Intramolecular Photoreactions of (5S)-5-Oxymethyl-2(5H)-furanones as a Tool for the Stereoselective Generation of Diverse Polycyclic Scaffolds

Article abstract of DOI:10.1021/acs.joc.5b01354

The photoactivated evolution of a series of enantiomerically pure 5-oxymethyl-2(5H)-furanones has been investigated. The observed intramolecular photoreactions have proven to be a straightforward entry to diverse and stereochemically rich fragment-molecul

Full text of DOI:10.1021/acs.joc.5b01354

Article
pubs.acs.org/joc
Intramolecular Photoreactions of (5S)‑5-Oxymethyl-2(5H)‑furanones
as a Tool for the Stereoselective Generation of Diverse Polycyclic
Scaffolds
Guillaume Lejeune,† Josep Font,† Teodor Parella,†,‡ Ramon Alibes,*,† and Marta Figueredo*,†
́
‡
†Departament de Química and Servei de RMN, Universitat Auton
̀
oma de Barcelona, 08193 Bellaterra, Spain
S
* Supporting Information
ABSTRACT: The photoactivated evolution of a series of
enantiomerically pure 5-oxymethyl-2(5H)-furanones has been
investigated. The observed intramolecular photoreactions have
proven to be a straightforward entry to diverse and
stereochemically rich fragment-molecules, most of which
contain the privileged tetrahydropyran (THP) scaffold. The
formation of the THP involves a 1,5-hydrogen atom transfer
process, leading to a diradical intermediate that recombines to
form a new σ C−C bond. These reactions take place under
both sensitized and nonsensitized conditions, and they are highly stereoselective. When the substrate contains an allyl residue,
the intramolecular [2 + 2] cycloaddition leading to cyclobutanes competes advantageously. When the substrate contains a THP
residue, the cyclization involves the concomitant formation of [6,6]-spiroketals with nonanomeric relationships.
programs. However, it would be desirable to explore fragments
with higher shape diversity in order to cover a more extensive
range of biological interactions.3 The use of diversity-oriented
synthesis and, in particular, the build/couple/pair strategy4 has
become a convenient approach to address this challenge. This
strategy requires short reaction sequences leading to molecules
with a high degree of structural and stereochemical complexity.
In this context, some photoactivated reactions may provide a
straightforward entry to increase molecular complexity from
simple, easily available substrates.5
Over several decades, our group has investigated the
photoinduced [2 + 2] cycloaddition of substituted 5-
oxymethyl-2(5H)-furanones to alkenes and alkynes, in both
the inter-6 and intramolecular7 versions, and explored its
application to the synthesis of natural products or analogues,
with recognized or potential biological activity.7 In the course
of these investigations, we discovered a competitive intra-
molecular reaction producing bicyclic tetrahydropyrans
(THPs) in a stereoselective manner. Thus, the irradiation of
lactone 1, bearing a benzyloxymethyl substituent at position 5,
in the presence of various alkenes such as ethylene,
tetramethylethylene, or vinylene carbonate, delivered, along
with the expected [2 + 2] cycloaddition products, the bridged
THP 2 (Scheme 1).6b Hypothetically, this product arises from a
hydrogen atom transfer (HAT) of [1]* to the β-carbon of the
excited enone, followed by subsequent recombination of the
diradical to form the new σ C−C bond. We reasoned that the
benzylic character of the intermediate radical I-1 could favor
this alternative pathway competing with the addition of the
INTRODUCTION
■
One of the purposes of medicinal chemistry is the discovery of
new molecules for influencing biological functions. Accordingly,
a main objective of drug discovery programs is to prepare
diverse sets of molecules, which when submitted to bioactivity
tests and absorption, distribution, metabolism, excretion
(ADME) screens may lead to the recognition of drug
candidates among the investigated structures. In the past
years, the fragment-based drug discovery (FBDD) approach1
has emerged as a plausible alternative to other consolidated
methods of hit identification, such as high throughput screening
(HTS). Fragment-molecules are small (typically less than 250
Da), and their binding affinity to the active site of the biological
target may be superior to other more intricate structures in
terms of ligand efficiency. Lipophilic molecules are more prone
to desolvate than polar ones and hence are more amenable for
binding to any protein pocket, but at the same time water
solubility is essential to conduct the bioactivity screening. A
convenient compromise may result by combining in the
candidate molecules a significant apolar structural fraction
and one or more functional groups amenable of chemical
transformation to modulate the overall polarity. Undoubtedly,
the synthesis of collections of original small molecules could be
an entry to important biochemical discoveries that may be
essential for the treatment of many diseases. When faced with
the problem of creating new druglike small molecule collections
oriented to a particular target, a plausible approach makes use
of the privileged scaffold concept. Privileged scaffolds are
structural motifs frequently present in both natural products
and pharmaceutical drugs.2 Among them, planar aromatic
heterocycles are the most frequent components of the
commercially available fragment libraries used in FBDD
Received: June 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01354
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a
Scheme 1. Formation of Bridged THP 2 by Irradiation of 1
Figure 1. Selected substrates for the photoactivated hydrogen atom
transfer study.
Formerly, we had prepared the benzyloxymethylfuranone 1
by reaction of the parent alcohol 13 (readily available from D-
manitol)12 with benzyl bromide and silver(I) oxide, but we
have now improved the benzylation efficiency by the use of
benzyltrichloroacetimidate in dichloromethane in the presence
of trifluoromethanesulfonic acid.13 Under these new conditions,
furanone 1 was isolated in 93% yield (Scheme 3). An analogous
a
(A) Ether/quartz (direct irradiation); (B) acetone/Pyrex (sensitized
irradiation).
alkene, and indeed, when lactone 1 was irradiated in the
absence of any alkene, THP 2 could be isolated in preparative
yields. However, this reaction was subsequently found to occur
in other analogous substrates lacking the benzyl residue. Thus,
in a project devoted to explore the application of C2-symmetric
bis-2(5H)-furanones as templates for asymmetric synthesis,
when the bislactones 3 were irradiated in the presence of
ethylene, in addition to the expected bis-photoadducts 4,
considerable amounts of THP photoproducts 5 and 6 were also
formed (Scheme 2).8b
Scheme 3. Preparation of Furanones 1 and 10−12 from 13
Considering the occurrence of the THP ring in many natural
products and drugs, including carbohydrates and macrolides as
the most abundant typologies,9 we judged it worthwhile to
explore the scope of this reaction as a straightforward access to
novel, stereochemically rich fragment-molecules, which may
eventually lead to the discovery of new privileged scaffolds.
Moreover, the lactone functionality would enable subsequent
transformations to prepare monocyclic polysubstituted THPs
and/or to modulate the lipophilicity of the fragments.10 The
results of this study are presented herein.
protocol applied to the preparation of the allyloxy derivative 11
worked less well, despite the reaction being attempted under
various conditions; the best yield (31%) was obtained using a
2:1 mixture of dichloromethane and cyclohexane as solvent.
The MEM, 10, and THP, 12, derivatives were prepared also
from alcohol 13 by standard procedures in good yields.14
Compound 12 was obtained as a 1:1 mixture of epimers at the
acetal center.15
RESULTS AND DISCUSSION
■
Synthesis of the Substrates. Figure 1 shows the set of
2(5H)-furanones 7−12 (complementary to 1) selected to
undertake the study. The methyl, butyl, and isopropyl
derivatives, 7−9, would provide evidence about the influence
of the stability of the intermediate diradical in the feasibility of
the process, while substrates 10−12 will give information
concerning its compatibility with additional functionalities. The
allyl derivative 11 was particularly interesting because it was
expected that alternative intramolecular [2 + 2] cycloaddition
pathways would also be at play. The photochemical behavior of
the racemic THP derivative 12 and other analogous substrates
has been recently published by Hoffmann and co-workers as
part of a study devoted to investigate the stereoelectronic
effects that control the HAT-cyclization process.11 We were
interested in comparing their results with our own.
