An efficient synthesis of a cyclic ether key intermediate for 9-membered masked enediyne using an automated synthesizer

Article abstract of DOI:10.1021/op9002455

Naturally occurring antibiotics containing 9-membered enediynes have received considerable attention for many years due to their potent DNA-cleaving activity. We previously reported the design and synthesis of a synthetic, masked 9-membered enediyne that

Full text of DOI:10.1021/op9002455

Organic Process Research & Development 2009, 13, 1111–1121
An Efficient Synthesis of a Cyclic Ether Key Intermediate for 9-Membered Masked
Enediyne Using an Automated Synthesizer
Yoshikazu Tanaka,† Shinichiro Fuse,† Hiroshi Tanaka,† Takayuki Doi,†,‡ and Takashi Takahashi*,†
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan, and
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aza-Aoba, Aramaki, Aoba, Sendai 980-8578, Japan
Abstract:
Moreover, it is sometimes necessary to modify reaction condi-
tions and/or experimental operations to utilize an automated
synthesizer.3,6,8 Therefore, in general, application of an auto-
mated process to solution-phase synthesis is challenging.
Nevertheless, it is important to apply various solution-phase
reactions to an automated synthesizer.
Naturally occurring antibiotics, such as kedarcidin chro-
mophore (1)10,11 and C-1027 chromophore (2),12,13 that contain
a 9-membered enediyne skeleton have potent antitumor activity
(Figure 1). In addition to their uses in pharmaceuticals,14-16 the
9-membered enediynes are powerful tools for chemical biology
because they cleave DNA strands via formation of a highly
active biradical.17,18 We previously demonstrated that the
masked 9-membered enediyne 319-21 exhibits DNA-cleaving
activity. In addition, its derivatives, 4,22 5, and 623,24 that contain
sugars and/or a naphthoate moiety, possess base-selective DNA-
cleaving activity (Figure 1).
Naturally occurring antibiotics containing 9-membered enediynes
have received considerable attention for many years due to their
potent DNA-cleaving activity. We previously reported the design
and synthesis of a synthetic, masked 9-membered enediyne that
possesses DNA-cleaving activity. Despite the importance of the
9-membered enediynes, application of these molecules is limited
by their difficult synthesis. Herein, we report an improved process
for the generation of a synthetic, masked 9-membered enediyne
that uses an automated synthesizer for the production of a key
synthetic intermediate.
Introduction
Automation of synthetic operations, such as mixing of
compounds, temperature control of reaction mixtures, quenching
of reactions, filtration, liquid-liquid extraction, and washing
and drying, effectively improves both the reproducibility and
reliability of the syntheses because automated synthesizers
minimize the variability of the experimental manipulations.1
Recently, automated synthesizers have been used for two to
four steps of the solution-phase synthesis of condensed-azoles,
tripeptides, quinazolinones, and spirooxazolinoisoxazolines.2-6
We previously reported a formal total synthesis of taxol using
an automated synthesizer that was developed in our laboratory.
Use of the ChemKonzert7 enabled production of a key synthetic
intermediate in a 36-step, solution-phase synthesis.8 However,
automation of general solution-phase syntheses is limited by
the wide variety of the experimental operations required
compared with those used for solid-phase synthesis. In particu-
lar, automation of liquid-liquid extractions is not simple.9
Despite the importance of the 9-membered enediynes, the
applications of these molecules are limited by the difficulty of
their syntheses. Synthesis of the 9-membered enediynes, which
are structurally complex and unstable, typically requires ad-
ditional synthetic steps and careful manipulation. Thus, only a
few laboratories can synthesize, modify, and utilize these
(10) Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem.
Soc. 2007, 129 (17), 5381–5383.
(11) Ogawa, K.; Koyama, Y.; Ohashi, I.; Sato, I.; Hirama, M. Angew.
Chem., Int. Ed. 2009, 48 (6), 1110–1113.
(12) Otani, T.; Minami, Y.; Marunaka, T.; Zhang, R.; Xie, M. Y. J. Antibiot.
1988, 41 (11), 1580–1585.
(13) Inoue, M.; Ohashi, I.; Kawaguchi, T.; Hirama, M. Angew. Chem., Int.
Ed. 2008, 47 (9), 1777–1779.
(14) Shao, R.-G. Curr. Mol. Pharmcol. 2008, 1 (1), 50–60.
(15) SMANCS is polymer anticancer drug in which butyl esterified styrene
maleic acid alternating copolymer is combined with neocarzinostatin
as a proteinaceous anticancer drug.
* Corresponding author. Telephone: +81-3-5734-2120. Fax: +81-3-5734-
2884. E-mail: ttak@apc.titech.ac.jp.
† Tokyo Institute of Technology.
(16) Zhen, Y. Z.; Lin, Y. J.; Shang, B. Y.; Zhen, Y. S. Int. J. Hematol.
2009, 90 (1), 44–51.
‡ Tohoku University.
(1) Cork, D. G.; Sugawara, T., Laboratory Automation in the Chemical
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10.1021/op9002455 CCC: $40.75  2009 American Chemical Society
Published on Web 11/02/2009
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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Figure 1. Chemical structures of kedarcidin chromophore (1), C-1027 chromophore (2), the masked 9-membered enediyne 3, and
their analogues 4-6.
“molecular scissors” to cleave DNA.10,11,13,25-29 Herein, we
report the details of the synthesis of the 12-membered cyclic
ether 7, which is a chemically stable, key synthetic intermediate
of 3-6. To improve the reproducibility and efficiency of the
synthesis, we used an automated synthesizer that was originally
developed in our labsthe ChemKonzert (Figure 2)sin a 16-
step process with some modifications of the reaction conditions.
Wittig rearrangement30 of the 12-membered cyclic ether
7 is the most crucial step in the construction of the highly
strained 9-membered diyne, in which the newly formed
secondary alcohol can be used to introduce a phthalic acid.
A ꢀ-elimination of the phthalate “triggers” biradical
formation. The cyclic ether 7 can be prepared via the
Sonogashira coupling reaction between 8 and 9, followed
by intramolecular etherification. Selection of an appropri-
ate protecting group for the allylic alcohol 9 is important.
The protecting group must be stable under palladium-
catalyzed reaction conditions. In addition, after the
coupling reaction, it must be removed without affecting
Results and Discussion
The synthetic route for the masked 9-membered ene-
diyne 3 is illustrated in Scheme 1. The transannular [2,3]-
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Org. Chem. 1991, 56 (8), 2650–2655.
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Figure 2. Full picture of ChemKonzert, which consists of two reaction vessels (RF1, RF2), a centrifugal separator (SF, 700 mL),
two receivers (SF1, SF2) (500 mL), two glass filters (FF1, FF2) (500 and 100 mL), twelve substrate and reagent reservoirs (RR1-
RR12) (100-200 mL), six solvent and wash-solution bottles (RS1-RS6) (500 mL), three drying pads (DT1-DT3), a round flask (CF),
two solvent tanks (WT1, WT2), and a computer controller. The glassware is interconnected with Teflon tubes, and solutions are
transferred under reduced pressure by using a diaphragm pump. Separation of organic and aqueous layers is performed by measuring
the electroconductivities of the two different phases with a sensor, and the liquid flow is regulated by solenoid valves controlled
with an originally developed Windows software (KonzertMeister). The users input the procedures into the computer and add substrates
and reagents to the reservoirs and fill the solvents. The synthesizer carried out the reaction procedures as follows: the substrate and
reagents in the reservoirs, RR, were added to the reaction vessel, RF, at a controlled reaction temperature under a nitrogen
atmosphere. After the reaction was complete (checking by TLC and/or HPLC by hand), quenching reagent in RR or RS was added
to the reaction vessel, RF, and the mixture was transferred to the centrifugal separator, SF, with removal of the precipitate through
the glass-filter, FF. After the centrifugal separation, the two resulting phases were separated by measurement of their
electroconductivities with a sensor and transferred to two receivers, SF1 and SF2. The aqueous solution in SF1 was taken back to
the reaction vessel, RF. After addition of the extraction solvent from the solvent bottle, RS, the mixuture was stirred and then
transferred to the centrifugal separator, SF. After two or three extractions, the combined organic solution in the receiver, SF2, was
washed with aqueous solutions of sodium bicarbonate and sodium chloride from the wash-solution bottles, RS, in the reaction flask,
RF. The organic layer was separated in the centrifugal separator, SF, and transferrred to the receiver, SF2. The organic layer in
SF2 was then passed through a MgSO4 or Na2SO4 plug, DT, for drying. The filtrate was stored in a round flask, CF, for purification
after evaporation of the solvent (manual). Unless purification was necessary, the filtrate was directly transferred to another reaction
vessel, RF, and concentrated under reduced pressure; the next reaction was carried out sequentially. Finally, the whole apparatus
was washed with water and acetone from the solvent tanks, WT, and dried under reduced pressure.
