Synthetic approaches to anti-inflammatory macrolactones of the oxacyclododecindione type

Article abstract of DOI:10.1002/ejoc.201500275

Abstract Various synthetic approaches to the oxacyclododecindione-type macrolactones, known for their potent anti-inflammatory activity, are presented. These include an attempted carbonylative ring closure, a hydroacylation route, and an approach by ring-

Full text of DOI:10.1002/ejoc.201500275

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FULL PAPER
DOI: 10.1002/ejoc.201500275
Synthetic Approaches to Anti-Inflammatory Macrolactones of the
Oxacyclododecindione Type
Johannes Tauber,[a] Kristina Rudolph,[b] Markus Rohr,[b] Gerhard Erkel,[b] and Till Opatz*[a]
Keywords: Medicinal chemistry / Natural products / Total synthesis / Ring-closing metathesis / Cross-coupling /
Macrocycles
Various synthetic approaches to the oxacyclododecindione-
erization, as well as a strategy including ring-closing metath-
type macrolactones, known for their potent anti-inflamma- esis/unsaturation. The last route allowed the preparation of
tory activity, are presented. These include an attempted
carbonylative ring closure, a hydroacylation route, and an
approach by ring-closing metathesis and double bond isom-
a bioactive analogue of the recently described 14-deoxy-
oxacyclododecindione.
therapy even some fifty years after their introduction, their
side effects or their failure to suppress inflammatory reac-
Introduction
Chronic inflammatory diseases such as asthma and rheu- tions in cells lacking appropriate receptors make the search
matoid arthritis are widespread, but in spite of the success for alternative effective anti-inflammatory agents a worth-
of molecular therapy in the past decades, this area still in- while task.
cludes many unmet medical needs. Although glucocortico-
The fungal secondary metabolite products (S)-curvularin
ids continue to be the gold standard for anti-inflammatory (1), (S)-10,11-dehydrocurvularin (2), and oxacyclododecin-
Figure 1. Structures of some natural anti-inflammatory macrolactones.
[a] Institute of Organic Chemistry,
dione (5), as well as oxacyclododecindione’s recently re-
ported 14-deoxy and 4-dechloro-14-deoxy analogues 4 and
3, share the same 12-membered macrolactone skeleton and
exhibit a variety of attractive biological activities (Fig-
ure 1).[1,2]
(S)-Curvularin (1), the least effective compound of the
series, inhibits cytokine-induced activity of the human
iNOS promoter, the cytokine-induced iNOS mRNA expres-
Johannes Gutenberg-University,
Duesbergweg 10-14, 55128 Mainz, Germany
E-mail: opatz@uni-mainz.de
http://www.chemie.uni-mainz.de/OC/AK-Opatz/
[b] Department of Molecular Biotechnology & Systems Biology,
University of Kaiserslautern,
Paul-Ehrlich-Str. 23, Building 23, 67663 Kaiserslautern,
Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500275.
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J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
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sion, and the cytokine-induced nitric oxide (NO) pro- the high anti-inflammatory activity. An attempted RCM
duction.[3] Furthermore, 1 has displayed the capacity for a approach with an enone precursor was unsuccessful.[21]
reduction of proinflammatory gene expression in an in vivo
For our studies, we chose 4 as our initial target molecule
model of rheumatoid arthritis.[4] Additionally, compounds because it already shows very high bioactivity and is struc-
1–5 are TGF-β inhibitors and are promising therapeutic turally simpler than 5 due to the absence of the 14-OH
agents for the suppression of cancer progression and metas- group. Although the stereochemistry at C14 could not be
tasis.[5] Studies have shown that oxacyclododecindione (5) elucidated with certainty, we tentatively assumed the S con-
is an effective anti-inflammatory compound and can be figuration for each of the two adjacent stereocenters, due to
used for treatment of chronic inflammatory and fibrotic dis- (i) the analogy with the simpler compounds 1 and 2 (config-
eases.[5] In vivo data in a mouse model of the disease sug- uration at C15), and (ii) a somewhat better agreement of
gest that this compound could be a new potential drug for the observed strong NOE contact between the neighboring
the treatment of lupus nephritis.[6] Here we report synthetic methyl groups with the corresponding molecular models.
studies directed towards this class of natural products in- This assignment should, however, be handled with care.
cluding the preparation of biologically active analogues.
All experiments have thus far been performed with the
racemic series. As the first key step, we envisioned a carb-
onylative cross-coupling reaction to form the C8–C9 and
the C9–C10 bonds in a single operation. The required seco-
precursor 6 can be synthesized by hydroboration or hydro-
Results and Discussion
Since the first isolation of 1, by Musgrave[7] in 1956, it stannylation of the coupled product of arylacetic acid 8 and
was an interesting target molecule in total synthesis, start- alkyne 9 (pathway A, Scheme 1). An alternative strategy
ing in 1967 with work by Baker, Bycroft, and Roberts.[8] In would be the formation of the β,γ-unsaturated lactone by
these efforts, the 12-membered lactone was formed by Frie- ring-closing metathesis (RCM) with subsequent isomeriza-
del–Crafts acylation,[8–13] by esterification with oxazoles as tion of the newly generated double bond into conjugation
masked activated carboxylates,[14,15] by ring-closing metath- with the carbonyl group (pathway B). A third route could
esis,[16–18] or by aryne acyl-alkylation.[19] In contrast, the involve an RCM/hydrogenation sequence to form the satu-
only synthetic route to the α,β-unsaturated series was re- rated macrolactone 7 and subsequent installation of the
ported in 2013 by Fürstner[20] and co-workers, with (S)- double bond (pathway C).
10,11-dehydrocurvularin (2) being made by an alkyne ring-
By starting from pent-3-yn-1-ol (12), 3-methyloctyn-2-ol
closing metathesis. However, there is no synthesis of a com- (14) was prepared by conversion to iodide 13, subsequent
pound containing a methyl substituent at the α-position of halogen–lithium exchange, transmetallation to copper, and
the unsaturated ketone, which appears to be essential for addition to cis-2,3-epoxybutane with ring opening in 39%
Scheme 1. Retrosynthetic analysis of 4 by (A) a carbonylative cross-coupling reaction, (B) RCM and isomerization, or (C) RCM/reduction
and unsaturation.
2
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Anti-Inflammatory Macrolactones
Scheme 2. Synthesis of alkyne ester 17 for a carbonylative cross-coupling reaction.
yield. The arylacetic acid ester 17 was synthesized by start-
ing from methyl 3,5-bis(benzyloxy)phenylacetate[22] (15),
which was iodinated with N-iodosuccinimide to afford acid
16 in 72% overall yield after basic hydrolysis. Steglich ester-
ification with octynol 14 furnished precursor 17 (Scheme 2).
Hydrostannylation of the internal triple bond turned out to
be cumbersome, with a regioisomeric mixture of all four
conceivable vinylstannanes being obtained in low yield. In
contrast, hydroboration with 9-BBN resulted in the exclus-
ive formation of the regioisomeric (E)-vinylboranes in al-
most equal amounts.
With catecholborane, formation of the desired exo-(E)-
vinylborane was slightly preferred. Because of reductive and
oxidative decomposition of the vinylboranes to the alkene
and the ketone during chromatographic purification, the
crude mixture was used for the subsequent carbonylative
Suzuki coupling. Unfortunately, all tested reaction condi-
tions resulted in complex reaction mixtures and the desired
macrolactone 18 was not detectable (Table 1).
Figure 2. Isolated products of the Suzuki coupling.
The 10-membered lactone 19 was presumably formed in
a Suzuki coupling of the undesired vinylborane regioisomer
without CO insertion but with a subsequent isomerization
of the double bond. Alongside, the ketene acetal 20 and its
hydrolysis product, carboxylic acid 21, were identified. This
suggested that the acylpalladium intermediate of the carb-
onylative cross-coupling reacted with the carbonyl function
instead of the vinylborane, and this route was eventually
given up.
Table 1. Reaction conditions for the Suzuki coupling.
Alternatively, ring closure could be effected by an intra-
molecular hydroacylation of aldehyde 23, available by ester-
ification of arylacetic acid[22] 22 with alkynol 14 and subse-
quent Vilsmeier formylation. Intermolecular reactions of
this type have been reported for internal alkynes.[23–26]
However, neither with the catalytic system Ni(COD)2/
PiPr3[27] nor with an NHC generated in situ from a thiazol-
ium salt[24] could any conversion of the starting material
be observed. The ruthenium-based catalyst RuCl2(p-cym-
Entry Catalyst
Ligand
Base
Solvent
Temperature
1
PEPPSI-iPr
–
–
–
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
PhCl
DMF
PhCl/H2O 80–120 °C
PhH
80 or 120 °C
100 °C
2
3
4
PEPPSI-iPr
PEPPSI-iPr
Pd(dba)2
[23]
ene)2 failed as well, with isomerization of 23 to diene 24
being the sole reaction detected (Scheme 3).
SPhos
Cy3P·HBF4 CsOPiv
110 °C
120 or 150 °C
5
Pd(dba)2
DMF
The strategy for the formation of the β,γ-unsaturated
ketone by ring-closing metathesis is related to the synthesis
of (S)-curvularin by Mohapatra.[18] By starting from aryl-
acetic acid 22, the protected alcohol 25 was prepared in
high yield by reduction with lithium aluminum hydride and
protection with PMBCl. Subsequently, Vilsmeier form-
ylation, a Grignard reaction with but-3-en-2-ylmagnesium
chloride, TBDMS protection of the secondary alcohol, and
6
7
8
9
10
11
12
13
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
PEPPSI-iPr
PEPPSI-iPr
SPhos
SPhos
Cy3P·HBF4 Cs2CO3
Cy3P·HBF4 NEt3
Cy3P·HBF4 Bu4NF
Cy3P·HBF4 CsOPiv
K3PO4
CsOPiv
PhH/H2O 80–100 °C
DMF
DMF
DMF
DMF
dioxane
dioxane
dioxane
120 °C
120 °C
120 °C
120 °C
reflux
–
–
Cs2CO3
CsOPiv
reflux
reflux
Three products were isolated and characterized from the cleavage of the PMB ether with DDQ afforded the desired
reaction mixtures (Figure 2).
alcohol 28a.
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resulted in the formation of a six-membered lactone, due to
the lability under these conditions of the silyl protecting
group, which has been reported as an excellent leaving
group in the synthesis of dehydrocurvularin.[20] TEMPO
oxidation with sodium hypochlorite and potassium brom-
ide also failed, but treatment with TEMPO and iodo-
benzene diacetate in the presence of sodium hydrogen carb-
onate yielded the desired carboxylic acid.[28] This com-
pound was subjected without further purification to a Steg-
lich esterification with 3-methylhex-5-en-2-ol because it
tended to decompose to a six-membered lactone during sil-
ica gel column chromatography. Diene 30a was obtained in
74% yield over two steps (Scheme 4). Ring-closing metathe-
sis furnished macrolactone 31a, which was characterized by
mass spectrometry, with NMR analysis turning out to be
troublesome, due to the presence of four diastereomers (ex-
cluding double bond isomers).
Scheme 3. Attempted intramolecular hydroacylation of alkyne 23.
O-Desilylation was problematic and required harsh con-
ditions, under which the six-membered lactone 33 was
Oxidation to the corresponding carboxylic acid was formed concomitantly (Scheme 5). On the assumption that
problematic. The use of Dess–Martin periodinane or IBX steric hindrance was responsible for the deprotection prob-
Scheme 4. Approach to lactones 31a, 31b, and 31c by RCM.
4
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lem, the macrolactone without the α-methyl substituent – within minutes, but the isolated yield of 40 was low, due to
compound 31b – was synthesized analogously to check the hydrolysis to 39 during purification.
double bond isomerization. In this case, deprotected
Changing the reaction sequence by performing the esteri-
alcohol 34a was obtained on treatment with TBAF in THF fication prior to the Friedel–Crafts acylation afforded diene
at room temperature in 45% yield, with subsequent oxid- 42 in high yield, and subsequent RCM produced macrolact-
ation with Dess–Martin-periodinane furnishing the corre- one 43 (Scheme 7). Attempted selective hydrogenation of
sponding ketone 35a. Isomerization under acidic (CSA) or the double bond without affecting the benzyl ethers by use
basic (pyridine, DBU, LDA) conditions or by using Wilkin- of hydrogen and palladium on charcoal with different
son’s catalyst only resulted in recovery of the starting mate- amine[30–32] or sulfide[33] additives failed. Use of homoge-
rial. The Baudry catalyst[29] furnished the γ,δ-unsaturated nous hydrogenation catalysts[34] (Wilkinson, Crabtree, Bau-
enone 36 (double bond geometry not determined). To ex- dry) furnished the saturated macrolactone 44, but in all
clude additional ring strain imposed by the C-14 methyl cases the reaction ceased at around 50% conversion. Fi-
group as a reason for the failure, the 14-unsubstituted nally, use of diimide, generated in situ,[35–37] selectively af-
macrolactone 35b was synthesized. Again, isomerization in forded 44 in 64% yield, with partial reduction of the carb-
the presence of Baudry’s catalyst afforded the γ,δ-unsatu- onyl group to the alcohol taking place.
rated enone. Heating at reflux in pyridine under argon re-
Introduction of the crucial 9,10-double bond turned out
sulted in isolation of starting material, but heating at reflux to be highly problematic. Attempts to transform the ketone
under air yielded the isomerized and oxidized product 37, into its TMS enol ether for a Saegusa oxidation or for treat-
which is related to the natural product 12-oxocurvularin[2] ment with phenylselenyl bromide under basic conditions
(Scheme 5).
followed by oxidative workup failed due to the high acidity
The formation of the saturated macrolactone was related of the benzylic methylene hydrogen. Thus, macrolactone 44
to the synthesis of (S)-curvularin reported by Kunz and co- was brominated with trimethylphenylammonium tribrom-
workers.[16,17] Friedel–Crafts acylation of the benzyl-pro- ide in 46% isolated yield.[38] Concomitant bromination of
tected methyl arylacetate 15 furnished ketone 38 quantita- the arene appeared to be avoided by addition of the brom-
tively. Saponification and esterification with 3-methyl- inating agent in portions over a period of 1.5 h at room
pent-4-en-2-ol under various conditions with different de- temperature with LC–MS monitoring. Dehydrobromin-
hydrating agents only yielded the isochromen-3-one deriva- ation under various sets of conditions only yielded small
tive 40 rather than the desired diene (Scheme 6). Complete amounts of the 9–10 unsaturated macrolactone 47, which
conversion of the starting material was observed by TLC proved to have a Z-configured double bond. The main
Scheme 5. Synthesis of lactones 36 and 37.
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Scheme 6. Synthesis of isochromen-3-one 40.
Scheme 7. Synthesis of 14-deoxyoxacyclododecindione isomer 50.
product was the transannular substitution product 46 con-
Treating bromide 45 with tetrakis(triphenylphosphine)-
taining a five-membered ring, which was formed exclusively palladium(0) to effect a β-hydride elimination afforded the
with strong bases such as DBU. exo-methylene derivative 48 in 30% yield. As a side prod-
6
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uct, the reduced macrolactone was obtained in nearly equal Table 2. HepG2 cells were transiently transfected with the indicated
reporter gene construct and the constitutively active pRL-EF1α re-
amounts. Changing the base (Cs2CO3, CsOPiv, pyridine),
ligand [PPh3, tri(2-furyl)phosphine] or the metal (Pd, Ir)
did not increase the yield of the unsaturated lactone 48.
Attempts to isomerize the double bond did not yield the
porter gene and stimulated with 5 ngmL–1 TGF-β or 5 ngmL–1 IL-
4 with or without test compounds for 16 h as described in Materials
and Methods (see Experimental Section).
pgl3-TK-7xN4
(Stat6)
(CAGA)9x-MLP-Luc
(Smad2/3)
desired target molecule. In order to assess the anti-inflam-
matory potency of this isomeric scaffold, deprotection with
boron trichloride and chlorination of the aromatic ring (4-
position) were performed to afford 50, the double bond iso-
mer of 14-deoxyoxacyclododecindione (4).
Furthermore, hydrogenolysis of intermediate 43 afforded
10,14-dimethyl-12,13-dehydrocurvularin (51) together with
10,14-dimethylcurvularin (52), allowing investigation of the
effect of the double bond on the anti-inflammatory potency
(Scheme 8).
IC50 [μgmL–1]
IC50 [μgmL–1]
10,14-Dimethyl-12,13-dehydro-
curvularin (51)
3Ϯ0.32
5Ϯ0.21
10,14-Dimethylcurvularin (52)
10,11-Dehydrocurvularin (2)
2-[3,5-Bis(benzyloxy)-2-(2-methyl- Ͼ 50
1-oxopent-4-enyl)phenyl]acetic
acid (39)
8Ϯ1.1
0.9Ϯ0.08
9Ϯ1.2
0.6Ϯ0.07
5Ϯ0.5
14-Methyl-10-exo-methylenecur- 0.750Ϯ0.13
1Ϯ0.22
vularin (49)
4-Chloro-14-methyl-10-
exo-methylenecurvularin (50)
14-Deoxyoxacyclo-
dodecindione (4)
Oxacyclododecindione (5)
Ͼ 5
0.80Ϯ0.1
0.050Ϯ0.003
0.025Ϯ0.002
0.075Ϯ0.006
0.050Ϯ0.005
respect to the TGF-β-induced signaling pathway, thus being
comparable in this regard to the naturally occurring α,β-
dehydrocurvularin (2) (IC50 values: 0.6–0.9 μgmL–1); this
indicates that the Δ10,11-double bond and/or the exo-meth-
ylene group at C-10 contribute to the biological activity.
The importance of the occurrence of a double bond at C-
10/11 in the lactone ring is also underlined by the fact that
the fully saturated compound 52 displayed 10-fold reduced
activity with respect to both IL-4- and TGF-β- induced re-
porter gene expression. The introduction of a double bond
between C-12 and C-13 as in compound 51 only partially
restored the inhibitory activity with respect to the IL-4- and
TGF-β-dependent reporter gene expression, with IC50 val-
ues of 3–5 μgmL–1. Interestingly, chlorination of the double
bond isomer of 14-deoxyoxacyclododecindione (50) at C-4
resulted in a greatly diminished inhibitory activity with re-
spect to IL-4 signaling but left the TGF-β inhibitory ac-
tivity unaffected. Of the compounds devoid of an intact
lactone ring, only compound 39 exhibited a significant bio-
logical activity, inhibiting TGF-β signaling with an IC50
value around 5 μgmL–1 without affecting IL-4-induced re-
porter gene expression.
Scheme 8. Synthesis of 10,14-dimethyl-12,13-dehydrocurvularin
(51) and 10,14-dimethylcurvularin (52).
Biological Evaluation
The synthetic analogues of oxacyclododecindione were
tested for their inhibitory activity on both an IL-4-inducible
Stat6-dependent and a TGF-β-inducible Smad2/3-depend-
ent transcriptional luciferase reporter in transiently
transfected HepG2 cells normalized against the constitutive
active EF1α-promoter in front of the luciferase gene in or-
der to exclude unspecific cytotoxic effects as described pre-
viously.[5,39]
The biological activities of the most active synthetic de-
rivatives in comparison with those of oxacyclododecidione
are shown in Table 2.
The natural product oxacyclododecindione (5) exhibits
highly potent inhibition of IL-4- and TGF-β-dependent
Conclusions
In summary, various attempts to synthesize oxacyclo-
reporter gene expression, with IC50 values in the 25– dodecindione-type macrolactones through carbonylative
50 ngmL–1 range. 14-Deoxyoxacyclododecindione (4), ring closure, intramolecular alkyne hydroacylation, or
which differs from the parent compound in the missing RCM/double bond isomerization failed. A biologically
hydroxy group at C-14, exhibited biological activities com- active analogue of 14-deoxyoxacyclododecindione – com-
parable to those of oxacyclododecindione (5). Compound pound 50 – could instead be synthesized by an RCM/
49, the double bond isomer of 14-deoxyoxacyclododecin- hydrogenation/unsaturation approach. The biological evalu-
dione, was about 25 times less active with respect to IL-4- ation of compounds and intermediates allowed the estab-
induced Stat signaling and about 13 times less active with lishment of preliminary structure–activity relationships.
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(Dual-Luciferase-Reporter-Assay). Luciferase-based reporter gene
expression was thereby normalized for transfection variability and
cytotoxicity against renilla luciferase expression of the constitu-
tively active control vector (pRL-EF1α) assayed in the same sam-
ple. HepG2 cells were transiently transfected by electroporating
(Bio-Rad, Gene-Pulser) 1ϫ107 cellsmL–1 in DMEM together with
50 μg of the indicated constructs and the internal control pRL-
EF1α vector at 500 Vcm–1. After electroporation the cells were
seeded at 2ϫ105 cellsmL–1 and allowed to recover for 16 h. For
induction of reporter gene expression, the cells were treated with
TGF-β (5 ngmL–1) with or without test compounds in DMEM
containing FCS (5%). Luciferase activity was measured 16 h after
induction by use of the luciferase assay system (Promega,
Mannheim, Germany) according to the manufacturer’s instructions
with a luminometer.
Experimental Section
Materials and Methods: All commercially available reagents were
reagent grade and used without further purification unless other-
wise noted. Reactions involving air- or moisture-sensitive reagents
were performed under argon or nitrogen in oven-dried glassware.
Reaction temperatures refer to the temperature of the particular
cooling or heating bath. Reaction monitoring was performed by
thin-layer chromatography (TLC) carried out on 0.25 mm silica gel
plates (60F254) with UV light as visualizing agent and colorized
with vanillin reagent [solution of vanillin (1.0 g) in methanol
(100 mL), glacial acetic acid (12 mL) and concentrated sulfuric acid
(4 mL)] or Seebach reagent [solution of cerium(IV) sulfate (1 g) and
phosphomolybdic acid (2.5 g) in water (95 mL) and concentrated
sulfuric acid (4 mL)] and heat as developing agent. Specific reac-
tions were monitored by LC–MS on an HPLC unit with a binary
pump and an integrated diode array detector coupled to an LC-
ion-trap mass spectrometer. Ionization was achieved with an elec-
trospray ionization (ESI) source. Flash chromatography was per-
formed on 35–70 μm silica gel with the indicated solvent system.
5-Iodopent-2-yne (13):[43] Triphenylphosphine (18.67 g, 71.2 mmol,
1.2 equiv.), imidazole (4.85 g, 71.2 mmol, 1.2 equiv.), and iodine
(18.07 g, 71.2 mmol, 1.2 equiv.) were added to a stirred solution of
pent-3-yn-1-ol (12, 4.99 g, 59.3 mmol, 1.0 equiv.) in dry diethyl
ether (150 mL) and dry acetonitrile (150 mL). After 2.5 h the reac-
tion mixture was quenched with saturated aqueous sodium
hydrogen carbonate solution (150 mL) and the organic layer was
washed with saturated aqueous sodium thiosulfate solution
(100 mL), dried with anhydrous magnesium sulfate, and filtered.
The solvent was removed in vacuo. The residue was passed through
a short plug of silica gel (pentane). Careful evaporation of the sol-
vent yielded 13 (11.00 g, 56.7 mmol, 96%, ref.[43]: quant.) as a col-
NMR spectra were recorded with
a 300 MHz spectrometer
(300 MHz 1H and 75.5 MHz 13C), a 400 MHz spectrometer
(400 MHz 1H and 100.6 MHz 13C), or a 600 MHz spectrometer
1
(600 MHz H, 150.9 MHz 13C). The chemical shifts are referenced
to the deuterated solvent (e.g., for CDCl3, δ = 7.26 ppm and
77.16 ppm for 1H and 13C NMR, respectively) and reported in
parts per million (ppm, δ) relative to tetramethylsilane (TMS, δ =
0.00 ppm).[40] Coupling constants (J) are reported in Hz and the
splitting abbreviations used are: s (singlet), d (doublet), t (triplet),
m (multiplet), and br (broad). High-resolution masses were re-
corded with a Q-TOF instrument with a dual source and a suitable
external calibrant. Melting points were determined in open capil-
lary tubes. Infrared spectra were recorded as FTIR spectra with a
diamond ATR unit and are reported in terms of frequency of ab-
orless, volatile liquid, Rf
=
0.85 (cHex/EtOAc). 1H NMR
(300 MHz, CDCl3): δ = 3.19 (t, J = 7.4 Hz, 2 H, CH2I), 2.71 (tq,
J = 7.4, 2.5 Hz, 2 H, CH2CH2I), 1.77 (t, J = 2.5 Hz, 3 H,
CH3) ppm. The data are in accordance with the literature.[43] 13
C
NMR (75.5 MHz, CDCl3): δ = 78.0 (C-3), 77.9 (C-4), 24.2 (C-1),
3.7 (C-2), 2.7 (C-5) ppm. The data are in accordance with the litera-
ture.[43]
sorption (ν, cm–1). Microwave-assisted reactions were carried out
˜
with a monomode-microwave. Toluene, tetrahydrofuran and diethyl
ether were distilled from sodium and benzophenone. EtOH was
distilled from sodium and diethyl phthalate. Dichloromethane was
distilled from calcium hydride. Dimethylformamide (DMF, extra
dry) and acetonitrile (extra dry) were purchased and used without
further purification. Preparative reversed-phase HPLC was carried
out with an HPLC system fitted with two pumps (pump head size:
each 100 mL) with mixtures of acetonitrile and water as eluent;
these were degassed by ultrasonication for 30 min. The system was
connected to a diode array detector and an injection loop with a
volume of 5 mL. An ACE5–C18PFP column (pore size: 5 μm,
length: 15 cm, diameter: 30.0 mm) with a flow of 17.5 mLmin–1 or
an ACE5–C18 column (pore size: 5 μm, length: 12.5 cm, diameter
21.2 mm) with a flow of 37.5 mLmin–1 was used.