The alkyloxy furanones 7−816 and 9 were more effectively
synthesized by an alternative methodology,17 involving
alkylation of phenylselenoacetic acid with the appropriate
epoxide, followed by acid-catalyzed lactonization and then
oxidation of the selenide with concomitant thermal elimination
(Scheme 4).
Photochemical Study. The irradiations of furanones 1 and
7−12 were performed in an immersion well photochemical
reactor, with a 125 W high pressure mercury lamp, cooling
externally the reactor to −20 °C and flowing methanol at −15
°C through the internal jacket. The reaction evolution was
monitored by gas chromatography, and the effect of the
experimental conditions (solvent, filter, and reaction time) was
Scheme 2. Irradiation of Bis-lactones 3a,b in the Presence of Ethylene
B
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Scheme 4. Preparation of Furanones 7−9 from Phenylselenoacetic Acid and Epoxides
a
Table 1. Irradiation of Furanones 1 and 7−9
b
c
entry
substrate
mmol L−1
solvent
filter
time (min)
conversion (%)
product (yield)
1
2
1
4.7
4.7
4.0
4.3
5.4
6.4
5.5
10.4
6.5
6.3
5.5
7.4
8.8
6.0
5.5
5.5
5.5
acetone
CH3CN
CH3CN
Et2O
pyrex
180
50
70
15
25
42
105
40
65
40
50
45
30
100
30
30
30
100
100
90
2 (38%)
2 (44%)
2 (70%)
2 (78%)
2 (48%)
14 (45%)
14 (52%)
e
1
quartz
quartz
quartz
quartz
pyrex
d
3
1
4
1
100
100
100
100
100
100
100
100
100
100
100
100
100
100
5
1
Et2O
6
7
acetone
CH3CN
Et2O
7
7
quartz
quartz
pyrex
8
7
9
8
acetone
CH3CN
Et2O
15 (42%)
15 (52%)
e
10
11
12
13
14
15
16
17
8
quartz
quartz
pyrex
8
9
acetone
CH3CN
Et2O
16 (38%)
16 (50%)
16 (30%)
e
9
quartz
quartz
pyrex
9
10
10
10
acetone
CH3CN
Et2O
quartz
quartz
e
e
a
Irradiations were performed in a nitrogen saturated solution; unless otherwise indicated, the external cooling bath was at −20 °C, and the jacket
b
c
d
cooling liquid was at −15 °C. The substrate conversion was monitored by GC. Yield of isolated products. The external cooling bath was at −40
°C. Unidentifiable degradation products.
e
evaluated. To avoid the addition of the solvent to the β-
carbonyl position of the excited furanone, all the irradiation
experiments were performed in aprotic solvents.18 The results
are summarized in Table 1. First, the previously observed
photochemical reaction of lactone 1 was reinvestigated in
several conditions. Under sensitized photoactivation (entry 1,
acetone/pyrex), 3 h of irradiation was required for the full
consumption of the furanone and, after chromatographic
purification, the expected bicyclic THP 2 was isolated in 38%
yield. The direct photoactivation (entries 2−5) proved more
efficient. It was observed that, in acetonitrile (entries 2−3), a
decrease in the temperature diminished the reaction rate but
improved notably the yield of isolated product, suggesting that
the THP 2 could partially decompose when subjected to
persistent irradiation. Diethyl ether gave the best results,
furnishing 78% yield of isolated product after only 15 min of
irradiation (entry 4). As before, prolonged irradiation time was
detrimental to the yield (entry 5). Next, the behavior of the
other alkyloxy derivatives 7−9 under similar conditions was
investigated. It was somewhat surprising that, under the
sensitized activation (entry 6), lactone 7 bearing the methyl
residue evolved faster than its benzylic analogue and furnished a
superior yield of the corresponding THP 14. However, direct
activation in acetonitrile was less effective (entry 7), and the
irradiation in ether leads to a complex mixture of unidentified
products (entry 8). Very similar results were obtained in the
photochemical experiments of the butyl derivative 8 (entries
9−11). The photochemical evolution of furanone 9 (entries
12−14), wherein the isopropyl group may originate a more
stable tertiary radical intermediate, was in good agreement with
that of 1, although the yield of the isolated THP 16 when
working in ether was lower in this case (compare entries 4/5
and 14). Surprisingly, the irradiation of lactone 10 in all
attempted solvents (entries 15−17) gave complex mixtures of
products, and NMR analysis did not allow the identification of
any compound containing the expected THP moiety.
The stereochemical course of the photoreactions was a main
concern of our study. In all the cases, the cyclization produces a
new stereogenic center at the bridgehead position, whose
configuration is determined by the chirality sense of the starting
furanone, since the opposite facial approach would be
geometrically impossible. However, in the case of lactones 1
and 8, an additional stereogenic center is generated at C-2 of
the THP products (Scheme 5). For compound 15, the relative
configuration was established through 1D NOESY experiments,
which revealed an increase of the signal of one of the protons
H-1′, H-5, and H-8 after selective irradiation of H-4. Therefore,
starting from (5S)-8, the stereochemistry of THP 15 was
established as (1R,2S,5S). This configuration matches the one
previously determined for 2, and it is probably governed by the
relative proportions of I-8 pro-R and I-8 pro-S which are in
equilibrium. When going from the excited lactone to the
subsequent diradical species, the transition state leading to the
intermediate diradical pro-S, with the bulky propyl chain distant
from the lactone ring, must be favored over that leading to
intermediate diradical pro-R, where the propyl chain is closer to
C
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selective NOE experiments, that showed signal enhancement of
protons H-2′ when the signal corresponding to the C-4
methylene group was selectively irradiated. The cyclobutanes
19 and 20 could not be separated by column chromatography.
Thus, their structural analysis was performed on a 1:0.7 mixture
of the two regioisomers, where most of the signals were clearly
distinguishable. Selective TOCSY experiments allowed fast
assignment of whole spin systems and were used to obtain
separate subspectra of each isomer, through the selective
irradiation of H-3a in 19 and H-7 in 20. For the HH
regioisomer 20, the attachment site of C-4 was established by
an HMBC experiment which showed cross-peak interactions
between one of the H-4 protons and the carbon atom C-3 and
between one of the H-2 protons and C-7. The connectivity of
the HT regioisomer 19 was evidenced by a diagnostic cross-
coupling between the carbonyl carbon C-2 and one of the
methylenic protons H-1.
Next, the photoreactivity of the furanone 12 bearing the
THP residue (1:1 mixture of epimers at the acetal center) was
investigated (Table 3). In the above-mentioned publication
from the Hoffmann laboratories,11 the irradiation of 12 (as a
mixture of the two diasteromeric racemates) was performed
with Rayonet reactors in quartz tubes, no transformation was
observed in the absence of acetone, and the authors concluded
that the reaction occurs through hydrogen transfer from the
acetal center to the β-carbonyl position in the triplet (*ππ)
excited state of the furanone. After irradiation of a 1:1 mixture
of 12 for 3 h, they isolated a 1:1 mixture of epimeric THPs 21
and 22 (entry 1).
The experiments performed in our laboratories showed some
differences with those reported. In our studies, when the
photoreaction was run in acetone through a pyrex filter (entry
2), we isolated THP (2R)-21 as the major product (30%),
along with minor amounts of its epimer (2S)-22 (6%) and a
third product that was identified as the 1,3-dioxocane 23 (10%)
and was a single diastereomer. Although this compound was
not observed in the Hoffmann laboratories, they did find
photoproducts with the same skeleton as 23 after irradiation of
closely related furanones bearing also tetrahydropyran moieties.
Experimental data as well as theoretical calculations with model
compounds led these authors to conclude that the hydrogen
abstraction step determines the reactivity and regioselectivity of
the process, and it is strongly dependent upon the relative
configuration of the substrate. Their calculations indicated that
the competitive 1,5- and 1,7-HAT processes may be more or
less favored by the geometry of the starting furanone. On the
Scheme 5. Stereochemical Course of the Photocyclization of
8
the lactone. However, the diradical is formed in a triplet state
and, before progressing to 15, requires a spin change; therefore,
it has sufficiently long lifetime for equilibrium to be established
between I-8 pro-R and I-8 pro-S.
