Short Total Synthesis of 12-Prostaglandin J2 and Related Prostaglandins. Design, Synthesis, and Biological Evaluation of Macrocyclic 12-Prostaglandin J2 Analogues

Article abstract of DOI:10.1021/acs.joc.8b03057

Comprised of a large collection of structurally diverse molecules, the prostaglandins exhibit a wide range of biological properties. Among them are ?"¹²-prostaglandin J₂ (?"¹²-PGJ₂) and ?"¹²-prostagla

Full text of DOI:10.1021/acs.joc.8b03057

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Article
Short Total Synthesis of #12-Prostaglandin J2 and
Related Prostaglandins. Design, Synthesis and Biological
Evaluation of Macrocyclic #12-Prostaglandin J2 Analogues
Kyriacos C. Nicolaou, Kiran Kumar Pulukuri, Stephan Rigol, Zisis Peitsinis, Ruocheng Yu, Satoshi
Kishigami, Nicholas Cen, Monette Aujay, Joseph Sandoval, Nancy Zepeda, and Julia Gavrilyuk
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03057 • Publication Date (Web): 17 Dec 2018
Downloaded from http://pubs.acs.org on December 17, 2018
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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
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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#
†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
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 (SARs) and trends and the discovery of a number of more potent
antitumor agents than their parent naturally occurring molecule.
Introduction
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Inspired by the important cytotoxicity properties of Δ12-prostaglandins 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 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
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In this Article, 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
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prostanoids. Specifically, we describe, (a) a metathesis-based short total synthesis of Δ -PGJ2;
(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.
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Figure 1. Molecular structures of ∆12-prostaglandin J2 (1, Δ12-PGJ2), ∆12-prostaglandin J3 (2, Δ12-
PGJ3), 10-Cl-∆12-prostaglandin J3 lactone (3) and ∆12-prostaglandin J2 lactone (4a).
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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.
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Figure 2. Designed macrocyclic ∆12-prostaglandin J2 analogues (4–9).
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 4a–7a
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(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 12, 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 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, Et3N, 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].
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Scheme 1. Synthesis of ∆12-Prostaglandin J2 (1) and Analogues 4a–7aa
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aReagents 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 °C to 25 °C,
4 h, 94%; (f) 1,2-dichlorobenzene, 200 °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
=
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trimethylsilyl, LDA = lithium diisopropylamide, Ms = mesyl, DMAP = N,N-dimethylpyridin-4-amine,
MNBA = (2-methyl-6-nitrobenzoyl) 2-methyl-6-nitrobenzoate.
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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 so-formed 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) through
chromatographic separation in 20%, 8% and 4% yields, respectively.
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Scheme 2. Synthesis of ∆12-Prostaglandin J2 Analogues 4b–7ba
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aReagents 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%
[90:10 (Z):(E)]; (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%).
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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 4-bromo-1,1,1-trifluorobutane) providing 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 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.
Scheme 3. Synthesis of ∆12-Prostaglandin J2 Analogues 4c–7ca
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aReagents 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%).
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 2112
[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
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macrolactone 7d were then synthesized in yields of 56% (high dilution), 22%, 14% and 8% (high
concentration, chromatographically separated), respectively, using the developed conditions as
summarized in Scheme 4.
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Scheme 4. Synthesis of ∆12-Prostaglandin J2 Analogues 4d–7da
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aReagents 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) 21 (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%).
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 multi-drug
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
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corresponding trimeric (6a, 6b, 6c) and tetrameric (7a, 7b, 7c) 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)] were 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), 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 tetramer (7d) proved significantly less active (or not active) against these cell lines (see Table
2).
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Table 1. Cytotoxicity Data Against Cell Lines MES SA, MES SA DX, and HEK 293Ta for the
Synthesized Δ12-Prostaglandin J2 Analogues 4a–d, 5a–d, 6a–d, and 7a–d (IC50 Values in nM)b
aIC50 = 50% inhibitory concentration of compound against cell growth; MES SA: uterine sarcoma
cell line; MES SA DX: MES SA cell line with marked multi-drug resistance; HEK 293T: human
b
embryonic kidney cell line; see 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
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aIC50 = 50% inhibitory concentration of compound against cell growth; OCI-AML3: acute myeloid
leukemia; EOL1: acute myeloid (eosinophilic) leukemia; NCI-N87: gastric carcinoma; SKOV3:
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b
adenocarcinoma; SKBR3: adenocarcinoma; H510A: small cell lung carcinoma; see Supporting
Information for further details; these studies were carried out at AbbVie Stemcentrx.
