[2+2] Photocycloaddition of symmetrically disubstituted alkenes to 2(5H)-furanones: Diastereoselective entry to 1,2,3,4-tetrasubstituted cyclobutanes

Article abstract of DOI:10.1002/ejoc.201100067

A study on the [2+2] photochemical cycloaddition of 1,4-difunctionalized 2-butenes to 2(5H)-furanones is presented. These reactions deliver 1,2,3,4-tetrasubstituted cyclobutanes with suitable functionalization in the four side chains for further synthetic elaboration. The effects of the substituents in both the lactone and the 2-butene on the stereoselectivity of the photochemical reaction have been evaluated. Starting from (Z)-2-butenes, under photosensitized conditions, a competitive cis/trans isomerization of the olefin inhibits the cycloaddition process. It was found that the presence of a cis double bond confined within a medium-size ring does not prevent bond rotation in the intermediate 1,4-biradicals. Copyright

Full text of DOI:10.1002/ejoc.201100067

FULL PAPER
DOI: 10.1002/ejoc.201100067
[
2+2] Photocycloaddition of Symmetrically Disubstituted Alkenes to 2(5H)-
Furanones: Diastereoselective Entry to 1,2,3,4-Tetrasubstituted Cyclobutanes
[
a]
[a]
[a]
[a]
[a]
Sònia Parés, Pedro de March, Josep Font, Ramon Alibés,* and Marta Figueredo*
Keywords: Photochemistry / Cycloaddition / Natural products / Small ring systems / Enantioselectivity
A study on the [2+2] photochemical cycloaddition of 1,4-di-
of the photochemical reaction have been evaluated. Starting
functionalized 2-butenes to 2(5H)-furanones is presented. from (Z)-2-butenes, under photosensitized conditions, a com-
These reactions deliver 1,2,3,4-tetrasubstituted cyclobutanes
with suitable functionalization in the four side chains for fur-
ther synthetic elaboration. The effects of the substituents in
both the lactone and the 2-butene on the stereoselectivity
petitive cis/trans isomerization of the olefin inhibits the cy-
cloaddition process. It was found that the presence of a cis
double bond confined within a medium-size ring does not
prevent bond rotation in the intermediate 1,4-biradicals.
Introduction
Nature synthesizes a variety of cyclobutane compounds
in which the four positions of the ring are substituted. The
majority of these compounds display bilateral symmetry
due to a dimerization process that takes place during their
biosynthesis. The most studied among these natural prod-
ucts is the alkaloid (–)-sceptrin (1), which was isolated from
the sea sponge Agelas Sceptrum in 1981[ and exhibits po-
tent activity as an antiviral, antimuscarinic, antibacterial,
and antihistaminic agent.[ Recently, other 1,2,3,4-tetrasub-
stituted cyclobutanes have also been isolated from natural
1]
2]
[
3]
sources, such as incarvilateine (2) from Incarvillea si-
[
4]
nensis, and dipiperamide A (3) from Piper nigrum (Fig-
[
5]
ure 1).
Despite the potent biological activity shown by sceptrin
(1), only three synthetic approaches to this interesting com-
pound have been described. In 2004, Birman and Jiang
published the first synthesis of racemic 1, where the key Figure 1. Tetrasubstituted natural cyclobutane compounds.
cyclobutane was constructed through a [2+2] photocycload-
dition of maleic anhydride (4), to (E)-1,4-dichloro-2-butene
[
6]
[
(E)-5], (Scheme 1). The same year, Baran and co-workers
disclosed another synthesis of racemic 1 using 2,5-dimeth-
ylfuran and dimethyl acetylenedicarboxylate as starting ma-
[
7]
terials. A modification of the latter approach by adding a
desymmetrization step led to the first enantioselective prep-
aration of (–)-sceptrin.[
8]
[
a] Department de Química, Universitat Autònoma de Barcelona,
0
8193 Bellaterra, Barcelona, Spain
Fax: +34-935811265
E-mail: ramon.alibes@uab.cat
marta.figueredo@uab.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100067.
Scheme 1. [2+2] Photochemical reaction of maleic anhydride (4)
and olefin (E)-5 for the synthesis of (Ϯ)-sceptrin.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3888–3895

1,2,3,4-Tetrasubstituted Cyclobutanes
As part of our research program directed towards the nished an 85:10:5 mixture of 6 and the cis cycloadducts 8
preparation of natural products and analogues containing (endo) and 9 (exo), in overall 71% yield (Scheme 2). The
a cyclobutane ring,[ we have studied in depth the [2+2] photochemical reaction between 4 and (E)-5 was also per-
photochemical cycloaddition of 1,4-difunctionalized 2-but- formed using our own photochemical methodology, which
enes to 2(5H)-furanones as a means to prepare 1,2,3,4-tet- was systemically applied to the complete study. Thus, sub-
rasubstituted cyclobutanes with suitable functionalization strates 4, 10, or 11 and a ninefold excess of 2-butenes 5,
in the four side chains for further synthetic elaboration. We 12, or 13 in either acetonitrile or acetone solutions, were
have evaluated the lactone and butene substituent effects on irradiated through a Quartz or Pyrex filter using a 125 W
the stereoselectivity of the photochemical reaction, as well high-pressure mercury lamp at 0 °C. The progress of the
9]
1
as the photoexcitation effect on the reactivity and its influ- cycloaddition was monitored by either GC or H NMR
ence on the side processes. The use of a chiral lactone as analysis, and the irradiation was prolonged until the conver-
the substrate gives access to enantiopure cyclobutane deriv- sion remained constant. The results are listed in Table 1.
atives, which might be useful precursors of the bioactive
To compare our results with the literature precedents, an-
compound (–)-sceptrin and other interesting natural prod- hydride maleic (4), and (E)- and (Z)-1,4-dichloro-2-butene,
ucts.
(E)-5 and (Z)-5, were first investigated (Table 1, entries 1–
). When the irradiation was performed through a Quartz
4
filter, in both cases, a mixture of the three possible cycload-
ducts 6, 8, and 9 was formed in similar yield and a compar-
Results and Discussion
Chiral 2(5H)-furanone 11 was prepared from 1,2:5,6-di- able ratio, with the trans cycloadduct 6 being the predomi-
O-isopropylidene-d-mannitol according to a previously re- nant isomer. When the irradiation was performed through
ported methodology.[ Selection of the protecting group a Pyrex filter, similar results were found starting from (E)-
was guided by the excellent results obtained by our group 5, but (Z)-5 did not furnish the expected cycloadducts and
in the [2+2] photocycloaddition of 11 to ethylene deriva- the only process observed in this case was isomerization to
10]
[
11]
tives. Literature precedents for the use of symmetrical 2- (E)-5. Chromatographic separation of cycloadducts 6/8/9
butenes in photocycloadditions to enones were limited to was not possible due to their degradation upon contact
[
12]
achiral substrates.
Therefore, the inclusion of a ste- with silica gel, therefore, for identification purposes, it was
reogenic center as in 11 entailed overcoming a new chal- necessary to perform NMR analyses of samples containing
lenge. Birman and Jiang described that, upon irradiation a mixture of isomers. The C-6/C-7 trans configuration of
through a Pyrex filter of a solution of maleic anhydride (4) the major cycloadduct 6 was assigned on the basis of a
and benzophenone in (E)-1,4-dichloro-2-butene [(E)-5], the NOESY experiment, which showed cross-peaks between
trans cycloadduct 6 was apparently formed as the only the protons at C-8 and the cyclobutane proton H-7, and
product; after methanolysis, this compound delivered dies- between the protons at C-9 and the cyclobutane proton H-
ter 7 in 76% yield (Scheme 1). In our hands, this photoreac- 6. This assignment was corroborated by the higher field
tion, performed under exactly the same conditions, fur- shift of C-9 in the 13C NMR spectra compared to that of
Scheme 2. [2+2] Photochemical reaction of lactones 4, 10, and 11 with 2-butenes 5, 12, and 13.
Eur. J. Org. Chem. 2011, 3888–3895
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. Alibés, M. Figueredo et al.
FULL PAPER
Table 1. [2+2] Photocycloaddition reaction of lactones 4, 10, and 11 to 2-butenes 5, 12, and 13.