3-Methyloct-6-yn-2-ol (14): 5-Iodopent-2-yne (13, 1.61 g,
8.32 mmol, 1.0 equiv.) was dissolved in dry and degassed diethyl
ether (10 mL) and cooled to –78 °C. Then a tBuLi solution (1.6 m
in pentane, 10.7 mL, 17.1 mmol, 2.05 equiv.) was added, and the
mixture was stirred for 25 min. It was then warmed to –40 °C and
stirred for an additional 50 min. This reaction mixture was added
to a suspension of copper(I) iodide (1.32 g, 6.93 mmol, 1.0 equiv.)
in dry and degassed THF (15 mL) at –78 °C. After 35 min, 2,3-
cis-epoxybutane (418 mg, 5.80 mmol, 1.0 equiv.) was added. The
reaction mixture was stirred at –78 °C for 6 h and was then allowed
to warm slowly to room temperature. After 2.5 d, the reaction mix-
ture was quenched with aqueous saturated ammonium chloride
solution (50 mL) and stirred for 2 h. The aqueous layer was ex-
tracted with diethyl ether (3ϫ75 mL), dried with anhydrous mag-
nesium sulfate, and filtered. The solvent was removed in vacuo.
Purification by flash chromatography on silica yielded 14 (813 mg,
2.27 mmol, 39%) as a yellow liquid, Rf = 0.11 (cHex/EtOAc 8:1).
1H NMR (300 MHz, CDCl3): δ = 3.74–3.64 (m, 1 H, 2-H), 2.32–
2.04 (m, 2 H, CH2-5), 1.77 (t, J = 2.5 Hz, 3 H, CH3-8), 1.73–1.60
(m, 1 H, 3-H), 1.37–1.22 (m, 2 H, CH2-4), 1.14 (d, J = 6.3 Hz, 3
H, CH3-1), 0.88 (d, J = 6.7 Hz, 3 H, CH3-3) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 79.2 (C-6), 75.8 (C-7), 71.6 (C-2), 39.3 (C-
3), 32.0 (C-4), 19.6 (C-1), 16.6 (C-5), 14.4 (CH3-3), 3.6 (C-8) ppm.
Biological Assays: HepG2 cells (DSMZ ACC 180) were maintained
in DMEM (Dulbecco’s modified Eagle’s medium) supplemented
with fetal calf serum (FCS, 10%) and penicillin G (65 μgmL–1) and
streptomycin sulfate (100 μgmL–1) in a humidified atmosphere.
The STAT6-driven reporter plasmid pGL3-TK-7xN4 contains the
Herpes simplex virus thymidine kinase promoter under the control
of seven copies of the palindromic sequence TTC(N)4GAA.[39] The
STAT6 expression plasmid (TOPO-Stat6) has been described pre-
viously.[41] The reporter plasmid (AGCCAGACA)9MLP-Luc con-
tains nine tandem copies of the CAGA Smad binding element up-
stream of the adenovirus major late promoter driving luciferase
expression.[42] The plasmid was kindly provided by Prof. S. Dooley
(University of Mannheim, Germany). The control reporter vector
pRL-EF1α for data normalization was purchased from Promega
IR (NaCl): ν = 3372, 2970, 2922, 2877, 1456, 1379, 1094, 1059,
˜
1005 cm–1.
Methyl [3,5-Bis(benzyloxy)-2-iodophenyl]acetate:[21] A solution of
methyl 3,5-bis(benzyloxy)phenylacetate (15, 4.90 g, 13.5 mmol,
1.0 equiv.) and N-iodosuccinimide (3.04 g, 13.5 mmol, 1.0 equiv.)
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 20-04-15 15:50:46
Pages: 23
Anti-Inflammatory Macrolactones
in dry acetonitrile (100 mL) was cooled to 0 °C and stirred with
protection from light. Trifluoroacetic acid (1.56 mL, 20.3 mmol,
1.5 equiv.) was added, and the reaction mixture was stirred for 24 h
and then allowed to warm to room temperature. The solvent was
removed in vacuo, and the residue was crystallized from methanol
to yield a colorless solid (4.72 g, 9.66 mmol, 72%, ref.[21] 90%), Rf
= 0.28 (cHex/EtOAc 10:1), m.p. 101.0–102.0 °C (methanol), m.p.
H, CH3-3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 170.2 (COO),
160.0 (Cq-3), 158.2 (Cq-5), 140.1 (Cq-1), 136.6 (Cq-1, Ph), 136.5
(Cq-1, Ph), 128.8 (CH-3, CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.3
(CH-4, Ph), 128.0 (CH-4, Ph), 127.7 (CH-2, CH-6, Ph), 127.1 (CH-
2, CH-6, Ph), 109.2 (CH-6), 100.0 (CH-4), 83.7 (Cq-2), 79.0 (Cq-
6), 75.8 (Cq-7), 75.0 (CHO), 71.2 (OCH2Ph), 70.4 (OCH2Ph), 47.3
(CH2COO), 36.7 (CH-3), 31.7 (CH2-4), 16.6 (CH2-5), 16.4 (CH3-
in ref.[21] 102–103 °C (cHex/EtOAc 10:1). 1H NMR (300 MHz, 1), 14.7 (CH -3), 3.6 (CH -8) ppm. IR (NaCl): ν = 3065, 3033,
˜
3
3
CDCl3): δ = 7.52–7.30 (m, 10 H, 2ϫPh), 6.63 (d, J = 2.7 Hz, 1 H,
2923, 2874, 2249, 1730, 1583, 1498, 1453, 1428, 1315, 1169, 1072,
4-H), 6.48 (d, J = 2.7 Hz, 1 H, 6-H), 5.10 (s, 2 H, OCH2Ph), 5.02 735 cm–1. HRMS (ESI): calcd. for [C31H33IO4 + Na]+ 619.1321;
(s, 2 H, OCH2Ph), 3.86 (s, 2 H, CH2), 3.73 (s, 3 H, OCH3) ppm.
The data are in accordance with the literature.[21] 13C NMR
(75.5 MHz, CDCl3): δ = 171.1 (COOMe), 160.1, 158.3 (C-3, C-5),
139.8 (C-1), 136.5 (C-1, Ph), 136.5 (C-1, Ph), 128.8 (C-3, C-5, Ph),
128.7 (C-3, C-5, Ph), 128.3 (C-4, Ph), 128.0 (C-4, Ph), 127.7 (C-2,
C-6, Ph), 127.1 (C-2, C-6, Ph), 109.2 (C-6), 100.0 (C-4), 83.6 (C-
2), 71.2 (OCH2Ph), 70.4 (OCH2Ph), 52.3 (OCH3), 46.8 (CH2) ppm.
C23H21IO4 (488.32): calcd. C 56.57, H 4.33; found C 56.62, H 4.32.
The data are in accordance with the literature.[21]
[3,5-Bis(benzyloxy)-2-iodophenyl]acetic Acid (16):[21] Methyl [3,5-
bis(benzyloxy)-2-iodophenyl]acetate (862 mg, 1.77 mmol, 1.0 equiv.)
was added to a solution of NaOH in methanol (2 m, 50 mL), and
the mixture was heated at reflux with protection from light for 4 h.
After removal of the solvent in vacuo, the residue was acidified with
HCl (2 m, 50 mL) and extracted with ethyl acetate (3ϫ30 mL). The
combined organic extracts were dried with magnesium sulfate and
filtered. Removal of the solvent in vacuo yielded acid 16 (839 mg,
1.77 mmol, quant.) as a colorless solid, which was used in the next
step without further purification, Rf = 0.64 (EtOAc/HOAc 100:1),
m.p. 128.0–130.0 °C (EtOAc), m.p. in ref.[21] 168.5–168.7 °C (de-
composition, EtOAc). 1H NMR (300 MHz, [D6]DMSO): δ = 7.53–
7.30 (m, 10 H, 2ϫPh), 6.78 (d, J = 2.7 Hz, 1 H, 4-H), 6.71 (d, J
= 2.7 Hz, 1 H, 6-H), 5.19 (s, 2 H, OCH2Ph), 5.09 (s, 2 H, OCH2Ph),
3.74 (s, 2 H, CH2), 3.74 (s, 3 H, OCH3) ppm. The data are in ac-
cordance with the literature.[21] 13C NMR (75.5 MHz, [D6]DMSO):
δ = 171.3 (COOH), 159.4, 157.5 (C-3, C-5), 140.4 (C-1), 136.8 (C-
1, Ph), 136.7 (C-1, Ph), 128.5 (2ϫC-3, 2ϫC-5, Ph), 128.0 (C-4,
Ph), 127.9 (C-2, C-6, Ph), 127.8 (C-4, Ph), 127.2 (C-2, C-6, Ph),
110.1 (C-6), 99.4 (C-4), 83.6 (C-2), 70.3 (OCH2Ph), 69.6
(OCH2Ph), 46.1 (CH2) ppm. The data are in accordance with the
literature.[21]
found 619.1326. C31H33IO4 (596.50): calcd. C 62.42, H 5.58; found
C 62.27, H 5.71.
[({[3,5-Bis(benzyloxy)-2-iodophenyl]acetyl}oxy)-6-methyloct-2-en-2-
yl]boronic Acid: Catecholborane (1 m in THF, 0.13 mL, 0.13 mmol,
1.5 equiv.) was added to alkyne 17 (50 mg, 84 μmol, 1.0 equiv.). The
reaction was performed under microwave irradiation (150 W, 80 °C,
2 h). The solvent was removed in vacuo to yield the hydroborated
product, which was used without further purification due to de-
composition during the purification step (reduction and oxidation).
An analytic sample was purified by HPLC and yielded a colorless
oil. 1H NMR COSY, NOESY (600 MHz, CDCl3): δ = 7.50–7.29
(m, 10 H, 2ϫPh), 6.68–6.63 (m, 1 H, 6Ј-H), 6.62 (d, J = 2.7 Hz, 1
H, 6-H), 6.45 (d, J = 2.6 Hz, 1 H, 4-H), 5.07 (s, 2 H, 3-OCH2Ph),
4.99 (s, 2 H, 5-OCH2Ph), 4.91–4.87 (m, 1 H, 2Ј-OCH), 3.84–3.78
(m, 2 H, CH2COO), 2.26–2.17 (m, 1 H, 5Ј-CH2A), 2.16–2.10 (m, 1
H, 5Ј-CH2B), 1.73 (s, 3 H, 8Ј-CH3), 1.72–1.69 (m, 1 H, 3Ј-CH),
1.57–1.50 (m, 1 H, 4Ј-CH2A), 1.24–1.20 (m, 1 H, 4Ј-CH2B), 1.17 (d,
J = 6.3 Hz, 3 H, 1Ј-CH3), 0.90 (d, J = 6.9 Hz, 3 H, 3Ј-CH3) ppm.
13C NMR HSQC, HMBC (150.9 MHz, CDCl3): δ = 170.2 (COO),
160.0 (Cq-5), 158.2 (Cq-3), 149.0 (CH-6Ј), 140.1 (Cq-1), 136.5 (Cq-
1, Ph), 136.5 (Cq-1, Ph), 129.5 (Cq-7Ј), 128.8 (CH-3, CH-5, Ph),
128.7 (CH-3, CH-5, Ph), 128.3 (CH-4, Ph), 128.0 (CH-4, Ph), 127.7
(CH-2, CH-6, Ph-5), 127.1 (CH-2, CH-6, Ph-3), 109.1 (CH-6),
100.0 (CH-4), 83.7 (Cq-2), 75.1 (CH-2Ј), 71.1 (OCH2, OBn-3), 70.4
(OCH2, OBn-5), 47.3 (CH2COO), 37.4 (CH-3Ј), 31.6 (CH2-4Ј), 26.8
(CH2-5Ј), 16.1 (CH3-1Ј), 14.9 (CH3-3Ј), 13.3 (CH3-8Ј) ppm. IR
(ATR): ν = 3065, 3032, 2926, 2873, 1728, 1581, 1498, 1452, 1365,
˜
1332, 1277, 1168, 1072 cm–1. HRMS (ESI): calcd. for [C31H36BIO6
+ Na]+ 665.1547; found 665.1544.
9,11-Bis(benzyloxy)-8-ethenyl-4,5-dimethyl-1,4,5,6,7,8-hexahydro-
2H-3-benzoxecin-2-one (19): A solution of alkyne 17 (1.62 g,
2.71 mmol, 1.0 equiv.) in dry dichloromethane (7 mL) was added
at 0 °C to a solution of pinacolborane (867 mg, 6.78 mmol,
2.5 equiv.) in dry dichloromethane (3 mL), and the mixture was
stirred under protection from light. After 5 h the reaction mixture
was allowed to warm to room temperature over 13 h. The solvent
was removed in vacuo. Purification by flash chromatography on
silica (cHex/EtOAc 15:1) yielded the boronic ester as a mixture of
both regioisomers (257 mg, 0.35 mmol, 13 %). Boronic ester
(56 mg, 77 μmol, 1.0 equiv.) and Cs2CO3 (75 mg, 231 μmol,
3.0 equiv.) were dissolved in dry and degassed chlorobenzene
(6 mL) and the solution was saturated with carbon monoxide.
PEPPSI-iPr[44] (10 mg, 15 μmol, 0.2 equiv.) was dissolved in chloro-
benzene (4 mL) and added. The reaction mixture was stirred under
carbon monoxide (balloon) at 80 °C for 6 h and then at 120 °C.
After 3 d, the solvent was removed in vacuo. Purification by flash
chromatography on silica (cHex/EtOAc 15:1) yielded 19 (8.8 mg,
19 μmol, 25%) as a colorless oil, Rf = 0.38 (cHex/EtOAc 10:1).
3-Methyloct-6-yn-2-yl
[3,5-Bis(benzyloxy)-2-iodophenyl]acetate
(17):[16,17] Acid 16 (1.59 g, 3.35 mmol, 1.0 equiv.), 3-methyloct-6-
yn-2-ol (14, 517 mg, 3.69 mmol, 1.1 equiv.), and DMAP (42 mg,
0.34 mmol, 0.1 equiv.) were dissolved in dry dichloromethane
(100 mL) and cooled to –10 °C with protection from light. N,NЈ-
Dicyclohexylcarbodiimide (0.83 g, 4.02 mmol, 1.2 equiv.) was dis-
solved in dry dichloromethane (15 mL), and this solution was
added. After the mixture had been stirred for 3 h, water (0.2 mL)
was added and stirring was continued for an additional 20 min.
The reaction mixture was filtered through a short plug of silica
gel and celite (CH2Cl2). The solvent was removed in vacuo, and
purification by flash chromatography on silica (cHex/EtOAc 15:1)
yielded ester 17 (1.73 g, 2.90 mmol, 86%) as a colorless solid, Rf =
1
0.53 (cHex/EtOAc 4:1), m.p. 64.0–65.0 °C (cHex/EtOAc 15:1). H
NMR (400 MHz, CDCl3): δ = 7.51–7.30 (m, 10 H, 2ϫPh), 6.65
(d, J = 2.6 Hz, 1 H, 4-H), 6.48 (d, J = 2.6 Hz, 1 H, 6-H), 5.10 (s,
2 H, OCH2Ph), 5.03 (s, 2 H, OCH2Ph), 4.88 (quint, J = 6.3 Hz, 1
H, OCH), 3.86 (d, J = 16.2 Hz, 1 H, CH2ACOO), 3.81 (d, J =
16.2 Hz, 1 H, CH2BCOO), 2.21–2.15 (m, 1 H, CH2A-5), 2.13–2.04
Diastereomer A: 1H NMR COSY (600 MHz, CDCl3): δ = 7.43–
(m, 1 H, CH2B-5), 1.84–1.77 (m, 1 H, CH-3), 1.76 (t, J = 2.5 Hz, 7.32 (m, 10 H, 2ϫPh), 6.56 (d, J = 2.4 Hz, 1 H, 6-H), 6.36 (d, J
3 H, CH3-8), 1.69–1.60 (m, 1 H, CH2A-4), 1.36–1.25 (m, 1 H, = 2.4 Hz, 1 H, 4-H), 6.28 (ddd, J = 17.2, 10.0, 7.5 Hz, 1 H,
CH2B-4), 1.20 (d, J = 6.4 Hz, 3 H, CH3-1), 0.88 (d, J = 6.8 Hz, 3 CH=CH2), 5.06–4.97 (m, 4 H, 2ϫOCH2Ph), 4.92 (d, J = 17.2 Hz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 20-04-15 15:50:46
Pages: 23
J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
FULL PAPER
1 H, CH=CH2A), 4.82 (d, J = 10.0 Hz, 1 H, CH=CH2B), 4.57–4.52
(m, 1 H, 13-H), 3.93 (d, J = 18.7 Hz, 1 H, CH2A-2), 3.55 (d, J =
H, CH3-3Ј) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3):
δ = 171.1 (COO), 165.3 (COOH), 162.0 (Cq-5), 159.4 (Cq-3), 141.9
18.7 Hz, 1 H, CH2B-2), 3.06–3.03 (m, 1 H, 9-H), 1.66–1.62 (m, 2 (Cq-1), 135.9 (Cq-1, Ph, OBn-5), 134.5 (Cq-1, Ph, OBn-3), 130.7
H, CH2A-10, 12-H), 1.27–1.24 (m, 5 H, CH2-11, CH3-13), 1.21– (CH-6Ј), 129.2 (CH-3, CH-5, Ph), 129.2 (CH-4, Ph), 128.9 (CH-3,
1.15 (m, 1 H, CH2B-10), 0.89 (d, J = 6.8 Hz, 3 H, CH3-12) ppm.
CH-5, Ph), 128.6 (CH-4, Ph), 128.0 (CH-2, CH-6, OBn-3), 127.7
13C NMR HSQC, HMBC (150.9 MHz, CDCl3): δ = 171.9 (COO), (CH-2, CH-6, OBn-5), 124.0 (CH-7Ј), 112.5 (CH-6), 111.9 (Cq-2),
157.9 (Cq-7), 157.7 (Cq-5), 142.6 (CH=CH2), 137.1 (Cq-1, Ph), 100.3 (CH-4), 75.0 (CHO-2Ј), 72.6 (OCH2Ph-3), 70.5 (OCH2Ph-5),
137.0 (Cq-1, Ph), 133.8 (Cq-3), 128.8 (CH-3, CH-5, Ph), 128.7 (CH- 42.4 (CH2COO), 37.0 (CH-3Ј), 32.4 (CH2-4Ј), 24.5 (CH2-5Ј), 15.9
3, CH-5, Ph), 128.2 (CH-4, Ph), 127.9 (CH-4, Ph), 127.8 (CH-2,
CH-6, Ph), 127.4 (CH-2, CH-6, Ph), 126.4 (Cq-8), 113.0 3010, 2928, 2854, 1729, 1604, 1498, 1453, 1318, 1291, 1167,
(CH=CH2), 108.5 (CH-4), 100.1 (CH-6), 78.3 (CH-13), 70.3
697 cm–1. HRMS (ESI): calcd. for [C32H36O6 + Na]+ 539.2410;
(CH -1Ј), 14.7 (CH -3Ј), 12.9 (CH -8Ј) ppm. IR (ATR): ν = 3064,
˜
3 3 3
(OCH2Ph), 70.2 (OCH2Ph), 48.0 (CH-9), 42.4 (CH2-2), 42.1 (CH- found 539.2392.
12), 33.5 (CH2-10), 29.9 (CH2-11), 20.0 (CH3-13), 19.0 (CH3-
3-Methyloct-6-yn-2-yl 2-[3,5-Bis(benzyloxy)phenyl]acetate:[16,17]
Acid 22 (1.98 g, 5.68 mmol, 1.0 equiv.), alcohol 14 (796 mg,
5.68 mmol, 1.0 equiv.), and DMAP (69 mg, 0.57 mmol, 0.1 equiv.)
were dissolved in dry dichloromethane (100 mL) and cooled to
12) ppm. IR (ATR): ν = 3067, 3033, 2959, 2928, 2873, 1720, 1603,
˜
1585, 1498, 1454, 1259, 1151, 1065, 1048 cm–1. HRMS (ESI): calcd.
for [C31H34O4 + Na]+ 493.2355; found 493.2341.
Diastereomer B: 1H NMR COSY (600 MHz, CDCl3): δ = 7.43– –20 °C. N,NЈ-Dicyclohexylcarbodiimide (1.41 g, 6.82 mmol,
7.30 (m, 10 H, 2ϫPh), 6.56 (d, J = 2.5 Hz, 1 H, 4-H), 6.53 (d, J 1.2 equiv.) was dissolved in dry dichloromethane (15 mL) and
= 2.5 Hz, 1 H, 6-H), 6.30 (ddd, J = 17.3, 10.1, 7.3 Hz, 1 H, added. After stirring for 4 h the reaction mixture was allowed to
CH=CH2), 5.04 (d, J = 11.2 Hz, 1 H, CH2A, OBn-5), 4.99 (d, J =
warm to room temperature. After 18 h water (0.1 mL) was added,
11.2 Hz, 1 H, CH2B, OBn-5), 4.99 (s, 2 H, CH2, OBn-7), 4.98–4.95 and stirring was carried out for an additional hour. The reaction
(m, 1 H, CH=CH2A), 4.89–4.87 (m, 1 H, CH=CH2B), 4.39 (dq, J mixture was filtered through a short plug of silica and celite
= 10.1, 6.2 Hz, 1 H, 13-H), 4.26 (ddd, J = 11.6, 7.3, 4.2 Hz, 1 H,
(CH2Cl2). The solvent was removed in vacuo, and purification by
9-H), 3.94 (d, J = 11.9 Hz, 1 H, CH2A-2), 3.27 (d, J = 11.9 Hz, 1 flash chromatography on silica (cHex/EtOAc 30:1) yielded a color-
H, CH2B-2), 2.62 (ddd, J = 13.7, 11.6, 8.3 Hz, 1 H, CH2A-10), 1.59– less oil (1.13 g, 2.40 mmol, 42%), Rf = 0.20 (cHex/EtOAc 15:1). 1H
1.55 (m, 1 H, 12-H), 1.47 (ddd, J = 14.4, 10.7, 4.2 Hz, 1 H, CH2B
10), 1.28 (d, J = 6.2 Hz, 3 H, CH3-13), 1.22–1.17 (m, 1 H, CH2A
-
-
NMR COSY (400 MHz, CDCl3): δ = 7.47–7.33 (m, 10 H, 2ϫPh),
6.60 (d, J = 2.2 Hz, 2 H, 2-H, 6-H), 6.58 (t, J = 2.2 Hz, 1 H, 4-H),
5.06 (s, 4 H, 2ϫOCH2Ph), 4.87 (quint, J = 6.3 Hz, 1 H, OCH),
3.57 (s, 2 H, CH2COO), 2.30–2.19 (m, 1 H, CH2A-5), 2.16–2.05 (m,
11), 0.91–0.86 (m, 1 H, CH2B-11), 0.89 (d, J = 7.0 Hz, 3 H, CH3-
12) ppm. 13C NMR HSQC, HMBC (150.9 MHz, CDCl3): δ =
171.6 (COO), 158.8 (Cq-7), 158.2 (Cq-5), 143.3 (CH=CH2), 137.1 1 H, CH2B-5), 1.86–1.77 (m, 1 H, CH-3), 1.78 (t, J = 2.6 Hz, 3 H,
(Cq-1, Ph), 137.0 (Cq-1, Ph), 136.3 (Cq-3), 128.7 (CH-3, CH-5, Ph), CH3-8), 1.69–1.61 (m, 1 H, CH2A-4), 1.34–1.25 (m, 1 H, CH2B-4),
128.6 (CH-3, CH-5, Ph), 128.2 (CH-4, Ph), 127.9 (CH-4, Ph), 127.9
1.19 (d, J = 6.3 Hz, 3 H, CH3-1), 0.90 (d, J = 6.8 Hz, 3 H, CH3-
(CH-2, CH-6, OBn-5), 127.4 (CH-2, CH-6, OBn-7), 123.6 (Cq-8), 3) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3): δ = 170.9
112.9 (CH=CH2), 108.8 (CH-4), 100.9 (CH-6), 76.9 (CH-13), 70.2 (COO), 160.0 (Cq-3, Cq-5), 136.9 (2ϫCq-1, Ph), 136.5 (Cq-1), 128.6
(OCH2Ph), 70.2 (OCH2Ph), 44.1 (CH-12), 42.8 (CH2-2), 42.6 (CH- (2ϫCH-3, 2ϫCH-5, Ph), 128.0 (2ϫCH-4, Ph), 127.6 (2ϫCH-2,
9), 34.8 (CH2-10), 32.2 (CH2-11), 20.1 (CH3-12), 19.6 (CH3-
2ϫCH-6, Ph), 108.5 (CH-2, CH-6), 100.9 (CH-4), 78.8 (Cq-6), 75.8
(Cq-7), 74.7 (CHO), 70.1 (2 ϫ OCH2Ph), 42.1 (CH2COO), 36.6
(CH-3), 31.6 (CH2-4), 16.6 (CH2-5), 16.3 (CH3-1), 14.5 (CH3-3),
13) ppm. IR (ATR): ν = 3065, 3033, 2959, 2924, 2872, 2856, 1730,
˜
1602, 1498, 1295, 1274, 1161, 1139, 1058 cm–1. HRMS (ESI): calcd.
for [C31H34O4 + Na]+ 493.2355; found 493.2374.
