted with EtOAc (50 mL × 4), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 1/1 to 1/2) to afford 19 (1.83 g, 7.15 mmol, 93%) as a colorless oil. [α]25D +2.5 (c 1.00, CHCl3); IR (neat) 3370, 2924, 2854, 1462, 972 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.15 (d, J = 6.3 Hz, 3H), 1.21− 1.45 (m, 18H), 2.04 (dt, J = 6.7, 6.7 Hz, 2H), 2.21−2.55 (br s, 2H), 3.62 (dq, J = 7.1, 6.3 Hz, 1H), 3.79 (dd, J = 7.3, 7.1 Hz, 1H), 5.43 (dd, J = 15.5, 7.3 Hz, 1H), 5.76 (dt, J = 15.5, 6.7 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.1 (CH3), 18.9 (CH3), 22.7 (CH2), 29.0 (CH2), 29.2 (CH2), 29.4 (CH2), 29.5 (CH2), 29.60 (CH2), 29.63 (CH2), 29.7 (CH2), 31.9 (CH2), 32.4 (CH2), 70.9 (CH), 77.9 (CH), 128.9 (CH), 135.3 (CH); HRMS-ESI: m/z [M + Na]+ calcd for C16H32O2Na: 279.2295, found 279.2297. (2S,3S,E)-Hexadec-4-ene-2,3-diyl Diacetate (7α). A mixture of 19 (1.21 g, 4.71 mmol), pyridine (1.9 mL, 23.5 mmol), Ac2O (2.2 mL, 23.3 mmol), and DMAP (61.0 mg, 0.500 mol) in CH2Cl2 (47 mL) was stirred at room temperature for 3.5 h. After the addition of sat. NH4Cl aq. (50 mL) at 0 °C, the mixture was extracted with EtOAc 11455