Entry Enone
Butene
Filter
Solvent
t [h]
Yield [%][b] Products[e]
Ratio[g]
anti/syn trans/cis[i]
75[
71[
73[
–
c]
6, 8, 9
6, 8, 9
6, 8, 9
–
88:9:3
86:9:5
83:9:8
–
–
–
–
–
–
–
–
–
7.3:1
6.1:1
4.9:1
–
1.8:1
1.9:1
1.5:1
–
1:0
1:2.3
–
1:2.2
1.2:1
1.3:1
–
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
4
(E)-5
(E)-5
(Z)-5
(Z)-5
(E)-5
(E)-5
(Z)-5
(Z)-5
(E)-5
quartz
pyrex
quartz
pyrex
quartz
pyrex
quartz
pyrex
quartz
quartz
pyrex
quartz
quartz
pyrex
acetonitrile 1.5
c]
c]
4
acetone
acetonitrile
acetone
4
4
4
4
4
58 (83)[
44 (75)[
46 (87)[
–
d]
d]
d]
14a, 15a, 16a, 17a 34:30:23:13
14a, 15a, 16a, 17a 37:28:23:12
14a, 15a, 16a, 17a 35:25:29:11
10
10
10
10
11
10
10
11
10
10
11
acetonitrile
acetone
9
11
acetonitrile 10
acetone
acetonitrile
10
4
–
–
68 (91)[
d]
18a, 19a, 23a
16b, 14b, 15b
–
40:33:27
70:15:15
–
2.7:1
–
–
0
1
2
3
4
5
(Z)-12[
(Z)-12
(Z)-12
(Z)-13[
(Z)-13
(Z)-13
a]
acetonitrile 3.5
70 (84)
–
[d]
acetone
6
4
3
4
4
70 (77)[
d]
20b, 25b, 19b, 18b 54:15:14:17 5.7:1
acetonitrile
acetonitrile
acetone
a]
[d]
[h]
69 (81)
35 (78)[
46 (69)[
16c, 14c, 15c
16c, 14c, 15c
18c, 19c, C
46:35:19
43:37:20
46:38:16
–
–
–
d]
d]
[h]
[f]
quartz
acetonitrile
[a] The E isomer is not commercially available. [b] Isolated yield of the mixture of stereoisomers after column chromatography except for
entries 1–4. [c] Isolated yield of the mixture of stereoisomers after removal of the excess of olefin 5 by kugelrohr distillation. [d] Isolated
yield considering the starting material recovered is given in parenthesis. [e] Products given in order of time retention on a GC column.
[
f] The third diastereoisomer C could not be fully characterized. [g] Isomer ratio from GC analysis of the crude reaction mixture. [h]
13
Isomer ratio from C NMR analysis of the crude reaction mixture. [i] C-6/C-7 relative configuration.
C-8, which was connected to the larger steric compression inducing its excitation to an orthogonal triplet state that
can undergo relaxation to either isomer of the olefin.[ It
13]
of the former.
The photoreaction of crotonolactone (10), with (E)- and is also plausible that the triplet state of acetone (Table 2,
Z)-5 in acetonitrile using a Quartz filter (Table 1, entries 5 entry 6) or crotonolactone (entry 8) reacted with olefin (Z)-
(
and 7) rendered, in moderate yields, the four possible cy- 5, but the intermediate biradical species did not evolve to
[
14]
cloadducts 14a, 15a, 16a, and 17a with a poor C-6/C-7 the oxetane or cyclobutane adducts because reversion to
trans/cis ratio of 1.8:1 and 1.5:1, respectively, which was de- the starting carbonyl compound and the olefin (Z or E) was
[
15]
termined by NOESY experiments and further corroborated more favored.
by the value of the coupling constant between H-6 and H- unable to react with crotonolactone to furnish the cycload-
. The relative configuration between H-5 and H-6 was in- ducts, it must be concluded that these competitive pathways
Because the newly formed olefin (E)-5 is
7
1
3
ferred from the chemical shift of C-4 in the C NMR spec- inhibit the photocycloaddition process.
tra. Thus, the signal of C-4 is high-field shifted when this
carbon atom is close to the bulky chloromethyl group, Table 2. Study of the of E/Z photoisomerization of 5.
namely, when H-5 and H-6 are in a cis relationship. Cross-
peaks on the NOESY experiments between H-4 and H-6 in
the 5,6-cis cycloadducts, and between H-4 and H-8 in the
Substrate Z/E[c]
Entry Olefin
Filter
Solvent
1
2
3
4
5
6
7
8
(E)-5[a]
(E)-5
quartz
pyrex
quartz
pyrex
quartz
pyrex
quartz
pyrex
acetonitrile
acetone
–
–
1:32
1:32
1:32
1:32
19:1
1:2.3
4.9:1
2.1:1
5,6-trans cycloadducts validated the diagnostic value of the
(E)-5
acetonitrile 10
above parameter. When the reaction with 10 was assayed
through a Pyrex filter in acetone as solvent and sensitizing
agent (Table 1, entries 6 and 8), olefin (E)-5 lead to the for-
mation of four expected cycloadducts 14a–17a in a 1.9:1,
(E)-5[
acetone
acetonitrile
acetone
10
–
–
b]
(Z)-5
(Z)-5
(Z)-5
(Z)-5
acetonitrile 10
acetone 10
6,7-trans/cis ratio and 46% yield, while the (Z)-5 isomer did
[
(
a] Commercial (E)-5 is contaminated with 3% of the Z isomer
not react. Similar to the case of maleic anhydride, instead
of the photocycloaddition, an isomerization from the (Z)-
olefin to (E)-5 was again observed as the only process.
In view of the above results, we wanted to examine the
effect of acetone and crotonolactone (10) as potential sensi-
Z/E ratio 1:32). [b] Commercial (Z)-5 is contaminated with 5% of
the E isomer (Z/E ratio 19:1). [c] Isomer ratio determined by GC
analysis of the crude reaction mixture after 2 h of irradiation.
Once the reaction of butene 5 with the achiral substrates
tizing agents for the E/Z isomerization of 5 (Table 2). When 4 and 10 had been investigated, the best synthetic condi-
E)-5 was irradiated, the isomerization of the double bond tions were applied to the enantiopure 2(5H)-furanone 11
(
was not observed in any of the four sets of conditions as- (Table 1, entry 9). Considering the mechanistic proposal for
sayed (Table 2, entries 1–4). In contrast, when (Z)-5 was this kind of photocycloaddition that postulates free rotation
irradiated, isomerization was observed in the presence of of the C-6/C-7 bond on the 1,4-biradical intermediates,[15]
either acetone (Table 2, entry 6), crotonolactone (10) (entry this reaction could lead to the formation of up to eight
7) or both (entry 8). These results may be explained by con- products, which can be classified into four different pairs:
sidering various mechanistic alternatives. Firstly, a photo- anti/trans, anti/cis, syn/trans, and syn/cis (Scheme 2). Re-
sensitized process may occur that transfers the energy from markably, irradiation of 11 in the presence of (E)-5 in aceto-
the triplet of acetone and/or the triplet of 10 to (Z)-5, hence nitrile through a Quartz filter provided exclusively three cy-
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Eur. J. Org. Chem. 2011, 3888–3895

1,2,3,4-Tetrasubstituted Cyclobutanes
cloadducts (18a, 19a, and 23a) in 68% overall yield. The C- rings are cis fused. For 18b, 19b, 20b, and 25b, the anti/syn
/C-7 trans/cis relative configuration was determined fol- configuration was assigned through the coupling constant
6
lowing the same method used for 14a/17a. The disposition J9,10. All the stereochemical assignments were confirmed by
between H-4 and H-5 was assigned on the basis of the value NOESY experiments. To extend their synthetic utility, the
of their coupling constant, which was lower for the anti mixture of oxepanes derived from either lactone were con-
(0 Hz for 18a and 1.7 Hz for 19a) than for the syn cycload- verted into the corresponding diols by treatment with
ducts (5.2 Hz for 23a); the results were corroborated by pTsOH in MeOH (Scheme 3).
NOESY experiments. Because the three isolated isomers
To complete the photochemical study, lactones 10 and 11
present C-6/C-7 trans relative configuration, all of them are were irradiated in the presence of (Z)-2-buten-1,4-diol [(Z)-
attractive precursors for the synthesis of enantiopure 13], which is more readily available than its E isomer
1,2,3,4-tetrasubstituted cyclobutanes with all the neighbor (Table 1, entries 13–15). The photoreaction with achiral fu-
substituents in a trans disposition, as in sceptrin (1). Specifi- ranone 10 in acetonitrile using a Quartz filter delivered
cally, 18a could lead to the natural alkaloid (–)-1, and 19a three isomeric cycloadducts 14c–16c in 69% isolated yield,
and 23a to the non natural sceptrin (+)-1, following the with a slight predominance of the C-6/C-7 trans relative
route described by Birman and Jiang for the synthesis of configuration. The same products in a similar proportion
the racemate.