Scheme 1. Synthetic strategy for the masked 9-membered enediyne 3
either the siloxy groups at the 10- and 11-positions or the
unstable, conjugated dienyne moiety. The enediyne 8 was
constructed by stereoselective 1,2-addition to ketone 11.
The second key reaction is the palladium-catalyzed
addition of BzOH to the diene monoepoxide 13.31,32 This
reaction induces trans stereochemistry between the hy-
droxy groups at the 10- and 11-positions and the ∆1,(12)
double-bond in 10. Although the palladium-catalyzed
reaction produces four possible regio- and stereoisomers
by BzOH displacement from the R and ꢀ faces at the 9-
and 12-positions via the π-allyl palladium complex 12,
all products could be converted into the enone 11 in three
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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Scheme 2. Automated synthesis of the diene monoepoxide 13a
a Reagents and conditions: (a) NEt3, DMAP, CH2Cl2, 25 °C, 10 min, then TBSCl, CH2Cl2, 25 °C, 10 h, 73%; (b) Bu4NHSO4, NaClO aq, CH2Cl2, 0 °C, 6 h, 70%;
(c) TBAF, THF, 0 °C, 5 min, 57%; (d) trimethylsilylacetylene, BuLi, THF, -78 to -40 °C, 1 h, then 14, THF, -78 °C, 30 min, 71%; (e) Tf2O, 2,6-lutidine, CH2Cl2,
-78 to 0 °C, 1 h, 70%. DMAP ) 4-(dimethylamino)pyridine, TBAF ) tetrabutylammonium fluoride, Tf2O ) triflic anhydride.
Scheme 3. Palladium-catalyzed addition of BzOH to diene monoepoxide 13 assisted by the automated synthesizera
a Reagents and conditions: (a) 5 mol % Pd(OAc)2, 20 mol % PPh3, THF, 25 °C, 20 min, then BzOH, THF, 25 °C, 1 h, then 13, THF, 0 to 25 °C, 10 h, 75%,
10/19a/19b ) 12:2:1; (b) 10 mol % Pd(OAc)2, 40 mol % PPh3, BzOH, THF, 25 °C, 1 h, then 10, THF, 0 to 25 °C, 24 h.
steps. This methodology offers an enantioselective ap-
proach to 3, starting from the optically active epoxide 14,
which is readily prepared from (S)-4-hydroxy-2-cyclo-
pentenone.33 Herein, we describe an efficient, automated
synthesis of racemic 7.
SF2 was then passed through an anhydrous Na2SO4 plug and
collected in a round flask, CF1. Finally, the entire apparatus
was washed with water and acetone that had been added to the
solvent tanks, WT1 and WT2, and was dried under reduced
pressure. The collected solution was manually concentrated in
Vacuo. The obtained residue was purified manually using flash
silica gel column chromatography to give silyl ether 16 in 73%
yield. Subsequent stereoselective epoxidation of the enone 16
afforded 14 as a single diastereomer. The relative stereochem-
istry of the epoxide and the hydroxy group in 14 was determined
to be the desired trans configuration on the basis of comparison
of the NMR spectra of 17 with previously reported data.34,35
Addition of lithium trimethylsilylacetylide to ketone 14 gave
the alcohol 18 in 71% yield. Treatment of the resultant alcohol
with Tf2O and 2,6-lutidine at -78 °C, followed by warming to
0 °C, afforded the desired alkene 13 in 70% yield. For the 1,2-
addition and subsequent ꢀ-elimination to afford enyne 13, the
reaction vessel, RF1, was dried by heating at 80 °C for 30 min
under reduced pressure and then automatically cooled to 25 °C
Epoxyalkene 13 was prepared with the use of the automated
synthesizer (Scheme 2). Protection of 4-hydroxy-2-cyclopen-
tenone (15) was carried out as follows. The computer controlling
the automated synthesizer was programmed with a specific
procedure. Substrate, reagents, solvents, and wash solutions
were respectively added to the reaction vessel, RF1, reagent
reservoir, RR1, solvent bottles, RS1, and wash-solution bottles,
RS4-RS6. Then, the operation of the automated synthesizer
was started. A solution of 15, NEt3, and DMAP in CH2Cl2 was
stirred at 25 °C for 10 min under a nitrogen atmosphere in the
reaction vessel, RF1. A solution of TBSCl in CH2Cl2, which
was originally loaded into the reagent reservoir, RR1, was added
to the reaction vessel, RF1. After stirring at 25 °C for 10 h, the
reaction mixture was cooled to 0 °C. The reaction was then
quenched by addition of 1 M HCl from the wash-solution bottle,
RS4, and the reaction mixture was transferred to a centrifugal
separator, SF. After centrifugation, the two resulting phases were
separated by measurement of their electroconductivities with a
sensor and transferred to two receivers, SF1 and SF2. The
aqueous phase in SF1 was taken back to the reaction vessel,
RF1. After addition of Et2O from the solvent bottle, RS1, the
mixture was stirred and then transferred to the centrifugal
separator, SF. After performing the extraction twice, the
combined organic mixture in the receiver, SF2, was washed
with 10% aqueous NaHCO3 and 10% aqueous NaCl from the
wash-solution bottles, RS5 and RS6, in the reaction flask, RF.
The organic layer was separated in the centrifugal separator,
SF, and transferred to the receiver, SF2. The organic layer in
(35) 1H NMR spectra of alcohol 17 was compared to the reported 1H NMR
spectra of its diastereomer 28 in ref 32. Since the observed coupling
constant between Ha and He of 17 was different from that of 28, the
relative stereochemistry of the epoxide and hydroxy group in 17 was
determined to be the desired trans configuration. 17: 1H NMR (CDCl3):
δ ) 2.04 (J ) 18.5 Hz, Ha), 2.65 (J ) 6.0, 18.5 Hz, Hb), 3.43 (J )
1
2.3 Hz, Hc), 3.92 (J ) 2.3 Hz, Hd), 4.70 (J ) 6.0 Hz, He). 28: H
NMR (CDCl3): δ ) 2.28 (J ) 6.6, 17.8 Hz, Ha), 2.52 (J ) 8.2, 17.8
Hz, Hb), 3.49 (J ) 2.5 Hz, Hc), 4.00 (J ) 2.2, 2.5 Hz, Hd), 4.46 (J
) 2.2, 6.6, 8.2 Hz, He).
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Scheme 4. Automated synthesis of diyne 23a
a Reagents and conditions: (a) imidazole, DMF, 25 °C, 10 min, then TBSCl, DMF, 25 °C, 10 h, 90%; (b) MeLi, Et2O, -78 to 0 °C, 1 h, 85%; (c) IBX, DMSO,
50 °C, 12 h, 55%; (d) ZnCl2, Et2O, -78°C, 1 h, then propargyl magnesium bromide, Et2O, -78°C, 30 min, 84%, 22a/22b ) 6:1; (e) NEt3, CH2Cl2, 0 °C, 10 min, then
TMSOTf, 0 °C, 15 min, 80%. IBX ) 2-iodoxybenzoic acid.
prior to addition of reagents and substrates to create an
anhydrous reaction environment.
decomposition of the substrate. The previously reported reaction
conditions for the oxidation of the allylic alcohol 21sPCC in
CH2Cl220swere not suited for use with the synthesizer, as a
large amount of chromium salts precipitated and obstructed the
solution-transfer tubes. Therefore, other oxidation conditions
were examined. IBX in DMSO was compatible with the
synthesizer, as no precipitate formed. By contrast, DMSO
oxidation, including both Swern and Parikh-Doering condi-
tions, Dess-Martin oxidation, and TEMPO-NaClO oxidation
gave unsatisfactory results. Subsequent 1,2-addition of propargyl
magnesium bromide to the enone 11 was carried out using the
automated synthesizer. Preparation of the Grignard reagent,
which requires careful temperature control, was performed
automatically. The reaction flasks, RF1 and RF2, were dried at
80 °C for 30 min under reduced pressure and were then cooled
to 25 °C. A mixture of magnesium turnings, HgCl2, and
propargyl bromide (20 mol %) in Et2O was stirred at 25 °C in
the reaction vessel, RF2, under a nitrogen atmosphere. Then, a
solution of 80 mol % of propargyl bromide in Et2O was added
to the mixture at -10 °C. The resulting mixture was stirred at
0 °C for 30 min to afford a solution of propargyl magnesium
bromide. The Grignard reagent solution was added to a solution
of 11 and ZnCl2 in Et2O at -78 °C in the reaction vessel, RF1.
