A unified stereodivergent strategy for prostaglandin and isoprostanoid synthesis

Article abstract of DOI:10.1021/jo500093k

Acetoxyfulvene surrended to asymmetric Diels-Alder cycloaddition, paving the way to the development of a unified strategy for the stereodivergent synthesis of both prostaglandins and isoprostanoids. In fact, the cycloadduct was subsequently converted to a common intermediate, which through two different stereoselective pathways afforded the two lactones 1 and 2, which are key building blocks in the synthesis of prostaglandins and isoprostanoids, respectively.

Full text of DOI:10.1021/jo500093k

Article
pubs.acs.org/joc
A Unified Stereodivergent Strategy for Prostaglandin and
Isoprostanoid Synthesis
Matteo Valli, Francesco Chiesa, Andrea Gandini, Alessio Porta, Giovanni Vidari, and Giuseppe Zanoni*
Department of Chemistry, University of Pavia, Viale Taramelli, 10, 27100 Pavia, Italy
S
* Supporting Information
ABSTRACT: Acetoxyfulvene surrended to asymmetric Diels−
Alder cycloaddition, paving the way to the development of a
unified strategy for the stereodivergent synthesis of both
prostaglandins and isoprostanoids. In fact, the cycloadduct was
subsequently converted to a common intermediate, which
through two different stereoselective pathways afforded the two
lactones 1 and 2, which are key building blocks in the synthesis of
prostaglandins and isoprostanoids, respectively.
1. INTRODUCTION
Prostaglandins (PGs) and isoprostanoids, such as isoprosta-
glandins (IsoPGs) and neuroprostanes (NeuroPs), are naturally
occurring metabolites derived from oxidation of polyunsatu-
rated fatty acids (PUFA).1 Mother Nature efficiently produces
both prostaglandins and series-2 isoprostaglandins from the
same precursor, i.e., arachidonic acid (AA), via two different
pathways: prostaglandins are formed through an enzymatic
cyclooxygenase (COX) controlled reaction cascade, while a
non-enzymatic free radical peroxidation of membrane-bound
AA, triggered by reactive oxygen species (ROS), leads to the
corresponding isoprostanes. As a consequence of these two
different pathways, the different relative stereochemistry of the
two side chains, i.e., trans vs cis, and the enantioselectivity of the
enzymatic vs the non-enzymatic transformations stand as
characteristic features of the two types of compounds (Figure
1).
Figure 1. Comparison between Nature and modern synthetic
chemistry for prostaglandin and isoprostanoid synthesis.
Thus, enzymatic transformation of AA affords only one
enantiopure stereomeric series of prostaglandins; instead, non-
enzymatic AA oxidation affords all possible stereoisomeric
isoprostanes in racemic form. A similar non-enzymatic radical
Moreover, the inversion of the configuration at C-12 of
lactone 1 to provide the all-cis stereochemistry of isoprosta-
noids is not a trivial task, since it is a counter-thermodynamic
transformation. In fact, the prostaglandin trans orientation of
mechanism leads to the formation of neuroprostanes by
peroxidation of docosahexaenoic acids (DHA).1
The potent pharmacological and biological activities of
prostaglandins and isoprostanes, respectively, have stimulated
the development of new methods of synthesis for a long
time.1,2
the two side chains is more stable than the cis stereochemistry
typical of isoprostanoids.1
In this communication we describe a unified strategy for the
synthesis of prostaglandins and isoprostanoids, which is based
on the common key building block 3. This is, indeed, a key
issue for a practicable divergent synthetic approach to the two
isomeric families, since we envisioned two efficient routes to
convert 3 into either Corey lactone 1 or lactone 2. The latter
compound was shown by us to be a versatile starting material
Modern synthetic approaches to prostaglandins are based
upon the monumental work of E. J. Corey, which is centered
on the Corey aldehyde-lactone 1 as a common building block.
This compound was prepared in an enantioselective fashion via
an atom-economical asymmetric Diels−Alder reaction.2
On the other hand, different avenues have been developed
for the total syntheses of isoprostanoids;1 however, none of
them resembles the Corey general atom economy strategy,
namely, the Diels−Alder approach.3
Received: January 15, 2014
Published: February 19, 2014
© 2014 American Chemical Society
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for the construction of several isoprostanes and neuro-
prostanes.4
Chart 1. Performance of a Group of C2-Symmetric
Bis(oxazoline) Ligands in the Enantioselective Diels−Alder
The bicyclo[2.2.1]heptane backbone of compound 3 was
ultimately assembled via an unprecedented asymmetric Diels−
Alder reaction between 6-acetoxyfulvene and 3-acryloyloxazo-
lidin-2-one, promoted by a catalytic amount of a chiral
bisoxazoline-Mg complex (Figure 1). Moreover, the following
conversion of 3 into lactones 1 and 2 was realized through a
careful control of the configuration at C-12 of the bicyclic
system to achieve either the prostaglandin or the isoprostanoid
stereochemistry.
Cycloaddition between Acetoxyfulvene and 3-Acryloyl-1,3-
a
oxazolidin-2-one
2. RESULTS AND DISCUSSION
The first example of 6-acetoxyfulvene [4π + 2π] cycloaddition,
using 2-chloroacrylonitrile as a dienophile, was reported by ICI
Ltd. chemists in their alternative route to the Corey aldehyde;5
however, the beauty of this approach was plagued in the
original work by a troublesome resolution of diastereomeric
salts, in order to achieve enantiopure compounds.6
Despite some advantages of this strategy,7 no asymmetric
variant of this useful transformation nor examples of
enantioselective fulvene cycloaddition have been reported to
date.2b,8 In this context, our first attempt to use copper(II) as a
Lewis acid catalyst for the cycloaddition of 6-acetoxyfulvene to
2-chloroacrylonitrile9 proved to be unsuccessful. Actually, we
observed extensive decomposition of the diene, even at −30
°C, while no reaction was observed by reducing the reaction
temperature to −78 °C.
We reasoned that the Lewis acid preferentially coordinated
to the diene rather than to the dienophile, thus decreasing the
HOMOdiene energy and consequently reducing the overall
Diels−Alder rate. A dienophile with greater aptitude for Lewis
acid coordination was then identified in the bidentate 3-
acryloyloxazolidin-2-one, which is known to form highly
organized complexes with an ample class of Lewis acids.10 In
the event, a few representative Lewis acids of moderate strength
were found to induce a significant acceleration of the reaction
compared to the thermal uncatalyzed version. After some trials,
Mg(ClO)4 and Cu(OTf)2 (Tf = CF3SO2) were selected for
further enantioselective experiments (Table 1).
a
MS = molecular sieves, MX2 metal salt (see text).
adduct 4 in 90% isolated yield with 95% ee and endo/exo ratio
>99:1. Enantiomeric excesses and endo/exo ratios were
determined by chiral HPLC on a Chiralpak IA-3 column,
after conversion of cycloadduct 4 into methyl ester acetal 3, as
detailed below. Under this condition, the exo isomer was not
detected. The enantiomeric excess of the endo cycloadduct was
then increased using the combination of Cu(OTf)2 and ligand
(S)-L4 (Chart 1), which afforded the endo adduct 4 in 92%
isolated yield and 98% ee, albeit with slightly lower
diastereoselectivity (endo/exo 97:3).