3.5 (CH -8) ppm. IR (NaCl): ν = 3090, 3065, 3033, 2976, 2920,
˜
3
2876, 2250, 1728, 1595, 1498, 1453, 1292, 1160, 1059, 734,
698 cm–1. HRMS (ESI): calcd. for [C31H34O4 + H]+ 471.2535;
found 471.2530.
Carboxylic Acid 21: Catecholborane (1 m in THF, 0.49 mL,
0.49 mmol, 2.0 equiv.) was added to alkyne 17 (145 mg, 243 μmol,
1.0 equiv.). The reaction was performed under microwave irradia-
tion (150 W, 80 °C, 2 h). The solvent was removed in vacuo. The
residue and CsOPiv (171 mg, 0.73 mmol, 3.0 equiv.) were dissolved
in dry DMF (4 mL), and the solution was saturated with carbon
monoxide. A solution of tricyclohexylphosphonium tetrafluoro-
borate (19 mg, 49 μmol, 0.2 equiv.) in dry DMF (2 mL) and a solu-
tion of Pd(dba)2 (14 mg, 24 μmol, 0.1 equiv.) in dry DMF (2 mL)
were added. The reaction mixture was stirred under carbon mon-
oxide (balloon) at 120 °C. After 16 h, water (30 mL) was added to
the cold reaction mixture, which was then extracted with diethyl
ether (3ϫ30 mL), dried with magnesium sulfate, and filtered. The
solvent was removed in vacuo. Purification by flash chromatog-
raphy on silica (cHex/EtOAc 20:1) yielded 21 (3.5 mg, 7 μmol, 3%)
as a yellow oil, Rf = 0.13 (cHex/EtOAc 15:1). 1H NMR COSY
3-Methyloct-6-yn-2-yl 2-[3,5-Bis(benzyloxy)-2-formylphenyl]acetate
(23):[21] Phosphoryl chloride (0.67 mL, 7.20 mmol, 3.0 equiv.) was
added at room temperature to a solution of 3-methyloct-6-yn-2-yl
2-[3,5-bis(benzyloxy)phenyl]acetate (1.13 g, 2.40 mmol, 1.0 equiv.)
in dry DMF (20 mL), and stirring was carried out at 75 °C. After
16 h, phosphoryl chloride (0.67 mL, 7.20 mmol, 3.0 equiv.) was
added, and stirring was carried out for an additional 5 h. The cold
reaction mixture was diluted with diethyl ether (200 mL), washed
with water (2ϫ100 mL), dried with magnesium sulfate, and fil-
tered. The solvent was removed in vacuo. Purification by flash
chromatography on silica (cHex/EtOAc 8:1) yielded 23 (921 mg,
1.85 mmol, 77%) as a colorless solid, Rf = 0.40 (cHex/EtOAc 4:1),
m.p. 116.0–118.0 °C (cHex/EtOAc 8:1). 1H NMR (400 MHz,
(400 MHz, CDCl3): δ = 7.43–7.35 (m, 10 H, 2ϫPh), 6.65 (d, J = CDCl3): δ = 10.54 (s, 1 H, CHO), 7.45–7.32 (m, 10 H, 2ϫPh), 6.58
2.4 Hz, 1 H, 4-H), 6.59 (d, J = 2.4 Hz, 1 H, 6-H), 5.47–5.39 (m, 1 (d, J = 2.3 Hz, 1 H, 4-H), 6.46 (d, J = 2.3 Hz, 1 H, 6-H), 5.11 (s,
H, 7Ј-H), 5.38–5.30 (m, 1 H, 6Ј-H), 5.18 (s, 2 H, OCH2Ph-3), 5.08 2 H, OCH2Ph), 5.09 (s, 2 H, OCH2Ph), 4.86 (quint, J = 6.3 Hz, 1
(s, 2 H, OCH2Ph-5), 4.89–4.80 (m, 1 H, OCH-2Ј), 4.00 (d, J =
H, CH-2Ј), 3.97 (d, J = 16.8 Hz, 1 H, CH2ACOO), 3.93 (d, J =
16.5 Hz, 1 H, CH2ACOO), 3.95 (d, J = 16.5 Hz, 1 H, CH2BCOO), 16.8 Hz, 1 H, CH2BCOO), 2.27–2.17 (m, 1 H, CH2A-5Ј), 2.15–2.04
2.10–1.98 (m, 2 H, CH2-5Ј), 1.74–1.66 (m, 1 H, CH-3Ј), 1.60–1.57
(m, 3 H, CH3-8Ј), 1.48–1.39 (m, 1 H, CH2A-4Ј), 1.17 (d, J = 6.4 Hz,
(m, 1 H, CH2B-5Ј), 1.86–1.78 (m, 1 H, CH-3Ј), 1.77 (t, J = 2.5 Hz,
3 H, CH3-8Ј), 1.72–1.63 (m, 1 H, CH2A-4Ј), 1.35–1.25 (m, 1 H,
3 H, CH3-1Ј), 1.16–1.09 (m, 1 H, CH2B-4Ј), 0.89 (d, J = 6.8 Hz, 3 CH2B-4Ј), 1.21 (d, J = 6.3 Hz, 3 H, CH3-1Ј), 0.92 (d, J = 6.8 Hz, 3
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50275
/KAP1
Date: 20-04-15 15:50:46
Pages: 23
Anti-Inflammatory Macrolactones
H, CH3-3Ј) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3): 6), 100.2 (C-4), 70.1 (2 ϫ OCH2Ph), 63.5 (CH2OH), 39.5
δ = 189.9 (CHO), 170.7 (COO), 164.4 (Cq-3), 163.8 (Cq-5), 139.6 (CH2CH2OH). The data are in accordance with the literature.[21]
(Cq-1), 135.9 (Cq-1, Ph), 135.9 (Cq-1, Ph), 128.8 (CH-3, CH-5, Ph),
1,3-Bis(benzyloxy)-5-{2-[(4-methoxybenzyl)oxy]ethyl}benzene
(25):[18,21] A suspension of sodium hydride (95 %, 1.10 g,
45.8 mmol, 2.0 equiv.) in dry DMF (50 mL) was cooled to 0 °C. A
solution of 2-[3,5-bis(benzyloxy)phenyl]ethanol (7.66 g, 22.9 mmol,
1.0 equiv.) in dry DMF (40 mL) was added, and stirring was car-
ried out for 30 min. Then, p-methoxybenzyl chloride (3.4 mL,
25.2 mmol, 1.1 equiv.) was added and the reaction mixture was
stirred for 16 h and allowed to warm to room temperature. The
reaction mixture was quenched with water (100 mL) and extracted
with diethyl ether (3 ϫ 150 mL). The combined organic extracts
were dried with magnesium sulfate and filtered. The solvent was
removed in vacuo. The protected alcohol 25 was obtained as a yel-
low oil (10.41 g, 22.9 mmol, quant., ref.[18] 81%). The crude prod-
uct can be used without further purification or can be purified
by flash chromatography on silica (cHex/EtOAc 20:1) to obtain a
colorless oil, Rf = 0.35 (cHex/EtOAc 10:1). 1H NMR (400 MHz,
CDCl3): δ = 7.51–7.37 (m, 10 H, 2ϫPh), 7.35–7.31 (m, 2 H, AAЈ-
part of AAЈBBЈ-spin system, 2-H, 6-H, PMB), 6.97–6.93 (m, 2 H,
BBЈ-part of AAЈBBЈ-spin system, 3-H, 5-H, PMB), 6.59 (s, 3 H, 2-
H, 4-H, 6-H), 5.07 (s, 4 H, 2ϫOCH2, Bn), 4.53 (s, 2 H, OCH2,
PMB), 3.84 (s, 3 H, OCH3), 3.74 (t, J = 7.1 Hz, 2 H, CH2OPMB),
2.95 (t, J = 7.1 Hz, 2 H, CH2CH2OPMB) ppm. The data are in
accordance with the literature.[21] 13C NMR (100.6 MHz, CDCl3):
δ = 159.9 (C-1, C-3), 159.2 (C-4, PMB), 141.1 (C-5), 137.0 (2ϫC-
1, Bn), 130.5 (C-1, PMB), 129.3 (CH-2, CH-6, PMB), 128.6
(2ϫCH-3, 2ϫCH-5, Bn), 128.0 (2ϫCH-4, Bn), 127.6 (2ϫCH-2,
2ϫCH-6, Bn), 113.8 (CH-3, CH-5, PMB), 108.2 (C-4, C-6), 99.9
(C-2), 72.8 (CH2, PMB), 70.7 (CH2OPMB), 70.0 (2ϫOCH2, Bn),
55.2 (OCH3), 36.7 (CH2CH2OPMB) ppm. The data are in accord-
ance with the literature.[21]
128.8 (CH-3, CH-5, Ph), 128.4 (CH-4, Ph), 128.3 (CH-4, Ph), 127.6
(CH-2, CH-6, Ph), 127.3 (CH-2, CH-6, Ph), 117.6 (Cq-2), 111.1
(CH-6), 99.2 (CH-4), 79.0 (Cq-6Ј), 75.6 (Cq-7Ј), 74.6 (CH-2Ј), 70.7
(OCH2Ph), 70.3 (OCH2Ph), 41.0 (CH2COO), 36.6 (CH-3Ј), 31.7
(CH2-4Ј), 16.6 (CH2-5Ј), 16.2 (CH3-1Ј), 14.6 (CH3-3Ј), 3.6 (CH3-
8Ј) ppm. IR (ATR): ν = 3034, 2919, 2875, 2250, 1726, 1672, 1598,
˜
1573, 1498, 1316, 1292, 1150, 1073, 730, 696 cm–1. HRMS (ESI):
calcd. for [C32H34O5 + H]+ 499.2484; found 499.2470. C32H34O5
(498.62): calcd. C 77.08, H 6.87; found C 76.79, H 6.58.
3-Methylocta-4,6-dien-2-yl 2-[3,5-Bis(benzyloxy)-2-formylphen-
yl]acetate (24):[23] Compound 23 (50 mg, 100 μmol, 1.0 equiv.), so-
dium formate (2 mg, 30 μmol, 0.3 equiv.), xantphos (11.6 mg,
20 μmol, 0.2 equiv.), and dichloro(p-cymene)ruthenium(II) dimer
(6.1 mg, 10 μmol, 0.1 equiv.) were dissolved in dry DMF (3 mL).
The reaction mixture was stirred at 150 °C under microwave irradi-
ation (150 W) for 75 min. The cold reaction mixture was diluted
with diethyl ether (50 mL), washed with water (2ϫ25 mL), dried
with magnesium sulfate, and filtered. The solvent was removed in
vacuo. Purification by flash chromatography on silica (cHex/EtOAc
20:1Ǟ10:1) yielded 24 (30 mg, 60 μmol, 60%) as a colorless oil, Rf
1
= 0.15 (cHex/EtOAc 10:1). H NMR COSY (400 MHz, CDCl3): δ
= 10.53 (s, 1 H, CHO), 7.42–7.32 (m, 10 H, 2ϫPh), 6.57 (d, J =
2.2 Hz, 1 H, 4-H), 6.45 (d, J = 2.2 Hz, 1 H, 6-H), 6.04–5.97 (m, 1
H, 5Ј-H), 5.69–5.51 (m, 1 H, 7Ј-H), 5.48–5.38 (m, 1 H, 4Ј-H), 5.37–
5.24 (m, 1 H, 6Ј-H), 5.11 (s, 2 H, OCH2Ph-3), 5.09 (s, 2 H,
OCH2Ph-5), 4.92–4.80 (m, 1 H, OCH-2Ј), 3.99–3.87 (m, 2 H,
CH2COO), 2.41–2.30 (m, 1 H, 3Ј-H), 1.72 (d, J = 6.3 Hz, 3 H,
CH3-8Ј), 1.18 (d, J = 6.4 Hz, 3 H, CH3-1Ј), 1.03 (d, J = 6.8 Hz, 3
H, CH3-3Ј) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3):
δ = 190.0 (CHO), 170.8 (COO), 163.8 (Cq-5), 164.5 (Cq-3), 139.7
(Cq-1), 136.0 (Cq-1, Ph), 135.9 (Cq-1, Ph), 132.6 (CH-4Ј), 131.7
(CH-6Ј), 131.5 (CH-5Ј), 128.9 (CH-3, CH-5, Ph), 128.8 (CH-3, CH-
5, Ph), 128.5 (CH-4, Ph), 128.4 (CH-4, Ph), 127.9 (CH-7Ј), 127.7
(CH-2, CH-6, OBn-5), 127.4 (CH-2, CH-6, OBn-3), 117.7 (Cq-2),
111.1 (CH-6), 99.2 (CH-4), 74.3 (CHO-2Ј), 70.8 (OCH2Ph-3), 70.4
(OCH2Ph-5), 41.0 (CH2COO), 41.6 (CH-3Ј), 18.3 (CH3-8Ј), 17.0
2,4-Bis(benzyloxy)-6-{2-[(4-methoxybenzyl)oxy]ethyl}benz-
aldehyde:[18] Phosphoryl chloride (1.03 mL, 11.0 mmol, 5.0 equiv.)
was added at room temperature to a solution of protected phenyl
ethanol 25 (1.00 g, 2.20 mmol, 1.0 equiv.) in dry DMF (50 mL).
The reaction mixture was heated to 75 °C. After 1.5 h, phosphoryl
chloride (1.03 mL, 11.0 mmol, 5.0 equiv.) was added, and stirring
was carried out for an additional 18.5 h. The reaction mixture was
quenched with water (100 mL), stirred for 5 min, extracted with
dichloromethane (3ϫ100 mL), dried with magnesium sulfate, and
filtered. The solvent was removed in vacuo. Purification by flash
chromatography on silica (cHex/EtOAc 10:1) yielded a colorless oil
(837 mg, 1.73 mmol, 79%, ref.[18] 82%), Rf = 0.29 (cHex/EtOAc
(CH -1Ј), 16.0 (CH -3Ј) ppm. IR (ATR): ν = 3032, 2964, 2929,
˜
3
3
2873, 1727, 1673, 1598, 1573, 1498, 1315, 1292, 1150, 1072, 735,
697 cm–1. HRMS (ESI): calcd. for [C32H34O5 + Na]+ 521.2304;
found 521.2324.
2-[3,5-Bis(benzyloxy)phenyl]ethanol:[45] A solution of acid 22
(5.39 g, 15.5 mmol, 1.0 equiv.) in dry THF (20 mL) was added to
a solution of LiAlH4 (1.01 g, 26.6 mmol, 1.7 equiv.) in dry THF
(30 mL) at 0 °C, and stirring was carried out for 4 h. The reaction
mixture was quenched with saturated aqueous sodium hydrogen
carbonate solution (3 mL), and stirring was carried out for an ad-
ditional 30 min. Water (5 mL) and ethyl acetate (30 mL) were
added, and the formed precipitate was removed by vacuum fil-
tration and washed with ethyl acetate. The solvent was removed in
vacuo, and purification by flash chromatography on silica (cHex/
EtOAc 5:1) yielded a colorless solid (5.02 g, 15.0 mmol, 97%, ref.[45]
1
5:1). H NMR (400 MHz, CDCl3): δ = 10.57 (s, 1 H, CHO), 7.48–
7.34 (m, 10 H, 2ϫPh), 7.26–7.23 (m, 2 H, AAЈ-part of AAЈBBЈ-
spin system, 2-H, 6-H, PMB), 6.87–6.84 (m, 2 H, BBЈ-part of
AAЈBBЈ-spin system, 3-H, 5-H, PMB), 6.55 (d, J = 2.4 Hz, 1 H,
3-H), 6.52 (d, J = 2.4 Hz, 1 H, 5-H), 5.10 (s, 2 H, OCH2, Bn), 5.07
(s, 2 H, OCH2, Bn), 4.47 (s, 2 H, OCH2, PMB), 3.78 (s, 3 H,
OCH3), 3.71 (t, J = 6.6 Hz, 2 H, CH2OPMB), 3.71 (t, J = 6.6 Hz,
2 H, CH2CH2OPMB) ppm. The data are in accordance with the
literature.[18] 13C NMR (100.6 MHz, CDCl3): δ = 190.4 (CHO),
164.5 (C-4), 163.6 (C-2), 159.1 (C-4, PMB), 145.5 (C-6), 136.1 (C-
94%), Rf = 0.49 (cHex/EtOAc/HOAc 100:100:1), m.p. 82.0–82.5
(cHex/EtOAc 5:1), m.p. in ref.[46] 83–84 °C (CHCl3/PE). H NMR 1, Bn), 136.1 (C-1, Bn), 130.9 (C-1, PMB), 129.3 (CH-2, CH-6,
1
(400 MHz, CDCl3): δ = 7.46–7.33 (m, 10 H, 2ϫPh), 6.55 (t, J =
2.2 Hz, 1 H, 4-H), 6.52 (d, J = 2.2 Hz, 2 H, 2-H, 6-H), 5.05 (s, 4 (CH-4, Bn), 128.4 (CH-4, Bn), 127.7 (CH-2, CH-6, Bn), 127.4 (CH-
H, CH2Ph), 3.85 (t, J = 6.5 Hz, 2 H, CH2OH), 2.82 (t, J = 6.5 Hz, 2, CH-6, Bn), 117.6 (C-1), 113.8 (CH-3, CH-5, PMB), 110.3 (C-5),
PMB), 128.8 (CH-3, CH-5, Bn), 128.8 (CH-3, CH-5, Bn), 128.4
2 H, CH2CH2OH), 1.68 (br. s, 1 H, OH) ppm. The data are in 98.5
(C-3),
72.5
(CH2OPMB),
70.8
(CH2,
PMB),
accordance with the literature.[46] 13C NMR (100.6 MHz, CDCl3): 70.3 (CH2, Bn), 70.3 (CH2, Bn), 55.3 (OCH3), 35.0
δ = 160.2 (C-3, C-5), 141.0 (C-1), 136.9 (2ϫC-1, Ph), 128.7 (2ϫC- (CH2CH2OPMB) ppm. The data are in accordance with the litera-
3, 2ϫC-5), 128.1 (2ϫC-4), 127.6 (2ϫC-2, 2ϫC-6), 108.3 (C-2, C-
ture.[18]
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O50275
/KAP1
Date: 20-04-15 15:50:46
Pages: 23
J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
FULL PAPER
Alcohol 26a:[18]
chloride (0.5 m in THF, 2.4 mL, 1.19 mmol, 1.5 equiv.) was added
to 2,4-bis(benzyloxy)-6-{2-[(4-methoxybenzyl)oxy]ethyl}benz-
A
solution of 1-methylprop-2-enylmagnesium
7.21 (m, 2 H, AAЈ-part of AAЈBBЈ-spin system, 2-H, 6-H, PMB),
6.88–6.84 (m, 2 H, BBЈ-part of AAЈBBЈ-spin system, 3-H, 5-H,
PMB), 6.54 (d, J = 2.4 Hz, 1 H, 4-H), 6.45 (d, J = 2.4 Hz, 1 H, 6-
H), 5.84–5.73 (m, 1 H, CH=CH2), 5.10–4.98 (m, 6 H, CH=CH2,
2ϫOCH2Ph), 4.97–4.90 (m, 1 H, CH-1Ј), 4.46 (d, J = 11.6 Hz, 1
H, CH2A, PMB), 4.42 (d, J = 11.6 Hz, 1 H, CH2B, PMB), 3.79 (s,
3 H, OCH3), 3.69–3.56 (m, 2 H, CH2O), 3.00–2.88 (m, 2 H,
CH2CH2O), 2.78–2.70 (m, 1 H, CH2A-2Ј), 2.54–2.47 (m, 1 H,
CH2B-2Ј) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3): δ
= 159.3 (Cq-4, PMB), 158.5 (Cq-5), 158.0 (Cq-3), 138.3 (Cq-1),
aldehyde (379 mg, 0.79 mmol, 1.0 equiv.), and stirring was carried
out at room temperature for 18 h. The reaction mixture was
quenched with saturated aqueous ammonium chloride solution
(100 mL), extracted with diethyl ether (3ϫ75 mL), dried with mag-
nesium sulfate, and filtered. The solvent was removed in vacuo to
yield 26a as a colorless oil (392 mg, 0.73 mmol, 92%), which can
be used without further purification, Rf = 0.30 (cHex/EtOAc 5:1).
1H NMR COSY (400 MHz, CDCl3, diastereomer A): δ = 7.49– 136.9 (Cq-1, Ph), 136.3 (Cq-1, Ph), 135.8 (CH=CH2), 130.4 (Cq-1,
7.36 (m, 10 H, 2ϫPh), 7.32–7.28 (m, 2 H, AAЈ-part of AAЈBBЈ-
spin system, 2-H, 6-H, PMB), 6.94–6.90 (m, 2 H, BBЈ-part of
PMB), 129.5 (CH-2, CH-6, PMB), 129.0 (CH-3, CH-5, Ph), 128.7
(CH-3, CH-5, Ph), 128.5 (CH-4, Ph), 128.2 (CH-4, Ph), 127.7 (CH-
AAЈBBЈ-spin system, 3-H, 5-H, PMB), 6.59 (d, J = 2.4 Hz, 1 H, 2, CH-6, Ph), 127.7 (CH-2, CH-6, Ph), 123.2 (Cq-2), 116.9
4-H), 6.51 (d, J = 2.4 Hz, 1 H, 6-H), 5.64 (ddd, J = 17.4, 10.4, (CH=CH2), 113.9 (CH-3, CH-5, PMB), 108.3 (CH-6), 99.5 (CH-
7.2 Hz, 1 H, CH=CH2), 4.95–4.85 (m, 2 H, CH=CH2), 5.09 (s, 2 4), 72.9 (OCH2, PMB), 70.7 (CH2O), 70.7 (OCH2Ph), 70.2
H, OCH2Ph), 5.02 (s, 2 H, OCH2Ph), 4.66 (t, J = 9.4 Hz, 1 H, CH- (OCH2Ph), 70.1 (CH-1Ј), 55.4 (OCH3), 42.4 (CH2-2Ј), 34.3
1Ј), 4.53 (d, J = 11.7 Hz, 1 H, CH2A, PMB), 4.47 (d, J = 11.7 Hz,
(CH CH O) ppm. IR (ATR): ν = 3558, 3066, 3033, 3003, 2932,
˜
2 2
1 H, CH2B, PMB), 3.80 (s, 3 H, OCH3), 3.79–3.62 (m, 2 H, CH2O), 2909, 2861, 1639, 1604, 1498, 1246, 1144, 1082, 1053, 1029, 736,
3.13–2.88 (m, 3 H, CH2CH2O, CH-2Ј), 1.28 (d, J = 6.6 Hz, 3 H, 698 cm–1. HRMS (ESI): calcd. for [C34H36O5 + Na]+ 547.2460;
CH3-2Ј) ppm. 1H NMR COSY (400 MHz, CDCl3, diastereomer
B): δ = 7.49–7.36 (m, 10 H, 2ϫPh), 7.32–7.28 (m, 2 H, AAЈ-part
of AAЈBBЈ-spin system, 2-H, 6-H, PMB), 6.94–6.90 (m, 2 H, BBЈ-
part of AAЈBBЈ-spin system, 3-H, 5-H, PMB), 6.60 (d, J = 2.4 Hz,
1 H, 4-H), 6.54 (d, J = 2.4 Hz, 1 H, 6-H), 6.00 (ddd, J = 17.2, 10.3,
7.9 Hz, 1 H, CH=CH2), 5.13–5.06 (m, 2 H, CH=CH2), 5.07 (s, 2
H, OCH2Ph), 5.04 (s, 2 H, OCH2Ph), 4.75 (t, J = 9.1 Hz, 1 H, CH-
1Ј), 4.53 (d, J = 11.7 Hz, 1 H, CH2A, PMB), 4.48 (d, J = 11.7 Hz,
1 H, CH2B, PMB), 3.80 (s, 3 H, OCH3), 3.79–3.62 (m, 2 H,
CH2CH2O), 3.42 (d, J = 9.1 Hz, 1 H, OH), 3.13–2.88 (m, 3 H,
CH2O, CH-2Ј), 0.90 (d, J = 6.9 Hz, 3 H, CH3-2Ј) ppm. 13C NMR
HSQC, HMBC (100.6 MHz, CDCl3, diastereomer A): δ = 159.2
(Cq-4, PMB), 158.3 (Cq-5), 157.7 (Cq-3), 141.0 (CH=CH2), 138.8
(Cq-1), 136.8 (Cq-1, Ph), 136.2 (Cq-1, Ph), 130.3 (Cq-1, PMB), 129.3
(CH-2, CH-6, PMB), 128.8 (CH-3, CH-5, Ph), 128.6 (CH-3, CH-
5, Ph), 128.2 (CH-4, Ph), 128.0 (CH-4, Ph), 127.6 (CH-2, CH-6,
Ph), 127.5 (CH-2, CH-6, Ph), 122.6 (Cq-2), 114.1 (CH=CH2), 113.8
(CH-3, CH-5, PMB), 108.0 (CH-6), 99.2 (CH-4), 74.3 (CH-1Ј), 72.7
(OCH2, PMB), 70.6 (CH2O), 70.5 (OCH2Ph), 70.0 (OCH2Ph), 55.2
(OCH3), 44.0 (CH-2Ј), 34.2 (CH2CH2O), 16.4 (CH3-2Ј) ppm. 13C
NMR HSQC, HMBC (100.6 MHz, CDCl3, diastereomer B): δ =
159.2 (Cq-4, PMB), 158.5 (Cq-5), 157.9 (Cq-3), 142.4 (CH=CH2),
139.1 (Cq-1), 136.8 (Cq-1, Ph), 136.3 (Cq-1, Ph), 130.3 (Cq-1, PMB),
129.3 (CH-2, CH-6, PMB), 128.7 (CH-3, CH-5, Ph), 128.6 (CH-3,
CH-5, Ph), 128.2 (CH-4, Ph), 128.0 (CH-4, Ph), 127.6 (CH-2, CH-
6, Ph), 127.6 (CH-2, CH-6, Ph), 122.1 (Cq-2), 114.6 (CH=CH2),
113.8 (CH-3, CH-5, PMB), 108.2 (CH-6), 99.3 (CH-4), 73.5 (CH-
1Ј), 72.7 (OCH2, PMB), 70.5 (CH2O), 70.4 (OCH2Ph), 70.0
(OCH2Ph), 55.2 (OCH3), 44.5 (CH-2Ј), 34.2 (CH2CH2O), 17.3
found 547.2477.
