European Journal of Organic Chemistry

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 oxacyclododecindionetype 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-closing metathesis and double bond isom-
erization, as well as a strategy including ring-closing metathesis/unsaturation. The last route allowed the preparation of
a bioactive analogue of the recently described 14-deoxyoxacyclododecindione.
Introduction
therapy even some fifty years after their introduction, their

side effects or their failure to suppress inflammatory reactions in cells lacking appropriate receptors make the search
for alternative effective anti-inflammatory agents a worthwhile task.
The fungal secondary metabolite products (S)-curvularin
(1), (S)-10,11-dehydrocurvularin (2), and oxacyclododecin-
Chronic inflammatory diseases such as asthma and rheumatoid arthritis are widespread, but in spite of the success
of molecular therapy in the past decades, this area still includes many unmet medical needs. Although glucocorticoids continue to be the gold standard for anti-inflammatory
Figure 1. Structures of some natural anti-inflammatory macrolactones.

[a] Institute of Organic Chemistry,
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.
Eur. J. Org. Chem. 2015, 35873608
dione (5), as well as oxacyclododecindiones recently reported 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 (Figure 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-
2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz
sion, and the cytokine-induced nitric oxide (NO) production.[3] Furthermore, 1 has displayed the capacity for a
reduction of proinflammatory gene expression in an in vivo
model of rheumatoid arthritis.[4] Additionally, compounds
15 are TGF- inhibitors and are promising therapeutic
agents for the suppression of cancer progression and metastasis.[5] Studies have shown that oxacyclododecindione (5)
is an effective anti-inflammatory compound and can be
used for treatment of chronic inflammatory and fibrotic diseases.[5] In vivo data in a mouse model of the disease suggest that this compound could be a new potential drug for
the treatment of lupus nephritis.[6] Here we report synthetic
studies directed towards this class of natural products including the preparation of biologically active analogues.
Results and Discussion

Since the first isolation of 1, by Musgrave[7] in 1956, it
was an interesting target molecule in total synthesis, starting in 1967 with work by Baker, Bycroft, and Roberts.[8] In
these efforts, the 12-membered lactone was formed by FriedelCrafts acylation,[813] by esterification with oxazoles as
masked activated carboxylates,[14,15] by ring-closing metathesis,[1618] or by aryne acyl-alkylation.[19] In contrast, the
only synthetic route to the ,-unsaturated series was reported in 2013 by Frstner[20] and co-workers, with (S)10,11-dehydrocurvularin (2) being made by an alkyne ringclosing metathesis. However, there is no synthesis of a compound containing a methyl substituent at the -position of
the unsaturated ketone, which appears to be essential for
the high anti-inflammatory activity. An attempted RCM

approach with an enone precursor was unsuccessful.[21]
For our studies, we chose 4 as our initial target molecule
because it already shows very high bioactivity and is structurally simpler than 5 due to the absence of the 14-OH
group. Although the stereochemistry at C14 could not be
elucidated with certainty, we tentatively assumed the S configuration for each of the two adjacent stereocenters, due to
(i) the analogy with the simpler compounds 1 and 2 (configuration at C15), and (ii) a somewhat better agreement of
the observed strong NOE contact between the neighboring
methyl groups with the corresponding molecular models.
This assignment should, however, be handled with care.
All experiments have thus far been performed with the
racemic series. As the first key step, we envisioned a carbonylative cross-coupling reaction to form the C8C9 and
the C9C10 bonds in a single operation. The required secoprecursor 6 can be synthesized by hydroboration or hydrostannylation of the coupled product of arylacetic acid 8 and
alkyne 9 (pathway A, Scheme 1). An alternative strategy
would be the formation of the ,-unsaturated lactone by
ring-closing metathesis (RCM) with subsequent isomerization of the newly generated double bond into conjugation
with the carbonyl group (pathway B). A third route could
involve an RCM/hydrogenation sequence to form the saturated macrolactone 7 and subsequent installation of the
double bond (pathway C).
By starting from pent-3-yn-1-ol (12), 3-methyloctyn-2-ol
(14) was prepared by conversion to iodide 13, subsequent
halogenlithium exchange, transmetallation to copper, and
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.
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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 starting 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 esterification 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 exclusive formation of the regioisomeric (E)-vinylboranes in almost 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 conditions resulted in complex reaction mixtures and the desired
macrolactone 18 was not detectable (Table 1).
Table 1. Reaction conditions for the Suzuki coupling.
Entry Catalyst
Ligand
Base
Solvent
Temperature
1
2
3
4
5
6
7
8
9
10
11
12
13
SPhos
Cy3PHBF4
SPhos
SPhos
Cy3PHBF4
Cy3PHBF4
Cy3PHBF4
Cy3PHBF4
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
CsOPiv
K3PO4
CsOPiv
Cs2CO3
NEt3
Bu4NF
CsOPiv
Cs2CO3
CsOPiv
PhCl
DMF
PhCl/H2O
PhH
DMF
PhH/H2O
DMF
DMF
DMF
DMF
dioxane
dioxane
dioxane
80 or 120 C
100 C
80120 C
110 C
120 or 150 C
80100 C
120 C
120 C
120 C
120 C
reflux
reflux
reflux
PEPPSI-iPr
PEPPSI-iPr
PEPPSI-iPr
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
PEPPSI-iPr
PEPPSI-iPr
Three products were isolated and characterized from the

reaction mixtures (Figure 2).
Eur. J. Org. Chem. 2015, 35873608
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 carbonylative cross-coupling reacted with the carbonyl function
instead of the vinylborane, and this route was eventually
given up.
Alternatively, ring closure could be effected by an intramolecular hydroacylation of aldehyde 23, available by esterification of arylacetic acid[22] 22 with alkynol 14 and subsequent Vilsmeier formylation. Intermolecular reactions of
this type have been reported for internal alkynes.[2326]
However, neither with the catalytic system Ni(COD)2/
PiPr3[27] nor with an NHC generated in situ from a thiazolium salt[24] could any conversion of the starting material
be observed. The ruthenium-based catalyst RuCl2(p-cymene)2[23] failed as well, with isomerization of 23 to diene 24
being the sole reaction detected (Scheme 3).
The strategy for the formation of the ,-unsaturated
ketone by ring-closing metathesis is related to the synthesis
of (S)-curvularin by Mohapatra.[18] By starting from arylacetic acid 22, the protected alcohol 25 was prepared in
high yield by reduction with lithium aluminum hydride and
protection with PMBCl. Subsequently, Vilsmeier formylation, a Grignard reaction with but-3-en-2-ylmagnesium
chloride, TBDMS protection of the secondary alcohol, and
cleavage of the PMB ether with DDQ afforded the desired
alcohol 28a.
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Scheme 3. Attempted intramolecular hydroacylation of alkyne 23.
Oxidation to the corresponding carboxylic acid was

problematic. The use of DessMartin periodinane or IBX
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 bromide also failed, but treatment with TEMPO and iodobenzene diacetate in the presence of sodium hydrogen carbonate yielded the desired carboxylic acid.[28] This compound was subjected without further purification to a Steglich esterification with 3-methylhex-5-en-2-ol because it
tended to decompose to a six-membered lactone during silica gel column chromatography. Diene 30a was obtained in
74 % yield over two steps (Scheme 4). Ring-closing metathesis furnished macrolactone 31a, which was characterized by
mass spectrometry, with NMR analysis turning out to be
troublesome, due to the presence of four diastereomers (excluding double bond isomers).
O-Desilylation was problematic and required harsh conditions, under which the six-membered lactone 33 was
formed concomitantly (Scheme 5). On the assumption that
steric hindrance was responsible for the deprotection prob-
Scheme 4. Approach to lactones 31a, 31b, and 31c by RCM.

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Eur. J. Org. Chem. 2015, 35873608
lem, the macrolactone without the -methyl substituent

compound 31b was synthesized analogously to check the
double bond isomerization. In this case, deprotected
alcohol 34a was obtained on treatment with TBAF in THF
at room temperature in 45 % yield, with subsequent oxidation with DessMartin-periodinane furnishing the corresponding ketone 35a. Isomerization under acidic (CSA) or
basic (pyridine, DBU, LDA) conditions or by using Wilkinsons catalyst only resulted in recovery of the starting material. The Baudry catalyst[29] furnished the ,-unsaturated
enone 36 (double bond geometry not determined). To exclude additional ring strain imposed by the C-14 methyl
group as a reason for the failure, the 14-unsubstituted
macrolactone 35b was synthesized. Again, isomerization in
the presence of Baudrys catalyst afforded the ,-unsaturated enone. Heating at reflux in pyridine under argon resulted in isolation of starting material, but heating at reflux
under air yielded the isomerized and oxidized product 37,
which is related to the natural product 12-oxocurvularin[2]
(Scheme 5).
The formation of the saturated macrolactone was related
to the synthesis of (S)-curvularin reported by Kunz and coworkers.[16,17] FriedelCrafts acylation of the benzyl-protected methyl arylacetate 15 furnished ketone 38 quantitatively. Saponification and esterification with 3-methylpent-4-en-2-ol under various conditions with different dehydrating agents only yielded the isochromen-3-one derivative 40 rather than the desired diene (Scheme 6). Complete
conversion of the starting material was observed by TLC
within minutes, but the isolated yield of 40 was low, due to

hydrolysis to 39 during purification.
Changing the reaction sequence by performing the esterification prior to the FriedelCrafts acylation afforded diene
42 in high yield, and subsequent RCM produced macrolactone 43 (Scheme 7). Attempted selective hydrogenation of
the double bond without affecting the benzyl ethers by use
of hydrogen and palladium on charcoal with different
amine[3032] or sulfide[33] additives failed. Use of homogenous hydrogenation catalysts[34] (Wilkinson, Crabtree, Baudry) furnished the saturated macrolactone 44, but in all
cases the reaction ceased at around 50 % conversion. Finally, use of diimide, generated in situ,[3537] selectively afforded 44 in 64 % yield, with partial reduction of the carbonyl group to the alcohol taking place.
Introduction of the crucial 9,10-double bond turned out
to be highly problematic. Attempts to transform the ketone
into its TMS enol ether for a Saegusa oxidation or for treatment with phenylselenyl bromide under basic conditions
followed by oxidative workup failed due to the high acidity
of the benzylic methylene hydrogen. Thus, macrolactone 44
was brominated with trimethylphenylammonium tribromide in 46 % isolated yield.[38] Concomitant bromination of
the arene appeared to be avoided by addition of the brominating agent in portions over a period of 1.5 h at room
temperature with LCMS monitoring. Dehydrobromination under various sets of conditions only yielded small
amounts of the 910 unsaturated macrolactone 47, which
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 containing a five-membered ring, which was formed exclusively
with strong bases such as DBU.
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Treating bromide 45 with tetrakis(triphenylphosphine)palladium(0) to effect a -hydride elimination afforded the

exo-methylene derivative 48 in 30 % yield. As a side prod-
Eur. J. Org. Chem. 2015, 35873608
uct, the reduced macrolactone was obtained in nearly equal

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
desired target molecule. In order to assess the anti-inflammatory potency of this isomeric scaffold, deprotection with
boron trichloride and chlorination of the aromatic ring (4position) were performed to afford 50, the double bond isomer 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).
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--inducible Smad2/3-dependent transcriptional luciferase reporter in transiently
transfected HepG2 cells normalized against the constitutive
active EF1-promoter in front of the luciferase gene in order to exclude unspecific cytotoxic effects as described previously.[5,39]
The biological activities of the most active synthetic derivatives 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--dependent
reporter gene expression, with IC50 values in the 25
50 ng mL1 range. 14-Deoxyoxacyclododecindione (4),
which differs from the parent compound in the missing
hydroxy group at C-14, exhibited biological activities comparable to those of oxacyclododecindione (5). Compound
49, the double bond isomer of 14-deoxyoxacyclododecindione, was about 25 times less active with respect to IL-4induced Stat signaling and about 13 times less active with
Eur. J. Org. Chem. 2015, 35873608
Table 2. HepG2 cells were transiently transfected with the indicated

reporter gene construct and the constitutively active pRL-EF1 reporter gene and stimulated with 5 ng mL1 TGF- or 5 ng mL1 IL4 with or without test compounds for 16 h as described in Materials
and Methods (see Experimental Section).
10,14-Dimethyl-12,13-dehydrocurvularin (51)
10,14-Dimethylcurvularin (52)
10,11-Dehydrocurvularin (2)
2-[3,5-Bis(benzyloxy)-2-(2-methyl1-oxopent-4-enyl)phenyl]acetic
acid (39)
14-Methyl-10-exo-methylenecurvularin (49)
4-Chloro-14-methyl-10exo-methylenecurvularin (50)
14-Deoxyoxacyclododecindione (4)
Oxacyclododecindione (5)
pgl3-TK-7xN4
(Stat6)
IC50 [gmL1]
(CAGA)9x-MLP-Luc
(Smad2/3)
IC50 [g mL1]
30.32
50.21
8 1.1
0.9 0.08
50
91.2
0.60.07
50.5
0.750 0.13
10.22
0.80 0.1
0.0500.003
0.0750.006
0.025 0.002
0.0500.005
respect to the TGF--induced signaling pathway, thus being

