Stereocontrolled Synthesis of Resolvin D4 - The Journal of Organic

Additionally, anti-4,5-dihydroxydodecanoic acid, a model compound of RvD4, in CD3OD was .... 10–20 °C) was monitored by 1H NMR spectroscopy. .... 8...
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Article Cite This: J. Org. Chem. 2018, 83, 3906−3914

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Stereocontrolled Synthesis of Resolvin D4 Masao Morita and Yuichi Kobayashi* Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan S Supporting Information *

ABSTRACT: The stereoselective synthesis of resolvin D4 (RvD4) was achieved using the Wittig reaction of the C1−C10 dienal with the known C11−C22 phosphonium salt. The (S,E)-enantiomer (S)-10, corresponding to the C1−C8 part, was synthesized in 95% ee by the asymmetric transfer hydrogenation reaction of the corresponding acetylenic ketone followed by Red-Al reduction. Sharpless epoxidation of this alcohol using Ti(O-i-Pr)4/L-(+)-DIPT as a catalyst produced anti epoxy alcohol with >99% ee as the sole product in 82% yield. A subsequent functional group manipulation, including removal of the PMB group, produced the alcohol, which upon Swern oxidation afforded anti 4-hydroxy-5-TBS-oxy enal via epoxide ring opening of the resulting aldehyde. The Horner− Wadsworth−Emmons reaction was used to add the C9−C10 enal part to this aldehyde, and the resulting dienal was subjected to the Wittig reaction with C11−C22 phosphonium salt to furnish the entire structure of RvD4. Conversion of the primary alcohol to the methyl ester and deprotection of the three TBS groups with TBAF afforded 5,17-dihydroxy-γ-lactone, which was hydrolyzed to RvD4. Additionally, anti-4,5-dihydroxydodecanoic acid, a model compound of RvD4, in CD3OD was observed to be stable at room temperature for several weeks, whereas 20% of the acid in CDCl3 was converted into the γ-lactone after 24 h at rt.

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INTRODUCTION Resolvin D4 (RvD4) is a lipoxygenase-induced metabolite of docosahexaenoic acid (DHA) and is assumed to play an important role in host protection and bacterial clearance on the basis of biological evidence such as reduction of neutrophilic infiltration, inhibition of cytokine production from glial cell, regulation of leukocyte diapedesis, and stimulation of uptake of apoptotic PMN by dermal fibroblasts.1,2 In analogy to the biosynthesis of leukotriene A4 from 5S-HpETE,3 RvD4 is likely to be formed by lipoxygenation of 17S-H(p)DHA at C4 followed by the epoxide ring formation of the resulting 4hydroperoxy derivative through hydrogen abstraction at C9 and subsequent enzymatic hydrolysis of the 4S,5S-epoxide at C5.2a,4 However, the stereochemistry at C5 and the conjugate triene was ambiguous until 2016, when chemically synthesized RvD4 with the defined structure drawn in Figure 1 was proven to be in agreement with endogenous RvD4 on LC−MS/MS data (retention time and MS fragmentation) and several biological properties.1 Although NMR data of RvD4 have been published, only a schematic abstract of the synthesis has been depicted without any yield. Furthermore, the synthesis suffers from the facile lactonization of the 4-hydroxy carboxylic acid moiety. According to the authors, a similar lactonization was observed during the synthesis of RvD3.5 The same substructure is also found in RvD6. However, the synthesis of RvD6 is not informative because no yields are provided for the last few steps of the synthesis.6 After considering these limited synthetic © 2018 American Chemical Society

Figure 1. Resolvin D series possessing a 4-hydroxy acid structure.

descriptions, a synthesis of RvD4 was undertaken, and the results are presented herein.

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RESULTS AND DISCUSSION Strategy. Wittig reaction of dihydroxy dienal A with a monohydroxy type of phosphonium salt B was envisaged to afford RvD4 (1) as outlined in Scheme 1. Salt B was recently synthesized by us using monohydroxy enal derivative D.7 On the other hand, dienal A was dissected to dihydroxy enal Received: January 28, 2018 Published: March 16, 2018 3906

DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914

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The Journal of Organic Chemistry

left unexplored. As described below, the synthesis of C suffered from considerably low efficiency. Therefore, a modification to the process was developed to mitigate this problem. Synthesis of Wittig Reagent B. Racemic allylic alcohol rac-2 was transformed to the Wittig reagent 9 (=B) according to a previous study7 with comparable yields (Scheme 2). Thus, asymmetric epoxidation9 of rac-2 using the published quantities of t-BuOOH (1.5 equiv) and Ti(O-i-Pr)4/D-(−)-DIPT (1 equiv) afforded epoxy alcohol 3 with 99% ee and allylic alcohol (R)-2 with >99% ee. The TMS group is responsible for the high ee.9,10 After routine chromatography, 3 was transformed to aldehyde 5 (=D in Scheme 1) via the reaction with Et2AlCN.11 Further, recovered allylic alcohol (R)-2 in several runs was combined and converted into nitrile 4, the precursor of 5, via the epoxidation, Mitsunobu inversion, and the reaction with Et2AlCN. A further four-step transformation of 5 produced Wittig reagent 9 successfully (=B in Scheme 1). Synthesis of Dienal A via Enal C. An attempted synthesis of dihydroxy enal C commenced with epoxidation/kinetic resolution of racemic allylic alcohol rac-10 using t-BuOOH (1 equiv) and the Ti(O-i-Pr)4/L-(+)-DIPT catalyst (1 equiv) at −18 °C for 6 h to produce a mixture of the desired epoxy alcohol 11, the syn isomer 12, and the remaining allylic alcohol (R)-10 (Scheme 3). Chromatography of the mixture afforded (R)-10 in 39% yield and a 90:10 mixture (1H NMR integration) of 11 and 12 in 58% yield, indicating the faster epoxidation of rac-10 and smaller krel (rate difference between the enantiomers) than those of the TMS-containing allylic alcohol rac-2. The assignment of anti stereochemsitry for the major epoxide was based on the established preference of the epoxidation/kinetic resolution of racemic secondary allylic alcohols.12,13 Because complete separation of the products was difficult, achieving high anti selectivity became an important issue for our synthesis. Epoxidation at a lower temperature (−30 °C) using 1 equiv of t-BuOOH improved diastereoselectivity (11 over 12) to 97%, and 11 with 96% ee was isolated in 44% yield along with 81% ee of (R)-10 in 52% yield.

Scheme 1. Retrosynthesis of RvD4

derivative C. To construct the anti diol and the enal moieties in C, we envisioned a Chakraborty8 sequence consisting of the construction of anti epoxide E by the asymmetric epoxidation/ kinetic resolution of the corresponding racemic allylic alcohol and subsequent oxidation to F, which would be rearranged to form enal C by the epoxide ring opening. However, both the anti selectivity in the construction of E and the reuse of the concomitantly produced enantioenriched allylic alcohol were

Scheme 2. Synthesis of Wittig Reagent 9 (=B) through Enal 5 (=D)

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DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914