Then, we investigated the reactivity of lactone 11 bearing an
allyl group under both sensitized and direct photoactivation
conditions (Table 2). In previously reported photoactivated
intramolecular [2 + 2] cycloadditions of 2(5H)-furanones7,19
and conjugated enones20 bearing a carbon−carbon double
bond at a suitable distance to furnish the corresponding
cyclobutanes, the competitive formation of photoproducts
arising from a 1,5-HAT pathway has not been described. From
our experiments we were able to isolate and characterize four
different products, the THP 17 and the oxocine 18, coming
from 1,5-HAT followed by C−C bond formation, and the
cyclobutanes 19 and 20, arising from intramolecular [2 + 2]
photocycloadditions with head to tail (HT) or head to head
(HH) orientation, respectively. In all the assayed conditions,
the cycloadducts predominated, and higher substrate concen-
trations favored the HT regioisomer over the HH one
(compare entries 1 and 2/3 and entries 4 and 5). The
concomitant formation of 17 and 18 can be reasonably
explained by the intermediacy of a delocalized allyl radical that
seems preferentially to evolve to the formation of the eight
member ring.
The structure of compound 18 was determined through
1
detailed NMR studies. Its H NMR spectrum displays two
signals of olefinic protons at δ 6.45 and 5.09, and an HMBC
experiment showed relevant cross-peaks between one of this
signals (H-5) and the α-carbonyl carbon atom C-7 and between
both protons H-2 and C-4. As before, the stereochemical
assignment of the THP 17 was unambiguously established by
a
Table 2. Irradiation of Furanone 11
b
c
entry
mmol L−1
solvent
filter
time (min)
conversion (%)
global yield
product ratio 17:18:19:20
1
2
3
4
5
6.8
acetone
acetone
acetone
CH3CN
CH3CN
pyrex
pyrex
pyrex
quartz
quartz
35
87
90
92
90
70
26%
39%
70%
36%
27%
−:1:1.7:1.7
1:2:5.7:4.4
1:1.5:4:2.2
1:1:1.2:1.2
−:1:2.6:1.8
8.9
72
21.6
6.3
180
35
12.7
45
a
b
Irradiations were performed in a nitrogen saturated solution; the external cooling bath was at −20 °C and the jacket cooling liquid at −15 °C. The
c
substrate conversion was monitored by GC. Yield of isolated products.
D
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a
Table 3. Irradiation of Furanone 12
c
d
entry
mmol L−1
solvent
filter
time (min)
conversion (%)
product (yield)
b
1
35
CH3CN/acetone (4.4:1)
acetone
quartz
pyrex
180
45
21 (22%), 22 (21%)
2
3
4
5.4
5.4
10.1
100
100
100
21 (30%), 22 (6%), 23 (10%)
21 (30%), 22 (10%), 23 (10%)
CH3CN
quartz
quartz
30
CH3CN
120
21 (50%), 22 (10%), 23 (14%)
a
b
Irradiations were performed in a nitrogen saturated solution; the external cooling bath was at −20 °C and the jacket cooling liquid at −15 °C. Data
c
d
reported in ref 9, this experiment was performed at room temperature or higher. The substrate conversion was monitored by GC. Yield of isolated
products.
Scheme 6. Mechanistic Scenario for the Photochemically Induced Evolution of 12
other hand, conversely to their observations, we discovered that
irradiation of 12 in exclusively acetonitrile as the solvent (entry
3), and hence under nonsensitized conditions, furnished similar
results as in acetone. Interestingly, by increasing the substrate
concentration in acetonitrile, the overall product yield could be
improved up to 76% (entry 4). The structural assignment of the
photoproducts was accomplished on the basis of their NMR
data, which matched with those described by the Hoffmann
group.
All our experiments were performed with a 1:1 mixture of
pure epimeric furanones 12 with S absolute configuration at C-
5. Our results indicate that the formation of the spiranic acetal
(2R)-21 is clearly favored over that of its epimer (2S)-22, and,
on the other hand, a diastereomeric 1,3-dioxocane with R
configuration in the acetal center was never detected. These
facts support that the relative configuration of the acetal center
plays indeed a primordial role in the evolution pathway of the
excited furanone. Hence, the irradiation of the initial mixture of
(1′R)-12 and (1′S)-12 should furnish the two corresponding
diastereomeric excited species, which will evolve either by 1,5-
or 1,7-abstraction of an axially oriented hydrogen atom
(Scheme 6). When the initial configuration of the acetal center
is S, after 1,5-HAT, recombination of the diradical I-12proR leads
to the [6,6]-spiroketal system (2R)-21, which presents one
anomeric and one nonanomeric relationship. In contrast, when
the initial configuration of the acetal center is R a parallel
sequence of events furnishes the spiroketal (2S)-22 with two
nonanomeric relationships. It is therefore reasonable to expect
that the cyclization of the diradical intermediate I-12proS was
disfavored compared to that of I-12proR and that other
alternative pathways could compete advantageously. Besides
reversion to the original species, I-12proS could evolve through
1,5-transannular hydrogen shift21 to give the regioisomeric
diradical I′-12, which is also available directly from the excited
enone [(1′R)-12]* by 1,7-HAT and that by cyclization
furnishes the dioxecane 23. This scenario is consistent with
the experimental results and in agreement with the reported
theoretical calculations.11 It is worth mentioning that the
preparation of [6,6]-spiroketals with one or two nonanomeric
relationships is not a trivial issue, since most of the standard
methods of ketal formation are equilibrium processes and lead
to the most stable anomeric systems.22
Methanolysis of 2 and (2R)-21. To explore the lactone
opening route, the bicycle 2 was transformed into the 2,3,5-
trisubstituted THP 24 by treatment with sodium methoxide in
refluxing methanol, followed by acidification with 1 M HCl, in
65% yield (Figure 2). When the same protocol was applied to
the tricycle (2R)-21, we isolated a mixture of the expected
[6,6]-spiroketal 25 and its epimer at C-5, but the epimerization
could be avoided by a milder acidic workup with saturated
E
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solution of LDA (5.9 mmol) in THF (16 mL) at 0 °C under nitrogen
and the mixture stirred for 30 min. Then, the corresponding epoxide
(2.8 mmol) was added, and the reaction mixture was stirred at 0 °C for
4 h. The cool slurry was acidified with glacial acetic acid, and then
heated at the reflux temperature for 16 h. Afterward, the reaction
mixture was cooled and neutralized by adding a saturated aqueous
solution of sodium bicarbonate (15 mL). The organic layer was
separated, and the aqueous phase was extracted with diethyl ether (3 ×
10 mL). The combined organic extracts were concentrated under
reduced pressure. The residue was taken up in CH2Cl2 (20 mL), and
then hydrogen peroxide (30%, 3 mL, 26.4 mmol) was added dropwise
at 0 °C. After 2 h, the reaction mixture was diluted with water (15
mL), the organic layer was separated, and the aqueous one was
extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts
were dried over anhydrous sodium sulfate and the solvent removed,
furnishing a crude material which was purified by column
chromatography.
Figure 2. Methanolysis products of of 2 and (2R)-21.
aqueous ammonium chloride, in which case the spirane 25 was
exclusively isolated in 62% yield. The two epimers were easily
distinguished by the coupling constant pattern of the 1H NMR
signal corresponding to the epimeric center. Thus, for isomer
25 proton H-5 (δ 2.67) displays J values typical of an equatorial
orientation (6.6 and 1.4 Hz), while for 5-epi-25 these values are
consistent with an axial geometry (13.1 and 4.2 Hz).