TBDMS Ether 27a:[18] Alcohol 26a (512 mg, 0.95 mmol, 1.0 equiv.)
and imidazole (194 mg, 2.85 mmol, 3.0 equiv.) were dissolved in
dry DMF (10 mL), and TBDMSOTf (0.52 mL, 2.28 mmol,
2.4 equiv.) was added. The reaction mixture was stirred at room
temperature. After 3 h the reaction mixture was quenched with
water (100 mL), extracted with diethyl ether (3ϫ150 mL), dried
with magnesium sulfate, and filtered. Removing the solvent in
vacuo yielded 27a (620 mg, 0.95 mmol, quant.) as a colorless oil,
1
Rf = 0.63 (cHex/EtOAc 5:1). H NMR COSY (400 MHz, CDCl3,
diastereomer A): δ = 7.44–7.32 (m, 10 H, 2ϫPh), 7.31–7.27 (m, 2
H, AAЈ-part of AAЈBBЈ-spin system, 2-H, 6-H, PMB), 6.90–6.86
(m, 2 H, BBЈ-part of AAЈBBЈ-spin system, 3-H, 5-H, PMB), 6.54
(d, J = 2.4 Hz, 1 H, 6-H), 6.39 (d, J = 2.4 Hz, 1 H, 4-H), 5.52
(ddd, J = 17.0, 10.5, 7.6 Hz, 1 H, CH=CH2), 5.08–4.96 (m, 5 H,
2ϫOCH2Ph, CH-1Ј), 4.76–4.70 (m, 2 H, CH=CH2), 4.51 (d, J =
11.6 Hz, 1 H, CH2A, PMB), 4.46 (d, J = 11.6 Hz, 1 H, CH2B
,
PMB), 3.79 (s, 3 H, OCH3), 3.71–3.64 (m, 2 H, CH2O), 3.59–3.45
(m, 1 H, CH2ACH2O), 3.19–3.12 (m, 1 H, CH2BCH2O), 2.73–2.62
(m, 1 H, CH-2Ј), 1.17 (d, J = 6.5 Hz, 3 H, CH3-2Ј), 0.85 [s, 9 H,
C(CH3)3], –0.01 (s, 3 H, SiCH3), –0.28 (s, 3 H, SiCH3) ppm. 1H
NMR COSY (400 MHz, CDCl3, diastereomer B): δ = 7.44–7.32
(m, 10 H, 2ϫPh), 7.31–7.27 (m, 2 H, AAЈ-part of AAЈBBЈ-spin
system, 2-H, 6-H, PMB), 6.90–6.86 (m, 2 H, BBЈ-part of AAЈBBЈ-
spin system, 3-H, 5-H, PMB), 6.57 (d, J = 2.4 Hz, 1 H, 6-H), 6.43
(d, J = 2.4 Hz, 1 H, 4-H), 5.96 (ddd, J = 17.4, 10.3, 7.3 Hz, 1
H, CH=CH2), 5.22–5.17 (m, 2 H, CH=CH2), 5.08–4.96 (m, 5 H,
2ϫOCH2Ph, CH-1Ј), 4.51 (d, J = 11.6 Hz, 1 H, CH2A, PMB), 4.46
(d, J = 11.6 Hz, 1 H, CH2B, PMB), 3.79 (s, 3 H, OCH3), 3.71–3.64
(m, 2 H, CH2O), 3.59–3.45 (m, 1 H, CH2ACH2O), 3.19–3.12 (m, 1
H, CH2BCH2O), 2.73–2.62 (m, 1 H, CH-2Ј), 0.71 (d, J = 6.8 Hz, 3
H, CH3-2Ј), 0.82 [s, 9 H, C(CH3)3], –0.04 (s, 3 H, SiCH3), –0.28 (s,
3 H, SiCH3) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3,
diastereomer A): δ = 159.3 (Cq-4, PMB), 158.2 (Cq-5), 157.2 (Cq-
3), 141.1 (CH=CH2), 140.8 (Cq-1), 137.5 (Cq-1, Ph), 137.1 (Cq-1,
Ph), 130.8 (Cq-1, PMB), 129.5 (CH-2, CH-6, PMB), 128.7 (CH-3,
CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.1 (CH-4, Ph), 127.9 (CH-
2, CH-6, Ph), 127.8 (CH-4, Ph), 127.0 (CH-2, CH-6, Ph), 123.8
(Cq-2), 114.0 (CH=CH2), 113.9 (CH-3, CH-5, PMB), 108.6 (CH-
6), 97.7 (CH-4), 72.7 (OCH2, PMB), 71.5 (CHO), 71.3 (CH2O),
70.3 (OCH2Ph), 70.0 (OCH2Ph), 55.4 (OCH3), 45.3 (CH-2Ј), 32.7
(CH2CH2O), 26.0 [(CH3)3], 18.4 (CH3), 18.3 [SiC(CH3)3], –4.7
(SiCH3), –5.2 (SiCH3) ppm. 13C NMR HSQC, HMBC
(CH -2Ј) ppm. IR (ATR): ν = 3556, 3065, 3033, 2958, 2932, 2865,
˜
3
1605, 1585, 1513, 1498, 1454, 1248, 1147, 1085, 1029 cm–1. HRMS
(ESI): calcd. for [C35H38O5 + Na]+ 561.2617; found 561.2609.
Alcohol 26b:[18] A solution of allylmagnesium bromide (1.0 m in
Et2O, 5.9 mL, 5.90 mmol, 1.5 equiv.) was added to 2,4-bis(benz-
yloxy)-6-{2-[(4-methoxybenzyl)oxy]ethyl}benzaldehyde
(1.90 g,
3.93 mmol, 1.0 equiv.), and stirring was carried out at room tem-
perature for 18 h. The reaction mixture was quenched with satu-
rated aqueous ammonium chloride solution (50 mL), extracted
with diethyl ether (3ϫ50 mL), dried with magnesium sulfate, and
filtered. The solvent was removed in vacuo to yield 26b as a yellow
oil (776 mg, 1.48 mmol, 38%, ref.[18] 88%), which can be used with-
out further purification, Rf = 0.08 (cHex/EtOAc 10:1). 1H NMR
COSY (400 MHz, CDCl3): δ = 7.43–7.31 (m, 10 H, 2ϫPh), 7.25–
12
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Eur. J. Org. Chem. 0000, 0–0

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/KAP1
Date: 20-04-15 15:50:46
Pages: 23
Anti-Inflammatory Macrolactones
(100.6 MHz, CDCl3, diastereomer B): δ = 159.2 (Cq-4, PMB),
C(CH3)3], 0.81 (dd, J = 6.9, 1.2 Hz, 3 H, CH3-2Ј), 0.12 (s, 6 H,
158.3 (Cq-5), 156.8 (Cq-3), 143.4 (CH=CH2), 140.8 (Cq-1), 137.5 2ϫSiCH3) ppm. 1H NMR COSY (400 MHz, CDCl3, diastereomer
(Cq-1, Ph), 137.1 (Cq-1, Ph), 130.8 (Cq-1, PMB), 129.4 (CH-2, CH- B): δ = 7.46–7.32 (m, 10 H, 2ϫPh), 6.49 (d, J = 2.2 Hz, 1 H, 4-
6, PMB), 128.6 (CH-3, CH-5, Ph), 128.6 (CH-3, CH-5, Ph), 128.1 H), 6.37 (d, J = 2.2 Hz, 1 H, 6-H), 5.76 (dddd, J = 17.4, 10.5, 6.8,
(CH-4, Ph), 127.9 (CH-2, CH-6, Ph), 127.8 (CH-4, Ph), 127.0 (CH- 1.2 Hz, 1 H, CH=CH2), 5.08–4.96 (m, 5 H, 2ϫOCH2Ph, CH-1Ј),
2, CH-6, Ph), 123.6 (Cq-2), 113.9 (CH-3, CH-5, PMB), 113.7
4.87–4.79 (m, 2 H, CH=CH2), 4.13–4.08 (m, 1 H, CH2AOH), 3.61–
(CH=CH2), 108.8 (CH-6), 97.7 (CH-4), 72.7 (OCH2, PMB), 71.6 3.52 (m, 1 H, CH2BOH), 3.18–3.11 (m, 1 H, CH-2Ј), 2.98–2.84 (m,
(CHO), 71.4 (CH2O), 70.3 (OCH2Ph), 70.1 (OCH2Ph), 55.4 1 H, CH2ACH2OH), 2.56–2.47 (m, 1 H, CH2BCH2OH), 1.65–1.60
(OCH3), 44.8 (CH-2Ј), 32.8 (CH2CH2O), 26.0 [(CH3)3], 18.3
[SiC(CH3)3], 16.2 (CH3), –4.7 (SiCH3), –5.0 (SiCH3) ppm. IR
(m, 1 H, OH), 1.23 (dd, J = 6.9, 1.2 Hz, 3 H, CH3-2Ј), 0.93 [s, 9 H,
C(CH3)3], 0.12 (s, 6 H, 2ϫSiCH3) ppm. 13C NMR HSQC, HMBC
(ATR): ν = 3066, 3033, 2955, 2929, 2856, 1659, 1498, 1247, 1143, (100.6 MHz, CDCl3, diastereomer A): δ = 158.1 (Cq-5), 156.2 (Cq-
˜
1085, 1039, 909, 834, 730, 697 cm–1. HRMS (ESI): calcd. for 3), 143.2 (CH=CH2), 138.6 (Cq-1), 137.1 (2ϫCq-1, Ph), 128.7 (CH-
[C41H52O5Si + Na]+ 675.3482; found 675.3466.
3, CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.2 (CH-4, Ph), 128.0
(CH-4, Ph), 127.7 (CH-2, CH-6, Ph), 127.2 (CH-2, CH-6, Ph),
118.5 (Cq-2), 113.5 (CH=CH2), 105.7 (CH-6), 98.8 (CH-4), 76.7
(CH-1Ј), 70.2 (OCH2Ph), 70.0 (OCH2Ph), 63.2 (CH2OH), 41.1
(CH-2Ј), 30.7 (CH2CH2O), 25.8 [(CH3)3], 18.1 [SiC(CH3)3], 12.5
(CH3-2Ј), –3.4 (2ϫSiCH3) ppm. 13C NMR HSQC, HMBC
(100.6 MHz, CDCl3, diastereomer B): δ = 158.0 (Cq-5), 156.1 (Cq-
3), 140.5 (CH=CH2), 138.5 (Cq-1), 136.9 (2ϫCq-1, Ph), 128.7 (CH-
3, CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.1 (CH-4, Ph), 127.9
(CH-4, Ph), 127.7 (CH-2, CH-6, Ph), 127.0 (CH-2, CH-6, Ph),
119.0 (Cq-2), 114.2 (CH=CH2), 105.7 (CH-6), 98.8 (CH-4), 76.7
(CH-1Ј), 70.2 (OCH2Ph), 70.0 (OCH2Ph), 62.8 (CH2OH), 41.2
(CH-2Ј), 30.5 (CH2CH2O), 25.8 [(CH3)3], 18.1 [SiC(CH3)3], 17.0
TBDMS Ether 27b:[18] Alcohol 26b (776 mg, 1.48 mmol, 1.0 equiv.)
and imidazole (187 mg, 2.20 mmol, 1.5 equiv.) were dissolved in
dry DMF (10 mL), and TBDMSCl (332 mg, 2.20 mmol, 1.2 equiv.)
was added. The reaction mixture was stirred at room temperature.
After 3 h imidazole (187 mg, 2.20 mmol, 1.5 equiv.) and TBDMSCl
(332 mg, 2.20 mmol, 1.2 equiv.) were added. After 6 h the reaction
mixture was quenched with water (100 mL), extracted with diethyl
ether (3ϫ100 mL), dried with magnesium sulfate, and filtered. Re-
moving the solvent in vacuo yielded 27b (946 mg, 1.02 mmol, 69%,
ref.[18] 98%) as a colorless oil, Rf = 0.53 (cHex/EtOAc 5:1). 1H
NMR COSY (400 MHz, CDCl3): δ = 7.45–7.33 (m, 10 H, 2ϫPh),
7.31–7.28 (m, 2 H, AAЈ-part of AAЈBBЈ-spin system, 2-H, 6-H,
PMB), 6.90–6.87 (m, 2 H, BBЈ-part of AAЈBBЈ-spin system, 3-H,
5-H, PMB), 6.55 (br. s, 1 H, 6-H), 6.46 (br. s, 1 H, 4-H), 5.77
(ddd, J = 17.2, 10.1, 7.1 Hz, 1 H, CH=CH2), 5.06–4.94 (m, 7 H,
(CH -2Ј), –3.4 (2ϫSiCH ) ppm. IR (ATR): ν = 3359, 3067, 3033,
˜
3
3
2956, 2929, 2856, 1605, 1592, 1498, 1147, 1094, 1056, 832, 734,
696 cm–1. HRMS (ESI): calcd. for [C33H44O4Si + Na]+ 555.2907;
found 555.2925.
Phenylethanol 28b:[18] DDQ (255 mg, 1.12 mmol, 1.1 equiv.) was
2ϫOCH2Ph, CH=CH2, CH-1Ј), 4.51 (d, J = 11.6 Hz, 1 H, CH2A
PMB), 4.47 (d, J = 11.6 Hz, 1 H, CH2B, PMB), 3.80 (s, 3 H,
OCH3), 3.73–3.63 (m, H, CH2O), 3.53–3.34 (m, H,
,
2
1
added at room temperature to a strongly stirred solution of PMB
CH2ACH2O), 3.28–3.15 (m, 1 H, CH2BCH2O), 2.79–2.57 (m, 1 H, ether 27b (654 mg, 1.02 mmol, 1.0 equiv.) in dichloromethane
CH2A-2Ј), 2.46–2.39 (m, 1 H, CH2B-2Ј), 0.85 [s, 9 H, C(CH3)3], 0.01 (20 mL) and phosphate buffer (pH 7, 63 mm, 1.0 mL). After
(s, 3 H, SiCH3), –0.17 (s, 3 H, SiCH3) ppm. 13C NMR HSQC, 40 min, saturated aqueous sodium hydrogen carbonate solution
HMBC (100.6 MHz, CDCl3): δ = 159.3 (Cq-4, PMB), 158.3 (Cq-
(75 mL) was added, and the mixture was extracted with dichloro-
5), 156.4 (br, Cq-3), 140.9 (br, Cq-1), 137.4 (Cq-1, Ph), 137.1 (Cq-1, methane (3ϫ70 mL), dried with magnesium sulfate, and filtered.
Ph), 136.4 (CH=CH2), 130.8 (Cq-1, PMB), 129.5 (CH-2, CH-6, The solvent was removed in vacuo. Purification by flash
PMB), 128.7 (2ϫCH-3, 2ϫCH-5, Ph), 128.6 (CH-4, Ph), 128.1 chromatography on silica (cHex/EtOAc 5:1) yielded 28b (410 mg,
(CH-4, Ph), 127.8 (CH-2, CH-6, Ph), 127.0 (CH-2, CH-6, Ph),
0.79 mmol, 77%, ref.[18] 93%) as a yellow oil, Rf = 0.27 (cHex/
124.2 (Cq-2), 116.3 (CH=CH2), 113.9 (CH-3, CH-5, PMB), 108.8 EtOAc 5:1). 1H NMR COSY (400 MHz, CDCl3): δ = 7.45–7.30
(br, CH-6), 98.2 (br, CH-4), 72.8 (OCH2, PMB), 71.5 (br, CH2O), (m, 10 H, 2ϫPh), 6.52 (d, J = 2.4 Hz, 1 H, 6-H), 6.47 (d, J =
70.3 (CH-1Ј), 70.1 (2ϫOCH2Ph), 55.4 (OCH3), 43.3 (br, CH2-2Ј), 2.4 Hz, 1 H, 4-H), 5.80–5.69 (m, 1 H, CH=CH2), 5.66–5.49 (m, 1
32.9 (br, CH2CH2O), 26.1 [(CH3)3], 18.4 [SiC(CH3)3], –4.6 (SiCH3), H, CH-1Ј), 5.05–4.94 (m,
2 H, CH=CH2), 5.02 (s, 4 H,
–4.9 (SiCH ) ppm. IR (ATR): ν = 3033, 3005, 2953, 2929, 1640, 2ϫOCH2Ph), 3.91–3.82 (m, 2 H, CH2O), 3.40–3.25 (m, 1 H,
˜
3
1499, 1247, 1146, 1075, 1037, 832, 775, 733, 696 cm–1. HRMS
(ESI): calcd. for [C40H50O5Si + Na]+ 661.3325; found 661.3304.
CH2ACH2O), 3.22–3.12 (m, 1 H, CH2BCH2O), 2.80–2.61 (m, 1 H,
CH2A-2Ј), 2.55–2.44 (m, 1 H, CH2B-2Ј), 0.85 [s, 9 H, C(CH3)3],
0.02 (s, 3 H, SiCH3), –0.14 (s, 3 H, SiCH3) ppm. 13C NMR HSQC
(75.5 MHz, CDCl3): δ = 158.4 (Cq-5), 156.8 (br, Cq-3), 140.3 (br,
Cq-1), 137.3 (Cq-1, Ph), 137.0 (Cq-1, Ph), 136.0 (br, CH=CH2),
128.7 (CH-3, CH-5, Ph), 128.6 (CH-3, CH-5, Ph), 128.1 (CH-4,
Ph), 127.8 (CH-4, Ph, CH-2, CH-6, Ph), 127.1 (CH-2, CH-6, Ph),
124.2 (Cq-2), 116.5 (CH=CH2), 108.5 (br, CH-6), 98.4 (br, CH-4),
70.3 (OCH2Ph), 70.1 (OCH2Ph), 68.0 (CH-1Ј), 64.1 (br, CH2O),
43.5 (br, CH2-2Ј), 35.9 (br, CH2CH2O), 26.1 [(CH3)3], 18.4
Phenylethanol 28a:[18] DDQ (50 mg, 0.22 mmol, 1.1 equiv.) was
added at room temperature to an intensely stirred solution of PMB
ether 27a (131 mg, 0.20 mmol, 1.0 equiv.) in dichloromethane
(6 mL) and phosphate buffer (pH = 7, 63 mm, 0.3 mL). After
45 min, saturated aqueous sodium hydrogen carbonate solution
(25 mL) was added, and the mixture was extracted with dichloro-
methane (3ϫ30 mL), dried with magnesium sulfate, and filtered.
The solvent was removed in vacuo. Purification by flash
chromatography on silica (cHex/EtOAc 7:1) yielded 28a (99 mg,
0.19 mmol, 93%) as a colorless oil, Rf = 0.30 (cHex/EtOAc 5:1).
1H NMR COSY (400 MHz, CDCl3, diastereomer A): δ = 7.46–
7.32 (m, 10 H, 2ϫPh), 6.51 (d, J = 2.2 Hz, 1 H, 4-H), 6.39 (d, J
= 2.2 Hz, 1 H, 6-H), 6.09 (dddd, J = 17.4, 10.5, 6.8, 1.2 Hz, 1 H,
[SiC(CH ) ], –4.5 (SiCH ), –4.9 (SiCH ) ppm. IR (ATR): ν = 3436,
˜
3 3
3
3
3068, 3033, 3008, 2954, 2929, 2884, 1599, 1499, 1258, 1158, 1146,
1070, 1052, 1027, 831 cm–1. HRMS (ESI): calcd. for [C32H42O4Si
+ Na]+ 541.2750; found 541.2745.
3-Methylhex-5-en-2-ol (29a):[47] Allylmagnesium bromide (1 m in
CH=CH2), 5.08–4.96 (m, 7 H, CH=CH2, 2ϫOCH2Ph, CH-1Ј), Et2O, 83 mL, 83.0 mmol, 1.5 equiv.) was added at –40 °C to a solu-
4.13–4.08 (m, 1 H, CH2AOH), 3.61–3.52 (m, 1 H, CH2BOH), 3.18– tion of copper(I) iodide (2.11 g, 11.1 mmol, 0.2 equiv.) in dry THF
3.11 (m, 1 H, CH-2Ј), 2.98–2.84 (m, 1 H, CH2ACH2OH), 2.56–2.47 (30 mL). After 30 min, 2,3-cis-epoxybutane (4.00 g, 55.5 mmol,
(m, 1 H, CH2BCH2OH), 1.65–1.60 (m, 1 H, OH), 0.93 [s, 9 H, 1.0 equiv.) was added. The reaction mixture was stirred at –40 °C
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
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Pages: 23
J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
[SiC(CH3)3], 17.1/15.3 (CH3-2Ј), –5.7/–5.7 (SiCH3), –6.0/–6.1
FULL PAPER
for 6 h and was then allowed to warm to room temperature over
2.5 d. The reaction mixture was quenched with saturated aqueous
ammonium chloride solution (100 mL) and stirred for 1 h. The or-
ganic layer was separated, and the aqueous layer was extracted with
diethyl ether (3ϫ100 mL), dried with magnesium sulfate, and fil-
(SiCH ). IR (ATR): ν = 3067, 3033, 2956, 2929, 2857, 1709, 1604,
˜
3
1499, 1150, 1056, 1030, 836, 736, 697 cm–1. HRMS (ESI): calcd.
for [C33H42O5Si + Na]+ 569.2699; found 569.2698. A solution of
the crude acid (87 mg, 159 μmol, 1.0 equiv.), DMAP (4 mg,
tered. Distillation yielded 29a (5.46 g, 47.8 mmol, 86%, ref.[47] 32 μmol, 0.2 equiv.), and alcohol 29a (45 mg, 398 μmol, 2.5 equiv.)
88%) as a colorless liquid, Rf = 0.20 (cHex/EtOAc 5:1), b.p. 130 °C.
in dry dichloromethane (5 mL) was cooled to 0 °C. N,NЈ-Dicyclo-
1H NMR (400 MHz, CDCl3): δ = 5.83–5.73 (m, 1 H, CH=CH2), hexylcarbodiimide (69 mg, 334 μmol, 2.1 equiv.) was dissolved in
5.04–4.96 (m, 2 H, CH=CH2), 3.63 (p, J = 6.3 Hz, 1 H, CH-2), dry dichloromethane (2 mL) and added. The reaction mixture was
2.26–2.19 (m, 1 H, CH2A-4), 1.96–1.85 (m, 2 H, CH2B-4, OH),
stirred for 15 h and then allowed to warm to room temperature.