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The Journal of Organic Chemistry

primary alcohol group of the diol was protected back to (S)-10. Epoxidation of the key allylic alcohol (S)-10 with Ti(O-i-Pr)4/ L-(+)-DIPT produced epoxide 11 in 82% yield. As expected, enantiopurity was increased to >99% ee as determined by 1H NMR spectroscopy of the MTPA ester. Furthermore, virtually no syn isomer could be detected in the expanded 1H NMR spectrum (see the Supporting Information), although the syn epoxy alcohol was possibly formed from the (R) isomer contaminated in 95% ee of (S)-10. This observation is understood by that the amount of (R)-10 was only 2.5%, and the given Ti(O-i-Pr)4/L-(+)-DIPT catalyst was mismatched with the epoxidation of (R)-10, thus producing the epoxy alcohol only in undetectable quantity. The hydroxy group in 11 was protected as the TBS ether, and the PMB group was removed to afford alcohol 19 in 69% yield. The key transformation by the Swern oxidation took place smoothly to give trans enal 20 in 68% yield. Transformation of 20 to dienal 23, corresponding to the key dienal A, was carried out efficiently by a sequence of reactions delineated in the scheme. The final stage of the synthesis commenced with the Wittig reaction of dienal 23 with an ylide derived from 9 and NaHMDS to produce olefin 24 as the sole product, which was exposed to PPTS in MeOH/CH2Cl2 to afford primary alcohol 25 in 70% yield from 23 (Scheme 5). High stereoisomeric purity of 25 was confirmed by 1H and 13C NMR spectroscopy. A two-step oxidation of 25 followed by esterification with CH2N2 furnished ester 26 in 40% yield from 25. Desilylation with excess TBAF produced lactone 28 in 46% yield, and hydroxy methyl ester 27 was not isolated, indicating facile lactonization of the resulting triol ester 27 under the basic conditions of TBAF. To find a suitable solvent, which practically retards the lactonization of resolvin D4 to 28, a model dihydroxy acid 31 was synthesized by a method depicted in Scheme 6. Thus, the dihydroxylation of olefin 29 gave a mixture of the corresponding dihydroxy ester and lactone 30 in a 4:6 ratio. Subsequently, treatment of the mixture with p-TsOH (cat.) in CHCl3 promoted rapid lactonization to afford 30 exclusively. Hydrolysis of the lactone, extraction with Et2O, and chromatographic purification using Et2O/MeOH as an eluent gave acid

Scheme 3. Attempted Synthesis of Dihydroxy Enal Derivative of Type Ca

a

(a) Relative syn stereochemistry.

Reaction using 0.6 equiv of t-BuOOH at −18 °C for 1 h gave 11 in 43% yield with 96% dr and >98% ee and (R)-10 in 56% yield with 78% ee. Because high diastereomeric and enantiomeric purity were obtained in 11, the conversion of recovered (R)-10 to 11 was examined next, with the first step being the Mitsunobu inversion with 4-NO2 C 6 H 4 COOH under the standard conditions. After hydrolysis of the resulting ester, however, a mixture of (S)-10 and the regioisomer 13 was obtained in a 65:35 ratio (Scheme 3). These products were close on TLC and separated partially by chromatography. The formation of such regioisomers has been reported;14 however, the low regioselectivity remains unsolved. On the basis of the above results, we envisaged that the epoxidation of enantioenriched (S)-10 would produce 11 with high anti selectivity and as the sole product. Scheme 4 presents the asymmetric reduction15 of ketone 16 derived from amide 14 and acetylene 15 to produce alcohol 17 with 95% ee. The reduction of 17 with Red-Al gave a mixture of (S)-10 and the desilylated diol in 57% and 26% yields, respectively, and the Scheme 4. Synthesis of Dihydroxy Dienal 23a

a

(a) (S,S)-Ru cat., Ru[(S,S)-TsDPEN](p-cymene). 3908

DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914

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The Journal of Organic Chemistry Scheme 5. Synthesis of Resolvin D4

dienal 23. The Wittig reaction of 23 with 9 followed by the functional group transformations afforded 5,17-dihydroxy-γlactone, which was hydrolyzed to RvD4. In addition, the stability of the 4,5-dihydroxy acid 31, a model compound of RvD4, in CD3OD and in CDCl3 was studied to detect only 3% lactonization after 30 days at rt, whereas 20% of the acid in CDCl3 underwent lactonization to form the γ-lactone after 24 h at rt.

Scheme 6. Synthesis of Acid 31 through Lactone 30

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EXPERIMENTAL SECTION

General Remarks. The 1H (300 and 400 MHz) and 13C NMR (75 and 100 MHz) spectroscopic data were recorded in CDCl3 using Me4Si (δ = 0 ppm) and the centerline of CDCl3 triplet (δ = 77.1 ppm), as internal standards, respectively. Signal patterns are indicated as br s (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), 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 APT experiments (APT: attached proton test). High-resolution mass spectroscopy (HRMS) was performed with a double-focusing mass spectrometer. The solvents that were distilled prior to use are THF (from Na/ benzophenone) and CH2Cl2 (from CaH2). After extraction of the products, the extracts were concentrated by using an evaporator, and then residues were purified by chromatography on silica gel (Kanto, spherical silica gel 60N). Phosphonium salt 9 was synthesized according to the published method.7 (S*)-5-[(R*)-1-Hydroxyoctyl]dihydrofuran-2(3H)-one (30). To a solution of ester 29 (600 mg, 2.83 mmol) in acetone (16 mL) and H2O (4 mL) were added NMO (498 mg, 4.25 mmol) and OsO4 (0.20 M in t-BuOH, 1.41 mL, 0.28 mmol). After 3 days of stirring at rt, 10% aqueous Na2S2O3 (30 mL) was added to the solution, and the resulting mixture was extracted with CHCl3 (×3). The organic solvents were removed by evaporation, and the residue was passed through a column of silica gel (hexane/EtOAc = 1:1) to afford a mixture of the dihydroxy ester (structure not shown) and lactone 30. To a solution of this mixture in CHCl3 (10 mL) was added cat. pTsOH·H2O (ca. 5 mg) at rt. After 10 min of stirring, the solution was diluted with saturated NaHCO3, and the resulting mixture was extracted with EtOAc (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/AcOEt = 1:1) to afford lactone 30 (542 mg, 89%): liquid; Rf = 0.49 (hexane/EtOAc = 1:1); IR (neat) 3462, 1767, 1185 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.21−1.56 (m, 12H), 1.96 (d, J = 3.6 Hz, 1H), 2.09−2.19 (m, 1H), 2.21−2.32 (m, 1H), 2.46−2.65 (m, 2H), 3.90−3.97 (m, 1H), 4.44 (td, J = 7.4 Hz, 3.2 Hz, 1H); 13C-APT NMR (100 MHz, CDCl3) δ 14.1 (+), 21.0 (−), 22.6 (−), 25.7 (−), 28.7 (−), 29.2 (−), 29.5 (−), 31.8 (−), 31.9 (−), 71.3 (+), 83.0 (+), 177.7 (−); 1H NMR (400 MHz, CD3OD) δ 0.91 (t, J = 7.4 Hz, 3H), 1.25−1.60 (m, 12H), 2.13− 2.27 (m, 2H), 2.51−2.57 (m, 2H), 3.71−3.79 (m, 1H), 4.45 (td, J =

31, which was devoid of lactone 30 as confirmed by 1H NMR spectroscopy in CDCl3 and in CD3OD: for 31 and 30, δ 3.60− 3.67 (m) and 4.44 (td) ppm in CDCl3; 1.91−2.01 (m) and 2.13−2.27 (m) ppm in CD3OD, respectively. The progress of lactonization in these solvents at room temperature (ca. 10−20 °C) was monitored by 1H NMR spectroscopy. After 24 h, the CDCl3 solution produced a mixture of 31 and 30 in a 8:2 ratio, whereas CD3OD prevented the lactonization. Thirty days later (at rt), most of acid 31 had converted to lactone 30 in CDCl3 (31:30 = 1:9), whereas the solution of acid 31 in CD3OD contained only 3% of the lactone. With the above results in hand, lactone 28 was hydrolyzed with LiOH and purified by chromatography using methanolic Et2O as an eluent to afford resolvin D4 (1) in 52% yield. The 1 H and 13C NMR spectra (400 and 100 MHz, respectively) of 1 measured in CD3OD depicted no contamination of lactone 28. Furthermore, the E,E,Z conjugated triene structure was securely confirmed by 1H−1H decoupling study. These data were consistent with those present in the literature.1,16 In addition, the 13C-APT NMR spectrum supported the structure as well.