Automated workup and manual silica gel column purification
afforded a separable 6:1 mixture of the R-alcohol 22a and its
ꢀ-isomer 22b in a combined yield of 84%. Addition of ZnCl2
is crucial to increase the R-selectivity of the reaction, as
demonstrated by the reduced stereoselectivity in the absence
of ZnCl2, i.e., 9R-OH:9ꢀ-OH ) 2:1. Protection of 22a with
TMSOTf gave the silyl ether 23 in 81% yield. NOE observation
suggested that the stereochemistry of the trimethylsiloxy group
of 23 was the desired R configuration (Scheme 4).
Palladium-catalyzed addition of BzOH to the diene mono-
epoxide 13 was carried out with the use of the automated
synthesizer (Scheme 3). A solution of BzOH in THF, which
had been added to the reagent reservoir, RR1, was added to a
solution of Pd(OAc)2 and PPh3 in THF at 25 °C in the reaction
vessel, RF1. After stirring for 1 h, a solution of the diene
monoepoxide 13 in THF was added to the reaction mixture at
0 °C. The resulting mixture was stirred at 25 °C for 10 h.
Automated workup and manual silica gel column purification
afforded a 12:2:1 mixture of the 1,4-adduct 10 and the 1,2-
adducts 19a and 19b in a combined yield of 75%. For the
manual reaction, BzOH solids were added directly to the
solution of Pd(OAc)2 and PPh3 in THF. However, the synthe-
sizer could not transfer solids automatically. Thus, we used a
solution of BzOH in THF. The relative stereochemistry of the
benzoyl group in 10 was determined by observation of the NOE
(4.4%) between Ha and Hb. In the 1,2-adducts, cis stereochem-
istry of the benzoyl and hydroxy groups in 19b was confirmed
by the large NOE (20%) between Hc and Hd. Because the
isolated 1,4-adduct 10 remained intact under the reaction
conditions used in the present study (30 mol % BzOH/10 mol
% Pd(OAc)2-PPh3/THF/25 °C/16 h), this reaction is not under
thermodynamic control. Ba¨ckvall et al. reported that carboxy-
lates are unique nucleophilessaddition of carboxylates to π-allyl
palladium complexes can occur from either the same or the
opposite sides of the palladium atom, depending on the reaction
conditions.36 It is conceivable that the 1,4-addition occurs
exclusively from the side opposite the bulky siloxy group, while
the 1,2-addition preferentially occurs from the side opposite the
somewhat smaller hydroxyl group.
The diyne 23 was prepared utilizing the automated synthe-
sizer (Scheme 4). The mixture of isomers 10, 19a, and 19b
was converted to two diastereomers of the silyl ether 20.
Without separation, 20 was treated with MeLi in Et2O to afford
the alcohol 21 in a combined yield of 85%. Treatment of 20
with K2CO3 in MeOH or with methyl Grignard reagent in Et2O
resulted in undesirable desilylation at the terminal alkyne or
The 12-membered cyclic ether 7 was prepared by using the
automated synthesizer (Scheme 5). Treatment of 23 with
ethylmagnesium bromide in THF followed by addition of
paraformaldehyde afforded the alcohol, which was converted
to diol 8 by removal of the TMS group. Protection of the tertiary
alcohol at the 9-position was essential for progression of the
1,2-addition reaction and, thus, the synthesis of the desired
product. When methanol was used as the solvent during removal
of the TMS group, automated extraction did not work because
(36) Backvall, J. E.; Nordberg, R. E.; Wilhelm, D. J. Am. Chem. Soc. 1985,
107 (24), 6892–6898.
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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Scheme 5. Automated synthesis of 12-membered cyclic ether 7a
a Reagents and conditions: (a) (i) EtMgBr, THF, 50 °C, 1 h, then paraformaldehyde, 25 °C, 10 h, 75%, (ii) K2CO3, MeOH/THF ) 1:3, 25 °C, 4 h, 90%; (b) 24b,
5 mol % Pd(OAc)2, 20 mol % PPh3, 10 mol % CuI, t-BuNH2, toluene, 25 °C, 6 h, 65%; (c) CBr4, PPh3, 2,6-lutidine, MeCN, 0 to 25 °C, 30 min; (d) DDQ, CH2Cl2/H2O
) 30:1, 0 to 25 °C, 2 h, 2 steps 70% from 25b; (e) NaH, THF, cat. H2O, 25 °C, 1 h, 65%. DDQ ) 2,3-dichloro-4,5-dicyanobenzoquinone.
the sensor could not detect a difference in electroconductivity
between the aqueous and organic layers. Therefore, we used a
solvent mixture, such as THF/MeOH, to overcome this problem.
We previously reported a palladium-catalyzed coupling reaction
between alkyne 8 and vinyl iodide 24a, followed by bromination
and selective deprotection of silyl ether to afford the cyclization
precursor 27. During selective deprotection, it is important to
monitor the reaction continuously and to adjust the reaction time
to prevent overdesilylation. However, the ChemKonzert begins
workup operations after the programmed reaction time has
elapsed. Therefore, this reaction cannot be performed using the
automated synthesizer. We examined the palladium-catalyzed
coupling reaction of the vinyl iodides 24b-d, which have
various protecting groups at the allylic hydroxyl group. Treat-
ment of 8 with 24b or 24d in the presence of Pd(OAc)2-PPh3
and CuI-induced smooth coupling afforded the desired coupling
products 25b and 25d, respectively. By contrast, treatment of
8 with 24c under identical reaction conditions resulted in
degradation of the vinyl iodides. After substitution of the
propargyl hydroxyl group in 25d with a bromide, selective
removal of the THP group in 26d was unsuccessful. On the
other hand, the MPM group was chemoselectively deprotected
by DDQ without affecting other functional groups to give the
cyclization precursor 27 in 57% yield from 25b. This depro-
tection condition is more suitable for use with the automated
synthesizer than the previously described desilylation conditions,
because the risk of overdesilylation during the deprotection step
is much lower. A macro-etherification was successfully per-
formed utilizing the automated synthesizer. A solution of 27 in
THF was added to a suspension of NaH in THF with a catalytic
amount of water in the reaction flask, RF1, under a nitrogen
atmosphere. When workup of this reaction was performed
manually, addition of a large amount of EtOAc enabled
liquid-liquid extraction. However, the addition of EtOAc was
not suitable for the synthesizer because the maximum solution
volume of the centrifugal separation is 700 mL. Therefore, the
reaction mixture was heated to 50 °C under reduced pressure
to remove THF. Automated workup and manual silica gel
column purification furnished the desired 12-membered cyclic
ether 7 as a chemically stable solid, which can be stored at room
temperature for long periods. For this cyclization, addition of a
catalytic amount of water is crucial to obtain reproducible
results. A catalytic amount of EtOH is also effective.37 In
addition, 7 can be converted to the masked 9-membered
enediyne 3 in four steps, using the previously reported
procedure.19,20,38
Conclusions
We developed an efficient synthetic route for 7, which is a
key synthetic intermediate of the 9-membered masked enediynes
that possess DNA-cleaving activity. After tuning the reaction
conditions, the automated synthesizer that was originally
developed in our labsthe ChemKonzertsallowed for an
efficient 16-step synthesis: two palladium-catalyzed reactions,
three C-C bond formations, two oxidations, six protection and
deprotection sequences, and three other transformation reactions
on a scale ranging from 9.8 to 0.83 g. We also applied the
automated synthesizer to a variety of other reactions. The
synthesis of a new base-recognition, DNA-cleaving molecule
from 7 is currently underway in our laboratory and will
be reported in due course.
Experimental Section
General. NMR spectra were recorded in the indicated
solvents. Chemical shifts are reported in units of parts per
million (ppm) from tetramethylsilane with the solvent resonance
as the internal standard (CHCl3: δ 7.26 ppm for 1H, CH2Cl2: δ
5.32 ppm for 1H, CDCl3: δ 77.0 ppm for 13C). Data are reported
as follows: chemical shift, multiplicity (s; singlet, d; doublet, t;
triplet, q; quartet, m; multiplet, br; broad), coupling constants
(Hz), and integration. All reactions were monitored by thin-
layer chromatography using E. Merck silica gel plates (60F-
254) precoated plates (0.25 mm). TLC visualization was done
with UV light and/or 5% ethanolic p-anisaldehyde or 10%
ethanolic phosphomolybdic acid followed by heating. Flash
column chromatography was performed on silica gel 60 N,
purchased from Kanto Chemical Co. THF, Et2O, and toluene
(37) The specific role of EtOH or water in the reaction remains unclear so
far.
