Stereodivergent strategy for neurofuran synthesis via palladium-catalyzed asymmetric allylic cyclization: Total synthesis of 7-epi-ST-Δ8- 10-neurofuran

Article abstract of DOI:10.1021/jo4004647

Neurofurans are formed in vivo in the human brain as a consequence of an increased oxidative stress, and they could be valuable biomarkers of the neuronal oxidative stress. In this paper, an enantioselective stereodivergent approach to two key neurofuran precursors, belonging to the AC and ST classes, has been developed starting from a single achiral precursor, the meso-diol 11. The absolute configuration of the THF cores was secured by a Pd-catalyzed asymmetric allylic alkylation using (S,S)-L1 and (R,R)-L2 ligands, respectively.

Full text of DOI:10.1021/jo4004647

Article
pubs.acs.org/joc
Stereodivergent Strategy for Neurofuran Synthesis via Palladium-
Catalyzed Asymmetric Allylic Cyclization: Total Synthesis of 7-epi-
ST‑Δ8‑10-Neurofuran
Matteo Valli, Paolo Bruno, Davide Sbarbada, Alessio Porta, Giovanni Vidari, and Giuseppe Zanoni*
Department of Chemistry, University of Pavia, Viale Taramelli, 10-27100 Pavia, Italy
S
* Supporting Information
ABSTRACT: Neurofurans are formed in vivo in the human
brain as a consequence of an increased oxidative stress, and
they could be valuable biomarkers of the neuronal oxidative
stress. In this paper, an enantioselective stereodivergent
approach to two key neurofuran precursors, belonging to the
AC and ST classes, has been developed starting from a single
achiral precursor, the meso-diol 11. The absolute configuration
of the THF cores was secured by a Pd-catalyzed asymmetric allylic alkylation using (S,S)-L1 and (R,R)-L2 ligands, respectively.
neuronal oxidative stress biomarkers. This discrepancy has been
ascribed to the retention of nFs in brain tissues enriched with
DHA or to their rapid metabolism to produce still unidentified
compounds. Investigation of the nF metabolism in the brain
remains, therefore, elusive.1a
INTRODUCTION
■
Neurofurans (nFs) are formed in vivo in the human brain as a
consequence of an increased oxidative stress; in particular, they
are produced by peroxidation of esterified docosahexaenoic acid
(DHA) in neuron membranes (Figure 1).1
This important goal can be pursued by using a suitably
labeled nF, which requires an unprecedented asymmetric total
synthesis. In this paper, we describe, for the first time, a general
synthetic strategy to nFs that, in principle, enables the
preparation of any of the possible 256 diastereomers and
regioisomers within the large family of alkenyl-nFs.1a,2 The total
synthesis of 7-epi-ST-Δ8-10-NeuroF 1 (Figure 2) was
developed as a representative example of this general strategy.2d
The first example of a synthesis of the THF core of related
products arising from the oxidative metabolism of arachidonic
acid, isofurans, was reported by Taber and co-workers.2d
In their approaches, two different asymmetric trasformations,
a Sharpless asymmetric epoxidation and Sharpless asymmetric
dihydroxylation, have been used. However, neither the
epoxidation nor the dihydroxylation proceeds with perfect
enantiocontrol, and a distereomeric mixture of key tetrahy-
drofuran building blocks was obtained. Moreover, the key
hydroxylic group on C-11 was epimeric to the natural product,
and a carbinol inversion by a Mistunobo reaction was then
required.
Figure 1. Representative examples of neurofuran families.
By contrast, in the present approach, only one enantiose-
lective reaction, i.e., the Trost AAA, has been used with very
high enantomeric excess (vide infra), and the C-11 hydroxylic
group was installed with the correct configuration.
In this effort, we focused our attention on the establishment
of the absolute configuration of the three tetrahydrofuran core
stereocenters, the stereoselective building of the four double
bonds and the introduction of the two hydroxyl groups on the
Along with neuroprostanes, isofurans, and isoprostanes,
neurofurans have been suggested to be possible biomarkers
of oxidative stress, which is considered the principal causative
agent of neurodegenerative diseases, such as Alzheimer’s,
Huntington’s, and Parkinson’s diseases.2 In fact, nFs were
found in significantly greater concentration in the brain tissue
extracts of Tg 2576 transgenic mice, a widely used model for
Alzheimer’s disease, over their control littermates;1a however,
they could not be detected in urine samples, therefore imposing
a severe limitation to the potential use of nFs as valuable
Received: April 4, 2013
© XXXX American Chemical Society
A
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Figure 2. Retrosynthetic analysis of 7-epi-ST-Δ8-10-neurofuran 1 and 4,5-dideuterio-7-epi-ST-Δ8-10-neurofuran 2. AAA = asymmetric allylic
alkylation.
α and ω chains. Equally crucial was the introduction of a
radioisotope labeling in the last step of the synthetic sequence,
for which the Lindlar hydrogenation of a triple bond was
deemed ideally suited. In the event, this labeling strategy has
been validated by synthesizing 4,5-dideuterio-7-epi-ST-Δ8-10-
NeuroF 2 (Figure 2).
meso diol 11, based on an intramolecular Pd-catalyzed Trost
asymmetric allylic alkylation to give tetrahydrofuran 10,
followed by a straighforward manipulation of the resulting
functional groups.
Synthesis of the Tetrahydrofuran Core 10. Diol 11 was
prepared as a single (E,E)-stereoisomer (13C NMR) in 55%
isolated yield, in a single step, via ring-opening cross-metathesis
of cis-cyclopent-4-ene-1,3-diol with (Z)-1,4-diacetoxybut-2-ene,
both commercially available, using Grubbs II catalyst (Scheme
1).3
RESULTS AND DISCUSSION
■
Retrosynthetic Approach. According to our synthetic
plan, both targets 1 and 2 appeared accessible from the key
alkyne 3 (Figure 2). Retrosynthetically, this intermediate was
envisaged to arise via sequential stereocontrolled installation of
the lower and upper side chains, respectively. An E-stereo-
selective Wittig olefination of aldehyde 5 (path a) will be
involved in the insallation of the lower side chain, while a Julia−
Kocienski Z-alkene disconnection (path b) to sulfone 6 and
alkyne aldehyde 7 will provide the upper side chian. The upper
side chain precursor 7 seemed to be readily available through a
regio- and stereocontrolled nucleophilic oxirane ring-opening
of PMB-protected (R)-glycidol 8 by 4-pentynoic acid TIPS
ester 9. Finally, stereocontrolled synthesis of the heterocyclic
core 6, featuring four of the five stereocenters of the targets,
could be traced back to an interesting desymmetrization of
Although compound 10 was reported in the literature as the
undesired product of Pd-catalyzed cyclization of diol 11 to a
key synthetic precursor of halichondrin F-ring, we were unable
a
Scheme 1. Synthesis of (R,S)-Diol 10
a
Mes: 2,4,6-trimethylphenyl.
B
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products distribution in favor of 10a, simply using the
anthracenyldiamine-derived ligand (R,R)-L2 instead of (S,S)-
L1. In fact, the dr of 10a:10 was 66:34 for the reaction carried
out at rt, the two diastereomers being obtained in 88% and 93%
ee, respectively (Table 1, entry 3). Furthermore, lowering the
reaction temperature to −20 °C resulted in an increase of the
dr to 83:17 with a concomitant improvement of the
enantiomeric excess of both 10a and 10 to 92 and 95%,
respectively (Table 1, entry 7).
Absolute configurations of 10R,11S,13R for 10 and
10S,11S,13R for 10a were established by studies of the
corresponding Mosher esters and n.O.e NMR spectra.6 The
Mosher method for enantioenriched 10 and 10a, has been
applied on the products of entry 2 and entry 7 (Table 1), while
NOE studies were carried out on chromatographically
separated O-TBDPS 12 and 12a ethers.
Thus, the simple use of (R,R)-L2 ligand enabled a
straightforward entry to the AC neurofuran class in good
yield and high enantiomeric excess, starting from the readily
available meso diol 11. This result stands in sharp contrast with
the method previously developed by Burke and co-workers to
build an enantioenriched trans-2,5-disubstituted THF-ring like
10a. Actually, in that approach, an enantioenriched chiral diol,7
prepared in 9.5% overall yield from prop-2-ynol and 4-
chlorobut-2-ynol, had to be submitted to two enantioselective
transformations, namely an asymmetric Sharpless epoxidation
and a Pd-mediated Trost AAA, to establish the absolute
stereochemistry.4
Figure 3. List of chiral ligands used in the Trost asymmetric
cycloheterification.
Table 1. Asymmetric Allylic Palladium-Mediated Cyclization
a
of meso-Diacetate 11
10 ee
c
10a ee
c
yield
(%)
b
entry
ligand
solvent
dr
(%)
(%)
d
1
2
3
4
5
6
7
(S,S)-L1
(S,S)-L1
(R,R)-L2
(S,S)-L3
(R,S)-L4
(R)-L5
THF
61:39
80:20
34:66
37:63
11:89
9:91
94
96
93
89
5
11
3
61
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
86
70
82
17
10
88
28
e
According to the asymmetric induction model proposed by
Trost for the Pd-catalyzed AAA,8 we can speculate that the
stereoisomer 10 would be produced by the preferential
coordination of the (S,S)-L1-Pd complex on the Si face of
the allylic acetate moiety in 10 near the (S)-OH group.
40
e
87
95
8
f
(R,R)-L2
17:83
92
65
a
Unless otherwise noted, reactions were carried out at rt with
Pd2(dba)3·CHCl3 adduct (3 mol %), chiral ligand L* (8 mol %), 11
b
(0.2 mmol), Cs2CO3 (1.05 equiv), solvent (2 mL, 0.1 M). dr 10:10a
c
was determined by HPLC. Enantiomeric excess was determined by
d
chiral HPLC on Chiralpak AS-H and AS-3 columns. Cs2CO3 was not
used; Pd2(dba)3·CHCl3 (8 mol %) and ligand (S,S)-L1 (31 mol %)
e
were employed. The corresponding ent-10a (10R,11R,13S) stereo-
f
isomer was obtained. Reaction was carried out at −20 °C.
to reproduce the original data under the described experimental
conditions.4 In fact, cyclization of 11 could be only promoted
by using 8 mol % of Pd2(dba)3·CHCl3 as the Pd source and 31
mol % of cyclohexyldiamine-derived ligand (S,S)-L1 in THF at
rt (Figure 3).
Under these conditions, mixture of two tetrahydrofurans ST-
like 10, 94% ee, and AC-like 10a, 11% ee, in 61% isolated yield
and 61:39 dr (HPLC) was obtained (Table 1, entry 1). This
result was, indeed, rather unexpected since the significant
formation of 10a was not reported in the original work.4
Catalyst loading could be reduced to 8 mol % of ligand and 3
mol % of Pd-precatalyst by adding Cs2CO3 and using DCM as
a solvent.5 Under these modified conditions (Table 1, entry 2),
ST-tetrahydrofuran 10 was obtained in 80:20 dr (HPLC) and
96% ee, accompanied by the AC-diastereomer 10a, 10% ee, in
an overall yield of 85%.
The two compounds 10 and 10a could not be separated by
preparative column chromatography; therefore, we attempted
to increase the diastereoselectivity of the cyclization step by
changing ligands and temperature (Table 1).
Although no significant dr improvement was obtained, some
results deserve an additional comment. In particular, we
observed an unanticipated inversion in the diastereomeric
Figure 4. Stereochemical picture of asymmetric allylic Pd-mediated
cyclization of meso-diacetate 11.