DOI: 10.1021/acs.joc.8b01825 J. Org. Chem. 2018, 83, 11450−11457

Note

The Journal of Organic Chemistry

Additive Effect. Org. Lett. 2007, 9, 1695−1698. (b) Raju, R.; Allen, L. J.; Le, T.; Taylor, C. D.; Howell, A. R. Cross Metathesis of αMethylene Lactones II: γ- and δ-Lactones. Org. Lett. 2007, 9, 1699− 1701. (c) Kutsumura, N.; Kiriseko, A.; Saito, T. Total Synthesis of (+)-Heteroplexisolide E. Heterocycles 2012, 86, 1367−1378. (7) (a) Ohgiya, T.; Nishiyama, S. Conversion of 3-O-Substituted 1,2-Dibromoalkanes into 2-Bromo-1-alkenes by the Selective Elimination: Its Application to Total Synthesis of 12-Oxygenated Tremetones. Chem. Lett. 2004, 33, 1084−1085. (b) Ohgiya, T.; Nishiyama, S. Total Synthesis of (+)-Tanikolide, Using Regioselective Elimination of a Vicinal Dibromoalkane. Bull. Chem. Soc. Jpn. 2005, 78, 1549−1554. (c) Ohgiya, T.; Kutsumura, N.; Nishiyama, S. DBUPromoted Elimination Reactions of Vicinal Dibromoalkanes Mediated by Adjacent O-Functional Groups, and Applications to the Synthesis of Biologically Active Natural Products. Synlett 2008, 2008, 3091− 3105. (d) Kutsumura, N.; Iijima, M.; Toguchi, S.; Saito, T. 1,8Diazabicyclo[5.4.0]undec-7-ene-promoted Regioselective Elimination of Vicinal Dibromides Having an Adjacent O- and/or N-Functional Group. Chem. Lett. 2011, 40, 1231−1232. (e) Kutsumura, N.; Toguchi, S.; Iijima, M.; Tanaka, O.; Iwakura, I.; Saito, T. DBUpromoted regioselective HBr-elimination of vicinal dibromides: effects of the adjacent oxygen and/or other heterofunctional groups. Tetrahedron 2014, 70, 8004−8009. (8) (a) Semmelhack, M. F.; Brickner, S. J. Intramolecular carbonylation of vinyl halides to form methylene lactones. J. Org. Chem. 1981, 46, 1723−1726. (b) Uenishi, J.; Ohmi, M. Synthesis and Reaction of Bromoallylsilane: A Short Access to β,γ-Disubstituted αMethylene-γ-butyrolactone. Heterocycles 2003, 61, 365−376. (c) Ohgiya, T.; Nishiyama, S. Synthesis of (−)-Tuliparin B Utilizing 2Bromo-1-alkenes Conveniently Synthesized from the 3-O-Substituted 1,2-Dibromoalkane System by Regioselective Elimination. Heterocycles 2004, 63, 2349−2354. (d) Yu, C.-M.; Youn, J.; Lee, M.-K. Regulation of Stereoselectivity Using Lewis Acid in the Cyclization of Allenic Aldehydes Catalyzed by Palladium Complex. Org. Lett. 2005, 7, 3733−3736. (e) Rauniyar, V.; Hall, D. G. Rationally Improved Chiral Brønsted Acid for Catalytic Enantioselective Allylboration of Aldehydes with an Expanded Reagent Scope. J. Org. Chem. 2009, 74, 4236−4241. (9) Tsai, I.-L.; Hung, C.-H.; Duh, C.-Y.; Chen, J.-H.; Lin, W.-Y.; Chen, I.-S. Cytotoxic Butanolides from the Stem Bark of Formosan Lindera commuis. Planta Med. 2001, 67, 865−867. (10) Tanaka, H.; Nakamura, T.; Ichino, K.; Ito, K.; Tanaka, T. Butanolides from Litsea japonica. Phytochemistry 1990, 29, 857−859. (11) (a) Rollinson, S. W.; Amos, R. A.; Katzenellenbogen, J. A. Total synthesis of Lauraceae lactones: obtusilactones, litsenolides, and mahubanolides. J. Am. Chem. Soc. 1981, 103, 4114−4125. (b) Garcez, F. R.; Garcez, W. S.; Martins, M.; Matos, M. F. C.; Guterres, Z. R.; Mantovani, M. S.; Misu, C. K.; Nakashita, S. T. Cytotoxic and Genotoxic Butanolides and Lignans from Aiouea trinervis. Planta Med. 2005, 71, 923−927. (12) (a) Mailar, K.; Choi, W. J. The first asymmetric of marliolide from readily accessible carbohydrate as chiral template. Carbohydr. Res. 2016, 432, 31−35. (b) Lee, J.; Mailar, K.; Yoo, O.-K.; Choi, W. J.; Keum, Y.-S. Marliolide inhibits skin carcinogenesis by activating NRF2/ARE to induce heme oxygenase-1. Eur. J. Med. Chem. 2018, 150, 113−126. (13) Tanaka, H.; Takaya, Y.; Toyoda, J.; Yasuda, T.; Sato, M.; Murata, J.; Murata, H.; Kaburagi, K.; Iida, O.; Sugimura, K.; Sakai, E. Two new butanolides from the roots of Litsea acuminata. Phytochem. Lett. 2015, 11, 32−36. (14) Tsai, I.-L.; Hung, C.-H.; Duh, C.-Y.; Chen, I.-S. Cytotoxic Butanolides and Secobutanolides from the Stem Wood of Formosan Lindera communis. Planta Med. 2002, 68, 142−145. (15) (a) Martinez, J. C. V.; Yoshida, M.; Gottlieb, O. R. Six groups of ω-ethenyl- and ω-ethynyl-α-alkylidene-γ-lactones. Tetrahedron Lett. 1979, 20, 1021−1024. (b) Martinez, J. C. V.; Yoshida, M.; Gottlieb, O. R. ω-Ethyl, ω-ethenyl and ω-ethynyl-α-alkylidene-γ-lactones from Clinostemon mahuba. Phytochemistry 1981, 20, 459−464.

chromatography (CHCl3 to hexane/EtOAc = 3/1) to afford lincomolide A (11) (30.2 mg, 0.107 mmol, 80%) as a colorless solid. [α]25D −93.7 (c 1.00, CHCl3); IR (neat) 3387, 1732, 1678 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.19− 1.41 (m, 16H), 1.46 (d, J = 6.6 Hz, 3H), 1.51 (m, 2H), 2.00 (br m, 1H), 2.40 (m, 2H), 4.54 (dq, J = 6.6, 5.1 Hz, 1H), 4.82 (dd, J = 5.1, 5.1 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.0 (CH3), 14.1 (CH3), 22.7 (CH2), 28.4 (CH2), 29.3 (CH2), 29.4 (CH2), 29.4 (CH2), 29.5 (CH2), 29.60 (CH2), 29.62 (CH2), 29.9 (CH2), 31.9 (CH2), 67.7 (CH), 79.0 (CH), 130.5 (C), 147.9 (CH), 170.3 (C); HRMS-ESI: m/z [M + Na]+ calcd for C17H30O3Na: 305.2087, found 305.2082.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01825. 1 H and 13C NMR spectra for all new compounds (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

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

Noriki Kutsumura: 0000-0002-1494-2133 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was partly supported by the Sasakawa Scientific Research Grant from The Japan Science Society, the Central Glass Co., Ltd. (Central Glass Co., Ltd. Award in Synthetic Organic Chemistry, Japan), Tokyo Ohka Foundation for The Promotion of Science and Technology, and JGC-S Scholarships Foundation. We thank Dr. Tadaaki Ohgiya (Laboratory Manager, Executive Officer, Medicinal Chemistry Dept., Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd.) for discussions.