(38) We have reported the resolution of the racemic 9-membered masked
enediyne via the separation of the diastereomeric MTPA ester in ref
19.
1116
•
Vol. 13, No. 6, 2009 / Organic Process Research & Development

were dried by distillation from sodium/benzophenone ketyl.
CH2Cl2 and Tf2O were dried by distillation from P2O5. MeCN
was dried by distillation from CaH2. Acetone was dried by
distillation from CaSO4. 2,6-Lutidine was dried by distillation
from BaO.
5.8 Hz, 1H), 1.95 (d, J ) 18.6, 1H), 0.89 (s, 9H), 0.12 (s, 3H),
0.10 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ 207.8, 67.6, 60.7,
54.1, 42.2, 25.6, 18.0, -4.8, -4.9; FT-IR (neat) 2931, 2859,
1758, 1472, 1259, 1084, 902, 780 cm-1.
Alcohol 18. RF1 was dried at 80 °C for 30 min under
reduced pressure and cooled to 25 °C. A solution of trimeth-
ylsilylacetylene (6.90 mL, 48.8 mmol, 1.1 equiv) in dry THF
(100 mL) was placed in RF1 under a nitrogen atmosphere. After
being cooled to -78 °C by attaching an acetone-dry ice bath
manually to RF1, BuLi in hexane (1.60 M, 30.1 mL, 48.8 mmol,
1.1 equiv) was added to the solution manually at the same
temperature. The resulting mixture was stirred at -40 °C for
1 h and cooled to -78 °C again. Then a dry THF (30 mL)
solution of epoxyketone 14 (11.2 g, 44.3 mmol, 1.0 equiv, RR1)
was dropwisely added to RF1 and stirred for 30 min at the same
temperature. The reaction was quenched by 10% aqueous
NH4Cl solution (140 mL, RS4), diluted with EtOAc (100 mL,
RS1), and transferred to SF. After centrifugation, two phases
were separated. The separated aqueous phase in SF1 was taken
back to RF1 and extracted with EtOAc (80 mL, RS1). The
mixture was transferred to SF and centrifuged, and the two
phases were separated. After repeating this extraction process
twice, the combined organic phase in SF2 was transferred to
RF1. The organic phase was washed with 10% aqueous NaCl
solution (80 mL, RS6). The resulting organic phase in SF2 was
dried by passing through anhydrous Na2SO4 (DT1) and
transferred to a round flask (CF1). After removal of the solvent,
the residue was purified by flash column chromatography on
silica gel (10% EtOAc in hexane) to give alcohol 18 (10.3 g,
Synthesis. 4-tert-Butyldimethylsilyloxy-2-cyclopentenone (16).
A solution of 4-hydroxy-2-cyclopentenone (15) (9.81 g, 100
mmol, 1.0 equiv), NEt3 (28.0 mL, 200 mmol, 2.0 equiv), and
DMAP (300 mg, 2.50 mmol, 0.025 equiv) in dry CH2Cl2 (100
mL) was stirred at 25 °C for 10 min under a nitrogen
atmosphere in RF1. The solution of TBSCl (19.6 g, 130 mmol,
1.3 equiv) in dry CH2Cl2 (30 mL, RR1) was added to the
reaction vessel. After being stirred at the same temperature for
10 h, the reaction mixture was cooled to 0 °C and then quenched
by addition of 1 M HCl (200 mL, RS4) and transferred to SF.
After centrifugation, two phases were separated. The separated
aqueous phase in SF1 was taken back to RF1 and extracted
with Et2O (100 mL, RS1). The mixture was transferred to SF
and centrifuged, and the two phases were separated. After
repeating this extraction process twice, the combined organic
phase in SF2 was transferred to RF1. The organic phase was
washed with 10% aqueous NaHCO3 solution (80 mL, RS5)
and 10% aqueous NaCl solution (80 mL, RS6). The resulting
organic phase in SF2 was dried by passing through anhydrous
Na2SO4 (DT1) and transferred to a round flask (CF1). After
removal of solvent, the residue was purified by flash column
chromatography on silica gel (5% EtOAc in hexane) to give
4-tert-butyldimethylsilyloxy-2-cyclopentenone (16) (15.5 g, 73.1
mmol, 73%) as a colorless liquid. 1H NMR (400 MHz, CDCl3)
δ 7.45 (dd, J ) 5.4, 2.4 Hz, 1H), 6.18 (dd, J ) 5.4, 1.0 Hz,
1H), 4.98 (m, 1H), 2.70 (dd, J ) 18.6, 5.9 Hz, 1H), 2.24 (dd,
J ) 18.6, 2.4 Hz, 1H), 0.90 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H);
13C NMR (67.8 MHz, CDCl3) δ 206.4, 163.9, 134.3, 70.8, 44.8,
25.6, 18.0, -3.6, -4.8; FT-IR (neat) 3433, 2956, 1724, 1572,
1355, 1254, 1109, 1072, 836, 670 cm-1.
Epoxide 14. A solution of 4-tert-butyldimethylsilyloxy-2-
cyclopentenone (15) (7.81 g, 36.8 mmol, 1.0 equiv) and
Bu4NHSO4 (375 mg, 1.10 mmol, 0.030 equiv) in CH2Cl2 (50
mL) was placed in RF2 under a nitrogen atmosphere. After
being cooled to 0 °C, aqueous NaClO solution (200 mL, RR2)
was dropwisely added to RF2. After being stirred for 6 h at the
same temperature, the reaction was quenched by addition of
50% aqueous Na2S2O3 solution (180 mL, RS4) and transferred
to SF. After centrifugation, two phases were separated. The
separated aqueous phase in SF1 was taken back to RF1 and
extracted with Et2O (80 mL, RS1). The mixture was transferred
to SF and centrifuged, and the two phases were separated. After
repeating this extraction process twice, the combined organic
phase in SF2 was transferred to RF1. The organic phase was
washed with 10% aqueous Na2S2O3 solution (100 mL, RS5)
and 10% aqueous NaCl solution (80 mL, RS6). The resulting
organic phase in SF2 was dried by passing through anhydrous
Na2SO4 (DT1) and transferred to a round flask (CF1). After
removal of the solvent, the residue was purified by flash column
chromatography on silica gel (5% EtOAc in hexane) to give
epoxide 14 (5.88 g, 25.7 mmol, 70%) as a colorless liquid. 1H
NMR (400 MHz, CDCl3) δ 4.59 (d, J ) 5.4 Hz, 1H), 3.79 (d,
J ) 2.0 Hz, 1H), 3.39 (d, J ) 2.0 Hz, 1H), 2.59 (dd, J ) 18.6,
1
31.4 mmol, 71%) as a colorless liquid. H NMR (400 MHz,
CDCl3) δ 4.39 (d, J ) 5.4 Hz, 1H), 3.62 (d, J ) 2.4 Hz, 1H),
3.43 (d, J ) 2.4 Hz, 1H), 2.13 (d, J ) 14.2 Hz, 1H), 1.86 (dd,
J ) 14.2, 5.4 Hz, 1H), 0.92 (s, 9H), 0.67 (s, 9H), 0.08 (s, 6H);
13C NMR (67.8 MHz, CDCl3) δ 104.9, 91.0, 73.1, 71.4, 61.9,
59.6, 46.3, 25.8, 18.0, -0.13, -4.7, -4.8; FT-IR (neat) 3422,
2957, 2857, 2171, 1472, 1361, 1251, 1059, 837 cm-1; HRMS
(ESI-TOF); [M + H]+ calcd for C16H31O3Si2, 327.1812; found
327.1807.