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 10-iodo
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 SARs trend observed in this study is 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 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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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.
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 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
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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 pre-dried, 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) homogenous 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, partical 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. High-resolution
mass spectra (HRMS) were recorded on an Agilent ESI-TOF (time of flight) mass spectrometer
using MALDI (matrix-assisted laser desorption ionization) or ESI (electrospray ionization). Optical
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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)].
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Experimental Procedures and Characterization Data
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(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 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.
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[ ]22
10: Rf =0.29 (silica gel, hexanes:EtOAc, 5:1, v/v); α =−3 (c=1.0 in C6H6); IR (film): νmax 3431,
D
2930, 2858, 1613, 1513, 1247, 1091, 1036, 820 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.26–7.22 (m,
2H), 6.89–6.85 (m, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.79–3.75 (m, 1H), 3.69 (dt, J=9.2, 5.2 Hz,
1H), 3.61 (ddd, J=9.3, 7.5, 5.1 Hz, 1H), 2.71 (br, 1H), 1.76–1.67 (m, 2H), 1.50–1.36 (m, 3H),
1.36–1.22 (m, 5H), 0.88 (t, J=6.9 Hz, 3H) 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 0ºC was 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 sat. 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), 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.
[ ]23
11: Rf =0.66 (silica gel, hexanes:Et2O, 10:1, v/v); α =+10 (c=1.0 in C6H6); IR (film): νmax 2953,
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2929, 2856, 1613, 1513, 1463, 1247, 1089, 1038, 834, 773 cm−1; H NMR (600 MHz, CDCl3) δ
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7.26 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.44 (d, J=11.5 Hz, 1H), 4.39 (d, J=11.5 Hz,
1H), 3.84–3.76 (m, 4H), 3.51 (t, J=6.7 Hz, 2H), 1.79–1.67 (m, 2H), 1.46–1.39 (m, 2H), 1.35–
1.21 (m, 6H), 0.90–0.87 (m, 12H), 0.04 (s, 3H), 0.03 (s, 3H) 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.
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(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, 40 mL) at 0°C was added
2,3-dichloro-5,6-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 sat. 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.
[ ]22
S1: Rf =0.50 (hexanes:EtOAc, 4:1, v/v); α =+12 (c=2.1, C6H6); FT-IR (film): νmax 3363, 2955,
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2930, 2858, 1601, 1471, 1463, 1378, 1256, 1058, 1005, 835, 774 cm−1; 1H NMR (600 MHz, CDCl3)
δ 3.93–3.89 (m, 1H), 3.87–3.82 (m, 1H), 3.71 (dt, J=10.8, 5.4 Hz, 1H), 2.44 (s, 1H), 1.85–1.79
(m, 1H), 1.67–1.62 (m, 1H), 1.54–1.50 (m, 2H), 1.32–1.24 (s, 6H), 0.89–0.88 (m, 12H), 0.09 (s,
3H), 0.08 (s, 3H) 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 sat. aqueous Na2S2O3 (4 mL) and sat. aqueous
NaHCO3 (4 mL) and stirred for 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.
[ ]22
12: Rf =0.60 (hexanes:EtOAc, 10:1, v/v); α =−6 (c=1.0, CHCl3); FT-IR (film): νmax 2956, 2929,
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2858, 1727, 1471, 1361, 1254, 1100, 1053, 1005, 835, 774 cm−1; H NMR (600 MHz, CDCl3) δ
9.81 (t, J=2.5 Hz, 1H), 4.18 (quint, J=5.9 Hz, 1H), 2.52–2.45 (m, 2H), 1.58–1.47 (m, 2H), 1.36–
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1.22 (m, 6H), 0.90–0.87 (m, 12H), 0.07 (s, 3H), 0.06 (s, 3H) 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.
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(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, allylmagnesium bromide (1.0 M
in ether; 81.2 mL, 81.2 mmol, 2.0 equiv) was added slowly 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
colored solution. The reaction was allowed to proceed for 6 h at −78°C and then slowly warm to
25°Cover 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.
