Stereoselective Total Synthesis of Macrophage-Produced Prohealing

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Cite This: J. Org. Chem. 2018, 83, 154−166

Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids Keita Nishimura,† Tsuyoshi Sakaguchi,† Yutaro Nanba,† Yuta Suganuma,† Masao Morita,† Song Hong,‡,§ Yan Lu,‡ Bokkyoo Jun,‡ Nicolas G. Bazan,‡,§ Makoto Arita,II,III and Yuichi Kobayashi*,† †

Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan ‡ Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, United States § Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, United States II Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan III Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan S Supporting Information *

ABSTRACT: Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a C20−C22 fragment (DHA numbering), was converted to the C17−C22 phosphonium salt, which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12−C16 part with the TMS and TBSoxy groups at C12 and C14, yielding the C12−C22 derivative with 14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with L-(+)-DIPT/Ti(O-i-Pr)4 afforded 14S-epoxy alcohol and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et2AlCN. The 14R-allylic alcohol was also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL afforded the key aldehyde corresponding to the C11− C22 moiety. The Wittig reaction of this aldehyde with a phosphonium salt of the remaining C1−C10 part followed by functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99% ee) was converted to 14S,21SdiHDHA. The chiral LC-UV-MS/MS analysis demonstrated that each of these two 14,21-diHDHAs synthesized using the presented total organic synthesis was highly stereoselective and identical to the macrophage-produced counterpart.

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wound closure.1a However, the biological properties and potency of these stereoisomers in pure forms have not been assessed to date. Because the 14S,21R-diHDHA, even though it is the most abundant of the four stereoisomers, has been obtained only in minute quantity by the enzymatic synthesis followed by chromatographic separation, organic synthesis of the isomers is required for supplying them for further investigation. In this report, we established for the first time the stereoselective synthesis of 14S,21R-diHDHA and 14S,21SdiHDHA. We also verified the stereochemistry of these diastereomers using aqueous reversed-phase chiral lipid chromatography coupled with ultraviolet spectrometry and tandem mass spectrometry (acLC-UV-MS/MS) and macrophage-produced counterparts of these diastereomers following the methodology we previously established.1−3 To develop a method for the synthesis of the four possible stereoisomers of 14,21-diHDHA, we chose 14S,21R-diHDHA

INTRODUCTION Dihydroxy docosahexaenoic acid (14,21-diHDHA) is a novel endogenous derivative of docosahexaenoic acid (DHA) by macrophages and in wounded skin.1,2 12-Lipoxygenase and cytochrome P450 are enzymes that catalyze the oxidation at the C14 and C21 carbons of DHA, respectively. Four possible stereoisomers have been detected by chiral liquid chromatography/mass spectrometry using 14S,21R/S- and 14R,21R/Sisomers as references, which were in turn synthesized by incubating 14S- and 14R-hydroxy-DHA with P450. Among the isomers, the 14S,21R-isomer was the major component and promoted wound healing in wounded macrophages and skin.1b These results suggest that 14S,21R- or 14,21-diHDHA will be a lead compound in the development of novel therapeutic drugs for ameliorating wound healing impaired by diabetes1b or ethanol intoxication/exposure2 as well as aging and/or other diseases.3 Formation of the 14S,21R-isomer has also been found from peripheral blood4 and leucocytes.5 During the investigation, the 14R,21R/S-isomer was found to be as efficient as the 14S-isomer in promoting splinted excisional © 2017 American Chemical Society

Received: October 3, 2017 Published: December 11, 2017 154

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

Article

The Journal of Organic Chemistry (1a) and 14S,21S-diHDHA (1b) as the synthetic targets (Figure 1). These are diastereomeric to each other, whereas

Scheme 1. Retrosynthetic Analysis of 1a

Figure 1. Two stereoisomers among four possible of 14,21-diHDHA.

the remaining two are enantiomers thereof. Retrosynthesis of 1a delineated in Scheme 1 disconnected the C10−C11 double bond to phosphonium salt 2 and aldehyde 3. Allylic alcohol 4, a diastereomeric mixture at C14, was envisaged to afford 3 by Sharpless asymmetric epoxidation6 using L-(+)-DIPT/Ti(O-iPr)4 followed by the addition of a formyl group to the resulting epoxide through a reaction with Et2AlCN.7 This intermediate 4 was disconnected in two ways: (1) via Castro−Stephens coupling8 of acetylene 5 with bromide 6 and (2) via Wittig reaction of aldehyde 7 with phosphonium salt 8. Compounds 6 and 8 would be synthesized from (R)-3-butyn-2-ol and (R)lactate, respectively. A similar disconnection of 1b reached (S)enantiomers. Both enantiomers are commercially available. Meanwhile, the use of D-(−)-DIPT/Ti(O-i-Pr)4 for the Sharpless asymmetric epoxidation would surely furnish R chirality on the C14 carbon for the synthesis of the remaining 14R-isomers of 14,21-diHDHA. Because the TBDPS-oxy group on the C21 stereogenic carbon is a large substituent, influence of the group on the construction of the diastereoisomeric R or S stereogenic center at C14 was a concern. In the following paragraphs, we will discuss the synthesis of 1a and 1b and the results associated with the substituent.

using 14. With these inconvenient steps in mind, we decided to move on to the other synthesis of 4. Silyl ether 20 obtained from commercially available methyl (R)-lactate (>97% ee, TCI) was converted to aldehyde 21 (Scheme 3), which was subjected to a Wittig reaction with 2210 using NaHMDS as a base. Subsequently, deprotection of the TBS group afforded cis olefin alcohol 23 as a sole product in 88% yield from ester 20. This product was then converted to phosphonium salt 8 in good yield via iodide 24. As delineated in Scheme 4, the DIBAL reduction of ester 25, prepared from propargyl alcohol in four steps,11 gave aldehyde 7, which upon a Wittig reaction with the ylide derived from 8 and NaHMDS afforded 26 stereoselectively. Attempts to remove the TBS group in 26 using PPTS in MeOH at ∼40 °C gave a mixture of 4, the corresponding diol, and unreacted 26 in varying ratios, whereas CAN12 however produced 4 in steady yields, though a small quantity of the diol and 26 was detected by TLC in every run. Epoxidation of 4 (diastereomeric mixture at C14) with L(+)-DIPT/Ti(O-i-Pr)4 proceeded under the reported conditions6a,b to afford 27 and 28 in 39 and 42% yields,

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RESULTS AND DISCUSSION The synthesis of 4 was first studied using the Castro−Stephens coupling of acetylene 5 with bromide rac-6 under the conditions of Spinella9 with modification (Bu4NI instead of NaI), which gave a mixture of 11 (99% ee by 1H NMR analysis of the derived MTPA ester) was converted to ent-8 in an overall yield similar to that calculated for 8. The Wittig reaction of 7 with ent-8 followed by the deprotection of TBS ether 47 with CAN furnished alcohol ent4 in 62% yield over two steps. The asymmetric epoxidation of ent-4 with L-(+)-DIPT/Ti(O-i-Pr)4 afforded ent-30 and 48 in 41 and 42% yields, respectively, and with >99% de for both products after chromatography on silica gel. The observed yield and de were comparable to those for 27 and 28 (Scheme 5), indicating that the asymmetric epoxidation was little affected by the TBDPS-oxy group at C21. The silylation of epoxy alcohol ent-30 with TBSOTf gave epoxide 49, which was then transformed to aldehyde 51 in 45% yield through nitrile 50.15 The Wittig reaction of aldehyde 51 with 2 followed by the selective desilylation of the TBS group afforded primary alcohol 52, which was converted to acid 53 by oxidation. Finally, desilylation gave 14S,21S-diHDHA (1b) in 30% yield from aldehyde 51 over five steps. The spectral data (1H and 13 C NMR, 13C-APT NMR, IR, and UV) as well as HRMS of 1b were in agreement with the structure. High purity of the olefins constructed by Wittig reaction was confirmed by the 1H and 13C NMR spectra of 1b as well as precursors 52 and 53. Moreover, the acLC-UV-MS/MS chromatogram and spectrum of 1b were in agreement with macrophage-produced 14S,21RdiHDHA (Figure 2).1a,b,3a

Scheme 2. Unsuccessful Castro−Stephens Coupling

Scheme 3. Synthesis of Phosphonium Salt 8

Scheme 4. Synthesis of Intermediate 4

respectively, with >99% diastereomeric excess (de) for both products (Scheme 5). These results indicated that the kinetic resolution was not affected by the TBDPS-oxy substituent. Silylation of 27 with TBSOTf13 followed by reaction with Et2AlCN afforded nitrile 29 in 87% yield via the epoxide ring opening by CN− followed by Peterson-type olefination. The other product 28 was also converted to nitrile 29 in five steps, which started with epoxidation using D-(−)-DIPT/Ti(O-i-Pr)4 to afford 30 in 87% yield. Subsequently, Mitsunobu inversion delivered alcohol 31 in 86% yield. Protection of 31 with 156

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

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The Journal of Organic Chemistry Scheme 5. Synthesis of Aldehyde 3 via Nitrile 29

Scheme 6. Synthesis of Phosphonium Salt 2

Scheme 7. Synthesis of 14S,21R-diHDHA 1a

useful for determination of the absolute configuration of 14,21diHDHA that will be isolated from natural sources: 1a, [α]D20 +19 (c 0.56, CHCl3); 1b, [α]D19 −24 (c 0.70, CHCl3). Furthermore, 1a and 1b were distinguished by acLC-UV-MS/ MS, and their acLC-UV-MS/MS chromatograms and spectra were in agreement with those of the same diastereomer produced by macrophages (Figure 2).1a,b,3a

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CONCLUSIONS A method for the synthesis of diastereomers 1a and 1b was developed. The C14 stereocenter was secured by the Sharpless asymmetric epoxidation, and the C21 center was derived from commercially available (R)- and (S)-lactates. This method is surely applicable to the synthesis of the remaining stereoisomers (enantiomers of 1a and 1b). Diagnostic absorbances of 1a and 1b in the 1H and 13C NMR spectra were found, and the observed [α]D values were different from each other. Moreover, the acLC-UV-MS/MS study indicated that the structures of 1a and 1b were in agreement with macrophageproduced 14S,21R- and 14S,21S-diHDHA, respectively. These

Comparison of the 1H and 13C NMR spectra of two diastereomer sets, i.e., 1a vs 1b and their silyl ethers 45 vs 53, revealed diagnostic absorbance in the former set as shown below in Table 1, whereas the spectra of the silyl ethers are superimposed on each other. Thus, the characteristic absorbances of 1a and 1b are useful for the determination of the stereochemistry at C14 and C21 of the 14,21-diHDHA diastereomers. Furthermore, the signs of the observed specific rotations of 1a and 1b are opposite, and the rotations would be 157

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

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The Journal of Organic Chemistry

Figure 2. acLC-UV-MS/MS chromatogram and spectra: acLC-MS/MS chromatogram (m/z 253.3 of MS/MS m/z 359.3, left) and spectrum (full scan MS/MS of m/z 359.3, right). (left insert) acLC-UV spectrum; (right insert) interpretation of MS/MS fragmentation. Parent or molecular ion: M − H+ = 359.3. (A) 1a (chemically synthesized 14S,21R-diHDHA). (B) 1b (chemically synthesized 14S,21S-diHDHA). (C) Four macrophageproduced 14,21-diHDHA diastereomers (i.e., 14R,21R-, 14R,21S-, 14S,21R-, and 14S,21S-diHDHA).1a,b,3a

Scheme 8. Synthesis of 14S,21S-diHDHA 1b

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DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