1.61–1.51 (m, 1 H, CH-3), 1.12 (d, J = 6.3 Hz, 3 H, CH3-1), 0.85 Water (0.1 mL) was added, and stirring was carried out for an ad-
(d, J = 6.9 Hz, 3 H, CH3-3) ppm. The data are in accordance with
the literature.[47] 13C NMR (100.6 MHz, CDCl3): δ = 137.5
ditional 30 min. The reaction mixture was filtered through a short
plug of silica (CH2Cl2). Purification by flash chromatography on
(CH=CH2), 116.0 (CH=CH2), 71.5 (C-2), 40.1 (C-3), 37.5 (C-4), silica (cHex/EtOAc 20:1 + 0.5% NEt3) yielded 30a (75 mg,
19.8 (C-1), 14.9 (CH3-3) ppm. The data are in accordance with the
117 μmol, 74% over two steps) as a yellow oil, Rf = 0.66 (cHex/
EtOAc 5:1). 1H NMR COSY (400 MHz, CDCl3, diastereomeric
mixture): δ = 7.45–7.31 (m, 10 H, 2ϫPh), 6.57–6.54 (m, 1 H, 6-
H), 6.50–6.44 (m, 1 H, 4-H), 5.98–5.88/5.59–5.50 (m, 1 H,
CHCH=CH2), 5.82–5.67 (m, 1 H, CH2CH=CH2), 5.23–5.14 (m, 1
H, CHO-1Ј), 5.10–5.02 + 4.89–4.75 (m, 8 H, 2ϫCH=CH2,
2ϫOCH2Ph), 4.88–4.82 (m, 1 H, CHO-2ЈЈ), 4.63–4.40 (m, 1 H,
CH2ACOO), 3.82–3.67 (m, 1 H, CH2BCOO), 2.78–2.66 (m, 1 H,
CH-2Ј), 2.24–2.09 (m, 1 H, CH2ACH=CH2), 1.93–1.83 (m, 1 H,
CH2BCH=CH2), 1.80–1.71 (m, 1 H, CH-3ЈЈ), 1.20–1.12 + 0.90–
0.76 (m, 9 H, 3ϫCH3), 0.86/0.83 [s, 9 H, 3ϫC(CH3)3], 0.01/–0.02
(s, 3 H, SiCH3), –0.25/–0.25/–0.26/–0.26 (s, 3 H, SiCH3). 13C NMR
HSQC, HMBC (100.6 MHz, CDCl3, diastereomeric mixture): δ =
172.2/172.1/172.1 (COO), 158.4/158.3 (Cq-5), 157.2/157.2/156.9
(Cq-3), 143.2/143.2/140.7 (CHCH=CH2), 136.8/136.8/136.8/136.7
(CH2CH=CH2), 137.3/137.2/137.0/136.9 (2ϫCq-1, Ph), 136.1/
136.1/135.9/135.8 (Cq-1), 128.7/128.7/128.6 (2ϫCH-3, 2ϫCH-5,
Ph), 128.1/128.1/127.8/127.8 (2ϫCH-4, Ph), 127.9/127.0 (2ϫCH-
2, 2ϫCH-6, Ph), 124.1/123.9/123.8 (Cq-2), 116.4/116.3
(CH2CH=CH2), 114.2/114.2/113.9/113.9 (CHCH=CH2), 108.8/
108.7/108.7/108.5 (CH-6), 98.7/98.7 (CH-4), 74.3/74.2/74.2/74.2
(CHO-2ЈЈ), 71.6/71.5/71.5/71.4 (CHO-1Ј), 70.3/70.3 (OCH2Ph),
70.1/70.1/70.0/70.0 (OCH2Ph), 45.1/45.1/45.0 (CH-2Ј), 38.9/38.8/
38.8/38.8 (CH2COO), 37.4/37.4/37.4/37.3/37.2/37.1 (CH-3ЈЈ,
CH2CH=CH2), 26.0/26.0 [(CH3)3], 18.3 [SiC(CH3)3], 17.6/17.5/
16.4/16.3/16.2/16.2/14.8/14.7 (3ϫCH3), –4.8/–5.1/–5.3 (2ϫSiCH3).
literature.[47]
Hex-5-en-2-ol (29b):[48] A suspension of lithium aluminum hydride
(6.45 g, 0.17 mol, 0.5 equiv.) in dry THF (500 mL) was cooled to
0 °C. Hex-5-en-2-one (33.60 g, 0.34 mol, 1.0 equiv.) was added, and
the reaction mixture was stirred for 22 h and then allowed to warm
to room temperature. The reaction mixture was quenched with
hydrochloric acid (3n, 500 mL), extracted with diethyl ether
(3ϫ200 mL), dried with magnesium sulfate, and filtered. Distil-
lation in vacuo (250 mbar) yielded 29b (32.29 g, 0.32 mol, 95%,
ref.[48] 93%) as a colorless liquid, Rf = 0.25 (cHex/EtOAc 6:1), b.p.
100.0–102.0 °C (250 mbar). 1H NMR COSY (400 MHz, CDCl3): δ
= 5.81 (ddt, J = 17.0, 10.2, 6.7 Hz, 1 H, CH=CH2), 5.05–4.93 (m,
2 H, CH=CH2), 3.83–3.76 (m, 1 H, CH-2), 2.21–2.05 (m, 2 H,
CH2-4), 1.59–1.45 (m, 2 H, CH2-3), 1.17 (d, J = 6.2 Hz, 3 H, CH3-
1) ppm. The data are in accordance with the literature.[48] 13C
NMR (100.6 MHz, CDCl3):
δ = 138.6 (CH=CH2), 114.8
(CH=CH2), 67.7 (C-2), 38.4 (C-3), 30.2 (C-4), 23.5 (C-1) ppm. The
data are in accordance with the literature.[48]
Diene 30a:[28] Sodium hydrogen carbonate (33 mg, 394 μmol,
2.0 equiv.) was added to a solution of alcohol 28a (84 mg,
159 μmol, 1.0 equiv.) in acetonitrile (1 mL) and water (1 mL).
TEMPO (20 mg, 127 μmol, 0.65 equiv.) and bis(acetoxy)iodo-
benzene (139 mg, 433 μmol, 2.2 equiv.) were added. The reaction
mixture was stirred at room temperature under argon. After 4.5 h
the reaction was stopped by addition of saturated aqueous ammo-
nium chloride solution (20 mL), and the mixture was extracted
with ethyl acetate (3ϫ20 mL), dried with magnesium sulfate, and
filtered. Removal of the solvent in vacuo yielded the crude acid,
which was used without further purification. An analytic sample
IR (ATR): ν = 3068, 3034, 2929, 2856, 1727, 1498, 1144, 1043, 910,
˜
864, 835, 775, 733, 696 cm–1. HRMS (ESI): calcd. for [C40H54O5Si
+ Na]+ 665.3638; found 665.3629.
Diene 30b:[28] Sodium hydrogen carbonate (168 mg, 2.00 mmol,
was purified by flash chromatography on silica (cHex/EtOAc 5:1) 2.5 equiv.), TEMPO (63 mg, 0.40 mmol, 0.5 equiv.), and [bis(acet-
to yield a colorless oil, Rf = 0.26 (cHex/EtOAc 5:1). 1H NMR
oxy)iodo]benzene (709 mg, 2.20 mmol, 2.8 equiv.) were added to a
COSY (400 MHz, CDCl3, diastereomeric mixture): δ = 7.44–7.30 solution of alcohol 28b (84 mg, 159 μmol, 1.0 equiv.) in acetonitrile
(m, 10 H, 2ϫPh), 6.54/6.52 (d, J = 2.5 Hz, 1 H, 6-H), 6.50/6.45 (4.5 mL) and water (4.5 mL). The reaction mixture was stirred at
(d, J = 2.5 Hz, 1 H, 4-H), 5.96–5.84/5.57–5.45 (m, 1 H, CH=CH2), 30 °C under argon for 4 h and was then quenched with saturated
5.23–5.16 (m,
2ϫOCH2Ph), 4.52/4.46 (d, J = 16.7 Hz, 1 H, CH2ACOO), 3.86/ ethyl acetate (3ϫ70 mL), dried with magnesium sulfate, and fil-
3.85 (d, J = 16.7 Hz, 1 H, CH2BCOO), 2.69–2.47 (m, 1 H, CH-2Ј), tered. Removing the solvent in vacuo yielded the crude acid, which
1 H, CHO), 5.07–4.72 (m, 6 H, CH=CH2, aqueous ammonium chloride solution (75 mL), extracted with
1.16/1.15 (d, J = 6.5 Hz, 3 H, CH3-2Ј), 0.84/0.80 [s, 9 H, was used without further purification. A solution of the crude acid
C(CH3)3], –0.01/–0.04 (s, 3 H, SiCH3), –0.26/–0.28 (s, 3 H, (432 mg, 0.79 mmol, 1.0 equiv.), DMAP (20 mg, 0.16 mmol,
SiCH3) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3, dia-
stereomeric mixture): δ = 177.2 (COOH), 157.5/157.4 (Cq-5), 156.2/
0.2 equiv.), and alcohol 29a (200 mg, 1.74 mmol, 2.2 equiv.) in dry
dichloromethane (25 mL) was cooled to 0 °C. N,NЈ-Dicyclohex-
156.0 (Cq-3), 142.1/139.7 (CH=CH2), 136.4/136.3 (Cq-1, Ph), 136.0/ ylcarbodiimide (359 mg, 1.74 mmol, 2.2 equiv.) was dissolved in
136.0 (Cq-1, Ph), 134.4/134.1 (Cq-1), 127.8/127.7 (2ϫCH-3, dry dichloromethane (5 mL) and added. The reaction mixture was
2ϫCH-5, Ph), 127.3/127.2 (CH-4, Ph), 127.1 (CH-2, CH-6, Ph),
stirred for 16 h and then allowed to warm to room temperature.
127.0/127.0 (CH-4, Ph), 126.1/126.1 (CH-2, CH-6, Ph), 123.3/123.1 Water (0.3 mL) was added, and stirring was carried out for an ad-
(Cq-2), 113.5/113.2 (CH=CH2), 108.5/108.3 (CH-6), 98.0/97.9 (CH- ditional 30 min. The reaction mixture was filtered through a short
4), 70.7/70.6 (CHO), 69.5/69.4 (OCH2Ph), 69.3/69.2 (OCH2Ph),
44.6/44.3 (CH-2Ј), 37.7 (CH2COOH), 25.1/25.1 [(CH3)3], 17.4
plug of silica (CH2Cl2). Purification by flash chromatography on
silica (cHex/EtOAc 30:1 + 0.5% NEt3) yielded 30b [397 mg,
14
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 20-04-15 15:50:46
Pages: 23
Anti-Inflammatory Macrolactones
0.63 mmol, 80% (over two steps)] as a yellow oil, Rf = 0.58 (cHex/
20.1/20.0 (CH3-1ЈЈ), 18.3 [SiC(CH3)3], –4.8 (SiCH3), –5.1 (SiCH3).
EtOAc 5:1). 1H NMR COSY (400 MHz, CDCl3, diastereomeric IR (ATR): ν = 3069, 3033, 2929, 2855, 2803, 1730, 1604, 1498,
˜
mixture): δ = 7.45–7.30 (m, 10 H, 2ϫPh), 6.53 (d, J = 2.4 Hz, 1 1145, 1066, 1047, 834, 776, 697 cm–1. HRMS (ESI): calcd. for
H, 6-H), 6.48 (d, J = 2.4 Hz, 1 H, 4-H), 5.82–5.67 (m, 2 H, [C38H50O5Si + Na]+ 637.3325; found 637.3314.
2ϫCH=CH2), 5.61–5.43 (m, 1 H, CHO-1Ј), 5.08–4.95 (m, 8 H,
Lactone 31a: Diene 30a (257 mg, 0.40 mmol, 1.0 equiv.) was dis-
2ϫCH=CH2, 2ϫOCH2Ph), 4.88–4.81 (m, 1 H, CHO-2ЈЈ), 4.61–
solved in dry and degassed toluene (30 mL). The ruthenium cata-
4.39 (m, 1 H, CH2ACOO), 3.86–3.74 (m, 1 H, CH2BCOO), 2.76–
lyst
{tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imid-
2.59 (m, 1 H, CH2A-2Ј), 2.46–2.38 (m, 1 H, CH2B-2Ј), 2.23–2.09
(m, 1 H, CH2A-4ЈЈ), 1.94–1.78 (m, 1 H, CH2B-4ЈЈ), 1.83–1.72 (m, 1
H, CH-3ЈЈ), 1.18/1.16 (d, J = 6.4 Hz, 3 H, CH3-1ЈЈ), 0.89/0.84 (d,
J = 6.6 Hz, 3 H, CH3-3ЈЈ), 0.84 [s, 9 H, 3ϫC(CH3)3], 0.00 (s, 3 H,
SiCH3), –0.18 (s, 3 H, SiCH3). 13C NMR HSQC, HMBC
(100.6 MHz, CDCl3, diastereomeric mixture): δ = 172.1 (COO),
158.3 (Cq-5), 156.4 (br, Cq-3), 137.2/137.0 (2ϫCq-1, Ph), 136.8
(CH=CH2), 136.8 (CH=CH2), 136.1 (br, Cq-1), 128.6 (CH-3, CH-
5, Ph), 128.6 (CH-3, CH-5, Ph), 128.1 (CH-4, Ph), 127.8 (CH-4,
Ph), 127.8 (CH-2, CH-6, Ph), 127.0 (CH-2, CH-6, Ph), 124.5/124.4
(Cq-2), 116.4/116.4 (CH=CH2), 116.3/116.3 (CH=CH2), 108.7
(CH-6), 99.1 (CH-4), 74.3/74.2 (CHO-2ЈЈ), 70.3 (OCH2Ph), 70.1
(OCH2Ph), 67.9 (br, CHO-1Ј), 43.2 (br, CH2-2Ј), 38.6 (br,
CH2COO), 37.1 (CH-3ЈЈ, CH2-4ЈЈ), 26.0 [(CH3)3], 18.3 [SiC(CH3)3],
16.4/16.2 (CH3-1ЈЈ), 14.8/14.7 (CH3-3ЈЈ), –4.8/–4.8 (SiCH3), –5.1
azol-2-ylidene](3-phenyl-1H-inden-1-ylidene)ruthenium(II)
di-
chloride,[49] 80 mg, 84 μmol, 0.2 equiv.} was added, and the reac-
tion mixture was heated to 80 °C for 40 h. The solvent was removed
in vacuo. Purification by flash chromatography on silica (cHex/
EtOAc/NEt3 200:10:1) yielded 31a (197 mg, 0.32 mmol, 80%) as a
brown oil, Rf = 0.57 (cHex/EtOAc 5:1), HRMS (ESI): calcd. for
[C38H50O5Si + H]+ 615.3506; found 615.3501.
6,8-Bis(benzyloxy)-1-(6-methyl-7-oxooct-3-en-2-yl)isochroman-3-
one (33): Diene 30a (1.409 g, 2.19 mmol, 1.0 equiv.) was dissolved
in dry and degassed toluene (140 mL). The ruthenium catalyst
{tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-
ylidene](3-phenyl-1H-inden-1-ylidene)ruthenium(II) dichloride,[49]
313 mg, 0.33 mmol, 0.15 equiv.} was added, and the reaction mix-
ture was heated to 80 °C for 40 h. The solvent was removed in
vacuo. TBAF (1 m in THF, 11.0 mL, 11.0 mmol, 5.0 equiv.) was
added to the obtained brown oil. The reaction mixture was heated
at reflux for 68 h, diluted with ethyl acetate (100 mL), washed with
water (100 mL), dried with magnesium sulfate, and filtered through
a short plug of silica (ethyl acetate). The solvent was removed in
vacuo. The residue was dissolved in dry dichloromethane (20 mL),
and Dess–Martin periodinane (15 wt.-% in CH2Cl2, 8.8 mL,
4.38 mmol, 2.0 equiv.) was added. The reaction mixture was stirred
at room temperature for 3 h. The solvent was removed in vacuo.
Purification by flash chromatography on silica (cHex/EtOAc
5:1Ǟ3:1) yielded 33 (53 mg, 107 μmol, 5%) as a brown oil, Rf =
0.11 (cHex/EtOAc 5:1). 1H NMR COSY, NOESY (400 MHz,
CDCl3, diastereomeric mixture): δ = 7.44–7.32 (m, 10 H, 2ϫPh),
6.53–6.50 (m, 1 H, 7-H), 6.36–6.31 (m, 1 H, 5-H), 5.60–5.54 (m, 1
H, 1-H), 5.49–5.40 (m, 1 H, 3Ј-H), 5.28–5.23 (m, 1 H, 4Ј-H), 5.03–
5.02 (m, 4 H, 2ϫOCH2Ph), 3.87–3.57 (m, 2 H, CH2-4), 3.08–2.98/
2.73–2.65 (m, 1 H, 2Ј-H), 2.50–2.39/2.26–2.20 (m, 1 H, 6Ј-H), 2.30–
2.12 (m, 1 H, CH2A-5Ј), 2.01–1.88 (m, 1 H, CH2B-5Ј), 2.09–1.97
(m, 3 H, CH3-8Ј), 1.03–0.91 (m, 6 H, CH3-1Ј, CH3-6Ј) ppm. 13C
NMR HSQC, HMBC (100.6 MHz, CDCl3, diastereomeric mix-
ture): δ = 212.3 (CO), 170.4 (COO), 160.0 (Cq-6), 155.7 (Cq-8),
136.4 (2ϫCq-1, Ph), 133.7 (CH-4Ј), 132.5 (Cq-4a), 128.8–127.4 (m,
11 C, CH-3Ј, 2ϫCH-2, 2ϫCH-3, 2ϫCH-4, 2ϫCH-5, 2ϫCH-6,
Ph), 114.2 (Cq-8a), 104.4 (CH-5), 99.2 (CH-7), 81.8 (CH-1), 70.4
(2ϫOCH2Ph), 46.9 (CH-6Ј), 44.0/38.6 (CH-2Ј), 35.8 (CH2-5Ј), 35.3
(CH2-4), 28.4 (CH3-8Ј), 16.6–15.6 (m, 2 C, CH3-1Ј, CH3-6Ј).
HRMS (ESI): calcd. for [C32H34O5 + Na]+ 521.2304; found
521.2315.
(SiCH ). IR (ATR): ν = 3070, 3033, 1729, 1604, 1498, 1145, 1067,
˜
3
1046, 834, 776, 735, 697 cm–1. HRMS (ESI): calcd. for [C39H52O5Si
+ Na+] 651.3482; found 651.3469.
Diene 30c:[18] Sodium hydrogen carbonate (664 mg, 7.90 mmol,
2.5 equiv.), TEMPO (247 mg, 1.58 mmol, 0.5 equiv.), and [bis(acet-
oxy)iodo]benzene (2.80 g, 8.69 mmol, 2.8 equiv.) was added to a
solution of alcohol 28b (1.63 g, 3.14 mmol, 1.0 equiv.) in aceto-
nitrile (18 mL) and water (18 mL). The reaction mixture was stirred
at 30 °C under argon for 5 h and was then quenched with saturated
aqueous ammonium chloride solution (100 mL), extracted with
ethyl acetate (3ϫ100 mL), dried with magnesium sulfate, and fil-
tered. Removing the solvent in vacuo yielded the crude acid, which
was used without further purification. A solution of the crude acid
(1.67 g, 3.14 mmol, 1.0 equiv.), DMAP (77 mg, 0.63 mmol,
0.2 equiv.), and alcohol 29b (378 mg, 3.77 mmol, 1.2 equiv.) in dry
dichloromethane (110 mL) was cooled to 0 °C. N,NЈ-Dicyclohex-
ylcarbodiimide (972 mg, 4.71 mmol, 1.5 equiv.) was dissolved in
dry dichloromethane (10 mL) and added. The reaction mixture was
stirred for 16 h and was then allowed to warm to room temperature
and filtered through a short plug of silica (CH2Cl2). Purification
by flash chromatography on silica (cHex/EtOAc 30:1 + 1% NEt3)
yielded 30c [922 mg, 1.50 mmol, 48% (over two steps)] as a color-
1
less oil, Rf = 0.65 (cHex/EtOAc 4:1). H NMR COSY (400 MHz,
CDCl3, diastereomeric mixture): δ = 7.45–7.30 (m, 10 H, 2ϫPh),
6.53–6.52 (m, 1 H, 6-H), 6.48 (d, J = 2.4 Hz, 1 H, 4-H), 5.82–5.71
(m, 2 H, 2ϫCH=CH2), 5.60–5.44 (m, 1 H, CHO-1Ј), 5.08–4.91 (m,
9 H, 2ϫCH=CH2, 2ϫOCH2Ph, CHO-2ЈЈ), 4.54–4.30 (m, 1 H,
CH2ACOO), 3.83–3.77 (m, 1 H, CH2BCOO), 2.74–2.58 (m, 1 H,
CH2A-2Ј), 2.46–2.39 (m, 1 H, CH2B-2Ј), 2.16–1.98 (m, 2 H, CH2- Lactone 34a:[18] Diene 30b (336 mg, 0.53 mmol, 1.0 equiv.) was
4ЈЈ), 1.79–1.70 (m, 1 H, CH2A-3ЈЈ), 1.61–1.53 (m, 1 H, CH2B-3ЈЈ), dissolved in dry and degassed toluene (90 mL). The ruthenium
1.24–1.20 (m, 3 H, CH3-1ЈЈ), 0.84 [s, 9 H, 3ϫC(CH3)3], 0.00 (s, 3 catalyst
H, SiCH3), –0.18 (s, 3 H, SiCH3) ppm. 13C NMR HSQC, HMBC imidazol-2-ylidene](3-phenyl-1H-inden-1-ylidene)ruthenium(II) di-
(100.6 MHz, CDCl3, diastereomeric mixture): δ = 172.1 (COO),
chloride,[49] 120 mg, 0.13 mmol, 0.24 equiv.} was added, and the
{tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-
158.4 (Cq-5), 156.5 (br, Cq-3), 137.9 (CH=CH2), 137.3/137.0 reaction mixture was heated to 80 °C for 3 h. The solvent was re-
(2ϫCq-1, Ph), 136.1 (CH=CH2), 136.1 (Cq-1), 128.7 (CH-3, CH- moved in vacuo. Purification by flash chromatography on silica
5, Ph), 128.6 (CH-3, CH-5, Ph), 128.1 (CH-4, Ph), 127.8 (CH-4,
(cHex/EtOAc 40:1) yielded 31b (185 mg, 0.31 mmol, 58%) as a
Ph), 127.8 (CH-2, CH-6, Ph), 127.1/127.0 (CH-2, CH-6, Ph), 124.4 brown oil, R = 0.50 (cHex/EtOAc 5:1), IR (ATR): ν = 3090, 3065,
˜
f
(br, Cq-2), 116.4/116.4 (CH=CH2), 115.0/115.0 (CH=CH2), 108.7
(CH-6), 99.1 (CH-4), 70.9/70.8 (CHO-2ЈЈ), 70.4 (OCH2Ph), 70.1 1030, 834, 734 cm–1. HRMS (ESI): calcd. for [C37H48O5Si + Na]+
(OCH2Ph), 67.9 (br, CHO-1Ј), 43.2 (br, CH2-2Ј), 38.6 (br, 623.3169; found 623.3155. TBAF (1 m in THF, 0.35 mL,
CH2COO), 35.2/35.2 (CH2-3ЈЈ), 29.8/29.7 (CH2-4ЈЈ), 26.0 [(CH3)3], 0.35 mmol, 1.5 equiv.) was added to the obtained brown oil. The
3032, 2954, 2929, 2884, 1721, 1604, 1498, 1148, 1082, 1066, 1048,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 23
J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
FULL PAPER
reaction mixture was stirred at room temperature for 4 d. Water
(30 mL) was added to the reaction mixture, which was then ex-
tracted with ethyl acetate (3ϫ30 mL), dried with magnesium sulf-
ate, and filtered. The solvent was removed in vacuo. Purification
by flash chromatography on silica (cHex/EtOAc 10:1Ǟ5:1) yielded
34a (diastereomer A: 22.5 mg, 46 μmol, 20%, diastereoisomer B:
27 mg, 56 μmol, 25%) as a colorless oil.
THF, 3.0 mL, 3.0 mmol, 4.0 equiv.) was added to TBDMS ether
31c (448 mg, 0.76 mmol, 1.0 equiv.). The reaction mixture was
stirred at room temperature. After 39 h, water (40 mL) was added,
and the mixture was extracted with ethyl acetate (2ϫ40 mL), dried
with magnesium sulfate, and filtered. The solvent was removed in
vacuo. Purification by flash chromatography on silica (cHex/EtOAc
10:1Ǟ5:1) yielded 34b (229 mg, 0.48 mmol, 64%, ref.[18] 97%) as
a yellow oil.
