Total Synthesis of Biselyngbyolide B and Its C21âC22 Z-Isomer - The

Article Cite This: J. Org. Chem. 2018, 83, 4554−4567

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Total Synthesis of Biselyngbyolide B and Its C21−C22 Z‑Isomer Lena Kam ̈ mler and Martin E. Maier* Institut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany S Supporting Information *

ABSTRACT: Investigations toward the synthesis of the 18membered macrolactone biselyngbyolide B (2) from a C1− C13 and a C14−C23 fragment are described. As a key reaction in the synthesis of the C1−C13 fragment, we used an asymmetric propargylation of chiral vinylketene silyl N,O-acetal 12. Access to a C14−C23 fragment featuring a skipped diene and a sensitive allyl alcohol function was initially attempted via reductive fragmentation of a pyran template. However, this ring opening on iodide 32 with t-BuLi led to dienynol 33 with a 21Z double bond. With a silyl protecting group at 3-OH and by implementing an intramolecular Stille coupling for macrolactonization, the 21Z-isomer of biselyngbyolide B (47) was obtained. For preparation of a C14−C23 fragment with the 21Econfiguration, a cross-coupling of vinylstannane 48 with 4-bromocrotonate (49) set the configuration of the two double bonds. Biselyngbyolide B (2) was then accessed by an intramolecular Heck coupling. In preliminary biological cytotoxicity assays, 2 turned out to be active, whereas the 21Z-isomer 47 was much less active. The 3-OMEM analogue 40 was devoid of activity. These results support the notion that the side chain with the correct configuration is relevant for binding to the Ca2+-ATPase and the biological activity.

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INTRODUCTION In 2009, the group of K. Suenaga et al. described the isolation of a novel 18-membered macrolactone called biselyngbyaside (1) from marine cyanobacteria (Figure 1).1 Since then, several related macrolides have been isolated.2 Some of these macrolides are glycosylated at the 3-OH function. These carry the name biselyngbyaside, whereas the corresponding compounds lacking the sugar were named biselyngbyolides. Three pairs of biselyngbyasides and matching biselyngbyolides are shown in Figure 1. In addition, the C18/C19 E-isomer of biselyngbyaside E, called biselyngbyaside F, was found in the bacterium. Moreover, two oxygenated metabolites are known in the literature. Common structural features include a conjugated E,E-diene at C12,C14, a trisubstituted E-double bond at C8 and a skipped diene in the side chain. In the region C3−C7, a syn,syn-triol, an enediol, or a syn-1,5-diol functionality is present. Biological studies, for example, on biselyngbyaside (1) or biselyngbyolide B (2) revealed a significant growth inhibitory activity [GI50 values (μM, HeLa cells): 1, 0.30;2c 2, 0.049;2b 3, 2.5;2a 4, 0.039;2b 5, 0.19;2c 6, 0.046]2c inhibition of RANKLinduced osteoclastogenesis and induction of apoptosis of mature osteoclast cells. 3 It also could be shown that biselyngbyasides inhibit the ATPase activity of sarco/ endoplasmatic reticulum Ca2+-ATPases (SERCA). An X-ray analysis revealed that in particular the diene and side chain have crucial interactions with SERCA.4 Due to the interesting structure and promising biological activity, these macrolides attracted attention of organic chemists. Our group published a synthesis of the C1−C13 fragment featuring an asymmetric propargylation on a © 2018 American Chemical Society

propionic acid derivative and chain extensions by Wittig reaction and Brown allylation.5 The group of Chandrasekhar later reported the synthesis of the C5−C23 segment of biselyngbyaside.6 Quite recently, a concise route to a C1−C13 fragment was described.7 Total syntheses of biselyngbyolide A8 (4), biselyngbyolide B9 (2), and biselyngbyaside10 (1) were achieved by the Suenaga team. It turned out that introduction of the sugar moiety at an early stage is crucial in the synthesis of 1. A total synthesis of biselyngbyolide B (2) was also achieved by Goswami et al.11 Common to the total syntheses of these macrolides is macrolactone formation by intramolecular crosscoupling, forming the C13−C14 bond. In our synthesis plan for biselyngbyolide B, we also considered formation of the conjugated diene by a crosscoupling reaction. Macrolactone formation would be realized either by macrolactonization (Yamaguchi- or Mitsunobu lactonization) or by an ester via intramolecular cross-coupling (Scheme 1). Possible problems during the synthesis might arise from the allylic OH functions at C3, C7, and C17. Moreover, establishing the configuration of the C18,C19 double bond posed a certain challenge. Finally, the skipped diene might isomerize to a conjugated diene under harsh conditions. Therefore, we initially planned to construct the C14−C23 section from a cyclic precursor like 11. A critical issue in our previous synthesis of the C1−C13 part was that we had to pass through an aldehyde [(S)-2-methyl-5-(trimethylsilyl)pent-4ynal], which is prone to racemization. In circumventing this, Received: February 1, 2018 Published: March 28, 2018 4554

DOI: 10.1021/acs.joc.8b00298 J. Org. Chem. 2018, 83, 4554−4567

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The Journal of Organic Chemistry

(3.1 equiv) in dichloromethane at a low temperature (Scheme 2). This way a reasonable yield (64%) of 2,4-dimethylhepten-6Scheme 2. Synthesis of the C1−C13 Fragments 19 and 20 Featuring Propargylation of Dienolate Equivalent 12

Figure 1. Structures of biselyngbyasides and biselyngbyolides.

Scheme 1. Retrosynthetic Considerations for Biselyngbyolide B (2)

ynoic acid derivative 14 could be realized. As this compound showed only one set of signals in the 13C NMR spectrum, a highly diastereoselective alkylation can be assumed. Reductive removal of the chiral auxiliary from 14 using NaBH4 in aqueous THF provided known alcohol5 15. For the subsequent steps, we relied on our previous work.5 Thus, the removal of the trimethylsilyl group from 15 using K2CO3 in MeOH was followed by hydrozirconation of the triple bond. Here, the free hydroxyl group was temporarily converted to the diisobutylalkoxy derivative prior to the hydrozirconation.15 Quenching of the vinylmetal intermediate with iodine furnished the corresponding vinyl iodide. Subsequently, the alcohol function was oxidized to give aldehyde 16 using the Dess−Martin periodinane16 reagent. Chain extension of aldehyde 16 by Brown allylation17 led to homoallylic alcohol 17. Here, the Brown reagent was generated from (−)-Ipc2BOMe.18 Conversion of alcohol 17 to the corresponding methyl ether 10 was achieved with trimethyloxonium tetrafluoroborate in the presence of a proton sponge.19 Finally, a cross-metathesis reaction between the two alkenes 10 and 185 provided C1− C13 fragment 19. Initially, we had in mind a cross-coupling reaction between an OH protected derivative of vinyl iodide 19 and a C14−C23 fragment with a silicon protecting group at 17OH. Therefore, we chose to protect 3-OH in fragment 19 as 2methoxyethoxymethyl (MEM) ether 20, which was obtained in 82% yield. Synthesis of a C14−C23 Fragment. As discussed before, a C14−C23 fragment would be prepared from a cyclic

we also were looking to a more concise route to fragment 10. To reach C1−C13 fragment 8, the two terminal alkenes 9 and 10 would be combined by a cross-metathesis reaction. In this paper, we describe these investigations and how we completed a total synthesis of biselyngbyolide B (2) and its C21,C22-Zisomer 47.

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RESULTS AND DISCUSSION Synthesis of the C1−C13 Fragment 10. A smart way of avoiding configurationally labile 2-methyl-5-(trimethylsilyl)pent-4-ynal was offered by a recent publication of Hosokawa et al. describing the stereoselective alkylation of chiral vinylketene silyl N,O-acetals.12 Thus, literature known dienolate equivalent13 12 was reacted with propargyl iodide14 13 in the presence of BF3·Et2O (0.2 equiv) and silver trifluoroacetate 4555


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assumed it to be the desired inversion product 31. However, as it later turned out, most likely the iodide had entered with retention of the configuration. We concluded this from the fact that the reductive fragmentation on 32 led to dienol 33 with the C21−C22 Z-configuration. This, however, only became evident on the final macrolactone. We assume that during the OH to I substitution neighboring group participation was operative (inset in Scheme 3). The reductive ring opening of cyclic haloether 32 was best performed with tert-butyllithium (3 equiv) in Et2O at −95 °C. Under these conditions, dienol 33 was obtained in 74% yield as a single isomer. Here an anionic mechanism is very likely, as a radical mechanism should lead to a mixture of E/Z-isomers. For example, using zinc in refluxing ethanol led to a low yield (22%) of a mixture of double bond isomers. After protection29 of the homopropargylic alcohol 33 as tert-butyldiphenylsilyl ether 34, a palladium-catalyzed hydrostannylation30 furnished vinylstannane 35 in an essentially quantitative yield. Following the plan with a macrolactonization, stannane 35 was subjected to a Stille coupling with vinyl iodide 20. Using well established conditions,31,32 polyene 36 was obtained in a reasonable yield (Scheme 4). Proceeding further, the pivaloyl

precursor. The plan was to prepare a dihydropyran of type 11 with a halide in the side chain so that a reductive fragmentation would set the C21−C22 double bond.20 Starting with MOM protected 2-hydroxypropanal21 21, a Hosomi−Sakurai reaction with 2-methylallylsilane22 22 (1.5 equiv) in the presence of tin tetrachloride (1.1 equiv) gave rise to alcohol 23 containing a vinylsilane moiety (Scheme 3). A silyl Prins reaction23−25 of 23 Scheme 3. Synthesis of Pyran 32 and Its Opening to Building Block 33 (C14−C23 Fragment)

Scheme 4. Synthesis of 21Z-Biselyngbyolide B Derivative 40a

a

26

with hydroxypropanal derivative 24 in the presence of trimethylsilyl triflate (1.5 equiv) in Et2O at −78 °C gave functionalized dihydropyran 25 in 73% yield. The cisconfiguration at C2 and C4 was evident from the NOESY spectrum of 25. Subsequent cleavage of the silyl ether and oxidation of the resulting primary alcohol 26 provided aldehyde 27. Its reaction with dimethyl (1-diazo-2-oxopropyl) phosphonate (28)27 in methanol in the presence of potassium carbonate furnished alkyne 29 in a good yield. In the next step, the MOM protecting group was removed under acid conditions. Now the secondary alcohol of 30 had to be replaced by a halide with inversion of configuration. This was best achieved with iodine in the presence of triphenylphosphine (Appel conditions).28 We isolated one haloether 32 as a single isomer. Initially, we

CuTC = copper(I) thiophene-2-carboxylate.

protecting group of 36 was removed under reductive conditions and the alcohol 37 oxidized to carboxylic acid 38 in a two-step sequence involving oxidation to the intermediate aldehyde using the Dess−Martin reagent and a subsequent Pinnick oxidation. Cleavage of the silyl ether at the 17-OH function using tetrabutylammonium fluoride hydrate delivered seco acid 39. As we had started the synthesis of fragment 35 from Llactate, a Mitsunobu lactonization was called for. Applying Ph3P (5 equiv) and DEAD (7 equiv) to seco acid 39 gave macrolactone 40, albeit in a moderate yield. Key chemical shifts, for example, 17-H (around 5.48 ppm), matched with the natural product, indicating that the lactonization had occurred with inversion of the configuration at C17. Unfortunately, we 4556


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fragment had given the wrong configuration of the C21−C22 double bond. To get the correct double bond isomer of a C14−C23 fragment, we started with known vinyl stannane33 48, which was coupled under palladium catalysis with 4-bromocrotonate 49 (Scheme 6). This gave dienoate 50 in 64% yield. Using the

were not able to cleave the mixed acetal at 3-OH even though a variety of conditions were tried. All conditions led to decomposition. Accordingly, we changed our strategy to macrolactone formation by an intramolecular coupling reaction. Thus, the silyl ether of fragment 35 was cleaved using TBAF in THF to give tributylstannyltrienol 41 (Scheme 5). In parallel, alcohol Scheme 5. Synthesis of 21Z-Biselyngbyolide B (47)

Scheme 6. Completion of the Synthesis of Biselyngbyolide B (2)

19 obtained from the cross-metathesis reaction was protected as tert-butyldiphenylsilyl ether 42. Reductive cleavage of the pivaloyl ester to alcohol 43 and oxidation gave carboxylic acid 44. Esterification of acid 44 with alcohol 41 under Mitsunobu conditions led to ester 45. The crucial intramolecular Stille coupling in the presence of Pd2(dba)3 and LiCl in DMF gave a good yield of macrolactone 46. A final deprotection furnished the 21Z-isomer of biselyngbyolide B (47). Comparison of the 13 C NMR data of 47 with literature values showed significant differences for C23 and other carbon atoms in that region. In particular, C23 of lactones 40, 46, and 47 appeared at 12.9 ppm, whereas the corresponding shift in biselyngbyolide B (2) amounts to 17.9 ppm. Calculations of the 13C chemical shift values of homopropargylic alcohol 33 supported the cisconfiguration at the double bond in question. Here the carbon atoms flanking the disubstituted double bond show large chemical shift differences for the double bond isomers [C10 (C23 in 2) cis-isomer = 11.7 ppm (measured 12.8 ppm), transisomer = 17.7 ppm; C7 (C20 in 2) cis-isomer = 29.8 ppm (measured 30.2 ppm), trans-isomer = 35.8 ppm]. It was at this point that we suspected that the pyran route to the C14−C23

crotonate averted the formation of regioisomers in the coupling reaction. Conversion of the ester to a methyl group was started with reduction of the ester using DIBAL-H. Thereafter, the primary alcohol was converted to the corresponding tosylate using p-toluenesulfonic anhydride.34 Treatment of the crude tosylate with LiEt3BH at 0 °C furnished 79% of dienol derivative 52. After cleavage of the silyl ether, allyl alcohol 53 was oxidized to known enal11 54 using the Dess−Martin periodinane reagent. For completion of the synthesis of biselyngbyolide B (2), we followed the strategy outlined by Goswami et al.11 Thus, Brown allylation on enal 54 furnished homoallylic alcohol 55 in 63% yield. Mosher analysis35 on 55 indicated an ee of 92%. In the next step, carboxylic acid 44 was esterified with alcohol 55 using the Shiina reagent36 (2-methyl6-nitrobenzoic anhydride, MNBA) to give ester 56 in 77% yield. A subsequent intramolecular Heck reaction37 using Pd(OAc)2 (1.3 equiv), Cs2CO3 (1.5 equiv), Et3N (1.1 equiv), and Bu4NBr (1.0 equiv) delivered macrolactone 57 in 72% yield. Final deprotection using a combination of TBAF and AcOH gave rise to biselyngbyolide B (2). Comparison of the 1 H and 13C NMR data of the synthetic material and the isolated 4557