comparable in this regard to the naturally occurring ,dehydrocurvularin (2) (IC50 values: 0.60.9 g mL1); this
indicates that the 10,11-double bond and/or the exo-methylene group at C-10 contribute to the biological activity.
The importance of the occurrence of a double bond at C10/11 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-- induced reporter 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--dependent reporter gene expression, with IC50 values of 35 g mL1. Interestingly, chlorination of the double
bond isomer of 14-deoxyoxacyclododecindione (50) at C-4
resulted in a greatly diminished inhibitory activity with respect to IL-4 signaling but left the TGF- inhibitory activity unaffected. Of the compounds devoid of an intact
lactone ring, only compound 39 exhibited a significant biological activity, inhibiting TGF- signaling with an IC50
value around 5 g mL1 without affecting IL-4-induced reporter gene expression.
Conclusions
In summary, various attempts to synthesize oxacyclododecindione-type macrolactones through carbonylative
ring closure, intramolecular alkyne hydroacylation, or
RCM/double bond isomerization failed. A biologically
active analogue of 14-deoxyoxacyclododecindione compound 50 could instead be synthesized by an RCM/
hydrogenation/unsaturation approach. The biological evaluation of compounds and intermediates allowed the establishment of preliminary structureactivity relationships.
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Experimental Section
Materials and Methods: All commercially available reagents were
reagent grade and used without further purification unless otherwise 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 reactions were monitored by LCMS on an HPLC unit with a binary
pump and an integrated diode array detector coupled to an LCion-trap mass spectrometer. Ionization was achieved with an electrospray ionization (ESI) source. Flash chromatography was performed on 3570 m silica gel with the indicated solvent system.
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
(600 MHz 1H, 150.9 MHz 13C). The chemical shifts are referenced
to the deuterated solvent (e.g., for CDCl3, = 7.26 ppm and
77.16 ppm for 1H and 13C NMR, respectively) and reported in
parts per million (ppm, ) relative to tetramethylsilane (TMS, =
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 recorded with a Q-TOF instrument with a dual source and a suitable
external calibrant. Melting points were determined in open capillary tubes. Infrared spectra were recorded as FTIR spectra with a
diamond ATR unit and are reported in terms of frequency of absorption ( , cm1). 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 ACE5C18PFP column (pore size: 5 m,
length: 15 cm, diameter: 30.0 mm) with a flow of 17.5 mL min1 or
an ACE5C18 column (pore size: 5 m, length: 12.5 cm, diameter
21.2 mm) with a flow of 37.5 mL min1 was used.
Biological Assays: HepG2 cells (DSMZ ACC 180) were maintained
in DMEM (Dulbeccos modified Eagles medium) supplemented
with fetal calf serum (FCS, 10 %) and penicillin G (65 g mL1) and
streptomycin sulfate (100 g mL1) 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 previously.[41] The reporter plasmid (AGCCAGACA)9MLP-Luc contains nine tandem copies of the CAGA Smad binding element upstream 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-EF1 for data normalization was purchased from Promega
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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 constitutively active control vector (pRL-EF1) assayed in the same sample. HepG2 cells were transiently transfected by electroporating
(Bio-Rad, Gene-Pulser) 1 107 cells mL1 in DMEM together with
50 g of the indicated constructs and the internal control pRLEF1 vector at 500 V cm1. After electroporation the cells were
seeded at 2 105 cells mL1 and allowed to recover for 16 h. For
induction of reporter gene expression, the cells were treated with
TGF- (5 ng mL1) 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 manufacturers instructions
with a luminometer.
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 reaction 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 solvent yielded 13 (11.00 g, 56.7 mmol, 96 %, ref.[43]: quant.) as a colorless, volatile liquid, Rf = 0.85 (cHex/EtOAc). 1H NMR
(300 MHz, CDCl3): = 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] 13C
NMR (75.5 MHz, CDCl3): = 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 literature.[43]
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, 2,3cis-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 mixture was quenched with aqueous saturated ammonium chloride
solution (50 mL) and stirred for 2 h. The aqueous layer was extracted with diethyl ether (3 75 mL), dried with anhydrous magnesium 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).
1
H NMR (300 MHz, CDCl3): = 3.743.64 (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), 1.731.60
(m, 1 H, 3-H), 1.371.22 (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): = 79.2 (C-6), 75.8 (C-7), 71.6 (C-2), 39.3 (C3), 32.0 (C-4), 19.6 (C-1), 16.6 (C-5), 14.4 (CH3-3), 3.6 (C-8) ppm.
IR (NaCl): = 3372, 2970, 2922, 2877, 1456, 1379, 1094, 1059,
1005 cm1.
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.)
Eur. J. Org. Chem. 2015, 35873608
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. 101.0102.0 C (methanol), m.p.
in ref.[21] 102103 C (cHex/EtOAc 10:1). 1H NMR (300 MHz,
CDCl3): = 7.527.30 (m, 10 H, 2 Ph), 6.63 (d, J = 2.7 Hz, 1 H,
4-H), 6.48 (d, J = 2.7 Hz, 1 H, 6-H), 5.10 (s, 2 H, OCH2Ph), 5.02
(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): = 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 (C2), 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 [3,5bis(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 (3 30 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. 128.0130.0 C (EtOAc), m.p. in ref.[21] 168.5168.7 C (decomposition, EtOAc). 1H NMR (300 MHz, [D6]DMSO): = 7.53
7.30 (m, 10 H, 2 Ph), 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 accordance with the literature.[21] 13C NMR (75.5 MHz, [D6]DMSO):
= 171.3 (COOH), 159.4, 157.5 (C-3, C-5), 140.4 (C-1), 136.8 (C1, Ph), 136.7 (C-1, Ph), 128.5 (2 C-3, 2 C-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]
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-6yn-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,NDicyclohexylcarbodiimide (0.83 g, 4.02 mmol, 1.2 equiv.) was dissolved 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 =
0.53 (cHex/EtOAc 4:1), m.p. 64.065.0 C (cHex/EtOAc 15:1). 1H
NMR (400 MHz, CDCl3): = 7.517.30 (m, 10 H, 2 Ph), 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), 2.212.15 (m, 1 H, CH2A-5), 2.132.04
(m, 1 H, CH2B-5), 1.841.77 (m, 1 H, CH-3), 1.76 (t, J = 2.5 Hz,
3 H, CH3-8), 1.691.60 (m, 1 H, CH2A-4), 1.361.25 (m, 1 H,
CH2B-4), 1.20 (d, J = 6.4 Hz, 3 H, CH3-1), 0.88 (d, J = 6.8 Hz, 3
Eur. J. Org. Chem. 2015, 35873608
H, CH3-3) ppm. 13C NMR (100.6 MHz, CDCl3): = 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 (CH2, CH-6, Ph), 109.2 (CH-6), 100.0 (CH-4), 83.7 (Cq-2), 79.0 (Cq6), 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 (CH31), 14.7 (CH3-3), 3.6 (CH3-8) ppm. IR (NaCl): = 3065, 3033,
2923, 2874, 2249, 1730, 1583, 1498, 1453, 1428, 1315, 1169, 1072,
735 cm1. HRMS (ESI): calcd. for [C31H33IO4 + Na]+ 619.1321;
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-2yl]boronic Acid: Catecholborane (1 m in THF, 0.13 mL, 0.13 mmol,
1.5 equiv.) was added to alkyne 17 (50 mg, 84 mol, 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 decomposition 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): = 7.507.29
(m, 10 H, 2 Ph), 6.686.63 (m, 1 H, 6-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), 4.914.87 (m, 1 H, 2-OCH), 3.843.78
(m, 2 H, CH2COO), 2.262.17 (m, 1 H, 5-CH2A), 2.162.10 (m, 1
H, 5-CH2B), 1.73 (s, 3 H, 8-CH3), 1.721.69 (m, 1 H, 3-CH),
1.571.50 (m, 1 H, 4-CH2A), 1.241.20 (m, 1 H, 4-CH2B), 1.17 (d,
J = 6.3 Hz, 3 H, 1-CH3), 0.90 (d, J = 6.9 Hz, 3 H, 3-CH3) ppm.
13
C NMR HSQC, HMBC (150.9 MHz, CDCl3): = 170.2 (COO),
160.0 (Cq-5), 158.2 (Cq-3), 149.0 (CH-6), 140.1 (Cq-1), 136.5 (Cq1, Ph), 136.5 (Cq-1, Ph), 129.5 (Cq-7), 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-2), 71.1 (OCH2, OBn-3), 70.4
(OCH2, OBn-5), 47.3 (CH2COO), 37.4 (CH-3), 31.6 (CH2-4), 26.8
(CH2-5), 16.1 (CH3 -1), 14.9 (CH 3-3), 13.3 (CH3 -8) ppm. IR
(ATR): = 3065, 3032, 2926, 2873, 1728, 1581, 1498, 1452, 1365,
1332, 1277, 1168, 1072 cm1. 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-hexahydro2H-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 mol, 1.0 equiv.) and Cs 2 CO 3 (75 mg, 231 mol,
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 mol, 0.2 equiv.) was dissolved in chlorobenzene (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 mol, 25 %) as a colorless oil, Rf = 0.38 (cHex/EtOAc 10:1).
Diastereomer A: 1H NMR COSY (600 MHz, CDCl3): = 7.43
7.32 (m, 10 H, 2 Ph), 6.56 (d, J = 2.4 Hz, 1 H, 6-H), 6.36 (d, J
= 2.4 Hz, 1 H, 4-H), 6.28 (ddd, J = 17.2, 10.0, 7.5 Hz, 1 H,
CH=CH2), 5.064.97 (m, 4 H, 2 OCH2Ph), 4.92 (d, J = 17.2 Hz,
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3595
FULL PAPER
1 H, CH=CH2A), 4.82 (d, J = 10.0 Hz, 1 H, CH=CH2B), 4.574.52

(m, 1 H, 13-H), 3.93 (d, J = 18.7 Hz, 1 H, CH2A-2), 3.55 (d, J =
18.7 Hz, 1 H, CH2B-2), 3.063.03 (m, 1 H, 9-H), 1.661.62 (m, 2
H, CH2A-10, 12-H), 1.271.24 (m, 5 H, CH2-11, CH3-13), 1.21
1.15 (m, 1 H, CH2B-10), 0.89 (d, J = 6.8 Hz, 3 H, CH3-12) ppm.
13
C NMR HSQC, HMBC (150.9 MHz, CDCl3): = 171.9 (COO),
157.9 (C q-7), 157.7 (C q-5), 142.6 (CH=CH 2), 137.1 (C q-1, Ph),
137.0 (Cq-1, Ph), 133.8 (Cq-3), 128.8 (CH-3, CH-5, Ph), 128.7 (CH3, 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 (C q -8), 113.0
(CH=CH 2 ), 108.5 (CH-4), 100.1 (CH-6), 78.3 (CH-13), 70.3
(OCH2Ph), 70.2 (OCH2Ph), 48.0 (CH-9), 42.4 (CH2-2), 42.1 (CH12), 33.5 (CH 2 -10), 29.9 (CH 2 -11), 20.0 (CH 3 -13), 19.0 (CH 3 12) ppm. IR (ATR): = 3067, 3033, 2959, 2928, 2873, 1720, 1603,
1585, 1498, 1454, 1259, 1151, 1065, 1048 cm1. HRMS (ESI): calcd.
for [C31H34O4 + Na]+ 493.2355; found 493.2341.
Diastereomer B: 1H NMR COSY (600 MHz, CDCl3): = 7.43
7.30 (m, 10 H, 2 Ph), 6.56 (d, J = 2.5 Hz, 1 H, 4-H), 6.53 (d, J
= 2.5 Hz, 1 H, 6-H), 6.30 (ddd, J = 17.3, 10.1, 7.3 Hz, 1 H,
CH=CH2), 5.04 (d, J = 11.2 Hz, 1 H, CH2A, OBn-5), 4.99 (d, J =
11.2 Hz, 1 H, CH2B, OBn-5), 4.99 (s, 2 H, CH2, OBn-7), 4.984.95
(m, 1 H, CH=CH2A), 4.894.87 (m, 1 H, CH=CH2B), 4.39 (dq, J
= 10.1, 6.2 Hz, 1 H, 13-H), 4.26 (ddd, J = 11.6, 7.3, 4.2 Hz, 1 H,
9-H), 3.94 (d, J = 11.9 Hz, 1 H, CH2A-2), 3.27 (d, J = 11.9 Hz, 1
H, CH2B-2), 2.62 (ddd, J = 13.7, 11.6, 8.3 Hz, 1 H, CH2A-10), 1.59
1.55 (m, 1 H, 12-H), 1.47 (ddd, J = 14.4, 10.7, 4.2 Hz, 1 H, CH2B10), 1.28 (d, J = 6.2 Hz, 3 H, CH3-13), 1.221.17 (m, 1 H, CH2A11), 0.910.86 (m, 1 H, CH2B-11), 0.89 (d, J = 7.0 Hz, 3 H, CH312) ppm. 13 C NMR HSQC, HMBC (150.9 MHz, CDCl 3 ): =
171.6 (COO), 158.8 (Cq-7), 158.2 (Cq-5), 143.3 (CH=CH2), 137.1
(Cq-1, Ph), 137.0 (Cq-1, Ph), 136.3 (Cq-3), 128.7 (CH-3, CH-5, Ph),
128.6 (CH-3, CH-5, Ph), 128.2 (CH-4, Ph), 127.9 (CH-4, Ph), 127.9
(CH-2, CH-6, OBn-5), 127.4 (CH-2, CH-6, OBn-7), 123.6 (Cq-8),
112.9 (CH=CH2), 108.8 (CH-4), 100.9 (CH-6), 76.9 (CH-13), 70.2
(OCH2Ph), 70.2 (OCH2Ph), 44.1 (CH-12), 42.8 (CH2-2), 42.6 (CH9), 34.8 (CH 2 -10), 32.2 (CH 2 -11), 20.1 (CH 3 -12), 19.6 (CH 3 13) ppm. IR (ATR): = 3065, 3033, 2959, 2924, 2872, 2856, 1730,
1602, 1498, 1295, 1274, 1161, 1139, 1058 cm1. HRMS (ESI): calcd.
for [C31H34O4 + Na]+ 493.2355; found 493.2374.
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 mol,
1.0 equiv.). The reaction was performed under microwave irradiation (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 tetrafluoroborate (19 mg, 49 mol, 0.2 equiv.) in dry DMF (2 mL) and a solution of Pd(dba)2 (14 mg, 24 mol, 0.1 equiv.) in dry DMF (2 mL)
were added. The reaction mixture was stirred under carbon monoxide (balloon) at 120 C. After 16 h, water (30 mL) was added to
the cold reaction mixture, which was then extracted with diethyl
ether (3 30 mL), dried with magnesium sulfate, and filtered. The
solvent was removed in vacuo. Purification by flash chromatography on silica (cHex/EtOAc 20:1) yielded 21 (3.5 mg, 7 mol, 3 %)
as a yellow oil, Rf = 0.13 (cHex/EtOAc 15:1). 1H NMR COSY
(400 MHz, CDCl3): = 7.437.35 (m, 10 H, 2 Ph), 6.65 (d, J =
2.4 Hz, 1 H, 4-H), 6.59 (d, J = 2.4 Hz, 1 H, 6-H), 5.475.39 (m, 1
H, 7-H), 5.385.30 (m, 1 H, 6-H), 5.18 (s, 2 H, OCH2Ph-3), 5.08
(s, 2 H, OCH2Ph-5), 4.894.80 (m, 1 H, OCH-2), 4.00 (d, J =
16.5 Hz, 1 H, CH2ACOO), 3.95 (d, J = 16.5 Hz, 1 H, CH2BCOO),
2.101.98 (m, 2 H, CH2-5), 1.741.66 (m, 1 H, CH-3), 1.601.57
(m, 3 H, CH3-8), 1.481.39 (m, 1 H, CH2A-4), 1.17 (d, J = 6.4 Hz,
3 H, CH3-1), 1.161.09 (m, 1 H, CH2B-4), 0.89 (d, J = 6.8 Hz, 3
3596
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H, CH3-3) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3):