were also formed when the irradiation was carried out in
To explore the possibility of achieving C-6/C-7 cis cy- acetone through a Pyrex filter, but, under these conditions,
cloadducts, we investigated the [2+2] photocycloaddition of the yield decreased to 35%. We believe that this loss of ef-
2(5H)-furanones 10 and 11 to (Z)-4,7-dihydro-1,3-dioxepin fectiveness when the cycloaddition is performed under pho-
[
(Z)-12], expecting that the occurrence of a more rigid cyclic tosensitized conditions may be related to the existence of a
moiety may prevent bond rotation in the intermediate 1,4- competitive cis/trans isomerization process of the olefin, as
biradical species. The photoreaction of 10 and (Z)-12 using was observed for (Z)-5, although in this case the corre-
a Quartz filter without a sensitizing agent, furnished a sponding trans isomer (E)-13 was not detected. Finally, di-
15:15:70 mixture of 14b, 15b, and 16b in 70% total yield rect irradiation conditions were applied to chiral furanone
(Table 1, entry 10), showing that the cyclic nature of the 11, providing a mixture of three cycloadducts, although
olefin does not entirely preclude C-6/C-7 bond rotation, al- only two could be identified (18c and 19c) due to severe
though the predominating isomer of the product displays difficulties encountered in the chromatographic purification
cis relative configuration, as expected. In a parallel experi- of the crude material. The relative configuration of 14c–
ment, carried out in acetone using a Pyrex filter (Table 1, 16c, 18c, and 19c was assigned as described above for the
entry 11), most of the starting material was recovered un- chlorinated cycloadducts and by correlation with the diox-
changed. Consequently, only the first protocol was applied epane derivatives through methanolysis.
to lactone 11 (Table 1, entry 12), resulting in the formation
of a mixture of four among the eight possible diastereomers
in a 1:2.2 C-6/C-7 trans/cis ratio, from which the major cy-
Conclusions
cloadduct could be isolated in 54% yield. The relative con-
It has been found that the [2+2] photocycloaddition of
figuration of the new stereogenic centers was determined by 2(5H)-furanones to 1,4-difunctionalized 2-butenes works
the value of the coupling constants J1,2 and J8,2 (numbering well upon direct irradiation of an acetonitrile solution of
shown in Scheme 3). Other useful data for the stereochemi- the reactants through a Quartz filter. Starting from (Z)-2-
cal assignment was the chemical shift of the diastereotopic butenes, under photosensitized conditions, a competitive
protons at C-5, which are isochronous when the four- and cis/trans isomerization of the olefin inhibits the cycload-
seven-member rings are trans fused, and display an AB sys- dition process. From a synthetic point of view, the most
tem with approximately 1 ppm separation when these two useful of the studied reactions was the photocycloaddition
of chiral furanone 11 to trans dichlorobutene (E)-5, leading
exclusively to C-6/C-7 trans-cyclobutanes, which can be ap-
propriate precursors for the enantioselective synthesis of
natural 1,2,3,4-tetrasubstituted cylobutanes such as sceptrin
(1), and others. Photocycloadditions performed with 1,3-
dioxepin (Z)-12 provided evidence that the presence of a cis
double bond confined within a medium-size ring does not
prevent bond rotation in the intermediate 1,4-biradicals, al-
though the sense of stereoselectivity is inverted from C-6/
C-7 trans to cis. Work is in progress to develop synthetic
applications of these photochemical reactions.
Experimental Section
General: Commercially available reagents were used as received.
Scheme 3. Methanolysis of the acetal to furnish the diol derivatives.
Solutions were concentrated using an evaporator at 15–20 Torr.
Eur. J. Org. Chem. 2011, 3888–3895
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. Alibés, M. Figueredo et al.
FULL PAPER
Flash column chromatography separations were carried out on sil-
ica gel (230–400 mesh). Melting points were determined on a hot
stage apparatus. 1H and C NMR spectra were recorded at the
Servei de Ressonància Magnètica Nuclear de la Universitat Autò-
reaction was monitored by GC analysis. Evaporation of the solvent
and column chromatography (hexane/EtOAc, 10:1) rendered a mix-
ture of 14a, 15a, 16a, and 17a (34:30:23:13 ratio; 217 mg,
1.03 mmol, 58% yield) and unreacted lactone (37 mg, 0.44 mmol).
13
noma de Barcelona at 250 and 62.5 MHz, 360 and 90 MHz, or 400 Repeated column chromatography (hexane to hexane/EtOAc, 3:1)
and 100 MHz. NMR signals were assigned with the help of DEPT,
COSY, HMBC, and HMQC experiments. High resolution mass
spectra (HRMS) and Microanalyses were performed at the Servei
d’Anàlisi Química de la Universitat Autònoma de Barcelona. Op-
tical rotations were measured at 22Ϯ2 °C.
provided an oily residue, which was identified as pure 14a, and
enriched fractions of compounds 15a–17a.
1
Compound 14a: H NMR (360 MHz, CDCl
3
, 25 °C): δ = 4.41 (ddd,
2
3
2
J
=
H,H = 9.7, JH,H = 5.9, J = 1.2 Hz, 1 H, 4-H), 4.32 (br. d, JH,H
2
3
9.7 Hz, 1 H, 4-H), 3.85 (dd, JH,H = 11.2, JH,H = 4.6 Hz, 1 H,
8-H), 3.75 (ddd, JH,H = 11.4, JH,H = 5.8, JH,H = 0.9 Hz, 1 H, 9-
JH,H = 11.2, JH,H = 8.3, JH,H = 0.8 Hz, 1 H, 8-
JH,H = 11.4, JH,H = 10.1, JH,H = 0.8 Hz, 1 H, 9-
JH,H = 9.4, 7.6 Hz, 1 H, 1-H), 2.96 (ddd, JH,H
(
1RS,5SR,6SR,7SR)-6,7-Bis(chloromethyl)-3-oxabicyclo[3.2.0]-
2
3
4
heptan-2,4-dione (6), (1RS,5SR,6SR,7RS)-6,7-Bis(chloromethyl)-3-
oxabicyclo[3.2.0]heptan-2,4-dione (8) and (1RS,5SR,6RS,7RS)-6,7-
Bis(chloromethyl)-3-oxabicyclo[3.2.0]heptan-2,4-dione (9). Birman
and Jiang Methodology: An oxygen-free solution of maleic anhy-
dride (4; 105 mg, 1.07 mmol) and benzophenone (49 mg,
H), 3.62 (ddd,
H), 3.50 (ddd,
H), 3.22 (dd,
2
3
4
2
3
4
3
3
=
7.6, 6.0, 5.9 Hz, 1 H, 5-H), 2.82 (m, 1 H, 7-H), 2.55 (m, 1 H, 6-
H) ppm. 13C NMR (62.9 MHz, CDCl , 25 °C): δ = 176.2 (C=O),
3
0.27 mmol) in (E)-1,4-dichloro-2-butene [(E)-5; 1.25 g, 10.0 mmol]
73.0 (CH , 4-C), 46.7 (CH , 8-C), 46.6 (CH, 6-C), 44.2 (CH , 9-C),
2
2
2
was placed in an NMR tube. This solution was irradiated through
a Pyrex filter for 60 h at room temperature under a nitrogen atmo-
sphere. The progress of the reaction was monitored by GC analysis.
Evaporation of the solvent and kugelrohr distillation of (E)-5 under
reduced pressure afforded a mixture of 6, 8 and 9 (86:9:5 ratio;
39.6 (CH, 7-C), 38.0 (CH, 1-C), 36.1 (CH, 5-C) ppm. IR (ATR): ν
˜
= 2960, 2907, 1757, 1477, 1261, 1161, 1042 cm–1. MS m/z (%) =
+
+
208 (0.4) [M]
, 175 (14), 173 (40), 85 (94), 67 (100). HRMS (ESI ):
calcd. for C H Cl O Na 230.9950; found 230.9950.
8
10
2
2
1
3
Compound 15a: H NMR (360 MHz, CDCl , 25 °C): δ = 4.58 (dd,
169 mg, 0.76 mmol, 71% yield). The cycloadducts 6, 8, and 9 de-
2
3
2
J
H,H = 10.7, JH,H = 2.4 Hz, 1 H, 4-H), 4.43 (dd, JH,H = 10.7,
composed upon contact with silica gel.
3JH,H = 8.2 Hz, 1 H, 4-H), 3.74 (m, 2 H, 9-H), 3.74–3.65 (m, 2 H,
8
1
Compound 6: H NMR (250 MHz, CDCl
3
, 25 °C): δ = 3.82 (m, 2
3
3
-H), 3.30 (dtd, JH,H = 8.2, 8.0, 2.4 Hz, 1 H, 5-H), 3.03 (dd, JH,H
H, 8-H), 3.74 (m, 2 H, 9-H), 3.59 (m, 1 H, 1-H), 3.46 (m, 1 H, 5-
=
8.2, 4.7 Hz, 1 H, 1-H), 2.86 (m, 1 H, 6-H), 2.56 (m, 1 H, 7-
H), 3.23 (m, 1 H, 7-H), 2.96 (m, 1 H, 6-H) ppm. 13C NMR
13
H) ppm. C NMR (90.6 MHz, CDCl
3
, 25 °C): δ = 178.1 (C=O),
, 9-C), 43.8 (CH, 7-C), 42.9 (CH , 8-C),
9.7 (CH, 6-C), 37.9 (CH, 1-C), 32.3 (CH, 5-C) ppm. MS m/z (%)
(
(
(
(
62.9 MHz, CDCl
3
, 25 °C): δ = 171.0 (C=O), 170.0 (C=O), 46.1
, 9-C), 39.5/39.2/38.9
6
3
7.9 (CH
2
, 4-C), 46.9 (CH
2
2
CH , 8-C), 43.8 (CH, 6-C), 43.5 (CH
2
2
3ϫCH, 1-C/5-C/7-C) ppm. MS: m/z (%) = 180 (1.5), 178 (2.5), 152
11), 150 (17), 117 (20), 115 (66), 103 (17), 101 (49), 79 (100).
