Intramolecular Photocycloaddition of 2(5 H)-Furanones to Temporarily Tethered Terminal Alkenes as a Stereoselective Source of Enantiomerically Pure Polyfunctionalyzed Cyclobutanes

Article abstract of DOI:10.1021/acs.joc.8b00088

Allyloxymethyloxymethyl and 4-pentenoyloxymethyl substituents have been used as tethering groups to study the intramolecular [2 + 2] photocycloaddition of chiral 5-substituted 2(5H)-furanones. The photoreactions proceed in good yield and provide the expected regio- and diastereoselective tricyclic compounds with complementary regioselectivity, which depends on whether the vinyl chain is attached to the furanone by an acetal or an ester linkage. Computational simulations agree with experimental observations and indicate that the origin of the different observed regioselectivity in the intramolecular photochemical reaction of lactones 5 and 6 arises from the relative stability of the initial conformers. The synthetic potential of the enantiomerically pure photoadducts is illustrated by preparing an all-cis 1,2,3-trisubstituted cyclobutane bearing fully orthogonally protected hydroxyl groups.

Full text of DOI:10.1021/acs.joc.8b00088

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Article
Intramolecular Photocycloaddition of 2(5H)-Furanones to
Temporarly Tethered Terminal Alkenes as a Stereoselective
Source of Enantiomerically Pure Polyfunctionalyzed Cyclobutanes
Yangchun Xin, Luis Rodríguez-Santiago, Mariona Sodupe,
Angel Alvarez-Larena, Felix Busque, and Ramon Alibés
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00088 • Publication Date (Web): 20 Feb 2018
Downloaded from http://pubs.acs.org on February 24, 2018
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Intramolecular Photocycloaddition of 2(5H)ꢀ
Furanones to Temporarly Tethered Terminal Alkenes
as a Stereoselective Source of Enantiomerically Pure
Polyfunctionalyzed Cyclobutanes
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Yangchun Xin, Luís Rodríguez-Santiago,* Mariona Sodupe, Angel Álvarez-Larena, Félix
†
,†
Busqué, and Ramon Alibés*
†
‡
Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
Unitat de Cristal·lografia. Universitat Autonòma de Barcelona, 08193 Bellaterra, Spain
ramon.alibes@uab.cat; luis.rodríguez.santiago@uab.cat
Abstract
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Allyloxymethyloxymethyl and 4ꢀpentenoyloxymethyl substituents have been used as tethered groups
to study the intramolecular [2+2] photocycloaddition of chiral 5ꢀsubstituted 2(5H)ꢀfuranones. The
photoreactions proceed in good yield and provide regioꢀ and diastereoselectively the expected
tricyclic compounds with complementary regioselectivity which depends on whether the vinyl chain
is attached to the furanone by an acetal or an ester linkage. Computational simulations agree with
experimental observations and indicate that the origin of the different observed regioselectivity in
the intramolecular photochemical reaction of lactones 5 and 6 arises from the relative stability of the
initial conformers. The synthetic potential of the enantiomerically pure photoadducts is illustrated by
preparing an allꢀcis 1,2,3ꢀtrisubstituted cyclobutane bearing fully orthogonallyꢀprotected hydroxyl
groups.
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Introduction
Cyclobutanes are found in many natural products and bioactive compounds, and also serve as
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useful intermediates in organic synthesis. There are different methods to accomplish the preparation
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of these privileged building blocks. Among them, [2+2] photocycloaddition reactions involving
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enones and alkenes have been extensively studied over the past decades.
Photochemical [2+2] cycloaddition of 2(5H)ꢀfuranones to symmetrical alkenes have been widely
used by our research group for the diastereoselective preparation of different bicyclo[3.2.0]heptanes
scaffolds with acceptable yields. On the basis of these studies, some natural products and
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cyclobutane fused nucleoside analogues have been synthesized. However, when unsymmetrical
alkenes are used, the utility of the intermolecular [2+2] photocycloaddition reaction is limited as a
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result of the low stereoꢀ and regioselectivity generally achieved in this process.
Unlike the intermolecular version, the intramolecular [2+2] photocycloaddition reaction between
two alkene moieties in the same molecule proceeds with excellent control of the regioꢀ and
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stereoselectivities. This is due to the decreased mobility of the reacting partners that are tethered
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together. In recent years, increasing attention has been given to the use of temporary tethers as
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stereocontrol elements in the intramolecular photoreactions.
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Our studies on the preparation of bicyclic tetrahydropyrans (THPs) by an intramolecular
photoreaction of enantiomerically pure 5ꢀoxymethylꢀ2(5H)ꢀfuranones, showed that the photoreaction
of lactone 1 bearing an allyloxymethyl substituent at Cꢀ5 delivers mainly a regioisomeric mixture of
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the [2+2] photocycloadducts 3 and 4, along with the targeted THP 2 (Scheme 1a). In all the assayed
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reactions, the head to tail (HT) isomer 3 was slightly favored over the head to head (HH) isomer 4.
The present work aims to broaden the scope of the intramolecular photochemical reactions of Cꢀ5
alkenyl substituted 2(5H)ꢀfuranones in order to develop an access to enantiopure all cis trisubstituted
cyclobutane compounds. To this end, we have explored the photoactivated intramolecular
cycloaddition of 2(5H)ꢀfuranones 5-8, bearing an alkenyl chain attached either by an easily
removable ester or ketal linkage, to prepare the corresponding [2+2] adducts, which by further
modifications will lead to triꢀ or tetrasubstituted cyclobutanes (Scheme 1b). Herein, we give a full
account of this study, which includes the preparation of several 2(5H)ꢀfuranones, their
intramolecular [2+2]ꢀphotoreactions as well as the synthesis of a new diversely functionalyzed (all
cis) trisubstituted cyclobutane from the photoadduct derived from 6.
Scheme 1. Intramolecular photocycloadditions of C5ꢀalkenyl substituted 2(5H)ꢀfuranones
Results and Discussion
Synthesis of 2(5H)-furanones
The new furanones 5-8 selected to undertake the photochemical study were prepared starting from
1
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the known enantiomerically pure 2(5H)ꢀfuranone 10 (Scheme 2). Initial attempts to synthesize the
2 2
ester derivative 5 by applying the Steglich procedure (DMAP (cat.), DCC, CH Cl ) were successful
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albeit in moderate yield (52%). Moreover, the formation of dicyclohexylurea in the process made
its purification a tedious process. On the other hand, the condensation of 10 with freshly prepared 3ꢀ
2 2 2 3
pentenoyl chloride (Cl SO, CH Cl ) in the presence of Et N afforded exclusively the elimination
product protoanemonin, 11, thereby indicating that 5 is unstable in basic conditions. It was
eventually found that treatment of 10 with freshly prepared chloride using oxalyl chloride and a
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catalytic amount of DMF in CH
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Cl
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delivered 5 in 77% yield. The acetal 6 was synthesized in 71%
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yield by condensation of 10 with freshly prepared allyl chloromethyl ether, DIPEA as a base and
NaI as a catalyst in THF at the reflux temperature. Other reaction conditions (rt, CH
be less efficient.
2 2
Cl ) proved to
Scheme 2. Synthesis of lactones 5 and 6
Next, the preparation of disubstituted olefins 7 and 8 was attempted through an olefin crossꢀ
metathesis (CM) reaction (Scheme 3). Initial efforts to carry out the CM reaction of 5 and 6 with
nd
allyl alcohol and 2 generation Grubbs catalyst GII (mol 4%) in CH
2
Cl
2
at rt, afforded the expected
compounds 7 and 8 only in 27% and 35% yield, respectively. Substantial amount of homodimeric
products 12, 13 and 14 was also obtained making the purification of 7 or 8 more difficult.
Unfortunately, all attempts to suppress the formation of the homodimers failed and the yield of the
desired compounds were slightly improved (up to 36% for compound 7). Thus, we decided to
prepare them by following a twoꢀstep procedure (olefin CM reaction with (E)ꢀ2ꢀbutenal and
subsequent carbonyl reduction). The treatment of 5 with aldehyde 15 and GII (5 mol%) in CH Cl at
2
2
rt provided the desired product 16 in 54% yield. The reaction did not proceed to completion and a
small amount of homodimer 12 was also observed. After considerable experimentation, it was found
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nd
that the CM reaction to produce the E olefin 16 proceeded in good yield (89%) by using the 2
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generation HoveydaꢀGrubbs catalyst (HGꢀII). In this case we did not observe any significant
amount of homodimers arising from either olefin. The following regioselective reduction of the
aldehyde moiety was achieved in 80% yield under Luche’s conditions. In an analogous manner, the
olefin 8 was prepared from ketal 6 by the twoꢀstep strategy in 68% overall yield.
Scheme 3. Synthesis of lactones 7 and 8
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Photochemical study
With 2(5H)ꢀfuranones 5-8 in hand, we next focused on their intramolecular [2+2]
photocycloaddition reactions by irradiation using a 125W highꢀpressure mercury lamp through a
quartz or Pyrex filter. Since the solvent and temperature play an important role in photochemical
processes, the photoreactions were studied in acetonitrile and acetone at different temperatures. The
progress of the reactions was monitored by GC analyses of aliquots of the reaction mixtures, and the
irradiation was prolonged until the conversion remained constant.
First, the intramolecular [2+2] photocycloaddition of 5 was investigated using experimental
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conditions usually applied in our laboratories for intermolecular photoreactions (Table 1, entry 1).
However, the irradiation of 5 in acetone through a Pyrex filter at different temperatures (from rt to ꢀ
78 °C) did not afford any of the expected photoproducts. Instead, complex mixtures were formed in
each case. Better results were found when the photoreaction was performed through a quartz filter
and with acetonitrile as a solvent (entry 2). Thus, irradiation of 5 at rt furnished in 52% overall yield
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a (15:67:18) mixture of the three cycloadducts: the HT isomers 18, 19 and the HH isomer 20.
Noteworthy, the selectivity and the yield of the photochemical process were enhanced when the
reaction was carried out at ꢀ20 °C (58% yield, 11:78:11) and at ꢀ40 °C (64% yield, 8:84:8) (entries 3
and 4). Finally, using acetone as solvent at ꢀ78 °C, the intramolecular photocycloaddition proceeded
smoothly delivering the same mixture of compounds in higher selectivity (7:86:7) and yield (78%)
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(entry 5), from which the major HT regioisomer 19 and the minor HH regioisomer 20 could be
isolated in 61% and 6% yield, respectively, after purification by column chromatography. Although
conversion was not always complete, longer reaction times tended to produce more complex
mixtures (by GC analysis) without increasing the yield of the desired photoadducts.
Table 1. Irradiation of 2(5H)ꢀfuranones 5 and 6
a
b
c
entry
substrate
solvent
acetone
filter
T (°C)
ꢀ78
25
time (min)
240
120
120
90
global yield
ꢀ
product (ratio)
ꢀ
1
2
3
4
5
6
7
8
9
5
5
5
5
5
6
6
6
6
6
pyrex
quartz
quartz
quartz
quartz
quartz
quartz
quartz
quartz
quartz
CH
3
CN
52%
58%
64%
78%
82%
73%
65%
70%
58%
18:19:20 (15:67:18)
18:19:20 (11:78:11)
18:19:20 (8:84:8)
18:19:20 (7:86:7)
21:22:23 (9:87:4)
21:22:23 (12:82:6)
21:22:23 (18:77:5)
21:22:23 (14:81:5)
21:22:23 (18:73:9)
CH CN
ꢀ20
ꢀ40
ꢀ78
ꢀ78
ꢀ40
ꢀ40
ꢀ40
25
3
3
CH CN
acetone
acetone
acetone
30
25
40
CH
CH
CH
2
3
3
Cl
2
40
CN
CN
40
10
60
a
ꢀ1
b
c
Irradiations were performed in a nitrogenꢀsaturated 6.3 mmol L solution. Yield of isolated mixture of products.