= 171.1 (COO), 165.3 (COOH), 162.0 (Cq-5), 159.4 (Cq-3), 141.9
(Cq-1), 135.9 (Cq-1, Ph, OBn-5), 134.5 (Cq-1, Ph, OBn-3), 130.7
(CH-6), 129.2 (CH-3, CH-5, Ph), 129.2 (CH-4, Ph), 128.9 (CH-3,
CH-5, Ph), 128.6 (CH-4, Ph), 128.0 (CH-2, CH-6, OBn-3), 127.7
(CH-2, CH-6, OBn-5), 124.0 (CH-7), 112.5 (CH-6), 111.9 (Cq-2),
100.3 (CH-4), 75.0 (CHO-2), 72.6 (OCH2Ph-3), 70.5 (OCH2Ph-5),
42.4 (CH2COO), 37.0 (CH-3), 32.4 (CH2-4), 24.5 (CH2-5), 15.9
(CH3-1), 14.7 (CH3-3), 12.9 (CH3-8) ppm. IR (ATR): = 3064,
3010, 2928, 2854, 1729, 1604, 1498, 1453, 1318, 1291, 1167,
697 cm1. HRMS (ESI): calcd. for [C32H36O6 + Na]+ 539.2410;
found 539.2392.
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
20 C. N,N-Dicyclohexylcarbodiimide (1.41 g, 6.82 mmol,
1.2 equiv.) was dissolved in dry dichloromethane (15 mL) and
added. After stirring for 4 h the reaction mixture was allowed to
warm to room temperature. After 18 h water (0.1 mL) was added,
and stirring was carried out for an additional hour. The reaction
mixture was filtered through a short plug of silica and celite
(CH2Cl2). The solvent was removed in vacuo, and purification by
flash chromatography on silica (cHex/EtOAc 30:1) yielded a colorless oil (1.13 g, 2.40 mmol, 42 %), Rf = 0.20 (cHex/EtOAc 15:1). 1H
NMR COSY (400 MHz, CDCl3): = 7.477.33 (m, 10 H, 2 Ph),
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, 2 OCH2Ph), 4.87 (quint, J = 6.3 Hz, 1 H, OCH),
3.57 (s, 2 H, CH2COO), 2.302.19 (m, 1 H, CH2A-5), 2.162.05 (m,
1 H, CH2B-5), 1.861.77 (m, 1 H, CH-3), 1.78 (t, J = 2.6 Hz, 3 H,
CH3-8), 1.691.61 (m, 1 H, CH2A-4), 1.341.25 (m, 1 H, CH2B-4),
1.19 (d, J = 6.3 Hz, 3 H, CH3-1), 0.90 (d, J = 6.8 Hz, 3 H, CH33) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3): = 170.9
(COO), 160.0 (Cq-3, Cq-5), 136.9 (2 Cq-1, Ph), 136.5 (Cq-1), 128.6
(2 CH-3, 2 CH-5, Ph), 128.0 (2 CH-4, Ph), 127.6 (2 CH-2,
2 CH-6, Ph), 108.5 (CH-2, CH-6), 100.9 (CH-4), 78.8 (Cq-6), 75.8
(C q -7), 74.7 (CHO), 70.1 (2 OCH 2Ph), 42.1 (CH 2COO), 36.6
(CH-3), 31.6 (CH2-4), 16.6 (CH2-5), 16.3 (CH3-1), 14.5 (CH3-3),
3.5 (CH3-8) ppm. IR (NaCl): = 3090, 3065, 3033, 2976, 2920,
2876, 2250, 1728, 1595, 1498, 1453, 1292, 1160, 1059, 734,
698 cm 1 . HRMS (ESI): calcd. for [C 31 H 34 O 4 + H] + 471.2535;
found 471.2530.
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 (2 100 mL), dried with magnesium sulfate, and filtered. 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. 116.0118.0 C (cHex/EtOAc 8:1). 1 H NMR (400 MHz,
CDCl3): = 10.54 (s, 1 H, CHO), 7.457.32 (m, 10 H, 2 Ph), 6.58
(d, J = 2.3 Hz, 1 H, 4-H), 6.46 (d, J = 2.3 Hz, 1 H, 6-H), 5.11 (s,
2 H, OCH2Ph), 5.09 (s, 2 H, OCH2Ph), 4.86 (quint, J = 6.3 Hz, 1
H, CH-2), 3.97 (d, J = 16.8 Hz, 1 H, CH2ACOO), 3.93 (d, J =
16.8 Hz, 1 H, CH2BCOO), 2.272.17 (m, 1 H, CH2A-5), 2.152.04
(m, 1 H, CH2B-5), 1.861.78 (m, 1 H, CH-3), 1.77 (t, J = 2.5 Hz,
3 H, CH3-8), 1.721.63 (m, 1 H, CH2A-4), 1.351.25 (m, 1 H,
CH2B-4), 1.21 (d, J = 6.3 Hz, 3 H, CH3-1), 0.92 (d, J = 6.8 Hz, 3
Eur. J. Org. Chem. 2015, 35873608
= 189.9 (CHO), 170.7 (COO), 164.4 (Cq-3), 163.8 (Cq-5), 139.6
(Cq-1), 135.9 (Cq-1, Ph), 135.9 (Cq-1, Ph), 128.8 (CH-3, CH-5, Ph),
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-6), 75.6 (Cq-7), 74.6 (CH-2), 70.7
(OCH2Ph), 70.3 (OCH2Ph), 41.0 (CH2COO), 36.6 (CH-3), 31.7
(CH2-4), 16.6 (CH2-5), 16.2 (CH3-1), 14.6 (CH3-3), 3.6 (CH38) ppm. IR (ATR): = 3034, 2919, 2875, 2250, 1726, 1672, 1598,
1573, 1498, 1316, 1292, 1150, 1073, 730, 696 cm1. 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-formylphenyl]acetate (24):[23] Compound 23 (50 mg, 100 mol, 1.0 equiv.), sodium formate (2 mg, 30 mol, 0.3 equiv.), xantphos (11.6 mg,
20 mol, 0.2 equiv.), and dichloro(p-cymene)ruthenium(II) dimer
(6.1 mg, 10 mol, 0.1 equiv.) were dissolved in dry DMF (3 mL).
The reaction mixture was stirred at 150 C under microwave irradiation (150 W) for 75 min. The cold reaction mixture was diluted
with diethyl ether (50 mL), washed with water (2 25 mL), dried
with magnesium sulfate, and filtered. The solvent was removed in
vacuo. Purification by flash chromatography on silica (cHex/EtOAc
20:1 10:1) yielded 24 (30 mg, 60 mol, 60 %) as a colorless oil, Rf
= 0.15 (cHex/EtOAc 10:1). 1H NMR COSY (400 MHz, CDCl3):
= 10.53 (s, 1 H, CHO), 7.427.32 (m, 10 H, 2 Ph), 6.57 (d, J =
2.2 Hz, 1 H, 4-H), 6.45 (d, J = 2.2 Hz, 1 H, 6-H), 6.045.97 (m, 1
H, 5-H), 5.695.51 (m, 1 H, 7-H), 5.485.38 (m, 1 H, 4-H), 5.37
5.24 (m, 1 H, 6-H), 5.11 (s, 2 H, OCH 2 Ph-3), 5.09 (s, 2 H,
OCH 2 Ph-5), 4.924.80 (m, 1 H, OCH-2), 3.993.87 (m, 2 H,
CH2COO), 2.412.30 (m, 1 H, 3-H), 1.72 (d, J = 6.3 Hz, 3 H,
CH3-8), 1.18 (d, J = 6.4 Hz, 3 H, CH3-1), 1.03 (d, J = 6.8 Hz, 3
= 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-4), 131.7
(CH-6), 131.5 (CH-5), 128.9 (CH-3, CH-5, Ph), 128.8 (CH-3, CH5, Ph), 128.5 (CH-4, Ph), 128.4 (CH-4, Ph), 127.9 (CH-7), 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-2), 70.8 (OCH2Ph-3), 70.4
(OCH2Ph-5), 41.0 (CH2COO), 41.6 (CH-3), 18.3 (CH3-8), 17.0
(CH3-1), 16.0 (CH3-3) ppm. IR (ATR): = 3032, 2964, 2929,
2873, 1727, 1673, 1598, 1573, 1498, 1315, 1292, 1150, 1072, 735,
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 additional 30 min. Water (5 mL) and ethyl acetate (30 mL) were
added, and the formed precipitate was removed by vacuum filtration 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]
94 %), Rf = 0.49 (cHex/EtOAc/HOAc 100:100:1), m.p. 82.082.5
(cHex/EtOAc 5:1), m.p. in ref.[46] 8384 C (CHCl3/PE). 1H NMR
(400 MHz, CDCl3): = 7.467.33 (m, 10 H, 2 Ph), 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
H, CH2Ph), 3.85 (t, J = 6.5 Hz, 2 H, CH2OH), 2.82 (t, J = 6.5 Hz,
2 H, CH2CH2OH), 1.68 (br. s, 1 H, OH) ppm. The data are in
accordance with the literature.[46] 13C NMR (100.6 MHz, CDCl3):
= 160.2 (C-3, C-5), 141.0 (C-1), 136.9 (2 C-1, Ph), 128.7 (2 C3, 2 C-5), 128.1 (2 C-4), 127.6 (2 C-2, 2 C-6), 108.3 (C-2, CEur. J. Org. Chem. 2015, 35873608
6), 100.2 (C-4), 70.1 (2 OCH 2 Ph), 63.5 (CH 2 OH), 39.5
(CH2CH2OH). The data are in accordance with the literature.[21]
1,3-Bis(benzyloxy)-5-{2-[(4-methoxybenzyl)oxy]ethyl}benzene
(25): [ 1 8 , 2 1 ] 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 carried 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 (3 150 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 yellow oil (10.41 g, 22.9 mmol, quant., ref.[18] 81 %). The crude product 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): = 7.517.37 (m, 10 H, 2 Ph), 7.357.31 (m, 2 H, AApart of AABB-spin system, 2-H, 6-H, PMB), 6.976.93 (m, 2 H,
BB-part of AABB-spin system, 3-H, 5-H, PMB), 6.59 (s, 3 H, 2H, 4-H, 6-H), 5.07 (s, 4 H, 2 OCH2, 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):
= 159.9 (C-1, C-3), 159.2 (C-4, PMB), 141.1 (C-5), 137.0 (2 C1, Bn), 130.5 (C-1, PMB), 129.3 (CH-2, CH-6, PMB), 128.6
(2 CH-3, 2 CH-5, Bn), 128.0 (2 CH-4, Bn), 127.6 (2 CH-2,
2 CH-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 (2 OCH2, Bn),
55.2 (OCH3), 36.7 (CH2CH2OPMB) ppm. The data are in accordance with the literature.[21]
2,4-Bis(benzyloxy)-6-{2-[(4-methoxybenzyl)oxy]ethyl}benzaldehyde:[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 (3 100 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
5:1). 1H NMR (400 MHz, CDCl3): = 10.57 (s, 1 H, CHO), 7.48
7.34 (m, 10 H, 2 Ph), 7.267.23 (m, 2 H, AA-part of AABBspin system, 2-H, 6-H, PMB), 6.876.84 (m, 2 H, BB-part of
AABB-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): = 190.4 (CHO),
164.5 (C-4), 163.6 (C-2), 159.1 (C-4, PMB), 145.5 (C-6), 136.1 (C1, Bn), 136.1 (C-1, Bn), 130.9 (C-1, PMB), 129.3 (CH-2, CH-6,
PMB), 128.8 (CH-3, CH-5, Bn), 128.8 (CH-3, CH-5, Bn), 128.4
(CH-4, Bn), 128.4 (CH-4, Bn), 127.7 (CH-2, CH-6, Bn), 127.4 (CH2, CH-6, Bn), 117.6 (C-1), 113.8 (CH-3, CH-5, PMB), 110.3 (C-5),
98.5
(C-3),
72.5
(CH2OPMB),
70.8
(CH2,
PMB),
70.3 (CH2, Bn), 70.3 (CH2, Bn), 55.3 (OCH3), 35.0
(CH2CH2OPMB) ppm. The data are in accordance with the literature.[18]
www.eurjoc.org
3597
FULL PAPER
Alcohol 26a:[18] A solution of 1-methylprop-2-enylmagnesium

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}benzaldehyde (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 (3 75 mL), dried with magnesium 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).
1
H NMR COSY (400 MHz, CDCl3, diastereomer A): = 7.49
7.36 (m, 10 H, 2 Ph), 7.327.28 (m, 2 H, AA-part of AABBspin system, 2-H, 6-H, PMB), 6.946.90 (m, 2 H, BB-part of
AABB-spin system, 3-H, 5-H, PMB), 6.59 (d, J = 2.4 Hz, 1 H,
4-H), 6.51 (d, J = 2.4 Hz, 1 H, 6-H), 5.64 (ddd, J = 17.4, 10.4,
7.2 Hz, 1 H, CH=CH2), 4.954.85 (m, 2 H, CH=CH2), 5.09 (s, 2
H, OCH2Ph), 5.02 (s, 2 H, OCH2Ph), 4.66 (t, J = 9.4 Hz, 1 H, CH1), 4.53 (d, J = 11.7 Hz, 1 H, CH2A, PMB), 4.47 (d, J = 11.7 Hz,
1 H, CH2B, PMB), 3.80 (s, 3 H, OCH3), 3.793.62 (m, 2 H, CH2O),
3.132.88 (m, 3 H, CH2CH2O, CH-2), 1.28 (d, J = 6.6 Hz, 3 H,
CH3-2) ppm. 1H NMR COSY (400 MHz, CDCl3, diastereomer
B): = 7.497.36 (m, 10 H, 2 Ph), 7.327.28 (m, 2 H, AA-part
of AABB-spin system, 2-H, 6-H, PMB), 6.946.90 (m, 2 H, BBpart of AABB-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), 5.135.06 (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, CH1), 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), 3.793.62 (m, 2 H,
CH2CH2O), 3.42 (d, J = 9.1 Hz, 1 H, OH), 3.132.88 (m, 3 H,
CH2O, CH-2), 0.90 (d, J = 6.9 Hz, 3 H, CH3-2) ppm. 13C NMR
HSQC, HMBC (100.6 MHz, CDCl3, diastereomer A): = 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, CH5, 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-1), 72.7
(OCH2, PMB), 70.6 (CH2O), 70.5 (OCH2Ph), 70.0 (OCH2Ph), 55.2
(OCH3), 44.0 (CH-2), 34.2 (CH2CH2O), 16.4 (CH3-2) ppm. 13C
NMR HSQC, HMBC (100.6 MHz, CDCl3, diastereomer B): =
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, CH6, 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 (CH1), 72.7 (OCH2, PMB), 70.5 (CH2O), 70.4 (OCH2Ph), 70.0
(OCH2Ph), 55.2 (OCH3), 44.5 (CH-2), 34.2 (CH2CH2O), 17.3
(CH3-2) ppm. IR (ATR): = 3556, 3065, 3033, 2958, 2932, 2865,
1605, 1585, 1513, 1498, 1454, 1248, 1147, 1085, 1029 cm1. 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(benzyloxy)-6-{2-[(4-methoxybenzyl)oxy]ethyl}benzaldehyde
(1.90 g,
3.93 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 (50 mL), extracted
with diethyl ether (3 50 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 without further purification, Rf = 0.08 (cHex/EtOAc 10:1). 1H NMR
COSY (400 MHz, CDCl3): = 7.437.31 (m, 10 H, 2 Ph), 7.25
3598
www.eurjoc.org
7.21 (m, 2 H, AA-part of AABB-spin system, 2-H, 6-H, PMB),

