Total Synthesis of Callyspongiolide: An Anticancer Marine Natural

Dec 4, 2018 - ... via an intramolecular Horner–Wadsworth–Emmons olefination in a Z-selective fashion. The other ... was introduced via stereoselec...
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Article Cite This: ACS Omega 2018, 3, 16563−16575

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Total Synthesis of Callyspongiolide: An Anticancer Marine Natural Product Ashish Sharma,†,‡ Sudhakar Athe,† and Subhash Ghosh*,†,‡ †

Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India ‡ Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India

ACS Omega 2018.3:16563-16575. Downloaded from pubs.acs.org by 79.110.18.145 on 12/05/18. For personal use only.

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ABSTRACT: The stereoselective total synthesis of cytotoxic marine macrolide callyspongiolide has been reported. The 14membered macrolactone ring along with Z-olefin in the molecule was constructed via an intramolecular Horner− Wadsworth−Emmons olefination in a Z-selective fashion. The other E-olefinic moiety as well as the C9 stereocenter was introduced via stereoselective addition of the methyl group in an SN2′ fashion. The C5 stereocenter was installed via Sakurai allylation, whereas the C7 center was fixed by Jacobsen hydrolytic kinetic resolution. The C12 methyl and C13 hydroxy centers were fixed via Macmillan coupling reaction. The macrolactone core with a vinyl iodide side chain was coupled with the known alkyne fragment to complete the synthesis.

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INTRODUCTION Secondary metabolites produced by marine organisms have attracted the considerable attention of synthetic organic chemists, because of their interesting structure and function.1 Among various marine organisms, sponge belonging to genus Callyspongia is a rich source of various potent antiproliferative agents, such as polyketides, polyacetylenes, alkaloids, and cyclic peptides.2 Callyspongiolide, a cytotoxic marine natural product, was isolated by Proksch and co-workers in 2014 from the marine sponge of Callyspongia sp.3 A detailed NMR study revealed that callyspongiolide has a 14-membered lactone ring having five stereocenters and two alkene functionalities connected to a brominated benzene ring with a diene-ynic chain (Figure 1). The relative stereochemistry of the lactone part was established via the detailed NMR study; however, Proksch et al. were unsuccessful in determining the absolute stereochemistry of the C21 center, as they failed to acylate the C21−OH group with Mosher’s acid. Apart from its complex architecture, callyspongiolide has shown promising cytotoxic activity against various cancer cell lines. It inhibits the

growth of mouse lymphoma (L5178Y) cells with an IC50 value of 320 nM. It was also found to be highly cytotoxic to human cell lines [Jurkat J16T (IC50 = 70 nM) and Ramos B lymphocytes (IC50 = 60 nM)].3 The complex architecture, important biological activity, and structural issue of callyspongiolide have become a synthetic target for synthetic organic chemists. The first elegant total synthesis and stereochemical assignment of callyspongiolide were reported by Ye and co-workers in 20 steps with an overall yield of 8.6%.4 Subsequently, Ghosh et al.5a reported the total synthesis of both epimers at C21 of the proposed structure of cytotoxic macrolide (+)-callyspongiolide in 22 steps with an overall yield of 3.32% and confirmed the stereochemical assignment at the C21 position established by Ye and co-workers. Furthermore, Ghosh et al. synthesized four different stereoisomers of callyspongiolide and unambiguously confirmed the absolute stereochemistry at the C21 center.5b Besides, Kotora and coworkers also synthesized the unsaturated fragment of callyspongiolide.6 Very recently, Harran and co-workers reported a well-designed total synthesis of (−)-callyspongiolide in 18 steps with an overall yield of 1% by using an unconventional fragment.7 Because of our constant interest in the area of total synthesis of marine natural products,8 we were attracted by callyspongiolide because of its interesting structure and function and reported a strategy for making the macrolactone part of (+)-callyspongiolide.9 In this article, we Received: August 24, 2018 Accepted: November 20, 2018 Published: December 4, 2018

Figure 1. Structure of callyspongiolide 1. © 2018 American Chemical Society

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Scheme 1. Retrosynthetic Analysis

Scheme 2. Synthesis of Alkyne Fragment 10

lactone 2 and ene-yne fragment terminated with the substituted bromobenzene ring 3 would give callyspongiolide. The 14-membered macrolactone ring would be obtained from compound 5 via installation of a Z-double bond at the C2−C3 position by intramolecular Z-selective Horner−Wadsworth− Emmons reaction (Scheme 1). The phosphonate 5 might be obtained from alcohol 6 via acylation with diaryl phosphono-

reported the total synthesis of callyspongiolide by utilizing the knowledge developed by us.

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RESULTS AND DISCUSSION

Inspection of the structure of callyspongiolide revealed that a Sonogashira coupling between vinyl iodide-containing macro16564

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Scheme 3. Synthesis of Aldehyde Fragment 11

Scheme 4. Synthesis of Compound 6

from alkyne 10 with the aldehyde 11 that could be obtained by proline-catalyzed aldol reaction developed by the Macmillan group. According to the retrosynthetic plan, our synthesis commenced from known compound 14, which was prepared on a multigram scale via conjugate addition of allyltrimethylsilane to α,β-unsaturated N-acyloxazolidinone 13.10 The removal of chiral auxiliary from 14 with LiBH4 produced an alcohol, which on protection with TBDPSCl in the presence of

acetic acid followed by functional group manipulation. The vinyl iodide 6 could be obtained from alcohol 7 through oxidation followed by Takai olefination. The C9-methyl center and C10−C11 E-olefinic moiety might be installed via addition of methyl on the C9 carbon in an SN2′ fashion. Thus, reduction of the alkyne functionality of 9 under Lindlar conditions followed by an esterification reaction with 2picolinic acid would give compound 8. The propargylic alcohol 9 could be obtained by the reaction of the anion generated 16565

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Scheme 5. Synthesis of Macrolactone Core 30

Scheme 6. Coupling of the Macrocyclic Core with the Ene-Yne Fragment and Completion of Synthesis 1

secondary hydroxyl group followed by TMS deprotection with K2CO3/MeOH provided alkyne compound 10 in 85% yield. After synthesizing the alkyne fragment, our next objective was to synthesize the aldehyde fragment 11, and this was planned via D-proline-catalyzed asymmetric aldol reaction developed by Macmillan. Accordingly, the known aldehyde compound was synthesized on a large scale12 (Scheme 3) and reduced with NaBH4 to give an alcohol 21, which on TBDPS deprotection with TBAF, followed by acetonide protection of the resulting triol, afforded compound 22 in 64% yield over two steps.13 Finally, DMP (Dess−Martin periodinane)mediated oxidation of the primary alcohol 22 furnished aldehyde 11. Having both fragments 10 and 11 in our hand, we planned to couple them together. Accordingly, alkyne compound 10 on

Et3N in CH2Cl2 furnished compound 12 in 89% over two steps. To fix the C7-hydroxy center of the molecule, the olefinic moiety of compound 12 was subjected to epoxidation with m-CPBA to furnish a diastereomeric mixture of terminal epoxide, which on hydrolytic kinetic resolution with (R,R)-12a salen provided diastereomerically pure terminal epoxide 15 (de > 92%, 40%) and diol compound 16 (de > 90%, 44%).11 The diol compound 16 was converted back into the required epoxide by following a three-step sequence, as shown in Scheme 2.7c The regioselective opening of terminal epoxide with TMS-acetylene in the presence of BF3·OEt2 as a Lewis acid took place from the less hindered side of the epoxide and afforded alcohol 17 in 89% yield with the required stereochemistry at the C7-position. Finally, TBS protection of the 16566

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treatment with n-BuLi gave an anion that on reaction with the aldehyde 11 gave a diastereomeric mixture of alcohols (2:1), which on DMP oxidation afforded alkynone 23 in 69% over two steps. Alkynone 23 was subjected to Noyori reduction with (S,S)-Ru catalyst in the presence of IPA to afford alcohol 9 in 88% yield (de > 95%).14 Now, to fix the C9 center and the C10−C11 E-olefinic moiety present in the molecule, the alkyne was partially reduced with H2 in the presence of 5% Pd on BaSO4 in a mixture of solvents EtOAc/Py/1-octene (10:1:1) to provide Z-allylic alcohol 24,15 which was acylated with 2-picolinic acid to give the precursor 8 (77% over two steps) for asymmetric allylic alkylation. Regio- and stereoselective allylic substitutions were performed via addition of MeMgBr in the presence of Me2S·CuBr complex to give compound 25 with good yield and excellent stereoselectivity.16 Acetonide deprotection in the presence of TBS and TBDPS was a tricky problem. However, compound 25 on treatment with ZnBr2 in CH2Cl2 furnished diol 26 in good yield.17 Protection of the diol as PMB acetal followed by opening of the acetal with DIBAL-H gave primary alcohol 7 in 78% over two steps.18 Oxidation of alcohol 7 under DMP conditions gave an aldehyde, which on Takai olefination afforded Ealkenyl iodide compound 28 in 87% yield (E:Z = 7:1).19 Selective oxidative removal of PMB from compound 28 was carried out with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) to afford secondary alcohol 6 in 94% yield (Scheme 4). Having the desired fragment 6 in hand, we planned to construct 14-membered macrocycle 2. Accordingly, under Yamaguchi conditions, 2-(bis(2-tert-butylphenoxy)phosphoryl) acetic acid was esterified with the alcohol 6 to provide compound 29 in 82% yield.20 Selectively, TBDPS was removed in the presence of NH4F to give primary alcohol 29A in 76% yield,21 which on DMP oxidation afforded aldehyde 5. At this stage, the crucial intramolecular Horner−Wadsworth− Emmons reaction was carried out by using NaH in THF at high dilution to furnish macrolactone 2 with good yield and Zselectivity (Z:E = 80:20).22 Finally, deprotection of TBS group from 2 provided secondary alcohol 30 (Scheme 5). The remaining part of the synthesis is depicted in Scheme 6. The known compound 32 was synthesized via minor modification of the existing route.4,5 Selective deprotection of TMS and TBS with K2CO3 in methanol followed by protection of the phenolic−OH group as TBS ether furnished compound 3. Sonogashira coupling between alkyne 3 and vinyl iodide 30 went smoothly in the presence of Pd(PPh3)4 and CuI in THF and furnished compound 33.4 Finally, installation of the carbamate group23 followed by global deprotection of the silyl groups completed the synthesis of (−)-callyspongiolide 1 in 86% yield over two steps as a white solid. The 1H and 13 C NMR spectral data of synthetic callyspongiolide exactly matched with the data reported in the literature.7 Furthermore, the optical rotation of synthetic callyspongiolide 1 [α]D = −20.8 (c 0.6, MeOH) was very close to those reported in the literature [α]D = −12.5,3 −13.1,7 −13.0,4 and −25.55a (c 0.1, MeOH).