■

REFERENCES

(1) Lee, S.-S.; Chang, S.-M.; Chen, C.-H. Chemical Constituents from Alseodaphne andersonii. J. Nat. Prod. 2001, 64, 1548−1551. (2) Takeda, K.; Sakurawi, K.; Ishii, H. Components of the Lauraceae family−I: New lactonic compounds from Litsea japonica. Tetrahedron 1972, 28, 3757−3766. (3) Zhang, H.-J.; Hung, N. V.; Cuong, N. M.; Soejarto, D. D.; Pezzuto, J. M.; Fong, H. H. S.; Tan, G. T. Sesquiterpenes and Butenolides, Natural Anti-HIV Constituents from Litsea verticillata. Planta Med. 2005, 71, 452−457. (4) (a) Xu, D.; Crispino, G. A.; Sharpless, K. B. Selective asymmetric dihydroxylation (AD) of dienes. J. Am. Chem. Soc. 1992, 114, 7570− 7571. (b) Becker, H.; Soler, M. A.; Sharpless, K. B. Selective asymmetric dihydroxylation of polyenes. Tetrahedron 1995, 51, 1345−1376. (c) Hunter, T. J.; O'Doherty, G. A. Enantioselective Syntheses of Colletodiol, Colletol, and Grahamimycin A. Org. Lett. 2002, 4, 4447−4450. (d) Matsushima, Y.; Kino, J. A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-vicenisamine and its epimers via iodocyclization of carbamate. Tetrahedron 2017, 73, 6831−6839. (5) The enantiomeric purity of diol 3 (ethyl (2E,4R,5R)-4,5dihydroxy-2-hexenoate) was estimated as ca. 80% ee by the specific optical rotation ([α]25D +55.5 (c = 1.00, EtOH)) {lit. 4 (a): [α]24D +64.0 (c = 1.10, EtOH), 92% ee}. (6) (a) Moïse, J.; Arseniyadis, S.; Cossy, J. Cross-Metathesis between α-Methylene-γ-butyrolactone and Olefins: A Dramatic 11456

DOI: 10.1021/acs.joc.8b01825 J. Org. Chem. 2018, 83, 11450−11457

Note

The Journal of Organic Chemistry (16) Diol 17α was derived from the enantiomer of 3 (ethyl (2E,4S,5S)-4,5-dihydroxy-2-hexenoate) in two steps. The (4S,5S)asymmetric centers of the starting material were constructed by Sharpless asymmetric dihydroxylation using 1 mol % of (DHQ)2PHAL as a chiral ligand. The enantiomeric purity was estimated as ca. 82% ee by the specific optical rotation ([α]25D −56.8 (c = 1.00, EtOH)) {lit. 4 (a): [α]24D +64.0 (c = 1.10, EtOH), 92% ee}. (17) Kumar, S. N.; Kumar, C. H. N. S. S. P.; Srihari, E.; Kancharla, S.; Srinivas, K.; Shrivastava, S.; Naidu, V. G. M.; Rao, V. J. First total synthesis of fuzanins C, D and their analogues as anticancer agents. RSC Adv. 2014, 4, 8365−8375. (18) Matsushima, Y.; Kino, J. A new simple route to deoxyamino sugars from non-sugar material: synthesis of D-tolyposamine and 4epi-D-tolyposamine and formal synthesis of D-vicenisamine. Tetrahedron Lett. 2005, 46, 8609−8612. (19) Sugimoto, K.; Kobayashi, Y.; Hori, A.; Kondo, T.; Toyooka, N.; Nemoto, H.; Matsuya, Y. Syntheses of aza-analogues of macrosphelides via RCM strategy and their biological evaluation. Tetrahedron 2011, 67, 7681−7685. (20) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Stefanelli, S. Stereoselective synthesis of polyols precursors by allyl sulphinyl anion addition to chiral alkoxy aldehydes. Tetrahedron 1986, 42, 5451−5456.

11457

DOI: 10.1021/acs.joc.8b01825 J. Org. Chem. 2018, 83, 11450−11457