C
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a
Scheme 2. Synthesis of Sulfone 6
a
Key: (a) TBDPSCl, Im, CH2Cl2, rt, 6 h, 74%, (ii) chromatographic separation; (b) (i) K2CO3, MeOH, rt, 20h, 94%, (ii) Ti(iOPr)4, (−)-DET, t-
BuOOH, CH2Cl2, −20 °C, 18 h, 89%; (c) Red-Al, THF, −30 to 0 °C, 6 h, 72%; (d) (i) TBSCl, Im, CH2Cl2, rt, 1 h, then TBDPSCl, Im, rt, 91%, (ii)
O3, CH2Cl2/MeOH (2:1), −78 °C, 1 h, then DMS, −78 °C to rt, 12 h, 89%, (iii) NaBH4, MeOH, 0 °C, 1 h, 91%; (e) (i) PTSH, DEAD, Ph3P,
toluene, rt, 3 h, 85%, (ii) H2O2, (NH4)2MoO4, i-PrOH, rt, 95%, (iii) TBSCl, Im, CH2Cl2, rt, 95%. PTSH = 1-phenyl-1H-tetrazole-5-thiol, Red-Al =
sodium bis(2-methoxyethoxy)aluminum dihydride.
a
Scheme 3
a
Key: (a) BuLi, BF3·Et2O, THF, −78 °C, 2 h, 71%; ( b) TBDPSCl, Im, CH2Cl2, rt, 2 h, 97%; (c) K2CO3, THF/H2O (1:1), rt, 16 h, followed by
CH3I, K2CO3, acetone, rt, 20 h, 79% over two steps; (d) DDQ, CH2Cl2/H2O (3:1), rt, 1.45 h, 88%; (e) DMP, CH2Cl2, rt, 2 h, 75%.
Furan ring closure would thus result from intramolecular anti
attack of the (R)-OH group on the Re face of the allylic Pd-
complex, affording the prevalent (10R,11S,13R)-stereochemis-
try observed for 10 (Figure 4, path A). On the other hand, we
assumed that the (R,R)-L2−Pd complex delivered the
corresponding trans-diatereoisomer 10a as preferentially the
(10S,11S,13R)-enantiomer by nucleophilic addition of the (R)-
OH onto the Si face of the (η3-allyl)palladium complex
intermediate (Figure 4, path B). Interestingly, using the
enatiomers of ligands L1 and L2, namely (R,R)-L1 and (S,S)-
L2, the corresponding enantiomers of 10 and 10a were
obtained with the same enantio- and diastereomeric excesses.
Synthesis of the Neurofurans 1 and 2. With a robust
enantioselective cycloetherification protocol in hand, the
synthesis of our two targets, nF 1 and the D2-analogue 2,
proceeded in a straightforward manner from diacetate 11
through the preparation of the functionalized core 6 (Scheme
2) and the α side-chain reaction partner 7 (Scheme 3).
After silylation of the diastereomeric mixture of alcohol 10
and 10a, silica gel chromatographic separation afforded
diastereochemically pure O-TBDPS ether 12. At this stage,
the stereocenter at C-14 was introduced with the desired
configuration by means of the asymmetric Sharpless
epoxidation procedure,9 followed by regioselective opening of
the oxirane ring in 13 upon exposure to Red-Al at −30 °C. Diol
14 was thus obtained as a single stereoisomer (1H NMR and
13C NMR) in 60% overall yield from 10 (Scheme 2).10
primary alcohol 15. The key sulfone 6 was obtained by
Mitsunobu thioetherification11 (1-phenyl-1H-tetrazole-5-thiol,
Ph3P, DEAD), followed by Mo(VI)-mediated H2O2 oxida-
tion.12
The α-side chain precursor 7 was obtained via nucleophilic
addition of 4-pentynoic acid TIPS ester 9 to enantiopure PMB-
protected (R)-glycidol 8 under Yamaguchi conditions (BuLi,
−78 °C, followed by BF3·Et2O and epoxide 8), as depicted in
Scheme 3.
The corresponding PMB ether 16 was obtained as a single
regioisomer in 71% isolated yield (1H NMR and 13C
NMR).13,14 Routine protective groups manipulation followed
by Dess−Martin periodinane oxidation of alcohol 19 delivered
the desired aldehyde 7 [α]20 = −25.7 (c = 1.63, CH2Cl2) in
D
75% isolated yield.15
For the completion of nF 1 and 2 synthesis, the upper and
lower side chains were sequentially installed on sulfone 6 with
the right E and Z stereochemistry, respectively, by means of a
Julia−Kocienski and a Wittig reaction, respectively (Scheme 4).
In detail, condensation of lithiated sulfone 6 with aldehyde 7,
under the original conditions described by Kocienski, smoothly
afforded the desired olefin 20 as a single (8E)-stereoisomer
(13C NMR) in 60% isolated yield.16 Subsequently, selective
TBS ether deprotection,17 followed by Dess−Martin period-
inane oxidation, delivered unstable aldehyde 5, which was
immediately exposed to a toluene solution of the ylide
generated from phosphonium salt 418 to afford the expected
olefin 22 as a single (16Z)-stereoisomer (13C NMR) in 63%
isolated yield from 20. Compound 22 was then elaborated into
Subsequently, diol 14 was fully protected as TBS ether and
then the double bond was subjected to reductive ozonation to
D
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a
Scheme 4. Final Steps of Neurofuran Synthesis
a
Key: 6, KHMDS, DME, −65 °C, 45 min, then 7, −65 °C to rt, 1 h, 60%; (b) PPTS, CH2Cl2/MeOH (1:1), rt, 6 h, 86%; (c) DMP, CH2Cl2, rt, 0.75
h, 100%; (d) 4, KHMDS, toluene, −95 °C to rt, 3.5 h, 74% over two steps; (e) TBAF, THF, rt, 2 days, followed by CH2N2, AcOEt, 0 °C, 0.25h, 55%
over two steps; (f) Lindlar cat., H2 (1 atm), quinoline, hexane/AcOEt (1:1), rt, 0.5 h, 80%; (g) Lindlar cat., D2 (1 atm), quinoline, AcOEt/hexane
(1:1), rt, 1 h, 73%; (h) H2O, CAL-B, MTBE, rt, 18 h, 78%; (i) H2O, CAL-B, MTBE, rt, 18 h, 81%. CAL-B = Candida antarctica lipase B.
key triene-yne triol 3 in 55% isolated yield by using routine
protective groups manipulation. Finally, chemo- and stereo-
selective Lindlar hydrogenation19 of the triple bond in 3,
afforded stereochemically pure Z-olefin 23 (13C NMR) which
was ezymatically hydrolyzed under “buffer-free” conditions,20
delivering the 7-epi-ST-Δ8-10-NeuroF 1 in 62% isolated yield,
over two steps.
both the AC and ST series of neurofurans, by simply switching
from an L1- to and L2-type chiral ligand. This streamlined
approach will soon be utilized for the preparation of tritium-
labeled neurofurans, to be employed for in vivo metabolism
studies of this class of recently described DHA peroxidation
products.21 Moreover, a detailed study of the crucial AAA
cycloetherification reaction is in progress in our laboratory.
The corresponding 4,5-dideuterio-7-epi-ST-Δ8-10-NeuroF 2
could be achieved in 59% isolated yield over two steps by using
D2 instead of H2 in the Lindlar-mediated reduction.
EXPERIMENTAL SECTION
■
General Procedures. All solvents were of commercial quality and
were purified by distillation over the drying agents indicated: THF
(Na/benzophenone), CH2Cl2, hexane, (CaH2), toluene (Na/K). All
other reagents were used as supplied. All moisture-sensitive reactions
were carried out under a positive static atmosphere of Ar in flame-
dried glassware. Syringes and needles for the transfer of reagents were
dried at 140 °C and allowed to cool in a desiccator over P2O5 before
use. Routine monitoring of reactions was performed using silica gel 60
(0.25 mm), aluminum-supported TLC plates. Compounds were
visualized by UV irradiation at a wavelength of 254 nm, or stained by
exposure to a 0.5% solution of vanillin in H2SO4/EtOH, followed by
CONCLUSION
■
In summary, we have developed a versatile strategy that has the
potential to give access, in an enantioselective fashion, to
different neurofurans via the highly convergent combination of
the common meso building-block 10 with an aldehyde, e.g., 6,
and a phosphonium salt, e.g., 4, both readily available.
Notably, the key Trost Pd-catalyzed cyclization protocol
could be employed to efficiently construct the THF core ring of
E
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charring. Flash column chromatography (FCC) was performed on
the sum of the area peaks: 17:83, 10:10a. Data for analytical sample of
10 obtained after silyl ether separation (vide infra). TLC (SiO2): Rf =
0.28 (hexane/EtOAc 6/4). [α]21D = +30.46 (c = 1.30, CH2Cl2). FTIR
(neat): 3427, 2957, 2922, 2872, 1737, 1643, 1369, 1230, 1025 cm−1.
1H NMR (300 MHz, CDCl3): δ (ppm) = 5.98−5.80 (m, 3H), 5.51
(dt, J = 17.3, 1.7 Hz, 1H), 5.40 (dt, J = 10.6, 1.6 Hz, 1H), 4.78 (dt, J =
10.0, 5.2 Hz, 1H), 4.59 (d, J = 5.1 Hz, 2H), 4.57−4.51 (m, 1H), 4.36
(m, 1H), 2.28 (ddd, J = 13.2, 6.1, 1.2 Hz, 1H), 2.11−2.05 (s, 3H), 1.90
(m, 2H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 170.7 (s), 134.8
(d), 133.4 (d), 125.3 (d), 118.7 (t), 83.4 (d), 77.7 (d), 73.6 (d), 64.1
(t), 41.6 (t), 20.9 (q). Anal. Calcd for C11H16O4: C, 62.25; H, 7.60.
Found: C, 62.26; H, 7.52.
silica gel (40−63 μm). Yields are reported for isolated compounds
1
with >96% purity established by NMR unless otherwise indicated. H
and 13C NMR spectra were recorded at 300 and 75 MHz, respectively,
in the solvents indicated; chemical shifts (δ) are given in ppm relative
to TMS, coupling constants (J) in Hz. The solvent signals were used as
references and the chemical shifts converted to the TMS scale
(CDCl3: δC 77.00; residual CHCl3 in CDCl3: δH 7.26; CD2Cl2: δC
53.8; residual CH2Cl2 in CD2Cl2: δH 5.32 ppm). COSY, DEPT,
NOESY spectra were recorded using a standard pulse program library.
The number of H-atoms attached to each C-atom (s = 0H, d = 1H, t =
2H, q = 3H) was determined by DEPT experiments. Optical rotations
were recorded on a digital polarimeter at 589 nm, concentration (c) in
g/100 mL. Mass spectrometry was performed by Q-TOF using
electrospray ionization (ESI) mode, [M + H+]. (S,S)-L1, (R,R)-L2,
(S,S)-L3, (R,S)-L4, and (R)-L5 are commercially available.
Synthesis of (E)-3-((2R,4S,5R)-4-((tert-Butyldiphenylsilyl)-
oxy)-5-vinyltetrahydrofuran-2-yl)allyl acetate (12). To a
magnetically stirred solution of 10 and 10a (1.95 g, 9.19 mmol) in
dry CH2Cl2 (90 mL) under Ar were added at rt imidazole (1.56 g, 22.9
mmol) and TBDPSCl (2.9 mL, 11.2 mmol). The reaction was
completed after 6 h and was quenched with H2O (90 mL). The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (3 ×
90 mL). The combined organic layers were dried over MgSO4, filtered,
and concentrated under vacuum. The residue was purified by
chromatography on silica gel column (hexane/EtOAc 98/2, 95/5
and 9/1 as eluent) to afford the product (3.05 g of 12, yield =74% and
370 mg of 12a, yield = 8.9%). TLC (SiO2): Rf = 0.2 (hexane/EtOAc
(2E,7E)-4,6-Dihydroxynona-2,7-diene-1,9-diyl Diacetate (11).
(Z)-1,4-Diacetoxy-2-butene (11868 mg, 69 mmol) was added to a dry
bottom flask under Ar atmosphere. cis-4-Cyclopentene-1,3-diol (600
mg, 6 mmol) was then added, and the suspension was stirred at rt.