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The Journal of Organic Chemistry

dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 23 (1.24 g, 88% over three steps) as a liquid: Rf = 0.29 (hexane/EtOAc 5:1); [α]D25 −18 (c 1.07, CHCl3); IR (neat) 3326, 1111, 703 cm−1; 1 H NMR (400 MHz, CDCl3) δ 1.04 (s, 9 H), 1.18 (d, J = 6.4 Hz, 3 H), 1.79−1.98 (m, 2 H), 3.39 (q, J = 6.4 Hz, 2 H), 4.58 (ddq, J = 8.4, 1.2, 6.4 Hz, 1 H), 5.17 (ddt, J = 11.2, 1.2, 7.4 Hz, 1 H), 5.65 (ddt, J = 11.2, 8.4, 1.6 Hz, 1 H), 7.32−7.45 (m, 6 H), 7.64−7.72 (m, 4 H); 13 C-APT NMR (100 MHz, CDCl3) δ 19.2 (−), 24.7 (+), 27.0 (+), 31.0 (−), 62.1 (−), 66.0 (+), 123.8 (+), 127.5 (+),127.6 (+), 129.57 (+), 129.63 (+), 134.3 (−), 134.5 (−), 135.9 (+), 136.0 (+), 137.7 (+); HRMS (FAB+) calcd for C22H31O2Si [(M + H)+] 355.2093, found 355.2096. (R,Z)-tert-Butyl[(6-iodohex-3-en-2-yl)oxy]diphenylsilane (24). To an ice-cold solution of alcohol 23 (2.88 g, 8.12 mmol) in CH2Cl2 (50 mL) were added PPh3 (3.25 g, 12.4 mmol), imidazole (855 mg, 12.6 mmol), and I2 (3.31 g, 12.6 mmol). The mixture was stirred at 0 °C for 3 h and diluted with aqueous Na2S2O3 with vigorous stirring. The resulting mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford iodide 24 (3.68 g, 97%) as a liquid: Rf = 0.80 (hexane/EtOAc 5:1); [α]D23 −15 (c 1.20, CHCl3); IR (neat) 1112, 702, 613 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.04 (s, 9 H), 1.19 (d, J = 6.2 Hz, 3 H), 2.07−2.23 (m, 2 H), 2.81 (t, J = 7.4 Hz, 2 H), 4.48 (ddq, J = 8.6, 1.2, 6.2 Hz, 1 H), 5.10 (ddt, J = 11.0, 1.2, 7.4 Hz, 1 H), 5.61 (ddt, J = 11.0, 8.6, 1.4 Hz, 1 H), 7.33−7.46 (m, 6 H), 7.62−7.71 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ 4.8 (−), 19.2 (−), 24.6 (+), 27.0 (+), 31.4 (−), 66.0 (+), 126.4 (+), 127.5 (+), 127.6 (+), 129.6 (+), 129.7 (+), 134.1 (−), 134.3 (−), 135.86 (+), 135.95 (+), 136.7 (+); HRMS (FAB+) calcd for C22H29OSiNaI [(M + Na)+] 487.0930, found 487.0931. (E)-3-{(tert-Butyldimethylsilyl)oxy}-5-(trimethylsilyl)pent-4enal (7). To a solution of ester 25 (2.00 g, 5.58 mmol) in CH2Cl2 (35 mL) was added a solution of DIBAL (1.02 M in hexane, 7.10 mL, 7.24 mmol) at −78 °C. The solution was stirred at −78 °C for 1.5 h and poured into a mixture of H2O (2.0 mL, 110 mmol) and NaF (2.34 g, 55.7 mmol). The resulting mixture was stirred at rt for 20 min and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (hexane/ EtOAc) to afford aldehyde 7 (1.46 g, 91%) as a liquid: Rf = 0.49 (hexane/EtOAc 5:1); IR (neat) 1729, 1250, 839 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3 H), 0.04 (s, 3 H), 0.05 (s, 9 H), 0.87 (s, 9 H), 2.50 (ddd, J = 15.6, 4.8, 2.4 Hz, 1 H), 2.58 (ddd, J = 15.6, 7.2, 2.4 Hz, 1 H), 4.61 (dddd, J = 7.2, 5.2, 4.8, 1.0 Hz, 1 H), 5.88 (dd, J = 18.6, 1.0 Hz, 1 H), 6.00 (dd, J = 18.6, 5.2 Hz, 1 H), 9.75 (t, J = 2.4 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.9 (+), −4.2 (+), −1.4 (+), 18.2 (−), 25.8 (+), 51.1 (−), 71.3 (+), 130.3 (+), 147.1 (+), 201.8 (+); HRMS (FAB+) calcd for C14H31O2Si2 [(M + H)+] 287.1863, found 287.1865. (1E,5Z,8Z,10R)-10-[(tert-Butyldiphenylsilyl)oxy]-1-(trimethylsilyl)undeca-1,5,8-trien-3-ol (4). A solution of iodide 24 (3.53 g, 7.60 mmol) and PPh3 (3.91 g, 14.9 mmol) in MeCN (76 mL) was heated under reflux for 17 h, cooled to rt, and concentrated. The residue was washed with ether six times to afford phosphonium salt 8 (5.04 g, 91%) as a solid: 1H NMR (300 MHz, CDCl3) δ 0.95 (s, 9 H), 1.07 (d, J = 6.3 Hz, 3 H), 1.80−2.06 (m, 2 H), 2.99−3.19 (m, 1 H), 3.57−3.78 (m, 1 H), 4.21 (dq, J = 7.2, 6.3 Hz, 1 H), 5.53−5.65 (m, 2 H), 7.18−7.82 (m, 25 H). To an ice-cold suspension of phosphonium salt 8 (4.96 g, 6.82 mmol) in THF (46 mL) was added a solution of NaHMDS (1.0 M in THF, 5.50 mL, 5.50 mmol). The mixture was stirred at 0 °C for 1.5 h and cooled to −90 °C (liquid N2 + hexane). A solution of aldehyde 7 (1.46 g, 5.09 mmol) in THF (5 mL) was added to the mixture dropwise. The solution was allowed to warm to rt gradually over 12 h and diluted with saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford olefin 26 (2.92 g, 94%) as a liquid: Rf = 0.74 (hexane/EtOAc

Table 1. Diagnostic NMR Spectra and [α]D Values of 1a and 1b H NMR spectraa 13 C NMR spectrab [α]D value 1

1a

1b

4.20−4.28 (m, 1 H) ppm 35.5, 72.0, 125.5 ppm

4.38−4.45 (m, 1 H) ppm 34.8, 71.5, 124.9 ppm

[α]D20 +19 (c 0.56, CHCl3)

[α]D19 −24 (c 0.70, CHCl3)

At 400 MHz in CDCl3. bAt 100 MHz in CDCl3; Δδ of >0.5 ppm.

a

data will be useful for the elucidation of the stereochemistry of 14,21-diHDHA newly isolated from cells and tissues. Furthermore, the method would spur the biological investigation and development of drugs against impaired wound healing.

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EXPERIMENTAL SECTION

General Remarks. The 1H (300 or 400 MHz) and 13C NMR (75 or 100 MHz) spectroscopic data were recorded in CDCl3 using Me4Si (δ = 0 ppm) and the centerline of the triplet (δ = 77.1 ppm), respectively, as internal standards. Signal patterns are indicated as br s (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Coupling constants (J) are given in hertz (Hz). Chemical shifts of carbons are accompanied by minus (for C and CH2) and plus (for CH and CH3) signs of the attached proton test (APT) experiments. High-resolution mass spectroscopy (HRMS) was performed with a double-focusing mass spectrometer with an ionization mode of positive FAB or EI as indicated for each compound. The solvents that were distilled prior to use are THF (from Na/benzophenone), Et2O (from Na/benzophenone), and CH2Cl2 (from CaH2). After the reactions were completed, the organic extracts were concentrated by using an evaporator, and then the residues were purified by chromatography on silica gel (Kanto, spherical silica gel 60N). (R,Z)-5-[(tert-Butyldiphenylsilyl)oxy]hex-3-en-1-ol (23). A solution of methyl lactate (>97% ee, 0.95 mL, 10.0 mmol), TBDPSCl (3.40 mL, 13.1 mmol), and imidazole (1.03 g, 15.1 mmol) in DMF (50 mL) was stirred at rt for 10 h and diluted with saturated NaHCO3. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford silyl ether 20 (3.39 g, 98%) as a liquid: Rf = 0.67 (hexane/EtOAc 3:1). To a solution of ester 20 (1.36 g, 3.97 mmol) in CH2Cl2 (20 mL) cooled to −78 °C was added a solution of DIBAL (1.02 M in hexane, 4.90 mL, 5.00 mmol) dropwise. The solution was stirred at −78 °C for 1.5 h and poured into a mixture of H2O (2.0 mL, 110 mmol) and NaF (3.20 g, 76.2 mmol). The resulting mixture was stirred at rt for 30 min and filtered through a pad of Celite. The filtrate was concentrated to afford aldehyde 21 as a liquid, which was used for the next reaction without further purification: Rf = 0.49 (hexane/EtOAc 10:1). To an ice-cold suspension of phosphonium salt 22 (2.56 g, 4.97 mmol) in THF (30 mL) was added a solution of NaHMDS (1.0 M in THF, 4.30 mL, 4.30 mmol). The mixture was stirred at 0 °C for 1 h and cooled to −90 °C (liquid N2 + hexane). A solution of the above aldehyde 21 in THF (4 mL) was added to the mixture. The mixture was allowed to warm to 0 °C gradually over 4.5 h and diluted with saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated to afford TBS ether of 23 as a liquid, which was used for the next reaction without further purification: Rf = 0.74 (hexane/EtOAc 10:1). A mixture of the above product and PPTS (955 mg, 3.80 mmol) in MeOH (30 mL) was stirred at rt for 14 h, diluted with brine, and concentrated to remove most of the MeOH. The resulting mixture was extracted with EtOAc three times. The combined extracts were 159