Enyne 13. RF1 was dried at 80 °C for 30 min under reduced
pressure and cooled to 25 °C. A solution of epoxyalcohol 18
(10.3 g, 31.4 mmol, 1.0 equiv) and 2,6-lutidine (20.2 mL, 173
mmol, 5.5 equiv) in dry CH2Cl2 (70 mL) was placed in RF1
under a nitrogen atmosphere. After being cooled to -78 °C by
attaching an acetone-dry ice bath manually to RF1, a solution
of Tf2O (10.6 mL, 62.8 mmol, 2.0 equiv) in dry CH2Cl2 (30
mL, RR1) was dropwisely added to RF1 and stirred at 0 °C
for 1 h. The reaction was quenched by addition of 10% aqueous
NH4Cl solution (200 mL, RS4), diluted with Et2O (120 mL,
RS1) and transferred to SF. After centrifugation, the two phases
were separated. The separated aqueous phase in SF1 was taken
back to RF1 and extracted with Et2O (80 mL, RS1). The
mixture was transferred to SF and centrifuged, and the two
phases were separated. After repeating this extraction process
twice, the combined organic phase in SF2 was transferred to
RF1. The organic phase was washed with 3 M HCl (60 mL,
RS4), 10% aqueous NaCl solution (60 mL, RS6), 10% aqueous
NaHCO3 solution (60 mL, RS5), and 10% aqueous NaCl
solution (60 mL, RS6). The resulting organic phase in SF2 was
Vol. 13, No. 6, 2009 / Organic Process Research & Development
•
1117

dried by passing through anhydrous Na2SO4 (DT1) and
transferred to a round flask (CF1). After removal of the solvent,
the residue was purified by flash column chromatography on
silica gel (3% EtOAc in hexane) to give enyne 13 (6.81 g, 22.0
mmol, 70%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ
6.12 (dd, J ) 2.4, 1.9 Hz, 1H), 4.61 (dd, J ) 1.5 Hz, 1H), 3.86
(ddd, J ) 1.5 Hz, 1H), 3.79 (dd, J ) 2.4 Hz, 1H), 0.91 (s, 9H),
0.21 (s, 9H), 0.13 (s, 3H,, 0.11 (s, 3H,); 13C NMR (67.8 MHz,
CDCl3) δ 144.5, 129.4, 101.1, 98.8, 73.9, 62.2, 60.3, 25.7, 18.1,
-0.3, -4.6, -4.7. FT-IR (neat) 2930, 2147, 1588, 1463, 1250,
844, 689 cm-1; HRMS (ESI-TOF); [M + H]+ calcd for
C16H29O2Si2, 309.1706; found 309.1705.
(dd, J ) 4.4 Hz, 1H), 0.92 (s, 9H), 0.19 (s, 6H), 0.13 (s, 9H);
13C NMR (67.8 MHz, CDCl3) δ 167.8, 141.6, 133.5, 129.9,
129.4, 128.4, 125.5, 99.3, 98.2, 87.3, 85.8, 79.8, 25.7, 18.0,
-0.3, -4.7, -5.0; FT-IR (solid) 3530, 3956, 2857, 2156, 1702,
1602, 1272, 1092, 844, 712 cm-1; HRMS (ESI-TOF); [M +
H]+ calcd for C23H35O4Si2, 431.2074; found 431.2089.
Silyl ether 20. A mixture of alcohols 10, 19a, and 19b (6.74
g, 15.6 mmol, 1.0 equiv) and imidazole (19.2 g, 28.2 mmol,
1.8 equiv) in DMF (30 mL) was stirred at 25 °C for 10 min in
RF1 under a nitrogen atmosphere. A solution of TBSCl (3.62
g, 23.5 mmol, 1.5 equiv) in DMF (15 mL, RR1) was added to
RF1 at the same temperature. After being stirred for 10 h, the
reaction mixture was cooled to 0 °C, then diluted with Et2O
(100 mL, RS1), quenched by addition of 1 M HCl (100 mL,
RS4), and transferred to SF. After centrifugation, two phases
were separated. The separated aqueous phase in SF1 was taken
back to RF1 and extracted with Et2O (80 mL, RS1). The
mixture was transferred to SF and centrifuged, and the two
phases were separated. After repeating this extraction process
twice, the combined organic phase in SF2 was transferred to
RF1. The organic phase was washed with 1 M HCl (60 mL,
RS4) twice, 10% aqueous NaHCO3 solution (80 mL, RS5) and
10% aqueous NaCl solution (80 mL, RS6). The resulting
organic phase in SF2 was dried by passing through anhydrous
Na2SO4 (DT1) and transferred to a round flask (CF1). After
removal of solvent, the residue was purified by flash column
chromatography on silica gel (2% Et2O in hexane) to give a
mixture of disilylether 20 (7.63 g, 14.0 mmol, 90%).
Alcohol 21. RF1 was dried at 80 °C for 30 min under
reduced pressure and cooled to 25 °C. The mixture of benzoates
20 (7.63 g, 14.3 mmol, 1.0 equiv) in dry Et2O (80 mL) was
placed in RF1 under a nitrogen atmosphere and cooled to -78
°C by attaching an acetone-dry ice bath manually to RF1. A
solution of MeLi in Et2O (1.09 M, 29.0 mL, 31.5 mmol, 2.2
equiv, RR1) was dropwisely added to RF1. The resulting
solution was warm to 0 °C and stirred for 1 h. The reaction
was quenched by addition of 10% aqueous NH4Cl solution (80
mL, RS4), diluted with Et2O (80 mL, RS1) and transferred to
SF. After centrifugation, two phases were separated. The
separated aqueous phase in SF1 was taken back to RF1 and
extracted with Et2O (80 mL, RS1). The mixture was transferred
to SF and centrifuged, and the two phases were separated. After
repeating this extraction process twice, the combined organic
phase in SF2 was transferred to RF1. The organic phase was
washed with 10% aqueous NaCl solution (80 mL, RS6). The
resulting organic phase in SF2 was dried by passing through
anhydrous Na2SO4 (DT1) and transferred to a round flask (CF1).
After removal of solvent, the residue was purified by flash
column chromatography on silica gel (2% Et2O in hexane) to
give a mixture of alcohol 21 (5.34 g, 12.2 mmol, 85%).
Enone 11. The mixture of alcohol 21 (1.75 g, 4.00 mmol,
1.0 equiv) and IBX (3.40 g, 12.0 mmol, 3.0 equiv) in DMSO
(20 mL) was heated to 50 °C in RF1 under a nitrogen
atmosphere. After being stirred at the same temperature for 12 h,
the reaction mixture was cooled to 25 °C. The solution was
diluted with EtOAc (80 mL, RS1) and filtered by passing
through FF1. A solution of 10% aqueous NaHCO3 (100 mL
RS5) was added to RF1, and the resulting mixture was
Benzoates 10, 19a and 19b. A solution of Pd(OAc)2 (235
mg, 1.05 mmol, 0.050 equiv) and PPh3 (1.10 g, 4.20 mmol,
0.20 equiv) in dry THF (50 mL) in RF1 was stirred for 20 min
at 25 °C under a nitrogen atmosphere. A solution of BzOH
(3.34 g, 27.2 mmol, 1.30 equiv) in dry THF (20 mL, RR1)
was added to RF1 and stirred for 1 h at 25 °C. After being
cooled to 0 °C, a solution of diene monoepoxide 13 (6.51 g,
21.0 mmol, 1.0 equiv) in dry THF (30 mL) was added to RF1.
After being stirred for 10 h at 25 °C, the reaction was quenched
by the addition of 10% aqueous NaHCO3 solution (100 mL,
RS4), diluted with Et2O (60 mL, RS1), and transferred to SF.
After centrifugation, two phases were separated. The separated
aqueous phase in SF1 was taken back to RF1 and extracted
with Et2O (80 mL, RS1). The mixture was transferred to SF
and centrifuged, and the two phases were separated. After
repeating this extraction process twice, the combined organic
phase in SF2 was transferred to RF1. The organic phase was
washed with 10% aqueous NaCl solution (60 mL, RS6). The
resulting organic phase in SF2 was dried by passing through
anhydrous Na2SO4 (DT1) and transferred to a round flask (CF1).
After removal of the solvent, the residue was purified by flash
column chromatography on silica gel (10-20% Et2O in hexane)
to give benzoates (6.75 g, 15.7 mmol, 75%) (10:19a:19b )
12:2:1).
1
10: H NMR (400 MHz, CDCl3) δ 8.08 (d, J ) 7.8 Hz,
2H), 7.57 (t, J ) 7.8 Hz, 1H), 7.45 (t, J ) 7.8 Hz, 2H), 6.14 (s,
1H), 5.82 (d, J ) 5.4 Hz, 1H), 4.59 (m, 1H), 4.29 (dd, J ) 4.9
Hz, 1H), 0.87 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H,), 0.00 (s, 9H);
13C NMR (67.8 MHz, CDCl3) δ 165.7, 138.9, 133.0, 130.0,
129.6, 128.2, 124.9, 100.1, 97.9, 86.0, 82.2, 79.2, 25.6, 17.8,
-0.7, -4.8, -4.9; FT-IR (neat) 3449, 2557, 2155, 1702, 1602,
1272, 1026, 861, 711 cm-1; HRMS (ESI-TOF); [M + H]+ calcd
for C23H35O4Si2, 431.2074; found 431.2094.