6.886.84 (m, 2 H, BB-part of AABB-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, 6H), 5.845.73 (m, 1 H, CH=CH2), 5.104.98 (m, 6 H, CH=CH2,
2 OCH2Ph), 4.974.90 (m, 1 H, CH-1), 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), 3.693.56 (m, 2 H, CH2O), 3.002.88 (m, 2 H,
CH2CH2O), 2.782.70 (m, 1 H, CH2A-2), 2.542.47 (m, 1 H,
CH2B-2) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3):
= 159.3 (Cq-4, PMB), 158.5 (Cq-5), 158.0 (Cq-3), 138.3 (Cq-1),
136.9 (Cq-1, Ph), 136.3 (Cq-1, Ph), 135.8 (CH=CH2), 130.4 (Cq-1,
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 (CH2, CH-6, Ph), 127.7 (CH-2, CH-6, Ph), 123.2 (Cq-2), 116.9
(CH=CH2), 113.9 (CH-3, CH-5, PMB), 108.3 (CH-6), 99.5 (CH4), 72.9 (OCH2, PMB), 70.7 (CH2O), 70.7 (OCH2Ph), 70.2
(OCH2Ph), 70.1 (CH-1), 55.4 (OCH3), 42.4 (CH2-2), 34.3
(CH2CH2O) ppm. IR (ATR): = 3558, 3066, 3033, 3003, 2932,
2909, 2861, 1639, 1604, 1498, 1246, 1144, 1082, 1053, 1029, 736,
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 (3 150 mL), dried
with magnesium sulfate, and filtered. Removing the solvent in
vacuo yielded 27a (620 mg, 0.95 mmol, quant.) as a colorless oil,
Rf = 0.63 (cHex/EtOAc 5:1). 1H NMR COSY (400 MHz, CDCl3,
diastereomer A): = 7.447.32 (m, 10 H, 2 Ph), 7.317.27 (m, 2
H, AA-part of AABB-spin system, 2-H, 6-H, PMB), 6.906.86
(m, 2 H, BB-part of AABB-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), 5.084.96 (m, 5 H,
2 OCH2Ph, CH-1), 4.764.70 (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), 3.713.64 (m, 2 H, CH2O), 3.593.45
(m, 1 H, CH2ACH2O), 3.193.12 (m, 1 H, CH2BCH2O), 2.732.62
(m, 1 H, CH-2), 1.17 (d, J = 6.5 Hz, 3 H, CH3-2), 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): = 7.447.32
(m, 10 H, 2 Ph), 7.317.27 (m, 2 H, AA-part of AABB-spin
system, 2-H, 6-H, PMB), 6.906.86 (m, 2 H, BB-part of AABBspin 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), 5.225.17 (m, 2 H, CH=CH2), 5.084.96 (m, 5 H,
2 OCH2Ph, CH-1), 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), 3.713.64
(m, 2 H, CH2O), 3.593.45 (m, 1 H, CH2ACH2O), 3.193.12 (m, 1
H, CH2BCH2O), 2.732.62 (m, 1 H, CH-2), 0.71 (d, J = 6.8 Hz, 3
H, CH3-2), 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): = 159.3 (Cq-4, PMB), 158.2 (Cq-5), 157.2 (Cq3), 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 (CH2, 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 (CH6), 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-2), 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
Eur. J. Org. Chem. 2015, 35873608
(100.6 MHz, CDCl3, diastereomer B): = 159.2 (Cq-4, PMB),
158.3 (Cq-5), 156.8 (Cq-3), 143.4 (CH=CH2), 140.8 (Cq-1), 137.5
(Cq-1, Ph), 137.1 (Cq-1, Ph), 130.8 (Cq-1, PMB), 129.4 (CH-2, CH6, PMB), 128.6 (CH-3, CH-5, Ph), 128.6 (CH-3, CH-5, Ph), 128.1
(CH-4, Ph), 127.9 (CH-2, CH-6, Ph), 127.8 (CH-4, Ph), 127.0 (CH2, CH-6, Ph), 123.6 (Cq-2), 113.9 (CH-3, CH-5, PMB), 113.7
(CH=CH2), 108.8 (CH-6), 97.7 (CH-4), 72.7 (OCH2, PMB), 71.6
(CHO), 71.4 (CH2O), 70.3 (OCH2Ph), 70.1 (OCH2Ph), 55.4
(OCH3), 44.8 (CH-2), 32.8 (CH2CH2O), 26.0 [(CH3)3], 18.3
[SiC(CH3)3], 16.2 (CH3), 4.7 (SiCH3), 5.0 (SiCH3) ppm. IR
(ATR): = 3066, 3033, 2955, 2929, 2856, 1659, 1498, 1247, 1143,
1085, 1039, 909, 834, 730, 697 cm1. HRMS (ESI): calcd. for
[C41H52O5Si + Na]+ 675.3482; found 675.3466.
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 (3 100 mL), dried with magnesium sulfate, and filtered. Removing 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
7.317.28 (m, 2 H, AA-part of AABB-spin system, 2-H, 6-H,
PMB), 6.906.87 (m, 2 H, BB-part of AABB-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), 5.064.94 (m, 7 H,
2 OCH2Ph, CH=CH2, CH-1), 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), 3.733.63 (m, 2 H, CH2O), 3.533.34 (m, 1 H,
CH2ACH2O), 3.283.15 (m, 1 H, CH2BCH2O), 2.792.57 (m, 1 H,
CH2A-2), 2.462.39 (m, 1 H, CH2B-2), 0.85 [s, 9 H, C(CH3)3], 0.01
(s, 3 H, SiCH3), 0.17 (s, 3 H, SiCH3) ppm. 13C NMR HSQC,
HMBC (100.6 MHz, CDCl3): = 159.3 (Cq-4, PMB), 158.3 (Cq5), 156.4 (br, Cq-3), 140.9 (br, Cq-1), 137.4 (Cq-1, Ph), 137.1 (Cq-1,
Ph), 136.4 (CH=CH2), 130.8 (Cq-1, PMB), 129.5 (CH-2, CH-6,
PMB), 128.7 (2 CH-3, 2 CH-5, Ph), 128.6 (CH-4, Ph), 128.1
(CH-4, Ph), 127.8 (CH-2, CH-6, Ph), 127.0 (CH-2, CH-6, Ph),
124.2 (Cq-2), 116.3 (CH=CH2), 113.9 (CH-3, CH-5, PMB), 108.8
(br, CH-6), 98.2 (br, CH-4), 72.8 (OCH2, PMB), 71.5 (br, CH2O),
70.3 (CH-1), 70.1 (2 OCH2Ph), 55.4 (OCH3), 43.3 (br, CH2-2),
32.9 (br, CH2CH2O), 26.1 [(CH3)3], 18.4 [SiC(CH3)3], 4.6 (SiCH3),
4.9 (SiCH3) ppm. IR (ATR): = 3033, 3005, 2953, 2929, 1640,
1499, 1247, 1146, 1075, 1037, 832, 775, 733, 696 cm1. HRMS
(ESI): calcd. for [C40H50O5Si + Na]+ 661.3325; found 661.3304.
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 dichloromethane (3 30 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).
1
H NMR COSY (400 MHz, CDCl3, diastereomer A): = 7.46
7.32 (m, 10 H, 2 Ph), 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,
CH=CH2), 5.084.96 (m, 7 H, CH=CH2, 2 OCH2Ph, CH-1),
4.134.08 (m, 1 H, CH2AOH), 3.613.52 (m, 1 H, CH2BOH), 3.18
3.11 (m, 1 H, CH-2), 2.982.84 (m, 1 H, CH2ACH2OH), 2.562.47
(m, 1 H, CH2BCH2OH), 1.651.60 (m, 1 H, OH), 0.93 [s, 9 H,
Eur. J. Org. Chem. 2015, 35873608
C(CH3)3], 0.81 (dd, J = 6.9, 1.2 Hz, 3 H, CH3-2), 0.12 (s, 6 H,

2 SiCH3) ppm. 1H NMR COSY (400 MHz, CDCl3, diastereomer
B): = 7.467.32 (m, 10 H, 2 Ph), 6.49 (d, J = 2.2 Hz, 1 H, 4H), 6.37 (d, J = 2.2 Hz, 1 H, 6-H), 5.76 (dddd, J = 17.4, 10.5, 6.8,
1.2 Hz, 1 H, CH=CH2), 5.084.96 (m, 5 H, 2 OCH2Ph, CH-1),
4.874.79 (m, 2 H, CH=CH2), 4.134.08 (m, 1 H, CH2AOH), 3.61
3.52 (m, 1 H, CH2BOH), 3.183.11 (m, 1 H, CH-2), 2.982.84 (m,
1 H, CH2ACH2OH), 2.562.47 (m, 1 H, CH2BCH2OH), 1.651.60
(m, 1 H, OH), 1.23 (dd, J = 6.9, 1.2 Hz, 3 H, CH3-2), 0.93 [s, 9 H,
C(CH3)3], 0.12 (s, 6 H, 2 SiCH3) ppm. 13C NMR HSQC, HMBC
(100.6 MHz, CDCl3, diastereomer A): = 158.1 (Cq-5), 156.2 (Cq3), 143.2 (CH=CH2), 138.6 (Cq-1), 137.1 (2 Cq-1, Ph), 128.7 (CH3, CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.2 (CH-4, Ph), 128.0
118.5 (Cq-2), 113.5 (CH=CH2), 105.7 (CH-6), 98.8 (CH-4), 76.7
(CH-1), 70.2 (OCH2Ph), 70.0 (OCH2Ph), 63.2 (CH2OH), 41.1
(CH-2), 30.7 (CH2CH2O), 25.8 [(CH3)3], 18.1 [SiC(CH3)3], 12.5
(CH3-2), 3.4 (2 SiCH3) ppm. 13C NMR HSQC, HMBC
(100.6 MHz, CDCl3, diastereomer B): = 158.0 (Cq-5), 156.1 (Cq3), 140.5 (CH=CH2), 138.5 (Cq-1), 136.9 (2 Cq-1, Ph), 128.7 (CH3, CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.1 (CH-4, Ph), 127.9
119.0 (Cq-2), 114.2 (CH=CH2), 105.7 (CH-6), 98.8 (CH-4), 76.7
(CH-1), 70.2 (OCH2Ph), 70.0 (OCH2Ph), 62.8 (CH2OH), 41.2
(CH-2), 30.5 (CH2CH2O), 25.8 [(CH3)3], 18.1 [SiC(CH3)3], 17.0
(CH3-2), 3.4 (2 SiCH3) ppm. IR (ATR): = 3359, 3067, 3033,
2956, 2929, 2856, 1605, 1592, 1498, 1147, 1094, 1056, 832, 734,
696 cm1. HRMS (ESI): calcd. for [C33H44O4Si + Na]+ 555.2907;
found 555.2925.
Phenylethanol 28b:[18] DDQ (255 mg, 1.12 mmol, 1.1 equiv.) was
added at room temperature to a strongly stirred solution of PMB
ether 27b (654 mg, 1.02 mmol, 1.0 equiv.) in dichloromethane
(20 mL) and phosphate buffer (pH 7, 63 mm, 1.0 mL). After
40 min, saturated aqueous sodium hydrogen carbonate solution
(75 mL) was added, and the mixture was extracted with dichloromethane (3 70 mL), dried with magnesium sulfate, and filtered.
The solvent was removed in vacuo. Purification by flash
chromatography on silica (cHex/EtOAc 5:1) yielded 28b (410 mg,
0.79 mmol, 77 %, ref.[18] 93 %) as a yellow oil, Rf = 0.27 (cHex/
EtOAc 5:1). 1H NMR COSY (400 MHz, CDCl3): = 7.457.30
(m, 10 H, 2 Ph), 6.52 (d, J = 2.4 Hz, 1 H, 6-H), 6.47 (d, J =
2.4 Hz, 1 H, 4-H), 5.805.69 (m, 1 H, CH=CH2), 5.665.49 (m, 1
H, CH-1), 5.054.94 (m, 2 H, CH=CH2), 5.02 (s, 4 H,
2 OCH2Ph), 3.913.82 (m, 2 H, CH2O), 3.403.25 (m, 1 H,
CH2ACH2O), 3.223.12 (m, 1 H, CH2BCH2O), 2.802.61 (m, 1 H,
CH2A-2), 2.552.44 (m, 1 H, CH2B-2), 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): = 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-1), 64.1 (br, CH2O),
43.5 (br, CH2-2), 35.9 (br, CH2CH2O), 26.1 [(CH3)3], 18.4
[SiC(CH3)3], 4.5 (SiCH3), 4.9 (SiCH3) ppm. IR (ATR): = 3436,
3068, 3033, 3008, 2954, 2929, 2884, 1599, 1499, 1258, 1158, 1146,
1070, 1052, 1027, 831 cm1. HRMS (ESI): calcd. for [C32H42O4Si
+ Na]+ 541.2750; found 541.2745.
3-Methylhex-5-en-2-ol (29a):[47] Allylmagnesium bromide (1 m in
Et2O, 83 mL, 83.0 mmol, 1.5 equiv.) was added at 40 C to a solution of copper(I) iodide (2.11 g, 11.1 mmol, 0.2 equiv.) in dry THF
(30 mL). After 30 min, 2,3-cis-epoxybutane (4.00 g, 55.5 mmol,
1.0 equiv.) was added. The reaction mixture was stirred at 40 C
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3599
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 organic layer was separated, and the aqueous layer was extracted with
diethyl ether (3 100 mL), dried with magnesium sulfate, and filtered. Distillation yielded 29a (5.46 g, 47.8 mmol, 86 %, ref.[47]
88 %) as a colorless liquid, Rf = 0.20 (cHex/EtOAc 5:1), b.p. 130 C.
1
H NMR (400 MHz, CDCl3): = 5.835.73 (m, 1 H, CH=CH2),
5.044.96 (m, 2 H, CH=CH2), 3.63 (p, J = 6.3 Hz, 1 H, CH-2),
2.262.19 (m, 1 H, CH2A-4), 1.961.85 (m, 2 H, CH2B-4, OH),
1.611.51 (m, 1 H, CH-3), 1.12 (d, J = 6.3 Hz, 3 H, CH3-1), 0.85
(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): = 137.5
(CH=CH2), 116.0 (CH=CH2), 71.5 (C-2), 40.1 (C-3), 37.5 (C-4),
19.8 (C-1), 14.9 (CH3-3) ppm. The data are in accordance with the
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 (3 n, 500 mL), extracted with diethyl ether
(3 200 mL), dried with magnesium sulfate, and filtered. Distillation 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.
100.0102.0 C (250 mbar). 1H NMR COSY (400 MHz, CDCl3):
= 5.81 (ddt, J = 17.0, 10.2, 6.7 Hz, 1 H, CH=CH2), 5.054.93 (m,
2 H, CH=CH2), 3.833.76 (m, 1 H, CH-2), 2.212.05 (m, 2 H,
CH2-4), 1.591.45 (m, 2 H, CH2-3), 1.17 (d, J = 6.2 Hz, 3 H, CH31) ppm. The data are in accordance with the literature.[48] 13C
NMR (100.6 MHz, CDCl3): = 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 mol,
2.0 equiv.) was added to a solution of alcohol 28a (84 mg,
159 mol, 1.0 equiv.) in acetonitrile (1 mL) and water (1 mL).
TEMPO (20 mg, 127 mol, 0.65 equiv.) and bis(acetoxy)iodobenzene (139 mg, 433 mol, 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 ammonium chloride solution (20 mL), and the mixture was extracted
with ethyl acetate (3 20 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
was purified by flash chromatography on silica (cHex/EtOAc 5:1)
to yield a colorless oil, Rf = 0.26 (cHex/EtOAc 5:1). 1H NMR
COSY (400 MHz, CDCl3, diastereomeric mixture): = 7.447.30
(m, 10 H, 2 Ph), 6.54/6.52 (d, J = 2.5 Hz, 1 H, 6-H), 6.50/6.45
(d, J = 2.5 Hz, 1 H, 4-H), 5.965.84/5.575.45 (m, 1 H, CH=CH2),
5.235.16 (m, 1 H, CHO), 5.074.72 (m, 6 H, CH=CH2,
2 OCH2Ph), 4.52/4.46 (d, J = 16.7 Hz, 1 H, CH2ACOO), 3.86/
3.85 (d, J = 16.7 Hz, 1 H, CH2BCOO), 2.692.47 (m, 1 H, CH-2),
1.16/1.15 (d, J = 6.5 Hz, 3 H, CH3-2), 0.84/0.80 [s, 9 H,
C(CH3)3], 0.01/0.04 (s, 3 H, SiCH3), 0.26/0.28 (s, 3 H,
SiCH3) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3, diastereomeric mixture): = 177.2 (COOH), 157.5/157.4 (Cq-5), 156.2/
156.0 (Cq-3), 142.1/139.7 (CH=CH2), 136.4/136.3 (Cq-1, Ph), 136.0/
136.0 (Cq-1, Ph), 134.4/134.1 (Cq-1), 127.8/127.7 (2 CH-3,
2 CH-5, Ph), 127.3/127.2 (CH-4, Ph), 127.1 (CH-2, CH-6, Ph),
127.0/127.0 (CH-4, Ph), 126.1/126.1 (CH-2, CH-6, Ph), 123.3/123.1
(Cq-2), 113.5/113.2 (CH=CH2), 108.5/108.3 (CH-6), 98.0/97.9 (CH4), 70.7/70.6 (CHO), 69.5/69.4 (OCH2Ph), 69.3/69.2 (OCH2Ph),
44.6/44.3 (CH-2), 37.7 (CH2COOH), 25.1/25.1 [(CH3)3], 17.4
3600
www.eurjoc.org
[SiC(CH3)3], 17.1/15.3 (CH3-2), 5.7/5.7 (SiCH3), 6.0/6.1