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CONCLUSION We investigated the synthesis of RvD4 through the Wittig reaction of a C1−C10 dienal 23 with the known C11−C22 phosphonium salt 9. Epoxy alcohol 11 (>99% ee), a precursor of 19, was synthesized anti stereoselectively via the asymmetric transfer hydrogenation of ketone 16 and subsequent Sharpless epoxidation of allylic alcohol (S)-10 using Ti(O-i-Pr)4/L(+)-DIPT. In contrast, Sharpless epoxidation of rac-10 gave a mixture of 11 and (R)-10, and the Mitsunobu inversion of (R)10 afforded a hardly separable mixture of regioisomers. Swern oxidation of 19, derived from 11, was followed by the in situ ring opening to afford enal 20, which was further converted to 3909

DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914

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The Journal of Organic Chemistry 7.0 Hz, 4.0 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 14.6, 22.8, 23.9, 26.9, 29.6, 30.6, 30.8, 33.2, 33.8, 72.8, 85.0, 180.5; HRMS (FAB+) calcd for C12H23O3 [(M + H)+] 215.1647, found 215.1646. (4S,5R)-4,5-Dihydroxydodecanoic Acid (31). To a solution of lactone 30 (80 mg, 0.373 mmol) in MeOH (1 mL) and H2O (1 mL) was added LiOH·H2O (31 mg, 0.74 mmol). After 15 min of stirring at rt, the McIlvaine’s phosphate buffer (pH 5.0, 10 mL) was added to the mixture, which was extracted with Et2O (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (Et2O/MeOH = 9:1) to afford dihydroxy acid 31 (65 mg, 75%): liquid; Rf = 0.51 (Et2O/ MeOH = 9:1); 1H NMR (400 MHz, CD3OD) δ 0.91 (t, J = 6.8 Hz, 3H), 1.24−1.43 (m, 10H), 1.46−1.68 (m, 3H), 1.91−2.01 (m, 1H), 2.38 (ddd, J = 16.2 Hz, 8.8 Hz, 7.2 Hz, 1H), 2.50 (ddd, J = 16.2 Hz, 9.2 Hz, 5.8 Hz, 1H), 3.34−3.41 (m, 2H); 13C-APT NMR (100 MHz, CD3OD) δ 14.6 (+), 23.9 (−), 27.2 (−), 29.0 (−), 30.6 (−), 31.0 (−), 31.6 (−), 33.2 (−), 34.1 (−), 75.3 (+), 76.0 (+), 178.0 (−); HRMS (FAB+) calcd for C12H25O4 [(M + H)+] 233.1753, found 233.1751. Note that two OH protons and COOH were overlapped with the residue of CD3OD at 3.3 ppm. Epoxidation/Kinetic Resolution of Racemic Allylic Alcohol rac-10. Alcohol rac-10 was synthesized by a method similar to that of (S)-10 shown below. To an ice-cold solution of Ti(O-i-Pr)4 (0.11 mL, 0.38 mmol) in CH2Cl2 (0.5 mL) was added L-(+)-DIPT (0.095 mL, 0.45 mmol). The solution was stirred for 10 min, and a solution of allylic alcohol rac-10 (150 mg, 0.38 mmol) in CH2Cl2 (1 mL) was added. The solution was stirred at −18 °C for 30 min and cooled to −30 °C. A solution of t-BuOOH (4.34 M in CH2Cl2, 0.053 mL, 0.23 mmol) was added dropwise. The solution was stirred at −18 °C for 1 h, Me2S (0.30 mL, 4.1 mmol) was added, it was stirred at −18 °C for a further 30 min, and aqueous 10% tartaric acid (3 mL) and NaF (300 mg, 7.1 mmol) were added to afford a mixture, which was vigorously stirred at rt for 10 min and filtered through a pad of Celite. The filtrate was concentrated and the residue was diluted with Et2O (4 mL) and aqueous 1 N NaOH (4 mL). The mixture was vigorously stirred at rt for 30 min and extracted with Et2O (×2). The combined extracts were dried over MgSO4 and concentrated to give a residual oil, which was purified by chromatography on silica gel (hexane/EtOAc) to afford epoxy alcohol 11 (68 mg, 43%) and allylic alcohol (R)-10 (85 mg, 56%). The 1H NMR spectra of the products were identified with those obtained from propargylic alcohol 17 as described below in detail. 11: 96% anti stereoselectivity over syn by 1H NMR spectroscopy; >98% ee by 1H NMR spectroscopy of the derived MTPA ester. (R)-10: 78% ee by 1H NMR spectroscopy of the derived MTPA ester. Epoxidation of rac-10 with m-CPBA. To a mixture of alcohol rac10 (150 mg, 0.380 mmol) and NaHCO3 (143 mg, 1.70 mmol) in CH2Cl2 (3 mL) was added m-CPBA (60% purity, 164 mg, 0.570 mmol). The mixture was stirred at rt for 1 h and diluted with aqueous Na2S2O3 (10%, 20 mL). The resulting mixture was extracted with CH2Cl2 (×3). The combined organic extracts were washed with saturated NaHCO3, dried (MgSO4), and concentrated in vacuo to leave an oil, which was purified by chromatography on silica gel (hexane/AcOEt = 3:1) to afford a mixture (156 mg, 100%) of rac-11 (anti epoxide) and rac-12 (syn epoxide) in a 26:74 ratio by 1H NMR integration at δ 3.11 (ddd, for 1H) and 3.05 (ddd, for 1H) ppm. A set of the signals was consistent with that of 11 (see below for the product-selective synthesis and characterization). The other set of the signals was assigned as rac-12. Because the diastereomeric epoxides showed the same Rf value of 0.20 (hexane/EtOAc = 3:1) on TLC, the mixture was subjected to recycling HPLC (LC-Forte/R equipped with YMC-Pack SIL-60, hexane/EtOAc = 3:1, rt, 25 mL/min) to isolate syn epoxide rac-12 for characterization: colorless oil; IR (neat) 3436, 1515, 1250, 1096, 835 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.89 (s, 9H), 1.57−1.72 (m, 4H), 1.80 (dq, J = 14.4 Hz, 6.0 Hz, 1H), 1.85−1.95 (m, 1H), 2.57 (d, J = 5.2 Hz, 1H), 2.79 (dd, J = 4.8 Hz, 2.4 Hz, 1H), 3.05 (ddd, J = 6.0 Hz, 4.6 Hz, 2.0 Hz, 1H), 3.46−3.53 (m, 1H), 3.54−3.59 (m, 2H), 3.61−3.67 (m, 2H), 3.80 (s, 3H), 4.43 (d, J = 11.6 Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −5.3 (+), 18.4 (−), 26.0 (+), 28.8 (−), 31.4 (−), 32.3 (−), 54.4 (+), 55.3