Diastereomer A: Rf = 0.19 (cHex/EtOAc 5:1). 1H NMR COSY
(400 MHz, CDCl3): δ = 7.45–7.32 (m, 10 H, 2ϫPh), 6.66 (d, J = Diastereomer A: Rf = 0.13 (cHex/EtOAc 10:1). 1H NMR COSY
2.4 Hz, 1 H, 4-H), 6.63 (d, J = 2.4 Hz, 1 H, 6-H), 5.55 (ddd, J =
(400 MHz, CDCl3): δ = 7.45–7.32 (m, 10 H, 2ϫPh), 6.64 (d, J =
14.6, 10.3, 3.6 Hz, 1 H, 12-H), 5.11–5.01 (m, 4 H, 2ϫOCH2Ph), 2.5 Hz, 1 H, 4-H), 6.63 (d, J = 2.5 Hz, 1 H, 6-H), 5.50 (ddd, J =
4.84 (dq, J = 9.9, 6.3 Hz, 1 H, 15-H), 4.80–4.75 (m, 1 H, 11-H), 14.6, 10.4, 3.7 Hz, 1 H, 12-H), 5.24–5.16 (m, 1 H, 15-H), 5.09 (d,
4.75–4.68 (m, 1 H, 9-H), 4.00 (d, J = 11.4 Hz, 1 H, OH), 3.70 (d, J = 11.2 Hz, 1 H, OCH2APh), 5.08 (s, 2 H, OCH2Ph), 5.03 (d, J =
J = 15.4 Hz, 1 H, CH2A-2), 3.33 (d, J = 15.4 Hz, 1 H, CH2B-2),
11.2 Hz, 1 H, OCH2BPh), 4.90–4.81 (m, 1 H, 11-H), 4.73–4.66 (m,
2.70 (td, J = 11.7, 5.6 Hz, 1 H, CH2A-10), 2.51 (ddd, J = 11.7, 9.8, 1 H, 9-H), 3.98 (d, J = 11.6 Hz, 1 H, OH), 3.71 (d, J = 15.5 Hz, 1
4.6 Hz, 1 H, CH2B-10), 2.10–1.91 (m, 2 H, CH2-13), 1.76–1.65 (m, H, CH2A-2), 3.34 (d, J = 15.5 Hz, 1 H, CH2B-2), 2.79–2.72 (m, 1
1 H, 14-H), 1.23 (d, J = 6.3 Hz, 3 H, CH3-15), 0.90 (d, J = 6.9 Hz, H, CH2A-10), 2.55–2.48 (m, 1 H, CH2B-10), 2.29–2.21 (m, 1 H,
3 H, CH3-14) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CH2A-13), 2.03–1.94 (m, 1 H, CH2B-13), 1.71–1.54 (m, 2 H, CH2-
CDCl3): δ = 171.1 (COO), 158.5 (Cq-5), 158.0 (Cq-7), 136.9 (Cq-1,
Ph), 136.0 (Cq-1, Ph), 135.5 (CH-12), 133.9 (Cq-3), 129.0 (CH-3, HMBC (100.6 MHz, CDCl3): δ = 171.4 (COO), 158.5 (Cq-5), 158.0
14), 1.23 (d, J = 6.3 Hz, 3 H, CH3-15) ppm. 13C NMR HSQC,
CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.6 (CH-4, Ph), 128.2 (CH-
4, Ph), 127.9 (CH-2, CH-6, Ph), 127.8 (CH-2, CH-6, Ph), 123.7
(Cq-7), 136.8 (Cq-1, Ph), 136.0 (Cq-1, Ph), 135.3 (CH-12), 134.0
(Cq-3), 129.0 (CH-3, CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.5
(CH-11), 122.2 (Cq-8), 109.5 (CH-4), 100.7 (CH-6), 76.9 (CH-15), (CH-4, Ph), 128.2 (CH-4, Ph), 127.9 (CH-2, CH-6, Ph), 127.8 (CH-
72.5 (CH-9), 70.7 (OCH2Ph), 70.2 (OCH2Ph), 40.4 (CH2-13), 40.3 2, CH-6, Ph), 124.8 (CH-11), 122.2 (Cq-8), 109.5 (CH-4), 100.7
(CH2-10), 38.6 (CH2-2), 38.6 (CH-14), 20.3 (CH3-15), 19.6 (CH3- (CH-6), 72.6 (CH-15), 72.5 (CH-9), 70.7 (OCH2Ph), 70.2
14) ppm. IR (ATR): ν = 3558, 3090, 3065, 3033, 2963, 2928, 1728,
(OCH2Ph), 40.7 (CH2-10), 38.7 (CH2-2), 34.4 (CH2-14), 30.8 (CH2-
˜
1606, 1498, 1298, 1202, 1143, 1053, 1020, 733, 698 cm–1. HRMS
(ESI): calcd. for [C31H34O5 + Na]+ 509.2304; found 509.2295.
13), 21.6 (CH -15) ppm. IR (ATR): ν = 3556, 3090, 3065, 3033,
˜
3
2975, 2930, 1726, 1606, 1498, 1298, 1142, 1060, 1013, 908, 728,
697 cm–1. HRMS (ESI): calcd. for [C30H32O5 + Na]+ 495.2147;
found 495.2154.
Diastereomer B: Rf = 0.09 (cHex/EtOAc 5:1). 1H NMR (400 MHz,
CDCl3): δ = 7.44–7.31 (m, 10 H, 2ϫPh), 6.63 (d, J = 2.4 Hz, 1 H,
6-H), 6.40 (d, J = 2.4 Hz, 1 H, 4-H), 5.29–5.20 (m, 1 H, 12-H),
Diastereomer B: Rf = 0.08 (cHex/EtOAc 10:1). 1H NMR
5.15–5.00 (m, 4 H, 2ϫOCH2Ph), 4.94–4.87 (m, 1 H, 15-H), 4.78– (400 MHz, CDCl3): δ = 7.45–7.31 (m, 10 H, 2ϫPh), 6.63 (d, J =
4.67 (m, 2 H, 11-H, 9-H), 3.83 (br. s, 1 H, OH), 3.71 (d, J = 2.4 Hz, 1 H, 6-H), 6.42 (d, J = 2.4 Hz, 1 H, 4-H), 4.89 (ddd, J =
16.5 Hz, 1 H, CH2A-2), 3.47 (d, J = 16.5 Hz, 1 H, CH2B-2), 2.82– 14.7, 9.3, 4.3 Hz, 1 H, 12-H), 5.15–5.02 (m, 2ϫOCH2Ph, 5 H, 15-
2.74 (m, 1 H, CH2A-10), 2.49–2.44 (m, 1 H, CH2B-10), 2.03–1.99 H), 5.30–5.21 (m, 1 H, 11-H), 4.70–4.63 (m, 1 H, 9-H), 3.75–3.66
(m, 1 H, CH2A-13), 1.93–1.84 (m, 1 H, CH2B-13), 1.50–1.40 (m, 1 (m, CH2A-2, 2 H, OH), 3.46 (d, J = 16.4 Hz, 1 H, CH2B-2), 2.85–
H, 14-H), 1.08 (d, J = 6.3 Hz, 3 H, CH3-15), 0.83 (d, J = 7.0 Hz, 2.77 (m, 1 H, CH2A-10), 2.49–2.44 (m, 1 H, CH2B-10), 2.17–2.09
3 H, CH3-14) ppm. 13C NMR HSQC (100.6 MHz, CDCl3): δ =
(m, 1 H, CH2A-13), 1.99–1.87 (m, 1 H, CH2B-13), 1.54–1.49 (m, 1
170.0 (COO), 158.1 (Cq-5), 157.8 (Cq-7), 136.9 (Cq-1, Ph), 136.1 H, CH2A-14), 1.40–1.31 (m, 1 H, CH2B-14), 1.09 (d, J = 6.4 Hz, 3
(Cq-1, Ph), 134.6 (CH-12), 134.5 (Cq-3), 129.0 (CH-3, CH-5, Ph), H, CH3-15) ppm. 13C NMR HSQC (100.6 MHz, CDCl3): δ = 170.0
128.7 (CH-3, CH-5, Ph), 128.5 (CH-4, Ph), 128.2 (CH-4, Ph), 127.7
(COO), 158.2 (Cq-5), 157.9 (Cq-7), 136.9 (Cq-1, Ph), 136.1 (Cq-1,
(CH-2, CH-6, Ph), 127.6 (CH-2, CH-6, Ph), 123.5 (CH-11), 123.2 Ph), 134.5 (Cq-3), 134.0 (CH-12), 129.1 (CH-3, CH-5, Ph), 128.8
(Cq-8), 109.8 (CH-4), 100.4 (CH-6), 76.7 (CH-15), 70.7 (OCH2Ph), (CH-3, CH-5, Ph), 128.6 (CH-4, Ph), 128.2 (CH-4, Ph), 127.8 (CH-
70.6 (CH-9), 70.3 (OCH2Ph), 41.1 (CH2-13), 40.5 (CH2-2), 40.4 2, CH-6, Ph), 127.6 (CH-2, CH-6, Ph), 124.6 (CH-11), 123.2 (Cq-
(CH2-10), 37.3 (CH-14), 19.9 (CH3-15), 19.0 (CH3-14) ppm. IR 8), 110.1 (CH-4), 100.4 (CH-6), 72.6 (CH-15), 70.7 (OCH2Ph), 70.6
(ATR): ν = 3559, 3090, 3064, 3033, 2972, 2963, 2930, 2880, 1718, (CH-9), 70.3 (OCH2Ph), 41.0 (CH2-2), 40.3 (CH2-10), 33.3 (CH2-
˜
1606, 1498, 1269, 1145, 1060, 1028, 735, 698 cm–1. HRMS (ESI):
calcd. for [C31H34O5 + Na]+ 509.2304; found 509.2292.
14), 31.1 (CH -13), 21.5 (CH -15) ppm. IR (ATR): ν = 3561, 3064,
˜
2 3
3032, 2974, 2929, 1720, 1607, 1588, 1498, 1268, 1146, 1055, 1038,
698 cm–1. HRMS (ESI): calcd. for [C30H32O5 + Na]+ 495.2147;
found 495.2159.
Lactone 34b:[18] Diene 30c (922 mg, 1.50 mmol, 1.0 equiv.) was dis-
solved in dry and degassed toluene (8 mL). The ruthenium catalyst
{tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2- 5,7-Di-O-benzyl-14-methyl-11,12-dehydrocurvularin (35a):[18]
ylidene](3-phenyl-1H-inden-1-ylidene)ruthenium(II) dichloride,[49]
145 mg, 0.15 mmol, 0.10 equiv.} was dissolved in dry and degassed
toluene (8 mL). Both solutions were added over 1 h to 80 °C warm
toluene (350 mL). After 3.5 h the solution was allowed to cool to
room temperature and stirred for an additional 18 h. The solvent
was removed in vacuo. Purification by flash chromatography on
Alcohol 34a (20 mg, 41 μmol, 1.0 equiv.) was dissolved in dry
dichloromethane (5 mL). Dess–Martin periodinane (15 wt.-%,
0.10 mL, 49 μmol, 1.2 equiv.) was added. After 17 h stirring at
room temperature the reaction mixture was quenched with satu-
rated aqueous sodium thiosulfate solution (10 mL) and saturated
aqueous sodium hydrogen carbonate solution (10 mL), extracted
silica (cHex/EtOAc 30:1 + 1 % NEt3) yielded 31c (593 mg, with dichloromethane (3ϫ30 mL), dried with magnesium sulfate,
1.01 mmol, 67%, ref.[18] 83%) as a yellow oil, Rf = 0.20 (cHex/
and filtered. Removing the solvent in vacuo yielded 35a (18 mg,
1
EtOAc 30:1). IR (ATR): ν = 3091, 3065, 3033, 2951, 2929, 1725, 37 μmol, 92%) as a colorless oil, Rf = 0.38 (cHex/EtOAc 5:1). H
˜
1605, 1498, 1256, 1151, 1068, 1030, 835 cm–1. HRMS (ESI): calcd.
NMR COSY (400 MHz, CDCl3): δ = 7.44–7.28 (m, 10 H, 2ϫPh),
6.61 (br. s, 1 H, 4-H), 6.53 (d, J = 2.2 Hz, 1 H, 6-H), 5.62–5.54 (m,
for [C36H46O5Si + Na]+ 609.3012; found 609.3019. TBAF (1 m in
16
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50275
/KAP1
Date: 20-04-15 15:50:46
Pages: 23
Anti-Inflammatory Macrolactones
1 H, 12-H), 5.23–5.15 (m, 1 H, 11-H), 5.09–5.01 (m, 4 H, 5), 156.7 (Cq-7), 136.5 (Cq-1, Ph), 136.3 (Cq-1, Ph), 134.5 (CH-13),
2ϫOCH2Ph), 4.75 (dq, J = 9.1, 6.3 Hz, 1 H, 15-H), 3.60–3.30 (m, 133.9 (Cq-3), 130.6 (CH-12), 128.8 (2ϫCH-3, 2ϫCH-5, Ph), 128.3
4 H, CH2-2, CH2-10), 2.18–2.12 (m, 1 H, CH2A-13), 2.01–1.92 (m, (CH-4, Ph), 128.3 (CH-4, Ph), 127.7 (CH-2, CH-6, Ph), 127.5 (CH-
1 H, CH2B-13), 1.75–1.65 (m, 1 H, 14-H), 1.16 (d, J = 6.3 Hz, 3 2, CH-6, Ph), 125.6 (Cq-8), 110.2 (CH-4), 99.5 (CH-6), 74.2 (CH-
H, CH3-15), 0.87 (d, J = 6.9 Hz, 3 H, CH3-14) ppm. 13C NMR
15), 70.3 (OCH2Ph), 70.3 (OCH2Ph), 45.8 (CH2-10), 44.7 (CH-14),
HSQC, HMBC (100.6 MHz, CDCl3): δ = 204.8 (CO), 170.7 38.6 (CH2-2), 24.4 (CH2-11), 18.5 (CH3-15), 17.2 (CH3-14) ppm.
(COO), 160.3 (Cq-5), 156.5 (Cq-7), 136.6 (Cq-1, Ph), 136.3 (Cq-1, The C-9 resonance could not be found due to an unfavorable S/N
Ph), 137.5 (CH-12), 134.2 (Cq-3), 128.8 (2ϫCH-3, 2ϫCH-5, Ph), ratio (long relaxation time and low sample concentration). IR
128.3 (CH-4, Ph), 128.2 (CH-4, Ph), 127.8 (CH-2, CH-6, Ph), 127.3
(ATR): ν = 3091, 3065, 3033, 2972, 2930, 2875, 1729, 1689, 1602,
˜
(CH-2, CH-6, Ph), 124.5 (Cq-8), 119.1 (CH-11), 109.2 (CH-4), 99.7 1580, 1498, 1310, 1285, 1192, 1157, 1071 cm–1. HRMS (ESI): calcd.
(CH-6), 76.7 (CH-15), 70.6 (OCH2Ph), 70.3 (OCH2Ph), 49.1 (CH2- for [C31H32O5 + Na]+ 507.2147; found 507.2155.
10), 39.8 (CH2-13), 38.2 (CH2-2), 38.2 (CH-14), 19.8 (CH3-15), 19.0
5,7-Di-O-benzyl-12-oxo-10,11-dehydrocurvularin (37): The β,γ-un-
(CH -14) ppm. IR (ATR): ν = 3090, 3065, 3033, 2974, 2931, 2880,
˜
3
saturated lactone 35b (5 mg, 11 μmol, 1.0 equiv.) was dissolved in
pyridine (0.6 mL), and the mixture was heated at reflux for 48 h.
The solvent was removed in vacuo. Purification by flash
chromatography on silica (cHex/EtOAc 5:1) yielded 37 (1.7 mg,
4 μmol, 34%) as a colorless oil, Rf = 0.13 (cHex/EtOAc 5:1). 1H
NMR COSY (600 MHz, CDCl3): δ = 7.44–7.26 (m, 10 H, 2ϫPh),
6.99 (d, J = 16.0 Hz, 1 H, CH-10), 6.80 (d, J = 2.2 Hz, 1 H, 6-H),
6.62 (d, J = 16.0 Hz, 1 H, CH-11), 6.59 (d, J = 2.2 Hz, 1 H, 4-H),
5.11–4.99 (m, 5 H, 2ϫOCH2Ph, OCH-15), 3.42 (d, J = 14.3 Hz, 1
H, CH2A-2), 3.25 (d, J = 14.3 Hz, 1 H, CH2B-2), 2.60–2.52 (m, 2
H, CH2-13), 2.10–2.04 (m, 1 H, CH2A-14), 1.91 (dtd, J = 15.3, 9.3,
2.6 Hz, 1 H, CH2B-14), 1.26–1.23 (m, 3 H, CH3-15) ppm. 13C NMR
HSQC, HMBC (150.9 MHz, CDCl3): δ = 201.6 (Cq-12), 196.3 (Cq-
9), 170.1 (Cq-1), 160.9 (Cq-5), 157.5 (Cq-7), 141.9 (CH-11), 138.1
(CH-10), 136.3 (Cq-1, Ph), 136.3 (Cq-1, Ph), 134.0 (Cq-3), 128.8
(CH-3, CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.4 (CH-4, Ph),
128.1 (CH-4, Ph), 127.8 (CH-2, CH-6, Ph), 127.1 (CH-2, CH-6,
Ph), 122.0 (Cq-8), 108.7 (CH-4), 101.1 (CH-6), 73.0 (CH-15), 70.7
(OCH2Ph), 70.4 (OCH2Ph), 39.7 (CH2-13), 39.6 (CH2-2), 33.4
2835, 1726, 1690, 1602, 1498, 1310, 1281, 1157, 1064, 735 cm–1.
HRMS (ESI): calcd. for [C31H32O5 + Na]+ 507.2147; found
507.2150.
5,7-Di-O-benzyl-11,12-dehydrocurvularin (35b):[18] Alcohol 34b
(194 mg, 0.41 mmol, 1.0 equiv.) was dissolved in dry dichlorometh-
ane (10 mL), and Dess–Martin periodinane (174 mg, 0.41 mmol,
1.0 equiv.) was added. After 18 h stirring at room temperature the
reaction mixture was quenched with saturated aqueous sodium
thiosulfate solution (13 mL) and saturated aqueous sodium
hydrogen carbonate solution (13 mL), extracted with dichlorometh-
ane (3ϫ40 mL), dried with magnesium sulfate, and filtered. The
solvent was removed in vacuo. Purification by flash chromatog-
raphy on silica (cHex/EtOAc 15:1) yielded 35b (115 mg, 0.24 mmol,
60%) as a colorless oil, Rf = 0.22 (cHex/EtOAc 10:1). 1H NMR
COSY (400 MHz, CDCl3): δ = 7.44–7.29 (m, 10 H, 2ϫPh), 6.60
(br. s, 1 H, 4-H), 6.54 (d, J = 2.1 Hz, 1 H, 6-H), 5.57–5.45 (m, 1
H, 12-H), 5.30–5.22 (m, 1 H, 11-H), 5.11–5.02 (m, 5 H,
2ϫOCH2Ph, 15-H), 3.70–3.27 (m, 4 H, CH2-2, CH2-10), 2.31–2.23
(m, 1 H, CH2A-13), 2.05–1.98 (m, 1 H, CH2B-13), 1.70–1.53 (m, 2 (CH -14), 19.8 (CH -15) ppm. IR (ATR): ν = 3065, 3033, 2953,
˜
2
3
H, CH2-14), 1.71 (d, J = 6.4 Hz, 3 H, CH3-15) ppm. 13C NMR
2924, 2854, 2783, 1729, 1696, 1660, 1601, 1498, 1311, 1263,
HSQC, HMBC (100.6 MHz, CDCl3): δ = 204.8 (CO), 171.0 1162 cm–1. HRMS (ESI): calcd. for [C30H28O6 + Na]+ 485.1964;
(COO), 160.3 (Cq-5), 156.7 (Cq-7), 136.5 (Cq-1, Ph), 136.3 (Cq-1,
Ph), 137.4 (CH-12), 134.2 (Cq-3), 128.8 (2ϫCH-3, 2ϫCH-5, Ph),
128.3 (CH-4, Ph), 128.2 (CH-4, Ph), 127.8 (CH-2, CH-6, Ph), 127.3
(CH-2, CH-6, Ph), 124.4 (Cq-8), 120.1 (CH-11), 109.5 (CH-4), 99.6
(CH-6), 72.6 (CH-15), 70.6 (OCH2Ph), 70.3 (OCH2Ph), 49.2 (CH2-
10), 38.1 (CH2-2), 33.8 (CH-14), 30.6 (CH2-13), 21.1 (CH3-
found 485.1953.
Methyl 2-[3,5-Bis(benzyloxy)-2-(2-methylpent-4-enoyl)phenyl]acet-
ate (38):[16,17] Trifluoroacetic acid (96 mL) and trifluoroacetic an-
hydride (48 mL) were added to methyl 3,5-bis(benzyloxy)phenyl-
acetate (5.64 g, 15.6 mmol, 1.0 equiv.) at –26 °C. Then, 2-meth-
ylpent-4-enoic acid (4.44 g, 38.9 mmol, 2.5 equiv.) was added, and
stirring was carried out at –26 °C for 64 h. The reaction mixture
was poured onto ice (500 g), saturated aqueous sodium hydrogen
carbonate solution (200 mL), and ethyl acetate (500 mL) and neu-
tralized with solid sodium hydrogen carbonate. The organic layer
was separated, washed with saturated aqueous sodium hydrogen
carbonate solution (2 ϫ 200 mL), dried with magnesium sulfate,
and filtered. The solvent was removed in vacuo to yield 38 (7.13 g,
15.6 mmol, quant.) as a colorless oil, which can be used without
further purification, Rf = 0.22 (cHex/EtOAc 10:1). 1H NMR
(400 MHz, CDCl3): δ = 7.44–7.31 (m, 10 H, 2ϫPh), 6.56 (d, J =
2.2 Hz, 1 H, 6-H), 6.54 (d, J = 2.2 Hz, 1 H, 4-H), 5.65–5.52 (m, 1
H, CH=CH2), 5.05 (s, 2 H, OCH2Ph), 5.02 (s, 2 H, OCH2Ph), 4.96–
4.86 (m, 2 H, CH=CH2), 3.70 (s, 3 H, COOCH3), 3.58 (d, J =
15) ppm. IR (ATR): ν = 3090, 3064, 3033, 2976, 2931, 1725, 1690,
˜
1602, 1581, 1498, 1311, 1283, 1157, 1072 cm–1. HRMS (ESI): calcd.
for [C30H30O5 + Na]+ 493.1991; found 493.1999.
5,7-Di-O-benzyl-14-methyl-12,13-dehydrocurvularin (36):[29,50]
A
solution of the Baudry catalyst [(1,5-cyclooctadiene)bis(methyl-di-
phenylphosphine)iridium(I) hexafluorophosphate, 7 mg, 8 μmol,
1.0 equiv.] in dry THF (2 mL) was saturated with hydrogen and
stirred at room temperature for 10 min. The hydrogen was ex-
changed for argon and the solution was degassed. A solution of
the β,γ-unsaturated lactone 35a (4 mg, 8 μmol, 1.0 equiv.) in dry
THF (1 mL) was added, and the reaction mixture was stirred at
room temperature. After 24 h the solvent was removed in vacuo.