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[ ]22
S2: Rf =0.70 (silica gel, hexanes:EtOAc, 4:1, v/v); α =+117 (c=1.0 in C6H6); IR (film): νmax
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3007, 2957, 2930, 2857, 1728, 1705, 1656, 1582, 1366, 1251, 1144, 1066, 834, 774 cm–1; H
NMR (600 MHz, CDCl3) δ 6.17 (dd, J=5.8, 3.0 Hz, 1H), 6.13 (dd, J=5.8, 2.9 Hz, 1H), 5.74 (ddt,
J=17.1, 10.3, 6.9 Hz, 1H), 5.07–5.03 (m, 2H), 3.18–3.17 (m, 1H), 3.04–3.02 (m, 1H), 2.92 (ddd,
J=9.5, 4.8, 1.8 Hz, 1H), 2.66 (dt, J=9.4, 3.9 Hz, 1H), 2.21–2.10 (m, 3H), 1.96 (ddd, J=18.8, 6.0,
2.0 Hz, 1H), 1.86–1.81 (m, 1H), 1.54 (dt, J=8.3, 1.8 Hz, 1H), 1.41 (dt, J=8.3, 1.5 Hz, 1H) 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 refluxed 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 n-pentane as eluant, to give the titled enone (14,
3.20 g, 26.2 mmol, 82% yield) as a colorless oil.
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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, 1H), 6.17 (dd, J=5.6, 2.0 Hz, 1H), 5.77 (ddt, J=16.8, 9.7, 6.9 Hz, 1H),
5.11–5.08 (m, 2H), 3.06–3.01 (m, 1H), 2.51 (dd, J=18.9, 6.4 Hz, 1H), 2.33–2.28 (m, 1H), 2.24–
2.19 (m, 1H), 2.05 (dd, J=18.9, 2.2 Hz, 1H) 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.
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(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 stirring 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 was 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 stirring for 12 h at this temperature, the reaction mixture was
brought to 25°C and 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.
[ ]22
15: Rf =0.60 (silica gel, hexanes:EtOAc, 4:1, v/v); α =+107 (c=1.0 in C6H6); IR (film): νmax 2955,
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2930, 2858, 1706, 1657, 1471, 1463, 1255, 1033, 836, 775 cm–1; H NMR (600 MHz, CDCl3) δ
7.52 (ddd, J=6.1, 2.7, 1.0 Hz, 1H), 6.61 (t, J=7.6 Hz, 1H), 6.33 (dd, J=6.0, 1.8 Hz, 1H), 5.76–
5.69 (m, 1H), 5.08–5.05 (m, 2H), 3.83 (quint, J=5.7 Hz, 1H), 3.51–3.48 (m, 1H), 2.69–2.64 (m,
1H), 2.47–2.37 (m, 2H), 2.18 (dt, J=14.5, 8.5 Hz, 1H), 1.46–1.43 (m, 2H), 1.40–1.21 (m, 6H),
0.91–0.84 (m, 12H), 0.05 (s, 3H), 0.05 (s, 3H) 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:
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363.2713.
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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 was 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,
pentane:Et2O, 90:10, v/v) gave pure title compound (16, 6.98 g, 41.5 mmol, 72% yield) as a
colorless oil.
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16: Rf = 0.60 (silica gel, hexanes:EtOAc, 95:5, v/v); IR (film): νmax = 3079, 2978, 2933, 1729, 1642,
1
1366, 1252, 1147, 911, 845, 752 cm–1; H NMR (600 MHz, CDCl3) δ 5.82–5.75 (m, 1H), 5.06–
4.94 (m, 2H), 2.22 (t, J=7.5 Hz, 2H), 2.07 (q, J=7.5 Hz, 2H), 1.69 (quint, J=7.5 Hz, 2H), 1.44
(s, 9H) 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.
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 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 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, 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 were recovered.
[ ]22
18: Rf =0.50 (silica gel, hexanes:EtOAc, 4:1, v/v); α =+89 (c=1.0 in C6H6); IR (film): νmax 3007,
D
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2957, 2930, 2857, 1728, 1705, 1656, 1582, 1366, 1251, 1144, 1066, 834, 774 cm–1; H NMR
(600 MHz, CDCl3) δ 7.49 (dd, J=5.7, 3.0 Hz, 1H), 6.60 (t, J=7.6 Hz, 1H), 6.32 (dd, J=6.0, 1.8 Hz,
1H), 5.49–5.45 (m, 1H), 5.38–5.34 (m, 1H), 3.83 (quint, J=5.8 Hz, 1H), 3.47–3.45 (m, 1H), 2.64–
2.60 (m, 1H), 2.46–2.38 (m, 2H), 2.21–2.16 (m, 3H), 2.04–2.00 (m, 2H), 1.62 (quint, J=7.5 Hz,
2H), 1.46–1.42 (m, 11H), 1.40–1.23 (m, 6H), 0.88–0.86 (m, 12H), 0.05 (s, 3H), 0.04 (s, 3H) 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,
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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.