After 10 min, Grubbs catalyst generation II (600 mg, 0.706 mmol) was
added, and the reaction was stirred at 40 °C for 16 h. The reaction was
monitored by TLC (hexane/EtOAc 3/7) and quenched by addition of
CH2Cl2 (10 mL) and bubbling O2 through reaction for 10 min. The
CH2Cl2 was removed under vacuum, and the residue was purified by
flash chromatography, eluting with hexane/EtOAc 4/6 to 3/7 to afford
the pure product 11 as a pale yellow oil (898 mg, yield = 55%). FTIR
(neat): 3432, 3006, 2942, 2882, 1739, 1436, 1382, 1366, 1242, 1027
95/5). [α]21 = +27.9 (c = 1.17, CH2Cl2). FTIR (neat): 2932, 2858,
D
1
1741, 1428, 1232 1113, 1078, 1026, 740, 703 cm−1. H NMR (300
MHz, CDCl3): δ (ppm) = 7.80−7.60 (m, 4H), 7.50−7.30 (m, 6H),
5.95−5.70 (m, 2H), 5.55−5.40 (m, 1H), 5.20−5.05 (dt, J = 17.1, 1.7
Hz, 1H), 5.05−4.95 (dt, J = 10.4, 1.4 Hz, 1H), 4.80−4.70 (m, 1H),
4.60.4−50 (d, J = 5.7 Hz, 2H), 4.35−4.20 (m, 1H), 4.20−4.10 (m,
1H), 2.08 (s, 3H), 2.00−1.90 (ddd, J = 12.8, 5.2, 1.7 Hz, 1H), 1.70−
1.55 (m, 1H), 1.10 (s, 9H). 13C NMR (75 MHz, CDCl3): δ (ppm) =
170.7 (s), 136.8 (d), 135.8 (d), 135.7 (d), 134.5 (d), 133.6 (s), 133.6
(s), 129.8 (d), 127.7 (d), 126.0 (d), 115.8 (t), 87.9 (d), 78.6 (d), 78.2
(d), 64.2 (t), 40.8 (t), 26.9 (q), 20.9 (q), 19.1 (s). HRMS: calcd for
C27H34O4Si 450.2226, found 450.2231
1
cm−1. H NMR (300 MHz, CDCl3): δ (ppm) = 5.86−5.72 (m, 4H),
4.54 (d, J = 4.1 Hz, 4H), 4.46−4.36 (m, 2H), 2.55−2.40 (bs, 2H), 2.05
(s, 6H), 1.70 (t, J = 6.4 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ
(ppm) = 170.7 (s), 136.4 (d), 124.6 (d), 72.0 (d), 64.1 (t), 43.0 (t),
20.9 (q). HRMS: calcd for C13H20O6 272.1260, found 272.1264
Trost Asymmetric Allylic Cyclization: Synthesis of (E)-3-
((2R,4S,5R)-4-Hydroxy-5-vinyltetrahydrofuran-2-yl)allyl Ace-
tate (10). Tetraol diacetate 11 (1.35 g, 4.96 mmol) was dissolved
in dry CH2Cl2 (25 mL) under Ar, and solid Cs2CO3 was added in one
portion. In a second two-necked round-bottom flask (S,S)-L1 (284
mg, 0.411 mmol) was dissolved in dry CH2Cl2 (25 mL), and
Pd2(dba)3 CHCl3 adduct was added at once (156 mg, 0.151 mmol).
After 20 min, the solution color changed form purple to orange,
indicating the chiral Pd complex formation. Subsequently, this solution
was cannulated to the substrate−Cs2CO3 suspension, and the mixture
was stirred until complete conversion. The reaction was then filtered
and concentrated under vacuum. The oily residue was purified by
column chromatography on silica gel (hexane/Et2O 4/6) to afford
products 10 and 10a (905 mg, 86% combined yield): 10 (HPLC:
Chiralpak AS-H, heptane/i-PrOH 80:20, 1 mL/min, DAD detection,
major peak at 12.2 min, minor peak at 6.6 min, 96% ee); 10a (same
conditions for 10: major peak at 8.8 min, minor peak at 18.3 min, 3%
ee); dr was calculated by the sum of the area peaks: 80:20, 10:10a.
Synthesis of ((2R,3R)-3-((2R,4S,5R)-4-((tert-Butyldiphenyl-
silyl)oxy)-5-vinyltetrahydrofuran-2-yl)oxiran-2-yl)methanol
(13). Acetate Hydrolysis. To a magnetically stirred solution of 12
(3.02 g, 6.70 mmol) in MeOH (67 mL) was added K2CO3 (51 mg,
0.369 mmol) at rt. After 20 h, the reaction was completed and was
filtered and concentrated under vacuum. The residue was purified by
chromatography on a silica gel column (hexane/EtOAc 8/2 as eluent)
to afford the corresponding primary alcohol as a light yellow oil (2.57
g, yield = 94%). TLC (SiO2): Rf = 0.24 (hexane/EtOAc 8/2). [α]21
=
D
+32.8 (c = 1.05, CH2Cl2). FTIR (neat): 3400, 3072, 2932, 2858, 1472,
1
1428, 1363, 1113, 740, 702 cm−1. H NMR (300 MHz, CDCl3): δ
(ppm) = 7.70−7.60 (m, 4H), 7.50−7.35 (m, 6H), 6.00−5.90 (dtd, J =
16.3, 5.3, 0.9 Hz, 1H), 5.80−5.65 (ddt, J = 15.4, 7.1, 1.4 Hz, 1H),
5.60−5.40 (m, 1H), 5.20−5.05 (dt, J = 17.1, 1.6 Hz, 1H), 5.05−4.95
(dt, J = 10.4, 1.4 Hz, 1H), 4.85−4.70 (m, 1H), 4.35−4.30 (m, 1H),
4.20−4.10 (m, 3H), 2.00−1.90 (ddd, J = 12.8, 5.2, 1.7 Hz, 1H), 1.65−
1.55 (m, 1H), 1.55−1.45 (m, 1H), 1.10 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ (ppm) = 136.9 (d), 135.8 (d), 135.7 (d), 134.5 (d), 133.7
(s), 133.6 (s), 131.5 (d), 131.5 (d), 129.8 (d), 127.7 (d), 115.7 (t),
87.8 (d), 78.8 (d), 78.3 (d), 62.9 (t), 40.8 (t), 26.9 (q), 19.1 (s).
HRMS: calcd for C25H32O3Si 408.2121, found 408.2127.
Sharpless Asymmetric Epoxidation. To a dry round-bottom flask
under Ar were added activated molecular sieves type 4 Å (200 mg),
dry CH2Cl2 (16 mL), D-(−)-DET (110 μL, 0.643 mmol), and t-
BuOOH (3.2 mL, 5.5 M in decane, 17.6 mmol), and the solution was
stirred for 20 min at rt. The suspension was cooled to −20 °C, and
Ti(O-i-Pr)4 (135 μL, 0.461 mmol) was added. The solution was
stirred at −20 °C for 20 min in order to obtain the chiral complex. In a
second round-bottom flask under Ar were added at rt the primary
alcohol (1.82 g, 4.45 mmol), dry CH2Cl2 (16 mL) and activated
molecular sieves type 4 Å (200 mg). The suspension was stirred at rt
for 20 min and then cooled to −20 °C. The solution of allylic alcohol
2121 was added dropwise to the solution of the chiral complex at −20
°C, and when the reaction was complete it was quenched at −20 °C
[α]20 = +27.8 (c = 1.00, CH2Cl2). Data for analytical sample of 10
D
obtained after silyl ether separation (vide infra). TLC (SiO2): Rf = 0.28
(hexane/EtOAc 6/4). [α]21 = +38.57 (c = 0.7, CH2Cl2). FTIR
D
(neat): 3427, 2957, 2922, 2872, 1737, 1643, 1369, 1230, 1025 cm−1.
1H NMR (300 MHz, CDCl3): δ (ppm) = 5.93−5.77 (m, 3H), 5.37
(dt, J = 17.1, 1.5 Hz, 1H), 5.19 (dt, J = 10.5, 1.5 Hz, 1H), 4.70−4.63
(m, 1H), 4.58 (dd, J = 5.0, 0.9 Hz, 2H), 4.27 (ddt, J = 6.0, 2.9, 1.4 Hz,
1H), 4.20 (dt, J = 5.5, 2.7 Hz, 1H), 2.11−1.99 (m, 5H), 1.94−1.82 (m,
1H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 170.8 (s), 136.7 (d),
134.3 (d), 126.1 (d), 116.6 (t), 87.6 (d), 78.1 (d), 76.7 (d), 64.1 (t),
40.4 (t), 20.9 (q). Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found:
C, 62.27; H, 7.49.
Trost Asymmetric Allylic Cyclization: Synthesis of (E)-3-
((2R,4S,5S)-4-Hydroxy-5-vinyltetrahydrofuran-2-yl)allyl Ace-
tate (10a). Under the same procedure, at −20 °C, (R,R)-L2 afforded
products 10 and 10a (65% yield): 7 (HPLC: Chiralpak AS-H, hexane/
i-PrOH 80:20, 1 mL/min, DAD detection, major peak at 10.7 min,
minor peak at 6.4 min, 95% ee); 10a (same conditions for 10: major
peak at 14.8 min, minor peak at 8.1 min, 92% ee); dr was calculated by
F
dx.doi.org/10.1021/jo4004647 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
with a solution of 10% (+)-tartaric acid (30 mL). The temperature was
allowed to reach rt, and H2O (30 mL) was added to the reaction in
order to dissolve the molecular sieves. The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by chromatog-
raphy on a silica gel column using hexane/EtOAc 8/2 as eluent to
afford the pure product 13 as a colorless to pale yellow oil (1.69 g,
(d), 127.6 (d), 127.4 (d), 127.4 (d), 116.3 (t), 87.5 (d), 81.3 (d), 77.6
(d), 72.3 (d), 59.8 (t), 37.5 (t), 36.2 (t), 27.0 (q), 26.9 (q), 25.9 (q),
19.5 (s), 19.1 (s), 18.2 (s), −5.4 (q), −5.4 (q). HRMS: calcd for
C47H66O4Si3 778.4269, found 778.4262.
Ozonolysis. To a magnetically stirred solution of bis-silyl ether (130
mg, 0.167 mmol) in CH2Cl2/MeOH 2/1 (15 mL) at −78 °C was
added a mixture of O3/O2 until the color of the solution became cyan
(45 min). When the starting material disappeared O2 was added at
−78 °C until the solution became colorless. N2 was then added in
order to move the residue away from O2. At −78 °C. a solution of
Pyridine (15 mg) in DMS (160 mL, 2.71 mmol) was added, and the
reaction was allowed to reach rt and was stirred for 1 h. The reaction
was concentrated under vacuum and to the residue were added Et2O
(15 mL) and H2O (15 mL). The layers were separated, and the aq
layer was extracted with Et2O (3 × 15 mL). The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel using hexane/EtOAc 95/5 as eluent to
afford the pure aldehyde product as a yellowish oil (116 mg, yield =
89%). TLC (SiO2): Rf = 0.2 (hexane/EtOAc 95/5). [α]21D = −7.7 (c =
1.13, CH2Cl2). FTIR (neat): 2930, 2857, 1735, 1472, 1428, 1256,
yield = 89%). TLC (SiO2): Rf = 0.24 (hexane/EtOAc 8/2). [α]21
=
D
+38.9 (c = 1.03, CH2Cl2). FTIR (neat): 3436, 3071, 2932, 2858, 1472,
1
1428, 1112, 1078, 997, 931, 823, 739, 703, 612 cm−1. H NMR (300
MHz, CDCl3): δ (ppm) = 7.75−7.60 (m, 4H), 7.55−7.35 (m, 6H),
5.60−5.40 (m, 1H), 5.20−5.05 (dt, J = 17.1, 1.4 Hz, 1H), 5.05−4.95
(dt, J = 10.4, 1.4 Hz, 1H), 4.40−4.25 (m, 2H), 4.24−4.10 (m, 1H),
4.00−3.85 (m, 1H), 3.75−3.55 (m, 1H), 3.15−3.00 (m, 2H), 2.10−
2.00 (t, J = 6.4 Hz, 1H), 2.00−1.90 (ddd, J = 12.7, 5.7, 2.2 Hz, 1H),
1.80−1.65 (m, 1H), 1.10 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
(ppm) = 136.4 (d), 135.8 (d), 135.7 (d), 133.5 (s), 133.5 (s), 129.8
(d), 127.7 (d), 116.2 (t), 87.8 (d), 78.0 (d), 77.8 (d), 61.2 (t), 56.8
(d), 56.2 (d), 36.4 (t), 26.9 (q), 19.0 (s). HRMS: calcd for C25H32O4Si
424.2017, found 424.2013.