Emmons reaction, organocatalytic Macmillan coupling, Cucatalyzed asymmetric allylic alkylation, Takai olefination, and Sonogashira coupling. Although the route of the present synthesis is a bit lengthy, the synthetic strategy reported here is quite different from the strategy developed by others. In addition, the key fragments can be synthesized easily on a large scale from commercially available cheap starting materials. Furthermore, the strategy is highly convergent and can be used for the synthesis of analogues. Currently, we are working in that direction, which will be reported in due course.

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EXPERIMENTAL SECTION General Methods. All reagents were purchased from available commercial sources. Moisture- and air-sensitive reactions were carried out under an argon atmosphere. Anhydrous dichloromethane and chloroform were prepared via distillation over calcium hydride. Diethyl ether, dioxane, and tetrahydrofuran were dried by using sodium metal and distilled before use. All reactions were monitored by thin-layer chromatography using UV light followed by PMA, iodine, ninhydrin, and p-anisaldehyde for visualization. All the compounds were purified via column chromatography by using a glass column packed with silica gel of 60−120, 100− 200, or 230−400 mesh size. All the solvents used for purification were of technical grade and distilled before use. All 1H spectra were recorded at 300, 400, and 500 MHz, whereas all the 13C NMR spectra were recorded at 75, 100, and 125 MHz at ambient temperature by using CDCl3 as solvent. In all spectra, coupling constant J was measured in Hz. Chemical shifts (δ) of all spectra data were reported in ppm scale downfield from TMS using the residual solvent peak in CDCl3 (H: δ = 7.26, C: δ = 77.0 ppm) or TMS (δ = 0.0) as internal standard. All splitting patterns in spectral data were indicated as follows: s = singlet, d = doublet, dd = doublet of doublet, dt = doublet of triplet, ddd = doublet of doublet of doublet, t = triplet, q = quartet, qd = quartet of doublet, m = multiplet, and br = broad. FTIR spectra of all compounds were reported as cm−1 and recorded on a Bruker infrared spectrophotometer. High-resolution mass spectra (HRMS) were recorded on Orbitrap and TOFMS spectrometers. (S)-tert-Butyl((3-methylhex-5-en-1-yl)oxy)diphenylsilane (12). LiBH4 (4.51 g, 205 mmol) was added portionwise to the stirred solution of compound 14 (28 g, 102 mmol) in dry diethyl ether (180 mL) at 0 °C. The reaction mixture was allowed to be stirred for 1 h at the same temperature followed by quenching with saturated aqueous NH4Cl (200 mL) and extraction with diethyl ether (500 mL). The combined organic extracts were washed with water (30 mL) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo at 20 °C to give crude alcohol (11.4 g, 101 mmol), which was dissolved in anhydrous CH2Cl2 (500 mL) and treated with Et3N (26 mL, 183 mmol), TBDPSCl (28.7 mL, 110 mmol), and DMAP (1.12 g, 9.16 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 24 h, and then it was quenched with a saturated aqueous solution of NH4Cl (200 mL) and extracted with EtOAc (700 mL). After washing the combined organic extracts with brine (100 mL), it was dried over Na2SO4 and concentrated in vacuo. Purification of the residue by column chromatography (SiO2, 2% EtOAc/hexane) afforded the title compound 12 as colorless oil (32 g, 89% over two steps). Rf = 0.8 (SiO2, 10% EtOAc/hexane); [α]27 D = +3.4 (c 1.1, CHCl3); IR (neat): νmax 3070, 2928, 2860, 1641, 1428, 1386, 1105, 700 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.71−7.61 (m, 4H),

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CONCLUSIONS In summary, the total synthesis of the anticancer marine natural product callyspongiolide has been achieved in 25 longest linear sequences from known compound 12 with an overall yield of 1.12%. The key reactions involved in our synthesis are Z-selective intramolecular Horner−Wadsworth− 16567

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chloride (5 mL, 40.4 mmol) at 0 °C and stirred for 5 h at the same temperature. Then, the reaction mixture was warmed to room temperature, and a saturated solution of aqueous NH4Cl solution was added. The reaction mixture was extracted with EtOAc (2 × 150 mL), and the combined organic layers were washed with saturated CuSO4 solution (100 mL), water (100 mL), and brine (100 mL). After drying the organic extracts over anhydrous Na2SO4, it was filtered and evaporated under reduced pressure. The pivaloyl-protected compound (Rf = 0.5, 40% EtOAc in hexane) thus obtained was used for the next step after passing through a silica gel column. To a solution of pivaloyl compound prepared above (15 g, 31.9 mmol) in anhydrous CH2Cl2 (70 mL) was added Et3N (8.9 mL, 63.8 mmol) at 0 °C and stirred for 10 min. Then, MsCl (3.7 mL, 47.25 mmol), followed by DMAP (40 mg, 0.47 mmol), was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. A saturated solution of aqueous NH4Cl was added to the reaction mixture, and it was extracted with EtOAc (200 mL). The combined organic extracts were washed successively with water (70 mL) and brine (70 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure provided a crude mesylate compound (Rf = 0.5, 20% EtOAc in hexane), which was used directly for the next reaction without purification. The crude mesylate (16 g, 29 mmol) was dissolved in dry methanol (100 mL) at room temperature and treated with anhydrous K2CO3 (8.1 g, 58.3 mmol) under a nitrogen atmosphere. After stirring for 6 h at room temperature, the reaction mixture was diluted with water and then extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with water (70 mL) and brine (50 mL) and dried over Na2SO4. Purification of the crude product by column chromatography (SiO2, 2% EtOAc in hexane) gave pure compound 15 (8 g, 59%, over three steps) as colorless oil. (4R,6R)-8-((tert-Butyldiphenylsilyl)oxy)-6-methyl-1(trimethylsilyl)oct-1-yn-4-ol (17). A stirred solution of TMS acetylene (8.63 mL, 61.10 mmol) in anhydrous THF (80 mL) was treated with n-BuLi (48.9 mL, 1 M in hexane) at −78 °C and stirred for 30 min. Then, BF3·OEt2 (5.7 mL, 46.8 mmol) was added to the above reaction mixture and stirred for 10 min. Epoxide 15 (15 g, 40.7 mmol) dissolved in THF (10 mL) was cannulated to the reaction mixture, and the mixture was stirred for 2 h at −78 °C. A saturated solution of aqueous NH4Cl (100 mL) was added to the reaction mixture. The reaction mixture was extracted with EtOAc (2 × 250 mL), and the combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na2SO4. Evaporation of organic solvents under reduced pressure provided a crude reaction product, which on purification via column chromatography (SiO2, 5% EtOAc/hexane) furnished the title compound 17 as colorless oil (17 g, 89%). Rf = 0.4 (SiO2, 10% EtOAc/hexane); [α]29 D = +11.3 (c 0.7, CHCl3); IR (neat) 3499, 2929, 2713, 1250, 1105, 842, 699 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.71−764 (m, 4H), 7.45−7.36 (m, 6H), 3.80 (m, 1H), 3.76− 3.66 (m, 2H), 2.42 (dd, J = 16.8, 4.6 Hz, 1H), 2.30 (dd, J = 16.8, 7.1 Hz, 1H), 2.01 (d, J = 4.1 Hz, 1H), 1.80 (m, 1H), 1.67 (m, 1H), 1.45−1.32 (m, 3H), 1.05 (s, 9H), 0.88 (d, J = 6.7 Hz, 3H), 0.17 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 135.55 (4C), 133.95, 129.54 (3C), 127.59 (4C), 103.38, 87.51, 67.97, 62.01, 43.70, 39.14, 29.10, 26.87 (3C), 26.46, 20.34, 19.16, 0.08 (3C); MS (ESI) m/z 467 [M + H]+; HRMS calcd for C28H42O2Si2Na [M + Na]+ 489.2615, found 489.2621.

