Chemoenzymatic asymmetric total synthesis of (R)-lasiodiplodin methyl ether through a sulfatase-based deracemization process

Article abstract of DOI:10.1002/ejoc.201201296

(R)-Lasiodiplodin methyl ether, a precursor of the antileukemic agent lasiodiplodin, was synthesized through a seven-step linear sequence. Chirality was introduced through a sulfatase-based deracemization process, in which a functionalized (rac)-sec-sulfate ester was enzymatically hydrolyzed with inversion of the stereocenter using an alkyl sulfatase. The remaining sulfate ester enantiomer was hydrolyzed with retention of configuration under acidic conditions, yielding the chiral key building block as the sole product in 93 % ee The total synthesis was completed through Negishi cross-coupling and ring-closing metathesis.

Full text of DOI:10.1002/ejoc.201201296

FULL PAPER
DOI: 10.1002/ejoc.201201296
Chemoenzymatic Asymmetric Total Synthesis of (R)-Lasiodiplodin Methyl
Ether through a Sulfatase-Based Deracemization Process
Michael Fuchs,[a] Michael Toesch,[a] Markus Schober,[a] Christiane Wuensch,[b] and
Kurt Faber*[a]
Keywords: Medicinal chemistry / Natural products / Total synthesis / Enantioselectivity / Chiral resolution / Asymmetric
catalysis / Cleavage reactions
(R)-Lasiodiplodin methyl ether, a precursor of the antileuke-
mic agent lasiodiplodin, was synthesized through a seven-
step linear sequence. Chirality was introduced through a
sulfatase-based deracemization process, in which a function-
alized (rac)-sec-sulfate ester was enzymatically hydrolyzed
with inversion of the stereocenter using an alkyl sulfatase.
The remaining sulfate ester enantiomer was hydrolyzed with
retention of configuration under acidic conditions, yielding
the chiral key building block as the sole product in 93% ee
The total synthesis was completed through Negishi cross-
coupling and ring-closing metathesis.
Introduction
Salicylic acid derivatives are important bioactive com-
pounds and thus are popular synthetic targets. In addition
to the most prominent representative – Aspirin® (acetyl
salicylic acid) – closely related resorcylic acid lactones have
gained attention since several natural products of this type
were indentified as pharmacophores (Figure 1). For exam-
ple, (S)-zearalenone exhibits anabolic, estrogenic, ute-
rotropic, and antibacterial activity,[1–4] and the nonsteroidal
animal growth-promoting antagonist zeranol is in clinical
trials for the treatment of (post)menopausal syndrome.[5]
cis-Resorcylide inhibits plant growth[6,7] and radicicol con-
stitutes an important antitumor agent.[8,9] Another member
of this family is lasiodiplodin, which displays antileukemia
activity,[10] and its demethylated congener, which efficiently
inhibits prostaglandin biosynthesis.[11]
Figure 1. Bioactive resorcylic acid lactones.
Many of the synthetic routes to lasiodiplodin either lead
To expand the catalytic toolbox for the preparation of
to the racemate[12–15] or are based on chiral starting materi- lasiodiplodin, we envisaged applying a chemoenzymatic de-
als (e.g., epoxides or alcohols)[16–19] or on chiral sulfoxide racemization process, which is based on inverting alkyl sulf-
auxiliaries.[20] The first catalytic asymmetric synthesis, re- atases. Sulfatases are a heterogenic group of enzymes that
ported by Jones and Huber, was based on Cr-catalyzed catalyze the cleavage of sulfate esters, yielding an alcohol
enantioselective addition of Me2Zn onto an aldehyde (86% and hydrogen sulfate.[24–27] Depending on their mode of ac-
ee).[21] Recently, the group of Feringa reported a highly ster- tion, sulfatases either cleave the S–O bond (leading to reten-
eoselective Cu-catalyzed allylic alkylation.[22,23]
tion of configuration at the sec-alcohol), or the C–O bond
(causing inversion at the stereogenic carbon atom).[25] The
sulfatase “Pisa1” from Pseudomonas sp. DSM 6611 was re-
cently identified as the first inverting sec-alkyl sulfatase pos-
sessing a broad substrate spectrum. Enantioconvergence
was achieved in combination with retaining acid-catalyzed
hydrolysis of the nonconverted sulfate ester to yield the cor-
responding sec-alcohol in high yield and enantiomeric pu-
rity as the sole product (Scheme 1).[28,29]
[a] Department of Chemistry, Organic and Bioorganic Chemistry,
University of Graz,
Heinrichstraße 28, 8010 Graz, Austria
E-mail: Kurt.Faber@uni-graz.at
Homepage: http://biocatalysis.uni-graz.at/
[b] Austrian Centre of Industrial Biotechnology,
8010 Graz, Austria
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201296.