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(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 stirring 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.
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[ ]22
1: Rf =0.40 (EtOAc); α =+108 (c=0.1 in C6H6); IR (film): νmax 3393, 3010, 2960, 2929, 2858,
D
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1706, 1647, 1408, 1239, 1084, 799 cm−1; H NMR (600 MHz, C6D6) δ 7.01 (dd, J=6.1, 2.5 Hz,
1H), 6.82 (t, J=7.7 Hz, 1H), 6.24 (dd, J=6.0, 1.8 Hz, 1H), 5.31–5.22 (m, 2H), 3.68–3.64 (m, 1H),
3.15–3.13 (m, 1H), 2.57 (ddd, J=14.1, 7.1, 4.4 Hz, 1H), 2.41 (dt, J=14.4, 7.1 Hz, 1H), 2.28 (ddd,
J=14.4, 8.0, 5.9 Hz, 1H), 2.14 (t, J=6.7 Hz, 2H), 2.01–1.95 (m, 3H), 1.57–1.36 (m, 5H), 1.32–
1.16 (m, 5H), 0.91 (t, J=7.2 Hz, 3H) 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-dimethylaminopyridine (22 mg,
180 µmol, 6.0 equiv) in CH2Cl2 (20 mL) was added a solution of ∆12-PGJ2 (1, 10 mg, 30 µmol,
1.0 equiv) in CH2Cl2 (10 mL) at 25°C dropwise via syringe pump over 15 h. After stirring for an
additional 2 h, the reaction mixture was washed sequentially with sat. 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.
[ ]22
4a: Rf =0.40 (silica gel, hexanes:EtOAc, 7:3, v/v); α =+26 (c=0.3 in C6H6); IR (film): νmax 2930,
D
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, 1H), 6.66 (ddt, J=11.4, 4.8, 1.3 Hz, 1H), 6.20 (dd, J=6.1, 1.9 Hz,
1H), 5.20–5.08 (m, 3H), 3.22–3.20 (m, 1H), 2.43 (ddd, J=14.5, 9.2, 5.7 Hz, 1H), 2.37–2.31 (m,
1H), 2.26 (ddd, J=15.1, 11.4, 9.5 Hz, 1H), 2.15–2.07 (m, 2H), 2.04–1.96 (m, 2H), 1.86–1.81 (m,
1H), 1.56–1.46 (m, 1H), 1.41–1.08 (m, 9H), 0.87 (t, J=7.2 Hz, 3H) ppm; 13C{1H} NMR (151 MHz,
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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; HR-MS (ESI-TOF): calcd for C20H28O3Na [M+Na]+:
339.1931, found: 339.1925.
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∆12-PGJ2 Macrolactones (5a, 6a and 7a): To a stirred solution of ∆12-PGJ2 (1, 49 mg, 150 µmol,
1.0 equiv) in CH2Cl2 (10 mL) at 25°C was added seqentially NEt3 (42 µL, 300 µmol, 2.0 equiv)
dimethylaminopyridine (1.8 mg, 15 µmol, 0.1 equiv) and 2-methyl-6-nitrobenzoic anhydride
(77 mg, 230 µmol, 1.5 equiv). After stirring for an additional 12 h, the reaction mixture was washed
sequentially with sat. aqueous NaHCO3 solution (10 mL), sat. 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 (silica gel, 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.