7.45−7.36 (m, 6H), 5.76 (m, 1H), 5.01−4.95 (m, 2H), 3.77− 3.67 (m, 2H), 2.05 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.63 (m, 1H), 1.38 (m, 1H), 1.05 (s, 9H), 0.84 (d, J = 6.7 Hz, 3H); 13 C NMR (125 MHz, CDCl3): δ 137.40, 135.57 (4C), 134.10, 129.49 (3C), 127.57 (4C), 115.64, 62.11, 41.35, 39.12, 29.37, 26.88 (3C), 19.49, 19.21; MS (ESI) m/z 353 [M + H]+; HRMS calcd for C23H33OSi [M + H]+ 353.2295, found 353.2304. tert-Butyl((R)-3-methyl-4-((R)-oxiran-2-yl)butoxy)diphenylsilane (15). To the solution of olefin 12 (32 g, 91 mmol) in CH2Cl2 (180 mL) at 0 °C was added m-CPBA (70%, 23.4 g, 136 mmol) and stirred at room temperature for 10 h. After completion of the reaction, the reaction mixture was quenched with a saturated solution of aqueous NaHCO3 (200 mL), and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2 × 200 mL). Combined organic extracts were washed successively with saturated NaHCO3 (100 mL) and brine (100 mL) and dried over anhydrous Na2SO4. Evaporation of the organic solvents followed by purification of the resulting crude product via silica gel flash column chromatography (SiO2, 2% EtOAc in hexane) furnished a diastereomeric mixture of epoxides (31.2 g, 93%) as colorless oil [Rf = 0.6 (SiO2, 10% EtOAc/hexane)]. A mixture of (R,R)-salen CoII precatalyst (246 mg, 0.407 mmol) in toluene (15 mL) and AcOH (94 μL, 1.63 mmol) was stirred in air for 1 h at room temperature. After 1.5 h, the solvent was removed by a rotary evaporator under reduced pressure, and the brown residue was dried under vacuum. The (+/−)-epoxide (30 g, 81.5 mmol) prepared above was added to the reaction flask, and the reaction mixture was cooled on an ice water bath. Water (880 μL, 49 mmol) was added to the reaction mixture and stirred for 24 h at room temperature. The enantiomerically pure epoxide and the diol were purified through column chromatography (SiO2, 2% EtOAc in hexane) to furnish epoxide 15 (de > 92%) as colorless oil (12 g, 40%) [Rf = 0.6 (SiO2, 10% EtOAc/hexane)] and diol 16 (14 g, 46%) (SiO2, 40% EtOAc in hexane) [Rf = 0.2 (SiO2, 10% EtOAc/ hexane)]; [α]28 D = +16.9 (c 1.8, CHCl3); IR (neat): νmax 3046, 2927, 2309, 1427, 1102, 698 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.69−7.65 (m, 4H), 7.48−7.36 (m, 6H), 3.77−3.66 (m, 2H), 2.90 (m, 1H), 2.73 (dd, J = 5.4, 3.9 Hz, 1H), 2.40 (dd, J = 5.1, 2.7 Hz, 1H), 1.91 (m, 1H), 1.68 (m, 1H), 1.55− 1.33 (m, 3H), 1.05 (s, 9H), 0.96 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 135.53 (4C), 133.96, 129.53 (3C), 127.58 (4C), 61.81, 51.16, 46.88, 39.79, 39.37, 28.15, 26.85 (3C), 20.03, 19.17; MS (ESI) m/z 369 [M + H]+; HRMS calcd for C23H32O2SiNa [M + Na]+ 391.2069, found 391.2071. (2R,4R)-6-((tert-Butyldiphenylsilyl)oxy)-4-methylhexane1,2-diol (16). [α]28 D = −1.5 (c 12.5, CHCl3); IR (neat): νmax 3337, 2931, 2861, 1427, 1214, 668 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.71−7.64 (m, 4H), 7.46−7.35 (m, 6H), 3.82−3.57 (m, 4H), 3.39 (dd, J = 11.0, 7.7 Hz, 1H), 1.84 (m, 1H), 1.64 (m, 1H), 1.57 (m, 1H), 1.55−1.33 (m, 2H), 1.05 (s, 9H), 0.88 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 136.62 (4C), 133.97, 129.63 (3C), 127.68 (4C), 70.20, 67.34, 62.06, 40.29, 40.11, 26.94 (3C), 26.16, 19.57, 19.23; MS (ESI) m/z 387 [M + H]+; HRMS calcd for C23H34O3SiNa [M + Na]+ 409.2174, found 409.2159. Experimental Procedure for the Conversion of Diol Compound 16 to the Required Epoxide 15. A solution of compound 16 (14 g, 36.4 mmol) in dry CH2Cl2 (100 mL) was treated with Et3N (6.2 mL, 43.7 mmol) followed by pivaloyl 16568

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EtOAc (2 × 200 mL). Washings were given to the combined organic extracts with water (2 × 50 mL) and brine (10 mL). After drying the organic extracts over anhydrous Na2SO4, solvents were evaporated in vacuo to give a crude product, which on purification via flash chromatography (SiO2, 15% EtOAc/hexane) afforded the title compound 20 as a clear, colorless oil (31 g, 86%, 98% ee) and a mixture of diastereomers (5:1 anti:syn). To a stirred solution of compound 20 (31 g, 86 mmol) dissolved in MeOH (200 mL) under a nitrogen environment at 0 °C was added NaBH4 (5.6 g, 150 mmol). After 1 h, the resulting mixture was quenched with H2O, the solvent mixture was removed under reduced pressure, and the residue was extracted with EtOAc (3 × 100 mL). Washings were given to the combined organic solvents with water (2 × 50 mL) and brine (50 mL). The organic extract was kept on anhydrous Na2SO4 and concentrated in vacuo to give a crude product that on purification via silica gel chromatography (SiO2, 30% EtOAc/hexane) afforded the title compound 21 as colorless oil (28.7 g, 93%, 99% ee). Rf = 0.2 (SiO2, 20% EtOAc/hexane); [α]26 D = +5.99 (c 10.4, CHCl3); IR (neat): νmax 3401 (br), 2931, 2861, 1465, 1105, 697 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.70−7.63 (m, 4H), 7.49−7.37 (m, 6H), 3.75 (m, 1H), 3.68−3.57 (m, 4H), 2.98 (br, OH, 1H), 1.77 (m, 1H), 1.07 (s, 9H), 0.75 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 135.39 (4C), 132.89, 129.75 (3C), 127.69 (4C), 77.32, 66.86, 66.34, 36.92, 26.75 (3C), 19.12, 13.35; MS (ESI) m/z 381 [M + Na]+; HRMS calcd for C21H30O3SiNa [M + Na]+ 381.1864, found 381.1865. (S)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)propan-1-ol (22). A solution of compound 21 (18 g, 50.2 mmol) in anhydrous THF (100 mL) was treated with TBAF (1 M, 75 mL, 75 mmol) at 0 °C and stirred for 5 h. The above reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (300 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to produce a triol (5.5 g, 91%). The triol compound (5.5 g, 45.8 mmol) thus obtained was dissolved in anhydrous CH2Cl2 (100 mL) and treated with 2,2-dimethoxypropane (6.1 mL, 50.3 mmol) followed by a catalytic amount of PTSA (879 mg, 0.45 mmol) at 0 °C. After stirring for 6 h, the reaction mixture was quenched with aqueous NaHCO3 solution and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with water (2 × 50 mL) and brine (50 mL), dried with Na2SO4, and concentrated in vacuo. Purification of the resulting residue by silica gel chromatography (SiO2, 12% EtOAc/hexane) afforded the title compound 22 as colorless oil (5.23 g, 71%). Rf = 0.5 (SiO2, 20% EtOAc/hexane); [α]29 D = +16.6 (c 0.8, CHCl3); IR (neat): νmax 3454 (br), 2984, 2308, 1458, 1040, 853 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.08 (m, 1H), 3.93 (m, 1H), 3.69−3.27 (m, 3H), 2.80 (br, OH, 1H), 1.82 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 0.82 (d, J = 6.9, 3H); 13C NMR (100 MHz, CDCl3): δ 109.33, 80.71, 68.71, 67.35, 39.15, 26.62, 25.65, 13.04; MS (ESI) m/z 183 [M + Na]+; HRMS calcd for C8H16O3Na [M + Na]+ 183.0992, found 183.0993. (2R,7R,9R)-7-((tert-Butyldimethylsilyl)oxy)-11-((tertbutyldiphenylsilyl)oxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4yl)-9-methylundec-4-yn-3-one (23). Alcohol 22 (3.5 g, 21.87 mmol) was dissolved in CH2Cl2 (40 mL) and cooled to 0 °C. To this, NaHCO3 (2.75 g, 32.81 mmol) and DMP (13.92 g, 32.81 mmol) were added sequentially. After stirring for 1 h at 0 °C, to the reaction mixture, saturated aqueous Na2S2O3 (50

(5R,7R)-2,2,3,3,7,12,12-Heptamethyl-11,11-diphenyl-5-(3(trimethylsilyl)prop-2-yn-1-yl)-4,10-dioxa-3,11-disilatridecane (17A). Compound 17 (12 g, 25.7 mmol) was dissolved in dry CH2Cl2 (50 mL) and treated with 2,6-lutidine (8.9 mL, 77.1 mmol) and TBSOTf (9 mL, 38.5 mmol) at 0 °C. The reaction mixture was stirred for 4 h, quenched with saturated aqueous NaHCO3 (100 mL), and then extracted with EtOAc (2 × 250 mL). Washings were given to the combined organic extracts with saturated aqueous CuSO4 solution (2 × 50 mL), water (2 × 50 mL), and brine (100 mL), in that order. After drying the organic extract over anhydrous Na2SO4, the solvent was evaporated in vacuo, and the crude product was purified via column chromatography (SiO2, 5% EtOAc/hexane) to afford the title compound 17A as colorless oil (13 g, 87%). Rf = 0.8 (SiO2, 10% EtOAc/hexane); [α]30 D = +5.2 (c 3.3, CHCl3); IR (neat): νmax 2928, 2858, 2309, 2176, 1251, 1032, 837 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.70−7.64 (m, 4H), 7.46−7.34 (m, 6H), 3.85 (p, J = 6.0 Hz, 1H), 3.72−3.65 (m, 2H), 2.36 (dd, J = 16.7, 5.7 Hz, 1H), 2.29 (dd, J = 16.7, 6.0 Hz, 1H), 1.75−1.62 (m, 2H), 1.50 (m, 1H), 1.40−1.30 (m, 2H), 1.05 (s, 9H), 0.88 (s, 9H), 0.88 (d, J = 6.7 Hz, 3H) 0.14 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 135.56 (4C), 134.05, 129.51 (3C), 127.59 (4C), 104.92, 85.99, 69.61, 62.08, 45.19, 39.72, 28.98, 26.89 (3C), 26.32, 25.90 (3C), 20.35, 19.18, 18.07, 0.09 (3C), −4.24, −4.48; MS (ESI) m/z 581 [M + H]+; HRMS calcd for C34H60O2Si3N [M + NH4]+ 598.3926, found 598.3938. (5R,7R)-2,2,3,3,7,12,12-Heptamethyl-11,11-diphenyl-5(prop-2-yn-1-yl)-4,10-dioxa-3,11-disilatridecane (10). Compound 17A (12 g, 20.7 mmol) was dissolved in anhydrous MeOH and treated with anhydrous K2CO3 (7.14 g, 71.34 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h and quenched with H2O (50 mL). MeOH was removed under reduced pressure, and the aqueous layer was extracted with EtOAc (2 × 100 mL). Washings were given to the combined organic extracts with water (2 × 50 mL) and brine (10 mL). After drying the organic extracts over anhydrous Na2SO4, the solvent was evaporated in vacuo to give a crude product, which on purification by flash chromatography (SiO2, 7% EtOAc/ hexane) afforded the title compound 10 as colorless oil (9 g, 85%). Rf = 0.6 (SiO2, 10% EtOAc/hexane); [α]30 D = +7.2 (c 6.5, CHCl3); IR (neat): νmax 3068, 2859, 1466, 1252, 1100, 832, 702 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.73−7.66, (m, 4H), 7.47−736 (m, 6H), 3.88 (p, J = 6.0 Hz, 1H), 3.79− 3.66 (m, 2H), 2.38−2.26 (m, 2H), 1.95 (t, J = 2.6 Hz, 1H), 1.79−1.66 (m, 2H), 1.59 (m, 1H), 1.45−1.33 (m, 2H), 1.07 (s, 9H), 0.91 (s, 9H), 0.89 (d, J = 6.8 Hz, 3H), 0.11 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 135.56 (4C), 134.05, 129.50 (3C), 127.58 (4C), 81.72, 69.90, 69.23, 62.03, 44.71, 39.56, 27.53, 26.89 (3C), 26.28, 25.87 (3C), 20.39, 19.18, 18.07, −4.34, −4.53; MS (ESI) m/z 526 [M + NH4]+; HRMS calcd for C31H52O2Si2N [M + NH4]+ 526.3531, found 526.3541. (2S,3S)-4-((tert-Butyldiphenylsilyl)oxy)-2-methylbutane1,3-diol (21).12 To a stirred solution of compound 19 (29.8, 100 mmol) in anhydrous dioxane (100 mL) at 4 °C was added D-proline (1.15 g, 10 mmol), and the reaction mixture was stirred for 30 min. To the above reaction mixture, freshly distilled propionaldehyde (36.1 mL, 500 mmol) in 100 mL of dioxane was added slowly over a period of 24 h followed by quenching with H2O (100 mL). After stirring for 30 min at room temperature, the reaction mixture was extracted with 16569