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was filtered through a pad of Celite, and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography (petroleum ether/EtOAc, 7:1) to afford the title compound 14 (178 mg, 0.53 mmol, 64%) as a white solid: Rf = 0.32 (petroleum ether/EtOAc, 7:1); 1 mp 61−63 °C; [α]22 D = −34.3 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 0.12 (s, 9H, Si(CH3)3), 0.90 (t, J = 7.1 Hz, 6H, CH(CH3)2), 1.10 (d, J = 6.7 Hz, 3H, 4′-CH3), 1.91 (d, J = 0.6 Hz, 3H, 2′-CH3), 2.20 (dd, J = 16.8, 7.5 Hz, 1H, 5′-Ha), 2.31 (d, J = 5.4 Hz, 1H, 5′-Hb), 2.34−2.40 (m, 1H, CH(CH3)2), 2.67−2.78 (m, 1H, 4′-H), 4.15 (dd, J = 8.9, 5.1 Hz, 1H, 5-Ha), 4.29 (t, J = 8.9 Hz, 1H, 5-Hb), 4.45−4.50 (m, 1H, 4-H), 5.83 (dd, J = 9.7, 0.6 Hz, 1H, 3′-H); 13C NMR (100 MHz, CDCl3) δ 0.1 (Si(CH3)3), 13.8 (2′-CH3), 15.0 (CH(CH3)2), 17.8 (CH(CH3)2), 18.8 (4′-CH3), 26.3 (C-5′), 28.2 (CH(CH3)2), 32.1 (C4′), 58.2 (C-4), 63.3 (C-5), 86.1 (C-7′), 104.8 (C-6′), 130.3 (C-2′), 141.6 (C-3′), 153.4 (C-2), 171.8 (C-1′); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C18H29NO3SiNa 358.1809, found 358.1813. (4S,2E)-2,4-Dimethyl-7-(trimethylsilyl)hept-2-en-6-yn-1-ol5 (15). A premixed solution of NaBH4 (56 mg, 1.49 mmol, 5.0 equiv) in H2O (2 mL) was added to a solution of oxazolidinone 14 (100 mg, 0.30 mmol) in THF (4 mL) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature overnight, before quenching it with a saturated NH4Cl solution (10 mL). The aqueous phase was extracted with CH2Cl2 (2 × 4 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/ EtOAc, 4:1) afforded alcohol 15 (51 mg, 0.24 mmol, 81%) as a colorless oil: Rf = 0.63 (petroleum ether/EtOAc, 1:1); [α]21 D = −10.1 1 (c 1.0, CHCl3); lit.5 [α]20 D = −13.4 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 0.13 (s, 9H, Si(CH3)3), 1.03 (d, J = 6.7 Hz, 3H, 4CH3), 1.37 (bs, 1H, OH), 1.68 (d, J = 1.2 Hz, 3H, 2-CH3), 2.17 (dd, J = 6.7, 2.5 Hz, 2H, 5-H), 2.60−2.69 (m, 1H, 4-H), 3.98 (bs, 2H, 1-H), 5.24 (dd, J = 9.5, 1.2 Hz, 1H, 3-H); 13C NMR (100 MHz, CDCl3) δ 0.1 (Si(CH3)3), 13.9 (2-CH3), 20.1 (4-CH3), 27.6 (C-5), 31.7 (C-4), 68.8 (C-1), 85.5 (C-7), 105.9 (C-6), 130.4 (C-3), 134.5 (C-2). (4S,5E,7S,9E)-10-Iodo-5,7-dimethyldeca-1,5,9-trien-4-ol (17). A freshly prepared allylmagnesium bromide solution (0.3 M in Et2O, 7.3 mL, 2.17 mmol, 1.15 equiv) was added dropwise to a solution of (−)-Ipc2BOMe (723 mg, 2.27 mmol, 1.2 equiv) in Et2O (4 mL) at −80 °C. After stirring for 15 min at −80 °C, the reaction mixture was allowed to warm to room temperature and stirred for an additional 1 h. The mixture was then cooled to −90 °C again, and aldehyde5 16 (500 mg, 1.89 mmol) dissolved in Et2O (4 mL) was added dropwise. The reaction mixture was stirred for 6 h at −90 °C, before quenching with a 30% H2O2 solution (4 mL) and 3 M NaOH solution (4 mL). The resulting mixture was allowed to stir at room temperature overnight. Afterward the aqueous layer was separated and extracted with Et2O (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. Purification of the residue by flash chromatography (petroleum ether/Et2O, 4:1) afforded homoallylic alcohol 17 (499 mg, 1.63 mmol, 86%) as a colorless oil: Rf = 0.35 1 (petroleum ether/Et2O, 4:1); [α]20 D = +7.2 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.7 Hz, 3H, 7-CH3), 1.58 (bd, J = 1.6, 1H, OH), 1.59 (d, J = 1.4 Hz, 3H, 5-CH3), 1.89−1.97 (m, 1H, 8Ha), 1.99−2.06 (m, 1H, 8-Hb), 2.27−2.31 (m, 2H, 3-H), 2.40−2.51 (m, 1H, 7-H), 4.01 (t, J = 6.6 Hz, 1H, 4-H), 5.08 (t, J = 1.2 Hz, 1H, 6H), 5.10−5.14 (m, 2H, 1-H), 5.66−5.77 (m, 1H, 2-H), 5.94 (dt, J = 14.3, 1.3 Hz, 1H, 10-H), 6.37−6.44 (m, 1H, 9-H); 13C NMR (100 MHz, CDCl3) δ 11.6 (7-CH3), 20.5 (5-CH3), 31.6 (C-7), 39.8 (C-3), 43.4 (C-8), 75.4 (C-10), 76.6 (C-4), 117.7 (C-1), 131.5 (C-6), 134.6 (C-2), 136.0 (C-5), 144.9 (C-9). (3S,4E,7S,8E,10S,12E)-13-Iodo-7-methoxy-3-((2-methoxyethoxy)methoxy)-8,10-dimethyltrideca-4,8,12-trien-1-yl pivalate (20). To a solution of alcohol5 19 (203 mg, 0.42 mmol) in CH2Cl2 (2.5 mL) were added DIPEA (1.1 mL, 6.36 mmol, 15.1 equiv), MEMCl (0.6 mL, 5.09 mmol, 12.1 equiv), and DMAP (10 mg, 0.08 mmol, 0.2 equiv) sequentially at 0 °C. The resulting mixture was allowed to stir at room temperature for 2.5 h before being quenched with a saturated NaHCO3 solution (4 mL). The aqueous layer was extracted with Et2O three times. The combined organic extracts were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated

natural product showed good agreement. The three macrolides 40, 47, and 2 were tested for cytotoxicity on cell lines L929, KB-3−1, and MCF-7. While 40 (IC50 > 100 μmol for all cell lines) was devoid of any activity and 47 [IC50 (μmol): L929 = 25, KB-3−1 = 50, MCF-7 = 24] was weakly active, our synthetic biselyngbyolide B (2) [IC50 (μmol): L929 = 1, KB-3− 1 = 0.2, MCF-7 = 26] did show significant activity. These results underscore the important role of the side chain and its correct configuration for biological activity.

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CONCLUSION The synthesis of biselyngbyolide B (2) is described based on the combination of a C1−C13 fragment and a C14−C23 fragment by palladium-catalyzed cross-coupling. Key steps in the synthesis of C1−C13 building blocks 19 and 44 are an asymmetric propargylation of a dienolate equivalent, a Brown allylation, and a cross-metathesis reaction. The initial strategy in the synthesis of a C14−C23 fragment of generating the C21− C22 trans double bond by reductive fragmentation unexpectedly led to dienynol 33 with a C21−C22 cis double bond. We explain this by retention of configuration during the substitution of a secondary alcohol with an iodide. Using dienynol 33 and the derived vinylstannanes 35 and 41, macrolactone 40, featuring a 3-OMEM group, and the 21Zisomer of biselyngbyolide B, lactone 47, were obtained. Here, inter- and intramolecular Stille couplings were used to create the C12,C14 diene part. The synthesis of C14−C23 fragment 55 with the correct configuration of the C21,C22 double bond, started with the coupling of vinylstannane 48 with γbromocrotonate 49. After reduction of the ester function to a methyl group, a Brown allylation on enal 54 set the stereochemistry at C17. Seco compound 56 was then cyclized to macrolactone 57 by an intramolecular Heck coupling. Preliminary biological studies showed that the configuration of the side chain double bond is important for cytotoxicity.

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EXPERIMENTAL SECTION

General. Reactions were generally run under a nitrogen atmosphere in oven-dried glassware. Progress of the reactions was followed using TLC plates “POLYGRAM SIL G/UV254”, petroleum ether, ethyl acetate (EtOAc), Et2O, dichloromethane, toluene, and mixtures of them as an eluent. Dry diethyl ether (Et2O) and tetrahydrofuran were distilled from sodium and benzophenone, whereas dry CH2Cl2, methanol, and EtOAc were distilled from CaH2. Distilled petroleum ether with a boiling range between 40 and 60 °C was used. 1H NMR (400.160 MHz) and 13C NMR (100.620 MHz) spectra were measured on a “Bruker Avance III HD 400" spectrometer using CDCl3 or C6D6 as a solvent at room temperature. Some of the spectra were acquired on a Bruker Avance III HD 600 spectrometer (1H NMR at 600.13 MHz, 13C NMR at 150.90 MHz) or Bruker Avance III HD 700 spectrometer (1H NMR at 700.29 MHz, 13 C NMR at 176.09 MHz). Peak assignments were done by NMR spectroscopy (1H, 13C, DEPT-135, H,H−COSY, HSQC, and HMBC). High-resolution mass spectra (HRMS) were recorded on a “Bruker maXis 4G" instrument with electron spray ionization (ESI) and TOF mass detector. (R)-3-((4S,2E)-2,4-Dimethyl-7-(trimethylsilyl)hept-2-en-6-ynoyl)4-isopropyloxazolidin-2-one (14). (3-Iodoprop-1-yn-1-yl)trimethylsilane14 (13) (703 mg, 2.50 mmol, 3.0 equiv), AgCO2CF3 (563 mg, 2.55 mmol, 3.1 equiv), and BF3·OEt2 (0.02 mL, 0.17 mmol, 0.2 equiv) were added sequentially to a solution of (R)-3-((1E,3E)-1((tert-butyldimethylsilyl)oxy)-2-methylpenta-1,3-dien-1-yl)-4-isopropyloxazolidin-2-one13 (12) (281 mg, 0.83 mmol) in CH2Cl2 (6 mL) at −80 °C. The reaction mixture was stirred for 16 h at −20 °C, before quenching it with a saturated NaHCO3 solution (6 mL). The mixture 4558


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The Journal of Organic Chemistry under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/EtOAc, 5:1) furnished the title compound 20 (198 mg, 0.35 mmol, 82%) as a colorless oil: Rf = 0.40 1 (petroleum ether/EtOAc, 5:1); [α]20 D = −31.6 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 0.95 (d, J = 6.6 Hz, 3H, 10-CH3), 1.17 (s, 9H, C(CH3)3), 1.50 (d, J = 1.2 Hz, 3H, 8-CH3), 1.75−1.82 (m, 1H, 2Ha), 1.83−2.03 (m, 3H, 2-Hb, 11-H), 2.12−2.19 (m, 1H, 6-Ha), 2.29− 2.36 (m, 1H, 6-Hb), 2.45−2.53 (m, 1H, 10-H), 3.12 (s, 3H, 7-OCH3), 3.36 (s, 3H, MEM OCH3), 3.36−3.40 (m, 1H, 7-H), 3.50−3.60 (m, 3H, MEM CH2), 3.72−3.77 (m, 1H, MEM CH2), 4.11 (t, J = 6.4 Hz, 3H, 1-H, 3-H), 4.58 (d, J = 6.9 Hz, 1H, MEM CH2), 4.75 (d, J = 7.0 Hz, 1H, MEM CH2), 5.09 (d, J = 9.4 Hz, 1H, 9-H), 5.31 (dd, J = 15.4, 8.2 Hz, 1H, 4-H), 5.54−5.61 (m, 1H, 5-H), 5.97 (d, J = 14.3 Hz, 1H, 13-H), 6.37−6.44 (m, 1H, 12-H); 13C NMR (100 MHz, CDCl3) δ 10.9 (8-CH3), 20.6 (10-CH3), 27.2 (C(CH3)3), 31.8 (C-10), 34.7 (C2), 36.9 (C-6), 38.7 (C(CH3)3), 43.4 (C-11), 55.7 (7-OCH3), 59.0 (MEM OCH3), 61.0 (C-1), 66.9 (MEM CH2), 71.7 (MEM CH2), 73.4 (C-3), 75.6 (C-13), 86.8 (C-7), 92.2 (MEM CH2), 131.0 (C-5), 131.4 (C-4), 133.2 (C-8), 133.9 (C-9), 144.9 (C-12), 178.4 (CO); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C25H43IO6Na 589.1997, found 589.2001. (2S,3S,E)-2-(Methoxymethoxy)-5-methyl-6-(trimethylsilyl)hex-5en-3-ol (23). To a solution of (S)-2-(methoxymethoxy)-propanal21 (21) (1.15 g, 9.73 mmol) in CH2Cl2 (97 mL) was added SnCl4 (1 M in CH2Cl2, 10.70 mL, 10.70 mmol, 1.1 equiv) at −78 °C. Stirring was continued for 5 min before (2-methylprop-2-en-1,1-diyl)bis(trimethylsilane)22 (22) (2.93 g, 14.61 mmol, 1.5 equiv) in CH2Cl2 (60 mL) was added to the reaction mixture. After being stirred for 5 min at −78 °C, the reaction mixture was quenched by the addition of MeOH (20 mL). The mixture was diluted with CH2Cl2, poured into a saturated Rochelle salt solution (300 mL), and stirred at room temperature until phase separation was completed (16 h). The aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were washed with H2O and a saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (twice, using petroleum ether/ Et2O, 4:1 to 3:1) to give homoallylalcohol 23 (1.78 g, 7.22 mmol, 74% over 2 steps) as a colorless oil: Rf = 0.33 (petroleum ether/Et2O, 4:1); 1 [α]20 D = −2.1 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 0.09 (s, 9H, SiCH3), 1.19 (d, J = 6.3 Hz, 3H, 1-H), 1.82 (s, 3H, 5-CH3), 2.18 (ddd, J = 13.6, 9.1, 0.8 Hz, 1H, 4-Ha), 2.30 (dd, J = 13.7, 3.0 Hz, 1H, 4Hb), 2.36 (d, J = 3.5 Hz, 1H, OH), 3.38 (s, 3H, CH2OCH3), 3.55− 3.65 (m, 2H, 2-H, 3-H), 4.65 (d, J = 6.8 Hz, 1H, CH2OCH3), 4.72 (d, J = 6.8 Hz, 1H, CH2OCH3), 5.30 (d, J = 0.8 Hz, 1H, 6-H); 13C NMR (100 MHz, CDCl3) δ 0.0 (Si(CH3)3), 16.6 (C-1), 21.6 (5-CH3), 46.4 (C-4), 55.5 (CH2OCH3), 72.4 (C-3), 76.7 (C-2), 95.7 (CH2OCH3), 127.1 (C-6), 151.7 (C-5); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C12H26O3SiNa 269.1543, found 269.1542. tert-Butyl(2-((2S,6S)-6-((S)-1-(methoxymethoxy)ethyl)-4-methyl5,6-dihydro-2H-pyran-2-yl)ethoxy)diphenylsilane (25). To a solution of 3-(tert-butyldiphenylsilyloxy)propanal26 (24) (2.23 g, 7.14 mmol, 2.0 equiv) in Et2O (30 mL) were added TMSOTf (0.97 mL, 5.36 mmol, 1.5 equiv) and vinylsilane 23 (0.88 g, 3.57 mmol) in Et2O (36 mL) at −78 °C. The reaction mixture was stirred for 16 h at −78 °C and then quenched by the addition of H2O. The aqueous phase was extracted with Et2O (3 × 30 mL). The combined organic extracts were washed with H2O and a saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (petroleum ether/Et2O, 15:1) afforded dihydropyran 25 (1.23 g, 2.62 mmol, 73%) as a sticky, colorless oil: Rf = 0.48 1 (petroleum ether/Et2O, 4:1); [α]21 D = −31.8 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.04 (s, 9H, C(CH3)3), 1.14 (d, J = 6.6 Hz, 3H, 2″-H), 1.67 (bs, 3H, 4′-CH3), 1.67−1.72 (m, 1H, 5′-Ha), 1.76 (q, J = 6.4 Hz, 2H, 2-H), 1.96−2.03 (m, 1H, 5′-Hb), 3.34 (s, 3H, CH2OCH3), 3.48−3.53 (m, 1H, 6′-H), 3.66−3.72 (m, 1H, 1″-H), 3.74−3.87 (m, 2H, 1-H), 4.23 (bs, 1H, 2′-H), 4.64 (d, J = 6.6 Hz, 1H, CH2OCH3), 4.69 (d, J = 6.8 Hz, 1H, CH2OCH3), 5.32 (d, J = 1.0 Hz, 1H, 3′-H), 7.34−7.43 (m, 6H, Ar−H), 7.64−7.67 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 16.0 (C-2″), 19.2 (C(CH3)3), 23.1 (4′-CH3), 26.8 (C(CH3)3), 31.4 (C-5′), 38.7 (C-2), 55.3 (CH2OCH3), 60.7 (C-