The absolute stereochemistry of (1S,2S,4S)-cycloadduct 4
was established by comparing the optical rotation of the
corresponding bicyclo[2.2.1]oxazolidinone derivative 6
(Scheme 1) with the literature.13 Norbornane 6 was obtained
from cycloadduct 4, via Ir(I)-mediated decarbonylation of free
aldehyde 5 (Scheme 1).14
Table 1. Lewis Acid Promoted Diels−Alder Reaction
between Acetoxyfulvene and 3-Acryloyl-1,3-oxazolidin-2-one
a
To Afford Cycloadduct 4
entry
catalyst
yield (%)
endo/exo
1
2
3
4
5
6
Mg(ClO4)2
89
51
35
57
34
70
80:20
77:23
81:19
49:51
81:19
MgBr2
In order to gain insight into the high endo preference for the
complex Mg(ClO4)2-(R,R)-L1, DFT calculations were carried
out using the B3LYP method with the 6-31G(d,p) basis set for
Mg(OSO2CF3)2
Zn(ClO4)2
Zn(OSO2CF3)2
Cu((OSO2CF3)2
b
85:15
Scheme 1. Absolute Configuration Determination of
Cycloadduct 4
a
Reactions were carried out at rt with metal catalyst (30 mol %) and 4
a
b
Å molecular sieves in CH2Cl2. Reaction was carried out at 4 °C.
Indeed, compared with other catalysts, both Mg(ClO4)2 and
Cu(OTf)2 afforded cycloadducts in better yields and higher
endo/exo selectivity (determined by HPLC), respectively.
Buoyed by the ligand-accelerated catalysis concept,11 chiral
C2-symmetric bis(oxazoline) ligands were selected on the basis
of their ability to promote the Diels−Alder reaction in a
catalytic asymmetric fashion.12 Indeed, the combination of
Mg(ClO4)2 and ligand (R,R)-L1 (Chart 1) afforded the endo
a
Reagents and conditions: (a) MeOH, cat. PTSA, 60 °C, 3 h, 80%; (b)
[IrCl(cod)2], Ph3P, dioxane, 110 °C, 24 h, 30%.
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Figure 2. Transition states for the Mg(ClO4)2-(R,R)-L1 catalyzed Diels−Alder cycloaddition between acetoxyfulvene and 3-acryloyloxazolidin-2-
one. The two low-energy orientations of the diene inside the catalyst chiral cavity are shown.
H, O, N, C and the 6-31+G(d,p) basis set for the Mg cation
(for computational details see the Supporting Information).
Calculations for the reaction leading to the exo adduct were
unable to locate the corresponding transition state (TS), which
might be due to steric hindrance between the acetoxy group of
fulvene and one of the phenyl group on the (R,R)-L1 ligand.
On the other hand, two endo TSs could be located on the
potential energy surface, which corresponded to two different
orientations of the diene inside the catalyst chiral cavity, both
positioning the acetoxy group far from the phenyl ring (Figure
2).
Scheme 2. Preparation of Key Intermediates for
Prostaglandin Synthesis
a
The energy difference between TS-A and TS-B was only 1
kcal/mol; however, both TS geometries clearly showed that
acetoxyfulvene attacked the more accessible C(α) re diastereo-
face of the dienophile.
Although the complex Cu(II)-(S)-L4 provided an almost
complete enantiocontrol for the endo adduct 4, we preferred to
use the complex Mg(ClO4)2-(R,R)-L1 to continue our
synthetic route; although it afforded the endo adduct with
slightly lower ee, it provided higher diastereocontrol (cf. L4 and
L1 in Chart 1).
As a matter of fact, both the endo and exo stereoadducts,
which belonged to the opposite enantiomeric series, sub-
sequently converged to the same intermediates 10 (Scheme 2)
and 14 (Scheme 3). As a consequence, the reaction catalyzed
by Mg(ClO4)2-(R,R)-L1, in which no exo stereoisomer was
formed, afforded a higher overall ee for 10 and 14 than the
reaction catalyzed by Cu(II)-(S)-L4, which provided the endo/
exo cycloadducts in a 97:3 ratio.
Interestingly, both enantiomeric catalysts Cu(II)-(S)-L4 and
Mg(ClO4)2-(R,R)-L1 showed the same sense of asymmetric
induction, as reported in the literature,12b providing the same
enantiomeric cycloadduct (S)-4.
a
Reagents and conditions: (a) (i) MeOH, cat. PTSA, 60 °C, 3 h, 80%;
(ii) MeOMgBr, MeOH/THF (2:1), 0 °C, 2 h, 70%; (b) (i) NaHMDS,
THF, −78 to 0 °C, 1 h, then O2, −78 °C, 1 h, then DMS, −78 to −20
°C, 16 h; (ii) PhCOCl, pyridine, 4-DMAP, CH2Cl2, rt, 24 h, 75%; (c)
2.17 M NaHSO4 in CH3CN/H2O (9:1), rt, 84%; (d) (i) 6 M HCl,
dioxane, 75 °C, 72 h, 72%; (ii) MeOH, PTSA, 60 °C, 3 h, 90%; (e) (i)
1 M LiAlH4 in THF, 0 °C to rt, 16 h; (ii) NaIO4, THF/H2O/pH 7
buffer (2:1:1), rt, 4 h, 57%.
of 3 to bicyclic ketones 10 and 14, respectively. Two major
tasks, however, had to be accomplished to fulfill our synthetic
plan: (1) the adjustment of the oxidation state at C-6 of adduct
3 for the subsequent transformations and (2) the careful
inversion of the stereochemistry at the C-12 stereocenter of 3
or the conservation of its stereochemical integrity to achieve the
prostaglandin or the isoprostanoid stereochemistry, respectively
(see compounds 1 and 2, respectively, in Figure 1).15
2.1. Prostaglandin Approach. The strategy for the
prostaglandin approach was based upon the preparation of
the bicyclic ketone 10, which has been used for the preparation
of building block 1 and then prostaglandins (Scheme 2).5 (S)-
Cycloadduct 4 was transformed into the corresponding masked
aldehyde-methyl ester 3 simply upon exposure to a catalytic
amount of p-toluenesulfonic acid (PTSA) in methanol at 60 °C
for 3 h (80% yield), followed by treatment with Evans’
MeOMgBr reagent (prepared in situ from MeMgBr and
MeOH)12a in THF at 0 °C for 1 h (70% yield). Noteworthy,
only the syn diastereoisomer 3 was obtained, as confirmed by
With a robust enantioselective Diels−Alder protocol in hand,
the stereodivergent synthesis of the two key building blocks 1
and 2 for prostaglandin and isoprostanoid synthesis,
respectively, proceeded straightforwardly, at first by conversion
of cycloadduct (S)-4 into the common methyl ester
intermediate 3, followed by the stereodivergent manipulation
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which the C-12 stereocenter had the correct configuration
required for isoprostanoid synthesis. The key building block 23
was then prepared using the synthetic sequence depicted in
Scheme 3, which was mainly focused on the modification of the
C-6 oxidation level.
Scheme 3. Preparation of the Key Intermediate 2 for
Isoprostanoid Synthesis
a
In the event, NaHSO4-mediated hydrolysis of acetal 3
afforded syn aldehyde 11 in quantitative yield, which was
reduced by NaBH(OAc)3 in THF at rt, followed by in situ
protection of the resulting alcohol as ethoxyethyl ether upon
exposure to ethyl vinyl ether (EVE) in CH2Cl2 in the presence
of a catalytic amount of pyridinium p-toluenesulfonate (PPTS).