Product ratio determined by GC.
The photoreaction of 6 was next performed under similar reaction conditions (entry 6). In the
event, irradiation of 6 in acetone through a quartz filter at ꢀ78 °C delivered a (9:87:4) mixture of the
two regioisomeric cyclobutanes 21 and 22 and the vinylic 1,3ꢀdioxocane 23 in 82% total yield.
Purification by column chromatography allowed the isolation of the HH isomer 22 in 67% yield and
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the dioxocane 23 in 3% yield. Enriched fractions of the HT isomer 21 could also be obtained
allowing its structural elucidation. Compound 23 arises from a 1,7ꢀhydrogen atom transfer (HAT) of
[
6]* to the βꢀcarbon of the excited lactone, followed by subsequent recombination of the diradical to
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form a new σ CꢀC bond. Interestingly, the regioselectivity in the photocycloaddition of 6 is
completely reversed regarding that obtained in the photoreaction of 5, thereby enabling the
preparation of enantiopure cyclobutanes with different substitution patterns.
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To study the selectivity of the process, irradiations of 6 were also performed at various solvents
and temperatures. As previously mentioned, we observed that the increase of the temperature was
accompanied by a diminution of the selectivity and the yield. Lower ratio of the major HH isomer 22
in similar yields was produced when the reaction was run at ꢀ40 °C in acetone, acetonitrile and
2 2
CH Cl (entries 7ꢀ9) and at rt in acetonitrile (entry 10). Therefore, the best results were achieved
when the photoreactions of lactones 5 and 6 were carried out in acetone with a quartz filter at ꢀ78 °C,
which furnished the HT isomer 19 in 61% yield and the HH isomer 22 in 67% yield, respectively,
indicating that the regioselectivity of the process is dependent on the functionality of the tether. In
both cases, the complete syn facial diastereoselectivity is cooperatively induced by the stereogenic
center in the lactones.
The success of photocycloaddition of 5 and 6 prompted us to expand this study to the preparation
of tetrasubstituted cyclobutanes by using the corresponding 1,2ꢀdisubstituted olefins tethered to the
2(5H)ꢀfuranone core. Thus, we evaluated the photochemical reactions involving lactones 7 and 8
bearing disubstituted olefins (Table 2). The intramolecular [2+2] photocycloaddition of 7 was
conducted under the optimized conditions previously established above by irradiation through a
quartz filter at ꢀ78 °C in acetone. Under these conditions, disappearance of the starting material was
observed after 30 min to deliver a 49:27:24 mixture of the two cyclobutane compounds 24 and 25
and the bisꢀlactone olefin 26 in 64% overall yield (entry 1). The two cycloadducts 24 and 25 could
be isolated and identified by NMR spectroscopy. Chromatographic separation of 26 was not
possible, therefore, for identification purposes, it was necessary to perform NMR analysis of samples
containing a mixture of isomers. When the reaction was carried out at higher temperature in
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acetonitrile, both the selectivity and the yield of the process slightly decreased (entries 2ꢀ4). In all
these assays, the formation of the photoadduct 24 was slightly favored. However, the low selectivity
of the reaction and the difficulty to separate the components of the mixture by chromatographic
means hampered its utilization as a synthetic process.
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Surprisingly, the irradiation of lactone 8 in all attempted reaction conditions (acetone or
acetonitrile; from rt to ꢀ78 °C) gave complex mixtures of products (entries 5ꢀ6), and NMR studies
did not allow the identification of any compound containing the expected cyclobutane structures.
Moreover, no starting furanone was recovered. In this case, the presence of an additional
hydroxymethyl substituent in the alkene moiety along with conformational requirements demanded
by the acetal linkage could favor the 1,7 and/or 1,5 hydrogen atom transfer processes over the
intramolecular [2+2] photocycloaddition evolving to the formation of different unidentified
decomposition products.
Table 2. Irradiation of 2(5H)ꢀfuranones 7 and 8
a
b
c
entry
substrate
solvent
acetone
T (°C)
ꢀ78
ꢀ40
ꢀ20
25
time (min)
global yield
product (ratio)
1
2
3
4
5
7
7
7
7
8
8
30
60
75
75
45
75
64%
58%
52%
44%
ꢀ
24:25:26 (49:27:24)
CH
CH
CH
3
3
3
CN
CN
CN
24:25:26 (46:24:30)
24:25:26 (40:29:31)
24:25:26 (37:29:34)
acetone
CH CN
ꢀ78
ꢀ40
ꢀ
ꢀ
6
3
ꢀ
a
ꢀ1
b
Irradiations were performed through a quartz filter in a nitrogenꢀsaturated 6.3 mmol L solution. Yield of isolated
c
mixture of products. Product ratio determined by NMR.
The structural assignment of the photoadducts was mainly based on detailed analysis of their 1D
and 2D spectra. The connectivity was established by HMBC experiments, wherein correlation
between the methylenic protons Hꢀ10 and the carbonyl carbon Cꢀ2 was observed for the HT isomers
18, 19 and 21 while the HH isomers 20 and 22 showed correlation between the methylenic protons
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Hꢀ2 and Cꢀ9. For the tetrasubstituted cyclobutanes 24 and 25, the connectivity was evidenced by
diagnostic cross couplings between the αꢀcarbonylic proton Hꢀ3 and Cꢀ1’ for 24 and between the βꢀ
carbonyl proton Hꢀ1 and Cꢀ1’ for 25.
The syn addition of the photoreactions was determined on the basis of the value of the coupling
constant between the γꢀlactone proton and its adjacent cyclobutane proton in the different
cycloadducts, which due to its cis disposition is expected to be large. Indeed the ester tethered
1
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compounds display values that range from J9,1 ~ 9.4 Hz for the HH regioisomers 20 and 25 to J9a,3a
~
4.8 Hz for the HT isomers 18 and 19, while the ketal tethered compounds show coupling constants
that vary from J9,1 ~ 10.3 Hz for the HH regioisomer 22 to J4,3a ~ 6.5 Hz for the HT isomer 21.
Therefore, as expected, the syn diastereoselectivity comes from the attack of the terminal alkene to
the face of the 2(5H)ꢀfuranone to which the alkyl chain is directed by the stereogenic center at Cꢀ5.
The relative configurations between the three newly formed stereogenic centers in the
cycloadducts 18-22 were established by NMR coupling patterns and by NOESY experiments. Thus,
the value of the coupling constants J3a,4 ~8 Hz for 19 and J12,3 ~9,5 Hz for 20 and 22 indicate a cis
disposition between both protons while the absence of coupling J3a,4 ~0 Hz for 18 suggests a trans
arrangement. In compound 21 the cis arrangement between Hꢀ3a and Hꢀ9a was assigned on the basis
of a NOESY experiment, which showed crossꢀpeaks between the Hꢀ9 protons and the cyclobutane
proton Hꢀ10 endo, and between Hꢀ3 and Hꢀ10 exo. Furthermore, we were able to obtain crystals of
19 and 22 for which Xꢀray structures were recorded, confirming unambiguously the relative and
absolute configuration of the three contiguous stereogenic centers created after irradiation.
For the tetrasubstituted cyclobutanes 24 and 25 four new stereocenters were generated and their
relative configurations were determined by the coupling constant patterns and further corroborated
by NOESY experiments. Thus, the cis arrangement between Hꢀ3a and Hꢀ4 and the trans disposition
between Hꢀ3 and Hꢀ10 in 24 were assigned by the value of the coupling constants J3a,4 ~7.5 Hz and
J
J
3,10 ~2.3 Hz. In a similar way, for compound 25 the value of the coupling constants J1,2 ~0 Hz and
12,3 ~10.2 Hz indicate trans and cis relationships, respectively. Crossꢀpeaks on the NOESY
experiments between the methylenic protons Hꢀ1’ and Hꢀ3 and Hꢀ3a in 24 and between Hꢀ1’ and Hꢀ
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and Hꢀ1 and between one of the protons Hꢀ8 and Hꢀ2 in 25 validated the diagnostic value of the
above parameters. Therefore, the NMR study confirmed that photocycloaddition of 7 has taken place
in a syn sense at the lactone double bond and with preservation of the original trans relationship
present in the unsaturated ester appendage.
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The structure of compounds 23 and 26 coming from a 1,7ꢀhydrogen atom transfer was determined
1
through detailed NMR studies. The H NMR spectrum of 23 displays the characteristic signals of the
olefinic protons of a vinyl group at δ 5.86, 5.35 and 5.17 and the HMBC experiment showed relevant
crossꢀpeaks between the allylic proton Hꢀ2 and the carbonyl carbon Cꢀ9 and between the αꢀ
carbonylic proton Hꢀ1 and the olefinic carbon Cꢀ1’.
Compound 26 could not be obtained in pure form, and its structure was elucidated analyzing a
1
sample containing the major cycloadduct 24. Two olefinic protons at δ 5.67 were observed in its H
NMR spectrum and the connectivity could be established with the help of the HMBC spectrum
wherein correlation between these protons and Cꢀ6 and between the methynic proton Hꢀ7 and Cꢀ1
were displayed. However, we were not able to unambiguously determine the configuration of the
new stereogenic center at Cꢀ6.
In order to rationalize the origin of the different observed regioselectivity in the intramolecular
photochemical reaction of lactones 5 and 6 we have carried out a computational study of the possible
15
reaction pathways (for Computational details see the Experimental Part). Previous studies on the [2
+
2] photocycloaddition reaction of 2(5H)ꢀfuranones to ethylene indicate that the reaction involves
the formation of a triplet 1,4ꢀbiradical intermediate that, after spin crossing, evolves to the
cyclobutane derivative. As previously commented, in the studied intramolecular photocycloadditions
two different regioisomers HH and HT are possible. For lactone 6 with the vinyl chain appended by
an acetal linkage, the main observed product is the HH regioisomer 22, while for lactone 5 bearing
the vinyl chain appended by an ester linkage is the HT isomer 19. Four different 1,4ꢀbiradical
intermediates leading to the HT or HH products could be envisaged depending on the bond that it is
formed in the first step of the process (Scheme 4).
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Scheme 4. 1,4ꢀBiradical intermediate species postulated for the [2+2] photocycloaddition of
(5H)ꢀfuranones 5 and 6
2
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In addition, different low lying conformers of 5 and 6 may exist. In particular, we have identified
several reactant conformers that can lead either to the final HH or HT regioisomers and explored all
the possible reaction pathways connecting those conformers with the final products. Figures S3ꢀS10
of the Supplementary Information show the schematic energy profiles obtained for all the paths
considered and the optimized geometries of the stationary points involved. Since it is known that the
1
6
reaction proceeds via the excitation of the furanone moiety, we have explored the paths involving
that excitation. For 6 we have found subtle differences between the possible reaction mechanisms
leading to the different products and thus, reactions of 6 are presented in detail first and then
reactions of 5 are also presented.
Figure 1 shows the schematic energy profile for the most stable conformers of 6 leading to the HH
and HT products. Different stationary points are labelled with the number of the reactant species (5
or 6) plus a superscript indicating the electronic state (1 for the singlet and 3 for the triplet), and a
lowerꢀcase letter (a and b) to indicate whether the structure corresponds to the path that leads to the
HT (a) or the HH (b) product. Transition structures are referred as TS before the two names of the
x
interconnected intermediates and biradical species are denoted as BR where x refers to the
electronic spin state.