356
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Eur. J. Org. Chem. 2013, 356–361

Total Synthesis of (R)-Lasiodiplodin Methyl Ether
using the one-pot procedure gave low yields due to the vola-
tility of (S)-3 causing losses during reflux at 60 °C over-
night. Consequently, the two-step process requiring only
40 °C for two hours was amended by cautiously concentrat-
ing the solution of (S)-3, which was directly employed in
the subsequent Mitsunobu esterification step to furnish (R)-
4 in 64% isolated yield and 93% ee over three steps
(Scheme 3). Because the enantiomeric excess of alcohol (S)-
3 obtained by deracemization was Ͼ 99%, the slight drop
of the enantiomeric excess must have been incurred during
the Mitsunobu inversion. Activation of the phenol moiety
in (R)-4 as the triflate gave (R)-6 in 95% yield. Employing
[Pd(PPh3)4] for Negishi cross-coupling with 4-pentenyl ZnII
Scheme 1. Enantioconvergent sulfate ester hydrolysis for the prepa-
ration of chiral alcohol 3.
Results and Discussion
Our retrosynthetic analysis is outlined in Scheme 2. The chloride (7) gave only 20% of the desired alkylation product
macrolactone is formed through ring-closing metathesis, (R)-5 but mainly furnished “dehalogenated” and homocou-
and the open-chain precursor 5 is prepared through Negishi pling products. The latter was most likely due to transme-
cross-coupling and Mitsunobu esterification from chiral tallation from palladium to zinc, which is facilitated by the
alcohol (S)-3, which may be obtained by the sulfatase-based presence of oxygen-containing substituents in the ortho-po-
deracemization process mentioned above.
sition relative to the (pseudo)halide.[31] Thus, the newly
To assess the feasibility of this strategy, the sulfatase-pro- formed Zn species couples with remaining triflate, yielding
cess was upscaled as follows: Alkyl sulfatase Pisa1 perfectly the undesired homocoupling product. Additionally, litera-
inverted the (R)-enantiomer of (rac)-2 [Ͼ 99% ee of (S)-3 at ture analysis revealed that this type of coupling was success-
50% conversion[30]], leaving (S)-2 untouched. For the acid- fully applied to salicylic triflates only in one case, when an
catalyzed hydrolysis of the latter, two protocols were estab- amide group was present in the molecule, which provided
lished: (i) A one-pot, two-step protocol, in which acidic hy- an alternative coordination site for the zinc metal core.[32]
drolysis of (S)-2 was performed in the presence of (S)-3 To overcome these problems, optimization studies were per-
formed during enzymatic hydrolysis, and (ii) a two-step pro- formed, which revealed the following crucial points: (i) Re-
cess involving extractive separation of enzymatically formed placement of the triphenylphosphane ligand of the Pd cata-
(S)-3 prior to acidic hydrolysis of (S)-2.[28] Initial attempts lyst by 1,1Ј-bis(diphenylphosphino)ferrocene (dppf), and
Scheme 2. Retrosynthetic analysis for the chemoenzymatic synthesis of (R)-lasiodiplodin methyl ether (1).
Scheme 3. Synthesis of (R)-lasidiplodin methyl ether (1). Reagents and conditions: (a) Tf2O, 2,6-lutidine, CH2Cl2, 30 min, 95%.