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(3aZ,6S,12Z,14aS,17aE,20S,26Z,28aS)-6,20-Dipentyl-5,10,11,14,14a,19,20,23,24,25,28,28a-
dodecahydro-3H,8H-dicyclopenta[e,r][1,14]dioxacyclohexacosine-3,8,17,22(6H,9H)-tetrone
[ ]22
(5a): Rf =0.40 (silica gel, hexanes:EtOAc, 3:1, v/v); α =+59 (c=1.2 in C6H6); IR (film): νmax
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3010, 2954, 2931, 2860, 1732, 1705, 1657, 1581, 1457, 1343, 1240, 1178, 1088, 823 cm−1; H
NMR (600 MHz, CDCl3) δ 7.52 (dd, J=6.0, 2.5 Hz, 2H), 6.49–6.46 (m, 2H), 6.33 (dd, J=6.0,
1.8 Hz, 2H), 5.49–5.44 (m, 2H), 5.41–5.36 (m, 2H), 5.04–5.00 (m, 2H), 3.43–3.41 (m, 2H), 2.75–
2.70 (m, 2H), 2.61 (ddd, J=14.6, 9.6, 7.9 Hz, 2H), 2.42 (dt, J=14.6, 6.0 Hz, 2H), 2.28–2.18 (m,
4H), 2.13–1.99 (m, 6H), 1.68–1.58 (m, 8H), 1.37–1.23 (m, 12H), 0.87 (t, J=6.7 Hz, 6H) 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,e1][1,14,27]trioxacyclononatriacontine-3,8,17,22,31,36(6H,9H,23H)-
[ ]22
hexone (6a): Rf =0.30 (silica gel, hexanes:EtOAc, 3:1, v/v); α =+87 (c=0.7 in C6H6); IR (film):
D
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, 3H), 6.51 (t, J=7.6 Hz, 3H), 6.33 (dd, J=6.0, 1.8 Hz,
3H), 5.47–5.43 (dt, J=10.8, 7.4 Hz, 3H), 5.36–5.32 (dt, J=11.0, 7.1 Hz, 3H), 5.00–4.96 (m, 3H),
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3.47–3.44 (m, 3H), 2.66–2.56 (m, 6H), 2.49 (ddd, J=14.8, 7.9, 6.1 Hz, 3H), 2.26 (td, J=7.8,
3.3 Hz, 6H), 2.19 (dt, J=15.6, 8.2 Hz, 3H), 2.02 (q, J=7.4 Hz, 6H), 1.70–1.54 (m, 12H), 1.38–
1.24 (m, 18H), 0.87 (t, J=6.7 Hz, 9H) 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.
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(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-
tetracosahydro-3H,8H,22H,36H-tetracyclopenta[e,r,e1,r1][1,14,27,40]tetraoxacyclo-
dopentacontine-3,8,17,22,31,36,45,50(6H,9H,23H,37H)-octone (7a): Rf = 0.10 (silica gel,
9
[ ]22
hexanes:EtOAc, 3:1, v/v); α =+110 (c=0.4 in C6H6); IR (film): νmax 3010, 2961, 2927, 2861,
D
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1731, 1704, 1656, 1535, 1456, 1346, 1207, 1033, 810 cm−1; H NMR (600 MHz, CDCl3) δ 7.50
(dd, J=6.1, 2.6 Hz, 4H), 6.52 (t, J=7.6 Hz, 4H), 6.32 (dd, J=6.0, 1.8 Hz, 4H), 5.47–5.43 (m, 4H),
5.35–5.31 (m, 4H), 5.02–4.95 (m, 4H), 3.48–3.46 (m, 4H), 2.64–2.49 (m, 12H), 2.28–2.18 (m,
12H), 2.02 (q, J=7.4 Hz, 8H), 1.68–1.53 (m, 16H), 1.37–1.25 (m, 24H), 0.87 (t, J=6.6 Hz,
12H) 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 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 room temperature was added anhydrous LiCl (8.42 g, 200 mmol, 10.0 equiv) followed by
Amberlyst 15 ion exchange 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.
[ ]22
19: Rf =0.30 (silica gel, hexanes:EtOAc, 10:1, v/v); α =+116 (c=1.0 in C6H6); IR (film): νmax
D
3079, 2925, 1724, 1642, 1597, 1404, 1288, 1171, 965 cm–1; 1H NMR (600 MHz, CDCl3) δ 7.52 (d,
J=2.8 Hz, 1H), 5.76 (ddt, J=17.0, 10.2, 6.9 Hz, 1H), 5.15–5.11 (m, 2H), 3.04–3.00 (m, 1H), 2.68
(dd, J=19.1, 6.4 Hz, 1H), 2.34–2.23 (m, 2H), 2.21 (dd, J=19.1, 2.0 Hz, 1H) ppm; 13C{1H} NMR
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(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.
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(4S,5E)-5-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}octylidene]-2-chloro-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 stirring
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.