The energetic profile is essentially the same in both cases. Geometrical relaxation of the furanone
3
3
centered excited triplet state leads to the 6 intermediates which evolve to the BR-6 biradicals
through the corresponding transition states. The Gibbs energy barrier is somewhat lower for the path
ꢀ1
ꢀ1
leading to the HT product (2.1 kcal mol ) than for that leading to the HH product (6.3 kcal mol ).
ꢀ1
However, both transition states are isoergonic (79.4 kcal mol with respect to the most stable
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1
starting conformer). Finally, the intermediates BR-6 must evolve to the singlet 1,4ꢀbiradicals BR-6
1
5,17,18
through an intersystem crossing.
It can be observed in Figures S7 and S8 (Supporting
Information) that the triplet and singlet biradical species present very close geometries. Moreover,
their energies are also very similar (see Figure 1), thereby indicating that both stationary points sit
near the intersystem crossing region between the singlet and triplet energy surfaces.
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Once formed, the singlet 1,4ꢀbiradical intermediates evolve to the HT isomer 21 and the HH
isomer 22, respectively, through the associated transition state. In this case the Gibbs energy barriers
ꢀ1
do not exceed 1 kcal mol .
Figure 1. Schematic potential energy profile (Gibbs energies are shown in parenthesis) for the
reactions of the most stable conformers of lactone 6 that lead to 21 and 22. The green line
corresponds to the formation of the HT product 21 and the blue line to the HH isomer 22. Energies
ꢀ1
are in kcal mol .
It should be noted that all energy barriers are accesible in the applied reaction conditions taking
into account the energy provided to the system by the photoexcitation. Thus, in these conditions the
observed regioselectivity would mainly be driven by the relative stability of the initial conformers.
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ꢀ1
1
The conformer 6b, prone to give the HH product, is 2.6 kcal mol more stable than the isomer 6a
that leads to the HT product. Other initial conformers have also been considered but they are all
higher in energy. This relative stability is mantained in the final products although the difference is
ꢀ1
1
reduced (0.5 kcal mol ). The larger stability of 6b is related to the gauche conformational
1
9
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preferences of the dihedral angles centered in the ketal moiety, which is generally attributed to the
soꢀcalled anomeric effect. The physical origin of this effect is controversial and several factors have
been proposed to explain it such as hyperconjugation (the interaction n(O) ꢀ σ∗(CꢀO) being the
19
1
largest individual contribution) or dipoleꢀdipole interactions. In our case, 6b presents a gaucheꢀ
1
gauche conformation while 6a shows an antiꢀgauche arrangement. Thus, the final observed
2
regioselectivity is dictated by the gauche preference of the –O–CH –O– unit in the ketal moiety.
Figure 2 shows the schematic energy profile for the most favorable conformers of lactone 5, with
the vinyl group attached by an ester linkage, leading to the HT and HH products 19 and 20.
Figure 2. Schematic potential energy profile (Gibbs energies are shown in parenthesis) for the
photochemical reaction involving the most stable conformers of 5 leading to 19 and 20. The green
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line corresponds to the formation of the HT product 19 and the blue line to the HH isomer 20.
ꢀ1
Energies are in kcal mol .
The computed pathways leading to both regioisomeric products will not be discussed in detail
because they are very similar to those found for 6. The main difference is the larger preference for
1
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one of the initial reactant conformers. Namely, conformer 5a, which leads to the HT isomer 19, is 8
ꢀ1
1
kcal mol more stable in terms of Gibbs energy than conformer 5b leading to the HH product 20. It
should be noted that the Gibbs energy barriers of the different individual steps are also lower for the
HT pathway. Thus, from a computational view, the pathway of the HT regioisomer is largely
preferred in front of the HH one, in agreement with the experimental results. The larger stability of
1
1
5a in front of 5b is maintained during the whole reaction path and carried over to the final product,
1
and is due to the different conformation of the ester moiety of the reactant, syn (Z) for 5a and anti
1
(
E) for 5b. Indeed, different experimental and computational studies on RꢀCOOꢀR’ molecules have
20
shown that the Z rotamer is more stable than the E form. Several factors have been proposed in the
literature to contribute to this difference, such as steric interactions, dipoleꢀdipole interactions
21ꢀ23
between the C=O and –OꢀR’ moieties,
a hyperconjugative effect due to the interaction between
2
4
the lone pair of the “ether” oxygen and the antibonding σ*(CꢀO) orbital or other conjugative
σ
25
20
effects. On the other hand, FerroꢀCostas et al. using a QTAIMꢀbased energy partitioning have
stated that in the case of formic acid the most important factor in the stabilization of the Z conformer
is the attraction of the carbonyl oxygen electron density by the acidic hydrogen. Replacement of
hydrogens by larger groups in different positions enhances the energy difference between the Z and
E rotamers due to the increase of repulsion, which destabilizes the E conformer, and the increase of
different attractive terms that favor the Z conformer.
Synthesis of all-cis 1,2,3-trisubstituted cyclobutane 30
The intramolecular photocycloaddition of lactones 5 and 6 proceeds with complementary
regioselectivity and good yields to furnish the photoadducts 19 and 22, respectively. Moreover,
considering the labile nature of the lactone ring and the ketal/ester moieties, these scaffolds might
represent attractive precursors for the preparation of allꢀcis trisubstituted cyclobutanes. To
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demonstrate some of its synthetic utility, further modifications on 22 to the cyclobutane 30, bearing
differently substituted orthogonally deprotectable groups, were undertaken (Scheme 5a).
Scheme 5. Preparation of allꢀcis 1,2,3ꢀtrisubstituted cyclobutane 30
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4
The ring opening lactone of 22 was performed by treatment with LiBH delivering diol 27 whose
primary hydroxyl group was selectively protected as the corresponding pivaloyl ester 28 in 65% for
1
the two steps. Both compounds showed H NMR spectra with wide broad signals due to the presence
of the nineꢀmembered ring. Next, a transacetalization reaction was attempted. During initial
exploratory studies, it was noted that treatment of cycloadduct 22 with pꢀtoluenesulfonic acid as a
catalyst afforded, through a sequential translactonization and transacetalization reactions, lactone 31
in good yield which in turn was converted to diol 32 after lactone reduction (Scheme 5b). Taking
26
2 2
this into account, ketal 28 was treated with Amberlystꢀ15 in CH Cl to furnish the rearranged
compound 29 in 73% yield. Finally, treatment of 29 with TBDPSCl and imidazole in CH Cl2
2
delivered the target allꢀcis 1,2,3ꢀtrisubstituted cyclobutane 30, with all the hydroxyl groups
orthogonally protected, in 77% yield thus illustrating the synthetic utility of photoadduct 22.
Conclusions
Several enantiomerically pure 2(5H)ꢀfuranones bearing temporary tethered alkenyl chains
appendage by an acetal or ester linkage have been prepared and their photochemical reactions
studied. The intramolecular [2+2] photocycloaddition reactions of lactones 5 and 6 proceed with
complete syn diastereoselectivity and are complementary allowing straightforward regioꢀ
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6
differentiated access to the trisubstituted cyclobutanes 19 and 22 in exploitable quantities. The major
cycloadduct obtained from 5 is the HT isomer, whereas that from 6 is the HH one. Calculations for
the intramolecular photochemical reaction of lactones 5 and 6 agree with the experimental
observations, the HT product being more(less) stable than the HH product for compounds 5(6). The
origin of the different observed regioselectivity in the intramolecular photochemical reaction of
lactones 5 and 6 arises, however, from the relative stability of the initial conformers. In the case of 6,
0
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the final observed regioselectivity is dictated by the gauche preference of the the –O–CH –O– unit
2
in the ketal moiety, whereas in the case of 5, it is determined by the larger stability of the RꢀCOOꢀR’
Z rotamer. Furthermore, the studied photoreactions give access to new ring systems, which are
difficult to prepare by other methods and open up new pathways to interesting molecular
frameworks. As a proof of synthetic feasibility, photoadduct 22 has been converted to 30 which
constitutes an 1,2,3ꢀtrisubstituted allꢀcis cyclobutane with the hydroxyl groups orthogonallyꢀ
protected.
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 chromatography was
1
13
performed using silica gel (230ꢀ400 mesh). H NMR and C NMR spectra were recorded at 250 and
2.5 MHz, 360 and 90 MHz. or 400 and 100 MHz. Proton chemical shifts are reported in ppm (
3
CDCl 7.26 or acetoneꢀd 2.05). Carbon chemical shifts are reported in ppm ( ) (CDCl , δ
6
δ)
(
3
,
δ
6
,
δ
δ
77.2). NMR signals were assigned with the help of COSY, HSQC, HMBC, and NOESY
experiments. Highꢀresolution mass spectrometry (HRMS) data were recorded on a Bruker
MicroTOFꢀQ spectrometrer with an electrospray ionization source in positive mode, with a tandem
QꢀTOF analyzer. Melting points were determined on hot stage and are uncorrected. Optical rotations
were measured at 22 ± 2 ˚C.
Computational details
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Molecular geometries and harmonic vibrational frequencies of all the considered structures were
2
7
obtained using the M06ꢀ2X density functional method which encloses a large amount of exact
exchange (54 %) necessary to appropriately describe radical species and reaction barriers of radical
15,28ꢀ31
27
processes.
In addition, M06ꢀ2X is able to account for midꢀrange dispersion forces. In order to
1
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confirm the nature (minimum or transition state) of the stationary points, harmonic vibrational
frequency calculations were carried out in all cases using the same level of calculation. The minima
connected by a given transition state were identified by intrinsic reaction coordinate calculations
(
IRC) or visual inspection. Some selected structures were optimized considering solvent (acetone)
32
effects using the SMD implicit solvation model. Open shell DFT calculations were performed
using a spin unrestricted formalism. For open shell singlet states, unrestricted calculations were
carried out by breaking the symmetry between the
α and β spin densities. As expected, for singlet
2
biradical intermediates the resulting
S
values lie between 0.9 and 1.0; namely they are biradicals
with an almost equal mixing of singlet and triplet spin states. Spin projected energies can be
3
3
obtained by using the spin correction procedure of Yamaguchi et al. This correction method was
applied in some selected cases, differences between spin projected and unprojected energies being
ꢀ1
less than 0.4 kcal mol . Thus, we only report the uncorrected values. All calculations were
3
5
performed using the 6ꢀ311++G(d,p) basis set with the Gaussian 09 package.