Eur. J. Org. Chem. 2013, 356–361
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M. Fuchs, M. Toesch, M. Schober, C. Wuensch, K. Faber
FULL PAPER
NMR spectra were recorded with a Bruker NMR instrument op-
erating at 300 (1H) and 75 (13C) MHz; chemical shifts (δ values)
are given in ppm and coupling constants (J) are given in Hz. GC–
MS measurements were performed with an Agilent 7890A GC sys-
tem, equipped with an Agilent 5975C mass-selective detector (EI
70 eV) and a HP-5-MS column (30 mϫ0.25 mm ϫ0.25 μm film)
using He at a flow rate of 0.55 mL/min. Temperature program:
200 °C, hold 0.5 min, 5 °C/min 300 °C, hold 2 min, inlet tempera-
ture: 300 °C. High-resolution mass spectra were recorded with a
Waters Synapt HDMS Q-TOF mass spectrometer (ESI ion source,
(ii) higher dilution of the reaction mixture (0.1 m triflate 6)
strongly favored cross-coupling over undesired side reac-
tions. Additionally, the preparation of the Zn reagent had
a significant impact on the product distribution, because
the use of Zn dust, according to Knochel et al.,[33] either
favored the second transmetallation step[31] or (more likely)
remaining Zn dust inserted into the Ar–OTf bond, yielding
undesired Ar-Zn species, which promote side-product for-
mation. As a consequence, when the organometallic reagent
7 was prepared through transmetallation of the correspond- positive mode, capillary voltage 2.6 kV) using a syringe pump to
directly infuse the sample, which was dissolved in MeCN. Chiral
GC-FID analysis was carried out with an Agilent Technologies
7890A GC-FID equipped with an Agilent Technologies 7693B
ing Grignard compound, an almost quantitative isolated
yield of diene (R)-5 was obtained. In agreement with our
observations, it has been shown that different cations (i.e.,
Li+ vs. Mg2+) can alter the outcome of similar cross-cou-
pling reactions significantly.[34]
To form the macrolactone ring, diene (R)-5 was subjected
to ring-closing metathesis, which gave a mixture of E/Z iso-
mers (65:35). However, it was difficult to isolate more than
80% of the unsaturated macrolactone intermediate despite
autosampler fitted with
a Varian Chirasil Dex CB column
(25 mϫ0.32 mm ϫ0.25 μm film) after derivatization using the fol-
lowing parameters: injector temperature: 200 °C, H2 flow rate
2.0 mL/min, injection pressure 0.60 bar, temperature program:
80 °C, hold for 1.0 min, 3 °C/min to 95 °C, 15 °C/min, to 150 °C.
Chiral HPLC analysis was performed with a Shimadzu HPLC sys-
tem using the columns and methods as specified below. Flash
the fact that full conversion was observed by GC analysis. chromatography was performed using Merck silica gel 60 (mesh
size 40–63 μm). Petroleum ether had a boiling range of 60–95 °C.
His-tagged alkyl sulfatase Pisa1 was prepared as recently re-
ported.[29]
Because we assumed that the latter might be caused by Ru-
catalyzed dimerization or oligomerization of the initially
formed macrocyclic alkene upon concentration of the reac-
tion mixture, we envisaged two possible solutions: (i) Re- (rac)-5-Hexen-2-yl Sulfate [(rac)-2]: Sodium hydride (0.400 g, 60%
dispersion in mineral oil, 9.99 mmol) was suspended in 1,4-dioxane
(20 mL) under an atmosphere of argon. To the suspension, (rac)-3
(1.21 mL, 1000 mg, 9.99 mmol) was added dropwise through a sep-
tum by using a syringe. The reaction was stirred for 1 h and a
solution of sulfurtrioxide triethylamine complex (1.63 g, 9.0 mmol)
in 1,4-dioxane (15 mL) was added dropwise over a period of
15 min. The mixture was stirred for 16 h, followed by quenching
with distilled H2O (ca. 5 mL). The obtained solution was concen-
trated until all dioxane was removed. The aqueous solution was
diluted with additional distilled H2O (15 mL) and lyophilized to
give (rac)-3 as a white powder (1.56 g, 7.7 mmol, 77%) with physi-
cal properties as reported recently.[28] 1H NMR (300 MHz, D2O):
δ = 5.85–5.72 (m, 1 H), 5.03–4.84 (m, 2 H), 4.44–4.34 (m, 1 H),
2.10–1.98 (m, 2 H), 1.69–1.50 (m, 2 H), 1.22 (d, J = 7.3 Hz, 3
H) ppm. 13C NMR (75 MHz, D2O): δ = 138.6, 114.7, 78.0, 35.2,
28.8, 19.9 ppm.