1
19a: H NMR (400 MHz, CDCl3) δ 8.08 (d, J ) 7.8 Hz,
2H), 7.58 (t, J ) 7.8 Hz, 1H), 7.45 (t, J ) 7.8 Hz, 2H), 6.25
(d, J ) 1.9, 1H), 5.87 (dd, J ) 5.4, 1.0 Hz, 1H), 4.82 (dd, J )
1.9 Hz, 1H), 4.24 (dd, J ) 5.4, 2.0 Hz, 1H), 0.90 (s, 9H), 0.15
(s, 9H), 0.12 (s, 3H), 0.10 (s, 3H,); 13C NMR (67.8 MHz,
CDCl3) δ 166.9, 144.0, 133.2, 129.9, 129.7, 128.3, 123.7, 99.4,
98.9, 80.8, 78.7, 78.5, 25.7, 18.1, -0.2, -4.7, -4.9; FT-IR
(solid) 3492, 2951, 2856, 2158, 1705, 1602, 1250, 1095, 762,
706 cm-1; HRMS (ESI-TOF); [M + H]+ calcd for C23H35O4Si2,
431.2074; found 431.2055.
1
19b: H NMR (400 MHz, CDCl3) δ 8.10 (d, J ) 7.8 Hz,
2H), 7.60 (t, J ) 7.8 Hz, 1H), 7.46 (t, J ) 7.8 Hz, 2H), 6.12 (s,
1H), 5.35 (d, J ) 4.4 Hz, 1H), 4.73 (dd, J ) 4.4 Hz, 1H), 4.17
1118
•
Vol. 13, No. 6, 2009 / Organic Process Research & Development

transferred to SF. After centrifugation, two phases were
separated. The separated aqueous phase in SF1 was taken back
to RF1 and extracted with EtOAc (60 mL, RS1). The mixture
was transferred to SF and centrifuged, and the two phases
were separated. After repeating this extraction process twice,
the combined organic phase in SF2 was transferred to RF1.
The organic phase was washed with 10% aqueous NaCl solution
(60 mL, RS6) twice. The resulting organic phase in SF2 was
dried by passing through anhydrous Na2SO4 (DT1) and
transferred to a round flask (CF1). After removal of solvent,
the residue was purified by flash column chromatography on
silica gel (3% Et2O in hexane) to give enone 11 (0.96 g, 2.2
mmol, 55%) as a colorless liquid. 1H NMR (400 MHz, CD2Cl2)
δ 7.27 (d, J ) 2.0 Hz, 1H), 4.66 (dd, J ) 2.0 Hz, 1H), 4.16 (d,
J ) 3.0 Hz, 1H), 0.92 (s, 9H), 0.91 (s, 9H), 0.21 (s, 9H), 0.19
(s, 3H), 0.13 (s, 3H), 0.15 (s, 3H), 0.13 (s, 6H); 13C NMR (67.8
MHz, CDCl3) δ 198.9, 159.6, 127.7, 103.4, 94.1, 82.6, 76.4,
25.77, 25.66, 18.2, 17.9, -0.4, -4.3, -4.7, -4.8, -5.1; FT-
IR (neat) 2957, 2858, 2160, 1744, 1598, 1251, 1094, 839, 780
cm-1; HRMS (ESI-TOF); [M + H]+ calcd for C22H43O3Si3,
439.2503; found 439.2520.
1H), 1.98 (t, J ) 2.9 Hz, 1H), 0.93 (s, 9H), 0.89 (s, 9H), 0.19
(s, 9H), 0.11 (s, 3H), 0.08 (s, 3H), 0.07 (s, 6H); 13C NMR (67.8
MHz, CDCl3) δ 138.8, 129.9, 100.8, 98.2, 87.5, 81.6, 78.5, 71.4,
26.0, 25.9, 25.8, 18.1, -0.2, -4.3, -4.5; FT-IR (neat) 3561,
3313, 2957, 2147, 1611, 1472, 1250, 1140, 1007, 837, 778,
675 cm-1; HRMS (ESI-TOF); [M + H]+ calcd for C52H47O3Si3,
479.2833; found 479.2828.
1
22b: H NMR (400 MHz, CDCl3) δ 6.07 (d, J ) 1.9 Hz,
1H), 4.58 (dd, J ) 3.4, 1.9 Hz, 1H), 4.14 (d, J ) 3.4 Hz, 1H),
2.68 (dd, J ) 17.1, 2.5 Hz, 1H), 2.54 (dd, J ) 17.1, 2.5 Hz,
1H), 2.00 (t, J ) 2.5 Hz, 1H), 0.93 (s, 9H), 0.89 (s, 9H), 0.20
(s, 9H), 0.18 (s, 6H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (67.8
MHz, CDCl3) δ 139.9, 130.1, 100.3, 98.4, 81.0, 80.9, 80.7, 80.0,
70.8, 27.8, 25.9, 25.7, 0.3, 0.0, -4.0, -4.5; FT-IR (solid) 3459,
3283, 2930, 2858, 2149, 1595, 1472, 1385, 1250, 1083, 839,
777, 686 cm-1; HRMS (ESI-TOF); [M + H]+ calcd for
C52H47O3Si3, 479.2833; found 479.2841.
Silyl ether 23. A solution of alcohol 22a (4.91 g, 10.3 mmol,
1.0 equiv) and NEt3 (2.86 mL, 20.5 mmol, 2.0 equiv) in dry
CH2Cl2 (50 mL) was cooled to 0 °C and stirred for 10 min at
the same temperature under a nitrogen atmosphere in RF1. A
solution of TMSOTf (2.22 mL, 12.3 mmol, 1.2 equiv, RR1)
was dropwisely added to RF1. After being stirred at the same
temperature for 15 min, the reaction was quenched by addition
of 10% aqueous NH4Cl solution (100 mL, RS4), diluted with
Et2O (80 mL, RS1), and transferred to SF. After centrifugation,
two phases were separated. The separated aqueous phase in SF1
was taken back to RF1 and extracted with Et2O (80 mL, RS1).
The mixture was transferred to SF, centrifuged, and the two
phases were separated. After repeating this extraction process
twice, the combined organic phase in SF2 was transferred to
RF1. The organic phase was washed with 10% aqueous NaCl
solution (80 mL, RS6). The resulting organic phase in SF2 was
dried by passing through anhydrous Na2SO4 (DT1) and
transferred to a round flask (CF1). After removal of solvent,
the residue was purified by flash column chromatography on
silica gel (2% Et2O in hexane) to give silyl ether 23 (4.53 g,
8.24 mmol, 80%) as a white solid. 1H NMR (400 MHz, CDCl3)
δ 6.07 (d, J ) 2.0 Hz, 1H), 4.49 (dd, J ) 4.9, 2.0 Hz, 1H),
4.07 (d, J ) 4.9 Hz, 1H), 2.54 (dd, J ) 6.4, 2.6 Hz, 2H), 1.86
(dd, J ) 2.6 Hz, 1H), 0.93 (s, 9H), 0.89 (s, 9H), 0.20 (s, 9H),
0.19 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H), 0.07 (s,
3H); 13C NMR (67.8 MHz, CDCl3) δ 140.3, 129.4, 100.0, 99.6,
90.3, 87.1, 90.3, 87.1, 80.8, 79.6, 69.6, 26.9, 26.0, 25.9, 18.1,
18.0, 2.7, -0.1, -4.0, -4.1, -4.4; FT-IR (solid) 3268, 2953,
2148, 1601, 1472, 1249, 1071, 838, 667 cm-1; HRMS (ESI-
TOF); [M + H]+ calcd for C28H55O3Si4, 551.3228; found
551.3229.