(+), 61.8 (+), 63.2 (−), 66.7 (−), 71.2 (+), 72.8 (−), 113.9 (+), 129.4 (+), 130.3 (−), 159.3 (−); HRMS (FAB+) calcd for C22H37O5Si [(M − H)+], found 409.2410, found 409.2406. Mitsunobu Inversion of (R)-10 To Afford a Mixture of (S,E)-1[(tert-Butyldimethylsilyl)oxy]-8-[(4-methoxybenzyl)oxy]oct-5-en-4ol [(S)-10] and (E)-8-[(tert-Butyldimethylsilyl)oxy]-1-[(4methoxybenzyl)oxy]oct-4-en-3-ol (13). To an ice-cold solution of alcohol (R)-10 (9.62 g, 24.4 mmol) in THF (200 mL) were added 4(NO2)C6H4COOH (6.12 g, 36.6 mmol) and Ph3P (9.06 g, 36.6 mmol). After 15 min of stirring at 0 °C, diisopropyl azodicarboxylate (7.12 mL, 3.66 mmol) was added. The solution was stirred at 0 °C for 2 h and diluted with saturated NaHCO3. The resulting mixture was extracted with EtOAc (×2), and the combined extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (hexane/AcOEt = 7:1) to afford a mixture of the desired ester and the regioisomer: Rf = 0.71 (hexane/EtOAc = 4:1) for both. A mixture of a small portion of the above product in Et2O (4 mL) and 1 N NaOH (4 mL) was stirred at 0 °C for 2 h and diluted with H2O. The resulting mixture was extracted with Et2O (×2). The combined organic layers were dried over MgSO4 and concentrated. The residue was passed through a short column of silica gel (hexane/ EtOAc = 4:1) to afford (S)-10 and 13 in a ratio of 65:35 by 1H NMR integration at δ 4.03−4.12 (m, for 1H) and 4.23−4.31 (m, for 1H). A set of the signals was consistent with that of (S)-10 (see below for characterization). The other set of the signals was assigned as 13. Because Rf values of the products (S)-10 and 13 were close on TLC (0.31 and 0.34 (hexane/EtOAc = 4:1), the mixture was subjected to recycling HPLC (LC-Forte/R equipped with YMC-Pack SIL-60, hexane/EtOAc = 4:1, rt, 25 mL/min) to afford 13 for characterization: colorless oil; IR (neat) 3422, 1514, 1249, 1097, 836 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.53−1.63 (m, 2H), 1.75−1.87 (m, 2H), 2.08 (q, J = 7.5 Hz, 2H), 2.73 (br s, 1H), 3.55− 1.63 (m, 3H), 3.66 (dq, J = 4.2 Hz, 5.4 Hz, 1H), 3.80 (s, 3H), 4.23− 4.31 (m, 1H), 4.44 (s, 2H), 5.48 (dd, J = 15.4 Hz, 6.4 Hz, 1H), 5.66 (dt, J = 15.4 Hz, 6.8 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −5.2 (+), 18.4 (−), 26.0 (+), 28.5 (−), 32.4 (−), 36.8 (−), 55.4 (+), 62.6 (−), 68.3 (−), 72.0 (+), 73.0 (−), 113.9 (+), 129.4 (+), 130.2 (−), 131.1 (+), 132.6 (+), 159.2 (−); HRMS (FAB+) calcd for C22H37O4Si [(M − H)+] 393.2461, found 393.2455. 1-[(tert-Butyldimethylsilyl)oxy]-8-[(4-methoxybenzyl)oxy]oct-5yn-4-one (16). To a solution of alkyne 15 (1.23 g, 6.49 mmol) in THF (20 mL) was added n-BuLi (1.64 M in hexane, 3.73 mL, 6.11 mmol) at −78 °C. The solution was stirred at −78 °C for 1 h. A solution of amide 14 (1.00 g, 3.82 mmol) in THF (5 mL) was added to the solution, and the cooling bath was removed. After 30 min of stirring at rt, the reaction was stopped by adding saturated NH4Cl solution. The mixture was extracted with EtOAc (×3). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (toluene/EtOAc = 19:1) to afford 16 (1.42 g, 95%): colorless oil; Rf = 0.43 (toluene/EtOAc = 19:1); IR (neat) 2214, 1675, 1514, 1250, 1101 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 6H), 0.89 (s, 9H), 1.83−1.89 (m, 2H), 2.62 (t, J = 7.0 Hz, 2H), 2.65 (t, J = 6.6 Hz, 2H), 3.61 (t, J = 7.0 Hz, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.81 (s, 3H), 4.49 (s, 2H), 6.89 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −5.3 (+), 18.4 (−), 20.5 (−), 26.0 (+), 27.1 (−), 42.1 (−), 55.4 (+), 61.9 (−), 67.0 (−), 72.9 (−), 81.5 (−), 90.6 (−), 113.9 (+), 129.5 (+), 129.8 (−), 159.4 (−), 188.8 (−); HRMS (FAB+) calcd for C22H35O4Si [(M + H)+] 391.2305, found 391.2306. (S)-1-[(tert-Butyldimethylsilyl)oxy]-8-[(4-methoxybenzyl)oxy]oct5-yn-4-ol (17). A mixture of RuCl(p-cymene)[(S,S)-TsDPEN] (113 mg, 0.179 mmol) and KOH (ca. 97 mg, 1.7 mmol) in CH2Cl2 (5 mL) was stirred at rt for 5 min. The mixture was washed with H2O (×6). The CH2Cl2 solution was transformed to another flask. The solution was dried over CaH2, decanted, and concentrated to afford a purple solid, to which i-PrOH (5 mL) and a solution of ketone 16 (1.40 g, 3.58 mmol) in i-PrOH (5 mL) were added. After 30 min of stirring at rt, organic solvents were removed by evaporation. The residue was purified by chromatography on silica gel (hexane/EtOAc = 4:1) to 3910

DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914

Article

The Journal of Organic Chemistry

−5.3 (+), 18.4 (−), 26.0 (+), 28.7 (−), 30.9 (−), 32.3 (−), 53.7 (+), 55.3 (+), 60.9 (+), 63.4 (−), 66.7 (−), 69.4 (+), 72.8 (−), 113.8 (+), 129.3 (+), 130.3 (−), 159.2 (−); HRMS (FAB+) calcd for C22H39O5Si [(M + H)+] 411.2567, found 411.2567. (S)-5-[(2R,3S)-3-[2-[(4-Methoxybenzyl)oxy]ethyl]oxiran-2-yl]2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disiladodecane (18). To an ice-cold solution of alcohol 11 (2.53 g, 6.16 mmol) in CH2Cl2 (15 mL) were added 2,6-lutidine (1.78 mL, 15.4 mmol) and TBSOTf (2.12 mL, 9.24 mmol). The solution was stirred at 0 °C for 30 min and diluted with saturated NaHCO3 solution. The resulting mixture was extracted with CH2Cl2 (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/AcOEt = 9:1) to afford silyl ether 18 (2.48 g, 77%): colorless oil; Rf = 0.63 (hexane/EtOAc = 9:1); [α]25D −13 (c 0.90, CHCl3); IR (neat) 1514, 1250, 1098, 836, 776 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 12H), 0.88 (s, 9H), 0.89 (s, 9H), 1.51−1.68 (m, 4H), 1.74 (dq, J = 14.4 Hz, 6.0 Hz, 1H), 1.92 (dtd, J = 14.4 Hz, 6.8 Hz, 4.6 Hz, 1H), 2.68 (dd, J = 4.6 Hz, 2.4 Hz, 1H), 3.00 (ddd, J = 6.8 Hz, 4.4 Hz, 2.4 Hz, 1H), 3.54−3.63 (m, 5H), 3.80 (s, 3H), 4.43 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −5.3 (+), −4.9 (+), −4.4 (+), 18.1 (−), 18.3 (−), 25.8 (+), 26.0 (+), 28.2 (−), 31.5 (−), 32.3 (−), 54.0 (+), 55.3 (+), 60.9 (+), 63.2 (−), 66.8 (−), 71.1 (+), 72.7 (−), 113.8 (+), 129.3 (+), 130.4 (−), 159.2 (−); HRMS (FAB+) calcd for C28H52O5Si2Na [(M + Na)+] 547.3251, found 547.3258. 2-[(2S,3R)-3-[(S)-2,2,3,3,10,10,11,11-Octamethyl-4,9-dioxa-3,10disiladodecan-5-yl]oxiran-2-yl]ethan-1-ol (19). To a mixture of PMB ether 18 (2.48 g, 4.73 mmol) in CH2Cl2 (40 mL) and phosphate buffer solution (pH 6.8, 40 mL) was added DDQ (1.61 g, 7.10 mmol). The mixture was stirred at rt for 1.5 h and diluted with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 (×2), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (toluene/AcOEt = 8:1) to afford alcohol 19 (1.72 g, 90%): colorless oil; Rf = 0.43 (toluene/EtOAc = 8:1); [α]23D −17 (c 0.76, CHCl3); IR (neat) 3433, 1255, 1099, 835 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 12H), 0.87 (s, 9H), 0.89 (s, 9H), 1.52−1.77 (m, 5H), 1.81− 1.88 (m, 1H), 1.93−2.02 (m, 1H), 2.76 (dd, J = 4.6 Hz, 2.4 Hz, 1H), 3.03 (ddd, J = 6.5 Hz, 4.6 Hz, 2.1 Hz, 1H), 3.55−3.65 (m, 3H), 3.75− 3.82 (m, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −5.3 (+), −4.9 (+), −4.4 (+), 18.1 (−), 18.3 (−), 25.8 (+), 26.0 (+), 28.1 (−), 31.6 (−), 33.8 (−), 54.6 (+), 60.1 (+), 60.2 (−), 63.2 (−), 71.1 (+); HRMS (FAB+) calcd for C20H44O4Si2Na [(M + Na)+] 427.2676, found 427.2667. (4R,5S,E)-5,8-Bis[(tert-butyldimethylsilyl)oxy]-4-hydroxyoct-2enal (20). To a solution of (COCl)2 (0.534 mL, 6.23 mmol) in CH2Cl2 (40 mL) was slowly added DMSO (0.888 mL, 12.5 mmol) at −78 °C. The solution was stirred at −78 °C for 15 min. A solution of alcohol 19 (1.10 g, 2.73 mmol) in CH2Cl2 (10 mL) was added to the solution at −78 °C. After an additional 5 min of stirring at −78 °C, Et3N (5.59 mL, 41.5 mmol) was added, and then the ice bath was removed. After being stirred for 30 min at rt, the reaction was quenched by adding saturated NaHCO3 solution, and the resulting mixture was extracted with CH2Cl2 (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/AcOEt = 4:1) to afford aldehyde 20 (1.14 g, 68%): pale yellow oil; Rf = 0.49 (hexane/ EtOAc = 4:1); [α]24D +36 (c 1.0, CHCl3); IR (neat) 3433, 1692, 1255, 1096 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 6H), 0.10 (s, 6H), 0.88 (s, 9H), 0.91 (s, 9H), 1.42−1.77 (m, 4H), 2.63 (br s, 1H), 3.60 (t, J = 5.8 Hz, 2H), 3.84 (dt, J = 6.4 Hz, 4.8 Hz, 1H), 4.37−4.43 (m, 1H), 6.37 (ddd, J = 15.8 Hz, 7.7 Hz, 1.7 Hz, 1H), 6.81 (dd, J = 15.8 Hz, 4.6 Hz, 1H), 9.58 (d, J = 7.7 Hz, 1H); 13C-APT NMR (100 MHz, CDCl3) δ −5.3 (+), −4.6 (+), −4.4 (+), 18.0 (−), 18.3 (−), 25.8 (+), 25.9 (+), 28.3 (−), 28.6 (−), 62.9 (−), 73.9 (+), 74.7 (+), 132.2 (+), 154.7(+), 193.3 (+); HRMS (FAB+) calcd for C20H43O4Si2 [(M + H)+] 403.2700, found 403.2698. (4R,5S,E)-4,5,8-Tris[(tert-butyldimethylsilyl)oxy]oct-2-enal (21). To an ice-cold solution of alcohol 20 (1.10 g, 2.73 mmol) in