moval of the Ru catalyst by filtration through silica gel
prior to concentration of the solution, which led to an iso-
lated yield of 91%, indicating that we were focusing on the
right parameters. (ii) In addition, we combined ring-closing
metathesis and hydrogenation of the macrocyclic C=C
bond in a one-pot fashion, which gave lasiodiplodin methyl
ether (R)-1 in 93% ee in 94% isolated yield in two steps.
Conclusions
We have successfully employed a sulfatase-based derace-
mization process in the chemoenzymatic asymmetric total
synthesis of (R)-lasiodiplodin methyl ether. The latter can
be easily transformed into lasiodiplodin and its demethyl-
ated congener,[17,20] which are natural products possessing
anti-leukemic and prostaglandin-inhibitor activities, respec-
tively. The title compound was obtained in 44% overall
yield and 93% ee over a seven-step linear synthesis. Yields
could be significantly improved by performing several steps
in a one-pot fashion without intermediate product isola-
tion.
Enantioconvergent Preparation of (S)-5-Hexen-2-ol [(S)-3]: (rac)-5-
Hexen-2-yl sulfate [(rac)-2; 200 mg, 494 mmol] was dissolved in
Tris/HCl buffer (40 mL, 100 mm, pH 8.0) in a round-bottomed
flask. Pisa1 enzyme (5.2 mg in 640 μL of the same buffer) was
added and the flask was sealed with a glass stopper fitted with a
teflon ring and shaken for 24 h at 120 rpm and 30 °C (vertical posi-
tion). The aqueous layer was extracted with tBuOMe (3ϫ 5 mL)
and the combined organic phase was kept on ice (organic phase
A). The remaining aqueous phase was evaporated at 60 °C and
5 mbar, and the residue was dissolved in water (2.8 mL), tBuOMe
(76 mL), and 1,4-dioxane (10 μL). p-Toluenesulfonic acid monohy-
drate (1.4 g, 7.4 mmol) was added, the flask was fitted with a reflux
condenser, and the mixture was stirred at 40 °C for 2 h. After cool-
ing to room temperature, saturated aqueous K2CO3 (15 mL) was
added, the phases were separated, the aqueous phase was extracted
with tBuOMe (2ϫ 5 mL), and the combined organic phases (in-
cluding organic phase A) were collected. 1,4-Dioxane (6 mL) was
added and the reaction mixture was concentrated to 6–8 mL end
volume. The latter solution was directly used for the subsequent
Mitsunobu esterification. For compound characterization, no 1,4-
dioxane was added and concentration under reduced pressure gave
Experimental Section
General: All chemicals were purchased from Sigma Aldrich, Acros
Organics, or Alfa Aesar and used as received; solvents were ob-
tained from Roth. All moisture- or air-sensitive operations were
conducted under dry argon in heat-dried glassware. Anhydrous
THF was distilled from potassium/benzophenone prior to use, tol-
uene was dried with molecular sieves (3 Å) after evaporation of the
toluene/water azeotrope. Biocatalytic reactions were performed in
a HT Infors Unitron AJ 260 incubator at 120 rpm shaking (hori-
zontal position) and 30 °C.