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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 stirring for 12 h at this temperature, the reaction mixture was brought
to 25°C and 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 (20, 284 mg, 0.717 mmol, 36% yield
for two steps) as a colorless oil.
[ ]22
20: Rf =0.50 (silica gel, hexanes:EtOAc, 10:1, v/v); α =+74 (c=1.0 in C6H6); IR (film): νmax 3010,
D
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, 1H), 6.76 (ddd, J=8.5, 7.1, 1.4 Hz, 1H), 5.72 (ddt, J=17.0, 10.2,
6.9 Hz, 1H), 5.12–5.08 (m, 2H), 3.85 (quint, J=5.9 Hz, 1H), 3.51 (dt, J=8.4, 4.2 Hz, 1H), 2.69
(dt, J=10.3, 5.2 Hz, 1H), 2.47–2.38 (m, 2H), 2.18 (dt, J=15.4, 8.8 Hz, 1H), 1.46–1.42 (m, 2H),
1.39–1.23 (m, 6H), 0.88–0.85 (m, 12H), 0.05 (s, 3H), 0.04 (s, 3H) 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 (ESI-TOF): calcd for C22H38O2SiCl+ [M+H]+:
397.2324, found: 397.2322.
tert-Butyl (5Z,12E,15S)-15-{[tert-butyl(dimethyl)silyl]oxy}-10-chloro-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-
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5-enoate (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 and 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,
0.420 mmol, 55% yield) as a colorless oil and 102 mg of trienone 20 was recovered.
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[ ]22
22: Rf =0.40 (silica gel, hexanes:EtOAc, 10:1, v/v); α =+100 (c=1.0 in C6H6); IR (film): νmax
D
1
3006, 2955, 2930, 2858, 1728, 1716, 1661, 1590, 1462, 1366, 1253, 1145, 836 cm–1; H NMR
(600 MHz, CDCl3) δ 7.36 (dd, J=2.9, 0.9 Hz, 1H), 6.76 (ddt, J=8.3, 6.9, 1.2 Hz, 1H), 5.52–5.48
(m, 1H), 5.37–5.32 (m, 1H), 3.84 (quint, J=5.9 Hz, 1H), 3.48–3.45 (m, 1H), 2.64 (dt, J=13.9,
5.9 Hz, 1H), 2.47–2.39 (m, 2H), 2.22–2.17 (m, 3H), 2.08–1.97 (m, 2H), 1.66–1.59 (m, 2H), 1.44
(s, 11H), 1.39–1.24 (m, 6H), 0.84–0.80 (m, 12H), 0.05 (s, 3H), 0.04 (s, 3H) 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-1-oic 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 stirring 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.
[ ]22
23: Rf =0.50 (silica gel, hexanes:EtOAc, 1:4, v/v); α =+102 (c=0.2 in C6H6); IR (film): νmax 3397,
D
1
2955, 2931, 2857, 1710, 1660, 1559, 1460, 1406, 1255, 1087, 836 cm−1; H NMR (600 MHz,
CDCl3) δ 7.43 (d, J=2.9 Hz, 1H), 6.73 (t, J=7.8 Hz, 1H), 5.54–5.50 (m, 1H), 5.44–5.40 (m, 1H),
3.89–3.85 (m, 1H), 3.49–3.46 (m, 1H), 2.76–2.72 (m, 1H), 2.56 (dt, J=14.0, 6.8 Hz, 1H), 2.47
(ddd, J=14.9, 8.5, 6.2 Hz, 1H), 2.35 (t, J=7.1 Hz, 2H), 2.17–2.04 (m, 3H), 1.73–1.66 (m, 2H),
1.59–1.43 (m, 3H), 1.37–1.22 (m, 9H), 0.88 (t, J=6.8 Hz, 3H) 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.
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(5Z,12E,15S)-10-Chloro-1,15-epoxyprosta-5,9,12-triene-1,11-dione (4b): To a stirred solution
of 2-methyl-6-nitrobenzoic anhydride (16 mg, 45 µmol, 1.5 equiv) and 4-dimethylaminopyridine
(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 stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. 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.