DOI: 10.1021/acsomega.8b02156 ACS Omega 2018, 3, 16563−16575

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Article

10% EtOAc/hexane); [α]30 D = +2.4 (c 0.8, CHCl3); IR (neat): νmax 3365 (br), 2932, 1464, 1253, 1099, 835, 775 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.70−7.64 (m, 4H), 7.45−7.35 (m, 6H), 4.42 (m, 1H), 4.25 (m, 1H), 4.07 (dd, J = 8.0, 6.1 Hz, 1H), 3.84 (p, J = 5.5 Hz, 1H), 3.74−3.62 (m, 3H), 3.43 (d, J = 8.8 Hz, 1H), 2.42−2.32 (m, 2H), 1.93 (m, 1H), 1.76− 1.66 (m, 2H), 1.54 (ddd, J = 13.4, 6.5 Hz, 1H), 1.41(s, 3H), 1.37 (s, 3H), 1.33 (m, 1H), 1.04 (s, 9H), 0.88 (s, 9H), 0.86 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 135.54 (4C), 134.02, 129.51 (3C), 127.58 (4C), 109.45, 83.62, 80.52, 78.07, 69.18, 68.47, 66.45, 62.13, 44.73, 42.34, 39.58, 27.79 26.87 (3C), 26.69, 26.27, 25.83 (3C), 25.77, 20.44, 19.17, 18.01, 12.39, −4.36, −4.57; MS (ESI) m/z 667 [M + H]+; HRMS calcd for C39H66O5Si2N [M + NH4]+ 684.4474, found 684.4488. (2S,3R,7R,9R,Z)-7-((tert-Butyldimethylsilyl)oxy)-11-((tertbutyldiphenylsilyl)oxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4yl)-9-methylundec-4-en-3-ol (24). Lindlar’s catalyst (100 mg) was added to a stirred solution of compound 9 (7 g, 10.5 mmol) in a mixture of EtOAc/pyridine/1-octene (10:1:1, 20 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (hydrogen-filled balloon was used) for 2 h and then filtered through a short pad of celite. Celite was washed with EtOAc (2 × 5 mL). Combined organic filtrate and washings were concentrated under reduced pressure to give crude compound 24, which was purified by column chromatography (SiO2, 10% EtOAc/hexane) to afford the title compound 24 as colorless oil (6.5g, 93%). Rf = 0.3 (SiO2, 10% EtOAc/hexane); [α]28 D = +3.57 (c 0.9, CHCl3); IR (neat): νmax 3480, 2927, 2857, 1592, 1464, 1063, 833, 738 cm−1; 1H NMR (400 MHz, CDCl3): 7.68−7.64 (m, 4H), 7.44−7.35 (m, 6H), 5.62−5.55 (m, 2H), 4.51 (m, 1H), 4.11− 4.02 (m, 2H), 3.79 (p, J = 6.2 Hz, 1H), 3.73−3.58 (m, 3H), 2.93 (br, OH, 1H), 2.34 (dt, J = 14.6, 5.0 Hz, 1H), 2.16 (dt, J = 14.6, 5.6 Hz, 1H), 1.86 (m, 1H), 1.71−1.55 (m, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.33−1.29 (m, 2H), 1.04 (s, 9H), 0.87 (s, 9H), 0.84 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 135.54 (4C), 134.01, 131.35, 129.51 (3C), 128.60, 127.58 (4C), 109.04, 77.95, 70.25, 69.62, 68.54, 62.02, 44.92, 42.30, 39.95, 35.19, 26.86 (3C), 26.72, 26.39, 25.93 (3C), 25.69, 20.12, 19.17, 18.11, 11.10, −4.25, −4.43; MS (ESI) m/z 669 [M + H]+; HRMS calcd for C39H64O5Si2Na [M + Na]+ 691.4184, found 691.4194. (2S,3R,7R,9R,Z)-7-((tert-Butyldimethylsilyl)oxy)-11-((tertbutyldiphenylsilyl)oxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4yl)-9-methylundec-4-en-3-yl picolinate (8). 2-Picolinic acid (3.32 g, 26.94 mmol) and DMAP (3.30 g, 26.94 mmol) were added to a stirred solution of compound 24 (6 g, 8.98 mmol) in dry CH2Cl2 (25 mL) at 0 °C under an argon atmosphere. After 5 min stirring at 0 °C, EDCI (5.164 g, 26.94 mmol) was added to the reaction mixture and stirred at room temperature for another 2 h for the completion of the reaction. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (2 × 50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent followed by purification of the crude product via flash chromatography (SiO2, 20% EtOAc/hexane) afforded the title compound 8 as colorless oil (6.18 g, 88%). Rf = 0.3 (SiO2, 20% EtOAc/hexane); [α]32 D = +35.79 (c 1.4, CHCl3); IR (neat): νmax 2931, 2858, 1719, 1464, 1289, 1044, 774 cm−1; 1H NMR (500 MHz, CDCl3): δ 8.76 (d, J = 4.0 Hz, 1H), 8.08 (d, J = 7.8

mL) and saturated aqueous NaHCO3 (50 mL) were added, and the biphasic mixture was stirred for 30 min. The reaction mixture was extracted with Et2O (2 × 200 mL). Water (50 mL) and brine (50 mL) washings were given to the combined organic extracts and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure furnished crude aldehyde 11 (Rf = 0.5, 20% EtOAc/hexane), which was passed through a short pad of Na2SO4 and used directly for the next reaction. To a solution of 10 (10.31 g, 20.29 mmol) in dry THF (45 mL), n-BuLi (1.6 M in hexane, 10.7 mL, 17.18 mmol) was added at −78 °C. After stirring for 40 min at −78 °C, the above aldehyde 11 (3.3 g, 20.75 mmol) in THF (2 × 10 mL) was added dropwise via cannula. After stirring for 45 min at −78 °C, saturated aqueous NH4Cl (50 mL) was added to the reaction mixture, and the temperature was raised to room temperature slowly. The reaction mixture was extracted with EtOAc (2 × 200 mL), and the combined organic extracts were washed with water (2 × 50 mL) and brine (50 mL). After drying, the organic extracts with anhydrous Na2SO4 solvent were evaporated in vacuo to give a crude product, which was subjected to flash chromatography (SiO2, 10% EtOAc/hexane) to afford the title compound 9A, as a mixture of diastereomers and as colorless oil (11.5 g, 83%). To a solution of compound 9A (11 g, 16.5 mmol) in CH2Cl2 (50 mL) at 0 °C was added NaHCO3 (2.07 g, 24.8 mmol) under a nitrogen atmosphere. To the above reaction mixture, DMP (8.39 g, 19.8 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 4 h. Saturated aqueous Na2S2O3 (50 mL) and saturated aqueous NaHCO3 (50 mL) were added. The resultant biphasic mixture was stirred for 50 min and then extracted with EtOAc (2 × 200 mL). Washings were given to the combined organic extracts with water (2 × 50 mL) and brine (50 mL). The organic extracts were dried with anhydrous Na2SO4 and concentrated in vacuo. Purification of the residue by column chromatography (SiO2, 10% EtOAc/ hexane) afforded the title compound 23 as colorless oil (9.2 g, 66% over three steps). Rf = 0.6 (SiO2, 20% EtOAc/hexane); [α]28 D = +8.2 (c 3, CHCl3); IR (neat): νmax 2928, 2858, 2212, 1673, 1463, 1086, 908, 735 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.72−7.63 (m, 4H), 7.47−7.34 (m, 6H), 4.42 (m, 1H), 4.05 (dd, J = 8.3, 6.3 Hz, 1H), 3.93 (m, 1H), 3.79−3.62 (m, 3H), 2.84 (m, 1H), 2.64−2.41 (m, 2H), 1.75−1.64 (m, 2H), 1.60−1.44 (m, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.15 (d, J = 7.1 Hz, 3H), 1.05 (s, 9H), 0.89 (s, 9H), 0.86 (d, J = 6.3Hz, 3H), 0.1 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 188.74, 135.51 (4C), 133.91, 129.53 (3C), 127.59 (4C), 109.22, 93.18, 81.30, 75.97, 68.53, 66.54, 61.88, 51.99, 44.93, 39.54, 28.02, 26.85 (3C), 26.56, 26.27, 25.76 (3C), 25.29, 20.20, 19.14, 17.94, 11.89, −4.48, −4.57; MS (ESI) m/z 665 [M + H]+; HRMS calcd for C39H60O5Si2Na [M + Na]+ 687.3877, found 687.3876. (2S,3S,7R,9R)-7-((tert-Butyldimethylsilyl)oxy)-11-((tertbutyldiphenylsilyl)oxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4yl)-9-methylundec-4-yn-3-ol (9). Alkynone 23 (9 g, 13.5 mmol) was dissolved in isopropanol (150 mL) at room temperature and treated with Ru[(S,S)-Tsdpen] (p-cymene) (86 mg, 135 μmol). After stirring for 24 h at room temperature, solvent was removed under reduced pressure to give a crude product that on purification via flash chromatography (SiO2, 10% EtOAc/hexane) afforded the title compound 9 as colorless oil (8 g, 88%). Rf = 0.4 (SiO2, 16570