[(2S)-1-oxo-2,1-dihydrofuran-2-yl]methyl pent-4-enoate, 5. To an iceꢀcooled solution of 4ꢀ
pentenoic acid (654 mg, 6.5 mmol) and DMF (2 drops) in anhydrous CH Cl (18 mL) was added
oxalyl chloride (2 M in CH Cl , 3.6 mL, 7.2 mmol), dropwise. The solution was stirred for 10 min at
rt, and heated to the reflux temperature for 1 h under a N flux. Then, 2(5H)ꢀfuranone 10 (688 mg,
2
2
2
2
2
6
.0 mmol) was added and the resulting mixture was refluxed for 7 h. The solvent was removed under
reduced pressure and the crude product was purified by column chromatography (hexaneꢀEtOAc
from 2:1 to 1:1) to afford compound 5 (909 mg, 4.6 mmol, 77% yield) as a colourless oil: [α] ꢀ114
); IR (ATR) 2922, 1735, 1641, 1259, 1156, 1094, 819 cm ; H NMR (360 MHz,
CDCl ) δ 7.41 (d, J3´´,4´´=5.7 Hz, 1H, Hꢀ3´´), 6.12 (dd, J4´´,3´´=5.7 Hz, J4´´,2´´=1.9 Hz, 1H, Hꢀ4´´), 5.72
D
ꢀ1
1
(c 0.9, CDCl
3
3
(
ddt, J4,5= 16.4 Hz, J4,5=10.4 Hz, J4,3=6.2 Hz, 1H, Hꢀ4), 5.22ꢀ5.15 (m, 1H, Hꢀ2´´), 5.05ꢀ4.84 (m, 2H,
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hꢀ5), 4.28 (dd, Jgem=12.1 Hz, J1’,2’=4.4 Hz, 1H, Hꢀ1’), 2.39ꢀ2.31 (m, 2H, Hꢀ3), 2.31ꢀ2.22 (t, J2,3=6.4
1
3
Hz, 2H, Hꢀ2); C NMR (90 MHz, CDCl ) δ 172.2 (Cꢀ5´´), 172.1 (Cꢀ1), 152.4 (Cꢀ3´´), 136.0 (Cꢀ4),
3
122.9 (Cꢀ4´´), 115.6 (Cꢀ5), 80.7 (Cꢀ2´´), 62.2 (Cꢀ1’), 32.9 (Cꢀ3), 28.4 (Cꢀ2). HRMS (ESIꢀTOF) m/z:
+
[M+Na] Calcd for C10
H
12NaO
4
219.0628; Found: 219.0631.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(4S)-4-{[(allyloxy)methoxy]methyl}-2(5H)-furanone, 6. To a solution of 10 (796 mg, 7.0 mmol),
DIPEA (4.8 mL, 28.0 mmol) and NaI (cat.) in anhydrous THF (50 mL), freshly prepared 3ꢀ
13
(
chloromethoxy)propꢀ1ꢀene (3.10 g, 29 mmol) was added and the reaction mixture was heated
under reflux for 3 h. Then, the solvent was removed under reduced pressure and CH
and H O (70 mL) were added. The two phases were separated and the aqueous layer was extracted
with CH Cl (2×70 mL). The combined organic phases were dried over MgSO and concentrated.
2 2
Cl (70 mL)
2
2
2
4
The crude product was purified by column chromatography (hexaneꢀEtOAc 2:1 to 1:1) to afford
compound 6 (907 mg, 4.9 mmol, 71% yield) as a colourless oil: [α] ꢀ76 (c 1.0, CDCl ); IR (ATR)
D
3
ꢀ1
1
2
889, 1756, 1161, 1033, 776 cm ; H NMR (360 MHz, CDCl
3
) δ 7.46 (dd, J4,3=4.0 Hz, J4,5=1.8 Hz,
H, Hꢀ4), 6.14 (dd, J3,4=4.0, J3,5=1.8 Hz, 1H, Hꢀ3), 5.84 (ddt, J2’’’,3’’’=14.4 Hz, J2’’’,3’’’=10.1 Hz,
2’’’,1’’’=4.5 Hz, 1H, Hꢀ2’’’), 5.33ꢀ5.19 (m, 1H, Hꢀ5), 5.18ꢀ5.09 (m, 2H, Hꢀ3’’’), 4.66 (d, Jgem=4.1 Hz,
1
J
13
2
3
H, Hꢀ1’’), 4.09ꢀ3.99 (m, 2H, Hꢀ1’’’), 3.84ꢀ3.69 (m, 2H, Hꢀ1’); C NMR (90 MHz, CDCl ) δ 172.5
(Cꢀ2), 153.5 (Cꢀ4), 133.7 (Cꢀ2’’’), 122.4 (Cꢀ3’’’), 117.0 (Cꢀ3), 94.5 (Cꢀ1’’), 81.9 (Cꢀ5), 68.2 (Cꢀ
+
1
2
’’’), 66.7 (Cꢀ1’). HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C
9
H
12NaO
4
207.0628; Found
07.0628.
[(2S)-5-oxo-2,5-dihydrofuran-2-yl]methyl (4E)-6-hydroxy-4-hexenoate, 7.
Method A: To a solution of 5 (50 mg, 0.26 mmol) and allyl alcohol (54 mg, 0.93 mmol) in
nd
anhydrous CH Cl (2.5 mL) was added 2 generation Grubbs catalyst (9 mg, 0.011 mmol, 4%). The
2
2
reaction mixture was stirred at rt for 26 h. The solvent was removed under reduced pressure and the
crude product was purified by column chromatography (hexaneꢀEtOAc1:1 to 0:1) to afford
compound 7 (16 mg, 0.07 mmol, 27% yield) as a colourless oil and the dimer 12 as a white solid.
ꢀ1
1
7
D 3
: [α] ꢀ73 (c 1.0, CDCl ); IR (ATR) 3409, 1736, 1159, 1095, 781, 632 cm ; H NMR (360 MHz,
CDCl ) δ 7.43 (dd, J3´´,4´´=5.7 Hz, J3´´,2´´=1.7 Hz, 1H, Hꢀ3´´), 6.20 (dd, J4´´,3´´=5.7 Hz, J4´´,2´´=2.0 Hz,
3
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9
1
H, Hꢀ4´´), 5.69ꢀ5.61 (m, 2H, Hꢀ4 and Hꢀ5), 5.27ꢀ5.19 (m, 1H, Hꢀ2´´), 4.42 (dd, Jgem=12.1 Hz,
J1’,2’’=3.7 Hz, 1H, Hꢀ1’), 4.30 (dd, Jgem=12.1 Hz, J1’,2’’=4.9 Hz, 1H, Hꢀ1’), 4.07 (dd, J =4.1 Hz,
6,5
1
3
J
6,4=1.0 Hz, 2H, Hꢀ6), 2.46ꢀ2.37 (m, 2H, Hꢀ3), 2.39ꢀ2.31 (m, 2H, Hꢀ2), 2.07 (br, 1H, HꢀOH);
C
NMR (90 MHz, CDCl
3
) δ 172.4 (2C, Cꢀ1, Cꢀ5´´), 152.6 (Cꢀ3´´), 130.6 (Cꢀ5), 129.4 (Cꢀ4), 123.0 (Cꢀ
+
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4´´), 80.8 (Cꢀ2´´), 62.9 (Cꢀ1’), 62.2 (Cꢀ6), 33.3 (Cꢀ3), 27.0 (Cꢀ2). HRMS (ESIꢀTOF) m/z: [M+Na]
Calcd for C11 249.0733; Found 249.0734.
Bis{[(2S)-5-oxo-2,5-dihydro-2-furanyl]methyl}(4E)-octenedioate, 12. Mp 77ꢀ78 °C (from
H14NaO
5
ꢀ1 1
EtOAcꢀhexane); [α]
CDCl
2H, Hꢀ4´´), 5.47ꢀ5.31 (m, 2H, Hꢀ4, Hꢀ5), 5.27ꢀ5.17 (m, 2H, Hꢀ2´´), 4.45ꢀ4.18 (m, 4H, Hꢀ1’), 2.39ꢀ
D 3
+11 (c 5.0, CDCl ); IR (ATR,) 1748, 1172, 995, 632 cm ; H NMR (250 MHz,
3
) δ 7.43 (dd, J3´´,4´´=5.7 Hz, J3´´, 2´´=1.6 Hz, 2H, Hꢀ3´´), 6.17 (dd, J4´´,3´´=5.7 Hz, J4´´,2´´=2.1 Hz,
1
3
2.28 (m, 4H, Hꢀ3, Hꢀ6), 2.31ꢀ2.18 (m, 4H, Hꢀ2, Hꢀ7); C NMR (62.5 MHz, CDCl
3
) δ 172.3 (2Cꢀ
5
3
´´), 172.2 (Cꢀ1, Cꢀ8), 152.4 (2Cꢀ3´´), 129.2 (Cꢀ4, Cꢀ5), 123.1 (2Cꢀ4´´), 80.7 (2Cꢀ2´´), 62.3 (2Cꢀ1’),
+
8
3.6 (Cꢀ3, Cꢀ6), 27.4 (Cꢀ2, Cꢀ7). HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C18H20NaO 387.1050;
Found 387.1055.
Method B. A solution of 5 (600 mg, 3 mmol) and (E)ꢀbutꢀ2ꢀenal (1.25 mL, 15 mmol) in anhydrous
nd
CH
2
Cl
2
(20 mL) was heated at the reflux temperature for 10 min. Then, 2 HoveydaꢀGrubbs catalyst
nd
(40 mg, 0.06 mmol, 2%) was added to the solution. After 2 h, more 2 HoveydaꢀGrubbs catalyst (17
mg, 0.03 mmol, 1%) was added. The solution was refluxed for another 2 h. The solvent was
removed to afford a crude, which was purified by column chromatography (hexaneꢀEtOAc 1:1 to
1
:4) to deliver [(2S)ꢀ5ꢀoxoꢀ2,5ꢀdihydrofuranꢀ2ꢀyl]methyl (4E)ꢀ6ꢀoxoꢀ4ꢀhexenoate, 16, (599 mg, 2.67
mmol, 89% yield) as a white solid. Mp 62ꢀ63 °C (from EtOAcꢀhexane); [α] ꢀ90 (c 1.0, CDCl ); IR
ATR) 2359, 1745, 1685, 1161, 787 cm ; H NMR (360 MHz, CDCl ) δ 9.45 (d, J =7.8 Hz, 1H,
D
3
ꢀ1 1
(
3
6,5
Hꢀ6), 7.41 (dd, J3´´,4´´=5.6 Hz, J3´´,2´´=1.6 Hz, 1H, Hꢀ3´´), 6.79 (dd, J4,5=15.8 Hz, J4,3=5.9 Hz, 1H, Hꢀ
4
5
), 6.17 (dd, J4´´,3´´=5.6 Hz, J4´´,2´´=2.1 Hz, 1H, Hꢀ4´´), 6.06 (dd, J5,4=15.8 Hz, J5,6= 7.8 Hz, 1H, Hꢀ5),
.22 (m, 1H, Hꢀ2´´), 4.39 (dd, Jgem=12.1 Hz, J1´,2´´= 3.7 Hz, 1H, Hꢀ1´), 4.29 (dd, Jgem=12.1, J1´,2´´=5.1
13
Hz, 1H, Hꢀ1´´), 2.59 (dt, J3,2=6.1 Hz, J3,4=5.9 Hz, 2H, Hꢀ3), 2.53 (t, J2,3=6.1 Hz, 2H, Hꢀ2); C NMR
(90 MHz, CDCl ) δ 193.6 (Cꢀ6), 172.0 (Cꢀ5´´), 171.4 (Cꢀ1), 155.2 (Cꢀ3´´), 152.2 (Cꢀ4), 133.3 (Cꢀ
3
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2
2
2
2
2
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5
5
5
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6
+
4
´´), 123.2 (Cꢀ5), 80.6 (Cꢀ2´´), 62.6 (Cꢀ1’), 31.6 (Cꢀ3), 27.2 (Cꢀ2). HRMS (ESIꢀTOF) m/z: [M+Na]
Calcd for C H NaO 247.0577; Found 247.0577.
11
12
5
.
3
To a mixture of 16 (252 mg, 1.1 mmol) and CeCl
was added NaBH (37 mg, 1 mmol) and MeOH (10 drops). After 3 h, another portion of NaBH
mg, 0.4 mmol) and MeOH (10 drops) was added to the mixture and stirred for additional 20 min.