+
=
208 (0.1) [M] , 175 (3.5), 173 (11), 85 (100).
1
Compound 16a: H NMR (360 MHz, CDCl
J
3
, 25 °C): δ = 4.41 (dd,
Compound 8: MS: m/z (%) = 180 (2.0), 178 (3.1), 152 (7.5), 150
12), 117 (16), 115 (50), 103 (18), 101 (50), 79 (100).
2
3
2
3
H,H = 9.7, JH,H = 5.9 Hz, 4-H), 4.32 (dd, JH,H = 9.7, JH,H
=
(
1
.0 Hz, 4-H), 3.88–3.60 (m, 4 H, 2ϫ 8-H, 2ϫ 9-H), 3.12–2.76 (m,
1
3
Compound 9: MS: m/z (%) = 180 (1.9), 178 (3.3), 152 (8), 150 (12),
17 (18), 115 (52), 103 (22), 101 (48), 79 (100).
4 H, 1-H, 5-H, 6-H, 7-H) ppm. C NMR (90.6 MHz, CDCl3,
1
25 °C): δ = 178.1 (C=O), 72.8 (CH , 4-C), 43.6/43.2 (CH/CH , 6-
2
2
2
C/8-C), 42.8 (CH , 9-C), 41.3 (CH), 38.9 (CH), 38.2 (CH) ppm.
MS: m/z (%) = 208 (0.5) [M] , 175 (13), 173 (41), 85 (100).
General Procedure for Photochemical Reactions: The irradiation
was performed in a small, conventional photochemical reactor
+
(two-necked vessel fitted with a Quartz or Pyrex immersion-type
1
Compound 17a: H NMR (250 MHz, CDCl
3
, 25 °C): δ = 4.55–4.10
cooling jacket) using a high pressure 125 W mercury lamp (Cath-
odeon HPK-125). Methanol at –15 °C was used to refrigerate the
immersion well jacket. The vessel was externally cooled to 0 °C.
The reaction mixture was initially degassed by passage of oxygen-
free nitrogen through the solution for 10 min and then irradiated
under an atmosphere of nitrogen. The progress of the reaction was
(
2
m, 2 H, 2ϫ 4-H), 3.84–3.58 (m, 4 H, 2ϫ 8-H, 2ϫ 9-H), 3.21–
13
.98 (m, 2 H, 1-H, 5-H), 2.50–2.20 (m, 2 H, 6-H, 7-H) ppm.
C
NMR (62.9 MHz, CDCl
C), 45.6 (CH ), 45.6 (CH
CH) ppm. MS: m/z (%) = 175 (0.3), 173 (2.7), 85 (100). Mixture
3
, 25 °C): δ = 178.6 (C=O), 63.5 (CH
2
, 4-
2
2
), 40.5 (CH), 39.7 (CH), 31.1 (CH), 29.1
(
1
2
+
8 2 2
5a–16a: HRMS (ESI ): calcd. for C H10Cl O Na 230.9950; found
1
13
monitored by GC or by H or C NMR analyses of sample ali-
quots.
30.9945.
Irradiation of a solution of lactone 10 (150 mg, 1.78 mmol) and
E)-5 (2.00 g, 16.0 mmol) in acetone (90 mL) through a Pyrex filter
Compounds 6, 8, and 9: A solution of maleic anhydride (4; 150 mg,
(
1
1
.53 mmol) and (E)-1,4-dichloro-2-butene [(E)-5; 1.721 g,
3.8 mmol] in acetonitrile (90 mL) was irradiated through a Quartz
for 11 h furnished a mixture of 14a, 15a, 16a, and 17a (37:28:23:12
ratio; 165 mg, 0.79 mmol, 44 % yield) and unreacted lactone
(
filter for 1.5 h. The progress of the reaction was monitored by GC
analysis. Evaporation of the solvent and kugelrohr distillation of
46 mg, 0.55 mmol) after purification of the crude material by silica
gel column chromatography.
(E)-5 under reduced pressure afforded a mixture of 6, 8, and 9
Irradiation of a solution of lactone 10 (150 mg, 1.78 mmol) and
(88:9:3 ratio; 255 mg, 1.14 mmol, 75% yield).
(
Z)-5 (2.00 g, 16.0 mmol) in acetonitrile (90 mL) through a Quartz
filter for 10 h furnished a mixture of 14a, 15a, 16a, and 17a
35:25:29:11 ratio; 171 mg, 0.82 mmol, 46% yield) and unreacted
(
1RS,5SR,6RS,7RS)-6,7-Bis(chloromethyl)-3-oxabicyclo[3.2.0]-
heptan-2-one (14a), (1RS,5SR,6SR,7SR)-6,7-Bis(chloromethyl)-3-
oxabicyclo[3.2.0]heptan-2-one (15a), (1RS,5SR,6RS,7SR)-6,7-
Bis(chloromethyl)-3-oxabicyclo[3.2.0]heptan-2-one (16a), and
(
lactone (61 mg, 0.73 mmol) after purification of the crude material
by silica gel column chromatography.
(
1RS,5SR,6SR,7RS)-6,7-Bis(chloromethyl)-3-oxabicyclo[3.2.0]-
heptan-2-one (17a): A solution of 2(5H)-furanone 10 (150 mg,
Irradiation of a solution of lactone 10 (150 mg, 1.78 mmol) and
1.78 mmol) and (E)-5 (2.00 g, 16.0 mmol) in acetonitrile (90 mL) (Z)-5 (2.00 g, 16.0 mmol) in acetone (90 mL) through a Pyrex filter
was irradiated through a Quartz filter for 9 h. The progress of the for 10 h delivered the unreacted lactone 10 (135 mg, 1.60 mmol)
3892
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3888–3895

1,2,3,4-Tetrasubstituted Cyclobutanes
after purification of the crude material by silica gel column
chromatography.
[7.3.0.02,8]dodecan-12-one (15b): A solution of 2(5H)-furanone 10
(150 mg, 1.78 mmol) and (Z)-12 (1.602 g, 16.0 mmol) in acetoni-
trile (90 mL) was irradiated through a Quartz filter for 3.5 h. The
progress of the reaction was monitored by GC analysis, where the
appearance of three new peaks was observed (70:15:15). Evapora-
tion of the solvent and column chromatography over silica gel (hex-
ane/EtOAc, 1:1) provided the following fractions: (i) a white solid
identified as 16b (160 mg, 0.87 mmol, 49% yield), (ii) a white solid
identified as a mixture of 14b and 15b (1:1 ratio; 68 mg, 0.37 mmol,
(
1S,4S,5R,6S,7S)-6,7-Bis(chloromethyl)-4-(pivaloyloxymethyl)-3-
oxabicyclo[3.2.0]heptan-2-one (18a), (1S,4S,5R,6R,7R)-6,7-Bis(chlo-
romethyl)-4-(pivaloyloxymethyl)-3-oxabicyclo[3.2.0]heptan-2-one
(
19a), and (1R,4S,5S,6S,7S)-6,7-Bis(chloromethyl)-4-(pivaloyloxy-
methyl)-3-oxabicyclo[3.2.0]heptan-2-one (23a): A solution of (S)-5-
(
(
pivaloyloxymethyl)-2(5H)-furanone (11; 150 mg, 0.76 mmol) and
E)-5 (856 mg, 6.84 mmol) in acetonitrile (90 mL) was irradiated
21% yield), and (iii) unreacted lactone (21 mg, 0.25 mmol).
through a Quartz filter for 4 h. The progress of the reaction was
monitored by GC analysis. Evaporation of the solvent and column
chromatography of the residue (hexane/EtOAc, 10:1 to 6:1) ren-
dered a mixture of 18a, 19a, and 23a (40:33:27 ratio; 166 mg,
Compound 16b: M.p. 93–95 °C (EtOAc/pentane). 1H NMR
2
(250 MHz, CDCl
3
, 25 °C): δ = 5.19 (d, JH,H = 7.3 Hz, 1 H, 5-H),
2
2
3
4.37 (d, JH,H = 7.3 Hz, 1 H, 5-H), 4.40 (dd, JH,H = 9.7, JH,H
6.8 Hz, 1 H, 10-H), 4.26 (dd, JH,H = 9.7, JH,H = 1.5 Hz, 1 H, 10-
H), 4.17 (dd, JH,H = 13.3, JH,H = 2.9 Hz, 1 H, 3-H), 3.99 (dd,
=
2
3
0
0
.51 mmol, 68% yield) and unreacted starting material 11 (34 mg,
.17 mmol). Repeated column chromatography (hexane to hexane/
2
3
2
3
2
EtOAc, 6:1) furnished the following fractions: (i) an oil identified
as pure 18a; (ii) an enriched fraction of 19a, and (iii) an enriched
fraction of 23a.