(SiCH3). IR (ATR): = 3067, 3033, 2956, 2929, 2857, 1709, 1604,
1499, 1150, 1056, 1030, 836, 736, 697 cm1. HRMS (ESI): calcd.
for [C33H42O5Si + Na]+ 569.2699; found 569.2698. A solution of
the crude acid (87 mg, 159 mol, 1.0 equiv.), DMAP (4 mg,
32 mol, 0.2 equiv.), and alcohol 29a (45 mg, 398 mol, 2.5 equiv.)
in dry dichloromethane (5 mL) was cooled to 0 C. N,N-Dicyclohexylcarbodiimide (69 mg, 334 mol, 2.1 equiv.) was dissolved in
dry dichloromethane (2 mL) and added. The reaction mixture was
stirred for 15 h and then allowed to warm to room temperature.
Water (0.1 mL) was added, and stirring was carried out for an additional 30 min. The reaction mixture was filtered through a short
plug of silica (CH2Cl2). Purification by flash chromatography on
silica (cHex/EtOAc 20:1 + 0.5 % NEt3) yielded 30a (75 mg,
117 mol, 74 % over two steps) as a yellow oil, Rf = 0.66 (cHex/
EtOAc 5:1). 1H NMR COSY (400 MHz, CDCl3, diastereomeric
mixture): = 7.457.31 (m, 10 H, 2 Ph), 6.576.54 (m, 1 H, 6H), 6.506.44 (m, 1 H, 4-H), 5.985.88/5.595.50 (m, 1 H,
CHCH=CH2), 5.825.67 (m, 1 H, CH2CH=CH2), 5.235.14 (m, 1
H, CHO-1), 5.105.02 + 4.894.75 (m, 8 H, 2 CH=CH2,
2 OCH2Ph), 4.884.82 (m, 1 H, CHO-2), 4.634.40 (m, 1 H,
CH2ACOO), 3.823.67 (m, 1 H, CH2BCOO), 2.782.66 (m, 1 H,
CH-2), 2.242.09 (m, 1 H, CH2ACH=CH2), 1.931.83 (m, 1 H,
CH2BCH=CH2), 1.801.71 (m, 1 H, CH-3), 1.201.12 + 0.90
0.76 (m, 9 H, 3 CH3), 0.86/0.83 [s, 9 H, 3 C(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): =
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 (2 Cq-1, Ph), 136.1/
136.1/135.9/135.8 (Cq-1), 128.7/128.7/128.6 (2 CH-3, 2 CH-5,
Ph), 128.1/128.1/127.8/127.8 (2 CH-4, Ph), 127.9/127.0 (2 CH2, 2 CH-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-2), 71.6/71.5/71.5/71.4 (CHO-1), 70.3/70.3 (OCH2Ph),
70.1/70.1/70.0/70.0 (OCH2Ph), 45.1/45.1/45.0 (CH-2), 38.9/38.8/
38.8/38.8 (CH2COO), 37.4/37.4/37.4/37.3/37.2/37.1 (CH-3,
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 (3 CH3), 4.8/5.1/5.3 (2 SiCH3).
IR (ATR): = 3068, 3034, 2929, 2856, 1727, 1498, 1144, 1043, 910,
864, 835, 775, 733, 696 cm1. HRMS (ESI): calcd. for [C40H54O5Si
+ Na]+ 665.3638; found 665.3629.
Diene 30b:[28] Sodium hydrogen carbonate (168 mg, 2.00 mmol,
2.5 equiv.), TEMPO (63 mg, 0.40 mmol, 0.5 equiv.), and [bis(acetoxy)iodo]benzene (709 mg, 2.20 mmol, 2.8 equiv.) were added to a
solution of alcohol 28b (84 mg, 159 mol, 1.0 equiv.) in acetonitrile
(4.5 mL) and water (4.5 mL). The reaction mixture was stirred at
30 C under argon for 4 h and was then quenched with saturated
aqueous ammonium chloride solution (75 mL), extracted with
ethyl acetate (3 70 mL), dried with magnesium sulfate, and filtered. Removing the solvent in vacuo yielded the crude acid, which
was used without further purification. A solution of the crude acid
(432 mg, 0.79 mmol, 1.0 equiv.), DMAP (20 mg, 0.16 mmol,
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,N-Dicyclohexylcarbodiimide (359 mg, 1.74 mmol, 2.2 equiv.) was dissolved in
stirred for 16 h and then allowed to warm to room temperature.
Water (0.3 mL) was added, and stirring was carried out for an additional 30 min. The reaction mixture was filtered through a short
plug of silica (CH2Cl2). Purification by flash chromatography on
silica (cHex/EtOAc 30:1 + 0.5 % NEt3) yielded 30b [397 mg,
Eur. J. Org. Chem. 2015, 35873608
0.63 mmol, 80 % (over two steps)] as a yellow oil, Rf = 0.58 (cHex/
EtOAc 5:1). 1H NMR COSY (400 MHz, CDCl3, diastereomeric
mixture): = 7.457.30 (m, 10 H, 2 Ph), 6.53 (d, J = 2.4 Hz, 1
H, 6-H), 6.48 (d, J = 2.4 Hz, 1 H, 4-H), 5.825.67 (m, 2 H,
2 CH=CH2), 5.615.43 (m, 1 H, CHO-1), 5.084.95 (m, 8 H,
2 CH=CH2, 2 OCH2Ph), 4.884.81 (m, 1 H, CHO-2), 4.61
4.39 (m, 1 H, CH2ACOO), 3.863.74 (m, 1 H, CH2BCOO), 2.76
2.59 (m, 1 H, CH2A-2), 2.462.38 (m, 1 H, CH2B-2), 2.232.09
(m, 1 H, CH2A-4), 1.941.78 (m, 1 H, CH2B-4), 1.831.72 (m, 1
H, CH-3), 1.18/1.16 (d, J = 6.4 Hz, 3 H, CH3-1), 0.89/0.84 (d,
J = 6.6 Hz, 3 H, CH3-3), 0.84 [s, 9 H, 3 C(CH3)3], 0.00 (s, 3 H,
SiCH3), 0.18 (s, 3 H, SiCH3). 13C NMR HSQC, HMBC
(100.6 MHz, CDCl3, diastereomeric mixture): = 172.1 (COO),
158.3 (Cq-5), 156.4 (br, Cq-3), 137.2/137.0 (2 Cq-1, Ph), 136.8
(CH=CH2), 136.8 (CH=CH2), 136.1 (br, Cq-1), 128.6 (CH-3, CH5, 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-2), 70.3 (OCH2Ph), 70.1
(OCH2Ph), 67.9 (br, CHO-1), 43.2 (br, CH2-2), 38.6 (br,
CH2COO), 37.1 (CH-3, CH2-4), 26.0 [(CH3)3], 18.3 [SiC(CH3)3],
16.4/16.2 (CH3-1), 14.8/14.7 (CH3-3), 4.8/4.8 (SiCH3), 5.1
(SiCH3). IR (ATR): = 3070, 3033, 1729, 1604, 1498, 1145, 1067,
1046, 834, 776, 735, 697 cm1. 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(acetoxy)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 acetonitrile (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 (3 100 mL), dried with magnesium sulfate, and filtered. 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,N-Dicyclohexylcarbodiimide (972 mg, 4.71 mmol, 1.5 equiv.) was dissolved in
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 colorless oil, Rf = 0.65 (cHex/EtOAc 4:1). 1H NMR COSY (400 MHz,
CDCl3, diastereomeric mixture): = 7.457.30 (m, 10 H, 2 Ph),
6.536.52 (m, 1 H, 6-H), 6.48 (d, J = 2.4 Hz, 1 H, 4-H), 5.825.71
(m, 2 H, 2 CH=CH2), 5.605.44 (m, 1 H, CHO-1), 5.084.91 (m,
9 H, 2 CH=CH2, 2 OCH2Ph, CHO-2), 4.544.30 (m, 1 H,
CH2ACOO), 3.833.77 (m, 1 H, CH2BCOO), 2.742.58 (m, 1 H,
CH2A-2), 2.462.39 (m, 1 H, CH2B-2), 2.161.98 (m, 2 H, CH24), 1.791.70 (m, 1 H, CH2A-3), 1.611.53 (m, 1 H, CH2B-3),
1.241.20 (m, 3 H, CH3-1), 0.84 [s, 9 H, 3 C(CH3)3], 0.00 (s, 3
H, SiCH3), 0.18 (s, 3 H, SiCH3) ppm. 13C NMR HSQC, HMBC
(100.6 MHz, CDCl3, diastereomeric mixture): = 172.1 (COO),
158.4 (Cq-5), 156.5 (br, Cq-3), 137.9 (CH=CH2), 137.3/137.0
(2 Cq-1, Ph), 136.1 (CH=CH2), 136.1 (Cq-1), 128.7 (CH-3, CH5, 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), 127.1/127.0 (CH-2, CH-6, Ph), 124.4
(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-2), 70.4 (OCH2Ph), 70.1
(OCH2Ph), 67.9 (br, CHO-1), 43.2 (br, CH2-2), 38.6 (br,
CH2COO), 35.2/35.2 (CH2-3), 29.8/29.7 (CH2-4), 26.0 [(CH3)3],
Eur. J. Org. Chem. 2015, 35873608
20.1/20.0 (CH3-1), 18.3 [SiC(CH3)3], 4.8 (SiCH3), 5.1 (SiCH3).

IR (ATR): = 3069, 3033, 2929, 2855, 2803, 1730, 1604, 1498,
[C38H50O5Si + Na]+ 637.3325; found 637.3314.
Lactone 31a: Diene 30a (257 mg, 0.40 mmol, 1.0 equiv.) was dissolved in dry and degassed toluene (30 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] 80 mg, 84 mol, 0.2 equiv.} was added, and the reaction 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-3one (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-2ylidene](3-phenyl-1H-inden-1-ylidene)ruthenium(II) dichloride,[49]
313 mg, 0.33 mmol, 0.15 equiv.} was added, and the reaction mixture 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 DessMartin 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
5:1 3:1) yielded 33 (53 mg, 107 mol, 5 %) as a brown oil, Rf =
0.11 (cHex/EtOAc 5:1). 1H NMR COSY, NOESY (400 MHz,
CDCl3, diastereomeric mixture): = 7.447.32 (m, 10 H, 2 Ph),
6.536.50 (m, 1 H, 7-H), 6.366.31 (m, 1 H, 5-H), 5.605.54 (m, 1
H, 1-H), 5.495.40 (m, 1 H, 3-H), 5.285.23 (m, 1 H, 4-H), 5.03
5.02 (m, 4 H, 2 OCH2Ph), 3.873.57 (m, 2 H, CH2-4), 3.082.98/
2.732.65 (m, 1 H, 2-H), 2.502.39/2.262.20 (m, 1 H, 6-H), 2.30
2.12 (m, 1 H, CH2A-5), 2.011.88 (m, 1 H, CH2B-5), 2.091.97
(m, 3 H, CH3-8), 1.030.91 (m, 6 H, CH3-1, CH3-6) ppm. 13C
NMR HSQC, HMBC (100.6 MHz, CDCl3, diastereomeric mixture): = 212.3 (CO), 170.4 (COO), 160.0 (Cq-6), 155.7 (Cq-8),
136.4 (2 Cq-1, Ph), 133.7 (CH-4), 132.5 (Cq-4a), 128.8127.4 (m,
11 C, CH-3, 2 CH-2, 2 CH-3, 2 CH-4, 2 CH-5, 2 CH-6,
Ph), 114.2 (Cq-8a), 104.4 (CH-5), 99.2 (CH-7), 81.8 (CH-1), 70.4
(2 OCH2Ph), 46.9 (CH-6), 44.0/38.6 (CH-2), 35.8 (CH2-5), 35.3
(CH2-4), 28.4 (CH3-8), 16.615.6 (m, 2 C, CH3-1, CH3-6).
HRMS (ESI): calcd. for [C32H34O5 + Na]+ 521.2304; found
521.2315.
Lactone 34a:[18] Diene 30b (336 mg, 0.53 mmol, 1.0 equiv.) was
dissolved in dry and degassed toluene (90 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] 120 mg, 0.13 mmol, 0.24 equiv.} was added, and the
reaction mixture was heated to 80 C for 3 h. The solvent was removed in vacuo. Purification by flash chromatography on silica
(cHex/EtOAc 40:1) yielded 31b (185 mg, 0.31 mmol, 58 %) as a
brown oil, Rf = 0.50 (cHex/EtOAc 5:1), IR (ATR): = 3090, 3065,
3032, 2954, 2929, 2884, 1721, 1604, 1498, 1148, 1082, 1066, 1048,
1030, 834, 734 cm1. HRMS (ESI): calcd. for [C37H48O5Si + Na]+
623.3169; found 623.3155. TBAF (1 m in THF, 0.35 mL,
0.35 mmol, 1.5 equiv.) was added to the obtained brown oil. The
www.eurjoc.org
3601
FULL PAPER
reaction mixture was stirred at room temperature for 4 d. Water