DOI: 10.1021/acsomega.8b02156 ACS Omega 2018, 3, 16563−16575

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26 as colorless oil (2.6 g, 92%). Rf = 0.2 (SiO2, 20% EtOAc/ hexane); [α]33 D = −21.3 (c 0.7 CHCl3); IR (neat): νmax 33587 (br), 2955, 2926, 2857, 2172, 1702, 1462, 1256, 1083, 798, 700 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.70−7.64 (m, 4H), 7.45−7.35 (m, 6H), 5.42 (dd, J = 15.5, 7.8 Hz, 1H), 5.27 (dd, J = 15.5, 7.8 Hz, 1H), 3.75−3.64 (m, 4H), 3.53 (dd, J = 11.2, 6.7 Hz, 1H), 3.40 (td, J = 6.9, 2.9 Hz, 1H), 2.35 (m, 1H), 2.24 (dd, J = 15.3, 6.0 Hz, 1H), 2.11 (br, OH, 1H), 1.98 (br, OH, 1H), 1.64 (m, 1H), 1.54 (m, 1H), 1.47−1.32 (m, 4H), 1.22 (m, 1H), 1.04 (s, 9H), 1.01 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.81 (d, J = 6.5 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 139.12, 135.55 (4C), 134.05, 129.95, 129.53 (3C), 127.59 (4C), 75.03, 69.21, 64.40, 61.93, 45.27, 44.30, 40.36, 40.26, 33.03, 26.89 (3C), 26.28, 25.99 (3C), 22.05, 19.95, 19.21, 18.14, 16.76, −3.88, −4.17; MS (ESI) m/z 628 [M + H]+; HRMS calcd for C37H66NO4Si2 [M + NH4]+ 644.4530, found 644.4571. (2S,3S,6R,8R,10R,E)-8-((tert-Butyldimethylsilyl)oxy)-12((tert-butyldiphenylsilyl)oxy)-2-((4-methoxybenzyl)oxy)3,6,10-trimethyldodec-4-en-1-ol (7). p-Anisaldehyde dimethyl acetal (0.35 mL, 2.10 mmol) and PPTS (238 mg, 0.95 mmol) were added sequentially to a solution of diol 26 (1.2 g, 1.9 mmol) in CH2Cl2 (10 mL) at 0 °C and stirred for 1 h at room temperature. Saturated aqueous NaHCO3 (20 mL) was added to the reaction mixture for quenching the reaction. The reaction mixture was extracted with EtOAc (2 × 50 mL), and the total organic extracts were washed with water (2 × 5 mL) and brine (5 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure provided p-methoxybenzylidene acetal (1.23 g, 1.62 mmol), which was dissolved in anhydrous CH2Cl2 (10 mL) and cooled to −78 °C. DIBAL-H (1.5 M in hexane, 5.1 mL, 7.6 mmol) was added to the reaction mixture, and the temperature of the reaction bath was slowly raised to −40 °C over a period of 2 h. The reaction mixture was quenched with MeOH (2 mL) and stirred with a saturated solution of sodium potassium tartrate (20 mL) for 1 h. The reaction mixture was extracted with EtOAc (2 × 40 mL), and the combined organic extracts were washed with water (2 × 5 mL) and brine (5 mL). Anhydrous Na2SO4 was added to the organic extracts and filtered. Solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography (SiO2, 10% EtOAc/hexane) to afford the title compound 7 as colorless oil (1.11 g, 78%) over two steps. Rf = 0.2 (SiO2, 10% EtOAc/hexane); [α]30 D = −4.8 (c 0.6, CHCl3); IR (neat): νmax 3498(br), 2954, 2927, 2585, 2713, 1612, 1512, 1305, 1175, 1048, 979, 829, 738 cm−1; 1 H NMR (500 MHz, CDCl3): δ 7.70−7.65 (m, 4H), 7.44− 7.35 (m, 6H), 7.29−7.26 (m, 2H), 6.90−6.85 (m, 2H), 5.45− 5.31 (m, 2H), 4.60 (d, J = 11.1 Hz, 1H), 4.46 (d, J = 11.1 Hz, 1H), 3.80 (s, 3H), 3.75−3.54 (m, 5H), 3.39 (m, 1H), 2.52 (p, J = 7.0 Hz, 1H), 2.30 (m, 1H), 1.70−1.53 (m, 3H), 1.44−1.35 (m, 3H), 1.22 (m, 1H), 1.05 (s, 9H), 1.02 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.81 (d, J = 6.5 Hz, 3H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 159.24, 136.66, 135.54 (4C), 134.04, 130.63, 130.08, 129.50 (2C), 129.35 (3C), 127.58 (4C), 113.86 (2C), 83.33, 72.09, 68.99, 62.31, 61.97, 55.26, 45.61, 44.64, 40.30, 37.64, 32.95, 26.87 (3C), 26.30, 25.98 (3C), 21.81, 19.98, 19.19, 18.07, 15.44, −3.86, −4.16; MS (ESI) m/z 769 [M + Na]+; HRMS calcd for C45H70O5Si2Na [M + Na]+ 769.4660, found 769.4650. (5R,7R)-5-((2R,3E,5S,6S,7E)-8-Iodo-6-((4-methoxybenzyl)oxy)-2,5-dimethylocta-3,7-dien-1-yl)-2,2,3,3,7,12,12-hepta-

Hz, 1H), 7.82 (td, J = 7.7, 1.5 Hz, 1H), 7.71−7.63 (m, 4H), 7.49−7.33 (m, 7H), 5.99 (dd, J = 8.9, 3.3 Hz, 1H), 5.74−5.56 (m, 2H), 4.08 (dd, J = 13.9, 7.4 Hz, 1H), 3.96 (dd, J = 8.0, 6.1 Hz, 1H), 3.89−3.79 (m, 1H), 3.75−3.61 (m, 3H), 2.48 (m, 1H), 2.28 (m, 1H), 2.05 (m, 1H), 1.73−1.62 (m, 2H), 1.40 (m, 1H), 1.37 (s, 3H), 1.35−1.31 (m, 2H), 1.30 (s 3H), 1.04 (d, J = 6.8 Hz, 3H), 1.04 (s, 9H), 0.90−0.82 (m, 12H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.86, 149.84, 148.39, 136.96, 135.54 (4C), 134.04, 131.38, 129.48 (3C), 127.57 (4C), 127.06, 126.64, 125.04, 108.63, 72.36, 70.06, 67.15, 62.26, 45.30, 41.60, 39.85, 35.59, 29.68, 26.86 (3C), 26.74, 26.54, 25.89 (3C), 25.54, 20.20, 19.15, 18.02, 9.75, −4.23, −4.42; MS (ESI) m/z 796 [M + Na]+; HRMS calcd for C45H68O6NSi2 [M + H]+ 774.4579, found 774.4597. (5R,7R)-5-((2R,5S,E)-5-((S)-2,2-Dimethyl-1,3-dioxolan-4yl)-2-methylhex-3-en-1-yl)-2,2,3,3,7,12,12-heptamethyl11,11-diphenyl-4,10-dioxa-3,11-disilatridecane (25). MeMgBr (3 M in ether, 8.6 mL, 25.84 mmol) was added dropwise to an ice-cold suspension of CuBr·SMe2 (2.67 g, 12.92 mmol) in anhydrous THF (25 mL) and stirred at the same temperature for 15 min. The resulting reaction mixture was cooled to −78 °C and treated with a solution of compound 8 (5 g, 6.46 mmol) in anhydrous THF (20 mL) via cannula. The temperature of the reaction bath was warmed to −30 °C over a period of 1 h, and the reaction was quenched via addition of a saturated solution of aqueous NH4Cl (25 mL). After stirring the biphasic mixture for 30 min, the reaction mixture was extracted with EtOAc (2 × 100 mL), and the combined organic extracts were washed with water (2 × 50 mL) and brine (50 mL). Anhydrous Na2SO4 was added to the combined organic extracts and filtered. Solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (SiO2, 4% EtOAc/hexane) to afford the title compound 25 as colorless oil (4.1 g, 95%). Rf = 0.6 (SiO2, 10% EtOAc/hexane); [α]29 D = −18.35 (c 0.8, CHCl3); IR (neat): νmax 2955, 2922, 2680, 2309, 1592, 1463, 1373, 1252, 1069, 979, 737 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.70−7.63 (m, 4H), 7.46−7.34 (m, 6H), 5.36 (dd, J = 15.6, 7.0 Hz, 1H), 5.29 (dd, J = 15.6, 7.4 Hz, 1H), 3.97−3.91 (m, 2H), 3.75−3.58 (m, 4H), 2.37−2.26 (m, 2H), 1.64 (m, 1H), 1.55 (m, 1H), 1.44−1.39 (m, 2H), 1.38 (s, 3H), 1.36 (m, 1H), 1.33 (s, 3H), 1.30 (m, 1H), 1.22 (m, 1H), 1.05 (s, 9H), 0.97 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.82 (d, J = 6.6 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 136.77, 135.55 (4C), 134.07, 130.06, 129.50 (3C), 127.57 (4C), 108.73, 79.51, 68.93, 67.05, 61.95, 45.73, 44.55, 40.48, 39.45, 33.04, 26.88 (3C), 26.59, 26.35, 26.00 (3C), 25.48, 22.05, 19.92, 19.21, 18.06, 15.77, −3.83, −4.16; MS (ESI) m/z 684 [M + NH4 ]+ ; HRMS calcd for C40H70O4Si2N [M + NH4]+ 684.4838, found 684.4850. (2S,3S,6R,8R,10R,E)-8-((tert-Butyldimethylsilyl)oxy)-12((tert-butyldiphenylsilyl)oxy)-3,6,10-trimethyldodec-4-ene1,2-diol (26). Compound 25 (3 g, 4.5 mmol) was dissolved in anhydrous CH2Cl2 (20 mL) and treated with ZnBr2 (1.52 g, 6.75 mmol) at 0 °C. After stirring the reaction mixture for 2 h at room temperature, aqueous NaHCO3 (30 mL) solution was added to the reaction mixture and stirred for 30 min. The reaction mixture was extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (2 × 30 mL) and brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of the solvents under reduced pressure provided a crude product that on purification through flash chromatography (SiO2, 18% EtOAc/hexane) afforded the title compound 16571