The expected ethoxyethyl ether 12 was thus obtained in 78%
isolated yield over two steps.
The proper oxidation state at C-6 was then adjusted using
the protocol previously optimized for compound 3. Hydrox-
ylation of the α-carbon of methyl ester 12 followed by
reduction with LiAlH4 provided diol 13 in 61% overall yield,
which was subsequently exposed to NaIO4 (buffered to pH 7)
to give the corresponding ketone 14 in 80% isolated yield.
Baeyer−Villiger oxidation of ketone 14 by slightly basic
hydrogen peroxide (NaHCO3, H2O2)17 gave the expected
[3.2.1]-bicyclic lactone 15, accompanied by chromatographi-
cally inseparable desired lactone 16 in 9:1 ratio (1H NMR).
SiO2-mediated rearrangement of labile lactone 15 in CH2Cl2/
hexane (3:1) at 40 °C for 18 h afforded pure lactone 16 in 68%
isolated yield.18
The key building block (+)-(3aR,4R,6aS)-γ-lactone 2,
required for isoprostanoid synthesis, was eventually produced,
in 80% yield and 97% ee, by simple deprotection of ethoxyethyl
ether 16 using a catalytic amount of PPTS in MeOH.
Compound 2 was identical in all respects with an authentic
sample prepared via a different route.3
a
Reagents and conditions: (a) 2.17 M NaHSO4 in CH3CN/H2O
(9:1), rt, 99%; (b) (i) NaBH(AcO)3, THF, rt; (ii) ethyl vinyl ether,
CH2Cl2, PPTS, rt, 78%; (c) (i) NaHMDS, THF, −78 to 0 °C, 1 h,
then O2, −78 °C, 1 h, then DMS, −78 to −20 °C, 16 h; (ii) 1 M
LiAlH4 in THF, THF, 0 °C to rt, 4 h, 61%; (d) NaIO4, THF/H2O/pH
7 buffer (2:1:1), rt, 4 h, 80%; (e) 10 M H2O2 in H2O, NaHCO3,
MeOH/MTBE (1:1), 0 °C, then SiO2, CH2Cl2/hexane (3:1), 40 °C,
57%; (f) MeOH, PPTS, 16 h, rt, 80%.
1H−1H COSY and 11H NMR experiments showing a diagnostic
Jw of 1.5 Hz5 between 12-H and 7-Hendo
.
15
After a few experiments, the key oxidation level of C-6 (cf.
compound 10) was adjusted via a one-pot oxidation of the
C(α)-carbon of methyl ester 3, using a modified Corey
protocol.16 In the event, a current of O2 was bubbled through a
solution of the enolate formed upon treatment of 3 with
NaHMDS (sodium hexamethyldisilazide) at −78 °C, followed
by dimethyl sulfide (DMS) quenching of the corresponding
hydroperoxide. Subsequently, the crude product was treated
with benzoyl chloride in the presence of pyridine and 4-
dimethylaminopyridine at rt, to afford the expected α-
benzoyloxy methyl ester 7 in a gratifying 76% overall yield as
a 6:1 mixture of endo:exo C-6 epimers. Aldehyde functionality
was restored at C-12 of compound 8 in 84% yield, with
complete conservation of the stereochemical integrity, by
exposing 7 to 2.17 M NaHSO4 in CH3CN/H2O (9:1) at rt.
The crucial epimerization of the C-12 stereocenter was then
smoothly accomplished by treating aldehyde 8 with 6 M HCl in
dioxane at 75 °C for 72 h.
3. CONCLUSION
In summary, an unified stereodivergent synthetic strategy for
the efficient preparation of both prostaglandins and isoprosta-
noids has been developed. The common key intermediate 4
was prepared in excellent enantiomeric excess through an
unprecedented asymmetric Diels−Alder reaction between
acetoxyfulvene and 3-acryloyloxazolidin-2-one promoted by a
chiral C2-symmetric bis(oxazoline) complex of Mg(ClO4)2.
Two other stereoselective reactions, namely, the hydrolysis of
the enol-acetate cycloadduct 4 and the epimerization of the
stereocenter in the α-position to aldehyde 8, secured a fast
route to prostaglandin and isoprostanoids via the key lactones 1
and 2, respectively. Further studies on the extension of this
methodology and its synthetic utility are in progress and will be
reported in due course.
The successful stereochemical inversion was witnessed by the
absence of the diagnostic Jw coupling between 12-H and 7-
Hendo5 in the anti diastereoisomer 9, which was obtained from 8
in 90% isolated yield upon exposure to a catalytic amount of
PTSA in MeOH. Computational studies showed that anti
diastereoisomer 9 was more stable then the corresponding syn
isomer by 2.7 kcal/mol.
Finally, ketone 10 was obtained in a single sequence by
reducing ester 9 with LiAlH4 in THF at rt for 4 h, followed by
sodium metaperiodate cleavage of the resulting diol in aqueous
THF (buffered to pH 7) at rt for 4 h. Optically active ketone
10, a key intermediate in the ICI prostaglandin synthesis,6 was
thus achieved in 57% overall yield from 9 with an enantiomeric
excess of 97.6% (chiral HPLC).
4. EXPERIMENTAL SECTION
General Procedures. All solvents were of commercial quality and
were purified by distillation over the drying agents indicated: THF
(Na/benzophenone), CH2Cl2 and 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
charring. Flash column chromatography (FCC) was performed on
silica gel (40−63 μm). Yields are reported for isolated compounds
Comparison between the optical rotation of our sample of 10
[α]20 = 550 (c 0.15, CH2Cl2) with the literature value for
D
enantiopure 10, [α]20 = 545 (c 0.16, CHCl3)5 clearly
D
confirmed the correct assignment of the absolute configuration.
2.2. Isoprostanoid Approach. The approach to the
synthesis of isoprostanoids exploited the advantage offered by
the stereoselective formation of the syn masked aldehyde 3 in
1
with >96% purity established by NMR unless otherwise indicated. H
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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, and coupling constants (J) are in hertz. The solvent signals
were used as references, and the chemical shifts were 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, and 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,
with concentration (c) in g/100 mL. Mass spectrometry was
performed by Q-TOF using electrospray ionization (ESI) mode [M
+ H+].
Diels−Alder: General Procedure without Chiral Ligands.
Molecular sieves type 4 Å (700 mg) and 3-acryloil-1,3-oxazolidin-2-
one (200 mg, 1.417 mmol) were mixed with dry dichloromethane
under an argon atmosphere (6 mL). The salt (0.425 mmol, 30% mol)
was then added to this suspension, and the resulting slurry was stirred
at room temperature for 40 min. Acetoxyfulvene solution (392 mg,
2.834 mmol) in dry CH2Cl2 (2 mL) was added dropwise to the slurry.
The reaction was stirred at rt for 48 h and then quenched with
saturated aqueous NH4Cl (15 mL). The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 15 mL). The
combined organic phases were dried with Na2SO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography on silica gel. Elution with hexane/
EtOAc (6:4) gave the desired diastereomeric mixture rac-4 (see the
Table 1 for yields and endo/exo ratios) as a pale yellow oil.