(30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 30 mL), dried with magnesium sulfate, and filtered. The solvent was removed in vacuo. Purification
by flash chromatography on silica (cHex/EtOAc 10:1 5:1) yielded
34a (diastereomer A: 22.5 mg, 46 mol, 20 %, diastereoisomer B:
27 mg, 56 mol, 25 %) as a colorless oil.
Diastereomer A: Rf = 0.19 (cHex/EtOAc 5:1). 1H NMR COSY
(400 MHz, CDCl3): = 7.457.32 (m, 10 H, 2 Ph), 6.66 (d, J =
2.4 Hz, 1 H, 4-H), 6.63 (d, J = 2.4 Hz, 1 H, 6-H), 5.55 (ddd, J =
14.6, 10.3, 3.6 Hz, 1 H, 12-H), 5.115.01 (m, 4 H, 2 OCH2Ph),
4.84 (dq, J = 9.9, 6.3 Hz, 1 H, 15-H), 4.804.75 (m, 1 H, 11-H),
4.754.68 (m, 1 H, 9-H), 4.00 (d, J = 11.4 Hz, 1 H, OH), 3.70 (d,
J = 15.4 Hz, 1 H, CH2A-2), 3.33 (d, J = 15.4 Hz, 1 H, CH2B-2),
2.70 (td, J = 11.7, 5.6 Hz, 1 H, CH2A-10), 2.51 (ddd, J = 11.7, 9.8,
4.6 Hz, 1 H, CH2B-10), 2.101.91 (m, 2 H, CH2-13), 1.761.65 (m,
1 H, 14-H), 1.23 (d, J = 6.3 Hz, 3 H, CH3-15), 0.90 (d, J = 6.9 Hz,
3 H, CH3-14) ppm. 13C NMR HSQC, HMBC (100.6 MHz,
CDCl3): = 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,
CH-5, Ph), 128.7 (CH-3, CH-5, Ph), 128.6 (CH-4, Ph), 128.2 (CH4, Ph), 127.9 (CH-2, CH-6, Ph), 127.8 (CH-2, CH-6, Ph), 123.7
(CH-11), 122.2 (Cq-8), 109.5 (CH-4), 100.7 (CH-6), 76.9 (CH-15),
72.5 (CH-9), 70.7 (OCH2Ph), 70.2 (OCH2Ph), 40.4 (CH2-13), 40.3
(CH2-10), 38.6 (CH2-2), 38.6 (CH-14), 20.3 (CH3-15), 19.6 (CH314) ppm. IR (ATR): = 3558, 3090, 3065, 3033, 2963, 2928, 1728,
1606, 1498, 1298, 1202, 1143, 1053, 1020, 733, 698 cm1. HRMS
(ESI): calcd. for [C31H34O5 + Na]+ 509.2304; found 509.2295.
Diastereomer B: Rf = 0.09 (cHex/EtOAc 5:1). 1H NMR (400 MHz,
CDCl3): = 7.447.31 (m, 10 H, 2 Ph), 6.63 (d, J = 2.4 Hz, 1 H,
6-H), 6.40 (d, J = 2.4 Hz, 1 H, 4-H), 5.295.20 (m, 1 H, 12-H),
5.155.00 (m, 4 H, 2 OCH2Ph), 4.944.87 (m, 1 H, 15-H), 4.78
4.67 (m, 2 H, 11-H, 9-H), 3.83 (br. s, 1 H, OH), 3.71 (d, J =
16.5 Hz, 1 H, CH2A-2), 3.47 (d, J = 16.5 Hz, 1 H, CH2B-2), 2.82
2.74 (m, 1 H, CH2A-10), 2.492.44 (m, 1 H, CH2B-10), 2.031.99
(m, 1 H, CH2A-13), 1.931.84 (m, 1 H, CH2B-13), 1.501.40 (m, 1
H, 14-H), 1.08 (d, J = 6.3 Hz, 3 H, CH3-15), 0.83 (d, J = 7.0 Hz,
3 H, CH3-14) ppm. 13C NMR HSQC (100.6 MHz, CDCl3): =
170.0 (COO), 158.1 (Cq-5), 157.8 (Cq-7), 136.9 (Cq-1, Ph), 136.1
(Cq-1, Ph), 134.6 (CH-12), 134.5 (Cq-3), 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-2, CH-6, Ph), 127.6 (CH-2, CH-6, Ph), 123.5 (CH-11), 123.2
(Cq-8), 109.8 (CH-4), 100.4 (CH-6), 76.7 (CH-15), 70.7 (OCH2Ph),
70.6 (CH-9), 70.3 (OCH2Ph), 41.1 (CH2-13), 40.5 (CH2-2), 40.4
(CH2-10), 37.3 (CH-14), 19.9 (CH3-15), 19.0 (CH3-14) ppm. IR
(ATR): = 3559, 3090, 3064, 3033, 2972, 2963, 2930, 2880, 1718,
1606, 1498, 1269, 1145, 1060, 1028, 735, 698 cm1. HRMS (ESI):
calcd. for [C31H34O5 + Na]+ 509.2304; found 509.2292.
Lactone 34b:[18] Diene 30c (922 mg, 1.50 mmol, 1.0 equiv.) was dissolved in dry and degassed toluene (8 mL). The ruthenium catalyst
{tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2ylidene](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
silica (cHex/EtOAc 30:1 + 1 % NEt 3 ) yielded 31c (593 mg,
1.01 mmol, 67 %, ref.[18] 83 %) as a yellow oil, Rf = 0.20 (cHex/
EtOAc 30:1). IR (ATR): = 3091, 3065, 3033, 2951, 2929, 1725,
1605, 1498, 1256, 1151, 1068, 1030, 835 cm1. HRMS (ESI): calcd.
for [C36H46O5Si + Na]+ 609.3012; found 609.3019. TBAF (1 m in
3602
www.eurjoc.org
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 (2 40 mL), dried
with magnesium sulfate, and filtered. The solvent was removed in
10:1 5:1) yielded 34b (229 mg, 0.48 mmol, 64 %, ref.[18] 97 %) as
a yellow oil.
Diastereomer A: Rf = 0.13 (cHex/EtOAc 10:1). 1H NMR COSY
(400 MHz, CDCl3): = 7.457.32 (m, 10 H, 2 Ph), 6.64 (d, J =
2.5 Hz, 1 H, 4-H), 6.63 (d, J = 2.5 Hz, 1 H, 6-H), 5.50 (ddd, J =
14.6, 10.4, 3.7 Hz, 1 H, 12-H), 5.245.16 (m, 1 H, 15-H), 5.09 (d,
J = 11.2 Hz, 1 H, OCH2APh), 5.08 (s, 2 H, OCH2Ph), 5.03 (d, J =
11.2 Hz, 1 H, OCH2BPh), 4.904.81 (m, 1 H, 11-H), 4.734.66 (m,
1 H, 9-H), 3.98 (d, J = 11.6 Hz, 1 H, OH), 3.71 (d, J = 15.5 Hz, 1
H, CH2A-2), 3.34 (d, J = 15.5 Hz, 1 H, CH2B-2), 2.792.72 (m, 1
H, CH2A-10), 2.552.48 (m, 1 H, CH2B-10), 2.292.21 (m, 1 H,
CH2A-13), 2.031.94 (m, 1 H, CH2B-13), 1.711.54 (m, 2 H, CH214), 1.23 (d, J = 6.3 Hz, 3 H, CH3-15) ppm. 13C NMR HSQC,
HMBC (100.6 MHz, CDCl3): = 171.4 (COO), 158.5 (Cq-5), 158.0
(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-4, Ph), 128.2 (CH-4, Ph), 127.9 (CH-2, CH-6, Ph), 127.8 (CH2, CH-6, Ph), 124.8 (CH-11), 122.2 (Cq-8), 109.5 (CH-4), 100.7
(CH-6), 72.6 (CH-15), 72.5 (CH-9), 70.7 (OCH 2 Ph), 70.2
(OCH2Ph), 40.7 (CH2-10), 38.7 (CH2-2), 34.4 (CH2-14), 30.8 (CH213), 21.6 (CH3-15) ppm. IR (ATR): = 3556, 3090, 3065, 3033,
2975, 2930, 1726, 1606, 1498, 1298, 1142, 1060, 1013, 908, 728,
found 495.2154.
Diastereomer B: R f = 0.08 (cHex/EtOAc 10:1). 1 H NMR
(400 MHz, CDCl3): = 7.457.31 (m, 10 H, 2 Ph), 6.63 (d, J =
2.4 Hz, 1 H, 6-H), 6.42 (d, J = 2.4 Hz, 1 H, 4-H), 4.89 (ddd, J =
14.7, 9.3, 4.3 Hz, 1 H, 12-H), 5.155.02 (m, 2 OCH2Ph, 5 H, 15H), 5.305.21 (m, 1 H, 11-H), 4.704.63 (m, 1 H, 9-H), 3.753.66
(m, CH2A-2, 2 H, OH), 3.46 (d, J = 16.4 Hz, 1 H, CH2B-2), 2.85
2.77 (m, 1 H, CH2A-10), 2.492.44 (m, 1 H, CH2B-10), 2.172.09
(m, 1 H, CH2A-13), 1.991.87 (m, 1 H, CH2B-13), 1.541.49 (m, 1
H, CH2A-14), 1.401.31 (m, 1 H, CH2B-14), 1.09 (d, J = 6.4 Hz, 3
H, CH3-15) ppm. 13C NMR HSQC (100.6 MHz, CDCl3): = 170.0
(COO), 158.2 (Cq-5), 157.9 (Cq-7), 136.9 (Cq-1, Ph), 136.1 (Cq-1,
Ph), 134.5 (Cq-3), 134.0 (CH-12), 129.1 (CH-3, CH-5, Ph), 128.8
(CH-3, CH-5, Ph), 128.6 (CH-4, Ph), 128.2 (CH-4, Ph), 127.8 (CH2, CH-6, Ph), 127.6 (CH-2, CH-6, Ph), 124.6 (CH-11), 123.2 (Cq8), 110.1 (CH-4), 100.4 (CH-6), 72.6 (CH-15), 70.7 (OCH2Ph), 70.6
(CH-9), 70.3 (OCH2Ph), 41.0 (CH2-2), 40.3 (CH2-10), 33.3 (CH214), 31.1 (CH2-13), 21.5 (CH3-15) ppm. IR (ATR): = 3561, 3064,
3032, 2974, 2929, 1720, 1607, 1588, 1498, 1268, 1146, 1055, 1038,
found 495.2159.
5,7-Di-O-benzyl-14-methyl-11,12-dehydrocurvularin (35a): [18]
Alcohol 34a (20 mg, 41 mol, 1.0 equiv.) was dissolved in dry
dichloromethane (5 mL). DessMartin periodinane (15 wt.-%,
0.10 mL, 49 mol, 1.2 equiv.) was added. After 17 h stirring at
room temperature the reaction mixture was quenched with saturated aqueous sodium thiosulfate solution (10 mL) and saturated
aqueous sodium hydrogen carbonate solution (10 mL), extracted
with dichloromethane (3 30 mL), dried with magnesium sulfate,
and filtered. Removing the solvent in vacuo yielded 35a (18 mg,
37 mol, 92 %) as a colorless oil, Rf = 0.38 (cHex/EtOAc 5:1). 1H
6.61 (br. s, 1 H, 4-H), 6.53 (d, J = 2.2 Hz, 1 H, 6-H), 5.625.54 (m,
Eur. J. Org. Chem. 2015, 35873608
1 H, 12-H), 5.235.15 (m, 1 H, 11-H), 5.095.01 (m, 4 H,
2 OCH2Ph), 4.75 (dq, J = 9.1, 6.3 Hz, 1 H, 15-H), 3.603.30 (m,
4 H, CH2-2, CH2-10), 2.182.12 (m, 1 H, CH2A-13), 2.011.92 (m,
1 H, CH2B-13), 1.751.65 (m, 1 H, 14-H), 1.16 (d, J = 6.3 Hz, 3
HSQC, HMBC (100.6 MHz, CDCl 3 ): = 204.8 (CO), 170.7
(COO), 160.3 (Cq-5), 156.5 (Cq-7), 136.6 (Cq-1, Ph), 136.3 (Cq-1,
Ph), 137.5 (CH-12), 134.2 (Cq-3), 128.8 (2 CH-3, 2 CH-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), 124.5 (Cq-8), 119.1 (CH-11), 109.2 (CH-4), 99.7
(CH-6), 76.7 (CH-15), 70.6 (OCH2Ph), 70.3 (OCH2Ph), 49.1 (CH210), 39.8 (CH2-13), 38.2 (CH2-2), 38.2 (CH-14), 19.8 (CH3-15), 19.0
(CH3-14) ppm. IR (ATR): = 3090, 3065, 3033, 2974, 2931, 2880,
2835, 1726, 1690, 1602, 1498, 1310, 1281, 1157, 1064, 735 cm1.
HRMS (ESI): calcd. for [C 31 H 32 O 5 + 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 dichloromethane (10 mL), and DessMartin 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 dichloromethane (3 40 mL), dried with magnesium sulfate, and filtered. The
solvent was removed in vacuo. Purification by flash chromatography 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): = 7.447.29 (m, 10 H, 2 Ph), 6.60
(br. s, 1 H, 4-H), 6.54 (d, J = 2.1 Hz, 1 H, 6-H), 5.575.45 (m, 1
H, 12-H), 5. 30 5 .2 2 ( m, 1 H , 1 1- H) , 5 .1 1 5. 02 (m , 5 H,
2 OCH2Ph, 15-H), 3.703.27 (m, 4 H, CH2-2, CH2-10), 2.312.23
(m, 1 H, CH2A-13), 2.051.98 (m, 1 H, CH2B-13), 1.701.53 (m, 2
HSQC, HMBC (100.6 MHz, CDCl 3 ): = 204.8 (CO), 171.0
(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 (2 CH-3, 2 CH-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 (CH210), 38.1 (CH 2 -2), 33.8 (CH-14), 30.6 (CH 2 -13), 21.1 (CH 3 15) ppm. IR (ATR): = 3090, 3064, 3033, 2976, 2931, 1725, 1690,
1602, 1581, 1498, 1311, 1283, 1157, 1072 cm1. 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-diphenylphosphine)iridium(I) hexafluorophosphate, 7 mg, 8 mol,
1.0 equiv.] in dry THF (2 mL) was saturated with hydrogen and
stirred at room temperature for 10 min. The hydrogen was exchanged for argon and the solution was degassed. A solution of
the ,-unsaturated lactone 35a (4 mg, 8 mol, 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 20:1 10:1)
yielded 36 (2.4 mg, 5 mol, 60 %) as a colorless oil, Rf = 0.05 (cHex/
EtOAc 20:1). 1H NMR COSY (600 MHz, CDCl3): = 7.427.31
(m, 10 H, 2 Ph), 6.51 (br. s, 1 H, 6-H), 6.45 (d, J = 2.2 Hz, 1 H,
4-H), 5.755.70 (m, 1 H, 12-H), 5.185.14 (m, 1 H, 13-H), 5.07
5.00 (m, 4 H, 2 OCH2Ph), 4.784.72 (m, 1 H, 15-H), 3.98 (d, J
= 17.2 Hz, 1 H, CH2A-2), 3.24 (d, J = 17.2 Hz, 1 H, CH2B-2), 3.04
2.98 (m, 2 H, CH2-10), 2.452.40 (m, 1 H, CH2A-11), 2.112.05 (m,
1 H, 14-H), 1.991.93 (m, 1 H, CH2B-11), 1.23 (d, J = 6.5 Hz, 3
HSQC, HMBC (150.9 MHz, CDCl3): = 171.3 (COO), 160.1 (CqEur. J. Org. Chem. 2015, 35873608
5), 156.7 (Cq-7), 136.5 (Cq-1, Ph), 136.3 (Cq-1, Ph), 134.5 (CH-13),
133.9 (Cq-3), 130.6 (CH-12), 128.8 (2 CH-3, 2 CH-5, Ph), 128.3
(CH-4, Ph), 128.3 (CH-4, Ph), 127.7 (CH-2, CH-6, Ph), 127.5 (CH2, CH-6, Ph), 125.6 (Cq-8), 110.2 (CH-4), 99.5 (CH-6), 74.2 (CH15), 70.3 (OCH2Ph), 70.3 (OCH2Ph), 45.8 (CH2-10), 44.7 (CH-14),
38.6 (CH2-2), 24.4 (CH2-11), 18.5 (CH3-15), 17.2 (CH3-14) ppm.
The C-9 resonance could not be found due to an unfavorable S/N
ratio (long relaxation time and low sample concentration). IR
(ATR): = 3091, 3065, 3033, 2972, 2930, 2875, 1729, 1689, 1602,
1580, 1498, 1310, 1285, 1192, 1157, 1071 cm1. HRMS (ESI): calcd.
for [C31H32O5 + Na]+ 507.2147; found 507.2155.
5,7-Di-O-benzyl-12-oxo-10,11-dehydrocurvularin (37): The ,-unsaturated lactone 35b (5 mg, 11 mol, 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 f lash
chromatography on silica (cHex/EtOAc 5:1) yielded 37 (1.7 mg,
4 mol, 34 %) as a colorless oil, Rf = 0.13 (cHex/EtOAc 5:1). 1H
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),
5.114.99 (m, 5 H, 2 OCH2Ph, OCH-15), 3.42 (d, J = 14.3 Hz, 1
H, CH2A-2), 3.25 (d, J = 14.3 Hz, 1 H, CH2B-2), 2.602.52 (m, 2
H, CH2-13), 2.102.04 (m, 1 H, CH2A-14), 1.91 (dtd, J = 15.3, 9.3,
2.6 Hz, 1 H, CH2B-14), 1.261.23 (m, 3 H, CH3-15) ppm. 13C NMR
HSQC, HMBC (150.9 MHz, CDCl3): = 201.6 (Cq-12), 196.3 (Cq9), 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
(OCH 2 Ph), 70.4 (OCH 2 Ph), 39.7 (CH 2-13), 39.6 (CH2 -2), 33.4
(CH2-14), 19.8 (CH3-15) ppm. IR (ATR): = 3065, 3033, 2953,
2924, 2854, 2783, 1729, 1696, 1660, 1601, 1498, 1311, 1263,
found 485.1953.
Methyl 2-[3,5-Bis(benzyloxy)-2-(2-methylpent-4-enoyl)phenyl]acetate (38):[16,17] Trifluoroacetic acid (96 mL) and trifluoroacetic anhydride (48 mL) were added to methyl 3,5-bis(benzyloxy)phenylacetate (5.64 g, 15.6 mmol, 1.0 equiv.) at 26 C. Then, 2-methylpent-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 neutralized with solid sodium hydrogen carbonate. The organic layer
was separated, washed with saturated aqueous sodium hydrogen
carbonate solution (2 200 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, R f = 0.22 (cHex/EtOAc 10:1). 1 H NMR
(400 MHz, CDCl3): = 7.447.31 (m, 10 H, 2 Ph), 6.56 (d, J =
2.2 Hz, 1 H, 6-H), 6.54 (d, J = 2.2 Hz, 1 H, 4-H), 5.655.52 (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 =
16.2 Hz, 1 H, CH2A-COOMe), 3.51 (d, J = 16.2 Hz, 1 H, CH2BCOOMe), 3.323.21 (m, 1 H, COCH), 2.482.37 (m, 1 H, CH2A3), 2.101.99 (m, 1 H, CH 2 B -3), 1.01 (d, J = 6.9 Hz, 3 H,
CH3) ppm. 13C NMR (75.5 MHz, CDCl3): = 209.5 (C=O), 171.2
(COOMe), 160.8 (C-5), 158.3 (C-3), 136.5 (CH=CH2), 136.4 (C-1),
136.0 (C-1, Ph-1), 135.4 (C-1, Ph-2), 128.8 (C-3, C-5, Ph-1), 128.8
(C-3, C-5, Ph-2), 128.4 (C-4, Ph-1), 128.4 (C-4, Ph-2), 128.0 (C-2,
C-6, Ph-1), 127.8 (C-2, C-6, Ph-2), 124.0 (C-2), 116.4 (CH=CH2),
109.2 (C-6), 99.5 (C-4), 70.9 (OCH 2 Ph), 70.3 (OCH 2 Ph), 52.2
(OCH3), 46.3 (COCH), 39.0 (CH2COOMe), 37.1 (CH2 -3), 15.8
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3603
FULL PAPER
(CH3) ppm. IR (ATR): = 3066, 3033, 2925, 2854, 1738, 1680,

