Total synthesis of (R)-sarkomycin via asymmetric rhodium-catalyzed conjugate addition

Article abstract of DOI:10.1021/jo4016979

(R)-Sarkomycin was prepared using a five-step total synthesis. Key steps in the enantioselective construction of the targeted scaffold were a rhodium-catalyzed asymmetric conjugate alkenyl addition with subsequent silyl trapping and a Mukaiyama aldol reaction with aqueous formaldehyde. Protection of the hydroxy group as a THP acetal and oxidative cleavage of the C,C-double bond provided a stable direct precursor to the natural product. The final liberation was carried out under slightly acidic conditions in a microwave-assisted reaction, resulting in a high yield of the deceptive sarkomycin. This represents the shortest enantioselective synthesis of this rather unstable compound to date and the first to employ asymmetric catalysis to introduce the stereogenic center.

Full text of DOI:10.1021/jo4016979

Article
pubs.acs.org/joc
Total Synthesis of (R)‑Sarkomycin via Asymmetric Rhodium-
Catalyzed Conjugate Addition
Johannes Westmeier, Steffen Kress, Christopher Pfaff, and Paultheo von Zezschwitz*
Fachbereich Chemie, Philipps-Universitat Marburg, 35032 Marburg, Germany
̈
S
* Supporting Information
ABSTRACT: (R)-Sarkomycin was prepared using a five-step total synthesis.
Key steps in the enantioselective construction of the targeted scaffold were a
rhodium-catalyzed asymmetric conjugate alkenyl addition with subsequent
silyl trapping and a Mukaiyama aldol reaction with aqueous formaldehyde.
Protection of the hydroxy group as a THP acetal and oxidative cleavage of the
C,C-double bond provided a stable direct precursor to the natural product.
The final liberation was carried out under slightly acidic conditions in a
microwave-assisted reaction, resulting in a high yield of the “deceptive”
sarkomycin. This represents the shortest enantioselective synthesis of this
rather unstable compound to date and the first to employ asymmetric catalysis
to introduce the stereogenic center.
cyclosarkomycin (4).7d,8a,c−g,11 However, it is quite difficult to
liberate the natural product from these precursors, and yields
for ester cleavages are 33% at best,7b while opening of
cyclosarkomycin (4) was reported in a maximum yield of
43%.7e
In addition to a number of racemic syntheses, enantiopure
precursors to sarkomycin have been obtained through (kinetic)
resolution,8a−e a chiral pool approach,8f and chiral auxiliary-
based strategies.8g−i Surprisingly, synthesis using asymmetric
catalysis has not been reported to date, even though this is
generally considered the most elegant and state-of-the-art
method for introducing stereogenic centers. To prove that
spirodionic acid (3) is biosynthesized through a Diels−Alder
reaction of sarkomycin, we pursued a total synthesis that could
be adapted to prepare 13C-labeled material cost efficiently. This
paper presents the first enantioselective preparation of
sarkomycin using asymmetric catalysis.
INTRODUCTION
■
Isolated from Streptomyces erythrochromogenes in 1953,1 the
secondary metabolite (R)-sarkomycin (1) was quickly garner-
ing significant interest for several reasons. Not only does it
show antibiotic activity, but, more importantly, it also
demonstrates a strong anticancer activity against various
carcinoma cell lines, including Ehrlich ascite tumors. As a
result, in the 1950s and 1960s, it was used as a prescription
drug for cancer treatments in Japan,2 as well as in clinical
studies in the US.3 Even though sarkomycin contains only one
stereogenic center, its configuration was initially inaccurately
assigned4 and only later corrected by Hill et al.5 In 2007,
Grond, Zezschwitz et al. reported on spirodionic acid (3),
another metabolite from Streptomyces, whose biosynthesis most
likely features a Diels−Alder type reaction of pyranone 2 with
sarkomycin (1) as formal dienophile.6 Over the years, more
than 30 synthetic approaches have been published,7,8 so
sarkomycin might seem to be an already solved synthetic
problem.
RESULTS AND DISCUSSION
■
The synthetic strategy is based on the asymmetric 1,4-addition
of alkenyl zirconocenes with subsequent silyl trapping (a
method we presented in a recent paper12) and on the total
synthesis of spirodionic acid (3), in which an ethenyl group was
used as a masked precursor to a carboxy moiety.6b First, a
racemic synthesis was developed: Cyclopentenone (5) was
transformed using a Cu-catalyzed, chlorotrimethylsilane-accel-
erated 1,4-addition of ethenylmagnesium bromide to yield silyl
enol ether 6 (Scheme 1). Next, a Yb(OTf)3-catalyzed
Mukaiyama aldol reaction with aqueous formaldehyde
(30 equiv) produced alcohol 7 in a trans/cis ratio of 71:29,13
and mesylation and concomitant elimination were performed
Yet the plain structure of the natural product is misleading.
