Short Total Synthesis of Î12-Prostaglandin J2 and Related

Article Cite This: J. Org. Chem. 2019, 84, 365−378

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Short Total Synthesis of Δ12-Prostaglandin J2 and Related Prostaglandins. Design, Synthesis, and Biological Evaluation of Macrocyclic Δ12-Prostaglandin J2 Analogues K. C. Nicolaou,*,† Kiran Kumar Pulukuri,†,§ Stephan Rigol,†,§ Zisis Peitsinis,† Ruocheng Yu,† Satoshi Kishigami,† Nicholas Cen,† Monette Aujay,# Joseph Sandoval,# Nancy Zepeda,# and Julia Gavrilyuk# Downloaded via UNIV OF NEW ENGLAND on January 9, 2019 at 13:20:15 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Department of Chemistry, BioScience Research Collaborative, Rice University, 6100 Main Street, Houston, Texas 77005, United States # Abbvie Stemcentrx, LLC, 450 East Jamie Court, South San Francisco, California 94080, United States S Supporting Information *

ABSTRACT: Comprised of a large collection of structurally diverse molecules, the prostaglandins exhibit a wide range of biological properties. Among them are Δ12-prostaglandin J2 (Δ12-PGJ2) and Δ12-prostaglandin J3 (Δ12-PGJ3), whose unusual structural motifs and potent cytotoxicities present unique opportunities for chemical and biological investigations. Herein, we report a short olefin-metathesis-based total synthesis of Δ12-PGJ2 and its application to the construction of a series of designed analogues possessing monomeric, dimeric, trimeric, and tetrameric macrocyclic lactones consisting of units of this prostaglandin. Biological evaluation of these analogues led to interesting structure−activity relationships and trends and the discovery of a number of more potent antitumor agents than their parent naturally occurring molecules.

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INTRODUCTION Inspired by the important cytotoxicity properties of Δ12prostaglandins J2 (Δ12-PGJ2, 1, Figure 1)1 and J3 (Δ12-PGJ3, 2, Figure 1),2 we initiated a program directed toward their total syntheses and analogue design, synthesis, and biological investigation aiming at the discovery of selective antitumor

agents. We recently reported several synthetic approaches to these naturally occurring molecules,3 their analogues, and their biological activities.4 From the numerous compounds synthesized in these studies,4 10-chloro-Δ12-PGJ3 lactone (3) and Δ12-PGJ2 lactone (4a) emerged as the two most promising lead compounds against the NCI-60 human tumor cell lines screen. In general, the macrolactones derived from the corresponding open-chain prostaglandins were found to be more potent than their parent counterparts. These observations led us to pose the question of how higher macrolactone oligomers such as dimeric, trimeric, and tetrameric macrolactones derived from the parent prostaglandins would behave as antitumor agents. Synthetic monomeric analogues of symmetrically built dimeric natural products, rare as they are, exist in the literature, and they often exhibit significantly lower potencies as compared to their parent dimeric natural products. Examples include those of marinomycin A5 and rhizopodin6 reported from our laboratories. A similar trend was observed with a series of designed synthetic macroheterocyclic furanoids where monomeric compounds were

Figure 1. Molecular structures of Δ12-prostaglandin J2 (1, Δ12-PGJ2), Δ12-prostaglandin J3 (2, Δ12-PGJ3), 10-Cl-Δ12-prostaglandin J3 lactone (3), and Δ12-prostaglandin J2 lactone (4a). © 2018 American Chemical Society

Received: November 29, 2018 Published: December 17, 2018 365

DOI: 10.1021/acs.joc.8b03057 J. Org. Chem. 2019, 84, 365−378

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The Journal of Organic Chemistry

Synthesis of Macrocyclic Analogues 4a−7a. Scheme 1 summarizes our new retrosynthetic analysis (Scheme 1A) and total synthesis of Δ12-PGJ2 (1) and its macrocyclic derivatives

found to be devoid of significant activity against certain cancer cell lines, while a number of dimeric structures showed impressive potencies against the same cell lines, as also demonstrated in our laboratories.7 In this paper, we report our findings of a study intended to explore “the oligomerization effect” and its limits on cytotoxicity of macrolactone versions of the Δ12-PGJ2 (1) family of compounds (e.g., 4a, Figure 1) and an expedient new approach to the Δ12-PGJ2 type of prostaglandins that could, in principle, be applied to the total synthesis of Δ12-PGJ3-type compounds as well as other prostanoids. Specifically, we describe (a) a metathesis-based short total synthesis of Δ12PGJ2;8 (b) its application to the construction of an array of designed macrocyclic lactone analogues of this natural product (i.e., 4a−d, 5a−d, 6a−d and 7a−d, Figure 2); (c) biological evaluation of the synthesized compounds; and (d) structure− activity relationships and conclusions derived from them.

Scheme 1. Synthesis of Δ12-Prostaglandin J2 (1) and Analogues 4a−7aa

a

Reagents and conditions: (a) 8 (1.0 equiv), CuI (0.17 equiv), then 9 (1.7 equiv), THF, −78 °C, 1 h; then 0 °C, 1 h, 72%; (b) TBSCl (1.3 equiv), imidazole (2.6 equiv), CH2Cl2, 0 to 25 °C, 12 h, 90%; (c) DDQ (1.5 equiv), CH2Cl2:H2O (10:1, v/v), 0 °C, 1.5 h, 90%; (d) DMP (2.0 equiv), CH2Cl2, 0 to 25 °C, 2 h, 84%; (e) CuI (2.2 equiv), LiCl (2.2 equiv), THF, 25 °C, 10 min; then allyl magnesium bromide (1.0 M in Et2O, 2.0 equiv), −78 °C; TMSCl (2.0 equiv), −78 °C for 6 h and −78 to 25 °C, 4 h, 94%; (f) 1,2-dichlorobenzene, 170 °C, 6 h, 82%; (g) 12 (1.5 equiv), LDA (0.66 M in THF, 2.0 equiv), THF, −78 °C, 0.5 h; (h) MsCl (3.0 equiv), DMAP (10.0 equiv), CH2Cl2, 0 °C, 12 h; 40% for two steps; (i) 16 (10.0 equiv), 17 (cat) (0.1 equiv), THF, 35 °C, 12 h, 42% [52% 15 recovered, >95% (Z)-isomer]; (j) HBF4 (48% aq, 25 equiv), CH3CN, 0 °C, 3 h, 71%; (k) MNBA (1.5 equiv), DMAP (3.0 equiv), CH2Cl2, c ∼ 0.8 mM, 25 °C, 12 h, 72%; (l) MNBA (1.5 equiv), Et3N (2.0 equiv), DMAP (0.1 equiv), CH2Cl2, c ∼ 10 mM, 25 °C, 12 h, 5a (27%), 6a (10%), and 7a (9%). THF = tetrahydrofuran, TBS = tert-butyldimethylsilyl, imid = 1H-imidazole, DDQ = 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile, DMP = Dess−Martin periodinane, TMS = trimethylsilyl, LDA = lithium diisopropylamide, Ms = mesyl, DMAP = N,N-dimethylpyridin-4-amine, MNBA = (2-methyl-6-nitrobenzoyl) 2-methyl-6-nitrobenzoate.

Figure 2. Designed macrocyclic Δ12-prostaglandin J2 analogues 4−7.

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RESULTS AND DISCUSSION From the two best lead compounds from our earlier studies (i.e., 3 and 4a, Figure 1)4 we chose macrolactone 4a, whose saturated side chain promised easier synthetic access while allowing the introduction of the potency enhancing C10 chloro substituent and its congeners as the parent compound from which to design our targeted monomeric (4a−d), dimeric (5a−d), trimeric (6a−d), and tetrameric (7a−d) macrolactones (Figure 2). As a prelude to their expedient construction, we set out to shorten and improve our previous total synthesis of the required precursors, Δ12-PGJ2 (1) and its analogues.3b,4 For comparison purposes we focused on the H, Cl, and I residues as C10 variations, CH3 and CF3 as C20 variations, and the mono- to tetracyclic nature of the macrocyclic framework. 366


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Scheme 2. Synthesis of Δ12-Prostaglandin J2 Analogues 4b− 7ba

4a−7a (Scheme 1B). Thus, enantiopure and readily available epoxide 89 reacted with n-BuMgBr in the presence of CuI to afford alcohol 10 (72% yield), whose silylation (TBSCl, imid) furnished TBS-ether 11 (90% yield). Removal of the PMB group from the latter (DDQ) followed by oxidation (DMP) of the resulting primary alcohol led to aldehyde 12 in 76% overall yield. Building block 14 was prepared from the readily available and enantiomerically pure enone 1310 through stereoselective Michael addition of the allyl copper reagent generated in situ from allyl magnesium bromide, CuI and LiCl in the presence of TMSCl, followed by thermally induced retro-Diels−Alder reaction, in 77% yield over the two steps. Enone 14 and aldehyde 124 were dissolved in THF and treated with LDA to afford a diastereomeric mixture of the expected aldol products, whose treatment with MsCl and DMAP furnished, in 40% overall yield from 14, the desired dienone 15, through the corresponding diastereomeric mesylates. Olefin metathesis between terminal olefins 15 and 16 (conveniently produced from commercially available 5-hexenoic acid, see the Experimental Section for details) as initiated by Grubbs catalyst 1711 furnished protected Δ12-PGJ2 derivative 18 in 42% yield [>95:5 (Z)/(E), plus 52% recovered starting material (15) translating in 90% yield of product 18 brsm]. Exposure of the latter precursor (18) to aq HBF4 then liberated Δ12-PGJ2 (1) in 71% yield as previously reported.3b This sequence represents the shortest route to Δ12-PGJ2 (1) from readily available starting materials (i.e., 13 and 8) and, in principle, could be improved and extended to other prostaglandin-like compounds [e.g., Δ12-PGJ3 (2)]. With seco acid 1 in hand, monomeric macrolactone 4a was prepared in 72% yield following our previously reported pseudo high dilution macrolactonization conditions4 (MNBA, DMAP, ca. 0.8 mM concentration). Dimeric (5a), trimeric (6a), and tetrameric (7a) macrolactones were produced simultaneously, and in the same pot, under modified macrolactonization conditions [MNBA, Et 3 N, DMAP (cat), ca. 10 mM concentration, CH2Cl2, 25 °C, 12 h, 27% (5a), 10% (6a), 9% (7a); chromatographically separated from each other and the unreacted minor (E)-olefinic precursor]. Synthesis of Macrocyclic Chloro Analogues 4b−7b. The synthesis of the C10-chloro macrolactones 4b−7b, whose design was based on our results from the Δ12-PGJ3 project,4 are shown in Scheme 2. Starting with enone 14, the required chloroenone 19 was prepared through the corresponding epoxy ketone by treatment with H2O2/KOH, followed by sequential oxirane opening (LiCl) and dehydration of the soformed chlorohydrin (Amberlyst 15, H+ form), in 60% overall yield. Enone 19 and aldehyde 124 were then treated with LDA, resulting in a mixture of diastereomeric aldol products, whose exposure to MsCl and DMAP furnished dienone 20 in 36% overall yield from 19. Reaction of 20 with excess of terminal olefin 16 in the presence of Grubbs catalyst 2112 gave selectively the desired (Z)-olefin 22 [55% yield, ca. 90:10 (Z)/ (E)]. The tert-butyl ester and TBS ether protecting groups of the latter precursor were efficiently cleaved in one step by exposure to aq HBF4, yielding seco acid 23 in 91% yield [ca. 90:10 (Z)/(E)]. This Δ12-PGJ2 analogue (i.e., 23) was converted to monomeric lactone 4b (69% yield) by treatment under the standard high dilution conditions (MNBA, DMAP, ca. 0.8 mM), while the dimeric (5b), trimeric (6b), and tetrameric (7b) macrocyclic lactones were secured from seco acid 23 under the modified high concentration macrolactonization conditions (MNBA, Et3N, DMAP, ca. 10 mM)

a

Reagents and conditions: (a) H2O2 (1.0 equiv), KOH (10 wt% in H2O, 0.2 equiv), MeOH, −20 °C, 2 h; (b) LiCl (10.0 equiv), Amberlyst 15 (600 wt%), MeCN, 25 °C, 24 h, 60% for two steps; (c) 12 (1.5 equiv), LDA (0.66 M in THF, 2.0 equiv), THF, −78 °C, 0.5 h; (d) MsCl (3.0 equiv), DMAP (10.0 equiv), CH2Cl2, 0 °C, 12 h, 36% for two steps; (e) 21 (cat) (0.1 equiv), 16 (6.0 equiv), THF, 35 °C, 12 h, 55% [81% brsm, (Z):(E) = 90:10]; (f) HBF4 (48% aq, 25 equiv), CH3CN, 0 °C, 3 h, 91% [(Z):(E) 90:10]; (g) MNBA (1.5 equiv), DMAP (3.0 equiv), CH2Cl2, c ∼ 0.8 mM, 25 °C, 12 h, 69%; (h) MNBA (1.5 equiv), Et3N (2.0 equiv), DMAP (0.1 equiv), CH2Cl2, c ∼ 10 mM, 25 °C, 12 h, 5b (20%), 6b (8%), 7b (4%).

through chromatographic separation in 20%, 8%, and 4% yields, respectively. Synthesis of Macrocyclic Chloro Analogues 4c−7c Bearing Terminal CF3 Groups. The synthesis of analogues 4c−7c from chloroenone 19 required a modified aldehyde building block (i.e., 27, Scheme 3) carrying a terminal CF3 moiety instead of the CH3 group. This structural modification was based on our previous structure−activity relationship studies on Δ12-PGJ3 analogues4a where the introduction of a terminal CF3 group proved beneficial. Thus, and as shown in Scheme 3, epoxide 89 was treated with Grignard reagent 24 (conveniently synthesized from commercially available 4bromo-1,1,1-trifluorobutane) to provide secondary alcohol 25 (76% yield), which was silylated (TBSCl, imid) to give ether 26 in 93% yield. Removal of the PMB group (DDQ) from 26 and oxidation of the resulting alcohol (DMP) gave aldehyde 27 in 67% yield over the two steps. The remaining steps from 19 and 27 proceeded similarly as described above for 19 and 12 (see Scheme 2) through an aldol/mesylation/elimination sequence to furnish dienone 28 in 33% yield over the two steps. Subsequent (Z)-selective olefin metathesis employing Grubbs catalyst 1711 and terminal olefins 16 and 28 yielded fully protected intermediate 29 in 61% yield [>95% (Z)isomer] after two cycles (plus 23% of 28 recovered, >95% (Z)isomer). Global deprotection of the latter through exposure to HBF4 liberated C20-trifluoromethyl Δ12-PGJ2 analogue 30, in 71% yield as shown in Scheme 3. Macrocyclization of hydroxy acid 30 using the two different dilution conditions as 367


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The Journal of Organic Chemistry Scheme 3. Synthesis of Δ12-Prostaglandin J2 Analogues 4c− 7ca