DOI: 10.1021/acsomega.8b02156 ACS Omega 2018, 3, 16563−16575

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Article

methyl-11,11-diphenyl-4,10-dioxa-3,11-disilatridecane (28). Alcohol compound 7 (900 mg, 1.2 mmol) was dissolved in anhydrous CH2Cl2 (6 mL) and cooled to 0 °C. NaHCO3 (201 mg, 2.4 mmol) and DMP (767 mg, 1.8 mmol) were added sequentially, and the resulting reaction mixture was stirred under a nitrogen atmosphere for 1 h. Saturated aqueous solutions of Na2S2O3 (10 mL) and NaHCO3 (10 mL) were added to the reaction mixture, and the resultant biphasic mixture was stirred for 30 min. The reaction mixture was extracted with Et2O (2 × 50 mL) and washed with water (10 mL) and brine (10 mL). Anhydrous Na2SO4 was added to the organic extracts and filtered. Solvents were evaporated in vacuo to give an aldehyde (Rf = 0.6, 20% EtOAc/hexane), which was used directly for the next reaction. CrCl2 (1.14 g, 7.2 mmol) was placed in a flame-dried roundbottom flask, filled with argon and added with 15 mL of anhydrous THF. The resulting solution was cooled to 0 °C and stirred for 10 min. Then, a solution of aldehyde (885 mg, 1.18 mmol) prepared above along with CHI3 (992 mg, 2.52 mmol) in anhydrous THF (10 mL) was cannulated to the reaction flask slowly. The temperature of the reaction mixture was raised slowly to room temperature over a period of 1 h, and the mixture was quenched with saturated aqueous NH4Cl (20 mL). The resulting biphasic mixture was stirred for 30 min and extracted with EtOAc (2 × 50 mL). The total organic extracts were washed with water (2 × 10 mL) and brine (30 mL) and dried over anhydrous Na2SO4. Evaporation of the solvents in vacuo followed by purification of the crude product via column chromatography (SiO2, 4% EtOAc/hexane) afforded the title compound 28 (E:Z = 7:1) as colorless oil (900 mg, 78%, over two steps). Rf = 0.2 (SiO2, 30% EtOAc/ hexane); [α]28 D = −21.9 (c 0.8, CHCl3); IR (neat): νmax 3068, 2927, 2857, 1610, 1513, 1463, 1248, 1173, 1053, 829, 773, 738 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.69−7.65 (m, 4H), 7.44−7.35 (m, 6H), 7.25−7.20 (m, 2H), 6.89−6.83 (m, 2H), 6.45 (dd, J = 14.5, 7.9 Hz, 1H), 6.22 (d, J = 14.5 Hz, 1H), 5.36 (dd, J = 15.4, 6.8 Hz, 1H), 5.29 (dd, J = 15.7, 7.1 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), 4.28 (d, J = 11.5 Hz, 1H), 3.8 (s, 3H), 3.69 (dt, J = 13.4, 4.6, 3H), 3.56 (dd, J = 7.7, 5.4 Hz, 1H), 2.39−2.22 (m, 2H), 1.69−1.57 (m, 2H), 1.44−1.29 (m, 4H), 1.21 (m, 1H), 1.05 (s, 9H), 0.97 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.81 (d, J = 6.5 Hz, 3H), 0.04 (s, 3H), 0.02 (s. 3H); 13C NMR (125 MHz, CDCl3): δ 159.08, 145.21, 136.93, 135.55 (4C), 134.07, 130.36, 129.81, 129.50 (3C), 129.16 (2C), 127.58 (4C), 113.71 (2C), 84.94, 78.32, 70.13, 69.00, 62.01, 55.25, 45.65, 44.65, 40.73, 40.35, 32.95, 26.89 (3C), 26.31, 26.00 (3C), 21.97, 20.14, 19.20, 18.07, 15.94, −3.83, −4.09; MS (ESI) m/z 886 [M + NH4]+; HRMS calcd for C46H69IO4Si2Na [M + Na]+ 891.3677, found 891.3685. (1E,3S,4S,5E,7R,9R,11R)-9-((tert-Butyldimethylsilyl)oxy)13-((tert-butyldiphenylsilyl)oxy)-1-iodo-4,7,11-trimethyltrideca-1,5-dien-3-ol (6). Compound 28 (700 mg, 0.80 mmol) was dissolved in anhydrous CH2Cl2 (20 mL), and to it phosphate buffer (1.5 mL) was added. The resulting biphasic solution was cooled to 0 ° and treated with DDQ (454 mg, 2 mmol). After stirring for 2 h, saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture, and the resulting reaction mixture was extracted with EtOAc (2 × 50 mL). The total organic extracts were washed with water (2 × 10 mL) and brine (10 mL) and dried over Na2SO4. Evaporation of the solvent gave a crude product, which was purified via column chromatography (SiO2, 9% EtOAc/hexane) affording the title

compound 6 as colorless oil (560 mg, 94%). Rf = 0.5 (SiO2, 20% EtOAc/hexane); [α]31 D = −24.5 (c 0.8, CHCl3); IR (neat): νmax 3577 (br), 2928, 1463, 1250, 1092, 834, 775 cm−1; 1 H NMR (500 MHz, CDCl3): δ 7.68−7.65 (m, 4H), 7.45− 7.35 (m, 6H), 6.54 (dd, J = 14.4, 6.5 Hz, 1H), 6.35 (dd, J = 14.4, 1.1 Hz, 1H), 5.44 (dd, J = 15.4, 7.9 Hz, 1H), 5.23 (dd, J = 15.4, 8.6 Hz, 1H), 3.80−3.62 (m, 4H), 2.34 (m, 1H), 2.18 (m, 1H), 1.89 (br, OH, 1H), 1.70−1.62 (m, 2H), 1.47−1.31 (m, 4H), 1.23 (m, 1H), 1.05 (s, 9H), 0.99 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H), 0.88 (s, 9H), 0.82 (d, J = 6.6 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 146.45, 139.83, 135.54 (4C), 134.03, 129.52 (3C), 129.19, 127.59 (4C), 78.07, 77.82, 69.12, 61.90, 45.28, 44.23, 43.28, 40.35, 33.10, 26.88 (3C), 26.26, 25.99 (3C), 22.08, 20.00, 19.20, 18.12, 16.31, −3.84, −4.09; MS (ESI) m/z 749 [M + H]+; HRMS calcd for C38H65IO3Si2N [M + NH4]+ 766.3542, found 766.3537. (1E,3S,4S,5E,7R,9R,11R)-9-((tert-Butyldimethylsilyl)oxy)13-((tert-butyldiphenylsilyl)oxy)-1-iodo-4,7,11-trimethyltrideca-1,5-dien-3-yl2-(bis(2-(tert-butyl)phenoxy)phosphoryl)acetate (29). To the solution of bis(2-tert-butylphenyl)phosphonoacetic acid (862 mg, 2.13 mmol) in dry toluene (10 mL) were added Et3N (1.5 mL, 10.68 mmol) and 2,4,6trichlorobenzoyl chloride (0.4 mL, 2.67 mmol) at 0 °C and kept stirred for 20 min at the same temperature. Alcohol 6 (399 mg, 0.534 mmol) dissolved in toluene (8 mL) was added to the reaction mixture by using cannula. The temperature of the reaction mixture was raised slowly to room temperature, and the reaction was continued for 2 h. The reaction mixture was diluted with EtOAc (100 mL), and the resultant reaction mixture was washed with water (2 × 10 mL) and brine (5 mL) and dried over Na2SO4. Solvent was evaporated under reduced pressure, and the crude residue was purified by flash chromatography (SiO2, 12% EtOAc/hexane) to afford the title compound 29 as colorless oil (500 mg, 82%). Rf = 0.4 (SiO2, 20% EtOAc/hexane); [α]26 D = −10.9 (c 1.2, CHCl3); IR (neat): νmax 2928, 1179, 1641, 1046, 944, 836, 766 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.72−7.62 (m, 6H), 7.44−7.33 (m, 8H), 7.15 (t, J = 7.7 Hz, 2H), 7.12−7.06 (m, 2H), 6.39 (d, J = 14.6, Hz, 1H), 6.30 (dd, J = 14.4, 7.0 Hz, 1H), 5.34 (dd, J = 15.6, 7.4 Hz, 1H), 5.22 (dd, J = 15.6, 7.5 Hz, 1H), 5.14 (dd, J = 6.7, 5.2 Hz, 1H), 3.37−3.62 (m, 3H), 3.35 (d, J = 21.5 Hz, 2H), 2.41−2.28 (m, 2H), 1.68−1.58 (m, 2H), 1.43−1.38 (m, 2H), 1.37 (s, 9H), 1.36 (s, 9H), 1.32−1.29 (m, 2H), 1.22 (m, 1H), 1.04 (s, 9H), 0.94 (d, J = 7.0, 3H), 0.92 (d, J = 7.0, 3H), 0.87 (s, 9H), 0.81 (d, J = 6.5 Hz, 3H), 0.02 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 163.51 (d, J = 5.1 Hz), 149.94 (dd, J = 5.9, 8.1 Hz), 140.54, 139.09 (d, J = 8.1 Hz), 138.51, 135.54 (4C), 134.78, 134.06, 129.50 (3C), 127.93, 127.70 (2C), 127.57 (4C), 127.44 (3C), 124.70 (2C), 119.68 (2C), 81.43, 80.52, 68.89, 61.99, 45.53, 44.42, 40.32, 39.87, 34.66 (2C), 32.81, 30.10 (6C), 26.88 (3C), 26.55, 26.28, 25.98 (3C), 21.77, 20.14, 19.20, 18.05, 15.20, −3.83, −4.06; MS (ESI) m/z 1152 [M + NH4]+; HRMS calcd for C60H92IO7PSi2N [M + NH4]+ 1152.5190, found 1152.5193. (1E,3S,4S,5E,7R,9R,11R)-9-((tert-Butyldimethylsilyl)oxy)13-hydroxy-1-iodo-4,7,11 trimethyltrideca-1,5-dien-3-yl2(bis(2-(tert-butyl)phenoxy)phosphoryl)acetate (29A). Phosphonate compound 29 (300 mg, 0.264 mmol) was dissolved in anhydrous MeOH (10 mL) and treated with NH4F (100 mg, 2.68 mmol) at 0 °C. The temperature of the reaction mixture was raised to 60 °C, and the mixture was stirred at this temperature for 10 h. The heating bath was removed, and 16572