Its sensitivity to acids and bases and its tendency to undergo
dimerization and polymerization cause some major difficulties.9
For example, they result in a very short shelf life and in the
substance’s attribution as the “deceptive” sarkomycin.7b,c,e,f,8b
Consequently, most approaches to its formation are formal
total syntheses that yield either sarkomycin esters8a,h,i,10 or
Received: August 2, 2013
Published: September 30, 2013
© 2013 American Chemical Society
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to acid 11 was achieved with KMnO4 in a benzene/water
biphasic mixture.20 A more efficient one-step cleavage from 9 to
11 was performed with RuCl3/NaIO4.21 This required carefully
adjusted conditions: For an optimum yield, precisely 4 equiv of
NaIO4 and a rather high dilution (a 0.03 M concentration of 9)
were used. Because acid 11 can be stored at −18 °C over
several months without decomposition, it is a remarkably stable
precursor to sarkomycin.
Scheme 1. First Approach to Sarkomycin via Diene 8
Crucial for the overall efficiency of the total synthesis of
sarkomycin (1) was its liberation from acid 11, which, due to
the instability of the natural product, had to be performed
under the mildest possible conditions. A similar conversion of
the dioxolane analogue of 11 has already been described by
Argade et al.7a and Marx et al.7e with 0.5 M HCl (30−33%
yield). Based on these results, a number of experiments were
carried out in deuterated solvents. This made it possible to
monitor the reaction by 1H NMR spectroscopy; Table 1
provides the maximum yields and respective reaction times.
with MsCl and NEt310e to yield diene 8 in a quantitative yield.14
The final step aimed to achieve a regioselective oxidative
cleavage of the more electron-rich isolated double bond. To
avoid racemization of the adjacent stereogenic center, this
required that special precautions be taken. Unfortunately, all
attempts with oxidants such as OsO4/Oxone, ozone with
subsequent oxidative or reductive workup, or RuCl3/NaIO4
failed to yield either the desired, or any other identifiable,
product. Similar problems have been noted in previous
syntheses of 17c,8i,10f and may be ascribed to the fast
decomposition of the intermediate aldehyde or related
structures.
Table 1. Optimization of the Liberation of Sarkomycin
a
entry
solvent
acid
T (°C)
t (h)
yield (%)
An alternative approach consisted of performing the
15
1
2
3
4
5
6
7
8
9
MeOH-d4
DMSO-d6
acetone-d6
acetone-d6
acetone-d6
acetone-d6
acetone-d6
acetone-d6
0.03 M DCl
0.03 M DCl
0.03 M DCl
Lewatit
85
85
45
45
1
25
40
41
58
84
66
29
63
16
Mukaiyama aldol reaction with 50 mol% of InCl3 and only
4
1 equiv of aqueous formaldehyde. The subsequent protection
led to THP acetal 9 in a 44% yield over two steps (Scheme 2).
10
24
1
b
Lewatit
60
Scheme 2. Racemic Synthesis of Precursor 11
b
Lewatit
80
0.75
0.5
2
b
Lewatit
100
c
b
Lewatit
60
b
benzene-d6
Lewatit
60
0.1
a
Yields determined by 1H NMR spectroscopy with mesitylene or
b
benzene as internal standard. Performed in a microwave reactor.
c
10:1 mixture of acetone-d6/D2O.
While a 0.03 M concentration of DCl in methanol was
sufficient to achieve the intended elimination at 85 °C, it
resulted in a substantial decomposition of 1 (entry 1). DMSO
proved to be more suitable, with no significant decrease in yield
noted even after prolonged reaction times (entry 2). With
acetone, a more easily removable solvent, the temperature was
lowered to 45 °C, resulting in an almost identical yield (entry
3). To facilitate removal of the acid, the ion-exchange resin
Lewatit K 2611 was used instead of DCl, providing sarkomycin
in 58% yield (entry 4). Further improvements were achieved by
microwave-assisted synthesis which, in particular, caused
tremendous rate acceleration. After a reaction time of only
1 h at 60 °C, a maximum yield of 84% was observed (entry 5),
while reactions at 80 °C and 100 °C led to significant
decomposition and inferior results (entries 6, 7). Mechanisti-
cally, the cleavage occurs as a two step-process: an initial acetal
hydrolysis, followed by the elimination of water. In an attempt
to speed up acetal cleavage and shorten the overall reaction
time, another experiment was performed in a 10:1 acetone-d6/
D2O mixture, but, surprisingly this led to a longer reaction time
and a lower yield (entry 8). Finally, very rapid conversion was
observed in benzene, but decomposition of 1 prevented its
synthetic use (entry 9).