358
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Total Synthesis of (R)-Lasiodiplodin Methyl Ether
(S)-3 (41 mg, 41% yield, Ͼ 99% ee) as a colorless oil. [α]2D0 = +15.6
319 Hz, C–F coupling), 115.0, 111.0, 98.7, 98.4, 72.7, 56.3, 55.9,
1
(c = 1.0, Et2O); ref.[35] +17.3 (c = 1.026, Et2O). H NMR (CDCl3, 35.0, 29.5, 19.7 ppm. GC-MS (EI; tR = 6.38 min): m/z (%) = 412
300 MHz): δ = 5.91–5.78 (m, 1 H), 5.68–4.96 (m, 2 H), 3.83 (sext,
(1), 331 (51), 313 (100), 286 (3), 180 (48), 152 (11), 137 (20), 82
J = 6.2 Hz, 1 H), 2.16 (nonet, J = 7.1 Hz, 2 H), 1.68 (br. s, 1 H), (24). HRMS (ESI): m/z calcd for C16H19SO7F3Na+ 435.0701 [M +
1.64–1.47 (m, 2 H), 1.20 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 138.5, 114.8, 67.7, 38.3, 30.2, 23.5 ppm.
Na]+; found 435.0712.
4-Pentenylzinc(II) Chloride (7): A 25 mL round-bottomed flask,
equipped with a reflux condenser and a glass stopper was dried in
high vacuum using a heat gun. The apparatus was vented with dry
Derivatization of 3 for Chiral GC-FID Analysis: A solution of
alcohol 3 in tBuOMe was treated with 4-(dimethylamino)pyridine
(2 mg, 0.016 mmol) and acetic anhydride (100 μL, 108 mg, argon, the stopper was removed, and magnesium turnings (111 mg,
1.06 mmol) and the mixture was shaken overnight at 120 rpm and
30 °C. The reaction was quenched by addition of H2O (300 μL),
the phases were separated, and the organic phase was dried with
Na2SO4 prior to injection. tR = 5.07 (R), 4.07 (S) min.
4.57 mmol) were added under a positive stream of argon. The
whole apparatus was again dried using a heat gun under high vac-
uum and vented with argon, followed by the addition of one small
crystal of iodine (ca. 2 mg, sublimed using a heat gun). The flask
was allowed to cool until all the iodine vapor had settled down and
anhydrous THF (2.2 mL) was added. The mixture was stirred at
room temperature during slow addition of 5-bromopent-1-ene
(504 μL, 643 mg, 4.25 mmol) in THF (2 mL). After addition of ca.
200 μL, the mixture was heated using a heat gun to initiate the
metal insertion and the reaction was kept at moderate reflux by
adding further 5-bromopent-1-ene over the time of addition. After
completion of the addition, the mixture was stirred at room tem-
perature for an additional 10 min, then cooled to 0 °C (ice bath)
and a solution of ZnCl2 (698 mg, 5.12 mmol) in anhydrous THF
(5 mL) was added over a period of 1 min. The obtained white slurry
was taken into a syringe by using a cannula and septum and used
as such for the next reaction step.
(R)-5-Hexen-2-yl 2-Hydroxy-4,6-dimethoxybenzoate [(R)-4]: 2-Hy-
droxy-4,6-dimethoxy benzoic acid (198 mg, 1.0 mmol) was dis-
solved in THF (3.5 mL) in a 100 mL round-bottomed flask. Di-
isopropyl azodicarboxylate (203 μL, 209 mg, 1.03 mmol) was
added and the flask was capped with a rubber septum. PPh3
(338 mg, 1.26 mmol) was dissolved in the solution of (S)-5-hexen-
2-ol obtained from the enantioconvergent process and the solution
was added by using a syringe and cannula over a period of 1.5 h.