Scheme 4. Synthesis of Δ12-Prostaglandin J2 Analogues 4d− 7da

a

Reagents and conditions: (a) I2 (1.1 equiv), DMAP (1.0 equiv), CH2Cl2, 0 to 25 °C, 2 h, 56%; (b) 27 (1.5 equiv), LDA (0.66 M in THF, 2.0 equiv), THF, −78 °C, 0.5 h; (c) MsCl (3.0 equiv), DMAP (10.0 equiv), CH2Cl2, 0 °C, 12 h, 30% for two steps; (d) 17 (cat) (0.1 equiv), 16 (6.0 equiv), THF, 35 °C, 12 h, 73% [after two cycles, >95% (Z)-isomer]; (e) HBF4 (48% aq, 25 equiv), CH3CN, 0 °C, 3 h, 69%; (f) MNBA (1.5 equiv), DMAP (3.0 equiv), CH2Cl2, c ∼ 0.8 mM, 25 °C, 12 h, 56%; (g) MNBA (1.5 equiv), Et3N (2.0 equiv), DMAP (0.1 equiv), CH2Cl2, c ∼ 10 mM, 25 °C, 12 h, 5d (22%), 6d (14%), and 7d (8%).

a Reagents and conditions: (a) 8 (1.0 equiv), CuI (0.17 equiv), then 24 (1.7 equiv), THF, −78 °C, 1 h; then 0 °C, 1 h, 76%; (b) TBSCl (1.3 equiv), imidazole (2.6 equiv), CH2Cl2, 0 to 25 °C, 12 h, 93%; (c) DDQ (1.5 equiv), CH2Cl2/H2O (20:1, v/v), 0 °C, 1.5 h, 88%; (d) DMP (2.0 equiv), CH2Cl2, 0 to 25 °C, 2 h, 76%; (e) 27 (1.5 equiv), LDA (0.66 M in THF, 2.0 equiv), THF, −78 °C, 0.5 h; (f) MsCl (3.0 equiv), DMAP (10.0 equiv), CH2Cl2, 0 °C, 12 h, 33% for two steps; (g) 16 (6.0 equiv), 17 (cat) (0.1 equiv), THF, 35 °C, 12 h, 61% after two cycles [23% 28 recovered, >95% (Z)-isomer]; (h) HBF4 (48% aq, 25 equiv), CH3CN, 0 °C, 3 h, 71%; (i) MNBA (1.5 equiv), DMAP (3.0 equiv), CH2Cl2, c ∼ 0.8 mM, 25 °C, 12 h, 73%; (j) MNBA (1.5 equiv), Et3N (2.0 equiv), DMAP (0.1 equiv), CH2Cl2, c ∼ 10 mM, 25 °C, 12 h, 5c (19%), 6c (9%), and 7c (8%).

separated), respectively, using the developed conditions as summarized in Scheme 4. Biological Evaluation of Synthesized Δ12-Prostaglandin J2 Macrocyclic Lactones. The synthesized Δ12-PGJ2 macrocyclic lactones were evaluated for their cytotoxicities through testing against the MES SA (uterine sarcoma), MES SA DX (uterine sarcoma with marked multidrug resistance), and HEK 293T (immortalized human embryonic kidney cells)13 cell lines using the previously synthesized and tested monomeric lactone 34a as standard positive control. Table 1 summarizes the results of these assays. Inspection of these data revealed comparable cytotoxicities (with somewhat higher potencies for the dimers over the monomers) for the monomeric (4a−c) and dimeric (5a−c) macrolactones but drastically weaker cytotoxicities for the corresponding trimeric (6a−c) and tetrameric (7a−c) macrocyclic oligomers (see Table 1 for IC50 values). A select representative subset of these analogues [i.e., 4d (monomeric), 5d (dimeric), 6d (trimeric), and 7d (tetrameric)] was tested against an additional set of cancer cell lines {OCI-AML3 (acute myeloid leukemia), EOL1 [acute myeloid (eosinophilic) leukemia], NCI-N87 (gastric carcinoma), SKOV3 (adenocarcinoma), SKBR3 (adenocarcinoma), and H510A (small cell lung carcinoma)} in order to obtain a wider picture of the potencies of the synthesized macrocyclic compounds. As seen in Table 2, the results from these additional in vitro assays confirmed the trend reflected in Table 1, with dimeric macrolactone 5d proving more potent than its monomeric counterpart (4d) consistently across the six cell line panel. Again, the corresponding trimer (6d) and

mentioned above furnished the targeted analogues 4c−7c in yields of 73% (4c, high dilution), 19%, 9% and 8% (5c−7c, high concentration, chromatographically separated), respectively. Synthesis of Macrocyclic Iodo Analogues 4d−7d Bearing Terminal CF3 Groups. The 10-iodo series of analogues (i.e, 4d−7d) was synthesized to test the effect of the larger iodo residue at this position starting from the common enone precursor 14 as shown in Scheme 4. Thus, the 10-iodo substituent was introduced into 14 by exposure to iodine and DMAP to provide, in 56% yield, required iodo building block 31. The latter was subjected to the same reaction sequence as described above [see 19 → 30, Scheme 3, for the conversion of its counterpart (19) to the corresponding Δ12-PGJ2 structure (30)], to afford Δ12-PGJ2 analogue 34 via intermediates terminal olefin 32 and precursor 33, through an aldol/ mesylation/elimination sequence (30% yield over two steps), a subsequent metathesis reaction with terminal olefin 16 facilitated by Grubbs catalyst 1711 [73%, two cycles, >95% (Z)-isomer], and global deprotection through the action of HBF4 (69% yield). Macrolactone 4d, dimeric macrolactone 5d, trimeric macrolactone 6d, and tetrameric macrolactone 7d were then synthesized in yields of 56% (high dilution), 22%, 14%, and 8% (high concentration, chromatographically 368


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consistent with our previous observations of dimeric macrocyclic compounds (natural or designed), showing stronger cytotoxicities than their monomeric counterparts (marinomycin vs synthetic monomer;5 rhizopodin vs synthetic monomer;6 and furanoid synthetic dimer vs synthetic monomer;7 see Figure 3 for structures). Interestingly, the reported

Table 1. Cytotoxicity Data Against Cell Lines MES SA, MES SA DX, and HEK 293Ta for the Synthesized Δ12Prostaglandin J2 Analogues 4a−d, 5a−d, 6a−d, and 7a−d (IC50 Values in nM)b

a IC50 = 50% inhibitory concentration of compound against cell growth; MES SA: uterine sarcoma cell line; MES SA DX: MES SA cell line with marked multidrug resistance; HEK 293T: human embryonic kidney cell line. bSee the Supporting Information for further details; these studies were carried out at AbbVie Stemcentrx.

Table 2. Cytotoxicity Data against Cell Lines OCU-AML3, EOL1, NCI-N87, SKOV3, SKBR3, and H510Aa for the Synthesized Δ12-Prostaglandin J2 Analogues 4d, 5d, 6d, and 7d (IC50 Values in nM)b

a

IC50 = 50% inhibitory concentration of compound against cell growth; OCI-AML3: acute myeloid leukemia; EOL1: acute myeloid (eosinophilic) leukemia; NCI-N87: gastric carcinoma; SKOV3: adenocarcinoma; SKBR3: adenocarcinoma; H510A: small cell lung carcinoma; bSee the Supporting Information for further details; these studies were carried out at AbbVie Stemcentrx.

tetramer (7d) proved significantly less active (or not active) against these cell lines (see Table 2). Structure−Activity Relationships (SARs). Inspection of Tables 1 and 2 reveals consistently similar potencies for the monomeric (4a−d) and dimeric (5a−d) macrocyclic lactones, but superior to those of their trimeric (6a−d) and tetrameric (7a−d) counterparts. Interestingly, however, all three monomeric macrolactones 4a, 4b, and 4c (Table 1) exhibited higher potencies than their dimeric relatives (5a, 5b, and 5c) against the multidrug resistant MES SA DX cancer cell line, making them valuable compounds for optimization and possible further development. Another noticeable trend toward higher cytotoxicities was observed within the monomeric and dimeric families of compounds with the 10-chloro derivative (i.e., 4b, 5b) showing on average somewhat higher potencies than their parent compounds (i.e., 4a, 5a), while the corresponding 10iodo derivatives (i.e., 4d, 5d) exhibited on average somewhat lower potencies than their 10-chloro counterparts (i.e., 4b, 4c and 5b, 5c). The general SAR trend observed in this study is

Figure 3. Molecular structures of natural products marinomycin A (35) and rhizopodin (39) and their respective monomeric counterparts 36−38 and designed furanoid macrocyclic monomer 40 and dimer 41.

observations in this and our previous disclosures4a,4−7 point to a consistent paradigm in which natural and designed dimeric macrocyclic compounds of C2 symmetrical nature exhibit higher cytotoxicities than their monomeric counterparts. This occurrence, however, should not be taken as a dogma in order to allow for variations and exceptions. Further investigations are warranted in order to shine more light on these interesting observations.

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CONCLUSIONS Employing a metathesis-based synthetic strategy, the described chemistry facilitated the synthesis of a series of Δ12-PGJ2-type monomeric, dimeric, trimeric, and tetrameric macrocyclic 369


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solution (40 mL). The layers were separated, and the aqueous layer was extracted with Et2O (3 × 50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2, hexanes/EtOAc, 15:1, v/v → 5:1, v/v) yielded the pure title compound (3.23 g, 12.1 mmol, 72% yield) as a colorless oil. 10: Rf = 0.29 (SiO2, hexanes/EtOAc, 5:1, v/v); [α]22 D = −3 (c = 1.0 in C6H6); IR (film) νmax 3431, 2930, 2858, 1613, 1513, 1247, 1091, 1036, 820 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.26−7.22 (m, 2 H), 6.89−6.85 (m, 2 H), 4.44 (s, 2 H), 3.79 (s, 3 H), 3.79−3.75 (m, 1 H), 3.69 (dt, J = 9.2, 5.2 Hz, 1 H), 3.61 (ddd, J = 9.3, 7.5, 5.1 Hz, 1 H), 2.71 (br, 1 H), 1.76−1.67 (m, 2 H), 1.50−1.36 (m, 3 H), 1.36−1.22 (m, 5 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 159.4, 130.2, 129.4, 113.9, 73.1, 71.6, 69.1, 55.4, 37.5, 36.5, 32.0, 25.4, 22.7, 14.2 ppm; HR-MS (ESI-TOF) calcd for C16H26O3Na+ [M + Na]+ 289.1774, found 289.1768. tert-Butyl({(3S)-1-[(4-methoxybenzyl)oxy]octan-3-yl}oxy)dimethylsilane (11). To a stirred solution of alcohol 10 (3.15 g, 11.8 mmol, 1.0 equiv) in CH2Cl2 (35 mL) at 0 °C were added imidazole (2.09 g, 30.8 mmol, 2.6 equiv) and TBSCl (2.32 g, 15.4 mmol, 1.3 equiv). The reaction mixture was warmed to 25 °C and stirred for 12 h. The resulting mixture was then quenched by addition of satd aqueous NH4Cl solution (80 mL) and stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 75 mL). The combined organic extracts were washed sequentially with H2O (2 × 125 mL) and brine (125 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/Et2O, 40:1, v/v →15:1, v/v) gave pure title compound (11, 4.06 g, 10.7 mmol, 90% yield) as a colorless oil. 11: Rf = 0.66 (SiO2, hexanes/Et2O, 10:1, v/v); [α]23 D = +10 (c = 1.0 in C6H6); IR (film) νmax 2953, 2929, 2856, 1613, 1513, 1463, 1247, 1089, 1038, 834, 773 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.26 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.39 (d, J = 11.5 Hz, 1 H), 3.84−3.76 (m, 4 H), 3.51 (t, J = 6.7 Hz, 2 H), 1.79−1.67 (m, 2 H), 1.46−1.39 (m, 2 H), 1.35−1.21 (m, 6 H), 0.90−0.87 (m, 12 H), 0.04 (s, 3 H), 0.03 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 159.2, 130.9, 129.4, 113.9, 72.8, 69.7, 67.1, 55.4, 37.7, 37.1, 32.2, 26.1, 24.9, 22.8, 18.3, 14.2, −4.2, −4.5 ppm; HR-MS (ESI-TOF) calcd for C22H40O3SiNa+ [M + H]+ 403.2639, found 403.2625. (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}octan-1-ol (S1). To a vigorously stirred solution of PMB ether 11 (3.75 g, 9.85 mmol, 1.0 equiv) in CH2Cl2/H2O (10:1, v/v, 40 mL) at 0 °C was added 2,3-dichloro5,6-dicyano-1,4-benzoquinone (3.35 g, 14.8 mmol, 1.5 equiv) at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for an additional 1.5 h before being quenched by the addition of satd aqueous NaHCO3 solution (50 mL), and the mixture was stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted with Et2O (3 × 75 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 15:1, v/v → 7:1, v/v) gave pure title compound (S1, 2.31 g, 8.87 mmol, 90% yield) as a colorless oil. S1: Rf = 0.50 (hexanes/EtOAc, 4:1, v/v); [α]22 D = +12 (c = 2.1, C6H6); FT-IR (film) νmax 3363, 2955, 2930, 2858, 1601, 1471, 1463, 1378, 1256, 1058, 1005, 835, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 3.93−3.89 (m, 1 H), 3.87−3.82 (m, 1 H), 3.71 (dt, J = 10.8, 5.4 Hz, 1 H), 2.44 (s, 1 H), 1.85−1.79 (m, 1 H), 1.67−1.62 (m, 1 H), 1.54− 1.50 (m, 2 H), 1.32−1.24 (s, 6 H), 0.89−0.88 (m, 12 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 72.2, 60.5, 37.7, 36.9, 32.1, 25.9, 25.1, 22.7, 18.1, 14.1, −4.3, −4.6 ppm; HR-MS (ESI-TOF) calcd for C14H33O2Si [M + H]+ 261.2244, found 261.2231. (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}octanal (12). To a solution of primary alcohol S1 (600 mg, 2.30 mmol, 1.0 equiv) in CH2Cl2 (20 mL) at 0 °C was added Dess−Martin periodinane (1.95 g, 4.60 mmol, 2.0 equiv). The reaction mixture was warmed to 25 °C and stirred for 90 min. The reaction was then quenched by addition of satd aqueous Na2S2O3 (4 mL) and satd aqueous NaHCO3 (4 mL) and stirred for

lactones, whose biological evaluation against certain cancer or cancer-like cell lines revealed a number of intriguing findings. First it was recognized that the monomeric (4a−d) and dimeric (5a−d) lactones were found consistently to possess nanomolar potencies, while their trimeric (6a−d) and tetrameric (7a−d) counterparts were devoid of significant cytotoxicities against the same cell lines. A second trend was recorded within the families of monomeric and dimeric macrolactones, with the latter exhibiting slightly, but consistently, higher potencies than the former. The third demonstrated trend in these in vitro cytotoxicity studies was the consistent superiority of the monomeric macrolactones (i.e., 4a−d) over their dimeric (5a−d) counterparts in terms of their potencies against the MES SA DX cell line with marked multidrug resistance. Given the difficulties in killing these types of cancer cell lines, this finding may prove important in fighting such malignancies and, therefore, worth pursuing further. The reported potency trends with these monomeric and dimeric prostanoid compounds seem to be in line with previous findings in our group with natural and designed monomeric/ dimeric pairs of macrocyclic molecules.5−7 Further studies are warranted to decipher further validations/conclusions regarding the generality and cause of the observed phenomena.