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

Article

The Journal of Organic Chemistry 10:1); 1H NMR (300 MHz, CDCl3) δ −0.002 (s, 6 H), 0.04 (s, 9 H), 0.87 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.0 Hz, 3 H), 2.06 (t, J = 6.3 Hz, 1 H), 2.23−2.48 (m, 2 H), 4.00 (dt, J = 5.4, 6.3 Hz, 1 H), 4.58 (dq, J = 8.4, 6.0 Hz, 1 H), 5.07−5.23 (m, 2 H), 5.25−5.36 (m, 1 H), 5.50 (dd, J = 10.5, 8.4 Hz, 1 H), 5.74 (d, J = 18.6 Hz, 1 H), 5.92 (dd, J = 18.6, 5.4 Hz, 1 H), 7.30−7.45 (m, 6 H), 7.63−7.71 (m, 4 H). To a solution of olefin 26 (1.20 g, 1.98 mmol) in EtOH (19 mL) was added CAN (1.63 g, 2.97 mmol) at 15 °C. The solution was stirred at 15 °C for 23 h and diluted with saturated NaHCO3. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with saturated NaHCO3, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 4 as a diastereomeric mixture (662 mg, 67%) as a liquid: Rf = 0.71 (hexane/ EtOAc 3:1); [α]D22 −8 (c 1.07, CHCl3); IR (neat) 3309, 1427, 1248, 1111, 867, 838; 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 9 H), 1.04 (s, 9 H), 1.17 (d, J = 6.0 Hz, 3 H), 1.516 and 1.521 (2 d, J = 4.4 and 4.4 Hz, 1 H), 2.04−2.18 (m, 2 H), 2.24−2.48 (m, 2 H), 4.00−4.08 (m, 1 H), 4.57 (dq, J = 8.4, 6.0 Hz, 1 H), 5.13 (dtt, J = 10.8, 7.2, 1.2 Hz, 1 H), 5.22−5.35 (m, 2 H), 5.52 (ddt, J = 10.8, 8.4, 1.6 Hz, 1 H), 5.84 (dd, J = 18.8, 1.2 Hz, 1 H), 6.00 (ddd, J = 18.8, 5.2, 0.4 Hz, 1 H), 7.31−7.48 (m, 6 H), 7.63−7.76 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −1.2 (+), 19.2 (−), 24.6 (+), 25.9 (−), 27.0 (+), 34.9 (−), 66.0 (+), 73.7 (+), 125.0 (+), 126.1 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 131.0 (+), 134.3 (−), 134.6 (−), 135.3 (+), 135.9 (+), 136.0 (+), 147.6 (+); HRMS (FAB+) calcd for C30H44O2Si2Na [(M + Na)+] 515.2778, found 515.2760. (1S,3Z,6Z,8R)-8-[(tert-Butyldiphenylsilyl)oxy]-1-[(2S,3S)-3(trimethylsilyl)oxiran-2-yl]nona-3,6-dien-1-ol (27). To a solution of Ti(O-i-Pr)4 (0.14 mL, 0.478 mmol) in CH2Cl2 (1.5 mL) at −10 °C was added L-(+)-DIPT (0.12 mL, 0.571 mmol). The solution was stirred at −10 °C for 30 min and cooled to −20 °C. A solution of allylic alcohol 4 (218 mg, 0.442 mmol) in CH2Cl2 (0.5 mL) was added. The solution was stirred at −20 °C for 30 min and cooled to −40 °C. A solution of t-BuOOH (3.50 M in CH2Cl2, 0.21 mL, 0.735 mmol) was added dropwise. After the addition, the solution was stirred at −18 °C for 6 h, and Me2S (0.11 mL, 1.5 mmol) was added. The solution was stirred at −20 °C for 30 min before addition of aqueous 10% tartaric acid (0.27 mL), NaF (308 mg, 7.33 mmol), and Celite (180 mg). The mixture was vigorously stirred at rt for 30 min and filtered through a pad of Celite. The filtrate was concentrated, and the residue was diluted with ether (2 mL) and aqueous 10% NaOH (1.6 mL) at 0 °C. The mixture was vigorously stirred at 0 °C for 20 min and extracted with ether three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford epoxy alcohol 27 (88 mg, 39%) and allylic alcohol 28 (91 mg, 42%). Diastereomeric excesses of the epoxy and allylic alcohols were determined to be >99% by 1H NMR spectroscopy of the derived MTPA esters. Epoxy alcohol 27 as a liquid: Rf = 0.43 (hexane/EtOAc 5:1); [α]D20 −9 (c 0.80, CHCl3); IR (neat) 3449, 1250, 1111, 1078, 842 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 9 H), 1.04 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 1.75 (d, J = 2.4 Hz, 1 H), 2.10−2.23 (m, 2 H), 2.30−2.49 (m, 2 H), 2.32 (d, J = 3.6 Hz, 1 H), 2.82 (t, J = 3.6 Hz, 1 H), 3.73−3.79 (m, 1 H), 4.58 (ddq, J = 8.4, 1.2, 6.4 Hz, 1 H), 5.13 (ddt, J = 10.8, 1.2, 7.6 Hz, 1 H), 5.27 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H), 5.36 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H), 5.53 (ddt, J = 10.8, 8.4, 2.0 Hz, 1 H), 7.32−7.45 (m, 6 H), 7.63−7.71 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −3.6 (+), 19.2 (−), 24.6 (+), 25.8 (−), 27.0 (+), 31.6 (−), 47.6 (+), 58.0 (+), 65.9 (+), 69.2 (+), 124.4 (+), 126.0 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.7 (+), 134.3 (−), 134.6 (−), 135.4 (+), 135.9 (+), 136.0 (+); HRMS (FAB+) calcd for C30H44O3Si2Na [(M + Na)+] 531.2727, found 531.2726. Allylic alcohol 28 as a liquid: Rf = 0.57 (hexane/EtOAc 5:1); [α]D19 −5 (c 1.05, CHCl3); IR (neat) 3327, 1427, 1248, 1110, 866, 838 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 9 H), 1.05 (s, 9 H), 1.17 (d, J = 6.0 Hz, 3 H), 1.59 (br s, 1 H), 2.12 (t, J = 6.0 Hz, 2 H), 2.29−2.49 (m, 2 H), 4.01−4.10 (m, 1 H), 4.58 (dq, J = 8.8, 6.0 Hz, 1 H), 5.14 (dt, J = 10.8, 7.2 Hz, 1 H), 5.24−5.38 (m, 2 H), 5.53 (dd, J = 10.4, 8.8 Hz, 1 H), 5.85 (d, J = 18.8 Hz, 1 H), 6.00 (dd, J = 18.8, 4.8 Hz, 1 H), 7.32−7.45 (m, 6 H), 7.64−

7.72 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −1.2 (+), 19.2 (−), 24.6 (+), 25.9 (−), 27.0 (+), 34.9 (−), 66.0 (+), 73.7 (+), 125.0 (+), 126.1 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 131.0 (+), 134.3 (−), 134.6 (−), 135.3 (+), 135.9 (+), 136.0 (+), 147.7 (+); HRMS (FAB+) calcd for C30H43O2Si2 [(M − H)+] 491.2802, found 491.2806. (5R,6Z,9Z,12S)-2,2,5,14,14,15,15-Heptamethyl-3,3-diphenyl-12-[(2S,3S)-3-(trimethylsilyl)oxiran-2-yl]-4,13-dioxa-3,14disilahexadeca-6,9-diene (TBS ether of 27). To an ice-cold solution of epoxy alcohol 27 (87 mg, 0.17 mmol) in CH2Cl2 (1.7 mL) were added 2,6-lutidine (0.10 mL, 0.86 mmol) and TBSOTf (0.12 mL, 0.52 mmol). The solution was stirred at 0 °C for 3.5 h and diluted with H2O. The resulting mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford TBS ether of 27 (107 mg, 100%) as a liquid: Rf = 0.80 (hexane/EtOAc 5:1); [α]D20 −4 (c 0.93, CHCl3); IR (neat) 1251, 1111, 839 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 6 H), 0.05 (s, 9 H), 0.86 (s, 9 H), 1.04 (s, 9 H), 1.16 (d, J = 6.4 Hz, 3 H), 2.11−2.26 (m, 2 H), 2.15 (d, J = 3.6 Hz, 1 H), 2.29−2.51 (m, 2 H), 2.68 (dd, J = 5.6, 3.6 Hz, 1 H), 3.43 (q, J = 5.6 Hz, 1 H), 4.59 (dq, J = 8.4, 6.4 Hz, 1 H), 5.14 (dt, J = 10.6, 7.6 Hz, 1 H), 5.20 (dt, J = 11.0, 6.8 Hz, 1 H), 5.37 (dt, J = 11.0, 6.8 Hz, 1 H), 5.52 (dd, J = 10.6, 8.4 Hz, 1 H), 7.31−7.44 (m, 6 H), 7.64−7.71 (m, 4 H); 13CAPT NMR (100 MHz, CDCl3) δ −4.6 (+), −4.3 (+), −3.5 (+), 18.2 (−), 19.3 (−), 24.7 (+), 25.87 (+), 25.91 (−), 27.0 (+), 33.7 (−), 49.9 (+), 58.5 (+), 66.0 (+), 73.2 (+), 125.4 (+), 126.3 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 134.3 (−), 134.7 (−), 135.2 (+), 135.9 (+), 136.0 (+); HRMS (FAB+) calcd for C36H58O3Si3Na [(M + Na)+] 645.3592, found 645.3575. (2E,4S,6Z,9Z,11R)-4-[(tert-Butyldimethylsilyl)oxy]-11-[(tertbutyldiphenylsilyl)oxy]dodeca-2,6,9-trienenitrile (29). To an ice-cold solution of TBS ether of 27 (191 mg, 0.307 mmol) in toluene (3 mL) was added a solution of Et2AlCN (0.67 M in toluene, 1.20 mL, 0.804 mmol). The reaction was carried out at rt for 4 h and quenched by adding H2O (0.20 mL, 11 mmol), NaF (386 mg, 9.19 mmol), and Celite at 0 °C. The resulting mixture was vigorously stirred at rt for 20 min and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (hexane/EtOAc) to afford nitrile 29 (150 mg, 87%) as a liquid: Rf = 0.69 (hexane/EtOAc 5:1); [α]D20 +5 (c 1.33, CHCl3); IR (neat) 2225, 1112, 1083, 837, 703 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 3 H), 0.04 (s, 3 H), 0.90 (s, 9 H), 1.05 (s, 9 H), 1.18 (d, J = 6.4 Hz, 3 H), 2.10 (t, J = 6.8 Hz, 2 H), 2.23−2.44 (m, 2 H), 4.22 (ddt, J = 3.6, 2.0, 6.0 Hz, 1 H), 4.56 (dq, J = 8.4, 6.4 Hz, 1 H), 5.12 (dt, J = 10.8, 6.8 Hz, 1 H), 5.23 (dt, J = 10.8, 6.8 Hz, 1 H), 5.26 (dt, J = 10.8, 6.8 Hz, 1 H), 5.55 (dd, J = 10.8, 8.4 Hz, 1 H), 5.58 (dd, J = 16.0, 2.0 Hz, 1 H), 6.64 (dd, J = 16.0, 3.6 Hz, 1 H), 7.33−7.47 (m, 6 H), 7.65−7.72 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.83 (+), −4.79 (+), 18.2 (−), 19.2 (−), 24.6 (+), 25.8 (+), 25.9 (−), 27.0 (+), 34.9 (−), 65.9 (+), 71.2 (+), 98.7 (+), 117.5 (−), 123.6 (+), 125.7 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.9 (+), 134.3 (−), 134.5 (−), 135.4 (+), 135.9 (+), 136.0 (+), 156.7 (+); HRMS (FAB+) calcd for C34H49NO2Si2Na [(M + Na)+] 582.3200, found 582.3208. (1R,3Z,6Z,8R)-8-[(tert-Butyldiphenylsilyl)oxy]-1-[(2R,3R)-3(trimethylsilyl)oxiran-2-yl]nona-3,6-dien-1-ol (30). To an icecold solution of Ti(O-i-Pr)4 (0.11 mL, 0.37 mmol) in CH2Cl2 (1 mL) was added D-(−)-DIPT (0.09 mL, 0.43 mmol). The solution was stirred at 0 °C for 30 min and cooled to −10 °C. A solution of allylic alcohol 28 (168 mg, 0.341 mmol) in CH2Cl2 (1 mL) was added. The solution was stirred at −10 °C for 30 min and cooled to −40 °C. A solution of t-BuOOH (2.96 M in CH2Cl2, 0.40 mL, 1.18 mmol) was added dropwise. After the addition, the solution was stirred at −18 °C for 24 h, and Me2S (0.15 mL, 2.0 mmol) was added. The solution was stirred at −18 °C for 30 min before the addition of aqueous 10% tartaric acid (0.1 mL), NaF (98 mg, 2.3 mmol), and Celite (60 mg). The mixture was vigorously stirred at rt for 30 min and filtered through a pad of Celite. The filtrate was mixed with 1 N NaOH (3.4 mL), and the mixture was vigorously stirred at rt for 30 min and 160