In addition to the desired product, significant amounts of 3-
ethenylcyclopentanone arising from hydrolysis of silyl enol
ether 6 were also isolated. The aldol reaction was then repeated
with an excess of formaldehyde in the hope of favoring
hydroxymethylation over protonation, but this led to products
with oligomeric acetal chains in the 2-position. The amount of
aldehyde was thus limited to 1 equiv, which is especially useful
in view of preparing 13C-labeled material. Further protocols for
hydroxymethylation,16,17 as well as the introduction of other
precursors18,19 to a methylene group, were also explored but
produced inferior results. The oxidative degradation of
compound 9 required neutral conditions to avoid both the
premature cleavage of the THP group that occurs under acidic
conditions, as well as the epimerization at C-3 observed under
alkaline conditions. Unlike diene 8, ozonolysis of THP acetal 9
and a reductive workup with dimethyl sulfide worked well,
delivering the aldehyde 10 in 57% yield, while transformation
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For an enantioselective approach, an asymmetric conjugate
alkenyl addition with subsequent silyl trapping was per-
formed.12 The required hex-1-enyl zirconocene was prepared
by hydrozirconation of hex-1-yne and underwent a 1,4-addition
catalyzed by a rhodium/(R)-segphos complex (Scheme 3).
(R)-enantiomer would thus have a value [α]D20 of −55.4, which
is significantly higher than the previously reported values of
−34.7 for the synthetic material8b and −45 for sarkomycin
isolated from natural sources.22 As stated in the literature, this
difference may be the result of the presence of degradation
products in previous measurements.8b In contrast, sarkomycin
prepared using the new approach described above appears to be
of very high purity: Storage in diethyl ether at −65 °C resulted
in the separation of solid product 1 (mp approximately
−14 °C), though unfortunately no crystals suitable for X-ray
analysis could be grown.
Scheme 3. Asymmetric Synthesis of Sarkomycin
The subsequent esterification into methyl ester 15 also
confirmed the yield and purity of 1 prepared in this manner. To
do so, the ion-exchange resin was simply filtered off after
complete conversion to 1, followed by the addition of
Me3OBF4 and diisopropylethylamine (DIPEA).23 Though
compound 15 also undergoes decomposition in neat form,8h
it was possible to use rapid column chromatography to purify it,
furnishing a 58% yield over the two steps from (R)-11.
Moreover, this material showed 96% ee, proving the integrity of
the stereogenic center throughout the total synthesis.
CONCLUSION
■
For the first time, asymmetric catalysis was used in the synthesis
of (R)-sarkomycin. While diene 8 turned out to be an
inappropriate precursor, acid 11 enabled a fast, efficient
liberation of the natural product. On the basis of the NMR
spectra and high value of the specific rotation, the material
obtained in this manner appears to be exceptionally pure.
Moreover, this approach can be used to prepare 13C-labeled
sarkomycin because it only requires the use of 1 equiv of
reasonably priced aqueous 13C-formaldehyde. Preparation of
this material and feeding experiments are currently in progress.
As a whole, this five-step synthesis is not only the shortest way
known to date for preparing enantiopure sarkomycin but is also
that with the highest overall yield of 19%.
Transmetalation of the enolate from zirconium to lithium was
then achieved with 2 equiv of MeLi before Me3SiCl was added.