(S)-5-Methoxymethyl-2(5H)-furanone (7).14 Following the general
procedure, from (S)-glycidyl methyl ether (250 μL, 2.8 mmol), after
purification by column chromatography (hexanes−EtOAc, 4:1),
furanone 7 (287 mg, 2.24 mmol, 80% yield) was obtained as an oil:
[α]D −90.1 (c 0.7, CDCl3); 1H NMR (250 MHz, CDCl3) δ 7.47 (dd,
J4,3 = 5.8 Hz, J4,5 = 1.6 Hz, 1H, H-4), 6.21 (dd, J3,4 = 5.8 Hz, J3,5 = 2.1
Hz, 1H, H-3), 5.19 (tdd, J5,6 = 5.0 Hz, J5,3 = 2.1 Hz, J5,4 = 1.6 Hz, 1H,
H-5), 3.59 (d, J1′,5 = 5.0 Hz, 2H, H-1′), 3.38 (s, 3H, H-3′).
CONCLUSIONS
■
The irradiation of a series of enantiomerically pure 5-
oxymethyl-2(5H)-furanones has proven to be a straightforward
entry to diverse and stereochemically rich fragment-molecules,
most of which contain the privileged tetrahydropyran scaffold.
The reactions take place under both sensitized (acetone) and
nonsensitized (acetonitrile, ether) conditions, and they are
highly stereoselective. The formation of the THP involves a
1,5-hydrogen atom transfer process in the excited state of the
furanone, leading to a diradical intermediate that recombines to
form a new σ C−C bond. When the substrate contains an allyl
residue the cyclization is not regioselective, and besides, the
intramolecular [2 + 2] cycloaddition leading to cyclobutanes
competes advantageously. When the substrate contains a THP
residue, the cyclization involves the concomitant formation of
[6,6]-spiroketals with nonanomeric relationships and competes
with the formation of an oxecane ring. The THP derivatives
prepared herein could be further elaborated to a plethora of
different tetrahydropyrans and [6,6]-spiroketals.
(S)-5-Butoxymethyl-2(5H)-furanone (8).14 Following the general
procedure, from (S)-glycidyl butyl ether (400 μL, 2.8 mmol), after
purification by column chromatography (hexanes−EtOAc, 4:1),
furanone 8 (471 mg, 2.77 mmol, 99% yield) was obtained as an oil:
[α]D −125.6 (c 1.0, CHCl3); 1H NMR (360 MHz, CDCl3) δ 7.48 (dd,
J4,3 = 6.4 Hz, J4,5 = 1.2 Hz, 1H, H-4), 6.11 (dd, J3,4 = 6.4 Hz, J3,5 = 2.0
Hz, 1H, H-3), 5.12−5.09 (m, 1H, H-5), 3.64 (dd, Jgem = 10.6 Hz, J1′,5
=
5.3 Hz, 1H, H-1′), 3.57 (dd, Jgem = 10.6 Hz, J1′,5 = 5.6 Hz, 1H, H-1′),
3.47−3.40 (m, 2H, H-3′), 1.51−1.46 (m, 2H, H-4′), 1.38−1.16 (m,
2H, H-5′), 0.84 (t, J4′,3′ = 7.2 Hz, 3H, H-6′).
(S)-5-Isopropoxymethyl-2(5H)-furanone (9). Following the general
procedure, from (S)-glycidyl isopropyl ether (354 μL, 2.8 mmol), after
purification by column chromatography (hexanes−EtOAc, 4:1),
furanone 9 (420 mg, 2.68 mmol, 96% yield) was obtained as a
colorless oil: [α]D −31 (c 0.7, CHCl3); IR (ATR) 2973, 1753, 1094
cm−1; 1H NMR (360 MHz, CDCl3) δ 7.54 (dd, J4,3 = 5.7 Hz, J4,5 = 1.8
Hz, 1H, H-4), 6.18 (dd, J3,4 = 5.7 Hz, J3,5 = 2.0 Hz, 1H, H-3), 5.13 (dd,
EXPERIMENTAL SECTION
■
General Methods. Commercially available reagents were used as
received. The solvents were dried by distillation over the appropriate
drying agents. All reactions were performed avoiding moisture by
standard procedures and under nitrogen atmosphere. Flash column
J
5,1′ = 5.5 Hz, J5,4 = 1.8 Hz, 1H, H-5), 3.75 (dd, Jgem = 10.3 Hz, J1′,5
=
=
5.5 Hz, 1H, H-1′), 3.67−3.55 (m, 2H, H-3′ and H-1′), 1.15 (d, J4′,3′
6.4 Hz, 3H, H-4′), 1.13 (d, J4′,3′ = 6.4 Hz, 3H, H-4′); 13C NMR (90
MHz) (CDCl3) δ 173.0 (C-2), 154.5 (C-4), 122.5 (C-3), 82.4 (C-5),
73.1 (C-3′), 68.0 (C-1′), 22.0 (C-4′), 21.9 (C-4′). HRMS m/z (ESI-
TOF) calcd for [C8H12O3 + Na]+: 179.0684. Found: 179.0680.
(S)-5-(2-Methoxyethoxy)methoxymethyl-2(5H)-furanone (10).
To a solution of furanone 13 (438 mg, 3.71 mmol) in dry CH2Cl2
(5 mL) at 0 °C was added DIPEA (970 μL, 5.55 mmol) dropwise, and
then 1-(chloromethoxy)-2-methoxyethane (636 μL, 5.57 mmol) was
added. After 24 h of stirring at rt, CH2Cl2 (10 mL) was added, and the
solution was successfully washed with 5% hydrochloric acid (2 × 5
mL), a solution aqueous saturated bicarbonate (2 × 5 mL), and brine
(2 × 5 mL). The layers were separated, and the organic extracts were
dried over sodium sulfate. Evaporation of the solvent gave a residue
which was purified by column chromatography (hexanes−EtOAc, 2:1)
to furnish furanone 10 (647 mg, 82% yield) as a colorless oil: [α]D
−91.7 (c 2.73, CHCl3); IR (ATR) 3093, 2927, 2891, 1756, 1602, 1454,
1164 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J4,3 = 5.5 Hz, J4,5
= 1.2 Hz, 1H, H-4), 6.12 (dd, J3,4 = 5.5 Hz, J3,5 = 1.8 Hz, 1H, H-3),
1
chromatography was performed using silica gel (230−400 mesh). H
NMR and 13C NMR spectra were recorded at 250.13 and 62.5 MHz,
360.11 and 90.55 MHz, or 500.13 and 125.75 MHz. Proton and
carbon chemical shifts are reported in ppm (δ) (CDCl3, δ 7.26 for 1H;
CDCl3, δ 77.2 for 13C). NMR signals were assigned with the help of
COSY, HSQC, HMBC, and NOESY experiments. Melting points were
determined on a hot stage and are uncorrected. Optical rotations were
measured at 22 2 °C.
(S)-5-Benzyloxymethyl-2(5H)-furanone (1).5b To a solution of
furanone 13 (335 mg, 2.94 mmol) in dry CH2Cl2 (26 mL) at 0 °C
under nitrogen was added benzyltrichloroacetimidate (600 μL, 3.23
mmol) and trifluoromethanesulfonic acid (26 μL, 0.3 mmol). The
resulting mixture was stirred for 4 h. After this period, the reaction
mixture was washed with 1 M HCl (5 mL), water (5 mL), and brine (5
mL) and the organic layer was separated. The organic extracts were
dried over anhydrous sodium sulfate. Evaporation of the solvent
followed by column chromatography (hexanes−Et2O, 1.5:1) afforded
the title compound 1 (557 mg, 2.73 mmol, 93% yield) as a colorless
1
5.13 (m, 1H, H-5), 4.66 (s, 2H, H-3′), 3.78 (dd, Jgem = 11.0 Hz, J1′,5
=
oil: [α]D −10.7 (c 1.6, EtOH); H NMR (250 MHz, CDCl3) δ 7.42
4.9 Hz, 1H, H-1′), 3.74 (dd, Jgem = 11.0 Hz, J1′,5 = 5.5 Hz, 1H, H-1′),
3.63 (m, 2H, H-5′), 3.49 (m, 2H, H-6′), 3.32 (s, 3H, H-8′); 13C NMR
(100 MHz, CDCl3) δ 172.6 (C-2), 153.0 (C-4), 122.6 (C-3), 95.6 (C-
3′), 81.9 (C-5), 71.5 (C-1′), 67.0 (C-5′), 66.9 (C-6′), 58.9 (C-8′). MS
(FAB+) 157 (M+ − 45.1), 127 (15), 59 (100). Anal. Calcd for
[C9H14O5]: C, 53.46; H, 6.98. Found: C, 53.33; H, 7.02.