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[ ]22
4b: Rf =0.60 (silica gel, hexanes:EtOAc, 4:1, v/v); mp=91–92°C; α =−44 (c=0.4 in C6H6); IR
D
(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, 1H), 6.67 (dd, J=11.6, 4.6 Hz, 1H), 5.41 (td, J=10.4, 5.8 Hz, 1H),
5.27–5.18 (m, 2H), 3.72–3.69 (m, 1H), 2.74–2.66 (m, 2H), 2.54–2.43 (m, 3H), 2.32 (ddd, J=15.5,
9.1, 2.9 Hz, 1H), 2.25 (ddd, J=15.5, 9.1, 2.6 Hz, 1H), 2.01–1.95 (m, 1H), 1.65–1.45 (m, 5H),
1.31–1.20 (m, 5H), 0.89 (t, J=6.7 Hz, 3H) 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-∆12-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 was added seqentially NEt3 (23 µL,
160 µmol, 2.0 equiv), dimethylaminopyridine (1.0 mg, 8.2 µmol, 0.1 equiv) and 2-methyl-6-
nitrobenzoic anhydride (42 mg, 120 µmol, 1.5 equiv). After stirring for an additional 12 h, the
reaction mixture was washed sequentially with sat. aqueous NaHCO3 solution (3 mL), sat.
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 (silica gel,
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,8H-dicyclopenta[e,r][1,14]dioxacyclohexacosine-
[ ]22
3,8,17,22(6H,9H)-tetrone (5b): Rf =0.50 (silica gel, hexanes:EtOAc, 4:1, v/v); α =+21 (c=0.6
D
in C6H6); IR (film): νmax 3011, 2954, 2930, 2859, 1731, 1715, 1662, 1589, 1457, 1378, 1284, 1148,
1
1042, 763 cm−1; H NMR (600 MHz, C6D6) δ 6.82 (d, J=2.9 Hz, 2H), 6.72–6.63 (m, 2H), 5.26–
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5.22 (m, 2H), 5.09–5.05 (m, 2H), 5.00–4.96 (m, 2H), 2.91–2.88 (m, 2H), 2.52–2.47 (m, 2H), 2.35
(ddd, J=14.6, 9.5, 7.3 Hz, 2H), 2.12–2.03 (m, 6H), 1.88–1.84 (m, 6H), 1.58–1.10 (m, 20H), 0.88
(t, J=7.2 Hz, 6H) 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.
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(3aE,6S,12Z,14aS,17aE,20S,26Z,28aS,31aE,34S,40Z,42aS)-2,16,30-Trichloro-6,20,34-tri-
pentyl-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,e1][1,14,27]trioxacyclononatriacontine-3,8,17,22,31,36(6H,9H,23H)-
[ ]22
hexone (6b): Rf =0.40 (silica gel, hexanes:EtOAc, 4:1, v/v); α =+103 (c=0.2 in C6H6); IR (film):
D
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, 3H), 6.65 (t, J=7.6 Hz, 3H), 5.50–5.46 (m, 3H),
5.35–5.30 (m, 3H), 5.00–4.96 (m, 3H), 3.49–3.46 (m, 3H), 2.67–2.51 (m, 9H), 2.31–2.19 (m, 9H),
2.03 (q, J=7.1 Hz, 6H), 1.70–1.54 (m, 12H), 1.38–1.22 (m, 18H), 0.88 (t, J=6.7 Hz, 9H) 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-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-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
[ ]22
(silica gel, hexanes:EtOAc, 4:1, v/v); α =+147 (c=0.1 in C6H6); IR (film): νmax 2952, 2930, 1730,
D
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, 4H), 6.66 (t, J=7.7 Hz, 4H), 5.50–5.45 (m, 4H), 5.34–5.30 (m, 4H), 5.01–4.97 (m,
4H), 3.51–3.49 (m, 4H), 2.63 (dt, J=11.8, 5.0 Hz, 4H), 2.60–2.54 (m, 8H), 2.28–2.20 (m, 12H),
2.02 (q, J=7.3 Hz, 8H), 1.71–1.49 (m, 16H), 1.37–1.22 (m, 24H), 0.87 (t, J=6.9 Hz, 12H) 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.
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(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-1,1,1-trifluorobutane)
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, 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.
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[ ]22
25: Rf =0.11 (silica gel, hexanes:EtOAc, 5:1); α =−4 (c=1.0 in C6H6); IR (film): νmax 3441, 2942,
D
2864, 1613, 1514, 1249, 1139, 1088, 1035, 821, 656 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.24 (d,
J=8.5 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 4.45 (s, 2H), 3.80 (s, 4H), 3.73–3.66 (m, 1H), 3.62 (ddd,
J=9.3, 7.9, 4.6 Hz, 1H), 2.57 (brs, 1H), 2.07 (qt, J=10.9, 7.8 Hz, 2H), 1.78–1.66 (m, 2H), 1.64–
1.35 (m, 6H) 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 (ESI-TOF): 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
0ºC was 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 sat. 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.