Alcohols 22a and 22b. A 500 mL three necked flask was
attached to ChemKonzert (RF2). The RF1 and RF2 were dried
at 80 °C for 30 min under reduced pressure and cooled to 25
°C. The mixture of magnesium turnings (1.20 g, 44.0 mmol,
1.1 equiv), HgCl2 (108 mg, 0.40 mmol, 0.010 equiv), and
propargyl bromide (0.600 mL, 8.00 mmol, 0.20 equiv) in dry
Et2O (20 mL) was stirred at 25 °C under a nitrogen atmosphere
in RF2. After being cooled to -10 °C, a solution of propargyl
bromide (2.40 mL, 32.0 mmol, 0.8 equiv) in dry Et2O (20 mL)
was added dropwisely to RF2. The resulting mixture was stirred
at 0 °C for 30 min to afford a solution of propargyl magnesium
bromide (c.a. 1.0 M). A solution of enone 11 (5.42 g, 12.3
mmol, 1.0 equiv) and ZnCl2 in Et2O (1.0 M, 13.5 mL, 13.5
mmol, 1.1 equiv) in dry Et2O (100 mL) was stirred at 25 °C
for 1 h under a nitrogen atmosphere in RF1 and being cooled
to -78 °C by attaching an acetone-dry ice bath manually to
RF1. The solution of propargyl magnesium bromide in Et2O
(20 mL) described above was added to RF1 at -78 °C. After
being stirred at the same temperature for 30 min, the reaction
was quenched by addition of 1 M HCl solution (120 mL, RS4),
diluted with Et2O (80 mL, RS1), and transferred to SF. After
centrifugation, two phases were separated. The separated
aqueous phase in SF1 was taken back to RF1 and extracted
with Et2O (80 mL, RS1). The mixture was transferred to SF
and centrifuged, and the two phases were separated. After
repeating this extraction process twice, the combined organic
phase in SF2 was transferred to RF1. The organic phase was
washed with 10% aqueous NaHCO3 solution (120 mL, RS5)
and 10% aqueous NaCl solution (80 mL, RS6). The resulting
organic phase in SF2 was dried by passing through anhydrous
Na2SO4 (DT1) and transferred to a round flask (CF1). After
removal of solvent, the residue was purified by flash column
chromatography on silica gel (40 to 50% toluene in hexane) to
give alcohols (4.95 g, 10.3 mmol, 84%) (22a:22b ) 6:1).
Alcohol 28. A solution of ethylmagnesium bromide (1.0 M,
23.0 mL, 23.0 mmol, 2.5 equiv) in dry THF was manually
added to a solution of alkyne 23 (5.08 g, 9.21 mmol, 1.0 equiv)
in dry THF (15 mL) in RF1 at 25 °C, and the resulting mixture
was heated to 50 °C. After being stirred at the same temperature
for 1 h, the mixture was cooled to 25 °C. Then paraformalde-
hyde (828 mg, 27.6 mmol, 3.0 equiv) was added to RF1
manually. After being stirred at the same temperature for 10 h,
the reaction was quenched by addition of 1 M HCl solution
(100 mL, RS4), diluted with EtOAc (80 mL, RS1), and
1
22a: H NMR (400 MHz, CDCl3) δ 6.01 (d, J ) 1.9 Hz,
1H), 4.46 (dd, J ) 5,4, 1.5 Hz, 1H), 4.01 (d, J ) 5.3 Hz, 1H),
2.67 (dd, J ) 16.4, 2.9 Hz, 1H), 2.44 (dd, J ) 17.1, 2.9 Hz,
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transferred to SF. After centrifugation, two phases were
separated. The separated aqueous phase in SF1 was taken back
to RF1 and extracted with EtOAc (80 mL, RS1). The mixture
was transferred to SF and centrifuged, and the two phases
were separated. After repeating this extraction process twice,
the combined organic phase in SF2 was transferred to RF1.
The organic phase was washed with 10% aqueous NaHCO3
solution (80 mL, RS5) and 10% aqueous NaCl solution (80
mL, RS6). The resulting organic phase in SF2 was dried by
passing through anhydrous Na2SO4 (DT1) and transferred to a
round flask (CF1). After removal of solvent, the residue was
purified by flash column chromatography on silica gel (15%
Et2O in hexane) to give alcohol 28 (4.28 g, 7.36 mmol, 75%)
as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.07 (d, J )
2.0 Hz, 1H), 4.47 (dd, J ) 5.0, 2.0 Hz, 1H), 4.18 (dd, J ) 2.2
Hz, 2H), 4.05 (d, J ) 5.0 Hz, 1H), 2.55 (dd, J ) 2.2 Hz, 2H),
0.93 (s, 9H), 0.92 (s, 9H), 0.21 (s, 9H), 0.20 (s, 9H), 0.12 (s,
3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (67.8
MHz, CDCl3) δ 140.3, 129.5, 100.2, 100, 90.1, 86.8, 83.1, 79.6,
79.4, 51.4, 27.1, 25.9, 25.8, 18.0, 17.9, 2.6, -0.2, -4.1, -4.2,
-4.4, -4.5; FT-IR (solid) 3420, 2956, 2858, 2148, 1472, 1250,
1067, 837, 776 cm-1; HRMS (ESI-TOF); [M + H]+ calcd for
C29H57O4Si4, 581.3334; found 581.3323.
Alcohol 8. Potassium carbonate (585 mg, 3.70 mmol, 0.50
equiv) was added to a solution of silyl ether 28 (4.28 g, 7.40
mmol, 1.0 equiv) in methanol (5 mL) and THF (15 mL) in
RF1 manually. After being stirred at 25 °C for 4 h, the reaction
mixture was diluted with EtOAc (80 mL, RR1), quenched by
addition of 1 M HCl solution (80 mL, RR4), and transferred to
SF. After centrifugation, two phases were separated. The
separated aqueous phase in SF1 was taken back to RF1 and
extracted with EtOAc (60 mL, RS1). The mixture was
transferred to SF and centrifuged, and the two phases were
separated. After repeating this extraction process twice, the
combined organic phase in SF2 was transferred to RF1. The
organic phase was washed with 10% aqueous NaHCO3 solution
(80 mL, RS5) and 10% aqueous NaCl solution (60 mL, RS6).
The resulting organic phase in SF2 was dried by passing through
anhydrous Na2SO4 (DT1) and transferred to a round flask (CF1).
After removal of solvent, the residue was purified by flash
column chromatography on silica gel (20% EtOAc in hexane)
to give alcohol 8 (2.90 g, 6.66 mmol, 90%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 6.08 (d, J ) 1.5 Hz, 1H), 4.46
(d, J ) 5.4 Hz, 1H), 4.22 (dd, J ) 2.3 Hz, 2H), 4.01 (d, J )
5.4 Hz, 1H), 3.14 (s, 1H), 2.68 (dt, J ) 17.1, 2.3 Hz, 1H), 2.47
(dt, J ) 17.1, 2.3 Hz, 1H), 0.92 (s, 9H), 0.89 (s, 9H), 0.14 (s,
3H), 0.11 (s, 3H), 0.08 (s, 6H); 13C NMR (67.8 MHz, CDCl3)
δ 140.1, 129.0, 87.7, 82.6, 81.8, 81.7, 81.4, 78.7, 77.6, 51.3,
26.0, 25.8, 25.7, 18.0, -4.4, -4.5, -4.6. FT-IR (solid) 3319,
3180, 2855, 1473, 1259, 1016, 834, 776, 603 cm-1; HRMS
(ESI-TOF); [M + H]+ calcd for C23H41O4Si2, 437.2543; found
437.2552.
(150 mL) at 25 °C under a nitrogen atmosphere in RF1. After
being stirred for 6 h at 25 °C, the reaction was quenched by
addition of pH 8 aqueous NH4Cl-NH4OH buffer (100 mL,
RR3) and diluted with EtOAc (80 mL, RS1) and transfer to
SF. After centrifugation, two phases were separated. The
separated aqueous phase in SF1 was taken back to RF1 and
extracted with EtOAc (80 mL, RS1). The mixture was
transferred to SF and centrifuged, and the two phases were
separated. After repeating this extraction process twice, the
combined organic phase in SF2 was transferred to RF1. The
organic phase was washed with 1 M HCl solution (100 mL,
RS4), 10% aqueous NaHCO3 solution (100 mL, RS5) and 10%
aqueous NaCl solution (80 mL, RS6). The resulting organic
phase in SF2 was dried by passing through anhydrous Na2SO4
(DT1) and transferred to a round flask (CF1). After removal of
solvent, the residue was purified by flash column chromatog-
raphy on silica gel (20% EtOAc in hexane) to give dienyne
25b (4.78 g, 7.81 mmol, 65%) as a white solid. 1H NMR (400
MHz, CDCl3) δ 7.28 (d, J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.8 Hz,
2H), 6.13 (dt, J ) 10.8, 5.8 Hz, 1H), 5.96 (d, J ) 2.0 Hz, 1H),
5.81 (d, J ) 10.8, 1.0 Hz, 1H), 4.84 (s, 2H), 4.45 (dd, J ) 5.4,
2.0 Hz, 1H), 4.33 (ddd, J ) 14.0, 5.8, 1.0 Hz, 2H), 4.24 (ddd,
J ) 14.0, 5.8, 1.0 Hz, 2H), 4.16 (d, J ) 5.9 Hz, 1H), 4.01 (d,
J ) 5.4 Hz, 1H), 3.80 (s, 3H), 2.69 (dt, J ) 17.1, 2.3 Hz, 1H),
2.40 (dt, J ) 16.6, 2.3 Hz, 1H), 0.94 (s, 9H), 0.90 (s, 9H), 0.15
(s, 3H), 0.12 (s, 3H), 0.08 (s, 6H); 13C NMR (67.8 MHz, CDCl3)
δ 159.2, 139.8, 137.8, 132.1, 129.9, 129.8, 129.6, 113.83, 11378,
111.6, 90.3, 89.1, 87.6, 81.9, 81.6, 81.1, 78.7, 72.2, 67.3, 55.2,
50.9, 26.2, 25.8, 25.7, 21.3, -4.4, -4.6; FT-IR (solid) 3415,
2930, 2857, 1612, 1513, 1249, 1102, 1037, 837, 775, 574 cm-1;
HRMS (ESI-TOF); [M + H]+ calcd for C34H53O6Si2, 613.3381;
found 613.3370.