(dd, J4,3 = 5.8 Hz, J4,5 = 1.6 Hz, 1H, H-4), 7.27 (s, 5H, C6H5), 6.07
(dd, J3,4 = 5.8 Hz, J3,5 = 1.7 Hz, 1H, H-3), 5.07 (m, 1H, H-5), 4.49 (s,
2H, H-3′), 3.62 (d, J1′.5 = 5.3 Hz, 2H, H-1′).
General Procedure for the Synthesis of 2(5H)-Furanones 7−9
from (S)-Alkyl Glycidil Ethers. A solution of 2-(phenylseleno)acetic
acid (600 mg, 2.8 mmol) in THF (8 mL) was added to a stirred
F
DOI: 10.1021/acs.joc.5b01354
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(S)-5-Allyloxymethyl-2(5H)-furanone (11). To a solution of
furanone 13 (500 mg, 4.38 mmol) in dry CH2Cl2 (85 mL) and dry
cyclohexane (35 mL) were added allyl trichloroacetimidate (1.20 mL,
7.45 mmol) and trifluoromethanesulfonic acid (0.58 mL, 1.32 mmol)
successively at 0 °C. After 2 h of stirring at 0 °C and 3 h at rt, the
reaction was quenched by addition of a sodium bicarbonate solution
(30 mL) and water (20 mL). The organic phase was separated, dried
over MgSO4, and concentrated under vacuum. The resulting oil was
purified by column chromatography (hexanes−EtOAc, 2:1) to give
furanone 11 (209 mg, 1.36 mmol, 31% yield) as a yellow oil: [α]D
compound 14 (82 mg, 0.64 mmol, 52% yield) as a colorless oil:
1
[α]D −3.0 (c 0.6, CDCl3); IR (ATR) 2919, 1729, 1463 cm−1; H
NMR (250 MHz, CDCl3) δ 4.72 (m, 1H, H-5), 4.11 (dt, Jgem = 10.7
Hz, J2eq,1 = J2eq,4eq = 2.7 Hz, 1H, H-2eq), 3.94 (dt, Jgem = 11.6 Hz, J4eq,5
= J4eq,2eq = 2.7 Hz, 1H, H-4eq), 3.70 (d, Jgem = 10.7 Hz, 1H, H-2ax), 3.66
(d, Jgem = 11.6 Hz, 1H, H-4ax), 2.66 (m, 1H, H-1), 2.56 (m, 1H, H-
8eq), 2.09 (d, Jgem = 11.3 Hz, 1H, H-8ax); 3C NMR (90 MHz, CDCl3)
δ 176.6 (C-7), 75.8 (C-5), 68.0 (C-2), 67.3 (C-4), 40.5 (C-1), 35.8
(C-8). HRMS m/z (ESI-TOF) calcd for [C6H8O3 + Na]+: 151.0363.
Found: 151.0366.
1
−71.7 (c 1.0, CHCl3); IR (ATR) 1745, 1261, 1167, 1086 cm−1; H
(1R,2S,5S)-2-Propyl-3,6-dioxabicyclo[3.2.1]octan-7-one (15). A
solution of furanone 8 (81 mg, 0.47 mmol) in acetonitrile (75 mL)
was irradiated through a quartz filter for 40 min at −20 °C. After total
conversion, the solvent was evaporated, and the residue was purified
by column chromatography (hexanes−Et2O, 2:1) to afford compound
15 (42 mg, 0.24 mmol, 52% yield) as a colorless oil. [α]D −10 (c 0.8,
NMR (250 MHz, CDCl3) δ 7.50 (dd, J4,3 = 5.7 Hz, J4,5 = 1.6 Hz, 1H,
H-4), 6.21 (dd, J3,4 = 5.7 Hz, J3,5 = 2.0 Hz, 1H, H-3), 5.96−5.74 (m,
1H, H-4′), 5.31 (m, 3H, H-5′, H-5), 4.05 (d, J3′,4′ = 5.7 Hz, 2H, H-3′),
3.70 (dd, Jgem = 10.5 Hz, J1′,5 = 5.3 Hz, 1H, H-1′), 3.64 (dd, Jgem = 10.5
Hz, J1′,5 = 5.1 Hz, 1H, H-1′); 13C NMR (62.5 MHz, CDCl3) δ 172.9
(C-2), 154.1 (C-4), 133.9 (C-4′), 122.7 (C-3), 117.9 (C-5′), 82.3 (C-
5), 72.8 (C-3′), 69.6 (C-1′). HRMS m/z (ESI-TOF) calcd for
[C8H10O3 + Na]+: 177.0528. Found: 177.0522.
1
CDCl3); IR (ATR) 2958, 1776, 1458, 1340, 1155 cm−1; H NMR
(360 MHz, CDCl3) δ 4.70 (m, 1H, H-5), 4.07 (ddd, J = 8.3 Hz, J = 5.1
Hz, J2,1 = 2.5 Hz, 1H, H-2), 3.77 (m, 2H, H-4), 2.54 (ddd, J1,8eq = 5.9
Hz, J1,2 = 2.5 Hz, J1,8ax = 1.2 Hz, 1H, H-1), 2.33 (m, 1H, H-8eq), 2.28
(dd, Jgem = 11.8 Hz, J8ax,1 = 1.2 Hz, 1H, H-8ax), 1.80 (m, 1H, H-1′),
1.54−1.31 (m, 3H, H-1′, 2 × H-2′), 0.97 (t, J3′,2′ = 7.2 Hz, 3H, H-3′);
13C NMR (90 MHz, CDCl3) δ 177.5 (C-7), 76.6 (C-5), 73.5 (C-2),
63.7 (C-4), 43.2 (C-1), 32.3 (C-1′), 29.0 (C-8), 18.9 (C-2′), 13.8 (C-
3′). HRMS (ESI-TOF) calcd for [C9H14O3 + Na]+: 193.0838. Found:
193.0835.
(S)-5-(Tetrahydro-2H-pyran-2-yl)oxymethyl-2(5H)-furanone
(12).13 To a solution of furanone 13 (347 mg, 3.04 mmol) in CH2Cl2
(35 mL) at rt were added dihydropyran (294 μL, 3.21 mmol) and p-
toluensulfonic acid (34 mg, 0.17 mmol). The resulting mixture was
stirred for 21 h. After this period, the reaction was quenched with the
addition of saturated sodium bicarbonate solution (15 mL). The
organic layer was separated and the aqueous one extracted with
CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over
anhydrous sodium sulfate. Evaporation of the solvent, followed by
purification by column chromatography (hexanes−EtOAc, 3:1),
afforded a 1:1 mixture of epimeric furanones 12 (482 mg, 2.43
mmol, 80% yield) as a colorless oil: IR (ATR) 3070, 1240, 1753, 1618,
(1R,5S)-2,2-Dimethyl-3,6-dioxabicyclo[3.2.1]octan-7-one (16). A
solution of furanone 9 (104 mg, 0.66 mmol) in acetonitrile (75 mL)
was irradiated through a quartz filter for 30 min at −20 °C. After total
conversion, the solvent was evaporated, and the residue was purified
by column chromatography (hexanes−Et2O, 2:1) to deliver
compound 16 (51 mg, 0.33 mmol, 50% yield) as a colorless oil:
[α]D20 −5.5 (c 0.7, CDCl3); IR (ATR) 2981, 1764, 1458, 1337, 1162,
1
1154 cm−1; H NMR (360 MHz, CDCl3) δ 7.47 (m, 2H, H-4), 6.09
(m, 2H, H-3), 5.20 (m, 2H, H-5), 4.62 (m, 1H, H-2′), 4.62 (m, 1H, H-
2″), 4.59 (m, 1H, H-2″), 3.94−3.87 (m, 2H, H-1′), 3.85−3.74 (m, 2H,
H-6″), 3.66−3.60 (m, 2H, H-1′), 3.55−3.45 (m, 2H, H-6″), 1.90−1.40
(m, 12H, H-3″, H-4″, H-5″).