Then, 3 mL saturated NH Cl was added and the layers were separated. The aqueous layer was
extracted with CH Cl (5×6mL). The combined organic extracts were dried over MgSO and
7H
2
O (420 mg, 1.1 mmol) in CH
Cl
2 2
(5 mL),
4
4
(15
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
2
2
4
concentrated. The crude product was purified by column chromatography (hexaneꢀEtOAc 1:5) to
afford compound 7 (200 mg, 0.88 mmol, 80% yield) as a colourless oil.
(5S)-5-[({[(2E)-4-hydroxy-2-buten-1-yl]oxy}methoxy)methyl]-2(5H)-furanone, 8.
Method A. To a solution of 6 (45 mg, 0.24 mmol) and allyl alcohol (44 mg, 0.76 mmol) in
nd
anhydrous CH Cl (2.5 mL) was added 2 generation Grubbs catalyst (11 mg, 0.013 mmol, 5%).
2
2
The reaction solution was stirred at rt for 24 h. The solvent was removed under reduced pressure and
the crude product was purified by column chromatography (hexaneꢀEtOAc 1:1 to 0:1) to afford
compound 8 (18 mg, 0.08 mmol, 35% yield) and variable amounts of the dimer (5S,5S)ꢀ5,5ꢀ[(6E)ꢀ
2
,4,9,11ꢀtetraoxododecꢀ6ꢀeneꢀ1,12ꢀdiyl]di[2(5H)ꢀhexanone], 14, both as colourless oils.
ꢀ
1
8: [α] ꢀ102 (c 0. 7, CDCl ); IR (ATR) 3416, 2872, 1750, 1460, 1167, 1091, 1029, 823, 632 cm ;
D
3
1
H NMR (250 MHz, CDCl
3,5=2.1 Hz, 1H, Hꢀ3), 5.93ꢀ5.63 (m, 2H, Hꢀ2’’’, Hꢀ3’’’), 5.21ꢀ5.09 (m, 1H, Hꢀ5), 4.69ꢀ4.60 (s, 2H,
Hꢀ1’’), 4.15ꢀ4.03 (d, J4’’’,3’’’= 4.7 Hz, 2H, Hꢀ4’’’), 4.07ꢀ3.96 (d, J1’’’,2’’’=5.6 Hz, 2H, Hꢀ1’’’), 3.85ꢀ
3
) δ 7.51 (dd, J4,3=5.7 Hz, J4,5=1.6 Hz, 1H, Hꢀ4), 6.12 (dd, J3,4=5.7 Hz,
J
13
3
3
.64 (m, 2H, Hꢀ1’), 2.57ꢀ2.54 (br, 1H, HꢀOH); C NMR (62.5 MHz, CDCl ) δ 172.9 (Cꢀ2), 153.6
(
Cꢀ4), 132.6 (Cꢀ2’’’), 126.4 (Cꢀ3’’’), 122.6 (Cꢀ3), 94.7 (Cꢀ1’’), 82.1 (Cꢀ5), 67.7 (Cꢀ1’’’), 66.8 (Cꢀ
+
1’), 62.4 (Cꢀ4’’’). HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C10
H14NaO
5
237.0733; Found
2
37.0736.
1
1
4: H NMR (250 MHz, CDCl
3
) δ 7.50 (dd, J4’,3’=5.7 Hz, J4’,5’=1.9 Hz, 2H, Hꢀ4’), 6.16 (dd,
J
3’,4’=5.7 Hz, J3’,5’=2.0 Hz, Hꢀ3’), 5.79 (m, 2H, Hꢀ6, Hꢀ7), 5.17 (ddd, J5’,1=4.9 Hz, J5’,1=3.1 Hz,
J5’,4’=1.9 Hz, 2H, Hꢀ5’), 4.68 (s, 4H, Hꢀ3, Hꢀ10), 4.08ꢀ4.03 (m, 4H, Hꢀ5, Hꢀ8), 3.79 (m, 4H, Hꢀ1, Hꢀ
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6
7
8
9
13
1
3
2 ); C NMR (62.5 MHz, CDCl ) δ 172.7 (2Cꢀ2’), 153.4 (2Cꢀ4’), 128.9 (Cꢀ6, 7), 122.8 (2Cꢀ3’),
9
4.9 (Cꢀ3, Cꢀ10), 81.9 (2Cꢀ5’), 67.5 (Cꢀ5, Cꢀ8), 67.0 (Cꢀ1, Cꢀ12).
Method B. A solution of 6 (813 mg, 4.4 mmol) and (E)ꢀbutꢀ2ꢀenal (1.9 mL, 22 mmol) in
nd
anhydrous CH
2
Cl
2
(15 mL) was heated at the reflux temperature for 20 min. 2 Generation
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HoveydaꢀGrubbs catalyst (64 mg, 0.1 mmol) was added in three portions. The solution was refluxed
for 3 h. The solvent was removed to afford a crude product, which was purified by column
chromatography
(hexaneꢀEtOAc
1:4)
to
furnish
(2E)ꢀ4ꢀ({[(2S)ꢀ5ꢀoxoꢀ2,5ꢀdihydroꢀ2ꢀ
furanyl]methoxy}methoxyꢀ2ꢀbutenal, 17, (851 mg, 4.0 mmol, 90% yield) as a colourless oil: [α]
D
ꢀ
ꢀ1
1
9
3 3
1 (c 0.5, CDCl ); IR (ATR) 1750, 1683, 1023, 819 cm ; H NMR (250 MHz, CDCl ) δ 9.53 (d,
J
J
1,2=7.9 Hz, 1H, Hꢀ1), 7.44 (dd, J3’’’,4’’’=5.8 Hz, J3’’’,2’’’=5.8 Hz, 1H, Hꢀ3’’’), 6.81 (dt, J3,2=15.8 Hz,
3,4=4.1 Hz, 1H, Hꢀ3), 6.28 (dd, J2,3= 15.8, J2,1=7.9 Hz, 1H, Hꢀ2), 6.14 (dd, J4’’’,3’’’=5.8 Hz, J4,2’’’=2.0
Hz, 1H, Hꢀ4’’’), 5.21ꢀ5.11 (m, 1H, Hꢀ2’’’), 4.70 (s, 2H, Hꢀ1’), 4.30 (dd, Jgem=4.2 Hz, J1’’’,2’’’= 2.0
Hz, 2H, Hꢀ1’’), 3.84 (dd, Jgem=11.1 Hz, J4,3=4.1 Hz, 1H, Hꢀ4), 3.73 (dd, Jgem=11.1 Hz, J4,3=5.2 Hz,
13
1
H, Hꢀ4); C NMR (62.5 MHz, CDCl
3
) δ 193.0 (Cꢀ1), 172.4 (Cꢀ5’’’), 153.1 (Cꢀ3’’’), 152.1 (Cꢀ3),
1
31.5 (Cꢀ2), 122.8 (Cꢀ4’’’), 95.2 (Cꢀ1’), 81.8 (Cꢀ2’’’), 67.1 (Cꢀ4), 66.1 (Cꢀ1’’). HRMS (ESIꢀTOF)
+
m/z: [M+Na] Calcd for C10
H12NaO
5
235.0577; Found 235.0585.
.
3
To a mixture of 17 (207 mg, 0.92 mmol), TBAB (10 mg, 0.03 mmol) and CeCl 7H O (346 mg,
2
0
.92 mmol) in CH
h of stirring at rt, another portion of NaBH
the mixture. After an additional hour, CH Cl
the two layers were separated. The aqueous layer was extracted with CH
Cl
2 2
(5 mL), NaBH
4
(25 mg, 0.65 mmol) and MeOH (5 drops) were added. After 1
(25 mg, 0.4 mmol) and MeOH (5 drops) were added to
(5 mL) and H O (5 mL) were added to the mixture and
Cl (5×5mL), and then the
4
2
2
2
2
2
combined organic extracts were dried over MgSO and concentrated affording a crude, which was
4
purified by column chromatography (hexaneꢀEtOAc 1:5) to give compound 8 (147 mg, 0.69 mmol,
7
5% yield) as a colourless oil.
General Procedure for the Photochemical Reactions. Irradiations were performed in a small
conventional photochemical reactor (twoꢀnecked vessel fitted with a Pyrex or quartz immersion type
cooling jacket) using a highꢀpressure 125W mercury lamp. Methanol at ꢀ15 °C was used for
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refrigeration of the immersion well jacket. The vessel was externally cooled at ꢀ20 °C with a dry iceꢀ
CCl bath or at ꢀ40 °C with a dry iceꢀacetonitrile bath or a ꢀ78°C with liquid nitrogen bath. The
4
photochemical reactions were initially degassed by passage of oxygenꢀfree 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.
0
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1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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9
0
(3S,3aR,4S,9aS)-
and
(3S,3aR,4R,9aS)-hexahydro-2H-3,4-methanofuro[2,3-c]oxocine-
3,12
2
,1(3H)-dione (18) and (19) and (1R,3S,9S,12S)-dioxatricyclo[7.3.0.0 ]dodecane-6,11-dione
(20). A solution of lactone 5 (80 mg, 0.41 mmol) in acetone (65 mL) was irradiated at ꢀ78 °C under
an atmosphere of N through a quartz filter for 30 min. Evaporation of the solvent and purification of
2
the residue by column chromatography (hexaneꢀEtOAc 1:1) afforded a 7:86:7 mixture of 18-20 (63
mg, 0.32 mmol, 78% global yield). Repeated column chromatography (hexaneꢀEtOAc from 2:1 to
1:1) provided the following fractions: i) an enriched sample of the HT isomer 18 (6 mg), ii) the HT
isomer 19 as a white solid (49 mg, 0.25 mmol, 61% yield), and the HH isomer 20 (5 mg, 0.03 mmol,
6% yield) as a white solid.
When the irradiation was performed through a quartz filter in acetonitrile at ꢀ40 °C for 90 min,
from lactone 5 (80 mg, 0.41 mmol), after chromatographic purification of the crude material, a
8:84:8 mixture of 18-20 (52 mg, 0.26 mmol, 64% global yield) was obtained.
When the irradiation was performed through a quartz filter in acetonitrile at ꢀ20 °C for 2 h, from
lactone 5 (80 mg, 0.41 mmol), after chromatographic purification of the crude material, a 11:78:11
mixture of 18-20 (46 mg, 0.23 mmol, 58% global yield) was obtained.
When the irradiation was performed through a quartz filter in acetonitrile at rt for 2 h, from lactone
5
(80 mg, 0.41 mmol), after chromatographic purification of the crude material, a 15:67:18 mixture
of 18-20 (41 mg, 0.20 mmol, 52% global yield) was obtained.