afford alcohol 17 (1.17 g, 83%): colorless oil; Rf = 0.46 (hexane/ EtOAc = 3:1); 95% ee determined by HPLC [Daicel Chiralcel OD-H; hexane/i-PrOH = 97:3, 1 mL/min, 35 °C; tR (min) = 13.8 (minor), 17.5 (major)]; [α]23D −8 (c 1.25, CHCl3); IR (neat) 3424, 1614, 1514, 1250 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.90 (s, 9H), 1.61−1.72 (m, 2H), 1.73−1.82 (m, 2H), 2.51 (td, J = 7.2 Hz, 2.0 Hz, 2H), 3.05 (d, J = 4.8 Hz, 1H), 3.55 (t, J = 7.2 Hz, 2H), 3.61− 3.72 (m, 2H), 3.80 (s, 3H), 4.36−4.43 (m, 1H), 4.47 (s, 2H), 6.89 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −5.4 (+), 18.3 (−), 20.1 (−), 26.0 (+), 28.5 (−), 35.5 (−), 55,2 (+), 62.3 (+), 63.2 (−), 68.1 (−), 72.6 (−), 81.7 (−), 82.3 (−), 113.8 (+), 129.4 (+), 130.1 (−), 159.2 (−); HRMS (FAB+) calcd for C22H37O4Si [(M + H)+] 393.2461, found 393.2463. (S,E)-1-[(tert-Butyldimethylsilyl)oxy]-8-[(4-methoxybenzyl)oxy]oct-5-en-4-ol [(R)-10]. To an ice-cold solution of alcohol 17 (503 mg, 1.28 mmol) in toluene (3 mL) was added Red-Al (3.60 M in toluene, 0.850 mL, 3.10 mmol). After 2 h of stirring at rt, the reaction was stopped by adding H2O (0.35 mL, 19 mmol), NaF (802 mg, 19.1 mmol), and Celite (750 mg). The resulting mixture was stirred at rt for 30 min and filtered through a pad of Celite. Organic solvents were removed by evaporation. The residue was purified by chromatography on silica gel (hexane/EtOAc = 3:1) to afford allylic alcohol (S)-10 (290 mg, 57%) [Rf = 0.50 (hexane/EtOAc = 4:1)] and the corresponding diol (95 mg, 26%) [Rf = 0.40 (EtOAc)]. To an ice-cold solution of the diol (95 mg, 0.339 mmol) in DMF (0.8 mL) were added imidazole (29 mg, 0.43 mmol) and TBSCl (53 mg, 0.35 mmol). After 30 min of stirring at rt, the solution was diluted with saturated NaHCO3 solution, and the mixture was extracted with EtOAc (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/AcOEt = 3:1) to afford allylic alcohol (R)-10 (89 mg, 67%). Allylic alcohol (R)-10: liquid; 379 mg, 75% yield in total; [α]20D −4 (c 0.99, CHCl3); IR (neat) 3428, 1613, 1514, 1250, 1097 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.90 (s, 9H), 1.53−1.68 (m, 4H), 2.35 (q, J = 6.7 Hz, 2H), 2.55 (d, J = 3.2 Hz, 1H), 3.48 (t, J = 6.7 Hz, 2H), 3.61−3.68 (m, 2H), 3.80 (s, 3H), 4.03−4.12 (m, 1H), 4.44 (s, 2H), 5.55 (dd, J = 15.7 Hz, 6.0 Hz, 1H), 5.67 (dd, J = 15.7 Hz, 6.7 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −5.3 (+), 18.4 (−), 26.0 (+), 28.9 (−), 32.7 (−), 34.5 (−), 55.3 (+), 63.4 (−), 69.5 (−), 72.5 (+), 72.6 (−), 113.8 (+), 127.6 (+), 129.3 (+), 130.5 (−), 135.0 (+), 159.2 (−); HRMS (FAB+) calcd for C22H37O4Si [(M − H)+] 393.2461, found 393.2455. (S)-4-[(tert-Butyldimethylsilyl)oxy]-1-[(2S,3S)-3-[2-{(4methoxybenzyl)oxy}ethyl]oxiran-2-yl]butan-1-ol (11). To an icecold solution of Ti(O-i-Pr)4 (0.223 mL, 0.760 mmol) in CH2Cl2 (1 mL) was added L-(+)-DIPT (0.191 mL, 0.912 mmol). After 30 min of stirring at 0 °C, the solution was cooled to −30 °C, and a solution of allylic alcohol (S)-10 (300 mg, 0.760 mmol) in CH2Cl2 (2 mL) was added. The solution was stirred at −30 °C for 20 min. To this solution was added t-BuOOH (4.34 M in CH2Cl2, 0.35 mL, 1.52 mmol) at −30 °C dropwise. The solution was stirred at −18 °C for 2 h, and then Me2S (0.5 mL, 6.84 mmol), 10% tartaric acid (5 mL), and NaF (319 mg, 7.60 mmol) were added. The resulting mixture was stirred at rt for 30 min and filtered through a pad of Celite. The mixture was extracted with CH2Cl2 (×3). The combined organic layers were concentrated to give a residue, to which were added Et2O (30 mL) and 1 N NaOH (30 mL, 30 mmol). After 20 min of stirring at rt, the mixture was extracted with Et2O (×4). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/EtOAc = 3:1) to afford epoxide alcohol 11 (235 mg, 82%): >99% ee by 1H NMR spectroscopy of the derived MTPA ester; liquid; Rf = 0.20 (hexane/EtOAc = 3:1); [α]23D −10 (c 1.37, CHCl3); IR (neat) 3446, 1609, 1514, 1250, 1097 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.90 (s, 9H), 1.50−1.57 (m, 1H), 1.64−1.84 (m, 4H), 1.87−1.98 (m, 1H), 2.79 (dd, J = 4.6 Hz, 2.4 Hz, 1H), 2.82 (d, J = 2.8 Hz, 1H), 3.11 (ddd, J = 6.7 Hz, 4.6 Hz, 2.1 Hz, 1H), 3.58 (t, J = 6.4 Hz, 2H), 3.62−3.70 (m, 3H), 3.80 (s, 3H), 4.43 (d, J = 11.2 Hz, 1H), 4.46 (d, J = 11.2 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H); 13C-APT NMR (100 MHz, CDCl3) δ 3911

DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914

Article

The Journal of Organic Chemistry

775 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 3H), 0.02 (s, 3H), 0.03 (s, 6H), 0.04 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H), 0.87 (s, 9H), 0.89 (s, 9H), 1.49−1.62 (m, 4H), 3.54−3.66 (m, 3H), 4.11 (t, J = 5.2 Hz, 1H), 6.13 (dd, J = 15.5 Hz, 8.0 Hz, 1H), 6.25 (dd, J = 15.2 Hz, 6.4 Hz, 1H), 6.42 (dd, J = 15.2 Hz, 10.9 Hz, 1H), 7.10 (dd, J = 15.5 Hz, 10.9 Hz, 1H), 9.57 (d, J = 8.0 Hz, 1H); 13C-APT NMR (100 MHz, CDCl3) δ −5.3 (+), −4.7 (+), −4.5 (+), −4.2 (+), −4.1 (+), 18.1 (−), 18.2 (−), 18.3 (−), 25.91 (+), 25.95 (+), 28.2 (−), 29.9 (−), 63.3 (−), 76.1 (+), 128.8 (+), 131.4 (+), 146.3 (+), 151.6 (+), 193.9 (+); HRMS (FAB+) calcd for C28H58O4Si3Na [(M + Na)+] 565.3541, found 565.3554. (4S,5R,6E,8E,10Z,13Z,15E,17S,19Z)-4,5,17-Tris[(tertbutyldimethylsilyl)oxy]docosa-6,8,10,13,15,19-hexaen-1-ol (25). To a solution of phosphonium salt 9 (2.16 g, 3.43 mmol) in THF (40 mL) was added NaHMDS (1.0 M in THF, 3.03 mL, 3.03 mmol) dropwise at −78 °C. The mixture was stirred at −78 °C for 30 min, and a solution of aldehyde 23 (1.10 g, 2.02 mmol) in THF (10 mL) was added. The cooling bath was then removed. After 10 min of stirring at 0 °C, saturated NH4Cl solution was added to the solution. The resulting mixture was extracted with EtOAc (×3). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was semipurified by chromatography on silica gel (hexane/ EtOAc = 97:3) for the next reaction: colorless oil; Rf = 0.86 (hexane/ EtOAc = 97:3): 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 3H), 0.018 (s, 3H), 0.023 (s, 3H), 0.04 (s, 6H), 0.05 (s, 6H), 0.06 (s, 3H), 0.86 (s, 9H), 0.88 (s, 18H), 0.92 (s, 9H), 0.95 (t, J = 7.6 Hz, 3H), 1.46−1.64 (m, 4H), 2.03 (quint, J = 7.3 Hz, 2H), 2.18−2.35 (m, 2H), 3.08 (t, J = 7.5 Hz, 2H), 3.53−3.65 (m, 3H), 3.98 (dd, J = 7.7 Hz, 4.8 Hz, 1H), 4.19 (q, J = 6.0 Hz, 1H), 5.29−5.51 (m, 4H), 5.65 (dd, J = 14.1 Hz, 7.7 Hz, 1H), 5.70 (dd, J = 15.3 Hz, 5.4 Hz, 1H), 5.95−6.27 (m, 4H), 6.40−6.54 (m, 2H). To a solution of the above product in CH2Cl2 (25 mL) and MeOH (25 mL) was added PPTS (254 mg, 1.01 mmol) at rt. After 3 h of stirring at rt, the solution was diluted with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 (×3). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/AcOEt = 9:1) to afford alcohol 25 (650 mg, 46%) as a pale yellow oil and the starting TBS ether, which was subjected to desilylation again with PPTS (254 mg, 1.01 mmol) at rt for 4 h to afford alcohol 25 (346 mg, 24%). Combined 25: 996 mg, 70% from the aldehyde; colorless oil; Rf = 0.29 (hexane/EtOAc = 9:1); [α]23D +12 (c 1.02, CHCl3); IR (neat) 3407, 1255, 1102, 836, 760 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 3H), 0.03 (s, 3H), 0.045 (s, 3H), 0.050 (s, 3H), 0.055 (s, 3H), 0.065 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 0.99 (s, 9H), 0.95 (t, J = 7.5 Hz, 3H), 1.47−1.75 (m, 5H), 2.03 (quint, J = 7.5 Hz, 1H), 2.23 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.30 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 3.09 (t, J = 7.4 Hz, 2H), 3.56−3.68 (m, 3H), 4.03 (dd, J = 7.2 Hz, 5.2 Hz, 1H), 4.20 (dd, J = 12.0 Hz, 6.0 Hz, 1H), 5.31−5.51 (m, 4H), 5.64 (dd, J = 14.0 Hz, 7.3 Hz, 1H), 5.70 (dd, J = 15.2 Hz, 6.0 Hz, 1H), 6.01 (t, J = 10.8 Hz, 1H), 6.05 (t, J = 11.0 Hz, 1H), 6.13−6.24 (m, 2H), 6.40− 6.52 (m, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −4.63 (+), −4.58 (+), −4.40 (+), −4.30 (+), −3.96 (+), −3.72 (+), 14.3 (+), 18.26 (−), 18.31 (−), 18.40 (−), 20.8 (−), 26.00 (+), 26.05 (+), 26.7 (−), 28.3 (−), 29.9 (−), 36.4 (−), 63.4 (−), 73.0 (+), 76.0 (+), 124.2 (+), 124.7 (+), 127.6 (+), 128.69 (+), 128.81 (+), 129.1 (+), 130.0 (+), 132.0 (+), 132.8 (+), 133.6 (+), 135.2 (+), 137.2 (+); HRMS (FAB+) calcd for C40H76O4Si3Na [(M + Na)+] 727.4949, found 727.4932. Methyl (4S,5R,6E,8E,10Z,13Z,15E,17S,19Z)-4,5,17-Tris[(tert-butyldimethylsilyl)-oxy]docosa-6,8,10,13,15,19-hexaenoate (26). To a solution of (COCl)2 (0.347 mL 4.05 mmol) in CH2Cl2 (50 mL) was slowly added DMSO (0.575 mL, 8.10 mmol) at −78 °C. A solution of alcohol 25 (950 mg, 1.35 mmol) in CH2Cl2 (10 mL) was added to the solution at −78 °C. After an additional 5 min of stirring at −78 °C, Et3N (1.89 mL, 13.5 mmol) was added, and then the ice bath was removed. The mixture was stirred at rt for 15 min, and saturated NaHCO3 solution was added to the mixture. The resulting mixture was extracted with CH2Cl2 (×3). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford a crude aldehyde, which was passed through a short silica gel column for