1
1125 cm−1; H NMR (360 MHz, CDCl3) δ 4.64 (m, 1H, H-5), 3.79
(m, 2H, H-4), 2.38 (m, 3H, H-1 and 2 × H-8), 1.40 (s, 3H, H-1′), 1.34
(s, 3H, H-1′); 13C NMR (90 MHz, CDCl3) δ 176.1 (C-7), 75.8 (C-5),
72.8 (C-2), 63.5 (C-4), 48.1 (C-1), 31.4 (C-8), 27.0 (C-1′), 21.7 (C-
1′). HRMS (ESI-TOF) calcd for [C8H12O3 + Na]+: 179.0684. Found:
179.0683.
(1R,2S,5S)-2-Vinyl-3,6-dioxabicyclo[3.2.1]octan-7-one (17),
(1S,7S,Z)-3,9-Dioxabicyclo[5.2.1]dec-4-en-8-one (18), (1aS,3a-
S,6aR,6bR)-Hexahydro-1H,2H-3,5-dioxacyclobuta[cd]inden-2-one
(19), and (1R,3S,7S,10S)-5,8-Dioxatricyclo[5.3.0.0]decan-9-one (20).
A solution of furanone 11 (250 mg, 1.62 mmol) in acetone (75 mL)
was irradiated through a pyrex filter for 180 min at −20 °C. Then, the
solvent was evaporated, and the oily residue was purified by column
chromatography (hexanes−Et2O, 4:1) to afford 17 (20 mg, 0.13
mmol, 8% yield), 18 (30 mg, 0.19 mmol, 12% yield), and a 1.8:1
mixture of 19 and 20 (125 mg, 0.81 mmol, 50% yield).
General Procedure for the Photochemical Reactions.
Irradiations were performed in a small conventional photochemical
reactor (two-necked vessel fitted with a pyrex or quartz immersion
type cooling jacket) using a high pressure 125 W mercury lamp.
Methanol at −15 °C was used for refrigeration of the immersion well
jacket. The vessel was externally cooled at −20 °C with a dry ice−CCl4
bath or at −40 °C with a dry ice−acetonitrile bath. The reaction
mixtures were initially degassed by bubbling oxygen-free argon
through the solution for 10 min and then irradiated under atmosphere
of argon. The progress of the reactions was monitored by GC analysis
of aliquot samples.
(1R,2S,5S)-2-Phenyl-3,6-dioxabicyclo[3.2.1]octan-7-one (2). A
solution of furanone 1 (98 mg, 0.49 mmol) in diethyl ether (75
mL) was irradiated through a quartz filter for 15 min at −20 °C. After
total conversion, the solvent was evaporated, and the residue was
purified by column chromatography (hexanes−Et2O, 3:1) to give
compound 2 (76 mg, 0.38 mmol, 78% yield) as a colorless solid: mp
114−112 °C (from EtOAc−pentane); [α]D −114.6 (c 1.15, CHCl3);
17: [α]D +10.2 (c 0.9, CDCl3); IR (ATR) 3469, 2960, 2871, 1774,
1157 cm−1; 1H NMR (360 MHz, CDCl3) δ 5.79 (ddd, J1,2′ = 17.3 Hz,
J
1,2′ = 10.8 Hz, J1′,2 = 3.3 Hz, 1H, H-1′), 5.45 (m, 2H, H-2′), 4.71 (br s,
2H, H-2 and H-5), 3.85 (br s, 2H, H-4), 2.68 (br s, 1H, H-1), 2.39−
2.34 (m, 1H, H-8eq), 2.26 (d, Jgem = 11.8 Hz, 1H, H-8ax); 13C NMR
(90 MHz, CDCl3) δ 176.4 (C-7), 133.6 (C-1′), 117.8 (C-2′), 76.5 (C-
5), 73.5 (C-2), 63.7 (C-4), 43.2 (C-1), 29.7 (C-8). HRMS (ESI-TOF)
calcd for [C8H10O3 + Na]+: 177.0528. Found: 177.0522.
1
IR (ATR) 2256, 1785, 1454, 1352, 1159 cm−1; H NMR (400 MHz,
C6D6) δ 7.10 (m, 5H, C6H5), 5.30 (d, J2,1 = 2.1 Hz, 1H, H-2), 3.81
(ddd, J5,8 = 5.9 Hz, J5,4 = J5,4 = 2.1 Hz, 1H, H-5), 3.61 (ddd, Jgem = 11.9
Hz, J4eq,8eq = 2.4 Hz, J4eq,5 = 2.1 Hz, 1H, H-4eq), 3.20 (dd, Jgem = 11.9
Hz, J4ax,5 = 2.1 Hz, 1H, H-4ax), 2.74 (ddd, J1,8eq = 5.9 Hz, J1,2 = 2.1 Hz,
J1,8ax = 1.2 Hz, 1H, H-1), 1.56 (dt, Jgem = 11.7 Hz, J8eq,5 = J8eq,1 = 5.9
Hz, 1H, H-8eq), 1.36 (dd, Jgem = 11.7 Hz, J8ax,1 = 1.2 Hz, 1H, H-8ax);
13C NMR (62.5 MHz, CDCl3) δ 137.9 (Ph), 129.7 (CH, Ph), 128.9
(Ph), 128.5 (Ph), 127.7 (Ph), 125.5 (Ph), 76.5 (C-2), 74.2 (C-5), 64.2
(C-4), 43.5 (C-1), 29.9 (C-8). Anal. Calcd for (C12H12O3): C, 70.58;
H, 5.92. Found: C, 70.48%, H: 5.87%.
(1R,5S)-3,6-Dioxabicyclo[3.2.1]octan-7-one (14). A solution of
furanone 7 (158 mg, 1.23 mmol) in acetonitrile (75 mL) was
irradiated through a quartz filter for 105 min at −20 °C. After total
conversion, the solvent was evaporated, and the residue was purified
by column chromatography (hexanes−Et2O, 2:1) to deliver
18: [α]D +8.0 (c 0.7, CDCl3); IR (ATR) 3433, 2940, 2872, 1753,
1719 cm−1; 1H NMR (360 MHz, CDCl3) δ 6.45 (d, J4,5 = 5.4 Hz, 1H,
H-4), 5.09 (q, J5,4 = 5.4 Hz, J5,6 = 5.4 Hz, 1H, H-5), 4.72 (m, 1H, H-1),
4.07 (br d, Jgem = 13.0 Hz, 1H, H-2), 3.72 (dd, Jgem = 13.0 Hz, J2.1 = 2.0
Hz, 1H, H-2), 3.02 (ddd, J = 10.4 Hz, J = 5.8 Hz, J = 1.4 Hz, 1H, H-7),
2.59 (m, 2H, H-6, H-10), 2.43 (m, 1H, H-6), 2.38 (m, 1H, H-10); 13C
NMR (90 MHz, CDCl3) δ 179.5 (C-8), 148.3 (C-4), 115.0 (C-5),
80.0 (C-2), 72.8 (C-1), 38.9 (C-7), 29.5 (C-6), 26.6 (C-10). HRMS
(ESI-TOF) calcd for [C8H10O3 + Na]+: 177.0522. Found: 177.0525.