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EXPERIMENTAL SECTION

General Methods. All reactions were carried out under an argon atmosphere with dry solvent under anhydrous conditions, unless otherwise noted. Dry acetonitrile (MeCN), dimethylformamide (DMF), dichloromethane (CH2Cl2), tetrahydrofuran (THF), and toluene were obtained by passing commercially available predried, oxygen-free formulations through activated alumina columns. Anhydrous benzene, acetone, chloroform (CHCl3), methanol (MeOH), ethanol (EtOH), and nitromethane (MeNO2) were purchased from commercial suppliers and stored under argon. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous material, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise noted. Reactions were monitored by thin-layer chromatography (TLC) carried out on S-2 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of phosphomolybdic acid, an aqueous solution of cerium sulfate or a basic aqueous solution of potassium permanganate as developing agents. E. Merck silica gel (60, particle size 0.040−0.063 mm) was used for flash column chromatography. NMR spectra were recorded on a Bruker DRX-600 instrument and calibrated using residual undeuterated solvent (CDCl3, δH = 7.26 ppm, δC = 77.16 ppm; C6D6, δH = 7.16 ppm, δC = 128.06 ppm) as an internal reference. The following abbreviations were used to designate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, br = broad. Infrared (IR) spectra were recorded on a Perkin−Elmer 100 FT-IR spectrometer. Highresolution mass spectra (HRMS) were recorded on an Agilent ESITOF (time-of-flight) mass spectrometer using MALDI (matrixassisted laser desorption ionization) or ESI (electrospray ionization). Optical rotations were recorded on a Schmidt+Haensch POLARTRONIC M100 polarimeter at 589 nm, using 100 mm cells and the solvent and concentration indicated [in units of 10−1 (deg cm2 g−1)]. Experimental Procedures and Characterization Data. (3S)-1[(4-Methoxybenzyl)oxy]octan-3-ol (10). To a stirred solution of cuprous iodide (544 mg, 2.86 mmol, 0.17 equiv) in THF (17 mL) at −78 °C was added butylmagnesium bromide (4.61 g, 28.6 mmol, 1.7 equiv; prepared from 1-bromobutane) in THF (100 mL), and the mixture was stirred for 15 min at −78 °C. Subsequently, a solution of epoxide 15 (3.50 g, 16.8 mmol, 1.0 equiv) in THF (10 mL) was slowly added, and the resulting mixture was stirred for an additional 1 h before the reaction mixture was allowed to warm to 0 °C over 1 h and then quenched by the addition of aqueous saturated NH4Cl 370


Article

The Journal of Organic Chemistry 10 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2, hexanes/EtOAc, 19:1, v/v → 9:1, v/v) yielded the title aldehyde (498 mg, 1.93 mmol, 84% yield) as a colorless oil. 12: Rf = 0.60 (hexanes/EtOAc, 10:1, v/v); [α]22 D = −6 (c = 1.0, CHCl3); FT-IR (film) νmax 2956, 2929, 2858, 1727, 1471, 1361, 1254, 1100, 1053, 1005, 835, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 9.81 (t, J = 2.5 Hz, 1 H), 4.18 (quint, J = 5.9 Hz, 1 H), 2.52−2.45 (m, 2 H), 1.58−1.47 (m, 2 H), 1.36−1.22 (m, 6 H), 0.90−0.87 (m, 12 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 202.6, 68.4, 50.9, 37.9, 31.9, 25.9, 24.9, 22.7, 18.1, 14.1, −4.3, −4.6 ppm; HR-MS (ESI-TOF) calcd for C14H30O2SiNa [M + Na]+ 281.1907, found 281.1909. (4R)-4-(Prop-2-en-1-yl)cyclopent-2-en-1-one (14). CuI (17.1 g, 90.2 mmol, 2.2 equiv) and dry LiCl (3.83 g, 90.2 mmol, 2.2 equiv) were placed in a flame-dried round-bottom flask. The flask was evacuated and purged with argon; the process was repeated three times. THF (240 mL) was injected, and the mixture was stirred for 15−20 min to yield a yellow, homogeneous solution which was then cooled to −78 °C. To the cooled yellow colored solution was slowly added allylmagnesium bromide (1.0 M in ether; 81.2 mL, 81.2 mmol, 2.0 equiv) over a period of 15 min. After 5 min of stirring at −78 °C, trimethylsilyl chloride (10.4 mL, 81.2 mmol, 2.0 equiv) was added followed immediately by the addition of enone 13 (6.00 g, 41.0 mmol, 1.0 equiv) in THF to the brown solution. The reaction was allowed to proceed for 6 h at −78 °C and then slowly warm to 25 °C over a period of 4 h before being quenched with aqueous saturated NH4Cl solution (50 mL). The phases were separated, the aqueous layer was extracted with Et2O (2 × 150 mL), and the combined organic extracts were washed with 1 M HCl (2 × 50 mL), water (50 mL), and brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 10:1, v/v) gave the pure addition product (S2, 7.30 g, 38.6 mmol, 94% yield) as a colorless oil. S2: Rf = 0.70 (SiO2, hexanes/EtOAc, 4:1, v/v); [α]22 D = +117 (c = 1.0 in C6H6); IR (film) νmax 3007, 2957, 2930, 2857, 1728, 1705, 1656, 1582, 1366, 1251, 1144, 1066, 834, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.17 (dd, J = 5.8, 3.0 Hz, 1 H), 6.13 (dd, J = 5.8, 2.9 Hz, 1 H), 5.74 (ddt, J = 17.1, 10.3, 6.9 Hz, 1 H), 5.07−5.03 (m, 2 H), 3.18−3.17 (m, 1 H), 3.04−3.02 (m, 1 H), 2.92 (ddd, J = 9.5, 4.8, 1.8 Hz, 1 H), 2.66 (dt, J = 9.4, 3.9 Hz, 1 H), 2.21−2.10 (m, 3 H), 1.96 (ddd, J = 18.8, 6.0, 2.0 Hz, 1 H), 1.86−1.81 (m, 1 H), 1.54 (dt, J = 8.3, 1.8 Hz, 1 H), 1.41 (dt, J = 8.3, 1.5 Hz, 1 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 201.1, 136.31, 136.28, 135.3, 116.9, 55.0, 52.4, 48.2, 47.6, 47.2, 46.6, 41.9, 36.2 ppm; HR-MS (ESI-TOF) calcd for C13H17O+ [M + H]+ 189.1274, found 189.1273. The above-prepared compound (S2, 6.00 g, 31.7 mmol, 1.0 equiv) was taken in 1,2-dichlorobenzene (60 mL), and the resulting mixture was heated at 170 °C for 6 h. After being cooled to room temperature, the reaction mixture was directly subjected to flash column chromatography on silica gel using n-pentane, then 30% Et2O in npentane as eluant, to give the titled enone (14, 3.20 g, 26.2 mmol, 82% yield) as a colorless oil. 14: Rf = 0.20 (SiO2, hexanes/EtOAc, 10:1, v/v); [α]22 D = +151 (c = 1.0 in C6H6); IR (film) νmax 3078, 2978, 2920, 1705, 1665, 1589, 1407, 1348, 1183, 916, 781 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.63 (dd, J = 5.7, 2.5 Hz, 1 H), 6.17 (dd, J = 5.6, 2.0 Hz, 1 H), 5.77 (ddt, J = 16.8, 9.7, 6.9 Hz, 1 H), 5.11−5.08 (m, 2 H), 3.06−3.01 (m, 1 H), 2.51 (dd, J = 18.9, 6.4 Hz, 1 H), 2.33−2.28 (m, 1 H), 2.24− 2.19 (m, 1 H), 2.05 (dd, J = 18.9, 2.2 Hz, 1 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 209.8, 167.7, 135.0, 134.2, 117.6, 40.8, 40.4, 38.6 ppm; HR-MS (ESI-TOF) calcd for C8H11O+ [M + H]+ 123.0804, found 123.0800. (4S,5E)-5-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}octylidene]-4(prop-2-en-1-yl)cyclopent-2-en-1-one (15). To a premixed solution of enone 14 (244 mg, 2.00 mmol, 1.0 equiv) and aldehyde 12 (774 mg, 3.00 mmol, 1.5 equiv) in THF (10 mL) at −78 °C was added dropwise LDA (0.66 M in THF, 6.04 mL, 4.00 mmol, 2.0 equiv) over

a period of 5 min. After being stirred for 30 min at this temperature, the light yellow reaction mixture was quenched with saturated aqueous NH4Cl solution (20 mL), diluted with Et2O (50 mL), and allowed to warm to 25 °C. The phases were separated, the aqueous layer was extracted with Et2O (2 × 75 mL), and the combined organic extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude aldol product was directly taken to the next step without further purification. To a stirred solution of the crude aldol product in CH2Cl2 (20 mL) at 0 °C were added DMAP (2.44 g, 20.0 mmol, 10.0 equiv) and then, slowly and dropwise, methanesulfonyl chloride (470 μL, 6.0 mmol, 3.0 equiv). After being stirred for 12 h at this temperature, the reaction mixture was brought to 25 °C, quenched with saturated aqueous NaHCO3 solution (3 mL), and diluted with CH2Cl2 (25 mL). Then the phases were separated, the aqueous layer was extracted with CH2Cl2 (2 × 25 mL), and the combined organic layers were washed with H2O (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 10:1, v/v) gave pure title compound (15, 289 mg, 0.798 mmol, 40% yield for two steps) as a colorless oil. 15: Rf = 0.60 (SiO2, hexanes/EtOAc, 4:1, v/v); [α]22 D = +107 (c = 1.0 in C6H6); IR (film) νmax 2955, 2930, 2858, 1706, 1657, 1471, 1463, 1255, 1033, 836, 775 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.52 (ddd, J = 6.1, 2.7, 1.0 Hz, 1 H), 6.61 (t, J = 7.6 Hz, 1 H), 6.33 (dd, J = 6.0, 1.8 Hz, 1 H), 5.76−5.69 (m, 1 H), 5.08−5.05 (m, 2 H), 3.83 (quint, J = 5.7 Hz, 1 H), 3.51−3.48 (m, 1 H), 2.69−2.64 (m, 1 H), 2.47−2.37 (m, 2 H), 2.18 (dt, J = 14.5, 8.5 Hz, 1 H), 1.46−1.43 (m, 2 H), 1.40−1.21 (m, 6 H), 0.91−0.84 (m, 12 H), 0.05 (s, 3 H), 0.05 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 196.4, 161.3, 138.5, 135.0, 134.3, 132.7, 117.7, 71.7, 43.1, 37.4, 37.1, 32.0, 26.0, 25.9, 25.0, 22.8, 18.2, 14.1, −4.3, −4.5 ppm; HR-MS (ESI-TOF) calcd for C22H39O2Si+ [M + H]+ 363.2714, found 363.2713. tert-Butyl Hex-5-enoate (16). To a stirred solution of hex-5-enoic acid (7.84 g, 57.7 mmol, 1.0 equiv) in tert-butanol (12.2 mL, 115 mmol, 2.0 equiv) at 40 °C were added anhydrous MgCl2 (612 mg, 5.77 mmol, 0.10 equiv) and Boc2O (18.2 mg, 75.0 mmol, 1.3 equiv). The mixture was stirred at 40 °C for 48 h, and the crude reaction mixture was diluted with H2O (50 mL) and extracted with Et2O (3 × 100 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, n-pentane/Et2O, 90:10, v/v) gave pure title compound (16, 6.98 g, 41.5 mmol, 72% yield) as a colorless oil. 16: Rf = 0.60 (SiO2, hexanes/EtOAc, 95:5, v/v); IR (film) νmax = 3079, 2978, 2933, 1729, 1642, 1366, 1252, 1147, 911, 845, 752 cm−1; 1 H NMR (600 MHz, CDCl3) δ 5.82−5.75 (m, 1 H), 5.06−4.94 (m, 2 H), 2.22 (t, J = 7.5 Hz, 2 H), 2.07 (q, J = 7.5 Hz, 2 H), 1.69 (quint, J = 7.5 Hz, 2 H), 1.44 (s, 9 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 173.1, 138.0, 115.2, 80.1, 35.0, 33.2, 28.2, 24.4 ppm; HRMS (ESI-TOF) calcd for C10H19O2+ [M + H]+ 171.1380, found 171.1386. tert-Butyl (5Z,12E,15S)-15-{[tert-Butyl(dimethyl)silyl]oxy}-11-oxoprosta-5,9,12-trien-1-oate (18). In a glovebox, trienone 15 (100 mg, 0.276 mmol, 1.0 equiv) and tert-butyl hex-5-enoate (16, 469 mg, 2.76 mmol, 10.0 equiv) were dissolved in 0.3 mL of THF. To this solution was added catalyst 17 (20.4 mg, 0.0276 mmol, 0.1 equiv). The reaction vial was capped and taken outside the glovebox and stirred for 12 h at 35 °C. Then H2O (1 mL) was added to the reddishbrown mixture and further diluted with Et2O (25 mL), the phases were separated, the aqueous layer was extracted with Et2O (2 × 50 mL), and the combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 10:1, v/v) gave pure title compound (18, 57.3 mg, 0.113 mmol, 42% yield) as a colorless oil, and 53.0 mg of trienone 15 was recovered. 18: Rf = 0.50 (SiO2, hexanes/EtOAc, 4:1, v/v); [α]22 D = +89 (c = 1.0 in C6H6); IR (film) νmax 3007, 2957, 2930, 2857, 1728, 1705, 1656, 1582, 1366, 1251, 1144, 1066, 834, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.49 (dd, J = 5.7, 3.0 Hz, 1 H), 6.60 (t, J = 7.6 Hz, 1 H), 371