1), 72.0 (C-2′), 74.7 (C-1″), 77.2 (C-6′), 95.8 (CH2OCH3), 124.2 (C3′), 127.6 (CAr), 129.5 (CAr), 131.7 (C-4′), 134.0 (CAr), 134.0 (CAr), 135.5 (CAr); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H40O4SiNa 491.2588, found 491.2589. 2-((2S,6S)-6-((S)-1-(Methoxymethoxy)ethyl)-4-methyl-5,6-dihydro-2H-pyran-2-yl)ethan-1-ol (26). To a solution of silyl ether 25 (609 mg, 1.30 mmol, 1.0 equiv) in THF (4 mL) was added a 4 Å molecular sieve (600 mg), and then the mixture was cooled to 0 °C followed by the dropwise addition of a TBAF solution (1 M in THF, 1.95 mL, 1.95 mmol, 1.5 equiv). The resulting mixture was allowed to stir at room temperature for 1 h before it was filtered to remove the molecular sieve. After washing with Et2O, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/EtOAc, 1:1) to give alcohol 26 (280 mg, 1.22 mmol, 94%) as a sticky, colorless oil: Rf = 0.26 (petroleum ether/ 1 EtOAc, 1:1); [α]20 D = −63.2 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 1.15 (d, J = 6.5 Hz, 3H, 2″-H), 1.62−1.74 (m, 2H, 5′-Ha, 2Ha), 1.69 (d, J = 0.9 Hz, 3H, 4′-CH3), 1.78−1.86 (m, 1H, 2-Hb), 2.00−2.08 (m, 1H, 5′-Hb), 2.98 (bs, 1H, OH), 3.36 (s, 3H, CH2OCH3), 3.48−3.54 (m, 1H, 6′-H), 3.64−3.80 (m, 3H, 1″-H, 1H), 4.31 (bs, 1H, 2′-H), 4.66 (d, J = 6.9 Hz, 1H, CH2OCH3), 4.71 (d, J = 6.9 Hz, 1H, CH2OCH3), 5.26−5.26 (m, 1H, 3′-H); 13C NMR (100 MHz, CDCl3) δ 16.0 (C-2″), 23.0 (4′-CH3), 31.3 (C-5′), 37.2 (C-2), 55.4 (CH2OCH3), 60.7 (C-1), 75.1 (C-2′), 75.1 (C-1″), 77.3 (C-6′), 95.7 (CH2OCH3), 123.3 (C-3′), 132.6 (C-4′); HRMS (ESI-TOF) m/ z [M + Na]+ calcd for C12H22O4Na 253.1410, found 253.1415. 2-((2S,6S)-6-((S)-1-(Methoxymethoxy)ethyl)-4-methyl-5,6-dihydro-2H-pyran-2-yl)acetaldehyde (27). A solution of alcohol 26 (1.60 g, 6.95 mmol) in CH2Cl2 (40 mL) was cooled to 0 °C before NaHCO3 (2.93 g, 34.83 mmol, 5.0 equiv) and DMP (7.39 g, 17.41 mmol, 2.5 equiv) were added successively. The resulting solution was allowed to stir at room temperature for 5 h. The reaction was then quenched by the addition of a mixture of H2O, a 10% Na2S2O3 solution, and a saturated NaHCO3 solution (1:1:1; 45 mL). The resulting mixture was stirred at rt until the phase separation was completed (5 h). The aqueous layer was separated and extracted with Et2O (3 × 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified using flash chromatography (petroleum ether/Et2O, 2:1) to furnish aldehyde 27 (1.19 g, 5.21 mmol, 75%) as a sticky, pale yellow oil: Rf = 0.4 1 (petroleum ether/Et2O, 2:1); [α]22 D = −56.3 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.14 (d, J = 6.3 Hz, 3H, 2″-H), 1.67−1.76 (m, 4H, 5′-Ha, 4′-CH3), 1.99−2.05 (m, 1H, 5′-Hb), 2.46−2.57 (m, 2H, 2H), 3.35 (s, 3H, CH2OCH3), 3.52−3.57 (m, 1H, 6′-H), 3.66−3.73 (m, 1H, 1″-H), 4.57 (bs, 1H, 2′-H), 4.68 (s, 2H, CH2OCH3), 5.31 (s, 1H, 3′-H), 9.76 (t, J = 2.3 Hz, 1H, 1-H); 13C NMR (100 MHz, CDCl3) δ 15.9 (C-2″), 23.0 (4′-CH3), 31.1 (C-5′), 48.8 (C-2), 55.3 (CH 2 OCH 3 ), 70.7 (C-2′), 74.5 (C-1″), 77.4 (C-6′), 95.7 (CH2OCH3), 122.0 (C-3′), 133.6 (C-4′), 201.8 (C-1); HRMS (ESITOF) m/z [M + Na + MeOH]+ calcd for C12H20O4Na·CH3OH 283.1516, found 283.1516. (2S,6S)-2-((S)-1-(Methoxymethoxy)ethyl)-4-methyl-6-(prop-2-yn1-yl)-3,6-dihydro-2H-pyran (29). Dimethyl (1-diazo-2-oxopropyl)phosphonate27 (28) (3.00 g, 15.61 mmol, 3.0 equiv) was dissolved in MeOH (90 mL). The resulting mixture was cooled to 0 °C before a solution of aldehyde 27 (1.19 g, 5.21 mmol) in MeOH (8 mL) and K2CO3 (2.16 g, 15.61 mmol, 3.0 equiv) were added sequentially. The reaction mixture was stirred for 1 h at 0 °C and was then allowed to warm to rt, and the stirring continued for 12 h. The reaction was quenched by the addition of a saturated NH4Cl solution (120 mL). The aqueous phase was separated and extracted with Et2O (5 × 150 mL). The combined organic phases were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (petroleum ether/ Et2O, 9:1) afforded terminal alkyne 29 (0.94 g, 4.19 mmol, 80%) as a sticky, colorless oil: Rf = 0.64 (petroleum ether/Et2O, 2:1); [α]20 D = −28.5 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.16 (d, J = 6.3 Hz, 3H, 2″-H), 1.71 (d, J = 1.3 Hz, 3H, 4-CH3), 1.71−1.77 (m, 1H, 3Ha), 1.97 (t, J = 2.8 Hz, 1H, 3′-H), 1.97−2.06 (m, 1H, 3-Hb), 2.26 4559


Article

The Journal of Organic Chemistry (ddd, J = 16.4, 8.1, 2.8 Hz, 1H, 1′-Ha), 2.48 (ddd, J = 16.4, 5.9, 2.7 Hz, 1H, 1′-Hb), 3.38 (s, 3H, CH2OCH3), 3.50−3.55 (m, 1H, 2-H), 3.68− 3.75 (m, 1H, 1″-H), 4.17−4.20 (m, 1H, 6-H), 4.71 (d, J = 6.8 Hz, 1H, CH2OCH3), 4.75 (d, J = 6.8 Hz, 1H, CH2OCH3), 5.52 (dd, J = 2.5, 1.3 Hz, 1H, 5-H); 13C NMR (100 MHz, CDCl3) δ 16.0 (C-2″), 23.0 (4CH3), 25.6 (C-1′), 31.3 (C-3), 55.4 (CH2OCH3), 69.7 (C-3′), 73.4 (C-6), 74.6 (C-1″), 77.5 (C-2), 81.0 (C-2′), 95.8 (CH2OCH3), 122.2 (C-5), 133.1 (C-4); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C13H20O3Na 247.1305, found 247.1304. (S)-1-((2S,6S)-4-Methyl-6-(prop-2-yn-1-yl)-3,6-dihydro-2H-pyran2-yl)ethan-1-ol (30). H2O (33 mL) and 6 M HCl (33 mL) were added successively to a solution of MOM ether 29 (920 mg, 4.10 mmol) in THF (66 mL, HPLC grade). The reaction mixture was allowed to stir at room temperature overnight before quenching with a saturated NaHCO3 solution (175 mL). The aqueous layer was extracted with Et2O (4 × 200 mL). The combined organic layers were then washed with H2O and a saturated NaCl solution, dried over MgSO4, filtrated, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/Et2O, 2:1) to furnish alcohol 30 (681 mg, 3.78 mmol, 92%) as a sticky, colorless oil: Rf = 0.46 (petroleum ether/Et2O, 1:1); [α]20 D = −4.4 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.15 (d, J = 6.3 Hz, 3H, 2-H), 1.72 (bs, 3H, 4′-CH3), 1.77 (td, J = 16.7, 3.0 Hz, 1H, 3′-Ha), 1.88−1.95 (m, 1H, 3′-Hb), 1.99 (t, J = 2.8 Hz, 1H, 3′′-H), 2.30 (ddd, J = 16.4, 7.6, 2.8 Hz, 1H, 1″-Ha), 2.48 (ddd, J = 16.4, 6.3, 2.8 Hz, 1H, 1″-Hb), 2.84 (d, J = 1.8 Hz, 1H, OH), 3.31 (ddd, J = 10.9, 7.5, 3.5 Hz, 1H, 2′-H), 3.60−3.68 (m, 1H, 1-H), 4.17−4.23 (m, 1H, 6′-H), 5.50− 5.51 (m, 1H, 5′-H); 13C NMR (100 MHz, CDCl3) δ 17.8 (C-2), 22.9 (4′-CH3), 25.6 (C-1″), 31.7 (C-3′), 70.0 (C-1), 70.3 (C-3′′), 73.1 (C6′), 78.9 (C-2′), 80.6 (C-2″), 122.2 (C-5′), 133.0 (C-4′); HRMS (ESITOF) m/z [M + Na]+ calcd for C11H16O2Na 203.1043, found 203.1042. (2S,6S)-2-((S)-1-Iodoethyl)-4-methyl-6-(prop-2-yn-1-yl)-3,6-dihydro-2H-pyran (32). To a solution of I2 (1.76 g, 6.94 mmol, 2.5 equiv) in toluene (300 mL) was added PPh3 (2.18 g, 8.32 mmol, 3.0 equiv) at room temperature. After stirring the resulting solution for 5 min, imidazole (1.13 g, 16.64 mmol, 6.0 equiv) was added and stirring went on for another 5 min before alcohol 30 (0.50 g, 2.77 mmol), dissolved in toluene (100 mL), was added dropwise. The reaction mixture was stirred at 75 °C for 5 h. After cooling to room temperature, the reaction mixture was quenched by the addition of a saturated NaHCO3 solution (100 mL) and 10% Na2S2O3 solution (100 mL). The aqueous layer was separated and extracted with petroleum ether (3 × 150 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The residual oil was extracted with petroleum ether several times to remove most of the Ph3PO. Purification of the residue by flash chromatography (petroleum ether/CH2Cl2, 10:1 to 3:1) furnished iodide 32 (496 mg, 1.71 mmol, 62%) as a sticky, pale yellow oil: Rf = 0.83 (petroleum ether/Et2O, 4:1); [α]22 D = −11.3 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.72 (d, J = 1.1 Hz, 3H, 4-CH3), 1.93 (d, J = 7.0 Hz, 3H, 2″-H), 1.97−2.02 (m, 1H, 3-Ha), 1.99 (t, J = 2.78 Hz, 1H, 3′-H), 2.14 (td, J = 16.8, 2.9 Hz, 1H, 3-Hb), 2.28 (ddd, J = 16.4, 8.1, 2.7 Hz, 1H, 1′-Ha), 2.50 (ddd, J = 16.4, 5.8, 2.8 Hz, 1H, 1′-Hb), 3.29 (ddd, J = 10.2, 6.5, 3.4 Hz, 1H, 2-H), 4.12−4.18 (m, 1H, 1″-H), 4.20−4.24 (m, 1H, 6-H), 5.49−5.50 (m, 1H, 5-H); 13C NMR (100 MHz, CDCl3) δ 22.9 (4-CH3), 24.2 (C-2″), 25.6 (C-1′), 30.9 (C-1″), 35.0 (C-3), 69.9 (C-3′), 73.8 (C-6), 78.0 (C-2), 80.7 (C2′), 121.9 (C-5), 133.2 (C-4); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C11H15IONa 313.0060, found 313.0058. (S,5Z,8Z)-6-Methyldeca-5,8-dien-1-yn-4-ol (33). t-BuLi (1.7 M in n-pentane, 2.2 mL, 3.74 mmol, 3.0 equiv) was added dropwise to a solution of iodide 32 (0.36 g, 1.24 mmol) in Et2O (13 mL) at −95 °C. The resulting bright yellow solution was stirred for 1 h at −95 °C before a saturated NH4Cl solution (20 mL) was added to quench the reaction. The mixture was allowed to warm to room temperature, and the aqueous phase was separated and extracted with Et2O (4 × 30 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The residual oil was purified by flash chromatography (petroleum ether/

Et2O, 3:1) to afford alcohol 33 (0.15 g, 0.91 mmol, 74%) as a colorless oil: Rf = 0.26 (petroleum ether/Et2O, 3:1); [α]20 D = −8.1 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.64−1.66 (m, 3H, 10-H), 1.55 (d, J = 1.5 Hz, 3H, 6-CH3), 1.89 (bs, 1H, OH), 2.04 (t, J = 2.6 Hz, 1H, 1-H), 2.35−2.46 (m, 2H, 3-H), 2.74−2.89 (m, 2H, 7-H), 4.53−4.58 (m, 1H, 4-H), 5.26−5.31 (m, 2H, 5-H, 8-H), 5.47−5.56 (m, 1H, 9-H); 13C NMR (100 MHz, CDCl3) δ 12.8 (C-10), 23.5 (6CH3), 27.8 (C-3), 30.2 (C-7), 66.5 (C-4), 70.5 (C-1), 80.8 (C-2), 125.2 (C-9), 126.3 (C-5), 127.5 (C-8), 139.8 (C-6); HRMS (ESITOF) m/z [M + Na]+ calcd for C11H16ONa 187.1093, found 187.1096. tert-Butyl(((S,5Z,8Z)-6-methyldeca-5,8-dien-1-yn-4-yl)oxy)diphenylsilane (34). To a solution of alcohol 33 (0.14 g, 0.85 mmol) in THF (0.5 mL) were added AgNO3 (0.17 g, 0.99 mmol, 1.2 equiv) and pyridine (0.33 mL, 4.11 mmol, 5.0 equiv). The resulting solution was allowed to stir under exclusion of light at room temperature for 10 min before TBDPSCl (0.28 mL, 1.07 mmol, 1.3 equiv) was added. After stirring at room temperature in the dark for 3.5 h, the reaction mixture was filtered through a pad of Celite and washed with Et2O. The filtrate was concentrated under reduced pressure, and the residue purified by flash chromatography (petroleum ether/Et2O, 100:1) to afford silyl ether 34 (0.31 g, 0.77 mmol, 90%) as a colorless oil: Rf = 1 0.42 (petroleum ether/Et2O, 100:1); [α]20 D = +4.0 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.07 (s, 9H, SiC(CH3)3), 1.44−1.46 (m, 3H, 10-H), 1.55 (d, J = 1.5 Hz, 3H, 6-CH3), 1.92 (t, J = 2.7 Hz, 1H, 1H), 2.21 (dd, J = 14.7, 7.3 Hz, 1H, 7-Ha), 2.32−2.45 (m, 3H, 3-H, 7Hb), 4.54−4.60 (m, 1H, 4-H), 4.96−5.04 (m, 1H, 8-H), 5.27 (dd, J = 9.0, 1.1 Hz, 1H, 5-H), 5.31−5.39 (m, 1H, 9-H), 7.33−7.45 (m, 6H, Ar−H), 7.67−7.73 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 12.6 (C-10), 19.3 (SiC(CH3)3), 23.1 (6-CH3), 26.9 (SiC(CH3)3), 28.6 (C-3), 29.9 (C-7), 68.5 (C-4), 69.7 (C-1), 81.4 (C-2), 124.5 (C-9), 127.3 (CAr), 127.5 (CAr), 127.6 (C-5), 127.7 (C-8), 129.4 (CAr), 129.6 (CAr), 134.1 (CAr), 134.1 (CAr), 135.9 (CAr), 136.0 (CAr), 136.3 (C-6); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H34OSiNa 425.2271, found 425.2273. tert-Butyl(((S,1E,5Z,8Z)-6-methyl-1-(tributylstannyl)deca-1,5,8trien-4-yl)oxy)diphenylsilane (35). Diisopropylethylamine (0.9 μL, 5.08 μmol, 0.04 equiv) was added dropwise to a solution of Pd2(dba)3 (0.6 mg, 0.64 μmol, 0.005 equiv) and Cy3PHBF4 (0.9 mg, 2.54 μmol, 0.02 equiv) in CH2Cl2 (1 mL). The reaction mixture was stirred at room temperature for 10 min, resulting in a color change from bright red to yellow. Now, a solution of alkyne 34 (51 mg, 0.127 mmol) in CH2Cl2 (0.5 mL) was added to the mixture, followed by dropwise addition of Bu3SnH (40 μL, 0.152 mmol, 1.20 equiv) at 0 °C. After stirring at 0 °C for 2.5 h, the reaction mixture was allowed to warm to room temperature before being concentrated in vacuo. The residual colorless oil (91 mg, quant) was used without further purification: Rf = 0.49 (petroleum ether/toluene, 50:1); 1H NMR (400 MHz, CDCl3) δ 0.80−0.90 (m, 15H, SnBu3 CH3, SnBu3 CH2), 1.03 (s, 9H, SiC(CH3)3), 1.24−1.33 (m, 6H, SnBu3 CH2), 1.40−1.51 (m, 12H, SnBu3 CH2, 6-CH3, 10-H), 2.13 (dd, J = 14.7, 7.3 Hz, 1H, 7-Ha), 2.27−2.40 (m, 3H, 3-H, 7-Hb), 4.42−4.47 (m, 1H, 4-H), 4.90−4.97 (m, 1H, 8-H), 5.17 (d, J = 8.0 Hz, 1H, 5-H), 5.27−5.34 (m, 1H, 9-H), 5.79 (dd, J = 40.2, 19.0 Hz, 1H, 1-H), 5.90−6.01 (m, 1H, 2-H), 7.30− 7.41 (m, 6H, CAr), 7.64−7.68 (m, 4H, CAr); 13C NMR (100 MHz, CDCl3) δ 9.3 (SnBu3 CH2), 12.6 (C-10), 13.7 (SnBu3 CH3), 19.3 (C(CH3)3), 23.1 (6-CH3), 27.0 (C(CH3)3), 27.3 (SnBu3 CH2), 29.1 (SnBu3 CH2), 29.8 (C-7), 47.3 (C-3), 70.1 (C-4), 124.2 (C-9), 127.2 (CAr), 127.4 (CAr), 127.9 (C-8), 128.8 (C-5), 129.3 (CAr), 129.4 (CAr), 130.3 (C-1), 134.5 (CAr), 134.6 (C-6), 135.9 (CAr), 136.0 (CAr), 145.4 (C-2); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C39H62OSiSnNa 717.3484, found 717.3495. (3S,4E,7S,8E,10S,12E,14E,17S,18Z,21Z)-17-((tertButyldiphenylsilyl)oxy)-7-methoxy-3-((2-methoxyethoxy)methoxy)8,10,19-trimethyltricosa-4,8,12,14,18,21-hexaen-1-yl Pivalate (36). Vinyl iodide 20 (44 mg, 78 μmol) and vinyl stannane 35 (55 mg, 79 μmol, 1.01 equiv) were dissolved in degassed DMF (2 mL) under an argon atmosphere. Then PPh3 (8 mg, 30 μmol, 0.4 equiv), [Ph2PO2−][NBu4+] (37 mg, 79 μmol, 1.01 equiv), CuTC (25 mg, 133 μmol, 1.7 equiv), and Pd(PPh3)4 (9 mg, 8 μmol, 0.1 equiv) were 4560