Asymmetric Diels−Alder Reaction with Chiral Ligand
Complex. Synthesis of (E)-((1S,4S,5S)-5-(2-Oxooxazolidine-3-
carbonyl)bicyclo[2.2.1]hept-2-en-7-ylidene)methyl Acetate (4). In a
dry Schlenk flask under an argon atmosphere were added, in this
order, molecular sieves type 4 Å (700 mg), 3-acryloil-1,3-oxazolidin-2-
one (200 mg, 1.417 mmol), chiral ligand (0.142 mmol, 10% mol), and
dry CH2Cl2 (6 mL). To this slurry was then added the salt (0.142
mmol, 10% mol), and the resulting suspension was stirred at room
temperature for 40 min. The slurry was then cooled at −55 °C, and
acetoxyfulvene solution (392 mg, 2.834 mmol) in dry CH2Cl2 (2 mL)
was added dropwise. The reaction was stirred at −55 °C for 72 h and
then quenched with saturated aqueous NH4Cl (15 mL). The layers
were separated, and the aqueous phase was extracted with CH2Cl2 (3
× 15 mL). The combined organic phases were dried with Na2SO4,
filtered, and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography on silica gel. Elution with
hexane/EtOAc (6:4) gave the desired norbornene cycloadducts 4 (see
Chart 1 for yields, ee, and endo/exo ratios) as a pale yellow oil. The
endo/exo ratio and the ee were determinated by HPLC after the
conversion of 4 into the compound syn-3. TLC (SiO2): Rf = 0.23
(hexane/EtOAc 7:3). FTIR (neat): 2989, 2360, 1778, 1696, 1478,
1388, 1312, 1225, 1077, 1043, 998, 923, 894, 859, 826, 762, 736, 709
cm−1. 1H NMR (300 MHz, CDCl3): δ (ppm) 6.64 (s, 1H), 6.32−6.41
(m, 1H), 6.03−6.41 (m, 1H), 4.42 (dt, J = 2.2, 7.7 Hz, 2H) 3.92−4.02
(m, 3H), 3.60 (d, J = 3.28 Hz, 2H), 2.08 (bs overlyed with m, 4H),
1.65 (dd, J = 4.6, 11.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm)
173.3 (s)*, 173.2 (s), 168.2 (s), 153.2 (s), 139.3 (s), 137.9 (d)*, 136.7
(d), 132.5 (d), 131.4 (d)*, 116.3 (d), 116.0 (d)*, 62.0 (t), 46.1 (d),
44.0 (d)*, 43.2 (d), 42.8 (t), 42.2 (d)*, 41.0 (d), 30.7 (t)*, 29.7 (t),
20.6 (q) [an asterisk indicates doubled signals due to the presence of
diastereoisomers]. HRMS: calcd for C14H15NO5 277.095; found
277.093
aqueous phase was extracted with CH2Cl2 (3 × 15 mL). The
combined organic phases were dried with Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash cromatography on silica gel. Elution with CH2Cl2/EtOAc 95:5
gave desired product (728 mg, yield = 80%). TLC (SiO2): Rf = 0.27
(CH2Cl2/EtOAc 95:5). IR (liquid film): 2950, 1760, 1490, 1350, 1100,
1030, 750, and 680 cm−1. 1H NMR (300 MHz, CD3COCD3): δ
(ppm) 6.25 (dd, J = 3.07, 5.6 Hz, 1H), 5.95 (dd, J = 2.91, 5.64 Hz,
1H), 4.41 (m, 2H), 4.15 (m, 1H), 4.11−3.85 (m, 2H), 3.39 (s, 3H),
3.30 (s, 3H), 3.20 (m, 1H), 3.15 (bs, 1H), 2.70 (bs, 1H), 1.95 (m,
1H), 1.80 (dd, J = 1.38, 8.76 Hz, 1H), 1.60−1.50 (ddd, J = 1.09 (Jw),
4.11, 5.44 Hz, 1H). 13C NMR (75 MHz, CD3COCD3): δ (ppm) 174.5
(s), 154.8 (s), 139.3 (d), 134.8 (d), 104.5 (d), 63.6 (d), 63.4 (t), 54.8
(q), 53.7 (q), 47.6 (d) 44.5 (d), 44.2 (t), 42.4 (d), 27.6 (t). ESI (m/z)
= 304.20 [(M + Na)+, 100], 585.06 [(2M + Na)+, 20]. HRMS: calcd
for C14H19NO5 281.1263; found 281.1261
Decarbonylation Reaction. The acetal of norbornene (220 mg,
0.782 mmol) was dissolved in 9:1 CH3CN/H2O (15 mL), aqueous
NaHSO4 (2.17M, 540 μL, 1.173 mmol) was added, and the reaction
was stirred at room temperature until complete deprotection of acetal.
The reaction was quenched with phosphate buffered solution (pH =
6.8, 15 mL), and the CH3CN was removed under vacuum. The residue
was diluted with CH2Cl2, and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (3 × 10 mL), dried over Na2SO4,
filtered, and concentrated under vacuum. The residue was filtered
using a little amount of silica gel with CH2Cl2/EtOAc 95:5 as eluent to
afford aldehyde 5.
Dioxane solution (1.5 mL) of [IrCl(cod)]2 (13 mg, 0.020 mmol)
and PPh3 (10 mg, 0.040 mmol) was stirred at room temperature for 30
min. Dioxane solution (0.5 mL) of 5 was added, and the reaction was
stirred at 110 °C until TLC (hexane/CH2Cl2/Et2O 6:2:2 as eluent)
showed a significative amount of desired product 6. The reaction
mixture was cooled to room temperature and diluted with water (7
mL) and hexane/Et2O 7:3 (10 mL). The layers were separated, and
the aqueous phase was extracted with Et2O (10 mL). The combined
organic phases were dried with Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
cromatography on silica gel. Elution with hexane/CH2Cl2/Et2O
6:2:2 gave desired product 6 (48 mg, yield = 30% over two steps)
as a pale yellow oil. [α]20 = −160 (c 0.13, CHCl3). ESI (m/z) =
D
230.08 [(M + Na)+, 100]. The spectroscopic data were in agreement
with the literature.5
Methyl (1R,2S,4S,7S)-7-(Dimethoxymethyl)bicyclo[2.2.1]hept-5-
ene-2-carboxylate (syn-3). To a solution of the imide-acetal of 4
(283 mg, 1 mmol) in a mixture of MeOH (5 mL) and THF (2.5 mL)
at 0 °C was added via cannula a suspension of MeOMgBr prepared by
addition of methylmagnesium bromide (370 μL, 3.2 M in diethyl
ether, 0.118 mmol) to anhydrous methanol (50 mL). After the
reaction mixture was stirred for 1 h at 0 °C, it was quenched by the
addition of satured NH4Cl (5 mL). Volatiles were removed in vacuo.