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(3aZ,6S,12Z,14aS,17aE,20S,26Z,28aS)-6,20-Dipentyl-5,10,11,14,14a,19,20,23,24,25,8,28a-dodecahydro-3H,8H-dicyclopenta[e,r][1,14]dioxacyclohexacosine-3,8,17,22(6H,9H)-tetrone (5a): Rf = 0.40 (SiO2, hexanes/EtOAc, 3:1, v/v); [α]22 D = +59 (c = 1.2 in C6H6); IR (film) νmax 3010, 2954, 2931, 2860, 1732, 1705, 1657, 1581, 1457, 1343, 1240, 1178, 1088, 823 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.52 (dd, J = 6.0, 2.5 Hz, 2 H), 6.49−6.46 (m, 2 H), 6.33 (dd, J = 6.0, 1.8 Hz, 2 H), 5.49−5.44 (m, 2 H), 5.41−5.36 (m, 2 H), 5.04−5.00 (m, 2 H), 3.43−3.41 (m, 2 H), 2.75−2.70 (m, 2 H), 2.61 (ddd, J = 14.6, 9.6, 7.9 Hz, 2 H), 2.42 (dt, J = 14.6, 6.0 Hz, 2 H), 2.28−2.18 (m, 4 H), 2.13−1.99 (m, 6 H), 1.68−1.58 (m, 8 H), 1.37−1.23 (m, 12 H), 0.87 (t, J = 6.7 Hz, 6 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 196.0, 172.8, 161.5, 139.8, 135.0, 131.6, 130.8, 126.1, 72.9, 43.4, 34.5, 34.3, 33.8, 31.7, 30.7, 26.9, 25.0, 24.8, 22.6, 14.1 ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents two equivalent C atoms; HR-MS (ESI-TOF) calcd for C40H56O6Na+ [M + Na]+ 655.3969, found 655.3966. (3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS)6,20,34-Tripentyl-5,10,11,14,14a,19,20,24,25,28,28a,33,34,37,38,39,42,42a-octadecahydro-3H,8H,22H-tricyclopenta[e,r,e 1 ][1,14,27]trioxacyclononatriacontine-3,8,17,22,31,36(6H,9H,23H)hexone (6a): Rf = 0.30 (SiO2, hexanes/EtOAc, 3:1, v/v); [α]22 D = +87 (c = 0.7 in C6H6); IR (film) νmax 3010, 2961, 2926, 2861, 1731, 1704, 1656, 1536, 1456, 1345, 1207, 1033, 808 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.50 (dd, J = 6.0, 2.5 Hz, 3 H), 6.51 (t, J = 7.6 Hz, 3 H), 6.33 (dd, J = 6.0, 1.8 Hz, 3 H), 5.47−5.43 (dt, J = 10.8, 7.4 Hz, 3 H), 5.36−5.32 (dt, J = 11.0, 7.1 Hz, 3 H), 5.00−4.96 (m, 3 H), 3.47−3.44 (m, 3 H), 2.66−2.56 (m, 6 H), 2.49 (ddd, J = 14.8, 7.9, 6.1 Hz, 3 H), 2.26 (td, J = 7.8, 3.3 Hz, 6 H), 2.19 (dt, J = 15.6, 8.2 Hz, 3 H), 2.02 (q, J = 7.4 Hz, 6 H), 1.70−1.54 (m, 12 H), 1.38−1.24 (m, 18 H), 0.87 (t, J = 6.7 Hz, 9 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 196.1, 172.9, 161.7, 139.6, 135.0, 131.7, 130.4, 125.9, 73.0, 43.3, 33.92, 33.87, 31.7, 30.3, 26.8, 25.1, 24.8, 22.6, 14.1 ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents three equivalent C atoms [exception: the signal at 33.87 ppm represents six C atoms]; HR-MS (ESI-TOF) calcd for C60H84O9Na+ [M + Na]+ 971.6008, found 971.6014. (3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS,45aE,48S,54Z)-6,20,34,48-Tetrapentyl-5,10,11,14,14a,19,20,24,25,28,28a,33,34,38,39,42,42a,47,48,51,52,53,56,56a-tetracosahydro3H,8H,22H,36H-tetracyclopenta[e,r,e1,r1][1,14,27,40]tetraoxacyclodopentacontine-3,8,17,22,31,36,45,50(6H,9H,23H,37H)-octone (7a): Rf = 0.10 (SiO2, hexanes/EtOAc, 3:1, v/v); [α]22 D = +110 (c = 0.4 in C6H6); IR (film) νmax 3010, 2961, 2927, 2861, 1731, 1704, 1656, 1535, 1456, 1346, 1207, 1033, 810 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.50 (dd, J = 6.1, 2.6 Hz, 4 H), 6.52 (t, J = 7.6 Hz, 4 H), 6.32 (dd, J = 6.0, 1.8 Hz, 4 H), 5.47−5.43 (m, 4 H), 5.35−5.31 (m, 4 H), 5.02−4.95 (m, 4 H), 3.48−3.46 (m, 4 H), 2.64− 2.49 (m, 12 H), 2.28−2.18 (m, 12 H), 2.02 (q, J = 7.4 Hz, 8 H), 1.68−1.53 (m, 16 H), 1.37−1.25 (m, 24 H), 0.87 (t, J = 6.6 Hz, 12 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 196.1, 173.0, 161.7, 139.6, 135.0, 131.7, 130.3, 125.8, 72.9, 43.3, 33.92, 33.89, 33.7, 31.6, 30.3, 26.8, 25.1, 24.8, 22.6, 14.1 ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents four equivalent C atoms; HR-MS (ESI-TOF) calcd for C80H112O12Na+ [M + Na]+ 1287.8046, found 1287.8052. (4R)-2-Chloro-4-(prop-2-en-1-yl)cyclopent-2-en-1-one (19). To a stirred solution of cyclopentenone 14 (2.44 g, 20.0 mmol, 1.0 equiv) in methanol (60.0 mL) at −10 °C was added a solution of 30% hydrogen peroxide (1.80 mL, 40.0 mmol, 2.0 equiv) in one portion. To the above mixture was added dropwise 10% KOH (2.20 mL, 4.00 mmol, 0.2 equiv) and the mixture continued to stir at −10 °C for 6 h. The reaction mixture was neutralized with 0.5 N HCl (6.0 mL), stirred for an additional 5 min at −10 °C, and concentrated by removal of methanol under reduced pressure. The resulting residual oil was dissolved in EtOAc and washed with H2O (2 × 10 mL) and brine (5 mL). The organic layer was then dried (Na2SO4) and concentrated under reduced pressure. The crude oil was taken to the next step without further purification. To a solution of above prepared epoxycyclopentanone in anhydrous acetonitrile (60 mL) at 25 °C was added anhydrous

6.32 (dd, J = 6.0, 1.8 Hz, 1 H), 5.49−5.45 (m, 1 H), 5.38−5.34 (m, 1 H), 3.83 (quint, J = 5.8 Hz, 1 H), 3.47−3.45 (m, 1 H), 2.64−2.60 (m, 1 H), 2.46−2.38 (m, 2 H), 2.21−2.16 (m, 3 H), 2.04−2.00 (m, 2 H), 1.62 (quint, J = 7.5 Hz, 2 H), 1.46−1.42 (m, 11 H), 1.40−1.23 (m, 6 H), 0.88−0.86 (m, 12 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 196.4, 172.9, 161.6, 138.7, 135.0, 132.7, 131.7, 125.9, 80.2, 71.6, 43.5, 37.41, 37.38, 35.0, 32.0, 30.6, 28.2, 26.8, 26, 25.1, 25, 22.7, 18.2, 14.1, −4.3, −4.5 ppm; HR-MS (ESI-TOF) calcd for C30H52O4SiNa+ [M + Na]+ 527.3527, found 527.3526. (5Z,12E,15S)-15-Hydroxy-11-oxoprosta-5,9,12-trien-1-oic Acid (Δ12-PGJ2, 1). To a stirred solution of tert-butyl ester 18 (100 mg, 0.198 mmol, 1.0 equiv) in MeCN (0.5 mL) at 0 °C was added dropwise a solution of HBF4 (48% aq, 500 μL, 4.96 mmol, 25 equiv). After being stirred for 3 h at this temperature, the reaction mixture was quenched with brine (30 mL) and extracted with EtOAc (5 × 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Flash column chromatography (SiO2; hexanes/EtOAc, 1:4, v/v) yielded pure title compound (1, 47.0 mg, 142 μmol, 71% yield) as a colorless oil. 1: Rf = 0.40 (EtOAc); [α]22 D = +108 (c = 0.1 in C6H6); IR (film) νmax 3393, 3010, 2960, 2929, 2858, 1706, 1647, 1408, 1239, 1084, 799 cm−1; 1H NMR (600 MHz, C6D6) δ 7.01 (dd, J = 6.1, 2.5 Hz, 1 H), 6.82 (t, J = 7.7 Hz, 1 H), 6.24 (dd, J = 6.0, 1.8 Hz, 1 H), 5.31−5.22 (m, 2 H), 3.68−3.64 (m, 1 H), 3.15−3.13 (m, 1 H), 2.57 (ddd, J = 14.1, 7.1, 4.4 Hz, 1 H), 2.41 (dt, J = 14.4, 7.1 Hz, 1 H), 2.28 (ddd, J = 14.4, 8.0, 5.9 Hz, 1 H), 2.14 (t, J = 6.7 Hz, 2 H), 2.01−1.95 (m, 3 H), 1.57−1.36 (m, 5 H), 1.32−1.16 (m, 5 H), 0.91 (t, J = 7.2 Hz, 3 H) ppm; 13C{1H} NMR (151 MHz, C6D6) δ 195.8, 177.5, 161.2, 139.8, 135.1, 132.2, 131.6, 126.6, 71.4, 43.9, 37.7, 37.1, 33.1, 32.2, 30.8, 26.7, 25.8, 24.8, 23.1, 14.3 ppm; HR-MS (ESI-TOF) calcd for C20H30O4Na [M + Na]+ 357.2036, found 357.2032. (5Z,12E,15S)-1,15-Epoxyprosta-5,9,12-triene-1,11-dione (4a). To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (15 mg, 42 μmol, 1.4 equiv) and 4-(dimethylamino)pyridine (22 mg, 180 μmol, 6.0 equiv) in CH2Cl2 (20 mL) was added a solution of Δ12-PGJ2 (1, 10 mg, 30 μmol, 1.0 equiv) in CH2Cl2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After being stirred for an additional 2 h, the reaction mixture was washed sequentially with satd aqueous NaHCO3 solution (10 mL), aqueous HCl (0.2 M; 10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2; hexanes/EtOAc, 3:1, v/v) yielded pure title compound (4a, 6.8 mg, 22 μmol, 72% yield) as a white amorphous solid. 4a: Rf = 0.40 (SiO2, hexanes/EtOAc, 7:3, v/v); [α]22 D = +26 (c = 0.3 in C6H6); IR (film) νmax 2930, 2859, 1727, 1704, 1655, 1581, 1456, 1328, 1243, 1151, 1048, 833 cm−1; 1H NMR (600 MHz, C6D6) δ 6.78 (ddd, J = 6.1, 2.6, 0.9 Hz, 1 H), 6.66 (ddt, J = 11.4, 4.8, 1.3 Hz, 1 H), 6.20 (dd, J = 6.1, 1.9 Hz, 1 H), 5.20−5.08 (m, 3 H), 3.22−3.20 (m, 1 H), 2.43 (ddd, J = 14.5, 9.2, 5.7 Hz, 1 H), 2.37−2.31 (m, 1 H), 2.26 (ddd, J = 15.1, 11.4, 9.5 Hz, 1 H), 2.15−2.07 (m, 2 H), 2.04− 1.96 (m, 2 H), 1.86−1.81 (m, 1 H), 1.56−1.46 (m, 1 H), 1.41−1.08 (m, 9 H), 0.87 (t, J = 7.2 Hz, 3 H) ppm; 13C{1H} NMR (151 MHz, C6D6) δ 194.7, 172.4, 159.6, 140.3, 135.6, 131.8, 130.9, 125.5, 73.2, 43.5, 34.4, 34.1, 32.8, 31.9, 28.5, 26.1, 25.5, 24.6, 22.9, 14.2 ppm; HRMS (ESI-TOF) calcd for C20H28O3Na [M + Na]+ 339.1931, found 339.1925. Δ12-PGJ2 Macrolactones 5a, 6a, and 7a. To a stirred solution of Δ12-PGJ2 (1, 49 mg, 150 μmol, 1.0 equiv) in CH2Cl2 (10 mL) at 25 °C was added seqentially Et3N (42 μL, 300 μmol, 2.0 equiv), (dimethylamino)pyridine (1.8 mg, 15 μmol, 0.1 equiv), and 2-methyl6-nitrobenzoic anhydride (77 mg, 230 μmol, 1.5 equiv). After being stirred for an additional 12 h, the reaction mixture was washed sequentially with satd aqueous NaHCO3 solution (10 mL), satd aqueous NH4Cl (10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by PTLC (SiO2, hexanes/EtOAc, 3:1, v/v) to give dimer 5a (13 mg, 20 μmol, 27% yield), trimer 6a (5.1 mg, 5.3 μmol, 10% yield), and tetramer 7a (4.6 mg, 3.6 μmol, 9% yield) as colorless oils. 372


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0.420 mmol, 55% yield) as a colorless oil, and 102 mg of trienone 20 was recovered. 22: Rf = 0.40 (SiO2, hexanes/EtOAc, 10:1, v/v); [α]22 D = +100 (c = 1.0 in C6H6); IR (film) νmax 3006, 2955, 2930, 2858, 1728, 1716, 1661, 1590, 1462, 1366, 1253, 1145, 836 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.36 (dd, J = 2.9, 0.9 Hz, 1 H), 6.76 (ddt, J = 8.3, 6.9, 1.2 Hz, 1 H), 5.52−5.48 (m, 1 H), 5.37−5.32 (m, 1 H), 3.84 (quint, J = 5.9 Hz, 1 H), 3.48−3.45 (m, 1 H), 2.64 (dt, J = 13.9, 5.9 Hz, 1 H), 2.47−2.39 (m, 2 H), 2.22−2.17 (m, 3 H), 2.08−1.97 (m, 2 H), 1.66− 1.59 (m, 2 H), 1.44 (s, 11 H), 1.39−1.24 (m, 6 H), 0.84−0.80 (m, 12 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.3, 172.9, 153.9, 137.2, 136.5, 135.6, 132.4, 125.3, 80.2, 71.5, 41.6, 37.5, 37.2, 35.0, 32.0, 30.6, 28.2, 26.8, 25.9, 25.0, 24.9, 22.7, 18.2, 14.1, −4.3, −4.5 ppm; HR-MS (ESI-TOF) calcd for C30H51O4SiClNa+ [M + Na]+ 561.3137, found 561.3141. (5Z,12E,15S)-10-Chloro-15-hydroxy-11-oxoprosta-5,9,12-trien-1oic Acid (23). To a stirred solution of tert-butylester 22 (100 mg, 0.185 mmol, 1.0 equiv) in MeCN (0.5 mL) at 0 °C was added dropwise a solution of HBF4 (48% aq, 580 μL, 4.62 mmol, 25 equiv). After being stirred for 3 h at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Flash column chromatography (SiO2; hexanes/EtOAc, 1:4, v/v) yielded pure title compound (23, 62.0 mg, 0.168 μmol, 91% yield) as a colorless oil. 23: Rf = 0.50 (SiO2, hexanes/EtOAc, 1:4, v/v); [α]22 D = +102 (c = 0.2 in C6H6); IR (film) νmax 3397, 2955, 2931, 2857, 1710, 1660, 1559, 1460, 1406, 1255, 1087, 836 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 2.9 Hz, 1 H), 6.73 (t, J = 7.8 Hz, 1 H), 5.54− 5.50 (m, 1 H), 5.44−5.40 (m, 1 H), 3.89−3.85 (m, 1 H), 3.49−3.46 (m, 1 H), 2.76−2.72 (m, 1 H), 2.56 (dt, J = 14.0, 6.8 Hz, 1 H), 2.47 (ddd, J = 14.9, 8.5, 6.2 Hz, 1 H), 2.35 (t, J = 7.1 Hz, 2 H), 2.17−2.04 (m, 3 H), 1.73−1.66 (m, 2 H), 1.59−1.43 (m, 3 H), 1.37−1.22 (m, 9 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.4, 177.4, 154.1, 137.4, 137.2, 134.4, 132.2, 125.6, 71.3, 42.0, 37.1, 36.8, 33.0, 31.8, 30.5, 26.6, 25.3, 24.5, 22.7, 14.1 ppm; HR-MS (ESI-TOF) calcd for C20H29O4ClNa+ [M + Na]+ 391.1647, found 391.1640. (5Z,12E,15S)-10-Chloro-1,15-epoxyprosta-5,9,12-triene-1,11dione (4b). To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (16 mg, 45 μmol, 1.5 equiv) and 4-(dimethylamino)pyridine (11 mg, 90 μmol, 3.0 equiv) in CH2Cl2 (20 mL) was added a solution of 10-chloro-Δ12-PGJ2 (23) (12 mg, 30.0 μmol, 1.0 equiv) in CH2Cl2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After being stirred for an additional 2 h, the reaction mixture was washed sequentially with satd aqueous NaHCO3 solution (10 mL), aqueous HCl (0.2 M; 10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2; hexanes/EtOAc, 4:1, v/v) yielded pure title compound (4b, 7.3 mg, 24 μmol, 69% yield) as a white solid. 4b: Rf = 0.60 (SiO2, hexanes/EtOAc, 4:1, v/v); mp = 91−92 °C; [α]22 D = −44 (c = 0.4 in C6H6); IR (film) νmax 3010, 2955, 2929, 2859, 1716, 1703, 1659, 1279, 1163, 939 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.41 (d, J = 2.9 Hz, 1 H), 6.67 (dd, J = 11.6, 4.6 Hz, 1 H), 5.41 (td, J = 10.4, 5.8 Hz, 1 H), 5.27−5.18 (m, 2 H), 3.72−3.69 (m, 1 H), 2.74−2.66 (m, 2 H), 2.54−2.43 (m, 3 H), 2.32 (ddd, J = 15.5, 9.1, 2.9 Hz, 1 H), 2.25 (ddd, J = 15.5, 9.1, 2.6 Hz, 1 H), 2.01−1.95 (m, 1 H), 1.65−1.45 (m, 5 H), 1.31−1.20 (m, 5 H), 0.89 (t, J = 6.7 Hz, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.3, 173.1, 153.5, 137.9, 137.3, 134.3, 132.5, 124.6, 73.2, 41.6, 34.3, 34.1, 32.8, 31.7, 28.5, 25.9, 25.1, 24.4, 22.6, 14.1 ppm; HR-MS (ESI-TOF) calcd for C20H27O3ClNa+ [M + Na]+ 373.1541, found 373.1545. 10-Chloro-Δ12-PGJ2 Macrolactones 5b, 6b, and 7b. To a stirred solution of 10-chloro-PGJ2 (23) (30 mg, 82 μmol, 1.0 equiv) in CH2Cl2 (10 mL) at 25 °C were added seqentially Et3N (23 μL, 160 μmol, 2.0 equiv), (dimethylamino)pyridine (1.0 mg, 8.2 μmol, 0.1 equiv), and 2-methyl-6-nitrobenzoic anhydride (42 mg, 120 μmol, 1.5 equiv). After being stirred for an additional 12 h, the reaction mixture