JH,H = 13.5, JH,H = 3.7 Hz, 1 H, 7-H), 3.79 (dd, JH,H = 13.3,
3JH,H = 2.2 Hz, 1 H, 3-H), 3.68 (dd, JH,H = 13.5, JH,H = 1.3 Hz,
2
3
3
1 H, 7-H), 3.37 (ddd, JH,H = 8.2, 6.8, 5.6 Hz, 1 H, 9-H), 3.10 (dd,
3
J
H,H = 8.2, 3.5 Hz, 1 H, 1-H), 2.74 (m, 1 H, 8-H), 2.82 (m, 1 H,
-H) ppm. 13C NMR (62.9 MHz, CDCl
, 25 °C): δ = 180.1 (2-C),
00.5 (CH , 5-C), 73.4 (CH , 3-C), 73.2 (CH , 10-C), 70.7 (CH
-C), 44.0 (CH, 8-C), 43.1 (CH, 2-C), 38.1 (CH, 1-C), 33.8 (CH,
1
Compound 18a: H NMR (250 MHz, CDCl
3
2
, 25 °C): δ = 4.65 (dd,
2
3
3
3
J
3
H, CH
3
=
1
H,H = 3.4, 3.1 Hz, 1 H, 4-H), 4.25 (dd,
J
H,H = 12.2,
H,H
J =
1
7
9
2
2
2
2
,
2
3
.4 Hz, 1 H, CH
2
OPiv), 4.12 (dd, JH,H = 12.2, JH,H = 3.1 Hz, 1
OPiv), 3.86 (dd, JH,H = 11.2, 3JH,H = 4.6 Hz, 1 H, 8-H),
2
2
–
1
-C) ppm. IR (ATR): ν˜ = 2908, 2872, 1745, 1475, 1153, 1015 cm .
MS: m/z (%) = 184 (24) [M] , 154 (10), 85 (100). C H O (184.19):
9 12 4
2
3
2
.75 (dd, JH,H = 11.3, JH,H = 5.6 Hz, 1 H, 9-H), 3.60 (dd, JH,H
11.2, JH,H = 8.6 Hz, 1 H, 8-H), 3.49 (dd, JH,H = 11.3, JH,H =
0.2 Hz, 1 H, 9-H), 3.27 (dd, JH,H = 9.5, 7.3 Hz, 1 H, 1-H), 2.82
m, 1 H, 7-H), 2.81 (dd, JH,H = 7.3, 6.4 Hz, 1 H, 5-H), 2.57 (m, 1 Compound 14b: H NMR (250 MHz, CDCl
+
3
2
3
calcd. C 58.69, H 6.57; found C 58.72, H 6.47.
3
3
1
(
3
, 25 °C): δ = 4.84 (s, 2
1
3
2
3
H, 6-H), 1.19 (s, 9 H, tBu) ppm. C NMR (62.9 MHz, CDCl
5 °C): δ = 177.8 (C=O, lactone), 175.2 (C=O, ester), 81.8 (CH, 4-
C), 65.0 (CH , CH OPiv), 46.6/46.5 (CH/CH , 6-C/8-C), 44.2
, 9-C), 40.1 (CH, 7-C), 39.0 (CH, 1-C), 38.8 [(CH C], 38.5
CH, 5-C), 27.1 [(CH C] ppm. IR (ATR): ν˜ = 2962, 2872, 1770,
724, 1479, 1283, 1145, 1086 cm . MS m/z (%) = 289 (1.4), 287
4.1), 222 (5), 220 (7), 57 (100). C14 (323.22): calcd. C (CH
40.4 (CH, 2-C), 38.3 (CH, 1-C), 36.7 (CH, 9-C) ppm. MS m/z (%)
3
,
H, 2ϫ 5-H), 4.31 (dd, JH,H = 9.6, JH,H = 4.9 Hz, 1 H, 10-H),
4.22 (d, JH,H = 9.6 Hz, 1 H, 10-H), 4.15 (dd, JH,H = 10.9, JH,H
= 4.7 Hz, 1 H), 4.06 (dd, JH,H = 11.1, JH,H = 5.5 Hz, 1 H), 3.56
(d, JH,H = 11.1 Hz, 1 H), 3.51 (d, JH,H = 10.9 Hz, 1 H), 3.20 (m,
1 H, 9-H), 3.08–2.55 (m, 3 H, 1 H, 2-H, 8-H) ppm. C NMR
(62.9 MHz, CDCl , 25 °C): δ = 176.5 (2-C), 92.8 (CH , 5-C), 71.9
, 3-C), 69.8 (CH , 10-C), 67.8 (CH , 7-C), 44.8 (CH, 8-C),
2
2
3
2
2
3
2
2
2
2
2
(CH
2
3
)
3
1
3
(
1
3
)
3
–1
3
2
(
H20Cl
2
O
4
2
2
2
5
2.02, H 6.24; found C 52.19, H 6.49.
+
=
184 (0.2) [M] , 154 (0.3), 85 (100).
1
3
Compound 19a: H NMR (360 MHz, CDCl , 25 °C): δ = 4.98 (ddd,
3
2
3
1
J
H,H = 3.4, 3.1, 1.7 Hz, 1 H, 4-H), 4.31 (dd, JH,H = 12.1, JH,H
Compound 15b: H NMR (250 MHz, CDCl
3
, 25 °C): δ = 4.84 (s, 2
2
3
2
3
=
3.1 Hz, 1 H, CH
H, CH OPiv), 3.77–3.64 (m, 4 H, 2ϫ 8-H, 2ϫ 9-H), 3.09 (m, 2 4.54 (d, JH,H = 10.4 Hz, 1 H, 10-H), 4.06 (dd, JH,H = 11.1, JH,H
H, 1-H, 5-H), 2.93 (m, 1 H, 6-H/7-H), 2.58 (m, 1 H, 6-H/7-H), 1.19 = 5.5 Hz, 1 H), 3.94 (dd, JH,H = 11.1, JH,H = 5.6 Hz, 1 H), 3.65
2
OPiv), 4.15 (dd, JH,H = 12.1, JH,H = 3.5 Hz,
H, 2ϫ 5-H), 4.61 (dd, JH,H = 10.4, JH,H = 6.5 Hz, 1 H, 10-H),
2
2
3
1
2
2
3
s, 9 H, tBu) ppm. 13C NMR (62.9 MHz, CDCl
C=O, lactone), 177.1 (C=O, ester), 76.7 (CH, 4-C), 65.8 (CH
OPiv), 46.8, 43.7, 42.9, 39.7, 39.0, 38.8 [(CH C], 35.0, 27.1
(CH C] ppm. MS: m/z (%) = 289 (1.2), 287 (3.4), 222 (0.8), 220
1.0), 57 (100).
, 25 °C): δ = 177.8
(d,
(m, 1 H, 9-H), 3.08–2.55 (m, 3 H, 1-H, 2-H, 8-H) ppm. C NMR
(62.9 MHz, CDCl , 25 °C): δ = 176.6 (2-C), 93.1 (CH , 5-C), 70.5
(CH , 3-C), 68.0 (CH , 10-C), 66.5 (CH , 7-C), 43.8 (CH, 8-C),
41.1 (CH, 2-C), 38.5 (CH, 1-C), 33.6 (CH, 9-C) ppm. MS m/z (%)
2
JH,H = 11.2 Hz, 1 H), 3.60 (d, JH,H = 11.1 Hz, 1 H), 3.20
2
(
(
3
13
2
,
CH
[
(
2
3
)
3
3
2
3
)
3
2
2
2
+
=
184 (0.4) [M] , 154 (28), 85 (100).
OPiv), 3.78 Mixture 14b–15b: C (184.19): calcd. C 58.69, H 6.57; found
m, 1 H, 8-H), 3.74 (m, 1 H, 9-H), 3.62 (dd, JH,H = 11.3, 3JH,H
C 58.69, H 6.65.