The residue was dissolved with water and extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated. Purification by flash chromatography on
silica gel, CH2Cl2/EtOAc 95:5 as eluent, afforded the desired methyl
ester syn-3 (210 mg, 92%) as a colorless oil. TLC (SiO2): Rf = 0.27
(CH2Cl2/EtOAc 95:5). [α]20 = −66.4 (c 2.76, CH2Cl2). FTIR
D
1
(neat): 3436, 1735, 1652, 1436, 1140, 1061 cm−1. H NMR (300
MHz, CD3COCD3): δ (ppm) δ 6.30−6.18 (dd, J = 3.2, 5.6 Hz 1H),
5.90 (dd, J = 3.3, 5.5 Hz, 1H), 4.20 (d, J = 8.85 Hz 1H), 3.62 (s, 3H),
3.30 (2s, 6H), 3.05 (m, 2H), 2.70 (bs, 1H) 2.05−1.85 (m, 1H), 1.70
(d, J = 8.77 1H), 1.57−1.42 (dd, J = 2.3, 12.28 Hz 1H). 13C NMR (75
MHz, CD3COCD3): δ (ppm) 175.2 (s), 139.9 (d), 135.0 (d), 103.8
(d), 62.6 (d), 53.6 (q), 53.4 (q), 52.0 (q), 47.1 (d), 44.1 (d), 42.1 (d),
27.5 (t). ESI (m/z) = 249.12 [(M + Na)+, 100]. HRMS: calcd for
C12H18O4 226.1205; found 226.1207
Methyl (1R,2R,4S,7S)-2-(Benzoyloxy)-7-formylbicyclo[2.2.1]hept-
5-ene-2-carboxylate (8). Oxidation of C-6. To a stirred solution of
NaHMDS (1730 μL, 1.730 mmol) in dry THF (6 mL) under an argon
atmosphere was added dry hexane (1 mL). The resulting clear solution
was cooled at −78 °C, and a THF solution (4 mL) of syn-3 (230 mg,
Determination of Absolute Configuration. Synthesis of
Norbornene Acetal 3-((1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-
carbonyl)oxazolidin-2-one (6). Compound 4 (903 mg, 3.235
mmol) was dissolved in dry MeOH (32 mL) at room temperature.
PTSA (62 mg, 0.324 mmol) was then added, and the solution was
heated to 60 °C for 4 h. The reaction mixture was cooled to room
temperature, solid NaHCO3 was added (27 mg, 0.325 mmol), and
MeOH was then removed under reduced pressure. The residue was
dissolved with saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (15
mL) under vigorous stirring. The layers were separated, and the
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The Journal of Organic Chemistry
Article
1.018 mmol) was added dropwise via cannula. The reaction mixture
was warmed to 0 °C and stirred at this temperature for 1 h, and after
recooling to −78 °C dry O2 was bubbled inside the enolate solution
for 1 h. The hydroperoxide was reduced using an excess of Me2S (750
μL, 10.18 mmol) at −40 °C for 1 h, the reaction was then quenched
with phosphate buffered solution at pH = 6.8 (10 mL), and the
resulting mixture was stirred at −20 °C for 16 h. The reaction mixture
was warmed to room temperature and diluited with ether (15 mL) and
water (5 mL), the organic phase was collected, and the aqueous phase
was extracted with Et2O (3 × 8 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was solved in dry CH2Cl2 (10 mL) under
Ar, and at 0 °C were added Py (165 μL, 2.036 mmol), BzCl (155 μL,
1.323 mmol), and DMAP. The reaction was allowed to reach the room
temperature and was stirred for 24 h. It was quenched with saturated
aqueous NaHCO3 (10 mL) and was diluted with CH2Cl2 (10 mL).
The layers were separated, and the aqueous layer was extracted with
CH2Cl2. The organic layers reunited were dried over Na2SO4, filtered,
and concentrated under vacuum. The residue was purified by column
cromatography on silica gel using CH2Cl2/EtOAc 95:5 as eluent to
afford the product 7 (260 mg, yield = 75% over two steps).
The residue was purified by column cromatography on silica gel
using CH2Cl2/EtOAc 95:5 as eluent to afford the oxidized product
(260 mg, yield = 75% over two steps). TLC (SiO2): Rf = 0.25
(CH2Cl2/EtOAc 95:5). FTIR (neat): 2952, 2829, 2754, 1721, 1602,
1452, 1287, 1161, 1111, 1072, 1010, 961, 876, 849, 801, 770 cm−1. 1H
NMR (300 MHz, CD2Cl2): δ (ppm) 8.16−8.12 (m, 2H), 7.68−7.61
(m, 1H), 7.56−7.45 (m, 2H), 6.49 (dd, J = 5.8, 3.2 Hz, 1H), 6.02 (dd,
J = 5.6, 3.4 Hz, 1H), 4.68−4.63 (m, 1H), 3.67 (bs, 3H), 3.34−3.28 (m,
7H), 2.97 (bs, 1H), 2.63 (dd, J = 13.6, 1.5 Hz, 1H), 2.32 (dd, J = 9.3,
1.3 Hz, 1H), 2.04 (dd, J = 13.7, 3.5 Hz, 1H). 13C NMR (75 MHz,
CD2Cl2): δ (ppm)171.4 (s), 166.5 (s), 142.9 (d), 134.2 (d), 132.7 (d),
130.5 (2 × d), 130.4 (s), 129.2 (2 × d), 102.4 (d), 87.6 (s), 64.5 (d),
53.3 (d), 52.9 (q), 52.7 (q), 52.5 (q), 44.0 (d), 36.6 (t). HRMS: calcd
for C19H22O6 346.1416; found 346.1414
Acetal Deprotection. Oxidized acetal (157 mg, 0.453 mmol) was
dissolved in 9:1 CH3CN/H2O (9 mL), aqueous NaHSO4 2.17 M (500
μL, 0.5 mmol) was added and the reaction was stirred at room
temperature until complete deprotection of acetal. The reaction was
quenched with phosphate buffered solution (pH = 6.8, 15 mL), and
the CH3CN was removed under vacuum. The residue was diluted with
CH2Cl2, and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (3 × 10 mL), dried over Na2SO4, filtered, and
concentrated under vacuum. The residue was filtered using a little
amount of silica gel with n-hexane/EtOAc 8:2 as eluent to afford the
product 8 (114 mg, yield = 84%). TLC (SiO2): Rf = 0.24 (hexane/
EtOAc 8:2). FTIR (neat): 2954, 1722, 1602, 1584, 1452, 1317, 1283,
1236, 1151, 1108, 1069, 1030, 1001, 962, 890, 846, 802, 715, 683
cm−1. 1H NMR (300 MHz, CDCl3): δ (ppm) 9.77 (s, 1H), 7.96−7.93
(m, 2H), 7.60−7.58 (m, 1H), 7.49−7.44 (m, 2H), 6.50 (dd, J = 5.8,
3.1 Hz, 1H), 6.07 (dd, J = 5.6, 3.4 Hz, 1H), 3.75 (dd, J = 1.4, 1.2 Hz,
1H), 3.72−3.71 (s, 3H), 3.38 (bs, 1H), 2.78 (bs, 1H), 2.53 (dd, J =
13.7, 2.1 Hz, 1H), 2.15 (dd, J = 13.7, 3.7 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ (ppm) 199.0 (d), 170.3 (s), 165.6 (s), 141.4 (d), 133.6 (d),
130.8 (d), 129.8 (2 × d), 128.9 (s), 128.6 (2 × d), 86.3 (s), 71.4 (d),
52.5 (d), 52.4 (q). 41.7 (d), 36.8 (t). ESI (m/z) = 323.14 [(M + Na)+,
12], 355.19 [(M + Na + MeOH)+, 33], 687.14 [(2M + Na +
2MeOH)+, 100]. HRMS: calcd for C17H16O5 300.0998; found
300.0996
Methyl (1R,2R,4S,7R)-2-(Benzoyloxy)-7-(dimethoxymethyl)-
bicyclo[2.2.1]hept-5-ene-2-carboxylate (9). Aldehyde 8 Epimeriza-
tion. HCl (6 M, 130 μL, 0.79 mmol) was added to a solution of
aldehyde 8 (95 mg, 0.316 mmol) in dioxane (2 mL) under an argon
atmosphere and then was heated at 75 °C for 96 h. The reaction
mixture was diluted with CH2Cl2 (10 mL), and a phosphate buffer (10
mL, pH) 6.95) was added. The layers were separated, and the aqueous
phase was extracted with CH2Cl2 (3 × 20 mL). The combined organic
phases were washed with H2O (10 mL) and brine (15 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography on silica gel.