DOI: 10.1021/acsomega.8b02156 ACS Omega 2018, 3, 16563−16575

ACS Omega

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NMR (100 MHz, CDCl3): δ 164.75, 146.37, 143.29, 138.26, 131.00, 121.54, 80.83, 77.55, 68.39, 47.60, 44.72, 42.35, 34.61, 31.16, 27.49, 26.05 (3C), 22.65, 20.10, 18.36, 17.43, −3.16, −3.43; MS (ESI) m/z 533 [M + H]+; HRMS calcd for C24H45IO3SiN [M + NH4]+ 550.2208, found 550.2210. (3Z,6R,8R,10R,11E,13S,14S)-8-((tert-Butyldimethylsilyl)oxy)-14-((E)-2-iodovinyl)-6,10,13-trimethyloxacyclotetradeca-3,11-dien-2-one (30). A solution of compound 2 (40 mg, 0.076 mmol) in dry acetonitrile (5 mL) in a polypropylene vial was added with HF-pyridine (50 μL) portionwise at 0 °C. After monitoring the reaction for 2 h, the reaction mixture was allowed to warm slowly to room temperature and stirred for 8 h. To the reaction mixture, a cooled solution of aqueous NaHCO3 solution (4 mL) was added and stirred for 20 min. The reaction mixture was extracted with EtOAc (2 × 25 mL) and washed with water (2 × 5 mL) and brine (3 mL). Organic extracts were dried over Na2SO4 and concentrated in vacuo to give a crude product, which was purified by column chromatography (SiO2, 10% EtOAc/hexane) producing compound 30 as colorless oil (28 mg, 89%). Rf = 0.2 (SiO2, 20% EtOAc/hexane); [α]28 D = −93.4 (c 0.3, CHCl3); IR (neat): νmax 3511 (br), 2933, 2855, 1718, 1457, 1415, 1173, 833, 800 cm−1; 1H NMR (400 MHz, CDCl3): δ 6.56−6.42 (m, 2H), 6.28 (m, 1H), 5.87 (dd, J = 11.6, 2.4 Hz, 1H), 5.17−5.10 (m, 2H), 5.02 (dd, J = 15.0, 9.2 Hz, 1H), 3.74 (td, J = 14.3, 4.9, 1H), 3.37 (t, J = 10.7 Hz, 1H), 2.30 (m, 1H), 2.25−2.10 (m, 2H), 1.96 (dd, J = 14.8, 2.8, 1H), 1.68−1.56 (m, 2H), 1.41−1.30 (m, 3H), 1.05 (d, J = 7.1 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.05, 146.49, 143.09, 137.72, 131.52, 121.60, 81.03, 77.56, 65.94, 45.97, 42.95, 42.66, 34.47, 31.21, 27.07, 22.33, 20.02, 17.51; MS (ESI) m/z 419 [M + H]+; HRMS calcd for C18H31IO3N [M + NH4]+ 436.1343, found 436.1343. (R,E)-2-Bromo-3-(2,2-dimethyl-1-((triethylsilyl)oxy)hex-3en-5-yn-1-yl)phenol (3A). Compound 32 (500 mg, 0.84 mmol) was dissolved in dry methanol (5 mL) and treated with anhydrous K2CO3 (289 mg, 2.1 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 4 h, diluted with water, and extracted with EtOAc (2 × 20 mL). The combined extracts were washed with water (5 mL) and brine (5 mL). The organic extracts were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The organic residue was subjected to column chromatography (SiO2, 5% EtOAc in hexane) to give compound 3A (320 mg, 93%) as colorless oil. Rf = 0.5 (SiO2, 5% EtOAc/hexane); [α]28 D = +79.8 (c 0.8, CHCl3); IR (neat); νmax 3308, 2958, 2952, 2372, 2103, 1398, 1466, 1412, 1090, 833, 737 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.17 (dd, J = 7.8, 7.9 Hz, 1H), 6.99 (dd, J = 7.8, 1.7 Hz, 1H), 6.93 (dd, J = 7.9, 1.7 Hz, 1H), 6.45 (d, J = 16.4 Hz, 1H), 5.64 (s, 1H), 5.28 (dd, J = 16.3, 2.2 Hz, 1H), 4.90 (s, 1H), 2.81 (d, J = 2.1 Hz, 1H), 1.09 (s, 3H), 1.0 (s, 3H), 0.84 (t, J = 8.0 Hz, 9H), 0.52−0.39 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 152.21, 151.31, 141.99, 127.54, 122.34, 114.63, 112.28, 106.87, 80.93, 79.05, 76.16, 43.99, 24.09, 22.07, 6.99 (3C), 4.66 (3C); MS (ESI) m/z 409 [M + H]+; HRMS calcd for C20H29BrO2SiNa [M + Na]+ 431.1017, found 431.1251. (R,E)-((1-(2-Bromo-3-((tert-butyldimethylsilyl)oxy)phenyl)2,2-dimethylhex-3-en-5-yn-1-yl)oxy)triethylsilane (3). Compound 3A (289 mg, 0.70 mmol) was dissolved in CH2Cl2 (5 mL) and treated with imidazole (79 mg, 1.43 mmol) followed by TBSCl (140 mg, 0.93 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 4 h at room

aqueous NH4Cl solution (5 mL) was added to the reaction mixture at room temperature. The reaction mixture was extracted with EtOAc (2 × 50 mL), and the total organic extracts were washed with water (2 × 5 mL) and brine (5 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude residue that on purification by flash chromatography (SiO2, 18% EtOAc/ hexane) afforded compound 29A as colorless oil (180 mg, 76%). Rf = 0.2 (SiO2, 20% EtOAc/hexane); [α]27 D = −13.49 (c 0.4, CHCl3); IR (neat): νmax 3615 (br), 2925, 2857, 2311, 1742, 1486, 1443, 1254, 1179, 1083, 947, 835, 763 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.68−7.62 (m, 2H), 7.39−7.34 (m, 2H), 7.19−7.13 (m, 2H), 7.12−7.06 (m, 2H), 6.41 (dd, J = 14.6, 0.8 Hz, 1H), 6.30 (dd, J = 14.5, 7.0, 1H), 5.35 (dd, J = 15.6, 7.5 Hz, 1H), 5.23 (dd, J = 15.6, 7.5 Hz, 1H), 5.13 (m, 1H), 3.74−3.60 (m, 3H), 3.35 (d, J = 21.5 Hz, 2H), 2.39−2.29 (m, 2H), 1.65 (m, 1H), 1.57 (m, 1H), 1.45−1.29 (m, 24H), 0.95 (d, J = 5.1 Hz, 3H), 0.93 (d, J = 5.0 Hz, 3H), 0.89 (d, J = 5.0 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.51 (d, J = 5.1 Hz), 149.95 (d, J = 7.4 Hz), 140.63, 139.14 (d, J = 8.1 Hz), 138.53, 127.95, 127.71 (d, J = 5.1 Hz), 127.45 (3C), 124.72 (2C), 119.67 (2C), 81.48, 80.59, 68.92, 60.87, 45.54, 44.56, 40.29, 39.99, 36.38, 34.994, 34.66 (2C), 32.97, 30.10 (6C), 29.69, 26.21, 25.96 (3C), 22.68, 21.67, 20.22, 15.34, −3.87, −4.02; MS (ESI) m/z 897 [M + H]+; HRMS calcd for C44H70IO7PSiNa [M + Na]+ 919.3571, found 919.3564. (3Z,6R,8R,10R,11E,13S,14S)-8-((tert-Butyldimethylsilyl)oxy)-14-((E)-2-iodovinyl)-6,10,13-trimethyloxacyclotetradeca-3,11-dien-2-one (2). Alcohol 29A (103 mg, 0.111 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 0 °C. To it NaHCO3 (18 mg, 0.222 mmol) and DMP (71 mg, 0.166 mmol) were added sequentially and stirred at room temperature for 1 h. Saturated aqueous solutions of Na2S2O3 (10 mL) and NaHCO3 (10 mL) were added to the reaction mixture. The resultant biphasic mixture was stirred for 30 min and then extracted with EtOAc (2 × 25 mL). Water washings (2 × 5 mL) followed by brine washing (5 mL) were given to the combined organic extracts. Anhydrous Na2SO4 was added to the combined organic extracts and filtered. The evaporation of the solvent produced a crude residue, which was purified by flash chromatography (SiO2, 15% EtOAc/hexane) to afford the aldehyde 5 (95 mg, 92%). The aldehyde 5 (Rf = 0.6, 10% EtOAc in petroleum ether) was dissolved in anhydrous THF (5 mL) and added with the help of a syringe pump to a suspension of NaH (60% dispersion in mineral oil, 21 mg, 0.55 mmol) in anhydrous THF (5 mL) at 0 °C over a period of 10 h. A saturated solution of aqueous NH4Cl (5 mL) was added to the reaction mixture, and it was extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (2 × 5 mL) and brine (5 mL). Organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude mass was purified by flash chromatography (SiO2, 1% EtOAc/hexane) to give compound 2 (35 mg 73%). Rf = 0.9 (SiO2, 10% EtOAc/hexane); [α]31 D = −131.4 (c 0.9, CHCl3); IR (neat): νmax 2929, 1721, 1462, 1181, 1075, 855, 775 cm−1; 1 H NMR (500 MHz, CDCl3): δ 6.56−6.43 (m, 2H), 6.23 (td, J = 12.2, 3.9 Hz, 1H), 5.84 (dd, J = 11.6, 2.0, 1H), 5.18−5.10 (m, 2H), 5.04 (dd, J = 15.1, 9.0 Hz, 1H), 3.62 (td, J = 12.2, 3.9 Hz, 1H), 3.45 (t, J = 9.7 Hz, 1H), 2.24−2.01 (m, 3H), 1.95 (dd, J = 14.4, 2.9 Hz, 1H), 1.38−1.29 (m, 3H), 1.06 (m, 1H), 1.0 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.86 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H); 13C 16573