This resulted in the formation of silyl enol ether 12 in 95%
yield with an excellent ee of 96%. Hydroxymethylation to
alcohol 13 and the subsequent conversion to the THP acetal 14
were then performed according to the racemic synthesis,
furnishing an only slightly lower yield. For the oxidative
cleavage of the hexenyl substituent, a modified solvent mixture
containing EtOAc instead of CCl4 was applied. By carrying out
the reaction at 0 °C it was possible to improve the preparation
of 11. Finally, while microwave-assisted elimination to (R)-
sarkomycin (1) succeeded just as well as with rac-11, isolation
of the natural product turned out to be problematic. While
sarkomycin is quite stable in acetone or chloroform solutions
and can thus be stored at −18 °C for at least two weeks without
decomposition, polymerization starts immediately upon re-
moval of the solvent, causing an insoluble film to form in the
flask.22 Quantification and analysis of product 1 were therefore
achieved using an unusual procedure: Sarkomycin was purified
by extraction of the reaction mixture with an alkaline aqueous
solution, and the reacidified phase was then extracted with
diethyl ether. After removal of the solvent at temperatures
below −40 °C, the residue was dissolved in CDCl3. NMR
spectra showed sarkomycin to be the sole product. Afterward,
the CDCl3 solution was thoroughly concentrated, and an 86%
yield was calculated, which is consistent with the yield
determined by NMR (Table 1, entry 5). To analyze the optical
rotation, the diethyl ether extract of the reacidified aqueous
solution was diluted with methanol, and the ether and majority
of methanol were removed under reduced pressure. The
remaining concentrated solution was used to determine the
optical rotation, and its concentration was calculated by
EXPERIMENTAL SECTION
■
General. Microwave reactions were carried out in a CEM Discover
LabMate microwave reactor in sealed 10 mL microwave synthesis
vessels. Microwave power was controlled internally and limited to 60
W; the temperature was measured using an external IR-sensor. The
reaction temperature and time are given with the respective
1
preparations. H NMR spectra were recorded at 250, 300, or 500
MHz. Chemical shifts are reported as δ values relative to the residual
proton signal (CHCl3: δ = 7.26 ppm) as internal reference. 13C NMR
spectra were recorded at 62.5, 75.5, or 125 MHz. Chemical shifts are
reported as δ values relative to CDCl3 (δ = 77.16 ppm) as internal
reference. IR spectra were recorded on a FT-IR spectrometer. MS and
HRMS spectra were acquired on a linear ion-trap Fourier transform
mass-analyzer. Optical rotations were measured with concentrations in
g/100 mL. Column chromatography was carried out on MN Kieselgel
60 M (Machery-Nagel, 0.04−0.063 mm). TLC analysis was carried out
on precoated sheets (Merck DC Kieselgel 60 F254). Solvents used for
extraction and chromatography were of technical grade and distilled
prior to use. All moisture-sensitive reactions were carried out under
dry nitrogen or argon in oven- and/or flame-dried glassware. THF was
distilled from sodium benzophenone ketyl. HMPA was distilled from
sodium. DIPEA, triethylamine, acetonitrile, and dichloromethane were
distilled from calcium hydride. All other chemicals are of commercial
origin and used as received.
3-Ethenyl-1-trimethylsiloxycyclopent-1-ene (6). A solution of
ethenyl magnesium bromide (18 mL, 18 mmol, 1.0 M in THF) and
HMPA (6.3 mL, 36 mmol) in THF (25 mL) was cooled to −55 °C,
(CuI)4(DMS)3 (319 mg, 336 μmol) was added, and the resulting
20
removing the solvent afterward. The specific rotation [α]D
was determined to be −53.2. On the basis of 96% ee, the pure
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suspension was stirred at this temperature for 20 min. A solution of
cyclopent-2-enone (5, 1.01 mL, 12.0 mmol) and Me3SiCl (3.6 mL, 28
mmol) in THF (10 mL) was added dropwise over 15 min, and stirring
was continued for 30 min. The solution was warmed to rt, and NEt3
(3.3 mL, 24 mmol) was added. The reaction mixture was poured into
n-pentane (500 mL) and washed with water (3 × 150 mL), and the
organic phase was dried over Na2SO4. Filtration over Celite/activated
charcoal and evaporation of the solvents yielded 2.14 g (97%) of the
title compound 6 as a colorless oil. Analytical data were in accordance
with those in the literature.24
(%): 246.9 (100) [M + Na]+. ESI-HRMS calcd for C13H20O3Na:
247.1316; found: 247.1308.