After complete addition, the reaction mixture was stirred overnight
at room temperature. The mixture was concentrated under reduced
pressure and the residue was taken up in EtOAc (10 mL) and
washed with an aqueous H2O2 solution (10%, 10 mL) to oxidize
remaining PPh3. The aqueous phase was extracted with EtOAc
(3ϫ 10 mL) and the combined organic phase was dried with (R)-5-Hexen-2-yl 2,4-Dimethoxy-6-(4-pentenyl)benzoate [(R)-5]:
Na2SO4, filtered, and concentrated under reduced pressure. The
remaining brown oil was subjected to dry flash column chromatog-
raphy through a silica gel pad (1 cm diameter, 5 cm height; petro-
leum ether/EtOAc, 10:1, 100 mL) to give pure (R)-4 (179 mg,
0.64 mmol, 64%, 93% ee). [α]2D0 = –38.3 (c = 1.0, acetone); HPLC
analysis (Diacel Chiralcel OJ; 18 °C; 0.3 mL/min; n-heptane/2-
PrOH, 99:1): tR = 25.64 (S), 28.12 (R) min. 1H NMR (CDCl3,
300 MHz): δ = 12.07 (s, 1 H), 6.12 (d, J = 2.4 Hz, 1 H), 5.97 (d, J
= 2.4 Hz, 1 H), 5.92–5.79 (m, 1 H), 5.16 (sext, J = 6.3 Hz, 1 H),
Triflate 6 (412 mg, 1.0 mmol) was added to a 20 mL biotage vial
equipped with a stir bar. The vial was capped and crimped with a
teflon septum and primed with argon for 45 min. [PdCl2dppf]
(36 mg, 0.05 mmol) was dissolved in anhydrous THF (2 mL) and
added to the starting material, followed by addition of 4-pent-
enylzinc(II) chloride (7; 0.42 m in anhydrous THF, 8 mL,
3.36 mmol) prepared as described above. The vial was placed into
a preheated oil bath (45 °C bath temperature) and stirred at this
temperature. After completion of the reaction (0.5–1 h as checked
5.08–4.97 (m, 2 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 2.32–2.13 (m, 2 H), by GC analysis) the vial was opened and the reaction was quenched
1.91–1.65 (m, 2 H), 1.37 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 170.8, 165.8, 165.1, 162.3, 138.0, 114.9, 97.2,
by addition of saturated ammonium chloride (10 mL). Extraction
with EtOAc (3ϫ 100 mL), drying of the combined organic phase
over Na2SO4, and concentration under reduced pressure, gave the
93.3, 91.6, 71.6, 55.9, 55.4, 35.1, 29.5, 20.0 ppm. GC-MS (EI; tR
=
5.89 min): m/z (%) = 280 (11), 198 (6), 180 (100), 166 (1), 152 (13), crude product, which was purified by flash chromatography (petro-
+
137 (10), 123 (2), 95 (3). HRMS (ESI): m/z calcd for C15H21O5
leum ether/EtOAc, 10:1) to give diene (R)-5 as a pale-yellow oil
(326 mg, 0.98 mmol, 98% yield). [α]2D0 = –19.4 (c = 1.0, acetone).
1H NMR (CDCl3, 300 MHz): δ = 6.34 (m, 2 H), 5.92–5.76 (m, 2
H), 5.20 (sext, J = 6.3 Hz, 1 H), 5.10–4.96 (m, 4 H), 3.82 (s, 3 H),
3.80 (s, 3 H), 2.63–2.57 (m, 2 H), 2.28–2.06 (m, 4 H), 1.88–1.60 (m,
4 H), 1.36 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 168.0, 161.2, 157.8, 142.2, 138.3, 137.9, 117.1, 115.0, 114.8,
105.7, 96.2, 71.2, 55.7, 55.4, 35.2, 33.6, 33.3, 30.4, 29.6, 20.1 ppm.
GC-MS (EI; tR = 8.59 min): m/z (%) = 332 (35), 278 (7), 263 (1),
250 (27), 233 (67), 211 (37), 196 (100), 191 (77), 178 (18), 165 (13),
152 (67), 137 (12), 120 (12), 91 (14), 77 (12). HRMS (ESI): m/z
calcd for C20H28O4Na+ 355.1885 [M + Na]+; found 355.1887.
281.1389 [M + H]+; found 281.1377.
(R)-5-Hexen-2-yl 4,6-Dimethoxy-2-(trifluoromethylsulfonyloxy)-
benzoate [(R)-6]: Compound (R)-4 (233 mg, 0.83 mmol) was placed
into an argon-flushed 50 mL round-bottomed flask and dissolved
in CH2Cl2 (6 mL). The reaction mixture was cooled to 0 °C (ice
bath), 2,6-lutidine (250 μL, 230 mg, 2.1 mmol) and triflic anhydride
(250 μL, 419 mg, 1.5 mmol) were added and the mixture was stirred
for 20 min at 0 °C, quenched with saturated ammonium chloride
(5 mL), and the organic phase was separated. The aqueous layer
was extracted with CH2Cl2 (2ϫ 10 mL) and the combined organic
phase was washed with 5 m HCl (2ϫ 20 mL), dried with Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether/EtOAc, 10:1) to
give triflate (R)-6 as a pale-yellow oil (324 mg, 0.79 mmol, 95%).