1
1111, 835, 777, 740, 701, 612 cm−1. H NMR (300 MHz, CDCl3): δ
Synthesis of (S)-1-((2R,4S,5R)-4-((tert-Butyldiphenylsilyl)-
oxy)-5-vinyltetrahydrofuran-2-yl)propane-1,3-diol (14). To a
magnetically stirred solution of 13 (1.69 g, 3.98 mmol) in dry THF
(40 mL) under Ar at −30 °C was added Red-Al (3.0 mL, 9.84 mmol),
and the temperature after 1 h was allowed to reach 0 °C. When the
reaction was complete, it was quenched with saturated aq potassium
sodium tartrate (40 mL), H2O (80 mL), and Et2O (40 mL). The
mixture was stirred at rt until two layers were observed. The layers
were separated, and the aq layer was extracted with CH2Cl2 (3 × 80
mL). The comined organic layers were dried over Na2SO4, filtered,
and concentrated under vacuum. The residue was purified by
chromatography on silica gel column using hexane/EtOAc 1/1 as
eluent to afford the product 14 as a yellowish oil (1.22 g, yield = 72%).
TLC (SiO2): Rf = 0.22 (hexane/EtOAc 1/1). [α]21D = +19.8 (c = 0.84,
CH2Cl2). FTIR (neat): 3392, 3071, 2931, 2858, 1472, 1428, 1363,
(ppm) = 9.20 (d, J = 1.6 Hz, 1H), 7.75−7.55 (m, 8H), 7.50−7.25 (m,
12H), 4.45−4.30 (m, 2H), 4.20−4.15 (m, 1H), 4.10−3.95 (m, 1H),
3.65−3.45 (m, 2H), 1.85−1.60 (m, 3H), 1.55−1.45 (m, 1H), 1.1 (s,
9H), 1.0 (s, 9H), 0.8 (s, 9H), −0.04 (m, 6H). 13C NMR (75 MHz,
CDCl3): δ (ppm) = 200.9 (d), 136.0 (d), 135.9 (d), 135.8 (d), 135.7
(d), 133.9 (s), 133.4 (s), 132.9 (s), 129.9 (d), 129.9 (d), 129.6 (d),
129.6 (d), 127.8 (d), 127.7 (d), 127.5 (d), 127.5 (d), 91.0 (d), 82.8
(d), 75.1 (d), 71.8 (d), 59.6 (t), 37.3 (t), 36.9 (t), 27.0 (q), 26.8 (q),
25.9 (q), 19.5 (s), 19.1 (s), 18.2 (s), −5.4 (q). HRMS: calcd for
C46H64O5Si3 780.4062, found 780.4068
Synthesis of 15. To a magnetically stirred solution of aldehyde (204
mg, 0.261 mmol) in MeOH (5 mL) was added NaBH4 (20 mg, 0.522
mmol) at 0 °C, and the reaction was stirred at 0 °C. After 1 h, the
reaction was completed and was quenched at 0 °C with acetone (1
mL) and then was allowed to reach rt. The reaction was concentrated
under vacuum, and to the residue were added saturated aq NH4Cl (10
mL) and CH2Cl2 (10 mL). The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under vacuum. The residue was purified by chromatography on silica
gel column (hexane/EtOAc 9/1 as eluent) to afford the desired
product 15 (166 mg, yield = 91%). TLC (SiO2): Rf = 0.25 (hexane/
1
1112, 1058, 998, 930, 823, 740, 702, 612 cm−1. H NMR (300 MHz,
CDCl3): δ (ppm) = 7.75−7.60 (m, 4H), 7.50−7.35 (m, 6H), 5.55−
5.40 (m, 1H), 5.10−4.95 (m, 2H), 4.35−4.20 (m, 2H), 4.20−4.10 (m,
1H), 4.10−3.95 (dt, J = 9.46, 3.59 Hz, 1H), 3.90−3.80 (t, J = 5.73 Hz,
2H), 2.60−2.30 (bs, 2H), 1.95−1.75 (m, 2H), 1.75−1.55 (m, 2H),
1.10 (s, 9H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 136.5 (d),
135.8 (d), 135.7 (d), 133.6 (s), 133.6 (s), 129.8 (d), 127.7 (d), 116.5
(t), 87.9 (d), 81.6 (d), 78.1 (d), 72.0 (d), 61.7 (t), 34.5 (t), 34.3 (t),
26.9 (q), 19.1 (s). HRMS: calcd for C25H34O4Si 426.2226, found
426.2231.
EtOAc 9/1). [α]21 = +9.0 (c = 1.21, CH2Cl2). FTIR (neat): 2931,
D
1560, 1474, 1427, 1113 cm−1. 1H NMR (300 MHz, CDCl3): δ (ppm)
= 7.80−7.55 (m, 8H), 7.55−7.30 (m, 12H), 4.33−4.22 (m, 1H),
4.20−4.10 (m, 1H), 4.10−4.00 (m, 1H), 3.90−3.80 (m, 1H), 3.65−
3.40 (m, 2H), 3.38−3.25 (m, 1H), 3.05−2.92 (m, 1H), 1.90−1.55 (m,
5H), 1.08 (s, 9H), 1.04 (s, 9H), 0.85 (s, 9H), −0.03 (s, 3H), −0.04 (s,
3H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 135.9 (d), 135.8 (d),
135.7 (d), 134.1 (s), 133.9 (s), 133.7 (s), 129.8 (d), 129.7 (d), 129.6
(d), 127.7 (d), 127.5 (d), 87.3 (d), 81.5 (d), 74.5 (d), 71.9 (d), 63.1
(t), 59.8 (t), 37.5 (t), 36.8 (t), 27.0 (q), 26.9 (q), 25.9 (q), 19.4 (s),
19.0 (s), 18.2 (s), −5.4 (q). HRMS: calcd for C46H66O5Si3 782.4218,
found 782.4222.
Synthesis of ((2R,3S,5R)-3-((tert-Butyldiphenylsilyl)oxy)-5-
((S)-2,2,9,9,10,10-hexamethyl-3,3-diphenyl-4,8-dioxa-3,9-disi-
laundecan-5-yl)tetrahydrofuran-2-yl)methanol (15). Diol 14
Protection. To a magnetically stirred solution of 14 (1.22 g, 2.86
mmol) in dry CH2Cl2 (28 mL) under Ar were added at rt imidazole
(238 mg, 3.50 mmol) and TBSCl (467 mg, 3.10 mmol). When the
primary alcohol was protected, imidazole (982 mg, 14.4 mmol) and
TBDPSCl (900 mL, 3.46 mmol) were added to the reaction in order
to complete the protection. The reaction was stirred at rt and was
quenched with H2O (50 mL). The layers were separated, and the aq
layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
vacuum. The residue was purified by chromatography on silica gel
column using hexane/Et2O 97/3 as eluent to afford the bis-silyl ether
product as a slight yellow oil (2.03 g, yield = 91%). TLC (SiO2): Rf =
Synthesis of 5-((((2S,3S,5R)-3-((tert-Butyldiphenylsilyl)oxy)-
5-((S)-2,2,9,9,10,10-hexamethyl-3,3-diphenyl-4,8-dioxa-3,9-
disilaundecan-5-yl)tetrahydrofuran-2-yl)methyl)thio)-1-phe-
nyl-1H-tetrazole (6). Mitsunobu Reaction. To a magnetically stirred
solution of 15 (154 mg, 0.196 mmol) in dry toluene (2 mL) under Ar
at rt were added PPh3 (67 mg, 0.255 mmol), PTSH (38.5 mg, 0.216
mmol), and DEAD (120 mL, 0.262 mmol). The reaction was
completed after 3 h and was concentrated under vacuum. The residue
was purified by column chromatography on silica gel using hexane/
EtOAc 95/5 as eluent to afford the sulfide product as white foam (158
0.22 (hexane/Et2O 97/3). [α]21 = −3.7 (c = 0.98, CH2Cl2). FTIR
D
(neat): 3071, 2930, 2857, 1472, 1428, 1258, 1111, 1006, 937, 834, 776,
1
739, 701, 612 cm−1. H NMR (300 MHz, CDCl3): δ (ppm) = 7.75−
7.55 (m, 8H), 7.50−7.25 (m, 12H), 5.50−5.35 (m, 1H), 5.15−5.00 (d,
J = 17.2 Hz, 1H), 5.00−4.85 (d, J = 10.4 Hz, 1H), 4.25−4.10 (m, 2H),
4.05−3.95 (m, 1H), 3.95−3.85 (m, 1H), 3.60−3.40 (m, 2H), 1.80−
1.55 (m, 4H), 1.1 (s, 9H), 1.0 (s, 9H), 0.8 (s, 9H), −0.1 (s, 6H). 13C
NMR (75 MHz, CDCl3): δ (ppm) = 136.7 (d), 136.0 (d), 135.9 (d),
135.8 (d), 134.2 (s), 133.9 (s), 133.6 (s), 129.7 (d), 129.5 (d), 129.4
mg, yield = 85%). TLC (SiO2): Rf = 0.2 (hexane/EtOAc 95/5). [α]21
D
= −1.9 (c = 1.58, CH2Cl2). FTIR (neat): 2930, 2857, 1500, 1472,
1
1428, 1251, 1111, 834, 776, 740, 702 cm−1. H NMR (300 MHz,
CDCl3): δ (ppm) = 7.70−7.20 (m, 25H), 4.30−4.20 (m, 1H), 4.20−
G
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4.05 (m, 2H), 4.05−3.95 (m, 1H), 3.60−3.40 (m, 2H), 3.39−3.34 (dd,
J = 12.9, 4.3 Hz, 1H), 2.93−2.86 (dd, J = 12.9, 8.2 Hz, 1H), 1.90−1.75
(m, 2H), 1.75−1.40 (m, 2H), 1.09 (s, 9H), 1.02 (s, 9H), 0.84 (s, 9H),
−0.04 (s, 6H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 154.1 (s),
136.0 (d), 135.9 (d), 135.8 (d), 135.7 (d), 134.0 (s), 133.9 (s), 133.2
(s), 129.9 (d), 129.8 (d), 129.8 (d), 129.7 (d), 129.5 (d), 129.4 (d),
127.8 (d), 127.7 (d), 127.4 (d), 127.3 (d), 123.7 (d), 84.1 (d), 81.8
(d), 76.5 (d), 71.6 (d), 59.6 (t), 37.4 (t), 35.9 (t), 27.0 (q), 26.9 (q),
25.9 (q), 19.4 (s), 19.0 (s), 18.2 (s), −5.4 (q). HRMS: calcd for
C53H70N4O4SSi3 942.4426, found 942.4433
Sulfone Oxidation. To a magnetically stirred solution of sulfide
(158 mg, 0.167 mmol) in iPrOH (3 mL) were added at rt
(NH4)6Mo7O24·4H2O (120 mg, 0.097 mmol) and H2O2 35 wt %
(800 μL, 9.1 mmol). The reaction was monitored by TLC (hexane/
EtOAc 8/2), and every day (NH4)6Mo7O24·4H2O (0.2 equiv) and
H2O2 (15 equiv) were added until complete conversion was reached.