trans-2-(Tetrahydropyran-2-yloxymethyl)cyclopentanone-
3-carbaldehyde (10). A solution of trans-3-ethenyl-2-(tetrahydro-
pyran-2-yloxymethyl)cyclopentanone (9, 33 mg, 0.15 mmol) in
CH2Cl2 (35 mL) was cooled to −78 °C. Ozone was introduced
into the solution over 90 s until a slightly blue color persisted, followed
by oxygen until the solution was colorless. Then, Me2S (66 μL, 0.90
mmol) was added, and the reaction mixture was allowed to warm to rt
and stirred for additional 12 h. The solvent was removed under
reduced pressure, and the crude product was purified by column
chromatography over aluminum oxide (Brockmann activity II, n-
hexane/EtOAc 1:1) to yield 19 mg, 57% of the title compound 10 (Rf
= 0.36) as highly viscous, colorless oil. 1H NMR (300 MHz, CDCl3): δ
= 9.77 (mc, 1H), 4.57−4.46 (m, 1H), 4.00−3.38 (m, 4H), 3.27−3.14
(m, 1H), 2.69−2.59 (m, 1H), 2.44−1.88 (m, 3H), 1.84−1.36 (m, 7H).
13C NMR (75 MHz, CDCl3): δ = 215.5, 215.2, 201.4, 201.3, 99.5,
trans-3-Ethenyl-2-hydroxymethylcyclopentanone (7). With
Yb(OTf)3. Yb(OTf)3 (620 mg, 1.00 mmol) and 3-ethenyl-1-
trimethylsiloxycyclopent-1-ene (6, 1.95 g, 10.7 mmol) were dissolved
in a mixture of aqueous formaldehyde (25 mL, 37% in H2O, 336
mmol) and dimethoxyethane (25 mL), and the solution was stirred for
24 h at rt. The reaction mixture was then concentrated under reduced
pressure, diluted with water (100 mL), and extracted with Et2O (3 ×
150 mL). The combined organic phases were dried over MgSO4, and
the solvent was removed under reduced pressure. Purification by
Kugelrohr distillation (80 °C, 0.01 mbar) afforded 808 mg, 54% of the
98.6, 65.4, 65.1, 62.5, 61.7, 52.0, 51.9, 49.9, 49.8, 37.64, 37.61, 30.4,
30.37, 25.4, 25.3, 21.54, 21.51, 19.5, 19.1. IR (neat): ν = 2941, 2872,
2725, 1739, 1723, 1121, 1012 cm−1. ESI-HRMS calcd for C12H19O4:
227.1278; found: 227.1260.
1
title compound 7 with a trans/cis ratio of 71:29 (determined by H
NMR) as colorless oil.
trans-2-(Tetrahydropyran-2-yloxymethyl)cyclopentanone-
3-carboxylic Acid (11). A solution of trans-3-ethenyl-2-(tetrahy-
dropyran-2-yloxymethyl)cyclopentanone (9, 328 mg, 1.46 mmol) in a
mixture of acetonitrile (21 mL), CCl4 (14 mL), and H2O (14 mL) was
treated with RuCl3 (61.0 mg, 293 μmol) and NaIO4 (625 mg, 2.92
mmol). Additional NaIO4 (625 mg, 2.92 mmol) was added after 30
min, and stirring was continued for 1.5 h before the reaction mixture
was filtered over activated charcoal/Celite. The filter cake was washed
with EtOAc (20 mL), and the filtrate was extracted with aqueous
NaHCO3 (0.6 M, 3 × 30 mL). The combined aqueous phases were
acidified with HCl (1 M) to pH 3 and extracted with EtOAc (5 × 15
mL), and the combined organic phases were dried over Na2SO4. The
solvent was removed under reduced pressure to yield 239 mg, 67% of
With InCl3. To solution of 3-ethenyl-1-trimethylsiloxycyclopent-1-
ene (6, 2.17 g, 11.9 mmol) and aqueous formaldehyde (0.89 mL, 37%
in H2O, 12 mmol) in THF (55 mL) was added InCl3 (1.33 g, 6.01
mmol), and the reaction mixture was stirred for 22 h at rt. THF was
removed under reduced pressure, and the reaction mixture was diluted
with CH2Cl2 (10 mL) and washed with water (20 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 20 mL), and the combined
organic phases were washed with brine (20 mL) and dried over
MgSO4. The solvent was removed under reduced pressure to yield
1.93 g of crude product with a trans/cis ratio of 85:15 (determined by
1H NMR). ESI-HRMS calcd for C8H12O2Na: 163.0730; found:
163.0729. Further analytical data were in accordance with those in the
literature.6b