9: Mp 87ꢀ88 °C (from EtOAcꢀhexane); [α] 17 (c 1.0, CDCl
NMR (400 MHz, CDCl ) δ 4.91 (dd, Jgem=13.3 Hz, J9,9a=2.4 Hz, 1H, Hꢀ9), 4.46 (dt, J9a,3a=4.8 Hz,
9a,9=2.4 Hz, J9a,9=2.4 Hz, 1H, Hꢀ9a), 4.32 (dd, Jgem=13.2 Hz, J9,9a=2.4 Hz, 1H, Hꢀ9), 3.18 (td,
ꢀ1 1
1
D
3
); IR (ATR) 1749, 778, 631 cm ; H
3
J
J3a,3=7.6 Hz, J3a,4=7.6 Hz, J3a,9a=4.8 Hz, 1H, Hꢀ3a), 3.12 (dddd, J3,10=9.0 Hz, J3,3a=7.6 Hz, J =2.4
3,4
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Hz, J3,10=2.4 Hz, 1H, Hꢀ3), 2.78ꢀ2.71 (m, 1H, Hꢀ10), 2.70ꢀ2.66 (m, 1H, Hꢀ6), 2.66ꢀ2.58 (m, 1H, Hꢀ
), 2.45 (tdd, Jgem=13.5 Hz, J =13.5 Hz, J =11.5 Hz, J =5.4 Hz, 1H, Hꢀ5), 2.16 (ddd, Jgem=13.0
4
5,6
5,6
5,4
Hz, J6,5=11.5 Hz, J6,5=5.7 Hz, 1H, Hꢀ6), 1.82 (dddd, Jgem=13.5 Hz, J5,6=5.7 Hz, J5,6=2.4 Hz, J5,4=2.4
13
3
Hz, 1H, Hꢀ5), 1.78ꢀ1.73 (m, 1H, Hꢀ10); C NMR (100 MHz, CDCl ) δ 179.7 (Cꢀ2), 176.9 (Cꢀ7),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
82.1 (Cꢀ9a), 62.5 (Cꢀ9), 40.0 (Cꢀ3a), 38.6 (Cꢀ3), 36.3 (Cꢀ4), 34.0 (Cꢀ6), 31.9 (Cꢀ5), 28.7 (Cꢀ10).
+
HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C10
H
12 NaO
4
219.0628; Found 219.0626.
2
0: Mp 166ꢀ167 °C (from EtOAcꢀhexane); [α] 87 (c 1.1, CDCl ); IR (ATR) 2923, 1725, 1172,
D
3
ꢀ1
1
1
3
057 cm ; H NMR (400 MHz, CDCl ) δ 4.86 (dd, J9,1=9.4 Hz, J9,8=2.2 Hz, 1H, Hꢀ9), 4.69 (d,
J
J
gem=12.1 Hz, 1H, Hꢀ8), 4.32 (dd, Jgem=12.1 Hz, J8,9=2.2 Hz, 1H, Hꢀ8), 3.47 (br t, J12,1=10.1 Hz,
12,3=10.1 Hz, 1H, Hꢀ12), 3.29ꢀ3.20 (m, 1H, Hꢀ3), 3.15 (dq, J1,9=10.1 Hz, J1,12=10.1 Hz, J1,2=10.1
Hz, J1,2=1.0 Hz 1H, Hꢀ1), 2.73 (ddd, Jgem=17.9 Hz, J5,4=4.6 Hz, J5,4=2.8 Hz, 1H, Hꢀ5), 2.53ꢀ2.41 (m,
1H, Hꢀ2), 2.38ꢀ2.27 (m, 1H, Hꢀ5), 2.25ꢀ2.14 (m, 1H, Hꢀ4), 1.86ꢀ1.76 (m, 1H, Hꢀ4), 1.68 (br d,
13
J
gem=14.0 Hz, 1H, Hꢀ2); C NMR (100 MHz, CDCl
3
) δ 177.0 (Cꢀ11), 174.9 (Cꢀ6), 79.7 (Cꢀ9), 65.9
(Cꢀ8), 43.0 (Cꢀ12), 33.6 (Cꢀ1), 32.7 (Cꢀ5), 31.4 (Cꢀ3), 22.0 (Cꢀ2), 21.8 (Cꢀ4). HRMS (ESIꢀTOF)
+
m/z: [M+Na] Calcd for C10
H
12NaO
4
219.0628; Found 219.0631.
) δ 5.10 (dd, Jgem=13.5 Hz, J9,9a=4.5 Hz, 1H, Hꢀ9),
1
1
8: (90% purity) H NMR (400 MHz, CDCl
3
4.48 (br t, J9a,3a=4.5 Hz, J9a,9=4.5 Hz, 1H, Hꢀ9a), 4.25 (d, Jgem=13.5 Hz, 1H, Hꢀ9), 3.21ꢀ3.00 (m, 1H,
Hꢀ4), 2.98 (dt, J3,10=7.7 Hz, J3,3a=6.4 Hz, J3,10=1.1 Hz, J=1.1 Hz, 1H, Hꢀ3), 2.63 (br dd, J3a,3=6.4 Hz,
J
3,9a=4.5 Hz, 1H, Hꢀ3a), 2.37ꢀ2.28 (m, 2H, Hꢀ6), 2.23ꢀ2.12 (m, 1H, Hꢀ10), 2.10ꢀ1.75 (m, 3H, Hꢀ10,
13
2
3
Hꢀ5); C NMR (100 MHz, CDCl
3
) δ 179.1 (Cꢀ2), 176.7 (Cꢀ7), 80.9 (Cꢀ9a), 63.0 (Cꢀ9), 46.0 (Cꢀ
a), 38.7 (Cꢀ3), 36.3 (Cꢀ4), 32.8 (Cꢀ6), 32.3 (Cꢀ5), 29.1 (Cꢀ10).
3S,3aR,4R,9aS)-hexahydro-2H-3,4-methanofuro[2,3-e][1,3]dioxocin-2-one
(
(21),
3,12
(1R,3S,9S,12S)-5,7,10-trioxatricyclo[7.3.0.0 ]dodecan-11-one (22) and (1R,2RS,7S)-2-vinyl-
trioxabicyclo[5.2.1]decan-9-one (23).
A solution of lactone 6 (77 mg, 0.42 mmol) in acetone (65 mL) was irradiated at ꢀ78 °C under an
2
atmosphere of N through a quartz filter for 25 min. Evaporation of the solvent and purification of
the residue by column chromatography (CHCl ꢀEtOAc 2:1) afforded a 9:87:4 mixture of 21-23 (63
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2
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2
2
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5
5
5
5
5
5
5
5
6
3
mg, 0.34 mmol, 82% global yield). Repeated column chromatography (CHCl ꢀEtOAc 3:1) provided
the following fractions: i) an enriched sample of the HT isomer 21 (7 mg), ii) the HH isomer 22 as a
white solid (52 mg, 0.28 mmol, 67% yield), and the vinylic compound 23 (3 mg, 0.02 mmol, 3%
yield) as colorless oil.
0
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9
0
When the irradiation was performed through a quartz filter in acetone at ꢀ40 °C for 40 min, from
lactone 6 (77 mg, 0.42 mmol), after chromatographic purification of the crude material, a 12:82:6
mixture of 21-23 (56 mg, 0.30 mmol, 73% global yield) was obtained.
2 2
When the irradiation was performed through a quartz filter in CH Cl at ꢀ40 °C for 40 min, from
lactone 6 (77 mg, 0.42 mmol), after chromatographic purification of the crude material, a 18:77:5
mixture of 21-23 (50 mg, 0.27 mmol, 65% global yield) was obtained.
When the irradiation was performed through a quartz filter in acetonitrile at ꢀ40 °C for 40 min,
from lactone 6 (77 mg, 0.42 mmol), after chromatographic purification of the crude material, a
14:81:5 mixture of 21-23 (54 mg, 0.29 mmol, 70% global yield) was obtained.
When the irradiation was performed through a quatz filter in acetonitrile at rt for 2 h, from lactone
(77 mg, 0.42 mmol), after chromatographic purification of the crude material, a 18:73:9 mixture of
1-23 (45 mg, 0.24 mmol, 58% global yield) was obtained.
6
2
22: Mp 108ꢀ110 °C (from EtOAcꢀhexane); [α] 29 (c 0.9, CDCl ); IR (ATR) 1754, 1187, 1041,
D
3
ꢀ1 1
7
3
76, 631 cm ; H NMR (250 MHz, CDCl ) δ 4.72 (s, 2H, Hꢀ6), 4.62 (ddd, J9,1=10.3 Hz, J9,8=3.0 Hz,
J
J
9,8=0.7 Hz, 1H, Hꢀ9), 4.30 (dd, Jgem=12.9 Hz, J4,3=4.4 Hz, 1H, Hꢀ4), 4.29 (dd, Jgem=14.7 Hz,
8,9=3.0 Hz, 1H, Hꢀ8), 4.03 (dd, Jgem=14.7 Hz, J8,9=0.7 Hz, 1H, Hꢀ8), 3.51 (d, Jgem=12.9 Hz, 1H, Hꢀ
4), 3.34 (t, J12,1=8.8 Hz, J12,3=8.8 Hz, 1H, Hꢀ12), 3.13 (ddddd, J1,9=10.3 Hz, J1,2=10.3 Hz, J1,12=8.8
Hz, J =2.1 Hz, J =2.1 Hz, 1H, Hꢀ1), 2.97ꢀ2.93 (m, 1H, Hꢀ2), 2.92ꢀ2.89 (m, 1H, Hꢀ3), 2.46 (ddd,
1,2
1,3
1
3
J
gem=12.9 Hz, J2,1=10.3 Hz, J2,3=9,4 Hz, 1H, Hꢀ2); C NMR (62.5 MHz, CDCl
3
) δ 179.5 (Cꢀ11),
95.9 (Cꢀ6), 80.7 (Cꢀ9), 73.0 (Cꢀ8), 71.3 (Cꢀ4), 39.8 (Cꢀ12), 37.9 (Cꢀ3), 34.0 (Cꢀ1), 25.1 (Cꢀ2).
+
HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C
9 4
H12NaO 207.0628; Found 207.0628.
ꢀ1
1
2
3: [α] 1.8 (c 1.0, CDCl ); IR (ATR) 1763, 1173, 1037 cm ; H NMR (400 MHz, CDCl ) δ 5.86
D
3
3
(ddd, J1’,2’=17.2 Hz, J1’,2’=10.4 Hz, J1’,2=5.1 Hz, 1H, Hꢀ1’), 5.35 (dt, J2’,1’=17.2 Hz, Jgem=1.5 Hz,
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J
2’,2=1.5 Hz, 1H, Hꢀ2’), 5.17 (dt, J2’,1’=10.4 Hz, Jgem=1.5 Hz, J2’,2=1.5 Hz, 1H, Hꢀ2’), 4.78 (d,
Jgem=6.3 Hz, 1H, Hꢀ4), 4.71 (d, Jgem=6.3 Hz, 1H, Hꢀ4), 4.64 (m, 1H, Hꢀ7), 4.23 (dq, J2,1’=5.0 Hz,
2,2’=1.5 Hz, J2,2’=1.5 Hz, J2,1=1.5 Hz, 1H, Hꢀ2), 4.14 (dd, Jgem=12.5 Hz, J6,7=3.9 Hz, 1H, Hꢀ6), 3.43
J
13
(d, Jgem=12.5 Hz, 1H, Hꢀ6), 2.71ꢀ2.64 (m, 1H, Hꢀ1), 2.39ꢀ2.33 (m, 2H, Hꢀ10); C NMR (100 MHz,
CDCl ) δ 178.7 (Cꢀ9), 138.0 (Cꢀ1’), 115.3 (Cꢀ2’), 94.5 (Cꢀ4), 77.2 (Cꢀ7), 76.3 (Cꢀ2), 70.7 (Cꢀ6),
5.4 (Cꢀ1), 26.9 (Cꢀ10).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
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8
9
0
1
2
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7
8
9
0
1
2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
4
1
2
1: (70% purity) H NMR (400 MHz, CDCl ) δ 4.70 (d, Jgem=5.7 Hz, 1H, Hꢀ7), 4.64 (d, Jgem=5.7
3
Hz, 1H, Hꢀ7), 4.50 (ddd, J4,3a=6.5 Hz, J4,5=5.0 Hz, J4,5=2.1 Hz, 1H, Hꢀ4), 4.24 (dd, Jgem=13.4 Hz,
5,4=5.0 Hz, 1H, Hꢀ5), 3.82 (d, Jgem=11.6 Hz, 1H, Hꢀ9), 3.70 (dd, Jgem=13.4 Hz, J5,4=2.1 Hz, 1H, Hꢀ
5), 3.67 (dd, Jgem=11.6 Hz, J9,9a=5.5 Hz 1H, Hꢀ9), 3.42ꢀ3.06 (m, 2H, Hꢀ3, Hꢀ3a), 3.02ꢀ2.81 (m, 1H,
J
1
3
Hꢀ9a), 2.71ꢀ2.54 (m, 1H, Hꢀ10), 1.90 (ddd, Jgem=12.5 Hz, J=5.9 Hz, J=3.1 Hz, 1H, Hꢀ10); C NMR
(100 MHz, CDCl ) δ 179.4 (Cꢀ2), 93.9 (Cꢀ7), 80.5 (Cꢀ4), 66.0/65.8 (Cꢀ5/Cꢀ9), 39.3 (Cꢀ3a), 37.6 (Cꢀ
3
3
), 34.8 (Cꢀ9a), 26.0 (Cꢀ10).