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

Article

The Journal of Organic Chemistry extracted with CH2Cl2 two times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford epoxy alcohol 30 (150 mg, 87%) as a liquid: Rf = 0.43 (hexane/EtOAc 5:1); IR (neat) 3461, 1250, 1111, 1079, 842 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 9 H), 1.05 (s, 9 H), 1.18 (d, J = 6.4 Hz, 3 H), 1.82 (br s, 1 H), 2.17 (t, J = 7.2 Hz, 2 H), 2.33 (d, J = 3.6 Hz, 1 H), 2.35 (dt, J = 15.6, 7.2 Hz, 1 H), 2.44 (dt, J = 15.6, 7.2 Hz, 1 H), 2.82 (t, J = 3.6 Hz, 1 H), 3.73−3.80 (m, 1 H), 4.59 (dq, J = 8.4, 6.4 Hz, 1 H), 5.15 (dt, J = 10.8, 7.2 Hz, 1 H), 5.28 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H), 5.37 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H), 5.54 (ddt, J = 10.8, 8.4, 2.0 Hz, 1 H), 7.32−7.46 (m, 6 H), 7.65−7.72 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −3.6 (+), 19.2 (−), 24.6 (+), 25.8 (−), 27.0 (+), 31.6 (−), 47.6 (+), 58.0 (+), 65.9 (+), 69.2 (+), 124.4 (+), 126.0 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.7 (+), 134.3 (−), 134.6 (−), 135.3 (+), 135.9 (+), 136.0 (+); HRMS (FAB+) calcd for C30H44O3Si2Na [(M + Na)+] 531.2727, found 531.2724. (1S,3Z,6Z,8R)-8-[(tert-Butyldiphenylsilyl)oxy]-1-[(2R,3R)-3(trimethylsilyl)oxiran-2-yl]nona-3,6-dien-1-ol (31). A mixture of epoxy alcohol 30 (201 mg, 0.395 mmol), 4-NO2-C6H4CO2H (104 mg, 0.622 mmol), DIAD (0.16 mL, 0.812 mmol), and PPh3 (162 mg, 0.618 mmol) in THF (4 mL) was stirred at rt for 4 h and diluted with saturated NaHCO3. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford the corresponding ester as a liquid, which was used for the next reaction: Rf = 0.63 (hexane/EtOAc 5:1). To an ice-cooled solution of the above ester in THF (3 mL) and MeOH (3 mL) was added 2 N NaOH (2 mL). The mixture was stirred at 0 °C for 1 h and diluted with saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford epoxy alcohol 31 (174 mg, 86%) as a liquid: Rf = 0.34 (hexane/EtOAc 5:1); [α]D20 −7 (c 1.03, CHCl3); IR (neat) 3431, 1250, 1111, 1078, 842 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 9 H), 1.04 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 1.93 (d, J = 5.2 Hz, 1 H), 2.14−2.28 (m, 2 H), 2.19 (d, J = 3.6 Hz, 1 H), 2.30−2.49 (m, 2 H), 2.77 (dd, J = 5.2, 3.6 Hz, 1 H), 3.38 (tt, J = 6.8, 5.2 Hz, 1 H), 4.58 (ddq, J = 8.4, 0.8, 6.4 Hz, 1 H), 5.13 (ddt, J = 10.8, 0.8, 7.2 Hz, 1 H), 5.26 (dt, J = 10.8, 7.2 Hz, 1 H), 5.32 (dt, J = 10.8, 7.2 Hz, 1 H), 5.53 (ddt, J = 10.8, 8.4, 1.6 Hz, 1 H), 7.32−7.45 (m, 6 H), 7.64−7.71 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −3.6 (+), 19.2 (−), 24.6 (+), 25.8 (−), 27.0 (+), 32.6 (−), 49.3 (+), 58.7 (+), 65.9 (+), 72.4 (+), 124.4 (+), 126.0 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.8 (+), 134.3 (−), 134.6 (−), 135.4 (+), 135.9 (+), 136.0 (+); HRMS (FAB+) calcd for C30H43O3Si2 [(M − H)+] 507.2751, found 507.2773. (5R,6Z,9Z,12S)-2,2,5,14,14,15,15-Heptamethyl-3,3-diphenyl-12-[(2R,3R)-3-(trimethylsilyl)oxiran-2-yl]-4,13-dioxa-3,14disilahexadeca-6,9-diene (32). To an ice-cold solution of epoxy alcohol 31 (172 mg, 0.338 mmol) in CH2Cl2 (3.4 mL) were added 2,6-lutidine (0.14 mL, 1.21 mmol) and TBSOTf (0.17 mL, 0.74 mmol). The solution was stirred at 0 °C for 2.5 h and diluted with H2O. The resulting mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/ EtOAc) to afford silyl ether 32 (173 mg, 82%) as a liquid: Rf = 0.77 (hexane/EtOAc 5:1); [α]D20 −2 (c 1.07, CHCl3); IR (neat) 1251, 1110, 839 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.026 (s, 9 H), 0.034 (s, 3 H), 0.10 (s, 3 H), 0.90 (s, 9 H), 1.05 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 2.01 (d, J = 3.6 Hz, 1 H), 2.14 (t, J = 7.2 Hz, 2 H), 2.27− 2.37 (m, 1 H), 2.38−2.49 (m, 1 H), 2.71 (dd, J = 6.8, 3.6 Hz, 1 H), 3.21 (q, J = 6.8 Hz, 1 H), 4.59 (dq, J = 8.4, 6.4 Hz, 1 H), 5.13 (dt, J = 10.8, 7.2 Hz, 1 H), 5.17 (dt, J = 10.8, 7.2 Hz, 1 H), 5.29 (dtt, J = 10.8, 7.2, 1.2 Hz, 1 H), 5.53 (ddt, J = 10.8, 8.4, 1.6 Hz, 1 H), 7.32−7.45 (m, 6 H), 7.64−7.72 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.9 (+), −4.3 (+), −3.5 (+), 18.2 (−), 19.3 (−), 24.6 (+), 25.8 (−), 25.9 (+), 27.0 (+), 33.2 (−), 49.0 (+), 59.5 (+), 66.0 (+), 75.9 (+),

125.4 (+), 126.2 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 134.3 (−), 134.6 (−), 135.3 (+), 135.9 (+), 136.0 (+); HRMS (FAB+) calcd for C36H57O3Si3 [(M − H)+] 621.3616, found 621.3611. (2E,4S,6Z,9Z,11R)-4-[(tert-Butyldimethylsilyl)oxy]-11-[(tertbutyldiphenylsilyl)oxy]dodeca-2,6,9-trienenitrile (29). To an ice-cold solution of epoxide 32 (168 mg, 0.270 mmol) in toluene (2.7 mL) was added a solution of Et2AlCN (0.70 M in toluene, 0.97 mL, 0.68 mmol). The solution was stirred at rt for 3 h, and H2O (0.40 mL, 22 mmol), NaF (361 mg, 8.60 mmol), and Celite were added at 0 °C. The resulting mixture was vigorously stirred at rt for 20 min and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (hexane/EtOAc) to afford nitrile 29 (134 mg, 88%). The 1H NMR spectrum and Rf value were identical to those prepared from epoxy alcohol 27. (2E,4S,6Z,9Z,11R)-4-{(tert-Butyldimethylsilyl)oxy}-11-{(tertbutyldiphenylsilyl)oxy}dodeca-2,6,9-trienal (3). To a solution of nitrile 29 (115 mg, 0.205 mmol) in toluene (2.1 mL) was added a solution of DIBAL (1.02 M in toluene, 0.26 mL, 0.265 mmol) at −78 °C. The solution was stirred at −78 °C for 1 h and poured into 3 N HCl. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed successively with saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford aldehyde 3 (109 mg, 94%) as a liquid: Rf = 0.41 (hexane/ EtOAc 10:1); [α]D22 +10 (c 0.75, CHCl3); IR (neat) 1695, 1256, 1109, 837 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3 H), 0.04 (s, 3 H), 0.90 (s, 9 H), 1.04 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 2.17 (t, J = 6.4 Hz, 2 H), 2.25−2.46 (m, 2 H), 4.35 (ddt, J = 4.4, 1.6, 6.4 Hz, 1 H), 4.56 (ddq, J = 8.2, 0.8, 6.4 Hz, 1 H), 5.07−5.16 (m, 1 H), 5.25 (dt, J = 10.8, 6.4 Hz, 1 H), 5.28 (dt, J = 10.8, 7.2 Hz, 1 H), 5.54 (ddt, J = 10.8, 8.2, 1.6 Hz, 1 H), 6.24 (ddd, J = 15.6, 8.0, 1.6 Hz, 1 H), 6.69 (dd, J = 15.6, 4.4 Hz, 1 H), 7.32−7.45 (m, 6 H), 7.64−7.72 (m, 4 H), 9.53 (d, J = 8.0 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.81 (+), −4.70 (+), 18.2 (−), 19.2 (−), 24.6 (+), 25.8 (+), 25.9 (−), 27.0 (+), 35.1 (−), 65.9 (+), 71.4 (+), 124.1 (+), 125.8 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.6 (+), 130.8 (+), 134.3 (−), 134.5 (−), 135.4 (+), 135.86 (+), 135.93 (+), 159.4 (+), 193.6 (+); HRMS (FAB+) calcd for C34H50O3Si2Na [(M + Na)+] 585.3196, found 585.3199. (Z)-7-[(tert-Butyldimethylsilyl)oxy]hept-3-en-1-ol (36). To a solution of Li (∼30 mg, 4.3 mmol) in liquid NH3 (∼30 mL) and THF (15 mL) was added Fe(NO3)3·9H2O (7 mg, 0.017 mmol) at −78 °C. The mixture was stirred under reflux for 20 min and cooled to −78 °C. Li (380 mg, 55 mmol) was added portionwise. The mixture was stirred under reflux for 1 h and cooled to −78 °C. 3Butyn-1-ol (34) (1.70 mL, 22.5 mmol) was added. The mixture was stirred under reflux for 1 h and cooled to −78 °C. A solution of silyl ether 33 (3.71 g, 14.6 mmol) in THF (5 mL) was added. The mixture was stirred under reflux for 2 h, and a mixed solution of H2O (10 mL) and THF (10 mL) was added carefully. The mixture was stirred at rt for 1 h and diluted with saturated NH4Cl. The resulting mixture was extracted with Et2O three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 35 (2.85 g, 80%) as a liquid: Rf = 0.27 (hexane/EtOAc 5:1); 1 H NMR (400 MHz, CDCl3) δ 0.03 (s, 6 H), 0.87 (s, 9 H), 1.67 (tt, J = 6.8, 6.0 Hz, 2 H), 2.22 (tt, J = 6.8, 2.4 Hz, 2 H), 2.40 (tt, J = 6.0, 2.4 Hz, 2 H), 3.66 (t, J = 6.0 Hz, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −5.3 (+), 15.2 (−), 18.4 (−), 23.2 (−), 26.0 (+), 32.0 (−), 61.4 (−), 61.7 (−), 76.6 (−), 82.1 (−). To a solution of alcohol 35 (854 mg, 3.52 mmol) in EtOAc (20 mL) were added 5% Pd/CaCO3 (poisoned with Pb, TCI, 9 mg, 0.0042 mmol) and quinoline (0.1 M in EtOAc, 1.4 mL, 0.14 mmol). The mixture was stirred at rt for 1 h under H2 and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 36 (835 mg, 97%) as a liquid: Rf = 0.27 (hexane/EtOAc 5:1); 1 H NMR (400 MHz, CDCl3) δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.56 (tt, J = 7.2, 6.4 Hz, 2 H), 1.81 (br s, 1 H), 2.12 (q, J = 7.2 Hz, 2 H), 2.32 161