1
the title compound 11 as highly viscous, colorless oil. H NMR (300
MHz, CDCl3, RCO2H not observed, signals marked with “*” belong
3-Ethenyl-2-methylenecyclopentanone (8). A solution of
trans-3-ethenyl-2-hydroxymethylcyclopentanone (7, 95.0 mg, 0.678
mmol from the Yb(OTf)3-catalyzed transformation) in CH2Cl2 (3.2
mL) was treated with NEt3 (395 μL, 2.83 mmol) and MsCl (309 mg,
2.70 mmol), and the reaction mixture was stirred for 24 h at rt. Then,
H2O (15 mL) was added, the phases were separated, and the aqueous
phase was extracted with CH2Cl2 (3 × 20 mL). The combined organic
phases were dried over Na2SO4, and the solvent was removed under
reduced pressure. Column chromatography over silica gel (n-pentane/
EtOAc 5:1) yielded 82.0 mg, 99% of the title compound 8 (Rf = 0.70)
as a viscous, colorless oil. ESI-HRMS calcd for C8H10ONa: 145.0624;
found: 145.0627. Further analytical data were in accordance with those
in the literature.14
2
to just one diasteromer): δ = 4.61−4.55 (m, 1H), 4.08 (dd, J = 10.0,
3J = 4.5 Hz, 1H*), 3.97 (dd, 2J = 9.9, 3J = 3.4 Hz, 1H*), 3.88−3.71 (m,
1H), 3.76 (dd, 2J = 9.9, 3J = 3.2 Hz, 1H*), 3.60 (dd, 2J = 10.0, 3J = 3.7
Hz, 1H*), 3.50 (mc, 1H), 3.34−3.22 (m, 1H), 2.64 (mc, 1H), 2.54−
2.33 (m, 2H), 2.31−2.14 (m, 1H), 2.11−1.95 (m, 1H), 1.76−1.43 (m,
6H). 13C NMR (75 MHz, CDCl3): δ = 215.9, 215.6, 179.6, 179.4,
99.5, 98.7, 64.9, 64.7, 62.5, 61.7, 52.4, 52.1, 43.7, 43.6, 38.25, 38.22,
30.43, 30.37, 25.41, 25.35, 24.72, 24.67, 19.5, 19.1. IR (neat): ν =
2943, 2875, 1733, 1705 cm−1. MS (ESI, 70 eV), m/z (%): 265 (100)
[M + Na]+, 141 (21) [M − OTHP]+. ESI-HRMS calcd for
C12H18O5Na: 265.1046; found: 265.1048.
(3S)-(Hex-1E-enyl)-1-trimethylsilyloxycyclopent-1-ene (12).
A solution of [Rh(cod)Cl]2 (24.7 mg, 50.1 μmol) and (R)-segphos
(73.3 mg, 120 μmol) in THF (4.0 mL) was stirred for 1 h at rt. In
parallel, a suspension of Cp2ZrHCl (671 mg, 2.60 mmol) in THF (8.0
mL) was treated with hex-1-yne (274 μL, 2.40 mmol), and stirring was
continued for 1 h at rt. Cyclopent-2-enone (5, 168 μL, 2.01 mmol)
was added to the catalyst mixture followed by the alkenyl zirconocene
solution. The reaction mixture was stirred for 1 h at rt and then cooled
to −78 °C followed by addition of methyllithium (3.5 mL, 5.3 mmol,
1.5 M in Et2O). After 1 h, Me3SiCl (0.76 mL, 6.0 mmol) was added,
and stirring was continued for 1 h at −78 °C. Triethylamine (3.3 mL,
24 mmol) and urea hydrogen peroxide (1.13 g, 12.0 mmol) were
added subsequently, and the reaction mixture was stirred for 24 h at rt.
The reaction mixture was diluted with THF (10 mL), filtered over
Celite, diluted with water (40 mL), and extracted with n-pentane (3 ×
50 mL). The combined organic phases were dried over Na2SO4,
suspended with activated charcoal (1 g), and filtered over Celite. The
solvents were removed under reduced pressure to furnish 455 mg, 95%
of the title compound 12. 96% ee was determined by GC on a chiral
stationary phase; analytical data were in accordance with those in the
literature.12
trans-3-Ethenyl-2-(tetrahydropyran-2-yloxymethyl)-
cyclopentanone (9). Crude trans-3-ethenyl-2-hydroxymethylcyclo-
pentanone (7, 1.93 g) from the InCl3-mediated transformation was
dissolved in CH2Cl2 (20 mL), and 3,4-dihydro-2H-pyran (3.3 mL, 36
mmol) and PPTS (301 mg, 1.20 mmol) were added subsequently at rt.
The reaction mixture was stirred for 17 h, water (50 mL) was added,
and the aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic phases were washed with brine (20 mL) and dried
over MgSO4, and the solvent was removed under reduced pressure.