Purification by flash chromatography (cHex/EtOAc 20:1Ǟ10:1)
yielded 36 (2.4 mg, 5 μmol, 60%) as a colorless oil, Rf = 0.05 (cHex/ 16.2 Hz, 1 H, CH2A-COOMe), 3.51 (d, J = 16.2 Hz, 1 H, CH2B
-
1
EtOAc 20:1). H NMR COSY (600 MHz, CDCl3): δ = 7.42–7.31 COOMe), 3.32–3.21 (m, 1 H, COCH), 2.48–2.37 (m, 1 H, CH2A
-
(m, 10 H, 2ϫPh), 6.51 (br. s, 1 H, 6-H), 6.45 (d, J = 2.2 Hz, 1 H, 3), 2.10–1.99 (m, 1 H, CH2B-3), 1.01 (d, J = 6.9 Hz, 3 H,
4-H), 5.75–5.70 (m, 1 H, 12-H), 5.18–5.14 (m, 1 H, 13-H), 5.07–
CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 209.5 (C=O), 171.2
5.00 (m, 4 H, 2ϫOCH2Ph), 4.78–4.72 (m, 1 H, 15-H), 3.98 (d, J (COOMe), 160.8 (C-5), 158.3 (C-3), 136.5 (CH=CH2), 136.4 (C-1),
= 17.2 Hz, 1 H, CH2A-2), 3.24 (d, J = 17.2 Hz, 1 H, CH2B-2), 3.04– 136.0 (C-1, Ph-1), 135.4 (C-1, Ph-2), 128.8 (C-3, C-5, Ph-1), 128.8
2.98 (m, 2 H, CH2-10), 2.45–2.40 (m, 1 H, CH2A-11), 2.11–2.05 (m,
1 H, 14-H), 1.99–1.93 (m, 1 H, CH2B-11), 1.23 (d, J = 6.5 Hz, 3 C-6, Ph-1), 127.8 (C-2, C-6, Ph-2), 124.0 (C-2), 116.4 (CH=CH2),
H, CH3-15), 0.96 (d, J = 6.8 Hz, 3 H, CH3-14) ppm. 13C NMR
109.2 (C-6), 99.5 (C-4), 70.9 (OCH2Ph), 70.3 (OCH2Ph), 52.2
HSQC, HMBC (150.9 MHz, CDCl3): δ = 171.3 (COO), 160.1 (Cq- (OCH3), 46.3 (COCH), 39.0 (CH2COOMe), 37.1 (CH2-3), 15.8
(C-3, C-5, Ph-2), 128.4 (C-4, Ph-1), 128.4 (C-4, Ph-2), 128.0 (C-2,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O50275
/KAP1
Date: 20-04-15 15:50:46
Pages: 23
J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
FULL PAPER
(CH ) ppm. IR (ATR): ν = 3066, 3033, 2925, 2854, 1738, 1680,
ture for 2.5 h and was then diluted with diethyl ether (25 mL),
washed with water (2ϫ25 mL), dried with magnesium sulfate, and
filtered. The solvent was removed in vacuo. Purification by flash
chromatography on silica (cHex/EtOAc 5:1) yielded 40 (18 mg,
43 μmol, 19%) as an orange oil, Rf = 0.12 (cHex/EtOAc/HOAc
500:100:1). 1H NMR COSY (400 MHz, CDCl3): δ = 7.46–7.34 (m,
10 H, 2ϫPh), 6.04 (d, J = 1.9 Hz, 1 H, 5-H), 5.95 (d, J = 1.9 Hz,
1 H, 7-H), 5.94 (s, 1 H, 4-H), 5.47–5.37 (m, 1 H, CH=CH2), 5.07
(s, 2 H, OCH2Ph), 5.05 (s, 2 H, OCH2Ph), 4.94–4.86 (m, 2 H,
˜
3
1601, 1577, 1434, 1318, 1286, 1161, 699 cm–1. HRMS (ESI): calcd.
for [C29H30O5 + Na]+ 481.1991; found 481.2001. C29H30O5
(458.55): calcd. C 75.96, H 6.59; found C 75.74, H 6.66.
2-[3,5-Bis(benzyloxy)-2-(2-methylpent-4-enoyl)phenyl]acetic Acid
(39):[16,17] An aqueous solution of sodium hydroxide (0.5 m,
200 mL) was added to a solution of ester 38 (5.05 g, 11.0 mmol,
1.0 equiv.) in THF (200 mL). The solution was stirred at room tem-
perature for 5 h. The solvent was removed in vacuo. Then HCl (2 n,
200 mL) was added, and the mixture was extracted with dichloro-
methane (3ϫ100 mL), dried with magnesium sulfate, and filtered.
The solvent was removed in vacuo. Purification by flash
chromatography on silica (cHex/EtOAc/HOAc 100:100:1) yielded
39 (4.58 g, 10.3 mmol, 94%) as a yellow solid, Rf = 0.20 (cHex/
EtOAc/HOAc 500:100:1), m.p. 111.0–111.5 (cHex/EtOAc/HOAc
50:10:1). 1H NMR (400 MHz, CDCl3): δ = 7.44–7.34 (m, 10 H,
2ϫPh), 6.65 (d, J = 2.0 Hz, 1 H, 6-H), 6.59 (d, J = 2.0 Hz, 1 H,
4-H), 5.53 (ddt, J = 17.1, 10.1, 7.0 Hz, 1 H, CH=CH2), 5.06 (s, 2
H, OCH2Ph), 5.05 (s, 2 H, OCH2Ph), 4.96–4.87 (m, 2 H,
CH=CH2), 3.51 (d, J = 13.3 Hz, 1 H, CH2A-COOH), 3.57–3.38 (m,
1 H, COCH), 3.42 (d, J = 13.3 Hz, 1 H, CH2B-COOH), 2.42–2.35
(m, 1 H, CH2A-3), 2.13–2.06 (m, 1 H, CH2B-3), 1.01 (d, J = 6.9 Hz,
3 H, CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 213.8 (C=O),
171.7 (COOH), 162.1 (C-5), 159.3 (C-3), 136.1 (C-1, Ph-1), 136.0
(C-1, Ph-2), 135.6 (CH=CH2), 135.4 (C-1), 128.9 (C-3, C-5, Ph-1),
128.9 (C-3, C-5, Ph-2), 128.8 (C-4, Ph-1), 128.5 (C-4, Ph-2), 128.2
(C-2, C-6, Ph-1), 127.8 (C-2, C-6, Ph-2), 122.8 (C-2), 117.0
(CH=CH2), 108.8 (C-6), 100.2 (C-4), 71.3 (OCH2Ph), 70.5
(OCH2Ph), 46.0 (COCH), 42.0 (CH2COOH), 37.8 (CH2-3), 16.4
CH=CH2), 4.21–4.13 (m, 1 H, CH-2), 2.55–2.49 (m, 1 H, CH2A
-
3), 2.28–2.21 (m, 1 H, CH2B-3), 1.20 (d, J = 6.8 Hz, 3 H,
CH3) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3): δ =
174.8 (C-1), 163.5 (C-6), 162.3 (C-3), 158.5 (C-8), 150.9 (C-4a),
135.7 (CH=CH2), 135.5 (C-1, Ph-1), 135.0 (C-1, Ph-2), 129.0 (C-3,
C-5, Ph-1), 128.9 (C-3, C-5, Ph-2), 128.7 (2ϫC-1, Ph), 128.3 (C-2,
C-6, Ph-1), 128.0 (C-2, C-6, Ph-2), 116.9 (CH=CH2), 107.7 (C-8a),
98.1 (C-4), 97.9 (C-7), 94.6 (C-5), 71.5 (OCH2Ph), 70.6 (OCH2Ph),
39.3 (CH -3), 37.5 (CH-2), 18.5 (CH ) ppm. IR (ATR): ν = 3066,
˜
2
3
3033, 2925, 1756, 1498, 1454, 1377, 1325, 1218, 1048, 1028,
912 cm–1. HRMS (ESI): calcd. for [C28H26O4 + H]+ 427.1909;
found 427.1908.
3-Methylpent-4-en-2-yl 2-[3,5-Bis(benzyloxy)phenyl]acetate
(41):[16,17] A solution of 3,5-bis(benzyloxy)phenylacetic acid (22,
3.30 g, 9.47 mmol, 1.0 equiv.), DMAP (116 mg, 0.95 mmol,
0.1 equiv.), and 3-methylpent-4-en-2-ol (1.04 g, 10.4 mmol,
1.1 equiv.) in dry dichloromethane (100 mL) was cooled to 0 °C.
N,NЈ-Dicyclohexylcarbodiimide (2.35 g, 11.4 mmol, 1.2 equiv.) was
dissolved in dry dichloromethane (10 mL) and added. The reaction
mixture was stirred for 5.5 h. Water (0.2 mL) was added and the
reaction mixture was stirred at room temperature for 16 h. The
reaction mixture was filtered through a short plug of silica
(CH2Cl2). Removing the solvent in vacuo yielded 41 (4.09 g,
9.47 mmol, quant.) as a yellow oil, Rf = 0.85 (cHex/EtOAc 2:1).
1H NMR (400 MHz, CDCl3): δ = 7.45–7.29 (m, 10 H, 2ϫPh),
6.60–6.50 (m, 3 H, 2-H, 4-H, 6-H), 5.73–5.64 (m, 1 H, CH=CH2),
5.04–4.99 (m, 2 H, CH=CH2), 5.02 (s, 4 H, 2ϫOCH2Ph), 4.91–
4.78 (m, 1 H, OCH), 3.52 (s, 2 H, CH2COO), 2.39–2.24 (m, 1 H,
CH-3), 1.15 (d, J = 6.4 Hz, 3 H, CH3-1), 0.96 (J = 6.9 Hz, 3 H,
CH3-3) ppm. 13C NMR DEPT (75.5 MHz, CDCl3): δ = 171.0
(COO), 160.1 (C-3, C-5), 139.6 (CH=CH2), 137.0 (2ϫC-1, Ph),
136.5 (C-1), 128.7 (2ϫC-3, 2ϫC-5, Bn), 128.1 (2ϫC-4, Bn), 127.7
(2ϫC-2, 2ϫC-6, Bn), 115.7 (CH=CH2), 108.7 (C-2, C-6), 101.0
(C-4), 74.1 (OCH-2), 70.2 (2 ϫ OCH2Ph), 42.8 (CH-3), 42.1
(CH ) ppm. IR (ATR): ν = 3065, 3033, 2975, 2932, 1709, 1678,
˜
3
1599, 1575, 1498, 1455, 1434, 1319, 1286, 1160, 984, 912, 736,
698 cm–1. HRMS (ESI): calcd. for [C28H28O5 + Na]+ 467.1834;
found 467.1839. C28H28O5 (444.53): calcd. C 75.65, H 6.35; found
C 75.42, H 6.54.
3-Methylpent-4-en-2-ol:[16,17,51] Vinylmagnesium bromide (0.7 m in
THF, 119 mL, 83.0 mmol, 1.5 equiv.) was added at –35 °C to a
solution of copper(I) iodide (2.11 g, 11.1 mmol, 0.2 equiv.) in dry
THF (40 mL). After the mixture had been stirred for 1 h at this
temperature, 2,3-cis-epoxybutane (4.00 g, 55.5 mmol, 1.0 equiv.)
was added. The reaction mixture was stirred at –35 °C for 2 h and
was then allowed to warm to room temperature over 16 h. The
reaction mixture was quenched with saturated aqueous ammonium
chloride solution (80 mL) and stirred for 24 h. The organic layer
was separated, and the aqueous layer was extracted with diethyl
ether (3ϫ100 mL). The combined organic layers were dried with
magnesium sulfate and filtered. Distillation yielded a colorless li-
quid (4.08 g, 40.7 mmol, 74%, ref.[51] 65%), Rf = 0.43 (cHex/EtOAc
(CH COO), 17.1 (CH -1), 15.7 (CH -3) ppm. IR (ATR): ν = 3066,
˜
2
3
3
3033, 2976, 2930, 2870, 1729, 1594, 1498, 1452, 1377, 1292, 1158,
1058, 736, 698 cm–1. HRMS (ESI): calcd. for [C28H30O4 + Na]+
453.2042; found 453.2025. C28H30O4 (430.54): calcd. C 78.11, H
7.02; found C 78.05, H 7.29.
1
3:1), b.p. 117 °C. H NMR (400 MHz, CDCl3): δ = 5.77–5.69 (m,
3-Methylpent-4-en-2-yl 2-[3,5-Bis(benzyloxy)-2-(2-methylpent-4-
enoyl)phenyl]acetate (42):[16,17] Trifluoroacetic acid (35 mL) and tri-
fluoroacetic anhydride (17.5 mL) were added to ester 41 (2.47 g,
5.74 mmol, 1.0 equiv.) at –26 °C. Then 2-methylpent-4-enoic acid
(1.64 g, 14.4 mmol, 2.5 equiv.) was added, and stirring was carried
out at –26 °C for 19 h. The reaction mixture was added to a satu-
rated aqueous sodium hydrogen carbonate solution (300 mL) and
ethyl acetate (300 mL) and neutralized with solid sodium hydrogen
carbonate. The organic layer was separated, washed with saturated
1 H, CH=CH2), 5.15–5.08 (m, 2 H, CH=CH2), 3.59–3.53 (m, 1 H,
CH-2), 2.17–2.08 (m, 1 H, CH-3), 1.18 (d, J = 6.2 Hz, 3 H, CH3-
1), 1.02 (d, J = 6.7 Hz, 3 H, CH3-3) ppm. The data are in accord-
ance with the literature.[52] 13C NMR (75.5 MHz, CDCl3): δ = 140.8
(CH=CH2), 116.6 (CH=CH2), 70.9 (C-2), 46.2 (C-3), 20.3 (C-1),
16.2 (CH3-3) ppm. The data are in accordance with the litera-
ture.[52]
6,8-Bis(benzyloxy)-1-(pent-4-en-2-yl)-3H-isochromen-3-one (40): N-
Methylmorpholine (89 μL, 0.81 mmol, 3.5 equiv.) was added to a aqueous sodium hydrogen carbonate solution (200 mL), dried with
solution of acid 39 (101 mg, 0.23 mmol, 1.0 equiv.), 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (48 mg,
0.25 mmol, 1.1 equiv.), HOBt·H2O (38 mg, 0.25 mmol, 1.1 equiv.),
and 3-methylpent-4-en-2-ol (25 mg, 0.25 mmol, 1.1 equiv.) in dry
DMF (5 mL). The reaction mixture was stirred at room tempera-
magnesium sulfate, and filtered. The solvent was removed in vacuo.
Purification by flash chromatography on silica (cHex/EtOAc 10:1)
yielded 42 (2.64 g, 5.01 mmol, 87%) as a colorless oil, Rf = 0.49
(cHex/EtOAc 5:1). H NMR COSY (400 MHz, CDCl3): δ = 7.44–
7.31 (m, 10 H, 2ϫPh), 6.54 (d, J = 2.1 Hz, 1 H, 6-H), 6.53 (d, J
1
18
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50275
/KAP1
Date: 20-04-15 15:50:46
Pages: 23
Anti-Inflammatory Macrolactones
= 2.1 Hz, 1 H, 4-H), 5.79–5.67 (m, 1 H, CHCH=CH2), 5.67–5.56 with ethyl acetate (50 mL). The combined organic layers were dried
(m, 1 H, CH2CH=CH2), 5.04 (s, 2 H, OCH2Ph), 5.02 (s, 2 H, with magnesium sulfate and filtered. The solvent was removed in
OCH2Ph), 5.04–4.98 (m, 2 H, CH2CH=CH2), 4.97–4.90 (m, 2 H, vacuo. Purification by flash chromatography on silica (cHex/EtOAc
CHCH=CH2), 4.91–4.81 (m, 1 H, OCH), 3.58 (d, J = 16.3 Hz, 1 10:1) yielded the saturated lactone 44 (46 mg, 92 μmol, 63%) as a
H, CH2ACOO), 3.52 (d, J = 16.3 Hz, 1 H, CH2BCOO), 3.33–3.18 colorless solid.
(m, 1 H, CHC=O), 2.50–2.42 (m, 1 H, CH2A-3Ј), 2.41–2.32 (m, 1
Diastereomer A: Rf = 0.20 (cHex/EtOAc 20:1), m.p. 108.0–110.0 °C
H, OCHCH), 2.09–2.02 (m, 1 H, CH2B-3Ј), 1.18 (d, J = 6.4 Hz, 3
(CH3CN/H2O). 1H NMR COSY (400 MHz, [D6]acetone): δ =
H, CH3-1), 1.04 (d, J = 7.0 Hz, 3 H, CH3-2Ј), 1.01 (d, J = 7.0 Hz,
7.51–7.31 (m, 10 H, 2ϫPh), 6.80–6.77 (m, 2 H, 4-H, 6-H), 5.17 (d,
3 H, CH3-3) ppm. 13C NMR HSQC (75.5 MHz, CDCl3): δ = 209.4
J = 11.8 Hz, 1 H, CH2A, OBn-7), 5.15 (s, 2 H, CH2, OBn-5), 5.14
(CO), 170.9 (COO), 160.5 (Cq -5), 158.0 (Cq -3), 139.7
(d, J = 11.8 Hz, 1 H, CH2B, OBn-7), 4.59 (dq, J = 9.5, 6.3 Hz, 1
(CH2CH=CH2), 136.4 (CHCH=CH2), 136.0 (2ϫCq-1, Ph), 135.3
H, 15-H), 4.06–3.98 (m, 1 H, CH2A-2), 3.34–3.26 (m, 2 H, CH2B
-
(Cq-1), 128.8 (CH-3, CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.3
(CH-4, Ph), 128.3 (CH-4, Ph), 127.8 (CH-2, CH-6, Ph), 127.7 (CH-
2, CH-6, Ph), 124.2 (Cq -2), 116.4 (CHCH=CH2), 115.5
(CH2CH=CH2), 108.8 (CH-6), 99.4 (CH-4), 74.1 (OCH), 70.8
(OCH2Ph), 70.2 (OCH2Ph), 46.4 (CHC=O), 42.6 (OCHCH), 39.1
(CH2COO), 36.9 (CH2CH=CH2), 17.0 (CH3-1), 15.7 (CH3-2Ј),
2, 10-H), 1.82–1.69 (m, 1 H, CH2A-11), 1.68–1.56 (m, 1 H, 14-H),
1.35–1.19 (m, 5 H, CH2B-11, CH2-12, CH2-13), 1.16 (d, J = 6.3 Hz,
3 H, CH3-15), 0.98 (d, J = 6.8 Hz, 3 H, CH3-10), 0.82 (d, J =
6.9 Hz, 3 H, CH3-14) ppm. 13C NMR HSQC, HMBC (75.5 MHz,
[D6]acetone): δ = 210.5 (Cq-9), 170.9 (Cq-1), 161.2 (Cq-5), 158.7
(Cq-7), 137.8 (Cq-1, Ph), 137.5 (Cq-1, Ph), 136.1 (Cq-1), 129.3
(2 ϫ CH-3, 2 ϫ CH-5, Ph), 128.9 (CH-4, Ph), 128.8 (CH-4, Ph),
128.7 (2ϫCH-2, 2ϫCH-6, Ph), 124.8 (Cq-8), 111.4 (CH-4), 100.0
(CH-6), 78.1 (CH-15), 71.4 (OCH2Ph), 70.7 (OCH2Ph), 47.5 (CH-
10), 38.0 (CH2-2), 37.0 (CH-14), 34.7 (CH2-11), 31.8 (CH2-13), 26.4
(CH2-12), 19.9 (CH3-15), 19.4 (CH3-14), 16.5 (CH3-10) ppm. IR
15.5 (CH -3) ppm. IR (ATR): ν = 3068, 3033, 2976, 2933, 2874,
˜
3
1730, 1686, 1601, 1578, 1498, 1313, 1159, 1070, 738, 698 cm–1
.
HRMS (ESI): calcd. for [C34H38O5 + Na]+ 549.2617; found
549.2640. C34H38O5 (526.67): calcd. C 77.54, H 7.27; found C
77.16, H 7.48.
5,7-Di-O-benzyl-10,14-dimethyl-12,13-dehydrocurvularin (43):
Diene 42 (534 mg, 1.01 mmol, 1.0 equiv.) was dissolved in dry and
degassed toluene (120 mL). The ruthenium catalyst {tri-
cyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylid-
ene](3-phenyl-1H-inden-1-ylidene)ruthenium(II) dichloride,[49]
100 mg, 0.11 mmol, 0.10 equiv.} was added, and the reaction mix-
ture was stirred at 80 °C for 2 h. The solvent was removed in vacuo.
Purification by flash chromatography on silica (cHex/EtOAc
20:1Ǟ15:1Ǟ10:1) yielded 43 (431 mg, 0.86 mmol, 85%) as a col-
(ATR): ν = 3065, 3032, 2963, 2926, 2855, 1726, 1680, 1600, 1498,
˜
1152, 1100, 1065, 1044, 1027, 752, 697 cm–1. HRMS (ESI): calcd.
for [C32H36O5 + Na]+ 523.2460; found 523.2440. C32H36O5
(500.63): calcd. C 76.77, H 7.25; found C 76.54, H 7.33.
Diastereomer B: Rf = 0.24 (cHex/EtOAc 10:1), m.p. 121.0–122.0 °C
(CH3CN/H2O). 1H NMR COSY (400 MHz, [D6]acetone): δ =
7.50–7.45 (m, 4 H, 2ϫ2-H, 2ϫ6-H, Bn), 7.43–7.38 (m, 4 H, 2ϫ3-
H, 2ϫ5-H, Bn), 7.37–7.32 (m, 2 H, 2ϫ4-H, Bn), 6.81 (d, J =
2.4 Hz, 1 H, 6-H), 6.62 (d, J = 2.4 Hz, 1 H, 4-H), 5.23 (d, J =
1
orless oil, Rf = 0.24 (cHex/EtOAc 15:1). H NMR COSY, HSQC
11.8 Hz, 1 H, CH2A, OBn-7), 5.18 (d, J = 11.8 Hz, 1 H, CH2B
,
(400 MHz, [D6]acetone): δ = 7.52–7.34 (m, 10 H, 2ϫPh), 6.81 (d,
J = 2.3 Hz, 1 H, 6-H), 6.73 (d, J = 2.3 Hz, 1 H, 4-H), 5.23 (d, J =
11.5 Hz, 1 H, CH2A, Bn-7), 5.18 (d, J = 11.5 Hz, 1 H, CH2B, Bn-
7), 5.16 (s, 2 H, CH2, Bn-5), 5.02 (td, J = 10.7, 2.2 Hz, 1 H, CH-
12), 4.75–4.68 (m, 1 H, CH-13), 4.51 (dq, J = 10.0, 6.4 Hz, 1 H,
OCH-15), 4.27 (d, J = 12.9 Hz, 1 H, CH2A-2), 3.62–3.56 (m, 1 H,
CH-10), 3.12 (d, J = 12.9 Hz, 1 H, CH2B-2), 2.58–2.51 (m, 1 H,
CH2A-11), 2.49–2.40 (m, 1 H, CH-14), 1.93 (dq, J = 15.3, 2.7 Hz,
1 H, CH2B-11), 1.22 (d, J = 6.4 Hz, 3 H, CH3-15), 0.96 (d, J =
6.6 Hz, 3 H, CH3-10), 0.87 (d, J = 6.7 Hz, 3 H, CH3-14) ppm. 13C
NMR HSQC, HMBC (75.5 MHz, [D6]acetone): δ = 210.0 (Cq-9),
170.7 (COO), 161.6 (Cq-5), 160.1 (Cq-7), 137.9 (Cq-1, Bn-5), 137.5
(Cq-1, Bn-7), 136.8 (Cq-3), 133.2 (CH-13), 130.3 (CH-12) 129.4
(CH-3, CH-5, Bn), 129.4 (CH-3, CH-5, Bn), 129.2 (CH-2, CH-6,
Bn-7), 129.1 (CH-4, Bn), 128.9 (CH-4, Bn), 128.8 (CH-2, CH-6,
Bn-5), 124.9 (Cq-8), 111.8 (CH-4), 100.0 (CH-6), 73.2 (CH-15), 71.7
(CH2, Bn-7), 70.8 (CH2, Bn-5), 48.1 (CH-10), 39.7 (CH-14), 37.9
(CH2-2), 35.6 (CH2-11), 18.5 (CH3-10), 18.4 (CH3-15), 17.0 (CH3-
OBn-7), 5.16 (s, 2 H, CH2, OBn-5), 4.51 (dq, J = 9.9, 6.2 Hz, 1 H,
15-H), 4.39 (d, J = 17.2 Hz, 1 H, CH2A-2), 3.63–3.58 (m, 1 H, 10-
H), 3.47 (d, J = 17.2 Hz, 1 H, CH2B-2), 1.74–1.65 (m, 1 H, CH2A
11), 1.62–1.54 (m, 1 H, 14-H), 1.51–1.41 (m, 2 H, CH2B-11, CH2A
-
-
13), 1.39–1.31 (m, 1 H, CH2A-12), 1.17–1.11 (m, 1 H, CH2B-13),
1.07 (d, J = 6.2 Hz, 3 H, CH3-15), 0.94 (d, J = 6.7 Hz, 3 H, CH3-
10), 0.99–0.92 (m, 1 H, CH2B-12), 0.81 (d, J = 6.9 Hz, 3 H, CH3-
14) ppm. 13C NMR HSQC, HMBC (100.6 MHz, [D6]acetone): δ =
209.4 (Cq-9), 170.1 (Cq-1), 161.4 (Cq-5), 159.7 (Cq-7), 137.9 (Cq-1,
Ph, OBn-5), 137.4 (Cq-1, Ph, OBn-7), 137.3 (Cq-1), 129.4 (CH-3,
CH-5, Ph), 129.3 (CH-3, CH-5, Ph), 129.0 (CH-4, Ph), 128.9 (CH-
2, CH-6, Ph), 128.8 (CH-4, Ph), 128.6 (CH-2, CH-6, Ph), 124.4
(Cq-8), 111.6 (CH-4), 100.1 (CH-6), 76.6 (CH-15), 71.6 (OCH2, Bn-
7), 70.6 (OCH2, Bn-5), 45.7 (CH-10), 39.7 (CH2-2), 36.5 (CH-14),
35.0 (CH2-13), 33.7 (CH2-11), 21.9 (CH2-12), 19.6 (CH3-15), 18.1
(CH -14), 16.4 (CH -10) ppm. IR (ATR): ν = 3091, 3065, 3033,
˜
3
3
2961, 2932, 2874, 1722, 1601, 1576, 1498, 1327, 1261, 1156, 1071,
698 cm–1. HRMS (ESI): calcd. for [C32H36O5 + Na]+ 523.2460;
found 523.2440. C32H36O5 (500.63): calcd. C 76.77, H 7.25; found
C 76.47, H 7.41.