19: 1H NMR (500 MHz, CDCl3) δ 4.60 (br d, J3a,4 = 8.9 Hz, 1H, H-
3a), 4.26 (d, Jgem = 13.5 Hz, 1H, H-4), 3.72 (d, Jgem = 12.4 Hz, 1H, H-
6), 3.41 (d, Jgem = 12.4 Hz, 1H, H-6), 3.41 (dd, Jgem = 13.5 Hz, J4,3a
=
8.9 Hz, 1H, H-4), 3.15 (m, 2H, H-6b, H-1a), 2.71−2.61 (m, 2H, H-6a,
G
DOI: 10.1021/acs.joc.5b01354
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The Journal of Organic Chemistry
Article
1
H-1), 2.32 (dd, Jgem = 11.2 Hz, J = 6.0 Hz, 1H, H-1); H NMR (500
MHz, C6D6) δ 4.03 (d, Jgem = 13.4 Hz, 1H, H-4), 3.84 (m, 1H, H-3a),
3.29 (d, Jgem = 12.2 Hz, 1H, H-6), 2.83 (dd, Jgem = 12.2 Hz, J6,6a = 3.5
Hz, 1H, H-6), 2.76 (dd, Jgem = 13.4 Hz, J4,3a = 2.0 Hz, 1H, H-4), 2.70
(m, 1H, H-1a), 2.23 (m, 1H, H-6b), 2.12 (m, 2H, H-1), 1.72 (m, 1H,
H-6a); 13C NMR (125 MHz, CDCl3) δ 179.2 (C-2), 74.8 (C-3a), 68.4
(C-6), 67.9 (C-4), 34.9 (C-6a), 29.7 (C-6b), 26.9 (C-1), 26.8 (C-1a).
GC/MS (m/z) 154.1 (M+).
stirring. After 12 h, the reaction was quenched by addition of 1 M HCl,
the organic phase was separated, dried with MgSO4, and concentrated
under vacuum. The resulting oil was purified by column chromatog-
raphy (hexanes−Et2O, 2:1) to give compound 24 (41 mg, 0.17 mmol,
65% yield) as a colorless oil: [α]D + 18.2 (c 0.6, CDCl3); IR (ATR)
1
3446, 2951, 2867, 1782, 1730 cm−1; H NMR (360 MHz, CDCl3) δ
7.34−7.28 (m, 5H, H-Ph), 4.45 (d, J2ax,3ax = 10.0 Hz, 1H, H-2), 4.15
(ddd, Jgem = 10.8 Hz, J6eq,5ax = 4.9 Hz, J6a,4eq = 2.2 Hz, 1H, H-6eq), 3.90
20: 1H NMR (500 MHz, CDCl3) δ 4.82 (dd, J7,1 = 7.2 Hz, J7,6 = 3.9
Hz, 1H, H-7), 4.14 (dd, Jgem = 13.2 Hz, J6,7 = 3.9 Hz, 1H, H-6), 4.06
(dd, Jgem = 12.3 Hz, J4,3 = 4.3 Hz, 1H, H-4), 4.00 (d, Jgem = 13.2 Hz,
1H, H-6), 3.61 (d, Jgem = 12.3 Hz, 1H, H-4), 3.15 (m, 3H, H-1, H-10,
H-3), 2.58 (m, 1H, H-2), 1.89 (d, Jgem = 12.4 Hz, 1H, H-2); 13C NMR
(125 MHz, CDCl3) δ 178.75 (C-9), 77.60 (C-7), 68.50 (C-4), 68.03
(C-6), 40.54 (C-3), 39.46 (C-10), 38.92 (C-1), 26.70 (C-2). GC/MS
(m/z) 154.1 (M+).
(m, 1H, H-5), 3.47 (s, 3H, CH3O), 3.36 (dd, Jgem = 10.8 Hz, J6ax,5ax
=
10.2 Hz, 1H, H-6ax), 2.82 (ddd, J3ax,4ax = 12.5 Hz, J3ax,2ax = 10.0 Hz,
J3ax,4eq = 3.9 Hz, 1H, H-3ax), 2.40 (ddd, Jgem = 12.5 Hz, J4eq,3ax = 3.9
Hz, J4eq,6eq = 2.2 Hz, 1H, H-4eq), 1.87 (q, Jgem = 12.5 Hz, J4ax,5ax = 12.5
Hz, J4ax,3ax = 12.5 Hz, 1H, H-4ax); 13C NMR (90 MHz, CDCl3) δ
172.5 (CO), 139.3 (C-Ar), 128.5 (4 × C, C-Ar), 126.9 (C-Ar), 81.1
(C-2), 72.9 (C-6), 65.26 (C-5), 51.8 (CH3O), 49.1 (C-3), 36.5 (C-4).
HRMS (ESI-TOF) calcd for [C13H16O4 + Na]+: 259.0941. Found:
259.0943.
(1R,2R,5S)-Tetrahydro-7H-spiro[3,6-dioxabicyclo[3.2.1]octane-
2,2′-pyran]-7-one (2R-21), (1R,2S,5S)-Tetrahydro-7H-spiro[3,6-
dioxabicyclo[3.2.1]octane-2,2′-pyran]-7-one (2S-22), and
(1RS,2R,5S,8RS)-4,7,12-Trioxatricyclo[6.3.1.12,5]tridecan-3-one (23).
A solution of furanone 12 (1:1 mixture of epimers at the acetal center,
150 mg, 0.76 mmol) in acetonitrile (75 mL) was irradiated through a
quartz filter for 120 min at −20 °C. The solvent was evaporated, and
the resulting residue was purified by column chromatography
(hexanes−AcOEt, 5:1) to deliver 2R-21 (75 mg, 0.38 mmol, 50%
yield) as a colorless oil, 2S-22 (21 mg, 0.11 mmol, 14% yield) as a
colorless oil, and 23 (16 mg, 0.08 mmol, 10% yield) as a colorless oil.
2R-21: [α]D −8.0 (c 0.8, CDCl3); IR (ATR) 3431, 2941, 2873,
(3S,5R,6R)-Methyl 3-hydroxy-1,7-dioxaspiro[5.5]undecane-5-car-
boxylate (25). To a solution of the tricyclic lactone 2R-21 (40 mg, 0.2
mmol) in methanol (3 mL) was added NaMeO (54.5 mg, 1.01 mmol),
and the reaction was heated to the reflux temperature while stirring.
After 12 h, the reaction was quenched by addition of saturated
aqueous ammonium chloride; the organic phase was separated, dried
with MgSO4, and concentrated under vacuum. The resulting oil was
purified by column chromatography (hexanes−Et2O, 1:1) to give 25
(28 mg, 0.12 mmol, 62% yield) as a colorless oil: [α]D −72.0 (c 0.4,
1
CDCl3); IR (ATR) 3468, 2952, 2870, 1775, 1731 cm−1; H NMR
(400 MHz, C6D6) δ 5.62 (d, JOH,3 = 11.2 Hz, 1H, OH), 3.82 (ddd, Jgem
= 11.7 Hz, J2eq,3eq = 3.9 Hz, J2eq,4eq = 1.9 Hz, 1H, H-2eq), 3.61 (dd, Jgem
= 11.7 Hz, J2ax,3eq = 2.2 Hz, 1H, H-2ax), 3.53 (ddd, J3eq,OH = 11.2 Hz,
J3eq,2eq = 3.9 Hz, J3eq,2ax = 2.2 Hz, 1H, H-3eq), 3.36 (m, 2H, H-8), 3.16
(s, 3H, CH3O), 2.67 (dd, J5eq,4ax = 6.6 Hz, J5eq,4a = 1.4 Hz, 1H, H-5eq),
2.12 (ddd, Jgem = 14.5 Hz, J4ax,5eq = 6.6 Hz, J4ax,3eq = 4.2 Hz, 1H, H-
4ax), 1.80 (m, 1H, H-4eq), 1.64 (m, 1H, H-11), 1.42 (m, 1H, H-11),
1.22 (m, 3H, H-9, 2 × H-10), 1.12 (m, 1H, H-9); 13C NMR (100
MHz, C6D6) δ 176.3 (CO), 94.9 (C-6), 66.2 (C-2), 62.7 (C-3),
61.3 (C-8), 52.1 (CH3O), 47.7 (C-5), 33.6 (C-11), 27.5 (C-4), 25.4
(C-10), 19.0 (C-9). HRMS (ESI-TOF) calcd for [C11H18O5 + Na]+:
253.1046. Found: 253.1049.
1764, 1720 cm−1; H NMR (400 MHz, CDCl3) δ 4.67 (d, J5.4 = 5.7
1
Hz, J5,8eq = 2.1 Hz, 1H, H-5), 3.88−3.67 (m, 4H, 2 × H-4, 2 × H-2′),
2.74 (d, Jgem = 11.6 Hz, 1H, H-8ax), 2.57 (d, J1,8eq = 5.4 Hz, 1H, H-1),
2.23 (ddd, Jgem = 11.6 Hz, J8eq,1 = 5.4 Hz, J8eq,5 = 2.1 Hz, 1H, H-8eq),
2.06 (m, 1H, H-5′), 1.78 (m, 1H, H-4′), 1.52 (m, 4H, 2 × H-3′, H-4′,
H-5′); 1H NMR (250 MHz, C6D6) δ 3.71 (dd, J5.8eq = 5.7 Hz, J5,4eq
=
3.0 Hz, 1H, H-5), 3.42 (td, Jgem = J2′ax,3′ax = 11.7 Hz, J2′ax,3′eq = 3.0 Hz,
1H, H-2ax), 3.35 (m, 1H, 2′eq), 3.42 (dt, Jgem = 11.4 Hz, J4eq,5 = J4eq,8eq
= 3.0 Hz, 1H, H-4eq), 3.11 (d, Jgem = 11.4 Hz, 1H, H-4ax), 2.29−2.16
(m, 3H, H-1, H-5′ax, H-8ax), 1.63 (m, 1H, H-5′eq), 1.47 (dtd, 1H,
Jgem = 11.0 Hz, J8eq,5 = J8eq,1 = 5.7 Hz, J8eq,4eq = 3.0 Hz, 1H, H-8eq),
1.38−1.11 (m, 4H, 2 × H3′, 2 × H-4′); 13C NMR (100 MHz, CDCl3)
δ 175.1 (C-7), 94.6 (C-2), 76.2 (C-5), 62.8 (C-4), 62.2 (C-2′), 48.8
(C-1), 32.9 (C-5′), 30.2 (C-8), 25.0 (C-3′), 18.0 (C-4′); 13C NMR
(62.5 MHz, C6D6) δ 174.1 (C-7), 94.8 (C-2), 75.5 (C-5), 62.8 (C-4),
61.9 (C-2′), 49.0 (C-1), 33.3 (C-5′), 30.0 (C-8), 25.3 (C-3′), 18.3 (C-
4′). HRMS m/z (ESI-TOF) calcd for [C10H14O4 + Na]+: 221.0790.
Found: 221.0782.
When the reaction was quenched with 1 M HCl, the epimer
(3S,5S,6R)-methyl 3-hydroxy-1,7-dioxaspiro[5.5]undecane-5-carboxy-
late (epi-25) was also isolated: [α]D − 1.5 (c 0.3, CDCl3); IR (ATR)
1
3436, 2941, 2872, 1740, 1720 cm−1; H NMR (400 MHz, C6D6) δ
3.46−3.37 (m, 4H, H-2ax, 2 × H-8, H-3), 3.35 (s, 3H, CH3O), 3.27
(ddd, Jgem = 11.9 Hz, J2eq,3eq = 2.5 Hz, J2eq,4eq = 1.9 Hz, 1H, H-2eq),
2.96 (dd, J5ax,4ax = 13.1 Hz, J5ax,4eq = 4.2 Hz, 1H, H-5ax), 2.46 (ddd, Jgem
= 13.8 Hz, J4ax,5ax = 13.1 Hz, J4ax,3eq = 2.9 Hz, 1H, H-4ax), 2.21 (m, 1H,
H-11), 1.90 (m, 1H, H-10), 1.78 (m, 1H, H-4eq), 1.70 (m, 1H, H-11),
1.40 (m, 2H, H-9, H-10), 1.10 (m, 1H, H-9); 13C NMR (100 MHz,
C6D6) δ 171.9 (CO), 96.2 (C-6), 64.8 (C-2), 64.5 (C-8), 61.6 (C-
3), 51.6 (CH3O), 45.7 (C-5), 33.6 (C-11), 29.5 (C-4), 25.5 (C-10),
19.2 (C-9). HRMS (ESI-TOF) calcd for [C11H18O5 + Na]+: 253.1046.
Found: 253.1048.
2S-22: [α]D −50.3 (c 0.3, CDCl3); IR (ATR) 3433, 2941, 2872,
1754, 1719 cm−1; H NMR (360 MHz, CDCl3) δ 4.72 (br t, J5,4eq
=
1
J5,8eq = 4.5 Hz, 1H, H-5), 4.00 (d, Jgem = 12.6 Hz, 1H, H-4ax), 3.80 (m,
3H, 2 × H-2′ and H-4eq), 2.67 (d, J1,8eq = 4.5 Hz, 1H, H-1), 2.35 (dt,
Jgem = 11.0 Hz, J8eq,1 = J8eq,5 = 4.5 Hz, 1H, H-8eq), 2.22 (d, Jgem = 11.0
Hz, 1H, H-8ax), 1.96 (m, 1H, H-5′), 1.81 (m, 1H, H-4′), 1.62 (m, 2H,
H-3′, H-4′), 1.47 (m, 2H, H-3′, H-5′); 13C NMR (62.5 MHz, CDCl3)
δ 175.5 (C-7), 96.9 (C-2), 77.3 (C-5), 65.1 (C-4), 62.5 (C-2′), 49.3
(C-1), 34.3 (C-5′), 29.8 (C-8), 24.6 (C-3′), 18.8 (C-4′). HRMS m/z
(ESI-TOF) calcd for [C10H14O4 + Na]+: 221.0790. Found: 221.0780.
23: [α]D −38.2 (c 1.2, CDCl3); IR (ATR) 3426, 2943, 2874, 1756,
1722 cm−1; 1H NMR (360 MHz, CDCl3) δ 4.87 (br s, 1H, H-8), 4.59
(ddd, J = 7.2 Hz, J = 4.1 Hz, J = 0.6 Hz, 1H, H-5), 4.07 (m, 2H, H-6
and H-1), 3.57 (d, Jgem = 12.4 Hz, 1H, H-6), 2.58 (m, 1H, H-2), 2.42
(m, 2H, H-13), 2.24 (d, Jgem = 12.6 Hz, 1H, H-11ax), 2.00 (m, 1H, H-
11eq), 1.75 (m, 1H, H-9), 1.60−1.38 (m, 3H, H-9, 2 × H-10); 13C
NMR (90 MHz, CDCl3) δ 177.9 (C-3), 96.2 (C-8), 76.8 (C-5), 69.2
(C-6), 68.2 (C-1), 44.5 (C-2), 31.0 (C-13), 29.1 (C-9), 24.3 (C-11),
12.7 (C-10). HRMS m/z (ESI-TOF) calcd for [C10H14O4 + Na]+:
221.0784. Found: 221.0785.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01354.
1H and 13C NMR spectra of all new compounds and 2D
NMR spectra for compounds 15, 17, 18, 19, 20, 21, 22,
and 23 (PDF)
AUTHOR INFORMATION
■
(2R,3R,5S)-Methyl 5-hydroxy-2-phenyltetrahydro-2H-pyran-3-
carboxylate (24). To a solution of the bicyclic lactone 2 (55 mg,
0.269 mmol) in methanol (2 mL) was added NaMeO (16 mg, 0.296
mmol), and the reaction was heated to the reflux temperature while
Corresponding Authors
*E-mail: ramon.alibes@uab.cat.
*E-mail: marta.figueredo@uab.es.
H
DOI: 10.1021/acs.joc.5b01354
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We acknowledge the Spanish Direccion
tigacio
■
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General de Inves-
n for financial support (Projects CTQ2010-15380,
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CTQ2012-32436, and CTQ2013-41161-R) and Universitat
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DOI: 10.1021/acs.joc.5b01354
J. Org. Chem. XXXX, XXX, XXX−XXX