Article

The Journal of Organic Chemistry added successively at 0 °C. After being stirred at room temperature for 3 h, the reaction mixture was treated with a saturated NaHCO3 solution (3 mL). The aqueous phase was separated and extracted with EtOAc (3 × 4 mL). The combined organic extracts were washed with a saturated NaCl solution (5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/EtOAc, 8:1) to furnish the polyene 36 (48 mg, 57 μmol, 73% over 2 steps) as a pale yellow oil: Rf = 0.50 (petroleum ether/EtOAc, 4:1); [α]21 D = −9.7 (c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.7 Hz, 3H, 10-CH3), 1.02 (s, 9H, C(CH3)3), 1.18 (s, 9H, C(CH3)3), 1.40 (dd, J = 6.7, 0.9 Hz, 3H, 23-H), 1.50−1.51 (m, 6H, 8-CH3, 19-CH3), 1.75−1.83 (m, 1H, 2Ha), 1.85−2.05 (m, 3H, 2-Hb, 11-H), 2.08−2.37 (m, 6H, 6-H, 16-H, 20-H), 2.41−2.52 (m, 1H, 10-H), 3.13 (s, 3H, 7-OCH3), 3.37 (s, 3H, MEM OCH3), 3.38−3.41 (m, 1H, 7-H), 3.51−3.53 (m, 2H, MEM CH2), 3.56−3.61 (m, 1H, MEM CH2), 3.73−3.78 (m, 1H, MEM CH2), 4.07−4.17 (m, 3H, 1-H, 3-H), 4.36−4.41 (m, 1H, 17-H), 4.59 (d, J = 6.9 Hz, 1H, MEM CH2), 4.76 (d, J = 7.0 Hz, 1H, MEM CH2), 4.90−4.97 (m, 1H, 21-H), 5.15−5.17 (m, 2H, 9-H, 18-H), 5.26−5.34 (m, 2H, 4-H, 22-H), 5.39−5.48 (m, 2H, 12-H, 15-H), 5.57−5.64 (m, 1H, 5-H), 5.82−5.95 (m, 2H, 13-H, 14-H), 7.29−7.41 (m, 6H, Ar− H), 7.61−7.69 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 11.0 (8-CH3), 12.6 (C-23), 19.3 (C(CH3)3), 20.4 (10-CH3), 23.1 (19CH3), 27.0 (C(CH3)3), 27.2 (C(CH3)3), 29.8 (C-20), 32.6 (C-10), 34.7 (C-2), 37.0 (C-6), 38.7 (C(CH3)3), 40.3 (C-11), 42.0 (C-16), 55.7 (7-OCH3), 59.0 (MEM OCH3), 61.0 (C-1), 67.0 (MEM CH2), 70.2 (C-17), 71.8 (MEM CH2), 73.5 (C-3), 86.8 (C-7), 92.3 (MEM CH2), 124.3 (C-22), 127.2 (CAr), 127.4 (CAr), 127.8 (C-21), 128.4 (C15), 128.7 (C-18), 129.3 (CAr), 129.4 (CAr), 130.4 (C-12), 130.9 (C4), 131.6 (C-5), 131.8 (C-14), 132.3 (C-8), 132.4 (C-13), 134.5 (CAr), 134.5 (CAr), 134.8 (C-19), 135.0 (C-9), 136.0 (CAr), 136.0 (CAr), 178.4 (CO); HRMS (ESI-TOF) [M + Na] + calcd for C52H78O7SiNa 865.5409, found 865.5416. (3S,4E,7S,8E,10S,12E,14E,17S,18Z,21Z)-17-((tertButyldiphenylsilyl)oxy)-7-methoxy-3-((2-methoxyethoxy)methoxy)8,10,19-trimethyltricosa-4,8,12,14,18,21-hexaen-1-ol (37). To a solution of pivaloate 36 (42 mg, 50 μmol) in CH2Cl2 (0.5 mL) was added DIBAL-H (1 M in n-hexane, 125 μL, 125 μmol, 2.5 equiv) dropwise at −90 °C. The reaction mixture was stirred for 2 h at −90 °C, before being quenched with MeOH (0.6 mL). The resulting mixture was allowed to warm to 0 °C, then poured into a Rochelle salt solution (1 M, 1.5 mL), and diluted with Et2O. The mixture was stirred rigorously at room temperature until the phase separation was completed (30 min). The aqueous layer was extracted with Et2O (4 × 3 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The residual oil was purified by flash chromatography (petroleum ether/EtOAc, 1:1) to afford primary alcohol 37 (29 mg, 38 μmol, 77%) as a colorless oil: Rf = 0.3 (petroleum ether/EtOAc, 1:1); 1H NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.7 Hz, 3H, 10-CH3), 1.02 (s, 9H, SiC(CH3)3), 1.39−1.41 (m, 3H, 23-H), 1.46−1.51 (m, 6H, 8CH3, 19-CH3), 1.72−1.77 (m, 2H, 2-H), 1.93−2.05 (m, 2H, 11-H), 2.08−2.20 (m, 3H, 6-Ha, 16-Ha, 20-Ha), 2.22−2.26 (m, 1H, 16-Hb), 2.28−2.37 (m, 2 H, 6-Hb, 20-Hb), 2.41−2.52 (m, 1H, 10-H), 2.85 (t, J = 6.0 Hz, 1H, OH), 3.13 (s, 3H, 7-OCH3), 3.38 (s, 3H, MEM OCH3), 3.39−3.43 (m, 1H, 7-H), 3.53−3.59 (m, 3H, MEM CH2), 3.62−3.69 (m, 1H, 1-Ha), 3.75−3.81 (m, 1H, 1-Hb), 3.83−3.88 (m, 1H, MEM CH2), 4.23−4.29 (m, 1H, 3-H), 4.35−4.41 (m, 1H, 17-H), 4.58 (d, J = 6.9 Hz, 1H, MEM CH2), 4.76 (d, J = 6.9 Hz, 1H, MEM-CH2), 4.90− 4.98 (m, 1H, 21-H), 5.14−5.17 (m, 2H, 9-H, 18-H), 5.26−5.38 (m, 2H, 4-H, 22-H), 5.41−5.48 (m, 2H, 12-H, 15-H), 5.58−5.65 (m, 1H, 5-H), 5.83−5.95 (m, 2H, 13-H, 14-H), 7.29−7.41 (m, 6H, Ar−H), 7.62−7.67 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 11.0 (8CH3), 12.6 (C-23), 19.3 (SiC(CH3)3), 20.5 (10-CH3), 23.1 (19-CH3), 27.0 (SiC(CH3)3), 29.8 (C-20), 32.6 (C-10), 36.9 (C-6), 38.2 (C-2), 40.3 (C-11), 42.0 (C-16), 55.6 (7-OCH3), 59.0 (MEM OCH3), 59.3 (C-1), 67.0 (MEM CH2), 70.2 (C-17), 71.8 (MEM CH2), 74.5 (C-3), 86.7 (C-7), 91.9 (MEM CH2), 124.3 (C-22), 127.2 (CAr), 127.4 (CAr), 127.8 (C-21), 128.4 (C-15), 128.7 (C-18), 129.3 (CAr), 129.4 (CAr), 130.4 (C-12), 130.8 (C-5), 131.2 (C-4), 131.8 (C-14), 132.2 (C-8),

132.4 (C-13), 134.5 (CAr), 134.5 (CAr), 134.8 (C-19), 135.0 (C-9), 136.0 (CAr), 136.0 (CAr). (3S,4E,7S,8E,10S,12E,14E,17S,18Z,21Z)-17-((tertButyldiphenylsilyl)oxy)-7-methoxy-3-((2-methoxyethoxy)methoxy)8,10,19-trimethyltricosa-4,8,12,14,18,21-hexaenoic Acid (38). NaHCO3 (12 mg, 140 μmol, 3.0 equiv) and DMP (30 mg, 70 μmol, 1.5 equiv) were added sequentially to a solution of alcohol 37 (36 mg, 47 μmol) in CH2Cl2 (1 mL) at 0 °C. The resulting mixture was allowed to stir at room temperature for 1 h, before quenching the reaction with a saturated NaHCO3 solution (2 mL) and saturated Na2S2O3 solution (2 mL). The mixture was stirred at room temperature until the phase separation was completed (30 min). The aqueous phase was extracted with CH2Cl2 (3 × 3 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the corresponding aldehyde as a pale yellow oil. To a solution of aldehyde in t-BuOH (1 mL) were added 2-methyl2-butene (100 μL, 940 μmol, 20.0 equiv), NaClO2 (19 mg, 210 μmol, 4.5 equiv), NaH2PO4 (17 mg, 140 μmol, 3.0 equiv), and H2O (0.5 mL) sequentially at room temperature. After stirring for 1 h at room temperature, the reaction mixture was diluted with H2O (4 mL). The aqueous phase was separated and extracted with EtOAc (4 × 5 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residual oil by flash chromatography (petroleum ether/EtOAc, 2:1; 0.1% AcOH) furnished carboxylic acid 38 (28 mg, 36 μmol, 76%) as a colorless oil: Rf = 0.6 (petroleum 1 ether/EtOAc, 1:1); [α]20 D = −8.8 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.7 Hz, 3H, 10-CH3), 1.02 (s, 9H, SiC(CH3)3), 1.39−1.41 (m, 3H, 23-H), 1.51 (bs, 6H, 8-CH3, 19-CH3), 1.95−2.05 (m, 2H, 11-H), 2.08−2.26 (m, 4H, 6-H, 16-H, 20-H), 2.28−2.38 (m, 2H, 6-H, 20-H), 2.41−2.47 (m, 1H, 10-H), 2.52 (dd, J = 15.3, 4.5 Hz, 1H, 2-H), 2.61 (dd, J = 15.4, 8.7 Hz, 1H, 2-H), 3.13 (s, 3H, 7-OCH3), 3.37 (s, 3H, MEM OCH3), 3.39−3.42 (m, 1H, 7-H), 3.50−3.59 (m, 3H, MEM OCH2), 3.75−3.81 (m, 1H, MEM OCH2), 4.36−4.41 (m, 1H, 17-H), 4.45−4.51 (m, 1H, 3-H), 4.61 (d, J = 7.1 Hz, 1H, MEM OCH2O), 4.76 (d, J = 7.0 Hz, 1H, MEM OCH2O), 4.90−4.98 (m, 1H, 21-H), 5.16 (m, 2H, 9-H, 18-H), 5.27−5.33 (m, 1H, 22-H), 5.33−5.37 (m, 1H, 4-H), 5.39−5.47 (m, 2H, 12-H, 15-H), 5.67−5.74 (m, 1H, 5-H), 5.86−5.95 (m, 2H, 13-H, 14-H), 7.30−7.41 (m, 6H, Ar−H), 7.62−7.67 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 11.0 (8-CH3), 12.6 (C-23), 19.3 (SiC(CH3)3), 20.5 (10CH3), 23.1 (19-CH3), 27.0 (SiC(CH3)3), 29.8 (C-6), 32.6 (C-10), 36.9 (C-20), 40.3 (C-11), 40.8 (C-2), 42.0 (C-16), 55.6 (7-OCH3), 59.0 (MEM OCH3), 67.0 (MEM CH2), 70.2 (C-17), 71.8 (MEM CH2), 73.0 (C-3), 86.6 (C-7), 92.4 (MEM OCH2O), 124.3 (C-22), 127.2 (CAr), 127.4 (CAr), 127.8 (C-21), 128.4 (C-15), 128.7 (C-18), 129.3 (C-4), 129.4 (CAr), 129.4 (CAr), 130.4 (C-12), 131.8 (C-14), 132.2 (C-8), 132.4 (C-13), 132.4 (C-5), 134.5 (CAr), 134.8 (C-19), 135.0 (C-9), 136.0 (CAr), 174.5 (C-1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C47H68O7SiNa 795.4627, found 795.4627. (3S,4E,7S,8E,10S,12E,14E,17S,18Z,21Z)-17-Hydroxy-7-methoxy-3((2-metho xyetho xy)met hoxy )-8,10,19-t rimet hylt rico sa 4,8,12,14,18,21-hexaenoic Acid (39). TBAF·3H2O (27 mg, 85 μmol, 2.5 equiv) was heated over 4 Å molecular sieves to 40 °C for 1 h and then dissolved in THF (1.7 mL) at room temperature. The resulting solution was added dropwise at 0 °C to silyl ether 38 (26 mg, 34 μmol) dissolved in THF (1 mL). After stirring at 0 °C for 30 min, the reaction mixture was allowed to warm to room temperature and was stirred for 4 days. The solution was then evaporated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/EtOAc, 1:1, 0.1% AcOH) afforded seco acid 39 (13 mg, 24 μmol, 72%) as a colorless oil: Rf = 0.21 (petroleum ether/ 1 EtOAc, 1:1; 0.1% AcOH); [α]20 D = −42.9 (c 0.7, CHCl3); H NMR (600 MHz, CDCl3) δ 0.96 (d, J = 6.7 Hz, 3H, 10-CH3), 1.50 (d, J = 1.1 Hz, 3H, 8-CH3), 1.64−1.65 (m, 3H, 23-H), 1.70 (d, J = 1.2 Hz, 3H, 19-CH3), 1.97−2.02 (m, 1H, 11-Ha), 2.03−2.08 (m, 1H, 11-Hb), 2.12−2.21 (m, 1H, 6-Ha), 2.26 (t, J = 6.7 Hz, 2H, 16-H), 2.30−2.36 (m, 1H, 6-Hb), 2.45−2.51 (m, 2H, 2-Ha, 10-H), 2.61 (dd, J = 15.2, 8.4 Hz, 1H, 2-Hb), 2.77−2.85 (m, 2H, 20-H), 3.13 (s, 3H, 7-OCH3), 3.38 4561