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

Article

The Journal of Organic Chemistry

0.89 (s, 9 H), 1.56 (tt, J = 7.2, 6.4 Hz, 2 H), 2.11 (q, J = 7.2 Hz, 2 H), 2.64 (q, J = 7.2 Hz, 2 H), 2.77 (t, J = 7.2 Hz, 2 H), 3.12 (t, J = 7.2 Hz, 2 H), 3.60 (t, J = 6.4 Hz, 2 H), 5.28−5.44 (m, 3 H), 5.49 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −5.2 (+), 5.4 (−), 18.4 (−), 23.7 (−), 25.9 (−), 26.1 (+), 31.5 (−), 32.8 (−), 62.6 (−), 127.7 (+), 128.2 (+), 130.1 (+), 130.8 (+); HRMS (FAB+) calcd for C16H32OSiI [(M + H)+] 395.1267, found 395.1264. (4Z,7Z,10Z,12E,14S,16Z,19Z,21R)-14-[(tert-Butyldimethylsilyl)oxy]-21-[(tert-butyldiphenylsilyl)oxy]docosa4,7,10,12,16,19-hexaen-1-ol (44). A solution of iodide 42 (418 mg, 1.06 mmol) and PPh3 (460 mg, 1.75 mmol) in MeCN (11 mL) was heated under reflux for 21 h, cooled to rt, and concentrated. The residue was washed with ether six times to afford phosphonium salt 2 (605 mg, 87%) as a viscous liquid: 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 6 H), 0.87 (s, 9 H), 1.50 (tt, J = 7.2, 6.6 Hz, 2 H), 1.95 (q, J = 7.2 Hz, 2 H), 2.40−2.60 (m, 2 H), 2.55 (t, J = 6.9 Hz, 2 H), 3.55 (t, J = 6.6 Hz, 2 H), 3.77−3.94 (m, 2 H), 5.10−5.47 (m, 3 H), 5.56−5.68 (m, 1 H), 7.66−7.91 (m, 15 H). To an ice-cold suspension of phosphonium salt 2 (364 mg, 0.554 mmol) in THF (3.7 mL) was added a solution of NaHMDS (1.0 M in THF, 0.48 mL, 0.48 mmol). The mixture was stirred at 0 °C for 1 h and cooled to −78 °C. A solution of aldehyde 3 (208 mg, 0.369 mmol) in THF (1 mL) was added to the mixture dropwise. The mixture was allowed to warm to rt gradually, stirred overnight, and diluted with saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was passed through a short silica gel column, and product 43 obtained as a liquid was used for the next reaction without further purification: Rf = 0.80 (hexane/EtOAc 5:1); 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 6 H), 0.04 (s, 6 H), 0.88 (s, 9 H), 0.89 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.0 Hz, 3 H), 1.54−1.63 (m, 2 H), 1.97−2.18 (m, 4 H), 2.22−2.48 (m, 2 H), 2.81 (t, J = 5.7 Hz, 2 H), 2.94 (t, J = 6.3 Hz, 2 H), 3.61 (t, J = 6.6 Hz, 2 H), 4.06−4.16 (m, 1 H), 4.57 (dq, J = 8.4, 6.0 Hz, 1 H), 5.05−5.22 (m, 2 H), 5.25−5.45 (m, 6 H), 5.50 (ddt, J = 10.8, 8.4, 1.5 Hz, 1 H), 5.58 (dd, J = 15.0, 6.3 Hz, 1 H), 5.95 (t, J = 11.1 Hz, 1 H), 6.43 (dd, J = 15.0, 11.1 Hz, 1 H), 7.29−7.45 (m, 6 H), 7.62−7.71 (m, 4 H). A mixture of the above olefin 43 and PPTS (97 mg, 0.39 mmol) in MeOH (4 mL) was stirred at rt for 7 h, diluted with brine, and concentrated to remove most of the MeOH. The resulting mixture was extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 44 (130 mg, 50% from aldehyde 3) as a liquid: Rf = 0.32 (hexane/EtOAc 5:1); [α]D21 +5 (c 1.08, CHCl3); IR (neat) 3316, 1255, 1110, 1075, 836 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 6 H), 0.88 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.4 Hz, 3 H), 1.27 (t, J = 5.6 Hz, 1 H), 1.64 (tt, J = 6.8, 6.4 Hz, 2 H), 2.04−2.20 (m, 4 H), 2.25−2.46 (m, 2 H), 2.83 (t, J = 5.2 Hz, 2 H), 2.94 (t, J = 6.2 Hz, 2 H), 3.65 (dt, J = 5.6, 6.4 Hz, 2 H), 4.12 (q, J = 6.0 Hz, 1 H), 4.57 (dq, J = 8.8, 6.4 Hz, 1 H), 5.12 (dt, J = 10.8, 7.2 Hz, 1 H), 5.17 (dt, J = 10.8, 7.2 Hz, 1 H), 5.26−5.46 (m, 6 H), 5.51 (dd, J = 10.8, 8.8 Hz, 1 H), 5.59 (dd, J = 15.2, 6.0 Hz, 1 H), 5.96 (t, J = 11.2 Hz, 1 H), 6.44 (dd, J = 15.2, 11.2 Hz, 1 H), 7.31−7.44 (m, 6 H), 7.63−7.71 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.7 (+), −4.3 (+), 18.3 (−), 19.2 (−), 23.6 (−), 24.6 (+), 25.7 (−), 25.9 (+), 26.1 (−), 27.0 (+), 32.5 (−), 36.3 (−), 62.5 (−), 66.0 (+), 72.8 (+), 124.3 (+), 125.8 (+), 126.4 (+), 127.5 (+), 127.6 (+), 127.8 (+), 128.3 (+), 128.5 (+), 128.7 (+), 129.36 (+), 129.42 (+), 129.5 (+), 129.57 (+), 129.58 (+), 134.3 (−), 134.6 (−), 135.1 (+), 135.87 (+), 135.94 (+), 136.8 (+); HRMS (FAB+) calcd for C44H66O3Si2Na [(M + Na)+] 721.4448, found 721.4450. (4Z,7Z,10Z,12E,14S,16Z,19Z,21R)-14-[(tert-Butyldimethylsilyl)oxy]-21-[(tert-butyldiphenylsilyl)oxy]docosa4,7,10,12,16,19-hexaenoic acid (45). A mixture of alcohol 44 (75 mg, 0.107 mmol), TPAP (5 mg, 0.014 mmol), NMO (20 mg, 0.171 mmol), and MS4A (55 mg) in CH2Cl2 (1.1 mL) was stirred at rt for 2.5 h and diluted with hexane. The resulting mixture was filtered through a pad of Celite. The filtrate was concentrated, and the residue

(q, J = 6.4 Hz, 2 H), 3.61 (t, J = 6.4 Hz, 2 H), 3.62 (t, J = 6.4 Hz, 2 H), 5.34−5.43 (m, 1 H), 5.49−5.58 (m, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −5.2 (+), 18.4 (−), 23.6 (−), 26.0 (+), 30.8 (−), 32.7 (−), 62.3 (−), 62.5 (−), 125.8 (+), 132.6 (+); HRMS (FAB+) calcd for C13H29O2Si [(M + H)+] 245.1937, found 245.1933. (Z)-tert-Butyl[(7-iodohept-4-en-1-yl)oxy]dimethylsilane (37). To an ice-cold solution of alcohol 36 (1.26 g, 5.15 mmol) in CH2Cl2 (30 mL) were added PPh3 (2.05 g, 7.82 mmol), imidazole (542 mg, 7.96 mmol), and I2 (2.04 g, 7.73 mmol). The mixture was stirred at 0 °C for 1.5 h and diluted with aqueous Na2S2O3. The resulting mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford iodide 37 (1.60 g, 88%) as a liquid: Rf = 0.78 (hexane/ EtOAc 5:1); 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6 H), 0.90 (s, 9 H), 1.58 (tt, J = 7.2, 6.4 Hz, 2 H), 2.09 (q, J = 7.2 Hz, 2 H), 2.63 (q, J = 7.2 Hz, 2 H), 3.13 (t, J = 7.2 Hz, 2 H), 3.61 (t, J = 6.4 Hz, 2 H), 5.29−5.38 (m, 1 H), 5.49−5.58 (m, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −5.2 (+), 5.6 (−), 18.4 (−), 23.8 (−), 26.1 (+), 31.5 (−), 32.6 (−), 62.5 (−), 128.3 (+), 132.1 (+); HRMS (FAB+) calcd for C13H28OSiI [(M + H)+] 355.0954, found 355.0957. (3Z,6Z)-10-[(tert-Butyldimethylsilyl)oxy]deca-3,6-dien-1-ol (41). A solution of iodide 37 (1.47 g, 4.15 mmol) and PPh3 (1.63 g, 6.21 mmol) in MeCN (40 mL) was heated under reflux for 19 h, cooled to rt, and concentrated. The residue was washed with ether six times to afford phosphonium salt 38 (2.34 g, 91%) as a viscous liquid.16 To an ice-cold suspension of phosphonium salt 38 (2.17 g, 3.52 mmol) in THF (20 mL) was added a solution of NaHMDS (1.0 M in THF, 2.80 mL, 2.80 mmol). The mixture was stirred at 0 °C for 1 h and cooled to −78 °C. A solution of aldehyde 39 (732 mg, 2.34 mmol) in THF (3 mL) was added to the mixture dropwise. The solution was allowed to warm to rt gradually, stirred overnight, and diluted with saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford olefin 40 as a liquid: Rf = 0.82 (hexane/EtOAc 5:1); 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 6 H), 0.89 (s, 9 H), 1.05 (s, 9 H), 1.51−1.63 (m, 2 H), 2.09 (dt, J = 7.5, 6.9 Hz, 2 H), 2.33 (dt, J = 5.7, 6.9 Hz, 2 H), 2.74 (t, J = 5.5 Hz, 2 H), 3.60 (t, J = 6.5 Hz, 2 H), 3.66 (t, J = 6.9 Hz, 2 H), 5.25−5.48 (m, 4 H), 7.32−7.46 (m, 6 H), 7.64−7.71 (m, 4 H). A solution of the above olefin 40, TBAF (1.0 M in THF, 0.66 mL, 0.66 mmol), and AcOH (0.040 mL, 0.70 mmol) in DMF (26 mL) was stirred at rt overnight and diluted with brine. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with saturated NaHCO3, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 41 (2.21 g, 58% from aldehyde 39) as a liquid: Rf = 0.46 (hexane/EtOAc 5:1); IR (neat) 3345, 1255, 1101, 836 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6 H), 0.89 (s, 9 H), 1.57 (tt, J = 7.2, 6.4 Hz, 2 H), 1.62 (br s, 1 H), 2.11 (q, J = 7.2 Hz, 2 H), 2.35 (dt, J = 7.2, 6.4 Hz, 2 H), 2.82 (t, J = 6.8 Hz, 2 H), 3.61 (t, J = 6.4 Hz, 2 H), 3.64 (t, J = 6.4 Hz, 2 H), 5.30−5.44 (m, 3 H), 5.53 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −5.2 (+), 18.4 (−), 23.6 (−), 25.8 (−), 26.0 (+), 30.9 (−), 32.8 (−), 62.3 (−), 62.7 (−), 125.5 (+), 128.0 (+), 129.9 (+), 131.4 (+); HRMS (FAB+) calcd for C16H33O2Si [(M + H)+] 285.2250, found 285.2243. tert-Butyl[{(4Z,7Z)-10-iododeca-4,7-dien-1-yl}oxy]dimethylsilane (42). To an ice-cold solution of alcohol 41 (320 mg, 1.12 mmol) in CH2Cl2 (11 mL) were added PPh3 (465 mg, 1.77 mmol), imidazole (115 mg, 1.69 mmol), and I2 (451 mg, 1.71 mmol). The mixture was stirred at 0 °C for 2 h and diluted with aqueous Na2S2O3 with vigorous stirring. The resulting mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford iodide 42 (418 mg, 94%) as a liquid: Rf = 0.83 (hexane/EtOAc 5:1); IR (neat) 1255, 1102, 836, 775 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 6 H), 162