(R)-12,14-Dimethoxy-3-methyl-3,4,5,8,9,10-hexahydro-1H-benzo-
[c][1]oxacyclododecin-1-one: A two-necked 500 mL round-bottomed
flask equipped with a reflux condenser and a stopper was dried
under high vacuum using a heat gun and the apparatus was vented
[α]2D0 = –12.4 (c = 1.0, acetone). H NMR (CDCl3, 300 MHz): δ =
1
6.48 (d, J = 2.1 Hz, 1 H), 6.45 (d, J = 2.1 Hz, 1 H), 5.91–5.78 (m, with dry argon. The stopper was replaced by a rubber septum,
1 H), 5.19 (sext, J = 6.3 Hz, 1 H), 5.09–4.98 (m, 2 H), 3.86 (s, 3
H), 3.85 (s, 3 H), 2.26–2.01 (m, 2 H), 1.91–1.81 (m, 1 H), 1.74–1.62
(m, 1 H), 1.37 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 162.9, 162.2, 159.3, 147.8, 137.8, 118.5 (q, J =
anhydrous toluene (120 mL) was introduced by using a syringe and
cannula, and heated to 85 °C (oil bath temperature). Diene (R)-5
(82 mg, 0.25 mmol) was dissolved in anhydrous toluene (20 mL),
Hoveyda–Grubbs catalyst (2nd generation, 8 mg, 0.013 mmol) was
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359

M. Fuchs, M. Toesch, M. Schober, C. Wuensch, K. Faber
FULL PAPER
dissolved in anhydrous toluene (8 mL) and both solutions were
added in portions over a period of 1 h. After completion of the
addition, the mixture was stirred for an additional 10 min at 85 °C
and then allowed to cool to room temperature. The mixture was
filtered through a pad of silica gel (ca. 1 g), the pad was washed
with EtOAc (20 mL), and the filtrate was concentrated under re-
duced pressure. The remaining crude product was subjected to col-
umn chromatography (petroleum ether/EtOAc, 15:1) to give an E/
5.34–5.25 (m, 1 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 2.74 (dt, J1 = 13.5,
J2 = 7.8 Hz, 1 H), 2.55 (dt, J1 = 13.5, J2 = 6.6 Hz, 1 H), 2.01–1.90
(m, 1 H), 1.73–1.60 (m, 4 H), 1.54–1.37 (m, 5 H), 1.34 (d, J =
6.3 Hz, 3 H), 1.31–1.22 (m, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 168.5, 161.1, 157.7, 142.8, 118.1, 105.8, 96.3, 72.0,
55.9, 55.3, 32.3, 30.6, 26.5, 25.5, 24.2, 21.2, 19.5 ppm. GC-MS (EI;
tR = 9.78 min): m/z (%) = 306 (73), 291 (11), 277 (2), 261 (4), 219
(8), 196 (100), 191 (61), 178 (22), 165 (19), 152 (90), 135 (12), 120
Z mixture of the title compound (69 mg, 0.23 mmol, 91% yield), (12), 91 (13), 77 (12).
which was separated by preparative TLC (Silica gel GF plates;
20ϫ20 cm; 1500 microns; petroleum ether/EtOAc, 20:1, eluted sev-
enfold) to give the single isomers.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra, chiral GC- and HPLC-chromato-
grams.