3S,3aR,4R,9aS,10R)-10-(hydroxymethyl)hexahydro-2H-3,4-methanofuro[2,3-c]oxocine-
,7(3H)-dione (24), (1R,2S,3S,9S,12S)-2-(hydroxymethyl)-7,10-
(
2
3
,12
dioxatricyclo[7.3.0.0 ]dodecane-6,11-dione (25) and (1S,6RS,7R)-6-[(E)-3-hydroxy-1-propen-
1-yl]-3,9-dioxabicyclo[5.2.1]decane-4,8-dione (26).
A solution of lactone 7 (104 mg, 0.46 mmol) in acetone (65 mL) at ꢀ78 °C was irradiated under an
atmosphere of N
the residue by column chromatography (hexaneꢀEtOAc 1:5) afforded a 49:27:24 mixture of 24-26
66 mg, 0.29 mmol, 64% global yield). Repeated column chromatography (hexaneꢀEtOAc from 1:5
2
through a quartz filter for 30 min. Evaporation of the solvent and purification of
(
to 1:10) provided the following fractions: i) a mixture of 24 and 26 and, ii) and an analytical sample
of 25 as colorless oil.
When the irradiation was performed through a quartz filter in acetonitrile at ꢀ40 °C for 1 h, from
lactone 7 (104 mg, 0.46 mmol), after chromatographic purification of the crude material, a 46:24:30
mixture of 24-26 (60 mg, 0.26 mmol, 58% global yield) was obtained.
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When the irradiation was performed through a quartz filter in acetonitrile at ꢀ20 °C for 75 min,
from lactone 7 (104 mg, 0.46 mmol), after chromatographic purification of the crude material, a
4
0:29:31 mixture of 24-26 (54 mg, 0.23 mmol, 52% global yield) was obtained.
When the irradiation was performed through a quartz filter in acetonitrile at rt for 75 min, from
0
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lactone 7 (104 mg, 0.46 mmol), after chromatographic purification of the crude material, a 37:29:34
mixture of 24-26 (46 mg, 0.20 mmol, 44% global yield) was obtained.
ꢀ1
1
2
4: [α] ꢀ2.0 (c 1.0, CDCl ); IR (ATR) 2923, 1742, 1176 cm ; H NMR (400 MHz, CDCl ) δ 4.92
D
3
3
(
dd, Jgem=13.3 Hz, J9,9a=2.6 Hz, 1H, Hꢀ9), 4.50 (dt, J9a,3a=5.1 Hz, J9a,9 =2.6 Hz, J9a,9 =2.6 Hz, 1H, Hꢀ
a), 4.34 (dd, Jgem=13.3 Hz, J9,9a=2.6 Hz, 1H, Hꢀ9), 3.79 (dd, Jgem=10.8 Hz, J1’,10 =5.8 Hz, 1H, Hꢀ
1’), 3.72 (dd, Jgem=10.8 Hz, J1’,10= 6.3 Hz, 1H, Hꢀ1’), 3.15 (dddd, J3a,3 =7.5 Hz, J3a,4 =7.5 Hz,
3a,9a=5.1 Hz, J=1.0 Hz, 1H, Hꢀ3a), 3.04 (dt, J3,3a=7.5 Hz, J3,4 =2.3 Hz, J3,10=2.3 Hz, 1H, Hꢀ3), 2.70
ddd, Jgem=12.2 Hz, J =5.7 Hz, J =2.1 Hz, 1H, Hꢀ6), 2.46ꢀ2.42 (m, 1H, Hꢀ5), 2.40ꢀ2.38 (m, 1H,
9
J
(
6,5
6,5
13
Hꢀ4), 2.23ꢀ2.18 (m, 1H, Hꢀ6), 2.17ꢀ2.15 (m, 1H, Hꢀ10), 1.84ꢀ1.78 (m, 1H, Hꢀ5); C NMR (100
MHz, CDCl ) δ 179.3 (Cꢀ2), 176.8 (Cꢀ7), 82.3 (Cꢀ9a), 64.2 (Cꢀ1’), 62.6 (Cꢀ9), 44.7 (Cꢀ10), 41.0 (Cꢀ
), 38.6 (Cꢀ3a), 38.3 (Cꢀ4), 33.9 (Cꢀ6), 31.5 (Cꢀ5).
5: [α] 101 (c 0.7, CDCl ); IR (ATR) 2925, 1739, 1193 cm ; H NMR (400 MHz, CDCl
(dd, J =9.5 Hz, J =2.0 Hz, 1H, Hꢀ9), 4.68 (d, Jgem=12.1 Hz, 1H, Hꢀ8), 4.33 (dd, Jgem=12.1 Hz,
3
3
ꢀ1 1
2
D
3
3
) δ 4.92
9,1
9,8
J
J
J
8,9=2.0 Hz, 1H, Hꢀ8), 3.72 (dd, Jgem=10.6 Hz, J1’,2=6.2 Hz, 1H, Hꢀ1’), 3.63 (dd, Jgem=10.6 Hz,
1’,2=7.0 Hz,1H, Hꢀ1’), 3.41 (t, J12,3=10.2 Hz, J12,1=10.2 Hz, 1H, Hꢀ12), 2.92 (br t, J1,12=10.2 Hz,
1,9=9.5 Hz, 1H, Hꢀ1), 2.83ꢀ2.77 (m, 1H, Hꢀ3), 2.75 (ddd, Jgem=18.0 Hz, J5,4=4.3 Hz, J5,4=2.9 Hz,
1
H, Hꢀ5), 2.35 (ddd, Jgem=18.0 Hz, J5,4=13.1 Hz, J5,4=4.4 Hz, 1H, Hꢀ5), 2.22 (tt, Jgem=14.1 Hz,
1
3
J =13.1 Hz, J =4.3 Hz, J =4.3Hz, 1H, Hꢀ4), 2.08ꢀ2.03 (m, 1H, Hꢀ2), 1.94ꢀ1.87 (m, 1H, Hꢀ4); C
4,5
4,5
4,3
NMR (100 MHz, CDCl
3
) δ 176.9 (Cꢀ11), 174.9 (Cꢀ6), 79.6 (Cꢀ9), 66.5 (Cꢀ1’), 66.1 (Cꢀ8), 41.1 (Cꢀ
1
2), 37.3 (Cꢀ1), 37.0 (Cꢀ2), 34.9 (Cꢀ3), 32.8 (Cꢀ5), 21.8 (Cꢀ4).
1
2
6: (from the mixture 24 and 26) H NMR (400 MHz, CDCl
3
) δ 5.67 (m, 2H, Hꢀ1’,Hꢀ2’), 4.74
(
dddd, J1,10=7.7 Hz, J1,10=6.7 Hz, J1,2=5.4 Hz, J1,2=3.1 Hz ,1H, Hꢀ1), 4.35 (dd, Jgem=12.3 Hz, J2,1=3.1
Hz, 1H, Hꢀ2), 4.12 (dd, Jgem=12.3 Hz, J =5.4 Hz, 1H, Hꢀ2), 4.09ꢀ4.06 (m, 2H, Hꢀ3’), 2.61ꢀ252 (m,
2,1
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9
13
1
H, Hꢀ7), 2.47ꢀ2.29 (m,4H, 2Hꢀ5, Hꢀ6, Hꢀ10), 2.10ꢀ1.99 (m, 1H, Hꢀ10); C NMR (100 MHz,
CDCl ) δ 176.8 (Cꢀ10), 172.5 (Cꢀ4), 130.7/129.7 (2C, Cꢀ1’/Cꢀ2’), 77.3 (Cꢀ1), 65.2 (Cꢀ2), 63.3 (Cꢀ
3
3
’), 33.5 (Cꢀ5), 28.2 (Cꢀ7), 27.3 (Cꢀ6), 23.8 (Cꢀ8).
[(1S,7S,8R,9S)-7-hydroxy-3,5-dioxabicyclo[6.1.1]dec-9-yl-]methyl-2,2-dimethylpropenoate
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(28). A 2.0 M solution of LiBH
2 (210 mg, 1.14 mmol) in dry THF (16 mL) and the mixture was heated at the reflux temperature
for 3.5 h. Then the reaction was allowed to cool to rt and the solvent was removed under reduced
pressure. The resulting crude was taken up with CH Cl (20 mL) and a saturated aqueous solution of
NH Cl (5 mL) was added dropwise. The layers were separated and the aqueous layer was extracted
with CH Cl (2x10 mL). The combined organic extracts were dried over Na SO , filtered and
4
in THF (1.75 mL, 3.5 mmol) was added dropwise to a solution of
2
2
2
4
2
2
2
4
evaporated to dryness affording the diol 27 (185 mg, 1.0 mmol), which was used in the next step
without purification.
To a solution of alcohol 27 (185 mg, 1.0 mmol) in pyridine (6 mL) was added PivCl (0.140 mL,
1
.14 mmol) and the resulting clear solution was stirred overnight at rt. The solvent was removed
under reduced pressure and the crude product was purified by column chromatography (hexaneꢀ
EtOAc 3:1) to afford compound 28 (202 mg, 0.74 mmol, 65% yield) as a white solid: Mp 32ꢀ33 °C
(from EtOAcꢀhexane); [α] 31 (c 0.6, CDCl ); IR (ATR) 3465, 2927, 1717, 1471, 1284, 1163, 1016
D
3
ꢀ1 1
cm ; H NMR (400 MHz, CDCl
3
, 323 K) δ 4.86 (br dd, Jgem=11.5 Hz, J1’,9=7.4 Hz, 1H, Hꢀ1’), 4.80ꢀ
4
.72 (br m, 2H, Hꢀ4), 4.59 (dd, Jgem=11.5 Hz, J1’,9=6.6 Hz, 1H, Hꢀ1’), 4.10ꢀ3.71 (m, 5H, 2Hꢀ6, 2Hꢀ2,
Hꢀ7), 3.15ꢀ3.08 (m, 1H, Hꢀ9), 3.04ꢀ2.92 (m, 1H), 2.69ꢀ2.47 (m, 2H), 2.35ꢀ2.17 (m, 1H) 1.18 (s, 9H,
13
(
3 3 3
(CH ) C); C NMR (62.5 MHz, CDCl ) δ 178.7 (C=O), 96.4 (Cꢀ4), 74.1 (Cꢀ7), 68.3/67.3 (Cꢀ6, Cꢀ
2
), 63.5 (Cꢀ1’), 39.1 (Cꢀ9), 38.7((CH ) C), 39.1/36.0 (Cꢀ1, Cꢀ8), 27.2 ((CH ) C), 19.5 (Cꢀ10).