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

Article

The Journal of Organic Chemistry was purified by chromatography on silica gel (hexane/EtOAc) to afford the corresponding aldehyde (51 mg, 68%) as a liquid: Rf = 0.57 (hexane/EtOAc 5:1); 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 6 H), 0.88 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.3 Hz, 3 H), 2.04−2.14 (m, 2 H), 2.23−2.45 (m, 4 H), 2.50 (tt, J = 6.9, 1.5 Hz, 2 H), 2.84 (t, J = 6.0 Hz, 2 H), 2.94 (t, J = 6.0 Hz, 2 H), 4.12 (q, J = 6.0 Hz, 1 H), 4.57 (dq, J = 8.7, 6.3 Hz, 1 H), 5.06−5.24 (m, 2 H), 5.24−5.45 (m, 6 H), 5.51 (dd, J = 10.8, 8.7 Hz, 1 H), 5.59 (dd, J = 15.0, 6.0 Hz, 1 H), 5.96 (t, J = 11.1 Hz, 1 H), 6.44 (dd, J = 15.0, 11.1 Hz, 1 H), 7.30−7.45 (m, 6 H), 7.60−7.72 (m, 4 H), 9.77 (t, J = 1.5 Hz, 1 H). A mixture of the above aldehyde (51 mg, 0.073 mmol), 2-methyl-2butene (0.16 mL, 1.51 mmol), and NaClO2 (79% purity, 16 mg, 0.14 mmol) in phosphate buffer (pH 5.0, 1.4 mL) and t-BuOH (1.4 mL) was stirred at rt for 1 h and diluted with H2O. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford acid 45 (42 mg, 81%) as a liquid: Rf = 0.20 (hexane/EtOAc 5:1); [α]D21 +5 (c 0.86, CHCl3); IR (neat) 1712, 1255, 1110, 1078, 836 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 6 H), 0.90 (s, 9 H), 1.06 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 2.04−2.18 (m, 2 H), 2.26−2.48 (m, 6 H), 2.85 (t, J = 5.6 Hz, 2 H), 2.96 (t, J = 6.2 Hz, 2 H), 4.13 (q, J = 6.0 Hz, 1 H), 4.59 (dq, J = 8.4, 6.4 Hz, 1 H), 5.14 (dt, J = 10.8, 7.2 Hz, 1 H), 5.19 (dt, J = 10.8, 7.2 Hz, 1 H), 5.26−5.57 (m, 7 H), 5.60 (dd, J = 15.0, 6.0 Hz, 1 H), 5.98 (t, J = 11.2 Hz, 1 H), 6.46 (dd, J = 15.0, 11.2 Hz, 1 H), 7.30−7.46 (m, 6 H), 7.62−7.74 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.7 (+), −4.3 (+), 18.3 (−), 19.2 (−), 22.5 (−), 24.6 (+), 25.7 (−), 25.9 (+), 26.1 (−), 27.0 (+), 34.0 (−), 36.3 (−), 66.0 (+), 72.9 (+), 124.3 (+), 125.8 (+), 126.4 (+), 127.5 (+), 127.6 (+), 127.7 (+), 128.1 (+), 128.3 (+), 128.4 (+), 129.4 (+), 129.5 (+), 129.6 (+), 134.3 (−), 134.6 (−), 135.1 (+), 135.88 (+), 135.95 (+), 136.8 (+), 179.2 (−); HRMS (FAB+) calcd for C44H64O4Si2Na [(M + Na)+] 735.4241, found 735.4239. 14S,21R-diHDHA (1a). A solution of acid 45 (21 mg, 0.029 mmol) and TBAF (1.0 M in THF, 0.29 mL, 0.29 mmol) in THF (0.3 mL) was stirred at rt for 8 h and diluted with phosphate buffer (pH 5.0). The resulting mixture was extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/ MeOH) to afford 14S,21R-diHDHA (1a) (10 mg, 94%) as a liquid: Rf = 0.37 (CH2Cl2/MeOH 10:1); [α]D20 +19 (c 0.56, CHCl3); UV (MeOH) λmax 235 nm; lit. UV (MeOH/H2O/AcOH) λmax 236 nm,1b UV (MeOH) λmax 235 nm;3a IR (neat) 3468, 1710, 1411, 1274, 1057 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.26 (d, J = 6.4 Hz, 3 H), 2.20−2.28 (m, 1 H), 2.32−2.50 (m, 5 H), 2.58−2.67 (m, 1 H), 2.72− 3.08 (m, 4 H), 3.12−3.23 (m, 1 H), 3.5−5.1 (m, 3 H), 4.20−4.28 (m, 1 H), 4.74 (dq, J = 8.0, 6.4 Hz, 1 H), 5.32−5.50 (m, 8 H), 5.57−5.68 (m, 1 H), 5.73 (dd, J = 15.2, 6.0 Hz, 1 H), 5.99 (t, J = 11.2 Hz, 1 H), 6.60 (dd, J = 15.2, 11.2 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ 22.9 (−), 23.0 (+), 25.8 (−), 26.25 (−), 26.31 (−), 33.9 (−), 35.5 (−), 63.4 (+), 72.0 (+), 125.5 (+), 125.8 (+), 127.5 (+), 127.7 (+), 127.9 (+), 128.8 (+), 129.1 (+), 129.4 (+), 130.5 (+), 130.7 (+), 133.4 (+), 135.3 (+), 176.8 (−); HRMS (FAB−) calcd for C22H31O4 [(M − H)−] 359.2222, found 359.2219. (S,Z)-5-[(tert-Butyldiphenylsilyl)oxy]hex-3-en-1-ol (ent-23). A solution of ethyl lactate (>99% ee, 2.03 mL, 17.2 mmol), TBDPSCl (5.80 mL, 22.3 mmol), and imidazole (1.87 g, 27.5 mmol) in DMF (50 mL) was stirred at rt for 16 h and diluted with saturated NaHCO3. The product was extracted with EtOAc and purified by chromatography on silica gel (hexane/EtOAc) to afford silyl ether 46 (5.87 g, 96%). The 1H NMR spectrum was identical with that reported.17 To a solution of ester 46 (1.29 g, 3.62 mmol) in CH2Cl2 (20 mL) cooled to −78 °C was added a solution of DIBAL (1.02 M in hexane, 4.60 mL, 4.69 mmol) dropwise. The solution was stirred at −78 °C for 1 h and poured into a mixture of H2O (1.3 mL, 72 mmol) and NaF (1.5 g, 36 mmol). The mixture was filtered through a pad of Celite, and the filtrate was concentrated to afford the corresponding aldehyde. A solution of the aldehyde dissolved in THF (4 mL) was

added to a suspension of phosphonium salt 22 (2.42 g, 4.69 mmol) and NaHMDS (1.0 M in THF, 3.96 mL, 3.96 mmol) in THF (27 mL) at −90 °C. The mixture was warmed to 0 °C over 5 h and diluted with saturated NH4Cl. The product was extracted with EtOAc to afford the corresponding olefin, which was mixed with PPTS (955 mg, 3.80 mmol) in MeOH (25 mL). After 12 h at rt, the solution was diluted with brine and concentrated to remove most of the MeOH. The product was extracted with EtOAc and purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol ent-23 (1.08 g, 84% from ester 46). The 1H NMR spectrum was identical with that of 23. (S,Z)-tert-Butyl[(6-iodohex-3-en-2-yl)oxy]diphenylsilane (ent-24). To an ice-cold solution of alcohol ent-23 (3.11 g, 8.77 mmol) in CH2Cl2 (50 mL) were added PPh3 (3.47 g, 13.2 mmol), imidazole (906 mg, 13.3 mmol), and I2 (3.45 g, 13.1 mmol). The mixture was stirred at 0 °C for 4 h and diluted with aqueous Na2S2O3 with vigorous stirring. The resulting mixture was extracted with CH2Cl2 three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford iodide ent-24 (3.84 g, 94%). The 1H NMR spectrum was coincident with that of 24. (1E,5Z,8Z,10S)-10-[(tert-Butyldiphenylsilyl)oxy]-1(trimethylsilyl)undeca-1,5,8-trien-3-ol (ent-4). A solution of the above iodide (1.22 g, 2.63 mmol) and PPh3 (1.41 g, 5.38 mmol) in MeCN (26 mL) was heated under reflux for 39 h, cooled to rt, and concentrated. The residue was washed with ether six times to afford phosphonium salt ent-8 (1.88 g, 98%). The 1H NMR spectrum was coincident with that of 8. To an ice-cold suspension of phosphonium salt ent-8 (3.25 g, 4.47 mmol) in THF (24 mL) was added a solution of NaHMDS (1.0 M in THF, 3.50 mL, 3.50 mmol). The mixture was stirred at 0 °C for 1 h and cooled to −90 °C (liquid N2 + hexane). A solution of the above aldehyde 7 (842 mg, 2.94 mmol) in THF (5 mL) was added to the mixture dropwise. The solution was allowed to warm to rt gradually over 17 h before addition of saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford olefin 47 (1.63 g, 91%): Rf = 0.83 (hexane/EtOAc 5:1). The 1 H NMR spectrum was consistent with that of 26. To a solution of olefin 47 (1.63 g, 2.68 mmol) in EtOH (24 mL) was added CAN (2.00 g, 3.65 mmol) at 15 °C. The solution was stirred at 15 °C for 21 h and diluted with saturated NaHCO3. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with saturated NaHCO3, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol ent-4 as a diastereomeric mixture (894 mg, 68%) as a liquid: Rf = 0.63 (hexane/ EtOAc 5:1); IR (neat) 3347, 1427, 1248, 1110, 866, 838; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 9 H), 1.05 (s, 9 H), 1.18 (d, J = 6.0 Hz, 3 H), 1.54−1.59 (m, 1 H), 2.06−2.19 (m, 2 H), 2.25−2.49 (m, 2 H), 4.01−4.09 (m, 1 H), 4.59 (dq, J = 8.4, 6.0 Hz, 1 H), 5.14 (dt, J = 10.8, 7.2 Hz, 1 H), 5.24−5.38 (m, 2 H), 5.54 (dd, J = 10.8, 8.4 Hz, 1 H), 5.86 (d, J = 18.8 Hz, 1 H), 6.01 (dd, J = 18.8, 4.8 Hz, 1 H), 7.32−7.46 (m, 6 H), 7.65−7.73 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −1.2 (+), 19.2 (−), 24.6 (+), 25.9 (−), 27.0 (+), 34.9 (−), 66.0 (+), 73.7 (+), 125.0 (+), 126.1 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 131.0 (+), 134.3 (−), 134.6 (−), 135.3 (+), 135.9 (+), 136.0 (+), 147.7 (+); HRMS (FAB+) calcd for C30H43O2Si2 [(M − H)+] 491.2802, found 491.2801. (1S,3Z,6Z,8S)-8-[(tert-Butyldiphenylsilyl)oxy]-1-[(2S,3S)-3(trimethylsilyl)oxiran-2-yl]nona-3,6-dien-1-ol (ent-30). To a solution of Ti(O-i-Pr)4 (0.53 mL, 1.81 mmol) in CH2Cl2 (5.5 mL) at −10 °C was added L-(+)-DIPT (0.46 mL, 2.19 mmol). The solution was stirred at −10 °C for 40 min and cooled to −20 °C. A solution of allylic alcohol ent-4 (881 mg, 1.79 mmol) in CH2Cl2 (2.5 mL) was added. The solution was stirred at −20 °C for 40 min and cooled to −40 °C. A solution of t-BuOOH (3.50 M in CH2Cl2, 0.77 mL, 2.70 mmol) was added dropwise. After the addition, the solution was stirred at −18 °C for 6 h, and Me2S (0.40 mL, 5.41 mmol) was 163

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

Article

The Journal of Organic Chemistry added. The solution was stirred at −20 °C for 30 min before addition of aqueous 10% tartaric acid (1.1 mL), NaF (1.25 g, 29.8 mmol), and Celite (720 mg). The mixture was vigorously stirred at rt for 30 min and filtered through a pad of Celite. The filtrate was concentrated, and the residue was diluted with ether (10 mL) and aqueous 10% NaOH (5 mL) at 0 °C. The mixture was vigorously stirred at 0 °C for 20 min and extracted with ether three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford epoxy alcohol ent-30 (377 mg, 41%) and allylic alcohol 48 (371 mg, 42%). Diastereomeric excesses of the epoxy and allylic alcohols were determined to be >99% by 1H NMR spectroscopy of the derived MTPA esters. Epoxy alcohol ent-30 as a liquid: Rf = 0.43 (hexane/ EtOAc 5:1); [α]D21 +11 (c 1.01, CHCl3); the 1H and 13C-APT NMR spectra were consistent with those of 30; HRMS (FAB+) calcd for C30H43O3Si2 [(M − H)+] 507.2751, found 507.2765. Allylic alcohol 48 as a liquid: Rf = 0.57 (hexane/EtOAc 5:1); [α]D20 +11 (c 1.08, CHCl3); IR (neat) 3346, 1248, 1111, 867, 838 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 9 H), 1.05 (s, 9 H), 1.18 (d, J = 6.0 Hz, 3 H), 1.54−1.67 (m, 1 H), 2.06−2.21 (m, 2 H), 2.26−2.50 (m, 2 H), 4.01− 4.10 (m, 1 H), 4.59 (dq, J = 8.4, 6.0 Hz, 1 H), 5.14 (dt, J = 10.8, 7.2 Hz, 1 H), 5.29 (dt, J = 10.8, 6.0 Hz, 1 H), 5.31 (dt, J = 10.8, 6.4 Hz, 1 H), 5.54 (dd, J = 10.8, 8.4 Hz, 1 H), 5.86 (dd, J = 18.8, 1.2 Hz, 1 H), 6.00 (dd, J = 18.8, 4.8 Hz, 1 H), 7.33−7.46 (m, 6 H), 7.65−7.73 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −1.2 (+), 19.2 (−), 24.6 (+), 25.9 (−), 27.0 (+), 34.9 (−), 66.0 (+), 73.7 (+), 125.0 (+), 126.1 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 131.0 (+), 134.3 (−), 134.6 (−), 135.3 (+), 135.9 (+), 136.0 (+), 147.7 (+); HRMS (FAB+) calcd for C30H43O2Si2 [(M − H)+] 491.2802, found 491.2806. (5S,6Z,9Z,12S)-2,2,5,14,14,15,15-Heptamethyl-3,3-diphenyl-12-[(2S,3S)-3-(trimethylsilyl)oxiran-2-yl]-4,13-dioxa-3,14disilahexadeca-6,9-diene (49). To an ice-cold solution of epoxy alcohol ent-30 (372 mg, 0.731 mmol) in CH2Cl2 (7.5 mL) were added 2,6-lutidine (0.30 mL, 2.58 mmol) and TBSOTf (0.35 mL, 1.52 mmol). The solution was stirred at 0 °C for 3.5 h and diluted with H2O. The resulting mixture was extracted with CH2Cl2 three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford silyl ether 49 (389 mg, 85%) as a liquid: Rf = 0.86 (hexane/EtOAc 5:1); [α]D20 +10 (c 1.08, CHCl3); IR (neat) 1251, 1111, 839 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 6 H), 0.05 (s, 9 H), 0.86 (s, 9 H), 1.05 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 2.16 (d, J = 3.2 Hz, 1 H), 2.20 (t, J = 7.2 Hz, 2 H), 2.31−2.50 (m, 2 H), 2.68 (dd, J = 5.6, 3.2 Hz, 1 H), 3.44 (q, J = 5.6 Hz, 1 H), 4.60 (dq, J = 8.4, 6.4 Hz, 1 H), 5.15 (dt, J = 10.8, 7.2 Hz, 1 H), 5.21 (dt, J = 10.4, 7.2 Hz, 1 H), 5.39 (dt, J = 10.4, 7.2 Hz, 1 H), 5.52 (dd, J = 10.8, 8.4 Hz, 1 H), 7.32−7.45 (m, 6 H), 7.64−7.72 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.6 (+), −4.3 (+), −3.5 (+), 18.2 (−), 19.3 (−), 24.7 (+), 25.9 (+), 27.0 (+), 33.7 (−), 50.0 (+), 58.5 (+), 66.0 (+), 73.2 (+), 125.4 (+), 126.3 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.57 (+), 129.59 (+), 134.3 (−), 134.7 (−), 135.1 (+), 135.9 (+), 136.0 (+); HRMS (FAB+) calcd for C36H57O3Si3 [(M − H)+] 621.3616, found 621.3611. (2E,4S,6Z,9Z,11S)-4-[(tert-Butyldimethylsilyl)oxy]-11-[(tertbutyldiphenylsilyl)oxy]dodeca-2,6,9-trienenitrile (50). To an ice-cold solution of epoxide 49 (386 mg, 0.619 mmol) in toluene (6 mL) was added a solution of Et2AlCN (0.70 M in toluene, 2.20 mL, 1.54 mmol). The reaction was carried out at rt for 4.5 h and quenched by adding H2O (0.80 mL, 44 mmol), NaF (792 mg, 18.9 mmol), and Celite at 0 °C. The resulting mixture was vigorously stirred at rt for 20 min and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (hexane/EtOAc) to afford nitrile 50 (285 mg, 82%) as a liquid: Rf = 0.49 (hexane/EtOAc 10:1); [α]D20 +23 (c 1.08, CHCl3); IR (neat) 2225, 1112, 1083, 837, 703 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 3 H), 0.06 (s, 3 H), 0.91 (s, 9 H), 1.07 (s, 9 H), 1.20 (d, J = 6.0 Hz, 3 H), 2.05−2.18 (m, 2 H), 2.25−2.45 (m, 2 H), 4.24 (ddt, J = 3.6, 1.8, 6.0 Hz, 1 H), 4.58 (dq, J = 8.4, 6.0 Hz, 1 H), 5.14 (dt, J = 10.8, 7.2 Hz, 1 H), 5.24 (dt, J = 10.8, 5.6 Hz, 1 H), 5.27