CH2Cl2 (10 mL) were added 2,6-lutidine (0.791 mL, 6.83 mmol) and TBSOTf (0.939 mL, 4.10 mmol). After the addition, the ice bath was removed, and the solution was stirred at rt for 1 h before addition of saturated NaHCO3 solution. The resulting mixture was extracted with CH2Cl2 (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to leave a residual oil, which was purified by chromatography on silica gel (hexane/AcOEt = 20:1) to afford silyl ether 21 (1.39 g, 99%): colorless oil; Rf = 0.50 (hexane/EtOAc = 20:1); [α]22D +14 (c 1.07, CHCl3); IR (neat) 1698, 1255, 1103, 836 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3H), 0.04 (s, 9H), 0.05 (s, 3H), 0.07 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 0.90 (s, 9H), 1.48− 1.69 (m, 4H), 3.56−3.62 (m, 2H), 3.67−3.72 (m, 1H), 4.28 (ddd, J = 5.4 Hz, 4.7 Hz, 1.3 Hz, 1H), 6.25 (ddd, J = 15.6 Hz, 8.0 Hz, 1.3 Hz, 1H), 6.87 (dd, J = 15.6 Hz, 4.7 Hz, 1H), 9.57 (d, J = 8.0 Hz, 1H); 13CAPT NMR (100 MHz, CDCl3) δ −5.3 (+), −4.7 (+), −4.5 (+), −4.4 (+), −4.1 (+), 18.1 (−), 18.2 (−), 18.3 (−), 25.88 (+), 25.91 (+), 25.95 (+), 28.3 (−), 30.1 (−), 63.1 (−), 75.5 (+), 76.3 (+), 132.2 (+), 158.1 (+), 193.6 (+); HRMS (FAB+) calcd for C26H56O4Si3Na [(M + Na)+] 539.3383, found 539.3367. Ethyl (2E,4E,6R,7S)-6,7,10-Tris[(tert-butyldimethylsilyl)oxy]deca2,4-dienoate (22). To an ice-cold solution of triethyl phosphonoacetate (1.17 g, 5.22 mmol) in THF (10 mL) was added NaH (60 wt %, 0.230 g, 5.74 mmol) portionwise. The mixture was stirred at 0 °C for 30 min. A solution of aldehyde 21 (1.35 g, 2.61 mmol) in THF (5 mL) was added to the mixture at 0 °C. After 30 min of stirring at 0 °C, the reaction was quenched by adding saturated NH4Cl solution. The mixture was extracted with AcOEt (×3). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/AcOEt = 20:1) to afford ester 22 (1.36 g, 89%): colorless oil; Rf = 0.57 (hexane/ EtOAc = 50:1); [α]22D +1.2 (c 0.82, CHCl3); IR (neat) 1718, 1256, 1101 cm−1; 1H NMR (400 MHz, CDCl3) δ −0.01 (s, 3H), 0.01 (s, 3H), 0.02 (s, 3H), 0.03 (s, 6H), 0.04 (s, 3H), 0.85 (s, 9H), 0.878 (s, 9H), 0.881 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H), 1.46−1.60 (m, 4H), 3.55−3.63 (m, 3H), 4.05 (t, J = 5.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 5.84 (d, J = 15.0 Hz, 1H), 6.08 (dd, J = 15.2 Hz, 6.6 Hz, 1H), 6.26 (dd, J = 15.2 Hz, 11.1 Hz, 1H), 7.26 (dd, J = 15.0 Hz, 11.1 Hz, 1H); 13CAPT NMR (100 MHz, CDCl3) δ −5.3 (+), −4.7 (+), −4.5 (+), −4.2 (+), −4.1 (+), 14.3 (+), 18.1 (−), 18.2 (−), 18.3 (−), 25.91 (+), 25.94 (+), 28.2 (−), 29.8 (−), 60.3 (−), 63.4 (−), 76.0 (+), 76.3 (+), 120.9 (+), 128.8 (+), 143.8 (+), 144.0 (+), 167.1 (+); HRMS (FAB+) calcd for C30H62O5Si3Na [(M + Na)+] 609.3803, found 609.3792. (2E,4E,6R,7S)-6,7,10-Tris[(tert-butyldimethylsilyl)oxy]deca-2,4-dienal (23). To a solution of ester 22 (1.33 g, 2.27 mmol) in CH2Cl2 (10 mL) was added DIBAL (1.02 M in hexane, 5.34 mL, 5.45 mmol) at −78 °C. After 30 min of stirring, the reaction was quenched by adding MeOH (10 mL) at −78 °C. The ice bath was removed, and saturated NH4Cl solution was added. The resulting mixture was extracted with CH2Cl2 (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a residue, which was passed through a column of silica gel (hexane/AcOEt = 20:1) to afford the corresponding allylic alcohol (1.16 g, 94%): colorless oil; Rf = 0.37 (hexane/EtOAc = 20:1): 1H NMR (300 MHz, CDCl3) δ −0.003 (s, 3H), 0.016 (s, 3H), 0.024 (s, 3H), 0.03 (s, 6H), 0.04 (s, 3H), 0.86 (s, 9H), 0.878 (s, 9H), 0.883 (s, 9H), 1.45−1.55 (m, 4H), 3.52−3.65 (m, 3H), 3.97 (dd, J = 7.1 Hz, 4.8 Hz, 1H), 4.15−4.23 (m, 2H), 5.65 (dd, J = 14.6 Hz, 7.1 Hz, 1H), 5.79 (dt, J = 14.9 Hz, 5.9 Hz, 1H), 6.11 (dd, J = 14.6 Hz, 10.3 Hz, 1H), 6.23 (dd, J = 14.9 Hz, 10.3 Hz, 1H). To a solution of (COCl)2 (0.268 mL 3.12 mmol) in CH2Cl2 (30 mL) was slowly added DMSO (0.473 mL, 6.66 mmol) at −78 °C. A solution of the above alcohol (1.13 g, 2.08 mmol) in CH2Cl2 (2 mL) was added to the solution at −78 °C. After an additional 10 min of stirring at −78 °C, Et3N (2.92 mL, 20.8 mmol) was added, and then the ice bath was removed. After being stirred for 10 min at rt, the mixture was diluted with saturated NaHCO3 solution and extracted with CH2Cl2 (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/AcOEt = 20:1) to afford aldehyde 23 (939 mg, 83%): pale yellow oil; Rf = 0.69 (hexane/EtOAc = 20:1); [α]22D +5 (c 1.52, CHCl3); IR (neat) 1688, 1255, 1100, 836, 3912

DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914

Article

The Journal of Organic Chemistry the next reaction: colorless oil; Rf = 0.77 (hexane/EtOAc = 9:1); 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 3H), 0.03 (s, 6H), 0.05 (s, 6H), 0.06 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 0.90 (s, 9H), 0.95 (t, J = 7.5 Hz, 3H), 1.78−1.93 (m, 2H), 2.03 (quint, J = 7.5 Hz, 1H), 2.18−2.36 (m, 2H), 2.51 (t, J = 7.5 Hz, 2H), 3.09 (t, J = 7.5 Hz, 2H), 3.59−3.67 (m, 1H), 3.99 (dd, J = 7.4 Hz, 5.0 Hz, 1H), 4.20 (q, J = 5.7 Hz, 1H), 5.28−5.51 (m, 4H), 5.57−5.75 (m, 2H), 5.95−6.27 (m, 4H), 6.40− 6.54 (m, 2H), 9.77 (s, 1H). To a solution of the above aldehyde in t-BuOH (11 mL) were added a phosphate buffer (pH 6.8, 3.8 mL), 2-methyl-2-butene (7.16 mL, 67.5 mmol), and NaClO2 (733 mg, 8.10 mmol). After 2 h of stirring at rt, aqueous Na2S2O3 (10%, 50 mL) was added, and the resulting mixture was extracted with CHCl3 (×4). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the corresponding acid, which was used for the next esterification without further purification: 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 3H), 0.03 (s, 3H), 0.04 (s, 3H), 0.05 (s, 3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 0.91 (s, 9H), 0.95 (t, J = 7.8 Hz, 3H), 1.75−1.98 (m, 2H), 2.03 (quint, J = 7.5 Hz, 2H), 2.18−2.35 (m, 2H), 2.45 (t, J = 7.8 Hz, 2H), 3.09 (t, J = 7.3 Hz, 2H), 3.59−3.67 (m, 1H), 3.98 (dd, J = 7.5 Hz, 4.8 Hz, 1H), 4.19 (q, J = 5.9 Hz, 1H), 5.29−5.52 (m, 4H), 5.58−5.74 (m, 2H), 5.96−6.25 (m, 4H), 6.39−6.54 (m, 2H). To an ice-cold solution of the above acid in Et2O (2 mL) was added an ice-cold ethereal solution of freshly prepared CH2N2 until a yellow color persisted. After the organic solvent was removed in vacuo, the residue was purified by chromatography on silica gel (hexane/AcOEt = 50:1) to afford ester 26 (394 mg, 40% from alcohol 25): colorless oil; Rf = 0.66 (hexane/EtOAc = 20:1); [α]20D +14 (c 1.26, CHCl3); IR (neat) 1741, 1255, 1101, 836, 776 cm−1; 1H NMR (400 MHz, CDCl3) δ −0.01 (s, 3H), 0.03 (s, 6H), 0.050 (s, 3H), 0.053 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 0.91 (s, 9H), 0.95 (t, J = 7.6 Hz, 3H), 1.75−1.90 (m, 2H), 2.03 (quint, J = 7.3 Hz, 2H), 2.17−2.35 (m, 2H), 2.38 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 2.40 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 3.08 (t, J = 7.6 Hz, 2H), 3.63 (dt, J = 10.3 Hz, 5.1 Hz, 1H), 3.66 (s, 3H), 4.00 (dd, J = 7.6 Hz, 4.9 Hz, 1H), 4.20 (q, J = 5.1 Hz, 1H), 5.30− 5.51 (m, 4H), 5.64 (dd, J = 14.6 Hz, 7.6 Hz, 1H), 5.70 (dd, J = 15.0 Hz, 5.1 Hz, 1H), 6.01 (t, J = 10.8 Hz, 1H), 6.05 (t, J = 11.0 Hz, 1H), 6.13−6.24 (m, 2H), 6.42−6.53 (m, 2H); 13C-APT NMR (100 MHz, CDCl3) δ −4.7 (+), −4.4 (+), −3.9 (+), 14.3 (+), 18.2 (−), 18.3 (−), 18.4 (−), 20.8 (−), 26.00 (+), 26.02 (+), 26.7 (−), 28.2 (−), 29.7 (−), 36.4 (−), 51.6 (+), 73.0 (+), 75.3 (+), 77.1 (+), 124.1 (+), 124.7 (+), 127.6 (+), 128.7 (+), 128.8 (+), 129.1 (+), 130.0 (+), 131.9 (+), 132.7 (+), 133.6 (+), 134.7 (+), 137.2 (+), 174.4 (−); HRMS (FAB+) calcd for C41H76O5Si3Na [(M + Na)+] 755.4898, found 755.4891. (S)-5-[(1R,2E,4E,6Z,9Z,11E,13S,15Z)-1,13-Dihydroxyoctadeca2,4,6,9,11,15-hexaen-1-yl]dihydrofuran-2(3H)-one (28). To an icecold solution of ester 26 (358 mg, 0.488 mmol) in THF (50 mL) was added TBAF (1.0 M in THF, 3.9 mL, 3.9 mmol) dropwise. The solution was stirred at 0 °C for 3 h and diluted with McIlvaine’s phosphate buffer (pH 5.0, 20 mL). The mixture was extracted with Et2O (×5). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/AcOEt = 1:2) to afford lactone 28 (81 mg, 46%), which was further purified by using recycling HPLC (LC-Forte/R equipped with YMC-Pack SIL-60, THF/CH2Cl2 = 1:9, 20 mL/min): Rf = 0.37 (hexane/EtOAc = 1:2); colorless oil; [α]21D +9 (c 0.34, MeOH); 1H NMR (400 MHz, CD3OD) δ 0.91 (t, J = 7.2 Hz, 3H), 2.02 (quint, J = 7.2 Hz, 2H), 2.14 (td, J = 8.4 Hz, 6.8 Hz, 2H), 2.17− 2.34 (m, 2H), 2.40−2.56 (m, 2H), 3.07 (t, J = 7.6 Hz, 2H), 4.09 (q, J = 6.4 Hz, 1H), 4.33−4.38 (m, 1H), 4.51 (td, J = 6.8 Hz, 3.2 Hz, 1H), 5.28−5.48 (m, 4H), 5.65 (dd, J = 14.9 Hz, 6.4 Hz, 2H), 5.96 (t, J = 11.0 Hz, 1H), 6.01 (t, J = 10.5 Hz, 1H), 6.21 (dd, J = 14.8 Hz, 10.8 Hz, 1H), 6.44 (dd, J = 14.8 Hz, 10.6 Hz, 1H), 6.53 (dd, J = 14.9 Hz, 10.6 Hz, 1H), 6.58 (dd, J = 14.9 Hz, 10.8 Hz, 1H); 13C-APT NMR (100 MHz, CD3OD) δ 14.5 (+), 21.7 (−), 22.5 (−), 27.5 (−), 29.4 (−), 36.3 (−), 73.2 (+), 73.6 (+), 84.2 (+), 125.5 (+), 126.2 (+), 129.6 (+), 129.7 (+), 130.0 (+), 130.1 (+), 131.2 (+), 131.9 (+), 133.5 (+), 134.0 (+), 134.7 (+), 137.6 (+), 180.4 (−); HRMS (FAB+) calcd for C22H30O4Na [(M + Na)+] 381.2042, found 381.2050.

Resolvin D4 (1). To a solution of lactone 28 (11 mg, 0.0307 mmol) in MeOH (1 mL), THF (1 mL), and H2O (1 mL) was added LiOH· H2O (3 mg, 0.07 mmol). After 15 min of stirring, McIlvaine’s phosphate buffer (pH 5.0, 10 mL) was added. The resulting mixture was extracted with Et2O (×5). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (Et2O/MeOH = 20:1) to afford RvD1 (1) (6 mg, 52%), which was further purified by using recycling HPLC (LC-Forte/R equipped with YMC-Pack SIL-60, AcOEt/MeOH = 9:1, 25 mL/min): colorless oil; Rf = 0.57 (Et2O/MeOH = 9:1); [α]20D +6 (c 0.25, MeOH); 1H NMR (400 MHz, CD3OD) δ 0.96 (t, J = 7.4 Hz, 3H), 1.57−1.69 (m, 1H), 1.84−1.95 (m, 1H), 2.06 (quint, J = 7.4 Hz, 2H), 2.22−2.54 (m, 4H), 3.11 (t, J = 7.8 Hz, 2H), 3.47−3.55 (m, 1H), 3.99 (t, J = 6.8 Hz, 1H), 4.14 (q, J = 6.6 Hz, 1H), 5.33−5.52 (m, 4H), 5.69 (dd, J = 15.2 Hz, 6.6 Hz, 1H), 5.81 (dd, J = 14.9 Hz, 6.8 Hz, 1H), 6.01 (t, J = 10.8 Hz, 1H), 6.05 (t, J = 11.2 Hz, 1H), 6.26 (dd, J = 14.6 Hz, 10.9 Hz, 1H), 6.38 (dd, J = 14.9 Hz, 10.9 Hz, 1H), 6.57 (dd, J = 15.2 Hz, 10.8 Hz, 1H), 6.59 (dd, J = 14.6 Hz, 11.2 Hz, 1H); 13C-APT NMR (100 MHz, CD3OD) δ 14.5 (+), 21.7 (−), 27.5 (−), 29.1 (−), 31.8 (−), 36.3 (−), 73.2 (+), 75.0 (+), 76.7 (+), 125.5 (+), 126.2 (+), 129.0 (+), 129.6 (+), 130.1 (+), 130.2 (+), 130.7 (+), 133.4 (+), 134.0 (+), 134.2 (+), 134.7 (+), 137.5 (+),178.1 (−); HRMS (FAB−) calcd for C22H32O5Na [(M + Na)+] 399.2147, found 399.2144. Note that three OH protons and COOH were overlapped with the residue of CD3OD at 3.3 ppm.

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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.8b00256. 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 JSPS KAKENHI grant number JP15H05904. REFERENCES

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DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914

Article

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DOI: 10.1021/acs.joc.8b00256 J. Org. Chem. 2018, 83, 3906−3914