Irradiation of a solution of lactone 10 (150 mg, 1.78 mmol) and
Z)-12 (2.00 g, 16.0 mmol) in acetone (90 mL) through a Pyrex fil-
1
Compound 23a: H NMR (360 MHz, CDCl
J
3
, 25 °C): δ = 4.72 (td,
3
H,H = 6.0, 5.2 Hz, 1 H, 4-H), 4.39–4.35 (m, 2 H, CH
2
9 12 4
H O
2
(
6
=
2
3
.9 Hz, 1 H, 8-H), 3.51 (dd, JH,H = 11.4, JH,H = 9.5 Hz, 1 H, 9-
H), 3.30 (dd, JH,H = 8.1, 7.4 Hz, 1 H, 1-H), 3.04 (ddd, JH,H
3
3
=
(
7
1
1
.4, 5.3, 5.2 Hz, 1 H, 5-H), 2.84 (m, 1 H, 7-H), 2.75 (m, 1 H, 6-H),
.22 (s, 9 H, tBu) ppm. 13C NMR (90.6 MHz, CDCl
, 25 °C): δ =
78.0 (C=O, lactone), 174.9 (C=O, ester), 78.6 (CH, 4-C), 62.4
, CH OPiv), 46.4 (CH , 8-C), 44.1 (CH , 9-C), 41.1 (CH, 6-
C), 39.7 (CH, 1-C), 39.3 (CH, 7-C), 38.9 [(CH C], 38.0 (CH, 5-
C), 27.1 [(CH C] ppm. MS: m/z (%) = 289 (1.6), 287 (4.6), 222
5), 220 (8), 57 (100).
ter for 6 h delivered the unreacted lactone 10 (129 mg, 1.53 mmol)
after purification of the crude material by silica gel column
chromatography.
3
(
CH
2
2
2
2
)
3
(1R,2S,8R,9S,10S)-10-(Pivaloyloxymethyl)-4,6,11-trioxatricyclo-
3
2
,8
)
3
[7.3.0.0 ]dodecan-12-one (20b), (1S,2R,8S,9R,10S)-10-(Pivalo-
3
2
,8
(
yloxymethyl)-4,6,11-trioxatricyclo[7.3.0.0 ]dodecan-12-one (25b),
1R,2S,8S,9S,10S)-10-(Pivaloyloxymethyl)-4,6,11-trioxatricyclo-
(
+
Mixture of 18a, 19a and 23a: HRMS (ESI ): calcd. for
Na 345.06309; found 345.06303.
2
,8
[7.3.0.0 ]dodecan-12-one (19b), and (1R,2R,8R,9S,10S)-10-(Pival-
14 2 4
C H20Cl O
2
,8
oyloxymethyl)-4,6,11-trioxatricyclo[7.3.0.0 ]dodecan-12-one (18b):
(
1RS,2SR,8RS,9SR)-4,6,11-Trioxatricyclo[7.3.0.02,8]dodecan-12-
A solution of 11 (150 mg, 0.76 mmol) and (Z)-12 (894 mg,
2
,8
one (16b), (1RS,2RS,8RS,9SR)-4,6,11-Trioxatricyclo[7.3.0.0 ]do- 6.84 mmol) in acetonitrile (90 mL) was irradiated through a Quartz
decan-12-one (14b), and (1RS,2SR,8SR,9SR)-4,6,11-Trioxatricyclo- filter for 4 h. The progress of the reaction was monitored by GC,
Eur. J. Org. Chem. 2011, 3888–3895
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3893

R. Alibés, M. Figueredo et al.
FULL PAPER
where the appearance of four new peaks was observed (54:15:14:17
ratio). Evaporation of the solvent and column chromatography
over silica gel (hexane/EtOAc, 10:1 to 1:1) provided the following
fractions: (i) a colorless oil identified as 25b (24 mg, 0.08 mmol,
(CH, 1-C), 39.4 (CH, 9-C), 38.9 (CH, 8-C), 38.8 [(CH
[(CH )
3 3
3
)
3
C], 27.2
C] ppm. MS m/z (%) = 298 (0.2) [M] , 268 (0.2), 197 (1.1),
183 (16), 57 (100).
+
+
22 6
Mixture 18b–19b: HRMS (ESI ): calcd. for C15H O Na 321.1309;
11% yield), (ii) a white solid identified as 20b (86 mg, 0.29 mmol,
38% yield), (iii) a 45:55 mixture of 19b and 18b (48 mg, 0.16 mmol,
21 % yield), and (iv) unreacted starting lactone 11 (10 mg,
0.05 mmol). All the attempts to separate the cycloadducts 19b and
18b were unsuccessful and enriched fractions were analyzed.
found 321.1302.
(1RS,5SR,6RS,7SR)-6,7-Bis(hydroxymethyl)-3-oxabicyclo[3.2.0]-
heptan-2-one (16c), (1RS,5SR,6RS,7RS)-6,7-Bis(hydroxymethyl)-3-
oxabicyclo[3.2.0]heptan-2-one (14c), and (1RS,5SR,6SR,7SR)-6,7-
Bis(hydroxymethyl)-3-oxabicyclo[3.2.0]heptan-2-one (15c): A solu-
tion of 2(5H)-furanone 10 (150 mg, 1.78 mmol) and (Z)-13
Compound 20b: M.p. 56–58 °C (EtOAc/pentane). 1H NMR
2
(
250 MHz, CDCl
3
, 25 °C): δ = 5.19 (d, JH,H = 7.4 Hz, 1 H, 5-H),
(
1.3 mL, 16.0 mmol) in acetonitrile (90 mL) was irradiated through
3
2
4
1
4
.61 (dd, JH,H = 3.7, 3.2 Hz, 1 H, 10-H), 4.36 (d, JH,H = 7.4 Hz,
H, 5-H), 4.24 (dd, JH,H = 12.0, JH,H = 3.2 Hz, 1 H, CH OPiv),
2
.17 (dd, JH,H = 13.5, JH,H = 2.6 Hz, 1 H, 3-H), 4.03 (dd, JH,H
2
OPiv), 3.99 (dd, JH,H = 13.4,
H,H = 3.2 Hz, 1 H, 7-H), 3.78 (dd, JH,H = 13.5, JH,H = 2.2 Hz,
H, 3-H), 3.67 (dd, JH,H = 13.4, JH,H = 1.0 Hz, 1 H, 7-H), 3.21
dd, JH,H = 8.1, 4.9 Hz, 1 H, 9-H), 3.14 (dd, JH,H = 8.1, 2.8 Hz,
a Quartz filter for 3 h. The progress of the reaction was monitored
by TLC (hexane/EtOAc, 1:3). Evaporation of the solvent, followed
by kugelrohr distillation of (Z)-13 under reduced pressure and sil-
ica gel column chromatography (hexane/EtOAc, 1:1 to EtOAc) ren-
dered a mixture of 16c, 14c, and 15c (46:35:19 ratio; 210 mg,
2
3
2
3
2
2
=
12.0, 3
JH,H = 3.7 Hz, 1 H, CH
3
2
3
J
2
3
1
(
1
0
.22 mmol, 69 % yield) and unreacted lactone 10 (18 mg,
.21 mmol). Repeated column chromatography (hexane/EtOAc, 2:1
3
3
1
H, 1-H), 2.84 (m, 1 H, 2-H), 2.78 (m, 1 H, 8-H), 1.18 (s, 9 H,
to EtOAc) provided the following fractions: (i) an oil identified as
6c, and (ii) a mixture of 14c and 15c. All attempts to separate the
13
tBu) ppm. C NMR (90.6 MHz, CDCl
3
, 25 °C): δ = 179.4 (12-C),
, 5-C), 82.0 (CH, 10-C), 73.3 (CH
, 7-C), 65.6 (CH , CH OPiv), 43.6/43.4 (2ϫ CH,
-C/8-C), 39.1 (CH, 1-C), 38.8 [(CH C], 36.1 (CH, 9-C), 27.1
C] ppm. IR (ATR): ν˜ = 2970, 2934, 2868, 1762, 1724, 1479,
1
1
3
2
78.0 (C=O, ester), 100.6 (CH
-C), 70.6 (CH
2
2
,
cycloadducts 14c and 15c were unsuccessful and enriched fractions
were analyzed.
2
2
2
3 3
)
1
[(CH
3
)
3
Compound 16c: H NMR (250 MHz, [D
6
]acetone, 25 °C): δ = 4.37
–1
2
3
2
1
279, 1145, 1085 cm . C15
H
22
O
6
(298.34): calcd. C 60.39, H 7.43;
(dd, JH,H = 9.3, JH,H = 6.3 Hz, 1 H, 4-H), 4.25 (d, JH,H = 9.3 Hz,
1 H, 4-H), 3.97–3.63 (m, 4 H, 2ϫ 8-H, 2ϫ 9-H), 2.96 (m, 1 H, 5-
found C 60.30, H 7.72.
3
H), 2.82 (dd, JH,H = 7.8, 2.6 Hz, 1 H, 1-H), 2.66 (m, 1 H, 6-H),
1
Compound 25b: H NMR (250 MHz, CDCl
3
, 25 °C): δ = 5.20 (d,
1
3
2
.63 (m, 1 H, 7-H) ppm. C NMR (62.9 MHz, [D
δ = 179.4 (2-C), 72.8 (CH , 4-C), 60.6, 61.2 (2ϫ CH
2.7/41.4 (2ϫ CH, 6-C/7-C), 37.7 (CH, 1-C), 36.0 (CH, 5-C) ppm.