Elution with CH2Cl2/EtOAc/hexane 47:3:50 as eluent gave the
desired aldehyde epimer (69 mg, yield = 72%). TLC (SiO2): Rf = 0.24
(CH2Cl2/EtOAc/hexane 47:3:50). FTIR (neat): 2954, 1722, 1602,
1584, 1452, 1317, 1283, 1236, 1151, 1108, 1069, 1030, 1001, 962, 890,
846, 802, 715, 683 cm−1. 1H NMR (300 MHz, CDCl3): δ (ppm) 9.73
(d, J = 1.9 Hz, 1H), 8.09−8.05 (m, 2H), 7.65−7.60 (m, 1H), 7.53−
7.46 (m, 2H), 6.47 (dd, J = 5.7, 3.0 Hz, 1H), 5.99 (dd, J = 5.6, 3.0 Hz,
1H), 3.73−3.66 (s, 3H), 3.60 (bs, 1H), 3.38 (bs, 1H), 3.12 (d, J = 1.5
Hz, 1H), 2.59 (d, J = 13.5 Hz, 1H), 2.02 (dd, J = 13.5, 3.7 Hz, 1H).
13C NMR (75 MHz, CDCl3): δ (ppm) 203.0 (d), 170.2 (s), 166.0 (s),
139.7 (d), 133.6 (d), 129.8 (2 × d), 129.2 (s), 128.6 (d), 128.5 (d),
85.6 (s), 70.6 (d), 52.7 (q), 52.6 (d), 43.7 (d), 39.3 (t). HRMS: calcd
for C17H16O5 300.0998; found 300.1000
Acetal Protection. Epimeric aldehyde (48 mg, 0.160 mmol) was
dissolved in dry MeOH (1.6 mL) at room temperature. PTSA (6 mg,
0.032 mmol) was then added, and the solution was heated to 60 °C for
3 h. The reaction mixture was cooled to room temperature, solid
NaHCO3 was added (15 mg, 0.176 mmol), and MeOH was then
removed under reduced pressure. The residue was dissolved with
saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (15 mL) under
vigorous stirring. The layer were separated, and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic phases
were dried with Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash cromatography on silica gel.
Elution with CH2Cl2/EtOAc 95:5 gave desired product 9 (50 mg,
yield = 90%). TLC (SiO2): Rf = 0.25 (CH2Cl2/EtOAc 95:5). FTIR
(neat): 2829, 2754, 1721, 1602, 1452, 1287, 1161, 1111, 1072, 1010,
961, 876, 849, 801, 770 cm−1. 1H NMR (300 MHz, CD2Cl2): δ (ppm)
8.08−8.05 (m, 2H), 7.67−7.62 (m, 1H), 7.54−7.48 (m, 2H), 6.38 (dd,
J = 5.7, 3.0 Hz, 1H), 5.86 (dd, J = 5.4, 2.9 Hz, 1H), 4.36 (d, J = 8.2 Hz,
1H), 3.65 (d, J = 1.2 Hz, 3H), 3.35−3.31 (m, 6H), 3.29−3.25 (m,
1H), 2.95 (dd, J = 1.4, 0.7 Hz, 1H), 2.75 (d, J = 8.2 Hz, 1H), 2.46 (d, J
= 13.3 Hz, 1H), 1.92 (dd, J = 13.3, 3.6 Hz, 1H). 13C NMR (75 MHz,
CD2Cl2): δ (ppm) 171.4 (s), 166.8 (s), 140.1 (d), 134.1 (d), 130.5 (s),
130.4 (d), 129.3 (d), 128.4 (d), 103.5 (d), 86.9 (s), 63.4 (d), 54.4 (q),
54.0 (q) 53.0 (2q), 44.3 (d), 40.1 (t). HRMS: calcd for C19H22O6
346.1416; found 346.1419
(1R,4S,7R)-7-(Dimethoxymethyl)bicyclo[2.2.1]hept-5-en-2-one
(10). LiAlH4 (1 M in THF, 770 μL, 0.773 mmol) was added under an
argon atmosphere to a solution of norbornene 9 (69 mg, 0.184 mmol)
in dry THF (2 mL) and cooled to 0 °C. The cooling bath was
removed, and the reaction mixture was stirred at rt overnight.
Rochelle’s salt (8 mL, satd aq) was added, and the resulting two layers
were vigorously stirred at rt for 4 h. After addition of DCM (8 mL) the
organic layer was then collected, the water phase was extracted with
DCM (3 × 10 mL), and the combined organic phases were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
compound was filtered through a pad of silica gel, washed with
hexane/EtOAc 2:8 (100 mL), and concentrated under reduced
pressure to yield the desired diol, which was directly used in the next
step. NaIO4 (78 mg, 0.368 mmol) was added to a stirred solution of
the diol in THF/H2O/phosphate buffered solution (pH = 6.8) 2:1:1
(2 mL) at rt, and the reaction mixture was stirred at room temperature
overnight. The reaction was quenched with saturated aqueous
NaHCO3 (2 mL) and saturated aqueous Na2S2O3 (2 mL), after 10
min the mixture was diluted with CH2Cl2 (10 mL), and the two layers
were separated. The aqueous phase was extracted with CH2Cl2 (4 ×
15 mL), and the combined organic phases were washed with brine,
dried with Na2SO4, filtered, and concentrated under reduced pressure
(>90 mmHg). The resulting residue was purified by flash
chromatography on silica gel. Elution with hexane/EtOAc 9:1 gave
compound 10 (19 mg, yield = 57% over two steps, ee 97%) as a
colorless oil. HPLC: (Chiralcel IA-3 column, hexane/i-PrOH = 90:10,
1 mL/min, 204 nm/208 nm). TLC (SiO2): Rf = 0.25 (hexane/EtOAc
9:1). [α]20 = −424.0 (c 0.2, CH2Cl2). 1H NMR (300 MHz,
D
CD3COCD3): δ (ppm) 6.50 (dd, J = 5.5, 2.8 Hz, 1H), 6.06−6.02 (m,
1H), 4.40 (d, J = 8.1 Hz, 1H), 3.31−3.29 (bs, 3H), 3.29−3.24 (bs,
3H), 3.14−3.10 (bs, 1H), 2.85−2.78 (m, 1H), 2.62 (d, J = 8.1 Hz,
1H), 2.10−2.01 (m, 1H), 1.86−1.80 (m, 1H). 13C NMR (75 MHz,
CD3COCD3): δ (ppm) 212.1 (s), 141.7 (d), 128.4 (d), 103.2 (d), 65.3
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(d) 58.8 (d), 53.7 (q), 53.6 (q), 43.0 (d), 39.2 (t). ESI (m/z) = 205.03
[(M + Na)+, 100]. HRMS: calcd for C10H14O3 182.0943; found
182.0945
mL, satd aq) was added, and resulting two layers was vigorously stirred
at rt for 4 h. After addition of DCM (8 mL) the organic layer was then
collected, the water phase was extracted with DCM (3 × 10 mL), and
the combined organic phases were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude compound was
filtered through a pad of silica gel, washed with hexane/EtOAc 2:8
(100 mL), and concentrated under reduced pressure to yield the
desired diol 13, which was directly used in the next step. IR (liquid
film): 3700−3150 (br), 3060, 2985, 2875, 1465, 1450, 1345, 1275,
1060, 1050, 1030, 990, 910.