Article


(3S,4E,7S,8E,10S,12E)-3-((tert-Butyldiphenylsilyl)oxy)-13-iodo-7methoxy-8,10-dimethyltrideca-4,8,12-trien-1-yl pivalate (42). To a solution of alcohol 19 (24 mg, 50 μmol) in CH2Cl2 (0.5 mL) were added imidazole (5 mg, 80 μmol, 1.6 equiv) and TBDPSCl (16 μL, 60 μmol, 1.2 equiv) successively at 0 °C. After being stirred at room temperature for 4 h, the reaction mixture was quenched by the addition of a saturated NH4Cl solution (2 mL). The aqueous layer was separated and extracted with EtOAc (2 × 2 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residual oil by flash chromatography (petroleum ether/Et2O, 10:1) furnished silyl ether 42 (30 mg, 42 μmol, 83%) as a colorless oil: Rf = 0.64 1 (petroleum ether/EtOAc, 5:1); [α]20 D = +4.1 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.6 Hz, 3H, 10-CH3), 1.04 (s, 9H, C(CH3)3), 1.10 (s, 9 H, C(CH3)3), 1.46 (d, J = 1.3 Hz, 3H, 8-CH3), 1.69−1.77 (m, 1H, 2-H), 1.84−2.03 (m, 4H, 2-H, 6-H, 11-H), 2.11− 2.18 (m, 1H, 6-H), 2.40−2.51 (m, 1H, 10-H), 3.09 (s, 3H, 7-OCH3), 3.21 (t, J = 6.9 Hz, 1H, 7-H), 4.03−4.07 (m, 2H, 1-H), 4.24 (q, J = 6.5 Hz, 1H, 3-H), 4.97 (dd, J = 9.4, 0.9 Hz, 1H, 9-H), 5.16−5.24 (m, 1H, 5-H), 5.41−5.47 (m, 1H, 4-H), 5.87−5.90 (m, 1H, 13-H), 6.32−6.40 (m, 1H, 12-H), 7.32−7.42 (m, 6H, Ar−H), 7.63−7.66 (m, 4H, Ar− H); 13C NMR (100 MHz, CDCl3) δ 10.8 (8-CH3), 19.3 (C(CH3)3), 20.5 (10-CH3), 27.0 (C(CH3)3), 27.1 (C(CH3)3), 31.7 (C-10), 36.7 (C-6), 37.0 (C-2), 38.6 (C(CH3)3), 43.4 (C-11), 55.6 (7-OCH3), 61.1 (C-1), 71.8 (C-3), 75.5 (C-13), 86.8 (C-7), 127.4 (CAr), 127.5 (CAr), 127.9 (C-5), 129.4 (CAr), 129.6 (CAr), 133.3 (C-8), 133.8 (C-9), 133.8 (C-4), 134.2 (CAr), 134.3 (CAr), 135.8 (CAr), 136.0 (CAr), 144.9 (C12), 178.4 (CO); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C37H53IO4SiNa 739.26501, found 739.26518. (3S,4E,7S,8E,10S,12E)-3-((tert-Butyldiphenylsilyl)oxy)-13-iodo-7methoxy-8,10-dimethyltrideca-4,8,12-trien-1-ol (43). To a solution of pivalate 42 (45 mg, 63 μmol) in CH2Cl2 (0.6 mL) was added DIBAL-H (1 M in n-hexane, 160 μmol, 160 μL, 2.5 equiv) dropwise at −90 °C. The reaction mixture was stirred for 2 h at −90 °C, before quenching it with MeOH (0.2 mL). The resulting mixture was allowed to warm to 0 °C, poured into a saturated solution of Rochelle salt (3 mL), and diluted with Et2O (2 mL). The mixture was stirred vigorously at room temperature until the phase separation was completed (15 min). The aqueous layer was extracted with Et2O (3 × 3 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residual oil was purified by flash chromatography (petroleum ether/EtOAc, 5:1) to afford primary alcohol 43 (34 mg, 54 μmol, 86%) as a colorless oil: Rf = 0.38 (petroleum ether/ 1 EtOAc, 4:1); [α]20 D = −10.2 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.7 Hz, 3H, 10-CH3), 1.05 (s, 9H, SiC(CH3)3), 1.47 (d, J = 1.2 Hz, 3H, 8-CH3), 1.61−1.78 (m, 2H, 2-H), 1.85−2.06 (m, 3H, 6-Ha, 11-H), 2.12−2.20 (m, 2H, 6-Hb, OH), 2.42−2.50 (m, 1H, 10-H), 3.10 (s, 3H, OCH3), 3.27 (t, J = 6.9 Hz, 1H, 7-H), 3.69 (q, J = 5.6 Hz, 2H, 1-H), 4.38 (q, J = 5.6 Hz, 1H, 3-H), 4.99 (d, J = 10.0 Hz, 1H, 9-H), 5.28−5.35 (m, 1H, 5-H), 5.52 (dd, J = 15.4, 6.6 Hz, 1H, 4-H), 5.89 (d, J = 14.3 Hz, 1H, 13-H), 6.32−6.40 (m, 1H, 12-H), 7.33−7.44 (m, 6H, Ar−H), 7.64−7.69 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 10.9 (8-CH3), 19.3 (SiC(CH3)3), 20.6 (10CH3), 27.0 (SiC(CH3)3), 31.7 (C-10), 36.8 (C-6), 40.0 (C-2), 43.4 (C-11), 55.6 (OCH3), 59.4 (C-1), 73.1 (C-3), 75.5 (C-13), 86.5 (C7), 127.2 (C-5), 127.4 (CAr), 127.6 (CAr), 129.6 (CAr), 129.7 (CAr), 133.3 (C-8), 133.7 (C-9), 133.9 (CAr), 133.9 (CAr), 134.3 (C-4), 135.9 (CAr), 136.0 (CAr), 144.9 (C-12); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C32H45IO3SiNa 655.2075, found 655.2078. (3S,4E,7S,8E,10S,12E)-3-((tert-Butyldiphenylsilyl)oxy)-13-iodo-7methoxy-8,10-dimethyltrideca-4,8,12-trienoic Acid (44). DMP (21 mg, 50 μmol, 1.5 equiv) and NaHCO3 (8 mg, 100 μmol, 3.0 equiv) were sequentially added to a solution of alcohol 43 (21 mg, 33 μmol) in CH2Cl2 (0.3 mL) at 0 °C. The resulting mixture was allowed to stir at room temperature for 2 h, before quenching it with a saturated NaHCO3 solution (1 mL) and saturated Na2S2O3 solution (1 mL). The mixture was stirred at room temperature until the phase separation was completed (10 min). Then the aqueous layer was extracted with CH2Cl2 (3 × 2 mL). The combined organic layers were

(s, 3H, MEM OCH3), 3.41 (t, J = 7.0 Hz, 1H, 7-H), 3.53−3.59 (m, 3H, MEM CH2), 3.78−3.81 (m, 1H, MEM CH2), 4.41−4.49 (m, 2H, 3-H, 17-H), 4.62 (d, J = 7.0 Hz, 1H, MEM CH2), 4.76 (d, J = 7.0 Hz, 1H, MEM CH2), 5.14 (d, J = 9.1 Hz, 1H, 9-H), 5.21 (d, J = 9.2 Hz, 1H, 18-H), 5.26−5.31 (m, 1H, 21-H), 5.36 (dd, J = 15.4, 8.2 Hz, 1H, 4-H), 5.48−5.56 (m, 3H, 12-H, 15-H, 22-H), 5.61−5.68 (m, 1H, 5-H), 5.96−6.01 (m, 1H, 14-H), 6.05−6.09 (m, 1H, 13-H); 13C NMR (150 MHz, CDCl3) δ 10.7 (8-CH3), 12.8 (C-23), 20.8 (10-CH3), 23.5 (19CH3), 30.2 (C-16), 32.5 (C-10), 36.7 (C-6), 40.4 (C-11), 40.9 (C-2), 41.0 (C-16), 55.6 (7-OCH3), 59.0 (MEM OCH3), 67.0 (MEM CH2), 68.1 (C-17), 71.8 (MEM CH2), 73.3 (C-3), 86.8 (C-7), 92.4 (MEM CH2), 125.0 (C-22), 127.3 (C-15), 127.6 (C-18), 127.7 (C-21), 129.6 (C-4), 131.3 (C-14), 131.5 (C-12), 132.1 (C-5), 132.4 (C-8), 133.6 (C-13), 135.3 (C-9), 138.5 (C-19), 173.4 (C-1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H50O7Na 557.3449, found 557.3449. (21Z)-3-OMEM-Biselyngbyolide B (40). PPh3 (20 mg, 75 μmol, 5.0 equiv) and DEAD (2.2 M in toluene, 50 μL, 105 μmol, 7.0 equiv) were dissolved in THF (2.0 mL), before a solution of seco acid 39 (8 mg, 15 μmol) in THF (5 mL) was added at room temperature over a period of 2 h using a syringe pump. The resulting mixture was stirred at room temperature for 22 h and concentrated in vacuo afterward. Purification of the residue by flash chromatography (petroleum ether/ EtOAc, 4:1) afforded macrolactone 40 (1.4 mg, 2.7 μmol, 18%) as a colorless oil: Rf = 0.73 (petroleum ether/EtOAc, 1:1); [α]20 D = −7.0 (c 0.1, CHCl3); 1H NMR (700 MHz, CDCl3) δ 0.99 (d, J = 6.7 Hz, 3H, 10-CH3), 1.51 (d, J = 1.1, 3H, 8-CH3), 1.65−1.66 (m, 3H, 23-H), 1.68 (d, J = 1.3 Hz, 3H, 19-CH3), 1.91−1.96 (m, 1H, 11-Ha), 2.22−2.29 (m, 5H, 2-Ha, 6-H, 11-Hb, 16-Ha), 2.33−2.36 (m, 1H, 16-Hb), 2.47 (dd, J = 14.2, 9.5 Hz, 1H, 2-Hb), 2.58−2.63 (m, 1H, 10-H), 2.76 (dd, J = 14.5, 7.0 Hz, 1H, 20-Ha), 3.04 (dd, J = 14.4, 7.7 Hz, 1H, 20-Hb), 3.13 (s, 3H, 7-OCH3), 3.34 (dd, J = 10.2, 5.1 Hz, 1H, 7-H), 3.39 (s, 3H, MEM OCH3), 3.53−3.61 (m, 3H, MEM CH2), 3.77−3.80 (m, 1H, MEM CH2), 4.27−4.33 (m, 1H, 3-H), 4.60 (d, J = 6.9 Hz, 1H, MEM CH2), 4.67 (d, J = 6.9 Hz, 1H, MEM CH2), 5.03 (dd, J = 9.7, 1.1 Hz, 1H, 9-H), 5.11 (d, J = 9.0 Hz, 1H, 18-H), 5.27−5.31 (m, 1H, 21-H), 5.32−5.37 (m, 2H, 4-H, 5-H), 5.43−5.53 (m, 4H, 12-H, 15-H, 17-H, 22-H), 6.00 (d, J = 7.7 Hz, 1H, 14-H), 6.02−6.03 (m, 1H, 13H); 13C NMR (176 MHz, CDCl3) δ 9.8 (8-CH3), 12.9 (C-23), 22.3 (10-CH3), 23.5 (19-CH3), 30.3 (C-20), 33.0 (C-10), 35.4 (C-6), 38.9 (C-16), 40.5 (C-11), 42.0 (C-2), 55.2 (7-OCH3), 59.0 (MEM OCH3), 67.0 (MEM CH2), 70.2 (C-17), 71.8 (MEM CH2), 75.6 (C-3), 87.6 (C-7), 92.7 (MEM CH2), 123.6 (C-18), 125.1 (C-22), 126.7 (C-15), 127.6 (C-21), 130.6 (C-4), 130.7 (C-14), 130.9 (C-5), 131.6 (C-8), 132.8 (C-12), 134.1 (C-13), 137.0 (C-9), 139.6 (C-19), 170.4 (C-1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H48O6Na 539.3343, found 539.3346. (S,1E,5Z,8Z)-6-Methyl-1-(tributylstannyl)deca-1,5,8-trien-4-ol (41). TBAF solution (1 M in THF, 28 μmol, 28 μL, 1.6 equiv) was added dropwise to a solution of silyl ether 35 (12 mg, 17 μmol) in THF (0.1 mL) at 60 °C. After being stirred for 1 h at 60 °C, the reaction mixture was allowed to cool to room temperature and quenched with a saturated NH4Cl solution (1 mL). The aqueous layer was separated and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ EtOAc, 20:1; 0.1% NEt3) to give alcohol 41 (3.2 mg, 7 μmol, 41%) as a colorless oil: Rf = 0.26 (petroleum ether/EtOAc, 20:1); 1H NMR (400 MHz, CDCl3) δ 0.78−0.95 (m, 15H, SnBu3 CH3, SnBu3 CH2), 1.25−1.34 (m, 6H, SnBu3 CH2), 1.42−1.52 (m, 6H, SnBu3 CH2), 1.64−1.66 (m, 3H, 10-H), 1.70 (d, J = 1.4 Hz, 3H, 6-CH3), 2.32−2.39 (m, 2H, 3-H), 2.83 (d, J = 7.3 Hz, 7-H), 4.41−4.47 (m, 1H, 4-H), 5.20 (dd, J = 8.7, 1.1 Hz, 1H, 5-H), 5.27−5.34 (m, 1H, 8-H), 5.47−5.55 (m, 1H, 9-H), 5.86−5.97 (m, 1H, 2-H), 6.02−6.16 (m, 1H, 1-H); 13C NMR (100 MHz, CDCl3) δ 9.4 (SnBu3 CH2), 12.8 (C-10), 13.7 (SnBu3 CH3), 23.5 (6-CH3), 27.3 (SnBu3 CH2), 29.1 (SnBu3 CH2), 30.2 (C-7), 46.5 (C-3), 67.4 (C-4), 124.9 (C-9), 127.8 (C-8), 127.9 (C-5), 132.6 (C-1), 138.1 (C-6), 144.6 (C-2); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C23H44OSnNa 479.2306, found 479.2313. 4562