IR (ATR): ν˜ = 3600–3000, 2922, 2852, 1752, 1464, 1260, 1167,
024 cm . HRMS (ESI ): calcd. for C
95.0631.
6
]acetone, 25 °C):
2
3
J
H,H = 7.2 Hz, 1 H, 5-H), 4.64 (ddd, JH,H = 7.3, 6.0, 5.8 Hz, 1
H, 10-H), 4.38 (dd, JH,H = 11.8, JH,H = 7.3 Hz, 1 H, CH OPiv),
2
.35 (d, JH,H = 7.2 Hz, 1 H, 5-H), 4.21 (dd, JH,H = 11.8, JH,H =
2
.8 Hz, 1 H, CH OPiv), 4.18 (dd, JH,H = 13.3, JH,H = 2.9 Hz, 1
2
2
, 8-C, 9-C),
2
3
4
2
2
3
4
5
2
3
–
1
+
1
8
H
12
O
4
Na 195.0628; found
2
3
H, 3-H), 3.88 (dd, JH,H = 13.4, JH,H = 3.9 Hz, 1 H, 7-H), 3.79
1
2
(
dd, 2 H,H = 13.3, 3
J JH,H = 2.8 Hz, 1 H, 3-H), 3.68 (dd, J =
H,H
3
3
1
1
9
2
3.4, JH,H = 1.2 Hz, 1 H, 7-H), 3.52 (dt, JH,H = 8.0, 6.0 Hz, 1 H,
Compound 14c: H NMR (250 MHz, [D
6
]acetone, 25 °C): δ = 4.36
3
2
3
2
-H), 3.12 (dd, JH,H = 8.0, 3.3 Hz, 1 H, 1-H), 2.95 (m, 1 H, 8-H),
(dd, JH,H = 9.3, JH,H = 6.0 Hz, 1 H, 4-H), 4.24 (dd, JH,H = 9.3,
H,H = 1.3 Hz, 1 H, 4-H), 3.70–3.40 (m, 4 H, 2ϫ 8-H, 2ϫ 9-H),
3.13 (ddd, JH,H = 9.3, 7.6, JH,H = 1.1 Hz, 1 H, 1-H), 2.90 (m, 1
.72 (m, 1 H, 2-H), 1.20 (s, 9 H, tBu) ppm. 13C NMR (62.9 MHz,
3
J
3
4
CDCl
C), 78.1 (CH, 10-C), 73.4 (CH
CH OPiv), 43.1 (CH, 2-C), 39.7 (CH, 1-C), 38.8 [(CH
CH, 8-C), 35.9 (CH, 9-C), 27.1 [(CH
C] ppm. IR (ATR): ν˜ = 64.1/62.7 (2ϫ CH
958, 2941, 2871, 1771, 1729, 1480, 1281, 1147, 1080 cm . HRMS
3
, 25 °C): δ = 179.1 (12-C), 178.0 (C=O, ester), 100.6 (CH
, 3-C), 70.6 (CH , 7-C), 62.3 (CH
C], 37.4
2
, 5-
2
,
1
3
H, 5-H), 2.59 (m, 1 H, 6-H), 2.27 (m, 1 H, 7-H) ppm. C NMR
(62.9 MHz, [D ]acetone, 25 °C): δ = 177.9 (2-C), 73.6 (CH , 4-C),
, 8-C/9-C), 46.5/39.9 (2ϫ CH, 6-C/7-C), 37.7
2
2
2
3
)
3
6
2
(
2
3
)
3
2
–1
(CH, 1-C), 35.0 (CH, 5-C) ppm.
+
22 6
(ESI ): calcd. for C15H O Na 321.1309; found 321.1301.
1
Compound 15c: H NMR (250 MHz, [D
6
]acetone, 25 °C): δ = 4.63
1
, 25 °C): δ = 5.01 (ddd, (dd, JH,H = 10.0, JH,H = 2.3 Hz, 1 H, 4-H), 4.34 (dd, 2JH,H
2
3
Compound 19b: H NMR (360 MHz, CDCl
3
=
3
2
3
J
H,H = 5.0, 4.3, 4.2 Hz, 1 H, 10-H), 4.89 (d, JH,H = 8.8 Hz, 1 H,
10.0, J
= 8.0 Hz, 1 H, 4-H), 3.70–3.40 (m, 4 H, 2ϫ 8-H, 2ϫ
H,H
2
3
5
4
3
-H), 4.83 (d, JH,H = 8.8 Hz, 1 H, 5-H), 4.16 (m, 1 H, CH
.25 (m, 1 H, CH
.66 (m, 1 H, 7-H), 3.58 (m, 1 H, 3-H), 3.03 (m, 1 H, 8-H), 2.95
2
OPiv),
9-H), 3.20 (dddd, J
H,H
= 10.4, 8.1, 2.3, 1.0 Hz, 1 H, 5-H), 2.90
1
3
2
OPiv), 4.08 (m, 1 H, 3-H), 3.95 (m, 1 H, 7-H), (m, 1 H, 1-H), 2.59 (m, 1 H, 7-H), 2.59 (m, 1 H, 6-H) ppm.
NMR (62.9 MHz, [D ]acetone, 25 °C): δ = 178.6 (2-C), 68.7 (CH ,
C
6
2
(
m, 1 H, 2-H), 2.89 (m, 1 H, 9-H), 2.80 (m, 1 H, 1-H), 1.20 (s, 9 4-C), 64.3/61.7 (2ϫ CH , 8-C/9-C), 43.3/38.9 (2ϫ CH, 6-C/7-C),
2
1
3
H, tBu) ppm. C NMR (90.6 MHz, CDCl
C=O), 177.9 (C=O), 93.3 (CH , 5-C), 76.9 (CH, 10-C), 70.6 (CH
-C), 66.6 (CH , 7-C), 65.1 (CH , CH OPiv), 44.2 (CH, 1-C), 41.2
CH, 2-C), 39.9 (CH, 8-C), 38.9 [(CH C], 36.7 (CH, 9-C), 27.1
(CH
C] ppm. MS m/z (%) = 298 (0.2) [M] , 268 (1.2), 197 (0.2), Irradiation of a solution of lactone 10 (150 mg, 1.78 mmol) and
3
, 25 °C): δ = 178.0
37.8 (CH, 1-C), 33.0 (CH, 5-C) ppm.
(
3
(
[
2
2
,
Mixture 14c–15c: IR (ATR): ν˜ = 3600–3000, 2912, 2873, 1737,
2
2
2
–
1
1473, 1373, 1167, 1082 cm .
3 3
)
+
3 3
)
1
83 (0.8), 57 (100).
(Z)-13 (1.3 mL, 16.0 mmol) in acetone (90 mL) through a Pyrex
filter for 4 h delivered a mixture of 16c, 14c, and 15c (43:37:20
ratio; 106 mg, 0.62 mmol, 35 % yield) and unreacted lactone 10
1
Compound 18b: H NMR (360 MHz, CDCl
3
, 25 °C): δ = 4.83 (s, 2
3
H, 5-H), 4.57 (dd, JH,H = 3.4, 3.0 Hz, 1 H, 10-H), 4.24 (m, 1 H,
CH OPiv), 4.14 (m, 1 H, 3-H), 4.10 (m, 1 H, CH OPiv), 4.06 (m,
H, 7-H), 3.54–3.49 (m, 2 H, 3-H, 7-H), 3.26 (m, 1 H, 9-H), 3.00
m, 1 H, 2-H), 2.83–2.97 (m, 1 H, 1-H), 2.78 (m, 1 H, 8-H), 1.18
s, 9 H, tBu) ppm. 13C NMR (90.6 MHz, CDCl
, 25 °C): δ = 175.7
C=O), 175.4 (C=O), 93.0 (CH , 5-C), 80.8 (CH, 10-C), 69.8 (CH
, 7-C), 65.0 (CH , CH OPiv), 45.0 (CH, 2-C), 41.2
(
64 mg, 0.76 mmol) after purification of the crude material by silica
2
2
gel column chromatography.
1
(
(
(
(1R,4S,5S,6R,7R)-6,7-Bis(hydroxymethyl)-4-(pivaloyloxymethyl)-
3-oxabicyclo[3.2.0]heptan-2-one (18c) and (1R,4S,5S,6S,7S)-6,7-
Bis(hydroxymethyl)-4-(pivaloyloxymethyl)-3-oxabicyclo[3.2.0]-
heptan-2-one (19c): A solution of 11 (150 mg, 0.76 mmol) and (Z)-
3
2
2
,
3
-C), 68.1 (CH
894
2
2
2
3
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3888–3895

1,2,3,4-Tetrasubstituted Cyclobutanes
13 (0.56 mL, 6.84 mmol) in acetonitrile (90 mL) was irradiated
through a Quartz filter for 4 h. The progress of the reaction was
monitored by GC analysis. Evaporation of the solvent, followed by
kugelrohr distillation of (Z)-13 under reduced pressure and silica
gel column chromatography (hexane/EtOAc, 1:1 to EtOAc), af-
forded a mixture of 18c, 19c, and another unidentified cycloadduct
[1] R. P. Walker, D. J. Faulkner, D. Van Engen, J. Clardy, J. Am.