Column chromatography over silica gel (n-pentane/EtOAc 5:1)
yielded 1.18 g of the title compound 9 (Rf = 0.35) in 44% yield
1
over the two steps from 6 as highly viscous, colorless oil. H NMR
(300 MHz, CDCl3, signals marked with “*” belong to just one
3
diasteromer): δ = 5.81 (ddd, J = 17.3, 10.0, 7.4 Hz, 1H), 5.16−5.01
(m, 2H), 4.54 (m, 1H), 4.08 (dd, 2J = 9.9, 3J = 3.6 Hz, 1H*), 3.83 (dd,
2J = 9.8, 3J = 3.2 Hz, 1H*), 3.81−3.75 (m, 1H), 3.72 (dd, 2J = 9.9, 3J =
2
3
3.2 Hz, 1H*), 3.49 (mc, 1H), 3.42 (dd, J = 9.9, J = 3.5 Hz, 1H*),
2.96−2.80 (m, 1H), 2.42−2.34 (m, 1H), 2.17 (mc, 2H), 2.04−1.95 (m,
1H), 1.82−1.42 (m, 7H). 13C NMR (75 MHz, CDCl3): δ = 217.9,
217.5, 140.3, 140.2, 115.3, 115.2, 99.1, 98.5, 63.5, 63.4, 61.9, 61.4, 55.0,
54.8, 43.2, 43.0, 38.5, 38.4, 31.0, 30.4, 27.5, 25.43, 25.41, 19.3, 19.0. IR
(neat): ν = 2940, 1743, 1032, 1020, 907 cm−1. MS (ESI, 70 eV), m/z
(3S)-(Hex-1E-enyl)-(2R)-(tetrahydropyran-2-yloxymethyl)-
cyclopentanone (14). To a solution of (3S)-(hex-1E-enyl)-1-
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trimethylsilyloxycyclopent-1-ene (12, 1.36 g, 5.70 mmol) in THF (30
mL) were added InCl3 (630 mg, 2.84 mmol) and aqueous
formaldehyde (424 μL, 37% in H2O, 5.70 mmol). The reaction
mixture was stirred for 40 h at rt, the solvent was removed under
reduced pressure, and the residue was diluted with Et2O (20 mL) and
water (20 mL). The aqueous phase was extracted with Et2O (3 × 50
mL). The combined organic phases were washed with brine (20 mL)
and dried over Na2SO4, and the solvent was removed under reduced
pressure to afford 1.29 g of crude (3S)-(hex-1E-enyl)-2-hydroxyme-
thylcyclopentanone (13) as a yellowish oil with a trans/cis ratio of
45.7, 36.7, 23.0. ESI-HRMS calcd for C7H7O3: 139.0401; found:
139.0405. [α]D −53.2 (c 0.56, MeOH).
20
Methyl 2-Methylenecyclopentanone-(3R)-carboxylate (15).
A 10 mL CEM microwave synthesis vessel was charged with a solution
of (2R)-(tetrahydropyran-2-yloxymethyl)cyclopentanone-(3R)-carbox-
ylic acid (11, 38.2 mg, 158 μmol) in acetone (1.5 mL), and ion-
exchange resin Lewatit K2611 (200 mg) was added. The vessel was
sealed, and the reaction was carried out in the microwave reactor (60
°C, 1 h, 60 W max.). Afterward, the ion-exchange resin was filtered off,
the filtrate was treated with DIPEA (40.2 μL, 236 μmol) and
Me3OBF4 (35.1 mg, 237 μmol), and the reaction mixture was stirred
for 1 h at rt. Then, H2O (10 mL) was added, the aqueous phase was
extracted with Et2O (4 × 5 mL), the combined organic phases were
dried over Na2SO4, and the solvent was removed under reduced
pressure. Column chromatography over silica gel (n-pentane/Et2O
1:1) afforded 14.0 mg, 58% of the title compound 15 (Rf = 0.46) as
colorless oil. 96% ee was determined by HPLC analysis on a chiral
1
85:15 (determined by H NMR).