The reaction was added dropwise to a stirred saturated aq Na2SO3 (5
mL) at 0 °C. The organic layer was concentrated under vacuum. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under vacuum.
cally stirred solution of 16 (1.65 g 3.68 mmol) in dry CH2Cl2 (30 mL)
under Ar were added imidazole (756 mg, 11.1 mmol) and TBDPSCl
(1.0 mL, 3.85 mmol). The reaction was completed after 2 h and was
quenched with H2O (30 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 30 mL), and the combined organic layers were dried on
MgSO4, filtered, and concentrated under vacuum. The residue was
purified by chromatography on silica gel column (hexane/EtOAc 95/
5) to afford the product 17 as a slightly yellow oil (2.45 g, yield =
97%). TLC (SiO2): Rf = 0.26 (hexane/EtOAc 95/5). [α]21D = +0.47 (c
= 0.85, CH2Cl2). FTIR (neat): 2946, 2867, 1719, 1514, 1465, 1428,
1
1368, 1301, 1248, 1174, 1112, 1038, 884, 822, 740, 702 cm−1. H
NMR (300 MHz, CDCl3): δ (ppm) = 7.75−7.65 (dd, J = 7.8, 1.4 Hz,
4H), 7.50−7.30 (m, 6H), 7.20−7.10 (d, J = 8.7 Hz, 2H), 6.90−6.80
(d, J = 8.6 Hz, 2H), 4.40−4.30 (d, J = 3.5 Hz, 2H), 4.00−3.90 (m,
1H), 3.82 (s, 3H), 3.53−3.40 (m, 2H), 2.50−2.25 (m, 6H), 1.40−1.20
(m, 3H), 1.15−1.05 (m, 27H). 13C NMR (75 MHz, CDCl3): δ (ppm)
= 172.1 (s), 159.0 (s), 136.0 (d), 135.9 (d), 134.1 (s), 133.9 (s), 130.5
(s), 129.6 (d), 129.5 (d), 129.1 (d), 127.5 (d), 113.6 (d), 80.1 (s),
72.8 (t), 72.8 (t), 71.0 (d), 55.3 (q), 35.4 (t), 26.9 (q), 24.5 (t), 19.3
(s), 17.7 (q), 15.1 (t), 11.9 (d). HRMS: calcd for C41H58O5Si2
686.3823, found 686.3799.
The residue was dissolved in dry CH2Cl2 (2 mL) under Ar and at rt
imidazole (55.8 mg, 0.820 mmol) and TBSCl (45 mg, 0.299 mmol)
were added. The reaction was stirred at rt for 2 h and was quenched
with H2O (2 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 5 mL). The combined combined
organic layers over Na2SO4, filtered, and concentrated under vacuum.
The residue was purified by column chromatography on silica gel
using hexane/EtOAc 95/5 as eluent to afford the product 6 as a
yellowish oil (155 mg, yield = 95%). TLC (SiO2): Rf = 0.2 (hexane/
EtOAc 95/5). [α]21D = +16.8 (c = 1.55, CH2Cl2). FTIR (neat): 2931,
2858, 1498, 1474, 1428, 1356, 1256, 1112, 835, 763, 740, 702 cm−1.
1H NMR (300 MHz, CDCl3): δ (ppm) = 7.75−7.25 (m, 25H), 4.20−
4.05 (m, 2H), 4.00−3.90 (m, 1H), 3.85−3.75 (m, 1H), 3.58−3.38 (m,
2H), 3.22−3.00 (m, 2H), 1.87−1.70 (m, 2H), 1.52−1.35 (m, 2H),
1.07 (s, 9H), 1.00 (s, 9H), 0.84 (s, 9H), −0.04 (s, 6H). 13C NMR (75
MHz, CDCl3): δ (ppm) = 153.7 (s), 136.0 (d), 135.9 (d), 135.7 (d),
135.7 (d), 134.0 (s), 133.6 (s), 133.0 (s), 131.2 (d), 130.2 (d), 130.0
(d), 129.6 (d), 129.6 (d), 129.4 (d), 128.0 (d), 127.8 (d), 127.5 (d),
127.5 (d), 125.6 (d), 82.1 (d), 79.2 (d), 76.2 (d), 71.7 (d), 59.4 (t),
58.4 (t), 36.8 (t), 35.4 (t), 27.0 (q), 26.8 (q), 25.9 (q), 19.4 (s), 18.9
(s), 18.2 (s), −5.4 (q). HRMS: calcd for C53H70N4O6SSi3 974.4324,
found 974.4319.
Synthesis of (R)-Methyl 7-((tert-butyldiphenylsilyl)oxy)-8-
((4-methoxybenzyl)oxy)oct-4-ynoate (18). To a magnetically
stirred solution of 17 (2.45 g, 3.57 mmol) in THF (10 mL) at rt
were added H2O (10 mL) and K2CO3 (1.51 g, 10.9 mmol). After 16 h
of stirring at rt, the reaction was quenched with saturated aq NaHSO4
(20 mL), H2O (20 mL), and CH2Cl2 (20 mL). The aqueous layer was
extracted with CH2Cl2 (4 × 30 mL), and the combined organic layers
were washed with brine, dried over Na2SO4, filtered, and concentrated
under vacuum. The residue was dissolved in acetone (20 mL), and
under stirring at rt K2CO3 (750 mg, 5.43 mmol) and MeI (2.3 mL,
36.6 mmol) were added. After 20 h of stirring at rt the reaction was
filtered, and the residue was washed with Et2O (20 mL). The filterate
was concentrated under vacuum, and the residue was recovered with
Et2O (30 mL) and H2O (30 mL). The aqueous layer separated was
extracted with Et2O (3 × 40 mL), and the combined organic layers
were washed with brine, dried over Na2SO4, filtered, and concentrated
under vacuum. The residue was purified by flash chromatography on
silica gel (hexane/EtOAc 95/5 as eluent) to afford the product 18 as a
limpid yellowish oil (1.53 g, yield =79%). TLC (SiO2): Rf = 0.30
(hexane/EtOAc 95/5). [α]21D = +2.0 (c = 3.6, CH2Cl2). FTIR (neat):
1
3448, 2933, 1735, 1654, 1618, 1560, 1509, 1458, 1174, 823 cm−1. H
NMR (300 MHz, CDCl3): δ (ppm) = 7.75−7.65 (m, 4H), 7.50−7.30
(m, 6H), 7.20−7.10 (d, J = 8.6 Hz, 2H), 6.90−6.80 (d, J = 8.6 Hz,
2H), 4.42−4.27 (m, 2H), 4.02−3.90 (m, 1H), 3.82 (s, 3H), 3.65 (s,
3H), 3.53−3.40 (m, 2H), 2.50−2.25 (m, 6H), 1.10 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ (ppm) = 172.5 (s), 159.0 (s), 135.9 (d), 135.9
(d), 134.0 (s), 133.9 (s), 130.5 (s), 129.6 (d), 129.5 (d), 129.2 (d),
127.5 (d), 113.6 (d), 79.8 (s), 77.5 (s), 72.8 (t), 72.7 (t), 70.9 (d),
55.2 (q), 51.7 (q), 33.6 (t), 26.9 (q), 24.5 (t), 19.3 (s), 14.7 (t).
HRMS: calcd for C33H40O5Si 544.2645, found 544.2648
Synthesis of (R)-Triisopropylsilyl 7-hydroxy-8-((4-methoxy-
benzyl)oxy)oct-4-ynoate (16). To a magnetically stirred solution of
9 (2.75 g, 10.8 mmol) in dry THF (40 mL) under Ar at −78 °C was
added dropwise n-BuLi (6.75 mL, 10.8 mmol). After 1 h, BF3·Et2O
(1.35 mL, 10.7 mmol) was added, and after 10 min, 8 (1.05 g, 5.41
mmol) in dry THF (5 + 5 mL) was added. The reaction was
monitored by TLC (hexane/EtOAc 8/2) and was quenched after 2 h
at −78 °C with saturated aq NH4Cl (60 mL) and CH2Cl2 (70 mL).
The aqueous layer was extracted with CH2Cl2 (4 × 70 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash
chromathography (hexane/EtOAc 9/1 as eluent) to afford the pure
product 25 as a pale yellow oil (1.72 g, yield =71%). TLC (SiO2): Rf =
Synthesis of (R)-Methyl 7-((tert-Butyldiphenylsilyl)oxy)-8-
hydroxyoct-4-ynoate (19). To a magnetically stirred solution of
18 (1.53 g, 2.81 mmol) in CH2Cl2 (20 mL) at rt were added H2O (7
mL) and DDQ (783 mg, 3.45 mmol). The reaction was completed
after 1 h 45 min and was quenched with saturated aqueous NaHCO3
(20 mL). The aqueous layer was extracted with Et2O, and the
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated under vacuum. The residue was purified by
flash chromatography (hexane/EtOAc 9/1 to 8/2 as eluent) to afford
the product 19 as a colorless oil (1.05 g, yield = 88%). TLC (SiO2): Rf
= 0.25 (hexane/EtOAc 8/2). [α]21D = −24.8 (c = 1.24, CH2Cl2). FTIR
(neat): 3467, 2932, 2858, 1740, 1473, 1428, 1364, 1167, 1112, 1047,
0.24 (hexane/EtOAc 9/1). [α]21 = −6.5 (c = 0.71, CH2Cl2). FTIR
D
(neat): 3430, 2946, 2868, 1718, 1613, 1514, 1466, 1369, 1248, 1174,
1
1105, 1037, 883, 820, 735 cm−1. H NMR (300 MHz, CDCl3): δ
(ppm) = 7.32−7.25 (m, 2H), 6.95−6.85 (dd, J = 6.6, 2.1 Hz, 2H),
4.55−4.45 (s, 2H), 3.95−3.85 (m, 1H), 3.83 (s, 3H), 3.63−3.53 (dd, J
= 9.5, 4.0 Hz, 1H), 3.50−3.42 (dd, J = 9.5, 6.7 Hz, 1H), 2.60−2.52 (m,
2H), 2.52−2.43 (m, 2H), 2.42−2.35 (m, 2H), 2.35−2.20 (bs, 1H),
1.40−1.20 (m, 3H), 1.15−1.05 (m, 18H). 13C NMR (75 MHz,
CDCl3): δ (ppm) = 172.0 (s), 159.3 (s), 130.0 (s), 129.4 (d), 113.8
(d), 81.0 (s), 77.2 (s), 73.0 (t), 72.7 (t), 69.0 (d), 55.3 (q), 35.4 (t),
23.8 (t), 17.7 (q), 15.1 (t), 11.9 (d). HRMS: calcd for C25H40O5Si
448.2645, found 448.2650
1
938, 822, 741, 703 cm−1. H NMR (300 MHz, CDCl3): δ (ppm) =
7.80−7.60 (m, 4H), 7.55−7.30 (m, 6H), 4.00−3.80 (m, 1H), 3.68 (s,
3H), 3.65−3.57 (d, J = 4.2 Hz, 2H), 2.50−2.35 (m, 5H), 2.35−2.20
(m, 1H), 1.95−1.65 (bs, 1H), 1.10 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ (ppm) = 172.5 (s), 135.8 (d), 135.7 (d), 133.5 (s), 129.9
(d), 129.9 (d), 127.8 (d), 127.7 (d), 80.3 (s), 77.2 (s), 72.4 (d), 65.5
Synthesis of (R)-Triisopropylsilyl 7-((tert-butyldiphenylsilyl)-
oxy)-8-((4-methoxybenzyl)oxy)oct-4-ynoate (17). To a magneti-
H
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The Journal of Organic Chemistry
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(t), 51.7 (q), 33.5 (t), 26.9 (q), 23.8 (t), 19.3 (s), 14.7 (t). HRMS:
calcd for C25H32O4Si 424.2070, found 424.2066.
Synthesis of (R,E)-Methyl 7-((tert-Butyldiphenylsilyl)oxy)-9-
((2R,3S,5R)-3-((tert-butyldiphenylsilyl)oxy)-5-((S)-1-((tert-butyl-
diphenylsilyl)oxy)-3-oxopropyl)tetrahydrofuran-2-yl)non-8-
en-4-ynoate (5). Primary alcohol 21 (87.0 mg, 0.0823 mmol) was
dissolved in dry CH2Cl2 (1 mL) under Ar, and Dess−Martin
periodinane (41.7 mg, 0.0983 mmol) was added at rt. The reaction
was stirred at rt for 45 min and was quenched with saturated aq
Na2S2O3 (3 mL), saturated aq NaHCO3 (3 mL), and H2O (3 mL).
The suspension was diluted with MTBE (6 mL), and the layers were
separated.
The aqueous layer was extracted with MTBE/hexane 9:1 (3 × 6
mL), and the organic layers were dried over Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel using hexane/EtOAc 9/1 as eluent to
afford the product 5 as a pale yellow oil (87.0 mg, yield = quantitative).