Alcohol 27. RF1 was dried at 80 °C for 30 min under
reduced pressure and cooled to 25 °C. A solution of MPM-ether
25b (4.78 g, 7.80 mmol, 1.0 equiv), CBr4 (4.38 g, 13.2 mmol,
1.5 equiv), and 2,6-lutidine (3.07 mL, 26.4 mmol, 3.0 equiv)
in dry MeCN (20 mL) was cool to 0 °C. A solution of PPh3
(2.25 g, 8.58 mmol, 1.1 equiv) in dry MeCN (10 mL) was
dropwisely added to RF1 at 0 °C. The resulting solution was
warmed to 25 °C and stirred for 30 min at the same temperature.
The reaction was quenched by addition of 10% aqueous NaCl
solution (80 mL, RS6), diluted with Et2O, and transferred to
SF. After centrifugation, two phases were separated. The
separated aqueous phase in SF1 was taken back to RF1 and
extracted with Et2O (80 mL, RS1). The mixture was transferred
to SF and centrifuged, and the two phases were separated. After
repeating this extraction process twice, the combined organic
phase in SF2 was transferred to RF1. The organic phase was
washed with 3 M HCl solution (80 mL, RS4), 10% aqueous
NaCl solution (80 mL, RS6), 10% aqueous NaHCO3 solution
(80 mL, RS5, and 10% aqueous NaCl solution (80 mL, RS6).
The resulting organic phase in SF2 was dried by passing through
anhydrous Na2SO4 (DT1) and transferred to a round flask (CF1).
After removal of solvent, the residue was used for the next
reaction without further purification.
Dienyne 25b. t-BuNH2 (3.80 mL, 36.0 mmol, 3.0 equiv
RR1) and a solution of Pd(OAc)2 (134 mg, 0.600 mmol, 0.050
equiv), PPh3 (629 mg, 2.40 mmol, 0.20 equiv), and CuI (228
mg, 1.20 mmol, 0.10 equiv) in toluene (30 mL, RR2) were
added to a solution of alkyne 8 (5.24 g, 12.0 mmol, 1.0 equiv)
and vinyl iodide 24b (5.47 g, 18.0 mmol, 1.5 equiv) in toluene
The solution of above residue in CH2Cl2 (30 mL) and H2O
(1.0 mL) was cooled to 0 °C. Then DDQ (3.54 g, 15.6 mmol)
was added manually. The solution was warmed to 25 °C and
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stirred for 2 h at the same temperature. The reaction was
quenched by addition of 10% aqueous NaHCO3 solution (80
mL, RS6), diluted with EtOAc and transferred to SF. After
centrifugation, two phases were separated. The separated
aqueous phase in SF1 was taken back to RF1 and extracted
with EtOAc (80 mL, RS1). The mixture was transferred to SF
and centrifuged, and the two phases were separated. After
repeating this extraction process twice, the combined organic
phase in SF2 was transferred to RF1. The organic phase was
washed with 10% aqueous NaCl solution (80 mL, RS6) twice.
The resulting organic phase in SF2 was dried by passing through
anhydrous Na2SO4 (DT1) and transferred to a round flask (CF1).
After removal of solvent, the residue was purified by flash
column chromatography on silica gel (10% Et2O in hexane) to
give alcohol 27 (3.03 g, 5.46 mmol, 70% for 2 steps) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.15 (dt, J ) 10.7,
6.3 Hz, 1H), 5.76 (d, J ) 10.7 Hz, 1H), 6.00 (s, 1H), 4.53 (d,
J ) 4.9 Hz, 1H), 4.43 (d, J ) 6.3 Hz, 2H), 4.00 (d, J ) 4.9
Hz, 1H), 3.89 (t, J ) 5.3 Hz, 2H), 2.67 (d, J ) 17.1 Hz, 1H),
2.54 (d, J ) 17.1 Hz, 1H), 0.94 (s, 9H), 0.89 (s, 9H), 0.14 (s,
3H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (67.8
MHz, CDCl3) δ 142.2, 138.4, 129.0, 110.4, 90.1, 88.7, 88.2,
83.4, 82.8, 78.9, 77.5, 60.9, 26.0, 25.8, 17.9, 15.2, -4.3, -4.5,
-4.6; FT-IR (solid) 3318, 3150, 2928, 2855, 1471, 1249, 835,
774 cm-1; HRMS (ESI-TOF); [M + H]+ calcd for
C26H44O4Si2Br, 555.1962; found 555.1965.
Cyclic ether 7. A suspension of NaH (55%, 1.18 g, 27.0
mmol, 10. eq.) in dry THF (700 mL) with a catalytic amount
of water (0.10 mL) was placed in RF1. A solution of
bromoalcohol 27 (1.50 g, 2.70 mmol, 1.0 equiv) in dry THF
(110 mL) was added to RF1. After being stirred at 25 °C for
1 h, the reaction mixture was heated to 50 °C under reduced
pressure for 5 min in order to remove THF. After being cooled
to 0 °C, the reaction was quenched by addition of 10% NH4Cl
aqueous solution (100 mL, RS6), diluted with EtOAc (100 mL,
RS1), and transferred to SF. After centrifugation, two phases
were separated. The separated aqueous phase in SF1 was taken
back to RF1 and extracted with EtOAc (100 mL, RS1). The
mixture was transferred to SF and centrifuged, and the two
phases were separated. After repeating this extraction process
twice, the combined organic phase in SF2 was transferred to
RF1. The organic phase was washed with 10% aqueous NaCl
solution (80 mL, RS6). The resulting organic phase in SF2 was
dried by passing through anhydrous Na2SO4 (DT1) and
transferred to a round flask (CF1). After removal of solvent,
the residue was purified by flash column chromatography on
silica gel (5% Et2O in hexane) to give cyclic ether 7 (833 mg,
1
1.75 mmol, 65% for 2 steps) as a white solid. H NMR (400
MHz, CDCl3) δ 6.15 (ddd, J ) 10.2, 9.3, 6.8 Hz, 1H), 5.96 (d,
J ) 10.2 Hz, 1H), 5.94 (d, J ) 2.0 Hz, 1H), 4.49 (dd, J )
10.8, 9.3 Hz, 1H), 4.34 (d, J ) 5.0 Hz, 1H), 4.26 (dd, J )
10.8, 10.2 Hz, 1H), 4.17 (d, J ) 13.6 Hz, 2H), 4.06 (d, J ) 5.0
Hz, 1H), 2.85 (dd, J ) 17.1, 1.9 Hz, 1H), 2.25 (dd, J ) 15.3,
1.0 Hz, 1H), 0.92 (s, 9H), 0.90 (s, 9H), 0.15 (s, 3H), 0.12 (s,
3H), 0.08 (s, 6H); 13C NMR (67.8 MHz, CDCl3) δ 137.4, 137.1,
130.1, 116.9, 90.5, 89.8, 87.4, 83.0, 80.5, 80.3, 78.5, 63.8, 56.5,
27.0, 25.9, 25.8, 18.0, 17.9, -4.3, -4.6; FT-IR (neat) 2950,
2854, 1469, 1360, 1250, 1143, 1117, 1072, 840, 778, 735 cm-1;
HRMS (ESI-TOF); [M + H]+ calcd for C26H43O4Si2, 475.2700;
found 475.2695.
Acknowledgment
We thank Dr. Tohru Sugawara, Mr. Kazuhiro Machida, Mr.
Yoichiro Hirose (ChemGenesis Inc.), and Dr. Shigetoshi
Sekiyama (SIC Co.) for their assistance with the development
and maintenance of the ChemKonzert. We also thank Sumi-
tomo Chemical Co., Ltd. for a generous supply of
4-hydroxy-2-cyclopentenone.
Supporting Information Available
Description of general experimental techniques, a detailed
procedure for the synthesis of compound 24b, and spectral data
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Received for review September 17, 2009.
OP9002455
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