[ ]22
26: Rf =0.70 (silica gel, hexanes:EtOAc, 5:1, v/v); α =+5 (c=1.0 in C6H6); IR (film): νmax 2951,
D
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2932, 2857, 1613, 1514, 1249, 1092, 1039, 835, 774 cm−1; H NMR (600 MHz, CDCl3) δ 7.28–
7.22 (m, 2H), 6.93–6.84 (m, 2H), 4.44 (d, J=11.5 Hz, 1H), 4.39 (d, J=11.5 Hz, 1H), 3.83 (quint,
J=5.7 Hz, 1H), 3.80 (s, 3H), 3.50 (t, J=6.5 Hz, 2H), 2.12–1.97 (m, 2H), 1.76–1.70 (m, 2H), 1.58–
1.48 (m, 2H), 1.49–1.32 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H) ppm; 13C{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,
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J=28.2 Hz), 26.0, 24.3, 22.3 (q, J=2.9 Hz), 18.2, −4.3, −4.5 ppm; HR-MS (ESI-TOF): calcd for
C22H37O3F3SiNa+ [M+Na]+: 457.2356, found: 457.2349.
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(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 sat. 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.
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[ ]22
S3: Rf =0.36 (silica gel, hexanes:EtOAc, 5:1, v/v); α =+15 (c=0.25 in C6H6); IR (film): νmax
D
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3351, 2951, 2931, 2886, 2859, 1256, 1141, 1057, 835, 774 cm−1; H NMR (600 MHz, CDCl3) δ
3.92 (ddd, J=12.3, 6.2, 4.2 Hz, 1H), 3.81 (ddd, J=10.7, 8.1, 4.6 Hz, 1H), 3.71 (dt, J=10.9, 5.5 Hz,
1H), 2.12 (s, 1H), 2.11–2.02 (m, 2H), 1.83–1.76 (m, 1H), 1.66 (dtd, J=14.3, 6.1, 4.6 Hz, 1H),
1.60–1.49 (m, 4H), 1.44–1.32 (m, 2H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H) 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 sat. aqueous Na2S2O3 (5 mL) and sat.
aqueous NaHCO3 (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.
[ ]22
27: Rf =0.63 (silica gel, hexanes:EtOAc, 5:1, v/v); α =−8 (c=1.0 in C6H6); IR (film): νmax 2953,
D
2932, 2859, 1726, 1254, 1139, 1088, 1052, 834, 774 cm−1; 1H NMR (600 MHz, CDCl3) δ 9.80 (t,
J=2.4 Hz, 1H), 4.19 (quint, J=5.8 Hz, 1H), 2.53 (ddd, J=5.7, 3.7, 2.4 Hz, 2H), 2.12–2.02 (m,
2H), 1.60–1.49 (m, 4H), 1.48–1.34 (m, 2H), 0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H) ppm; 13C{1H}
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The Journal of Organic Chemistry
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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.
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(4S,5E)-5-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-8,8,8-trifluorooctylidene]-2-chloro-4-
(prop-2-en-1-yl)cyclopent-2-en-1-one (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 stirring 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.
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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 stirring for 12 h at this temperature, the reaction mixture was brought
to 25°C and quenched with saturated aqueous NaHCO3 solution (3 mL), 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.
[ ]22
28: Rf =0.60 (silica gel, hexanes:EtOAc, 4:1, v/v); α =+75 (c=1.0 in C6H6); IR (film): νmax 2952,
D
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, 1H), 6.73 (ddt, J=8.3, 7.0, 1.2 Hz, 1H), 5.72 (dddd, J=16.7, 10.3, 7.8,
6.3 Hz, 1H), 5.13–5.08 (m, 2H), 3.88–3.85 (m, 1H), 3.52–3.49 (m, 1H), 2.70–2.66 (m, 1H), 2.49–
2.38 (m, 2H), 2.21–2.16 (m, 1H), 2.11–2.03 (m, 2H), 1.60–1.52 (m, 2H), 1.51–1.34 (m, 4H), 0.88
13
(s, 9H), 0.05 (s, 6H) ppm; C{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.
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