1H NMR (300 MHz, CDCl3): δ (ppm) = 9.60−9.55 (t, J = 2.3 Hz,
1H), 7.79−7.24 (m, 30H), 5.63 (t, J = 10.2 Hz, 1H), 4.91 (t, J = 10.3
Hz, 1H), 4.53 (m, 1H), 4.19−3.97 (m, 3H), 3.83−3.76 (m, 1H),
3.73−3.68 (s, 3H), 2.48−2.33 (m, 6H), 2.18−1.98 (m, 2H), 1.69−
1.61 (m, 1H), 1.35−1.21 (m, 1H), 1.07 (s, 9H), 1.02 (s, 9H), 0.98 (s,
9H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 201.0, 172.5, 135.9,
135.7, 135.6, 134.5, 133.6, 133.2, 133.2, 129.9, 129.7, 129.7, 129.6,
129.5, 128.1, 127.7, 127.6, 127.5, 127.5, 82.0, 80.7, 79.9, 77.9, 77.4,
71.7, 67.3, 53.4, 51.6, 47.9, 37.9, 33.6, 28.7, 26.9, 26.8, 19.3, 19.2, 18.9,
14.7. ESI: 1078 (M + Na+).
Synthesis of (R)-Methyl 7-((tert-Butyldiphenylsilyl)oxy)-8-
oxooct-4-ynoate (7). To a magnetically strirred solution of alcohol
19 (250 mg, 0.586 mmol) in dry CH2Cl2 (5 mL) was added Dess−
Martin periodinane (DMP) (281 mg, 0.663 mmol). The reaction was
completed after 2 h and was quenched with H2O (10 mL), MTBE (70
mL), saturated aq NaHCO3 (35 mL), and saturated aq Na2S2O3 (35
mL). The layers were separated, and the aqueous layer was extracted
with MTBE/hexane 9/1. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under vacuum. The residue was
filtered on silica gel (hexane/EtOAc 9/1 as eluent) to afford the
product 7 as colorless oil (185 mg, yield = 75%) that was submitted to
the next step without further purification.
Sunthesis of (R,E)-Methyl 7-((tert-Butyldiphenylsilyl)oxy)-9-
((2R,3S,5R)-3-((tert-butyldiphenylsilyl)oxy)-5-((S)-2,2,9,9,10,10-
hexamethyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecan-5-yl)-
tetrahydrofuran-2-yl)non-8-en-4-ynoate (20). Sulfone 6 (171
mg, 0.175 mmol) was dissolved in dry DME (3 mL) under Ar. The
solution was cooled to −65 °C and KHMDS (390 mL, solution 0.5 M
in toluene, 0.195 mmol) added dropwise. After 40 min, a solution of 7
(101 mg, 0.239 mmol) in dry DME (1.5 mL) under Ar was added
dropwise to the reaction. The reaction mixture was stirred at −65 °C
for 1 h and then allowed to reach rt. The reaction was quenched with
saturated aq NH4Cl (5 mL), H2O (5 mL), and Et2O (10 mL). The
layers were separated, and the aqueous layer was extracted with Et2O
(3 × 10 mL). The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated under vacuum. The
residue was purified by column chromatography on silica gel using
hexane/EtOAc 98/2 to afford the pure product 20 (123 mg, yield =
60%). TLC (SiO2): Rf = 0.2 (hexane/EtOAc 98/2). [α]21D = −26.5 (c
= 1.39, CH2Cl2). FTIR (neat): 2931, 2858, 1743, 1473, 1428, 1362,
1256, 1112, 938, 823, 776, 740, 702 cm−1. 1H NMR (300 MHz,
CDCl3): δ (ppm) = 7.76−7.20 (m, 30H), 5.65 (t, J = 10.2 Hz, 1H),
4.99 (t, J = 10.4 Hz, 1H), 4.57 (dt, J = 8.8, 4.6 Hz, 1H), 4.04−3.96 (m,
2H), 3.91−3.82 (m, 2H), 3.68 (s, 3H), 3.53−3.39 (m, 2H), 2.47−2.34
(m, 4H), 2.18−1.96 (m, 2H), 1.68−1.45 (m, 4H), 1.08 (s, 9H), 0.99
(s, 9H), 0.97 (s, 9H), 0.83 (s, 9H), −0.06 (s, 3H), −0.07 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ (ppm) = 172.6 (s), 136.0 (d), 135.9 (d),
135.8 (d), 135.6 (d), 134.3 (d), 134.0 (s), 133.8 (s), 133.7 (s), 129.7
(d), 129.6 (d), 129.5 (d), 129.4 (d), 129.4 (d), 128.8 (d), 127.7 (d),
127.6 (d), 127.4 (d), 127.3 (d), 81.4 (d), 80.8 (d), 79.8 (s), 78.0 (d),
77.6 (s), 72.1 (d), 67.4 (d), 59.8 (t), 51.7 (q), 37.5 (t), 36.1 (t), 33.6
(t), 28.8 (t), 27.0 (q), 27.0 (q), 26.9 (q), 25.9 (q), 19.4 (s), 19.3 (s),
19.0 (s), 18.2 (s), 14.8 (t), −5.4 (q), −5.4 (q). HRMS: calcd for
C71H94O7Si4 1170.6077, found 1170.6075
Synthesis of (R,E)-Methyl 7-((tert-Butyldiphenylsilyl)oxy)-9-
((2R,3S,5R)-3-((tert-butyldiphenylsilyl)oxy)-5-((S,3Z,6Z)-1-((tert-
butyldiphenylsilyl)oxy)nona-3,6-dien-1-yl)tetrahydrofuran-2-
yl)non-8-en-4-ynoate (22). Phosphonium salt 422 (156.6 mg, 0.332
mmol) was dissolved in dry PhMe (1.7 mL) under Ar, and KHMDS
(650 μL, 0.325 mmol) was added dropwise at 0 °C. The suspension
was stirred for 45 min at 0 °C, and then the stirring was stopped in
order to separate the liquid layer from the solid residue. The red liquid
layer was transferred to another dry round-bottom flask under Ar and
was cooled to −95 °C. In another dry two-neck round-bottom flask
the compound 5 (87.0 mg, 0.0821 mmol) was dissolved in dry PhMe
(1.5 mL) under Ar, and the solution was cooled to −78 °C. The
solution of the aldehyde was added to the solution of the ylide
dropwise, and the solution was allowed to reach rt. The reaction was
monitored by TLC (hexane/EtOAc 8/2), and when it was complete,
the reaction was stirred at rt for 15 min and was quenched with
saturated aq NH4Cl (5 mL) and Et2O (5 mL). The layers were
separated, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated under vacuum. The residue was
purified by column chromatography on silica gel using hexane,
hexane/Et2O 98/2, hexane/Et2O 95/5 as eluent to afford the product
22 (68.5 mg, yield = 74%). TLC (SiO2): Rf = 0.25 (hexane/Et2O 95/
5). [α]21D = −11.4 (c = 1.37, CH2Cl2). FTIR (neat): 2932, 1743, 1654,
Synthesis of (R,E)-Methyl 7-((tert-Butyldiphenylsilyl)oxy)-9-
((2R,3S,5R)-3-((tert-butyldiphenylsilyl)oxy)-5-((S)-1-((tert-
butyldiphenylsilyl)oxy)-3-hydroxypropyl)tetrahydrofuran-2-
yl)non-8-en-4-ynoate (21). Compound 20 (120 mg, 0.102 mmol)
was solved in CH2Cl2/MeOH 1/1 (4 mL) and at rt was added PPTS
(33 mg, 0.123 mmol). The reaction was stirred for 6h and was
quenched with NaHCO3 (21 mg, 0.250 mmol), filtered and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel using hexane/EtOAc 9/1 as eluent to
afford the primary alcohol 21 as a slight yellow oil (92.4 mg, yield
1
1560, 1474, 1428, 1112, 823, 739, 702 cm−1. H NMR (300 MHz,
CDCl3): δ (ppm) = 7.78−7.24 (m, 30H), 5.68 (t, J = 10.1 Hz, 1H),
5.42−5.06 (m, 5H), 4.59 (m, 1H), 4.08−4.00 (m, 2H), 3.94−3.83 (m,
2H), 3.73−3.71 (s, 3H), 2.52−2.36 (m, 6H), 2.20−1.90 (m, 6H),
1.85−1.50 (m, 2H), 1.09 (s, 9H), 1.15−0.90 (m, 21H). 13C NMR (75
MHz, CDCl3): δ (ppm) = 172.6 (s), 136.1 (d), 136.0 (d), 135.9 (d),
135.8 (d), 135.6 (d), 134.4 (d), 133.8 (s), 133.7 (s), 133.6 (s), 133.5
(s), 133.2 (s), 131.9 (d), 130.0 (d), 129.7 (d), 129.6 (d), 129.5 (d),
129.4 (d), 128.8 (d), 127.5 (d), 127.4 (d), 127.4 (d), 127.0 (d), 124.9
(d), 81.3 (d), 79.8 (d), 78.1 (d), 77.5 (s), 73.8 (d), 67.4 (d), 51.6 (q),
35.3 (t), 33.6 (t), 32.3 (t), 28.7 (t), 27.0 (q), 26.9 (q), 26.9 (q), 25.5
(t), 20.5 (t), 19.3 (s), 19.0 (s), 14.7 (t), 14.3 (d). HRMS: calcd for
C71H88O6Si3 1120.5889, found 1120.5891.
Synthesis of (R,E)-Methyl 7-Hydroxy-9-((2R,3S,5R)-3-hy-
droxy-5-((S,3Z,6Z)-1-hydroxynona-3,6-dien-1-yl)tetrahydro-
furan-2-yl)non-8-en-4-ynoate (3). To a magnetically stirred
solution of silyl ether 22 (68.5 mg, 0.0611 mmol) in dry THF (1
mL) at rt, under Ar, was added TBAF (550 μL, 0.55 mmol). The
reaction was stirred at rt and was monitored by TLC (silica gel RP-18,
MeOH/H2O 7/3). When the reaction was complete, AcOH was
added (33 μL, 0.58 mmol), and the solvent was removed under
vacuum. The residue was dissolved in EtOAc (2 mL), and CH2N2 in
=86%). TLC (SiO2): Rf = 0.25 (hexane/EtOAc 9/1). [α]21 = −35.0
D
(c = 1.07, CH2Cl2). FTIR (neat): 2932, 1742, 1474, 1428, 1363, 1112,
1
937, 823, 740, 702 cm−1. H NMR (300 MHz, CDCl3): δ 7.76−7.24
(m, 30H), 5.59 (t, J = 10.3 Hz, 1H), 4.91 (t, J = 10.2 Hz, 1H), 4.51 (m,
1H), 4.13−4.01 (m, 2H), 3.79−3.75 (m, 1H), 3.68−3.45 (m, 6H),
2.47−2.34 (m, 4H), 2.21−1.96 (m, 3H), 1.75−1.61 (m, 3H), 1.36−
1.26 (m, 1H), 1.06 (s, 9H), 1.01 (s, 9H), 0.99 (s, 9H). 13C NMR (75
MHz, CDCl3): δ (ppm) = 172.5 (s), 135.9 (d), 135.7 (d), 135.6 (d),
134.3 (d), 134.2 (d), 133.8 (s), 133.7 (s), 133.6 (s), 133.5 (s), 133.2
(s), 129.7 (d), 129.6 (d), 129.5 (d), 128.3 (d), 127.6 (d), 127.5 (d),
82.3 (d), 80.9 (d), 79.9 (s), 78.0 (d), 74.6 (d), 67.3 (d), 59.1 (t), 51.7
(q), 38.4 (t), 37.6 (t), 33.6 (t), 28.7 (t), 27.0 (q), 26.9 (q), 26.9 (q),
19.3 (s), 19.3 (s), 19.0 (s), 14.7 (t). HRMS: calcd for C65H80O7Si3
1056.5830, found 1056.5829
I
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Et2O was added at 0 °C until the solution became yellow. The solvent
was removed under vacuum, and the residue was purified by column
chromatography on silica gel using hexane/EtOAc 4/6 as eluent to
afford the pure product 3 (14 mg, yield =55%). TLC (SiO2): Rf = 0.23
(hexane/EtOAc 4/6). [α]21D = +41.7 (c = 0.41, MeOH). FTIR (neat):
3402, 2921, 1734, 1438, 1169, 1038 cm−1. 1H NMR (300 MHz,
CDCl3): δ (ppm) = 5.75−5.20 (m, 6H), 4.75−4.55 (m, 2H), 4.30−
4.05 (m, 2H), 3.95−3.80 (m, 1H), 3.72 (s, 3H), 2.90−2.70 (m, 3H),
2.60−2.35 (m, 6H), 2.30−2.15 (m, 3H), 2.15−1.95 (m, 2H), 1.95−
1.50 (m, 3H), 1.15−0.95 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ (ppm) = 172.9 (s), 134.2 (d), 132.2 (d), 131.1 (d), 130.9
(d), 126.7 (d), 124.9 (d), 82.5 (d), 81.2 (d), 81.0 (s), 77.2 (s), 77.1
(d), 71.0 (d), 66.7 (d), 51.9 (q), 33.5 (t), 33.2 (t), 30.8 (t), 27.5 (t),
25.6 (t), 20.6 (t), 14.7 (t), 14.2 (q). HRMS: calcd for C23H34O6
406.2355, found 406.2345.