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The Journal of Organic Chemistry dried over MgSO4, filtered, and concentrated in vacuo to afford the corresponding aldehyde (Rf = 0.66; petroleum ether/EtOAc, 4:1) as a pale yellow oil. The aldehyde was dissolved in t-BuOH (0.6 mL) containing 2methyl-2-butene (70 μL, 660 μmol, 20.0 equiv), before a freshly prepared solution of NaClO2 (14 mg, 150 μmol, 4.5 equiv) and NaH2PO4 (12 mg, 100 μmol, 3.0 equiv) in H2O (0.3 mL) was added at room temperature. After stirring for 1.5 h at room temperature, the reaction mixture was diluted with H2O. The aqueous mixture was extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residual oil by flash chromatography (petroleum ether/EtOAc, 6:1; 0.1% AcOH) furnished carboxylic acid 44 (21 mg, 32 μmol, 98%) as a colorless oil: Rf = 0.48 (petroleum ether/EtOAc, 4:1); [α]20 D = −0.4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.7 Hz, 3H, 10-CH3), 1.03 (s, 9H, SiC(CH3)3), 1.45 (d, J = 1.2 Hz, 3H, 8-CH3), 1.84−1.93 (m, 1H, 11-Ha), 1.95−2.02 (m, 2H, 6-Ha, 11-Hb), 2.10− 2.17 (m, 1H, 6-Hb), 2.42−2.58 (m, 3H, 2-H, 10-H), 3.08 (s, 3H, 7OCH3), 3.21 (t, J = 6.9 Hz, 1H, 7-H), 4.52−4.58 (m, 1H, 3-H), 4.97 (d, J = 9.5 Hz, 1H, 9-H), 5.26−5.33 (m, 1H, 5-H), 5.51 (dd, J = 15.4, 7.3 Hz, 1H, 4-H), 5.89 (d, J = 14.4 Hz, 1H, 13-H), 6.32−6.39 (m, 1H, 12-H), 7.33−7.44 (m, 6H, Ar−H), 7.64−7.67 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 10.9 (8-CH3), 19.2 (SiC(CH3)3), 20.6 (10-CH3), 26.9 (SiC(CH3)3), 31.7 (C-10), 36.6 (C-6), 43.0 (C-2), 43.4 (C-11), 55.6 (OCH3), 71.2 (C-3), 75.5 (C-13), 86.6 (C-7), 127.5 (CAr), 127.6 (CAr), 129.0 (C-5), 129.7 (CAr), 129.8 (CAr), 132.3 (C-4), 133.2 (C-8), 133.4 (CAr), 133.5 (CAr), 133.8 (C-9), 135.9 (CAr), 136.0 (CAr), 144.9 (C-12), 175.1 (C-1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C32H43IO4SiNa 669.1868, found 669.1862. (R,1E,5Z,8Z)-6-Methyl-1-(tributylstannyl)deca-1,5,8-trien-4-yl (3S,4E,7S,8E,10S,12E)-3-((tert-Butyldiphenylsilyl)oxy)-13-iodo-7-methoxy-8,10-dimethyltrideca-4,8,12-trienoate (45). Carboxylic acid 44 (4 mg, 6 μmol) and alcohol 41 (3 mg, 7 μmol, 1.2 equiv) were dissolved in toluene (0.1 mL). PPh3 (3 mg, 12 μmol, 2.0 equiv) and DEAD (2.2 M in toluene, 8.2 μL, 18 μmol, 3.0 equiv) were added sequentially to the solution at room temperature. The resulting mixture was allowed to stir for 22 h at room temperature, before quenching with H2O and diluting with EtOAc. The aqueous layer was separated and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/EtOAc, 30:1; 0.1% NEt3) afforded ester 45 (3.0 mg, 2.8 μmol, 45%) as a colorless oil: Rf = 0.73 (petroleum ether/EtOAc, 9:1); [α]20 D = +5.0 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.81−0.89 (q, J = 7.6 Hz, 15H, SnBu3 CH3, SnBu3 CH2), 0.93 (d, J = 6.6 Hz, 3H, 10-CH3), 1.00 (s, 9H, SiC(CH3)3), 1.24−1.33 (m, 6H, SnBu3 CH2), 1.42−1.50 (m, 9H, 8-CH3, SnBu3 CH2), 1.62−1.65 (m, 6H, 6′-CH3, 10′-H), 1.84− 1.97 (m, 3H, 6-Ha, 11-H), 2.05−2.12 (m, 1H, 6-Hb), 2.25−2.32 (m, 1H, 3′-Ha), 2.35−2.46 (m, 3H, 2-Ha, 10-H, 3′-Hb), 2.50−2.55 (m, 1H, 2-Hb), 2.72 (dd, J = 15.0, 7.2 Hz, 1H, 7-Ha), 2.95 (dd, J = 13.5, 8.4 Hz, 1H, 7′-Hb), 3.07 (s, 3H, 7-OCH3), 3.15−3.19 (m, 1H, 7-H), 4.54− 4.61 (m, 1H, 3-H), 4.95 (d, J = 8.8 Hz, 1H, 9-H), 5.06 (d, J = 9.3 Hz, 1H, 5′-H), 5.19−5.26 (m, 2H, 5-H, 8′-H), 5.41−5.53 (m, 3H, 4-H, 4′H, 9′-H), 5.72−5.82 (m, 1H, 2′-H), 5.89 (d, J = 14.3 Hz, 1H, 13-H), 5.91−6.06 (m, 1H, 1′-H), 6.32−6.39 (m, 1H, 12-H), 7.32−7.41 (m, 6H, Ar−H), 7.64−7.68 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 9.4 (SnBu3 CH2), 10.9 (8-CH3), 12.9 (C-10′), 13.7 (SnBu3 CH3), 19.3 (SiC(CH3)3), 20.5 (10-CH3), 23.4 (6′-CH3), 26.9 (SiC(CH3)3), 27.3 (SnBu3 CH2), 29.1 (SnBu3 CH2), 30.4 (C-7′), 31.7 (C-10), 36.6 (C-6), 43.4 (C-11), 43.5 (C-3′), 44.0 (C-2), 55.6 (7OCH3), 70.5 (C-4′), 71.5 (C-3), 75.5 (C-13), 86.6 (C-7), 123.8 (C5′), 124.9 (C-9′), 127.3 (CAr), 127.5 (CAr), 127.8 (C-8′), 128.1 (C-5), 129.4 (CAr), 129.6 (CAr), 131.9 (C-1′), 133.2 (C-4), 133.3 (C-8), 133.7 (C-9), 134.3 (CAr), 134.8 (CAr), 135.9 (CAr), 136.0 (CAr), 139.7 (C-6′), 143.4 (C-2′), 144.9 (C-12), 169.9 (C-1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C55H85IO4SiSnNa 1107.4176, found 1107.4186.

(21Z)-3-OTBDPS-Biselyngbyolide B (46). Dry LiCl (2.3 mg, 54.0 μmol, 32.0 equiv) and Pd2(dba)3 (0.6 mg, 0.7 μmol, 0.4 equiv) were added sequentially to a degassed solution of ester 45 (1.8 mg, 1.7 μmol) in DMF (1 mL) at room temperature. After stirring for 2.5 h at room temperature, the reaction was quenched with H2O. The aqueous phase was separated and extracted with Et2O (3 × 3 mL). The combined organic phases were washed with a saturated NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo. The residual oil was purified by flash chromatography (short column, petroleum ether/ EtOAc, 20:1) to furnish macrolactone 46 (1.0 mg, 1.5 μmol, 90%) as a colorless oil: Rf = 0.56 (petroleum ether/EtOAc, 9:1); [α]20 D = −18.0 (c 0.1, CHCl3); 1H NMR (700 MHz, CDCl3) δ 0.98 (d, J = 6.7 Hz, 3H, 10-CH3), 1.02 (s, 9H, SiC(CH3)3), 1.44 (d, J = 1.1 Hz, 3H, 8CH3), 1.62−1.65 (m, 6H, 23-H, 19-CH3), 1.73−1.78 (m, 1H, 11-Ha), 2.04−2.09 (m, 2H, 6-H), 2.11−2.16 (m, 1H, 16-Ha), 2.18−2.22 (m, 1H, 11-Hb), 2.24−2.28 (m, 1H, 16-Hb), 2.31 (dd, J = 14.5, 5.8 Hz, 1H, 2-Ha), 2.53 (dd, J = 14.6, 6.9 Hz, 2H, 2-Hb, 10-H), 2.71 (dd, J = 14.6, 7.1 Hz, 1H, 20-Ha), 3.02 (dd, J = 14.6, 7.6 Hz, 1H, 20-Hb), 3.10 (s, 3H, 7-OCH3), 3.13 (dd, J = 9.7, 4.9 Hz, 1H, 7-H), 4.49−4.52 (m, 1H, 3-H), 4.84 (dd, J = 9.7, 1.0 Hz, 1H, 9-H), 5.02 (d, J = 9.7 Hz, 1H, 18H), 5.06−5.10 (m, 1H, 5-H), 5.26−5.30 (m, 3H, 12-H, 15-H, 21-H), 5.38−5.43 (m, 2H, 17-H, 4-H), 5.48−5.51 (m, 1H, 22-H), 5.73 (dd, J = 15.2, 10.5 Hz, 1H, 13-H), 5.82 (dd, J = 15.1, 10.3 Hz, 1H, 14-H), 7.34−7.38 (m, 6H, Ar−H), 7.66−7.68 (m, 4H, Ar−H); 13C NMR (150 MHz, CDCl3) δ 9.9 (8-CH3), 12.9 (C-23), 19.3 (SiC(CH3)3), 22.1 (10-CH3), 23.5 (19-CH3), 27.0 (SiC(CH3)3), 30.3 (C-20), 32.6 (C-10), 36.0 (C-6), 38.1 (C-16), 40.3 (C-11), 44.7 (C-2), 55.2 (7OCH3), 70.4 (C-17), 72.3 (C-3), 87.4 (C-7), 123.6 (C-18), 125.0 (C22), 126.4 (C-15), 127.4 (CAr), 127.5 (CAr), 127.7 (C-21), 127.8 (C5), 129.5 (CAr), 129.6 (CAr), 130.7 (C-13), 131.8 (C-12), 132.0 (C-8), 133.6 (C-4), 133.8 (C-14), 134.3 (CAr), 134.4 (CAr), 136.0 (CAr), 136.1 (CAr), 136.4 (C-9), 139.0 (C-19), 169.9 (C-1); HRMS (ESITOF) m/z [M + Na]+ calcd for C43H58O4SiNa 689.3997, found 689.3996. (21Z)-Biselyngbyolide B (47). A solution of silyl ether 46 (1.3 mg, 1.9 μmol) in THF (0.2 mL) was cooled to 0 °C, before a TBAF solution (1 M in THF, 15 μL, 15 μmol, 8.0 equiv) and AcOH (1.5 μL) were added dropwise. The resulting mixture was allowed to stir at 50 °C for 11 h. The reaction mixture was concentrated under reduced pressure afterward. Purification of the residue by flash chromatography (petroleum ether/EtOAc, 3:1) afforded 21Z-biselyngbyolide B (47) (0.7 mg, 1.6 μmol, 84%) as a colorless oil: Rf = 0.56 (petroleum ether/ 1 EtOAc, 2:1); [α]20 D = −48.0 (c 0.05, CHCl3); H NMR (600 MHz, C6D6) δ 0.88 (d, J = 6.9 Hz, 3H, 10-CH3), 1.51 (d, J = 1.3, 3H, 8CH3), 1.58−1.59 (m, 3H, 23-H), 1.62 (d, J = 1.3 Hz, 3H, 19-CH3), 1.74−1.80 (m, 1H, 11-Ha), 2.10 (bd, J = 13.2 Hz, 1H, 11-Hb), 2.25− 2.41 (m, 7H, 2-H, 6-H, 10-H, 16-H), 2.81 (dd, J = 14.6, 6.9 Hz, 1H, 20-Ha), 3.08 (s, 3H, 7-OCH3), 3.14 (dd, J = 14.5, 7.5 Hz, 1H, 20-Hb), 3.34 (dd, J = 10.5, 4.8 Hz, 1H, 7-H), 4.48 (t, J = 7.5 Hz, 1H, 3-H), 4.87 (d, J = 9.7, Hz, 1H, 9-H), 5.27 (d, J = 9.7 Hz, 1H, 18-H), 5.32−5.52 (m, 6H, 4-H, 5-H, 12-H, 15-H, 21-H, 22-H), 5.89 (dt, J = 9.5, 3.3 Hz, 1H, 17-H), 5.96 (dd, J = 15.0, 11.6 Hz, 1H, 13-H), 6.05 (dd, J = 14.9, 10.3 Hz, 1H, 14-H); 13C NMR (150 MHz, C6D6) δ 9.9 (8-CH3), 12.9 (C-23), 22.4 (10-CH3), 23.5 (19-CH3), 30.6 (C-20), 33.1 (C-10), 35.5 (C-6), 39.8 (C-16), 40.9 (C-11), 43.7 (C-2), 55.2 (7-OCH3), 70.1 (C17), 71.3 (C-3), 88.0 (C-7), 124.4 (C-18), 125.3 (C-15), 126.9 (C21), buried under benzene residual signal (C-22), 128.9 (C-5), 130.8 (C-13), 132.6 (C-8), 133.3 (C-12), 133.7 (C-4), 134.7 (C-14), 136.4 (C-9), 140.0 (C-19), 171.6 (C-1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H40O4Na 451.2819, found 451.2814. Ethyl (2E,5Z)-7-((tert-Butyldiphenylsilyl)oxy)-5-methylhepta-2,5dienoate (50). Vinylstannane33 (48) (69.0 mg, 115 μmol) was dissolved in CHCl3 (0.5 mL), which had been freshly filtered through basic Al2O3. Ethyl-4-bromocrotonate (49) (22.0 mg, 115 μmol, 1.0 equiv), PPh3 (0.8 mg, 3 μmol, 0.025 equiv), and bis(acetonitril)dichloropalladium(II) (1.5 mg, 5.8 μmol, 0.05 equiv) were added successively to this solution. The reaction mixture was stirred for 20 h at 65 °C, before it was allowed to cool to room temperature, diluted with Et2O (1 mL), and quenched with a saturated NH4Cl solution (1 mL). The aqueous layer was separated and extracted with Et2O (3 × 2 4563