1601, 1577, 1434, 1318, 1286, 1161, 699 cm1. HRMS (ESI): calcd.
for [C 29 H 30 O 5 + Na] + 481.1991; found 481.2001. C 2 9 H 30 O 5
(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 temperature for 5 h. The solvent was removed in vacuo. Then HCl (2 n,
200 mL) was added, and the mixture was extracted with dichloromethane (3 100 mL), dried with magnesium sulfate, and filtered.
The solvent was removed in vacuo. Purification by f lash
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. 111.0111.5 (cHex/EtOAc/HOAc
50:10:1). 1H NMR (400 MHz, CDCl3): = 7.447.34 (m, 10 H,
2 Ph), 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, OCH 2 Ph), 5.05 (s, 2 H, OCH 2 Ph), 4.964.87 (m, 2 H,
CH=CH2), 3.51 (d, J = 13.3 Hz, 1 H, CH2A-COOH), 3.573.38 (m,
1 H, COCH), 3.42 (d, J = 13.3 Hz, 1 H, CH2B-COOH), 2.422.35
(m, 1 H, CH2A-3), 2.132.06 (m, 1 H, CH2B-3), 1.01 (d, J = 6.9 Hz,
3 H, CH3) ppm. 13C NMR (75.5 MHz, CDCl3): = 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=CH 2 ), 108.8 (C-6), 100.2 (C-4), 71.3 (OCH 2 Ph), 70.5
(OCH2Ph), 46.0 (COCH), 42.0 (CH2COOH), 37.8 (CH2-3), 16.4
(CH3) ppm. IR (ATR): = 3065, 3033, 2975, 2932, 1709, 1678,
1599, 1575, 1498, 1455, 1434, 1319, 1286, 1160, 984, 912, 736,
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 (3 100 mL). The combined organic layers were dried with
magnesium sulfate and filtered. Distillation yielded a colorless liquid (4.08 g, 40.7 mmol, 74 %, ref.[51] 65 %), Rf = 0.43 (cHex/EtOAc
3:1), b.p. 117 C. 1H NMR (400 MHz, CDCl3): = 5.775.69 (m,
1 H, CH=CH2), 5.155.08 (m, 2 H, CH=CH2), 3.593.53 (m, 1 H,
CH-2), 2.172.08 (m, 1 H, CH-3), 1.18 (d, J = 6.2 Hz, 3 H, CH31), 1.02 (d, J = 6.7 Hz, 3 H, CH3-3) ppm. The data are in accordance with the literature.[52] 13C NMR (75.5 MHz, CDCl3): = 140.8
(CH=CH2), 116.6 (CH=CH2), 70.9 (C-2), 46.2 (C-3), 20.3 (C-1),
16.2 (CH 3 -3) ppm. The data are in accordance with the literature.[52]
6,8-Bis(benzyloxy)-1-(pent-4-en-2-yl)-3H-isochromen-3-one (40): NMethylmorpholine (89 L, 0.81 mmol, 3.5 equiv.) was added to a
solution of acid 39 (101 mg, 0.23 mmol, 1.0 equiv.), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (48 mg,
0.25 mmol, 1.1 equiv.), HOBtH2O (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 tempera3604
www.eurjoc.org
ture for 2.5 h and was then diluted with diethyl ether (25 mL),
washed with water (2 25 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 mol, 19 %) as an orange oil, Rf = 0.12 (cHex/EtOAc/HOAc
500:100:1). 1H NMR COSY (400 MHz, CDCl3): = 7.467.34 (m,
10 H, 2 Ph), 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), 5.475.37 (m, 1 H, CH=CH2), 5.07
(s, 2 H, OCH 2 Ph), 5.05 (s, 2 H, OCH 2 Ph), 4.944.86 (m, 2 H,
CH=CH2), 4.214.13 (m, 1 H, CH-2), 2.552.49 (m, 1 H, CH2A3), 2.282.21 (m, 1 H, CH 2 B -3), 1.20 (d, J = 6.8 Hz, 3 H,
CH3) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3): =
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 (2 C-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 (CH2-3), 37.5 (CH-2), 18.5 (CH3) ppm. IR (ATR): = 3066,
3033, 2925, 1756, 1498, 1454, 1377, 1325, 1218, 1048, 1028,
912 cm 1 . HRMS (ESI): calcd. for [C 28 H 26 O 4 + 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,N-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
(CH 2 Cl 2 ). 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).
1
H NMR (400 MHz, CDCl3): = 7.457.29 (m, 10 H, 2 Ph),
6.606.50 (m, 3 H, 2-H, 4-H, 6-H), 5.735.64 (m, 1 H, CH=CH2),
5.044.99 (m, 2 H, CH=CH2), 5.02 (s, 4 H, 2 OCH2Ph), 4.91
4.78 (m, 1 H, OCH), 3.52 (s, 2 H, CH2COO), 2.392.24 (m, 1 H,
CH-3), 1.15 (d, J = 6.4 Hz, 3 H, CH3-1), 0.96 (J = 6.9 Hz, 3 H,
CH 3 -3) ppm. 13 C NMR DEPT (75.5 MHz, CDCl 3 ): = 171.0
(COO), 160.1 (C-3, C-5), 139.6 (CH=CH2), 137.0 (2 C-1, Ph),
136.5 (C-1), 128.7 (2 C-3, 2 C-5, Bn), 128.1 (2 C-4, Bn), 127.7
(2 C-2, 2 C-6, Bn), 115.7 (CH=CH2), 108.7 (C-2, C-6), 101.0
(C-4), 74.1 (OCH-2), 70.2 (2 OCH 2 Ph), 42.8 (CH-3), 42.1
(CH2COO), 17.1 (CH3-1), 15.7 (CH3-3) ppm. IR (ATR): = 3066,
3033, 2976, 2930, 2870, 1729, 1594, 1498, 1452, 1377, 1292, 1158,
1058, 736, 698 cm1. 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.
3-Methylpent-4-en-2-yl 2-[3,5-Bis(benzyloxy)-2-(2-methylpent-4enoyl)phenyl]acetate (42):[16,17] Trifluoroacetic acid (35 mL) and trifluoroacetic 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 saturated 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
aqueous sodium hydrogen carbonate solution (200 mL), dried with
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). 1H NMR COSY (400 MHz, CDCl3): = 7.44
7.31 (m, 10 H, 2 Ph), 6.54 (d, J = 2.1 Hz, 1 H, 6-H), 6.53 (d, J
Eur. J. Org. Chem. 2015, 35873608
= 2.1 Hz, 1 H, 4-H), 5.795.67 (m, 1 H, CHCH=CH2), 5.675.56
(m, 1 H, CH 2 CH=CH 2 ), 5.04 (s, 2 H, OCH 2 Ph), 5.02 (s, 2 H,
OCH2Ph), 5.044.98 (m, 2 H, CH2CH=CH2), 4.974.90 (m, 2 H,
CHCH=CH2), 4.914.81 (m, 1 H, OCH), 3.58 (d, J = 16.3 Hz, 1
H, CH2ACOO), 3.52 (d, J = 16.3 Hz, 1 H, CH2BCOO), 3.333.18
(m, 1 H, CHC=O), 2.502.42 (m, 1 H, CH2A-3), 2.412.32 (m, 1
H, OCHCH), 2.092.02 (m, 1 H, CH2B-3), 1.18 (d, J = 6.4 Hz, 3
H, CH3-1), 1.04 (d, J = 7.0 Hz, 3 H, CH3-2), 1.01 (d, J = 7.0 Hz,
3 H, CH3-3) ppm. 13C NMR HSQC (75.5 MHz, CDCl3): = 209.4
(CO), 170.9 (COO), 160.5 (Cq-5), 158.0 (Cq-3), 139.7
(CH2CH=CH2), 136.4 (CHCH=CH2), 136.0 (2 Cq-1, Ph), 135.3
(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 (CH2 , C H - 6 , P h ) , 1 2 4 . 2 ( C q - 2 ) , 1 1 6 .4 (C HC H= CH 2 ) , 1 15 .5
(CH 2 CH=CH 2 ), 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 (CH 2CH=CH 2), 17.0 (CH 3-1), 15.7 (CH 3-2),
15.5 (CH3-3) ppm. IR (ATR): = 3068, 3033, 2976, 2933, 2874,
1730, 1686, 1601, 1578, 1498, 1313, 1159, 1070, 738, 698 cm1.
HRMS (ESI): calcd. for [C 34 H 38 O 5 + Na] + 549.2617; found
549.2640. C 34 H 38 O 5 (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 {tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene](3-phenyl-1H-inden-1-ylidene)ruthenium(II) dichloride, [49]
100 mg, 0.11 mmol, 0.10 equiv.} was added, and the reaction mixture was stirred at 80 C for 2 h. The solvent was removed in vacuo.
20:1 15:1 10:1) yielded 43 (431 mg, 0.86 mmol, 85 %) as a colorless oil, Rf = 0.24 (cHex/EtOAc 15:1). 1H NMR COSY, HSQC
(400 MHz, [D6]acetone): = 7.527.34 (m, 10 H, 2 Ph), 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, Bn7), 5.16 (s, 2 H, CH2, Bn-5), 5.02 (td, J = 10.7, 2.2 Hz, 1 H, CH12), 4.754.68 (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), 3.623.56 (m, 1 H,
CH-10), 3.12 (d, J = 12.9 Hz, 1 H, CH2B-2), 2.582.51 (m, 1 H,
CH2A-11), 2.492.40 (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): = 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 (CH314) ppm. IR (ATR): = 3064, 3032, 2971, 2931, 2876, 1728, 1600,
1498, 1304, 1288, 1157, 1106, 1070, 699 cm1. 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-toluenesulfonyl 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.)
was added, and sodium acetate (240 mg, 2.92 mmol, 20.0 equiv.)
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 (3 20 mL). The combined aqueous layers were extracted
Eur. J. Org. Chem. 2015, 35873608
with ethyl acetate (50 mL). The combined organic layers were dried
with magnesium sulfate and filtered. The solvent was removed in
10:1) yielded the saturated lactone 44 (46 mg, 92 mol, 63 %) as a
colorless solid.
Diastereomer A: Rf = 0.20 (cHex/EtOAc 20:1), m.p. 108.0110.0 C
(CH 3 CN/H 2 O). 1 H NMR COSY (400 MHz, [D 6 ]acetone): =
7.517.31 (m, 10 H, 2 Ph), 6.806.77 (m, 2 H, 4-H, 6-H), 5.17 (d,
J = 11.8 Hz, 1 H, CH2A, OBn-7), 5.15 (s, 2 H, CH2, OBn-5), 5.14
(d, J = 11.8 Hz, 1 H, CH2B, OBn-7), 4.59 (dq, J = 9.5, 6.3 Hz, 1
H, 15-H), 4.063.98 (m, 1 H, CH2A-2), 3.343.26 (m, 2 H, CH2B2, 10-H), 1.821.69 (m, 1 H, CH2A-11), 1.681.56 (m, 1 H, 14-H),
1.351.19 (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): = 210.5 (Cq-9), 170.9 (Cq-1), 161.2 (Cq-5), 158.7
(C q -7), 137.8 (C q -1, Ph), 137.5 (C q -1, Ph), 136.1 (C q -1), 129.3
(2 CH-3, 2 CH-5, Ph), 128.9 (CH-4, Ph), 128.8 (CH-4, Ph),
128.7 (2 CH-2, 2 CH-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 (CH10), 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
(ATR): = 3065, 3032, 2963, 2926, 2855, 1726, 1680, 1600, 1498,
1152, 1100, 1065, 1044, 1027, 752, 697 cm1. HRMS (ESI): calcd.
for [C 32 H 36 O 5 + Na] + 523.2460; found 523.2440. C 3 2 H 36 O 5
(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. 121.0122.0 C
(CH 3 CN/H 2 O). 1 H NMR COSY (400 MHz, [D 6 ]acetone): =
7.507.45 (m, 4 H, 2 2-H, 2 6-H, Bn), 7.437.38 (m, 4 H, 2 3H, 2 5-H, Bn), 7.377.32 (m, 2 H, 2 4-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 =
11.8 Hz, 1 H, CH2A, OBn-7), 5.18 (d, J = 11.8 Hz, 1 H, CH2B,
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), 3.633.58 (m, 1 H, 10H), 3.47 (d, J = 17.2 Hz, 1 H, CH2B-2), 1.741.65 (m, 1 H, CH2A11), 1.621.54 (m, 1 H, 14-H), 1.511.41 (m, 2 H, CH2B-11, CH2A13), 1.391.31 (m, 1 H, CH2A-12), 1.171.11 (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, CH310), 0.990.92 (m, 1 H, CH2B-12), 0.81 (d, J = 6.9 Hz, 3 H, CH314) ppm. 13C NMR HSQC, HMBC (100.6 MHz, [D6]acetone): =
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 (CH2, 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, Bn7), 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
(CH3-14), 16.4 (CH3-10) ppm. IR (ATR): = 3091, 3065, 3033,
2961, 2932, 2874, 1722, 1601, 1576, 1498, 1327, 1261, 1156, 1071,
found 523.2440. C32H36O5 (500.63): calcd. C 76.77, H 7.25; found
C 76.47, H 7.41.
5,7-Di-O-benzyl-10-bromo-10,14-dimethylcurvularin (45):[38] Trimethylphenylammonium tribromide (357 mg, 0.95 mmol,
1.15 equiv.) was added at 0 C in 10 portions over 90 min to a solution 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
a short plug of silica (CH2Cl2). Purification by HPLC (column:
ACE5C18, gradient: H2O/CH3CN 15:85, flow: 17.5 mL min1, 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
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3605
FULL PAPER
(600 MHz, [D6]acetone): = 7.537.50 (m, 4 H, 2 2-H, 2 6-H,