LiCl (8.42 g, 200 mmol, 10.0 equiv) followed by Amberlyst 15 ionexchange resin (12.0 g, 600 wt%, H+ form). The reaction flask was covered with aluminium foil, and the reaction was allowed to stir in the dark for 24 h. The reaction mixture was filtered through a plug of Celite and concentrated to dryness. Flash column chromatography (SiO2; n-pentane/Et2O, 4:1, v/v) yielded pure title compound (19, 1.86 g, 11.9 mmol, 60% yield for two steps) as a colorless oil. 19: Rf = 0.30 (SiO2, hexanes/EtOAc, 10:1, v/v); [α]22 D = +116 (c = 1.0 in C6H6); IR (film) νmax 3079, 2925, 1724, 1642, 1597, 1404, 1288, 1171, 965 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.52 (d, J = 2.8 Hz, 1 H), 5.76 (ddt, J = 17.0, 10.2, 6.9 Hz, 1 H), 5.15−5.11 (m, 2 H), 3.04−3.00 (m, 1 H), 2.68 (dd, J = 19.1, 6.4 Hz, 1 H), 2.34−2.23 (m, 2 H), 2.21 (dd, J = 19.1, 2.0 Hz, 1 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 200.5, 160.2, 136.1, 134.2, 118.3, 39.4, 38.6, 37.8 ppm; HR-MS (ESI-TOF) calcd for C8H10OCl+ [M + H]+ 157.0415, found 157.0413. (4S,5E)-5-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}octylidene]-2chloro-4-(prop-2-en-1-yl)cyclopent-2-en-1-one (20). To a premixed solution of enone 19 (314 mg, 2.01 mmol, 1.0 equiv) and aldehyde 12 (774 mg, 3.01 mmol, 1.5 equiv) in THF (10 mL) at −78 °C was added dropwise LDA (0.66 M in THF, 6.04 mL, 4.00 mmol, 2.0 equiv) over a period of 5 min. After being stirred for 20 min at this temperature, the light yellow reaction mixture was quenched with saturated aqueous NH4Cl solution (5 mL), diluted with Et2O (50 mL), and allowed to warm to 25 °C. Then the phases were separated, the aqueous layer was extracted with Et2O (2 × 75 mL), and the combined organic extracts were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/ EtOAc, 4:1, v/v) gave the expected aldol products, which were directly taken to the next step without further characterization. To a stirred solution of the aldol products in CH2Cl2 (20 mL) at 0 °C was added DMAP (2.44 g, 20.1 mmol, 10.0 equiv), and then, slowly and dropwise, methanesulfonyl chloride (440 μL, 6.03 mmol, 3.0 equiv). After being stirred for 12 h at this temperature, the reaction mixture was brought to 25 °C, quenched with saturated aqueous NaHCO3 solution (3 mL), and diluted with CH2Cl2 (25 mL). Then the phases were separated, the aqueous layer was extracted with CH2Cl2 (2 × 25 mL), and the combined organic layers were washed with H2 O (20 mL), dried (Na2 SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 10:1, v/v) gave pure title compound (20, 284 mg, 0.717 mmol, 36% yield for two steps) as a colorless oil. 20: Rf = 0.50 (SiO2, hexanes/EtOAc, 10:1, v/v); [α]22 D = +74 (c = 1.0 in C6H6); IR (film) νmax 3010, 2955, 2858, 1715, 1661, 1590, 1661, 1463, 1361, 1255, 1054, 835, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 2.9 Hz, 1 H), 6.76 (ddd, J = 8.5, 7.1, 1.4 Hz, 1 H), 5.72 (ddt, J = 17.0, 10.2, 6.9 Hz, 1 H), 5.12−5.08 (m, 2 H), 3.85 (quint, J = 5.9 Hz, 1 H), 3.51 (dt, J = 8.4, 4.2 Hz, 1 H), 2.69 (dt, J = 10.3, 5.2 Hz, 1 H), 2.47−2.38 (m, 2 H), 2.18 (dt, J = 15.4, 8.8 Hz, 1 H), 1.46−1.42 (m, 2 H), 1.39−1.23 (m, 6 H), 0.88−0.85 (m, 12 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.3, 153.7, 137.2, 136.3, 135.6, 133.7, 118.3, 71.5, 41.2, 37.5, 37.2, 37.0, 32.0, 25.9, 25.0, 22.7, 18.2, 14.1, −4.3, −4.5 ppm; HR-MS (ESITOF) calcd for C22H38O2SiCl+ [M + H]+ 397.2324, found 397.2322. tert-Butyl (5Z,12E,15S)-15-{[tert-Butyl(dimethyl)silyl]oxy}-10chloro-11-oxoprosta-5,9,12-trien-1-oate (22). In a glovebox, trienone 20 (300 mg, 0.757 mmol, 1.0 equiv) and tert-butyl hex-5enoate (16, 1.28 g, 7.57 mmol, 10.0 equiv) were dissolved in THF (1.0 mL). To this solution was added catalyst 21 (50.4 mg, 0.0757 mmol). The reaction vial was capped, taken outside the glovebox, and stirred for 12 h at 25 °C. The reddish-brown mixture was quenched with H2O (1 mL) and diluted with Et2O (25 mL). Then the phases were separated, the aqueous layer was extracted with Et2O (2 × 50 mL), and the combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 97:3, v/v) gave pure title compound (22, 226 mg, 373


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and concentrated under reduced pressure. Flash column chromatography (SiO2, hexanes/EtOAc, 10:1, v/v → 4:1, v/v) yielded the pure title compound (1.17 g, 3.35 mmol, 76% yield) as a colorless oil. 25: Rf = 0.11 (SiO2, hexanes/EtOAc, 5:1, v/v); [α]22 D = −4 (c = 1.0 in C6H6); IR (film) νmax 3441, 2942, 2864, 1613, 1514, 1249, 1139, 1088, 1035, 821, 656 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.24 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 4.45 (s, 2 H), 3.80 (s, 4 H), 3.73−3.66 (m, 1 H), 3.62 (ddd, J = 9.3, 7.9, 4.6 Hz, 1 H), 2.57 (brs, 1 H), 2.07 (qt, J = 10.9, 7.8 Hz, 2 H), 1.78−1.66 (m, 2 H), 1.64−1.35 (m, 6 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 159.5, 130.0, 129.5, 127.3 (q, J = 276.3 Hz), 114.0, 73.2, 71.4, 69.1, 55.4, 37.1, 36.5, 33.9 (q, J = 28.5 Hz), 24.9, 22.1 (q, J = 2.8 Hz) ppm; HR-MS (ESITOF) calcd for C16H23O3F3Na+ [M + Na]+ 343.1492, found 343.1483. tert-Butyl(dimethyl)({(3S)-8,8,8-trifluoro-1-[(4-methoxybenzyl)oxy]octan-3-yl}oxy)silane (26). To a stirred solution of alcohol 25 (1.53 g, 4.79 mmol, 1.0 equiv) in CH2Cl2 (15 mL) at 0 °C were added imidazole (0.848 g, 12.5 mmol, 2.6 equiv) and TBSCl (0.940 g, 6.23 mmol, 1.3 equiv). The reaction mixture was warmed to 25 °C and stirred for 12 h. The resulting mixture was then quenched by addition of satd aqueous NH4Cl solution (40 mL) and stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 40 mL). The combined organic extracts were washed sequentially with H2O (2 × 75 mL), brine (75 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 20:1, v/v →10:1, v/v) gave pure title compound (26, 1.94 g, 4.46 mmol, 93% yield) as a colorless oil. 26: Rf = 0.70 (SiO2, hexanes/EtOAc, 5:1, v/v); [α]22 D = +5 (c = 1.0 in C6H6); IR (film) νmax 2951, 2932, 2857, 1613, 1514, 1249, 1092, 1039, 835, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.28−7.22 (m, 2 H), 6.93−6.84 (m, 2 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.39 (d, J = 11.5 Hz, 1 H), 3.83 (quint, J = 5.7 Hz, 1 H), 3.80 (s, 3 H), 3.50 (t, J = 6.5 Hz, 2 H), 2.12−1.97 (m, 2 H), 1.76−1.70 (m, 2 H), 1.58−1.48 (m, 2 H), 1.49−1.32 (m, 4 H), 0.88 (s, 9 H), 0.04 (s, 6 H) ppm; 13 C{1H} NMR (151 MHz, CDCl3) δ 159.3, 130.8, 129.4, 127.4 (q, J = 276.3 Hz), 113.9, 72.8, 69.3, 66.9, 55.4, 37.13, 37.12, 33.9 (q, J = 28.2 Hz), 26.0, 24.3, 22.3 (q, J = 2.9 Hz), 18.2, −4.3, −4.5 ppm; HRMS (ESI-TOF) calcd for C22H37O3F3SiNa+ [M + Na]+ 457.2356, found 457.2349. (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-8,8,8-trifluorooctan-1-ol (S3). To a vigorously stirred solution of PMB ether 26 (1.79 g, 4.12 mmol, 1.0 equiv) in CH2Cl2/H2O (10:1, v/v, 22 mL) at 0 °C was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.40 g, 6.18 mmol, 1.5 equiv) at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for an additional 1.5 h before being quenched by the addition of satd aqueous NaHCO3 solution (25 mL), and the mixture was stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted with Et2O (3 × 40 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 15:1, v/v →5:1, v/v) gave pure title compound (S3, 1.14 g, 3.63 mmol, 88% yield) as a colorless oil. S3: Rf = 0.36 (SiO2, hexanes/EtOAc, 5:1, v/v); [α]22 D = +15 (c = 0.25 in C6H6); IR (film) νmax 3351, 2951, 2931, 2886, 2859, 1256, 1141, 1057, 835, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 3.92 (ddd, J = 12.3, 6.2, 4.2 Hz, 1 H), 3.81 (ddd, J = 10.7, 8.1, 4.6 Hz, 1 H), 3.71 (dt, J = 10.9, 5.5 Hz, 1 H), 2.12 (s, 1 H), 2.11−2.02 (m, 2 H), 1.83−1.76 (m, 1 H), 1.66 (dtd, J = 14.3, 6.1, 4.6 Hz, 1 H), 1.60− 1.49 (m, 4 H), 1.44−1.32 (m, 2 H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 127.3 (q, J = 276.3 Hz), 71.3, 60.3, 38.1, 36.6, 33.9 (q, J = 28.5 Hz), 26.0, 24.6, 22.3 (q, J = 2.9 Hz), 18.1, −4.3, −4.5 ppm; HR-MS (ESI-TOF) calcd for C14H30O2F3Si+ [M + H]+ 315.1962, found 315.1962. (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-8,8,8-trifluorooctanal (27). To a solution of primary alcohol S3 (675 mg, 2.59 mmol, 1.0 equiv) in CH2Cl2 (25 mL) at 0 °C was added Dess−Martin periodinane (2.20 g, 5.18 mmol, 2.0 equiv). The reaction mixture was warmed to 25 °C and stirred for 2 h. The reaction was then quenched by addition of satd aqueous Na2S2O3 (5 mL) and satd aqueous NaHCO3