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The Journal of Organic Chemistry mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (petroleum ether/ Et2O, 20:1) furnished coupling product 50 (31 mg, 73 μmol, 64%) as a colorless oil: Rf = 0.46 (petroleum ether/Et2O, 9:1); 1H NMR (400 MHz, CDCl3) δ 1.04 (s, 9H, SiC(CH3)3), 1.26 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.69 (d, J = 1.1 Hz, 3H, 5-CH3), 2.71 (dd, J = 6.6, 0.7 Hz, 2H, 4-H), 4.13−4.18 (m, 4H, 7-H, OCH2CH3), 5.54 (t, J = 6.5 Hz, 1H, 6-H), 5.70 (dt, J = 15.5, 1.6 Hz, 1H, 2-H), 6.77 (dt, J = 15.5, 6.7 Hz, 1H, 3-H), 7.36−7.44 (m, 6H, Ar−H), 7.66−7.68 (m, 4H, Ar−H); 13 C NMR (100 MHz, CDCl3) δ 14.2 (OCH2CH3), 19.1 (SiC(CH3)3), 23.5 (5-CH3), 26.8 (SiC(CH3)3), 34.9 (C-4), 60.2 (C-7), 60.5 (OCH2CH3), 122.0 (C-2), 127.0 (C-6), 127.6 (CAr), 129.6 (CAr), 133.3 (C-5), 133.8 (CAr), 135.6 (CAr), 145.8 (C-3), 166.5 (C-1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H34O3SiNa 445.2156, found 445.2171. (2E,5Z)-7-((tert-Butyldiphenylsilyl)oxy)-5-methylhepta-2,5-dien1-ol (51). DIBAL-H solution (1 M in n-hexane, 60.0 mL, 60.0 mmol, 2.3 equiv) was slowly added to a solution of ester 50 (11.0 g, 26.1 mmol) in CH2Cl2 (150 mL) at −40 °C using a syringe pump. The resulting mixture was stirred for 2 h at −40 °C, before it was quenched by the dropwise addition of MeOH (about 10 mL). The mixture was poured into a Rochelle salt solution (1 M, 250 mL) and vigorously stirred at room temperature until phase separation was completed (2 h). The aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/EtOAc, 4:1) to give allylic alcohol 51 (8.8 g, 23.1 mmol, 89%) as a colorless oil: Rf = 0.36 (petroleum ether/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 1.03 (s, 9H, C(CH3)3), 1.68 (d, J = 1.3 Hz, 3H, 5-CH3), 2.58 (d, J = 5.8 Hz, 2H, 4-H), 4.01 (t, J = 5.3 Hz, 2H, 1-H), 4.19 (dd, J = 6.4, 1.0 Hz, 2H, 7-H), 5.43−5.57 (m, 3H, 2-H, 3-H, 6-H), 7.35−7.44 (m, 6H, Ar−H), 7.66−7.69 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 19.2 (SiC(CH3)3), 23.4 (5-CH3), 26.8 (SiC(CH3)3), 35.0 (C-4), 60.7 (C7), 63.5 (C-1), 125.6 (C-6), 127.6 (CAr), 129.6 (CAr), 129.8, 130.0 (C2 and C-3), 133.9 (CAr), 135.3 (C-5), 135.6 (CAr); HRMS (ESI-TOF) [M + Na]+ calcd for C24H32O2SiNa 403.2064, found 403.2066. tert-Butyl(((2Z,5E)-3-Methyl hepta-2,5-dien-1-yl)oxy)diphenylsilane (52). To a solution of allylic alcohol 51 (730 mg, 1.92 mmol) in CH2Cl2 (20 mL) were added NEt3 (0.53 mL, 3.84 mmol, 2.0 equiv) and p-toluenesulfonic anhydride (940 mg, 2.88 mmol, 1.5 equiv) sequentially at −10 °C. The reaction mixture was allowed to stir at −10 °C for 1 h, before being concentrated under reduced pressure. The resulting tosylate was dissolved in THF (20 mL), and a LiEt3BH solution (1 M in THF, 7.70 mL, 7.70 mmol, 4.0 equiv) was added at 0 °C. After stirring at 0 °C for 1 h, TLC showed an incomplete consumption of the starting material, and therefore an additional LiEt3BH solution (1 M in THF, 3.8 mL, 3.80 mmol, 2.0 equiv) was added. The reaction mixture was allowed to stir at 0 °C for another 1 h, before being quenched with a saturated NaHCO3 solution (15 mL). The mixture was warmed to room temperature and diluted with H2O (15 mL). The aqueous phase was separated and extracted with Et2O (3 × 50 mL). The combined organic layers were washed with a saturated NaCl solution (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (petroleum ether/Et2O, 100:1) afforded the title compound 52 (551 mg, 1.51 mmol, 79%) as a colorless oil: Rf = 0.91 (petroleum ether/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H, SiC(CH3)3), 1.59 (dd, J = 6.2, 1.3 Hz, 3H, 7-H), 1.67 (d, J = 1.2 Hz, 3H, 3-CH3), 2.53 (d, J = 6.4 Hz, 2H, 4-H), 4.20 (d, J = 6.5 Hz, 2H, 1-H), 5.18−5.26 (m, 1H, 5-H), 5.29−5.38 (m, 1H, 6-H), 5.42 (t, J = 6.4 Hz, 1H, 2-H), 7.36−7.44 (m, 6H, Ar−H), 7.68−7.71 (m, 4H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 17.8 (C-7), 19.2 (SiC(CH3)3), 23.3 (3-CH3), 26.8 (SiC(CH3)3), 35.4 (C-4), 60.7 (C1), 124.9 (C-2), 125.9 (C-6), 127.6 (CAr), 128.2 (C-5), 129.5 (CAr), 134.0 (CAr), 135.6 (CAr), 136.3 (C-3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C24H32OSiNa 387.2115, found 387.2120. (2Z,5E)-3-Methylhepta-2,5-dien-1-ol (53). A solution of silyl ether 52 (522 mg, 1.43 mmol) in THF (14 mL) was cooled to 0 °C, before

a TBAF solution (1 M in THF, 2.2 mL, 2.15 mmol, 1.5 equiv) was added dropwise. The resulting solution was allowed to stir at room temperature for 3 h. The reaction mixture was then carefully concentrated under reduced pressure (150 mbar, 40 °C). Purification of the residual oil by flash chromatography (petroleum ether/Et2O, 2:1) furnished alcohol 53 (164 mg, 1.30 mmol, 91%) as a colorless oil: Rf = 0.34 (petroleum ether/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 1.62−1.64 (m, 3H, 7-H), 1.70 (d, J = 1.0 Hz, 3H, 3-CH3), 2.72 (d, J = 6.5 Hz, 2H, 4-H), 4.11 (d, J = 7.1 Hz, 2H, 1-H), 5.30−5.38 (m, 1H, 5-H), 5.40−5.49 (m, 2H, 2-H, 6-H); 13C NMR (100 MHz, CDCl3) δ 17.8 (C-7), 23.5 (3-CH3), 35.2 (C-4), 59.0 (C-1), 124.2 (C2), 126.2 (C-6), 128.3 (C-5), 138.9 (C-3). (2Z,5E)-3-Methylhepta-2,5-dienal (54). To a solution of alcohol 53 (368 mg, 2.92 mmol) in CH2Cl2 (15 mL) was added DMP (1.86 g, 4.40 mmol, 1.5 equiv) at 0 °C. The resulting mixture was allowed to stir at room temperature for 2 h and then quenched by the addition of a 10% Na2S2O3 solution (30 mL) and saturated NaHCO3 solution (30 mL). The resulting mixture was stirred at room temperature until the phases were separated (2 h). The aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure (100 mbar, 40 °C). The residue was purified by flash chromatography (petroleum ether/Et2O, 5:1) to furnish enal 54 (304 mg, 2.45 mmol, 84%) as a pale yellow oil: Rf = 0.65 (petroleum ether/Et2O, 1:1); 1H NMR (400 MHz, CDCl3) δ 1.67 (dd, J = 6.3, 1.3 Hz, 3H, 7-H), 1.93 (d, J = 1.2 Hz, 3H, 3-CH3), 3.21 (d, J = 6.5 Hz, 2H, 4-H), 5.37−5.45 (m, 1H, 5-H), 5.51−5.59 (m, 1H, 6-H), 5.86 (dd, J = 8.2, 0.6 Hz, 1H, 2-H), 9.94 (d, J = 8.1 Hz, 1H, 1-H); 13C NMR (100 MHz, CDCl3) δ 17.8 (C-7), 24.9 (3-CH3), 35.7 (C-4), 126.5 (C-5), 128.2 (C-2), 128.4 (C-6), 162.6 (C-3), 190.8 (C1); HRMS (ESI-TOF) m/z [M + H]+ calcd for C8H13O 147.0780, found 147.0783. (R,5Z,8E)-6-Methyldeca-1,5,8-trien-4-ol (55). A freshly prepared allylmagnesium bromide solution38 (1.44 M in Et2O, 2.1 mL, 2.94 mmol, 1.2 equiv) was added dropwise to a solution of (+)-Ipc2BOMe (930 mg, 2.94 mmol, 1.2 equiv) in Et2O (10 mL) at −80 °C. After stirring for 15 min at −80 °C, the reaction mixture was allowed to warm to room temperature and stirred for an additional 1.5 h. The mixture was then cooled to −90 °C before aldehyde 54 (304 mg, 2.45 mmol), dissolved in Et2O (5 mL), was added dropwise. The reaction mixture was stirred for 8 h at −90 °C, before quenching with a 30% H2O2 solution (7 mL) and 3 M NaOH solution (15 mL). The resulting mixture was allowed to stir at room temperature overnight. Afterward the aqueous layer was separated and extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. Purification of the residue by flash chromatography (petroleum ether/Et2O, 4:1) afforded alcohol 55 (256 mg, 1.54 mmol, 63%, ee = 92%) as a colorless oil. The absolute configuration at C-4 and the enantiomeric excess were determined by Mosher ester analysis. 55: Rf = 0.33 (petroleum ether/EtOAc, 5:1); 1 [α]19 D = +0.1 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 1.64 (dd, J = 6.2, 1.3 Hz, 3H, 10-H), 1.7 (d, J = 1.4 Hz, 3H, 6-CH3), 2.25 (d, J = 7.0 Hz, 1H, 3-H), 2.27−2.28 (m, 1H, 3-H), 2.69−2.80 (m, 2H, 7-H), 4.38−4.44 (m, 1H, 4-H), 5.08−5.15 (m, 2H, 1-H), 5.22 (dd, J = 8.4, 0.9 Hz, 1H, 5-H), 5.32−5.39 (m, 1H, 8-H), 5.42−5.5 (m, 1H, 9-H), 5.75−5.85 (m, 1H, 2-H); 13C NMR (100 MHz, CDCl3) δ 17.8 (C10), 23.5 (6-CH3), 35.6 (C-7), 42.2 (C-3), 67.4 (C-4), 117.8 (C-1), 126.4 (C-9), 127.9 (C-5), 128.3 (C-8), 134.6 (C-2), 138.1 (C-6); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C11H18ONa 189.1250, found 189.1253. Mosher Analysis of Alcohol 55. (R,5Z,8E)-6-Methyldeca-1,5,8trien-4-yl (S)-3,3,3-Trifluor-2-methoxy-2-phenylpropanoate ((S)Mosher ester 55). The allylic alcohol 55 (1.8 mg, 11 μmol, 1.0 equiv) was dissolved in CDCl3 (0.2 mL, freshly filtered over silica gel), and pyridine (2.7 μL, 33 μmol, 3.0 equiv) and (R)-(−) MTPA-Cl (8 μL, 41 μmol, 3.7 equiv) were added sequentially at room temperature. The reaction mixture was stirred at room temperature until TLC indicated complete consumption of the starting material (2 h). The mixture was then diluted with additional CDCl3, and the 1H and 19F NMR spectra were recorded for determination of the dr value. The 4564


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117.5 (C-1′), 123.7 (C-5′), 126.4 (C-9′), 127.4 (CAr), 127.5 (CAr), 128.1 (C-8′), 128.1 (C-5), 129.4 (CAr), 129.6 (CAr), 133.2 (C-4), 133.3 (C-8), 133.6 (C-2′), 133.7 (C-9), 134.0 (CAr), 134.2 (CAr), 135.9 (CAr), 136.0 (CAr), 139.5 (C-6′), 144.9 (C-12), 169.9 (C-1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C43H59IO4SiNa 817.3120, found 817.3120. 3-OTBDPS-Biselyngbyolide B (57). Dry Cs2CO3 (4.0 mg, 13.0 μmol, 1.5 equiv), Pd(OAc)2 (3.0 mg, 12.0 μmol, 1.3 equiv), NEt3 (1.4 μL, 10.0 μmol, 1.1 equiv), and Bu4NBr (3.0 mg, 9.0 μmol, 1.0 equiv) were added sequentially to a solution of ester 56 (7.0 mg, 8.8 μmol) in degassed DMF (2 mL) at room temperature. After stirring for 3 h at 40 °C, the reaction solution was allowed to cool to room temperature. The mixture was filtered through a pad of Celite and the filtrate concentrated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/EtOAc, 50:1) afforded macrolactone 57 (4.2 mg, 6.3 μmol, 72%) as a colorless oil: Rf = 0.39 (petroleum ether/EtOAc, 19:1); [α]20 D = −22.0 (c 0.1, CHCl3); 1 H NMR (700 MHz, CDCl3) δ 0.98 (d, J = 6.7 Hz, 3H, 10-CH3), 1.02 (s, 9H, SiC(CH3)3), 1.44 (d, J = 1.1, 3H, 8-CH3), 1.63 (d, J = 1.3 Hz, 3H, 23-H), 1.64 (d, J = 1.1 Hz, 3H, 19-CH3), 1.72−1.77 (m, 1H, 11Ha), 2.03−2.09 (m, 2H, 6-H), 2.13 (dd, J = 14.5, 7.6 Hz, 1H, 16-Ha), 2.18−2.21 (m, 1H, 11-Hb), 2.24−2.27 (m, 1H, 16-Hb), 2.31 (dd, J = 14.6, 5.8 Hz, 1H, 2-Ha), 2.53 (dd, J = 14.6, 6.9 Hz, 2H, 2-Hb, 10-H), 2.64 (dd, J = 14.9, 6.9 Hz, 1H, 20-Ha), 2.92 (dd, J = 15.3, 6.4 Hz, 1H, 20-Hb), 3.10 (s, 3H, 7-OCH3), 3.12−3.16 (m, 1H, 7-H), 4.48−4.50 (m, 1H, 3-H), 4.84 (d, J = 9.9 Hz, 1H, 9-H), 5.02 (d, J = 8.4 Hz, 1H, 18-H), 5.06−5.09 (m, 1H, 5-H), 5.26−5.30 (m, 2H, 12-H, 15-H), 5.33−5.38 (m, 2H, 17-H, 21-H), 5.40−5.45 (m, 2H, 4-H, 22-H), 5.73 (dd, J = 15.1, 10.3 Hz, 1H, 13-H), 5.82 (dd, J = 15.1, 10.3 Hz, 1H, 14H), 7.34−7.37 (m, 6H, Ar−H), 7.66−7.69 (m, 4H, Ar−H); 13C NMR (176 MHz, CDCl3) δ 9.9 (8-CH3), 17.9 (C-23), 19.3 (SiC(CH3)3), 22.1 (10-CH3), 23.4 (19-CH3), 27.0 (SiC(CH3)3), 32.5 (C-10), 35.7 (C-20), 36.0 (C-6), 38.1 (C-16), 40.2 (C-11), 44.6 (C-2), 55.2 (7OCH3), 70.3 (C-17), 72.2 (C-3), 87.3 (C-7), 123.6 (C-18), 126.4 (C15), 126.4 (C-21), 127.4 (CAr), 127.5 (CAr), 127.8 (C-22), 128.1 (C5), 129.4 (CAr), 129.6 (CAr), 130.6 (C-13), 131.8 (C-12), 131.9 (C-8), 133.6 (C-4), 133.8 (C-14), 134.2 (CAr), 134.3 (CAr), 135.9 (CAr), 136.1 (CAr), 136.4 (C-9), 138.6 (C-19), 169.9 (C-1); HRMS (ESITOF) m/z [M + Na]+ calcd for C43H58O4SiNa 689.3997, found 689.4000. Biselyngbyolide B (2). A solution of silyl ether 57 (3.0 mg, 4.5 μmol) in THF (0.3 mL) was cooled to 0 °C, before a TBAF solution (1 M in THF, 32.0 μL, 32.0 μmol, 8.0 equiv) and AcOH (3.0 μL) were added dropwise. The resulting mixture was allowed to stir at room temperature for 12 h and was then heated to 50 °C for an additional 4 h until TLC indicated complete consumption of the starting material. Afterward the reaction mixture was concentrated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/EtOAc, 3:1) afforded biselyngbyolide B (2) (1.6 mg, 3.7 μmol, 83%) as a colorless oil: Rf = 0.33 11 (petroleum ether/EtOAc, 3:1); [α]20 D = −55.2 (c 0.15, CHCl3), lit. 9 27 1 [α]28 D = −51.7 (c 0.48, CHCl3), lit. [α]D = −85.4 (c 0.19, CHCl3); H NMR (700 MHz, CDCl3) δ 0.99 (d, J = 6.7 Hz, 3H, 10-CH3), 1.51 (d, J = 1.3 Hz, 3H, 8-CH3), 1.63 (dd, J = 6.4, 1.4 Hz, 3H, 23-H), 1.69 (d, J = 1.3 Hz, 3H, 19-CH3), 1.91−1.96 (m, 1H, 11-Ha), 2.20−2.23 (m, 1H, 6-Ha), 2.24−2.30 (m, 3H, 6-Hb, 11-Hb, 16-Ha), 2.33−2.38 (m, 3H, 2H, 16-Hb), 2.53 (bs, 1H, 3-OH), 2.56−2.61 (m, 1H, 10-H), 2.71 (dd, J = 14.4, 6.5 Hz, 1H, 20-Ha), 2.91 (dd, J = 14.3, 6.8 Hz, 1H, 20-Hb), 3.14 (s, 3H, 7-OCH3), 3.39 (dd, J = 11.0, 4.7 Hz, 1H, 7-H), 4.27−4.30 (m, 1H, 3-H), 5.04 (dd, J = 9.7, 1.1 Hz, 1H, 9-H), 5.17 (d, J = 9.5 Hz, 1H, 18-H), 5.31−5.36 (m, 2H, 5-H, 21-H), 5.42−5.50 (m, 4H, 4-H, 12-H, 15-H, 22-H), 5.87 (dt, J = 9.3, 3.4 Hz, 1H, 17-H), 5.96 (dd, J = 14.7, 10.8 Hz, 1H, 13-H), 6.05 (dd, J = 14.6, 10.4 Hz, 1H, 14-H); 13C NMR (176 MHz, CDCl3) δ 9.7 (8-CH3), 17.9 (C-23), 22.4 (10-CH3), 23.4 (19-CH3), 33.0 (C-10), 34.7 (C-6), 35.7 (C-20), 39.3 (C-16), 40.6 (C-11), 43.0 (C-2), 55.3 (7-OCH3), 70.1 (C-17), 71.3 (C-3), 87.6 (C-7), 123.3 (C-18), 126.4 (C-15), 126.6 (C-21), 127.8 (C-22), 129.5 (C-5), 130.1 (C-13), 131.6 (C-8), 132.5 (C-12), 133.5 (C-4), 134.3 (C-14), 137.0 (C-9), 140.0 (C-19), 172.0 (C-1); 1H NMR (700 MHz, C6D6) δ 0.87 (d, J = 6.9 Hz, 3H, 10-CH3), 1.51 (d, J = 1.3 Hz,