Synthesis of (R,4Z,8E)-Methyl 7-Hydroxy-9-((2R,3S,5R)-3-
hydroxy-5-((S,3Z,6Z)-1-hydroxynona-3,6-dien-1-yl)tetrahydro-
furan-2-yl)nona-4,8-dienoate (23). To a magnetically stirred
solution of 3 (9.5 mg, 0.023 mmol) in hexane/EtOAc 1:1 (2 mL),
were added quinoline (2 μL) and Lindlar catalyst (palladium on
calcium carbonate poisoned with lead, 1 mg). The suspension was
stirred at rt under H2 atmosphere. The reaction was monitored by
TLC (silica gel RP-18, MeOH/H2O 6/4) and after 30 min was
completed. The suspension was filtered, and the solvent was removed
under vacuum. The residue was purified by column chromatography
(silica gel RP-18, MeOH/H2O 6:4 to 7:3 as eluent) to afford the
6/4). [α]21 = +26.4 (c = 0.27, CH2Cl2). 1H NMR (300 MHz,
D
CDCl3): δ (ppm) = 5.68−5.29 (m, 6H), 4.65−4.54 (m, 2H), 4.23−
4.11 (m, 2H), 3.90−3.85 (m, 1H), 3.69−3.66 (s, 3H), 2.84−2.74 (m,
2H), 2.48−2.00 (m, 13H) 1.86 (dt, J = 6.6, 3.3 Hz, 1H), 0.99 (t, J =
7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 174.2 (s), 135.2
(d), 132.2 (d), 131.2 (d), 130.0 (d), 126.7 (d), 124.9 (d), 82.7 (d),
81.1 (d), 77.2 (d), 71.1 (d), 68.1 (d), 51.8 (q), 35.1 (t), 33.7 (t), 33.5
(t), 30.9 (t), 25.7 (t), 22.7 (t), 20.6 (t), 14.2 (q). ESI-MS m/z 433.33
[(M + Na)+, 100].
Synthesis of 4,5-Dideuterio-7-epi-ST-Δ8-10-NeuroF 2. To a
magnetically stirred solution of ester 24 (4 mg, 0.010 mmol) in
HPLC-grade MTBE (800 μL) was added HPLC-grade H2O (9 μL, 0.5
mmol). To the resulting stirred solution was added solid-supported
CAL-B (6 mg), and the suspension was stirred at rt for 24 h. The
enzyme was filtered off over a sintered glass funnel, the solid was
carefully washed with MeCN−MTBE, and the solution was
concentrated under vacuum. The residue was purified by column
chromatography using silica gel RP-18 (MeOH/H2O 6:4 as eluent) to
afford the product 2 (3.2 mg, yield = 81%). TLC (silica gel RP-18): Rf
1
= 0.30 (MeOH/H2O 6/4). [α]21 = +25.45 (c = 0.22, MeOH). H
D
NMR (300 MHz, CD3OD): δ (ppm) = 5.54−5.34 (m, 6H), 4.57−
4.50 (m, 2H), 4.05−4.02 (m, 2H), 3.63 (m, 1H), 2.83−2.80 (m, 2H),
2.35−2.05 (m, 11H), 1.88 (ddd, J = 12.9, 6.4, 3.4 Hz, 1H), 0.99 (t, J =
7.5 Hz, 3H). 13C NMR (75 MHz, CD3OD): δ (ppm) = 177.7 (s),
136.3 (d), 133.1 (d), 131.5 (d), 131.3 (d), 128.5 (d), 127.1 (d), 83.8
(d), 82.8 (d), 78.3 (d), 74.3 (d), 68.6 (d), 36.6 (t), 35.4 (t), 33.1 (t),
31.1 (t), 26.9 (t), 24.3 (t), 21.8 (t), 14.9 (q). ESI-MS m/z 791.70
[(2M − H)−, 100]; 419.19 [(M + Na)+, 100]. HRMS: calcd for
C23H34D2O6 396.2481, found 396.2478.
product 23 (7.5 mg, yield = 80%). TLC (silica gel RP-18): Rf = 0.23
1
(MeOH/H2O 6/4). [α]21 = +26.9 (c = 0.27, CH2Cl2). H NMR
D
(300 MHz, CDCl3): δ (ppm) = 5.64−5.29 (m, 8H), 4.65−4.56 (m,
2H), 4.21−4.12 (m, 2H), 3.89−3.86 (m, 1H), 3.72−3.68 (m, 3H),
2.82 (t, J = 6.9 Hz, 2H), 2.45−2.03 (m, 13H), 1.84 (ddd, J = 13.0, 6.4,
3.2 Hz, 1H), 0.99 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
(ppm) = 174.2 (s), 135.2 (d), 132.2 (d), 131.2 (d), 130.7 (d), 129.9
(d), 126.7 (d), 126.4 (d), 124.9 (d), 82.6 (d), 81.1 (d), 77.2 (d), 71.1
(d), 68.1 (d), 51.8 (q), 35.2 (t), 33.7 (t), 33.5 (t), 30.9 (t), 25.7 (t),
22.8 (t), 20.6 (t), 14.2 (q). ESI-MS m/z 409.3 [(M + H)+, 30], 431.6
[(M + Na)+, 100], 447.4 [(M + K)+, 18]. HRMS: calcd for C23H36O6
408.2512, found 408.2515.
Synthesis of Mosher Esters. Separation of Tetrahydrofuran
10b via Silyl Ether 12a. To a magnetically stirred solution of 10 and
10a (73 mg, 0.343 mmol, from entry 7, Table 1) in dry CH2Cl2 (4
mL) under Ar were added at rt imidazole (59 mg, 0.860 mmol) and
TBDPSCl (110 μL, 0.411 mmol). The reaction was completed after 6
h and was quenched with H2O (5 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (hexane/EtOAc 98/2, 95/5 and 9/1 as
eluent) to afford the desired product 12a (90 mg, yield = 59%). TLC
Synthesis of 7-epi-ST-Δ8-10-NeuroF 1. To a magnetically stirred
solution of methyl ester 23 (5.2 mg, 0.013 mmol) in HPLC-grade
MTBE (1 mL) was added HPLC-grade H2O (11 μL, 0.65 mmol). To
the resulting stirred solution was added solid supported CAL-B (5.2
mg), and the suspension was stirred at rt for 24 h. The enzime was
filtered off over a sintered glass funnel and the solid was carefully
washed with MeCN-MTBE and the solution was concentrated under
vacuum. The residue was purified by column chromatography using
silica gel RP-18 (MeOH/H2O 6/4 as eluent) to afford the product 1
(SiO2): Rf = 0.23 (hexane/EtOAc 9/1). [α]21 = +14.25 (c = 0.4,
D
CH2Cl2). FTIR (neat): 2932, 2858, 1741, 1428, 1232 1113, 1078,
1026, 740, 703 cm−1. 1H NMR (300 MHz, CDCl3): δ (ppm) = 7.71−
7.64 (m, 4H), 7.48−7.35 (m, 6H), 6.12 (ddd, J = 17.4, 10.2, 7.3 Hz,
1H), 5.83−5.67 (m, 2H), 5.35−5.24 (m, 2H), 4.78−4.73 (m, 1H),
4.53 (d, J = 5.1 Hz, 2H), 4.48 (m, 1H), 4.32 (dd, J = 7.3, 3.8 Hz, 1H),
2.04 (s, 3H), 1.92 (ddd, J = 13.0, 6.0, 2.0 Hz, 1H), 1.64−1.55 (m, 1H),
1.09 (s, 9H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 170.7 (s), 135.9
(d), 135.8 (d), 135.2 (d), 135.0 (d), 134.0 (s), 133.3 (s), 129.8 (d),
127.7 (d), 127.6 (d), 125.3 (d), 117.8 (t), 84.5 (d), 75.8 (d), 64.2 (t),
41.8 (t), 26.9 (3q), 20.9 (q), 19.3 (s). HRMS: calcd for C27H34O4Si
450.2226, found 450.2231.
Synthesis of Pure 10a. To a magnetically stirred solution of 12a
(60 mg, 0.133 mmol) in dry THF (2 mL) under Ar was added TBAF
(270 μL, 0.266 mmol) at 0 °C. The reaction was stirred at rt until
complete conversion. The reaction was quenched with saturated aq
NH4Cl (2 mL) and was diluted with Et2O (2 mL). The layers were
separated, and the aqueous layer was extracted with Et2O (3 × 5 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated under vacuum. The residue was
purified by column chromatography on silica gel (hexane/EtOAc 6/4
as eluent) to afford the product 10a (26 mg, yield = 92%). TLC
(SiO2): Rf = 0.28 (hexane/EtOAc 6/4).
(4.0 mg, yield = 78%). TLC (silica gel RP-18): Rf = 0.30 (MeOH/
1
H2O 6/4). [α]21 = +25.5 (c = 0.22, MeOH). H NMR (300 MHz,
D
CD3OD): δ (ppm) = 5.57−5.30 (m, 8H), 4.58−4.50 (m, 2H), 4.10−
4.01 (m, 2H), 3.66−3.60 (m, 1H), 2.83 (t, J = 5.8 Hz, 2H), 2.41−2.04
(m, 11H), 1.88 (ddd, J = 12.9, 6.4, 3.3 Hz, 1H), 0.99 (t, J = 7.5 Hz,
3H). 13C NMR (75 MHz, CD3OD): δ (ppm) = 136.3 (d), 133.1 (d),
132.0 (d), 131.4 (d), 131.3 (d), 128.5 (d), 127.2 (d), 127.1 (d), 83.8
(d), 82.8 (d), 78.3 (d), 74.3 (d), 68.7 (d), 37.0 (t), 36.8 (t), 36.7 (t),
33.1 (t), 26.9 (t), 25.1 (t), 21.8 (t), 15.0 (q). ESI-MS m/z 393.3 [(M
− -H)−, 100], 788.0 [(2M − H)−, 82]. HRMS: calcd for C22H34O6
394.2355, found 394.2358.
Synthesis of (R,4Z,8E)-Methyl 7-Hydroxy-9-((2R,3S,5R)-3-
hydroxy-5-((S,3Z,6Z)-1-hydroxynona-3,6-dien-1-yl)tetrahydro-
furan-2-yl)-4,5-dideuterionona-4,8-dienoate (24). To a magneti-
cally stirred solution of 3 (8 mg, 0.020 mmol) in hexane/AcOEt 1/1
(2 mL), were added quinoline (2 μL) and Lindlar catalyst (palladium
on calcium carbonate poisoned with lead, 1 mg). The suspension was
stirred at rt under D2 atmosphere. The reaction was monitored by
TLC (silica gel RP-18, MeOH/H2O 6/4) and after 30′ was completed.