A solution of the crude alcohol 13 (866 mg) in CH2Cl2 (20 mL)
was treated with 3,4-dihydro-2H-pyran (1.04 mL, 11.5 mmol) and
PPTS (96 mg, 0.38 mmol), and the reaction mixture was stirred for 24
h at rt. Afterward, H2O (50 mL) was added, and the aqueous phase
was extracted with CH2Cl2 (3 × 50 mL). The combined organic
phases were washed with brine (50 mL) and dried over Na2SO4, and
the solvent was removed under reduced pressure. Column
chromatography over silica gel (n-pentane/EtOAc 10:1) yielded 395
mg of the title compound 14 (Rf = 0.32) as a colorless oil. This
1
2
stationary phase. H NMR (500 MHz, CDCl3): δ = 6.16 (d, J = 2.6
Hz, 1H), 5.58 (d, 2J = 2.4 Hz, 1H), 3.76−3.72 (m, 1H), 3.74 (s, 3 H),
2.59−2.52 (m, 1H), 2.39−2.31 (m, 1H), 2.31−2.24 (m, 1H), 2.21−
2.13 (m, 1H). 13C NMR (125 MHz, CDCl3): δ = 204.7, 173.0, 142.5,
120.5, 52.5, 45.9, 36.8, 23.1. ESI-HRMS calcd for C8H10O3Na:
177.0522; found: 177.0529.
1
corresponds to 37% yield over the two steps from compound 12. H
NMR (300 MHz, CDCl3, signals marked with “*” belong to just one
diasteromer): δ = 5.61−5.46 (m, 1H), 5.45−5.34 (m, 1H), 4.56 (mc,
2
3
2
1H), 4.05 (dd, J = 9.9, J = 3.5 Hz, 1H*), 3.82 (dd, J = 9.9, 3J = 3.2
2
3
Hz, 1H*), 3.79−3.72 (m, 1H), 3.68 (dd, J = 9.8, J = 3.2 Hz, 1H*),
ASSOCIATED CONTENT
■
2
3
3.48 (mc, 1H), 3.39 (dd, J = 9.9, J = 3.5 Hz, 1H*), 2.83 (mc, 1H),
2.39−2.29 (m, 1H), 2.20−2.06 (m, 2H), 2.06−1.96 (m, 2H), 1.96−
1.87 (m, 1H), 1.77−1.41 (m, 7H), 1.39−1.23 (m, 4H), 0.87 (t, 3J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 218.4, 218.0, 131.9, 131.8,
99.1, 98.6, 63.6, 63.4, 61.9, 61.4, 55.5, 55.3, 42.3, 42.2, 38.7, 38.6, 32.3,
31.8, 30.52, 30.49, 28.18, 28.16, 25.6, 25.5, 22.28, 22.26, 19.3, 19.1,
14.0. IR (neat): ν = 2927, 2870, 1744, 1124, 1032, 1020 cm−1. MS (EI,
70 eV), m/z (%): 280 (1) [M]+, 178 (15) [M−HOTHP]+, 85 (100)
[THP]+. ESI-HRMS calcd for C17H28O3Na: 303.1931; found:
303.1929.
S
* Supporting Information
1H and 13C NMR spectra of all compounds as well as
chromatograms for the determination of the enantiomeric
excesses of compounds 12 and 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zezschwitz@chemie.uni-marburg.de.
■
(2R)-(Tetrahydropyran-2-yloxymethyl)cyclopentanone-(3R)-
carboxylic Acid (11). A solution of (3S)-(hex-1E-enyl)-(2R)-
(tetrahydropyran-2-yloxymethyl)cyclopentanone (14, 300 mg, 1.07
mmol) in a mixture of acetonitrile (18 mL), EtOAc (12 mL), and H2O
(12 mL) was cooled to 0 °C and treated with RuCl3 (44 mg, 0.21
mmol) and NaIO4 (915 mg, 4.28 mmol). Stirring was continued for 30
min at 0 °C and for 15 min at rt. Activated charcoal (100 mg) was
added, and the reaction mixture was filtered over Celite. The filter cake
was washed with EtOAc (20 mL), and the filtrate was extracted with
half saturated aqueous NaHCO3 (3 × 36 mL). The combined aqueous
phases were acidified with HCl (6 M) to pH 2 and extracted with
EtOAc (3 × 75 mL), and the combined organic phases were dried
over Na2SO4. The solvents and valeric acid were removed under
reduced pressure to yield 161 mg, 62% of the title compound as highly
viscous, yellowish oil.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.W. is indebted to the Konrad-Adenauer-Stiftung for a doctoral
scholarship. The authors are indebted to Sophie Schlondorff for
careful proofreading of the manuscript.
REFERENCES
■
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1
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2
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2
1H), 5.68 (d, J = 2.3 Hz, 1H), 3.80−3.72 (m, 1H), 2.65−2.16 (m,
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10722
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10723
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