Ph), 7.497.39 (m, 4 H, 2 3-H, 2 5-H, Ph), 7.377.34 (m, 2 H,
2 4-H, Ph), 6.76 (d, J = 2.2 Hz, 1 H, 6-H), 6.71 (d, J = 2.2 Hz, 1
H, 4-H), 5.27 (d, J = 11.2 Hz, 1 H, CH2A, OBn-7), 5.195.16 (m,
2 H, CH2, OBn-5), 5.14 (d, J = 11.2 Hz, 1 H, CH2B, OBn-7), 4.58
(dq, J = 10.0, 6.2 Hz, 1 H, 15-H), 3.98 (d, J = 16.3 Hz, 1 H, CH2A2), 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), 2.011.96 (m, 1 H, CH2B-11), 1.761.70 (m,
1 H, 14-H), 1.69 (s, 3 H, CH3-10), 1.681.64 (m, 1 H, CH2A-12),
1.611.51 (m, 1 H, CH2A-13), 1.361.29 (m, 1 H, CH2B-12), 1.20
(d, J = 6.2 Hz, 3 H, CH3-15), 0.990.93 (m, 1 H, CH2B-13), 0.89
(d, J = 6.9 Hz, 3 H, CH 3 -14) ppm. 13 C NMR HSQC, HMBC
(150.9 MHz, [D6]acetone): = 207.6 (Cq-9), 171.3 (Cq-1), 161.5
(Cq-5), 159.0 (Cq-7), 137.8 (Cq-1, Ph-5), 137.0 (Cq-1, Ph-7), 135.9
(Cq-1), 129.8 (CH-2, CH-6, Ph-7), 129.3 (CH-3, CH-5, Ph), 129.3
(CH-3, CH-5, Ph), 129.2 (CH-4, Ph), 128.9 (CH-4, Ph), 128.8 (CH2, CH-6, Ph-5), 124.1 (Cq-8), 112.6 (CH-4), 99.0 (CH-6), 75.5 (CH15), 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
(CH2-13), 19.7 (CH3-15), 17.4 (CH3-14) ppm. IR (ATR): = 3064,
3033, 2961, 2930, 2875, 1730, 1603, 1584, 1498, 1313, 1200, 1160,
1068, 699 cm 1 . HRMS (ESI): calcd. for [C 32 H 35 BrO 5 + 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 mol,
1.0 equiv.) and Et3N (29 L, 207 mol, 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 20 mL), dried with magnesium
sulfate, and filtered. The solvent was removed in vacuo. Purificat i o n by H P LC ( AC E 5 C 1 8 , H 2 O / C H 3 C N, 2 5 : 7 5 , f l ow =
17.5 mL min1, Rt = 12.2 min) yielded 47 (2.1 mg, 4 mol, 6 %) as
a colorless oil, R f = 0.10 (cHex/EtOAc 15:1). 1 H NMR COSY
(600 MHz, CDCl3): = 7.437.27 (m, 10 H, 2 OBn), 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
= 12.3 Hz, 1 H, OCH2A-Ph), 4.99 (d, J = 12.3 Hz, 1 H, OCH2BPh), 4.674.65 (m, 1 H, 15-H), 3.773.73 (m, 1 H, CH2A-2), 3.33
3.30 (m, 1 H, CH2B-2), 2.582.50 (m, 1 H, 12-HA), 1.981.90 (m,
1 H, 12-HB), 1.89 (s, 3 H, CH3-10), 1.651.60 (m, 1 H, 13-HA),
1.501.45 (m, 1 H, 14-H), 1.231.16 (m, 1 H, 13-HB), 1.12 (d, J =
NMR HSQC, HMBC (150.9 MHz, CDCl3): = 198.4 (Cq-9), 168.7
(Cq-1), 155.6 (Cq-7), 155.1 (Cq-5), 152.8 (CH-11), 136.5 (Cq-10, Cq1, 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
(CH-2, CH-6, Ph), 127.1 (CH-2, CH-6, Ph), 125.7 (Cq-8), 107.8
(C q -4), 99.6 (CH-6), 76.8 (CH-15), 71.3 (OCH 2 Ph), 71.0
(OCH2Ph), 40.6 (CH2-2), 38.9 (CH-14), 34.2 (CH2-13), 29.2 (CH212), 19.4 (CH3-14), 18.9 (CH3-15), 10.2 (CH3-10) ppm. IR (ATR):
= 3033, 2924, 2855, 1725, 1498, 1330, 1252, 1161, 1069, 909, 732,
696 cm1. HRMS (ESI): calcd. for [C32H33BrO5 + Na]+ 599.1409;
found 599.1382.
Lactone 46: DBU (12 L, 82 mol, 2.0 equiv.) was added to a solution of brominated lactone 45 (24 mg, 41 mol, 1.0 equiv.) in dry
acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue
was dissolved in ethyl acetate (30 mL), washed with HCl (2 n,
2 20 mL), dried with magnesium sulfate, and filtered. Removing
the solvent in vacuo yielded 46 (20 mg, 41 mol, quant.) as a light
yellow oil, R f = 0.10 (cHex/EtOAc 15:1). 1 H NMR COSY
(400 MHz, CDCl3): = 7.537.28 (m, 10 H, 2 OBn), 6.51 (d, J
= 1.9 Hz, 1 H, 6-H), 6.50 (d, J = 1.9 Hz, 1 H, 4-H), 5.235.17 (m,
3606
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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),
3.79 (s, 1 H, 2-H), 2.072.02 (m, 1 H, CH2A-11), 1.681.56 (m, 1
H, 14-H), 1.621.55 (m, 1 H, CH2A-13), 1.511.40 (m, 3 H, CH2B11, CH2-12), 1.29 (s, 3 H, CH3-10), 1.18 (d, J = 6.3 Hz, 3 H, CH315), 1.161.08 (m, 1 H, CH2B-13), 0.78 (d, J = 6.7 Hz, 3 H, CH314) ppm. 13C NMR HSQC, HMBC (75.5 MHz, CDCl3): = 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 (CH3, CH-5, Ph), 128.5 (CH-4, Ph), 127.9 (CH-4, Ph), 127.6 (CH-2,
CH-6, Ph), 126.7 (CH-2, CH-6, Ph), 118.3 (Cq-8), 102.7 (CH-4),
100.9 (CH-6), 78.5 (CH-15), 70.7 (OCH2Ph), 70.3 (OCH2Ph), 57.6
(CH-2), 54.7 (Cq-10), 37.2 (CH-14), 36.9 (CH2-13), 34.8 (CH2-11),
23.8 (CH3-10), 22.3 (CH2-12), 19.5 (CH3-15), 18.2 (CH3-14) ppm.
IR (ATR): = 3065, 3034, 2959, 2929, 2873, 1700, 1599, 1588,
[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 dissolved 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.
35:1 10:1) 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):
= 7.437.26 (m, 10 H, 2 OBn), 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), 5.074.98 (m, 4 H,
2 OCH2-Ph), 4.65 (dq, J = 12.3, 6.3 Hz, 1 H, 15-H), 3.68 (d, J =
16.2 Hz, 1 H, CH2A-2), 3.323.19 (br. s, 1 H, CH2B-2), 3.072.93
(m, 1 H, CH2A-11), 1.771.65 (m, 1 H, CH2B-11), 1.541.47 (m, 1
H, 14-H), 1.281.22 (m, 4 H, CH2-12, CH2-13), 1.16 (d, J = 6.3 Hz,
3 H, CH3-15), 0.90 (d, J = 7.0 Hz, 3 H, CH3-14) ppm. 13C NMR
HSQC, HMBC (150.9 MHz, CDCl3): = 199.0 (Cq-9), 170.5 (Cq1), 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
(CH-4), 99.7 (CH-6), 77.9 (CH-15), 70.4 (OCH 2 Ph), 70.3
(OCH2Ph), 38.9 (CH2-2), 38.4 (CH-14), 33.5 (CH2-13), 30.2 (CH211), 22.9 (CH2-12), 19.7 (CH3-14), 19.7 (CH3-15) ppm. IR (ATR):
= 3090, 3065, 3033, 2957, 2926, 2872, 1732, 1659, 1603, 1582,
1313, 1199, 1156 cm1. HRMS (ESI): calcd. for [C32H34O5 + Na]+
521.2304; found 521.2316.
14-Methyl-10-exo-methylenecurvularin (49): A solution of the
benzyl-protected lactone 48 (34 mg, 68 mol, 1.0 equiv.) in dry
dichloromethane (15 mL) was cooled to 78 C. Boron trichloride
(1 m in hexane, 0.14 mL, 0.14 mmol, 2.1 equiv.) was added, and the
mixture was stirred. After 3 h, further boron trichloride (1 m in
hexane, 0.28 mL, 0.28 mmol, 4.1 equiv.) was added, and stirring
was carried out for an additional 2.5 h. The reaction mixture was
quenched with saturated aqueous sodium hydrogen carbonate solution (50 mL) and allowed to warm to room temperature. The organic layer was separated, and the aqueous layer was extracted with
ethyl acetate (3 50 mL). The combined organic layers were dried
with magnesium sulfate and filtered. The solvent was removed in
2:1) yielded 49 (20 mg, 64 mol, 94 %) as a colorless oil, Rf = 0.14
(cHex/EtOAc 2:1). 1H NMR COSY (600 MHz, [D4]MeOH): =
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
2.60 (m, 1 H, CH2A-11), 2.112.05 (m, 1 H, CH2B-11), 1.551.48
Eur. J. Org. Chem. 2015, 35873608
(m, 3 H, CH2-12, 14-H), 1.271.22 (m, 2 H, CH2-13), 1.16 (d, J =
NMR HSQC, HMBC (150.9 MHz, [D4]MeOH): = 201.5 (Cq-9),
172.5 (Cq-1), 160.4 (Cq-7), 157.5 (Cq-5), 149.6 (Cq-10), 135.0 (Cq3), 132.3 (=CH2), 120.7 (Cq-8), 111.9 (CH-4), 102.6 (CH-6), 78.0
(CH-15), 40.1 (CH2-2), 39.6 (CH-14), 33.7 (CH2-13), 31.3 (CH211), 26.8 (CH2-12), 19.6 (CH3-15), 18.8 (CH3-14) ppm. IR (ATR):
= 3351, 2925, 2874, 2855, 1703, 1609, 1460, 1335, 1316, 1264,
1155, 1031 cm 1 . HRMS (ESI): calcd. for [C 18 H 22 O 5 + Na] +
341.1365; found 341.1361.
4-Chloro-14-methyl-10-exo-methylenecurvularin (50): Lactone 49
(22 mg, 69 mol, 1.0 equiv.) and NCS (9.2 mg, 69 mol, 1.0 equiv.)
were dissolved in dry DMF (10 mL), and trifluoroacetic acid (8 L,
104 mol, 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 (2 30 mL). Purification by flash chromatography on silica (cHex/EtOAc 4:1) yielded
50 (13 mg, 38 mol, 55 %) as a colorless oil, Rf = 0.14 (cHex/EtOAc
2:1). 1H NMR COSY (600 MHz, [D4]MeOH): = 6.44 (s, 1 H, 6H), 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), 2.862.78 (m, 1 H, CH2A-11), 1.941.84
(m, 1 H, CH2B-11), 1.501.39 (m, 2 H, 14-H, CH2A-12), 1.641.55
(m, 1 H, CH2B-12), 1.291.22 (m, 1 H, CH2A-13), 1.181.12 (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): = 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
(CH3-14) ppm. IR (ATR): = 3368, 2962, 2935, 2876, 1705, 1654,
1603, 1441, 1319, 1229, 1200, 1160, 733 cm1. HRMS (ESI): calcd.
for [C18H21ClO5 + Na]+ 375.0975; found 375.0972.
10,14-Dimethyl-12,13-dehydrocurvularin (51) and 10,14-Dimethylcurvularin (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.)
in ethanol (50 mL). The suspension was stirred under hydrogen for
44 h. The solution was filtered through a short plug of silica
(EtOAc), and the solvent was removed in vacuo. Purification by
flash chromatography on silica (cHex/EtOAc 5:1) yielded a mixture
of the deprotected saturated lactone 52 (514 mg, ca. 57 %) as a colorless oil, as well as the deprotected unsaturated lactone 51
(141 mg, 0.44 mmol, 16 %) as a colorless solid, Rf = 0.28 (cHex/
EtOAc 2:1), m.p. 83.085.0 C (cHex/EtOAc 5:1). 1H NMR COSY,
HSQC, NOESY (400 MHz, [D4]MeOH): = 6.29 (d, J = 2.3 Hz,
1 H, 6-H), 6.16 (d, J = 2.3 Hz, 1 H, 4-H), 5.195.08 (m, 1 H, CH12), 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), 4.574.38 (m, 1 H, CH2A-2), 3.753.65 (m,
1 H, CH-10), 3.343.28 (m, 1 H, CH2B-2), 2.252.07 (m, 2 H, CH211), 2.011.89 (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, CH314) ppm. 13C NMR HSQC, HMBC (75.5 MHz, [D4]MeOH): =
212.3 (C-9), 171.8 (C-1), 161.6 (C-5), 161.1 (C-7), 137.8 (C-3), 134.6
(C-13), 130.6 (C-12), 120.7 (C-8), 113.7 (C-4), 102.9 (C-6), 75.1 (C15), 47.3 (C-10), 46.1 (C-14), 41.2 (C-2), 32.1 (C-11), 18.4 (CH315), 18.4 (CH3-10), 17.5 (CH3-14) ppm. IR (ATR): = 3307, 2975,
2933, 1691, 1609, 1590, 1268, 1235, 1166, 1149, 754 cm1. HRMS
(ESI): calcd. for [C18H22O5 + Na]+ 341.1365; found 341.1355. The
obtained mixture was dissolved in ethanol (40 mL), and palladium
on charcoal (10 wt.-%, 50 mg) was added. The suspension was
stirred under hydrogen for 64 h. The solution was filtered through
a short plug of silica (EtOAc), and the solvent was removed in
vacuo. Crystallization with chloroform yielded 52 (464 mg,
Eur. J. Org. Chem. 2015, 35873608
1.45 mmol, 52 %) as a colorless solid, Rf = 0.21 (cHex/EtOAc 2:1),

m.p. 67.069.0 C (CHCl3). 1H NMR COSY (400 MHz, [D4]MeOH): = 6.27 (d, J = 2.3 Hz, 1 H, 6-H), 6.15 (d, J = 2.3 Hz, 1
H, 4-H), 4.564.47 (m, 1 H, OCH-15), 4.50 (d, J = 17.2 Hz, 1 H,
CH2A-2), 3.793.71 (m, 1 H, CH-10), 3.36 (d, J = 17.2 Hz, 1 H,
CH2B-2), 1.681.60 (m, 3 H, CH2-11, CH-14), 1.531.45 (m, 1 H,
CH2A-13), 1.381.26 (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), 1.091.03 (m, 1 H,
CH2B-13), 0.950.88 (m, 1 H, CH2B-12), 0.84 (d, J = 6.9 Hz, 3 H,
CH3-14) ppm. 13C NMR HSQC, HMBC (100.6 MHz, [D4]MeOH): = 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 (C12), 19.4 (CH3-15), 17.6 (CH3-10, CH3-14) ppm. IR (ATR): =
3307, 2928, 2855, 1689, 1610, 1593, 1490, 1460, 1266, 1245, 1165,
found 343.1512.
Acknowledgments
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, Brazil) for helpful discussions and interpretation of NMR spectra.
[1] J. Richter, L. P. Sandjo, J. C. Liermann, T. Opatz, G. Erkel,
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Received: February 26, 2015
Published Online: April 21, 2015
Eur. J. Org. Chem. 2015, 35873608

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FULL PAPER

Synthetic Approaches to Anti-Inflammatory Macrolactones of the

therapy even some fifty years after their introduction, their

Figure 1. Structures of some natural anti-inflammatory macrolactones.

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz

Results and Discussion

the high anti-inflammatory activity. An attempted RCM

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Eur. J. Org. Chem. 2015, 35873608

Scheme 2. Synthesis of alkyne ester 17 for a carbonylative cross-coupling reaction.

Three products were isolated and characterized from the

Figure 2. Isolated products of the Suzuki coupling.

The 10-membered lactone 19 was presumably formed in

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz

Scheme 3. Attempted intramolecular hydroacylation of alkyne 23.

Oxidation to the corresponding carboxylic acid was

resulted in the formation of a six-membered lactone, due to

Scheme 4. Approach to lactones 31a, 31b, and 31c by RCM.

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Eur. J. Org. Chem. 2015, 35873608

lem, the macrolactone without the -methyl substituent

within minutes, but the isolated yield of 40 was low, due to

Scheme 5. Synthesis of lactones 36 and 37.

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz

Scheme 6. Synthesis of isochromen-3-one 40.

Scheme 7. Synthesis of 14-deoxyoxacyclododecindione isomer 50.

Treating bromide 45 with tetrakis(triphenylphosphine)palladium(0) to effect a -hydride elimination afforded the

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Eur. J. Org. Chem. 2015, 35873608

uct, the reduced macrolactone was obtained in nearly equal

Scheme 8. Synthesis of 10,14-dimethyl-12,13-dehydrocurvularin

Table 2. HepG2 cells were transiently transfected with the indicated

respect to the TGF--induced signaling pathway, thus being

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz

(Dual-Luciferase-Reporter-Assay). Luciferase-based reporter gene

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Eur. J. Org. Chem. 2015, 35873608

H, CH3-3) ppm. 13C NMR (100.6 MHz, CDCl3): = 170.2 (COO),

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz

1 H, CH=CH2A), 4.82 (d, J = 10.0 Hz, 1 H, CH=CH2B), 4.574.52

H, CH3-3) ppm. 13C NMR HSQC, HMBC (100.6 MHz, CDCl3):

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Eur. J. Org. Chem. 2015, 35873608

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz

Alcohol 26a:[18] A solution of 1-methylprop-2-enylmagnesium

7.21 (m, 2 H, AA-part of AABB-spin system, 2-H, 6-H, PMB),

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Eur. J. Org. Chem. 2015, 35873608

C(CH3)3], 0.81 (dd, J = 6.9, 1.2 Hz, 3 H, CH3-2), 0.12 (s, 6 H,

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz

for 6 h and was then allowed to warm to room temperature over

[SiC(CH3)3], 17.1/15.3 (CH3-2), 5.7/5.7 (SiCH3), 6.0/6.1

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Eur. J. Org. Chem. 2015, 35873608

20.1/20.0 (CH3-1), 18.3 [SiC(CH3)3], 4.8 (SiCH3), 5.1 (SiCH3).

2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Tauber, K. Rudolph, M. Rohr, G. Erkel, T. Opatz