The suspension was filtered and the solvent was removed under
vacuum. The residue was purified by column chromatography (silica
gel RP-18, MeOH/H2O 6/4 to 7/3 as eluent) to afford the product 24
(6 mg, yield =73%). TLC (Silica gel RP-18): Rf = 0.23 (MeOH/H2O
Synthesis of Mosher Ester of 10a with (S)-(+)-α-Methoxy-α-
trifluoromethylphenylacetyl Chloride. General method: To a
magnetically stirred solution of 10a (8 mg, 0.038 mmol) in dry
CH2Cl2 (1 mL) under Ar were added at 0 °C pyridine (12 μL, 0.152
mmol) and (S)-(+)-MTPA-Cl (14 μL, 0.076 mmol). The reaction was
allowed to reach rt and was quenched after 4 h with saturated aq
NaHCO3 (2 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
J
dx.doi.org/10.1021/jo4004647 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5 mL), and the combined organic layers were washed with saturated
aq CuSO4, dried over Na2SO4, filtered, and concentrated under
vacuum. The residue was purified by column chromatography on silica
gel (hexane/EtOAc 8/2 as eluent) to afford the Mosher ester (11 mg,
ASSOCIATED CONTENT
■
S
* Supporting Information
Nomenclature system for neurofurans; copies of H, 13C, and
HPLC profiles. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
yield = 68%). TLC (SiO2): Rf = 0.28 (hexane/EtOAc 8/2). [α]21
=
D
+34.16 (c = 0.57, CH2Cl2). FTIR (neat): 2951, 1748, 1498, 1452,
1
1369, 1241, 1170, 1124, 1082, 1028, 990, 896, 766, 717 cm−1. H
AUTHOR INFORMATION
Corresponding Author
*E-mail: gz@unipv.it.
Notes
■
NMR (300 MHz, CDCl3): δ (ppm) = 7.60−7.51 (m, 2H), 7.49−7.38
(m, 3H), 5.92−5.76 (m, 2H), 5.70−5.58 (m, 2H), 5.33 (dt, J = 17.0,
1.4 Hz, 1H), 5.13 (dt, J = 10.3, 1.4 Hz, 1H), 4.71−4.52 (m, 4H),
3.60−3.52 (s, 3H), 2.33 (ddd, J = 14.0, 6.1, 1.4 Hz, 1H), 2.19−2.01
(m, 4H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 170.7 (s), 165.7
(s), 133.6 (d), 132.2 (d), 131.8 (s), 129.7 (d), 128.4 (d), 127.4 (d),
126.3 (d), 125.1 (s), 121.3 (s) 118.9 (t), 82.3 (d), 78.3 (d), 77.6 (d),
63.9 (t), 55.4 (q), 39.4 (t), 20.9 (q). HRMS: calcd for C21H23F3O6
428.1447, found 428.1449.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Regione Lombardia (Direzione
■
Generale Sanita
̀
and Iniziativa Lombardia Eccellente), Fonda-
Synthesis of Mosher Ester of 10a with (R)-(−)-α-Methoxy-α-
trifluoromethylphenylacetyl Chloride. The Mosher ester was
prepared following the general method using (R)-(−)-MTPA-Cl as
zione di Piacenza e Vigevano, and MIUR (funds PRIN). We are
indebted to Prof. Barry M. Trost and Dr. Maurizio Franzini for
their advice.
acyl chloride. TLC (SiO2): Rf = 0.23 (hexane/EtOAc 9/1). [α]21
=
D
−7.27 (c = 0.22, CH2Cl2). FTIR (neat): 2951, 1748, 1498, 1452, 1369,
1241, 1170, 1124, 1082, 1028, 990, 896, 766, 717 cm−1. 1H NMR (300
MHz, CDCl3): δ (ppm) = 7.57−7.51 (m, 2H), 7.47−7.38 (m, 3H),
5.88−5.73 (m, 3H), 5.60 (t, J = 3.8 Hz, 1H), 5.38 (dt, J = 17.2, 1.4 Hz,
1H), 5.24 (dt, J = 10.4, 1.3 Hz, 1H), 4.64−4.50 (m, 4H), 3.56−3.53 (s,
3H), 2.25 (ddd, J = 14.0, 5.9, 1.3 Hz, 1H), 2.11−2.01 (m, 4H). 13C
NMR (75 MHz, CDCl3): δ (ppm) = 170.6 (s), 165.9 (s), 133.5 (d),
132.7 (d), 131.8 (s), 129.7 (d), 128.4 (d), 127.4 (d), 126.3 (d), 125.2
(s), 118.8 (t), 82.1 (d), 78.8 (d), 77.2 (d), 63.9 (t), 55.5 (q), 39.5 (t),
29.7 (s), 20.9 (q). HRMS: calcd for C21H23F3O6 428.1447, found
428.1448.
REFERENCES
■
(1) (a) Song, W.-L.; Lawson, J. A.; Reilly, D.; Rokach, J.; Chang, C.-
T.; Giasson, B.; FitzGerald, G. A. J. Biol. Chem. 2008, 283, 6. (b) For
the nomenclature systems of neurofurans, see: Taber, D. F.; Roberts,
L. J., II. Prostaglandins & Other Lipid Mediators 2005, 78, 14.
(c) Browne, S. E.; Jackson Roberts, L., II; Dennery, P. A.; Doctrow, S.
R.; Flint Beal, M.; Barlow, C.; Levine, R. L. Free Radical Biol. Med.
2004, 36, 938.
(2) (a) Jahn, U.; Galano, J.-M.; Durand, T. Angew. Chem., Int. Ed.
2008, 47, 5894. (b) Sayre, L. M.; Perry, G.; Smith, M. Chem. Res.
Toxicol. 2008, 21, 172. (c) Andersen, J. K. Nature Med. 2004, 10, S18.
See the Supporting Information for the nomenclature system.
(d) Taber, D. F.; Pan, Y.; Zhao, X. J. Org. Chem. 2004, 69, 7234.
Taber, D. F.; Pieming, G.; Li, R. J. Org. Chem. 2009, 74, 5516.
(3) (a) Randl, S.; Connon, S. J.; Blechert, S. Chem. Commun. 2001,
1796. (b) Morgan, J. P.; Morrill, C.; Grubbs, R. H. Org. Lett. 2002, 4,
67 Diol 11 was obtained in three steps, 45% isolated yield, from cis-
3,5-diacetoxycyclopent-1-ene.4.
(4) Jiang, L.; Burke, S. D. Org. Lett. 2002, 4, 3411.
(5) Organic bases such as Et3N and 1,1,3,3-tetramethylguanidine
were unable to accomplish the cyclization.
(6) (a) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17.
(b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. For the
application of the Mosher method to 2,5-disubstituted-3-hydroxyte-
trahydrofuran derivatives, see: Capon, R. J.; Barrow, R. A.; Rochfort,
S.; Jobling, M.; Skene, C.; Lacey, E.; Gill, J. H.; Friedel, T.; Wadsworth,
D. Tetrahedron 1998, 54, 2227.
Synthesis of Pure 10. Pure alcohol 10 was synthetized from the
starting material 12 (entry 2, Table 1) following the same procedure
described for the synthesis of the compound 10a from 12a. TLC
(SiO2): Rf = 0.28 (hexane/EtOAc 6/4).
Synthesis of the Mosher Ester of 10 with (S)-(+)-α-Methoxy-α-
trifluoromethylphenylacetyl Chloride. The Mosher ester was
prepared from the starting material 10 following the general method
using (S)-(+)-MTPA-Cl as acyl chloride. TLC (SiO2): Rf = 0.28
(hexane/EtOAc 8/2). [α]21D = +61.0 (c = 0.4, CH2Cl2). FTIR (neat):
2951, 1748, 1498, 1452, 1369, 1241, 1170, 1124, 1082, 1028, 990, 896,
1
766, 717 cm−1. H NMR (300 MHz, CDCl3): δ (ppm) = 7.56−7.50
(m, 2H), 7.50−7.40 (m, 3H), 5.99−5.77 (m, 3H), 5.40 (dt, J = 17.1,
1.5 Hz, 1H), 5.32−5.22 (m, 2H), 4.59 (d, J = 5.0 Hz, 2H), 4.58−4.49
(m, 1H), 4.39 (dq, J = 5.4, 1.9 Hz, 1H), 3.59−3.52 (s, 3H), 2.30−1.87
(m, 5H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 170.6 (s), 166.1
(s), 135.3 (d), 132.9 (d), 131.8 (s), 129.8 (d), 128.5 (d), 127.3 (d),
127.1 (d), 125.1 (s), 121.3 (s), 117.1 (t), 84.4 (d), 80.9 (d), 78.5 (d),
63.9 (t), 55.4 (q), 37.4 (t), 20.9 (q). HRMS: calcd for C21H23F3O6
428.1447, found 428.1443.
(7) Hoffmann, R. W.; Kahrs, C. B.; Schiffer, J.; Fleischhauer, J. J.
Chem. Soc., Perkin Trans. 2 1996, 2407.
(8) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(b) Trost, B. M.; Machacek, B. M.; Aponick, M. R. Acc. Chem. Res.
2006, 39, 747. (c) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999,
121, 4545.
(9) (a) Mohapatra, D. K.; Dasari, P.; Rahaman, H.; Pal, R.
Tetrahedron Lett. 2009, 50, 6276. (b) Gao, Y.; Hanson, R. M.;
Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem.
Soc. 1987, 109, 5165.
(10) Maemoto, M.; Kimishima, A.; Nakata, T. Org. Lett. 2009, 11,
4814.
(11) Mitsunobu, O. Synthesis 1981, 1.
(12) Earl, H. A.; Stirling, C. J. M. J. Chem. Soc., Perkin Trans. 2 1987,
Synthesis of Mosher Ester of 10 with (R)-(-)-α-Methoxy-α-
trifluoromethylphenylacetyl Chloride. Prepared from the starting
material 10 following the general method using (R)-(−)-MTPA-Cl as
acyl chloride. TLC (SiO2): Rf = 0.28 (hexane/EtOAc 8/2). [α]21
=
D
−19.59 (c = 0.49, CH2Cl2). FTIR (neat): 2951, 1748, 1498, 1452,
1
1369, 1241, 1170, 1124, 1082, 1028, 990, 896, 766, 717 cm−1. H
NMR (300 MHz, CDCl3): δ (ppm) = 7.56−7.50 (m, 2H), 7.48−7.42
(m, 3H), 5.99−5.77 (m, 3H), 5.44 (dt, J = 17.1, 1.5 Hz, 1H), 5.29−
5.23 (m, 2H), 4.59 (d, J = 4.7 Hz, 2H), 4.54−4.46 (m, 2H), 3.59−3.55
(s, 3H), 2.14−1.93 (m, 5H). 13C NMR (75 MHz, CDCl3): δ (ppm) =
170.7 (s), 166.1 (s), 135.4 (d), 133.0 (d), 131.9 (s), 129.8 (d), 128.5
(d), 127.5 (d), 127.2 (d), 127.1 (d), 125.1 (s), 121.3 (s), 117.3 (t),
84.2 (d), 80.9 (d), 78.6 (d), 63.9 (t), 55.5 (q), 37.2 (t), 20.9 (q).
HRMS: calcd for C21H23F3O6 428.1447, found 428.1450.
1273.
(13) Gaunt, M. J.; Hook, D. F.; Tanner, H. R.; Ley, S. V. Org. Lett.
2003, 5, 4815.
(14) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(b) Seike, H.; Ghosh, I.; Kishi, Y. Org. Lett. 2006, 8, 3865.
(15) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
K
dx.doi.org/10.1021/jo4004647 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(16) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26. (b) For a review, see: Blakemore, P. R. J. Chem. Soc.,
Perkin Trans. 1 2002, 2563.
(17) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1989, 30, 19.
(18) Jacobo, S. H.; Chang, C.-T.; Lee, G.-J.; Lawson, J. A.; Powell, W.
S.; Pratico, D.; FitzGerald, G. A.; Rokach, J. J. Org. Chem. 2006, 71,
1370.
(19) Lindlar, H.; Dubuis, R. Org. Synth. 1973, 5, 880.
(20) Zanoni, G.; Valli, M.; Bendjeddou, L.; Porta, A.; Bruno, P.;
Vidari, G. J. Org. Chem. 2010, 75, 8311.
(21) Milne, G. L.; Gao, L.; Porta, A.; Zanoni, G.; Vidari, G.; Morrow,
J. D. J. Biol. Chem. 2005, 280, 25178.
(22) Kojioama, K.; Koyama, K.; Amemiya, S. Tetrahedron 1985, 41,
4449.
L
dx.doi.org/10.1021/jo4004647 | J. Org. Chem. XXXX, XXX, XXX−XXX