sample was concentrated afterward, and purification of the residue by flash chromatography (petroleum ether/Et2O, 100:1) furnished the (S)-Mosher ester 55 (1.2 mg, 3 μmol, 29%; dr = 25:1) as a colorless oil: Rf = 0.7 (petroleum ether/EtOAc, 5:1); dr = 25:1 (from 19F NMR); 1H NMR (400 MHz, CDCl3) δ 1.64 (dd, J = 6.3, 1.4 Hz, 3H, 10-H), 1.68 (d, J = 1.5 Hz, 3H, 6-CH3), 2.33−2.40 (m, 1H, 3-Ha), 2.43−2.51 (m, 1H, 3-Hb), 2.73 (dd, J = 14.5, 6.4 Hz, 1H, 7-Ha), 2.96 (ddd, J = 16.8, 14.4, 1.0 Hz, 1H, 7-Hb), 3.53 (d, J = 1.2 Hz, 3H, OCH3), 5.07−5.13 (m, 3H, 1-H, 5-H), 5.28−5.36 (m, 1H, 8-H), 5.42−5.52 (m, 1H, 9-H), 5.67−5.79 (m, 2H, 2-H, 4-H), 7.33−7.40 (m, 3H, Ar−H), 7.48−7.50 (m, 2H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 17.8 (C-10), 23.4 (6-CH3), 35.8 (C-7), 39.2 (C-3), 55.5 (OCH3), 73.4 (C-4), 118.3 (C-1), 122.2 (C-5), 126.8 (C-9), 127.5 (CAr), 127.8 (C-8), 128.2 (CAr), 129.4 (CAr), 132.5 (CAr), 141.3 (C O); 19F NMR (376 MHz, CDCl3) δ −71.59 (s, 3F, CF3). (R,5Z,8E)-6-Methyldeca-1,5,8-trien-4-yl (R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate ((R)-Mosher ester 55). Allylic alcohol 55 (3.3 mg, 20 μmol, 1.0 equiv) and (R)-(+) MTPA−OH (14 mg, 62 μmol, 3.1 equiv) were dissolved in CH2Cl2. DCC (13 mg, 62 μmol, 3.1 equiv) and DMAP (13 mg, 62 μmol, 3.1 equiv) were sequentially added to this solution at room temperature. After stirring for 3.5 h at room temperature, the reaction mixture was filtered through a cotton plug and washed with CH2Cl2. The filtrated was evaporated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/EtOAc, 100:1) furnished (R)-Mosher ester 55 (5.3 mg, 14 μmol, 70%) as a colorless oil: Rf = 0.7 (petroleum ether/ EtOAc, 5:1); 1H NMR (400 MHz, CDCl3) δ 1.62 (dd, J = 6.4, 1.3 Hz, 3H, 10-H), 1.72 (d, J = 1.5 Hz, 3H, 6-CH3), 2.27−2.43 (m, 1H, 3-Ha), 2.36−2.43 (m, 1H, 3-Hb), 2.75 (dd, J = 14.5, 6.4 Hz, 1H, 7-Ha), 2.94 (dd, J = 14.0, 6.2 Hz, 1H, 7-Hb), 3.53 (d, J = 1.2 Hz, 3H, OCH3), 4.99−5.03 (m, 2H, 1-H), 5.22 (d, J = 9.8 Hz, 1H, 5-H), 5.28−5.36 (m, 1H, 8-H), 5.42−5.52 (m, 1H, 9-H), 5.56−5.66 (m, 1H, 2-H), 5.77− 5.83 (m, 1H, 4-H), 7.33−7.40 (m, 3H, Ar−H), 7.48−7.50 (m, 2H, Ar−H); 13C NMR (100 MHz, CDCl3) δ 17.8 (C-10), 23.5 (6-CH3), 35.8 (C-7), 39.2 (C-3), 55.4 (OCH3), 73.1 (C-4), 118.2 (C-1), 122.4 (C-5), 126.8 (C-9), 127.4 (CAr), 127.7 (C-8), 128.2 (CAr), 129.4 (CAr), 132.7 (CAr), 141.5 (CO). The Mosher analysis (Supporting Information) confirmed the (R)configuration at C-4. (R,5Z,8E)-6-Methyldeca-1,5,8-trien-4-yl (3S,4E,7S,8E,10S,12E)-3((tert-Butyldiphenylsilyl)oxy)-13-iodo-7-methoxy-8,10-dimethyltrideca-4,8,12-trienoate (56). Carboxylic acid 44 (20.0 mg, 31 μmol, 1.0 equiv) and alcohol 55 (6.7 mg, 40 μmol, 1.3 equiv) were dissolved in CH2Cl2 (1.2 mL). DMAP (5.3 mg, 43 μmol, 1.4 equiv), MNBA (17.0 mg, 50 μmol, 1.6 equiv), and NEt3 (22 μL, 160 μmol, 5.0 equiv) were added sequentially to the solution at room temperature. The resulting mixture was allowed to stir for 2 h at room temperature, before it was quenched with H2O. The aqueous layer was separated and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with a saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/EtOAc, 50:1) afforded ester 56 (19 mg, 24 μmol, 77%) as a colorless oil: Rf = 0.72 (petroleum 1 ether/EtOAc, 6:1); [α]20 D = −8.1 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 0.92 (d, J = 6.7 Hz, 3H, 10-CH3), 1.00 (s, 9H, SiC(CH3)3), 1.44 (d, J = 1.2 Hz, 3H, 8-CH3), 1.62 (dd, J = 6.2, 1.4 Hz, 3H, 10′-H), 1.65 (d, J = 1.3 Hz, 3H, 6′-CH3), 1.68−1.98 (m, 3H, 6-Ha, 11-H), 2.07−2.14 (m, 1H, 6-Hb), 2.18−2.33 (m, 2H, 3′-H), 2.40 (dd, J = 14.6, 6.5 Hz, 1H, 2-Ha), 2.44−2.48 (m, 1H, 10-H), 2.53 (dd, J = 14.7, 6.5 Hz, 1H, 2-Hb), 2.63 (dd, J = 14.4, 5.9 Hz, 1H, 7′-Ha), 2.88 (dd, J = 14.4, 6.7 Hz, 1H, 7′-Hb), 3.08 (s, 3H, 7-OCH3), 3.18 (t, J = 6.9 Hz, 1H, 7-H), 4.57 (q, J = 6.6 Hz, 1H, 3-H), 4.96 (d, J = 10.5 Hz, 1H, 9H), 4.99−5.03 (m, 2H, 1′-H), 5.09 (d, J = 9.2 Hz, 1H, 5′-H), 5.20− 5.33 (m, 2H, 5-H, 8′-H), 5.38−5.52 (m, 3H, 4-H, 4′-H, 9′-H), 5.59− 5.70 (m, 1H, 2′-H), 5.89 (d, J = 14.3 Hz, 1H, 13-H), 6.32−6.39 (m, 1H, 12-H), 7.32−7.41 (m, 6H, Ar−H), 7.63−7.67 (m, 4H, Ar−H); 13 C NMR (100 MHz, CDCl3) δ 10.9 (8-CH3), 17.9 (C-10′), 19.3 (SiC(CH3)3), 20.5 (10-CH3), 23.4 (6′-CH3), 26.9 (SiC(CH3)3), 31.7 (C-10), 35.8 (C-7′), 36.6 (C-6), 39.5 (C-3′), 43.4 (C-11), 43.9 (C-2), 55.6 (7-OCH3), 70.3 (C-4′), 71.4 (C-3), 75.5 (C-13), 86.6 (C-7), 4565


Article

The Journal of Organic Chemistry 3H, 8-CH3), 1.56−1.57 (m, 3H, 23-H), 1.63 (d, J = 1.3 Hz, 3H, 19CH3), 1.72−1.78 (m, 1H, 11-Ha), 2.08 (bd, J = 13.8 Hz, 1H, 11-Hb), 2.25−2.43 (m, 7H, 2-H, 6-H, 10-H, 16-H), 2.77−2.79 (m, 1H, 20-Ha), 3.05 (bs, 1H, 20-Hb), 3.08 (s, 3H, 7-OCH3), 3.35 (dd, J = 10.8, 4.7 Hz, 1H, 7-H), 4.47−4.50 (m, 1H, 3-H), 4.84 (dd, J = 9.9, 1.1 Hz, 1H, 9H), 5.29 (d, J = 9.7 Hz, 1H, 18-H), 5.32−5.39 (m, 3H, 5-H, 12-H, 21H), 5.41−5.46 (m, 3H, 4-H, 15-H, 22-H), 5.89 (dt, J = 9.5, 3.2 Hz, 1H, 17-H), 5.97 (dd, J = 15.0, 11.3 Hz, 1H, 13-H), 6.05 (dd, J = 15.1, 10.5 Hz, 1H, 14-H); 13C NMR (176 MHz, C6D6) δ 9.9 (8-CH3), 18.1 (C23), 22.5 (10-CH3), 23.5 (19-CH3), 33.1 (C-10), 35.4 (C-6), 36.2 (C20), 39.9 (C-16), 40.8 (C-11), 43.7 (C-2), 55.2 (7-OCH3), 70.0 (C17), 71.6 (C-3), 88.0 (C-7), 124.5 (C-18), 126.6 (C-15), 127.0 (C21), 128.5 (C-22), 129.0 (C-5), 130.7 (C-13), 132.4 (C-8), 133.4 (C12), 133.6 (C-4), 134.7 (C-14), 136.5 (C-9), 139.6 (C-19), 171.7 (C1); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H40O4Na 451.2819, found 451.2817.

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(7) Thorat, R. G.; Harned, A. M. Chem. Commun. 2018, 54, 241− 243. (8) Tanabe, Y.; Sato, E.; Nakajima, N.; Ohkubo, A.; Ohno, O.; Suenaga, K. Org. Lett. 2014, 16, 2858. (9) Sato, E.; Tanabe, Y.; Nakajima, N.; Ohkubo, A.; Suenaga, K. Org. Lett. 2016, 18, 2047. (10) Sato, E.; Sato, M.; Tanabe, Y.; Nakajima, N.; Ohkubo, A.; Suenaga, K. J. Org. Chem. 2017, 82, 6770. (11) Das, S.; Paul, D.; Goswami, R. K. Org. Lett. 2016, 18, 1908. (12) Nakamura, T.; Kubota, K.; Ieki, T.; Hosokawa, S. Org. Lett. 2016, 18, 132. (13) (a) Shirokawa, S.-i.; Shinoyama, M.; Ooi, I.; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2007, 9, 849. (b) Schmauder, A.; Müller, S.; Maier, M. E. Tetrahedron 2008, 64, 6263. (c) Hartmann, O.; Kalesse, M. Angew. Chem., Int. Ed. 2014, 53, 7335. (14) Langille, N. F.; Jamison, T. F. Org. Lett. 2006, 8, 3761. (15) Zhu, G.; Negishi, E.-i. Chem. - Eur. J. 2008, 14, 311. (16) (a) Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2003, 77, 141. (b) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537. (17) (a) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432. (b) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401. (c) Lautens, M.; Maddess, M. L.; Sauer, E. L. O.; Ouellet, S. G. Org. Lett. 2002, 4, 83. (d) Sun, H.; Roush, W. R. Org. Synth. 2011, 88, 87. (18) (a) Brown, H. C.; Desai, M. C.; Jadhav, P. K. J. Org. Chem. 1982, 47, 5065. (b) Abbott, J. R.; Allais, C.; Roush, W. R. Org. Synth. 2016, 92, 26. (19) Diem, M. J.; Burow, D. F.; Fry, J. L. J. Org. Chem. 1977, 42, 1801. (20) For some examples of reductive ring opening reactions of oxacycles to alkenols, see (a) Crombie, L.; Harper, S. H. J. Chem. Soc. 1950, 0, 1707. (b) Ansell, M. F.; Brown, S. S. J. Chem. Soc. 1957, 0, 1788. (c) Fürstner, A.; Jumbam, D.; Teslic, J.; Weidmann, H. J. Org. Chem. 1991, 56, 2213. (d) Oikawa, M.; Ueno, T.; Oikawa, H.; Ichihara, A. J. Org. Chem. 1995, 60, 5048. (e) Saito, N.; Masuda, M.; Saito, H.; Takenouchi, K.; Ishizuka, S.; Namekawa, J.-i.; TakimotoKamimura, M.; Kittaka, A. Synthesis 2005, 2005, 2533. (f) Yadav, J. S.; Mallikarjuna Reddy, N.; Ataur Rahman, M.; Mallikarjuna Reddy, A.; Prasad, A. R. Helv. Chim. Acta 2014, 97, 491. (21) (a) Banfi, L.; Bernardi, A.; Colombo, L.; Gennari, C.; Scolastico, C. J. Org. Chem. 1984, 49, 3784. (b) Wasserman, H. H.; Gambale, R. J. Tetrahedron 1992, 48, 7059. (c) Loza, V. V.; Vostrikov, N. S.; Miftakhov, M. S. Russ. J. Org. Chem. 2008, 44, 1804. (22) Williams, D. R.; Morales-Ramos, A. I.; Williams, C. M. Org. Lett. 2006, 8, 4393. (23) For Prins cyclizations of bis(silyl)homoallylic alcohols, see: (a) Lu, J.; Song, Z.; Zhang, Y.; Gan, Z.; Li, H. Angew. Chem., Int. Ed. 2012, 51, 5367. (b) Li, H.; Xie, H.; Zhang, Z.; Xu, Y.; Lu, J.; Gao, L.; Song, Z. Chem. Commun. 2015, 51, 8484. (24) Dobbs, A. P.; Martinović, S. Tetrahedron Lett. 2002, 43, 7055. (25) For recent reviews on Prins cyclizations, see: (a) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2006, 2045. (b) Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron 2010, 66, 413. (c) Crane, E. A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2010, 49, 8316. (d) Han, X.; Peh, G.; Floreancig, P. E. Eur. J. Org. Chem. 2013, 2013, 1193. (26) (a) Heumann, L. V.; Keck, G. E. Org. Lett. 2007, 9, 4275. (b) Ferrié, L.; Boulard, L.; Pradaux, F.; Bouzbouz, S.; Reymond, S.; Capdevielle, P.; Cossy, J. J. Org. Chem. 2008, 73, 1864. (c) Wullschleger, C. W.; Gertsch, J.; Altmann, K.-H. Chem. - Eur. J. 2013, 19, 13105. (d) Brandt, D.; Dittoo, A.; Bellosta, V.; Cossy, J. Org. Lett. 2015, 17, 816. (27) Pietruszka, J.; Witt, A. Synthesis 2006, 2006, 4266. (28) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980, 1, 2866. (b) Garegg, P. J.; Regberg, T.; Stawinski, J.; Stromberg, R. J. Chem. Soc., Perkin Trans. 2 1987, 2, 271. (29) Hakimelahi, G. H.; Proba, Z. A.; Ogilvie, K. K. Can. J. Chem. 1982, 60, 1106.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00298. Copies of NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Martin E. Maier: 0000-0002-3570-4943 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Deutsche Forschungsgemeinschaft (Grant no. Ma 1012/32-1) and the state of BadenWürttemberg. The authors acknowledge the networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature−from natural products chemistry to drug discovery”. We also thank Claudia Braun and student Dovilė Rudalevičienė for contributions to this project. The biological assays were performed by Professor Mark Brönstrup and Bianca Karge (Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany) to whom we are very grateful.

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REFERENCES

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