was washed sequentially with satd aqueous NaHCO3 solution (3 mL), satd aqueous NH4Cl (3 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by PTLC (SiO2, hexanes/EtOAc, 3:1, v/v) to give dimer 5b (6.2 mg, 3.0 μmol, 20% yield), trimer 6b (2.8 mg, 2.7 μmol, 8% yield), and tetramer 7b (1.4 mg, 1.0 μmol, 4% yield) as colorless oils. (3aZ,6S,12Z,14aS,17aE,20S,26Z,28aS)-2,16-Dichloro-6,20-dipentyl-5,10,11,14,14a,19,20,23,24,25,28,28a-dodecahydro-3H,8Hdicyclopenta[e,r][1,14]dioxacyclohexacosine-3,8,17,22(6H,9H)-tetrone (5b): Rf = 0.50 (SiO2, hexanes/EtOAc, 4:1, v/v); [α]22 D = +21 (c = 0.6 in C6H6); IR (film) νmax 3011, 2954, 2930, 2859, 1731, 1715, 1662, 1589, 1457, 1378, 1284, 1148, 1042, 763 cm−1; 1H NMR (600 MHz, C6D6) δ 6.82 (d, J = 2.9 Hz, 2 H), 6.72−6.63 (m, 2 H), 5.26− 5.22 (m, 2 H), 5.09−5.05 (m, 2 H), 5.00−4.96 (m, 2 H), 2.91−2.88 (m, 2 H), 2.52−2.47 (m, 2 H), 2.35 (ddd, J = 14.6, 9.5, 7.3 Hz, 2 H), 2.12−2.03 (m, 6 H), 1.88−1.84 (m, 6 H), 1.58−1.10 (m, 20 H), 0.88 (t, J = 7.2 Hz, 6 H) ppm; 13C{1H} NMR (151 MHz, C6D6) δ 185.2, 170.5, 151.3, 136.1, 135.9, 130.6, 130.2, 124.0, 70.8, 39.7, 32.4, 31.8, 30.0, 28.8, 25.1, 23.5, 23.1, 21.1, 12.3 ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents two equivalent C atoms; HR-MS (ESI-TOF) calcd for C40H54O6Cl2Na+ [M + Na]+ 723.3190, found 723.3162. (3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS)2,16,30-Trichloro-6,20,34-tripentyl-5,10,11,14,14a,19,20,24,25,28,28a,33,34,37,38,39,42,42a-octadecahydro-3H,8H,22Htricyclopenta[e,r,e1][1,14,27]trioxacyclononatriacontine-3,8,17,22,31,36(6H,9H,23H)-hexone (6b): Rf = 0.40 (SiO2, hexanes/EtOAc, 4:1, v/v); [α]22 D = +103 (c = 0.2 in C6H6); IR (film) νmax 3011, 2954, 2928, 2858, 1730, 1716, 1662, 1589, 1457, 1377, 1284, 1147, 1033, 737 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.37 (d, J = 2.9 Hz, 3 H), 6.65 (t, J = 7.6 Hz, 3 H), 5.50−5.46 (m, 3 H), 5.35−5.30 (m, 3 H), 5.00−4.96 (m, 3 H), 3.49−3.46 (m, 3 H), 2.67−2.51 (m, 9 H), 2.31− 2.19 (m, 9 H), 2.03 (q, J = 7.1 Hz, 6 H), 1.70−1.54 (m, 12 H), 1.38− 1.22 (m, 18 H), 0.88 (t, J = 6.7 Hz, 9 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.2, 172.9, 154.1, 137.4, 137.2, 133.1, 132.3, 125.3, 72.8, 41.4, 33.9, 33.8, 33.7, 31.6, 30.3, 26.8, 25.1, 24.7, 22.6, 14.1 ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents three equivalent C atoms; HR-MS (ESI-TOF) calcd for C60H81O9Cl3Na+ [M + Na]+ 1073.4838, found 1073.4848. (3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS,45aE,48S,54Z,56aS)-2,16,30,44-Tetrachloro-6,20,34,48-tetrapentyl5,10,11,14,14a,19,20,24,25,28,28a,33,34,38,39,42,42a,47,48,51,52,53,56,56a-tetracosahydro-3H,8H,22H,36H-tetracyclopenta[e,r,e1,r1][1,14,27,40]tetraoxacyclodopentacontine-3,8,17,22,31,36,45,50(6H,9H,23H,37H)-octone (7b): Rf = 0.30 (SiO2, hexanes/ EtOAc, 4:1, v/v); [α]22 D = +147 (c = 0.1 in C6H6); IR (film) νmax 2952, 2930, 1730, 1717, 1662, 1589, 1458, 1285, 1174, 1040, 867, 761 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.38 (dd, J = 2.9, 0.9 Hz, 4 H), 6.66 (t, J = 7.7 Hz, 4 H), 5.50−5.45 (m, 4 H), 5.34−5.30 (m, 4 H), 5.01−4.97 (m, 4 H), 3.51−3.49 (m, 4 H), 2.63 (dt, J = 11.8, 5.0 Hz, 4 H), 2.60−2.54 (m, 8 H), 2.28−2.20 (m, 12 H), 2.02 (q, J = 7.3 Hz, 8 H), 1.71−1.49 (m, 16 H), 1.37−1.22 (m, 24 H), 0.87 (t, J = 6.9 Hz, 12 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ188.2, 172.9, 154.2, 137.4, 137.1, 133.0, 132.3, 125.2, 72.7, 41.4, 33.92, 33.85, 33.6, 31.6, 30.2, 26.8, 25.1, 24.8, 22.6, 14.1 ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents four equivalent C atoms; HR-MS (ESI-TOF) calcd for C80H108O12Cl4Na+ [M + Na]+ 1423.6487, found 1423.6504. (3S)-8,8,8-Trifluoro-1-[(4-methoxybenzyl)oxy]octan-3-ol (25). To a stirred solution of cuprous iodide (155 mg, 814 μmol, 0.17 equiv) in THF (5 mL) at −78 °C was added (4,4,4-trifluorobutyl)magnesium bromide (1.75 g, 8.14 mmol, 1.7 equiv; prepared from 4-bromo-1,1,1trifluorobutane) in THF (30 mL), and the mixture was stirred for 15 min at −78 °C. Subsequently, a solution of epoxide 8 (997 mg, 4.79 mmol, 1.0 equiv) in THF (2 mL) was slowly added, and the resulting mixture was stirred for an additional 1 h before the reaction mixture was allowed to warm to 0 °C over 1 h and then quenched by the addition of aqueous saturated NH4Cl solution (15 mL). The layers were separated, and the aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic layers were dried (MgSO4), filtered, 374


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compound (29, 166 mg, 0.280 mmol, 61% yield after two cycles) as a colorless oil. 29: Rf = 0.45 (SiO2, hexanes/EtOAc, 4:1, v/v); [α]22 D = +89 (c = 1.0 in C6H6); IR (film) νmax 3007, 2951, 2931, 2858, 1716, 1661, 1590, 1367, 1256, 1142, 1088, 836, 775 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.37 (dd, J = 3.0, 0.9 Hz, 1 H), 6.73 (ddt, J = 8.0, 6.8, 1.2 Hz, 1 H), 5.53−5.49 (m, 1 H), 5.36−5.31 (m, 1 H), 3.86 (quint, J = 5.6 Hz, 1 H), 3.48−3.46 (m, 1 H), 2.64−2.61 (m, 1 H), 2.49−2.39 (m, 2 H), 2.24−2.16 (m, 3 H), 2.11−1.99 (m, 4 H), 1.68−1.52 (m, 5 H), 1.50− 1.34 (m, 12 H), 0.88 (s, 9 H), 0.05 (s, 6 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.3, 172.8, 154.0, 137.2, 136.7, 134.9, 132.5, 127.2 (q, J = 281.9 Hz), 125.0, 80.3, 71.0, 41.6, 37.2, 37.0, 35.0, 33.8 (q, J = 29.2 Hz), 30.5, 28.2, 26.8, 25.9, 24.9, 24.5, 22.1 (q, J = 3.2 Hz), 18.1, −4.3, −4.6 ppm; HR-MS (ESI-TOF) calcd for C30H48O4F3SiClNa+ [M + Na]+ 615.2855, found 615.2861. (5Z,12E,15S)-10-Chloro-20,20,20-trifluoro-15-hydroxy-11-oxoprosta-5,9,12-trien-1-oic Acid (30). To a stirred solution of tert-butyl ester 29 (120 mg, 0.203 mmol, 1.0 equiv) in MeCN (0.5 mL) at 0 °C was dropwise added a solution of HBF4 (48% aq, 610 μL, 5.07 mmol, 25 equiv). After being stirred for 3 h at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Flash column chromatography (SiO2; hexanes/EtOAc, 1:4, v/v) yielded pure title compound (30, 60.0 mg, 142 μmol, 71% yield) as a colorless oil. 30: Rf = 0.30 (SiO2, hexanes/EtOAc, 1:4, v/v); [α]22 D = +78 (c = 1.0 in C6H6); IR (film) νmax 3424, 3012, 2942, 2873, 1705, 1655, 1587, 1439, 1390, 1254, 1137, 1041, 836 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.44 (dd, J = 2.9, 0.9 Hz, 1 H), 6.71 (t, J = 7.6 Hz, 1 H), 5.55−5.50 (m, 1 H), 5.44−5.39 (m, 1 H), 3.89−3.85 (m, 1 H), 3.49− 3.46 (m, 1 H), 2.74 (dddd, J = 13.9, 7.6, 4.3, 1.5 Hz, 1 H), 2.58 (dt, J = 14.2, 6.9 Hz, 1 H), 2.47 (ddd, J = 14.8, 8.3, 6.3 Hz, 1 H), 2.36 (t, J = 6.8 Hz, 2 H), 2.15−2.04 (m, 5 H), 1.73−1.68 (m, 2 H), 1.64−1.42 (m, 6 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.5, 177.3, 154.2, 137.6, 137.2, 134.0, 132.3, 127.1 (q, J = 281.9 Hz), 125.5, 70.9, 41.9, 37.3, 36.4, 33.7 (q, J = 29.2 Hz), 32. 9, 30.5, 26.6, 24.9, 24.4, 21.9 (q, J = 3.2 Hz) ppm; HR-MS (ESI-TOF) calcd for C20H26O4F3ClNa+ [M + Na]+ 445.1364, found 445.1352. (5Z,12E,15S)-10-Chloro-20,20,20-trifluoro-1,15-epoxyprosta5,9,12-triene-1,11-dione (4c). To a stirred solution of 2-methyl-6nitrobenzoic anhydride (9.8 mg, 29 μmol, 1.5 equiv) and 4(dimethylamino)pyridine (6.9 mg, 57 μmol, 3.0 equiv) in CH2Cl2 (20 mL) was added a solution of Δ12-PGJ2 analogue 30 (8.0 mg, 19 μmol, 1.0 equiv) in CH2Cl2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After being stirred for an additional 2 h, the reaction mixture was washed sequentially with satd aqueous NaHCO3 solution (10 mL), aqueous HCl (0.2 M; 10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2; hexanes/ EtOAc, 3:1, v/v) yielded pure title compound (4c, 5.6 mg, 14 μmol, 73% yield) as a white solid. 4c: Rf = 0.60 (SiO2, hexanes/EtOAc, 3:1, v/v); mp = 92−93 °C; [α]22 D = −14 (c = 0.5 in C6H6); IR (film) νmax 3010, 2954, 2928, 2858, 1729, 1713, 1661, 1589, 1456, 1436, 1377, 1239, 1172, 109, 801 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.41 (dd, J = 3.0, 0.9 Hz, 1 H), 6.65 (dd, J = 11.5, 4.8 Hz, 1 H), 5.42 (td, J = 10.3, 5.7 Hz, 1 H), 5.27−5.21 (m, 2 H), 3.71−3.69 (m, 1 H), 2.74−2.68 (m, 2 H), 2.54− 2.43 (m, 3 H), 2.26 (ddd, J = 15.5, 9.1, 2.6 Hz, 1 H), 2.12−2.04 (m, 2 H), 2.01−1.95 (m, 1 H), 1.76−1.50 (m, 7 H), 1.48−1.38 (m, 2 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.2, 173.1, 153.5, 138.0, 137.3, 133.7, 132.5, 127.2 (q, J = 281.9 Hz), 124.6, 72.7, 41.5, 34.2, 34.0, 33.6 (q, J = 29.2 Hz), 32.7, 28.5, 25.9, 24.7, 24.4, 21.9 (q, J = 3.2 Hz) ppm; HR-MS (ESI-TOF) calcd for C20H25O3F3Cl+ [M + H]+ 405.1439, found 405.1429. Δ12-PGJ2 Macrolactones 5c, 6c, and 7c. To a stirred solution of Δ12-PGJ2 derivative 30 (40 mg, 100 μmol, 1.0 equiv) in CH2Cl2 (10 mL) at 25 °C were added seqentially Et3N (28 μL, 200 μmol, 1.0 equiv), dimethylaminopyridine (1.2 mg, 10 μmol, 0.1 equiv), and 2methyl-6-nitrobenzoic anhydride (52 mg, 150 μmol, 1.5 equiv). After

(5 mL) and stirred for 15 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 15 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2, hexanes/EtOAc, 20:1, v/v →10:1, v/v) yielded the title aldehyde (27, 511 mg, 1.98 mmol, 76% yield) as a colorless oil. 27: Rf = 0.63 (SiO2, hexanes/EtOAc, 5:1, v/v); [α]22 D = −8 (c = 1.0 in C6H6); IR (film) νmax 2953, 2932, 2859, 1726, 1254, 1139, 1088, 1052, 834, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 9.80 (t, J = 2.4 Hz, 1 H), 4.19 (quint, J = 5.8 Hz, 1 H), 2.53 (ddd, J = 5.7, 3.7, 2.4 Hz, 2 H), 2.12−2.02 (m, 2 H), 1.60−1.49 (m, 4 H), 1.48−1.34 (m, 2 H), 0.87 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 202.0, 127.3 (q, J = 276.3 Hz), 67.9, 51.0, 37.5, 33.8 (q, J = 28.4 Hz), 25.9, 24.4, 22.1 (q, J = 2.9 Hz), 18.1, −4.4, −4.5 ppm; HR-MS (ESI-TOF) calcd for C14H27O2F3SiNa+ [M + Na]+ 335.1625, found 335.1627. (4S,5E)-5-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}8,8,8trifluorooctylidene]-2-chloro-4-(prop-2-en-1-yl)cyclopent-2-en-1one (28). To a premixed solution of enone 19 (314 mg, 2.01 mmol, 1.0 equiv) and aldehyde 27 (936 mg, 3.01 mmol, 1.5 equiv) in THF (10 mL) at −78 °C was added dropwise LDA (0.66 M in THF, 6.02 mL, 4.09 mmol, 2.0 equiv) over a period of 5 min. After being stirred for 20 min at this temperature, the light yellow reaction mixture was quenched with saturated aqueous NH4Cl solution (5 mL), diluted with Et2O (50 mL), and allowed to warm to 25 °C. Then the phases were separated, the aqueous layer was extracted with Et2O (2 × 75 mL), and the combined organic extracts were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 4:1, v/v) gave the expected aldol products, which were directly taken to the next step without further characterization. To a stirred solution of the aldol products in CH2Cl2 (20 mL) at 0 °C was added DMAP (2.44 g, 20.1 mmol, 10.0 equiv) and then, slowly and dropwise, methanesulfonyl chloride (440 μL, 6.03 mmol, 3.0 equiv). After being stirred for 12 h at this temperature, the reaction mixture was brought to 25 °C, quenched with saturated aqueous NaHCO3 solution (3 mL), and diluted with CH2Cl2 (25 mL), the phases were separated, the aqueous layer was extracted with CH2Cl2 (2 × 25 mL), and the combined organic layers were washed with H2O (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 10:1, v/v) gave pure title compound (28, 309 mg, 0.668 mmol, 33% yield) as a colorless oil. 28: Rf = 0.60 (SiO2, hexanes/EtOAc, 4:1, v/v); [α]22 D = +75 (c = 1.0 in C6H6); IR (film) νmax 2952, 2931, 2859, 1714, 1661, 1590, 1463, 1257, 1140, 1081, 836 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.40 (dd, J = 2.9, 0.9 Hz, 1 H), 6.73 (ddt, J = 8.3, 7.0, 1.2 Hz, 1 H), 5.72 (dddd, J = 16.7, 10.3, 7.8, 6.3 Hz, 1 H), 5.13−5.08 (m, 2 H), 3.88− 3.85 (m, 1 H), 3.52−3.49 (m, 1 H), 2.70−2.66 (m, 1 H), 2.49−2.38 (m, 2 H), 2.21−2.16 (m, 1 H), 2.11−2.03 (m, 2 H), 1.60−1.52 (m, 2 H), 1.51−1.34 (m, 4 H), 0.88 (s, 9 H), 0.05 (s, 6 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.3, 153.4, 137.3, 136.5, 134.9, 133.6, 127.3 (q, J = 281.9 Hz), 118.4, 71.0, 41.2, 37.2, 37.03, 37.00, 33.8 (q, J = 29.2 Hz), 25.9, 24.5, 22.1 (q, J = 3.2 Hz), 18.1, −4.3, −4.6 ppm; HR-MS (ESI-TOF) calcd for C22H35O2F3SiCl+ [M + H]+ 451.2041, found 451.2032. tert-Butyl (5Z,12E,15S)-15-{[tert-Butyl(dimethyl)silyl]oxy}-10chloro-20,20,20-trifluoro-11-oxoprosta-5,9,12-trien-1-oate (29). In a glovebox were dissolved trienone 28 (220 mg, 0.478 mmol, 1.0 equiv) and tert-butyl hex-5-enoate (16, 800 mg, 4.78 mmol, 10.0 equiv) in THF (0.80 mL). To this solution was added catalyst 17 (33.2 mg, 0.0478 mmol, 0.1 equiv). The reaction vial was capped, taken outside the glovebox, and stirred for 12 h at 35 °C. The reddishbrown mixture was quenched with H2O (1 mL) and diluted with Et2O (25 mL), the phases were separated, the aqueous layer was extracted with Et2O (2 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 10:1, v/v) gave pure title 375