(1R,4S,7S)-7-((1-Ethoxyethoxy)methyl)bicyclo[2.2.1]hept-5-en-2-
one (14). NaIO4 (86 mg, 0.428 mmol) was added to a stirred solution
of 13 (52 mg, 0.214 mmol) in THF/H2O/phosphate buffered solution
(pH = 6.8) 2:1:1 (1.5 mL) at rt, and the reaction mixture was stirred at
room temperature overnight. The reaction was quenched with
saturated aqueous NaHCO3 (2 mL) and saturated aqueous Na2S2O3
(2 mL), after 10 min the mixture was diluted with CH2Cl2 (10 mL),
and the two layers were separated. The aqueous phase was extracted
with CH2Cl2 (4 × 15 mL), and the combined organic phases were
washed with brine, dried with Na2SO4, filtered, and concentrated
under reduced pressure (>90 mmHg). The resulting residue was
purified by flash chromatography on silica gel. Elution with hexane/
EtOAc 9:1 gave compound 14 (36 mg, yield = 80% over three steps)
as a colorless oil. TLC (SiO2): Rf = 0.24 (hexane/EtOAc 9:1). FTIR
(neat): 3061, 1724, 1708, 1176. cm−1. 1H NMR (300 MHz,
CD3COCD3): δ (ppm) 6.75−6.60 (dd, J = 5.63, 2.94 Hz, 1H),
6.25−6.14 (dd, J = 4.5, 3.6 Hz, 1H), 4.75−4.58 (m, 1H), 3.30−4.70
(m, 4H), 3.10 (bs, 1H), 2,80 (bs, 1H), 2.70−2.55 (t, J = 7.52 Hz, 1H),
2.15−2.00 (m, 1H), 1.80−1.65 (dd, J = 16.7, 2.4 Hz, 1H), 1.25 (d, J =
5.31 Hz, 3H), 1.20−1.10 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CD3COCD3): δ (ppm) 214.2 (s), 145.9 (d), 132.6 (d), 100.6 (d), 63.8
(t), 63.6 (t)*, 62.8 (d), 62.7 (d)*, 61.8 (t), 61.6 (t)*, 58.6 (d), 42.4
(d), 33.5 (t), 20.4 (q), 16.0 (q). HRMS: calcd for C12H18O3 210.1256;
found 210.1258
Methyl (1R,2S,4S,7S)-7-Formylbicyclo[2.2.1]hept-5-ene-2-carbox-
ylate (11). Acetal syn-3 (177 mg, 0.783 mmol) was dissolved in 9:1
CH3CN/H2O (15 mL), aqueous NaHSO4 (2.17 M, 540 μL, 1.175
mmol) was added, and the reaction was stirred at room temperature
until complete deprotection of acetal. The reaction was quenched with
phosphate buffered solution (pH = 6.8, 15 mL), and the CH3CN was
removed under vacuum. The residue was diluted with CH2Cl2, and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(3 × 15 mL), dried over Na2SO4, filtered, and concentrated under
vacuum. The residue was filtered using a small amount of silica gel
with n-hexane/EtOAc 9:1 as eluent to afford the product 11 (140 mg,
yield = 99%). TLC (SiO2): Rf = 0.25 (hexane/EtOAc 9:1). [α]20
=
D
−81.7 (c 2.8, CH2Cl2). FTIR (neat): 3474, 2954, 1732, 1436, 1325,
1
1203, 1030, 906, 719 cm−1. H NMR (300 MHz, CDCl3): δ (ppm)
9.58 (s, 1H), 6.27 (dd, J = 5.5, 3.0 Hz, 1H), 6.05 (dd, J = 5.6, 2.9 Hz,
1H), 3.66 (s, 3H), 3.48 (bs, 1H), 3.20 (bs, 1H), 3.02 (dt, J = 7.95, 4.0
Hz, 1H), 2.50 (d, Jw = 1.5 Hz, 1H), 1.93 (ddd, J = 12.6, 9.3, 3.7 Hz,
1H), 1.58 (dddd, J = 12.5, 5.8, 3.8, 1.7 (Jw), 1H). 13C NMR (75 MHz,
CDCl3): δ (ppm) 200.8 (d), 174.2 (s), 137.7 (d), 133.3 (d), 69.5 (d),
51.7 (q), 44.9 (d), 42.3 (d), 41.1 (d), 26.9 (t). HRMS: calcd for
C10H12O3 180.0786; found 180.0788
Methyl (1R,2S,4S,7S)-7-((1-Ethoxyethoxy)methyl)bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (12). Na(AcO)3BH (330 mg, 1.556
mmol) was added under an argon atmosphere to a solution of
compound 11 (140 mg, 0.778 mmol) in dry THF (4 mL) cooled to 0
°C. The cooling bath was removed, and the reaction mixture was
stirred at rt until complete conversion. The reaction was quenched
with a phosphate buffered solution (pH = 6.8, 4 mL) and was diluted
with DCM. The organic layer was then collected, the aqueous phase
was extracted with DCM (3 × 10 mL), and the combined organic
phases were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude compound was directly submitted to the
next synthetic step. The crude was dissolved in CH2Cl2 (8 mL), and
ethyl vinyl ether (1490 μL, 15.56 mmol) and PPTS (39 mg, 0.156
mmol) were added. The resulting mixture was stirred for 2 h, and then
excess solid NaHCO3 was added, followed by a saturated solution of
NaHCO3 (15 mL). The layers were separated, and the aqueous phase
was extracted with DCM (3 × 15 mL). The combined organic phases
were washed with brine, dried with Na2SO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel. Elution with nHexane/EtOAc (9:1) gave
the desired acetal 12 (166 mg, 84% over two steps, 1:1 mixture of
anomers). TLC (SiO2): Rf = 0.26 (hexane/EtOAc 95:5). FTIR (neat):
3447, 3061, 2979, 1736, 1438, 1381, 1336, 1296, 1274, 1201, 1134,
1059, 982, 930, 872, 846, 753, 709 cm−1. 1H NMR (300 MHz,
CD3CN): δ (ppm) 6.27 (dd, J = 5.7, 3.1 Hz, 1H), 6.00 (dd, J = 5.7, 2.9
Hz, 1H), 4.66−4.59 (m, 1H), 3.68−3.57 (bs overlyed m, 4H), 3.50−
3.40 (m, 1H), 3.34 (ddt, J = 10.1, 7.4, 2.6 Hz, 1H), 3.22 (ddt, J = 10.2,
6.8, 3.3 Hz, 1H), 3.02−2.92 (m, 2H), 2.71 (bs, 1H), 1.98−1.86 (m,
2H), 1.46−1.39 (dddd, J = 12.3, 5.2, 4.0, 1.3 (Jw) Hz, 1H), 1.26−1.20
(d, J = 5.3 Hz, 3H), 1.20−1.11 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CD3CN): δ (ppm) 174.7 (s), 139.1 (d), 134.1 (d), 99.5 (d),
63.6 (t)*, 63.6 (t), 60.7 (t)*, 60.6 (t), 59.7 (d), 51.0 (d), 46.3 (d), 43.2
(d), 40.6 (d), 25.9 (t), 19.3 (q), 14.7 (q) [an asterisk indicates doubled
signals due to the presence of diastereoisomers]. HRMS: calcd for
C14H22O4 254.1518; found 254.1520
(3aR,4R,6aS)-4-((1-Ethoxyethoxy)methyl)-3,3a,4,6a-tetrahydro-
2H-cyclopenta[b]furan-2-one (16). NaHCO3 (287 mg, 3.42 mmol)
was added to a solution of 14 (36 mg, 0.171 mmol) in MeOH/methyl
tert-butyl ether 1:1. The suspension was cooled at 4 °C, and H2O2 10
M (171 μL, 1.71 mmol) was added under vigorous stirring. The
reaction mixture was stirred at 4 °C for 18 h and then was diluted with
Et2O (10 mL), and organic layer was colected and washed with fresh
H2O (2 × 5 mL). The organic layer was washed with aqueous
saturated Na2S2O3 (8 mL), aqueous saturated NaHCO3 (8 mL), water
(4 mL), and finally brine (4 mL). The organic layer was dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography on silica gel.