(E)-Isomer: Yield 17 mg (0.06 mmol, 23%). [α]2D0 = +16.8 (c = 1.0,
acetone).1H NMR (CDCl3, 300 MHz): δ = 6.28 (d, J = 2.1 Hz, 1
H), 6.23 (d, J = 2.1 Hz, 1 H), 5.26 (dt, J1 = 31.4, J2 = 10.6 Hz, 2
H), 4.84 (septet, J = 5.7 Hz, 1 H), 3.73 (s, 3 H), 3.71 (s, 3 H), 2.53–
2.36 (m, 3 H), 2.11 (sext, J = 9.0 Hz, 1 H), 1.78–1.57 (m, 6 H),
Acknowledgments
This work has been supported by the Austrian Science Fund
(FWF) (project W9), Evonik Degussa GmbH, the Federal Ministry
1.31 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = of Education and Research (BMBF, Germany), and the Austrian
168.6, 161.0, 157.2, 142.0, 131.7, 129.4, 119.1, 105.5, 96.3, 70.1,
55.9, 55.3, 33.6, 31.0, 29.8, 23.8, 23.1, 20.4 ppm. GC-MS (EI; tR
Forschungs-Förderungsgesellschaft (FFG) via the COMET pro-
gram (borne by BMWFJ, BMVIT, SFG, Standort-
agentur Tirol and ZIT). We would like to thank Klaus Zanger and
his group (Graz) for NMR measurements. Wolfgang Kroutil
(Graz), Jan Pfeffer and Thomas Haas (Evonik GmbH, Marl, Ger-
many) thankfully assisted with encouraging and fruitful dis-
cussions.
=
9.69 min): m/z (%) = 304 (66), 287 (13), 275 (26), 259 (21), 247 (39),
233 (11), 220 (29), 203 (35), 191 (100), 178 (59), 164 (20), 152 (66),
135 (15), 120 (10), 105 (6), 91 (17), 77 (20). HRMS (ESI): m/z calcd
for C18H25O4 305.1753 [M + H]+; found 305.1771.
+
(Z)-Isomer: Yield 27 mg (0.09 mmol, 35%). [α]2D0 = –30.4 (c = 1.4,
1
acetone). H NMR (CDCl3, 300 MHz): δ = 6.38 (d, J = 2.0 Hz, 1
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=
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233 (13), 220 (30), 203 (42), 191 (100), 178 (57), 164 (21), 152 (75),
135 (14), 120 (11), 105 (8), 91 (19), 77 (23). HRMS (ESI): m/z calcd
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+
(R)-Lasiodiplodin Methyl Ether [(R)-12,14-Dimethoxy-3-methyl-
3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1]oxacyclododecin-1-one;
(R)-1]: A two-necked 500 mL round-bottomed flask equipped with
a reflux condenser and a stopper was dried under high vacuum
using a heat gun and the apparatus was vented with dry argon.
The stopper was replaced by a rubber septum, anhydrous toluene
(120 mL) was introduced by using a syringe and cannula and
heated to 85 °C (oil bath temperature). Diene (R)-4 (82 mg,
0.25 mmol) was dissolved in anhydrous toluene (20 mL), Hoveyda–
Grubbs catalyst (2nd generation, 8 mg, 0.013 mmol) was dissolved
in anhydrous toluene (8 mL) and both solutions were added por-
tionwise over a period of 1 h. After completion of the addition, the
mixture was stirred for an additional 10 min at 85 °C and then
allowed to cool to room temperature, Pd/C (10%, 40 mg) was
added and the apparatus was placed under vacuum and vented
with H2 five times and the mixture was stirred at room temperature
under a hydrogen atmosphere (1 atm) for 1.5 days. The mixture was
filtered through a pad of silica gel (ca. 1 g), the pad was washed
with EtOAc (20 mL) and the filtrate was concentrated under re-
duced pressure. The remaining crude product was subjected to col-
umn chromatography (petroleum ether/EtOAc, 15:1) to give lasiod-
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iplodin methyl ether [(R)-1; 72 mg, 23 mmol, 94%, 93% ee]. [α]2D0
=
+7.17 (c = 1.0, CHCl3), ref.[19] +8.7 (c = 1.63, CH3Cl); HPLC
analysis (Diacel Chiralcel OD-H; 20 °C; 0.7 mL/min; n-heptane/2-
PrOH, 85:15): tR = 6.44 (R), 7.59 (S) min. 1H NMR (CDCl3,
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360
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 356–361

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Received: September 28, 2012
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Published Online: November 27, 2012
Eur. J. Org. Chem. 2013, 356–361
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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