DOI: 10.1021/acsomega.8b02156 ACS Omega 2018, 3, 16563−16575

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dissolved in MeOH (4 mL), and K2CO3 was added to the resulting solution. After stirring for 1 h, the reaction mixture was quenched with saturated aqueous solution of NH4Cl (15 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the corresponding carbamate (6.5 mg, 95%) as colorless oil. A stirred solution of carbamate (6.5 mg, 0.007 mmol) in dry CH3CN (2 mL) was placed in a polypropylene vial and treated slowly with HF-pyridine complex (40%, 3.6 μL) at 0 °C. After stirring for 12 h at room temperature, the reaction was quenched with aqueous NaHCO3 solution (3 mL) and stirred continuously for 30 min. After 30 min, the reaction mixture was extracted with EtOAc (2 × 5 mL). The combined organic extracts were washed with water (2 × 2 mL) and brine (3 mL), dried over Na2SO4, and concentrated in vacuo. The organic residue thus obtained was purified by flash column chromatography (SiO2, 40% EtOAc/hexane) to give compound 1 as a white solid (4 mg, 86%, over two steps). Rf = 0.4 (SiO2, 20% EtOAc/hexane); [α]28 D = −20.83 (c 0.6, MeOH); IR (neat): νmax 3727, 3494, 3365, 2959, 2924, 2858, 2190, 1705, 1642, 1598, 1459, 1386, 1294, 1181, 1053, 963.37, 833, 796 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.23 (apt, t, 1H), 7.03 (dd, J = 7.8, 1.6 Hz, 1H), 6.97 (dd, J = 8.1, 1.6 Hz, 1H), 6.35 (d, J = 16.3 Hz, 1H), 6.12 (td, J = 12.1, 3.5 Hz, 1H), 6.02 (dd, J = 15.8, 8.1 Hz, 1H), 5.92−5.83 (m, 2H), 5.79 (s, 1H), 5.56 (dd, J = 16.3, 2.0 Hz, 1H), 5.32 (dd, J = 15.0, 9.4 Hz, 1H), 5.25 (dd, J = 10.1, 8.1 Hz, 1H), 5.05 (dd, J = 15.0, 9.3 Hz, 1H), 5.0 (s, 1H), 4.60 (app, t, 1H), 4.54 (br, 2H), 3.72− 3.61 (m, 1H), 2.28−2.18 (m, 1H), 2.12−2.05 (m, 1H), 2.01− 1.97 (m, 1H), 1.94 (d, J = 2.71 Hz, 1H), 1.91−1.81 (m, 1H), 1.54−1.45 (m, 2H), 1.14 (s, 3H), 1.12−1.05 (m, 2H), 1.04 (s, 3H), 1.01 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.70, 156.76, 151.77, 149.88, 143.46, 141.04, 139.56, 136.62, 132.76, 128.05, 122.42, 121.30, 115.13, 113.93, 112.63, 108.94, 89.53, 87.02, 78.38, 76.15, 71.23, 44.28, 43.55, 42.74, 41.28, 33.94, 31.58, 27.28, 24.43, 22.24, 21.78, 20.16, 17.52; MS (ESI) m/z 650 [M + Na]+; HRMS calcd for C33H42BrNO6Na [M + Na]+ 650.2088, found 650.2082.

temperature, quenched with saturated aqueous NH4Cl (5 mL), and extracted with EtOAc (2 × 50 mL). Washings were given to the combined organic extracts with water (2 × 5 mL) and brine (5 mL). Combined organic extracts were dried over anhydrous Na2SO4. Solvent was evaporated in vacuo, and the residue was purified via column chromatography (SiO2, 2% EtOAc in hexane) to give compound 3 (370 mg, 90%) as colorless oil. Rf = 0.5 (SiO2, 2% EtOAc/hexane); [α]26 D = +56.5 (c 0.4, CHCl3); IR (neat); reported [α]20 D = +55.8 (c 0.5, CHCl3); νmax 2956, 2880, 1573, 1461, 1286, 1085, 834, 729 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.12 (t, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.8, 1.6 Hz, 1H), 6.79 (dd, J = 7.8, 1.6 Hz, 1H), 6.51 (d, J = 16.5 Hz, 1H), 5.27 (dd, J = 16.5, 2.2 Hz, 1H), 5.06 (s, 1H), 2.8 (d, J = 2.1 Hz, 1H), 1.09 (s, 3H), 1.04 (s, 3H), 0.98 (s, 9H), 0.84 (t, J = 7.9 Hz, 9H), 0.54−0.34 (m, 6H), 0.23 (s, 3H), 0.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 152.63, 151.79, 143.15, 126.59, 123.11, 119.02 (2C), 106.55, 83.11, 78.88, 75.96, 43.99, 25.89 (3C), 24.31, 22.00, 18.46, 6.71 (3C), 4.6 (3C), −4.18, −4.28. (3Z,6R,8R,10R,11E,13S,14R)-14-((R,1E,5E)-8-(2-Bromo-3((tert-butyldimethylsilyl)oxy)phenyl)-7,7-dimethyl-8((triethylsilyl)oxy)octa-1,5-dien-3-yn-1-yl)-8-hydroxy6,10,13-trimethyloxacycloxacyclotetradeca-3,11-dien-2-one (33). To the stirred degassed solution of 30 (4.5 mg, 0.01 mmol), 3 (10 mg, 0.018 mmol), and Et3N (1.5 uL, 0.015 mmol) in dry THF (2 mL) under argon were added Pd(PPh3)4 (6 mg, 0.005 mmol) and CuI (4.7 mg, 0.025 mmol) at room temperature. After being stirred for 30 min at room temperature, the reaction mixture was concentrated in vacuo and quenched with saturated aqueous solution of NH4Cl (5 mL). EtOAc (2 × 5 mL) was added to the reaction mixture, and the compound was extracted. The combined organic extracts were washed with water (2 × 5 mL) and brine (3 mL), dried over Na2SO4, and concentrated in vacuo. Thus, the obtained organic residue was purified by column chromatography (SiO2, 0.4% EtOAc/hexane) to give title compound 33 as colorless oil (7 mg, 80%). Rf = 0.2 (SiO2, 20% EtOAc/ hexane); [α]28 D = −27.49 (c 0.4, CHCl3); IR (neat): νmax 3510 (br), 2955, 2926, 2859, 1716, 1460, 1287, 1177, 1058, 1002, 968, 839 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.11 (t, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.8, 1.7 Hz, 1H), 6.78 (dd, J = 7.8, 1.7 Hz, 1H), 6.40 (d, J = 16.4 Hz, 1H), 6.26 (td, J = 12.8, 3.4 Hz, 1H), 6.01 (dd, J = 15.9, 8.0 Hz, 1H), 5.90−5.81 (m, 2H), 5.38 (dd, J = 16.4, 2.0 Hz, 1H), 5.22−5.11 (m, 2H), 5.08−4.98 (m, 2H), 3.76 (m, 1H), 3.42 (t, J = 10.5 Hz, 1H), 2.30 (m, 1H), 2.23−2.10 (m, 2H), 1.95 (m, 1H), 1.69−1.60 (m, 2H), 1.40− 1.28 (m, 3H), 1.10 (s, 3H), 1.07−1.02 (m, 12H), 0.99−0.92 (m, 9H), 0.84 (t, J = 7.9 Hz, 9H), 0.52−0.39 (m, 6H), 0.22 (s, 3H), 0.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.17, 151.76, 151.16, 146.06, 143.21, 138.67, 137.44, 132.04, 126.60, 123.12, 121.89, 119.02, 117.60, 114.03, 107.43, 90.45, 86.04, 79.00, 76.07, 66.00, 46.01, 44.08, 43.21, 42.98, 34.49, 31.19, 29.70, 27.11, 25.89 (3C), 24.43, 22.36 (2C), 20.03, 17.66, 6.73 (3C), 4.68 (3C), −4.19, −4.29; MS (ESI) m/z 812.3867 [M + H]+; HRMS calcd for C44H73BrO5Si2N [M + NH4]+ 830.4205, found 830.4199. (2R,3S,4E,6R,8R,10R,12Z)-2-((R,1E,5E)-8-(2-Bromo-3-hydroxyphenyl)-8-hydroxy-7,7-dimethylocta-1,5-dien-3-yn-1yl)-3,6,10-trimethyl-14-oxooxacyclotetradeca-4,12-dien-8-yl carbamate (1). To a solution of 33 (7 mg, 0.008 mmol) in CH2Cl2 (4 mL) was added trichloroacetylisocyanate (1.2 μL, 0.009 mmol) at room temperature and stirred for 30 min. The reaction mixture was concentrated in vacuo, the residue was

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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/acsomega.8b02156. 1

H and 13C spectral copies for all new compounds and comparison of spectroscopic data of synthetic callyspongiolide with the reported literature are shown in table form (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +91-40-27193108. Tel: +9140-27191604. ORCID

Subhash Ghosh: 0000-0002-5877-8910 Notes

The authors declare no competing financial interest. 16574

DOI: 10.1021/acsomega.8b02156 ACS Omega 2018, 3, 16563−16575

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ACKNOWLEDGMENTS We are thankful to the Science and Engineering Research Board, Department of Science and Technology, India for funding this project (grant no. EMR/2017/000414) and INSPIRE fellowship to A.S.

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REFERENCES

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DOI: 10.1021/acsomega.8b02156 ACS Omega 2018, 3, 16563−16575