Elution with n-hexane/AcOEt (7:3) gave a mixture of lactones 16 and
15 (1:9 ratio). Silica gel (108 mg) was added to a solution of lactones
16 and 15 (1:9 ratio) in dry CH2Cl2/hexane 3:1 (0.5 mL). The
reaction mixture was stirred at 40 °C, and the conversion was
1
monitorated by H NMR until complete conversion of the [3.2.1]
structure into the [3.3.0] structure. The reaction was filtered over a
short pad of Celite and concentrated under vacuum to afford the pure
lactone 16 (22 mg, yield = 57% over two steps). TLC (SiO2): Rf =
0.23 (hexane/EtOAc 7:3). FTIR (neat): 3016, 2927, 1764, 1291, 1173,
1
1139, 1023, 973, 759. cm−1. H NMR (300 MHz, CD2Cl2): δ (ppm)
6.02−5.95 (m, 2H), 5.46 (dd, J = 7.4, 0.8 Hz, 1H), 4.66 (m, 1H),
3.74−3.36 (m, 4H), 3.30−3.20 (m, 1H), 3.17−3.09 (m, 1H), 2.65−
2.55 (m, 2H), 1.28 (d, J = 4.6 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ (ppm) 177.4 (s), 138.5 (d), 138.4 (d)*,
129.8 (d), 100.3 (d), 100.0 (d)*, 89.0 (d), 64.8 (t), 64.6 (t)*, 61.2 (t),
47.5 (d), 47.4 (d)*, 38.5 (d), 29.9 (t), 29.9 (t)*, 19.8 (q), 15.5 (q).
ESI (m/z) = 249.07 [(M + Na)+, 100], 475.06 [(2M + Na)+, 15].
HRMS: calcd for C12H18O4 226.1205; found 226.1202
(3aR,4R,6aS)-4-(Hydroxymethyl)-3,3a,4,6a-tetrahydro-2H-
cyclopenta[b]furan-2-one (2). PPTS (cat.) was added to a stirred
solution of acetal 16 (22 mg, 0.097 mMol) in MeOH (1 mL), and the
resulting mixture was stirred for 16 h. An excess of solid NaHCO3 was
added, and the resulting mixture was filtered and concentrated under
reduced pressure. The resulting residue was purified by flash
(1R,2R,4S,7S)-7-((1-Ethoxyethoxy)methyl)-2-(hydroxymethyl)-
bicyclo[2.2.1]hept-5-en-2-ol (13). To a stirred solution of NaHMDS
(1.326 mL, 1.326 mmol) in dry THF (5 mL) under an argon
atmosphere was added dry hexane (0.8 mL). The resulting clear
solution was cooled at −78 °C, and THF solution (2 mL) of 3 (198
mg, 0.780 mmol) was added dropwise via cannula. The reaction
mixture was warmed to 0 °C and stirred at this temperature for 1 h,
and after recooling to −78 °C dry O2 was bubbled inside the enolate
solution for 1 h. The hydroperoxide was reduced using an excess of
LiAlH4 (2 M in THF, 4.056 mmol, 2.028 mL) at −78 °C, and the
reaction was stirred at room temperature overnight. Rochelle’s salt (8
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dx.doi.org/10.1021/jo500093k | J. Org. Chem. 2014, 79, 2632−2639

The Journal of Organic Chemistry
Article
chromatography on silica gel. Elution with hexane/EtOAc (1:1) gave
the desired alcohol 2 (12 mg, yield = 80%, ee = 97%) as a pale yellow
oil. HPLC: (Chiralcel AS-H column, hexane/i-PrOH = 70:30, 1 mL/
min, 204 nm/208 nm). TLC (SiO2): Rf = 0.22 (hexane/EtOAc 1:1).
(11) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059.
(12) (a) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am.
Chem. Soc. 1999, 121, 7559. (b) Desimoni, G.; Faita, G.; Jørgensen, K.
A. Chem. Rev. 2006, 106, 3561.
(13) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.;
Tanaka, J.; Eiji, W.; Curran, D. P. J. Am. Chem. Soc. 1998, 120, 3074.
(14) Iwai, T.; Fujihara, T.; Tsuji, Y. Chem. Commun. 2008, 6215.
(15) (a) For the sake of clarity, the prostaglandin numbering system
has been used throughout the text. (b) For the explanation of unique
behavior of acetal formation, see ref 5.
(16) Corey, E. J.; Ensle, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
(17) Weinshenker, N. M.; Stephenson, R. J. Org. Chem. 1972, 37,
3741.
[α]20 = +7.17 (c 0.265, CH2Cl2). ESI (m/z) = 176.99 [(M + Na)+,
D
100], 331.08 [(2M + Na)+, 85]. The spetroscopic data were in
agreement with the literature.3
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H, 13C, HPLC profiles, computational details for the
TS-A and TS-B and for the thermodinamic stability of aldehyde
8. This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Grieco, P. A.; Srinivasan, C. V. J. Org. Chem. 1981, 46, 2591.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gz@unipv.it.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to Prof. G. Desimoni and Prof. G. Faita
for the generous gift of ligand (R,R)-L1. Authors are also
̀
grateful to Regione Lombardia (Direzione Generale Sanita and
Iniziativa Lombardia Eccellente), Fondazione di Piacenza e
Vigevano, and MIUR (funds PRIN) for financial support.
REFERENCES
■
(1) Jahn, U.; Galano, J. M.; Durand, T. Angew. Chem., Int. Ed. 2008,
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́
(3) The Diels−Alder approach developed by Rokach et al. involving
the cycloaddition between an enantiopure dienophile and a
Danishesky diene, is far from the Corey general strategy2 dictates: S.
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(7) The very well-known 1,3-diene [1,5]-H sigmatropic shift
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(8) (a) Ishihara, K.; Sakakura, A. In Science of Synthesis, Stereoselective
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Am. Chem. Soc. 1969, 91, 5675. For two examples of asymmetric DA
involving 2-chloroacrylonitrile, see: (b) Wang, Y.; Li, H.; Wang, Y.-Q.;
Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129, 6364.
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(b) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
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