14) ppm. IR (ATR): ν = 3064, 3032, 2971, 2931, 2876, 1728, 1600,
˜
1498, 1304, 1288, 1157, 1106, 1070, 699 cm–1. HRMS (ESI): calcd.
for [C32H34O5 + Na]+ 499.2484; found 499.2489.
5,7-Di-O-benzyl-10,14-dimethylcurvularin (44): A solution of the
unsaturated lactone 43 (73 mg, 0.15 mmol, 1.0 equiv.) and p-tolu-
enesulfonyl hydrazide (273 mg, 1.46 mmol, 10.0 equiv.) in THF
(10 mL) was heated at reflux. Sodium acetate (120 mg, 1.46 mmol,
10.0 equiv.) was dissolved in water (2 mL) and added over 2 h.
Then, p-toluenesulfonyl hydrazide (546 mg, 2.92 mmol, 20.0 equiv.)
5,7-Di-O-benzyl-10-bromo-10,14-dimethylcurvularin (45):[38] Tri-
methylphenylammonium tribromide (357 mg, 0.95 mmol,
1.15 equiv.) was added at 0 °C in 10 portions over 90 min to a solu-
tion of lactone 44 (416 mg, 0.83 mmol, 1.0 equiv.) in acetonitrile
(50 mL). The reaction mixture was stirred for an additional 30 min.
The solvent was removed in vacuo. The residue was filtered through
was added, and sodium acetate (240 mg, 2.92 mmol, 20.0 equiv.) a short plug of silica (CH2Cl2). Purification by HPLC (column:
dissolved in water (4 mL) was added over 4 h. The cold reaction
mixture was diluted with ethyl acetate (50 mL) and washed with
water (3ϫ20 mL). The combined aqueous layers were extracted
ACE5–C18, gradient: H2O/CH3CN 15:85, flow: 17.5 mLmin–1, Rt1
= 5.35 min, Rt2 = 6.0 min) yielded 45 (220 mg, 0.38 mmol, 46%)
as a yellow oil, Rf = 0.41 (cHex/EtOAc 10:1). 1H NMR COSY
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O50275
/KAP1
Date: 20-04-15 15:50:46
Pages: 23
J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
FULL PAPER
(600 MHz, [D6]acetone): δ = 7.53–7.50 (m, 4 H, 2ϫ2-H, 2ϫ6-H,
Ph), 7.49–7.39 (m, 4 H, 2ϫ3-H, 2ϫ5-H, Ph), 7.37–7.34 (m, 2 H,
2 H, OCH2Ph), 5.09 (d, J = 11.6 Hz, 1 H, OCH2A-Ph), 5.05 (d, J
= 11.6 Hz, 1 H, OCH2B-Ph), 4.72 (dq, J = 9.6, 6.3 Hz, 1 H, 15-H),
2ϫ4-H, Ph), 6.76 (d, J = 2.2 Hz, 1 H, 6-H), 6.71 (d, J = 2.2 Hz, 1 3.79 (s, 1 H, 2-H), 2.07–2.02 (m, 1 H, CH2A-11), 1.68–1.56 (m, 1
H, 4-H), 5.27 (d, J = 11.2 Hz, 1 H, CH2A, OBn-7), 5.19–5.16 (m, H, 14-H), 1.62–1.55 (m, 1 H, CH2A-13), 1.51–1.40 (m, 3 H, CH2B
2 H, CH2, OBn-5), 5.14 (d, J = 11.2 Hz, 1 H, CH2B, OBn-7), 4.58 11, CH2-12), 1.29 (s, 3 H, CH3-10), 1.18 (d, J = 6.3 Hz, 3 H, CH3-
-
(dq, J = 10.0, 6.2 Hz, 1 H, 15-H), 3.98 (d, J = 16.3 Hz, 1 H, CH2A
-
15), 1.16–1.08 (m, 1 H, CH2B-13), 0.78 (d, J = 6.7 Hz, 3 H, CH3-
14) ppm. 13C NMR HSQC, HMBC (75.5 MHz, CDCl3): δ = 204.3
(Cq-9), 172.1 (Cq-1), 166.2 (Cq-5), 158.7 (Cq-7), 154.8 (Cq-3), 136.3
(Cq-1, Ph), 135.9 (Cq-1, Ph), 128.9 (CH-3, CH-5, Ph), 128.7 (CH-
2), 3.47 (d, J = 16.3 Hz, 1 H, CH2B-2), 2.28 (ddd, J = 14.4, 6.9,
3.2 Hz, 1 H, CH2A-11), 2.01–1.96 (m, 1 H, CH2B-11), 1.76–1.70 (m,
1 H, 14-H), 1.69 (s, 3 H, CH3-10), 1.68–1.64 (m, 1 H, CH2A-12),
1.61–1.51 (m, 1 H, CH2A-13), 1.36–1.29 (m, 1 H, CH2B-12), 1.20 3, CH-5, Ph), 128.5 (CH-4, Ph), 127.9 (CH-4, Ph), 127.6 (CH-2,
(d, J = 6.2 Hz, 3 H, CH3-15), 0.99–0.93 (m, 1 H, CH2B-13), 0.89 CH-6, Ph), 126.7 (CH-2, CH-6, Ph), 118.3 (Cq-8), 102.7 (CH-4),
(d, J = 6.9 Hz, 3 H, CH3-14) ppm. 13C NMR HSQC, HMBC 100.9 (CH-6), 78.5 (CH-15), 70.7 (OCH2Ph), 70.3 (OCH2Ph), 57.6
(150.9 MHz, [D6]acetone): δ = 207.6 (Cq-9), 171.3 (Cq-1), 161.5 (CH-2), 54.7 (Cq-10), 37.2 (CH-14), 36.9 (CH2-13), 34.8 (CH2-11),
(Cq-5), 159.0 (Cq-7), 137.8 (Cq-1, Ph-5), 137.0 (Cq-1, Ph-7), 135.9 23.8 (CH3-10), 22.3 (CH2-12), 19.5 (CH3-15), 18.2 (CH3-14) ppm.
(Cq-1), 129.8 (CH-2, CH-6, Ph-7), 129.3 (CH-3, CH-5, Ph), 129.3
IR (ATR): ν = 3065, 3034, 2959, 2929, 2873, 1700, 1599, 1588,
˜
(CH-3, CH-5, Ph), 129.2 (CH-4, Ph), 128.9 (CH-4, Ph), 128.8 (CH- 1498, 1213, 1161, 1030, 730, 696 cm–1. HRMS (ESI): calcd. for
2, CH-6, Ph-5), 124.1 (Cq-8), 112.6 (CH-4), 99.0 (CH-6), 75.5 (CH-
15), 74.8 (Cq-10), 71.7 (CH2Ph-7), 70.7 (CH2Ph-5), 46.5 (CH-11),
38.6 (CH-14), 38.0 (CH2-2), 35.5 (CH2-12), 32.8 (CH3-10), 23.0
[C32H34O5 + Na]+ 521.2304; found 521.2314.
5,7-Di-O-benzyl-10-exo-methylene-14-methylcurvularin (48): The
brominated lactone 45 (255 mg, 0.44 mmol, 1.0 equiv.) was dis-
solved in dry DMF (5 mL) and added to a solution of Pd(PPh3)4
(254 mg, 0.22 mmol, 0.5 equiv.) and Cs2CO3 (143 mg, 0.44 mmol,
1.0 equiv.) in dry DMF (25 mL). The reaction mixture was stirred
at room temperature for 5 h. The solvent was removed in vacuo.
Purification by flash chromatography on silica (cHex/EtOAc
35:1Ǟ10:1) yielded 48 (66 mg, 0.13 mmol, 39%) as a colorless oil,
Rf = 0.17 (cHex/EtOAc 15:1). 1H NMR COSY (600 MHz, CDCl3):
δ = 7.43–7.26 (m, 10 H, 2ϫOBn), 6.54 (br. s, 1 H, 4-H), 6.52 (d,
J = 2.1 Hz, 1 H, 6-H), 5.84 (br. s, 2 H, =CH2), 5.07–4.98 (m, 4 H,
(CH -13), 19.7 (CH -15), 17.4 (CH -14) ppm. IR (ATR): ν = 3064,
˜
2
3
3
3033, 2961, 2930, 2875, 1730, 1603, 1584, 1498, 1313, 1200, 1160,
1068, 699 cm–1. HRMS (ESI): calcd. for [C32H35BrO5 + Na]+
601.1566; found 601.1566.
5,7-Di-O-benzyl-4-bromo-10,14-dimethyl-10,11-dehydrocurvularin
(47): A solution of brominated lactone 45 (40 mg, 69 μmol,
1.0 equiv.) and Et3N (29 μL, 207 μmol, 3.0 equiv.) in dry DMF
(1 mL) was stirred for 1 h at 140 °C under microwave irradiation
(150 W). The reaction mixture was diluted with ethyl acetate
(30 mL), washed with water (3 ϫ 20 mL), dried with magnesium 2ϫOCH2-Ph), 4.65 (dq, J = 12.3, 6.3 Hz, 1 H, 15-H), 3.68 (d, J =
sulfate, and filtered. The solvent was removed in vacuo. Purifica- 16.2 Hz, 1 H, CH2A-2), 3.32–3.19 (br. s, 1 H, CH2B-2), 3.07–2.93
tion by HPLC (ACE5–C1 8 , H2 O/CH3 CN, 25:75, flow = (m, 1 H, CH2A-11), 1.77–1.65 (m, 1 H, CH2B-11), 1.54–1.47 (m, 1
17.5 mLmin–1, Rt = 12.2 min) yielded 47 (2.1 mg, 4 μmol, 6%) as
H, 14-H), 1.28–1.22 (m, 4 H, CH2-12, CH2-13), 1.16 (d, J = 6.3 Hz,
a colorless oil, Rf = 0.10 (cHex/EtOAc 15:1). 1H NMR COSY 3 H, CH3-15), 0.90 (d, J = 7.0 Hz, 3 H, CH3-14) ppm. 13C NMR
(600 MHz, CDCl3): δ = 7.43–7.27 (m, 10 H, 2ϫOBn), 6.70 (d, J
= 11.2 Hz, 1 H, 11-H), 6.51 (s, 1 H, 6-H), 5.12 (d, J = 12.1 Hz, 1
H, OCH2A-Ph), 5.07 (d, J = 12.1 Hz, 1 H, OCH2B-Ph), 5.03 (d, J
HSQC, HMBC (150.9 MHz, CDCl3): δ = 199.0 (Cq-9), 170.5 (Cq-
1), 160.1 (Cq-7), 156.3 (Cq-5), 147.3 (Cq-10), 136.7 (Cq-1, Ph), 136.6
(Cq-1, Ph), 133.3 (=CH2), 133.3 (Cq-3), 128.8 (CH-3, CH-5, Ph),
128.6 (CH-3, CH-5, Ph), 128.3 (CH-4, Ph), 127.9 (CH-4, Ph), 127.8
(CH-2, CH-6, Ph), 127.0 (CH-2, CH-6, Ph), 123.7 (Cq-8), 110.1
= 12.3 Hz, 1 H, OCH2A-Ph), 4.99 (d, J = 12.3 Hz, 1 H, OCH2B
-
Ph), 4.67–4.65 (m, 1 H, 15-H), 3.77–3.73 (m, 1 H, CH2A-2), 3.33–
3.30 (m, 1 H, CH2B-2), 2.58–2.50 (m, 1 H, 12-HA), 1.98–1.90 (m, (CH-4), 99.7 (CH-6), 77.9 (CH-15), 70.4 (OCH2Ph), 70.3
1 H, 12-HB), 1.89 (s, 3 H, CH3-10), 1.65–1.60 (m, 1 H, 13-HA), (OCH2Ph), 38.9 (CH2-2), 38.4 (CH-14), 33.5 (CH2-13), 30.2 (CH2-
1.50–1.45 (m, 1 H, 14-H), 1.23–1.16 (m, 1 H, 13-HB), 1.12 (d, J = 11), 22.9 (CH2-12), 19.7 (CH3-14), 19.7 (CH3-15) ppm. IR (ATR):
6.2 Hz, 3 H, CH3-15), 0.91 (d, J = 7.2 Hz, 3 H, CH3-14) ppm. 13C ν = 3090, 3065, 3033, 2957, 2926, 2872, 1732, 1659, 1603, 1582,
˜
NMR HSQC, HMBC (150.9 MHz, CDCl3): δ = 198.4 (Cq-9), 168.7 1313, 1199, 1156 cm–1. HRMS (ESI): calcd. for [C32H34O5 + Na]+
(Cq-1), 155.6 (Cq-7), 155.1 (Cq-5), 152.8 (CH-11), 136.5 (Cq-10, Cq- 521.2304; found 521.2316.
1, Ph), 136.2 (Cq-1, Ph) 133.4 (Cq-3), 128.8 (CH-3, CH-5, Ph),
128.7 (CH-3, CH-5, Ph), 128.3 (CH-4, Ph), 128.1 (CH-4, Ph), 127.2
14-Methyl-10-exo-methylenecurvularin (49): A solution of the
benzyl-protected lactone 48 (34 mg, 68 μmol, 1.0 equiv.) in dry
(CH-2, CH-6, Ph), 127.1 (CH-2, CH-6, Ph), 125.7 (Cq-8), 107.8
dichloromethane (15 mL) was cooled to –78 °C. Boron trichloride
(Cq-4), 99.6 (CH-6), 76.8 (CH-15), 71.3 (OCH2Ph), 71.0
(1 m in hexane, 0.14 mL, 0.14 mmol, 2.1 equiv.) was added, and the
(OCH2Ph), 40.6 (CH2-2), 38.9 (CH-14), 34.2 (CH2-13), 29.2 (CH2-
mixture was stirred. After 3 h, further boron trichloride (1 m in
12), 19.4 (CH3-14), 18.9 (CH3-15), 10.2 (CH3-10) ppm. IR (ATR):
hexane, 0.28 mL, 0.28 mmol, 4.1 equiv.) was added, and stirring
ν = 3033, 2924, 2855, 1725, 1498, 1330, 1252, 1161, 1069, 909, 732,
˜
was carried out for an additional 2.5 h. The reaction mixture was
quenched with saturated aqueous sodium hydrogen carbonate solu-
tion (50 mL) and allowed to warm to room temperature. The or-
ganic layer was separated, and the aqueous layer was extracted with
ethyl acetate (3ϫ50 mL). The combined organic layers were dried
with magnesium sulfate and filtered. The solvent was removed in
vacuo. Purification by flash chromatography on silica (cHex/EtOAc
696 cm–1. HRMS (ESI): calcd. for [C32H33BrO5 + Na]+ 599.1409;
found 599.1382.
Lactone 46: DBU (12 μL, 82 μmol, 2.0 equiv.) was added to a solu-
tion of brominated lactone 45 (24 mg, 41 μmol, 1.0 equiv.) in dry
acetonitrile (3 mL). The reaction mixture was stirred at room tem-
perature for 2 h. The solvent was removed in vacuo. The residue
was dissolved in ethyl acetate (30 mL), washed with HCl (2 n, 2:1) yielded 49 (20 mg, 64 μmol, 94%) as a colorless oil, Rf = 0.14
2ϫ20 mL), dried with magnesium sulfate, and filtered. Removing
the solvent in vacuo yielded 46 (20 mg, 41 μmol, quant.) as a light
yellow oil, Rf = 0.10 (cHex/EtOAc 15:1). 1H NMR COSY
(400 MHz, CDCl3): δ = 7.53–7.28 (m, 10 H, 2ϫOBn), 6.51 (d, J
(cHex/EtOAc 2:1). 1H NMR COSY (600 MHz, [D4]MeOH): δ =
6.26 (s, 2 H, 4-H, 6-H), 5.85 (d, J = 1.5 Hz, 1 H, =CH2A), 5.83 (s,
1 H, =CH2B), 4.61 (dq, J = 10.1, 6.2 Hz, 1 H, 15-H), 3.62 (d, J =
16.6 Hz, 1 H, CH2A-2), 3.43 (d, J = 16.6 Hz, 1 H, CH2B-2), 2.68–
= 1.9 Hz, 1 H, 6-H), 6.50 (d, J = 1.9 Hz, 1 H, 4-H), 5.23–5.17 (m, 2.60 (m, 1 H, CH2A-11), 2.11–2.05 (m, 1 H, CH2B-11), 1.55–1.48
20
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/KAP1
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Pages: 23
Anti-Inflammatory Macrolactones
(m, 3 H, CH2-12, 14-H), 1.27–1.22 (m, 2 H, CH2-13), 1.16 (d, J = 1.45 mmol, 52%) as a colorless solid, Rf = 0.21 (cHex/EtOAc 2:1),
6.2 Hz, 3 H, CH3-15), 0.91 (d, J = 7.0 Hz, 3 H, CH3-14) ppm. 13C m.p. 67.0–69.0 °C (CHCl3). 1H NMR COSY (400 MHz, [D4]-
NMR HSQC, HMBC (150.9 MHz, [D4]MeOH): δ = 201.5 (Cq-9), MeOH): δ = 6.27 (d, J = 2.3 Hz, 1 H, 6-H), 6.15 (d, J = 2.3 Hz, 1
172.5 (Cq-1), 160.4 (Cq-7), 157.5 (Cq-5), 149.6 (Cq-10), 135.0 (Cq- H, 4-H), 4.56–4.47 (m, 1 H, OCH-15), 4.50 (d, J = 17.2 Hz, 1 H,
3), 132.3 (=CH2), 120.7 (Cq-8), 111.9 (CH-4), 102.6 (CH-6), 78.0
CH2A-2), 3.79–3.71 (m, 1 H, CH-10), 3.36 (d, J = 17.2 Hz, 1 H,
(CH-15), 40.1 (CH2-2), 39.6 (CH-14), 33.7 (CH2-13), 31.3 (CH2- CH2B-2), 1.68–1.60 (m, 3 H, CH2-11, CH-14), 1.53–1.45 (m, 1 H,
11), 26.8 (CH2-12), 19.6 (CH3-15), 18.8 (CH3-14) ppm. IR (ATR):
ν = 3351, 2925, 2874, 2855, 1703, 1609, 1460, 1335, 1316, 1264,
CH2A-13), 1.38–1.26 (m, 1 H, CH2A-12), 1.11 (d, J = 6.7 Hz, 3 H,
CH3-10), 1.11 (d, J = 6.1 Hz, 3 H, CH3-15), 1.09–1.03 (m, 1 H,
˜
1155, 1031 cm–1. HRMS (ESI): calcd. for [C18H22O5 + Na]+ CH2B-13), 0.95–0.88 (m, 1 H, CH2B-12), 0.84 (d, J = 6.9 Hz, 3 H,
341.1365; found 341.1361.
CH3-14) ppm. 13C NMR HSQC, HMBC (100.6 MHz, [D4]-
MeOH): δ = 212.1 (C-9), 172.5 (C-1), 161.6 (C-5), 160.8 (C-7),
138.4 (C-3), 120.6 (C-8), 112.8 (C-4), 102.9 (C-6), 76.7 (C-15), 45.2
(C-10), 41.4 (C-2), 37.3 (C-14), 34.3 (C-11), 33.8 (C-13), 21.1 (C-
4-Chloro-14-methyl-10-exo-methylenecurvularin (50): Lactone 49
(22 mg, 69 μmol, 1.0 equiv.) and NCS (9.2 mg, 69 μmol, 1.0 equiv.)
were dissolved in dry DMF (10 mL), and trifluoroacetic acid (8 μL,
104 μmol, 1.5 equiv.) was added. The reaction mixture was stirred
at room temperature for 3.5 d. The solvent was removed in vacuo
and the residue was coevaporated with toluene (2ϫ30 mL). Purifi-
cation by flash chromatography on silica (cHex/EtOAc 4:1) yielded
50 (13 mg, 38 μmol, 55%) as a colorless oil, Rf = 0.14 (cHex/EtOAc
12), 19.4 (CH -15), 17.6 (CH -10, CH -14) ppm. IR (ATR): ν =
˜
3
3
3
3307, 2928, 2855, 1689, 1610, 1593, 1490, 1460, 1266, 1245, 1165,
755 cm–1. HRMS (ESI): calcd. for [C18H24O5 + Na]+ 343.1521;
found 343.1512.
1
2:1). H NMR COSY (600 MHz, [D4]MeOH): δ = 6.44 (s, 1 H, 6-
Acknowledgments
H), 5.86 (s, 1 H, =CH2A), 5.82 (s, 1 H, =CH2B), 4.64 (dq, J = 10.0,
6.3 Hz, 1 H, 15-H), 4.00 (d, J = 17.1 Hz, 1 H, CH2A-2), 3.51 (d, J
= 17.1 Hz, 1 H, CH2B-2), 2.86–2.78 (m, 1 H, CH2A-11), 1.94–1.84
(m, 1 H, CH2B-11), 1.50–1.39 (m, 2 H, 14-H, CH2A-12), 1.64–1.55
(m, 1 H, CH2B-12), 1.29–1.22 (m, 1 H, CH2A-13), 1.18–1.12 (m, 1
H, CH2B-13), 1.17 (d, J = 6.3 Hz, 3 H, CH3-15), 0.91 (d, J = 7.0 Hz,
3 H, CH3-14) ppm. 13C NMR HSQC, HMBC (150.9 MHz, [D4]-
MeOH): δ = 200.7 (Cq-9), 171.1 (Cq-1), 156.4 (Cq-7), 154.8 (Cq-5),
149.1 (Cq-10), 132.9 (br, =CH2), 131.9 (Cq-3), 122.3 (Cq-8), 115.0
(Cq-4), 103.6 (CH-6), 78.6 (CH-15), 39.8 (CH-14), 36.1 (CH2-2),
34.3 (CH2-13), 30.9 (CH2-11), 28.2 (CH2-12), 19.7 (CH3-15), 16.4
J. T. is grateful to the Fonds der Chemischen Industrie for a PhD
fellowship. The authors thank the Rhineland Palatinate Center for
Natural Product Research for financial support, as well as Dr. J. C.
Liermann (Mainz) for NMR spectroscopy, Dr. N. Hanold (Mainz)
for mass spectrometry, and Dr. L. Sandjo (now Florianopolis, Bra-
zil) for helpful discussions and interpretation of NMR spectra.
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˜
3
1603, 1441, 1319, 1229, 1200, 1160, 733 cm–1. HRMS (ESI): calcd.
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for [C18H21ClO5 + Na]+ 375.0975; found 375.0972.
10,14-Dimethyl-12,13-dehydrocurvularin (51) and 10,14-Dimethyl-
curvularin (52):[16,17] Palladium on charcoal (10 wt.-%, 120 mg) was
added to a solution of lactone 43 (1.396 g, 2.80 mmol, 1.0 equiv.)
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(141 mg, 0.44 mmol, 16%) as a colorless solid, Rf = 0.28 (cHex/
EtOAc 2:1), m.p. 83.0–85.0 °C (cHex/EtOAc 5:1). 1H NMR COSY,
HSQC, NOESY (400 MHz, [D4]MeOH): δ = 6.29 (d, J = 2.3 Hz,
1 H, 6-H), 6.16 (d, J = 2.3 Hz, 1 H, 4-H), 5.19–5.08 (m, 1 H, CH-
12), 5.01 (dd, J = 15.2, 9.5 Hz, 1 H, CH-13), 4.65 (dq, J = 10.3,
6.3 Hz, 1 H, OCH-15), 4.57–4.38 (m, 1 H, CH2A-2), 3.75–3.65 (m,
1 H, CH-10), 3.34–3.28 (m, 1 H, CH2B-2), 2.25–2.07 (m, 2 H, CH2-
11), 2.01–1.89 (m, 1 H, CH-14), 1.15 (d, J = 6.4 Hz, 3 H, CH3-15),
1.12 (d, J = 6.7 Hz, 3 H, CH3-10), 0.89 (d, J = 6.7 Hz, 3 H, CH3-
14) ppm. 13C NMR HSQC, HMBC (75.5 MHz, [D4]MeOH): δ =
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˜
3
3
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
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Received: February 26, 2015
Published Online: ᭿
22
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/KAP1
Date: 20-04-15 15:50:46
Pages: 23
Anti-Inflammatory Macrolactones
Anti-Inflammatory Macrolactones
The oxacyclododecindione-type macro-
lactones are known for their potent anti-
J. Tauber, K. Rudolph, M. Rohr, G. Erkel,
T. Opatz* ........................................ 1–23
inflammatory
activity.
A
bioactive
analogue of the recently described 14-de-
oxyoxacyclododecindione was synthesized
by an RCM/hydrogenation/dehydrogen-
ation sequence. Various other approaches
such as carbonylative cross-coupling or in-
tramolecular hydroacylation failed to pro-
duce the 12-membered lactone skeleton.
Synthetic Approaches to Anti-Inflamma-
tory Macrolactones of the Oxacyclodo-
decindione Type
Keywords: Medicinal chemistry / Natural
products / Total synthesis / Ring-closing
metathesis
/
Cross-coupling
/
Macrocycles
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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