3 3 3 3
+
HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C14
H
24NaO
5
295.1516; Found 295.1522.
[
(1S,2R,4S)-2-[(4S)-1,3-dioxolan-4-yl]-4-(hydroxymethyl)cyclobutyl]methyl pivalate (29). A
solution of 28 (55 mg, 0.2 mmol) and Amberlystꢀ15 (220 mg) in CH Cl (4 mL) was heated to the
2
2
reflux temperature for 5 h. Then, the reaction was cooled to rt and stirred overnight. Amberlystꢀ15
was removed by filtration, and the solvent was removed under reduced pressure. The resulting
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction crude was purified by column chromatography (hexaneꢀEtOAc 2:1) to furnish compound 29
(
40 mg, 0.15 mmol, 73% yield) as a colourless oil: [α] ꢀ20 (c 0.6, CDCl ); IR (ATR) 3433, 2931,
D
3
ꢀ1 1
1
721, 1472, 1160, 1038 cm ; H NMR (250 MHz, CDCl
3
) δ 5.01 (s, 1H, Hꢀ2’’), 4.85 (s, 1H, Hꢀ2’’),
4.39 (d, J1’,1=7.8 Hz, 2H, Hꢀ1’), 4.09 (ddd, J4’’,5’’=6.9 Hz, J4’’,5’’=6.9 Hz, J4’’,2=5.4 Hz, 1H, Hꢀ4’’),
3.91 (dd, Jgem=7.8 Hz, J5’’, 4’’=6.9 Hz, 1H, Hꢀ5’’), 3.72 (dd, Jgem=11.2 Hz, J1’’’,4=8.2 Hz, 1H, Hꢀ1’’’),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
1
.59 (dd, Jgem=11.2 Hz, J1’’’,4=6.1 Hz, 1H, Hꢀ1’’’), 3.35 (dd, Jgem=7.8 Hz, J5’’,4’’=6.9 Hz, 1H, Hꢀ5’’),
.90ꢀ2.75 (m, 1H, Hꢀ1), 2.69ꢀ2.59 (m, 1H, Hꢀ4), 2.59ꢀ2.47 (m, 1H, Hꢀ2), 2.15ꢀ2.03 (m, 1H, Hꢀ3),
13
3 3 3
.95ꢀ1.83 (m, 1H, Hꢀ3), 1.19 (s, 9H, (CH ) C)); C NMR (62.5 MHz, CDCl ) δ 178.3 (Cꢀ2’), 95.4
(
Cꢀ2’’), 75.4 (Cꢀ4’’), 68.2 (Cꢀ5’’), 63.0 (Cꢀ1’’’), 62.3 (Cꢀ1’), 38.7 (CH
35.3 (Cꢀ2), 27.2 (CH
295.1516; Found 295.1524.
(1S,2S,4R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(4S)-1,3-dioxolan-4-
3
)
3
C), 37.5 (Cꢀ1), 35.5 (Cꢀ4),
+
3
)
3
C), 23.4 (Cꢀ3). HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C14
H
24NaO
5
{
yl]cyclobutyl}methyl pivalate (30). tertꢀButyldiphenylsilyl chloride (0.018 mL, 0.07 mmol) was
added to a solution of alcohol 29 (16 mg, 0.06 mmol) and imidazole (5.5 mg, 0.08 mmol ) in
2 2 2
anhydrous CH Cl (0.8 mL) at rt under N . The reaction mixture was stirred at rt for 36 h and the
solvent was removed under reduced pressure. Purification by preparative TLC (hexaneꢀEtOAc 20:1)
provided the desired compound 30 (24 mg, 0.05 mmol, 77% yield) as a colourless oil: [α] 8.7 (c
D
ꢀ1 1
0
.5, CDCl
3 3
); IR (ATR) 2933, 2861, 1727, 1471, 1155, 1100 cm ; H NMR (250 MHz, CDCl ) δ
7.70ꢀ7.59 (m, 4H, PhꢀH), 7.46ꢀ7.32 (m, 6H, PhꢀH), 4.97 (s, 1H, Hꢀ2’’’), 4.83 (s, 1H, Hꢀ2’’’), 4.39 (d,
J
1’,1=7.6 Hz, 2H, Hꢀ1’), 4.11 (ddd, J4’’’,5’’’=6.7 Hz, J4’’’,5’’’=6.7 Hz, J4’’’,4=6.7 Hz, 1H, Hꢀ4’’’), 3.91
(
dd, Jgem=7.6 Hz, J5’’’,4’’’=6.7 Hz, 1H, Hꢀ5’’’), 3.73 (dd, Jgem=10.5 Hz, J1’’,2=6.7 Hz, 1H, Hꢀ1’’), 3.64
dd, Jgem=10.5 Hz, J1’’,2=6.7 Hz, 1H, Hꢀ1’’), 3.37 (dd, Jgem=7.6 Hz, J5’’’,4’’’=6.7 Hz, 1H, Hꢀ5’’’), 2.78
(
(br dquint, J1,1’=7.6 Hz, J1,2=7.6 Hz, J1,4=7.6 Hz, J1,3=2.3 Hz, 1H, Hꢀ1), 2.83ꢀ2.70 (m, 1H, Hꢀ1),
2
1
.70ꢀ2.57 (m, 1H, Hꢀ2), 2.54ꢀ2.39 (m, 1H, Hꢀ4), 2.16ꢀ2.04 (m, 1H, Hꢀ3), 2.05ꢀ1.91 (m, 1H, Hꢀ3),
13
.13 (s, 9H, (CH
3
)
3
C)), 1.05 (s, 9H, (CH
3
)
3
C)); C NMR (62.5 MHz, CDCl
3
) δ 178.3 (Cꢀ2’), 135.6
(
CꢀPh), 133.8 (CtertꢀPh), 129.6 (CꢀPh), 127.6 (CꢀPh), 95.3 (Cꢀ2’’’), 75.8 (Cꢀ4’’’), 68.4 (Cꢀ5’’’), 64.1
Cꢀ1’’), 62.6 (Cꢀ1’), 38.6 (CH ) C), 37.6 (Cꢀ1), 35.8 (Cꢀ4), 35.4 (Cꢀ2), 27.2 (CH ) C), 26.9
(
3
3
3 3
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7
8
9
+
(
CH
3
)
3
C), 24.4 (Cꢀ3), 19.2 (CH
3
)
3
4 9 42 5
CSi). HRMS (ESIꢀTOF) m/z: [Mꢀ C H ] Calcd for C30H O Si
4
53.2098; Found 453.2098.
(
1S,5S,7S)-7-[(4R)-1,3-dioxolan-4-yl]-7-oxa-bicyclo[3.2.0]heptan-2-one (31). A solution of 22
.
(31 mg, 0.17 mmol) and TsOH H
2
O (13 mg, 0.07 mmol) in anhydrous CH
2
Cl
2
(1 mL) was stirred at
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
rt for 24h. Then, the solvent was removed under reduced pressure affording a crude which was
purified by column chromatography (hexaneꢀEtOAc 1:5) to furnish compound 31 (25 mg, 0.14
mmol, 82% yield) as a white solid: Mp 108ꢀ110 °C (from EtOAcꢀhexane); [α] 29 (c 0.9, CDCl ); IR
D
3
ꢀ
1 1
(
3
ATR) 1754, 1187, 1041, 776 cm ; H NMR (250 MHz, CDCl ) δ 5.00 (s, 1H, Hꢀ2’), 4.83 (s, 1H,
Hꢀ2’), 4.36 (dd, Jgem=9.5 Hz, J4,5=6.1 Hz, 1H, Hꢀ4), 4.25 (dd, Jgem=9.5 Hz, J4,5=1.4 Hz, 1H, Hꢀ4),
4.16 – 3.96 (m, 2H, Hꢀ4’, Hꢀ5’), 3.49 (dd, Jgem=8.0 Hz, J5’,4’=5.3 Hz, 1H, Hꢀ5’), 3.20 – 3.11 (m, 1H,
Hꢀ5), 3.11 – 3.01 (m, 1H, Hꢀ1), 2.86 – 2.69 (m, 1H, Hꢀ7), 2.64 – 2.50 (m, 1H, Hꢀ6), 2.13 – 2.03 (m,
1
3
1
H, Hꢀ6); C NMR (62.5 MHz, CDCl ) δ 177.9 (Cꢀ2), 95.3 (Cꢀ2’), 76.5 (Cꢀ4’), 74.3 (Cꢀ4), 68.2 (Cꢀ
3
+
5
’), 40.0 (Cꢀ1), 36.5 (Cꢀ7), 31.1 (Cꢀ5), 28.9 (Cꢀ6). HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for
C
9
H
12NaO
4
207.0628; Found 207.0628.
(1S,2S,3R)-3-[(4S)-1,3-dioxolan-4-yl]cyclobutane-1,2-diyl}dimethanol (32). To an iceꢀcooled
solution of lactone 31 (19 mg, 0.1 mmol) in anhydrous THF (3 mL), LiAlH (0.44 mL, 0.44 mmol,
{
4
1.0 M in THF) was added dropwise. After stirring for 2 h, a mixture of CH Cl and H O (trace) was
2
2
2
added until no bubbles appeared and the resulting mixture was dried over MgSO
4
and concentrated.
The crude product was purified by column chromatography (EtOAc) to afford compound 32 (14 mg,
0
.07 mmol, 70% yield) as a colourless oil: [α]
D
10.2 (c 0.3, CDCl
3
); IR (ATR) 3366, 2930, 1445,
ꢀ1 1
1
082, 1021, 935 cm ; H NMR (360 MHz, CDCl ) δ 4.99 (d, 1H, J=1.3 Hz, Hꢀ2’’’), 4.87 (s, 1H,
3
Hꢀ2’’’), 4.11 (d, J1’’, 2=1.3 Hz, 1H, Hꢀ1’’), 4.06ꢀ4.00 (m, 1H, Hꢀ4’’’), 3.91 (dd, Jgem=8.0 Hz, J5’’’, 4’’’
=1.5 Hz, 1H, Hꢀ5’’’), 3.75ꢀ3.71 (m, 1H, Hꢀ1’), 3.70ꢀ3.66 (m, 1H, Hꢀ1’’), 3.65ꢀ3.60 (m, 1H, Hꢀ1’),
3
2
.49 (br s, 1H, HꢀOH), 3.34 (dd, Jgem=8.0 Hz, J5’’’, 4’’’ =1.5 Hz, 1H, Hꢀ5’’’), 2.80ꢀ2.72 (m, 1H, Hꢀ2),
.69ꢀ2.65 (m, 1H, Hꢀ1), 2.58ꢀ2.47 (m, 1H, Hꢀ3), 2.05ꢀ1.95 (m, 1H, Hꢀ4), 1.91ꢀ1.80 (m, 1H, Hꢀ4);
13
C NMR (62.5 MHz, CDCl
3
) δ 95.3 (Cꢀ2’’’), 75.5 (Cꢀ4’’’), 68.1 (Cꢀ5’’’), 62.4 (Cꢀ1’), 59.7 (Cꢀ1’’),
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