(dt, J = 10.8, 6.8 Hz, 1 H), 5.57 (dd, J = 10.8, 8.4 Hz, 1 H), 5.58 (dd, J = 16.0, 1.8 Hz, 1 H), 6.64 (dd, J = 16.0, 3.6 Hz, 1 H), 7.34−7.48 (m, 6 H), 7.66−7.75 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.82 (+), −4.78 (+), 18.2 (−), 19.2 (−), 24.6 (+), 25.8 (+), 25.9 (−), 27.0 (+), 34.9 (−), 65.9 (+), 71.2 (+), 98.7 (+), 117.5 (−), 123.6 (+), 125.7 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.9 (+), 134.3 (−), 134.5 (−), 135.5 (+), 135.9 (+), 136.0 (+), 156.7 (+); HRMS (FAB+) calcd for C34H48NO2Si2 [(M − H)+] 558.3224, found 558.3230. (2E,4S,6Z,9Z,11S)-4-[(tert-Butyldimethylsilyl)oxy]-11-[(tertbutyldiphenylsilyl)oxy]dodeca-2,6,9-trienal (51). To a solution of nitrile 50 (285 mg, 0.509 mmol) in toluene (5 mL) was added a solution of DIBAL (1.03 M in toluene, 0.65 mL, 0.670 mmol) at −78 °C. The solution was stirred at −78 °C for 1 h and allowed to warm to 0 °C gradually over 1.5 h; then, 3 N HCl was added. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed successively with saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford aldehyde 51 (184 mg, 64%) as a liquid: Rf = 0.57 (hexane/EtOAc 5:1); [α]D20 +39 (c 0.90, CHCl3); IR (neat) 1696, 1256, 1109, 837 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3 H), 0.04 (s, 3 H), 0.89 (s, 9 H), 1.04 (s, 9 H), 1.16 (d, J = 6.0 Hz, 3 H), 2.10−2.23 (m, 2 H), 2.25−2.44 (m, 2 H), 4.35 (ddt, J = 4.0, 1.6, 6.4 Hz, 1 H), 4.55 (dq, J = 8.4, 6.0 Hz, 1 H), 5.11 (dt, J = 10.8, 7.2 Hz, 1 H), 5.24 (dt, J = 10.8, 6.4 Hz, 1 H), 5.27 (dt, J = 10.8, 6.8 Hz, 1 H), 5.53 (dd, J = 10.8, 8.4 Hz, 1 H), 6.23 (ddd, J = 15.6, 8.0, 1.6 Hz, 1 H), 6.68 (dd, J = 15.6, 4.0 Hz, 1 H), 7.31−7.45 (m, 6 H), 7.63−7.71 (m, 4 H), 9.52 (d, J = 8.0 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.8 (+), −4.7 (+), 18.2 (−), 19.2 (−), 24.6 (+), 25.8 (+), 25.9 (−), 27.0 (+), 35.1 (−), 65.9 (+), 71.4 (+), 124.2 (+), 125.8 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.6 (+), 130.9 (+), 134.3 (−), 134.6 (−), 135.4 (+), 135.9 (+), 136.0 (+), 159.5 (+), 193.6 (+); HRMS (FAB+) calcd for C34H50O3Si2Na [(M + Na)+] 585.3196, found 585.3217. (4Z,7Z,10Z,12E,14S,16Z,19Z,21S)-14-[(tertButyldimethylsilyl)oxy]-21-[(tert-butyldiphenylsilyl)oxy]docosa-4,7,10,12,16,19-hexaen-1-ol (52). To an ice-cold suspension of phosphonium salt 2 (450 mg, 0.685 mmol) in THF (3 mL) was added a solution of NaHMDS (1.0 M in THF, 0.42 mL, 0.42 mmol). The mixture was stirred at 0 °C for 1 h and cooled to −90 °C (liquid N2 + hexane). A solution of the above aldehyde 51 (184 mg, 0.327 mmol) in THF (1 mL) was added to the mixture dropwise. The solution was allowed to warm to 0 °C gradually over 7 h before addition of saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford the TBS ether of 52 (236 mg, 89%) as a liquid: Rf = 0.83 (hexane/EtOAc 5:1); 1 H NMR (400 MHz, CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.05 (s, 6 H), 0.88 (s, 9 H), 0.89 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.0 Hz, 3 H), 1.58 (tt, J = 7.2, 6.4 Hz, 2 H), 2.00−2.16 (m, 4 H), 2.25−2.45 (m, 2 H), 2.81 (t, J = 6.0 Hz, 2 H), 2.94 (t, J = 6.4 Hz, 2 H), 3.61 (t, J = 6.4 Hz, 2 H), 4.11 (q, J = 6.0 Hz, 1 H), 4.57 (dq, J = 8.4, 6.0 Hz, 1 H), 5.12 (dt, J = 10.8, 7.2 Hz, 1 H), 5.17 (dt, J = 10.8, 7.2 Hz, 1 H), 5.26−5.46 (m, 6 H), 5.50 (dd, J = 10.8, 8.4 Hz, 1 H), 5.58 (dd, J = 15.2, 6.0 Hz, 1 H), 5.96 (t, J = 11.2 Hz, 1 H), 6.43 (dd, J = 15.2, 11.2 Hz, 1 H), 7.29−7.44 (m, 6 H), 7.63−7.70 (m, 4 H). A mixture of the TBS ether of 52 (236 mg, 0.290 mmol) and PPTS (81 mg, 0.322 mmol) in EtOH (3 mL) was stirred at rt for 9 h, diluted with saturated NaHCO3, and concentrated to remove most of EtOH. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with saturated NaHCO3, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 52 (103 mg, 51%) as a liquid: Rf = 0.43 (hexane/EtOAc 3:1); [α]D20 +18 (c 1.02, CHCl3); IR (neat) 3345, 1255, 1110, 1076, 836 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 3 H), 0.04 (s, 3 H), 0.90 (s, 9 H), 1.05 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 1.36 (br s, 1 H), 1.65 (tt, J = 7.2, 6.4 Hz, 2 H), 2.03−2.20 (m, 4 H), 2.27−2.47 (m, 2 H), 2.84 (t, J = 5.2 Hz, 2 H), 2.96 (t, J = 6.2 Hz, 2 H), 3.66 (t, J = 6.4 Hz, 2 H), 164