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concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/Et2O, 20:1, v/v → 6:1, v/v) gave pure title compound (31, 1.57 g, 6.34 mmol, 62% yield) as a pale yellow oil. 31: Rf = 0.40 (SiO2, hexanes/EtOAc, 10:1, v/v); [α]22 D = +52.9 (c = 1.0 in CHCl3); IR (film) νmax 3076, 2978, 2918, 1802, 1708, 1640, 1573, 1279, 1157, 994, 917, 903, 740 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.95 (dd, J = 2.7, 0.9 Hz, 1 H), 5.80−5.71 (m, 1 H), 5.15− 5.10 (m, 2 H), 3.11−3.06 (m, 1 H), 2.66 (ddd, J = 18.9, 6.5, 1.5 Hz, 1 H), 2.34−2.29 (m, 1 H), 2.27−2.22 (m, 1 H), 2.18 (dt, J = 18.9, 1.9 Hz, 1 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 203.2, 172.5, 134.1, 118.2, 102.8, 43.0, 38.4, 37.3 ppm; HR-MS (ESI-TOF) calcd for C8H10OI+ [M + H]+ 248.9771, found 248.9766. (4S,5E)-5-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-8,8,8-trifluorooctylidene]-2-iodo-4-(prop-2-en-1-yl)cyclopent-2-en-1-one (32). To a premixed solution of iodo enone 31 (917 mg, 3.69 mmol, 1.0 equiv) and aldehyde (1.40 g, 5.55 mmol, 1.5 equiv) in THF (40 mL) at −78 °C was added dropwise LDA (1 M in THF, 7.4 mL, 7.4 mmol, 2.0 equiv) over a period of 5 min. After being stirred for 30 min at this temperature, the orange reaction mixture was quenched with saturated aqueous NH4Cl solution (50 mL), diluted with Et2O (50 mL), and allowed to warm to 25 °C. The phases were separated, the aqueous layer was extracted with Et2O (2 × 75 mL), and the combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/ EtOAc, 20:1, v/v →18:1, v/v) gave the pure aldol products (1.55 g, 2.76 mmol, 75% yield) as an orange oil. To a stirred solution of the aldol products (1.55 g, 2.76 mmol, 1.0 equiv) in CH2Cl2 (30 mL) at 0 °C was added DMAP (3.36 g, 27.6 mmol, 10.0 equiv) and then, slowly and dropwise, methanesulfonyl chloride (640 μL, 5.97 mmol, 3.0 equiv). After being stirred for 12 h at the same temperature, the reaction mixture was brought to 25 °C, quenched with saturated aqueous NaHCO3 solution (5 mL), and diluted with CH2Cl2 (25 mL). Then the phases were separated, the aqueous layer was extracted with CH2Cl2 (2 × 25 mL), and the combined organic layers were washed with H2O (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/Et2O, 20:1, v/v →15:1, v/v) gave pure title compound (32, 600 mg, 1.11 mmol, 30% yield for two steps) as a pale yellow oil. 32: Rf = 0.62 (SiO2, hexanes/EtOAc, 4:1, v/v); [α]22 D = +37.9 (c = 0.8 in CHCl3); IR (film) νmax 2951, 2930, 2858, 1707, 1658, 1569, 1471, 1463, 1389, 1257, 1139, 1080, 918, 836, 775 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 2.8 Hz, 1 H), 6.73 (t, J = 7.7 Hz, 1 H), 5.75−5.68 (m, 1 H), 5.14−5.06 (m, 2 H), 3.86 (p, J = 5.8 Hz, 1 H), 3.57 (dt, J = 8.1, 3.6 Hz, 1 H), 2.67−2.62 (m, 1 H), 2.48−2.36 (m, 2 H), 2.18 (dt, J = 14.6, 8.5 Hz, 1 H), 2.10−2.02 (m, 2 H), 1.64− 1.50 (m, 2 H), 1.50−1.33 (m, 4 H), 0.88 (s, 9 H), 0.05 (s, 6 H) ppm; 13 C{1H} NMR (151 MHz, CDCl3) δ 190.8, 166.1, 134.5, 134.2, 133.6, 127.2 (q, J = 276.4 Hz), 118.4, 104.2, 71.0, 45.8, 37.3, 37.0, 36.9, 33.8 (q, J = 28.4 Hz), 25.9, 24.5, 22.1 (q, J = 3.4 Hz), 18.1, −4.3, −4.6 ppm; HR-MS (ESI-TOF) calcd for C22H35O2F3ISi+ [M + H]+ 543.1398, found 543.1401. tert-Butyl (5Z,12E,15S)-15-{[tert-Butyl(dimethyl)silyl]oxy}20,20,20-trifluoro-10-iodo-11-oxoprosta-5,9,12-trien-1-oate (33). In a glovebox, trienone (126 mg, 0.231 mmol, 1.0 equiv) and tertbutyl-hex-5-enoate (16, 400 mg, 2.24 mmol, 10.0 equiv) were dissolved in 0.6 mL of THF. To this solution was added catalyst 17 (17.2 mg, 0.0232 mmol, 0.1 equiv). The reaction vial was capped and taken outside the glovebox and stirred for 12 h at 35 °C. Then H2O (1 mL) was added to the reddish-brown mixture and further diluted with Et2O (25 mL), the phases were separated, the aqueous layer was extracted with Et2O (2 × 50 mL), and the combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, hexanes/EtOAc, 22:1, v/v) gave pure title compound (33, 115 mg, 0.17 mmol, 73% yield after two cycles) as a colorless oil.

being stirred for an additional 12 h, the reaction mixture was washed sequentially with satd aqueous NaHCO3 solution (10 mL), satd aqueous NH4Cl (10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by PTLC (SiO2, hexanes/EtOAc, 3:1, v/v) to give dimer 5c (7.6 mg, 9.4 μmol, 19% yield), trimer 6c (3.7 mg, 3.0 μmol, 9% yield), and tetramer 7c (3.0 mg, 1.9 μmol, 8% yield) as colorless oils. (3aZ,6S,12Z,14aS,17aE,20S,26Z,28aS)-2,16-Dichloro-6,20-bis(5,5,5-trifluoropentyl)-5,10,11,14,14a,19,20,23,24,25,28,28a-dodecahydro-3H,8H-dicyclopenta[e,r][1,14]dioxacyclohexacosine-3,8,17,22(6H,9H)-tetrone (5c): Rf = 0.40 (SiO2, hexanes/EtOAc, 3:1, v/ v); [α]22 D = +10 (c = 0.6 in C6H6); IR (film) νmax 2947, 2873, 1732, 1662, 1589, 1256, 1143, 1044 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 2.8 Hz, 2 H), 6.61 (t, J = 7.7 Hz, 2 H), 5.52−5.48 (m, 2 H), 5.40−5.36 (m, 2 H), 5.04−5.00 (m, 2 H), 3.45−3.42 (m, 2 H), 2.76−2.72 (m, 2 H), 2.65 (ddd, J = 14.6, 9.5, 7.4 Hz, 2 H), 2.45 (dt, J = 14.7, 6.2 Hz, 2 H), 2.31−2.19 (m, 4 H), 2.17−2.03 (m, 10 H), 1.68−1.36 (m, 16 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.1, 172.7, 153.9, 137.8, 137.3, 132.8, 132.2, 127.2 (q, J = 281.9 Hz), 125.5, 72.4, 41.5, 34.2, 33.8, 33.69, 33.67 (q, J = 31.2 Hz), 30.6, 26.9, 24.6, 24.5, 21.8 (q, J = 3.2 Hz) ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents two equivalent C atoms; HR-MS (ESI-TOF) calcd for C40H49O6F6Cl2+ [M + H]+ 809.2805, found 809.2780. (3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS)2,16,30-Trichloro-6,20,34-tris(5,5,5-trifluoropentyl)-5,10,11,14,14a,19,20,24,25,28,28a,33,34,37,38,39,42,42a-octadecahydro3H,8H,22H-tricyclopenta[e,r,e1][1,14,27]trioxacyclononatriacontine-3,8,17,22,31,36(6H,9H,23H)-hexone (6c): Rf = 0.30 (SiO2, hexanes/EtOAc, 3:1, v/v); [α]22 D = +40 (c = 0.3 in C6H6); IR (film) νmax 2922, 2927, 2852, 1733, 1661, 1589, 1440, 1258, 1143, 1033 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.38 (t, J = 2.6 Hz, 3 H), 6.63 (t, J = 7.6 Hz, 3 H), 5.50−5.46 (m, 3 H), 5.35−5.30 (m, 3 H), 5.00−4.96 (m, 3 H), 3.49−3.46 (m, 3 H), 2.66−2.50 (m, 9 H), 2.30− 2.19 (m, 9 H), 2.11−2.01 (m, 12 H), 1.70−1.35 (m, 24 H) ppm; 13 C{1H} NMR (151 MHz, CDCl3) δ 188.1, 172.9, 154.2, 137.6, 137.2, 132.5, 132.3, 127.2 (q, J = 281.9 Hz), 125.2, 72.3, 41.4, 33.7, 33.6 (q, J = 31.2 Hz), 33.6, 33.5, 30.3, 26.7, 24.7, 24.6, 21.8 (q, J = 3.2 Hz) ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents three equivalent C atoms; HR-MS (ESITOF) calcd for C60H73O9F9Cl3+ [M + H]+ 1213.4171, found 1213.4179. (3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS,45aE,48S,54Z,56aS)-2,16,30,44-Tetrachloro-6,20,34,48-tetrakis(5,5,5-trifluoropentyl)-5,10,11,14,14a,19,20,24,25,28,28a,33,34,38,39,42,42a,47,48,51,52,53,56,56a-tetracosahydro-3H,8H,22H,36Htetracyclopenta[e,r,e1,r1][1,14,27,40]tetraoxacyclodopentacontine3,8,17,22,31,36,45,50(6H,9H,23H,37H)octone (7c): Rf = 0.20 (silica gel, hexanes/EtOAc, 3:1, v/v); [α]22 D = +13 (c = 0.3 in C6H6); IR (film) νmax 2945, 1731, 1661, 1541, 1440, 1257, 1142, 1033 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.38 (d, J = 2.6 Hz, 4 H), 6.64 (t, J = 7.6 Hz, 4 H), 5.50−5.46 (m, 4 H), 5.34−5.29 (m, 4 H), 5.01−4.97 (m, 4 H), 3.59−3.49 (m, 4 H), 2.64−2.50 (m, 12 H), 2.29−2.21 (m, 12 H), 2.12−2.00 (m, 16 H), 1.70−1.34 (m, 32 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 188.2, 172.9, 154.3, 137.6, 137.1, 132.5, 132.3, 127.1 (q, J = 281.9 Hz), 125.2, 72.2, 41.3, 33.8, 33.61 (q, J = 29.2 Hz), 33.59, 30.2, 26.8, 24.7, 24.6, 21.8 (q, J = 3.2 Hz) ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents four equivalent C atoms; HR-MS (ESI-TOF) calcd for C80H96O12F12Cl4+ [M + Na]+ 1639.5357, found 1639.5395. (4R)-2-Iodo-4-(prop-2-en-1-yl)cyclopent-2-en-1-one (31). To a solution of the enone (1.25 g, 10.23 mmol, 1.0 equiv) in a mixture of THF/H2O (10:1, v/v) (50 mL) was added K2CO3 (1.35 g, 12.79 mmol, 1.25 equiv), followed by I2 (2.00 g, 15.34 mmol, 1.5 equiv) and DMAP (250 mg, 2.00 mmol, 0.2 equiv) at 25 °C. The reaction was vigorously stirred for 2 h, and then the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aq Na2S2O3 solution (20 mL). The phases were separated, the aqueous layer was extracted with EtOAc (2 × 25 mL), and the combined organic layers were washed with H2 O (20 mL), dried (Na2 SO4), filtered, and 376