Chem. Soc. 1981, 103, 6772–6773.
[2] a) P. A. Keifer, R. E. Schwartz, M. E. S. Koker, R. G. Hughes,
D. Rittschof, K. L. Rinehart, J. Org. Chem. 1991, 56, 2965–
2975; b) R. Rosa, W. Silva, E. de Motta, A. D. Rodríguez, J. J.
Morales, M. Ortiz, Experientia 1992, 48, 885–887; c) V. S.
Bernan, D. M. Roll, C. M. Ireland, M. Greenstein, W. M.
Maiese, D. A. Steinberg, J. Antimicrob. Chemother. 1993, 32,
(46:38:16 ratio; 101 mg, 0.35 mmol, 46% yield). By successive col-
umn chromatography purifications, fractions enriched in 18c and
19c were obtained.
5
39–550; d) F. Cafieri, R. Carnuccio, E. Fattorusso, O. Tag-
lialatela-Scafati, T. Vallefuoco, Bioorg. Med. Chem. Lett. 1997,
, 2283–2288; e) A. Cipres, D. P. O’Malley, K. Li, D. Finlay,
1
Compound 18c: H NMR (360 MHz, CDCl
3
2
, 25 °C): δ = 4.64 (dd,
7
3
3
J
H,H = 3.1, 2.5 Hz, 1 H, 4-H), 4.24 (dd,
.5 Hz, 1 H, CH
J
H,H = 12.2,
H,H
J =
P. S. Baran, K. Vuori, ACS Chem. Biol. 2010, 5, 195–202.
3] V. M. Dembitsky, J. Nat. Med. 2008, 62, 1–33.
2
3
2
2
OPiv), 4.08 (dd, JH,H = 12.2, JH,H = 3.1 Hz, 1
[
H, CH
2
OPiv), 3.80–3.60 (m, 4 H, 2ϫ 8-H, 2ϫ 9-H), 3.25 (ddd, [4] Y. Chi, W. Yan, J. Li, Phytochemistry 1990, 29, 2376–2378.
3
4
J
H,H = 9.2, 7.3, JH,H = 1.1 Hz, 1 H, 1-H), 2.64 (m, 1 H, 7-H), [5] a) Y. Fujiwara, K. Naithou, T. Miyazaki, K. Hashimoto, K.
2
.70 (dd, 3JH,H = 7.3, 6.4 Hz, 1 H, 5-H), 2.38 (m, 1 H, 6-H), 1.17
Mori, Y. Yamamoto, Tetrahedron Lett. 2001, 42, 2497–2499; b)
S. Tsukamoto, B.-C. Cha, T. Ohta, Tetrahedron 2002, 58, 1667–
s, 9 H, tBu) ppm. 1 C NMR (90.6 MHz, CDCl
3
(
(
3
, 25 °C): δ = 179.0
2-C), 178.1 (C=O, ester), 82.4 (CH, 4-C), 65.4 (CH , CH OPiv),
4.0/62.6 (2ϫ CH , 8-C/9-C), 44.8 (CH, 6-C), 38.8 (CH C, 38.7
1
671; c) K. Wei, W. Li, K. Koike, Y. Chen, T. Nikaido, J. Org.
2
2
Chem. 2005, 70, 1164–1176.
6
2
3 3
)
[
[
6] V. B. Birman, X.-T. Jiang, Org. Lett. 2004, 6, 2369–2371.
7] P. S. Baran, A. L. Zografos, D. P. O’Malley, J. Am. Chem. Soc.
2004, 126, 3726–3727.
3 3
(2ϫ CH, 1-C, 7-C), 36.7 (CH, 5-C), 27.1 [(CH ) C] ppm.
1
Compound 19c: H NMR (360 MHz, CDCl
3
2
, 25 °C): δ = 5.00 (dd,
3
3
[8] P. S. Baran, K. Li, D. P. O’Malley, C. Mitsos, Angew. Chem.
Int. Ed. 2006, 45, 249–252.
J
H,H = 3.6, 3.1 Hz, 1 H, 4-H), 4.25 (dd,
.1 Hz, 1 H, CH
J
H,H = 12.0,
H,H
J =
2
3
3
2
OPiv), 4.08 (dd, JH,H = 12.0, JH,H = 3.6 Hz, 1
[
9] a) R. Alibés, J. L. Bourdelande, J. Font, T. Parella, Tetrahedron
H, CH
2
OPiv), 3.80–3.60 (m, 4 H, 2ϫ 8-H, 2ϫ 9-H), 3.00 (m, 1 H,
-H), 3.00 (m, 1 H, 1-H), 2.65 (m, 1 H, 6-H), 2.38 (m, 1 H, 7-H),
.17 [s, 9 H, (tBu)] ppm. 13C NMR (90.6 MHz, CDCl
, 25 °C): δ
178.0 (C=O, ester), 177.9 (2-C), 77.8 (CH, 4-C), 66.0 (CH
CH OPiv), 64.5/61.8 (2ϫ CH , 8-C/9-C), 42.9 (CH, 7-C), 40.2
CH, 6-C), 38.8 [(CH C], 38.7 (CH, 1-C), 35.1 (CH, 5-C), 27.1
(CH C] ppm.
1996, 52, 1279–1292; b) P. de March, M. Figueredo, J. Font, J.
5
1
Raya, Org. Lett. 2000, 2, 163–165; c) R. Alibés, P. de March,
M. Figueredo, J. Font, M. Racamonde, T. Parella, Org. Lett.
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M. Figueredo, J. Font, Org. Lett. 2007, 9, 2827–2830; e) M.
Racamonde, R. Alibés, M. Figueredo, J. Font, P. de March, J.
Org. Chem. 2008, 73, 5944–5952.
3
=
2
,
2
2
(
3 3
)
[
3 3
)
[
10] a) J. Mann, N. K. Parlett, A. Thomas, J. Chem. Res., Synop.
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Asymmetry 1991, 2, 1391–1402.
General Procedure for Photoisomerization of (E)- and (Z)-1,4-
Dichloro-2-butene (5): A solution of (E)-5 or (Z)-5 (2.00 g,
[
11] a) R. Alibés, J. L. Bourdelande, J. Font, Tetrahedron Lett. 1993,
16.0 mmol) in acetonitrile (90 mL) was irradiated through a Quartz
34, 7455–7458; b) R. Alibés, J. L. Bourdelande, J. Font, Tetra-
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anone 10 (150 mg, 1.78 mmol). The E/Z ratio was monitored by
GC analysis.
hedron Lett. 1994, 35, 2587–2588; c) R. Alibés, J. L. Bourdel-
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Methanolysis of a Mixture of 16b, 43b, and 15b: To a solution of a
mixture of 16b, 43b, and 15b (30 mg, 0.15 mmol) in MeOH (5 mL),
pTsOH (15 mg, 0.07 mmol) was added and the mixture was stirred
at room temperature for 48 h. The reaction progress was monitored
by TLC (EtOAc). After evaporation of the solvent, the residue was
purified by silica gel column chromatography, affording a mixture
of 16c, 14c, and 15c (70:15:15 ratio; 20 mg, 0.11 mmol, 76% yield).
Alibes, J. L. Bourdelande, J. Font, Tetrahedron Lett. 1998, 39,
6963–6966; f) R. Alibés, P. de March, M. Figueredo, J. Font,
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Methanolysis of a Mixture of 20b, 25b, 19b, and 18b: To a solution
of a mixture of 20b, 25b, 19b, and 18 (38 mg, 0.12 mmol) in MeOH
[
[
12] a) E. J. Corey, J. D. Bass, R. LeMathieu, R. B. Mitra, J. Am.
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d) M. Ohkita, K. Sano, T. Suzuki, T. Tsuji, Tetrahedron Lett.
(4 mL), pTsOH (12 mg, 0.06 mmol) was added and the mixture was
stirred at room temperature for 4 h. The reaction progress was
monitored by GC. After evaporation of the solvent, the residue was
purified by silica gel column chromatography, affording a mixture
of 20c, 25c, 19c, and 18c (54:15:14:17 ratio; 26 mg, 0.08 mmol, 74%
yield).
2
001, 42, 7295–7297; e) I. Shinohara, H. Nagaoka, Tetrahedron
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Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra of selected compounds.
[
[
Acknowledgments
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9
3, 3–22; b) D. Andrew, A. C. Weedon, J. Am. Chem. Soc.
We acknowledge financial support from the Dirección General de
Investigación (project CTQ2007-60613) and a grant from the Min-
isterio de Educación y Ciencia (MEC) (to S. P.).
1995, 117, 5647–5663.
Received: January 17, 2011
Published Online: May 6, 2011
Eur. J. Org. Chem. 2011, 3888–3895
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3895