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

Article

The Journal of Organic Chemistry 4.14 (q, J = 6.0 Hz, 1 H), 4.59 (dq, J = 8.4, 6.4 Hz, 1 H), 5.14 (dt, J = 10.8, 7.6 Hz, 1 H), 5.18 (dt, J = 10.8, 7.2 Hz, 1 H), 5.27−5.48 (m, 6 H), 5.52 (dd, J = 10.8, 8.4 Hz, 1 H), 5.60 (dd, J = 15.2, 6.0 Hz, 1 H), 5.97 (t, J = 11.2 Hz, 1 H), 6.46 (dd, J = 15.2, 11.2 Hz, 1 H), 7.32− 7.45 (m, 6 H), 7.65−7.72 (m, 4 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.7 (+), −4.3 (+), 18.3 (−), 19.2 (−), 23.6 (−), 24.7 (+), 25.7 (−), 25.9 (+), 26.1 (−), 27.0 (+), 32.5 (−), 36.3 (−), 62.5 (−), 66.0 (+), 72.8 (+), 124.3 (+), 125.8 (+), 126.4 (+), 127.5 (+), 127.6 (+), 127.8 (+), 128.3 (+), 128.5 (+), 128.7 (+), 129.36 (+), 129.42 (+), 129.51 (+), 129.57 (+), 129.58 (+), 134.3 (−), 134.6 (−), 135.1 (+), 135.87 (+), 135.94 (+), 136.8 (+); HRMS (FAB+) calcd for C44H65O3Si2 [(M − H)+] 697.4472, found 697.4488. (4Z,7Z,10Z,12E,14S,16Z,19Z,21S)-14-[(tert-Butyldimethylsilyl)oxy]-21-[(tert-butyldiphenylsilyl)oxy]docosa4,7,10,12,16,19-hexaenoic acid (53). A mixture of alcohol 52 (102 mg, 0.146 mmol), TPAP (7 mg, 0.020 mmol), NMO (28 mg, 0.239 mmol), and MS4A (75 mg) in CH2Cl2 (2 mL) was stirred at rt for 3 h and diluted with hexane. The resulting mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford the corresponding aldehyde (86 mg, 84%) as a liquid: Rf = 0.63 (hexane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.88 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.4 Hz, 3 H), 2.00−2.16 (m, 2 H), 2.26−2.45 (m, 4 H), 2.50 (t, J = 6.8 Hz, 2 H), 2.83 (t, J = 6.0 Hz, 2 H), 2.94 (t, J = 6.4 Hz, 2 H), 4.12 (q, J = 6.0 Hz, 1 H), 4.57 (dq, J = 8.4, 6.4 Hz, 1 H), 5.12 (dt, J = 10.8, 7.2 Hz, 1 H), 5.17 (dt, J = 10.8, 6.8 Hz, 1 H), 5.26−5.47 (m, 6 H), 5.51 (dd, J = 10.8, 8.4 Hz, 1 H), 5.59 (dd, J = 15.2, 6.0 Hz, 1 H), 5.96 (t, J = 11.2 Hz, 1 H), 6.44 (dd, J = 15.2, 11.2 Hz, 1 H), 7.31−7.44 (m, 6 H), 7.63−7.77 (m, 4 H), 9.75−9.78 (m, 1 H). A mixture of the above aldehyde (85 mg, 0.122 mmol), 2-methyl-2butene (0.26 mL, 2.45 mmol), and NaClO2 (79% purity, 21 mg, 0.183 mmol) in phosphate buffer (pH 5.0, 1.2 mL) and t-BuOH (1.2 mL) was stirred at rt for 2.5 h and diluted with H2O. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to afford acid 53 (73 mg, 84%) as a liquid: Rf = 0.17 (hexane/EtOAc 5:1); [α]D20 +18 (c 1.09, CHCl3); IR (neat) 3588, 1711, 1255, 1110, 1078, 836 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 3 H), 0.05 (s, 3 H), 0.91 (s, 9 H), 1.06 (s, 9 H), 1.18 (d, J = 6.4 Hz, 3 H), 2.08 (dt, J = 14.8, 7.2 Hz, 1 H), 2.14 (dt, J = 14.8, 7.2 Hz, 1 H), 2.28−2.48 (m, 6 H), 2.86 (t, J = 5.8 Hz, 2 H), 2.96 (t, J = 6.6 Hz, 2 H), 4.14 (q, J = 6.0 Hz, 1 H), 4.60 (dq, J = 8.4, 6.4 Hz, 1 H), 5.15 (dt, J = 10.8, 7.2 Hz, 1 H), 5.19 (dt, J = 10.8, 7.2 Hz, 1 H), 5.28−5.49 (m, 6 H), 5.53 (dd, J = 10.8, 8.4 Hz, 1 H), 5.61 (dd, J = 15.2, 6.0 Hz, 1 H), 5.98 (t, J = 11.2 Hz, 1 H), 6.46 (dd, J = 15.2, 11.2 Hz, 1 H), 7.33−7.46 (m, 6 H), 7.65−7.73 (m, 4 H), 9.0−13.0 (br s, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −4.6 (+), −4.3 (+), 18.3 (−), 19.2 (−), 22.5 (−), 24.7 (+), 25.7 (−), 25.9 (+), 26.1 (−), 27.0 (+), 34.0 (−), 36.3 (−), 66.0 (+), 72.8 (+), 124.3 (+), 125.8 (+), 126.4 (+), 127.5 (+), 127.6 (+), 127.7 (+), 128.1 (+), 128.3 (+), 128.4 (+), 129.4 (+), 129.5 (+), 129.6 (+), 134.3 (−), 134.6 (−), 135.1 (+), 135.88 (+), 135.95 (+), 136.8 (+), 179.4 (−); HRMS (FAB+) calcd for C44H63O4Si2 [(M − H)+] 711.4265, found 711.4300. 14S,21S-diHDHA (1b). A solution of acid 53 (50 mg, 0.070 mmol) and TBAF (1.0 M in THF, 0.70 mL, 0.70 mmol) in THF (0.7 mL) was stirred at rt for 8 h and diluted with phosphate buffer (pH 5.0). The resulting mixture was extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/ MeOH) to afford 14S,21S-diHDHA (1b) (24 mg, 95%) as a liquid: Rf = 0.34 (CH2Cl2/MeOH 10:1); [α]D19 −24 (c 0.70, CHCl3); UV (MeOH) λmax 235 nm; IR (neat) 3503, 1717, 1419, 1271, 1058 cm−1; 1 H NMR (400 MHz, CDCl3) δ 1.26 (d, J = 6.4 Hz, 3 H), 2.24−2.46 (m, 5 H), 2.52−2.61 (m, 1 H), 2.63−3.21 (m, 6 H), 4.38−4.45 (m, 1 H), 4.75 (dq, J = 8.4, 6.4 Hz, 1 H), 5.31−5.56 (m, 8 H), 5.56−5.69 (m, 1 H), 5.74 (dd, J = 15.2, 5.2 Hz, 1 H), 5.99 (t, J = 10.8 Hz, 1 H), 6.63 (dd, J = 15.2, 10.8 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ 22.9 (−), 23.2 (+), 25.8 (−), 26.3 (−), 26.4 (−), 33.9 (−), 34.8

(−), 63.6 (+), 71.5 (+), 124.9 (+), 125.5 (+), 127.5 (+), 127.6 (+), 128.0 (+), 128.7 (+), 129.3 (+), 129.4 (+), 130.4 (+), 130.9 (+), 133.6 (+), 135.1 (+), 177.0 (−); HRMS (FAB−) calcd for C22H31O4 [(M − H)−] 359.2222, found 359.2222. (E)-11-(Trimethylsilyl)undeca-10-en-3,6-diyne-2,9-diol (17). To a mixture of acetylene 518 (46 mg, 0.273 mmol), CuI (80 mg, 0.420 mmol), Cs2CO3 (136 mg, 0.417 mmol), and TBAI (151 mg, 0.409 mmol) in DMF (2 mL) was added bromide 1419 (70 mg, 0.429 mmol) in DMF (1 mL). After being stirred at rt for 8 h, the mixture was diluted with saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc 2:1) to afford diyne 17 (53 mg, 77%) as a liquid: Rf = 0.10 (hexane/EtOAc 4:1); IR (neat) 3372, 1249, 867, 839 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 9 H), 1.43 (d, J = 6.6 Hz, 3 H), 1.6−2.2 (br s, 2 H), 2.38 (ddt, J = 16.4, 7.0, 2.4 Hz, 1 H), 2.46 (ddt, J = 16.4, 5.2, 2.4 Hz, 1 H), 3.19 (dt, J = 2.0, 2.4 Hz, 2 H), 4.23 (ddt, J = 7.0, 1.2, 5.2 Hz, 1 H), 4.52 (tq, J = 2.0, 6.6 Hz, 1 H), 5.93 (dd, J = 18.8, 1.2 Hz, 1 H), 6.06 (dd, J = 18.8, 5.2 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −1.3 (+), 9.8 (−), 24.3 (−), 27.5 (−), 58.3 (+), 72.3 (+), 76.4 (−), 76.9 (−), 78.5 (−), 82.4 (−), 130.6 (+), 146.1 (+); HRMS (FAB+) calcd for C14H22O2SiNa [(M + Na)+] 273.1287, found 273.1293. (E)-1-(Trimethylsilyl)tetradeca-1-en-5,8-diyn-3-ol (18). According to the above procedure, a mixture of acetylene 518 (55 mg, 0.327 mmol), bromide 15 (0.080 mL, 0.50 mmol), CuI (101 mg, 0.530 mmol), Cs2CO3 (203 mg, 0.623 mmol), and TBAI (190 mg, 0.514 mmol) in DMF (3 mL) was stirred at rt for 16 h to afford diyne 17 (67 mg, 75%) as a liquid: Rf = 0.53 (hexane/EtOAc 4:1); IR (neat) 3394, 1248, 867, 839 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 9 H), 0.89 (t, J = 7.2 Hz, 3 H), 1.25−1.39 (m, 4 H), 1.49 (quint., J = 7.2 Hz, 2 H), 2.05 (br s, 1 H), 2.14 (tt, J = 7.2, 2.2 Hz, 2 H), 2.39 (ddt, J = 16.6, 4.8, 2.4 Hz, 1 H), 2.46 (ddt, J = 16.6, 5.0, 2.4 Hz, 1 H), 3.13 (quint, J = 2.2 Hz, 2 H), 4.19−4.27 (m, 1 H), 5.93 (dd, J = 18.8, 1.2 Hz, 1 H), 6.07 (dd, J = 18.8, 5.0 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −1.4 (+), 9.8 (−), 14.0 (+), 18.7 (−), 22.2 (−), 27.6 (−), 28.4 (−), 31.1 (−), 72.3 (+), 73.9 (−), 76.1 (−), 77.5 (−), 80.8 (−), 130.5 (+), 146.1 (+); HRMS (FAB+) calcd for C17H28OSi [(M + Na)+] 299.1807, found 299.1809. (E)-1,9-Bis(trimethylsilyl)nona-1-en-5,8-diyn-3-ol (19). According to the above procedure, a mixture of acetylene 518 (49 mg, 0.291 mmol), bromide 16 (82 mg, 0.429 mmol), CuI (73 mg, 0.38 mmol), Cs2CO3 (124 mg, 0.381 mmol), and TBAI (136 mg, 0.368 mmol) in DMF (3 mL) was stirred at rt for 21 h to afford diyne 19 (61 mg, 76%) as a liquid: Rf = 0.57 (hexane/EtOAc 4:1); IR (neat) 3398, 1249, 839, 759 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 9 H), 0.16 (s, 9 H), 2.05 (br d, J = 3.6 Hz, 1 H), 2.39 (ddt, J = 16.4, 6.8, 2.4 Hz, 1 H), 2.46 (ddt, J = 16.4, 5.2, 2.4 Hz, 1 H), 3.21 (t, J = 2.4 Hz, 2 H), 4.20−4.28 (m, 1 H), 5.94 (dd, J = 18.8, 1.2 Hz, 1 H), 6.07 (dd, J = 18.8, 4.8 Hz, 1 H); 13C-APT NMR (100 MHz, CDCl3) δ −1.3 (+), −0.0 (+), 11.0 (−), 27.7 (−), 72.3 (+), 76.4 (−), 76.8 (−), 85.1 (−), 100.2 (−), 130.7 (+), 146.1 (+); HRMS (FAB+) calcd for C15H26OSi2Na [(M + Na)+] 301.1420, found 301.1422. Verification of the Stereochemistry of Synthesized 14,21diHDHAs Using Chiral LC-UV-MS/MS and MacrophageProduced Prohealing 14,21-diHDHAs. This was conducted using the method that we established previously with a different manufacturer of the equipment.1a,b,3a,20 The acLC-UV-MS/MS [Xevo TQ-S triple quadruple tandem mass spectrometer coupled to a UV spectrometer and an Acquity I Class LC (Waters)] was equipped with a chiral column (Chiralpak-IA, 150 mm × 2.1 mm x 5 μm) (Chiral Technologies, West Chester, PA). The mobile phase had a flow rate of 0.2 mL/min eluted as 73% A (water:acetic acid = 99.99:0.01) + 27% B (methanol:acetic acid = 99.99:0.01) (0−1 min); ramped to 70.8% A + 29.2% B (1−5 min, to 14.6% A + 85.4% B (5−50 min) and then to 100% B (50−51 min); stayed as 100% B (51−56 min); and finally returned to the initial composition (73% A + 27% B). The MeOH solutions of organic synthesis and macrophage extraction with prostaglandin D2-d4 added as the internal standard were injected to the acLC-UV-MS/MS. The effluent of the chiral LC-UV went 165

DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166

Article

The Journal of Organic Chemistry

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through the electrospray, and the ionized compounds from the effluent were analyzed by the MS/MS. Therefore, compounds in the solutions were differentiated by both chiral LC chromatograph and MS/MS. Macrophage Production of Prohealing 14,21-diHDHAs. Human macrophages were prepared based on the established protocol.20−26 Briefly, human monocytes were isolated via centrifugation and immunomagnetic negative selection from the whole blood of healthy human donors (provided by the Blood Center, New Orleans, LA). These monocytes (∼95% CD14+) were differentiated under 10 ng/mL of GM-CSF for 7 days to macrophages. The production of 14S,21R-diHDHA and 14S,21R-diHDHA by macrophages were conducted by incubation of macrophages (3 × 106) in PBS containing 3 μM DHA (20 min, then with addition of 10 ng/mL of TNFα, 10 ng/mL of IL-1β, and 100 ng/mL of LPS for the stimulation of macrophages, 1 h, 37 °C) as we had done previously.1a,b,3a,20 The final incubations were extracted and analyzed by acLC-UV-MS/MS.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02510. Determination of enantiomeric purity and 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yuichi Kobayashi: 0000-0002-4385-9531 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by KAKENHI Grants JP15H05904, 15H05898, 15H05897, and 15H04648 and the Kobayashi International Scholarship. This work was also supported by R01 DK087800-06A1 grant (S.H.), 5P30GM103340-03 (to N.B.), and by an unrestricted departmental grant from Research to Prevent Blindness, Inc., New York, NY.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02510 J. Org. Chem. 2018, 83, 154−166