Article

The Journal of Organic Chemistry 33: Rf = 0.60 (SiO2, hexanes/EtOAc, 5:1, v/v); [α]22 D = +48.4 (c = 1.0 in CHCl3); IR (film) νmax 2930, 2857, 1728, 1708, 1659, 1568, 1462, 1367, 1257, 1144, 1087, 836, 775 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.84 (dd, J = 2.9, 0.9 Hz, 1 H), 6.76−6.68 (m, 1 H), 5.55− 5.46 (m, 1 H), 5.38−5.28 (m, 1 H), 3.86 (p, J = 5.9 Hz, 1 H), 3.57− 3.50 (m, 1 H), 2.62−2.57 (m, 1 H), 2.49−2.38 (m, 2 H), 2.23−2.18 (m, 3 H), 2.10−1.99 (m, 3 H), 1.64 (p, J = 7.1 Hz, 2 H), 1.59−1.50 (m, 4 H), 1.44 (s, 12 H), 0.88 (s, 9 H), 0.05 (s, 6H) ppm; 13C{1H} NMR (151 MHz, CDCl3) 190.9, 172.9, 166.4, 134.5, 132.5, 127.2 (q, J = 276.4 Hz), 125.1, 104.2, 80.3, 71.1, 46.2, 37.4, 37.1, 35.0, 33.4 (q, J = 28.4 Hz), 30.5, 28.3, 26.8, 25.9, 24.9, 24.5, 22.1 (q, J = 3.4 Hz), 18.1, −4.3, −4.5 ppm, HR-MS (ESI-TOF) calcd for C30H48O4F3SiINa+ [M + Na]+ 707.2211, found 707.2237. (5Z,12E,15S)-20,20,20-Trifluoro-15-hydroxy-10-iodo-11-oxoprosta-5,9,12-trien-1-oic Acid (34). To a stirred solution of tert-butyl ester 33 (68 mg, 0.099 mmol, 1.0 equiv) in MeCN (1 mL) at 0 °C was dropwise added a solution of HBF4 (48% aq, 500 μL, 3.3 mmol, 25 equiv). After being stirred for 3 h at this temperature, the reaction mixture was quenched with brine (5 mL) and extracted with EtOAc (5 × 20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Flash column chromatography (SiO2; hexanes/EtOAc, 1:1, v/v →1:3, v/v) yielded pure title compound (34, 45.5 mg, 0.0883 mmol, 89% yield) as a colorless oil. 34: Rf = 0.70 (EtOAc); [α]22 D = +47.2 (c = 2.6 in CHCl3); IR (film) νmax 3423, 3010, 2929, 2871, 1704, 1654, 1565, 1438, 1255, 1138, 1044, 872, 751 cm−1; 1H NMR (600 MHz, C6D6) δ 7.48 (d, J = 2.8 Hz, 1 H), 6.86 (t, J = 7.7 Hz, 1 H), 5.39−5.30 (m, 1 H), 5.13−5.08 (m, 1 H), 3.50 (s, 1 H), 3.09−3.07 (m, 1 H), 2.52 (ddd, J = 13.3, 7.6, 4.2 Hz, 1 H), 2.37 (dt, J = 14.5, 7.1 Hz, 1 H), 2.15−2.06 (m, 4 H), 1.94−1.81 (m, 3 H), 1.74−1.66 (m, 2 H), 1.62−1.52 (m, 2 H), 1.49− 1.29 (m, 2 H), 1.17 (qd, J = 10.1, 6.7, 6.0 Hz, 1 H) ppm; 13C{1H} NMR (151 MHz, C6D6) δ 190.6, 178.0, 166.4, 135.5, 133.9, 132.0, 127.9 (q, J = 276.4 Hz), 125.9, 104.6, 70.8, 46.6, 37.6, 36.5, 33.8 (q, J = 28.4 Hz), 30.4, 28.6, 26.6, 25.0, 24.7, 22.0 (q, J = 2.9 Hz) ppm; HRMS (ESI-TOF) calcd for C20H26O4F3INa+ [M + Na]+ 537.0720, found 537.0707. (5Z,12E,15S)-20,20,20-Trifluoro-10-iodo-1,15-epoxyprosta5,9,12-triene-1,11-dione (4d). To a stirred solution of 2-methyl-6nitrobenzoic anhydride (10.4 mg, 29.2 μmol, 1.5 equiv) and 4(dimethylamino)pyridine (6.9 mg, 58.4 μmol, 3.0 equiv) in CH2Cl2 (20 mL) was added a solution of 10-iodo-Δ12-PGJ2 derivative (34, 10 mg, 19.4 μmol, 1.0 equiv) in CH2Cl2 (5 mL) at 25 °C dropwise via syringe pump over 15 h. After being stirred for an additional 2 h, the reaction mixture was washed sequentially with satd aqueous NaHCO3 solution (10 mL), aqueous HCl (0.2 M; 10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2; hexanes/EtOAc, 4:1, v/v) yielded pure title compound (4d, 5.4 mg, 10.8 μmol, 56% yield) as a white amorphous solid. 4d: Rf = 0.60 (SiO2, hexanes/EtOAc, 7:3, v/v); [α]22 D = +60 (c = 0.5 in C6H6); IR (film) νmax 2927, 2855, 1719, 1697, 1654, 1563, 1256, 1150, 1034, 935 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 2.8 Hz, 1 H), 6.64 (dd, J = 11.6, 4.6 Hz, 1 H), 5.41 (td, J = 10.4, 5.8 Hz, 1 H), 5.28−5.16 (m, 2 H), 3.77 (s, 1 H), 2.72−2.66 (m, 2 H), 2.55−2.43 (m, 3 H), 2.33 (ddd, J = 15.5, 9.1, 2.8 Hz, 1 H), 2.25 (ddd, J = 15.5, 9.1, 2.6 Hz, 1 H), 2.08 (dtd, J = 18.6, 10.7, 7.7 Hz, 2 H), 1.99 (dt, J = 14.0, 6.9 Hz, 1 H), 1.76−1.49 (m, 6 H), 1.47−1.40 (m, 2 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 190.8, 173.1, 165.9, 135.8, 133.3, 132.5, 127.1 (q, J = 274.3 Hz), 124.7, 104.1, 72.7, 46.3, 33.6 (q, J = 28.6 Hz), 34.2, 34.0, 32.7, 28.5, 25.8, 24.7, 24.3, 21.9 (q, J = 3.3 Hz) ppm; HR-MS (ESI-TOF) calcd for C20H24O3F3INa+ [M + Na]+ 519.0616, found 519.0614. 10-Iodo-Δ12-PGJ2 Macrolactones 5d, 6d, and 7d. To a stirred solution of 10-iodo-Δ12-PGJ2 derivative (34, 16 mg, 31 μmol, 1.0 equiv) in CH2Cl2 (3 mL) at 25 °C were added sequentially Et3N (8.6 μL, 62 μmol, 2.0 equiv), (dimethylamino)pyridine (0.38 mg, 3.1 μmol, 0.1 equiv), and 2-methyl-6-nitrobenzoic anhydride (16.5 mg, 48 μmol, 1.5 equiv). After being stirred for an additional 12 h, the reaction mixture was washed sequentially with satd aqueous NaHCO3

solution (3 mL), satd aqueous NH4Cl (3 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by PTLC (SiO2, hexanes/EtOAc, 7:3, v/v) to give dimer 5d (3.3 mg, 3.4 μmol, 22% yield), trimer 6d (2.1 mg, 1.4 μmol, 14% yield), and tetramer 7d (1.2 mg, 0.6 μmol, 8% yield) as colorless oils. (3aZ,6S,12Z,14aS,17aE,20S,26Z,28aS)-2,16-Diiodo-6,20-bis(5,5,5-trifluoropentyl)-5,10,11,14,14a,19,20,23,24,25,28,28a-dodecahydro-3H,8H-dicyclopenta[e,r][1,14]dioxacyclohexacosine-3,8,17,22(6H,9H)-tetrone (5d): Rf = 0.50 (SiO2, hexanes/EtOAc, 4:1, v/ v); [α]22 D = +20 (c = 0.3 in C6H6); IR (film) νmax 2949, 1732, 1659, 1257, 1145, 1034 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 2.8 Hz, 1 H), 6.63−6.58 (m, 1 H), 5.50 (dt, J = 11.0, 7.5 Hz, 1 H), 5.38 (dt, J = 11.0, 7.3 Hz, 1 H), 5.01 (p, J = 6.3 Hz, 1 H), 3.51−3.48 (m, 1 H), 2.73−2.69 (m, 1 H), 2.64 (ddd, J = 14.6, 9.4, 7.3 Hz, 1 H), 2.44 (dt, J = 14.7, 6.3 Hz, 1 H), 2.29−2.18 (m, 2 H), 2.18−2.00 (m, 5 H), 1.71−1.58 (m, 6 H), 1.49−1.34 (m, 2 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 190.7, 172.7, 166.3, 135.7, 132.4, 132.2, 127.1 (q, J = 274.3 Hz), 125.6, 104.2, 72.4, 46.2, 34.3, 33.8, 33.7, 33.6 (q, J = 28.5 Hz), 30.5, 26.9, 24.64, 24.55, 21.8 (q, J = 3.3 Hz) ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents two equivalent C atoms; HR-MS (ESI-TOF) calcd for C40H48O6F6I2Na+ [M + Na]+ 1015.1373, found 1015.1377. (3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS)2,16,30-Triiodo-6,20,34-tris(5,5,5-trifluoropentyl)-5,10,11,14,14a,19,20,24,25,28,28a,33,34,37,38,39,42,42a-octadecahydro3H,8H,22H-tricyclopenta[e,r,e1][1,14,27]trioxacyclononatriacontine-3,8,17,22,31,36(6H,9H,23H)-hexone (6d). Rf = 0.40 (SiO2, hexanes/EtOAc, 7:3, v/v); [α]22 D = +13 (c = 0.2 in C6H6); IR (film) νmax 2943, 1731, 1707, 1659, 1257, 1142, 1038, 745 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 2.9 Hz, 3 H), 6.63 (t, J = 7.6 Hz, 3 H), 5.50−5.45 (m, 3 H), 5.35−5.30 (m, 3 H), 5.01−4.97 (m, 3 H), 3.57−3.53 (m, 3 H), 2.65−2.46 (m, 9 H), 2.29−2.18 (m, 9 H), 2.09−2.00 (m, 12 H), 1.71−1.50 (m, 18 H), 1.47−1.34 (m, 6 H) ppm; 13C{1H} NMR (151 MHz, CDCl3) δ 190.7, 172.9, 166.6, 135.4, 132.3, 132.1, 127.1 (q, J = 274.3 Hz), 125.3, 104.0, 72.4, 46.0, 33.80, 33.77, 33.63 (q, J = 28.4 Hz), 33.55, 30.2, 26.8, 24.7, 24.7, 21.8 (q, J = 3.3 Hz) ppm, due to the inherent symmetry of the molecule each 13C NMR resonance represents three equivalent C atoms; HR-MS (ESITOF) calcd for C60H72O9F9I3Na+ [M + Na]+ 1511.2059, found 1511.2065. (3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS,45aE,48S,54Z,56aS)-2,16,30,44-Tetraiodo-6,20,34,48-tetrakis(5,5,5-trifluoropentyl)-5,10,11,14,14a,19,20,24,25,28,28a,33,34,38,39,42,42a,47,48,51,52,53,56,56a-tetracosahydro-3H,8H,22H,36Htetracyclopenta[e,r,e1,r1][1,14,27,40]tetraoxacyclodopentacontine3,8,17,22,31,36,45,50(6H,9H,23H,37H)-octone (7d): Rf = 0.30 (silica gel, hexanes/EtOAc, 7:3, v/v); [α]22 D = +21 (c = 0.1 in C6H6); IR (film) νmax 2919, 1729, 1659, 1258, 1040, 728 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 2.9 Hz, 4 H), 6.63 (t, J = 7.6 Hz, 4 H), 5.50−5.45 (m, 4 H), 5.35−5.30 (m, 4 H), 5.01−4.97 (m, 4 H), 3.59− 3.58 (m, 4 H), 2.65−2.46 (m, 12 H), 2.29−2.18 (m, 12 H), 2.09− 2.00 (m, 16 H), 1.71−1.50 (m, 24 H), 1.47−1.34 (m, 8 H) ppm; 13 C{1H} NMR (151 MHz, CDCl3) δ 190.7, 172.9, 166.6, 135.4, 132.3, 132.1, 127.1 (q, J = 274.3 Hz), 125.3, 104.0, 72.4, 46.0, 33.8, 33.7, 33.64 (q, J = 28.4 Hz), 33.55, 30.2, 26.8, 24.73, 24.66, 21.8 (q, J = 3.3 Hz) ppm, due to the inherent symmetry of the molecule each 13 C NMR resonance represents three equivalent C atoms; HR-MS (ESI-TOF) calcd for C80H97O12F12I4+ [M + H]+ 1985.2962, found 1985.3029.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b03057. 1

H and 13C{1H} NMR spectra for all new compounds; cytotoxicity data [HEK 293T, MES SA, MES SA DX, OCI-AML3, EOL1, NCI-N87, SKOV3, SKBR3, and H510A (AbbVie Stemcentrx)] (PDF) 377


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For the first C1−C15 macrolactonization of a prostaglandin, see: (b) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S., Jr. Synthesis of Novel Macrocyclic Lactones in the Prostaglandin and Polyether Antibiotic Series. J. Am. Chem. Soc. 1975, 97, 653−654. (5) Nicolaou, K. C.; Nold, A. L.; Milburn, R. R.; Schindler, C. S.; Cole, K. P.; Yamaguchi, J. Total Synthesis of Marinomycins A−C and of Their Monomeric Counterparts Monomarinomycin A and isoMonomarinomycin A. J. Am. Chem. Soc. 2007, 129, 1760−1768. (6) Nicolaou, K. C.; Jiang, X.; Lindsay-Scott, P. J.; Corbu, A.; Yamashiro, S.; Bacconi, A.; Fowler, V. M. Total Synthesis and Biological Evaluation of Monorhizopodin and 16-epi-Monorhizopodin. Angew. Chem., Int. Ed. 2011, 50, 1139−1144. (7) Nicolaou, K. C.; Nilewski, C.; Hale, C. R. H.; Ahles, C. F.; Chiu, C. A.; Ebner, C.; ElMarrouni, A.; Yang, L.; Stiles, K.; Nagrath, D. Synthesis and Biological Evaluation of Dimeric Furanoid Macroheterocycles: Discovery of New Anticancer Agents. J. Am. Chem. Soc. 2015, 137, 4766−4770. (8) For a similar metathesis-based approach to this family of compounds, see: Li, J.; Ahmed, T. S.; Xu, C.; Stoltz, B. M.; Grubbs, R. H. Concise Syntheses of Δ12-Prostaglandin J Natural Products via Stereoretentive Metathesis. J. Am. Chem. Soc. 2018, DOI: 10.1021/ jacs.8b12816. (9) (a) Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.; Rapoport, H. An Efficient Synthesis of Enantiomerically Pure (R)-(2Benzyloxyethyl)oxirane from (S)-Aspartic Acid. Synthesis 1992, 1992, 621−623. (b) Wullschleger, C. W.; Gertsch, J.; Altmann, K.-H. Stereoselective Synthesis of a Monocyclic Peloruside A Analogue. Org. Lett. 2010, 12, 1120−1123. (10) (a) Tanaka, K.; Ogasawara, K. An Expedient Route to Optically Pure 3-endo-Hydroxydicyclopentadiene. Synthesis 1995, 1995, 1237− 1239. (b) Verdaguer, X.; Lledó, A.; López-Mosquera, C.; Maestro, M. A.; Pericàs, M. A.; Riera, A. PuPHOS: A Synthetically Useful Chiral Bidentate Ligand for the Intermolecular Pauson−Khand Reaction. J. Org. Chem. 2004, 69, 8053−8061. (11) (a) Cannon, J. S.; Grubbs, R. H. Alkene Chemoselectivity in Ruthenium-Catalyzed Z-Selective Olefin Metathesis. Angew. Chem., Int. Ed. 2013, 52, 9001−9004. (b) Quigley, B. L.; Grubbs, R. H. Ruthenium-catalysed Z-selective cross metathesis of allylic-substituted olefins. Chem. Sci. 2014, 5, 501−506. (12) Hartung, J.; Grubbs, R. H. Highly Z-Selective and Enantioselective Ring-Opening/Cross-Metathesis Catalyzed by a Resolved Stereogenic-at-Ru Complex. J. Am. Chem. Soc. 2013, 135, 10183−10185. (13) Stepanenko, A. A.; Dmitrenko, V. V. HEK293 in Cell Biology and Cancer Research: Phenotype, Karyotype, Tumorigenicity, and Stress-Induced Genome-Phenotype Evolution. Gene 2015, 569, 182− 190.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

K. C. Nicolaou: 0000-0001-5332-2511 Stephan Rigol: 0000-0003-2470-3512 Ruocheng Yu: 0000-0001-7268-7508 Author Contributions §

K.K.P. and S.R. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Drs. Lawrence B. Alemany and Quinn Kleerekoper (Rice University) for NMR-spectroscopic assistance, Drs. Christopher L. Pennington (Rice University) and Ian Riddington (University of Texas at Austin) for massspectrometric assistance, and Prof. Robert H. Grubbs for a generous gift of catalyst 17. This work was supported by the Cancer Prevention & Research Institute of Texas (CPRIT), and The Welch Foundation (Grant No. C-1819).

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REFERENCES

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